U.S. patent application number 13/594376 was filed with the patent office on 2012-12-20 for hexahydro-pyrrolo-isoquinoline compounds.
Invention is credited to Richard Apodaca, Ann J. Barbier, Nicholas I. Carruthers, Leslie A. Gomez, John M. Keith, Timothy W. Lovenberg, Ronald L. Wolin.
Application Number | 20120321559 13/594376 |
Document ID | / |
Family ID | 36942601 |
Filed Date | 2012-12-20 |
United States Patent
Application |
20120321559 |
Kind Code |
A1 |
Apodaca; Richard ; et
al. |
December 20, 2012 |
HEXAHYDRO-PYRROLO-ISOQUINOLINE COMPOUNDS
Abstract
Certain hexahydro-pyrrolo-isoquinoline compounds are histamine
H.sub.3 receptor and serotonin transporter modulators useful in the
treatment of histamine H.sub.3 receptor- and serotonin-mediated
diseases.
Inventors: |
Apodaca; Richard; (La Jolla,
CA) ; Barbier; Ann J.; (Cambridge, MA) ;
Carruthers; Nicholas I.; (Poway, CA) ; Gomez; Leslie
A.; (San Diego, CA) ; Keith; John M.; (San
Diego, CA) ; Lovenberg; Timothy W.; (San Diego,
CA) ; Wolin; Ronald L.; (San Diego, CA) |
Family ID: |
36942601 |
Appl. No.: |
13/594376 |
Filed: |
August 24, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12792675 |
Jun 2, 2010 |
8273762 |
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13594376 |
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Current U.S.
Class: |
424/1.65 ;
514/233.2; 514/294; 544/120; 544/126; 546/94 |
Current CPC
Class: |
A61P 25/36 20180101;
A61P 1/14 20180101; A61P 25/16 20180101; C07D 471/04 20130101; A61P
3/04 20180101; A61P 25/08 20180101; A61P 1/08 20180101; A61P 25/28
20180101; A61P 25/06 20180101; A61P 25/18 20180101; A61P 25/26
20180101; A61P 25/20 20180101; A61P 29/00 20180101; A61P 43/00
20180101; A61P 25/24 20180101; A61P 25/00 20180101 |
Class at
Publication: |
424/1.65 ;
546/94; 514/294; 544/126; 514/233.2; 544/120 |
International
Class: |
A61K 31/4545 20060101
A61K031/4545; A61P 25/00 20060101 A61P025/00; A61K 31/5377 20060101
A61K031/5377; A61P 25/24 20060101 A61P025/24; C07D 471/04 20060101
C07D471/04; A61K 51/04 20060101 A61K051/04 |
Claims
1. A compound of formula (I): ##STR00104## wherein n is 0 or 1; m
is 0, 1, or 2; R.sup.2 and R.sup.3 are independently selected from
--H, or from the group consisting of: A) --C.sub.1-6alkyl,
--C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, benzyl; B) phenyl or pyridyl,
optionally fused at two adjacent carbon ring members to a three- or
four-membered hydrocarbon moiety to form a fused five- or
six-membered aromatic ring, which moiety has one carbon atom
replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), and
which moiety has up to one additional carbon atom optionally
replaced by --N.dbd.; C) a 4-8 membered heterocyclic ring, said
heterocyclic ring having a carbon atom which is the point of
attachment, having 1 or 2 heteroatom members selected from >O,
>S(O).sub.0-2, and >NH, and having 0 or 1 double bonds; and
D) a monocyclic aromatic hydrocarbon group having five or six ring
atoms, having a carbon atom which is the point of attachment,
having one carbon atom replaced by >O, >S, >NH, or
>N(C.sub.1-4alkyl), having up to one additional carbon atom
optionally replaced by --N.dbd., and optionally benzofused or
pyridofused; where each of A)-D) is optionally mono-, di-, or
tri-substituted with a moiety selected from the group consisting of
--OH, --C.sub.1-4alkylOH, --OC.sub.1-6alkyl, --CN, --NO.sub.2,
--N(Rd)R.sup.e (wherein R.sup.d and R.sup.e are independently --H
or --C.sub.1-6alkyl), --C(O)N(Rd)R.sup.e, --N(R)C(O)Rd,
--N(Rd)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(Rd)R.sup.e,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --COOH,
--COOC.sub.1-6alkyl, --OC(O)N(Rd)R.sup.e, and --OC(O)OR.sup.d; or,
alternatively, R.sup.2 and R.sup.3 may be taken together with the
nitrogen to which they are attached to form a 4-8 membered
heterocyclic ring, said heterocyclic ring having 0 or 1 additional
heteroatom members separated from the nitrogen of attachment by at
least one carbon member and selected from >O, >S(O).sub.0-2,
>NH, and >NR.sup.f, having 0 or 1 double bonds, having 0, 1,
or 2 carbon members separated from the nitrogen of attachment by at
least one carbon member which is a carbonyl, optionally benzo or
pyrido fused, optionally having one carbon member that forms a
bridge, and having 0-5 carbon member substituents R.sup.ff, R.sup.f
is selected from the group consisting of --C.sub.1-6alkyl
optionally mono-, di-, or tri-substituted with halo,
--C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, --C.sub.2-6alkylOH,
--C(O)N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are
independently --H or --C.sub.1-6alkyl), --C(O)R.sup.i (where
R.sup.i is --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5-
or 6-membered aromatic heterocyclyl, each optionally mono-, di-, or
tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl,
--CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl, and
--COOC.sub.1-6alkyl; R.sup.ff is selected from the group consisting
of --C.sub.1-6alkyl optionally mono-, di-, or tri-substituted with
halo, --C.sub.2-6alkenyl, --C.sub.2-6alkynyl,
--C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, halo,
--OH, --C.sub.1-6alkylOH, --OC.sub.1-6alkyl, --OC.sub.2-3alkylO--,
--CN, --NO.sub.2, --N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h
are independently --H or --C.sub.1-6alkyl),
--C(O)N(R.sup.g)R.sup.h, --N(R.sup.g)C(O)R.sup.g,
--N(R.sup.g)SO.sub.2C.sub.1-6alkyl, --C(O)R.sup.i (where R.sup.i is
--C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5- or
6-membered aromatic heterocyclyl, each optionally mono-, di-, or
tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl,
--CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl,
--SO.sub.2N(R.sup.y)R.sup.z, --SCF.sub.3, --OCF.sub.3, --COOH, and
--COOC.sub.1-6alkyl; R.sup.4 is --OH, --OC.sub.1-6alkyl,
--CF.sub.3, --C.sub.1-6alkyl, or halo; two R.sup.4 substituents may
be taken together to form methylene or ethylene; or one of R.sup.4
is taken together with R.sup.2 to form methylene, ethylene, or
propylene; wherein each methylene, ethylene, or propylene is
optionally substituted with --OH, --OC.sub.1-6alkyl,
--SC.sub.1-6alkyl, --CF.sub.3, --C.sub.1-6alkyl, amino, or halo;
R.sup.5 is selected from the group consisting of --H,
--C.sub.1-6alkyl, --OH, --OC.sub.1-6alkyl, --SC.sub.1-6alkyl, and
halo; Ar.sup.1 is an aryl or heteroaryl ring selected from the
group consisting of: a) phenyl, optionally mono-, di-, or
tri-substituted with RJ or di-substituted on adjacent carbons with
--OC.sub.1-4alkyleneO-- optionally mono- or di-substituted with
fluoro, --(CH.sub.2).sub.2-3NH--,
--(CH.sub.2).sub.1-2NH(CH.sub.2)--,
--(CH.sub.2).sub.2-3N(C.sub.1-4alkyl)-, or
--(CH.sub.2).sub.1-2N(C.sub.1-4alkyl)(CH.sub.2)--; R.sup.j is
selected from the group consisting of 1) --OH, --C.sub.1-6alkyl,
--OC.sub.1-6alkyl optionally mono-, di-, or tri-substituted with
halo, --C.sub.2-6alkenyl, --OC.sub.3-6alkenyl, --C.sub.2-6alkynyl,
--OC.sub.3-6alkynyl, --C.sub.3-6cycloalkyl, --OC.sub.3-6cycloalkyl,
--CN, --NO.sub.2, --N(R.sup.k)R.sup.l (wherein R.sup.k and R.sup.l
are independently --H or --C.sub.1-6alkyl), --N(R.sup.k)COR.sup.l,
--N(R.sup.k)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --C(O)N(R.sup.m)R.sup.n (wherein
R.sup.m and R.sup.n are independently --H or --C.sub.1-6alkyl, or
R.sup.m and R.sup.n taken together with their nitrogen of
attachment form a 4-8 membered heterocyclic ring having 1 or 2
heteroatom members selected from >O, >S(O).sub.0-2, >NH,
and >NC.sub.1-6alkyl, having 0 or 1 double bonds, having 0 or 1
carbonyl members), --SO.sub.2N(R.sup.m)R.sup.n, --SCF.sub.3, halo,
--CF.sub.3, --COOH, --COOC.sub.1-6alkyl, and
--COOC.sub.3-7cycloalkyl; and 2) a 4-8 membered saturated or
partially saturated heterocyclic ring, having 1 or 2 heteroatom
members selected from >O, >S(O).sub.0-2, >NH, and
>NC.sub.1-6alkyl, having 0 or 1 carbonyl members; said ring
optionally mono-, di-, or tri-substituted with RP; R.sup.p is a
substituent independently selected from the group consisting of:
--OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN,
--NO.sub.2, --N(R.sup.q)R.sup.r (wherein R.sup.q and R.sup.r are
independently --H, --C.sub.1-6alkyl, or --C.sub.2-6alkenyl),
--C(O)N(R.sup.q)R.sup.r, --N(R.sup.q)C(O)R.sup.r,
--N(R.sup.q)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.q)R.sup.r,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH,
and --COOC.sub.1-6alkyl; b) phenyl or pyridyl fused at two adjacent
carbon ring members to a three membered hydrocarbon moiety to form
a fused five membered aromatic ring, which moiety has one carbon
atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl) and
which moiety has up to one additional carbon atom optionally
replaced by --N.dbd., the fused rings optionally mono-, di-, or
tri-substituted with R.sup.t; R.sup.t is a substituent
independently selected from the group consisting of: --OH,
--C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN, --NO.sub.2,
--N(R.sup.u)R.sup.v (wherein R.sup.u and R.sup.v are independently
--H or --C.sub.1-6alkyl), --C(O)N(R.sup.u)R.sup.v,
--N(R.sup.u)C(O)R.sup.v, --N(R.sup.u)SO.sub.2C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl,
--SO.sub.2N(R.sup.u)R.sup.v, --SCF.sub.3, halo, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.2, --COOH, and --COOC.sub.1-6alkyl; c)
phenyl fused at two adjacent ring members to a four membered
hydrocarbon moiety to form a fused six membered aromatic ring,
which moiety has 0, 1, or 2 carbon atoms replaced by --N.dbd., the
fused rings optionally mono-, di-, or tri-substituted with R.sup.t;
d) a monocyclic aromatic hydrocarbon group having five ring atoms,
having a carbon atom which is the point of attachment, having one
carbon atom replaced by >O, >S, >NH, or
>N(C.sub.1-4alkyl), having up to one additional carbon atom
optionally replaced by --N.dbd., optionally mono- or di-substituted
with R.sup.t, and optionally benzofused or pyridofused at two
adjacent carbon atoms, where the benzofused or pyridofused moiety
is optionally mono-, di-, or tri-substituted with R.sup.t; and e) a
monocyclic aromatic hydrocarbon group having six ring atoms, having
a carbon atom which is the point of attachment, having one or two
carbon atoms replaced by --N.dbd., optionally mono- or
di-substituted with R.sup.t, and optionally benzofused or
pyridofused at two adjacent carbon atoms, where the benzofused or
pyridofused moiety is optionally mono- or di-substituted with
R.sup.t; and enantiomers, diastereomers, hydrates, solvates
thereof, and pharmaceutically acceptable salts, esters and amides
thereof.
2. The compound of claim 1 wherein n is 0 or 1.
3. The compound of claim 1 wherein m is 0.
4. The compound of claim 1 wherein R.sup.2 and R.sup.3 are
independently selected from --H, or optionally substituted, from
the group consisting of: A) methyl, ethyl, isopropyl, butyl,
pentyl, hexyl, allyl, propargyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cyclopropylmethyl, benzyl, B) phenyl,
pyridyl, 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or
7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or
7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or
7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,
imidazo[1,2-a]pyridin-5,6,7 or 8-yl, pyrazolo[1,5-a]pyridin-4,5,6
or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,
1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4,
5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl, C) azetidinyl,
pyrrolidinyl, piperidinyl, and D) furanyl, oxazolyl, isoxazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or
3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl,
and 3-indazolyl.
5. The compound of claim 1 wherein R.sup.2 and R.sup.3, optionally
substituted, are independently selected from methyl, ethyl,
isopropyl, pyrrolidinyl, piperidinyl, 2-benzothiazolyl, and
methoxyethyl.
6. The compound of claim 1 wherein R.sup.2 and R.sup.3 are,
independently, ethyl, isopropyl, methoxyethyl, or
2-benzothiazolyl.
7. The compound of claim 1 wherein R.sup.2 and R.sup.3, optionally
substituted, are taken together with the nitrogen to which they are
attached to form a ring selected from the group consisting of
azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, homopiperidinyl,
1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, and
1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl.
8. The compound of claim 1 wherein R.sup.2 and R.sup.3 are taken
together with the nitrogen to which they are attached to form a 4-8
membered heterocyclic ring, said heterocyclic ring selected from
piperidine, pyrrolidine, and morpholine, said ring substituted with
1 or 2 substituents R.sup.ff.
9. The compound of claim 1 wherein R.sup.ff is selected from the
group consisting of methyl, ethyl, isopropyl, butyl, hexyl,
--CF.sub.3, --CHF.sub.2, vinyl, allyl, propargyl, cyclopropyl,
cyclopentyl, cyclopropylmethyl, cyclobutylethyl, bromo, chloro,
fluoro, iodo, --OH, hydroxymethyl, hydroxyethyl, methoxy, ethoxy,
isopropoxy, pentyloxy, --O(CH.sub.2).sub.2O--,
--O(CH.sub.2).sub.3O--, --CN, amino, methylamino, dimethylamino,
diethylamino, diethylcarbamoyl, methanesulfanyl, methanesulfonyl,
methanesulfonamido, --C(O)R.sup.i, --COOH, and ethoxycarbonyl.
10. The compound of claim 1 wherein R.sup.ff is selected from the
group consisting of methyl, fluoro, --OH, --CF.sub.3,
hydroxymethyl, hydroxyethyl, dimethylamino, ethoxycarbonyl, and
--O(CH.sub.2).sub.2O--.
11. The compound of claim 1 wherein R.sup.i is selected from the
group consisting of methyl, pyridyl, isopropyl, cyclobutyl,
cyclopropyl, N-methylpyrrolyl, and 1-methylimidazolyl.
12. The compound of claim 1 wherein R.sup.2 and R.sup.3 are taken
together with the nitrogen to which they are attached to form
azetidinyl, 2-methylpyrrolidinyl, 3-hydroxypyrrolidinyl,
3-dimethylaminopyrrolidinyl, 2,5-dimethylpyrrolidinyl,
2-trifluoromethylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl,
piperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl,
4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl,
4-trifluoromethylpiperidinyl, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl,
morpholinyl, 4-cyanopiperidinyl, 4-carboethoxypiperidinyl,
3-hydroxypiperidinyl, 4-hydroxypiperidinyl,
2-hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl,
4-hydroxymethylpiperidinyl, 4-hydroxyethylpiperidinyl,
3-methylmorpholin-4-yl, 3-hydroxymethylmorpholin-4-yl,
2-hydroxymethylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl,
1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl,
1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl, or
2-methylmorpholin-4-yl.
13. The compound of claim 1 wherein R.sup.2 and R.sup.3 are taken
together with the nitrogen to which they are attached to form
4-fluoropiperidinyl, morpholinyl, or 3-methylmorpholin-4-yl.
14. The compound of claim 1 wherein R.sup.4 is methoxy, ethoxy,
isopropoxy, pentyloxy, --CF.sub.3, methyl, ethyl, propyl, isobutyl,
pentyl, chloro, or fluoro.
15. The compound of claim 1 wherein R.sup.4 is hydroxy, methyl,
methoxy, fluoro, or --CF.sub.3.
16. The compound of claim 1 wherein two R.sup.4 are taken together
to form methylene.
17. The compound of claim 1 wherein R.sup.2 and one of R.sup.4 are
taken together form methylene, ethylene, or propylene, each
optionally substituted with --OH, --OC.sub.1-6alkyl,
--SC.sub.1-6alkyl, --CF.sub.3, --C.sub.1-6alkyl, amino, or
halo.
18. The compound of claim 1 wherein R.sup.2 and one of R.sup.4 are
taken together to form methylene or ethylene.
19. The compound of claim 1 wherein R.sup.5 is hydrogen, methyl,
ethyl, isopropyl, hexyl, hydroxyl, methoxy, ethoxy, isopropoxy,
methylsulfanyl, bromo, chloro, fluoro, or iodo.
20. The compound of claim 1 wherein R.sup.5 is hydrogen.
21. The compound of claim 1 wherein Ar.sup.1, optionally
substituted, is selected from the group consisting of: a) phenyl,
5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-, 7-benzo-1,3-dioxolyl,
4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-, 7-isoindolinyl,
1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl,
1,2,3,4-tetrahydro-isoquinolin-4,5,6 or 7-yl, b) 4-, 5-, 6- or
7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or
7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or
7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or
7-indazolyl, imidazo[1,2-a]pyridin-5,6,7 or 8-yl,
pyrazolo[1,5-a]pyridin-4,5,6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5
or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,
1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5,
6 or 7-yl, c) naphthyl, 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7-
or 8-quinolinyl, 5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or
8-quinazolinyl, d) furanyl, oxazolyl, isoxazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,
1,3,4-oxadiazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl,
imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
3-indoxazinyl, 2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or
3-benzofuranyl, 2- or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl,
3-indazolyl, and e) pyridinyl, pyridinyl-N-oxide, pyrazinyl,
pyrimidinyl, pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or
4-quinolinyl, 2- or 3-quinoxalinyl, 2- or 4-quinazolinyl, [1,5],
[1,6], [1,7], or [1,8]naphthyridin-2-, 3-, or 4-yl, [2,5], [2,6],
[2,7], [2,8]naphthyridin-1-, 3-, or 4-yl.
22. The compound of claim 1 wherein Ar.sup.1, optionally
substituted, is selected from the group consisting of phenyl,
pyridyl, pyrazinyl, thiazolyl, pyrazolyl, and thiophenyl.
23. The compound of claim 1 wherein Ar.sup.1 is selected from the
group consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl,
3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,
3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl,
4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,
4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,
4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 3-cyanophenyl,
4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl,
3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl,
2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,
3,5-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl,
3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl,
3-chloro-4-difluoromethoxyphenyl, 3-fluoro-4-chlorophenyl,
benzo[1,3]dioxol-4 or 5-yl, 2-hydroxyphenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,
4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 4-aminophenyl,
4-dimethylaminophenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl,
4-methanesulfanylphenyl, 4-methanesulfinylphenyl,
4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl,
thiophen-2-yl, thiophen-3-yl, 2-pyridinyl, 3-pyridinyl,
4-pyridinyl, 2-chloro-5-pyridinyl, 2-dimethylamino-5-pyridinyl,
2-methoxy-5-pyridinyl, 2-thiomethyl-5-pyridinyl,
2-hydroxy-5-pyridinyl, oxazol-5-yl, thiazol-5-yl, thiazol-2-yl,
2H-pyrazol-3-yl, pyrazin-2-yl, 1-naphthyl, 2-naphthyl,
4-imidazol-1-ylphenyl, 4-pyrazol-1-ylphenyl, 1H-indol-5-yl,
1H-benzimidazol-5-yl, benzo[b]thiophen-7-yl, and 4-biphenyl.
24. The compound of claim 1 wherein Ar.sup.1, optionally
substituted with halo, is 4-methoxyphenyl or
4-methanesulfanylphenyl.
25. The compound of claim 1 wherein Ar.sup.1 is cis to the
pyrrolidine ring of formula (I).
26. The compound of claim 1 wherein the R.sup.3R.sup.2N-containing
ether substituent of formula (I) is at the 9-position.
27. A compound selected from the group consisting of:
Cis-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1a]isoquinoline;
Trans-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrro-
lo[2,1a]isoquinoline;
Trans-6-Phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrro-
lo[2,1a]isoquinoline;
Cis-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-phenylamine;
Cis-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(3-nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(3-nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyrro-
lo[2,1-a]isoquinoline;
Trans-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyr-
rolo[2,1-a]isoquinoline;
Trans-7-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyr-
rolo[2,1-a]isoquinoline;
Cis-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Trans-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Trans-7-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
1S,6R-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline;
1R,6S-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline;
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-phenol;
Trans-4-[7-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
-a]isoquinolin-6-yl]-phenol;
Cis-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
Cis-3-[9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-phenol;
Cis-2-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-phenol;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethoxy-phenyl)-1,2,3,5,6,-
10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(3,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(2,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(2,5-dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(3,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(3,4,5-Trimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-hexahydro--
pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydro--
pyrrolo[2,1-a]isoquinoline;
Trans-9-(3-piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydr-
o-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline;
Trans-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-
-pyrrolo[2,1-a]isoquinoline;
Cis-7-(1-Isopropyl-piperidin-4-yloxy)-4-(4-methoxy-phenyl)-2-methyl-1,2,3-
,4-tetrahydro-isoquinoline;
Cis-9-(1-Isopropyl-piperidin-4-ylmethoxy)-6-(4-methoxy-phenyl)-1,2,3,5,6,-
10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-Dimethyl-{4-[9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyr-
rolo[2,1-a]isoquinolin-6-yl]-phenyl}-amine;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-m-tolyl-1,2,3,5,6,10b-hexahydro-pyrrol-
o[2,1-a]isoquinoline;
Cis-6-(3-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydr-
o-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trimethylsilanylethynyl-phenyl)-1,2-
,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(3-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydr-
o-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trimethylsilanylethynyl-phenyl)-1,2-
,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,-
10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
6-(4-Methylsulfanyl-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline;
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-benzonitrile;
Trans-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
-a]isoquinolin-6-yl]-benzonitrile;
Trans-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline;
Cis-4-[8-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-benzonitrile;
Trans-6-Phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrro-
lo[2,1-a]isoquinoline;
Cis-6-Phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1-a]isoquinoline;
Cis-6-(4-Methoxy-phenyl)-9-[3-(3S-methyl-morpholin-4-yl)-propoxy]-1,2,3,5-
,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-9-[3-(4-Fluoro-piperidin-1-yl)-propoxy]-6-(4-methoxy-phenyl)-1,2,3,5,-
6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-pyrazol-1-yl-phenyl)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline;
Trans-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-
-pyrrolo[2,1-a]isoquinoline;
Cis-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-pyridin-2-ol;
Trans-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
-a]isoquinolin-6-yl]-pyridin-2-ol;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-5-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-2-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(2H-pyrazol-3-yl)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline;
Cis-6-Imidazo[1,2-a]pyridin-3-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydro--
pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-hexahydro--
pyrrolo[2,1-a]isoquinoline;
Cis-3-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-benzonitrile;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-trifluoromethylsulfanyl-phenyl)-1,2-
,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(3-trifluoromethylsulfanyl-phenyl)-1,2-
,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(3-Chloro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,-
10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(3-Fluoro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,-
10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trifluoromethyl-phenyl)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline;
6-Biphenyl-4-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrr-
olo[2,1-a]isoquinoline;
9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-2-yl-1,2,3,5,6,10b-hexahydro-py-
rrolo[2,1-a]isoquinoline;
9-(3-Morpholin-4-yl-propoxy)-6-quinolin-7-yl-1,2,3,5,6,10b-hexahydro-pyrr-
olo[2,1-a]isoquinoline;
6-(1H-Indol-5-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-py-
rrolo[2,1-a]isoquinoline;
6-(1H-Benzoimidazol-5-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
6-(1H-Benzoimidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
6-(1-Methyl-1H-benzoimidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-1-yl-1,2,3,5,6,10b-hexahydro-py-
rrolo[2,1-a]isoquinoline;
6-Benzo[b]thiophen-7-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline;
6-(6-Chloro-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline;
Dimethyl-{5-[9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1-a]isoquinolin-6-yl]-pyridin-2-yl}-amine;
6-(6-Methoxy-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline;
9-(3-Morpholin-4-yl-propoxy)-6-oxazol-5-yl-1,2,3,5,6,10b-hexahydro-pyrrol-
o[2,1-a]isoquinoline;
6-(1H-Imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
-pyrrolo[2,1-a]isoquinoline;
6-(1-Methyl-1H-imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline;
6-(3H-Imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
-pyrrolo[2,1-a]isoquinoline;
6-(3-Methyl-3H-imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline;
6-(3-Chloro-4-Difluoromethoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,-
5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
(4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquin-
olin-9-yloxy]-propyl}-morpholin-2-yl)-methanol;
(4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquin-
olin-9-yloxy]-propyl}-morpholin-3-yl)-methanol; and
6-(3,5-Bis-trifluoromethyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline.
28. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and an effective amount of at least one compound
of formula (I).
29. A method for the treatment or prevention of a CNS disorder
selected from the group consisting of: sleep/wake and
arousal/vigilance disorders, insomnia, jet lag, disturbed sleep,
attention deficit hyperactivity disorders (ADHD), attention-deficit
disorders, learning and memory disorders, learning impairment,
memory impairment, memory loss, cognitive dysfunction, migraine,
neurogenic inflammation, dementia, mild cognitive impairment,
pre-dementia, Alzheimer's disease, epilepsy, narcolepsy with or
without associated cataplexy, cataplexy, disorders of sleep/wake
homeostasis, idiopathic somnolence, excessive daytime sleepiness
(EDS), circadian rhythm disorders, sleep/fatigue disorders,
fatigue, drowsiness associated with sleep apnea, sleep impairment
due to perimenopausal hormonal shifts, Parkinson's-related fatigue,
MS-related fatigue, depression-related fatigue,
chemotherapy-induced fatigue, work-related fatigue, lethargy,
eating disorders, obesity, motion sickness, vertigo, schizophrenia,
substance abuse, bipolar disorders, manic disorders and depression
in mammals, comprising the step of administering to a mammal
suffering therefrom an effective amount of at least one compound of
formula (I).
30. A method according to claim 29, further comprising
administering one or more therapeutic agents selected from the
group consisting of H.sub.1 receptor antagonists, H.sub.2 receptor
antagonists, H.sub.3 receptor antagonists, serotonin-norepinephrine
reuptake inhibitors, selective serotonin reuptake inhibitors,
noradrenergic reuptake inhibitors, non-selective serotonin
re-uptake inhibitors, acetylcholinesterase inhibitors, and
modafinil.
31. A method for the treatment or prevention of a CNS disorder
selected from the group consisting of: depression, disturbed sleep,
fatigue, lethargy, cognitive impairment, memory impairment, memory
loss, learning impairment, and attention-deficit disorders in
mammals, comprising the step of administering to a mammal suffering
therefrom an effective amount of at least one compound of formula
(I).
32. A compound of claim 1 isotopically-labelled to be detectable by
PET or SPECT.
33. A method for studying disorders mediated by the histamine
H.sub.3 receptor and the serotonin transporter comprising the step
of using an .sup.18F-labeled or .sup.11C-labelled compound of
formula (I) as a positron emission tomography (PET) molecular
probe.
34. A method for the treatment or prevention of a disease selected
from the group consisting of: depression, disturbed sleep, fatigue,
lethargy, cognitive impairment, memory impairment, memory loss,
learning impairment, and attention-deficit disorders in mammals,
comprising the step of administering to a mammal suffering
therefrom an effective amount of a compound having both H.sub.3
receptor modulating activity and serotonin transporter modulating
activity.
35. The method of claim 34, wherein the H.sub.3 receptor binding
activity is at least 20 nM in the human H.sub.3 binding assay.
36. The method of claim 34, wherein the serotonin transporter
binding activity is at least 20 nM in the human SERT binding
assay.
37. The method of claim 34, wherein the ratio of the H.sub.3
receptor binding activity in the human H.sub.3 binding assay and
the serotonin transporter binding activity in the human SERT
binding assay is between 10:1 and 1:10.
38. A compound selected from the group consisting of:
(1R,6S)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,-
6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
(1S,6R)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,-
6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
(1S,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline;
(1S,6S)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline;
(1R,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline; and
(1S,6S)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline.
39. A compound of formulae (II) or (III): ##STR00105## wherein
R.sup.2 and R.sup.3 are independently selected from --H, or from
the group consisting of: A) --C.sub.1-6alkyl, --C.sub.3-6alkenyl,
--C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, benzyl; B) phenyl or pyridyl,
optionally fused at two adjacent carbon ring members to a three- or
four-membered hydrocarbon moiety to form a fused five- or
six-membered aromatic ring, which moiety has one carbon atom
replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), and
which moiety has up to one additional carbon atom optionally
replaced by --N.dbd.; C) a 4-8 membered heterocyclic ring, said
heterocyclic ring having a carbon atom which is the point of
attachment, having 1 or 2 heteroatom members selected from >O,
>S(O).sub.0-2, and >NH, and having 0 or 1 double bonds; and
D) a monocyclic aromatic hydrocarbon group having five or six ring
atoms, having a carbon atom which is the point of attachment,
having one carbon atom replaced by >O, >S, >NH, or
>N(C.sub.1-4alkyl), having up to one additional carbon atom
optionally replaced by --N.dbd., and optionally benzofused or
pyridofused; where each of A)-D) is optionally mono-, di-, or
tri-substituted with a moiety selected from the group consisting of
--OH, --C.sub.1-4alkylOH, --OC.sub.1-6alkyl, --CN, --NO.sub.2,
--N(Rd)R.sup.e (wherein Rd and R.sup.e are independently --H or
--C.sub.1-6alkyl), --C(O)N(Rd)R.sup.e, --N(Rd)C(O)Rd,
--N(Rd)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(Rd)R.sup.e,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --COOH,
--COOC.sub.1-6alkyl, --OC(O)N(Rd)R.sup.e, and --OC(O)OR.sup.d; or,
alternatively, R.sup.2 and R.sup.3 may be taken together with the
nitrogen to which they are attached to form a 4-8 membered
heterocyclic ring, said heterocyclic ring having 0 or 1 additional
heteroatom members separated from the nitrogen of attachment by at
least one carbon member and selected from >O, >S(O).sub.0-2,
>NH, and >NR.sup.f, having 0 or 1 double bonds, having 0, 1,
or 2 carbon members separated from the nitrogen of attachment by at
least one carbon member which is a carbonyl, optionally benzo or
pyrido fused, optionally having one carbon member that forms a
bridge, and having 0-5 carbon member substituents R.sup.ff, R.sup.f
is selected from the group consisting of --C.sub.1-6alkyl
optionally mono-, di-, or tri-substituted with halo,
--C.sub.3-6alkenyl, --C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, --C.sub.2-6alkylOH,
--C(O)N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are
independently --H or --C.sub.1-6alkyl), --C(O)R.sup.i (where
R.sup.i is --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5-
or 6-membered aromatic heterocyclyl, each optionally mono-, di-, or
tri-substituted with --C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl,
--CF.sub.3, or halo), --S(O).sub.0-2--C.sub.1-6alkyl, and
--COOC.sub.1-6alkyl; R.sup.ff is selected from the group consisting
of --C.sub.1-6alkyl optionally mono-, di-, or tri-substituted with
halo, --C.sub.2-6alkenyl, --C.sub.2-6alkynyl,
--C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl, halo,
--OH, --C.sub.1-6alkylOH, --OC.sub.2-3alkylO--, --CN, --NO.sub.2,
--N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are independently
--H or --C(O)N(R.sup.g)R.sup.h, --N(R.sup.g)C(O)R.sup.g,
--N(R.sup.g)SO.sub.2C.sub.1-6alkyl, --C(O)R.sup.i (where R.sup.i is
--C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl, or 5- or
6-membered aromatic heterocyclyl, each optionally mono-, di-, or
tri-substituted with --C.sub.1-3alkyl, --OH, --CF.sub.3, or halo),
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.y)R.sup.z,
--SCF.sub.3, --OCF.sub.3, --COOH, and --COOC.sub.1-6alkyl; R.sup.5
is selected from the group consisting of --H, --OH,
--OC.sub.1-6alkyl, --SC.sub.1-6alkyl, and halo; and Ar.sup.1 is an
aryl or heteroaryl ring selected from the group consisting of: a)
phenyl, optionally mono-, di-, or tri-substituted with W or
di-substituted on adjacent carbons with --OC.sub.1-4alkyleneO--
optionally mono- or di-substituted with fluoro,
--(CH.sub.2).sub.2-3NH--, --(CH.sub.2).sub.1-2NH(CH.sub.2)--,
--(CH.sub.2).sub.2-3N(C.sub.1-4alkyl)-, or
--(CH.sub.2).sub.1-2N(C.sub.1-4alkyl)(CH.sub.2)--; R.sup.j is
selected from the group consisting of 1) --OH, --C.sub.1-6alkyl,
--OC.sub.1-6alkyl optionally mono-, di-, or tri-substituted with
halo, --C.sub.2-6alkenyl, --OC.sub.3-6alkenyl, --C.sub.2-6alkynyl,
--OC.sub.3-6alkynyl, --C.sub.3-6cycloalkyl, --OC.sub.3-6cycloalkyl,
--CN, --NO.sub.2, --N(R.sup.k)R.sup.l (wherein R.sup.k and R.sup.l
are independently --H or --C.sub.1-6alkyl), --N(R.sup.k)COR.sup.l,
--N(R.sup.k)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --C(O)N(R.sup.m)R.sup.n (wherein
R.sup.m and R.sup.n are independently --H or --C.sub.1-6alkyl, or
R.sup.m and R.sup.n taken together with their nitrogen of
attachment form a 4-8 membered heterocyclic ring having 1 or 2
heteroatom members selected from >O, >S(O).sub.0-2, >NH,
and >NC.sub.1-6alkyl, having 0 or 1 double bonds, having 0 or 1
carbonyl members), --SO.sub.2N(R.sup.m)R.sup.n, --SCF.sub.33 halo,
--CF.sub.33--COOH, --COOC.sub.1-6alkyl, and
--COOC.sub.3-7cycloalkyl; and 2) a 4-8 membered saturated or
partially saturated heterocyclic ring, having 1 or 2 heteroatom
members selected from >O, >S(O).sub.0-2, >NH, and
>NC.sub.1-6alkyl, having 0 or 1 carbonyl members; said ring
optionally mono-, di-, or tri-substituted with R.sup.p; R.sup.p is
a substituent independently selected from the group consisting of:
--OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN,
--NO.sub.2, --N(R.sup.q)R.sup.r (wherein R.sup.q and R.sup.r are
independently --H, --C.sub.1-6alkyl, or --C.sub.2-6alkenyl),
--C(O)N(R.sup.q)R.sup.r, --N(R.sup.q)C(O)R.sup.r,
--N(R.sup.q)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.q)R.sup.r,
--SCF.sub.33 halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH,
and --COOC.sub.1-6alkyl; b) phenyl or pyridyl fused at two adjacent
carbon ring members to a three membered hydrocarbon moiety to form
a fused five membered aromatic ring, which moiety has one carbon
atom replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl) and
which moiety has up to one additional carbon atom optionally
replaced by --N.dbd., the fused rings optionally mono-, di-, or
tri-substituted with R.sup.t; R.sup.t is a substituent
independently selected from the group consisting of: --OH,
--C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN, --NO.sub.2,
--N(R.sup.u)R.sup.v (wherein R.sup.u and R.sup.v are independently
--H or --C.sub.1-6alkyl), --C(O)N(R.sup.u)R.sup.v,
--N(R.sup.u)C(O)R.sup.v, --N(R.sup.u)SO.sub.2C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl, --S(O).sub.0-2--C.sub.1-6alkyl,
--SO.sub.2N(R.sup.u)R.sup.v, --SCF.sub.33 halo, --CF.sub.3,
--OCF.sub.3, --OCHF.sub.23--COOH, and --COOC.sub.1-6alkyl; c)
phenyl fused at two adjacent ring members to a four membered
hydrocarbon moiety to form a fused six membered aromatic ring,
which moiety has 0, 1, or 2 carbon atoms replaced by --N.dbd., the
fused rings optionally mono-, di-, or tri-substituted with R.sup.t;
d) a monocyclic aromatic hydrocarbon group having five ring atoms,
having a carbon atom which is the point of attachment, having one
carbon atom replaced by >O, >S, >NH, or
>N(C.sub.1-4alkyl), having up to one additional carbon atom
optionally replaced by --N.dbd., optionally mono- or di-substituted
with R.sup.t, and optionally benzofused or pyridofused at two
adjacent carbon atoms, where the benzofused or pyridofused moiety
is optionally mono-, di-, or tri-substituted with R.sup.t; and e) a
monocyclic aromatic hydrocarbon group having six ring atoms, having
a carbon atom which is the point of attachment, having one or two
carbon atoms replaced by --N.dbd., optionally mono- or
di-substituted with R.sup.t, and optionally benzofused or
pyridofused at two adjacent carbon atoms, where the benzofused or
pyridofused moiety is optionally mono- or di-substituted with
R.sup.t; and enantiomers, diastereomers, hydrates, solvates
thereof, and pharmaceutically acceptable salts, esters, and amides
thereof.
40. The compound of claim 39 wherein R.sup.2 and R.sup.3 are taken
together with the nitrogen to which they are attached to form
piperidinyl, 4-fluoropiperidinyl, morpholinyl, or 3-methyl
morpholin-4-yl.
41. The compound of claim 39 wherein Ar.sup.1 is 4-methoxyphenyl or
4-methylsulfanylphenyl.
42. The compound of claim 39 wherein R.sup.5 is --H.
43. A compound selected from the group consisting of:
Cis-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Trans-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5-
,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline;
Cis-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; and
Trans-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5-
,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline.
44. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and an effective amount of at least one compound
of formulae (II) or (III).
45. A method for the treatment or prevention of a CNS disorder
selected from the group consisting of: depression, disturbed sleep,
fatigue, lethargy, cognitive impairment, memory impairment, memory
loss, learning impairment, and attention-deficit disorders in
mammals, comprising the step of administering to a mammal suffering
therefrom an effective amount of at least one compound of formulae
(II) or (III).
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit under 35 U.S.C.
.sctn.119(e) of provisional application Ser. No. 60/691,958, filed
on Jun. 17, 2005, which is incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
[0002] There is provided by the present invention compounds that
are modulators of the histamine H.sub.3 receptor and the serotonin
transporter. More particularly, there is provided by the present
invention hexahydro-pyrrolo-isoquinoline compounds and methods for
using them to treat disorders and conditions mediated by the
histamine H.sub.3 receptor and the serotonin transporter. As a
consequence of these activities the compounds of the present
invention will have therapeutic utility for the treatment of
depression and a range of related disorders.
BACKGROUND OF THE INVENTION
[0003] Depression is a chronic illness with an estimated lifetime
prevalence of 17%. The total annual cost of depression in the USA
is estimated at $44 billion. As such, it represents a major health
problem with a serious pharmacoeconomic impact (Griffiths, R. I. et
al. Pharmacoeconomics 1999, 15(5), 495-505). Although the
biochemical basis of depression is not completely elucidated, the
most commonly accepted hypothesis states that depression occurs
when monoaminergic neurotransmission in the brain is impaired. This
theory is largely based on the observation that compounds that
improve noradrenergic and/or serotoninergic neurotransmission often
have beneficial effects in depression. Such an improvement in
monoaminergic neurotransmission can be achieved in several ways.
The biological effect of noradrenaline is terminated by two
mechanisms: reuptake from the synaptic cleft into the neuron via
the norepinephrine transporter (NET), and degradation by monoamine
oxidase (MAO). For serotonin, reuptake in the neuron via the
serotonin transporter (SERT) likewise limits its availability in
the synaptic cleft.
[0004] Currently, clinical treatment of depression relies mainly on
four types of drugs: 1) MAO inhibitors; 2) tricyclic
antidepressants (TCA); 3) selective serotonin reuptake inhibitors
(SSRI); and 4) other drugs such as reboxetine and venlafaxine. MAOs
have long been used as second-line drugs because of their
potentially dangerous side effects, and more recently, reversible
MAO-A selective inhibitors with improved profiles have been
described (Bonnet, U. CNS Drug Rev. 2002, 8(3), 283-308). TCAs such
as amitryptiline display complex pharmacological activities. They
inhibit reuptake of noradrenaline and serotonin via their
respective transporters, but also have affinity at muscarinic and
histamine H.sub.1 receptors. Thus, their efficacy in treating
depression is counterbalanced by numerous unwanted side effects.
The SSRIs, which represent the largest and most successful group of
antidepressants, show a higher selectivity for the SERT than for
the NET, although the exact affinity ratio varies from drug to
drug. This class of drugs is characterized by a milder side-effect
profile than the MAO-inhibitors or the TCAs. Other drugs have been
described, such as reboxetine, which preferentially targets the
NET, and venlafaxine, which has dual activity at the SERT and NET
(Olver, J. S. et al. CNS Drugs 2001, 15(12), 941-954).
[0005] Although remarkable progress has been made in the treatment
of depression, there remains opportunity for improvement. The delay
between start of treatment and subjective improvement is a case in
point. Most drugs do not cause an improvement in the Hamilton
Rating Scale for Depression until after several weeks of treatment,
potentially leaving the patient subject to severe mental anguish
during this time. Currently available drugs have a limited response
rate and in most clinical trials only about 30% of patients show
clinical improvement (Menza, M. A. et al. J. Clin. Psych. 2000,
61(5), 378-381). Psychiatrists frequently have to evaluate several
drugs for individual patients before a satisfactory therapeutic
response is observed. Consequently there is a significant
therapeutic need for drugs with a faster onset of action, improved
side effect profiles and higher response ratio.
[0006] In order to appreciate the rationale for a combined
SERT/H.sub.3 antagonist, it is necessary to understand the
physiology of the histamine H.sub.3 receptor. This receptor was
described in 1983 (Arrang, J.-M. et al. Nature (London) 1983,
302(5911), 832-837) as a presynaptic, auto-inhibitory receptor on
histaminergic neurons with a characteristic pharmacology.
Activation of the H.sub.3 receptor was shown to decrease the amount
of histamine released from the nerve terminals and to inhibit the
activity of histidine decarboxylase, the rate-limiting enzyme in
the synthesis of histamine. The cloning and characterization of the
human H.sub.3 receptor made it possible to explore its pharmacology
(Lovenberg, T. W. et al. Molec. Pharmacol. 1999, 55(6), 1101-1107).
It is now known that the H.sub.3 receptor is expressed on a variety
of neurons and thus, when activated, decreases the release of a
number of other neurotransmitters including noradrenaline,
dopamine, and acetylcholine (Hill, S. J. et al. Pharmacol. Rev.
1997, 49(3), 253-278). For the purpose of this discussion, we will
focus on its known effects on the release of the neurotransmitters
involved in depression, noradrenaline and serotonin. Although the
serotoninergic cell bodies are found in the dorsal raphe nucleus
while the histaminergic cells are located in the tuberomammillary
nucleus of the hypothalamus, both systems have extensive
projections throughout the brain. In several regions, such as the
suprachiasmatic nucleus (Laitinen, K. S. M. et al. Eur. J.
Pharmacol. 1995, 285(2), 159-164) and striatum both
neurotransmitters are present. It is known that activation of the
H.sub.3 receptor leads to a decreased release of serotonin, for
instance in rat cortex slices (Fink, K. et al.
Naunyn-Schmiedeberg's Arch. Pharmacol. 1990, 342(5), 513-519;
Schlicker, E. et al. Naunyn-Schmiedeberg's Arch. Pharmacol. 1988,
337(5), 588-590). Functional antagonists of the H.sub.3 receptor
lead to an increased release of noradrenaline in the central (mouse
cortex slices, Leurs, R. et al. J. Pharmacol. Exp. Ther. 1996,
276(3), 1009-1015; the rat hippocampus, Alvez-Rodrigues, A. et al.
Brain Res. 1998, 788(1-2), 179-186) and peripheral nervous system
(human myocardial nerves, Hatta, E. et al. J. Pharmacol. Exp. Ther.
1997, 283(2), 494-500; guinea-pig intestinal sympathetic nerves,
Blandizzi, C. et al. Br. J. Pharmacol. 2000, 129(7), 1387-1396).
However, there is little evidence that H.sub.3 receptor antagonists
alone are capable of increasing serotonin levels in vivo to those
required for antidepressant effects. Microdialysis studies of the
effect of H.sub.3 antagonists on serotonin levels in the brain of
live animals are lacking. There are sparse reports indicating that
thioperamide, an H.sub.3 receptor antagonist, may have an
antidepressant effect per se in the mouse or rat forced swim test
(Lamberti, C. et al. Br. J. Pharmacol. 1998, 123(7), 1331-1336;
Perez-Garcia, C. et al. Psychopharmacology 1999, 142(2),
215-220).
[0007] The rationale for combining H.sub.3 receptor blockade and
SERT activity in one single molecule is the expectation that both
mechanisms will contribute synergistically to enhanced
concentrations of serotonin in the synaptic cleft. Antagonism at
the H.sub.3 receptor will provide increased release of
serotonin-containing vesicles into the synaptic cleft, and
concomitant blockade of the SERT will decrease the neuronal
reuptake of these neurotransmitter molecules. Thus, higher
concentrations of serotonin will be achieved, leading to an
enhanced therapeutic effect.
[0008] Among the prominent vegetative symptoms of depression are
disturbed sleep and the daytime fatigue associated with it.
Polysomnographic investigations have shown severe disturbances in
the sleep architecture of depressed patients. Among the typical
abnormalities observed are: discontinuous sleep, decreased
slow-wave sleep, shorter latency to REM sleep and an increased
intensity and duration of REM sleep (Riemann, D. et al.
Neuropsychobiology 2002, 45(Suppl. 1), 7-12). It is believed that
suppression of REM sleep is involved in antidepressant efficacy.
This is illustrated by the dramatic success of overnight
deprivation of (REM) sleep (Riemann et al. 2002). Another
non-pharmacological treatment for depression, electroconvulsant
therapy, likewise decreases REM sleep. Virtually all of the
available antidepressant drugs, regardless of their neurochemical
mechanism of action, suppress REM sleep, nefazodone (a 5-HT.sub.2A
antagonist) being the exception (Sharpley, A. L., Cowen, P. J.
Biol. Psych. 1995, 37(2), 85-98). Antidepressant drugs also affect
slow-wave-sleep, although in a less clear manner. H.sub.3
antagonists share this REM-sleep suppressing property and one of
the main biological effects of histamine H.sub.3 antagonists is to
improve wakefulness. Administration of H.sub.3 antagonists has been
shown to decrease REM and non-REM sleep in several animal species.
For example, the H.sub.3 antagonist carboperamide induces waking in
rats (Monti, J. M. et al. Neuropsychopharmacology 1996, 15(1),
31-35). Another H.sub.3 antagonist, thioperamide, decreased both
REM and non-REM sleep in rats (Monti, J. M. et al. Eur. J.
Pharmacol. 1991, 205(3), 283-287) and cats (Lin, J.-S. et al. Brain
Res. 1990, 523(2), 325-330). It is of interest to note that
although H.sub.3 antagonists promote wakefulness, they do so much
less potently than amphetamine derivatives. They may thus be
considered mild stimulants. The daytime correlate of disturbed
sleep is fatigue. Indeed, fatigue and lethargy are prominent
symptoms of depression, and there is considerable interest in the
use of stimulants to augment antidepressant therapy (Menza et al.,
2000). However, most of the available stimulants, like the
amphetamine derivatives and methylphenidate, carry a considerable
risk of abuse and are not ideal therapeutic choices. Modafinil, a
wake-promoting compound of unknown mechanism with a lower addictive
potential, is marketed for the treatment of narcolepsy. In a small
series of patients it was shown that addition of a low dose of
modafinil to traditional antidepressant therapy resulted in a
faster onset of action. Fatigue was particularly responsive to this
therapy, but the cognitive and physical subscales of the Hamilton
Rating Scale for Depression also improved (Menza et al., 2000). The
behavioral profile of H.sub.3 antagonists (suppression of sleep
with no stimulation of locomotor activity and limited addictive
potential) is much like that of modafinil. Therefore, a combined
H.sub.3/SSRI compound would provide symptomatic relief for the
fatigue during the first weeks of treatment, before the
mood-elevating effect of the SSRI can be noticed.
[0009] Depression is also associated with a number of cognitive
symptoms such as impaired memory and concentration difficulties.
H.sub.3 antagonists have been shown to improve memory in a variety
of memory tests, including the elevated plus maze in mice
(Miyazaki, S. et al. Life Sci. 1995, 57(23), 2137-2144), a
two-trial place recognition task (Orsetti, M. et al. Behav. Brain
Res. 2001, 124(2), 235-242), the passive avoidance test in mice
(Miyazaki, S. et al. Meth. Find. Exp. Clin. Pharmacol. 1995,
17(10), 653-658) and the radial maze in rats (Chen, Z. Acta
Pharmacol. Sin. 2000, 21(10), 905-910). Also, in the spontaneously
hypertensive rat, an animal model for the learning impairments in
attention-deficit disorders, H.sub.3 antagonists were shown to
improve memory (Fox, G. B. et al. Behav. Brain Res. 2002, 131(1-2),
151-161). Although no human studies are available, the evidence
indicates that a combined SERT/H.sub.3 antagonist will provide
additional benefit in combating the cognitive impairments
associated with depression.
[0010] In summary, the combination of H.sub.3 receptor antagonism
with SERT activity will result in the production of drugs with an
improved antidepressant profile compared to an SSRI alone. These
drugs will be especially efficacious in ameliorating the symptoms
of fatigue, disturbed sleep and memory loss associated with
depression.
[0011] The features and advantages of the invention are apparent to
one of ordinary skill in the art. Based on this disclosure,
including the summary, detailed description, background, examples,
and claims, one of ordinary skill in the art will be able to make
modifications and adaptations to various conditions and usages.
Publications described herein are incorporated by reference in
their entirety.
[0012] References cited herein, including U.S. Patent Appl. No.
60/637,173, U.S. patent application Ser. No. 11/300,880, and U.S.
Provisional Appl. No. 60/692,003, are incorporated by reference in
their entirety.
SUMMARY OF THE INVENTION
[0013] The invention features a compound of formula (I):
##STR00001##
wherein [0014] n is 0 or 1; [0015] m is 0, 1, or 2; [0016] R.sup.2
and R.sup.3 are independently selected from --H, or from the group
consisting of: [0017] A)-C.sub.1-6alkyl, --C.sub.3-6alkenyl,
--C.sub.3-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, benzyl; [0018] B) phenyl or
pyridyl, optionally fused at two adjacent carbon ring members to a
three- or four-membered hydrocarbon moiety to form a fused five- or
six-membered aromatic ring, which moiety has one carbon atom
replaced by >O, >S, >NH, or >N(C.sub.1-4alkyl), and
which moiety has up to one additional carbon atom optionally
replaced by --N.dbd.; [0019] C) a 4-8 membered heterocyclic ring,
said heterocyclic ring having a carbon atom which is the point of
attachment, having 1 or 2 heteroatom members selected from >O,
>S(O).sub.0-2, and >NH, and having 0 or 1 double bonds; and
[0020] D) a monocyclic aromatic hydrocarbon group having five or
six ring atoms, having a carbon atom which is the point of
attachment, having one carbon atom replaced by >O, >S,
>NH, or >N(C.sub.1-4alkyl), having up to one additional
carbon atom optionally replaced by --N.dbd., and optionally
benzofused or pyridofused; [0021] where each of A)-D) is optionally
mono-, di-, or tri-substituted with a moiety selected from the
group consisting of --OH, --C.sub.1-4alkylOH, --OC.sub.1-6alkyl,
--CN, --NO.sub.2, --N(Rd)R.sup.e (wherein Rd and R.sup.e are
independently --H or --C.sub.1-6alkyl), --C(O)N(Rd)R.sup.e,
--N(Rd)C(O)Rd, --N(Rd)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(Rd)R.sup.e,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --COOH,
--COOC.sub.1-6alkyl, --OC(O)N(Rd)R.sup.e, and --OC(O)OR.sup.d;
[0022] or, alternatively, [0023] R.sup.2 and R.sup.3 may be taken
together with the nitrogen to which they are attached to form a 4-8
membered heterocyclic ring, said heterocyclic ring having 0 or 1
additional heteroatom members separated from the nitrogen of
attachment by at least one carbon member and selected from >O,
>S(O).sub.0-2, >NH, and >NR.sup.f, having 0 or 1 double
bonds, having 0, 1, or 2 carbon members separated from the nitrogen
of attachment by at least one carbon member which is a carbonyl,
optionally benzo or pyrido fused, optionally having one carbon
member that forms a bridge, and having 0-5 carbon member
substituents R.sup.ff, [0024] R.sup.f is selected from the group
consisting of --C.sub.1-6alkyl optionally mono-, di-, or
tri-substituted with halo, --C.sub.3-6alkenyl, --C.sub.3-6alkynyl,
--C.sub.3-7cycloalkyl, --C.sub.1-6alkylC.sub.3-7cycloalkyl,
--C.sub.2-6alkylOH, --C(O)N(R.sup.g)R.sup.h (wherein R.sup.g and
R.sup.h are independently --H or --C.sub.1-6alkyl), --C(O)R.sup.i
(where R.sup.i is --C.sub.1-6alkyl, --C.sub.3-8cycloalkyl, phenyl,
or 5- or 6-membered aromatic heterocyclyl, each optionally mono-,
di-, or tri-substituted with --C.sub.1-3alkyl, --OH,
--OC.sub.1-6alkyl, --CF.sub.3, or halo),
--S(O).sub.0-2--C.sub.1-6alkyl, and --COOC.sub.1-6alkyl; [0025]
R.sup.ff is selected from the group consisting of --C.sub.1-6alkyl
optionally mono-, di-, or tri-substituted with halo,
--C.sub.2-6alkenyl, --C.sub.2-6alkynyl, --C.sub.3-7cycloalkyl,
--C.sub.1-6alkylC.sub.3-7cycloalkyl, halo, --OH,
--C.sub.1-6alkylOH, --OC.sub.1-6alkyl, --OC.sub.2-3alkylO--, --CN,
--NO.sub.2, --N(R.sup.g)R.sup.h (wherein R.sup.g and R.sup.h are
independently --H or --C.sub.1-6alkyl), --C(O)N(R.sup.g)R.sup.h,
--N(R.sup.g)C(O)R.sup.g, --N(R.sup.g)SO.sub.2C.sub.1-6alkyl,
--C(O)R.sup.i (where R.sup.i is --C.sub.1-6alkyl,
--C.sub.3-8cycloalkyl, phenyl, or 5- or 6-membered aromatic
heterocyclyl, each optionally mono-, di-, or tri-substituted with
--C.sub.1-3alkyl, --OH, --OC.sub.1-6alkyl, --CF.sub.3, or halo),
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.y)R.sup.z,
--SCF.sub.3, --OCF.sub.3, --COOH, and --COOC.sub.1-6alkyl; [0026]
R.sup.4 is --OH, --OC.sub.1-6alkyl, --CF.sub.3, --C.sub.1-6alkyl,
or halo; two R.sup.4 substituents may be taken together to form
methylene or ethylene; or one of R.sup.4 is taken together with
R.sup.2 to form methylene, ethylene, or propylene; wherein each
methylene, ethylene, or propylene is optionally substituted with
--OH, --OC.sub.1-6alkyl, --SC.sub.1-6alkyl, --CF.sub.3,
--Cl.sub.1-6alkyl, amino, or halo; [0027] R.sup.5 is selected from
the group consisting of --H, --C.sub.1-6alkyl, --OH,
--OC.sub.1-6alkyl, --SC.sub.1-6alkyl, and halo; [0028] Ar.sup.1 is
an aryl or heteroaryl ring selected from the group consisting of:
[0029] a) phenyl, optionally mono-, di-, or tri-substituted with RJ
or di-substituted on adjacent carbons with --OC.sub.1-4alkyleneO--
optionally mono- or di-substituted with fluoro,
--(CH.sub.2).sub.2-3NH--, --(CH.sub.2).sub.1-2NH(CH.sub.2)--,
--(CH.sub.2).sub.2-3N(C.sub.1-4alkyl)-, or
--(CH.sub.2).sub.1-2N(C.sub.1-4alkyl)(CH.sub.2)--; [0030] R.sup.j
is selected from the group consisting of [0031] 1) --OH,
--C.sub.1-6alkyl, --OC.sub.1-6alkyl optionally mono-, di-, or
tri-substituted with halo, --C.sub.2-6alkenyl, --OC.sub.3-6alkenyl,
--C.sub.2-6alkynyl, --OC.sub.3-6alkynyl, --C.sub.3-6cycloalkyl,
--OC.sub.3-6cycloalkyl, --CN, --NO.sub.2, --N(R.sup.k)R.sup.l
(wherein R.sup.k and R.sup.l are independently --H or
--C.sub.1-6alkyl), --N(R.sup.k)COR.sup.l,
--N(R.sup.k)SO.sub.2C.sub.1-6alkyl, C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --C(O)N(R.sup.m)R.sup.n (wherein
R.sup.m and R.sup.n are independently --H or --C.sub.1-6alkyl, or
R.sup.m and R.sup.n taken together with their nitrogen of
attachment form a 4-8 membered heterocyclic ring having 1 or 2
heteroatom members selected from >O, >S(O).sub.0-2, >NH,
and >NC.sub.1-6alkyl, having 0 or 1 double bonds, having 0 or 1
carbonyl members), --SO.sub.2N(R.sup.m)R.sup.n, --SCF.sub.3, halo,
--CF.sub.3, --COOH, --COOC.sub.1-6alkyl, and
--COOC.sub.3-7cycloalkyl; and [0032] 2) a 4-8 membered saturated or
partially saturated heterocyclic ring, having 1 or 2 heteroatom
members selected from >O, >S(O).sub.0-2, >NH, and
>NC.sub.1-6alkyl, having 0 or 1 carbonyl members; said ring
optionally mono-, di-, or tri-substituted with RP; [0033] R.sup.p
is a substituent independently selected from the group consisting
of: [0034] --OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl, --CN,
--NO.sub.2, --N(R.sup.q)R.sup.r (wherein R.sup.q and R.sup.r are
independently --H, --C.sub.1-6alkyl, or --C.sub.2-6alkenyl),
--C(O)N(R.sup.q)R.sup.r, --N(R.sup.q)C(O)R.sup.r,
--N(R.sup.q)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.q)R.sup.r,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH,
and --COOC.sub.1-6alkyl; [0035] b) phenyl or pyridyl fused at two
adjacent carbon ring members to a three membered hydrocarbon moiety
to form a fused five membered aromatic ring, which moiety has one
carbon atom replaced by >O, >S, >NH, or
>N(C.sub.1-4alkyl) and which moiety has up to one additional
carbon atom optionally replaced by --N.dbd., the fused rings
optionally mono-, di-, or tri-substituted with R.sup.t; [0036]
R.sup.t is a substituent independently selected from the group
consisting of: --OH, --C.sub.1-6alkyl, --OC.sub.1-6alkyl, phenyl,
--CN, --NO.sub.2, --N(R.sup.u)R.sup.v (wherein R.sup.u and R.sup.v
are independently --H or --C.sub.1-6alkyl),
--C(O)N(R.sup.u)R.sup.v, --N(R.sup.u)C(O)R.sup.v,
--N(R.sup.u)SO.sub.2C.sub.1-6alkyl, --C(O)C.sub.1-6alkyl,
--S(O).sub.0-2--C.sub.1-6alkyl, --SO.sub.2N(R.sup.u)R.sup.v,
--SCF.sub.3, halo, --CF.sub.3, --OCF.sub.3, --OCHF.sub.2, --COOH,
and --COOC.sub.1-6alkyl; [0037] c) phenyl fused at two adjacent
ring members to a four membered hydrocarbon moiety to form a fused
six membered aromatic ring, which moiety has 0, 1, or 2 carbon
atoms replaced by --N.dbd., the fused rings optionally mono-, di-,
or tri-substituted with R.sup.t; [0038] d) a monocyclic aromatic
hydrocarbon group having five ring atoms, having a carbon atom
which is the point of attachment, having one carbon atom replaced
by >O, >S, >NH, or >N(C.sub.1-4alkyl), having up to one
additional carbon atom optionally replaced by --N.dbd., optionally
mono- or di-substituted with R.sup.t, and optionally benzofused or
pyridofused at two adjacent carbon atoms, where the benzofused or
pyridofused moiety is optionally mono-, di-, or tri-substituted
with R.sup.t; and [0039] e) a monocyclic aromatic hydrocarbon group
having six ring atoms, having a carbon atom which is the point of
attachment, having one or two carbon atoms replaced by --N.dbd.,
optionally mono- or di-substituted with R.sup.t, and optionally
benzofused or pyridofused at two adjacent carbon atoms, where the
benzofused or pyridofused moiety is optionally mono- or
di-substituted with R.sup.t; [0040] and enantiomers, diastereomers,
hydrates, solvates thereof, and pharmaceutically acceptable salts,
esters, and amides thereof.
[0041] The invention also features a compound of formulae (II) or
(III):
##STR00002##
wherein [0042] R.sup.2, R.sup.3, R.sup.5, and Ar.sup.1 are as
defined for formula (I); [0043] and enantiomers, diastereomers,
hydrates, solvates thereof, and pharmaceutically acceptable salts,
esters, and amides thereof.
[0044] Isomeric forms of the compounds of formulae (I), (II), and
(III), and of their pharmaceutically acceptable salts, esters, and
amides, are encompassed within the present invention, and reference
herein to one of such isomeric forms is meant to refer to at least
one of such isomeric forms. One of ordinary skill in the art will
recognize that compounds according to this invention may exist, for
example in a single isomeric form whereas other compounds may exist
in the form of a regioisomeric mixture.
[0045] The invention also features pharmaceutical compositions
containing such compounds and methods of using such compounds and
compositions in the treatment or prevention of disease states
mediated by the histamine H.sub.3 receptor and the serotonin
transporter.
[0046] Compounds of the present invention are useful in combination
with other therapeutic agents as a combination therapy method,
including use in combination with H.sub.1 receptor antagonists,
H.sub.2 receptor antagonists, H.sub.3 receptor antagonists, and
neurotransmitter modulators such as serotonin-norepinephrine
reuptake inhibitors, selective serotonin reuptake inhibitors
(SSRIs), noradrenergic reuptake inhibitors, non-selective serotonin
re-uptake inhibitors (NSSRIs), acetylcholinesterase inhibitors, and
modafinil.
[0047] Additional features and advantages of the invention will
become apparent from the detailed description and examples below,
and the appended claims.
BRIEF DESCRIPTION OF DRAWINGS
[0048] FIG. 1 shows the results of measuring levels of serotonin
and dopamine in the cortex of freely moving rats after subcutaneous
injection of 1 mg/kg of Example 8A.
DETAILED DESCRIPTION
[0049] Particular preferred compounds of the invention comprise a
compound of formula (I), or an enantiomer, diastereomer, hydrate,
solvate thereof, or a pharmaceutically acceptable salt, amide or
ester thereof, wherein n, m, R.sup.2-5, and Ar.sup.1 have any of
the meanings defined hereinabove and equivalents thereof, or at
least one of the following assignments and equivalents thereof.
Such assignments may be used where appropriate with any of the
definitions, claims or embodiments defined herein:
[0050] Preferably, n is 0 or 1.
[0051] Preferably, m is 0.
[0052] Preferably, R.sup.2 and R.sup.3 are independently selected
from --H, or optionally substituted, from the group consisting of:
[0053] A) methyl, ethyl, isopropyl, butyl, pentyl, hexyl, allyl,
propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cyclopropylmethyl, benzyl, [0054] B) phenyl, pyridyl, 4-, 5-, 6- or
7-benzoxazolyl, 4-, 5-, 6- or 7-benzothiophenyl, 4-, 5-, 6- or
7-benzofuranyl, 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6- or
7-benzthiazolyl, 4-, 5-, 6- or 7-benzimidazolyl, 4-, 5-, 6- or
7-indazolyl, imidazo[1,2-a]pyridin-5,6,7 or 8-yl,
pyrazolo[1,5-a]pyridin-4,5,6 or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5
or 6-yl, 1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl,
1H-pyrrolo[2,3-c]pyridin-4, 5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5,
6 or 7-yl, [0055] C) azetidinyl, pyrrolidinyl, piperidinyl, and
[0056] D) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,
2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2-
or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, and
3-indazolyl.
[0057] More preferably, R.sup.2 and R.sup.3, optionally
substituted, are independently selected from methyl, ethyl,
isopropyl, pyrrolidinyl, piperidinyl, 2-benzothiazolyl, and
methoxyethyl.
[0058] Even more preferably, R.sup.2 and R.sup.3 are,
independently, ethyl, isopropyl, methoxyethyl, or
2-benzothiazolyl.
[0059] In a preferred embodiment, R.sup.2 and R.sup.3, optionally
substituted, are taken together with the nitrogen to which they are
attached to form a ring selected from the group consisting of
azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, homopiperidinyl,
1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl, and
1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl.
[0060] Preferably, R.sup.2 and R.sup.3 are taken together with the
nitrogen to which they are attached to form a 4-8 membered
heterocyclic ring, said heterocyclic ring selected from piperidine,
pyrrolidine, and morpholine, said ring substituted with 1 or 2
substituents R.sup.ff.
[0061] Preferably, R.sup.ff is selected from the group consisting
of methyl, ethyl, isopropyl, butyl, hexyl, --CF.sub.3, --CHF.sub.2,
vinyl, allyl, propargyl, cyclopropyl, cyclopentyl,
cyclopropylmethyl, cyclobutylethyl, bromo, chloro, fluoro, iodo,
--OH, hydroxymethyl, hydroxyethyl, methoxy, ethoxy, isopropoxy,
pentyloxy, --O(CH.sub.2).sub.2O--, --O(CH.sub.2).sub.3O--, --CN,
amino, methylamino, dimethylamino, diethylamino, diethylcarbamoyl,
methanesulfanyl, methanesulfonyl, methanesulfonamido,
--C(O)R.sup.i, --COOH, and ethoxycarbonyl.
[0062] More preferably, R.sup.if is selected from the group
consisting of methyl, fluoro, --OH, --CF.sub.3, hydroxymethyl,
hydroxyethyl, dimethylamino, ethoxycarbonyl, and
--O(CH.sub.2).sub.2O--.
[0063] Preferably, R.sup.i is selected from the group consisting of
methyl, pyridyl, isopropyl, cyclobutyl, cyclopropyl,
N-methylpyrrolyl, and 1-methylimidazolyl.
[0064] More preferably, R.sup.2 and R.sup.3 are taken together with
the nitrogen to which they are attached to form azetidinyl,
2-methylpyrrolidinyl, 3-hydroxypyrrolidinyl,
3-dimethylaminopyrrolidinyl, 2,5-dimethylpyrrolidinyl,
2-trifluoromethylpyrrolidinyl, 2-hydroxymethylpyrrolidinyl,
piperidinyl, 4-fluoropiperidinyl, 3,3-difluoropiperidinyl,
4,4-difluoropiperidinyl, 3-trifluoromethylpiperidinyl,
4-trifluoromethylpiperidinyl, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl,
morpholinyl, 4-cyanopiperidinyl, 4-carboethoxypiperidinyl,
3-hydroxypiperidinyl, 4-hydroxypiperidinyl,
2-hydroxymethylpiperidinyl, 3-hydroxymethylpiperidinyl,
4-hydroxymethylpiperidinyl, 4-hydroxyethylpiperidinyl,
3-methylmorpholin-4-yl, 3-hydroxymethylmorpholin-4-yl,
2-hydroxymethylmorpholin-4-yl, 2,6-dimethylmorpholin-4-yl,
1,3-dihydro-isoindol-2-yl, 5,6-dihydro-4H-pyrimidin-1-yl,
1,1-dioxo-1.lamda..sup.6-thiomorpholin-4-yl, or
2-methylmorpholin-4-yl.
[0065] Even more preferably, R.sup.2 and R.sup.3 are taken together
with the nitrogen to which they are attached to form
4-fluoropiperidinyl, morpholinyl, or 3-methylmorpholin-4-yl.
[0066] Preferably, R.sup.4 is methoxy, ethoxy, isopropoxy,
pentyloxy, --CF.sub.3, methyl, ethyl, propyl, isobutyl, pentyl,
chloro, or fluoro.
[0067] More preferably, R.sup.4 is hydroxy, methyl, methoxy,
fluoro, or --CF.sub.3.
[0068] Preferably, two R.sup.4 are taken together to form
methylene.
[0069] Preferably, R.sup.2 and one of R.sup.4 are taken together
form methylene, ethylene, or propylene, each optionally substituted
with --OH, --OC.sub.1-6alkyl, --SC.sub.1-6alkyl, --CF.sub.3,
--C.sub.1-6alkyl, amino, or halo.
[0070] More preferably, R.sup.2 and one of R.sup.4 are taken
together form methylene or ethylene.
[0071] Preferably, R.sup.5 is hydrogen, methyl, ethyl, isopropyl,
hexyl, hydroxyl, methoxy, ethoxy, isopropoxy, methylsulfanyl,
bromo, chloro, fluoro, or iodo.
[0072] More preferably, R.sup.5 is hydrogen.
[0073] Preferably, Ar.sup.1, optionally substituted, is selected
from the group consisting of:
[0074] a) phenyl, 5-, 6-, 7-, 8-benzo-1,4-dioxanyl, 4-, 5-, 6-,
7-benzo-1,3-dioxolyl, 4-, 5-, 6-, 7-indolinyl, 4-, 5-, 6-,
7-isoindolinyl, 1,2,3,4-tetrahydro-quinolin-4,5,6 or 7-yl,
1,2,3,4-tetrahydro-isoquinolin-4,5,6 or 7-yl,
[0075] b) 4-, 5-, 6- or 7-benzoxazolyl, 4-, 5-, 6- or
7-benzothiophenyl, 4-, 5-, 6- or 7-benzofuranyl, 4-, 5-, 6- or
7-indolyl, 4-, 5-, 6- or 7-benzthiazolyl, 4-, 5-, 6- or
7-benzimidazolyl, 4-, 5-, 6- or 7-indazolyl,
imidazo[1,2-a]pyridin-5,6,7 or 8-yl, pyrazolo[1,5-a]pyridin-4,5,6
or 7-yl, 1H-pyrrolo[2,3-b]pyridin-4, 5 or 6-yl,
1H-pyrrolo[3,2-c]pyridin-4, 6 or 7-yl, 1H-pyrrolo[2,3-c]pyridin-4,
5 or 7-yl, 1H-pyrrolo[3,2-b]pyridin-5, 6 or 7-yl,
[0076] c) naphthyl, 5-, 6-, 7- or 8-isoquinolinyl, 5-, 6-, 7- or
8-quinolinyl, 5-, 6-, 7- or 8-quinoxalinyl, 5-, 6-, 7- or
8-quinazolinyl,
[0077] d) furanyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl,
pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 3-indoxazinyl,
2-benzoxazolyl, 2- or 3-benzothiophenyl, 2- or 3-benzofuranyl, 2-
or 3-indolyl, 2-benzthiazolyl, 2-benzimidazolyl, 3-indazolyl,
and
[0078] e) pyridinyl, pyridinyl-N-oxide, pyrazinyl, pyrimidinyl,
pyridazinyl, 1-, 3- or 4-isoquinolinyl, 2-, 3- or 4-quinolinyl, 2-
or 3-quinoxalinyl, 2- or 4-quinazolinyl, [1,5], [1,6], [1,7], or
[1,8]naphthyridin-2-, 3-, or 4-yl, [2,5], [2,6], [2,7],
[2,8]naphthyridin-1-, 3-, or 4-yl.
[0079] More preferably, Ar.sup.1, optionally substituted, is
selected from the group consisting of phenyl, pyridyl, pyrazinyl,
thiazolyl, pyrazolyl, and thiophenyl.
[0080] Even more preferably, Ar.sup.1 is selected from the group
consisting of phenyl, 2-methoxyphenyl, 3-methoxyphenyl,
4-methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl,
3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl,
2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-ethylphenyl,
3-ethynylphenyl, 4-ethynylphenyl, 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-iodophenyl,
4-iodophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,
4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,
4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl, 3-cyanophenyl,
4-cyanophenyl, 3-acetylphenyl, 4-acetylphenyl, 3,4-difluorophenyl,
3,4-dichlorophenyl, 2,3-difluorophenyl, 2,3-dichlorophenyl,
2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,
3,5-dichlorophenyl, 3-nitrophenyl, 4-nitrophenyl,
3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl,
3-chloro-4-difluoromethoxyphenyl, 3-fluoro-4-chlorophenyl,
benzo[1,3]dioxol-4 or 5-yl, 2-hydroxyphenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 4-hydroxy-2-methylphenyl,
4-hydroxy-3-fluorophenyl, 3,4-dihydroxyphenyl, 4-aminophenyl,
4-dimethylaminophenyl, 4-carbamoylphenyl, 4-fluoro-3-methylphenyl,
4-methanesulfanylphenyl, 4-methanesulfinylphenyl,
4-methanesulfonylphenyl, 4-trifluoromethanesulfanylphenyl,
thiophen-2-yl, thiophen-3-yl, 2-pyridinyl, 3-pyridinyl,
4-pyridinyl, 2-chloro-5-pyridinyl, 2-dimethylamino-5-pyridinyl,
2-methoxy-5-pyridinyl, 2-thiomethyl-5-pyridinyl,
2-hydroxy-5-pyridinyl, oxazol-5-yl, thiazol-5-yl, thiazol-2-yl,
2H-pyrazol-3-yl, pyrazin-2-yl, 1-naphthyl, 2-naphthyl,
4-imidazol-1-ylphenyl, 4-pyrazol-1-ylphenyl, 1H-indol-5-yl,
1H-benzimidazol-5-yl, benzo[b]thiophen-7-yl, and 4-biphenyl.
[0081] In a particular embodiment, Ar.sup.1, optionally substituted
with halo, is 4-methoxyphenyl or 4-methanesulfanylphenyl.
[0082] Preferably, Ar.sup.1 is cis to the pyrrolidine ring of
formula (I).
[0083] Preferably, the R.sup.3R.sup.2N-containing ether substituent
of formula (I) is at the 9-position.
[0084] With respect to compounds of formulae (II) and (III),
preferably, R.sup.2 and R.sup.3 are taken together with the
nitrogen to which they are attached to form piperidinyl,
4-fluoropiperidinyl, morpholinyl, or 3-methylmorpholin-4-yl.
[0085] Preferably, Ar.sup.1 is 4-methoxyphenyl or
4-methylsulfanylphenyl.
[0086] Preferably, R.sup.5 is --H.
[0087] It is understood that some compounds referred to herein are
chiral and/or have diastereomeric or geometric isomeric centers,
for example cis- and trans-isomers. The present invention
encompasses all such isomers, including optical isomers, such as
stereoisomers and racemic mixtures, diastereomers, regioisomers,
and geometric isomers that possess the activity that characterizes
the compounds of this invention. Compounds of the invention may
exist as single enantiomers, mixtures of enantiomers, or racemic
mixtures. In certain embodiments, the absolute configuration of a
single enantiomer may be unknown. Compounds of the invention may
exist as a single diastereomers, or as a mixture of diastereomers.
In addition, certain compounds referred to herein can exist in
solvated as well as unsolvated forms. It is understood that this
invention encompasses all such solvated and unsolvated forms that
possess the activity that characterizes the compounds of this
invention.
[0088] Compounds according to the present invention that have been
modified to be detectable by some analytic technique are also
within the scope of this invention. The compounds of the present
invention may be labeled with radioactive elements such as
.sup.125I .sup.18F, .sup.11C, .sup.64Cu, and the like for use in
imaging or for radioactive treatment of patients. An example of
such compounds is an isotopically labeled compound, such as an
.sup.18F isotopically labeled compound that may be used as a probe
in detection and/or imaging techniques, such as positron emission
tomography (PET) and single-photon emission computed tomography
(SPECT). Preferably, compounds of the present invention labeled
with .sup.18F or .sup.11C may be used as a positron emission
tomography (PET) molecular probe for studying disorders mediated by
the histamine H.sub.3 receptor and the serotonin transporter.
Another example of such compounds is an isotopically labeled
compound, such as a deuterium and/or tritium labeled compound that
may be used in reaction kinetic studies. The compounds described
herein may be reacted with appropriate functionalized radioactive
reagents using conventional chemistry to provide radiolabeled
compounds.
[0089] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds that are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with a compound of formulae (I), (II), or
(III), or with a compound that converts to a compound of formulae
(I), (II), or (III) in vivo after administration to the patient.
Conventional procedures for the selection and preparation of
suitable prodrug derivatives are described, for example, in "Design
of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. In addition to
salts, the invention provides the esters, amides, and other
protected or derivatized forms of the described compounds.
[0090] Preferred compounds, which are
hexahydro-pyrrolo-isoquinoline compounds, are selected from the
group consisting of:
TABLE-US-00001 EX CHEMICAL NAME 1A
Cis-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1a]isoquinoline; 1B
Trans-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1a]isoquinoline; 1C
Trans-6-Phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1a]isoquinoline; 2A
Cis-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 2B
Trans-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 2C
Trans-6-(4-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 3
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-phenylamine; 4A
Cis-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 4B
Trans-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 4C
Cis-6-(3-nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 4D
Trans-6-(3-nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 5A
Cis-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 5B
Trans-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 5C
Trans-7-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 6A
Cis-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 6B
Trans-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 6C
Cis-6-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 7A
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 7B
Trans-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 7C
Trans-7-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 8A
Cis-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 8B
1S,6R-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 8C
1R,6S-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 8D
Trans-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 8E
Cis-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 8F
Trans-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 9A
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-phenol; 9B
Trans-4-[7-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-phenol; 10A
Cis-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 10B
Trans-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 10C
Trans-6-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 11A
Cis-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 11B
Trans-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 11C
Trans-6-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 12A
Cis-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 12B
Trans-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 12C
Cis-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 12D
Trans-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 13A
Cis-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 13B
Trans-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 14A
Cis-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 14B
Trans-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 14C
Trans-6-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 15
Cis-3-[9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-phenol; 16
Cis-2-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-phenol; 17
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethoxy-phenyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 18
Cis-6-(3,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 19
Cis-6-(2,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 20
Cis-6-(2,5-dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 21
Cis-6-(3,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 22
Cis-6-(3,4,5-Trimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 23
Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 24A
Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 24B
Trans-9-(3-piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 25
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 26
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 27A
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 27B
Trans-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 28
Cis-7-(1-Isopropyl-piperidin-4-yloxy)-4-(4-methoxy-phenyl)-2-
methyl-1,2,3,4-tetrahydro-isoquinoline; 29
Cis-9-(1-Isopropyl-piperidin-4-ylmethoxy)-6-(4-methoxy-phenyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 30
Cis-Dimethyl-{4-[9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-phenyl}-amine; 31
Cis-9-(3-Piperidin-1-yl-propoxy)-6-m-tolyl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 32
Cis-6-(3-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 33
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trimethylsilanylethynyl-
phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 34
Cis-6-(3-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 35A
Cis-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 35B
Trans-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 36
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trimethylsilanylethynyl-
phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 37
Cis-6-(4-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 38
Cis-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 39A
Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 39B
Trans-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 39C
6-(4-Methylsulfanyl-phenyl)-7-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 40
Cis-6-(4-Bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 41A
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile; 41B
Trans-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile; 42
Trans-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 43
Cis-4-[8-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile; 44
Trans-6-Phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 45
Cis-6-Phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 46
Cis-6-(4-Methoxy-phenyl)-9-[3-(3S-methyl-morpholin-4-yl)-
propoxy]-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 47
Cis-9-[3-(4-Fluoro-piperidin-1-yl)-propoxy]-6-(4-methoxy-phenyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 48A
Cis-6-(4-imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 48B
Trans-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 49
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-pyrazol-1-yl-phenyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 50A
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 50B
Trans-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 51A
Cis-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol; 51B
Trans-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-ol; 52
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-5-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 53
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-2-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 54
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(2H-pyrazol-3-yl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 55
Cis-6-Imidazo[1,2-a]pyridin-3-yl-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 56
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 57
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 58
Cis-3-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
pyrrolo[2,1-a]isoquinolin-6-yl]-benzonitrile; 59
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 60
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 61
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-trifluoromethylsulfanyl-
phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 62
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(3-trifluoromethylsulfanyl-
phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 63
Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 64
Cis-6-(3-Chloro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 65
Cis-6-(3-Fluoro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 66A
Cis-6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 66B
Trans-6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 67
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trifluoromethyl-phenyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 68
6-Biphenyl-4-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 69
9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-2-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 70
9-(3-Morpholin-4-yl-propoxy)-6-quinolin-7-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 71
6-(1H-Indol-5-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 72
6-(1H-Benzoimidazol-5-yl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 73
6-(1H-Benzoimidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 74
6-(1-Methyl-1H-benzoimidazol-2-yl)-9-(3-morpholin-4-yl-
propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 75
9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-1-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 76
6-Benzo[b]thiophen-7-yl-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 77
6-(6-Chloro-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 78
Dimethyl-{5-[9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-yl}-amine; 79
6-(6-Methoxy-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 80
9-(3-Morpholin-4-yl-propoxy)-6-oxazol-5-yl-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 81
6-(1H-Imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 82
6-(1-Methyl-1H-imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 83
6-(3H-Imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-
hexahydro-pyrrolo[2,1-a]isoquinoline; 84
6-(3-Methyl-3H-imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 85
6-(3-Chloro-4-difluoromethoxy-phenyl)-9-(3-morpholin-4-yl-
propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 86
(4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
a]isoquinolin-9-yloxy]-propyl}-morpholin-2-yl)-methanol; 87
(4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
a]isoquinolin-9-yloxy]-propyl}-morpholin-3-yl)-methanol; 88
6-(3,5-Bis-trifluoromethyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 89
(1R,6S)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-
propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 90
(1S,6R)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-
propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 91
(1S,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 92
(1R,6S)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 93
Trans-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 94
(1R,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 95
(1S,6S)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 96A
Cis-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 96B
Trans-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 97A
Cis-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 97B
Trans-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; 98A
Cis-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline; and 98B
Trans-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline.
[0091] The features and advantages of the invention are apparent to
one of ordinary skill in the art. Based on this disclosure,
including the summary, detailed description, background, examples,
and claims, one of ordinary skill in the art will be able to make
modifications and adaptations to various conditions and usages.
Publications described herein are incorporated by reference in
their entirety. Where chemical symbols are used, it is understood
that they are read from left to right, and that otherwise their
spatial orientation has no significance.
[0092] The compounds as described above may be made according to
processes within the skill of the art and/or that are described in
the schemes and examples that follow. To obtain the various
compounds herein, starting materials may be employed that carry the
ultimately desired substituents though the reaction scheme with or
without protection as appropriate. This may be achieved by means of
conventional protecting groups, such as those described in
"Protective Groups in Organic Chemistry", ed. J. F. W. McOmie,
Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts,
"Protective Groups in Organic Synthesis", 3.sup.rd ed., John Wiley
& Sons, 1999. The protecting groups may be removed at a
convenient subsequent stage using methods known from the art.
Alternatively, it may be necessary to employ, in the place of the
ultimately desired substituent, a suitable group that may be
carried through the reaction scheme and replaced as appropriate
with the desired substituent. Such compounds, precursors, or
prodrugs are also within the scope of the invention. Reactions may
be performed between the melting point and the reflux temperature
of the solvent, and preferably between 0.degree. C. and the reflux
temperature of the solvent.
[0093] The hexahydro-pyrrolo-isoquinoline compounds of formulae
(I), (II), and (III) may be prepared by a number of reaction
schemes. Access to compounds of formula (I) is described in Schemes
A-C. Persons skilled in the art will recognize that certain
compounds are more advantageously produced by one scheme as
compared to the other. In addition, synthetic sequences described
in U.S. Pat. Appl. No. 60/637,173 are incorporated by reference and
may be applied to the preparation of compounds of formula (I).
##STR00003##
[0094] Referring to Scheme A, methyl 3-hydroxybenzoate derivatives
A1 may be alkylated with reagents A2, where Y is Cl, OH, a
protected alcohol, or NR.sup.2R.sup.3, to form ethers A3. Where X
is a suitable leaving group, such as Br, I, or OTs, alkylations may
be performed by Williamson ether synthesis, using a suitable base
such as K.sub.2CO.sub.3, Na.sub.2CO.sub.3, or NaH, in a solvent
such as acetonitrile, with or without catalytic KI or NaI.
Alternatively, where X is OH, and Y is a protected hydroxyl or
NR.sup.2R.sup.3, ethers of formula A3 may be prepared under
Mitsunobu conditions. Where Y is Cl, ethers A3 may be converted to
the corresponding amines (where Y is NR.sup.2R.sup.3) using
standard methods. Alternatively, where Y is OH or protected
hydroxyl, the amine group NR.sup.2R.sup.3 may be installed at a
later stage in the synthesis.
[0095] Esters of formula A3 are condensed with
N-vinylpyrrolidin-2-one to form imines of formula A5, which are
subsequently reduced, preferably with LiAlH.sub.4, to pyrrolidines
A6.
##STR00004##
[0096] Referring to Scheme B, alkylation of pyrrolidines A6 with
alpha-haloketones B1 to form ketones B2 is accomplished in the
presence of a tertiary amine base such as Et.sub.3N or
iPr.sub.2NEt, in a suitable solvent such as THF or
CH.sub.2Cl.sub.2. Cyclization to form tetrahydroisoquinolinium
salts B3 is effected by exposure to a suitable protic or Lewis
acid, such as methanesulfonic acid (MSA), trifluoroacetic acid,
AlCl.sub.3, TiCl.sub.4, or BF.sub.3.OEt.sub.2 with or without a
solvent such as CH.sub.2Cl.sub.2. Preferred conditions are neat MSA
or MSA in CH.sub.2Cl.sub.2. The intermediate salts B3 may be
reduced using standard reducing agents such as NaCNBH.sub.3 in an
acidic methanol medium to form tricyclic amines B6.
[0097] Alternatively, pyrrolidines A6 may be reacted with styrene
oxides B4 to form alcohols B5. Ketones B2 may also be reduced by
known methods, including NaBH.sub.4, to the corresponding alcohols
B5. Treatment of the intermediate alcohols B5 with MSA in
CH.sub.2Cl.sub.2 provides cyclic species B6 directly. Where the OR
group has been left as OH, the amino side chain may be installed at
this stage using methods described above or methods known in the
art. Alternatively, the OR group may be carried through the
sequence as a suitably substituted 3-hydroxypropyloxy or
4-hydroxybutyloxy group (protected or unprotected as appropriate),
and the terminal hydroxyl group may be converted to the desired
amine functionality at an appropriate point during the synthetic
sequence using standard methods such as those described above.
[0098] In another embodiment, pyrrolidines A6 may be coupled with
mandelic acid derivatives B7 to form amides B8. Cyclization to form
tricyclic amides B9 is performed as described above. Reduction of
the carbonyl to provide compounds of formula B6 is accomplished
with a reducing agent such as BH.sub.3, in a solvent such as
THF.
[0099] Although Scheme B is depicted to produce regioisomers B6 in
which the OR substituent is at the 9-position of the tricyclic ring
system, those skilled in the art will recognize that cyclization of
compounds of formula B2, B5, and B8 may also provide regioisomers
where the OR substituent is in the 7-position. Such regioisomers
may be converted to compounds of formula (I) according to the
procedures described above.
##STR00005##
[0100] Compounds of formula C8, where OR is defined as in Scheme B,
are alternatively prepared according to Scheme C. Intermediates of
formula C1 may be commercially available or may be prepared by a
variety of methods. Those skilled in the art will recognize that
the amine side chain of compounds of formula (I) may be installed
at an appropriate point during the sequence using standard methods
including those described in Schemes A and B. If required, a
protected amino group or surrogate may be used and later
transformed into the amino group --NR.sup.2R.sup.3.
[0101] Formation of the aryl Grignard reagent, followed by reaction
with malonic ester analogs C2, hydrolysis of the resulting diester,
and decarboxylation provide acids of formula C3. Hydrolysis may be
performed using methods known to one skilled in the art, including
KOH in EtOH. Decarboxylation is typically accomplished through the
application of heat. Curtius rearrangement, preferably using
Et.sub.3N and diphenylphosphoryl azide in a suitable solvent,
installs a protected amine functionality. Where the solvent is
t-BuOH, a Boc protecting group results. The protecting group may be
subsequently removed under standard conditions, such as TFA in DCM,
to form amines of formula C5.
[0102] Alternatively, halogen-metal exchange of the aryl bromides
C1, followed by reaction with nitroalkenes C4, and subsequent
reduction of the nitro group will provide amines of formula C5
directly. Reduction of the nitro group is accomplished using
procedures well-known to those skilled in the art. Reaction of
amines C5 with succinic anhydride, followed by ring closure, gives
rise to the corresponding succinimides (structure not shown). The
ring closure may preferably be accomplished using acetyl chloride,
with or without the application of heat. Succinimides C6 are then
reduced to hemiaminals C6 using a suitable reducing agent, such as
NaBH.sub.4, in a solvent such as dioxane.
[0103] Reaction under acidic conditions, such as MSA, leads to
formation of the tricyclic system of compounds of formula C7. The
lactam ring may be reduced to form compounds of formula C8 using a
suitable reducing agent, such as BH.sub.3, in a solvent such as
THF. Where OR is OMe, the methyl protecting group may be removed at
the C7 or C8 stage and replaced by the amine-containing side chain
described in formula (I).
[0104] Compounds of formulae (II) and (III) are prepared according
to procedures described above and those described in U.S. patent
application Ser. No. 11/300,880 and U.S. Patent Appl. No.
60/692,003, as well as those described in the Examples below.
[0105] Compounds prepared according to the schemes described above
may be obtained as single enantiomers, diastereomers, or
regioisomers, or as racemic mixtures or mixtures of enantiomers,
diastereomers, or regioisomers. Where regioisomeric or
diastereomeric mixtures are obtained, isomers may be separated
using conventional methods such as chromatography or
crystallization. Where racemic (1:1) and non-racemic (not 1:1)
mixtures of enantiomers are obtained, single enantiomers may be
isolated using conventional separation methods known to one skilled
in the art. Particularly useful separation methods may include
chiral chromatography, recrystallization, resolution,
diastereomeric salt formation, or derivatization into
diastereomeric adducts followed by separation.
[0106] For therapeutic use, salts of the compounds of the present
invention are those that are pharmaceutically acceptable. However,
salts of acids and bases that are non-pharmaceutically acceptable
may also find use, for example, in the preparation or purification
of a pharmaceutically acceptable compound. All salts, whether
pharmaceutically acceptable or not are included within the ambit of
the present invention.
[0107] Pharmaceutically acceptable salts, esters, and amides of
compounds according to the present invention refer to those salt,
ester, and amide forms of the compounds of the present invention
which would be apparent to the pharmaceutical chemist, i.e., those
which are non-toxic and which would favorably affect the
pharmacokinetic properties of said compounds of the present
invention. Those compounds having favorable pharmacokinetic
properties would be apparent to the pharmaceutical chemist, i.e.,
those which are non-toxic and which possess such pharmacokinetic
properties to provide sufficient palatability, absorption,
distribution, metabolism and excretion. Other factors, more
practical in nature, which are also important in the selection, are
cost of raw materials, ease of crystallization, yield, stability,
hygroscopicity and flowability of the resulting bulk drug.
[0108] Examples of acids that may be used in the preparation of
pharmaceutically acceptable salts include the following: acetic
acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid,
alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid,
benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric
acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, cinnamic acid, citric
acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric
acid, ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucuronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, hydroiodic acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid,
lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid,
malonic acid, (.+-.)-DL-mandelic acid, methanesulfonic acid,
naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,
1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic
acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,
perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic
acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic
acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric
acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid,
and valeric acid.
[0109] Compounds of the present invention containing acidic protons
may be converted into their therapeutically active non-toxic metal
or amine addition salt forms by treatment with appropriate organic
and inorganic bases. Appropriate base salt forms comprise, for
example, the ammonium salts; the alkali and earth alkaline metal
salts (e.g. lithium, sodium, potassium, magnesium, calcium salts,
which may be prepared by treatment with, for example, magnesium
hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide,
or sodium hydroxide); and amine salts made with organic bases (e.g.
primary, secondary and tertiary aliphatic and aromatic amines such
as L-arginine, benethamine, benzathine, choline, deanol,
diethanolamine, diethylamine, dimethylamine, dipropylamine,
diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine,
ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine,
hydrabamine, 1H-imidazole, L-lysine, morpholine,
4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine,
propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine,
quinuclidine, quinoline, isoquinoline, secondary amines,
triethanolamine, trimethylamine, triethylamine,
N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol,
and tromethamine). See, e.g., S. M. Berge, et al., "Pharmaceutical
Salts", J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein
by reference.
[0110] Pharmaceutically acceptable esters and amides are those that
are within a reasonable benefit/risk ratio, pharmacologically
effective and suitable for contact with the tissues of patients
without undue toxicity, irritation, or allergic response.
Representative pharmaceutically acceptable amides of the invention
include those derived from ammonia, primary C.sub.1-6alkyl amines
and secondary di(C.sub.1-6alkyl) amines. Secondary amines include
5- or 6-membered heterocyclic or heteroaromatic ring moieties
containing at least one nitrogen atom and optionally between 1 and
2 additional heteroatoms. Preferred amides are derived from
ammonia, C.sub.1-3alkyl primary amines, and
di(C.sub.1-2alkyl)amines.
[0111] Representative pharmaceutically acceptable esters of the
invention include C.sub.1-7alkyl, C.sub.5-7cycloalkyl, phenyl,
substituted phenyl, and phenylC.sub.1-6alkyl-esters. Preferred
esters include methyl esters. Furthermore, examples of suitable
esters include such esters where one or more carboxyl substituents
is replaced with p-methoxybenzyloxy-carbonyl,
2,4,6-trimethylbenzyloxy-carbonyl, 9-anthryloxycarbonyl,
CH.sub.3SCH.sub.2COO--, tetrahydrofur-2-yloxycarbonyl,
tetrahydropyran-2-yloxy-carbonyl, fur-2-yloxycarbonyl, benzoyl
methoxy-carbonyl, p-nitrobenzyloxy-carbonyl,
4-pyridylmethoxycarbonyl, 2,2,2-trichloro-ethoxycarbonyl,
2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl,
t-amyloxy-carbonyl, diphenylmethoxycarbonyl,
triphenylmethoxycarbonyl, adamantyloxy-carbonyl,
2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl, or
tetrahydropyran-2-yloxycarbonyl.
[0112] The compounds of the present invention are modulators of the
histamine H.sub.3 receptor and of the serotonin transporter, and as
such, the compounds are useful in the treatment of histamine
H.sub.3 and serotonin-mediated disease states. Compounds of the
present invention possess serotonin transporter and H.sub.3
receptor modulating activity. As such modulators, the compounds may
act as antagonists or agonists. The effect of an antagonist may
also be produced by an inverse agonist.
[0113] The compounds of the present invention are useful in methods
for treating or preventing neurologic or CNS disorders including
sleep/wake and arousal/vigilance disorders (e.g. insomnia, jet lag,
and disturbed sleep), attention deficit hyperactivity disorders
(ADHD), attention-deficit disorders, learning and memory disorders,
learning impairment, memory impairment, memory loss, cognitive
dysfunction, migraine, neurogenic inflammation, dementia, mild
cognitive impairment (pre-dementia), Alzheimer's disease, epilepsy,
narcolepsy with or without associated cataplexy, cataplexy,
disorders of sleep/wake homeostasis, idiopathic somnolence,
excessive daytime sleepiness (EDS), circadian rhythm disorders,
sleep/fatigue disorders, fatigue, drowsiness associated with sleep
apnea, sleep impairment due to perimenopausal hormonal shifts,
Parkinson's-related fatigue, MS-related fatigue, depression-related
fatigue, chemotherapy-induced fatigue, work-related fatigue,
lethargy, eating disorders, obesity, motion sickness, vertigo,
schizophrenia, substance abuse, bipolar disorders, manic disorders
and depression. Said methods comprise the step of administering to
a mammal suffering therefrom an effective amount of at least one
compound of the present invention.
[0114] Particularly, as modulators of the histamine H.sub.3
receptor and the serotonin transporter, the compounds of the
present invention may be used in the treatment or prevention of
depression, disturbed sleep, fatigue, lethargy, cognitive
impairment, memory impairment, memory loss, learning impairment,
and attention-deficit disorders.
[0115] The present invention also contemplates a method of treating
or preventing a disease or condition mediated by the histamine
H.sub.3 receptor and the serotonin transporter with a combination
therapy, comprising administering at least one compound of the
present invention in combination with one or more therapeutic
agents. Suitable therapeutic agents include: H.sub.1 receptor
antagonists, H.sub.2 receptor antagonists, H.sub.3 receptor
antagonists, and neurotransmitter modulators such as
serotonin-norepinephrine reuptake inhibitors, selective serotonin
reuptake inhibitors (SSRIs), noradrenergic reuptake inhibitors,
non-selective serotonin re-uptake inhibitors (NSSRIs),
acetylcholinesterase inhibitors, and modafinil. In a particular
embodiment, a combination therapy method includes administering at
least one compound of present invention and administering
modafinil, for example, for the treatment of narcolepsy, excessive
daytime sleepiness (EDS), Alzheimer's disease, depression,
attention-deficit disorders, MS-related fatigue, post-anesthesia
grogginess, cognitive impairment, schizophrenia, spasticity
associated with cerebral palsy, age-related memory decline,
idiopathic somnolence, or jet-lag.
[0116] The present invention also contemplates a method for the
treatment or prevention of a disease selected from the group
consisting of: depression, disturbed sleep, fatigue, lethargy,
cognitive impairment, memory impairment, memory loss, learning
impairment, and attention-deficit disorders in mammals, comprising
the step of administering to a mammal suffering therefrom an
effective amount of a compound having both H.sub.3 receptor
modulating activity and serotonin transporter modulating activity.
Preferably, said compound has an H.sub.3 receptor binding activity
of at least 20 nM in the human H.sub.3 binding assay. Preferably,
said compound has a serotonin transporter binding activity of at
least 20 nM in the human SERT binding assay. Preferably, the ratio
of the H.sub.3 receptor binding activity in the human H.sub.3
binding assay and the serotonin transporter binding activity in the
human SERT binding assay for said compound is between 10:1 and
1:10.
[0117] Compounds of the present invention may be administered in
pharmaceutical compositions to treat patients (humans and other
mammals) with disorders mediated by the H.sub.3 receptor and
serotonin transporter. Thus, the invention features pharmaceutical
compositions containing at least one compound of the present
invention and a pharmaceutically acceptable carrier. A composition
of the invention may further include at least one other therapeutic
agent (for example, a combination formulation or combination of
differently formulated active agents for use in a combination
therapy method).
[0118] The present invention also features methods of using or
preparing or formulating such pharmaceutical compositions. The
pharmaceutical compositions can be prepared using conventional
pharmaceutical excipients and compounding techniques known to those
skilled in the art of preparing dosage forms. It is anticipated
that the compounds of the invention can be administered by oral,
parenteral, rectal, topical, or ocular routes, or by inhalation.
Preparations may also be designed to give slow release of the
active ingredient. The preparation may be in the form of tablets,
capsules, sachets, vials, powders, granules, lozenges, powders for
reconstitution, liquid preparations, or suppositories. Preferably,
compounds may be administered by intravenous infusion or topical
administration, but more preferably by oral administration.
[0119] For oral administration, the compounds of the invention can
be provided in the form of tablets or capsules, or as a solution,
emulsion, or suspension. Tablets for oral use may include the
active ingredient mixed with pharmaceutically acceptable excipients
such as inert diluents, disintegrating agents, binding agents,
lubricating agents, sweetening agents, flavoring agents, coloring
agents and preservatives agents. Suitable inert fillers include
sodium and calcium carbonate, sodium and calcium phosphate,
lactose, starch, sugar, glucose, methyl cellulose, magnesium
stearate, mannitol, sorbitol, and the like; typical liquid oral
excipients include ethanol, glycerol, water and the like. Starch,
polyvinyl-pyrrolidone, sodium starch glycolate, microcrystalline
cellulose, and alginic acid are suitable disintegrating agents.
Binding agents may include starch and gelatin. The lubricating
agent, if present, will generally be magnesium stearate, stearic
acid or talc. If desired, the tablets may be coated with a material
such as glyceryl monostearate or glyceryl distearate to delay
absorption in the gastrointestinal tract, or may be coated with an
enteric coating. Capsules for oral use include hard gelatin
capsules in which the active ingredient is mixed with a solid,
semi-solid, or liquid diluent, and soft gelatin capsules wherein
the active ingredient is mixed with water, an oil such as peanut
oil or olive oil, liquid paraffin, a mixture of mono and
di-glycerides of short chain fatty acids, polyethylene glycol 400,
or propylene glycol.
[0120] Liquids for oral administration may be suspensions,
solutions, emulsions or syrups or may be presented as a dry product
for reconstitution with water or other suitable vehicles before
use. Compositions of such liquid may contain
pharmaceutically-acceptable excipients such as suspending agents
(for example, sorbitol, methyl cellulose, sodium alginate, gelatin,
hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate
gel and the like); non-aqueous vehicles, which include oils (for
example, almond oil or fractionated coconut oil), propylene glycol,
ethyl alcohol or water; preservatives (for example, methyl or
propyl p-hydroxybenzoate or sorbic acid); wetting agents such as
lecithin; and, if needed, flavoring or coloring agents.
[0121] The compounds of this invention may also be administered by
non-oral routes. The compositions may be formulated for rectal
administration as a suppository. For parenteral use, including
intravenous, intramuscular, intraperitoneal, or subcutaneous
routes, the compounds of the invention will generally be provided
in sterile aqueous solutions or suspensions, buffered to an
appropriate pH and isotonicity or in parenterally acceptable oil.
Suitable aqueous vehicles include Ringer's solution and isotonic
sodium chloride. Such forms will be presented in unit dose form
such as ampules or disposable injection devices, in multi-dose
forms such as vials from which the appropriate dose may be
withdrawn, or in a solid form or pre-concentrate that can be used
to prepare an injectable formulation. Another mode of
administration of the compounds of the invention may utilize a
patch formulation to affect transdermal delivery. The compounds of
this invention may also be administered by inhalation, via the
nasal or oral routes using a spray formulation consisting of the
compound of the invention and a suitable carrier.
[0122] Methods are known in the art for determining effective doses
for therapeutic and prophylactic purposes for the pharmaceutical
compositions or the drug combinations of the present invention,
whether or not formulated in the same composition. The specific
dosage level required for any particular patient will depend on a
number of factors, including severity of the condition being
treated, the route of administration, and the weight of the
patient. For therapeutic purposes, "effective dose" or "effective
amount" refers to that amount of each active compound or
pharmaceutical agent, alone or in combination, that elicits the
biological or medicinal response in a tissue system, animal, or
human that is being sought by a researcher, veterinarian, medical
doctor, or other clinician, which includes alleviation of the
symptoms of the disease or disorder being treated. For prophylactic
purposes (i.e., inhibiting the onset or progression of a disorder),
the term "effective dose" or "effective amount" refers to that
amount of each active compound or pharmaceutical agent, alone or in
combination, that inhibits in a subject the onset or progression of
a disorder as being sought by a researcher, veterinarian, medical
doctor, or other clinician, the delaying of which disorder is
mediated, at least in part, by the modulation of the histamine
H.sub.3 receptor and/or the serotonin transporter. Thus, the
present invention provides combinations of two or more drugs
wherein, for example, (a) each drug is administered in an
independently therapeutically or prophylactically effective amount;
(b) at least one drug in the combination is administered in an
amount that is sub-therapeutic or sub-prophylactic if administered
alone, but is therapeutic or prophylactic when administered in
combination with the second or additional drugs according to the
invention; or (c) both drugs are administered in an amount that is
sub-therapeutic or sub-prophylactic if administered alone, but are
therapeutic or prophylactic when administered together.
Combinations of three or more drugs are analogously possible.
Methods of combination therapy include co-administration of a
single formulation containing all active agents; essentially
contemporaneous administration of more than one formulation; and
administration of two or more active agents separately
formulated.
[0123] It is anticipated that the daily dose (whether administered
as a single dose or as divided doses) will be in the range 0.01 to
1000 mg per day, more usually from 1 to 500 mg per day, and most
usually from 10 to 200 mg per day. Expressed as dosage per unit
body weight, a typical dose will be expected to be between 0.0001
mg/kg and 15 mg/kg, especially between 0.01 mg/kg and 7 mg/kg, and
most especially between 0.15 mg/kg and 2.5 mg/kg.
[0124] Preferably, oral doses range from about 0.05 to 200 mg/kg,
daily, taken in 1 to 4 separate doses. Some compounds of the
invention may be orally dosed in the range of about 0.05 to about
50 mg/kg daily, others may be dosed at 0.05 to about 20 mg/kg
daily, while still others may be dosed at 0.1 to about 10 mg/kg
daily. Infusion doses can range from about 1 to 1000 .mu.g/kg/min
of inhibitor, admixed with a pharmaceutical carrier over a period
ranging from several minutes to several days. For topical
administration compounds of the present invention may be mixed with
a pharmaceutical carrier at a concentration of about 0.1% to about
10% of drug to vehicle.
EXAMPLES
[0125] In order to illustrate the invention, the following examples
are included. These examples do not limit the invention. They are
only meant to suggest a method of practicing the invention. Those
skilled in the art may find other methods of practicing the
invention, which are obvious to them. However, those methods are
deemed to be within the scope of this invention.
Protocol for Preparative Reversed-Phase HPLC
Gilson.RTM.
Column: YMC-Pack ODS-A, 5 .mu.m, 75.times.30 mm
[0126] Flow rate: 25 mL/min
Detection: .lamda.=220 & 254 nm
[0127] Gradient (acetonitrile/water, 0.05% trifluoroacetic acid) 1)
0.0 min 15% acetonitrile/85% water 2) 20.0 min 99% acetonitrile/1%
water
Protocol for HPLC (Reversed-Phase)
Method A:
Hewlett Packard Series 1100
Column: Agilent ZORBAX.RTM. Bonus RP, 5 .mu.m, 4.6.times.250 mm
[0128] Flow rate: 1 mL/min
Detection: .lamda.=220 & 254 nm
[0129] Gradient (acetonitrile/water, 0.05% trifluoroacetic acid) 1)
0.0 min 1% acetonitrile/99% water 2) 20.0 min 99% acetonitrile/1%
water
Method B:
Hewlett Packard HPLC
Column: Agilent ZORBAX.RTM. Eclipse XDB-C8, 5 .mu.m, 4.6.times.150
mm
[0130] Flow rate: 1 mL/min
Detection: .lamda.=220 & 254 nm
[0131] Gradient (acetonitrile/water, 0.05% trifluoroacetic acid) 1)
0.0 min 1% acetonitrile/99% water 2) 8.0 min 99% acetonitrile/1%
water 3) 12.0 min 99% acetonitrile/1% water
Protocol for Preparative SFC
Thar Technologies.RTM.
Column: Chiracel AD, 10 .mu.m, 250.times.20 mm
[0132] Flow rate: 37 gm/min
Detection: .lamda.=220 & 254 nm
[0133] Mobile phase: Isocratic 30% IPA/70% CO.sub.2
Pressure: 150 Bar
Temperature: 35.degree. C.
Protocol for Analytical SFC
Jasco.RTM.
Column: Chiracel AD, 10 .mu.m, 250.times.4.6 mm
[0134] Flow rate: 1 gm/min
Detection: .lamda.=220 & 254 nm
[0135] Mobile phase: Isocratic 30% IPA/70% CO.sub.2
Pressure: 150 Bar
Temperature: 35.degree. C.
[0136] Mass spectra were obtained on an Agilent series 1100 MSD
using electrospray ionization (ESI) in positive mode unless
otherwise indicated. Calculated mass corresponds to the exact
mass.
[0137] Thin-layer chromatography was performed using Merck silica
gel 60 F.sub.254 2.5 cm.times.7.5 cm 250 .mu.m or 5.0 cm.times.10.0
cm 250 .mu.m pre-coated silica gel plates. Preparative thin-layer
chromatography was performed using EM Science silica gel 60
F.sub.254 20 cm.times.20 cm 0.5 mm pre-coated plates with a 20
cm.times.4 cm concentrating zone.
[0138] NMR spectra were obtained on either a Bruker model DPX400
(400 MHz), DPX500 (500 MHz), or DPX600 (600 MHz) spectrometer. The
format of the .sup.1H NMR data below is: chemical shift in ppm down
field of the tetramethylsilane reference (multiplicity, coupling
constant J in Hz, integration).
[0139] Normal phase flash column chromatography (FCC) was typically
performed with RediSep.RTM. silica gel columns using 2 M ammonia in
methanol/dichloromethane as eluent.
[0140] Chiral chromatography was performed using SFC HPLC
(Chiralpak AD-h column), IPA/MeOH/CO.sub.2, or by chiral HPLC
(21.times.250 mm Chiracel AD-H, 5 .mu.M (Chiral Technologies), 0.2%
diethylamine in EtOH, 8 mL/min). Where a potential chiral center is
designated with a solid bond (not bold or hashed), the structure is
meant to refer to a racemic mixture, a mixture of enantiomers, or a
single enantiomer as described. Where a single enantiomer is
described without enantiomeric designation at the chiral center, it
is understood that the absolute configuration of the single
enantiomer is unknown.
Example 1-(A-C)
[0141] ##STR00006## [0142] 1A:
Cis-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1a]isoquinoline [0143] 1B:
Trans-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrro-
lo[2,1a]isoquinoline [0144] 1C:
Trans-6-Phenyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrro-
lo[2,1a]isoquinoline
Step 1. 3-(3-Chloro-propoxy)-benzoic acid methyl ester
[0145] A mixture of methyl 3-hydroxybenzoate (100.4 g, 0.657 mol),
1-bromo-3-chloropropane (78 mL, 0.789 mol), and K.sub.2CO.sub.3
(136.4 g, 0.986 mol) in acetone (430 mL) was heated to 60.degree.
C. for 42 h. The reaction mixture was cooled to 0.degree. C. and
then treated with diethyl ether (500 mL). The resultant mixture was
filtered and concentrated to give a viscous oil. Short-path
distillation (bp=134-136.degree. C. at 1 torr) gave the product as
colorless oil (138.85 g, 92%). .sup.1H NMR (acetone-d.sub.6): 7.58
(dt, J=1.4, 7.7, 1H), 7.53 (dd, J=1.5, 2.6, 1H), 7.40 (t, J=8.0,
1H), 7.18 (ddd, J=0.9, 2.7, 8.3, 1H), 4.18 (t, J=5.9, 2H), 3.87 (s,
3H), 3.80 (t, J=6.5, 2H), 2.24 (quint, J=6.2, 2H).
Step 2. 3-(3-Iodo-propoxy)-benzoic acid methyl ester
[0146] A mixture of NaI (318.4 g, 2.12 mol) and
3-(3-chloro-propoxy)-benzoic acid methyl ester (138.5 g, 0.606 mol)
in acetone (1.2 L) was heated to 60.degree. C. for 2 d. The
reaction mixture was concentrated and then diluted with
CH.sub.2Cl.sub.2 (1 L) and water (500 mL). After mixing thoroughly,
the layers were separated and the organic layer was washed with
water (2.times.500 mL) and brine (1.times.200 mL), dried
(MgSO.sub.4), filtered and concentrated to give the desired product
as a pale-yellow oil (190.95 g, 98%). The product was protected
from light by wrapping the flask in aluminum foil. bp=154.degree.
C. at 1 torr. .sup.1H NMR (acetone-d.sub.6): 7.61 (d, J=7.6, 1H),
7.56 (s, 1H), 7.44 (t, J=8.0, 1H), 7.23 (d, J=8.1, 1H), 4.16 (t,
J=5.6, 2H), 3.89 (s, 3H), 3.48 (t, J=6.7, 2H), 2.31 (m, 2H).
Step 3. 3-(3-Piperidin-1-yl-propoxy)-benzoic acid methyl ester
[0147] A mixture of 3-(3-iodo-propoxy)-benzoic acid methyl ester
(190.9 g, 0.596 mol), Na.sub.2CO.sub.3(94.9 g, 0.894 mol), and
piperidine (80 mL, 0.80 mol) in dry ethanol (400 mL) was protected
from light with aluminum foil, and was heated to 60.degree. C.
under nitrogen for 22 h. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (1 L), washed with water (4.times.600 mL) and
brine (1.times.300 mL), dried (K.sub.2CO.sub.3), and concentrated
to give the crude product as a biphasic (solid/liquid) mixture.
Purification by Kugelrohr distillation (bp=215.degree. C. at 1
torr) yielded a pale-yellow oil (143.4 g, 87%). MS (ESI): exact
mass calcd for C.sub.16H.sub.23NO.sub.3, 277.2; m/z found, 278.2
[M+H].sup.+. .sup.1H NMR (DMSO-d.sub.6): 7.51 (d, J=7.6, 1H), 7.4
(m, 2H), 7.18 (m, 1H), 4.02 (t, J=6.4, 2H), 3.83 (s, 3H), 2.37 (t,
J=7.0, 2H), 2.30 (br s, 4H), 1.84 (m, 2H), 1.46 (m, 4H), 1.35 (br
m, 2H).
Step 4.
1-{3-[3-(4,5-Dihydro-3H-pyrrol-2-yl)-phenoxy]-propyl}-piperidine
[0148] To a 0.degree. C. solution of NaH (95%, 17.4 g, 0.723 mol)
in dry THF (500 mL) was added a solution of
3-(3-piperidin-1-yl-propoxy)-benzoic acid methyl ester (143.2 g,
0.516 mol) and N-vinylpyrrolidin-2-one (66.0 mL, 0.620 mol) in dry
THF (172 mL), via cannula, over the course of 18 min. The resultant
mixture was stirred at 0.degree. C. for 1 h (until gas evolution
subsided) before heating to reflux for 5 h. The reaction mixture
was then cooled to 0.degree. C. and slowly treated with 12 N HCl
(150 mL). The THF was removed in vacuo and an additional 12 N HCl
(150 mL) and water (220 mL) was added and the mixture heated to
110.degree. C. under nitrogen for 2 d. The reaction mixture was
again cooled to 0.degree. C. before slowly adding a solution of
NaOH (150 g, 3.75 mol) in water (400 mL). The aqueous mixture was
extracted with CH.sub.2Cl.sub.2 (2.times.500 mL). The combined
extracts were washed with brine (1.times.500 mL), dried
(Na.sub.2CO.sub.3), filtered and concentrated to give the crude
product as a nearly black oil. Kugelrohr distillation of the crude
product (bp=226-228.degree. C. at 1 torr) yielded a pale-yellow oil
(106.35 g, 72%). MS: exact mass calcd for C.sub.18H.sub.26N.sub.2O,
286.2; m/z found, 287.2 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
7.37 (d, J=1.5, 1H), 7.32 (m, 2H), 7.00 (m, 1H), 3.96 (m, 4H), 2.95
(m, 2H), 2.49 (m, 6H), 1.99 (m, 4H), 1.59 (m, 4H), 1.45 (br m,
2H).
Step 5. 1-[3-(3-Pyrrolidin-2-yl-phenoxy)-propyl]-piperidine
[0149] To a 0.degree. C. mixture of LiAlH.sub.4 (14.28 g, 0.376
mol) in dry THF (200 mL) under nitrogen was added a solution of
1-{3-[3-(4,5-dihydro-3H-pyrrol-2-yl)-phenoxy]-propyl}-piperidine
(106.4 g, 0.371 mol) in THF (200 mL) via cannula. Once addition was
complete, the mixture was allowed to warm to room temperature (rt)
and stir for 18 h. The mixture was then cooled to 0.degree. C. and
slowly treated with water (14.3 mL), followed by 15% aq. NaOH (14.3
mL), an additional 43 mL of water and 200 mL of THF. The resultant
mixture was stirred for 2 h before filtering and concentrating to
give a nearly colorless oil (94.4 g, 88%). MS: exact mass calcd for
C.sub.18H.sub.28N.sub.2O, 288.2; m/z found, 289.2 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.20 (t, J=7.8, 1H), 6.9 (d, J=7.8,
2H), 6.77 (dd, J=2.0, 8.2, 1H), 4.91 (s, 1H), 3.97 (m, 3H), 3.13
(m, 1H), 2.90 (m, 1H), 2.49 (m, 6H), 2.16 (m, 1H), 1.95 (m, 4H),
1.7 (m, 1H), 1.60 (m, 4H), 1.47 (br m, 2H).
Step 6.
1-Phenyl-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-y-
l}-ethanol
[0150] A solution of
1-[3-(3-pyrrolidin-2-yl-phenoxy)-propyl]-piperidine (3.50 mmol) and
styrene oxide (1.0 equiv.) in ethanol (0.5 molar) was heated at
reflux until conversion was complete. The ethanol was removed in
vacuo and the residue was then either passed through a plug of
silica gel (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2) or taken on to the
next step without purification to yield 1.12 g (79%) of the desired
product as a mixture of diastereomers (colorless oil). MS: exact
mass calcd for C.sub.26H.sub.36N.sub.2O.sub.2, 408.3; m/z found,
409.3 [M+H].sup.+.
Step 7
[0151] A solution of
1-phenyl-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-etha-
nol (1.7 mmol) and MSA (5 mL/g of amino-alcohol) under nitrogen was
stirred at rt. When the reaction was complete, the mixture was
cooled to 0.degree. C., diluted with 2 N NaOH and extracted with
CH.sub.2Cl.sub.2. The organic extract was washed with brine, dried
(Na.sub.2CO.sub.3), filtered and concentrated to give the crude
products as a mixture of diastereomers. Purification by column
chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2) followed by
reverse-phase HPLC provided Examples 1A-C in a combined yield of
41%.
1A:
Cis-6-phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrr-
olo[2,1a]isoquinoline
[0152] 18.4 mg (2%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.34N.sub.2O, 390.3; m/z found, 391.4 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.28 (m, 2H), 7.24 (m, 1H), 7.13 (d,
J=7.0, 2H), 6.76 (d, J=2.5, 1H), 6.67 (d, J=8.6, 1H), 6.58 (d,
J=8.7, 1H), 4.74 4.25 (m, 1H), 3.97 (t, J=5.8, 2H), 3.72 (m, 1H),
3.45 (m, 3H), 3.17 (m, 2H), 2.83 (m, 2H), 2.73 (m, 1H), 2.15 (m,
6H), 1.83 (d, J=14.7, 2H), 1.67 (m, 3H), 1.40 (m, 1H).
1B:
Trans-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-py-
rrolo[2,1a]isoquinoline
[0153] 299.0 mg (27%) as the TFA salt. MS: exact mass calcd exact
mass calcd for C.sub.26H.sub.34N.sub.2O, 390.3; m/z found, 391.4
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.37 (m, 2H), 7.31 (m,
1H), 7.17 (br s, 2H), 6.92 (br m, 3H), 5.10 (br s, 3H), 4.98 (br s,
1H), 4.52 (br s, 1H), 4.14 (t, J=5.6, 2H), 3.77 (br s, 2H), 3.65
(m, 2H), 3.49 (br s, 1H), 2.28 (m, 2H), 2.10 (br s, 2H), 1.96 (d,
J=14.6, 2H), 1.90 (m, 3H), 1.54 (m, 1H).
1C:
Trans-6-Phenyl-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-py-
rrolo[2,1-a]isoquinoline
[0154] 129.8 mg (12%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.34N.sub.2O, 390.3; m/z found, 391.4 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.38 (m, 4H), 7.10 (d, J=7.3, 2H), 7.01
(d, J=7.8, 1H), 6.97 (d, J=8.2, 1H), 5.00 (s, 4H), 4.76 (m, 2H),
4.11 (d, J=4.6, 1H), 3.7 (m, 4H), 3.30 (m, 3H), 2.75 (br m, 1H),
2.60 (m, 3H), 2.45 (m, 1H), 2.23 (m, 3H), 2.05 (br m, 1H), 1.75 (m,
5H), 1.45 (m, 1H).
Example 2-(A-C)
[0155] ##STR00007## [0156] 2A:
Cis-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline [0157] 2B:
Trans-6-(4-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline [0158] 2C:
Trans-6-(4-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(4-Nitrophenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrro-
lidin-1-yl}-ethanol
[0159] Prepared as described in Example 1, Step 6, on a 3.47 mmol
scale, to yield 1.57 g (quant.) of the desired product as a mixture
of diastereomers (yellow oil). MS: exact mass calcd for
C.sub.26H.sub.35N.sub.3O.sub.4, 453.3; m/z found, 454.2
[M+H].sup.+.
Step 2
[0160] Performed as described in Example 1, Step 7, on a 3.47 mmol
scale, to give a 3% combined yield of the products 2A, 2B, and
2C.
2A:
Cis-6-(4-Nitrophenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,6a,10a,10-
b-octahydro-pyrrolo[2,1a]isoquinoline
[0161] 30.2 mg (1%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33N.sub.3O.sub.3, 435.3; m/z found, 436.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 8.17 (d, J=8.8, 2H), 7.44
(d, J=8.6, 2H), 6.82 (d, J=2.5, 1H), 6.72 (dd, J=2.5, 8.7, 1H),
6.56 (d, J=8.7, 1H), 4.50 (m, 1H), 4.00 (t, J=5.7, 2H), 4.81 (br m,
1H), 3.56 (m, 1H), 3.48 (d, J=12.3, 2H), 3.38 (m, 2H), 3.19 (m,
2H), 2.85 (m, 2H), 2.72 (m, 1H), 2.15 (m, 5H), 1.85 (d, J=14.6,
2H), 1.68 (m, 3H), 1.42 (m, 1H).
2B:
Trans-6-(4-Nitrophenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,6a,10a,-
10b-octahydro-pyrrolo[2,1a]isoquinoline
[0162] 21.4 mg (1%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33N.sub.3O.sub.3, 435.3; m/z found, 436.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 8.23 (d, J=8.8, 2H), 7.43
(m, 3H), 7.02 (d, J=7.8, 1H), 6.95 (br d, J=7.8, 1H), 4.77 (br s,
1H), 3.97 (br s, 1H), 3.70 (br m, 3H), 3.29 (br m, 4H), 2.77 (m,
1H), 2.70 (m, 3H), 2.57 (br m, 1H), 2.22 (br s, 3H), 1.9 (br d,
J=14.8, 2H), 1.75 (m, 1H), 1.73 (m, 5H), 1.49 (m, 1H).
2C:
Trans-6-(4-Nitrophenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,6a,10a,-
10b-octahydro-pyrrolo[2,1a]isoquinoline
[0163] 28.7 mg (1%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33N.sub.3O.sub.3, 435.3; m/z found, 436.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 8.20 (d, J=8.8, 2H), 7.46
(t, J=8.0, 1H), 7.34 (br d, J=6.6, 2H), 7.04 (d, J=7.9, 1H), 7.00
(d, J=8.3, 1H), 4.88 (m, 1H), 3.86 (s, 6H), 4.08 (br s, 1H), 3.88
(br s, 2H), 3.76 (br s, 2H), 3.30 (m, 2H), 2.77 (m, 2H), 2.65 (m,
3H), 2.18 (m, 3H), 1.99 (br m, 1H), 1.82 4H), 1.70 (m, 2H), 1.47
(m, 1H).
##STR00008##
Example 3
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]-
isoquinolin-6-yl]-phenylamine
[0164] A mixture of
cis-6-(4-nitrophenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,6a,10a,10b-o-
ctahydro-pyrrolo[2,1a]isoquinoline (Example 2, 310 mg, 0.71 mmol),
PtO.sub.2 (20 wt %, 62 mg), and ammonium formate (1.01 g, 16.0
mmol) in ethanol (13 mL) was purged with nitrogen and then heated
to 75.degree. C. overnight. The reaction mixture was filtered
through a pad of diatomaceous earth and the filtrate was
concentrated. Purification by normal phase column chromatography
(NH.sub.3 in MeOH/CH.sub.2Cl.sub.2) followed by reverse-phase HPLC
gave 19.6 mg (4%) of the desired product as the TFA salt. MS mass
calcd for C.sub.26H.sub.35N.sub.3O, 405.3. found 406.5 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.28 (m, 4H), 6.78 (d, J=2.5, 1H), 6.69
(m, 1H), 6.55 (d, J=8.7, 1H), 4.74 (m, 1H), 4.37 (m, 1H), 3.97 (t,
J=5.8, 2H), 3.76 (m, 1H), 3.46 (m, 3H), 3.33 (m, 2H), 3.18 (m, 2H),
2.83 (m, 2H), 2.69 (m, 1H), 2.13 (m, 5H), 1.83 (d, J=14.6, 2H),
1.65 (m, 3H), 1.40 (m, 1H), 1.89 (t, J=7.3, 1H).
Example 4-(A-D)
[0165] ##STR00009## [0166] 4A:
Cis-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline [0167] 4B:
Trans-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline [0168] 4C:
Cis-6-(3-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline [0169] 4D:
Trans-6-(3-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(3-Nitrophenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrro-
lidin-1-yl}-ethanol
[0170] Prepared as described in Example 1, Step 6, on a 3.47 mmol
scale, to yield 1.31 g (83%) of the desired product as a mixture of
diastereomers (yellow oil). MS: exact mass calcd for
C.sub.26H.sub.36N.sub.3O.sub.4, 453.3; m/z found, 454.5
[M+H].sup.+.
Step 2
[0171] Performed as described in Example 1, Step 7, on a 2.88 mmol
scale to give a 34% combined yield of the products 4A, 4B, 4C, and
4D.
4A:
Cis-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
[0172] 73.2 mg (4%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33N.sub.3O.sub.3, 435.3; m/z found, 436.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 13.30 (br s, 1H), 11.68
(br s, 1H), 11.04 (br s, 1H), 8.23 (m, 1H), 8.16 (s, 1H), 7.80 (d,
J=7.6, 1H), 7.73 (m, 1H), 6.98 (d, J=2.4, 1H), 6.79 (m, 1H), 6.67
(d, J=8.6, 1H), 4.93 (br s, 1H), 4.82 (m, 1H), 4.13 (t, J=5.9, 2H),
3.96 (br s, 1H), 3.77 (m, 1H), 3.65 (d, J=11.2, 3H), 3.45 (br s,
1H), 3.35 (br s, 2H), 3.01 (br s, 2H), 2.90 (m, 1H), 2.35 (m, 5H),
1.90 (br s, 4H), 1.75 (m, 1H), 1.5 (m, 1H).
4B:
Trans-6-(3-Nitro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
[0173] 201.4 mg (10%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33N.sub.3O.sub.3, 435.3; m/z found, 436.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 13.22 (br s, 1H), 11.5
(br s, 1H), 8.16 (m, 1H), 8.09 (s, 1H), 7.69 (m, 1H), 7.64 (m, 1H),
7.01 (br s, 1H), 6.87 (br m, 2H), 5.15 (br s, 1H), 4.83 (br s, 1H),
4.15 (m, 2H), 3.80 (br s, 3H), 3.64 (d, J=11.7, 2H), 3.57 (br s,
1H), 3.33 (s, 2H), 2.99 (s, 2H), 2.38 (br s, 1H), 2.32 (m, 2H),
2.20 (br m, 3H), 1.91 (m, 4H), 1.79 (m, 1H), 1.49 (m, 1H).
4C:
Cis-6-(3-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
[0174] 38.3 mg (2%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33N.sub.3O.sub.3, 435.3; m/z found, 436.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 13.56 (br s, 1H), 11.42
(br s, 1H), 8.17 (d, J=7.4, 1H), 8.03 (s, 1H), 7.70 (br m, 2H),
7.40 (m, 1H), 7.06 (d, J=7.8, 1H), 6.95 (d, J=8.1, 1H), 4.94 (m,
2H), 4.01 (s, 1H), 3.83 (m, 1H), 3.74 (m, 1H), 3.48 (br s, 1H),
3.40 (m, 2H), 3.26 (m, 1H), 2.75 (m, 5H), 2.32 (m, 1H), 2.20 (m,
2H), 1.85 (m, 7H), 1.42 (br m, 1H).
4D:
Trans-6-(3-Nitro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
[0175] 369.1 mg (18%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33N.sub.3O.sub.3, 435.3; m/z found, 436.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 13.29 (br s, 1H), 11.52
(br s, 1H), 8.16 (m, 1H), 8.10 (s, 1H), 7.67 (m, 2H), 7.02 (s, 1H),
6.88 (s, 2H), 6.23 (br s, 1H), 5.08 (s, 1H), 4.83 (br s, 1H), 4.17
(m, 2H), 3.78 (br s, 2H), 3.65 (d, J=11.2, 2H), 3.55 (br s, 1H),
3.35 (s, 2H), 2.99 (s, 2H), 2.70 (br s, 1H), 2.33 (m, 2H), 2.12 (m,
3H), 1.93 (m, 4H), 1.79 (m, 1H), 1.28 (m, 1H).
Example 5-(A-C)
[0176] ##STR00010## [0177] 5A:
Cis-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyrro-
lo[2,1-a]isoquinoline [0178] 5B:
Trans-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyr-
rolo[2,1-a]isoquinoline [0179] 5C:
Trans-7-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro-pyr-
rolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-p-tolyl-
-ethanol
[0180] Prepared as described in Example 1, Step 6, on a 3.47 mmol
scale, to yield 1.3 g (87%) of the desired product as a mixture of
diastereomers. MS: exact mass calcd for
C.sub.27H.sub.38N.sub.2O.sub.2, 422.3; m/z found, 423.4
[M+H].sup.+.
Step 2
[0181] Performed as described in Example 1, Step 7, on a 3.08 mmol
scale, to give a 19% combined yield of the products 5A, 5B, and
5C.
5A:
Cis-9-(3-Piperidine-1-yl-propoxy)-6-D-tolyl-1,2,3,5,6,10b-hexahydro-py-
rrolo[2,1-a]isoquinoline
[0182] 22.0 mg (1%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O, 404.3; m/z found, 405.4 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.09 (d, J=8.0, 2H), 7.04 (d, J=8.0,
2H), 6.82 (m, 1H), 6.66 (m, 1H), 6.53 (d, J=8.7, 1H), 4.79 (m, 1H),
4.40 (m, 1H), 4.00 (t, J=6.0, 2H), 3.82 (m, 1H), 3.50 (m, 3H), 3.30
(m, 1H), 3.25 (m, 1H), 3.18 (t, J=7.6, 2H), 2.79 (m, 3H), 2.22 (s,
3H), 2.17 (m, 4H), 2.09 (m, 1H), 1.76 (m, 4H), 1.67 (m, 1H), 1.39
(m, 1H).
5B:
Trans-9-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro--
pyrrolo[2,1-a]isoquinoline
[0183] 200.1 mg (10%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O, 404.3; m/z found, 405.4 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 12.50 (br s, 1H), 11.21 (br s, 1H),
7.19 (d, J=8.0, 2H), 7.13 (d, J=7.9, 2H), 7.00 (br s, 1H), 6.84 (m,
2H), 5.18 (br s, 1H), 4.54 (s, 1H), 4.17 (m, 2H), 3.87 (m, 1H),
3.67 (m, 4H), 3.61 (br s, 1H), 3.37 (m, 2H), 3.03 (m, 2H), 2.76 (br
s, 1H), 2.36 (m, 3H), 2.33 (m, 3H), 2.23 (m, 1H), 2.12 (m, 1H),
1.93 (m, 4H), 1.83 (m, 1H), 1.54 (m, 1H).
5C:
Trans-7-(3-Piperidine-1-yl-propoxy)-6-p-tolyl-1,2,3,5,6,10b-hexahydro--
pyrrolo[2,1-a]isoquinoline
[0184] 153.5 mg (8%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O, 404.3; m/z found, 405.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 11.61 (br s, 1H), 10.54 (br s, 1H),
7.42 (m, 1H), 7.14 (d, J=7.4, 2H), 7.07 (m, 1H), 7.02 (d, J=7.3, 2
H), 6.98 (d, 8.2, 1H), 5.16 (br s, 1H), 4.79 (s, 1H), 4.17 (m, 1H),
3.97 (m, 1H), 3.89 (m, 2H), 3.80 (m, 1H), 3.50 (m, 1H), 3.34 (m,
2H), 2.89 (m, 1H), 2.69 (m, 1H), 2.60 (m, 3H), 2.30 (s, 2H), 2.27
(m, 3H), 2.18 (m, 1H), 2.06 (m, 1H), 1.77 (m, 5H), 1.75 (m, 1H),
1.45 (m, 1H).
Example 6-(A-B)
[0185] ##STR00011## [0186] 6A:
Cis-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline [0187] 6B:
Trans-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline [0188] 6C.
Cis-6-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-(3,4-Dichloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-
-pyrrolidin-1-yl}-ethanol
[0189] Prepared as described in Example 1, Step 6, on a 2.53 mmol
scale, to yield 0.96 g (80%) of the desired product as a mixture of
diastereomers (yellow oil). MS: exact mass calcd for
C.sub.26H.sub.34Cl.sub.2N.sub.2O.sub.2, 476.2; m/z found, 477.3
[M+H].sup.+.
Step 2
[0190] Performed as described in Example 1, Step 7, on a 2.01 mmol
scale, to give a 25% combined yield of the desired products 6A and
6B.
6A:
Cis-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline
[0191] 20.0 mg (1%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.32Cl.sub.2N.sub.2O, 458.2; m/z found, 459.4
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.61 (d, J=8.3, 1H),
7.51 (m, 1H), 7.32 (m, 1H), 6.95 (m, 1H), 6.79 (m, 1H), 6.68 (d,
J=8.7, 1H), 4.90 (m, 1H), 4.66 (m, 1H), 4.12 (t, J=6.0, 2H), 3.93
(m, 1H), 3.70 (m, 1H), 3.61 (m, 2H), 3.51 (m, 1H), 3.38 (m, 1H),
3.29 (t, J=7.6, 2H), 2.89 (m, 3H), 2.27 (m, 5H), 1.93 (m, 4H), 1.79
(m, 1H), 1.49 (m, 1H).
6B:
Trans-6-(3,4-Dichloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0192] 338.0 mg (24%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.32Cl.sub.2N.sub.2O, 458.2; m/z found, 459.3
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 11.35 (br s, 1H), 7.56
(d, J=10.1, 1H), 7.46 (m, 1H), 7.22 (m, 1H), 7.00 (br s, 1H), 6.89
(m, 2H), 5.13 (br s, 1H), 4.69 (br s, 1H), 4.18 (m, 2H), 3.76 (m,
2H), 3.67 (d, J=11.7, 2H), 3.56 (m, 1H), 3.35 (m, 2H), 3.03 (m,
2H), 2.79 (br s, 1H), 2.34 (m, 2H), 2.21 (m, 1H), 2.13 (m, 2H),
1.92 (m, 4H), 1.82 (m, 1H), 1.51 (m, 1H).
6C.
Cis-6-(3,4-Dichloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline
[0193] 85 mg (6%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.32Cl.sub.2N.sub.2O, 458.2; m/z found, 459.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.41 (m, 3H), 7.06 (m,
2H), 6.98 (d, J=8.2, 1H), 5.09 (br s, 1H), 4.84 (br s, 1H), 4.15
(m, 1H), 3.92 (m, 3H), 3.76 (br s, 1H), 3.43 (m, 3H), 2.85 (m, 2H),
2.68 (m, 3H), 2.23 (m, 4H), 1.84 (m, 6H), 1.46 (m, 1H).
Example 7-(A-C)
[0194] ##STR00012## [0195] 7A:
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline [0196] 7B:
Trans-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline [0197] 7C:
Trans-7-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-2-(4-t-
rifluoromethyl-phenyl)-ethanol
[0198] Prepared as described in Example 1, Step 6, on a 3.47 mmol
scale, to yield 1.27 g (77%) of the desired product as a mixture of
diastereomers (yellow oil). MS: exact mass calcd for
C.sub.27H.sub.35F.sub.3N.sub.2O.sub.2, 476.3; m/z found, 477.4
[M+H].sup.+.
Step 2
[0199] Performed as described in Example 1, Step 7, on a 2.66 mmol
scale, to give a 2% combined yield of the desired products 7A, 7B,
and 7C.
7A:
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,5,-
6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0200] 6.4 mg (0.3%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.33F.sub.3N.sub.2O, 458.3; m/z found, 459.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.74 (d, J=7.9, 2H),
7.54 (d, J=7.9, 2H), 6.96 (br s, 1H), 6.78 (m, 1H), 6.61 (m, 1H),
4.89 (m, 1H), 4.73 (m, 1H), 4.11 (t, J=6.0, 2H), 3.71 (m, 1H), 3.69
(m, 1H), 3.60 (m, 2H), 3.49 (m, 1H), 3.36 (m, 1H), 3.28 (t, J=7.0,
2H), 2.91 (m, 3H), 2.27 (m, 5H), 1.87 (m, 4H), 1.77 (br s, 1H),
1.50 (m, 1H).
7B:
Trans-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,-
5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0201] 16.0 mg (1%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.33F.sub.3N.sub.2O, 458.3; m/z found, 459.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.70 (d, J=8.1, 2H),
7.49 (d, J=8.0, 2H), 7.01 (br s, 1H), 6.90 (m, 1H), 6.79 (m, 1H),
5.14 (br s, 1H), 4.76 (br s, 1H), 4.16 (m, 2H), 3.75 (m, 2H), 3.65
(m, 2H), 3.55 (m, 1H), 3.34 (m, 2H), 2.99 (m, 2H), 2.78 (m, 1H),
2.33 (m, 2H), 2.22 (m, 1H), 2.13 (m, 1H), 1.94 (m, 6H), 1.81 (m,
1H), 1.52 (m, 1H).
7C:
Trans-7-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethyl-phenyl)-1,2,3,-
5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0202] 16.0 mg (1%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.33F.sub.3N.sub.2O, 458.3; m/z found, 459.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.56 (d, J=11.3, 2H),
7.40 (t, J=8.0, 1H), 7.34 (d, J=7.9, 2H), 7.06 (d, J=7.8, 1H), 6.96
(d, J=8.2, 1H), 5.01 (br s, 1H), 4.87 (m, 1H), 4.11 (m, 1H), 3.87
(m, 1H), 3.76 (br s, 3H), 3.27 (m, 3H), 2.82 (m, 1H), 2.74 (m, 1H),
2.62 (m, 3H), 2.20 (m, 3H), 2.00 (m, 1H), 1.80 (m, 6H), 1.43 (m,
1H).
Example 8-(A-F)
[0203] ##STR00013## [0204] 8A:
Cis-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline [0205] 8B:
1S,6R-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline [0206] 8C:
1R,6S-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline [0207] 8D:
Trans-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline [0208] 8E:
Cis-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline [0209] 8F:
Trans-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(4-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-py-
rrolidin-1-yl}-ethanone
[0210] To a solution of
1-[3-(3-pyrrolidin-2-yl-phenoxy)-propyl]-piperidine (6.93 mmol) and
triethylamine (3.0 equiv.) in THF (0.1 M) under nitrogen was added
2-bromo-1-(4-methoxyphenyl)-ethanone (1.05-1.20 equiv.) and the
reaction mixture was stirred at rt for 30 min. The reaction mixture
was diluted with CH.sub.2Cl.sub.2 and washed with 1.0 N NaOH
followed by brine. The organic solution was dried
(Na.sub.2CO.sub.3) and concentrated to give the crude product,
which was purified by normal phase column chromatography (NH.sub.3
in MeOH/CH.sub.2Cl.sub.2) to provide 2.21 g (73%) of the desired
product as a yellow oil. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.3, 436.3; m/z found, 437.4
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.86 (dd, J=2.1, 6.9,
2H), 7.22 (m, 1H), 7.00 (d, J=1.6, 1H), 6.97 (m, 3H), 6.81 (m, 1H),
4.01 (m, 3H), 3.85 (s, 3H), 3.48 (t, J=8.0, 1H), 3.30 (m, 2H), 2.39
(m, 8H), 2.15 (m, 1H), 1.89 (m, 5H), 1.67 (m, 1H), 1.51 (m, 5H),
1.38 (br m, 1H). Alternatively, the reaction mixture may be
concentrated and taken on to the next synthetic step without
purification.
Step 2.
1-(4-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-py-
rrolidin-1-yl}-ethanol
[0211] To a 0.degree. C. solution of the aminoalcohol obtained from
Step 1 (2.29 mmol) in ethanol (0.1 M) was added NaBH.sub.4 (1.5
equiv.), and the mixture was allowed to warm to rt. After
completion of the reaction, the mixture was diluted with
CH.sub.2Cl.sub.2 and washed with water and brine. The organic layer
was dried (Na.sub.2CO.sub.3), filtered and concentrated to give the
crude product. Normal phase chromatographic purification (NH.sub.3
in MeOH/CH.sub.2Cl.sub.2) gave the desired product (820.7 mg, 83%)
as a mixture of diastereomers. MS: exact mass calcd for
C.sub.27H.sub.38N.sub.2O.sub.3, 438.3; m/z found, 439.4
[M+H].sup.+.
Step 3
[0212] Performed as described in Example 1, Step 7, on a 1.72 mmol
scale, to give a combined yield of 33% for the four
diastereomers.
8A:
Cis-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
[0213] 27.5 mg (2%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found, 421.3
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.18 (d, J=8.6, 2H), 6.97
(d, J=8.8, 2H), 6.89 (d, J=2.4, 1H), 6.82 (dd, J=2.4, 8.7, 1H),
6.75 (d, J=8.7, 1H), 4.87 (m, 1H), 4.33 (m, 1H), 4.11 (t, J=5.8,
2H), 3.9 (m, 1H), 3.82 (s, 3H), 3.59 (m, 3H), 3.42 (m, 2H), 3.31
(m, 2H), 2.97 (m, 2H), 2.85 (m, 1H), 2.27 (m, 5H), 1.98 (d, J=14.6,
2H), 1.82 (m, 3H), 1.53 (m, 1H). The enantiomers were separated
using a Chiralpak.RTM. AD column. The first eluting enantiomer was
Example 8B:
1S,6R-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline.
([.alpha.].sub.D.sup.20=-66.degree., c=0.006, CH.sub.2Cl.sub.2).
The second eluting compound was Example 8C:
1R,6S-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline.
([.alpha.].sub.D.sup.20=+68.degree., c=0.011,
CH.sub.2Cl.sub.2).
8D:
Trans-6-(4-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
[0214] 101.5 mg (9%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found, 421.3
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.06 (br m, 2H), 6.91 (m,
5H), 4.95 (br s, 1H), 4.46 (br s, 1H), 4.14 (t, J=5.5, 2H), 3.79
(s, 3H), 3.76 (br s, 1H), 3.62 (m, 2H), 3.45 (br s, 1H), 3.33 (m,
2H), 2.98 (t, J=12.4, 2H), 3.74 (br s, 1H), 2.27 (m, 2H), 2.16 (br
s, 2H), 1.97 (m, 2H), 1.85 (m, 3H), 1.54 (m, 1H).
8E:
Cis-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
[0215] 18.0 mg (2%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found, 421.2
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.42 (m, 1H), 7.07 (br s,
2H), 6.98 (m, 4H), 4.56 (br s, 1H), 4.02 (br s, 1H), 3.78 (s, 3H),
3.70 (br m, 3H), 3.38 (m, 1H), 3.30 (m, 3H), 3.20 (m, 1H), 2.73 (br
s, 1H), 2.63 (m, 3H), 2.35 (br m, 1H), 2.14 (br m, 3H), 1.80 (m,
4H), 1.69 (m, 3H), 1.49 (m, 1H).
8F:
Trans-6-(4-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
[0216] 176.6 mg (20%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found, 421.2
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.37 (t, J=8.0, 1H), 6.96
(d, J=8.0, 3H), 6.92 (d, J=8.2, 1H), 6.87 (d, J=8.7, 2H), 4.78 (m,
1H), 4.66 (s, 1H), 4.08 (br m, 1H), 3.82 (m, 1H), 3.75 (m, 2H),
3.73 (s, 3H), 3.61 (br m, 1H), 3.27 (m, 3H), 2.75 (br m, 1H), 2.58
(m, 3H), 2.41 (m, 1H), 2.1-1.6 (m, 10H), 1.41 (m, 1H).
Example 9-(A-B)
[0217] ##STR00014## [0218] 9A:
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-phenol [0219] 9B:
Trans-4-[7-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
-a]isoquinolin-6-yl]-phenol
Step 1. Acetic acid
4-(2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-acetyl)-ph-
enyl ester
[0220] Prepared as described in Example 8, Step 1, on a 4.51 mmol
scale. Chromatographic purification as described provided 450.1 mg
(28%) of the desired product as yellow oil. MS: exact mass calcd
for C.sub.28H.sub.36N.sub.2O.sub.4, 464.3; m/z found, 465.4
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.98 (m, 2H), 7.26 (m,
1H), 7.24 (m, 2H), 7.06 (d, J=1.5, 1H), 7.02 (d, J=7.5, 1H), 6.88
(m, 1H), 4.05 (m, 3H), 3.56 (m, 1H), 3.44 (d, J=15.5, 1H), 3.37 (m,
1H), 2.50 (m, 2H), 2.45 (m, 4H), 2.33 (s, 3H), 2.22 (m, 1H), 1.90
(m, 4H), 1.75 (m, 1H), 1.58 (m, 4H), 1.46 (br m, 2H).
Step 2.
4-(1-Hydroxy-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-
-1-yl}-ethyl)-phenol
[0221] Prepared as described in Example 8, Step 2, on a 0.896 mmol
scale, to give crude material that was taken on to the next step
without purification. MS: exact mass calcd for
C.sub.26H.sub.36N.sub.2O.sub.3, 424.3; m/z found, 425.5
[M+H].sup.+.
Step 3
[0222] Performed as described in Example 1, Step 7, on a 0.896 mmol
scale, to give a combined yield of 16% of two diastereomers.
9A:
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,-
1-a]isoquinolin-6-yl]-phenol
[0223] 27.2 mg (5%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.34N.sub.2O.sub.2, 406.3; m/z found, 407.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 12.51 (br s, 1H), 11.35
(br s, 1H), 7.63 (br s, 3H), 7.04 (d, J=8.4, 2H), 6.95 (s, 1H),
6.82 (m, 4H), 5.14 (br s, 1H), 4.44 (br s, 1H), 4.13 (br m, 2H),
3.84 (br s, 1H), 3.64 (m, 5H), 3.34 (br s, 2H), 2.99 (br m, 2H),
2.72 (br s, 1H), 2.30 (m, 2H), 2.17 (br m, 1H), 2.09 (br m, 1H),
1.91 (m, 4H), 1.80 (m, 1H), 1.48 (m, 1H).
9B:
Trans-4-[7-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[-
2,1-a]isoquinolin-6-yl]-phenol
[0224] 68.8 mg (11%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.34N.sub.2O.sub.2, 406.3; m/z found, 407.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 10.96 (br s, 1H), 10.36
(br s, 3H), 9.59 (br s, 1H), 7.39 (m, 1H), 7.03 (d, J=7.5, 1H),
6.94 (m, 4H), 6.77 (d, J=7.8, 2H), 5.13 (br s, 1H), 4.69 (br s,
1H), 4.14 (br m, 1H), 3.84 (m, 4H), 3.49 (br s, 1H), 3.39 (m, 2H),
2.87 (d, J=8.4, 1H), 2.64 (br m, 3H), 2.53 (br m, 1H), 2.24 (m,
3H), 2.05 (br s, 1H), 1.80 (m, 5H), 1.46 (br m, 1H).
Example 10-(A-C)
[0225] ##STR00015## [0226] 10A:
Cis-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline [0227] 10B:
Trans-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline [0228] 10C:
Trans-6-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(3-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-py-
rrolidin-1-yl}-ethanone
[0229] Prepared as described in Example 8, Step 1, on a 4.33 mmol
scale. Chromatographic purification provided 1.37 g (72%) of the
desired product as an orange oil. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.3, 436.3; m/z found, 437.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.44 (m, 2H), 7.28 (m,
1H), 7.21 (m, 1H), 7.07 (d, J=2.6, 1H), 6.97 (m, 2H), 6.79 (m, 1H),
4.07 (d, J=16.3, 1H), 3.98 (m, 2H), 3.83 (s, 3H), 3.45 (m, 3H),
2.54 (m, 3H), 2.47 (m, 3H), 2.37 (m, 1H), 2.19 (m, 1H), 2.00 (m,
3H), 1.82 (m, 2H), 1.63 (m, 4H), 1.45 (m, 2H).
Step 2.
1-(3-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-py-
rrolidin-1-yl}-ethanol
[0230] Prepared as described in Example 8, Step 2, on a 1.8 mmol
scale, to give 420 mg (53%) of the desired product as a mixture of
diastereomers which were not separated. MS: exact mass calcd for
C.sub.27H.sub.38N.sub.2O.sub.3, 438.3; m/z found, 439.5
[M+H].sup.+.
Step 3
[0231] Performed as described in Example 1, Step 7, on a 0.91 mmol
scale, to give a 48% combined yield of the desired products.
10A:
Cis-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline
[0232] 57.3 mg (10%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found, 421.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.32 (t, J=8.1, 1H),
6.93 (m, 2H), 6.91 (m, 2H), 6.78 (dd, J=2.6, 8.7, 1H), 6.68 (d,
J=8.7, 1H), 4.91 (m, 1H), 4.54 (dd, J=4.6, 12.1, 1H), 4.12 (t,
J=6.0, 2H), 3.88 (m, 1H), 3.78 (s, 3H), 3.64 (m, 3H), 3.47 (m, 1H),
3.38 (m, 1H), 3.30 (m, 2H), 2.93 (m, 3H), 2.31 (m, 4H), 2.86 (m,
1H), 1.84 (m, 4H), 1.78 (m, 1H), 1.50 (m, 1H).
10B:
Trans-6-(3-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline
[0233] 122.0 mg (21%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found, 421.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.30 (t, J=7.9, 1H),
6.98 (br s, 1H), 6.91 (m, 1H), 6.83 (m, 4H), 5.15 (br s, 1H), 4.57
(br s, 1H), 4.16 (m, 2H), 3.86 (br s, 1H), 3.77 (s, 3H), 3.66 (m,
4H), 3.36 (m, 2H), 3.01 (br s, 2H), 2.75 (m, 1H), 2.34 (m, 2H),
2.22 (m, 1H), 2.15 (m, 1H), 1.91 (m, 4H), 1.80 (m, 1H), 1.55 (m,
1H).
10C:
Trans-6-(3-Methoxy-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline
[0234] 85.0 mg (14%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found, 421.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.41 (t, J=8.0, 1H),
7.22 (m, 1H), 7.06 (m, 1H), 6.97 (d, J=8.2, 1H), 6.84 (m, 1H), 6.76
(s, 1H), 6.67 (m, 1H), 5.16 (br s, 1H), 4.79 (br s, 1H), 4.16 (br
s, 1H), 3.90 (m, 4H), 3.77 (s, 3H), 3.37 (m, 3H), 2.86 (m, 1H),
2.65 (m, 4H), 2.23 (m, 3H), 2.10 (m, 1H), 2.05 (br s, 1H), 1.77 (m,
5H), 1.49 (m, 1H).
Example 11-(A-C)
[0235] ##STR00016## [0236] 11A:
Cis-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline [0237] 11B:
Trans-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline [0238] 11C:
Trans-6-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(3-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyr-
rolidin-1-yl}-ethanone
[0239] Prepared as described in Example 8, Step 1, on a 5.63 mmol
scale. Chromatographic purification gave 1.35 g (71%) of the
desired product as an orange oil. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O.sub.2, 440.2; m/z found, 441.5
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.85 (m, 1H), 7.73 (m, 1H),
7.48 (m, 1H), 7.33 (t, J=3.9, 1H), 7.23 (t, J=7.8, 1H), 6.95 (m,
2H), 6.78 (dd, J=1.9, 8.2, 1H), 4.01 (d, J=15.9, 1H), 3.98 (t,
J=6.3, 2 H), 3.43 (m, 1H), 3.36 (m, 2H), 2.58 (m, 2H), 2.51 (m,
4H), 2.35 (m, 1H), 2.20 (m, 1H), 2.01 (m, 4H), 1.81 (m, 2H), 1.66
(m, 4H), 1.47 (m, 2H).
Step 2.
1-(3-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyr-
rolidin-1-yl}-ethanol
[0240] Prepared as described in Example 8, Step 2, on a 1.83 mmol
scale, to give 610 mg (75%) of the desired product as a mixture of
diastereomers, which were not separated. MS: exact mass calcd for
C.sub.26H.sub.36ClN.sub.2O.sub.2, 442.2; m/z found, 443.5
[M+H].sup.+.
Step 3
[0241] Performed as described in Example 1, Step 7, on a 1.35 mmol
scale, to give a 16% combined yield of the desired products.
11A:
Cis-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
[0242] 37.0 mg (4%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O, 424.2; m/z found, 425.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.45 (m, 2H), 7.33 (m, 2H), 6.97 (m,
1H), 6.81 (dd, J=2.6, 8.7, 1H), 6.68 (d, J=8.7, 1H), 4.95 (m, 2H),
4.63 (m, 1H), 4.14 (m, 2H), 3.98 (m, 1H), 3.72 (m, 3H), 3.55 (m,
1H), 3.46 (m, 1H), 3.36 (m, 2H), 3.01 (m, 2H), 2.91 (m, 1H), 2.36
(m, 5H), 1.94 (s, 3H), 1.80 (m, 1H), 1.52 (m, 1H).
11B:
Trans-6-(3-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
[0243] 38 mg (4%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O, 424.2; m/z found, 425.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.36 (m, 3H), 7.24 (m, 1H), 6.99 (br
s, 1H), 6.85 (m, 1H), 6.81 (m, 1H), 5.14 (br s, 2H), 4.65 (br s,
1H), 4.17 (m, 2H), 3.68 (m, 6H), 3.33 (m, 2H), 2.98 (m, 2H), 2.76
(m, 1H), 2.32 (m, 2H), 2.22 (m, 2H), 1.91 (m, 4H), 1.80 (m, 1H),
1.53 (m, 1H).
11C:
Trans-6-(3-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
[0244] 69 mg (8%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O, 424.2; m/z found, 425.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.43 (t, J=8.0, 1H), 7.30 (br s,
2H), 7.26 (s, 1H), 7.07 (m, 2H), 6.99 (d, J=8.2, 1H), 5.15 (br s,
1H), 4.85 (br s, 1H), 4.15 (m, 1H), 3.89 (m, 3H), 3.78 (m, 1H),
3.44 (m, 3H), 2.86 (m, 1H), 2.78 (m, 1H), 2.62 (m, 3H), 2.23 (m,
3H), 2.10 (m, 2H), 1.85 (m, 5H), 1.49 (m, 1H).
Example 12-(A-D)
[0245] ##STR00017## [0246] 12A:
Cis-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline [0247] 12B:
Trans-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline [0248] 12C:
Cis-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline [0249] 12D:
Trans-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(2-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyr-
rolidin-1-yl}-ethanone
[0250] Prepared as described in Example 8, Step 1, on a 5.63 mmol
scale. Chromatographic purification gave 1.37 g (72%) of the
desired product as an orange oil. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O.sub.2, 440.2; m/z found, 441.5
[M+H].sup.+.
Step 2.
1-(2-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyr-
rolidin-1-yl}-ethanol
[0251] Prepared as described in Example 8, Step 2, on a 1.83 mmol
scale, to give 375 mg (46%) of the desired product as a mixture of
diastereomers, which were not separated. MS: exact mass calcd for
C.sub.26H.sub.35ClN.sub.2O.sub.2, 442.2; m/z found, 443.5
[M+H].sup.+.
Step 3
[0252] Performed as described in Example 1, Step 7, on a 1.35 mmol
scale, to give a 24% combined yield of the desired products.
12A:
Cis-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
[0253] 13.3 mg (2%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O, 424.2; m/z found, 425.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.54 (m, 1H), 7.37 (m, 2H), 7.20 (br
s, 1H), 7.02 (s, 1H), 6.80 (m, 1H), 6.61 (d, J=8.8, 1H), 5.13 (br
s, 1H), 4.86 (br s, 1H), 4.13 (s, 2H), 3.88 (br s, 1H), 3.74 (m,
3H), 3.44 (m, 2H), 3.30 (m, 2H), 2.89 (m, 4H), 2.30 (m, 5H), 1.92
(m, 4H), 1.58 (m, 1H).
12B:
Trans-6-(2-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
[0254] 53 mg (8%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O, 424.2; m/z found, 425.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.51 (m, 1H), 7.35 (m, 1H), 7.29 (m,
1H), 7.08 (m, 2H), 6.87 (m, 2H), 5.15 (m, 1H), 4.99 (m, 1H), 4.71
(m, 2H), 4.19 (m, 2H), 3.76 (m, 2H), 3.65 (m, 2H), 3.35 (m, 2H),
3.00 (m, 2H), 2.82 (br s, 1H), 2.34 (m, 2H), 2.19 (m, 3H), 1.92 (m,
4H), 1.81 (m, 1H), 1.54 (m, 1H).
12C:
Cis-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
[0255] 49.2 mg (7%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O, 424.2; m/z found, 425.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.45 (d, J=7.9, 1H), 7.20 (m, 2H),
7.07 (m, 1H), 6.87 (d, J=7.7, 1H), 6.76 (m, 2H), 4.91 (br s, 1H),
3.89 (m, 1H), 3.56 (m, 1H), 3.40 (m, 2H), 3.24 (1H), 3.11 (m, 2H),
3.79 (m, 4H), 2.62 (m, 3H), 2.46 (m, 2H), 2.02 (m, 2H), 1.77 (m,
4H), 1.61 (m, 2H), 1.40 (m, 1H).
12D:
Trans-6-(2-Chloro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
[0256] 50 mg (7%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O, 424.2; m/z found, 425.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.57 (d, J=11.4, 1H), 7.43 (m, 1H),
7.31 (m, 1H), 7.08 (m, 2H), 6.97 (d, J=8.2, 1H), 6.73 (br s, 1H),
5.19 (br s, 1H), 5.07 (br s, 1H), 4.29 (m, 1H), 3.86 (m, 4H), 3.53
(m, 2H), 3.38 (m, 1H), 2.89 (m, 1H), 2.69 (m, 4H), 2.30 (m, 3H),
2.10 (m, 1H), 1.90 (m, 1H), 1.87 (m, 5H), 1.51 (m, 1H).
Example 13-(A-B)
[0257] ##STR00018## [0258] 13A:
Cis-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline [0259] 13B:
Trans-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(2-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-py-
rrolidin-1-yl}-ethanone
[0260] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale. Chromatographic purification gave 1.12 g (74%) of the
desired product as an orange semi-solid. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.3, 436.3; m/z found, 437.5
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.63 (dd, J=1.8, 7.7, 1H),
7.40 (m, 1H), 7.18 (m, 1H), 6.94 (m, 3H), 6.87 (d, J=8.3, 1H), 6.75
(m, 1H), 4.10 (d, J=18.0, 1H), 3.96 (t, J=6.4, 2H), 3.72 (s, 3H),
3.52 (m, 3H), 2.50 (m, 2H), 2.45 (m, 4H), 2.16 (m, 1H), 1.97 (m,
3H), 1.84 (m, 2H), 1.75 (m, 1H), 1.60 (m, 4H), 1.44 (m, 2H).
Step 2.
1-(2-Methoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-py-
rrolidin-1-yl}-ethanol
[0261] Prepared as described in Example 8, Step 2, on a 2.18 mmol
scale, to give 930 mg (97%) of the desired product as a mixture of
diastereomers, which were not separated. MS: exact mass calcd for
C.sub.27H.sub.38N.sub.2O.sub.3, 438.3; m/z found, 439.6
[M+H].sup.+.
Step 3
[0262] Performed as described in Example 1, Step 7, on a 2.05 mmol
scale, to give a 20% combined yield of two diastereomers.
13A:
Cis-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline
[0263] 27.3 mg (2%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found, 421.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.35 (m, 1H), 7.14 (br
s, 1H), 7.09 (d, J=8.2, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 6.75 (m,
1H), 6.63 (d, J=8.6, 1H), 4.92 (m, 2H), 4.11 (t, J=6.0, 2H), 3.95
(m, 1H), 3.76 (m, 3H), 3.62 (m, 4H), 3.37 (m, 1H), 3.30 (m, 2H),
2.97 (m, 2H), 2.88 (m, 1H), 2.30 (m, 5H), 2.0 (m, 4H), 1.79 (m,
1H), 1.51 (m, 1H).
13B:
Trans-6-(2-Methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline
[0264] 235 mg (18%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found, 421.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 11.54 (br s, 1H), 10.48
(m, 2H), 7.42 (m, 1H), 7.27 (m, 1H), 7.11 (d, J=8.1, 1H), 7.06 (m,
1H), 6.98 (d, J=11.8, 1H), 6.74 (m, 1H), 6.51 (m, 1H), 5.11 (br s,
1H), 4.96 (br s, 1H), 4.13 (m, 1H), 3.98 (s, 3H), 3.89 (m, 2H),
3.70 (m, 1H), 3.43 (m, 2H), 3.33 (m, 1H), 2.87 (m, 1H), 2.62 (m,
3H), 2.25 (m, 3H), 2.03 (m, 1H), 1.82 (m, 5H), 1.48 (m, 1H).
Example 14-(A-C)
[0265] ##STR00019## [0266] 14A:
Cis-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline [0267] 14B:
Trans-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline [0268] 14C:
Trans-6-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(4-Fluoro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyr-
rolidin-1-yl}-ethanone
[0269] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale. Chromatographic purification gave 1.24 g (84%) of the
desired product. MS: exact mass calcd for
C.sub.26H.sub.33FN.sub.2O.sub.2, 424.3; m/z found, 425.5
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 7.90 (m, 2H), 7.22 (m, 1H),
7.06 (m, 2H), 7.95 (m, 2H), 6.79 (m, 1H), 4.03 (d, J=15.7, 1H),
3.98 (m, 2H), 3.39 (m, 3H), 2.52 (t, J=7.4, 2H), 2.45 (br s, 3H),
2.36 (m, 1H), 2.18 (m, 2H), 2.00 (m, 3H), 1.80 (m, 2H), 1.62 (m,
4H), 1.45 (m, 2H).
Step 2.
1-(4-Fluoro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyr-
rolidin-1-yl}-ethanol
[0270] Prepared as described in Example 8, Step 2, on a 2.47 mmol
scale, to give 980 mg (93%) of the desired product as a mixture of
diastereomers and regioisomers, which were not separated. MS: exact
mass calcd for C.sub.26H.sub.35FN.sub.2O.sub.2, 426.3; m/z found,
427.5 [M+H].sup.+.
Step 3
[0271] Performed as described in Example 1, Step 7, on a 2.23 mmol
scale to give a 12% combined yield of the desired products.
14A:
Cis-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
[0272] 28.0 mg (2%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33FN.sub.2O, 408.3; m/z found, 409.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.33 (m, 2H), 7.17 (t, J=8.8, 2H),
6.95 (d, J=2.6, 1H), 6.78 (dd, J=2.6, 8.7, 1H), 6.64 (d, J=8.7,
1H), 4.91 (m, 1H), 4.61 (m, 1H), 4.26 (m, 4H), 4.12 (t, J=6.0, 2H),
3.94 (m, 1H), 3.62 (m, 3H), 3.45 (m, 2H), 3.31 (m, 2H), 2.92 (m,
3H), 2.32 (m, 5H), 1.78 (m, 1H), 1.50 (m, 1H).
14B:
Trans-6-(4-Fluoro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
[0273] 9.7 mg (0.6%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33FN.sub.2O, 408.3; m/z found, 409.5 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.30 (m, 2H), 7.13 (t, J=8.7, 2H),
7.00 (br s, 1H), 6.85 (m, 2H), 5.15 (br s, 1H), 4.63 (br s, 1H),
4.17 (m, 2H), 3.85 (m, 1H), 3.66 (m, 4H), 3.59 (m, 1H), 3.33 (m,
2H), 3.01 (m, 2H), 2.78 (m, 1H), 2.34 (m, 2H), 2.22 (m, 2H), 2.14
(m, 1H), 1.92 (m, 4H), 1.82 (m, 1H), 1.53 (m, 1H).
14C:
Trans-6-(4-Fluoro-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline. 124.8 mg (9%) as the TFA
salt. MS: exact mass calcd for C.sub.26H.sub.33FN.sub.2O, 408.3;
m/z found, 409.5 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.42
(m, 1H), 7.17 (m, 2H), 7.06 (m, 3H), 6.98 (d, J=8.2, 1H), 5.12 (br
s, 1H), 4.83 (s, 1H), 4.15 (br s, 1H), 3.89 (m, 3H), 3.77 (m, 1H),
3.43 (m, 3H), 3.78 (m, 5H), 2.24 (m, 4H), 1.85 (m, 6H), 1.49 (m,
1H)
Example 15
##STR00020##
[0274]
Cis-3-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1-a]isoquinolin-6-yl]-phenol
[0275] To a solution of
cis-6-(3-methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline (27.0 mg, 0.042 mmol) in
CH.sub.2Cl.sub.2 (0.2 mL) was added BBr.sub.3 (1 M in
CH.sub.2Cl.sub.2, 0.21 mL) and the reaction mixture was stirred at
rt for 15 min. The reaction was quenched with water and the mixture
was concentrated under a stream of N.sub.2. The crude material was
purified by reverse-phase HPLC to give 14.1 mg (53%) of the desired
product as a TFA salt. MS: exact mass calcd for
C.sub.26H.sub.34N.sub.2O.sub.2, 406.3; m/z found, 407.5
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.20 (m, 1H), 6.92 (m,
1H), 6.78 (m, 5H), 4.83 (m, 1H), 4.46 (m, 1H), 4.11 (t, J=7.2, 2H),
3.87 (m, 1H), 3.59 (m, 2H), 3.38 (m, 2H), 3.28 (m, 2H), 2.89 (m,
3H), 2.87 (m, 2H), 2.29 (m, 5H), 1.88 (m, 4H), 1.57 (m, 2H).
Example 16
##STR00021##
[0276]
Cis-2-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1-a]isoquinolin-6-yl]-phenol
[0277] Prepared as described in Example 15, on a 0.030 mmol scale,
to give 3.6 mg (19%) of the desired product after chromatography.
MS: exact mass calcd for C.sub.26H.sub.34N.sub.2O.sub.2, 406.3; m/z
found, 407.4 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 6.87 (m,
7H), 4.92 (br s, 1H), 4.10 (t, J=5.9, 2H), 3.61 (m, 3H), 3.41 (m,
1H), 3.30 (m, 2H), 2.95 (m, 5H), 2.29 (m, 4H), 2.07 (m, 2H), 1.89
(m, 6H), 1.52 (m, 1H).
Example 17
##STR00022##
[0278]
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethoxy-phenyl)-1,2,-
3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-t-
rifluoromethoxy-phenyl)-ethanone
[0279] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 1.35 g (79%) of the desired product as a viscous oil
after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS: exact
mass calcd for C.sub.27H.sub.33F.sub.3N.sub.2O.sub.3, 474.2; m/z
found, 475.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.77 (d,
J=8.7, 2H), 7.11 (d, J=8.5, 2H), 7.05 (t, J=7.9, 1H), 6.82 (d,
J=1.4, 1H), 6.78 (d, J=7.5, 1H), 6.64 (dd, J=2.3, 8.1, 1H), 3.80
(m, 3H), 3.3 (m, 2H), 2.31 (m, 5H), 2.21 (m, 1H), 1.96 (m, 1H),
1.81 (m, 3H), 1.60 (m, 2H), 1.45 (m, 4H), 1.31 (m, 2H).
Step 2.
9-(3-Piperidin-1-yl-propoxy)-6-(4-trifluoromethoxy-phenyl)-2,3-dih-
ydro-1H-pyrrolo[2,1-a]isoquinolinylium salt
[0280] Prepared as described in Example 1, Step 7, on a 1.03 mmol
scale, to give 445 mg (85%) of crude product, which was carried
forward without purification. MS: exact mass calcd for
C.sub.27H.sub.30F.sub.3N.sub.2O.sub.2.sup.+, 471.2; m/z found,
471.5 [M].sup.+.
Step 3
[0281] A mixture of isoquinolinium salt (Step 2, 0.878 mmol),
bromocresol green (1-5 mg), and NaCNBH.sub.3 (approx. 10 equiv.) in
methanol (0.1 M) was stirred for 10 min at rt. The mixture was
treated with methanolic HCl until the pH=4-5 (indicator turned
yellow). More methanolic HCl was added when the solution takes on a
green cast. When the reaction was complete, the mixture was diluted
with CH.sub.2Cl.sub.2, and washed with 2 N NaOH, water (.times.2),
and brine. The organic extract was dried (Na.sub.2CO.sub.3),
filtered, and concentrated to provide the crude product.
Purification by normal phase column chromatography (NH.sub.3 in
MeOH/CH.sub.2Cl.sub.2) followed by reverse-phase HPLC gave the
desired compound (311.6 mg, 48%) as the TFA salt. MS: exact mass
calcd for C.sub.27H.sub.33F.sub.3N.sub.2O.sub.2, 474.3; m/z found,
475.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.53 (d, J=8.6, 2H),
7.46 (d, J=8.1, 2H), 7.05 (d, J=2.4, 1H), 6.97 (dd, J=2.3, 8.7,
1H), 6.84 (d, J=8.7, 1H), 5.03 (m, 1H), 4.65 (m, 1H), 4.25 (t,
J=5.7, 2H), 4.01 (m, 1H), 3.74 (m, 3H), 3.57 (m, 2H), 3.45 (m, 2H),
3.11 (m, 2H), 2.95 (m, 1H), 2.41 (m, 5H), 2.10 (m, 2H), 1.99 (m,
3H), 1.69 (m, 1H).
Example 18
##STR00023##
[0282]
Cis-6-(3,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1. 2-Bromo-1-(3,4-dimethoxy-phenyl)-ethanone
[0283] To a 0.degree. C. solution of 3,4-dimethoxyacetophenone
(5.00 g, 27.8 mmol) in diethyl ether (200 mL) and CHCl.sub.3 (30
mL) was added, dropwise over 1.5 h, a solution of Br.sub.2 (1.45
mL, 27.8 mmol) in CHCl.sub.3 (30 mL). Once the addition was
complete, the mixture was stirred for 1 h at 0.degree. C., and then
was allowed to warm to rt. The reaction mixture was concentrated
and the residue chromatographed (CH.sub.2Cl.sub.2/hexanes) to give
5.23 g (73%) of the ketone as a pale yellow solid. .sup.1H NMR
(DMSO-d.sub.6): 7.68 (dd, J=2.0, 8.4, 1H), 7.47 (d, J=2.0, 1H),
7.08 (d, J=8.5, 1H), 4.85 (s, 2H), 3.85 (s, 3H), 3.81 (s, 3H).
Step 2.
1-(3,4-Dimethoxy-Phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl-
]-pyrrolidin-1-yl}-ethanone
[0284] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 1.30 g (77%) of the desired product as a pale yellow
oil after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS:
exact mass calcd for C.sub.28H.sub.38N.sub.2O.sub.4, 466.3; m/z
found, 467.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.40 (m, 1H),
7.35 (d, J=2.0, 1H), 7.17 (m, 1H), 6.96 (m, 1H), 6.91 (d, J=7.6,
1H), 6.81 (d, J=8.5, 1H), 6.76 (m, 1H), 3.91 (m, 3H), 3.80 (s, 3H),
3.74 (s, 3H), 3.40 (m, 3H), 2.40 (m, 6H), 2.28 (m, 1H), 2.11 (m,
1H), 1.91 (m, 3H), 2.75 (m, 1H), 2.62 (m, 1H), 1.54 (m, 4H), 1.41
(m, 2H).
Step 3.
6-(3,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro--
1H-pyrrolo[2,1-a]isoquinolinylium salt
[0285] Prepared as described in Example 17, Step 2, on a 2.42 mmol
scale, to give 1.05 g (89%) of crude product. MS: exact mass calcd
for C.sub.28H.sub.36N.sub.2O.sub.3.sup.+, 447.3; m/z found, 447.5
[M].sup.+.
Step 4
[0286] Prepared as described in Example 17, Step 3, on a 2.16 mmol
scale, to give 420.2 mg (27%) of the desired product as the TFA
salt after normal phase chromatography and HPLC. MS: exact mass
calcd for C.sub.28H.sub.38N.sub.2O.sub.3, 450.3; m/z found, 451.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.12 (d, J=8.4, 1H), 7.03
(d, J=2.3, 1H), 6.95 (m, 3H), 6.90 (d, J=8.7, 1H), 5.02 (m, 1H),
4.51 (m, 1H), 4.25 (t, J=5.7, 2H), 4.01 (m, 1H), 3.97 (s, 3H), 3.93
(s, 3H), 3.74 (d, J=11.9, 3H), 3.45 (m, 2H), 3.10 (m, 2H), 2.92 (m,
1H), 2.43 (m, 5H), 2.10 (d, J=14.9, 2H), 1.97 (m, 3H), 1.68 (m,
1H).
Example 19
##STR00024##
[0287]
Cis-6-(2,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(2,4-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl-
]-pyrrolidin-1-yl}-ethanone
[0288] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 1.28 g (78%) of the desired product as a pale yellow
oil after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS:
exact mass calcd for C.sub.28H.sub.38N.sub.2O.sub.4, 466.3; m/z
found, 467.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.16 (m, 1H),
7.10 (d, J=3.2, 1H), 6.97 (dd, J=3.2, 9.0, 1H), 6.93 (d, J=1.6,
1H), 6.87 (m, 2H), 6.76 (m, 1H), 4.04 (m, 1H), 3.91 (m, 2H), 3.69
(s, 3H), 3.63 (s, 3H), 3.43 (m, 3H), 2.39 (m, 6H), 2.30 (m, 1H),
2.11 (m, 1H), 1.92 (m, 3H), 1.82 (m, 1H), 1.75 (m, 1H), 1.55 (m,
4H), 1.42 (m, 2H).
Step 2.
6-(2,4-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro--
1H-pyrrolo[2,1-a]isoquinolinylium salt
[0289] Prepared as described in Example 17, Step 2, on a 2.90 mmol
scale, to give 1.15 g (82%) of crude product. MS: exact mass calcd
for C.sub.28H.sub.35N.sub.2O.sub.3.sup.+, 447.3; m/z found, 447.5
[M].sup.+.
Step 3
[0290] Prepared as described in Example 17, Step 3, on a 2.39 mmol
scale, to give 91.9 mg (8%) of the desired product as the TFA salt
after chromatography and HPLC. MS: exact mass calcd for
C.sub.28H.sub.38N.sub.2O.sub.3, 450.3; m/z found, 451.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 6.76 (d, J=8.0, 1H), 6.67
(m, 2H), 6.59 (dd, J=2.5, 8.5, 1H), 6.52 (d, J=2.5, 1H), 6.37 (dd,
J=2.5, 8.3, 1H), 4.53 (br s, 1H), 3.94 (t, J=6.0, 2H), 3.75 (s,
3H), 3.73 (s, 3H), 2.89 (m, 2H), 2.79 (m, 1H), 2.71 (dd, J=5.5,
11.0, 1H), 2.50 (t, J=7.5, 2H), 2.44 (br s, 3H), 2.31 (m, 1H), 1.93
(m, 3H), 1.85 (m, 2H), 1.60 (m, 4H), 1.46 (br s, 2H).
Example 20
##STR00025##
[0291]
Cis-6-(2,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(2,5-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl-
]-pyrrolidin-1-yl}-ethanone
[0292] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 1.27 g (78%) of the desired product as a pale yellow
oil after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS:
exact mass calcd for C.sub.28H.sub.38N.sub.2O.sub.4, 466.3; m/z
found, 467.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.14 (m, 1H),
7.09 (d, J=3.2, 1H), 6.97 (dd, J=3.2, 9.0, 1H), 6.93 (d, J=1.6,
1H), 6.88 (m, 1H), 6.75 (m, 1H), 4.03 (d, J=18.4, 1H), 3.91 (m,
2H), 3.69 (s, 3H), 3.63 (s, 3H), 3.43 (m, 3H), 2.40 (m, 6H), 2.30
(m, 1H), 2.15 (m, 1H), 1.90 (m, 3H), 1.80 (m, 1H), 1.75 (m, 1H),
1.55 (m, 4H), 1.41 (m, 2H).
Step 2.
6-(2,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro--
1H-pyrrolo[2,1-a]isoquinolinylium salt
[0293] Prepared as described in Example 17, Step 2, on a 2.38 mmol
scale, to give 1.01 g (88%) of crude product. MS: exact mass calcd
for C.sub.28H.sub.35N.sub.2O.sub.3.sup.+, 447.3; m/z found, 447.5
[M].sup.+.
Step 3
[0294] Prepared as described in Example 17, Step 3, on a 2.10 mmol
scale, to give 354.4 mg (38%) of the desired product after
recrystallization from methanol. MS: exact mass calcd for
C.sub.28H.sub.38N.sub.2O.sub.3, 450.3; m/z found, 451.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 6.87 (d, J=8.9, 1H), 6.78
(d, J=8.4, 1H), 6.67 (m, 3H), 6.55 (d, J=3.1, 1H), 4.55 (d, 2.9,
1H), 3.99 (m, 2H), 3.84 (s, 3H), 3.57 (s, 3H), 3.15 (m, 1H), 3.03
(m, 1H), 2.91 (m, 1H), 2.70 (m, 1H), 2.3 (m, 8H), 1.51 (m, 4H),
1.40 (m, 2H).
Example 21
##STR00026##
[0295]
Cis-6-(3,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1. 2-Bromo-1-(3,5-dimethoxy-phenyl)-ethanone
[0296] Prepared as described in Example 18, Step 1, on a 11.1 mmol
scale, to give 2.70 g (85%) of the ketone as a white solid. MS:
exact mass calcd for C.sub.10H.sub.11BrO.sub.3, 258.0; m/z found,
281.2 [M+Na].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.15 (d, J=2.3,
2H), 6.75 (d, J=2.2, 1H), 4.75 (s, 2H), 3.85 (s, 6H).
Step 2.
1-(3,5-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl-
]pyrrolidin-1-yl}-ethanone
[0297] Prepared as described in Example 8, Step 1, on a 3.80 mmol
scale, to give 1.10 g (90%) of the desired product as a pale yellow
oil after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS:
exact mass calcd for C.sub.28H.sub.38N.sub.2O.sub.4, 466.3; m/z
found, 467.4 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.16 (t,
J=7.8, 1H), 6.95 (m, 3H), 6.90 (d, J=7.5, 1H), 6.75 (m, 1H), 6.33
(m, 1H), 3.93 (m, 3H), 3.76 (s, 6H), 3.43 (m, 2H), 3.37 (m, 1H),
2.48 (m, 6H), 2.33 (m, 1H), 2.15 (m, 1H), 1.95 (m, 3H), 1.80 (m,
1H), 1.69 (m, 1H), 1.60 (m, 4H), 1.46 (br s, 2H).
Step 3.
6-(3,5-Dimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro--
1H-pyrrolo[2,1-a]isoquinolinylium salt
[0298] Prepared as described in Example 17, Step 2, on a 2.03 mmol
scale to give 700 mg (71%) of crude product. The crude product was
taken on to the next step without characterization.
Step 4
[0299] Prepared as described in Example 17, Step 3, on a 1.45 mmol
scale, to give 52.2 mg (5%) of the desired product as the TFA salt.
MS: exact mass calcd for C.sub.28H.sub.38N.sub.2O.sub.3, 450.3; m/z
found, 451.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 6.89 (d,
J=2.2, 1H), 6.83 (m, 2H), 6.49 (m, 1H), 6.42 (s, 2H), 4.87 (m, 1H),
4.37 (m, 1H), 4.11 (t, J=5.7, 2H), 3.87 (m, 1H), 3.77 (s, 6H), 3.61
(m, 3H), 3.44 (m, 2H), 3.31 (m, 2H), 2.94 (m, 2H), 2.81 (m, 1H),
2.27 (m, 5H), 1.97 (m, 2H), 1.85 (m, 3H), 1.60 (m, 1H).
Example 22
##STR00027##
[0300]
Cis-6-(3,4,5-Trimethoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,-
5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1. 2-Bromo-1-(3,4,5-trimethoxy-phenyl)-ethanone
[0301] Prepared as described in Example 18, Step 1, on a 9.51 mmol
scale, to give 2.23 g (80%) of the ketone as a white solid. MS
(electron impact): exact mass calcd for C.sub.11H.sub.13BrO.sub.4,
288.0; m/z found, 288 [M].sup.+. .sup.1H NMR (acetone-d.sub.6):
7.35 (s, 2H), 4.76 (s, 2H), 3.90 (s, 6H), 3.81 (s, 3H).
Step 2.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(3,4-
,5-trimethoxy-phenyl)-ethanone
[0302] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 1.47 g (85%) of the desired product as a pale yellow
oil after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS:
exact mass calcd for C.sub.29H.sub.40N.sub.2O.sub.6, 496.3; m/z
found, 497.4 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.10 (m, 3H),
6.86 (m, 2H), 6.68 (m, 1H), 3.85 (m, 3H), 3.72 (s, 6H), 3.71 (s,
3H), 3.35 (m, 2H), 3.22 (m, 1H), 2.36 (m, 6H), 2.07 (m, 1H), 1.86
(m, 3H), 1.72 (m, 1H), 1.65 (m, 1H), 1.50 (m, 4H), 1.37 (br s,
2H).
Step 3.
9-(3-Piperidin-1-yl-propoxy)-6-(3,4,5-trimethoxy-phenyl)-2,3-dihyd-
ro-1H-pyrrolo[2,1-a]isoquinolinylium salt
[0303] Prepared as described in Example 17, Step 2, on a 2.76 mmol
scale to give 1.17 g (83%) of crude product. MS: exact mass calcd
for C.sub.29H.sub.37N.sub.2O.sub.4.sup.+, 477.3; m/z found, 477.5
[M].sup.+.
Step 4
[0304] Prepared as described in Example 17, Step 3, on a 2.28 mmol
scale, to give 175.0 mg (10%) of the desired product as the TFA
salt. MS: exact mass calcd for C.sub.29H.sub.40N.sub.2O.sub.4,
480.3; m/z found, 481.6 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
6.78 (d, J=2.3, 1H), 6.73 (m, 2H), 6.46 (s, 2H), 4.24 (m, 1H), 4.00
(t, J=5.7, 2H), 3.77 (m, 1H), 3.70 (s, 6H), 3.67 (s, 3H), 3.49 (m,
3H), 3.35 (m, 2H), 3.20 (m, 2H), 2.85 (m, 2H), 2.72 (m, 1H), 2.20
(m, 5H), 1.86 (d, J=14.6, 2H), 1.72 (m, 3H), 1.42 (m, 1H).
Example 23
##STR00028##
[0305]
Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thio-
phen-2-yl-ethanone
[0306] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 1.24 g (85%) of the desired product as an oil after
chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS: exact mass
calcd for C.sub.24H.sub.32N.sub.2O.sub.2S, 412.2; m/z found, 413.6
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.75 (m, 2H) 7.18 (t,
J=8.0, 1H), 7.09 (dd, J=4.0, 5.0, 1H), 7.0 (m, 1H), 6.94 (d, J=7.6,
1H), 6.77 (m, 1H), 4.88 (s, 1H), 3.96 (m, 2H), 3.88 (d, J=16.4,
1H), 3.47 (d, J=8.8, 1H), 3.42 (d, J=16.0, 1H), 3.37 (m, 1H), 3.34
(s, 2H), 2.43 (m, 7H), 2.18 (m, 1H), 1.94 (m, 3H), 1.86 (m, 1H),
1.76 (m, 1H), 1.59 (m, 4H), 1.45 (br m, 2H).
Step 2.
9-(3-Piperidin-1-yl-propoxy)-6-thiophen-2-yl-2,3-dihydro-1H-pyrrol-
o[2,1-a]isoquinolinylium salt
[0307] Prepared as described in Example 17, Step 2, on a 2.90 mmol
scale, to give 1.14 g (92%) of crude product. MS: exact mass calcd
for C.sub.24H.sub.29N.sub.2OS.sup.+, 393.2; m/z found, 393.5
[M].sup.+.
Step 3
[0308] Prepared as described in Example 17, Step 3, on a 2.90 mmol
scale, to give 725.8 mg (41%) of the desired product as the TFA
salt. MS: exact mass calcd for C.sub.24H.sub.32N.sub.2OS, 396.2;
m/z found, 397.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.43 (m,
1H), 7.12 (s, 1H), 7.08 (m, 1H), 6.90 (m, 3H), 4.84 (m, 1H), 4.83
(m, 1H), 4.12 (t, J=5.7, 2H), 3.92 (br m, 1H), 3.71 (m, 1H), 3.60
(d, J=11.5, 2H), 3.46 (m, 2H), 3.31 (m, 2H), 2.97 (m, 2H), 2.85 (m,
1H), 2.25 (m, 5H), 1.95 (d, J=14.8, 2H), 1.84 (m, 3H), 1.53 (m,
1H).
Example 24-(A-B)
[0309] ##STR00029## [0310] 24A:
Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydro--
pyrrolo[2,1-a]isoquinoline [0311] 24B:
Trans-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahydr-
o-pyrrolo[2,1-a]isoquinoline
Step 1. 2-Bromo-1-thiophen-3-yl-ethanone
[0312] Prepared as described in Example 18, Step 1, on a 39.6 mmol
scale, to give 6.89 g (85%) of the ketone as a white solid. .sup.1H
NMR (acetone-d.sub.6): 8.46 (m, 1H), 7.56 (m, 2H), 4.63 (s,
2H).
Step 2.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thio-
phen-3-yl-ethanone
[0313] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 1.19 g (82%) of the desired product as an oil after
chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS: exact mass
calcd for C.sub.24H.sub.32N.sub.2O.sub.2S, 412.2; m/z found, 413.4
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 8.18 (m, 1H), 7.40 (m,
2H), 7.19 (m, 1H), 7.01 (s, 1H), 6.95 (d, J=7.6, 1H), 6.80 (m, 1H),
4.87 (s, 1H), 4.02 (m, 2H), 3.44 (m, 3H), 3.00 (m, 8H), 2.34 (m,
1H), 2.13 (m, 4H), 1.91 (m, 1H), 1.83 (m, 1H), 1.76 (m, 6 H), 1.57
(m, 3H).
Step 3.
9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-2,3-dihydro-1H-pyrrol-
o[2,1-a]isoquinolinylium salt
[0314] Prepared as described in Example 17, Step 2, on a 2.46 mmol
scale, to give 779.2 mg (74%) of crude product. The crude product
was taken on to the next step without characterization.
Step 4
[0315] Performed as described in Example 17, Step 3, on a 1.82 mmol
scale, to give the diastereomers in a combined yield of 56%.
24A:
Cis-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline
[0316] 587.7 mg (51%) as the TFA salt. MS: exact mass calcd for
C.sub.24H.sub.32N.sub.2OS, 396.2; m/z found, 397.5 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.44 (m, 1H), 7.36 (s, 1H), 6.92 (d,
J=4.4, 1H), 6.86 (d, J=2.2, 1H), 6.76 (m, 2H), 4.84 (m, 1H), 4.58
(m, 1H), 4.06 (t, J=5.8, 2H), 3.85 (m, 1H), 3.55 (m, 3H), 3.35 (m,
2H), 3.26 (m, 2H), 2.93 (m, 2H), 2.78 (m, 1H), 2.23 (m, 5H), 1.91
(m, 2H), 1.82 (m, 3H), 1.51 (m, 1H).
24B:
Trans-9-(3-Piperidin-1-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
[0317] 51.2 mg (4%) as the TFA salt. MS: exact mass calcd for
C.sub.24H.sub.32N.sub.2OS, 396.2; m/z found, 397.5 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.38 (br s, 1H), 6.96 (br s, 1H), 6.94
(br d, J=1.5, 1H), 6.83 (m, 3H), 4.78 (m, 1H), 4.48 (br s, 1H),
4.04 (t, J=5.7, 2H), 3.69 (br m, 2H), 3.51 (d, J=12.0, 3H), 3.33
(br s, 1H), 3.21 (m, 2H), 2.88 (m, 2H), 2.67 (br s, 1H), 2.15 (m,
2H), 2.07 (br m, 3H), 1.87 (d, J=14.5, 2H), 1.73 (m, 3H), 1.46 (m,
1H).
Example 25
##STR00030##
[0318]
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyri-
din-2-yl-ethanone
[0319] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 749.2 mg (52%) of crude product after chromatography
(NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS: exact mass calcd for
C.sub.25H.sub.33N.sub.3O.sub.2, 407.3; m/z found, 408.5
[M+H].sup.+.
Step 2.
9-(3-Piperidin-1-yl-propoxy)-6-pyridin-2-yl-2,3-dihydro-1H-pyrrolo-
[2,1-a]isoquinolinylium salt
[0320] Prepared as described in Example 17, Step 2, on a 1.36 mmol
scale to give 243.8 mg (42%) of crude product. MS: exact mass calcd
for C.sub.25H.sub.30N.sub.3O.sup.+, 388.2; m/z found, 388.5
[M].sup.+.
Step 3
[0321] Prepared as described in Example 17, Step 3, on a 0.575 mmol
scale, to give 100.0 mg (23%) of the desired product as the TFA
salt. MS: exact mass calcd for C.sub.25H.sub.33N.sub.3O, 391.3; m/z
found, 392.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 8.62 (d,
J=4.4, 1H), 8.04 (m, 1H), 7.63 (d, J=7.8, 1H), 7.53 (m, 1H), 6.94
(d, J=2.4, 1H), 6.85 (m, 1H), 6.88 (br s, 1H), 4.88 (m, 1H), 4.72
(m, 1H), 4.13 (t, J=5.8, 2H), 3.88 (br s, 1H), 3.76 (m, 2H), 3.61
(d, J=12.1, 2H), 3.53 (br s, 1H), 2.98 (m, 2H), 2.84 (m, 1H), 2.35
(m, 3H), 2.26 (m, 2H), 1.97 (m, 2H), 1.82 (m, 3H), 1.57 (m,
1H).
Example 26
##STR00031##
[0322]
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyri-
din-3-yl-ethanone
[0323] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 1.176 g (82%) of crude product after chromatography
(NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS: exact mass calcd for
C.sub.25H.sub.33N.sub.3O.sub.2, 407.3; m/z found, 408.5
[M+H].sup.+.
Step 2.
9-(3-Piperidin-1-yl-propoxy)-6-pyridin-3-yl-2,3-dihydro-1H-pyrrolo-
[2,1-a]isoquinolinylium salt
[0324] Prepared as described in Example 17, Step 2, on a 2.52 mmol
scale, to give 749.9 mg (70%) of crude product. MS: exact mass
calcd for C.sub.25H.sub.30N.sub.3O.sup.+, 388.2; m/z found, 388.5
[M].sup.+.
Step 3
[0325] Prepared as described in Example 17, Step 3, on a 1.77 mmol
scale, to give 208.4 mg (16%) of the desired product as the TFA
salt. MS: exact mass calcd for C.sub.25H.sub.33N.sub.3O, 391.3; m/z
found, 392.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 8.91 (m, 2H),
8.51 (d, J=8.1, 1H), 8.08 (m, 1H), 6.98 (d, J=2.4, 1H), 6.89 (m,
1H), 6.73 (d, J=8.5, 1H), 4.95 (m, 1H), 4.85 (m, 1H), 4.14 (t,
J=5.7, 2H), 3.94 (br s, 1H), 3.75 (m, 1H), 3.61 (d, J=11.2, 3H),
3.48 (m, 1H), 3.22 (m, 2H), 2.98 (m, 2H), 2.88 (m, 1H), 2.30 (m,
5H), 1.96 (d, J=14.6, 2H), 1.83 (m, 3H), 1.54 (m, 1H).
Example 27-(A-B)
[0326] ##STR00032## [0327] 27A:
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline [0328] 27B:
Trans-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahydro-
-pyrrolo[2,1-a]isoquinoline
Step 1. 2-Bromo-1-pyridin-4-yl-ethanone
[0329] To a 0.degree. C. solution of 4-acetylpyridine (4.90 g, 41.3
mmol) and 48% HBr (7.0 mL) in acetic acid (46.0 mL) was added,
dropwise over 15 min, a solution of Br.sub.2 (2.3 mL, 45 mmol) in
acetic acid (8.0 mL). After the addition was complete, the mixture
was allowed to warm to rt and then was heated at 70.degree. C. for
1 h. The mixture was cooled to 0.degree. C. and treated with
diethyl ether. The resultant white solid was isolated by vacuum
filtration to give 9.90 g (87%) of the ketone as the HBr salt. MS:
exact mass calcd for C.sub.7H.sub.6BrNO, 199.0; m/z found, 200.2
[M+H].sup.+.
Step 2.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyri-
din-4-yl-ethanone
[0330] Prepared as described in Example 8, Step 1, on a 6.93 mmol
scale, to give crude product that was taken directly to the next
step.
Step 3.
9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-2,3-dihydro-1H-pyrrolo-
[2,1-a]isoquinolinylium salt
[0331] Prepared as described in Example 17, Step 2, on a 6.93 mmol
scale to give crude product that was taken directly to the next
step.
Step 4
[0332] Prepared as described in Example 17, Step 3, on a 6.93 mmol
scale, to give the diastereomers in a combined yield of 2.6%.
27A:
Cis-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline
[0333] 3.1 mg (0.6%) as the TFA salt. MS: exact mass calcd for
C.sub.25H.sub.33N.sub.3O, 391.3; m/z found, 392.4 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 8.73 (br s, 2H), 7.66 (br s, 2H), 6.93
(d, J=2.5, 1H), 6.85 (dd, J=2.5, 8.7, 1H), 6.68 (d, J=8.7, 1H),
4.86 (m, 1H; obscured by solvent signal), 4.61 (m, 1H), 4.10 (5.7,
2H), 3.88 (m, 1H), 3.68 (m, 1H), 3.58 (d, J=12.0, 2H), 3.41 (m,
1H), 2.95 (m, 2H), 2.83 (m, 1H), 2.26 (m, 3H), 1.96 (d, J=14.7,
2H), 1.78 (m, 3H), 1.53 (m, 1H).
27B:
Trans-9-(3-Piperidin-1-yl-propoxy)-6-pyridin-4-yl-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
[0334] 9.1 mg (2%) as the TFA salt. MS: exact mass calcd for
C.sub.25H.sub.33N.sub.3O, 391.3; m/z found, 392.5 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 9.03 (br s, 2H), 7.85 (br s, 2H), 6.99
(m, 3H), 4.91 (m, 1H; partially obscured by solvent signal), 4.15
(t, J=5.7, 2H), 3.88 (br s, 2H), 3.70 (m, 1H), 3.60 (d, J=12.2,
3H), 3.48 (br s, 1H), 3.32 (m, 2H; partially obscured by solvent
signal), 2.97 (m, 2H), 2.82 (br m, 1H), 2.20 (m, 5H), 1.97 (d,
J=14.6, 2H), 1.82 (m, 3H), 1.54 (m, 1H).
Example 28
##STR00033##
[0335]
Cis-7-(1-Isopropyl-piperidin-4-yloxy)-4-(4-methoxy-phenyl)-2-methyl-
-1,2,3,4-tetrahydro-isoquinoline
Step 1. 4-(3-Methoxycarbonyl-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester
[0336] A solution of 4-hydroxy-piperidine-1-carboxylic acid
tert-butyl ester (10.0 g, 49.8 mmol), methyl 3-hydroxybenzoate
(9.94 g, 65.3 mmol), and polymer-bound triphenylphosphine (21.5 g,
64.6 mmol) in CH.sub.2Cl.sub.2 (100 mL) was cooled to 0.degree. C.
and treated with di-tert-butyl azodicarboxylate (15.0 g, 65.2
mmol). The mixture was kept at 0.degree. C. for 1.5 h with
occasional swirling. The mixture was then allowed to warm to rt and
the flask clamped onto a shaker table and the mixture swirled for 4
d. The resin was filtered off and the filtrate was washed with 1 N
NaOH and brine. The organic layer was dried (MgSO.sub.4), and
concentrated to give the crude product as a brown solid.
Chromatographic purification (EtOAc/hexanes) gave the desired
product as a colorless oil (16.58 g, 99%). .sup.1H NMR
(acetone-d.sub.6): 7.57 (m, 2H), 7.40 (m, 1H), 7.23 (m, 1H), 4.65
(m, 1H), 3.86 (s, 3H), 3.73 (m, 2H), 3.29 (m, 2H), 1.95 (m, 2H),
1.65 (m, 2H), 1.44 (s, 9H).
Step 2. 3-(Piperidin-4-yloxy)-benzoic acid methyl ester
[0337] A mixture of
4-(3-methoxycarbonyl-phenoxy)-piperidine-1-carboxylic acid
tert-butyl ester (16.5 g, 49.0 mmol) and TFA (50 mL) was stirred
under a stream of nitrogen for 1 h. Evolution of gas was evident.
The mixture was concentrated to provide the desired product as the
TFA salt, (21.7 g, >100%). MS: exact mass calcd for
C.sub.13H.sub.17NO.sub.3, 235.1; m/z found, 236.4 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.60 (m, 2H), 7.39 (m, 1H), 7.23 (m,
1H), 5.08 (s, 4H), 4.76 (m, 1H), 3.88 (s, 3H), 3.39 (m, 2H), 3.22
(m, 2H), 2.16 (m, 2H), 2.02 (m, 2H).
Step 3. 3-(1-Isopropyl-piperidin-4-yloxy)-benzoic acid methyl
ester
[0338] A mixture of 3-(piperidin-4-yloxy)-benzoic acid methyl ester
(TFA salt, 21.7 g, 46.8 mmol), Et.sub.3N (39.0 mL, 0.281 mol), and
2-iodopropane (7.1 mL, 70.2 mmol) in THF (95 mL) was heated at
55.degree. C. for 2 d, treated with additional 2-iodopropane (4 mL,
40.1 mmol), and heated for 1d further. The reaction mixture was
diluted with Et.sub.2O, washed with 1 N NaOH and brine, dried
(Na.sub.2CO.sub.3), and concentrated to give a yellow oil.
Chromatographic purification (EtOAc/hexanes) gave the desired
product as a pale-yellow oil (8.17 g, 63%). MS: exact mass calcd
for C.sub.16H.sub.23NO.sub.3, 277.2; m/z found, 278.4 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.55 (m, 1H), 7.51 (m, 1H), 7.38 (m,
1H), 7.18 (m, 1H), 4.40 (m, 1H), 3.87 (s, 3H), 2.74 (m, 3H), 2.38
(m, 2H), 1.99 (m, 2H), 1.68 (m, 2H), 1.00 (d, J=6.6, 6H).
Step 4.
4-[3-(4,5-Dihydro-3H-pyrrol-2-yl)-phenoxy]-1-isopropyl-piperidine
[0339] Prepared as described in Example 1, Step 4, on a 29.2 mmol
scale, to give 5.92 g (71%) of the desired product as a colorless
oil after column chromatography (NH.sub.3 in
MeOH/CH.sub.2Cl.sub.2). MS: exact mass calcd for
C.sub.18H.sub.26N.sub.2O, 286.2; m/z found, 287.5 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.41 (s, 1H), 7.31 (m, 2H), 7.01 (m,
1H), 4.40 (m, 1H), 3.96 (m, 2H), 2.95 (m, 2H), 2.78 (m, 2H), 2.71
(heptet, J=6.6, 1H), 2.43 (m, 2H), 2.01 (m, 4H), 1.76 (m, 2H), 1.07
(d, J=6.6, 6H).
Step 5. 1-Isopropyl-4-(3-pyrrolidin-2-yl-phenoxy)-piperidine
[0340] Prepared as described in Example 1, Step 5, on a 20.4 mmol
scale, to give 5.79 g (99%) of the desired product as a colorless
oil after column chromatography (NH.sub.3 in
MeOH/CH.sub.2Cl.sub.2). A small sample was purified by
reverse-phase HPLC to give a clear film (TFA salt). MS: exact mass
calcd for C.sub.18H.sub.28N.sub.2O, 288.2; m/z found, 289.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.41 (m, 1H), 7.12 (m,
3H), 4.63 (m, 1H), 3.6-3.3 (m, 8H), 2.45 (m, 2H), 2.24 (m, 5H),
1.95 (m, 1H), 1.40 (m, 6H).
Step 6.
2-{2-[3-(1-Isopropyl-piperidin-4-yloxy)-phenyl]-pyrrolidin-1-yl}-1-
-(4-methoxy-phenyl)-ethanone
[0341] Prepared as described in Example 8, Step 1, on a 3.47 mmol
scale, to give 1.28 g (84%) of the desired product as a pale yellow
foam after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS:
exact mass calcd for C.sub.27H.sub.36N.sub.2O.sub.3, 436.3; m/z
found, 437.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.82 (dd,
J=1.9, 7.0, 2H), 7.22 (m, 1H), 7.06 (d, J=1.3, 1H), 6.97 (d, J=7.5,
1H), 6.91 (dd, J=1.9, 7.0, 2H), 6.86 (m, 1H), 4.86 (s, 1H), 4.61
(br s, 1H), 3.96 (d, J=16.7, 1H), 3.83 (s, 3H), 3.55 (m, 2H), 3.42
(m, 2H), 3.27 (m, 2H), 3.16 (m, 2H), 2.36 (m, 1H), 2.19 (m, 3H),
2.0 (m, 3H), 1.75 (m, 1H), 1.74 (m, 1H), 1.34 (d, J=6.7, 6H).
Step 7.
9-(1-Isopropyl-piperidin-4-yloxy)-6-(4-methoxy-phenyl)-2,3-dihydro-
-1H-pyrrolo[2,1-a]isoquinolinylium salt
[0342] Prepared as described in Example 17, Step 2, on a 2.92 mmol
scale, to give 860 mg (65%) of crude product. MS: exact mass calcd
for C.sub.27H.sub.33N.sub.2O.sub.2.sup.+, 417.3; m/z found, 417.5
[M].sup.+.
Step 8
[0343] Prepared as described in Example 17, Step 3, on a 1.89 mmol
scale, to give 28.3 mg (3%) of the desired product as the TFA salt.
MS: exact mass calcd for C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z
found, 421.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.20 (d,
J=8.2, 2H), 7.03 (m, 1H), 6.97 (d, J=8.1, 2H), 6.87 (m, 1H), 6.74
(m, 1H), 4.92 (m, 1H), 4.41 (m, 1H), 3.89 (m, 1H), 3.86 (s, 3H),
3.58 (m, 3H), 3.44 (m, 3H), 3.32 (m, 2H), 2.89 (m, 1H), 2.35 (m,
6H), 1.99 (m, 1H), 1.42 (m, 6H).
##STR00034##
Example 29
Cis-9-(1-Isopropyl-piperidin-4-ylmethoxy)-6-(4-methoxy-phenyl)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1. 4-(3-Methoxycarbonyl-phenoxymethyl)-piperidine-1-carboxylic
acid tert-butyl ester
[0344] Prepared as described in Example 28, Step 1, on a 45.0 mmol
scale, yielding 13.66 g (87%) of the desired product as a colorless
oil. MS: exact mass calcd for C.sub.19H.sub.27NO.sub.6, 349.2; m/z
found, 372.4 [M+Na].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.57 (d,
J=7.6, 1H), 7.51 (m, 1H), 7.38 (m, 1H), 7.19 (m, 1H), 4.10 (m, 2H),
3.90 (m, 2H), 3.86 (s, 3H), 2.79 (br s, 2H), 1.97 (m, 1H), 1.82 (m,
2H), 1.43 (s, 9H), 1.23 (m, 2H).
Step 2. 3-(Piperidin-4-ylmethoxy)-benzoic acid methyl ester
[0345] Prepared as described in Example 28, Step 2, on a 39.0 mmol
scale. The crude product was diluted with in 1 N NaOH and extracted
with diethyl ether. The organic layer was washed with brine, dried
over Na.sub.2CO.sub.3, and concentrated to give the desired product
as an oil that crystallized on standing (7.14 g, 73%). MS: exact
mass calcd for C.sub.14H.sub.19NO.sub.3, 249.1; m/z found, 250.4
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.66 (d, J=6.8, 1H), 7.60
(s, 1H), 7.45 (m, 1H), 7.22 (d, J=7.3, 1H), 4.98 (s, 1H), 3.98 (s,
3H), 3.92 (d, J=4.6, 2H), 3.18 (d, J=11.4, 2H), 2.72 (t, J=12.0,
2H), 2.02 (br s, 1H), 1.92 (d, J=12.4, 2H), 1.44 (m, 2H).
Step 3. 3-(1-Isopropyl-piperidin-4-ylmethoxy)-benzoic acid methyl
ester
[0346] A mixture of 3-(piperidin-4-ylmethoxy)-benzoic acid methyl
ester (6.82 g, 27.4 mmol), acetone (40 mL), acetic acid (1.6 mL,
27.4 mmol), and NaB(OAc).sub.3H (18.4 g, 86.8 mmol) in THF (110 mL)
was stirred for 4.5 h. The mixture was diluted with
CH.sub.2Cl.sub.2, washed with 1 N NaOH and brine, dried
(Na.sub.2CO.sub.3), and concentrated to give the crude product.
Chromatographic purification (EtOAc/hexanes) yielded the desired
product as a pale yellow oil (6.43 g, 81%). MS: exact mass calcd
for C.sub.17H.sub.25NO.sub.3, 291.2; m/z found, 292.5 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.55 (dd, J=1.0, 7.7, 1H), 7.49 (m,
1H), 7.33 (m, 1H), 7.12 (m, 1H), 3.87 (s, 3H), 3.82 (d, J=6.2, 2H),
2.91 (d, J=11.6, 2H), 2.69 (heptet, J=6.6, 1H), 2.18 (m, 2H), 1.83
(d, J=13.2, 2H), 1.77 (m, 1H), 1.40 (m, 2H), 1.05 (d, J=6.6,
6H).
Step 4.
4-[3-(4,5-Dihydro-3H-pyrrol-2-yl)-phenoxymethyl]-1-isopropyl-piper-
idine
[0347] Prepared as described in Example 1, Step 4, on a 21.8 mmol
scale, to give 4.92 g (75%) of the desired product as a colorless
oil after column chromatography (NH.sub.3 in
MeOH/CH.sub.2Cl.sub.2). A small sample was purified by
reverse-phase HPLC to give a clear film (TFA salt). MS: exact mass
calcd for C.sub.19H.sub.28N.sub.2O, 300.2; m/z found, 301.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.63 (m, 2H), 7.57 (m,
1H), 7.39 (m, 1H), 4.24 (t, J=7.8, 2H), 4.0 (d, J=5.8, 2H), 3.64
(m, 2H), 3.52 (m, 3H), 3.10 (m, 2H), 2.42 (quintet, J=7.9, 2H),
2.17 (m, 3H), 1.76 (m, 2H), 1.37 (m, 6H).
Step 5.
1-Isopropyl-4-(3-pyrrolidin-2-yl-phenoxymethyl)-piperidine
[0348] Prepared as described in Example 1, Step 5, on a 20.4 mmol
scale, to give 5.79 g (99%) of the desired product as a colorless
oil after column chromatography (NH.sub.3 in
MeOH/CH.sub.2Cl.sub.2). A small sample was purified by
reverse-phase HPLC to give a clear film (TFA salt). MS: exact mass
calcd for C.sub.19H.sub.30N.sub.2O, 302.2; m/z found, 303.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4, TFA salt): 7.36 (m, 1H),
7.06 (m, 2H), 6.98 (m, 1H), 4.93 (s, 5H), 4.59 (m, 1H), 3.92 (d,
J=5.5, 2H), 3.40 (m, 5H), 3.08 (m, 2H), 2.47 (m, 1H), 2.18 (m, 6H),
1.71 (m, 2H), 1.37 (m, 6H).
Step 6.
2-{2-[3-(1-Isopropyl-piperidin-4-ylmethoxy)-phenyl]-pyrrolidin-1-y-
l}-1-(4-methoxy-phenyl)-ethanone
[0349] Prepared as described in Example 8, Step 1, on a 3.31 mmol
scale, to give 1.04 g (70%) of the desired product as a pale yellow
oil after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS:
exact mass calcd for C.sub.27H.sub.36N.sub.2O.sub.3, 450.3; m/z
found, 451.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.84 (m, 2H),
7.20 (m, 1H), 7.01 (d, J=1.5, 1H), 6.96 (d, J=7.5, 1H), 6.92 (m,
2H), 6.81 (m, 1H), 4.89 (s, 1H), 3.96 (d, J=16.6, 1H), 3.86 (m,
5H), 3.46 (m, 3H), 3.29 (m, 3H), 2.80 (t, J=12.3, 2H), 2.33 (m,
1H), 2.18 (m, 1H), 2.02 (m, 4H), 1.87 (m, 1H), 1.75 (m, 1H), 1.64
(m, 2H), 1.28 (d, J=6.7, 6H).
Step 7.
9-(1-Isopropyl-piperidin-4-ylmethoxy)-6-(4-methoxy-phenyl)-2,3-dih-
ydro-1H-pyrrolo[2,1-a]isoquinolinylium salt
[0350] Prepared as described in Example 17, Step 2, on a 2.05 mmol
scale, to give 740 mg (77%) of crude product. MS: exact mass calcd
for C.sub.28H.sub.35N.sub.2O.sub.2.sup.+, 431.3; m/z found, 431.5
[M].sup.+.
Step 8
[0351] Prepared as described in Example 17, Step 3, on a 1.58 mmol
scale to give 102.3 mg (12%) of the desired product as the TFA
salt. MS: exact mass calcd for C.sub.28H.sub.38N.sub.2O.sub.2,
434.3; m/z found, 435.6 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
7.15 (d, J=8.6, 2H), 6.93 (d, J=8.8, 2H), 6.85 (d, J=2.3, 1H), 6.76
(m, 1H), 6.70 (d, J=8.7, 1H), 4.85 (m, 1H), 4.34 (m, 1H), 3.88 (m,
3H), 3.78 (s, 3H), 3.53 (m, 4H), 3.38 (m, 2H), 3.06 (t, J=11.8,
2H), 2.81 (m, 1H), 2.25 (m, 3H), 2.11 (d, J=12.2, 3H), 1.72 (m,
2H), 1.35 (d, J=6.7, 6H).
##STR00035##
Example 30
Cis-Dimethyl-{4-[9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrr-
olo[2,1-a]isoquinolin-6-yl]-phenyl}-amine
Step 1.
1-(4-Dimethylamino-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phen-
yl]-pyrrolidin-1-yl}-ethanone
[0352] Prepared as described in Example 8, Step 1, on a 2.70 mmol
scale, to give 0.93 g (77%) of the desired product as a viscous oil
after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS: exact
mass calcd for C.sub.28H.sub.39F.sub.3N.sub.3O.sub.2, 449.3; m/z
found, 450.5 [M+H].sup.+.
Step 2.
6-(4-Dimethylamino-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydr-
o-1H-pyrrolo[2,1-a]isoquinolinylium salt
[0353] Prepared as described in Example 17, Step 2, on a 2.07 mmol
scale, to give 740 mg (83% crude) of the desired product. MS: exact
mass calcd for C.sub.28H.sub.36N.sub.3O.sup.+, 430.3; m/z found,
430.5 [M].sup.+.
Step 3
[0354] Prepared as described in Example 17, Step 3, on a 1.72 mmol
scale, to give 87.6 mg (14%) of the desired product as the TFA salt
after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2) and HPLC.
MS: exact mass calcd for C.sub.28H.sub.39N.sub.3O, 433.3; m/z
found, 434.5 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.19 (d,
J=8.6, 2H), 7.03 (d, J=8.7, 2H), 6.95 (m, 1H), 6.80 (m, 1H), 6.72
(d, J=8.7, 1H), 4.94 (m, 1H), 4.49 (m, 1H), 4.15 (t, J=5.9, 2H),
3.98 (br s, 1H), 3.68 (m, 3H), 3.40 (m, 4H), 3.04 (s, 6H), 2.91 (m,
1H), 2.33 (m, 6H), 2.06 (m, 5H), 1.82 (m, 1H), 1.53 (m, 1H).
Example 31
##STR00036##
[0355]
Cis-9-(3-Piperidin-1-yl-propoxy)-6-m-tolyl-1,2,3,5,6,10b-hexahydro--
pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-m-to-
lyl-ethanone
[0356] Prepared as described in Example 8, Step 1, on a 2.70 mmol
scale, to give 610 mg (54%) of the desired product as an orange oil
after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2). MS: exact
mass calcd for C.sub.27H.sub.36N.sub.2O.sub.2, 420.3; m/z found,
421.5 [M+H].sup.+.
Step 2.
9-(3-Piperidin-1-yl-propoxy)-6-m-tolyl-2,3-dihydro-1H-pyrrolo[2,1--
a]isoquinolinylium salt
[0357] Prepared as described in Example 17, Step 2, on a 1.45 mmol
scale, to give 560 mg (96%) of crude product. MS: exact mass calcd
for C.sub.27H.sub.33N.sub.2O.sup.+, 401.3; m/z found, 401.5
[M].sup.+.
Step 3
[0358] Prepared as described in Example 17, Step 3, on a 0.25 mmol
scale, to give 3.1 mg (1.3%) of the desired product as the TFA salt
after chromatography (NH.sub.3 in MeOH/CH.sub.2Cl.sub.2) and HPLC.
MS: exact mass calcd for C.sub.27H.sub.36N.sub.2O, 404.3; m/z
found, 405.5 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.14 (m,
1H), 7.01 (m, 2H), 6.95 (d, J=7.3, 1H), 6.80 (s, 1H), 6.64 (d,
J=8.7, 1H), 6.57 (d, J=8.6, 1H), 4.47 (br s, 1H), 4.32 (m, 1H),
4.00 (m, 2H), 3.52 (br s, 1H), 3.35 (m, 1H), 3.24 (m, 1H), 3.13 (m,
4H), 2.70 (m, 4H), 2.33 (m, 1H), 2.17 (m, 7H), 1.78 (m, 5H), 1.53
(m, 1H).
Example 32
##STR00037##
[0359]
Cis-6-(3-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(3-Iodo-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrro-
lidin-1-yl}-ethanone
[0360] Prepared as described in Example 8, Step 1, on a 3.46 mmol
scale, to give 1.0 g (54%) of the desired product as an orange
semi-solid after chromatography (NH.sub.3 in
MeOH/CH.sub.2Cl.sub.2). MS: exact mass calcd for
C.sub.26H.sub.33IN.sub.2O.sub.2, 532.2; m/z found, 533.4
[M+H].sup.+. .sup.1H NMR (CDCl.sub.3): 8.20 (m, 1H), 7.82 (m, 2H),
7.24 (t, J=7.9, 1H), 7.12 (t, J=7.9, 1H), 6.97 (d, J=7.6, 1H), 6.93
(m, 1H), 6.78 (m, 1H), 3.97 (m, 2H), 3.42 (t, J=8.7, 1H), 3.35 (m,
2H), 2.61 (m, 6H), 2.34 (m, 1H), 2.18 (m, 1H), 2.05 (m, 4H), 1.85
(m, 2H), 1.68 (m, 4 h), 1.48 (m, 2H).
Step 2.
6-(3-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro-1H-pyrr-
olo[2,1-a]isoquinolinylium salt
[0361] Prepared as described in Example 17, Step 2, on a 1.90 mmol
scale, to give 800 mg (82%) of crude product. MS: exact mass calcd
for C.sub.26H.sub.30IN.sub.2O.sup.+, 513.1; m/z found, 513.4
[M].sup.+.
Step 3
[0362] Prepared as described in Example 17, Step 3, on a 1.54 mmol
scale, to give 165 mg (14%) of the desired product after
chromatography and HPLC. MS: exact mass calcd for
C.sub.26H.sub.33IN.sub.2O, 516.2; m/z found, 517.4 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.76 (d, J=7.8, 1H), 7.69 (s, 1H),
7.38 (m, 1H), 7.26 (m, 1H), 6.97 (m, 1H), 6.81 (m, 1H), 6.67 (d,
J=8.7, 1H), 4.91 (m, 1H), 4.59 (m, 1H), 4.14 (m, 2H), 3.71 (br s,
1H), 3.66 (m, 3H), 3.53 (m, 1H), 3.42 (m, 1H), 3.32 (br s, 2H),
2.91 (m, 3H), 2.34 (m, 5H), 1.95 (m, 5H), 1.51 (m, 1H).
Example 33
##STR00038##
[0363]
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trimethylsilanylethynyl-pheny-
l)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0364] To a high-pressure reaction vial was added
cis-6-(3-iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydr-
o-pyrrolo[2,1-a]isoquinoline (Example 32, 40.0 mg, 0.08 mmol),
trimethylsilylacetylene (9.0 mg, 0.093 mmol),
Pd(PPh.sub.3).sub.2Cl.sub.2 (6.0 mg, 0.008 mmol), CuI (2.0 mg,
0.008 mmol), PPh.sub.3 (4.0 mg, 0.016 mmol), Et.sub.2NH (0.12 mL,
1.2 mmol), and DMF (0.1 mL). The sealed vial was placed in a
120.degree. C. preheated oil bath for 30 min, cooled to rt,
concentrated under a stream of nitrogen, and purified by
reverse-phase HPLC to give 27.0 mg (47%) of the desired product as
a TFA salt. MS: exact mass calcd for C.sub.31H.sub.42N.sub.2OSi,
486.3; m/z found, 487.6 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6):
7.46 (m, 2H), 7.36 (m, 2H), 6.97 (d, J=2.5, 1H), 6.80 (dd, J=2.6,
8.7, 1H), 6.65 (d, J=8.7, 1H), 4.92 (m, 1H), 4.63 (m, 1H), 4.14 (t,
J=6.0, 2H), 3.95 (m, 1H), 3.66 (m, 3H), 3.51 (m, 1H), 3.41 (m, 1H),
3.31 (m, 2H), 2.95 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.50 (m,
1H), 0.22 (s, 9H).
Example 34
##STR00039##
[0365]
Cis-6-(3-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline
[0366] A solution of
cis-9-(3-piperidin-1-yl-propoxy)-6-(3-trimethylsilanylethynyl-phenyl)-1,2-
,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 33, 40.0
mg, 0.082 mmol) and K.sub.2CO.sub.3 (2.0 mg, 0.008 mmol) in MeOH
(4.1 mL, 0.2 M) was stirred for 2 h at rt. The crude reaction
mixture was purified directly after filtration by reverse-phase
HPLC to give 19.0 mg (36%) of the desired product as a TFA salt.
MS: exact mass calcd for C.sub.28H.sub.34N.sub.2O, 414.3; m/z
found, 415.5 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.45 (m,
4H), 6.96 (m, 1H), 6.79 (dd, J=3.2, 10.9, 1H), 6.64 (d, J=10.9,
1H), 4.92 (m, 1H), 4.62 (m, 1H), 4.12 (t, J=7.5, 2H), 3.93 (m, 1H),
3.66 (m, 4H), 3.51 (m, 1H), 3.39 (m, 1H), 3.31 (m, 2H), 2.93 (m,
3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.51 (m, 1H).
Example 35-(A-B)
[0367] ##STR00040## [0368] 35A:
Cis-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydr-
o-pyrrolo[2,1-a]isoquinoline [0369] 35B:
Trans-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(4-Iodo-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrro-
lidin-1-yl}-ethanone
[0370] Prepared as described in Example 8, Step 1, on a 3.08 mmol
scale. The crude product was used without purification in the next
step. MS: exact mass calcd for C.sub.26H.sub.33IN.sub.2O.sub.2,
532.2; m/z found, 533.4 [M+H].sup.+.
Step 2.
6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3-dihydro-1H-pyrr-
olo[2,1-a]isoquinolinylium salt
[0371] Prepared as described in Example 17, Step 2, to give 3.5 g
(>100%) of crude product. MS: exact mass calcd for
C.sub.26H.sub.30IN.sub.2O.sup.+, 513.1; m/z found, 513.4
[M].sup.+.
Step 3
[0372] Performed as described in Example 17, Step 3, to give a
combined yield of 20% (over three steps) of two diastereomers.
35A:
Cis-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
[0373] 248.0 mg (13% over 3 steps) as the TFA salt. MS: exact mass
calcd for C.sub.26H.sub.33IN.sub.2O, 516.46; m/z found, 517.4
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 13.46 (br s, 1H), 11.49
(br s, 1H), 7.89 (d, J=8.3, 2H), 7.12 (d, J=11.6, 2H), 6.96 (m,
1H), 6.80 (dd, J=2.6, 8.7, 1H), 6.65 (d, J=11.2, 1H), 4.91 (m, 1H),
4.59 (dd, J=4.6, 12.1, 1H), 4.14 (t, J=6.0, 2H), 3.96 (m, 1H), 3.69
(m, 3H), 3.41 (m, 4H), 3.00 (m, 2H), 2.91 (m, 1H), 2.33 (m, 5H),
1.91 (m, 4H), 1.80 (m, 1H), 1.53 (m, 1H).
35B:
Trans-6-(4-Iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
[0374] 138 mg (7.3% over 3 steps) as the TFA salt. MS: exact mass
calcd for C.sub.26H.sub.33IN.sub.2O, 516.46; m/z found, 517.4
[M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.74 (d, J=8.2, 2H),
7.09 (d, J=8.3, 2H), 6.98 (m, 1H), 6.80 (m, 2H), 5.15 (br s, 1H),
4.60 (m, 1H), 4.17 (m, 2H), 3.63 (m, 6H), 3.41 (m, 2H), 2.92 (m,
2H), 2.77 (br s, 1H), 2.32 (m, 2H), 2.20 (m, 2H), 1.92 (m, 6H),
1.54 (m, 1H).
Example 36
##STR00041##
[0375]
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(4-trimethylsilanylethynyl-pheny-
l)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0376] Performed as described in Example 33, on a 0.27 mmol scale,
to yield 131.0 mg (77%) of the desired product as the TFA salt. MS:
exact mass calcd for O.sub.31H.sub.42N.sub.2OSi, 486.3; m/z found,
487.6 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.32 (m, 2H),
7.26 (m, 2H), 6.78 (d, J=8.5, 1H), 6.72 (m, 1H), 6.68 (m, 1H), 4.12
(m, 1H), 4.01 (m, 2H), 3.18 (m, 1H), 3.05 (m, 1H), 2.93 (m, 1H),
2.79 (m, 2H), 2.37 (m, 7H), 1.89 (m, 4H), 1.73 (m, 1H), 1.53 (m,
4H), 1.41 (m, 2H), 0.23 (s, 9H).
Example 37
##STR00042##
[0377]
Cis-6-(4-Ethynyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline
[0378] Prepared as described in Example 34, on a 0.18 mmol scale,
to yield 43.0 mg (57%) of the desired product as the TFA salt. MS:
exact mass calcd for C.sub.28H.sub.34N.sub.2O, 414.3; m/z found,
415.5 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.43 (d, J=8.3,
2H), 7.34 (d, J=8.2, 2H), 6.88 (d, J=9.8, 1H), 6.79 (m, 1H), 6.75
(m, 1H), 4.18 (m, 1H), 4.07 (m, 2H), 3.62 (s, 1H), 3.24 (m, 1H),
3.13 (m, 1H), 3.00 (m, 1H), 2.93 (m, 1H), 2.45 (m, 8H), 1.95 (m,
4H), 1.82 (1H), 1.59 (m, 4H), 1.47 (m, 2H).
Example 38
##STR00043##
[0379]
Cis-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1. 3-[3-(tert-Butyl-dimethyl-silanyloxy)-propoxy]-benzoic acid
methyl ester
[0380] Prepared as described in Example 1, Step 1, on a 0.330 mol
scale, using (3-bromopropoxy)-tert-butyldimethylsilane, to give
92.3 g (86%) of the desired product after vacuum distillation (bp
177.degree. C. @ 1 torr). MS: exact mass calcd for
C.sub.17H.sub.28O.sub.4Si, 324.2; m/z found, 325.4 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.56 (m, 1H), 7.52 (m, 1H), 7.40 (m,
1H), 7.18 (m, 1H), 4.14 (t, J=6.0, 2H), 3.86 (s, 3H), 3.84 (t,
J=6.0, 2H), 1.98 (m, 2H), 0.88 (s, 9H), 0.05 (s, 6H).
Step 2. 3-[3-(4,5-Dihydro-3H-pyrrol-2-yl)-phenoxy]-propan-1-ol
[0381] Prepared as described in Example 1, Step 4, on 0.284 mol
scale, to give 33.0 g (52%) of the desired product as a pale-yellow
solid after filtering through a plug of silica gel and distilling
with a Kugelrohr apparatus. The silyl protecting group was removed
during the reaction. MS: exact mass calcd for
C.sub.13H.sub.17NO.sub.2, 219.1; m/z found, 220.4 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.38 (s, 1H), 7.32 (m, 2H), 7.02 (m,
1H), 4.99 (s, 1H), 4.10 (t, J=6.0, 2H), 3.96 (t, J=7.0, 2H), 3.76
(t, J=6.0, 2H), 2.92 (t, J=8.0, 2H), 1.99 (m, 4H).
Step 3. 3-(3-Pyrrolidin-2-yl-phenoxy)-propan-1-ol
[0382] Prepared as described in Example 1, Step 5, on a 0.149 mol
scale, to give 27.2 g (82%) of the desired product as a colorless
oil. MS: exact mass calcd for C.sub.13H.sub.19NO.sub.2, 221.1; m/z
found, 222.4 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.21 (m, 1H),
6.92 (d, J=1.5, 1H), 6.90 (d, J=7.5, 1H), 6.80 (dd, J=2.5, 8.0,
1H), 4.89 (s, 2H), 4.06 (t, J=6.5, 2H), 3.98 (t, J=9.0, 1H), 3.73
(t, J=6.0, 2H), 3.15 (m, 1H), 2.91 (m, 1H), 2.18 (m, 1H), 1.96 (m,
2H), 1.87 (m, 2H), 1.69 (m, 1H).
Step 4.
2-{2-[3-(3-Hydroxy-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-methoxy--
phenyl)-ethanone
[0383] Prepared as described in Example 8, Step 1, on a 82.2 mmol
scale, to give 36.59 g (>100%) of the desired product after
column chromatography (EtOAc/hexanes). MS: exact mass calcd for
C.sub.22H.sub.27NO.sub.4, 369.2; m/z found, 370.4 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.87 (m, 2H), 7.22 (m, 1H), 7.03 (m,
1H), 6.94 (m, 3H), 6.81 (m, 1H), 4.09 (m, 2H), 4.02 (d, J=19.0,
1H), 3.84 (s, 3H), 3.74 (t, J=8.0, 2H), 3.47 (t, J=10.0, 1H), 3.28
(m, 2H), 2.36 (m, 1H), 2.15 (m, 1H), 1.96 (m, 2H), 1.84 (m, 2H),
1.68 (m, 1H).
Step 5.
9-(3-Hydroxy-propoxy)-6-(4-methoxy-phenyl)-2,3-dihydro-1H-pyrrolo[-
2,1-a]isoquinolinylium salt
[0384] Prepared as described in Example 17, Step 2, on an 82.2 mmol
scale, to give 30.09 g (95%) of crude product. The product was
taken on to the next step without purification. MS: exact mass
calcd for C.sub.22H.sub.24NO.sub.3.sup.+, 350.2; m/z found, 350.4
[M+H].sup.+.
Step 6.
Cis-3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]-
isoquinolin-9-yloxy]-propan-1-ol
[0385] Prepared as described in Example 17, Step 3, on 78.1 mmol
scale, to give 10.09 g (37%) of the desired product after column
chromatography (EtOAc) and reverse-phase HPLC. The product was
characterized as the TFA salt. MS: exact mass calcd for
C.sub.22H.sub.27NO.sub.3, 353.2; m/z found, 354.4 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.16 (d, J=8.5, 2H), 6.93 (d, J=9.0,
2H), 6.85 (d, J=2.5, 1H), 6.76 (m, 1H), 6.69 (d, J=8.5, 1H), 4.84
(m, 1H), 4.33 (m, 1H), 4.06 (t, J=6.5, 2H), 3.87 (m, 1H), 3.77 (s,
3H), 3.71 (t, J=6.3, 2H), 3.55 (m, 1H), 3.37 (m, 2H), 2.81 (m, 1H),
2.25 (m, 3H), 1.96 (m, 2H).
Step 7. Cis-Methanesulfonic acid
3-[6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-
-9-yloxy]-propyl ester
[0386] A solution of
cis-3-[6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquin-
olin-9-yloxy]-propan-1-ol (28.5 mmol) and Hunig's base (3 equiv.)
in THF (0.2 M) was cooled to 0.degree. C. and treated with
methanesulfonyl chloride (2.1 equiv.). The mixture was stirred at
0.degree. C. for 1 h. The mixture was then diluted with methylene
chloride, washed with 1 N NaOH and brine, dried (Na.sub.2CO.sub.3),
and concentrated to give the crude product, which was immediately
taken on to the next step. MS: exact mass calcd for
C.sub.22H.sub.27NO.sub.4, 431.2; m/z found, 432.4 [M+H].sup.+.
Step 8
[0387] A mixture of crude cis-methanesulfonic acid
3-[6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinolin-
-9-yloxy]-propyl ester (28.5 mmol), Na.sub.2CO.sub.3 (4 equiv.), KI
(0.5 equiv.), and morpholine (7.52 mmol, 10 equiv.) in ethanol (0.2
M) was heated to 50.degree. C. overnight. The mixture was cooled to
rt, diluted with CH.sub.2Cl.sub.2, and filtered. The filtrate was
concentrated to give the crude product. Column chromatography
(NH.sub.3 in MeOH/CH.sub.2Cl.sub.2) followed by HPLC give the
desired product (8.19 g, 68%). The enantiomers were separated using
a Chiralcel AD-h column on a SFC HPLC eluting with IPA/MeOH with
0.2% DEA. MS: exact mass calcd for C.sub.26H.sub.34N.sub.2O.sub.3,
422.3; m/z found, 423.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
7.06 (d, J=8.5, 2H), 6.82 (d, J=8.5, 2H), 6.70 (d, J=2.5, 1H), 6.67
(d, J=8.5, 1H), 6.61 (dd, J=2.5, 8.5 1H), 4.08 (dd, J=8.5, 5.5,
1H), 3.97 (t, J=6.5, 2H), 3.79 (m, 1H), 3.74 (s, 3H), 3.67 (m, 4H),
2.91 (m, 3H), 2.78 (dd, J=5.0, 11.2, 1H), 2.47 (m, 6H), 2.34 (m,
1H), 1.91 (m, 5H).
Example 39-(A-C)
[0388] ##STR00044## [0389] 39A:
Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline [0390] 39B:
Trans-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,-
10b-hexahydro-pyrrolo[2,1-a]isoquinoline [0391] 39C:
6-(4-Methylsulfanyl-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline
Step 1. 5-(3-Methoxy-phenyl)-3,4-dihydro-2H-pyrrole
[0392] Prepared as described in Example 1, Step 4, on a 0.24 mol
scale, using 3 N HCl in place of 12 N HCl during the workup
procedure, to give 37.8 g of the desired product. MS: exact mass
calcd for C.sub.11H.sub.13NO, 175.1; m/z found, 176.1 [M+H].sup.+.
.sup.1H NMR (DMSO-d.sub.6): 7.36 (m, 3H), 7.03 (m, 1H), 3.94 (m,
J=7.4, 2H), 3.79 (s, 3H), 2.89 (t, J=8.0, 2H), 1.93 (m, 2H).
Step 2. 2-(3-Methoxy-phenyl)-pyrrolidine
[0393] A solution of 5-(3-methoxy-phenyl)-3,4-dihydro-2H-pyrrole
(0.21 mol) in absolute ethanol (1.2 M) was treated portionwise with
NaBH.sub.4 (1.0 equiv.). The resultant mixture was stirred at rt
overnight. The mixture was cooled to 0.degree. C. and slowly
quenched with 1 N HCl. The mixture was acidified to a pH of 1 with
3 N HCl and was stirred at rt for 45 min. The resulting mixture was
again cooled to 0.degree. C., and was treated with 1 N NaOH until
basic. The aqueous mixture was extracted with CH.sub.2Cl.sub.2
(.times.3). The combined extracts were washed with brine, dried
(MgSO.sub.4), filtered and concentrated to give the crude product.
Chromatography (EtOAc/hexanes) gave 37.0 g (99%) of the desired
product. MS: exact mass calcd for C.sub.11H.sub.16NO, 177.1; m/z
found, 178.1 [M+H].sup.+. .sup.1H NMR (DMSO-d.sub.6): 7.23 (m, 1H),
7.05 (m, 1H), 6.98 (d, J=7.6, 1H), 6.79 (dd, J=2.8, 8.0, 1H), 4.20
(m, 1H), 3.74 (s, 3H), 3.15 (m, 1H), 3.03 (m, 1H), 2.19 (m, 1H),
1.86 (m, 2H), 1.69 (m, 1H).
Step 3.
2-Hydroxy-1-[2-(3-methoxy-phenyl)-pyrrolidin-1-yl]-2-(4-methylsulf-
anyl-phenyl)-ethanone
[0394] A mixture of 2-(3-methoxy-phenyl)-pyrrolidine (59.2 mmol),
hydroxy-(4-methylsulfanyl-phenyl)-acetic acid (1.05 equiv.),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU, 1.2 equiv.), and Hunig's base (1.5
equiv.) in CH.sub.2Cl.sub.2 (0.2 M) was stirred at rt overnight
under nitrogen. The reaction mixture was filtered to remove a white
precipitate and the filtrate was washed with 1 N HCl, water, 1 N
NaOH, water, and brine, dried (MgSO.sub.4), and concentrated to
give the crude product as a mixture of diastereomers. The crude
product was purified by normal phase column chromatography
(EtOAc/hexanes) to give 29.6 g (37%) of the product as a mixture of
diastereomers. MS: exact mass calcd for C.sub.20H.sub.23NO.sub.3S,
357.1; m/z found, 358.1 [M+H].sup.+.
Step 4.
9-Methoxy-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrr-
olo[2,1-a]isoquinolin-5-one
[0395] A solution of amide from Step 1 (33.3 mmol) and
polyphosphoric acid (5 g/g amide) was heated at 105.degree. C.
under nitrogen until the starting material was consumed (2 h). The
reaction mixture was poured into water and extracted with
CH.sub.2Cl.sub.2 (.times.2). The combined extracts were washed with
satd. aq. NaHCO.sub.3 and brine, dried (MgSO.sub.4), and
concentrated to provide the crude product. The crude material was
purified by chromatography to give 9.3 g (82%) of the product as a
mixture of diastereomers and regioisomers. MS: exact mass calcd for
C.sub.20H.sub.21NO.sub.2S, 339.1; m/z found, 340.0 [M+H].sup.+.
Step 5.
9-Hydroxy-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrr-
olo[2,1-a]isoquinolin-5-one
[0396] A solution of amino-ketone (Step 2; 0.15 mmol, 1.0 equiv.)
in CH.sub.2Cl.sub.2 (0.5 M) was treated dropwise with BBr.sub.3
(5.0 equiv.). The reaction mixture was stirred at rt until
complete. The reaction was cooled to 0.degree. C. and quenched with
water. The crude mixture was sonicated, extracted with
CH.sub.2Cl.sub.2, washed with brine, dried (MgSO.sub.4), and
concentrated to give 50 mg (>100%) of the crude product as a
mixture of diastereomers and regioisomers. MS: exact mass calcd for
C.sub.19H.sub.19NO.sub.2S, 325.1; m/z found, 326.1 [M+H].sup.+.
Step 6.
9-(3-Chloro-propoxy)-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahy-
dro-1H-pyrrolo[2,1-a]isoquinolin-5-one
[0397] Prepared as described in Example 1, Step 1, on a 1.23 mmol
scale, to give 330 mg (67%) of the crude product as a mixture of
diastereomers and regioisomers after normal phase column
chromatography (EtOAc/hexanes). MS: exact mass calcd for
C.sub.22H.sub.24ClNO.sub.2S, 401.1; m/z found, 402.0
[M+H].sup.+.
Step 7.
6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3,6,10b-
-tetrahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one
[0398] A solution of amino-ketone (Step 4; 0.82 mmol),
Na.sub.2CO.sub.3 (1.5 equiv.), KI (0.05 equiv.), and piperidine
(1.5 equiv.) in n-butanol (0.3 M) was heated at 100.degree. C.
overnight. The reaction mixture was cooled to rt, diluted with
CH.sub.2Cl.sub.2, and filtered. The filtrate was concentrated to
give the crude product (350 mg, 95%) as a mixture of diastereomers
and regioisomers. MS: exact mass calcd for
C.sub.27H.sub.34N.sub.2O.sub.2S, 450.2; m/z found, 451.2
[M+H].sup.+.
Step 8
[0399] To a 0.degree. C. solution of BH.sub.3.THF (1 M in THF, 2.5
equiv.) was added a solution of amino-ketone (Step 5, 0.75 mmol, 1
equiv.) in THF (2 M) and the resulting solution was heated at
reflux for 1 h. The mixture was cooled to rt, quenched with water,
and acidified with 12 N HCl. The THF was removed in vacuo and the
aqueous mixture was heated at reflux for 15 min. The reaction
mixture was again cooled to rt, made basic with 3 N NaOH, and
extracted with CH.sub.2Cl.sub.2. The organic extract was washed
with brine, dried (MgSO.sub.4), and concentrated to give the crude
products as a mixture (29%). The products were purified by
reverse-phase HPLC.
39A:
Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,-
6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0400] 26.0 mg (5%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2OS, 436.3; m/z found, 437.2 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.30 (d, J=8.4, 2H), 7.23 (d, J=8.2,
2H), 6.95 (m, 1H), 6.78 (m, 1H), 6.67 (d, J=8.6, 1H), 4.89 (m, 1H),
4.54 (m, 1H), 4.13 (t, J=6.0, 2H), 3.93 (m, 1H), 3.64 (m, 2H), 3.39
(m, 2H), 3.29 (m, 2H), 3.15 (m, 2H), 2.91 (m, 3H), 2.51 (s, 3H),
2.29 (m, 3H), 2.23 (m, 1H), 1.92 (m, 4H), 1.79 (m, 1H), 1.47 (m,
1H), 1.32 (m, 2H).
39B:
Trans-6-(4-Methylsulfanyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,-
5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0401] 82.0 mg (16%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2OS, 436.3; m/z found, 437.2 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 13.02 (br s, 1H), 11.64 (br s, 1H),
7.26 (d, J=10.4, 2H), 7.19 (d, J=10.4, 2H), 6.98 (br s, 1H), 6.83
(m, 2H), 5.65 (br s, 2H), 5.07 (br s, 1H), 4.52 (br s, 1H), 4.15
(t, J=5.6, 2H), 3.82 (m, 1H), 3.65 (m, 3H), 3.57 (m, 1H), 3.34 (m,
2H), 2.99 (m, 2H), 2.74 (m, 1H), 2.49 (s, 3H), 2.32 (m, 2H), 2.20
(m, 2H), 1.92 (m, 4H), 1.84 (m, 1H), 1.52 (m, 1H).
39C:
6-(4-Methylsulfanyl-phenyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0402] 39.0 mg (8%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2OS, 436.3; m/z found, 437.2 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 11.85 (br s, 1H), 11.31 (br s, 1H),
7.41 (m, 1H), 7.20 (d, J=9.7, 2H), 7.07 (m, 3H), 6.97 (d, 10.3,
1H), 5.13 (br s, 1H), 4.75 (s, 1H), 4.13 (m, 1H), 3.85 (m, 4H),
3.36 (m, 3H), 2.86 (m, 1H), 2.62 (m, 2H), 2.51 (m, 1H), 2.46 (s,
3H), 2.23 (m, 3H), 2.06 (m, 2H), 1.80 (m, 6H), 1.47 (m, 1H).
Example 40
##STR00045##
[0403]
Cis-6-(4-Bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-h-
exahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-(4-Bromo-phenyl)-2-hydroxy-1-[2-(3-methoxy-phenyl)-pyrrolidin-1--
yl]-ethanone
[0404] A solution of 2-(3-methoxy-phenyl)-pyrrolidine (16.9 mmol,
1.0 equiv.) and hydroxy-(4-bromo-phenyl)-acetic acid (1.0 equiv.)
in xylenes (0.2 M) was heated at reflux for 3 d under nitrogen. The
bulk of the xylenes was removed by distillation and the residue was
purified by chromatography (EtOAc/hexanes) to give the desired
product as a mixture of diastereomers (3.66 g, 55%). MS: exact mass
calcd for C.sub.19H.sub.20BrNO.sub.3, 389.1; m/z found, 390.0
[M+H].sup.+, 392.0 [M+H].sup.+.
Step 2
[0405] A solution of
2-(4-bromo-phenyl)-2-hydroxy-1-[2-(3-methoxy-phenyl)-pyrrolidin-1-yl]-eth-
anone (3.6 g, 9.2 mmol) and PPA (15.0 g) was heated at 100.degree.
C. for 1 h. The mixture was cooled to rt, poured into water, and
extracted with CH.sub.2Cl.sub.2. The combined organic layers were
washed with brine, dried (MgSO.sub.4), filtered and concentrated.
Purification by normal phase column chromatography (EtOAc/hexanes)
gave 87% combined yield of four isomeric products.
Cis-6-(4-Bromo-phenyl)-9-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]iso-
quinolin-5-one
[0406] 500 mg (15%). MS: exact mass calcd for
C.sub.19H.sub.18BrNO.sub.2, 371.1 m/z found, 372.0 [M+H].sup.+,
374.0 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.62 (d, J=8.4,
2H), 7.22 (d, J=8.4, 2H), 6.95 (m, 1H), 6.80 (dd, J=2.6, 8.6, 1H),
6.48 (m, 1H), 4.78 (m, 1H), 4.73 (s, 1H), 3.84 (s, 3H), 3.63 (m,
1H), 3.52 (m, 1H), 2.82 (m, 1H), 2.20 (m, 1H), 2.08 (m, 2H).
Trans-6-(4-Bromo-phenyl)-9-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]i-
soquinolin-5-one
[0407] 170.0 mg (6%). MS: exact mass calcd for
C.sub.19H.sub.18BrNO.sub.2, 371.1; m/z found, 372.0 [M+H].sup.+,
374.0 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.41 (d, J=8.5,
2H), 7.22 (d, J=9.3, 1H), 7.08, (d, J=8.2, 2H), 6.95 (m, 2H), 4.77
(s, 1H), 4.57 (m, 1H), 3.84 (s, 3H), 3.48 (m, 2H), 2.69 (m, 1H),
2.04 (m, 1H), 1.86 (m, 2H).
Cis-6-(4-Bromo-phenyl)-7-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]iso-
quinolin-5-one
[0408] 420 mg (14%). MS: exact mass calcd for
C.sub.19H.sub.18BrNO.sub.2, 371.1; m/z found, 372.0 [M+H].sup.+,
374.0 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.49 (d, J=8.5,
2H), 7.38 (m, 1H), 7.09 (d, J=8.5, J=2H), 7.06 (d, J=7.8, 1H), 6.88
(d, J=8.2, 1H), 4.74 (m, 1H), 4.70 (m, 1H), 3.82 (m, 1H), 3.58 (s,
3H), 3.36 (m, 1H), 2.73 (m, 1H), 2.10 (m, 2H), 1.87 (m, 1H).
Trans-6-(4-Bromo-phenyl)-7-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]i-
soquinolin-5-one
[0409] The material obtained from the purification by normal phase
column chromatography was recrystallized from acetone to give 48.3
mg (2%) of the desired product as white crystals. .sup.1H NMR
(acetone-d.sub.6): 7.45 (d, J=8.5, 2H), 7.37 (m, 1H), 7.02 (m, 3H),
6.96 (m, 1H), 4.89 (s, 1H), 4.58 (m, 1H), 3.74 (s, 3H), 3.41 (m,
2H), 2.65 (m, 1H), 2.00 (m, 1H), 1.88 (m, 1H), 1.73 (m, 1H).
Step 3.
Cis-6-(4-Bromo-phenyl)-9-hydroxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2-
,1-a]isoquinolin-5-one
[0410] Prepared from
cis-6-(4-bromo-phenyl)-9-methoxy-2,3,6,10b-tetrahydro-1H-pyrrolo[2,1-a]is-
oquinolin-5-one (3.49 mmol) as described in Example 39, Step 5. The
crude mixture was sonicated and extracted with diethyl ether. The
organic layer was washed with brine, dried (MgSO.sub.4), and
concentrated to give 1.08 g (86%) of crude product. A small amount
was purified by reverse phase HPLC to give the product as the TFA
salt. MS: exact mass calcd for C.sub.18H.sub.16BrNO.sub.2, 357.0;
m/z found, 358.0 [M+H].sup.+, 360.0 [M+H].sup.+. .sup.1H NMR
(acetone-d.sub.6): 7.55 (d, J=8.4, 2H), 7.16 (d, J=8.4, 2H), 6.79
(m, 1H), 6.64 (dd, J=2.4, 8.5, 1H), 6.31 (m, 1H), 4.70 (m, 1H),
4.64 (s, 1H), 3.58 (m, 1H), 3.44 (m, 2H), 2.70 (m, 1H), 2.14 (m,
1H), 2.09 (m, 1H), 1.97 (m, 1H).
Step 4.
Cis-6-(4-Bromo-phenyl)-9-(3-chloro-propoxy)-2,3,6,10b-tetrahydro-1-
H-pyrrolo[2,1-a]isoquinolin-5-one
[0411] Prepared as described in Example 39, Step 6, on a 0.56 mmol
scale, to give 205 mg (84%) of the desired product. MS: exact mass
calcd for C.sub.21H.sub.21BrCINO.sub.2, 433.0; m/z found, 434.0
[M+H].sup.+, 436.0 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.27
(d, J=8.5, 2H), 7.09 (m, 1H), 6.95 (d, J=8.2, 2H), 6.82 (m, 2H),
4.58 (s, 1H), 4.42 (m, 1H), 4.04 (t, J=6.0, 2H), 3.66 (t, J=6.5,
2H), 3.32 (m, 2H), 2.56 (m, 1H), 2.10 (m, 2H), 1.92 (m, 1H), 1.81
(m, 1H), 1.70 (m, 1H).
Step 5.
Cis-6-(4-Bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-2,3,6,10b-tetr-
ahydro-1H-pyrrolo[2,1-a]isoquinolin-5-one
[0412] Prepared as described in Example 39, Step 7, on a 0.46 mmol
scale, to give 190 mg (86%) of the desired product. MS: exact mass
calcd for C.sub.26H.sub.31BrN.sub.2O.sub.2, 482.2; m/z found, 483.1
[M+H].sup.+, 485.1 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.46
(d, J=8.5, 2H), 7.25 (d, J=8.2, 1H), 7.10 (d, J=7.0, 2H), 6.97 (m,
2H), 4.76 (s, 1H), 4.59 (m, 1H), 4.12 (t, J=6.5, 2H), 3.49 (m, 2H),
2.85 (m, 2H), 2.74 (m, 1H), 2.45 (t, J=7.0, 2H), 2.39 (m, 4H), 1.94
(3H), 1.57 (m, 4H), 1.39 (m, 2H).
Step 6
[0413] Prepared as described in Example 39, Step 8, on a 0.93 mmol
scale, to give 88.0 mg (14%) of the desired product as the TFA
salt. MS: exact mass calcd for C.sub.26H.sub.33BrN.sub.2O, 468.2;
m/z found, 469.1 [M+H].sup.+, 471.1 [M+H].sup.+. .sup.1H NMR
(acetone-d.sub.6): 7.55 (d, J=8.4, 2H), 7.22 (d, J=8.4, 2H), 6.99
(br s, 1H), 6.85 (m, 2H), 5.15 (br s, 1H), 4.70 (m, 3H), 4.16 (m,
2H), 3.84 (br s, 1H), 3.66 (m, 3H), 3.58 (m, 1H), 3.36 (m, 2H),
3.00 (m, 2H), 2.77 (m, 1H), 2.33 (m, 2H), 2.20 (m, 2H), 1.92 (m,
4H), 1.85 (m, 1H), 1.53 (m, 1H).
Example 41-(A-B)
[0414] ##STR00046## [0415] 41A:
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-benzonitrile [0416] 41B:
Trans-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
-a]isoquinolin-6-yl]-benzonitrile
[0417] To a sealed tube reaction vessel were added
cis-6-(4-bromo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline (0.21 mmol), CuCN (5.2 equiv.), and
DMF (1.7 M). The tube was purged with nitrogen, sealed, and heated
at 150.degree. C. overnight. The reaction mixture was cooled to rt,
diluted with aqueous NaCN, and extracted with diethyl ether. The
organic layer was washed with water, satd. aq. NaHCO.sub.3, and
brine, dried (Na.sub.2CO.sub.3), and concentrated to give the crude
product. Chromatographic purification (NH.sub.3 in
MeOH/CH.sub.2Cl.sub.2) followed by reverse-phase HPLC gave the
desired product as a mixture with the 6-trans isomer (7% combined
yield).
41A:
Cis-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2-
,1-a]isoquinolin-6-yl]-benzonitrile
[0418] 5.2 mg (4%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.33N.sub.3O, 415.3; m/z found, 416.2 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.74 (d, J=8.1, 2H), 7.46 (d, J=8.1,
2H), 7.00 (m, 1H), 6.85 (m, 2H), 6.80 (d, J=8.6, 1H), 5.07 (br s,
1H), 4.74 (m, 1H), 4.16 (m, 2H), 3.71 (m, 1H), 3.62 (m, 2H), 3.50
(m, 4H), 3.30 (m, 2H), 2.94 (m, 2H), 2.77 (m, 1H), 2.32 (m, 2H),
2.19 (m, 1H), 2.10 (m, 1H), 1.94 (m, 3H), 1.79 (m, 1H), 1.42 (m,
1H).
41B:
Trans-4-[9-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1-a]isoquinolin-6-yl]-benzonitrile
[0419] 4.6 mg (3%) as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.33N.sub.3O, 415.3; m/z found, 416.2 [M+H].sup.+.
.sup.1H NMR (acetone-d.sub.6): 7.82 (d, J=8.2, 2H), 7.54 (d, J=8.0,
2H), 7.02 (s, 1H), 6.79 (dd, J=2.1, 8.7, 1H), 6.62 (d, J=8.7, 1H),
4.91 (m, 1H), 4.74 (m, 1H), 4.13 (m, 2H), 3.93 (m, 1H), 3.70 (m,
1H), 3.61 (m, 3H), 3.50 (t, J=11.7, 2H), 3.37 (m, 4H), 3.29 (m,
8H), 2.93 (m, 3H).
Example 42
##STR00047##
[0420]
Trans-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1. 2-(4-Bromo-benzylidene)-malonic acid diethyl ester
[0421] A mixture of 4-bromobenzaldehyde (118.3 g, 0.639 mol),
diethyl malonate (105.5 mL, 0.6243 mol), and p-toluic acid (9.40 g,
62.6 mmol), in toluene (220 mL) was stirred under nitrogen until
homogeneous and then was treated with piperidine (7.50 mL, 75.8
mmol). The flask was fitted with a Dean-Stark trap and a condenser
and was heated at between 128-135.degree. C. overnight. The mixture
was diluted with toluene, washed with 10% aq. HCl, 1 N NaOH, and
brine (.times.2). The organic layer was dried (MgSO.sub.4) and
concentrated to give the crude product as a pale-red oil. Vacuum
distillation (bp=159.degree. C. @ 1 torr) of the crude material
yielded 142.1 g (70%) of the desired product as a pale-yellow oil.
.sup.1H NMR (acetone-d.sub.6): 7.67 (d, J=2.9, 1H), 7.62 (br s,
2H), 7.47 (br s, 2H), 4.29 (m, 4H), 1.26 (m, 6H).
Step 2. 2-[(4-Bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid
diethyl ester
[0422] A 0.degree. C. solution of 3-methoxyphenyl magnesium bromide
(1 M in THF; 414 mL, 0.414 mol) was treated with a solution of
2-(4-bromo-benzylidene)-malonic acid dimethyl ester (114.7 g,
0.3506 mol) in diethyl ether (250 mL), via cannula, over the course
of 18 min. The mixture was stirred at 0.degree. C. for 1 h and then
was allowed to warm to rt. After 2 h, the reaction was quenched
with satd. aq. NH.sub.4Cl, and extracted with diethyl ether. The
organic layer was washed with satd. aq. NH.sub.4Cl and brine, dried
(MgSO.sub.4), and concentrated to give the crude product as a
yellow oil (163.5 g, >100%). The bulk of the crude product was
taken on to the next step without purification, but a small portion
was purified by normal phase column chromatography (EtOAc/hexanes)
for characterization. MS: exact mass calcd for
O.sub.21H.sub.23BrO.sub.5, 434.1; m/z found, 457.0 [M+Na].sup.+,
459.0 [M+Na].sup.+. .sup.1H NMR (acetone-d.sub.6): 7.42 (m, 4H),
7.17 (d, J=7.9, 1H), 6.98 (m, 2H), 6.35 (m, 1H), 4.67 (d, J=12.3,
1H), 4.47 (d, J=12.2, 1H), 3.98 (m, 4H), 3.95 (s, 3H), 1.00 (m,
6H).
Step 3. 2-[(4-Bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic
acid
[0423] A mixture of crude
2-[(4-bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid diethyl
ester (131.3 g, est. 0.3016 mol) in 150 mL hot ethanol was treated
with a solution of KOH (85%; 99.6 g, 1.51 mol) in water (301 mL).
The mixture was heated overnight at 105.degree. C. and then was
allowed to cool to rt. The mixture was diluted with water and
extracted with diethyl ether (500 mL, .times.3). The aqueous phase
was acidified with 12 N HCl until the pH=1 and was extracted with
diethyl ether (500 mL, .times.3). The latter organic extracts were
combined, dried (Na.sub.2CO.sub.3), and concentrated to give 107.97
g of a white-grey solid. The crude product was divided into two
equal portions and each was suspended in 700 mL toluene. The
toluene suspensions were heated at 105.degree. C. for 3 h and then
allowed to slowly cool to rt. The white solid was filtered off,
rinsed with toluene, the portions combined and dried under high
vacuum to give 68.8 g (60%) of the desired product as a white
solid. MS (ESI, negative ionization): exact mass calcd for
C.sub.17H.sub.15BrO.sub.5, 378.0; m/z found, 377.9 [M-H].sup.-,
379.9 [M-H].sup.-. .sup.1H NMR (DMSO-d.sub.6): 12.68 (br s, 2H),
7.41 (m, 4H), 7.15 (m, 1H), 6.97 (m, 2H), 6.70 (m, 1H), 4.52 (d,
J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.69 (s, 3H).
Step 4. 3-(4-Bromo-phenyl)-3-(3-methoxy-phenyl)-propionic acid
[0424] To a 1-L round bottomed flask was added 79.9 g (0.211 mol)
2-[(4-bromo-phenyl)-(3-methoxy-phenyl)-methyl]-malonic acid, the
flask fitted with a septum, and the system subjected to a
continuous stream of nitrogen (nitrogen line into septum and a
needle as a bleed). The flask was then heated slowly in an oil bath
to 160.degree. C. for 2 h. Gas evolution was evident beginning at
140.degree. C. The mixture was allowed to cool to rt to give 70.1 g
(99%) of the desired product as a white solid. MS (ESI, negative
ionization): exact mass calcd for C.sub.16H.sub.16BrO.sub.3, 334.0;
m/z found, 333.0 [M-H].sup.-, 335.0 [M-H].sup.-. .sup.1H NMR
(DMSO-d.sub.6): 12.14 (br s, 1H), 7.42 (dd, J=1.8, 6.6, 2H), 7.28
(m, 2H), 7.17 (m, 1H), 6.88 (m, 2H), 6.73 (m, 1H), 4.38 (t, J=7.9,
1H), 3.70 (s, 3H), 3.00 (dd, J=3.6, 8.0, 2H).
Step 5. [2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-carbamic
acid tert-butyl ester
[0425] A mixture of
3-(4-bromo-phenyl)-3-(3-methoxy-phenyl)-propionic acid (24.99 g,
74.55 mmol), triethylamine (12.5 mL, 89.5 mmol) and
diphenylphosphoryl azide (17.0 mL, 78.3 mmol) in tert-butanol (250
mL) was heated at 85.degree. C. overnight. The reaction mixture was
then concentrated and the residue was purified by normal phase
column chromatography (EtOAc/hexanes) to give 24.19 g (80%) of the
desired product as a viscous colorless oil. MS: exact mass calcd
for C.sub.20H.sub.24BrNO.sub.3, 405.1; m/z found, 428.1
[M+Na].sup.+, 430.1 [M+Na].sup.+. .sup.1H NMR (acetone-d.sub.6):
7.45 (d, J=8.4, 2H), 7.27 (d, J=8.4, 2H), 7.20 (m, 1H), 6.86 (m,
2H), 6.76 (dd, J=1.9, 7.8, 1H), 5.96 (br s, 1H), 4.25 (t, J=7.9,
1H), 3.76 (s, 3H), 3.70 (m, 1H), 1.34 (s, 9H).
Step 6. 2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethylamine
[0426] Prepared as described in Example 29, Step 2, on a 59.5 mmol
scale, to give 16.8 g (92%) product as the free base. MS: exact
mass calcd for C.sub.16H.sub.16BrNO, 305.0; m/z found, 306.1
[M+H].sup.+, 308.1 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.24
(m, 2H), 7.03 (m, 3H), 6.64 (m, 3H), 4.66 (br s, 2H), 3.76 (m, 1H),
3.57 (s, 3H), 3.01 (m, 2H).
Step 7.
N-[2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-succinamic
acid
[0427] A solution of succinic anhydride (5.77 g, 57.6 mmol) in
CH.sub.2Cl.sub.2 (55 mL) was stirred under nitrogen until
homogeneous, cooled to 0.degree. C., and then treated with a
solution of 2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-ethylamine
(16.8 g, 54.9 mmol) in CH.sub.2Cl.sub.2 (55 mL). Once the addition
was complete, the ice bath was removed and the mixture was stirred
at rt for 2.5 h. The mixture was concentrated to give the crude
product. The crude material was immediately taken on to the next
step without purification. MS: exact mass calcd for
C.sub.19H.sub.20BrNO.sub.4, 405.1; m/z found, 406.0 [M+H].sup.+,
408.0 [M+H].sup.+.
Step 8.
1-[2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-pyrrolidine-2,5--
dione
[0428] A solution of the crude product from Step 7 (54.9 mmol) in
EtOAc (55 mL) was treated with acetyl chloride (14.0 mL) and then
was heated at reflux overnight. The mixture was cooled, and a
precipitate formed. The solid was filtered to provide 15.9 g (75%)
of the desired product. The filtrate was purified by chromatography
(EtOAc/hexanes) to give an additional 3.28 g, for a combined yield
of 19.2 g (90%). MS: exact mass calcd for
C.sub.19H.sub.18BrNO.sub.3, 387.1; m/z found, 410.0 [M+Na].sup.+,
412.0 [M+Na].sup.+. .sup.1H NMR (CDCl.sub.3): 7.38 (m, 2H), 7.19
(m, 3H), 6.81 (d, J=7.6, 1H), 6.73 (m, 2H), 4.60 (t, J=8.4, 1H),
4.06 (m, 2H), 3.74 (s, 3H), 2.51 (s, 4H).
Step 9.
1-[2-(4-Bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-5-ethoxy-pyrroli-
din-2-one
[0429] A mixture of
1-[2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-pyrrolidine-2,5-dione
(5.21 g, 13.4 mmol) in 1,4-dioxane (65 mL) was stirred until
homogeneous and then was treated with ethanol (65 mL) and cooled to
0.degree. C. Once cold, the mixture was treated with NaBH.sub.4
(2.13 g, 56.4 mmol), followed by MSA (2 N in ethanol, 5 drops).
Equivalent portions of MSA were added every 15 min over 5.5 h,
after which time additional MSA was added to quench the NaBH.sub.4
and to lower the pH to 1. The resulting viscous mixture was stirred
for 3.5 h. The mixture was diluted with diethyl ether, washed with
satd. aq. NaHCO.sub.3, water, and brine, dried (MgSO.sub.4), and
concentrated to give the crude product. Chromatographic
purification (EtOAc/hexanes) yielded 4.30 g (76%) of the desired
product. MS: exact mass calcd for C.sub.21H.sub.24BrNO.sub.3,
417.1; m/z found, 440.0 [M+Na].sup.+, 442.0 [M+Na].sup.+. .sup.1H
NMR (acetone-d.sub.6): 7.46 (m, 2H), 7.32 (m, 2H), 7.23 (m, 1H),
6.90 (m, 2H), 6.76 (m, 1H), 4.63 (m, 1H), 4.42 (m, 1H), 4.15 (m,
1H), 3.75 (m, 3H), 3.61 (m, 1H), 3.41 (m, 2H), 2.29 (m, 1H), 2.04
(m, 1H), 1.84 (m, 2H), 1.13 (m, 3H).
Step 10
[0430] A mixture of
1-[2-(4-bromo-phenyl)-2-(3-methoxy-phenyl)-ethyl]-5-ethoxy-pyrrolidin-2-o-
ne (472.2 mg, 1.13 mmol) and MSA (2 N in ethanol, 10 mL) was
stirred for 2 h at rt. The mixture was diluted with EtOAc, washed
with satd. aq. NaHCO.sub.3 and brine, dried (MgSO.sub.4), and
concentrated to give a colorless oil. Chromatographic purification
(EtOAc/hexanes) yielded 325.4 mg (78%) of the desired product as a
mixture of cis and trans diastereomers. The diastereomers were
separated by normal-phase HPLC.
Trans-6-(4-Bromo-phenyl)-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]i-
soquinolin-3-one
[0431] MS: exact mass calcd for C.sub.19H.sub.18BrNO.sub.2, 371.1;
m/z found, 372.0 [M+H].sup.+, 374.0 [M+H].sup.+. .sup.1H NMR
(CDCl.sub.3): 7.45 (m, 2H), 7.07 (m, 3H), 6.82 (m, 1H), 6.29 (d,
J=1.9, 1H), 4.87 (m, 1H), 4.41 (m, 1H), 4.10 (m, 1H), 3.62 (s, 3H),
3.00 (m, 1H), 2.55 (m, 1H), 2.47 (m, 1H), 2.42 (m, 1H).
Cis-6-(4-Bromo-phenyl)-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]iso-
quinol in-3-one
[0432] The cis isomer was processed as described in Example 43
below. MS: exact mass calcd for C.sub.19H.sub.18BrNO.sub.2, 371.1;
m/z found, 372.3 [M+H].sup.+, 374.3 [M+H].sup.+. .sup.1H NMR
(acetone-d.sub.6): 7.36 (m, 2H), 6.98 (m, 3H), 6.70 (d, J=8.0, 1H),
6.24 (d, J=7.5, 1H), 4.89 (m, 1H), 4.34 (dd, J=6.0, 12.8, 1H), 3.98
(dd, J=5.5, 11.2, 1H), 3.79 (s, 3H), 2.89 (m, 1H), 2.83 (m, 1H),
2.48 (m, 1H), 2.33 (m, 1H), 1.64 (m, 1H).
Step 11.
Trans-6-(4-Bromo-phenyl)-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrol-
o[2,1-a]isoquinolin-3-one
[0433] A solution of the product from Step 10 (2.56 mmol, 1.0
equiv.) in CH.sub.2Cl.sub.2 (0.1 M) was treated with BBr.sub.3 (1.0
M in CH.sub.2Cl.sub.2, 5 equiv.). The mixture was stirred overnight
and then poured onto a mixture of crushed ice and CH.sub.2Cl.sub.2.
The mixture was diluted with water and the layers were separated.
The organic layer was washed with water (.times.2) and brine, dried
(MgSO.sub.4), and concentrated to give the crude product (776.0 mg)
as a mixture of the desired product and the corresponding des-bromo
material
(trans-6-phenyl-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinol-
in-3-one). The crude product was taken on to the next step without
purification. Brominated product: MS (ESI, negative ionization):
exact mass calcd for C.sub.18H.sub.16BrNO.sub.2, 357.0; m/z found,
355.9 [M-H].sup.-, 357.9 [M-H].sup.-. Des-bromo product: MS: exact
mass calcd for C.sub.18H.sub.17NO.sub.2, 279.1; m/z found, 278.0
[M-H].sup.-.
Step 12.
Trans-6-(4-Bromo-phenyl)-8-(3-chloro-propoxy)-1,5,6,10b-tetrahydr-
o-2H-pyrrolo[2,1-a]isoquinolin-3-one
[0434] A mixture of the crude material from Step 11 (2.43 mmol, 1.0
equiv.), K.sub.2CO.sub.3(5 equiv.), and 1,3-bromochloropropane
(5.12 mmol, 3 equiv.) in acetone (0.1 M) was heated at 60.degree.
C. overnight. The reaction mixture was diluted with
CH.sub.2Cl.sub.2, filtered and concentrated. The crude product was
purified by chromatography (EtOAc/hexanes) to provide a mixture of
the desired product and
trans-6-phenyl-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinoli-
n-3-one (637.6 mg). Brominated product: MS: exact mass calcd for
C.sub.21H.sub.2iBrCINO.sub.2, 433.0; m/z found, 434.0 [M+H].sup.+,
436.0 [M+H].sup.+. Des-bromo product: MS: exact mass calcd for
O.sub.21H.sub.22ClNO.sub.2, 355.1; m/z found, 356.1
[M+H].sup.+.
Step 13.
Trans-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-t-
etrahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one
[0435] Prepared from the product mixture from Step 12 (est. 1.61
mmol), as described in Example 39, Step 7. The reaction was
performed in a glass pressure tube. Chromatographic purification
(NH.sub.3 in MeOH/CH.sub.2Cl.sub.2) gave a mixture of the desired
product and
trans-6-phenyl-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrro-
lo[2,1-a]isoquinolin-3-one (683.9 mg). The product mixture was
taken on to the next step without characterization.
Step 14
[0436] Prepared as described in Example 39, Step 8, on a 1.54 mmol
scale (est.). Purification of the crude mixture of bromo and
des-bromo compounds by reverse-phase HPLC gave the desired product
(25.6 mg, 2%) as the TFA salt as well as 45.4 mg (4%) of the
des-brominated product (Example 49). MS: exact mass calcd for
C.sub.26H.sub.33N.sub.2OBr, 468.2; m/z found, 469.1 [M+H].sup.+,
471.1 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.51 (d, J=8.2, 2H),
7.29 (br d, J=7.8, 1H), 7.11 (br s, 2H), 6.98 (br d, J=6.9, 1H),
6.52 (br s, 1H), 4.57 (br s, 1H), 3.99 (m, 2H), 3.75 (br d, 2H),
3.53 (d, J=11.7, 2H), 4.45 (br m, 1H), 3.22 (t, J=7.8, 2H), 2.72
(br s, 1H), 2.15 (m, 5H), 1.91 (m, 2H), 1.79 (m, 3H), 1.50 (m,
1H).
Example 43
##STR00048##
[0437]
Cis-4-[8-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1-a]isoquinolin-6-yl]-benzonitrile
Step 1.
Cis-6-(4-Bromo-phenyl)-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2-
,1-a]isoquinolin-3-one
[0438] Prepared as described in Example 42, Step 11, on a 1.89 mmol
scale, to yield 654.3 mg of a mixture of the desired product and
cis-6-phenyl-8-hydroxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin--
3-one, the product of debromination under the reaction conditions.
The crude product was taken on to the next step without
purification or characterization.
Step 2.
Cis-6-(4-Bromo-phenyl)-8-(3-chloro-propoxy)-1,5,6,10b-tetrahydro-2-
H-pyrrolo[2,1-a]isoquinolin-3-one
[0439] Prepared as described in Example 42, Step 12, on a 1.71 mmol
scale, to yield 486.4 mg of a mixture of the desired product and
cis-6-phenyl-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]isoquinolin--
3-one. Brominated product: MS: exact mass calcd for
C.sub.21H.sub.21BrCINO.sub.2, 433.0; m/z found, 434.0 [M+H].sup.+,
436.0 [M+H].sup.+. Des-bromo product: MS: exact mass calcd for
C.sub.21H.sub.22ClNO.sub.2, 355.1; m/z found, 356.0
[M+H].sup.+.
Step 3.
Cis-6-(4-Bromo-phenyl)-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetr-
ahydro-2H-pyrrolo[2,1-a]isoquinolin-3-one
[0440] Prepared as described in Example 42, Step 13, on a 1.23 mmol
scale to yield 308.1 mg of a mixture of the desired product and
cis-6-phenyl-8-(3-piperidin-1-yl-propoxy)-1,5,6,10b-tetrahydro-2H-pyrrolo-
[2,1-a]isoquinolin-3-one.
Step 4
[0441] Prepared as described in Example 42, Step 14, on a 0.694
mmol scale. The crude product was divided into two equal portions.
One portion was carried forward to prepare the nitrile and the
other portion was subjected to reverse-phase HPLC to yield pure
des-bromo product (Example 50). The bromo-product was not isolated
as a pure substance.
Step 5.
Cis-4-[8-(3-Piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrol-
o[2,1-a]isoquinolin-6-yl]-benzonitrile
[0442] To a high-pressure reaction vial was added the product of
Step 4 (1.06 mmol), CuCN (1.2 equiv.), and DMF (2.0 M). The sealed
vial was heated at 150.degree. C. for 2 d. The mixture was cooled
to rt, diluted with aqueous NaCN, and extracted with diethyl ether.
The combined organic extracts were combined, washed with water,
satd. aq. NaHCO.sub.3, and brine, dried (Na.sub.2CO.sub.3) and
concentrated to give the crude product. The product was purified by
reverse-phase HPLC to give 4.7 mg (0.7%) of the desired product as
the TFA salt. MS: exact mass calcd for C.sub.27H.sub.33N.sub.3O,
415.3; m/z found, 416.2 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
4.72 (d, J=8.4, 2H), 7.31 (m, 3H), 7.03 (d, J=8.3, 1H), 6.59 (d,
J=7.7, 1H), 5.02 (br m, 1H), 4.69 (m, 1H), 4.24 (m, 1H), 4.18 (m,
1H), 3.66 (m, 6H), 3.33 (m, 1H), 3.00 (m, 2H), 2.90 (br s, 1H),
2.32 (m, 2H), 2.19 (m, 2H), 1.98 (m, 2H), 1.81 (m, 4H), 1.55 (m,
1H).
Example 44
##STR00049##
[0443]
Trans-6-Phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
-pyrrolo[2,1-a]isoquinoline
[0444] Product was isolated by HPLC from the reaction described in
Example 42, Step 14 (1.54 mmol scale), to yield 45.4 mg (4%) of the
desired product as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.34N.sub.2O, 390.3; m/z found, 391.2 [M+H].sup.+.
.sup.1H NMR (MeOH-d.sub.4): 7.37 (m, 2H), 7.32 (m, 2H), 7.18 (br s,
1H), 6.98 (br s, 1H), 6.53 (br s, 1H), 4.56 (br s, 1H), 3.98 (br m,
2H), 3.77 (br s, 1H), 3.66 (br s, 1H), 3.53 (d, J=11.7, 2H), 3.48
(br s, 1H), 3.22 (m, 2H), 2.90 (t, J=12.2, 2H), 2.74 (br s, 1H),
2.15 (br m, 5H), 1.90 (d, J=14.0, 2H), 1.77 (m, 3H), 1.48 (m,
1H).
Example 45
##STR00050##
[0445]
Cis-6-Phenyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline
[0446] Prepared as described in Example 42, Step 14, 0.694 mmol
scale, to yield 15.3 mg (3%) of the desired product as the TFA
salt. .sup.1H NMR (MeOH-d.sub.4): 7.34 (m, 5H), 7.14 (d, J=7.2,
2H), 7.02 (d, J=8.2, 1H), 6.62 (d, J=7.7, 1H), 5.08 (m, 1H), 4.57
(m, 1H), 4.22 (m, 2H), 0.374 (m, 1H), 3.64 (m, 3H), 3.54 (m, 1H),
3.30 (m, 3H), 3.01 (m, 2H), 2.90 (m, 1H), 2.34 (m, 2H), 2.20 (m,
2H), 2.05 (m, 3H), 1.85 (m, 3H), 1.56 (m, 1H), 1.04 (m, 1H).
Example 46
##STR00051##
[0447]
Cis-6-(4-Methoxy-phenyl)-9-[3-(3S-methyl-morpholin-4-yl)-propoxy]-1-
,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0448] Prepared as described in Example 38, Step 8, using
(3S)-methylmorpholine, to give 62.0 mg (12%) of the desired product
as the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.36N.sub.2O.sub.3, 436.3; m/z found, 437.5
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.15 (d, J=8.5, 2H), 6.94
(d, J=8.5, 2H), 6.87 (br d, J=2.0, 1H), 6.80 (dd, J=2.0, 8.8, 1H),
6.72 (d, J=8.5, 1H), 4.84 (m, 1H), 4.33 (dd, J=4.5, 12.0, 1H), 4.11
(t, J=5.5, 2H), 4.00 (m, 2H), 3.85 (m, 2H), 3.79 (s, 3H), 3.56 (m,
4H), 3.31 (m, 6H), 2.82 (m, 1H), 2.27 (m, 5H), 1.33 (d, J=6.5,
3H).
Example 47
##STR00052##
[0449]
Cis-9-[3-(4-Fluoro-piperidin-1-yl)-propoxy]-6-(4-methoxy-phenyl)-1,-
2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0450] Prepared as described in Example 38, Step 8, using
4-fluoropiperidine, to give 77.7 mg (14%) of the desired product as
the TFA salt. MS: exact mass calcd for
C.sub.27H.sub.35FN.sub.2O.sub.2, 438.3; m/z found, 439.3
[M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.15 (d, J=8.5, 2H), 6.94
(d, J=9.0, 2H), 6.87 (d, J=2.5, 1H), 6.79 (dd, J=2.0, 8.8, 1H),
6.72 (d, J=9.0, 1H), 4.98 (m, 1H), 4.84 (m, 1H), 4.34 (dd, J=4.5,
12.0, 1H), 4.09 (t, J=6.0, 2H), 3.86 (m, 1H), 3.79 (s, 3H), 3.68
(m, 1H), 3.56 (m, 2H), 3.32 (m, 6H), 2.82 (m, 1H), 2.24 (m,
8H).
Example 48(A-B)
[0451] ##STR00053## [0452] 48A:
Cis-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-
-hexahydro-pyrrolo[2,1-a]isoquinoline [0453] 48B:
Trans-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(4-Imidazol-1-yl-phenyl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-phen-
yl]-pyrrolidin-1-yl}-ethanone
[0454] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.77 g (>100%) of crude product. MS: exact mass
calcd for C.sub.28H.sub.34N.sub.4O.sub.3, 474.3; m/z found, 475.5
[M+H].sup.+.
Step 2.
6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydr-
o-1H-pyrrolo[2,1-a]isoquinolinylium
[0455] Prepared as described in Example 17, Step 2, on a 3.43 mmol
scale, to give 1.60 g (95%) of crude product. MS: exact mass calcd
for C.sub.28H.sub.31N.sub.4O.sub.2.sup.+, 455.2; m/z found, 455.5
[M].sup.+.
Step 3
[0456] Prepared as described in Example 17, Step 3, on a 3.43 mmol
scale, to give 579 mg (37%) of 48A and 63 mg (4%) of 48B after
column chromatography and HPLC
48A:
Cis-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0457] MS: exact mass calcd for C.sub.26H.sub.33N.sub.4O.sub.2,
458.3; m/z found, 459.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
9.52 (s, 1H), 8.10 (s, 1H), 7.79 (m, 3H), 7.57 (d, J=8.4, 2H), 6.93
(d, J=2.4, 1H), 6.82 (dd, J=1.8, 8.4, 1H), 6.71 (d, J=8.4, 1H),
4.92 (t, J=7.2, 1H), 4.61 (dd, J=4.2, 12.0, 1H), 4.12 (t, J=6.0,
2H), 4.05 (d, J=12.0, 2H), 3.92 (m, 1H), 3.82 (t, J=12.0, 2H), 3.69
(dd, J=4.8, 11.7, 1H), 3.57 (d, J=12.6, 2H), 3.51 (t, J=12.0, 1H),
3.45 (m, 1H), 3.39 (t, J=7.8, 2H),3.18 (m, 2H), 2.87 (m, 1H), 2.30
(br m, 5H).
48B:
Trans-6-(4-Imidazol-1-yl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5-
,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0458] MS: exact mass calcd for C.sub.26H.sub.33N.sub.4O.sub.2,
458.3; m/z found, 459.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
9.47 (s, 1H), 8.06 (s, 1H), 7.77 (s, 1H), 7.73 (d, J=6.0, 2H), 7.44
(br s, 2H), 6.93 (m, 3H), 4.71 (br s, 1H), 4.15 (t, J=5.4, 2H),
4.07 (d, J=12.0, 2H), 3.82 (m, 4H), 3.58 (d, J=11.4, 2H), 3.40 (t,
J=7.8, 2H), 3.21 (br m, 2H), 2.82 (br s, 1H), 2.29 (m, 2H), 2.19
(br s, 2H).
Example 49
##STR00054##
[0459]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-pyrazol-1-yl-phenyl)-1,2,3,5,-
6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-p-
yrazol-1-yl-phenyl)-ethanone
[0460] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.91 g (>100%) of crude product. MS: exact mass
calcd for C.sub.28H.sub.34N.sub.4O.sub.3, 474.3; m/z found, 475.5
[M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-(4-pyrazol-1-yl-phenyl)-2,3-dihydro-
-1H-pyrrolo[2,1-a]isoquinolinylium
[0461] Prepared as described in Example 17, Step 2, on a 3.44 mmol
scale, to give 1.56 g (92%) of crude product. MS: exact mass calcd
for C.sub.28H.sub.31N.sub.4O.sub.2.sup.+, 455.2; m/z found, 455.5
[M].sup.+.
Step 3
[0462] Prepared as described in Example 17, Step 3, on a 3.17 mmol
scale, to give 135 mg (9%) of the desired product after column
chromatography and recrystallization from hot IPA. .sup.1H NMR
(CDCl.sub.3): 7.86 (d, J=2.0, 1H), 7.69 (d, J=1.6, 1H), 7.56 (d,
J=6.8, 2H), 7.30 (d, J=8.4, 2H), 6.81 (d, J=8.4, 1H), 6.69 (d,
J=2.4, 1H), 6.65 (dd, J=2.8, 8.4, 1H), 6.42 (m, 1H), 4.15 (t,
J=4.8, 1H), 3.99 (t, J=6.4, 2H), 3.72 (m, 4H), 3.46 (m, 1H), 3.02
(dd, J=4.8, 11.2, 1H), 2.96 (m, 1H), 2.86 (dd, J=4.8, 11.0, 1H),
2.61-2.46 (br m, 8H), 2.34 (m, 1H), 1.95 (m, 3H), 1.82 (m, 2H).
Example 50(A-B)
[0463] ##STR00055## [0464] 50A:
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinoline [0465] 50B:
Trans-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahydro-
-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyra-
zin-2-yl-ethanone
[0466] Prepared as described in Example 8, Step 1, on a 3.43 mmol
scale, to give 1.40 g (>100%) of crude product. MS: exact mass
calcd for C.sub.23H.sub.30N.sub.4O.sub.3, 410.2; m/z found, 411.4
[M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-2,3-dihydro-1H-pyrrolo-
[2,1-a]isopuinolinylium
[0467] Prepared as described in Example 17, Step 2, on a 3.43 mmol
scale, to give the crude product. MS: exact mass calcd for
C.sub.23H.sub.27N.sub.4O.sub.2.sup.+, 391.2; m/z found, 391.5
[M].sup.+.
Step 3
[0468] Prepared as described in Example 17, Step 3, on a 3.17 mmol
scale, to give 155 mg (11%) of product A and 23 mg (2%) of product
B after column chromatography and HPLC.
50A:
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexahyd-
ro-pyrrolo[2,1-a]isoquinoline
[0469] MS: exact mass calcd for C.sub.23H.sub.30N.sub.4O.sub.2,
394.2; m/z found, 395.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
8.48 (d, J=1.8, 1H), 8.37 (d, J=2.4, 1H), 8.32 (d, J=0.6, 1H), 6.77
(d, J=8.4, 1H), 6.73 (d, J=2.4, 1H), 6.67 (dd, J=2.4, 8.4, 1H),
4.31 (t, J=4.2, 1H), 3.97 (m, 2H), 3.65 (m, 4H), 3.37 (dd, J=7.2,
9.9, 1H), 3.21 (dd, J=4.2, 11.4, 1H), 2.89 (m, 2H), 2.49 (t, J=7.8,
2H), 2.43 (br s, 4H), 2.34 (m, 1H), 1.91 (m, 3H), 1.83-1.73 (m,
2H).
50B:
Trans-9-(3-Morpholin-4-yl-propoxy)-6-pyrazin-2-yl-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
[0470] MS: exact mass calcd for C.sub.23H.sub.30N.sub.4O.sub.2,
394.2; m/z found, 395.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
8.53 (d, J=1.2, 1H), 8.36 (d, J=2.4, 1H), 7.97 (d, J=1.2, 1H), 7.25
(m, 1H), 6.84 (d, J=7.8, 1H), 6.78 (d, J=8.4, 1H), 4.40 (d, J=4.2,
1H), 4.03 (t, J=6.0, 1H), 3.91 (m, 1H), 3.70 (m, 2H), 3.62 (m, 4H),
3.29 (m, 1H), 3.25 (m, 1H), 2.84 (m, 2H), 2.53 (m, 1H), 2.47 (br s,
1H), 2.40 (m, 1H), 2.30 (m, 5H), 1.96 (m, 3H), 1.84 (m, 2H), 1.73
(m, 1H), 1.61 (m, 1H), 1.56 (m, 1H).
Example 51(A-B)
[0471] ##STR00056## [0472] 51A:
Cis-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinolin-6-yl]-pyridin-2-ol [0473] 51B:
Trans-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-
-a]isoquinolin-6-yl]-pyridin-2-ol
Step 1.
1-(6-Hydroxy-pyridin-3-yl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-phen-
yl]-pyrrolidin-1-yl}-ethanone
[0474] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 590 mg (40%) of product after column chromatography.
MS: exact mass calcd for C.sub.24H.sub.31N.sub.3O.sub.4, 425.2; m/z
found, 426.5 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 8.37 (d,
J=2.4, 1H), 7.82 (dd, J=3.0, 9.6, 1H), 7.22 (t, J=7.8, 1H), 6.96
(m, 2H), 6.79 (m, 1H), 6.34 (d, J=10.2, 1H), 4.03 (m, 2H), 3.78 (d,
J=14.4, 1H), 3.60 (m, 4H), 3.41 (t, J=8.4, 1H), 3.27 (m, 1H), 3.25
(d, J=14.4, 1H), 2.47 (t, J=6.6, 2H), 2.38 (m, 5H), 2.19 (m, 1H),
1.92 (m, 3H), 1.84 (m, 1H), 1.73 (m, 1H).
Step 2.
6-(6-Hydroxy-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydr-
o-1H-pyrrolo[2,1-a]isoquinolinylium
[0475] Prepared as described in Example 17, Step 2, on a 1.32 mmol
scale, to give 230 mg (40%) of crude product. MS: exact mass calcd
for C.sub.24H.sub.28N.sub.3O.sub.3.sup.+, 406.2; m/z found, 406.5
[M].sup.+.
Step 3
[0476] Prepared as described in Example 17, Step 3, on a 0.453 mmol
scale, to give 71.9 mg (25%) of 50A and 71.3 mg (25%) of 50B after
column chromatography and HPLC.
51A:
Cis-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2-
,1-a]isoquinolin-6-yl]-pyridin-2-ol
[0477] MS: exact mass calcd for C.sub.24H.sub.31N.sub.3O.sub.3,
409.2; m/z found, 410.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
7.37 (5, 1H), 7.21 (d, J=8.4, 1H), 6.68 (m, 3H), 6.40 (d, J=9.6,
1H), 4.67 (m, 1H), 4.11 (dd, J=4.2, 12.0, 1H), 3.91 (t, J=5.4, 2H),
3.86 (br d, J=12.6, 2H), 3.67 (m, 1H), 3.60 (t, J=12.0, 2H), 3.37
(m, 3H), 3.22 (m, 1H), 3.18 (m, 2H), 2.97 (m, 2H), 2.06 (m,
5H),
51B:
Trans-5-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1-a]isoquinolin-6-yl]-pyridin-2-ol
[0478] MS: exact mass calcd for C.sub.24H.sub.31N.sub.3O.sub.3,
409.2; m/z found, 410.5 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4):
7.32 (br s, 1H), 6.84 (br s, 1H), 6.72 (m, 2H), 6.37 (d, J=9.6,
1H), 4.69 (br s, 1H), 4.18 (br s, 1H), 3.92 (t, J=5.4, 2H), 3.85
(d, J=12.6, 2H), 3.76 (5, 1H), 3.59 (t, J=12.0, 3H), 3.35 (d,
J=12.0, 2H), 3.17 (m, 3H), 2.96 (br t, J=11.4, 2H), 2.55 (br s,
1H), 2.05 (m, 2H), 1.94 (br s, 3H).
Example 52
##STR00057##
[0479]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-5-yl-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thia-
zol-5-yl-ethanone
[0480] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.18 g (81%) of product after column chromatography.
MS: exact mass calcd for C.sub.22H.sub.29N.sub.3O.sub.3S, 415.2;
m/z found, 416.4 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 9.21
(s, 1H), 8.57 (s, 1H), 7.22 (t, J=7.8, 1H), 7.03 (m, 1H), 6.98 (d,
J=7.8, 1H), 6.81 (m, 1H), 5.62 (s, 1H), 4.02 (m, 3H), 3.89 (d,
J=16.2, 1H), 3.60 (m, 5H), 3.52 (t, J=8.4, 1H), 3.38 (d, J=15.6,
1H), 3.30 (m, 1H), 2.45 (m, 9H), 2.22 (m, 1H), 1.90 (m, 5H), 1.78
(m, 1H).
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-thiazol-5-yl-2,3-dihydro-1H-pyrrolo-
[2,1-a]isoquinolinylium
[0481] Prepared as described in Example 17, Step 2, on a 2.77 mmol
scale, to give 680 mg (57%) of crude product. MS: exact mass calcd
for C.sub.22H.sub.26N.sub.3O.sub.2S.sup.+, 396.2; m/z found, 396.4
[M].sup.+.
Step 3
[0482] Prepared as described in Example 17, Step 3, on a 1.57 mmol
scale, to give 538 mg (86%) of product after column chromatography.
MS: exact mass calcd for C.sub.22H.sub.29N.sub.3O.sub.2S, 399.2;
m/z found, 400.4 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 8.63 (s,
1H), 7.72 (s, 1H), 6.90 (s, 1H), 6.62 (m, 2H), 4.39 (s, 1H), 3.90
(m, 2H), 3.61 (m, 4H), 3.24 (m, 1H), 2.97 (m, 2H), 2.75 (dd, J=4.2,
11.4, 1H), 2.38 (m, 7H), 2.30 (m, 1H), 1.80 (m, 4H), 1.66 (m,
1H).
Example 53
##STR00058##
[0483]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiazol-2-yl-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thia-
zol-2-yl-ethanone
[0484] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 680 mg (46%) of product after column chromatography.
MS: exact mass calcd for C.sub.22H.sub.29N.sub.3O.sub.3S, 415.2;
m/z found, 416.4 [M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-thiazol-2-yl-2,3-dihydro-1H-pyrrolo-
[2,1-a]isoquinolinylium
[0485] Prepared as described in Example 17, Step 2, on a 1.64 mmol
scale, to give 1.00 g (>100%) of crude product. MS: exact mass
calcd for C.sub.22H.sub.26N.sub.3O.sub.2S.sup.+, 396.2; m/z found,
396.4 [M].sup.+.
Step 3
[0486] Prepared as described in Example 17, Step 3, on a 1.64 mmol
scale, to give 237 mg (38%) of product after column chromatography.
MS: exact mass calcd for C.sub.22H.sub.29N.sub.3O.sub.2S, 399.2;
m/z found, 400.4 [M+H].sup.+. .sup.1H NMR (MeOH-d.sub.4): 7.58 (d,
J=3.6, 1H), 7.29 (d, J=3.6, 1H), 7.00 (m, 1H), 6.66 (m, 2H), 4.46
(m, 1H), 3.93 (m, 2H), 3.63 (m, 4H), 3.26 (m, 2H), 2.99 (m, 1H),
2.83 (dd, J=4.2, 11.4, 1H), 2.43 (m, 7H), 2.33 (m, 1H), 1.90 (m,
3H), 1.80 (m, 1H), 1.69 (m, 1H),
Example 54
##STR00059##
[0487]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(2H-pyrazol-3-yl)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(2H--
pyrazol-3-yl)-ethanone
[0488] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 940 mg (65%) of product after filtration and
evaporation to dryness. MS: exact mass calcd for
C.sub.22H.sub.30N.sub.4O.sub.3, 398.2; m/z found, 399.5
[M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-(2H-pyrazol-3-yl)-2,3-dihydro-1H-py-
rrolo[2,1-a]isoquinolinylium
[0489] Prepared as described in Example 17, Step 2, on a 2.36 mmol
scale, to give the crude product. MS: exact mass calcd for
C.sub.22H.sub.27N.sub.4O.sub.2.sup.+, 379.2; m/z found, 379.5
[M].sup.+.
Step 3
[0490] Prepared as described in Example 17, Step 3, on a 2.36 mmol
scale, to give 467 mg (52%) of product after column chromatography.
MS: exact mass calcd for C.sub.22H.sub.30N.sub.4O.sub.2, 382.2; m/z
found, 383.5 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 11.56 (br
s, 1H), 7.35 (s, 1H), 7.00 (m, 1H), 6.68 (m, 2H), 6.06 (s, 1H),
4.22 (br s, 1H), 4.01 (m, 2H), 3.59 (m, 4H), 3.22 (m, 2H), 3.10 (br
m, 1H), 2.76 (dd, J=4.2, 11.1, 1H), 2.45 (t, J=7.2, 2H), 2.37 (m,
6H), 1.98 (m, 1H), 1.90 (t, J=7.2, 2H), 1.88 (m, 1H), 1.75 (m,
1H).
Example 55
##STR00060##
[0491]
Cis-6-Imidazo[1,2-a]pyridin-3-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3-
,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-Imidazo[1,2-a]pyridin-3-yl-2-{2-[3-(3-morpholin-4-yl-propoxy)-ph-
enyl]-pyrrolidin-1-yl}-ethanone
[0492] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.38 g (85%) of product after chromatography. MS:
exact mass calcd for C.sub.26H.sub.32N.sub.4O.sub.3, 448.2; m/z
found, 449.5 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 9.55 (d,
J=7.0, 1H), 8.44 (s, 1H), 7.73 (d, J=9.0, 1H), 7.60 (m, 1H), 7.21
(m, 2H), 7.02 (d, J=1.5, 1H), 6.97 (d, J=7.5, 1H), 6.77 (dd, J=2.0,
8.2, 1H), 5.62 (s, 1H), 3.99 (m, 2H), 3.92 (d, J=15.0, 1H), 3.58
(m, 4H), 3.52 (t, J=8.5, 1H), 3.38 (m, 1H), 3.37 (d, J=14.5, 1H),
2.49 (m, 1H), 2.45 (t, J=7.0, 2H), 2.38 (br s, 4H), 2.20 (m, 1H),
1.89 (m, 4H), 1.75 (m, 1H).
Step 2.
6-Imidazo[1,2-a]pyridin-3-yl-9-(3-morpholin-4-yl-propoxy)-2,3-dihy-
dro-1H-pyrrolo[2,1-a]isopuinolinylium
[0493] Prepared as described in Example 17, Step 2, on a 2.94 mmol
scale, to give 1.74 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.29N.sub.4O.sub.2.sup.+, 429.2; m/z
found, 429.3 [M].sup.+.
Step 3
[0494] Prepared as described in Example 17, Step 3, on a 2.94 mmol
scale, to give 652 mg (51%) of product after column chromatography.
MS: exact mass calcd for C.sub.26H.sub.35N.sub.4O.sub.2, 432.2; m/z
found, 433.3 [M+H].sup.+. .sup.1H NMR (acetone-d.sub.6): 8.57 (m,
1H), 7.48 (m, 1H), 7.23 (s, 1H), 7.12 (m, 1H), 6.87 (d, J=9.0, 1H),
6.70 (m, 3H), 4.67 (m, 1H), 4.02 (m, 2H), 3.59 (m, 4H), 3.26 (m,
2H), 2.97 (m, 1H), 2.87 (m, 2H), 2.46 (t, J=6.6, 2H), 2.37 (m, 6H),
1.85 (m, 6H).
Example 56
##STR00061##
[0495]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-3-yl-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thio-
phen-3-yl-ethanone
[0496] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.58 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.23H.sub.30N.sub.2O.sub.3S, 414.2; m/z found,
415.4 [M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-thiophen-3-yl-2,3-dihydro-1H-pyrrol-
o[2,1-a]isopuinolinylium
[0497] Prepared as described in Example 17, Step 2, on a 3.44 mmol
scale, to give 1.34 g (99%) of the crude product. MS: exact mass
calcd for C.sub.23H.sub.30N.sub.2O.sub.3S.sup.+, 395.2; m/z found,
395.4 [M+H].sup.+.
Step 3
[0498] Prepared as described in Example 17, Step 3, on a 3.39 mmol
scale, to give 612 mg (38%) of product after column chromatography.
MS: exact mass calcd for C.sub.23H.sub.30N.sub.2O.sub.2S, 398.2;
m/z found, 399.4 [M+H].sup.+. .sup.1H NMR (500 MHz, MeOH-d.sub.4):
7.47 (m, 1H), 7.39 (m, 1H), 6.94 (m, 1H), 6.91 (m, 1H), 6.80 (m,
2H), 4.60 (m, 1H), 4.11 (m, 2H), 4.05 (m, 2H), 3.83 (m, 3H), 3.57
(m, 3H), 3.49 (m, 1H), 3.37 (m, 4H), 3.18 (m, 2H), 2.84 (m, 1H),
2.26 (m, 5H).
Example 57
##STR00062##
[0499]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-thiophen-2-yl-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-thio-
phen-2-yl-ethanone
[0500] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.83 g (>100% %) of the crude product. MS: exact
mass calcd for C.sub.23H.sub.30N.sub.2O.sub.3S, 414.2; m/z found,
415.4 [M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-thiophen-2-yl-2,3-dihydro-1H-pyrrol-
o[2,1-a]isoquinolinylium
[0501] Prepared as described in Example 17, Step 2, on a 3.44 mmol
scale, to give 1.50 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.23H.sub.30N.sub.2O.sub.3S.sup.+, 395.2; m/z
found, 395.4 [M+H].sup.+.
Step 3
[0502] Prepared as described in Example 17, Step 3, on a 3.44 mmol
scale, to give 370 mg (17% over 3 steps) of product after column
chromatography. MS: exact mass calcd for
C.sub.23H.sub.30N.sub.2O.sub.2S, 398.2; m/z found, 399.5
[M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6): 7.50 (m, 1H),
7.16 (m, 1H), 7.11 (m, 1H), 6.93 (d, J=2.5, 1H), 6.87 (d, J=8.7,
1H), 6.82 (dd, J=2.5, 8.7, 1H), 4.93 (m, 2H), 4.13 (t, J=6.0, 2H),
3.96 (m, 5H), 3.78 (dd, J=4.6, 12.0, 1H), 3.61 (d, J=12.2, 2H),
3.44 (m, 4H), 3.19 (m, 2H), 2.89 (m, 1H), 2.30 (m, 5H).
Example 58
##STR00063##
[0503]
Cis-3-[9-(3-Morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1-a]isoquinolin-6-yl]-benzonitrile
Step 1.
3-(2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ace-
tyl)-benzonitrile
[0504] Prepared as described in Example 8, Step 1, on a 1.72 mmol
scale, to give 0.86 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.31N.sub.3O.sub.3, 433.2; m/z found,
434.5 [M+H].sup.+.
Step 2.
6-(3-Cyano-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihydro-1H-pyr-
rolo[2,1-a]isoquinolinylium
[0505] Prepared as described in Example 17, Step 2, on a 1.72 mmol
scale, to give 0.81 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.28N.sub.3O.sub.2.sup.+, 414.2; m/z
found, 414.5 [M+H].sup.+.
Step 3
[0506] Prepared as described in Example 17, Step 3, on a 1.72 mmol
scale, to give 70 mg (6% over 3 steps) of product after column
chromatography. MS: exact mass calcd for
C.sub.26H.sub.31N.sub.3O.sub.2, 417.2; m/z found, 418.5
[M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6): 7.77 (m, 1H),
7.67 (m, 3H), 6.96 (m, 1H), 6.79 (dd, J=2.5, 8.7, 1H), 6.62 (d,
J=8.6, 1H), 4.93 (m, 1H), 4.73 (m, 1H), 4.13 (t, J=6.0, 2H), 3.94
(m, 5H), 3.72 (m, 1H), 3.59 (m, 3H), 3.40 (m, 3H), 3.14 (m, 2H),
2.89 (m, 1H), 2.33 (m, 5H).
Example 59
##STR00064##
[0507]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-3-yl-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyri-
din-3-yl-ethanone
[0508] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.52 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.24H.sub.31N.sub.3O.sub.3, 409.2; m/z found,
410.5 [M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-pyridin-3-yl-2,3-dihydro-1H-pyrrolo-
[2,1-a]isoquinolinylium
[0509] Prepared as described in Example 17, Step 2, on a 3.44 mmol
scale, to give 1.00 g (75%) of the crude product. MS: exact mass
calcd for C.sub.24H.sub.28N.sub.3O.sub.2.sup.+, 390.2; m/z found,
390.4 [M+H].sup.+.
Step 3
[0510] Prepared as described in Example 17, Step 3, on a 2.56 mmol
scale, to give 285 mg (18%) of product after column chromatography.
MS: exact mass calcd for C.sub.24H.sub.31N.sub.3O.sub.2, 393.2; m/z
found, 394.5 [M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6):
8.50 (m, 1H), 8.34 (dd, J=1.6, 4.7, 1H), 7.59 (m, 1H), 7.17 (m,
1H), 6.81 (d, J=8.5, 1H), 6.72 (m, 1H), 6.67 (dd, J=2.6, 8.5, 1H),
4.13 (m, 1H), 4.01 (m, 2H), 3.58 (m, 4H), 3.15 (m, 1H), 3.07 (m,
1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.38 (m, 8H), 1.88 (m, 4H), 1.74
(m, 1H).
Example 60
##STR00065##
[0511]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-pyridin-2-yl-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-pyri-
din-2-yl-ethanone
[0512] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.61 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.24H.sub.31N.sub.3O.sub.3, 409.2; m/z found,
410.5 [M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-pyridin-2-yl-2,3-dihydro-1H-pyrrolo-
[2,1-a]isoquinolinylium
[0513] Prepared as described in Example 17, Step 2, on a 3.44 mmol
scale, to give 1.34 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.24H.sub.28N.sub.3O.sub.2.sup.+, 390.2; m/z
found, 390.5 [M+H].sup.+.
Step 3
[0514] Prepared as described in Example 17, Step 3, on a 3.44 mmol
scale, to give 200 mg (13% over 3 steps) of product after column
chromatography. MS: exact mass calcd for
C.sub.24H.sub.31N.sub.3O.sub.2, 393.2; m/z found, 394.5
[M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6): 8.47 (m, 1H),
7.53 (m, 1H), 7.10 (m, 2H), 6.88 (d, J=11.3, 1H), 6.70 (m, 2H),
4.22 (m, 1H), 4.02 (m, 2H), 3.58 (m, 4H), 3.28 (dd, J=2.2, 11.2,
1H), 3.16 (m, 1H), 2.91 (m, 1H), 2.79 (m, 1H), 2.39 (m, 8H), 1.85
(m, 4H), 1.69 (m, 1H).
Example 61
##STR00066##
[0515]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(4-trifluoromethylsulfanyl-pheny-
l)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-t-
rifluoromethylsulfanyl-phenyl)-ethanone
[0516] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 2.10 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.28F.sub.3N.sub.2O.sub.3S, 508.2; m/z
found, 509.4 [M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-(4-trifluoromethylsulfanyl-phenyl)--
2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium
[0517] Prepared as described in Example 17, Step 2, on a 3.34 mmol
scale, to give 2.30 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.28F.sub.3N.sub.2O.sub.2S.sup.+, 489.2;
m/z found, 489.4 [M+H].sup.+.
Step 3
[0518] Prepared as described in Example 17, Step 3, on a 3.34 mmol
scale, to give 568 mg (24% over 3 steps) of product after column
chromatography. MS: exact mass calcd for
C.sub.26H.sub.31F.sub.3N.sub.2O.sub.2S, 492.2; m/z found, 493.4
[M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6): 7.75 (d,
J=8.1, 2H), 7.47 (d, J=8.1, 2H), 6.96 (m, 1H), 6.80 (dd, J=2.5,
8.6, 1H), 6.61 (d, J=10.9, 1H), 4.93 (m, 1H), 4.69 (dd, J=4.6,
12.0, 1H), 4.14 (t, J=6.0, 2H), 3.95 (m, 5H), 3.72 (m, 1H), 3.61
(m, 2H), 3.51 (m, 1H), 3.41 (m, 3H), 3.18 (m, 2H), 2.88 (m, 1H),
2.30 (m, 5H).
Example 62
##STR00067##
[0519]
Cis-9-(3-Morpholin-4-yl-propoxy)-6-(3-trifluoromethylsulfanyl-pheny-
l)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Morpholin-4-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(3-t-
rifluoromethylsulfanyl-phenyl)-ethanone
[0520] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 2.00 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.31F.sub.3N.sub.2O.sub.3S, 508.2; m/z
found, 509.4 [M+H].sup.+.
Step 2.
9-(3-Morpholin-4-yl-propoxy)-6-(3-trifluoromethylsulfanyl-phenyl)--
2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium
[0521] Prepared as described in Example 17, Step 2, on a 3.44 mmol
scale, to give 1.80 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.28F.sub.3N.sub.2O.sub.2S.sup.+, 489.2;
m/z found, 489.4 [M+H].sup.+.
Step 3
[0522] Prepared as described in Example 17, Step 3, on a 3.44 mmol
scale, to give 247 mg (10% over 3 steps) of product after column
chromatography. MS: exact mass calcd for
C.sub.26H.sub.31F.sub.3N.sub.2O.sub.2S, 492.2; m/z found, 493.5
[M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6): 7.83 (d,
J=16.7, 1H), 7.66 (5, 1H), 7.58 (m, 2H), 6.97 (m, 1H), 6.79 (dd,
J=2.6, 8.7, 1H), 6.62 (d, J=8.6, 1H), 4.92 (m, 1H), 4.70 (m, 1H),
4.14 (m, 2H), 3.95 (m, 5H), 3.74 (m, 1H), 3.59 (m, 3H), 3.41 (m,
3H), 3.17 (m, 2H), 2.90 (m, 1H), 2.31 (m, 5H).
Example 63
##STR00068##
[0523]
Cis-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,-
5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(4-Methylsulfanyl-phenyl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-phe-
nyl]-pyrrolidin-1-yl}-ethanone
[0524] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.95 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.34N.sub.2O.sub.3S, 454.2; m/z found,
455.5 [M+H].sup.+.
Step 2.
6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dihyd-
ro-1H-pyrrolo[2,1-a]isoquinolinylium
[0525] Prepared as described in Example 17, Step 2, on a 3.44 mmol
scale, to give 1.45 g (97%) of the crude product. MS: exact mass
calcd for C.sub.26H.sub.31N.sub.2O.sub.2S.sup.+, 435.2; m/z found,
435.4 [M+H].sup.+.
Step 3
[0526] Prepared as described in Example 17, Step 3, on a 3.33 mmol
scale, to give 82 mg (4%) of product after column chromatography.
MS: exact mass calcd for C.sub.26H.sub.34N.sub.2O.sub.2S, 438.2;
m/z found, 439.5 [M+H].sup.+. .sup.1H NMR (500 MHz,
acetone-d.sub.6): 7.29 (d, J=8.4, 2H), 7.21 (d, J=8.3, 2H), 6.94
(m, 1H), 6.78 (m, 1H), 6.66 (d, J=8.7, 1H), 4.92 (m, 1H), 4.53 (m,
1H), 4.13 (t, J=6.0, 2H), 3.94 (m, 5H), 3.63 (m, 3H), 3.43 (m, 4H),
3.16 (m, 2H), 2.89 (m, 1H), 2.49 (5, 3H), 2.30 (m, 5H).
Example 64
##STR00069##
[0527]
Cis-6-(3-Chloro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,-
3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(3-Chloro-4-methoxy-phenyl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-p-
henyl]-pyrrolidin-1-yl}-ethanone
[0528] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.92 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.33ClN.sub.2O.sub.4, 472.2; m/z found,
473.5 [M+H].sup.+.
Step 2.
6-(3-Chloro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dih-
ydro-1H-pyrrolo[2,1-a]isoquinolinylium
[0529] Prepared as described in Example 17, Step 2, on a 3.44 mmol
scale, to give 1.85 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.30ClN.sub.2O.sub.3.sup.+, 453.2; m/z
found, 453.4 [M+H].sup.+.
Step 3
[0530] Prepared as described in Example 17, Step 3, on a 3.44 mmol
scale, to give 340 mg (14% over 3 steps) of product after column
chromatography. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O.sub.3, 456.2; m/z found, 457.5
[M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6): 7.26 (m, 2H),
7.14 (d, J=8.4, 1H), 6.94 (m, 1H), 6.79 (dd, J=2.5, 8.7, 1H), 6.68
(d, J=8.7, 1H), 4.91 (m, 1H), 4.53 (dd, J=4.6, 12.1, 1H), 4.13 (t,
J=6.0, 2H), 3.99 (m, 2H), 3.90 (m, 7H), 3.64 (m, 3H), 3.50 (m, 1H),
3.40 (m, 3H), 3.17 (m, 2H), 2.88 (m, 1H), 2.34 (m, 5H), 2.25 (m,
1H).
Example 65
##STR00070##
[0531]
Cis-6-(3-Fluoro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,-
3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(3-Chloro-4-fluoro-phenyl)-2-{2-[3-(3-morpholin-4-yl-propoxy)-ph-
enyl]-pyrrolidin-1-yl}-ethanone
[0532] Prepared as described in Example 8, Step 1, on a 3.44 mmol
scale, to give 1.80 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.33FN.sub.2O.sub.4, 456.2; m/z found,
457.5 [M+H].sup.+.
Step 2.
6-(3-Fluoro-4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-2,3-dih-
ydro-1H-pyrrolo[2,1-a]isoquinolinylium
[0533] Prepared as described in Example 17, Step 2, on a 3.44 mmol
scale, to give 1.50 g (>100%) of the crude product. MS: exact
mass calcd for C.sub.26H.sub.30FN.sub.2O.sub.3.sup.+, 437.2; m/z
found, 437.4 [M+H].sup.+.
Step 3
[0534] Prepared as described in Example 17, Step 3, on a 3.44 mmol
scale, to give 415 mg (18% over 3 steps) of product after column
chromatography. MS: exact mass calcd for
C.sub.26H.sub.33FN.sub.2O.sub.3, 440.3; m/z found, 441.5
[M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6): 7.15 (m, 1H),
7.09 (m, 1H), 7.02 (dd, J=1.9, 12.4, 1H), 6.93 (m, 1H), 6.79 (dd,
J=2.5, 8.7, 1H), 6.68 (d, J=8.7, 1H), 4.90 (m, 1H), 4.52 (dd,
J=4.5, 12.0, 1H), 4.13 (t, J=6.0, 2H), 3.93 (m, 8H), 3.63 (m, 3H),
3.44 (m, 1H), 3.39 (m, 3H), 3.15 (m, 2H), 2.88 (m, 1H), 2.33 (m,
5H).
Example 66-(A-B)
[0535] ##STR00071## [0536] 66A:
Cis-6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline [0537] 66B:
Trans-6-(4-chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexa-
hydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-(4-Chloro-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyr-
rolidin-1-yl}-ethanol
[0538] Prepared as described in Example 1, Step 6, on a 3.47 mmol
scale to give 1.70 g (>100%) of the desired product as a mixture
of diastereomers. MS: exact mass calcd for
C.sub.26H.sub.36ClN.sub.2O.sub.2, 476.3; m/z found, 477.4
[M+H].sup.+.
Step 2
[0539] Performed as described in Example 1, Step 7, on a 3.19 mmol
scale, to give the desired products 66A and 66B, which were
separated by HPLC.
66A:
6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline
[0540] 8.0 mg (0.4%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O, 424.2; m/z found, 425.4 [M+H].sup.+.
.sup.1H NMR (500 MHz, acetone-d.sub.6): 7.44 (d, J=8.4, 2H), 7.33
(d, J=8.3, 2H), 6.96 (s, 1H), 6.80 (d, 8.7, 1H), 6.66 (d, J=8.7,
1H), 4.92 (m, 1H), 4.62 (m, 1H), 4.13 (m, 2H), 3.95 (m, 1H), 3.65
(m, 3H), 3.46 (m, 1H), 3.40 (m, 1H), 3.33 (m, 2H), 2.91 (m, 3H),
2.34 (m, 5H), 1.90 (m, 4H), 1.81 (m, 1H), 1.52 (m, 1H).
66B:
6-(4-Chloro-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline
[0541] 205 mg (9%) as the TFA salt. MS: exact mass calcd for
C.sub.26H.sub.33ClN.sub.2O, 424.2; m/z found, 425.4 [M+H].sup.+.
.sup.1H NMR (500 MHz, acetone-d.sub.6): 7.40 (d, J=8.8, 2H), 7.29
(d, J=8.4, 2H), 6.99 (br s, 1H), 6.86 (dd, J=2.5, 8.6, 1H), 6.82
(d, J=8.7, 1H), 5.14 (br s, 1H), 4.64 (br s, 1H), 4.17 (m, 2H),
3.81 (br s, 1H), 3.65 (m, 4H), 3.53 (br s, 1H), 3.34 (m, 2H), 2.99
(m, 2H), 2.77 (br s, 1H), 2.35-2.32 (m, 2H), 2.20 (m, 2H), 2.10 (m,
1H), 1.92 (m, 4H), 1.80 (m, 1H), 1.54 (m, 1H).
Example 67
##STR00072##
[0542]
Cis-9-(3-Piperidin-1-yl-propoxy)-6-(3-trifluoromethyl-phenyl)-1,2,3-
,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
2-{2-[3-(3-Piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-1-(3-t-
rifluoromethyl-phenyl)-ethanol
[0543] Prepared as described in Example 1, Step 6, on a 3.47 mmol
scale to give 1.52 g (92%) of product. MS: exact mass calcd for
C.sub.27H.sub.35F.sub.3N.sub.2O.sub.2, 476.3; m/z found, 477.4
[M+H].sup.+.
Step 2
[0544] Performed as described in Example 1, Step 7, on a 3.19 mmol
scale to give 36.0 mg (2%) of product after chromatography. MS:
exact mass calcd for C.sub.27H.sub.33F.sub.3N.sub.2O, 458.3; m/z
found, 459.5 [M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6):
7.90 (m, 1H), 7.82 (m, 3H), 7.13 (s, 1H), 6.95 (d, J=8.6, 1H), 6.78
(d, 8.7, 1H), 5.09 (m, 1H), 4.91 (m, 1H), 4.28 (t, J=5.8, 2H), 3.90
(m, 1H), 3.88 (m, 1H), 3.76 (m, 3H), 3.57 (m, 1H), 3.48 (m, 2H),
3.14 (m, 2H), 3.05 (m, 1H), 2.46 (m, 4H), 2.21 (m, 1H), 2.05 (m,
4H), 1.95 (m, 1H), 1.66 (m, 1H).
[0545] The following compounds in Examples 68-87 may be prepared
according to the methods described above.
Example 68
##STR00073##
[0546]
6-Biphenyl-4-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydr-
o-pyrrolo[2,1-a]isoquinoline
Example 69
##STR00074##
[0547]
9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-2-yl-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline
Example 70
##STR00075##
[0548]
9-(3-Morpholin-4-yl-propoxy)-6-quinolin-7-yl-1,2,3,5,6,10b-hexahydr-
o-pyrrolo[2,1-a]isoquinoline
Example 71
##STR00076##
[0549]
6-(1H-Indol-5-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline
Example 72
##STR00077##
[0550]
6-(1H-Benzoimidazol-5-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline
Example 73
##STR00078##
[0551]
6-(1H-Benzoimidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline
Example 74
##STR00079##
[0552]
6-(1-Methyl-1H-benzoimidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2-
,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Example 75
##STR00080##
[0553]
9-(3-Morpholin-4-yl-propoxy)-6-naphthalen-1-yl-1,2,3,5,6,10b-hexahy-
dro-pyrrolo[2,1-a]isoquinoline
Example 76
##STR00081##
[0554]
6-Benzo[b]thiophen-7-yl-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
Example 77
##STR00082##
[0555]
6-(6-Chloro-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline
Example 78
##STR00083##
[0556]
Dimethyl-{5-[9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexahydro-p-
yrrolo[2,1-a]isoquinolin-6-yl]-pyridin-2-yl}-amine
Example 79
##STR00084##
[0557]
6-(6-Methoxy-pyridin-3-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline
Example 80
##STR00085##
[0558]
9-(3-Morpholin-4-yl-propoxy)-6-oxazol-5-yl-1,2,3,5,6,10b-hexahydro--
pyrrolo[2,1-a]isoquinoline
Example 81
##STR00086##
[0559]
6-(1H-Imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline
Example 82
##STR00087##
[0560]
6-(1-Methyl-1H-imidazol-2-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,-
6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Example 83
##STR00088##
[0561]
6-(3H-Imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hex-
ahydro-pyrrolo[2,1-a]isoquinoline
Example 84
##STR00089##
[0562]
6-(3-Methyl-3H-imidazol-4-yl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,-
6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Example 85
##STR00090##
[0563]
6-(3-Chloro-4-difluoromethoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)--
1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Example 86
##STR00091##
[0564]
(4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]i-
soquinolin-9-yloxy]-propyl}-morpholin-2-yl)-methanol
Example 87
##STR00092##
[0565]
(4-{3-[6-(4-Methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]i-
soquinolin-9-yloxy]-propyl}-morpholin-3-yl)-methanol
Example 88
##STR00093##
[0566]
6-(3,5-Bis-trifluoromethyl-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2-
,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Example 89
##STR00094##
[0567]
(1R,6S)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,-
2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0568] Separation of the enantiomers from racemic
cis-6-(4-methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline gave the title compound and
Example 90. MS: exact mass calcd for
C.sub.26H.sub.34N.sub.2O.sub.2S, 438.23; m/z found, 439.2
[M+H].sup.+.
Example 90
##STR00095##
[0569]
(1S,6R)-6-(4-Methylsulfanyl-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,-
2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0570] MS: exact mass calcd for C.sub.26H.sub.34N.sub.2O.sub.2S,
438.23; m/z found, 439.2 [M+H].sup.+.
Example 91
##STR00096##
[0571]
(1S,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0572] Separation of the enantiomers from racemic
cis-6-(4-methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,10b-hexah-
ydro-pyrrolo[2,1-a]isoquinoline gave the title compound and Example
92. MS: exact mass calcd for C.sub.26H.sub.34N.sub.2O.sub.3,
422.26; m/z found, 423.5 [M+H].sup.+.
Example 92
##STR00097##
[0573]
(1R,65)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0574] MS: exact mass calcd for C.sub.26H.sub.34N.sub.2O.sub.3,
422.26; m/z found, 423.5 [M+H].sup.+.
Example 93
##STR00098##
[0575]
Trans-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6,1-
0b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0576] The title compound was prepared as described in the
preceding examples. The racemic material was separated by chiral
HPLC to provide Examples 94 and 95. MS: exact mass calcd for
C.sub.26H.sub.34N.sub.2O.sub.3, 422.26; m/z found, 423.5
[M+H].sup.+.
Example 94
##STR00099##
[0577]
(1R,6R)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0578] MS: exact mass calcd for C.sub.26H.sub.34N.sub.2O.sub.3,
422.26; m/z found, 423.5 [M+H].sup.+.
Example 95
##STR00100##
[0579]
(1S,6S)-6-(4-Methoxy-phenyl)-9-(3-morpholin-4-yl-propoxy)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0580] MS: exact mass calcd for C.sub.26H.sub.34N.sub.2O.sub.3,
422.26; m/z found, 423.5 [M+H].sup.+.
Example 96-(A-B)
[0581] ##STR00101## [0582] 96A:
Cis-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b-he-
xahydro-pyrrolo[2,1-a]isoquinoline [0583] 96B:
Trans-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10b--
hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1. 5-(3-Bromo-phenyl)-3,4-dihydro-2H-pyrrole
[0584] Prepared as described in Example 1, Step 4, on a 0.19 mol
scale, using 3 N HCl in place of 12 N HCl during the workup
procedure, to give 47.4 g of the desired product. MS (ESI): exact
mass calcd for C.sub.10H.sub.10BrN, 223.0; m/z found, 224.0
[M+].sup.+, 226.0 [M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6):
8.00 (m, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.65 (m, 1H), 7.41 (m, 1H),
3.97 (t, J=6.9 Hz, 2H), 2.91 (t, J=7.7 Hz, 2H), 1.93 (m, 2H).
Step 2. 2-(3-Bromo-phenyl)-pyrrolidine
[0585] A solution of 5-(3-bromo-phenyl)-3,4-dihydro-2H-pyrrole
(0.21 mol) in absolute ethanol (1.2 M) was treated portionwise with
NaBH.sub.4 (1.0 equiv.). The resultant mixture was stirred at room
temperature overnight. The mixture was cooled to 0.degree. C. and
slowly quenched with 1 N HCl. The mixture was acidified to a pH of
1 with 3 N HCl and was stirred at room temperature for 45 min. The
resulting mixture was again cooled to 0.degree. C., and was treated
with 1 N NaOH until basic. The aqueous mixture was extracted with
CH.sub.2Cl.sub.2 (.times.3). The combined extracts were washed with
brine, dried (MgSO.sub.4), filtered and concentrated to give the
crude product. Chromatography (EtOAc/hexanes) gave 39.8 g (84%) of
the desired product. MS (ESI): exact mass calcd for
C.sub.10H.sub.12BrN, 225.1; m/z found, 226.0 [M+H].sup.+, 228.0
[M+H].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6): 7.74 (m, 1H),
7.57 (m, 1H), 7.53 (m, 1H), 7.40 (m, 1H), 4.37 (m, 1H), 3.24 (m,
1H), 3.16 (m, 1H), 2.32 (m, 1H), 2.00 (m, 1H), 1.94 (m, 1H), 1.81
(m, 1H).
Step 3.
2-[2-(3-Bromo-phenyl)-pyrrolidin-1-yl]-1-(4-methoxy-phenyl)-ethano-
ne
[0586] To a solution of 2-(3-bromo-phenyl)-pyrrolidine (3.8 g, 16.8
mmol) and Hunig's base (5.9 mL, 33.6 mmol) in THF (170 mL) was
added 2-bromo-1-(4-methoxy-phenyl)-ethanone (4.6 g, 20.2 mmol). The
mixture was stirred at room temperature for 5 h, concentrated, and
purified by normal phase column chromatography (NH.sub.3 in
MeOH/CH.sub.2Cl.sub.2) to give 4.75 g (75%) of the product as a
yellow oil. MS (ESI): exact mass calcd for
C.sub.19H.sub.20BrNO.sub.2, 373.1; m/z found, 374.3 [M+H].sup.+,
376.3 [M+H].sup.+. .sup.1H NMR (500 MHz, CDCl.sub.3): 7.84 (d,
J=9.0 Hz, 2H), 7.58 (m, 1H), 7.38 (m, 1H), 7.31 (m, 1H), 7.18 (m,
1H), 6.87 (d, J=9.0 Hz, 2H), 3.99 (d, J=15.6 Hz, 1H), 3.85 (s, 3H),
3.50 (t, J=8.1 Hz, 1H), 3.39 (m, 1H), 2.42 (m, 1H), 2.21 (m, 1H),
1.97 (m, 1H), 1.86 (m, 1H), 1.73 (m, 1H), 1.61 (s, 1H).
Step 4.
2-[2-(3-Bromo-phenyl)-pyrrolidin-1-yl]-1-(4-methoxy-phenyl)-ethano-
l
[0587] Prepared as described in Example 8, Step 2, on a 6.68 mmol
scale, to give 2.26 g (90%) of the crude product as a mixture of
diastereomers. MS (ESI): exact mass calcd for
C.sub.19H.sub.22BrNO.sub.2, 375.1; m/z found, 376.3 [M+H].sup.+,
378.3 [M+H].sup.+.
Step 5.
9-Bromo-6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a-
]isoquinoline and
7-Bromo-6-(4-methoxy-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoqui-
noline
[0588] Prepared as described in Example 1, Step 7, to give a 48%
combined yield (over 2 steps) of the two regioisomers, each as a
set of two diastereomers. MS (ESI): exact mass calcd for
C.sub.19H.sub.20BrNO, 357.1, m/z found, 358.3 [M+H].sup.+, 360.3
[M+H].sup.+.
Step 6
[0589] Performed on the mixture of isomers from Step 5 as described
in Example 33, on a 1.73 mmol scale, using 1-but-3-ynylpiperidine,
to give a 20% combined yield of two diastereomers. After HPLC
purification, the products were converted from their TFA salts to
their corresponding HCl salts by azeotrope (3.times.) with HCl in
dioxane.
96A:
Cis-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,10-
b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0590] 15.0 mg (2%) as the HCl salt. MS (ESI): exact mass calcd for
C.sub.26H.sub.34N.sub.2O, 414.3; m/z found, 415.5 [M+H].sup.+.
.sup.1H NMR (500 MHz, acetone-d.sub.6): 7.45 (br s, 1H), 7.26 (d,
J=7.8 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 6.80
(d, J=7.9 Hz, 1H), 4.46 (d, 1H), 3.90 (m, 1H), 3.81 (s, 3H), 3.76
(m, 1H), 3.44 (m, 4H), 3.04 (m, 5H), 2.87 (br s, 1H), 2.22 (m, 3H),
2.00 (m, 3H), 1.86 (m, 4H), 1.56 (m, 1H).
96B:
Trans-6-(4-methoxy-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6,-
10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0591] 31.0 mg (4% yield) as the HCl salt. MS (ESI): exact mass
calcd for C.sub.26H.sub.34N.sub.2O, 414.3; m/z found, 415.5
[M+H].sup.+.
Example 97-(A-B)
[0592] ##STR00102## [0593] 97A:
Cis-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline [0594] 97B:
Trans-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5-
,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1. 5-(4-Bromo-phenyl)-3,4-dihydro-2H-pyrrole
[0595] Prepared as described in Example 39, Step 1, on a 93.0 mmol
scale, to give 14.1 g (68%) of the desired product. MS (ESI): exact
mass calcd for C.sub.10H.sub.10BrN, 223.0; m/z found, 224.0, 226.0
[M+H].sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6): 7.73 (d, J=8.5
Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 3.91 (2H), 2.86 (m, 2H), 1.91 (m,
2H).
Step 2. 2-(4-Bromo-phenyl)-pyrrolidine
[0596] Prepared as described in Example 39, Step 2, on a 87.2 mmol
scale, to give 12.9 g (65%) of the desired product. MS (ESI): exact
mass calcd for C.sub.10H.sub.12BrN, 225.0; m/z found, 226.1
[M+H].sup.+, 228.1 [M+H].sup.+. .sup.1H NMR (500 MHz,
DMSO-d.sub.6): 7.44 (m, 2H), 7.30 (d, J=6.6 Hz, 2H), 3.99 (m, 1H),
2.96 (m, 1H), 2.88 (m, 1H), 2.31 (br s, 1H), 2.07 (m, 1H), 1.70 (m,
2H), 1.40 (m, 1H).
Step 3.
1-[2-(4-Bromo-phenyl)-pyrrolidin-1-yl]-2-hydroxy-2-(4-methylsulfan-
yl-phenyl)-ethanone
[0597] A solution of 2-(4-bromo-phenyl)-pyrrolidine (16.8 mmol, 1.0
equiv.) and hydroxy-(4-methylsulfanyl-phenyl)-acetic acid (1.0
equiv.) in xylenes (0.2 M) was heated at reflux for 3 d under
nitrogen. The bulk of the xylenes was removed by distillation and
the residue was purified by chromatography to give the desired
product as a mixture of diastereomers (5.22 g, 77%). MS (ESI):
exact mass calcd for C.sub.19H.sub.20BrNO.sub.2S, 405.0; m/z found,
406.0 [M+H].sup.+, 408.0 [M+H].sup.+.
Step 4. Cis- and
Trans-8-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo-
[2,1-a]isopuinolin-5-one
[0598] A solution of amide from Step 3 (12.1 mmol) and
polyphosphoric acid (5 g/g amide) was heated at 105.degree. C.
under nitrogen until the starting material was consumed (2 h). The
reaction mixture was poured into water and extracted with
CH.sub.2Cl.sub.2 (.times.2). The combined extracts were washed with
satd. aq. NaHCO.sub.3 and brine, dried (MgSO.sub.4), and
concentrated to provide the crude product. The diastereomers were
separated by chromatographic purification (EtOAc/Hexanes).
Cis-8-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,-
1-a]isoquinolin-5-one
[0599] 1.39 g (30%). MS (ESI): exact mass calcd for
C.sub.19H.sub.18BrNOS, 387.0; m/z found, 388.0 [M+H].sup.+, 390.0
[M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6): 7.40 (m, 2H),
7.18 (d, J=8.0 Hz, 1H), 7.02 (m, 2H), 6.93 (d, J=8.2 Hz, 2H), 4.61
(s, 1H), 4.44 (m, 1H), 3.34 (m, 2H), 2.56 (m, 1H), 2.28 (s, 3H),
1.92 (m, 2H), 1.81 (m, 1H), 1.68 (m, 1H).
Trans-8-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[-
2,1-a]isopuinolin-5-one
[0600] 849.4 mg (18%). MS (ESI): exact mass calcd for
C.sub.19H.sub.18BrNOS, 387.0; m/z found, 388.0 [M+H].sup.+, 390.0
[M+H].sup.+. .sup.1H NMR (500 MHz, acetone-d.sub.6): 7.36 (m, 1H),
7.21 (m, 3H), 7.07 (m, 2H), 6.60 (m, 1H), 4.62 (m, 1H), 3.49 (m,
1H), 3.37 (m, 1H), 2.66 (m, 1H), 2.44 (s, 3H), 1.97 (m, 4H).
Step 5. Cis- and
Trans-8-bromo-6-(4-methylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo-
[2,1-a]isopuinoline
[0601] To a 0.degree. C. solution of BH.sub.3.THF (1 M in THF, 2.5
equiv.) was added a solution of cis-amino-ketone (Step 4, 3.45
mmol, 1 equiv.) in THF (2 M) and the resulting solution was heated
at reflux for 1 h. The mixture was cooled to room temperature,
quenched with water, and acidified with 12 N HCl. The THF was
removed in vacuo and the aqueous mixture was heated at reflux for
15 min. The reaction mixture was again cooled to room temperature,
made basic with 3 N NaOH, and extracted with CH.sub.2Cl.sub.2. The
organic extract was washed with brine, dried (MgSO.sub.4), and
concentrated to give the crude products. A small portion of the
crude product was purified by Gilson to give analytically pure
products. The bulk of the material was carried forward without
purification.
Cis-8-bromo-6-(4-methylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,-
1-a]isoquinoline
[0602] 1.21 g (94%) as the TFA salt. MS (ESI): exact mass calcd for
C.sub.19H.sub.20BrNS, 373.1; m/z found, 374.0 [M+H].sup.+, 376.0
[M+H].sup.+. .sup.1H NMR (500 MHz, MeOH-d.sub.4): 7.54 (d, J=8.0
Hz, 1H), 7.28 (m, 3H), 7.17 (br s, 1H), 7.09 (br s, 2H), 4.56 (br
s, 1H), 3.70 (br m, 3H), 3.43 (br s, 1H), 2.76 (br s, 1H), 2.49 (s,
3H), 2.16 (br s, 3H).
Trans-8-bromo-6-(4-methylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[-
2,1-a]isoquinoline
[0603] Prepared as described for the cis isomer, on a 0.856 mmol
scale, to give 119.5 mg (37%) of the desired product as the TFA
salt. MS (ESI): exact mass calcd for C.sub.19H.sub.20BrNS, 373.1;
m/z found, 374.0 [M+H].sup.+, 376.0 [M+H].sup.+.
Step 6
[0604] Prepared on the cis-isomer from Step 5, as described in
Example 33, on a 0.267 mmol scale. After the reaction was complete,
the reaction mixture was diluted with diethyl ether, washed with
water (.times.2), and filtered through a pad of diatomaceous earth.
The filtrate was dried (Na.sub.2CO.sub.3) and concentrated to
provide the crude product. Purification by reverse-phase HPLC
afforded 22.1 mg (12%) of the desired product as the TFA salt.
97A:
Cis-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2,3-
,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0605] MS (ESI): exact mass calcd for C.sub.28H.sub.34N.sub.2S,
430.2; m/z found, 431.2 [M+H].sup.+. .sup.1H NMR (500 MHz,
MeOH-d.sub.4): 7.40 (d, J=7.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.27
(d, J=8.4 Hz, 2H), 7.10 (br s, 2H), 7.02 (br s, 1H), 4.54 (br s,
1H), 3.74 (br s, 3H), 3.56 (d, J=12.1 Hz, 2H), 3.30 (m, 3H), 2.96
(m, 2H), 2.90 (m, 2H), 2.78 (br s, 1H), 2.47 (s, 3H), 2.15 (br s,
3H), 1.92 (d, J=14.6 Hz, 2H), 1.80 (m, 3H), 1.49 (m, 1H).
97B:
Trans-6-(4-methylsulfanyl-phenyl)-8-(4-piperidin-1-yl-but-1-ynyl)-1,2-
,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0606] Prepared as described for the cis-isomer above, on a 0.0751
mmol scale, to give 34.4 mg (66%) of the desired product as the TFA
salt. MS (ESI): exact mass calcd for C.sub.28H.sub.34N.sub.2S,
430.2; m/z found, 431.2 [M+H].sup.+. .sup.1H NMR (400 MHz,
MeOH-d.sub.4): 7.33 (d, J=8.1 Hz, 1H), 7.29 (m, 3H), 7.17 (d, J=8.2
Hz, 2H), 6.79 (s, 1H), 4.36 (m, 1H), 3.86 (m, 1H), 3.44 (m, 5H),
3.26 (m, 3H), 2.90 (m, 5H), 2.47 (s, 3H), 2.25 (m, 3H), 1.87 (d,
J=14.6 Hz, 2H), 1.68 (m, 3H), 1.44 (m, 1H).
Example 98-(A-B)
[0607] ##STR00103## [0608] 98A:
Cis-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5,6-
,10b-hexahydro-pyrrolo[2,1-a]isoquinoline [0609] 98B:
Trans-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3,5-
,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
Step 1.
1-[2-(3-Bromo-phenyl)-pyrrolidin-1-yl]-2-hydroxy-2-(4-methylsulfan-
yl-phenyl)-ethanone
[0610] A mixture of 2-(3-bromo-phenyl)-pyrrolidine (1.01 mmol, 1.0
equiv.), hydroxy-(4-methylsulfanyl-phenyl)-acetic acid (1.05
equiv.), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU, 1.2 equiv.), and Hunig's base (1.5
equiv.) in CH.sub.2Cl.sub.2 (0.2 M) was stirred at room temperature
overnight under nitrogen. The reaction mixture was filtered to
remove a white precipitate and the filtrate was washed with 1 N
HCl, water, 1 N NaOH, water, and brine, dried (MgSO.sub.4), and
concentrated to give the crude product as a mixture of
diastereomers. The crude product was purified by normal phase
column chromatography (EtOAc/hexanes) to give 220 mg (56%) of the
desired product as a mixture of diastereomers. MS (ESI): exact mass
calcd for C.sub.19H.sub.20BrNO.sub.2S, 405.0; m/z found, 406.0,
408.0 [M+H].sup.+.
Step 2
[0611] Prepared as described in Example 1, Step 7, on a 1.23 mmol
scale. Purification by column chromatography (EtOAc/Hexanes) gave a
75% combined yield of two diastereomers, which were separated by
reverse phase HPLC.
Cis-9-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[2,-
1-a]isoquinolin-5-one
[0612] 140 mg (29%) as the TFA salt. MS (ESI): exact mass calcd for
C.sub.19H.sub.18BrNOS, 387.0; m/z found, 388.0, 390.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, MeOH-d.sub.4): 7.48 (m, 1H), 7.30 (m, 3H),
7.11 (d, J=8.3 Hz, 2H), 6.47 (m, 1H), 4.76 (m, 1H), 4.73 (m, 1H),
3.68 (m, 1H), 3.51 (m, 1H), 2.77 (m, 1H), 2.49 (s, 3H), 2.20 (m,
1H), 2.12 (m, 1H), 2.10 (m, 1H).
Trans-9-bromo-6-(4-methylsulfanyl-phenyl)-2,3,6,10b-tetrahydro-1H-pyrrolo[-
2,1-a]isoquinolin-5-one
[0613] 220 mg (46%) as the TFA. MS (ESI): exact mass calcd for
C.sub.19H.sub.18BrNOS, 387.0; m/z found, 387.9, 390.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, MeOH-d.sub.4): 7.54 (s, 1H), 7.50 (m, 1H),
7.21 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.3 Hz,
2H), 4.79 (s, 1H), 4.63 (m, 1H), 3.55 (m, 2H), 2.71 (m, 1H), 2.41
(s, 3H), 2.12 (m, 1H), 1.99 (m, 1H), 1.86 (m, 1H).
Step 3
[0614] Performed as described in Example 97, Step 5, on a 7.7 mmol
scale, to give a 78% combined yield of a 1:1 mixture of
diastereomers. MS (ESI): exact mass calcd for C.sub.19H.sub.20BrNS,
374.3; m/z found, 374.0, 376.0 [M+H].sup.+. The cis diastereomer
was isolated by column chromatography and an analytical sample
further purified by reverse phase HPLC.
Cis-9-bromo-6-(4-methylsulfanyl-phenyl)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,-
1-a]isoquinoline
[0615] 1.13 g (39%) as the TFA salt. MS (ESI): exact mass calcd for
C.sub.19H.sub.20BrNS, 373.1; m/z found, 374.0, 376.0 [M+H].sup.+.
.sup.1H NMR (500 MHz, acetone-d.sub.6): 7.60 (m, 1H), 7.40 (m, 1H),
7.31 (d, J=8.5 Hz, 2H), 7.23 (d, J=6.6 Hz, 2H), 7.98 (m, 1H), 4.59
(m, 1H), 3.96 (m, 1H), 3.71 (m, 2H), 3.50 (m, 1H), 3.41 (m, 1H),
2.95 (m, 1H), 2.49 (s, 3H), 2.37 (m, 2H), 2.28 (m, 1H).
Step 4
[0616] Prepared as described in Example 97, Step 6, on a 1.47 mmol
scale, to give a 15% combined yield of a mixture of diastereomers.
The diastereomers were isolated by reverse-phase HPLC.
98A:
Cis-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2,3-
,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0617] 45.0 mg (5%) as the TFA salt. MS (ESI): exact mass calcd for
C.sub.28H.sub.34N.sub.2S, 430.2; m/z found, 431.2 [M+H].sup.+.
.sup.1H NMR (500 MHz, acetone-d.sub.6): 7.44 (s, 1H), 7.31 (d,
J=8.4 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 6.75 (d, J=8.1 Hz, 1H), 4.95
(m, 1H), 4.63 (m, 1H), 3.94 (m, 2H), 3.70 (m, 3H), 3.50 (m, 1H),
3.40 (m, 3H), 3.06 (m, 4H), 2.91 (m, 1H), 2.51 (s, 3H), 2.35 (m,
2H), 2.27 (m, 1H), 1.90 (m, 4H), 1.79 (m, 1H), 1.52 (m, 1H).
98B:
Trans-6-(4-methylsulfanyl-phenyl)-9-(4-piperidin-1-yl-but-1-ynyl)-1,2-
,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline
[0618] 103 mg (11%) as the TFA salt. MS (ESI): exact mass calcd for
C.sub.28H.sub.34N.sub.2S, 430.2; m/z found, 431.2 [M+H].sup.+.
.sup.1H NMR (500 MHz, acetone-d.sub.6): 7.47 (br s, 1H), 7.30 (m,
3H), 7.21 (d, J=8.4 Hz, 2H), 6.88 (d, J=8.1 Hz, 1H), 5.13 (br s,
1H), 4.67 (br s, 1H), 3.70 (m, 5H), 3.43 (t, J=7.5 Hz, 2H), 3.07
(m, 4H), 2.79 (br s, 1H), 2.49 (s, 3H), 2.18 (m, 3H), 1.90 (m, H),
1.82 (m, 1H), 1.52 (m, 1H).
Biological Method 1. In Vitro Screening
H.sub.3 Receptor Binding
[0619] Binding of compounds to the cloned human H.sub.3 receptor,
stably expressed in SK-N-MC cells, was performed (Lovenberg, T. W.
et al. J. Pharmacol. Exp. Ther. 2000, 293, 771-778). Briefly, cell
pellets from SK-N-MC cells expressing the human H.sub.3 receptor
were homogenized in 50 mM Tris-HCl/5 mM EDTA and re-centrifuged at
30,000 g for 30 min. Pellets were re-homogenized in 50 mM Tris/5 mM
EDTA (pH 7.4). Membranes were incubated with 0.8 nM
N-[.sup.3H]-.alpha.-methylhistamine plus/minus test compounds for
60 min at 25.degree. C. and harvested by rapid filtration over GF/C
glass fiber filters (pretreated with 0.3% polyethylenimine)
followed by four washes with ice-cold buffer. Nonspecific binding
was defined in the presence of 10 .mu.M histamine. IC.sub.60 values
were determined by a single site curve-fitting program (GraphPad,
San Diego, Calif.) and converted to K, values based on a
N-[.sup.3H]-.alpha.-methylhistamine K.sub.d of 800 pM and a ligand
concentration of 800 pM (Cheng & Prusoff, Biochem. Pharmacol.
1973, 22, 3099-3108). Data for compounds testing in this assay are
presented in Table 1.
Rat Brain SERT
[0620] A rat brain without cerebellum (Zivic Laboratories,
Inc.--Pittsburgh, Pa.) was homogenized in a 52.6 mM Tris pH 8/126.4
mM NaCl/5.26 mM KCl mixture and centrifuged at 1,000 rpm for 5 min.
The supernatant was removed and re-centrifuged at 15,000 rpm for 30
min. Pellets were re-homogenized in a 52.6 mM Tris pH8/126.4 mM
NaCl/5.26 mM KCl mixture. Membranes were incubated with 0.6 nM
[.sup.3H]-Citalopram plus/minus test compounds for 60 min at
25.degree. C. and harvested by rapid filtration over GF/C glass
fiber filters (pretreated with 0.3% polyethylenimine) followed by
four washes with ice-cold buffer. Nonspecific binding was defined
in the presence of 100 .mu.M fluoxetine. IC.sub.50 values were
determined by a single site curve-fitting program (GraphPad, San
Diego, Calif.) and converted to K, values based on a
[.sup.3H]-Citalopram K.sub.d of 0.6 nM and a ligand concentration
of 0.6 nM. Data for compounds tested in this assay are presented in
Table 1.
TABLE-US-00002 TABLE 1 Rat SERT Human H.sub.3 Rat SERT Human
H.sub.3 EX K.sub.i (nM) K.sub.i (nM) EX K.sub.i (nM) K.sub.i (nM)
1A 2 0.9 24B 36 0.3 1B 138 0.2 25 3 0.8 1C 4000 68 26 2 0.8 2A 5 1
27A 20 1 2B 544 31 27B 26 0.3 2C 4000 29 28 4 0.4 3 3 0.5 29 2 0.9
4A 15 1 30 3 2 4B 151 1 31 163 12 4C 471 98 32 20 1 4D 154 1 33 33
7 5A 3 2 34 9 2 5B 37 1 35A 15 4 5C 3000 85 35B 4 2 6A 1 3 36 15 4
6B 14 1 37 7 4 6C 291 76 38 10 6 7A 27 5 39A 3 2 7B 25 2 39B 3 1 7C
630 31 39C 69 36 8A 2 0.7 40 12 3 8B 50 0.75 41A 25 1 8C 2 2 41B 6
1 8D 3 1 42 221 2 8E 477 226 43 6000 30 8F 4000 482 44 4000 1 9A 9
2 45 6000 16 9B 6000 1000 46 14 4 10A 5 2 47 9 3 10B 37 2 48A 7 6
10C 2000 82 48B 20 5 11A 4 1 49 6 5 11B 91 1 50A 23 4 11C 1000 136
50B 363 181 12A 11 2 51A 130 3 12B 52 1 51B 161 5 12C 2000 91 52 6
4 12D 280 74 53 53 3 13A 14 1 54 24 4 13B 2000 129 55 39 2 14A 4 2
56 2 3 14B 67 1 57 3 3 14C 3000 200 58 8 2 15 1 0.7 59 4 2 16 21 4
60 8 3 17 11 4 61 10 29 18 12 0.9 62 15 6 19 12 1 63 5 16 20 21 1
64 3 3 21 7 1 65 4 4 22 64 0.8 66A 6 2 23 1 1 66B 18 1 24A 0.7 0.7
67 22 2 89 3 16 95 11 6 90 24 10 96A 10 1 91 60 64 97A 51 3 92 2.2
16 97B 407 12 93 13 5 98A 10 4 94 53 4 98B 7 3
Human SERT
[0621] Homogenized HEK293 (Human Embryonic Kidney) membranes
expressing the human SERT (Perkin-Elmer) were incubated with
.sup.3H-citalopram (SERT) at rt for 1 h in 50 mM Tris, 120 mM NaCl,
5 mM KCl (pH 7.4). Nonspecific binding was determined in the
presence of 10 .mu.M fluoxetine for the SERT. The membranes were
washed and the radioactivity was counted as above. Calculations for
K at the SERT were based on a K.sub.d value for .sup.3H-citalopram
and a ligand concentration of 3.1 nM. Data for compounds testing in
this assay are presented in Table 2.
TABLE-US-00003 TABLE 2 Human SERT Human SERT Human SERT EX K.sub.i
(nM) EX K.sub.i (nM) EX K.sub.i (nM) 1A 4 15 3 29 2 2A 6 16 112 30
2 3 8 17 7 31 28 4A 4 18 13 32 11 5A 4 19 5 34 3 6A 4 20 43 35A 7
7A 12 21 5 37 0.8 8A 2 22 220 38 7 8B 128 23 2 39A 4 8C 1 24A 1 40
18 9A 58 25 18 41A 59 10A 2 26 6 46 9 11A 0.6 27A 15 47 5 12A 8 27B
112 66A 6 13A 21 28 5 67 9 14A 3 94 111 96A 9 92 4 95 13 97A 2000
98A 2
Cyclic AMP Accumulation
[0622] Sublines of SK-N-MC cells were created that expressed a
reporter construct and the human H.sub.3 receptor. The reporter
gene (.beta.-galactosidase) is under the control of multiple cyclic
AMP responsive elements. In 96-well plates, histamine was added
directly to the cell media followed 5 min later by an addition of
forskolin (5 .mu.M final concentration). When appropriate,
antagonists were added 10 min prior to agonist addition. After a
6-h incubation at 37.degree. C., the media was aspirated and the
cells washed with 200 .mu.L of phosphate-buffered saline followed
by a second aspiration. Cells were lysed with 25 .mu.L 0.1.times.
assay buffer (10 mM Na-phosphate, pH 8, 0.2 mM MgSO.sub.4, 0.01 mM
MnCl.sub.2) and incubated at rt for 10 min. Cells were then
incubated for 10 min with 100 .mu.L of 1.times. assay buffer
containing 0.5% Triton and 40 mM .beta.-mercaptoethanol. Color was
developed using 25 .mu.L of 1 mg/mL substrate solution
(chlorophenolred .beta.-D galactopyranoside; Roche Molecular
Biochemicals, Indianapolis, Ind.). Color was quantitated on a
microplate reader at absorbance 570 nM. The pA.sub.2 values were
calculated by Schild regression analysis of the pEC.sub.50 values
and are presented in Table 3.
TABLE-US-00004 TABLE 3 EX H.sub.3 pA.sub.2 EX H.sub.3 pA.sub.2 EX
H.sub.3 pA.sub.2 1A 9.7 10A 9.8 23 9.7 1B 9.6 10B 9.6 24A 9.9 2A
9.4 11A 9.5 24B 10.0 2B 8.8 11B 9.3 25 10.0 3 10.1 12A 8.9 26 10.1
4A 9.9 12B 9.2 32 9.5 4B 9.8 14A 9.0 33 8.1 5A 8.6 14B 9.1 34 9.0
6A 8.2 15 9.9 35A 8.4 7A 8.2 16 8.9 35B 8.5 7B 8.2 17 8.2 36 8.0 8A
8.8 18 9.3 37 8.8 8B 9.2 19 9.4 41A 9.1 8C 8.8 20 9.0 41B 9.1 8D
8.8 21 9.1 67 9.3 9A 9.5 22 9.2 97B 8.0 91 8.5 96A 8.2 98A 8.0 92
7.8 97A 8.8 98B 8.6
Biological Method 2. In Vivo Screening.
[0623] Animal experiments were performed to illustrate that
6-(4-methoxy-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-
-pyrrolo[2,1-a]isoquinoline (Example 8A) is both an H.sub.3
receptor antagonist and a blocker of serotonin reuptake in
vivo.
A. Imetit-Induced Drinking Model
[0624] Histamine H.sub.3 receptors play an important role in the
regulation of drinking behavior. For instance, it is known that
administration of H.sub.3 antagonists can decrease the drinking
response to histamine by about 40% (Kraly, F. S. et al. Pharmacol.,
Biochem. Behav. 1996, 53, 347-354). Indeed, it is possible to
induce drinking behavior in rodents by administering a selective
agonist for the H.sub.3 receptor, such as R-.alpha.-methylhistamine
(Fox, G. B. et al. Pharmacol., Biochem. Behav. 2002b, 72, 741-750)
or imetit.
[0625] The imetit-induced drinking model was used to provide
evidence of in vivo antagonism of an H.sub.3 mediated behavior. In
this model, animals were introduced into a cage containing a
fully-automated water drinking monitoring system. The animals were
injected i.p. with Example 8A. After 24 h, 1 mg/kg imetit, which
was shown during preliminary experiments to induce a robust
drinking response, was administered i.p., and drinking was measured
for a period of 60 min (imetit-induced drinking). Example 8A
inhibited imetit-induced drinking with a statistically significant
effect at 10 mg/kg i.p. Data are presented in Table 4. Results are
shown as averages.+-.s.e.m. of n=8-13 animals.
TABLE-US-00005 TABLE 4 Treatment Water Consumed (mL) n Vehicle
(saline) 1.05 .+-. 0.34 10 Imetit (1 mg/kg) 2.53 .+-. 0.60 13
Example 8A (1 mg/kg) + 1.99 .+-. 0.68 10 Imetit (1 mg/kg) Example
8A (3 mg/kg) + 1.65 .+-. 0.51 8 Imetit (1 mg/kg) Example 8A (10
mg/kg) + *0.25 .+-. 0.15 10 Imetit (1 mg/kg) *p = 0.022 compared to
imetit-treated animals
B. 5-HTP Potentiation Test
[0626] The co-administration of the 5-HT precursor 5-HTP
(5-hydroxytryptophan) and a decarboxylase inhibitor, carbidopa
(Darmani, N. A. and S. L. Reeves. Pharmacol., Biochem. Behav. 1996,
55, 1-10) is known to induce a mild serotoninergic syndrome, mainly
characterized by head twitches. In the presence of a compound
blocking the synaptic reuptake of 5-HT, the syndrome will be
potentiated.
[0627] Mice were injected with Example 8A (3 mg/kg and 10 mg/kg).
Group 1 (1 h): 1) at t=0, mice were injected with carbidopa (10
mg/kg) and Example 8A (3 mg/kg or 10 mg/kg); 2) at t=20 min, mice
were injected with 5-HTP (40 mg/kg); 3) at t=55 min, head twitch
frequency was measured for a 5 min interval. Group 2 (24 h): 1) at
t=0, mice were injected with Example 8A (3 mg/kg or 10 mg/kg); 2)
at t=23 h, mice were injected with carbidopa (10 mg/kg); 3) at t=23
h, 20 min, mice were injected with 5-HTP (40 mg/kg); 4) at t=24 h,
25 min, head twitch frequency was measured for a 5 min interval.
The data are presented in Table 5 as an average.+-.s.e.m. The n
value is given between brackets.
TABLE-US-00006 TABLE 5 Group 1 (1 h) Group 2 (24 h) Vehicle 3.5
.+-. 0.6 (5) 6.2 .+-. 1.2 (4) 3 mg/kg Example 8A 6.0 .+-. 1.2 (3)
24.0 .+-. 2.1 (4) 10 mg/kg Example 8A 2.0 .+-. 0.6 (3) 41.3 .+-.
5.2 (3)
C. Microdialysis
[0628] Microdialysis is used to measure the concentration of small
biological molecules in the extracellular fluid of the brain
(Parent, M. et al. Methods 2001, 23, 11-20). A small probe,
containing a fine microdialysis membrane at its tip, is introduced
into the brain of an animal. A buffered solution is infused through
the catheter. Small molecules, such as monoamine neurotransmitters,
diffuse through the pores in the microdialysis membrane and are
captured in the solution. The samples are then analyzed by
analytical techniques to quantitate the amount of neurotransmitter
in the brain extracellular fluid. This technique has been used
extensively to measure the effects of SERT inhibitors on levels of
extracellular serotonin.
[0629] Microdialysis was used to measure the levels of serotonin
and dopamine in the brain of freely moving rats after subcutaneous
injection of Example 8A. FIG. 1 shows the results of microdialysis
of dopamine (DA) and serotonin (5-HT) in the cortex of freely
moving rats after subcutaneous injection of 1 mg/kg of Example 8A
at t=0. As shown in FIG. 1, injection of Example 8A caused a slow,
persistent increase in serotonin and dopamine levels. Results are
represented as the average.+-.s.d. of n=2-4 rats.
* * * * *