U.S. patent application number 13/487300 was filed with the patent office on 2012-09-20 for novel unsaturated tetracyclic tetrahydrofuran derivatives.
Invention is credited to Jose Maria CID-N NEZ, Antonius Adrianus Hendrikus Petrus Megens, Andres Avelino Trabanco-Suarez.
Application Number | 20120238563 13/487300 |
Document ID | / |
Family ID | 34957911 |
Filed Date | 2012-09-20 |
United States Patent
Application |
20120238563 |
Kind Code |
A1 |
CID-N NEZ; Jose Maria ; et
al. |
September 20, 2012 |
NOVEL UNSATURATED TETRACYCLIC TETRAHYDROFURAN DERIVATIVES
Abstract
This invention concerns novel substituted unsaturated
tetracyclic tetrahydrofuran derivatives with binding affinities
towards serotonine receptors, in particular 5-HT.sub.2A and
5-HT.sub.2C receptors, and towards dopamine receptors, in
particular dopamine D2 receptors and with norepinephrine reuptake
inhibition properties, pharmaceutical compositions comprising the
compounds according to the invention, the use thereof as a
medicine, in particular for the prevention and/or treatment of a
range of psychiatric and neurological disorders, in particular
certain psychotic, cardiovascular and gastrokinetic disorders and
processes for their production. The compounds according to the
invention can be represented by general Formula (I) ##STR00001##
and comprises also the pharmaceutically acceptable acid or base
addition salts thereof, the stereochemically isomeric forms
thereof, the N-oxide form thereof and prodrugs thereof, wherein all
substituents are defined as in claim 1.
Inventors: |
CID-N NEZ; Jose Maria;
(Toledo, ES) ; Megens; Antonius Adrianus Hendrikus
Petrus; (Beerse,, BE) ; Trabanco-Suarez; Andres
Avelino; (Toledo, ES) |
Family ID: |
34957911 |
Appl. No.: |
13/487300 |
Filed: |
June 4, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13214344 |
Aug 22, 2011 |
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13487300 |
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11571090 |
Dec 21, 2006 |
8022102 |
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PCT/EP2005/052891 |
Jun 21, 2005 |
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13214344 |
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Current U.S.
Class: |
514/232.8 ;
514/254.11; 514/410; 514/431; 514/468; 544/153; 544/375; 548/418;
549/12; 549/457 |
Current CPC
Class: |
C07D 303/10 20130101;
C07D 495/14 20130101; C07D 405/06 20130101; C07D 405/12 20130101;
C07D 491/10 20130101; C07D 493/04 20130101; C07D 317/26 20130101;
A61P 15/00 20180101; A61P 25/06 20180101; A61P 3/04 20180101; A61P
25/28 20180101; C07D 333/80 20130101; A61P 25/20 20180101; C07D
335/04 20130101; C07D 491/04 20130101; C07D 495/04 20130101; A61P
25/30 20180101; A61P 25/18 20180101; A61P 25/00 20180101; A61P
25/24 20180101; C07D 307/935 20130101; A61P 43/00 20180101; A61P
25/22 20180101 |
Class at
Publication: |
514/232.8 ;
549/457; 514/468; 549/12; 514/431; 548/418; 514/410; 544/375;
514/254.11; 544/153 |
International
Class: |
C07D 307/93 20060101
C07D307/93; C07D 495/04 20060101 C07D495/04; A61K 31/38 20060101
A61K031/38; C07D 495/14 20060101 C07D495/14; A61K 31/407 20060101
A61K031/407; C07D 405/06 20060101 C07D405/06; A61K 31/496 20060101
A61K031/496; C07D 413/06 20060101 C07D413/06; A61K 31/5377 20060101
A61K031/5377; A61P 25/00 20060101 A61P025/00; A61P 25/22 20060101
A61P025/22; A61P 25/24 20060101 A61P025/24; A61P 25/18 20060101
A61P025/18; A61P 25/06 20060101 A61P025/06; A61P 25/28 20060101
A61P025/28; A61P 25/30 20060101 A61P025/30; A61P 3/04 20060101
A61P003/04; A61K 31/343 20060101 A61K031/343 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 23, 2004 |
EP |
PCT/EP2004/051204 |
Claims
1. A compound of Formula (I) ##STR00183## the pharmaceutically
acceptable acid or base addition salts thereof, the
stereochemically isomeric forms thereof, the N-oxide form thereof
and prodrugs thereof, wherein: n is an integer, equal to zero, 1,
2, 3, 4, 5 or 6; i, j are integers, independently from each other,
equal to zero, 1, 2, 3 or 4; r is an integer, equal to zero, 1, 2
or 3; R.sup.1 and R.sup.2 are, each independently from each other,
selected from the group of hydrogen; alkyl; alkenyl; aryl;
arylalkyl; arylalkenyl; alkyloxyalkyl; arylcarbonylalkyl;
alkylcarbonyloxyalkyl; alkyloxycarbonylalkyl; alkylcarbonyl;
arylcarbonyl; arylalkylcarbonyl; alkyloxycarbonyl; aryloxycarbonyl;
alkyloxycarbonylalkylcarbonyl; mono- or di(alkyl)aminocarbonyl;
mono- or di(aryl)aminocarbonyl; mono- or
di(arylalkyl)aminocarbonyl; aminocarbonylalkyl; mono- or
di(alkyloxycarbonylalkyl)aminocarbonyl; mono- or
di(alkyl)aminocarbonylalkyl; mono- or di(aryl)aminocarbonylalkyl;
mono- or di(alkyl)aminocarbonylalkenyl; mono- or
di(alkylsulphonyl)-aminocarbonylalkyl; mono- or
di(arylsulphonyl)aminocarbonylalkyl; alkylsulphonyl; arylsulphonyl;
arylalkylsulphonyl; mono- or di(alkyl)aminothiocarbonyl; mono- or
di(aryl)aminothiocarbonyl; mono- or di(arylalkyl)aminothiocarbonyl;
mono-, di- or tri(alkyl)amidino; mono-, di- or
tri(alkyl)amidinoalkyl; mono-, di- or tri(aryl)amidino and mono-,
di- or tri(arylalkyl)amidino; pyrrolidinyl, optionally substituted
with one or more oxo moieties; tetrazolylalkyl; or R.sup.1 and
R.sup.2 taken together with the nitrogen atom to which they are
attached may form a radical of Formula (a-1) to (a-7): ##STR00184##
wherein: P is an integer, equal to zero, 1, 2, 3 or 4; q is an
integer, equal to 1 or 2; m is an integer, equal to zero, 1, 2 or
3; each R.sup.3 is, independently from each other, selected from
the group of halo; hydroxy; alkyloxy; aryloxy; alkyl; aryl;
alkylcarbonyl; alkyloxycarbonyl; arylcarbonyl; aryloxycarbonyl and
mono- or di(alkyl)amino; or two R.sup.3-radicals may form together
a bivalent radical of Formula
--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O-- (b-1);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5-- (b-2);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O-- (b-3);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5-- (b-4);
--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O-- (b-5);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O-- (b-6);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--
(b-7);
--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.s-
up.5--O-- (b-8); and
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O-- (b-9);
wherein R.sup.5 is selected from the group of hydrogen; halo;
hydroxy; alkyloxy and alkyl; R.sup.4 is selected from the group of
hydrogen; alkyl; alkylcarbonyl; arylcarbonyl; alkyloxycarbonyl;
aryloxycarbonyl; arylalkylcarbonyl; alkyloxycarbonylalkylcarbonyl;
arylalkyl; alkyloxyalkyl; alkylcarbonyloxyalkyl;
alkyloxycarbonylalkyl; mono- or di(alkyl)aminocarbonyl; mono- or
di(aryl)aminocarbonyl; mono- or di(arylalkyl)aminocarbonyl; mono-
or di(alkyloxycarbonylalkyl)aminocarbonyl; alkylsulphonyl;
arylsulphonyl; arylalkylsulphonyl; mono- or
di(alkyl)aminothiocarbonyl; mono- or di(aryl)aminothiocarbonyl;
mono- or di(arylalkyl)aminothiocarbonyl; mono-, di- or
tri(alkyl)amidino; mono-, di- or tri(aryl)amidino and mono-, di- or
tri(arylalkyl)amidino; A and B are, each independently from each
other, aryl or an heteroaryl radical selected from the group of
furyl; thienyl; pyrrolyl; oxazolyl; thiazolyl; imidazolyl;
isoxazolyl; isothiazolyl; oxadiazolyl; triazolyl; pyridinyl;
pyridazinyl; pyrimidinyl; pyrazinyl; indolyl; indolizinyl;
isoindolyl; benzofuryl; isobenzofuryl; benzothienyl; indazolyl;
benzimidazolyl; benzthiazolyl; quinolizinyl; quinolinyl;
isoquinolinyl; phthalazinyl; quinazolinyl; quinoxalinyl; chromenyl;
naphthyridinyl and naphthalenyl; each R.sup.9 is, independently
from each other, selected from the group of hydrogen; halo; cyano;
hydroxy; carboxyl; nitro; amino; mono- or di(alkyl)amino;
alkylcarbonylamino; aminosulfonyl; mono- or di(alkyl)aminosulfonyl;
alkyl; alkenyl; alkyloxy; alkylcarbonyl and alkyloxycarbonyl;
R.sup.10 is selected from the group of hydrogen; alkyl; halo and
cyano; Y is O; X is O or S; wherein R.sup.6 and R.sup.7 each
independently from each other, are selected from the group of
hydrogen; hydroxy; alkyl and alkyloxy; or R.sup.6 and R.sup.7 taken
together may form a radical selected from the group of methylene
(.dbd.CH.sub.2); mono- or di(cyano)methylene; a bivalent radical of
Formula --(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--,
--(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
--O--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.3O--; or, together
with the carbon atom to which they are attached, a carbonyl;
R.sup.8 is selected from the group of hydrogen; alkyl;
alkylcarbonyl; arylcarbonyl; arylalkyl; arylalkylcarbonyl;
alkylsulfonyl; arylsulfonyl and arylalkylsulfonyl; aryl is phenyl,
optionally substituted with 1, 2 or 3 substituents independently
from each other, selected from the group of halo, hydroxy, alkyloxy
and alkyl; alkyl is a straight or branched saturated hydrocarbon
radical having from 1 to 6 carbon atoms; or a cyclic saturated
hydrocarbon radical having from 3 to 6 carbon atoms; each radical
optionally substituted with one or more radicals selected from the
group of halo, cyano, oxo, hydroxy, formyl, carboxyl and amino;
alkenyl is a straight or branched unsaturated hydrocarbon radical
having from 1 to 6 carbon atoms; or a cyclic unsaturated
hydrocarbon radical having from 3 to 6 carbon atoms; each radical
optionally substituted with one or more radicals selected from the
group of halo, cyano, oxo, hydroxy, formyl, carboxyl or amino
radicals; and halo is fluoro, chloro, bromo or iodo.
2. A compound according to claim 1, characterized in that n is
equal to 1 or 2; i, j are, independently from each other, equal to
zero or 1; r is equal to 0 or 1; R.sup.1 and R.sup.2 are, each
independently from each other, hydrogen; alkyl; alkenyl; aryl;
arylalkenyl; arylcarbonylalkyl; alkyloxycarbonylalkyl;
aryloxycarbonyl; alkyloxycarbonylalkylcarbonyl; aminocarbonylalkyl;
mono- or di(alkyl)aminocarbonylalkyl; mono- or
di(aryl)aminocarbonylalkyl; mono- or di(alkyl)aminocarbonylalkenyl;
mono- or di(alkylsulphonyl)-aminocarbonylalkyl; mono- or
di(arylsulphonyl)aminocarbonylalkyl; alkylsulphonyl; mono-, di- or
tri(alkyl)amidinoalkyl; pyrrolidinyl, optionally substituted with
one or more oxo moieties; tetrazolylalkyl; or R.sup.1 and R.sup.2
taken together with the nitrogen atom to which they are attached
may form a radical of Formula (a-1), (a-3), (a-5), (a-6) or (a-7)
wherein: p is equal to zero, 1 or 2; q is equal to 1; m is equal to
1 or 2; each R.sup.3 is, independently from each other, selected
from the group of hydroxy; alkyloxy; alkyl; and mono- or
di(alkyl)amino; or two R.sup.3-radicals may form together a
bivalent radical of Formula (b-3) wherein R.sup.5 is hydrogen;
R.sup.4 is selected from the group of alkyl; alkylcarbonyl;
arylcarbonyl; alkyloxycarbonyl; aryloxycarbonyl; arylalkylcarbonyl;
alkyloxycarbonylalkylcarbonyl; mono- or di(alkyl)aminocarbonyl;
mono- or di(aryl)aminocarbonyl; mono- or
di(arylalkyl)aminocarbonyl; mono- or
di(alkyloxycarbonylalkyl)aminocarbonyl; alkylsulphonyl;
arylsulphonyl and arylalkylsulphonyl; A and B are, each
independently from each other, aryl or an heteroaryl radical
selected from the group of thienyl; pyridinyl and indolyl; each
R.sup.9 is, independently from each other, selected from the group
of hydrogen; halo; cyano; alkyl and alkenyl; R.sup.10 is hydrogen;
Y is O; X is O or S; wherein R.sup.6 and R.sup.7 each independently
from each other are selected from the group of hydrogen and alkyl;
or R.sup.6 and R.sup.7 taken together may form the radical
methylene (.dbd.CH.sub.2); or, together with the carbon atom to
which they are attached, a carbonyl; R.sup.8 is selected from the
group of alkyl and arylalkyl; aryl is phenyl, optionally
substituted with 1 substituent selected from the group of halo,
hydroxy, alkyloxy and alkyl; alkyl is a straight saturated
hydrocarbon radical having from 1 to 6 carbon atoms, optionally
substituted with one or more hydroxy, cyano or carboxyl radicals;
alkenyl is a straight unsaturated hydrocarbon radical having from 1
to 6 carbon atoms; and halo is fluoro, chloro or bromo.
3-4. (canceled)
5. A method for the treatment of conditions, either prophylactic or
therapeutic or both, mediated through the 5-HT.sub.2, and D2
receptor, as well as the through norepinephrine reuptake
inhibition, wherein said method comprises the step of administering
a therapeutic amount of a compound of claim 1.
6. A method for the treatment and/or prevention of central nervous
system disorders like anxiety, depression and mild depression,
bipolar disorders, sleep- and sexual disorders, psychosis,
borderline psychosis, schizophrenia, migraine, personality
disorders or obsessive-compulsive disorders, social phobias or
panic attacks, organic mental disorders, mental disorders in
children, aggression, memory disorders and attitude disorders in
older people, addiction, obesity, bulimia and similar disorders,
wherein said method comprises the step of administering a
therapeutic amount of a compound of claim 1.
7. A method for the treatment and/or prevention of anxiety,
depression, psychosis, schizophrenia, migraine and addictive
properties of drugs of abuse, wherein said method comprises the
step of administering a therapeutic amount of a compound of claim
1.
8. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and, as active ingredient, a therapeutically
effective amount of a compound claim 1.
9. A process for the preparation of a composition as claimed in
claim 8, characterized in that a pharmaceutically acceptable
carrier is intimately mixed with a therapeutically effective amount
of a compound of claim 1.
10-13. (canceled)
Description
FIELD OF THE INVENTION
[0001] This invention concerns novel substituted unsaturated
tetracyclic tetrahydrofuran derivatives with binding affinities
towards serotonin receptors, in particular 5-HT.sub.2A and
5-HT.sub.2C receptors, and towards dopamine receptors, in
particular dopamine D2 receptors and with norepinephrine reuptake
inhibition properties, pharmaceutical compositions comprising the
compounds according to the invention, the use thereof as a
medicine, in particular for the prevention and/or treatment of a
range of psychiatric and neurological disorders, in particular
certain psychotic, cardiovascular and gastrokinetic disorders and
processes for their production.
BACKGROUND PRIOR ART
[0002] WO 97/38991, published Oct. 23, 1997 (Janssen Pharmaceutica
N.V.) discloses substituted tetracyclic tetrahydrofuran derivatives
that may be used as therapeutic agents in the treatment or
prevention of CNS disorders, cardiovascular disorders or
gastrointestinal disorders. In particular, the compounds show
affinity for the serotonin 5-HT.sub.2 receptors, particularly for
the 5-HT.sub.2A and 5-HT.sub.2C-receptors.
[0003] WO 99/19317, published Apr. 22, 1999 (Janssen Pharmaceutica
N.V.) discloses substituted tetracyclic tetrahydrofuran derivatives
with a specific halogen substitution pattern on the dibenzoazepine,
dibenzooxepine, dibenzothiepine or dibenzosuberane ring. The
compounds are useful in the treatment or prevention of CNS
disorders, cardiovascular disorders or gastrointestinal disorders
and show a faster onset of action over the compounds as disclosed
in WO 97/38991.
[0004] Both WO 03/048146, published Jun. 12, 2003 (Janssen
Pharmaceutica N.V.) and WO 03/048147, published Jun. 12, 2003
(Janssen Pharmaceutica N.V.) disclose processes for the preparation
of each of the 4 diastereomers of cis-, respectively trans-fused
3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan
derivatives in a stereochemically pure form from a single
enantiomerically pure precursor. The compounds show affinity for
the serotonin 5-HT.sub.2A, 5-HT.sub.2C and 5-HT.sub.7 receptors and
the H.sub.1-receptors (pIC.sub.50=7.15-7.89), D2 and/or D3
receptors and for the norepinephrine reuptake transporters
(pIC.sub.50=6.01-7.34).
[0005] WO 03/040122, published May 15, 2003 (Janssen Pharmaceutica
N.V.) discloses mandelate salts of the compounds according to WO
97/38991 and WO 99/19317. Said salts were surprisingly found to be
more stable at enhanced temperature and relative humidity than the
compounds disclosed in WO 97/38991 and WO 99/19317.
[0006] Since the compounds of WO 97/38991 and WO 99/19317 exist as
8 stereoisomers, each with a different pharmacological profile, the
yield of their production process is very low.
DESCRIPTION OF THE INVENTION
[0007] It is the object of the present invention to provide novel
analogues of the tetracyclic tetrahydrofuran derivatives of WO
97/38991 and WO 99/19317, which are easier to synthesize and the
synthesis of which has a higher yield, yet which have a similar or
even better profile than the compounds disclosed in WO 97/38991 and
WO 99/19317.
[0008] This goal is achieved by the present novel compounds
according to Formula (I)
##STR00002##
the pharmaceutically acceptable acid or base addition salts
thereof, the stereochemically isomeric forms thereof, the N-oxide
form thereof and prodrugs thereof, wherein: [0009] n is an integer,
equal to zero, 1, 2, 3, 4, 5 or 6; [0010] i, j are integers,
independently from each other, equal to zero, 1, 2, 3 or 4; [0011]
r is an integer, equal to zero, 1, 2 or 3; [0012] R.sup.1 and
R.sup.2 are, each independently from each other, selected from the
group of hydrogen; alkyl; alkenyl; aryl; arylalkyl; arylalkenyl;
alkyloxyalkyl; arylcarbonylalkyl; alkylcarbonyloxyalkyl;
alkyloxycarbonylalkyl; alkylcarbonyl; arylcarbonyl;
arylalkylcarbonyl; alkyloxycarbonyl; aryloxycarbonyl;
alkyloxycarbonylalkylcarbonyl; mono- or di(alkyl)amino-carbonyl;
mono- or di(aryl)aminocarbonyl; mono- or
di(arylalkyl)aminocarbonyl; aminocarbonylalkyl; mono- or
di(alkyloxycarbonylalkyl)aminocarbonyl; mono- or
di(alkyl)aminocarbonylalkyl; mono- or di(aryl)aminocarbonyl-alkyl;
mono- or di(alkyl)aminocarbonylalkenyl; mono- or
di(alkylsulphonyl)aminocarbonylalkyl; mono- or
di(arylsulphonyl)aminocarbonylalkyl; alkylsulphonyl; arylsulphonyl;
arylalkylsulphonyl; mono- or di(alkyl)aminothiocarbonyl; mono- or
di(aryl)aminothiocarbonyl; mono- or di(arylalkyl)aminothiocarbonyl;
mono-, di- or tri(alkyl)amidino; mono-, di- or
tri(alkyl)amidinoalkyl; mono-, di- or tri(aryl)amidino and mono-,
di- or tri(arylalkyl)amidino; pyrrolidinyl, optionally substituted
with oxo; tetrazolylalkyl; or [0013] R.sup.1 and R.sup.2 taken
together with the nitrogen atom to which they are attached may form
a radical of Formula (a-1) to (a-7):
[0013] ##STR00003## [0014] wherein: [0015] p is an integer, equal
to zero, 1, 2, 3 or 4; [0016] q is an integer, equal to 1 or 2;
[0017] m is an integer, equal to zero, 1, 2 or 3; [0018] each
R.sup.3 is, independently from each other, selected from the group
of halo; hydroxy; alkyloxy; aryloxy; alkyl; aryl; alkylcarbonyl;
alkyloxycarbonyl; arylcarbonyl; aryloxycarbonyl and mono- or
di(alkyl)amino; or [0019] two R.sup.3-radicals may form together a
bivalent radical of Formula
[0019] --CR.sup.5R.sup.5--CR.sup.5R.sup.5--O-- (b-1);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5-- (b-2);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O-- (b-3);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5-- (b-4);
--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O-- (b-5);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O--
(b-6);
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--
- (b-7);
--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O--
- (b-8); and
--O--CR.sup.5R.sup.5--CR.sup.5R.sup.5--CR.sup.5R.sup.5--O-- (b-9);
[0020] wherein R.sup.5 is selected from the group of hydrogen;
halo; hydroxy; alkyloxy and alkyl; [0021] R.sup.4 is selected from
the group of hydrogen; alkyl; alkylcarbonyl; arylcarbonyl;
alkyloxycarbonyl; aryloxycarbonyl; arylalkylcarbonyl;
alkyloxycarbonylalkylcarbonyl; arylalkyl; alkyloxyalkyl;
alkylcarbonyloxyalkyl; alkyloxycarbonylalkyl; mono- or
di(alkyl)aminocarbonyl; mono- or di(aryl)aminocarbonyl; mono- or
di(arylalkyl)aminocarbonyl; mono- or
di(alkyloxycarbonylalkyl)-aminocarbonyl; alkylsulphonyl;
arylsulphonyl; arylalkylsulphonyl; mono- or
di(alkyl)aminothiocarbonyl; mono- or di(aryl)aminothio-carbonyl;
mono- or di(arylalkyl)aminothiocarbonyl; mono-, di- or
tri(alkyl)amidino; mono-, di- or tri(aryl)amidino and mono-, di- or
tri(arylalkyl)amidino; [0022] A and B are, each independently from
each other, aryl or an heteroaryl radical selected from the group
of furyl; thienyl; pyrrolyl; oxazolyl; thiazolyl; imidazolyl;
isoxazolyl; isothiazolyl; oxadiazolyl; triazolyl; pyridinyl;
pyridazinyl; pyrimidinyl; pyrazinyl; indolyl; indolizinyl;
isoindolyl; benzofuryl; isobenzofuryl; benzothienyl; indazolyl;
benzimidazolyl; benzthiazolyl; quinolizinyl; quinolinyl;
isoquinolinyl; phthalazinyl; quinazolinyl; quinoxalinyl; chromenyl;
naphthyridinyl and naphthalenyl; [0023] each R.sup.9 is,
independently from each other, selected from the group of hydrogen;
halo; cyano; hydroxy; carboxyl; nitro; amino; mono- or
di(alkyl)amino; alkylcarbonylamino; aminosulfonyl; mono- or
di(alkyl)aminosulfonyl; alkyl; alkenyl; alkyloxy; alkylcarbonyl and
alkyloxycarbonyl; [0024] R.sup.10 is selected from the group of
hydrogen; alkyl; halo and cyano; [0025] Y is O; S; S(.dbd.O);
S(.dbd.O).sub.2 or NR.sup.8; [0026] X is CR.sup.6R.sup.7; O; S;
S(.dbd.O); S(.dbd.O).sub.2 or NR.sup.8; wherein [0027] R.sup.6 and
R.sup.7 each independently from each other, are selected from the
group of hydrogen; hydroxy; alkyl and alkyloxy; or [0028] R.sup.6
and R.sup.7 taken together may form a radical selected from the
group of methylene (.dbd.CH.sub.2); mono- or di(cyano)methylene; a
bivalent radical of Formula --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4--, --(CH.sub.2).sub.5--,
--O--(CH.sub.2).sub.2--O--, --O--(CH.sub.2).sub.3O--; or, together
with the carbon atom to which they are attached, a carbonyl; [0029]
R.sup.8 is selected from the group of hydrogen; alkyl;
alkyl-carbonyl; arylcarbonyl; arylalkyl; arylalkylcarbonyl;
alkylsulfonyl; arylsulfonyl and arylalkylsulfonyl; [0030] aryl is
phenyl, optionally substituted with 1, 2 or 3 substituents
independently from each other, selected from the group of halo,
hydroxy, alkyloxy and alkyl; [0031] alkyl is a straight or branched
saturated hydrocarbon radical having from 1 to 6 carbon atoms; or a
cyclic saturated hydrocarbon radical having from 3 to 6 carbon
atoms; each radical optionally substituted with one or more
radicals selected from the group of halo, cyano, oxo, hydroxy,
formyl, carboxyl and amino; [0032] alkenyl is a straight or
branched unsaturated hydrocarbon radical having from 1 to 6 carbon
atoms; or a cyclic unsaturated hydrocarbon radical having from 3 to
6 carbon atoms; each radical optionally substituted with one or
more radicals selected from the group of halo, cyano, oxo, hydroxy,
formyl, carboxyl or amino radicals; and [0033] halo is fluoro,
chloro, bromo or iodo.
[0034] The present compounds differ structurally from the compounds
of WO 97/38991 and WO 99/19317 by inter alia the presence of a
double bond between carbon atoms 3a and 12b, thereby reducing the
number of asymmetric centers from 3 to 1 and, thus, the number of
possible enantiomers from 8 to 2. Consequently, the compounds of
the present invention have a much simpler structure than the prior
art compounds, which facilitates chemical synthesis enormously.
[0035] More in particular, the invention relates to a compound
according to the general Formula (I), the pharmaceutically
acceptable acid or base addition salts thereof, the
stereochemically isomeric forms thereof, the N-oxide form thereof
and a prodrug thereof, wherein: [0036] n is equal to 1 or 2; [0037]
i, j are, independently from each other, equal to zero or 1; [0038]
r is equal to 0 or 1; [0039] R.sup.1 and R.sup.2 are, each
independently from each other, hydrogen; alkyl; alkenyl; aryl;
arylalkenyl; arylcarbonylalkyl; alkyloxycarbonylalkyl;
aryloxycarbonyl; alkyloxycarbonylalkylcarbonyl; aminocarbonylalkyl;
mono- or di(alkyl)aminocarbonylalkyl; mono- or
di(aryl)aminocarbonylalkyl; mono- or
di(alkyl)aminocarbonyl-alkenyl; mono- or
di(alkylsulphonyl)aminocarbonylalkyl; mono- or
di(arylsulphonyl)aminocarbonylalkyl; alkylsulphonyl; mono-, di- or
tri(alkyl)amidinoalkyl; pyrrolidinyl, optionally substituted with
oxo; tetrazolylalkyl; or [0040] R.sup.1 and R.sup.2 taken together
with the nitrogen atom to which they are attached may form a
radical of Formula (a-1), (a-3), (a-5), (a-6) or (a-7) wherein:
[0041] p is equal to zero, 1 or 2; [0042] q is equal to 1; [0043] m
is equal to 1 or 2; [0044] each R.sup.3 is, independently from each
other, selected from the group of hydroxy; alkyloxy; alkyl; and
mono- or di(alkyl)amino; or two R.sup.3-radicals may form together
a bivalent radical of Formula (b-3) wherein R.sup.5 is hydrogen;
[0045] R.sup.4 is selected from the group of alkyl; alkylcarbonyl;
arylcarbonyl; alkyloxycarbonyl; aryloxycarbonyl; arylalkylcarbonyl;
alkyloxycarbonylalkylcarbonyl; mono- or di(alkyl)aminocarbonyl;
mono- or di(aryl)aminocarbonyl; mono- or
di(arylalkyl)aminocarbonyl; mono- or
di(alkyloxycarbonylalkyl)aminocarbonyl; alkylsulphonyl;
arylsulphonyl and arylalkylsulphonyl; [0046] A and B are, each
independently from each other, aryl or an heteroaryl radical
selected from the group of thienyl; pyridinyl and indolyl; [0047]
each R.sup.9 is, independently from each other, selected from the
group of hydrogen; halo; cyano; alkyl and alkenyl; [0048] R.sup.10
is hydrogen; [0049] Y is O; [0050] X is CR.sup.6R.sup.7, O, S or
NR.sup.8; wherein [0051] R.sup.6 and R.sup.7 each independently
from each other are selected from the group of hydrogen and alkyl;
or [0052] R.sup.6 and R.sup.7 taken together may form the radical
methylene (.dbd.CH.sub.2); or, together with the carbon atom to
which they are attached, a carbonyl; [0053] R.sup.8 is selected
from the group of alkyl and arylalkyl; [0054] aryl is phenyl,
optionally substituted with 1 substituent selected from the group
of halo, hydroxy, alkyloxy and alkyl; [0055] alkyl is a straight
saturated hydrocarbon radical having from 1 to 6 carbon atoms,
optionally substituted with one or more hydroxy, cyano or carboxyl
radicals; [0056] alkenyl is a straight unsaturated hydrocarbon
radical having from 1 to 6 carbon atoms; and [0057] halo is fluoro,
chloro or bromo.
[0058] More in particular, the invention relates to a compound
according to the general Formula (I), the pharmaceutically
acceptable acid or base addition salts thereof, the
stereochemically isomeric forms thereof, the N-oxide form thereof
and a prodrug thereof, wherein:
n is equal to 1; i is equal to 0; j is equal to 1; r is equal to 0;
R.sup.1 and R.sup.2 are, each independently from each other,
hydrogen or methyl A and B are phenyl; R.sup.9 is halo; R.sup.10 is
hydrogen;
Y is O;
X is CH.sub.2 and
[0059] halo is fluoro, chloro or bromo.
DETAILED DESCRIPTION OF THE INVENTION
[0060] In the framework of this application, alkyl is defined as a
monovalent straight or branched saturated hydrocarbon radical
having from 1 to 6 carbon atoms, for example methyl, ethyl, propyl,
butyl, 1-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl; alkyl
further defines a monovalent cyclic saturated hydrocarbon radical
having from 3 to 6 carbon atoms, for example cyclopropyl,
methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The
definition of alkyl also comprises an alkyl radical that is
optionally substituted on one or more carbon atoms with one or more
phenyl, halo, cyano, oxo, hydroxy, formyl and amino radicals, for
example hydroxyalkyl, in particular hydroxymethyl and hydroxyethyl
and polyhaloalkyl, in particular difluoromethyl and
trifluoromethyl.
[0061] In the framework of this application, halo is generic to
fluoro, chloro, bromo and iodo.
[0062] In the framework of this application, with "compounds
according to the invention" is meant a compound according to the
general Formula (I), the pharmaceutically acceptable acid or base
addition salts thereof, the stereochemically isomeric forms
thereof, the N-oxide form thereof and a prodrug thereof.
[0063] The pharmaceutically acceptable salts are defined to
comprise the therapeutically active non-toxic acid addition salts
forms that the compounds according to Formula (I) are able to form.
Said salts can be obtained by treating the base form of the
compounds according to Formula (I) with appropriate acids, for
example inorganic acids, for example hydrohalic acid, in particular
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and
phosphoric acid; organic acids, for example acetic acid,
hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid,
oxalic acid, malonic acid, succinic acid, maleic acid, mandelic
acid, fumaric acid, malic acid, tartaric acid, citric acid,
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, cyclamic acid, salicylic acid,
p-aminosalicylic acid and pamoic acid.
[0064] The compounds according to Formula (I) containing acidic
protons may also be converted into their therapeutically active
non-toxic metal or amine addition salts forms by treatment with
appropriate organic and inorganic bases. Appropriate base salts
forms comprise, for example, the ammonium salts, the alkaline and
earth alkaline metal salts, in particular lithium, sodium,
potassium, magnesium and calcium salts, salts with organic bases,
e.g. the benzathine, N-methyl-D-glucamine, hybramine salts, and
salts with amino acids, for example arginine and lysine.
[0065] Conversely, said salts forms can be converted into the free
forms by treatment with an appropriate base or acid.
[0066] The term addition salt as used in the framework of this
application also comprises the solvates that the compounds
according to Formula (I) as well as the salts thereof, are able to
form. Such solvates are, for example, hydrates and alcoholates.
[0067] The N-oxide forms of the compounds according to Formula (I)
are meant to comprise those compounds of Formula (I) wherein one or
several nitrogen atoms are oxidized to the so-called N-oxide,
particularly those N-oxides wherein one or more tertiary nitrogens
(e.g of the piperazinyl or piperidinyl radical) are N-oxidized.
Such N-oxides can easily be obtained by a skilled person without
any inventive skills and they are obvious alternatives for the
compounds according to Formula (I) since these compounds are
metabolites, which are formed by oxidation in the human body upon
uptake. As is generally known, oxidation is normally the first step
involved in drug metabolism (Textbook of Organic Medicinal and
Pharmaceutical Chemistry, 1977, pages 70-75). As is also generally
known, the metabolite form of a compound can also be administered
to a human instead of the compound per se, with much the same
effects.
[0068] The compounds according to the invention possess at least 1
oxydizable nitrogen (tertiary amines moiety). It is therefore
highly likely that N-oxides are to form in the human
metabolism.
[0069] The compounds of Formula (I) may be converted to the
corresponding N-oxide forms following art-known procedures for
converting a trivalent nitrogen into its N-oxide form. Said
N-oxidation reaction may generally be carried out by reacting the
starting material of Formula (I) with an appropriate organic or
inorganic peroxide. Appropriate inorganic peroxides comprise, for
example, hydrogen peroxide, alkali metal or earth alkaline metal
peroxides, e.g. sodium peroxide, potassium peroxide; appropriate
organic peroxides may comprise peroxy acids such as, for example,
benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic
acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids,
e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl
hydroperoxide. Suitable solvents are, for example, water, lower
alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene,
ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g.
dichloromethane, and mixtures of such solvents.
[0070] The term "stereochemically isomeric forms" as used
hereinbefore defines all the possible isomeric forms that the
compounds of Formula (I) may possess. Unless otherwise mentioned or
indicated, the chemical designation of compounds denotes the
mixture of all possible stereochemically isomeric forms, said
mixtures containing all diastereomers and enantiomers of the basic
molecular structure. More in particular, stereogenic centers may
have the R- or S-configuration; substituents on bivalent cyclic
(partially) saturated radicals may have either the cis- or
trans-configuration. Compounds encompassing double bonds can have
an E or Z-stereochemistry at said double bond. Stereochemically
isomeric forms of the compounds of Formula (I) are obviously
intended to be embraced within the scope of this invention.
[0071] Following CAS nomenclature conventions, when two stereogenic
centers of known absolute configuration are present in a molecule,
an R or S descriptor is assigned (based on Cahn-Ingold-Prelog
sequence rule) to the lowest-numbered chiral center, the reference
center. R* and S* each indicate optically pure stereogenic centers
with undetermined absolute configuration. If ".alpha." and ".beta."
are used: the position of the highest priority substituent on the
asymmetric carbon atom in the ring system having the lowest ring
number, is arbitrarily always in the ".alpha." position of the mean
plane determined by the ring system. The position of the highest
priority substituent on the other asymmetric carbon atom in the
ring system (hydrogen atom in compounds according to Formula (I))
relative to the position of the highest priority substituent on the
reference atom is denominated ".alpha.", if it is on the same side
of the mean plane determined by the ring system, or ".beta.", if it
is on the other side of the mean plane determined by the ring
system.
[0072] The numbering of the tetracyclic ring-system present in the
compounds of Formula (I) when A and B are phenyl, as defined by
Chemical Abstracts nomenclature is shown below.
##STR00004##
[0073] The compounds of Formula (I) have at least one asymmetric
center at carbon atom 2. Said asymmetric center and any other
asymmetric center, which may be present (e.g. at atom 8), are
indicated by the descriptors R and S. When e.g. a
monocyanomethylene moiety is present in the compounds of Formula
(I) at position 8, said moiety may have the E- or
Z-configuration.
[0074] The invention also comprises derivative compounds (usually
called "pro-drugs") of the pharmacologically active compounds
according to the invention, which are degraded in vivo to yield the
compounds according to the invention. Pro-drugs are usually (but
not always) of lower potency at the target receptor than the
compounds to which they are degraded. Pro-drugs are particularly
useful when the desired compound has chemical or physical
properties that make its administration difficult or inefficient.
For example, the desired compound may be only poorly soluble, it
may be poorly transported across the mucosal epithelium, or it may
have an undesirably short plasma half-life. Further discussion on
pro-drugs may be found in Stella, V. J. et al., "Prodrugs", Drug
Delivery Systems, 1985, pp. 112-176, and Drugs, 1985, 29, pp.
455-473.
[0075] Pro-drugs forms of the pharmacologically-active compounds
according to the invention will generally be compounds according to
Formula (I), the pharmaceutically acceptable acid or base addition
salts thereof, the stereochemically isomeric forms thereof and the
N-oxide form thereof, having an acid group which is esterified or
amidated. Included in such esterified acid groups are groups of the
Formula --COOR.sup.x, where R.sup.x is a C.sub.1-6alkyl, phenyl,
benzyl or one of the following groups:
##STR00005##
[0076] Amidated groups include groups of the Formula
--CONR.sup.yR.sup.z, wherein R.sup.y is H, C.sub.1-6alkyl, phenyl
or benzyl and R.sup.z is --OH, H, C.sub.1-6alkyl, phenyl or benzyl.
Compounds according to the invention having an amino group may be
derivatised with a ketone or an aldehyde such as formaldehyde to
form a Mannich base. This base will hydrolyze with first order
kinetics in aqueous solution.
[0077] The compounds of Formula (I) as prepared in the processes
described below may be synthesized in the form of racemic mixtures
of enantiomers that can be separated from one another following
art-known resolution procedures. The racemic compounds of Formula
(I) may be converted into the corresponding diastereomeric salt
forms by reaction with a suitable chiral acid. Said diastereomeric
salt forms are subsequently separated, for example, by selective or
fractional crystallization and the enantiomers are liberated
therefrom by alkali. An alternative manner of separating the
enantiomeric forms of the compounds of Formula (I) involves liquid
chromatography using a chiral stationary phase. Said pure
stereochemically isomeric forms may also be derived from the
corresponding pure stereochemically isomeric forms of the
appropriate starting materials, provided that the reaction occurs
stereospecifically. Preferably if a specific stereoisomer is
desired, said compound would be synthesized by stereospecific
methods of preparation. These methods will advantageously employ
enantiomerically pure starting materials.
Pharmacology
[0078] The compounds of the present invention show affinity for
5-HT.sub.2 receptors, particularly for 5-HT.sub.2A and 5-HT.sub.2C
receptors (nomenclature as described by D. Hoyer in "Serotonin
(5-HT) in neurologic and psychiatric disorders" edited by M.D.
Ferrari and published in 1994 by the Boerhaave Commission of the
University of Leiden) and affinity for the D2 receptor as well as
norepinephrine reuptake inhibition activity. The serotonin
antagonistic properties of the present compounds may be
demonstrated by their inhibitory effect in the "5-hydroxytryptophan
Test on Rats" which is described in Drug Dev. Res., 13, 237-244
(1988).
[0079] The compounds of the present invention also have favourable
physicochemical properties. For instance, they are chemically
stable compounds.
[0080] In view of their capability to block 5-HT.sub.2 receptors,
and in particular to block 5-HT.sub.2A and 5-HT.sub.2C receptors,
as well as the D2 receptor and by also effecting the norepinephrine
reuptake inhibition activity, the compounds according to the
invention are useful as a medicine, in particular in the
prophylactic and therapeutic treatment of conditions mediated
through either of these receptors.
[0081] The invention therefore relates to a compound according to
the general Formula (I), the pharmaceutically acceptable acid or
base addition salts thereof, the stereochemically isomeric forms
thereof, the N-oxide form thereof and prodrugs thereof, for use as
a medicine.
[0082] The invention also relates to the use of a compound
according to the general Formula (I), the pharmaceutically
acceptable acid or base addition salts thereof, the
stereochemically isomeric forms thereof, the N-oxide form thereof
and prodrugs thereof for the manufacture of a medicament for
treating, either prophylactic or therapeutic or both, conditions
mediated through the 5-HT.sub.2, and D2 receptor, as well as the
through norepinephrine reuptake inhibition.
[0083] In view of these pharmacological and physicochemical
properties, the compounds of Formula (I) are useful as therapeutic
agents in the treatment or the prevention of central nervous system
disorders like anxiety, depression and mild depression, bipolar
disorders, sleep- and sexual disorders, psychosis, borderline
psychosis, schizophrenia, migraine, personality disorders or
obsessive-compulsive disorders, social phobias or panic attacks,
organic mental disorders, mental disorders in children such as
ADHD, aggression, memory disorders and attitude disorders in older
people, addiction, obesity, bulimia and similar disorders. In
particular, the present compounds may be used as anxiolytics,
antidepressants, antipsychotics, anti-schizophrenia agents,
anti-migraine agents and as agents having the potential to overrule
the addictive properties of drugs of abuse.
[0084] The compounds of Formula (I) may also be used as therapeutic
agents in the treatment of motoric disorders. It may be
advantageous to use the present compounds in combination with
classical therapeutic agents for such disorders.
[0085] The compounds of Formula (I) may also serve in the treatment
or the prevention of damage to the nervous system caused by trauma,
stroke, neurodegenerative illnesses and the like; cardiovascular
disorders like high blood pressure, thrombosis, stroke, and the
like; and gastrointestinal disorders like dysfunction of the
motility of the gastrointestinal system and the like.
[0086] In view of the above uses of the compounds of Formula (I),
it follows that the present invention also provides a method of
treating warm-blooded animals suffering from such diseases, said
method comprising the systemic administration of a therapeutic
amount of a compound of Formula (I) effective in treating the above
described disorders, in particular, in treating anxiety, psychosis,
depression, migraine and addictive properties of drugs of
abuse.
[0087] The present invention thus also relates to compounds of
Formula (I) as defined hereinabove for use as a medicine, in
particular, the compounds of Formula (I) may be used for the
manufacture of a medicament for treating anxiety, psychosis,
depression, migraine and addictive properties of drugs of
abuse.
[0088] Those of skill in the treatment of such diseases could
determine the effective therapeutic daily amount from the test
results presented hereinafter. An effective therapeutic daily
amount would be from about 0.01 mg/kg to about 10 mg/kg body
weight, more preferably from about 0.05 mg/kg to about 1 mg/kg body
weight.
[0089] The invention also relates to a pharmaceutical composition
comprising a pharmaceutically acceptable carrier and, as active
ingredient, a therapeutically effective amount of a compound
according to the invention, in particular a compound according to
Formula (I), the pharmaceutically acceptable acid or base addition
salts thereof, the stereochemically isomeric forms thereof, the
N-oxide form thereof and a prodrug thereof.
[0090] The compounds according to the invention, in particular the
compounds according to Formula (I), the pharmaceutically acceptable
acid or base addition salts thereof, the stereochemically isomeric
forms thereof, the N-oxide form thereof and the prodrugs thereof,
or any subgroup or combination thereof may be Formulated into
various pharmaceutical forms for administration purposes. As
appropriate compositions there may be cited all compositions
usually employed for systemically administering drugs. To prepare
the pharmaceutical compositions of this invention, an effective
amount of the particular compound, optionally in addition salt
form, as the active ingredient is combined in intimate admixture
with a pharmaceutically acceptable carrier, which carrier may take
a wide variety of forms depending on the form of preparation
desired for administration. These pharmaceutical compositions are
desirable in unitary dosage form suitable, in particular, for
administration orally, rectally, percutaneously, by parenteral
injection or by inhalation. For example, in preparing the
compositions in oral dosage form, any of the usual pharmaceutical
media may be employed such as, for example, water, glycols, oils,
alcohols and the like in the case of oral liquid preparations such
as suspensions, syrups, elixirs, emulsions and solutions; or solid
carriers such as starches, sugars, kaolin, diluents, lubricants,
binders, disintegrating agents and the like in the case of powders,
pills, capsules and tablets. Because of their ease in
administration, tablets and capsules represent the most
advantageous oral dosage unit forms in which case solid
pharmaceutical carriers are obviously employed. For parenteral
compositions, the carrier will usually comprise sterile water, at
least in large part, though other ingredients, for example, to aid
solubility, may be included. Injectable solutions, for example, may
be prepared in which the carrier comprises saline solution, glucose
solution or a mixture of saline and glucose solution. Injectable
suspensions may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employed. Also
included are solid form preparations that are intended to be
converted, shortly before use, to liquid form preparations. In the
compositions suitable for percutaneous administration, the carrier
optionally comprises a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with suitable additives
of any nature in minor proportions, which additives do not
introduce a significant deleterious effect on the skin. Said
additives may facilitate the administration to the skin and/or may
be helpful for preparing the desired compositions. These
compositions may be administered in various ways, e.g., as a
transdermal patch, as a spot-on, as an ointment.
[0091] It is especially advantageous to Formulate the
aforementioned pharmaceutical compositions in unit dosage form for
ease of administration and uniformity of dosage. Unit dosage form
as used herein refers to physically discrete units suitable as
unitary dosages, each unit containing a predetermined quantity of
active ingredient calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier.
Examples of such unit dosage forms are tablets (including scored or
coated tablets), capsules, pills, powder packets, wafers,
suppositories, injectable solutions or suspensions and the like,
and segregated multiples thereof.
[0092] Since the compounds according to the invention are potent
orally administrable compounds, pharmaceutical compositions
comprising said compounds for administration orally are especially
advantageous.
[0093] In order to enhance the solubility and/or the stability of
the compounds of Formula (I) in pharmaceutical compositions, it can
be advantageous to employ .alpha.-, .beta.- or
.gamma.-cyclodextrins or their derivatives, in particular
hydroxyalkyl substituted cyclodextrins, e.g.
2-hydroxypropyl-.beta.-cyclodextrin. Also co-solvents such as
alcohols may improve the solubility and/or the stability of the
compounds according to the invention in pharmaceutical
compositions.
[0094] The following examples are intended to illustrate and not to
limit the scope of the present invention.
Preparation
[0095] Suitable preparation schemes for the compounds of the
invention are the following:
##STR00006##
[0096] Step 1: Reaction of an intermediate compound of Formula (IV)
with a reagent of Formula (V). This reaction can be done by any one
of the art-known procedures for alkylation of ketones in position a
under acidic or basic reaction conditions (for example the reaction
can be done in an organic solvent such as, for example,
dichloromethane, with a base such as, for example, lithium
diisopropylamine and using allyl bromide as the alkylating agent)
and yields an intermediate compound of Formula (III) wherein
R.sup.9, i, j, ring A, ring B and X all have the meaning as
described above for a final compound of Formula (I). For a compound
of Formula (V), M is a suitable group for an alkylation reaction,
such as, for example halo, hydroxy or acetoxy.
[0097] Alternatively an intermediate of Formula (III) can be
obtained via a Claisen rearrangement by heating an intermediate of
Formula (Ma), for example at 220.degree. C., in an organic solvent
such as toluene. Intermediates of Formula (Ma) can be prepared by
an O-allylation reaction of an intermediate of Formula (IV) with
allylbromide, in an organic solvent such as DMF, in the presence of
a suitable base such as, for example, potassium carbonate. The
reaction is best conducted at elevated temperatures such as, for
example, 60.degree. C.
##STR00007##
[0098] Step 2: Reaction of an intermediate compound of Formula
(III) with a cyclizating agent, such as, for example,
bis(pyridine)iodonium(I) tetrafluoroborate, in an organic solvent,
such as, for example dichloromethane, gives an intermediate
compound of Formula (II) wherein W represents a suitable leaving
group, preferably a halo, alkyl- or arylsulphonyloxy-, in
particular 4-(methylphenyl)sulphonyloxy- or iodo. An intermediate
compound of Formula (II) wherein R.sup.9, i, j, ring A, ring B and
X all have the meaning as described above for a final compound of
Formula (I), and wherein W represents said leaving group, is
new.
Step 3: N-alkylation of an intermediate compound of Formula (II)
with an amine of Formula HNR.sup.1R.sup.2, wherein R.sup.1 and
R.sup.2 are defined as in Formula (I), by any of the art-known
procedures gives a final compound of Formula (I). For instance,
said N-alkylation can conveniently be carried out as described in
WO 97/38991 in a reaction-inert solvent such as, for example,
methanol, methylisobutyl ketone, N,N-dimethylformamide or
dimethylsulfoxide, and optionally in the presence of a suitable
base. Stirring and elevated temperatures, for instance reflux
temperature, may enhance the rate of the reaction. Typical reaction
conditions are 8 hours at 130.degree. C.
[0099] Alternatively, said N-alkylation may also be performed using
the procedure described by Monkovic et al. (J. Med. Chem. (1973),
16(4), p. 403-407) which involves the use of a pressurised reaction
vessel.
[0100] Alternatively, said N-alkylation may also be performed by
heating at high temperature, for example 120.degree. C., an
intermediate of Formula (II), an amine of Formula NHR.sup.1R.sup.2
and a base, for example calcium oxide, in an organic solvent such
as THF, in a pressurised reaction vessel.
##STR00008##
[0101] Step 1: Cyclization of an intermediate compound of Formula
(VI) (which can be prepared according to WO 03/048146 and WO
03/048147) in an acidic reaction media, such as, for example,
hydrochloric acid in isopropyl alcohol, gives an intermediate
compound of Formula (VII) wherein R.sup.9, i, j, ring A, ring B and
X all have the meaning as described above for a final compound of
Formula (I).
[0102] Step 2: O-alkylation of an intermediate compound of Formula
(VII) with a suitable alkylating agent, such as, for example,
4-(methylphenyl)sulphonylchloride, by any of the art-known
procedures gives an intermediate compound of Formula (II) which is
new. This intermediate compound can be treated, for example, as in
Step (3) for Route A, yielding a final compound of Formula (I).
##STR00009##
[0103] Step 1: Epoxydation of the double bond of an intermediate
compound of Formula (III) by any of the art-known procedures, such
as, for instance, using 3-chloroperbenzoic acid, in an inert
solvent such as, for example, dichloromethane, yields an
intermediate compound of Formula (VIII). Typical reaction
conditions are stirring at room temperature for 8 hours. An
intermediate compound of Formula (VIII), wherein R.sup.9, i, j,
ring A, ring B and X have the meaning as described above for a
final compound of Formula (I), is new.
[0104] Step 2: Rearrangement of an intermediate compound of Formula
(VIII) under acidic conditions, such as, for example, Amberlyst 15,
in an inert solvent such as, for example, dichloromethane, yields
an intermediate compound of Formula (VII). This intermediate
compound can be treated, for example, as in Step (2) for Route B,
yielding a final compound of Formula (II) which can be treated, for
example, as in Step (3) for Route A, yielding a compound of Formula
(I).
##STR00010##
[0105] A final compound of Formula (Ib) wherein R.sup.9, i, j, ring
A, ring B, X, R.sup.3, R.sup.4, p and q all have the meaning as
described above, can be prepared by reaction of a compound of
Formula (Ia) (prepared by any of the preparation routes A, B, C as
mentioned above) with a suitable alkylating agent, such as an acid
halide-, isocyanate-, sulphonylchloride derivatives, by any of the
art-known procedures (such as, for example, in the presence of a
suitable base such as polymer bound supported
diisopropylethylamine, in an inert solvent such as, for example,
dichloromethane).
##STR00011##
[0106] A preparation route for compound 3 with Formula (Ia) is
shown in the above scheme. Synthesis of the intermediate (VIa) is
described in WO 03/049146 A1, which is included herein by
reference.
[0107] Step 1: The same procedure described in Step 1 for route B.
Cyclization of an intermediate of Formula (VIa) in an acidic
reaction media, such as, for example hydrochloric acid in
isopropylic alcohol at room temperature gives an intermediate
compound of Formula (VIIa), which is novel.
[0108] Step 2: The same procedure described in step 2 of Route B.
O-Alkylation of an intermediate compound of Formula (VIIa) with a
suitable alkylating agent such as for example
4-(methylphenyl)sulphonyl chloride, by any of the art known
procedures, gives an intermediate compound of Formula (IIa), which
is new.
[0109] Step 3: This intermediate of Formula (IIa) can be treated,
for example as in step 3 for route A, with an amine such as, for
example methylamine, and a base such as, for example CaO, in an
organic solvent such as, for example THF, at high temperatures, for
example 120.degree. C., in pressurised reaction vessel for 8 hours,
yielding a final compound of Formula (Ia), which is novel.
[0110] Pure stereochemically isomeric forms of the compounds of
Formula (I) may be obtained by the application of art-known
procedures. Diastereomers may be separated by physical methods such
as selective crystallization and chromatographic techniques, e.g.
counter-current distribution, liquid chromatography and the
like.
[0111] The compounds of Formula (I) as prepared in the hereinabove
described processes are generally racemic mixtures of enantiomers
which can be separated from one another following art-known
resolution procedures. The racemic compounds of Formula (I) which
are sufficiently basic or acidic may be converted into the
corresponding diastereomeric salt forms by reaction with a suitable
chiral acid respectively with a suitable chiral base. Said
diastereomeric salt forms are subsequently separated, for example,
by selective or fractional crystallization and the enantiomers are
liberated therefrom by alkali or acid. An alternative manner of
separating the enantiomeric forms of the compounds of Formula (I)
involves liquid chromatography using a chiral stationary phase.
Said pure stereochemically isomeric forms may also be derived from
the corresponding pure stereochemically isomeric forms of the
appropriate starting materials, provided that the reaction occurs
stereospecifically. Preferably if a specific stereoisomer is
desired, said compound will be synthesized by stereospecific
methods of preparation. These methods will advantageously employ
enantiomerically pure starting materials.
EXPERIMENTAL PART
A. Preparation of the Intermediate Compounds
[0112] Hereinafter "RT" means room temperature, "HATU" means
1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide,
1-[bis(dimethylamino)methylene]hexafluorophoshate, "THF" means
tetrahydrofuran, "MTBE" means tert-butyl methyl ester, "DMAP" means
4-dimethylaminopyridine, "DIPEA" means diisopropylethylamine,
"DIPE" means diisopropylether and "DMF" means
N,N-dimethylformamide.
Example A1
a1. Preparation of Intermediate Compound 19
##STR00012##
[0114] A solution of 2,2-dimethyl-1,3-dioxane-4-carboxaldehyde (6.5
g; 0.050 mol) in THF (20 mL) was added slowly to a stirred solution
of
##STR00013##
((prepared according to teachings in WO03/048146 A1, of which the
content is herein included) (8.7 g; 0.038 mol) in THF (40 mL) at
20.degree. C. under N.sub.2-flow. Subsequently, anhydrous
MgCl.sub.2 (4.94 g) and potassium tert-butoxide (0.75 g) were added
at 20.degree. C. After stirring for 22 hours at 20-25.degree. C.,
HCl cp (1.3 mL) in H.sub.2O (69 mL) was added dropwise maintaining
the temperature between 20 and 25.degree. C. After 10 minutes of
stirring, the organic layer was separated and the solvent
evaporated to obtain 6.6 g of intermediate compound 19 (92%).
a2. Preparation of Intermediate Compound 20
##STR00014##
[0116] A mixture of intermediate compound 19 (15 g; 0.044 mol),
Pd/C 10% (1 g), MeOH (100 mL) was hydrogenated at 40 psi and rt for
16 hours. Then the catalyst was filtered off through celite. The
filtrated was collected and the solvent was evaporated under
reduced pressure to obtain 13 g of intermediate compound 20
(86%).
a3. Preparation of Intermediate Compound 1
##STR00015##
[0118] A mixture of
##STR00016##
(prepared according to teachings in WO03/048146 A1, of which the
content is herein included) (350 g; 1.028 mol), HCl (340 mL),
H.sub.2O (1.83 L) and THF (1.83 L) was stirred at room temperature
overnight. Subsequently, the reaction mixture was extracted with
toluene (2.times.2 L), the combined organic layers were washed with
1 N NaHCO.sub.3/H.sub.2O-solution (4 L) and dried over MgSO.sub.4.
After evaporation of the solvent under reduced pressure, the
residue was redissolved in DIPE (980 mL) and refluxed until a clear
solution was obtained. The solution was cooled to 40.degree. C.,
seeded and further cooled to room temperature while stirring
overnight. The precipitate was filtered off and dried under reduced
pressure overnight at 45.degree. C.
[0119] Yield: 198 g of intermediate compound 1 (68%).
a4. Preparation of Intermediate Compound 11
##STR00017##
[0121] A mixture of intermediate compound 20 (0.0499 mol) in
HCl/2-propanol (100 mL) and 2-propanol (250 mL) was stirred for 1.5
hours at room temperature. The solvent was evaporated under reduced
pressure. The residue as dissolved in CH.sub.2Cl.sub.2 (300 mL).
The organic solution was washed with an aqueous NaHCO.sub.3
solution (3.times.200 mL), water (2.times.200 mL), and brine
(2.times.100 mL), then dried (Na.sub.2SO.sub.4), filtered and the
solvent was evaporated. Yield: 14 g of intermediate compound 11
(99%).
b1. Preparation of Intermediate Compound 2
##STR00018##
[0123] To a stirred mixture of intermediate compound 1 (320 g;
1.134 mol), Et.sub.3N (253 g; 2.5 mol) and CH.sub.2Cl.sub.2 (4.8
L), DMAP (144 g; 1.18 mol) and 4-(methylphenyl)sulphonyl chloride
(480 g; 2.5 mol) were added at room temperature. After stirring
overnight at room temperature, the reaction mixture was washed
twice with 3 L H.sub.2O, dried over MgSO.sub.4 and concentrated
under vacuum. The residue was redissolved in 2.3 L of iPrOH and 1.4
L of toluene and refluxed until a clear solution was obtained. The
solution was cooled to 30.degree. C., seeded and further cooled to
room temperature while stirring overnight. The precipitate was
filtered off and dried under reduced pressure overnight at
45.degree. C. Yield: 312 g of intermediate compound 2 (63%).
b2. Preparation of Intermediate Compound 12
##STR00019##
[0125] A mixture of intermediate compound 11 (prepared according to
A1.a-4) (0.0496 mol) and Et.sub.3N (0.0496 mol) in
CH.sub.2Cl.sub.2, dry (500 mL) was stirred for 15 minutes at room
temperature. The reaction mixture was washed with an aqueous
NH.sub.4Cl solution (2.times.100 mL), 1 N HCl (2.times.200 mL), an
aqueous NaHCO.sub.3 solution (2.times.200 mL) and brine
(2.times.200 mL). The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvent was evaporated. The
residue was purified by short open column chromatography over
silica gel (eluent: heptane/EtOAc 6/4). The product fractions were
collected and the solvent was evaporated. Yield: 16.4 g of
intermediate compound 12.
Example A2
a. Preparation of Intermediate Compound 3
##STR00020##
[0127] Reaction under N.sub.2: a mixture of
2-fluoro-dibenzo[b,f]thiepin-11-(10H)-one (0.0347 mol) in dry THF
(40 mL) was added dropwise to a suspension of NaH (60% in mineral
oil) (0.0371 mol) in dry THF (80 mL). The reaction mixture was
cooled on an ice-bath and then allowed to reach room temperature,
then the mixture was stirred for 1 hour and a mixture of
3-bromo-1-propene (0.0347 mol) in dry THF (30 mL) was added
dropwise. The reaction mixture was stirred at room temperature for
16 hours, then quenched with a saturated NH.sub.4Cl solution and
extracted with CH.sub.2Cl.sub.2. The organic layer was dried
(Na.sub.2SO.sub.4) and the solvent was evaporated. This residue was
purified by short open column chromatography, the product fractions
were collected and the solvent was evaporated. Yield: 7.57 g of
intermediate compound 3 (77%).
b. Preparation of Intermediate Compound 4
##STR00021##
[0129] Reaction under N.sub.2:
bis(pyridine)iodine(I)tetrafluoroborate (0.0015 mol) was added to a
solution of intermediate compound 3 (prepared according to A2.a)
(0.00145 mol) in dry CH.sub.2Cl.sub.2 (50 mL) at room temperature,
then the reaction mixture was quenched with aqueous sodium
thiosulphate. The organic layer was separated, washed with brine
and with water, dried (Na.sub.2SO.sub.4) and the solvent was
evaporated (vacuum). The residue was purified by short open column
chromatography. The product fractions were collected and the
solvent was evaporated. Yield: 0.3 g of intermediate compound 4
(50%).
Example A3
a. Preparation of Intermediate Compound 5
##STR00022##
[0131] A mixture of
2-fluoro-5,10-dihydro-11H-dibenzo[a,d]cyclohepten-11-one (0.3027
mol), 3-bromo-1-propene (0.303 mol), K.sub.2CO.sub.3 (0.605 mol) in
N,N-dimethylformamide (500 mL) was mixed and heated overnight at
60.degree. C. Water and toluene were added and the organic layer
was separated, then the aqueous layer was extracted 2 times with
toluene. The organic layers were combined, washed 2 times with
water and with brine, then dried (Na.sub.2SO.sub.4) and the solvent
was evaporated (vacuum). The residue was purified by
high-performance liquid chromatography; the product fractions were
collected and the solvent was evaporated. Yield: 40 g of
intermediate compound 5 (49.6%).
b. Preparation of Intermediate Compound 6
##STR00023##
[0133] A solution of intermediate compound 5 (prepared according to
A3.a) (0.150 mol) in toluene (200 mL) was heated at 220.degree. C.
(reaction temperature) for 10 hours in a high pressure Parr reactor
vessel, then the reaction mixture was cooled to room temperature
and the solvent was evaporated (vacuum). The residue was purified
by short open column chromatography over silica gel (eluent:
CH.sub.2Cl.sub.2). The product fractions were collected and the
solvent was evaporated. Yield: 20 g of intermediate compound 6
(50%).
c. Preparation of Intermediate Compound 7
##STR00024##
[0135] Reaction under N.sub.2: bis(pyridine)iodine(I)
tetrafluoroborate (0.0826 mol) was added to a solution of
intermediate compound 6 (prepared according to A3.b) (0.07515 mol)
in dry CH.sub.2Cl.sub.2 (q.s.) at room temperature and the reaction
mixture was stirred for 0.5 h, then the reaction mixture was
quenched with aqueous sodium thiosulphate. The organic layer was
separated, washed with brine and with water, dried
(Na.sub.2SO.sub.4) and the solvent was evaporated (vacuum). The
residue was purified by short open column chromatography, then the
product fractions were collected and the solvent was evaporated
giving the intermediate compound 7 (92%).
d. Preparation of Intermediate Compound 18
##STR00025##
[0137] A mixture of intermediate compound 7 (prepared according to
A3.c) (0.0051 mol) and KCN (0.0102 mol) in DMF (5 mL) and H.sub.2O
(1 mL) was stirred for 4 hours at 60.degree. C. in a sealed tube.
The resultant mixture was diluted with water, then extracted with
EtOAc. The organic layer was separated, dried, filtered and the
solvent evaporated under reduced pressure. The residue was purified
by short column chromatography over silica gel. The product
fractions were collected and the solvent was evaporated.
[0138] Yield: 0.98 g of intermediate compound 18 (66%).
Example A4
a. Preparation of Intermediate Compound 8
##STR00026##
[0140] A mixture of NaH (60% in mineral oil) (0.00746 mol) in THF
(q.s.) was stirred under N.sub.2 at room temperature and a mixture
of 6H-[1]benzothiepino[2,3-b]indol-11(12H)-one (0.00678 mol) in THF
(q.s.) was added, then the resulting suspension was stirred for 3
hours and a mixture of 3-bromo-1-propene (0.00746 mol) in THF
(q.s.) was added dropwise. The resulting solution became gradually
a suspension and the reaction mixture was stirred for 16 hours,
then a saturated NH.sub.4Cl solution was added. The organic layer
was separated, washed with water and with brine, dried, filtered
off and the solvent was evaporated. The residue was purified by
short open column chromatography. The product fractions were
collected and the solvent was evaporated.
[0141] Yield: 1.8 g intermediate compound 8.
b. Preparation of Intermediate Compound 9
##STR00027##
[0143] A mixture of NaH (60%) (0.0046 mol) in THF (q.s.) was
stirred under N.sub.2 and a mixture of intermediate compound 8
(0.00418 mol) in THF (q.s.) was added, then the resulting mixture
was stirred for 4 hours at room temperature and a mixture of
3-bromo-1-propene (0.0046 mol) in THF (q.s.) was added dropwise.
The reaction mixture was stirred for 16 hours and a satd.
NH.sub.4Cl solution was added. The organic layer was separated,
dried, filtered off and the solvent was evaporated. Yield: 0.848 g
of intermediate compound 9 (used as such in the next reaction step
without further purification).
c. Preparation of Intermediate Compound 10
##STR00028##
[0145] A mixture of intermediate compound 9 (0.00029 mol) in
CH.sub.2Cl.sub.2 (15 mL) was stirred under N.sub.2 at room
temperature and bis(pyridine)iodine(I) tetrafluoroborate (0.00035
mol) was added, then the reaction mixture was stirred for 30
minutes and a saturated Na.sub.2S.sub.2O.sub.3 solution was added.
The organic layer was separated, dried and the solvent was
evaporated. The residue was purified by short open column
chromatography (eluent: EtOAc/Heptane 1/4). The product fractions
were collected and the solvent was evaporated. Yield: 0.1 g of
intermediate compound 10.
Example A5
a. Preparation of Intermediate Compound 13
##STR00029##
[0147] 3-chlorobenzenecarboperoxoic acid (previously dried, 0.07
mol) in CH.sub.2Cl.sub.2 (q.s.) was added dropwise to a mixture of
2-fluoro-5H-dibenzo[a,d]cycloheptene (prepared according to the
teachings in WO 03/040122 and WO 99/19317 of which the content is
included herein) (0.046 mol), hydroquinone (catalytic quantity) and
NaHCO.sub.3 (0.093 mol) in CH.sub.2Cl.sub.2 (q.s.), stirred an
refluxed. The reaction mixture was stirred and refluxed for 3
hours, then cooled and washed three times with a saturated
NaHCO.sub.3 solution. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered and the solvent was evaporated. Yield:
10.05 g of intermediate compound 13.
b. Preparation of Intermediate Compound 14
##STR00030##
[0149] A solution of intermediate compound 13 (prepared according
to A5.a) (0.044 mol) in THF (100 mL) was cooled on an ice-water
bath under N.sub.2 and then bromo-2-propenyl magnesium (0.05745
mol; 1.0 M) was added dropwise. The reaction mixture was stirred
and refluxed for 2 hours. The mixture was cooled, then carefully
treated with a NH.sub.4Cl solution and extracted with EtOAc. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered off
and the solvent was evaporated. The dry residue was purified by
short open column chromatography (eluent: Heptane/EtOAc 85/15). The
product fractions were collected and the solvent was evaporated.
Yield: 6 g of intermediate compound 14 (51%).
c. Preparation of Intermediate Compounds 15 and 16
##STR00031##
[0151] A mixture of intermediate compound 14 (prepared according to
A5.b) (0.00473 mol), Pyridinium chlorochromate (0.0071 mol) and
NaOAc (0.0123 mol) in CH.sub.2Cl.sub.2 (100 mL) was stirred for 2
hours at room temperature, then the reaction mixture was diluted
with CH.sub.2Cl.sub.2 (100 mL) and filtered over silica gel. The
organic layer was concentrated and the solvent was evaporated under
reduced pressure. The obtained residue (1 g) was purified by short
open column chromatography (eluent: Heptane/EtOAc 95/5). Two
product fractions were collected and the solvent was evaporated.
Yield fraction 1: 0.21 g of intermediate compound 15 and yield
fraction 2: 0.3 g of intermediate compound 16.
d. Preparation of Intermediate Compound 17
##STR00032##
[0153] A mixture of intermediate compound 16 (prepared according to
A5.c) (0.0011265 mol) and bis(pyridine)iodine(I) tetrafluoroborate
(0.0013518 mol) in CH.sub.2Cl.sub.2 (50 mL) was stirred under
N.sub.2 for 1 hour at room temperature and then the reaction
mixture was washed with Na.sub.2S.sub.2O.sub.3, with 1N HCl, with
H.sub.2O and with brine. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered off and the solvent was evaporated.
The residual oil was purified by short open column chromatography
(eluent: Heptane/EtOAc 9/1). The product fractions were collected
and the solvent was evaporated. Yield: 0.330 g of intermediate
compound 17 (75%).
Example A6
a. Preparation of Intermediate Compounds 27, 28
##STR00033##
[0155] A mixture of 2-bromo-5H-Dibenzo[a,d]cycloheptene (5.38 g;
0.02 mol) in THF (250 mL) at r.t., NaBH.sub.4 (3 g; 0.079 mol) was
added portionwise. A solution of boron trifluorate etherate (12.93
mL, 0.105 mol) in THF (40 mL) was added dropwise. The resulting
mixture was stirred at rt for 24 h. Water (30 mL) and methanol (30
mL) were carefully added. NaOH (3 M; 100 mL) was added followed of
15 mL of H.sub.2O.sub.2 (30% v/v). The resulting mixture was
stirred at room temperature for 4 hours. Et.sub.2O (150 mL) and
EtOAc (100 mL) were added. Layers were separated and the organic
one was washed with brine and water, dried (Na.sub.2SO.sub.4) and
vacumm concentrated, affording a mixture of intermediate compounds
27 and 28
b. Preparation of Intermediate Compounds 29, 30
##STR00034##
[0157] To a mixture of intermediate compounds 27 and 28 (2 g; 6.92
mmol) in CH.sub.2Cl.sub.2 (40 mL), pyridinium chlorochromate (2.84
g; 13.14 mmol) was added and the resulting mixture was stirred for
3 hours. The mixture was filtered over silicagel and the filtrate
was vacumm concentrate. The residue thus obtained was purified by
flash chromatography (eluent: heptane/CH.sub.2Cl.sub.2, 4:1) to
give intermediate compound 29 and intermediate compound 30.
c. Preparation of Intermediate Compound 21
##STR00035##
[0159] A mixture of intermediate compound 29 (0.0021 mol),
Zn(CN).sub.2 (0.00136 mol) and Pd(PPh.sub.3).sub.4 (0.00021 mol) in
DMF (5 ml; previously deoxygenated) was stirred at room temperature
and the reaction mixture was heated under microwave conditions for
15 minutes at 120.degree. C. The mixture was filtered and the
solvent (DMF) was evaporated. The obtained residue was diluted with
EtOAc and then washed with H.sub.2O and with brine. The organic
layer was separated, dried (Na.sub.2SO.sub.4), filtered off and the
solvent was evaporated. The residual oil was purified by column
chromatography over silica gel (eluent: Heptane/EtOAc 85/15). The
product fractions were collected and the solvent was evaporated.
Yield: 0.350 g of intermediate compound 21 (58%).
d. Preparation of Intermediate Compound 22
##STR00036##
[0161] A mixture of intermediate compound 21 (prepared according to
A6.c) (0.0015 mol), 3-bromo-1-propene (0.00165 mol) and
K.sub.2CO.sub.3 (0.003 mol) in DMF (15 mL) was stirred for 16 hours
at 60.degree. C. and then H.sub.2O and EtOAc were added. The
organic layer was separated and the aqueous layer was extracted 2
times with EtOAc. The organic layers were combined, washed 2 times
with brine and with water, then dried (Na.sub.2SO.sub.4), filtered
and the solvent was evaporated. Yield: 0.330 g of intermediate
compound 22 (80%).
e. Preparation of Intermediate Compound 23
##STR00037##
[0163] A mixture of intermediate compound 22 (prepared according to
A6.d) (0.001 mol) in toluene (25 mL) was stirred for 16 hours at
190.degree. C. and then the solvent was evaporated. Yield: 0.1 g of
intermediate compound 23 (33%).
f. Preparation of Intermediate Compound 23
##STR00038##
[0165] A mixture of intermediate compound 23 (prepared according to
A6.e) (0.000366 mol) and bis(pyridine) iodine (1.sup.+),
tetrafluorate (1.sup.-) (0.000439 mol) in CH.sub.2Cl.sub.2 (20 ml)
was stirred for 1 hour at room temperature and under N.sub.2, then
the reaction mixture was washed with Na.sub.2S.sub.2O.sub.3, with
H.sub.2O and with brine. The organic layer was separated, dried
(Na.sub.2SO.sub.4), filtered off and the solvent was evaporated.
The residual oil was purified by short open column chromatography
over silica gel (eluent: Heptane/EtOAc 9/1). The product fractions
were collected and the solvent was evaporated. Yield: 0.04 g of
intermediate compound 24 (27%).
[0166] This intermediate compound 24 is used as starting material
for final compound 133 which is prepared according to B2.b.
Example A7
a. Preparation of Intermediate Compound 25
##STR00039##
[0168] A mixture of NaH (60%) (0.059 mol) in THF (q.s.) was stirred
at -30.degree. C. under N.sub.2 and a mixture of
5,10-dihydro-4H-benzo[5,6]cyclohepta[1,2-b]thiophen-4-one (0.056
mol) in THF (q.s.) was added dropwise in 30 minutes, then the
resulting mixture was gradually warmed to room temperature and
stirred for 1 hour. A mixture of 3-bromo-1-propene (0.056 mol) in
THF (50 mL) was added dropwise in 30 minutes and the reaction
mixture was stirred for 16 hours. A 10% NH.sub.4Cl solution was
added and the mixture was stirred for 15 minutes, water was added
and the aqueous solution was extracted with CH.sub.2Cl.sub.2. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered off
and the solvent was evaporated under reduced pressure. The residue
was purified by short open column chromatography (eluent:
CH.sub.2Cl.sub.2). The product fractions were collected and the
solvent was evaporated. Yield: 9.82 g of intermediate compound 25
(68%).
b. Preparation of Intermediate Compound 26
##STR00040##
[0170] I.sub.2 (0.005 mol) was added to a solution of intermediate
compound 25 (prepared according to A7.a) (0.001 mol) in THF (4 mL)
and the resultant reaction mixture was stirred overnight at room
temperature. A saturated aqueous Na.sub.2S.sub.2O.sub.3 solution (2
mL) was added and the mixture was stirred vigorously. Then, the
mixture was extracted with EtOAc (3.times.5 mL). The organic layer
was separated, dried (MgSO.sub.4), filtered and the solvent was
evaporated. The residue was purified by column chromatography over
silica gel (eluent: EtOAc/heptane 5/95). The product fractions were
collected and the solvent was evaporated. Yield: 0.083 g of
intermediate compound 26 (39%).
c. Preparation of Intermediate Compound 31
##STR00041##
[0172] A mixture of intermediate compound
##STR00042##
(1.6 g; 4.08 mmol, prepared according to A5.d) NaN.sub.3 (0.56 g;
8.57 mmol) in DMF (20 mL) was heated at 85.degree. C. (oil bath
temperature) for 16 hours. The solvent was evaporated in vacuo and
the resulting residue was taken up in CH.sub.2Cl.sub.2 and washed
with water and brine, dried (Na.sub.2SO.sub.4), filtered and vacuum
concentrated to give 1.13 g of intermediate compound 31. (Yield:
90%)
B. Preparation of the Final Compounds
[0173] The compounds prepared hereinunder all are mixtures of
isomeric forms, unless otherwise specified.
Example B1
a) Preparation of Final Compound 3
##STR00043##
[0175] A solution of intermediate compound 2 (prepared according to
A1.b1) (290 g; 0.664 mol) and N-methylamine, 40% aqueous solution
(1.2 L) in 700 mL toluene was stirred during 16 hours at 90.degree.
C. in a high-pressure Parr apparatus. Subsequently, the layers were
separated and 1 L of toluene was added to the organic layer. After
washing the organic layer three times with water (3.times.1.5 L),
1.5 L of 10% CH.sub.3COOH/H.sub.2O was added and the layers were
separated. The water layer was neutralized to pH=10 with a
saturated aqueous K.sub.2CO.sub.3 solution and extracted with 2 L
of toluene. The toluene layer was dried over MgSO.sub.4, filtered
and concentrated under vacuum. Subsequently, the residue was
refluxed in 1.1 L of MTBE and 85 mL of HCl/iPrOH 6N was added over
30 minutes, after which the solution was refluxed for an additional
hour. The precipitate was filtered off and dried under reduced
pressure at 45.degree. C. Yield: 132 g of final compound 3
(60%).
b) Preparation of Final Compound 139
##STR00044##
[0177] A mixture of intermediate compound 2 (prepared according to
A1.b1) (0.0023 mol) and CaO (q.s.) in CH.sub.3NH.sub.2 (40 mL; 2.0
M) and THF (30 mL) was stirred for 16 hours in a high-pressure Parr
reactor vessel at 120.degree. C., then the resulting suspension was
filtered over celite and the filtrate was evaporated under reduced
pressure. The obtained residue was dissolved in CH.sub.2Cl.sub.2
and the solution was washed with NaHCO.sub.3, with brine and water,
then dried (Na.sub.2SO.sub.4), filtered off and the solvent was
evaporated. The residual oil was purified by short open column
chromatography (eluent: CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3)
97/3). The product fractions were collected and the solvent was
evaporated. Yield: 0.46 g of final compound 139 (68%).
c) Preparation of Final Compound 103
##STR00045##
[0179] A mixture of intermediate compound 12 (prepared according to
A1.b1 (0.000343 mol), phenylamine (0.00103 mol) and KI (0.000343
mol) in CH.sub.3CN (2 mL) was stirred for 45 minutes at 195.degree.
C. in a microwave oven. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (40 mL), then washed several times with water and
brine. The organic layer was separated, dried (Na.sub.2SO.sub.4),
filtered and the solvent was evaporated. The residue (oil) was
purified by short open column chromatography over silica gel
(eluent: CH.sub.2Cl.sub.2/heptane 1/1). The product fractions were
collected and the solvent was evaporated to give final compound
103.
Example B2
a. Preparation of Final Compound 18
##STR00046##
[0181] A mixture of intermediate compound 4 (prepared according to
A2.b) (0.00085 mol), ethylamine (0.0085 mol) and CaO (0.0085 mol)
in THF (q.s.) was heated at 140.degree. C. for 16 hours, then the
suspension was filtered through celite and the filtrate was
evaporated. The residue was dissolved in CH.sub.2Cl.sub.2, washed
with a 10% NaHCO.sub.3 solution and dried (Na.sub.2SO.sub.4). The
solvent was evaporated and the residue was purified by short open
column chromatography (eluent:
CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3 saturated) 97/3. The product
fractions were collected and the solvent was evaporated. The oily
residue was converted into the ethanedioic acid salt and the
desired product was collected by filtration and dried in vacuo.
Yield: 0.140 g of final compound 18 (m.p.: 240.7.degree. C.).
b. Preparation of Final Compound 134
##STR00047##
[0183] A mixture of intermediate compound 17 (prepared according to
A5.d) (0.00084 mol) and CaO (1 g) in CH.sub.3NH.sub.2 (15 mL; 2.0M
in THF) and THF (15 mL) was stirred in a high-pressure Parr reactor
vessel for 16 hours at 120.degree. C. The reaction mixture was
filtered over celite and the filtrate was evaporated under reduced
pressure. The residue was dissolved in CH.sub.2Cl.sub.2 (100 mL),
then this solution was washed with NaHCO.sub.3 (3.times.50 mL),
with water (3.times.50 mL) and with brine (2.times.50 mL). The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered off
and the solvent was evaporated. The residual oil was purified by
short open column chromatography (eluent:
CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3) 95/5). The product fractions
were collected and the solvent was evaporated. The residue was
converted into the ethanedioic acid salt and then the resulting
solid was collected and dried in vacuo.
[0184] Yield: 0.170 g of final compound 134 (68%).
c. Preparation of Final Compound 100 and 27 (Oxalate Salt)
##STR00048##
[0186] A mixture of
##STR00049##
(prepared according to A2.b) (0.00176 mol) and CaO (0.300 g) in
N,N-dimethylamine (10 mL, 2 M in THF) and THF (15 mL) was mixed and
heated at 130.degree. C. (oil bath temperature) for 8 hours in a
Parr reactor vessel, then the reaction mixture was cooled to room
temperature and the solids were filtered off. The solvent was
evaporated and the residue was purified by short open column
chromatography. The product fractions were collected and the
solvent was evaporated. Yield: 0.605 g (92.5%) of final compound
100. A part of the residue was treated with oxalic acid in
EtO.sub.2 and converted into the ethanedioic acid salt. The
resulting precipitate was collected and dried in vacuo. Yield: 57.2
mg of final compound 27.
Example B3
Preparation of Final Compounds 93 and 94
##STR00050##
[0188] A mixture of
##STR00051##
(prepared according to A4.c) (0.00019 mol) in methanol (15 mL) was
hydrogenated with Pd/C (0.050 g) as a catalyst. After uptake of
H.sub.2 (1 equivalent), the catalyst was filtered off and the
filtrate was evaporated and then evaporated under reduced pressure.
The residue was purified by short open column chromatography over
silica gel (eluent: CH.sub.2Cl.sub.2/CH.sub.3OH 98/2). Two product
fractions were collected and the solvent was evaporated. Yield
Fraction 1: 0.017 g of final compound 93. Yield Fraction 2: 0.0143
g of final compound 94.
Example B4
Preparation of Final Compound 31
##STR00052##
[0190] Procedure for compound 31, 33, 35, 36, 37, 38, 39, 40, 41
and 43: (reaction performed in a microwave oven). A mixture of
intermediate compound 7 (prepared according to A3.c) (0.00043 mol)
and 2-(methylamino)ethanol (0.00172 mol) in CH.sub.3CN (10 mL) was
mixed and heated at 130.degree. C. under microwave conditions (from
room temperature to 130.degree. C. in 5 min., P (max.): 600 W) for
20 minutes. The solvent CH.sub.3CN was evaporated and the resulting
concentrate was taken up in CH.sub.2Cl.sub.2, then, washed with a
saturated aqueous NaHCO.sub.3 solution. The organic layer was
separated, dried (Na.sub.2SO.sub.4) and the solvent was evaporated
(vacuum). The residue was taken up in CH.sub.2Cl.sub.2 (4 mL) and
PS-isocyanate (nucleophile scavenger) (0.00344 mol) was added. The
resulting mixture was shaken overnight in a Bohdan apparatus and
the resin was filtered off. PS-TsOH (polymer bound acid) (0.00344
mol) was added to the solution and the mixture was shaken for 3
hours. The solvent was removed by filtration and CH.sub.3OH was
added to the residue. The resulting mixture was shaken for 30
minutes and the solvent was filtered off again. Liquids were
discarded. A saturated CH.sub.3OH/NH.sub.3 solution was added to
the residue and the mixture was shaken for 1 hour, then the resin
was filtered off and the solvent was evaporated. The residue thus
obtained was treated with oxalic acid in EtO.sub.2 and converted
into the ethanedioic acid salt. The resulting precipitate was
collected and dried under vacuo yielding final compound 31.
Example B5
a. Preparation of Final Compound 22
##STR00053##
[0192] A mixture of final compound 21 (prepared according to B2.a
except for the last step where the compound was converted into its
salt) (0.00243 mol) in methanol (30 mL) was hydrogenated for 12
hours at 60 psi with Pd/C 10% (cat. quant.) as a catalyst. After
uptake of H.sub.2 (1 equivalent), the catalyst was filtered off and
the filtrate was evaporated. The residue was crystallised from
Et.sub.2O/CH.sub.2Cl.sub.2 and then the resulting precipitate was
collected. Yield: 0.450 g of final compound 22 (m.p.: 172.8.degree.
C.).
b. Preparation of Final Compounds 101 and 25
##STR00054##
[0194] Reaction under N.sub.2: a solution of final compound 100
(prepared according to B2.b) (0.00158 mol) in THF, dry (25 mL) was
cooled to -78.degree. C. and then n-BuLi, 1.6 M in Hexane (0.0016
mol) was added dropwise. The reaction mixture was allowed to slowly
reach room temperature, water was added and the organic solvent
(THF) was evaporated. The aqueous concentrate was extracted 2 times
with CH.sub.2Cl.sub.2 and the organic layers were combined, then
dried (Na.sub.2SO.sub.4). The solvent was evaporated (vacuum) and
the residue was purified by short open column chromatography over
silica gel (eluent: CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3) 100/0,
98/2). The product fractions were collected and the solvent was
evaporated. Yield: 70 mg of final compound 101. The residue was
treated with oxalic acid in EtO.sub.2 and converted into the
ethanedioic acid salt. The resulting precipitate was collected and
dried. Yield: 69 mg of final compound 25.
[0195] Intermediate compound 7 (prepared according to A3.c) (1
equivalent) was dissolved in CH.sub.2Cl.sub.2 (q.s) and
butylisocyanate (1 equivalent) was added at once. The vials were
shaken overnight in a Bohdan apparatus. PS-triamine (3 equivalents,
electrophile scavenger) and PS-isocyanate (3 equivalents,
(nucleophile scavenger) were added to the vials, to scavenge the
reactants, and the reaction mixtures was shaken for 6 hours. The
resins were filtered off and washed twice with CH.sub.2Cl.sub.2.
The combined organic layers were shaken with Amberlyst 15 (3
equivalents) in a Bohdan apparatus overnight (first step of a catch
and release process). The resin was filtered off and washed twice
with MeOH. The liquids were discarded. The resin was shaken twice
with MeOH(NH.sub.3) for 3 hours and filtered off (second step of a
catch and release process). The combined methanolic phases were
evaporated. This residue was taken up in CH.sub.2Cl.sub.2 and
trifluoroacetic acid (2 equivalents) was added; after stirring for
2 hours at room temperature volatiles were evaporated and the
residue was dried, affording the final compound 77.
Example B6
a. Preparation of Final Compound 51
##STR00055##
[0197] Reaction procedure for compounds 44, 46, 48, 49 and 51.
[0198] Intermediate compound 7 (prepared according to A3.c) (1
equivalent) was dissolved in CH.sub.2Cl.sub.2 (q.s.) and PS-DIEA
(polymer bound base) (3 equivalents) was added at room temperature.
Benzenemethanesulfonyl chloride (1 equivalent) was added at once.
The vial was shaken overnight in a Bohdan apparatus. PS-trisamine
(3 equivalents, electrophile scavenger) and PS-isocyanate (3
equivalents, nucleophile scavenger) were added to the vial and the
reaction mixture was shaken for 6 hours. The resins were filtered
off and washed twice with CH.sub.2Cl.sub.2. The combined organic
layers were shaken with Amberlyst 15 (3 equivalents) in a Bohdan
apparatus overnight (first step of a catch and release process).
The resin was filtered off and washed twice with
CH.sub.3OH(NH.sub.3) for 3 hours and filtered off (second step of a
catch and release process). The combined methanolic phases were
evaporated and the residue thus obtained was analysed by LCMS (if
the compound is not pure enough, it is purified by HPLC before the
treatment with trifluoroacetic acid). This residue was taken up in
CH.sub.2Cl.sub.2 and trifluoroacetic acid (2 equivalents) was
added; after stirring for 2 hours at room temperature volatiles
were evaporated and the residue was dried, affording the final
compound 51. Yield (Model Reaction): 0.137 g of final compound
51.
b. Preparation of Final Compound 77
##STR00056##
[0200] Reaction procedure for compounds 77, 79, 81, 83, 85, 87 and
89.
[0201] Intermediate compound 7 (prepared according to A3.c) (1
equivalent) was dissolved in CH.sub.2Cl.sub.2 (q.s.) and
butylisocyanate (1 equivalent) was added at once. The vials were
shaken overnight in a Bohdan apparatus. PS-trisamine (3
equivalents, electrophile scavenger) and PS-isocyanate (3
equivalents, nucleophile scavenger) were added to the vials, to
scavenge the reactants, and the reaction mixtures was shaken for 6
hours. The resins were filtered off and washed twice with
CH.sub.2Cl.sub.2. The combined organic layers were shaken with
Amberlyst 15 (3 equivalents) in a Bohdan apparatus overnight (first
step of a catch and release process). The resin was filtered off
and washed twice with CH.sub.3OH. The liquids were discarded. The
resin was shaken twice with CH.sub.3OH(NH.sub.3) for 3 hours and
filtered off (second step of a catch and release process). The
combined methanolic phases were evaporated. This residue was taken
up in CH.sub.2Cl.sub.2 and trifluoroacetic acid (2 equivalents) was
added; after stirring for 2 hours at room temperature volatiles
were evaporated and the residue was dried, affording the final
compound 77.
Example B7
a. Preparation of Final Compound 140
##STR00057##
[0203] A mixture of intermediate compound 18 (prepared according to
A3.d) (0.00336 mol) in saturated NH.sub.3/CH.sub.3OH (q.s.) was
hydrogenated for 2 hours at room temperature under 40 psi of
pressure with Raney Nickel as a catalyst. After uptake of H.sub.2
(2 equivalents), the catalyst was filtered off and the filtrate was
evaporated under reduced pressure. The residue was taken up into
CH.sub.2Cl.sub.2, washed with a saturated aqueous NaHCO.sub.3
solution, dried (Na.sub.2SO.sub.4), filtered and the solvent
evaporated. The residue was purified by short open column
chromatography over silica gel (eluent:
CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3) 96/4). The product fractions
were collected and the solvent was evaporated. Yield: 0.760 g of
final compound 140.
b. Preparation of Final Compounds 137 and 141
##STR00058##
[0205] A mixture of final compound 140 (prepared according to B7.a)
(0.000339 mol), HCHO, 37 wt % in water (0.00135 mol) and formic
acid (0.00271 mol) in CH.sub.3OH (5 mL) was stirred and refluxed
for 6 hours. The solvent was evaporated under reduced pressure. The
residue was redissolved in CH.sub.2Cl.sub.2. The organic solution
was washed with a saturated aqueous NaHCO.sub.3 solution, dried
(Na.sub.2SO.sub.4), filtered and the solvent evaporated under
reduced pressure. The residue was purified by short open column
chromatography over silica gel (eluent:
CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3) 97/3). The product fractions
were collected and the solvent was evaporated. Yield: 0.0815 g of
final compound 141 (74.4%). Final compound 141 was converted into
the hydrochloric acid salt (1:1), filtered off and dried. Yield:
0.080 g of final compound 137.
Example B8
a. Preparation of Final Compound 142
##STR00059##
[0207] A mixture of final compound 139 (prepared according to B1.b)
(0.01439 mol), chloroacetonitrile (0.01439 mol) and K.sub.2CO.sub.3
(0.036 mol) ub DMF (q.s.) was stirred for 16 hours at 100.degree.
C. The reaction mixture was diluted with EtOAc, then washed with
water, dried (Na.sub.2SO.sub.4), filtered and the solvent
evaporated affording final compound 142.
b. Preparation of Final Compound 125
##STR00060##
[0209] A mixture of final compound 142 (prepared according to B8.a)
(0.00060 mol), azidotrimethyl silane (0.00180 mol) and
dibutyloxystannane (0.00012 mol) in toluene (3 mL) was heated for 5
minutes at 170.degree. C. The solvent was evaporated. The residue
was purified by short open column chromatography (eluent:
CH.sub.2Cl.sub.2/CH.sub.3OH 96/4; then 80/20). The product
fractions were collected and the solvent was evaporated. The
residue was washed with diethyl ether, then dried. Yield: 0.108 g
of final compound 125 (48%).
c. Preparation of Final Compound 138
##STR00061##
[0211] Reaction under N.sub.2 atmosphere. Al(CH.sub.3).sub.3, 2
M/hexane (0.0015 mol) was added dropwise to a mixture of
methylamine (0.0015 mol) in toluene, dry (1 mL), stirred at
0.degree. C. The reaction mixture was stirred for 2 hours at room
temperature. A solution of final compound 142 (prepared according
to B8.a) (0.00075 mol) in toluene, dry (1.5 mL) was added. The
reaction mixture was heated in the microwave oven for 5 minutes at
150.degree. C. Methanol (1 mL) was added. The mixture was treated
with an aqueous NaHCO.sub.3 solution and CH.sub.2Cl.sub.2. The
organic layer was separated, dried (Na.sub.2SO.sub.4), filtered and
the solvent was evaporated. The residue was purified by short open
column chromatography (eluent: CH.sub.2Cl.sub.2/CH.sub.3OH 4/1),
then by HPLC. The product fractions were collected and the solvent
was evaporated. Yield: 0.017 g of final compound 138.
Example B9
a. Preparation of Final Compound 143 and 113
##STR00062##
[0213] A mixture of final compound 139 (prepared according to B1.b)
(0.021 mol), bromoacetic acid ethyl ester (0.021 mol) and
K.sub.2CO.sub.3 (0.053 mol) in DMF (30 mL) was stirred and heated
in a sealed tube for 16 hours at 100.degree. C. The reaction
mixture was cooled, diluted with EtOAc, washed with water
(2.times.), dried, filtered and the solvent evaporated under
reduced pressure. The residue was purified by short open column
chromatography over silica gel (eluent gradient:
CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3) 100/0 to 99/1). The product
fractions were collected and the solvent was evaporated. Yield:
7.65 g of final compound 143. An aliquot of final compound 143 was
converted into the hydrochloric acid salt (1:1). The precipitate
was filtered off and dried in vacuo to give final compound 113.
b. Preparation of Final Compound 107
##STR00063##
[0215] A solution of final compound 143 (prepared according to
B9.a) (0.0181 mol) in THF (40 mL) was stirred at room temperature.
A solution of LiOH (0.0199 mol) in H.sub.2O (20 mL) was added
dropwise and the resultant reaction mixture was stirred for 16
hours at room temperature. The mixture was acidified carefully with
2 N HCl until pH reached value 7. The resultant mixture was
extracted with CH.sub.2Cl.sub.2, washed with brine, dried
(Na.sub.2SO.sub.4), filtered and the solvent evaporated under
reduced pressure. The residue was treated with diethyl ether, then
dried. Yield: 4.58 g of final compound 107 (mp: 194.7.degree.
C.).
c. Preparation of Final Compound 120
##STR00064##
[0217] A mixture of final compound 107 (prepared according to B9.b)
(0.00042 mol), HATU, (0.00051 mol) and Et.sub.3N (0.00102 mol) in
CH.sub.2Cl.sub.2 (5 mL) was stirred at room temperature.
Methanesulfonamide (0.00127 mol) was added and the resultant
reaction mixture was stirred for 16 hours at room temperature. The
reaction mixture was washed with a saturated aqueous NaHCO.sub.3
solution, dried (Na.sub.2SO.sub.4), filtered and the solvent was
evaporated. The residue was purified by preparative HPLC. The
product fractions were collected and the solvent was evaporated.
Yield: 0.0982 g of final compound 120 (mp: 88.5.degree. C.).
d. Preparation of Final Compound 123
##STR00065##
[0219] A mixture of final compound 108 (prepared according to B9.b)
(0.000527 mol), HATU (0.000527 mol) and Et.sub.3N (0.0012648 mol)
in CH.sub.2Cl.sub.2 (q.s.) was stirred for 10 minutes at room
temperature. CH.sub.3NH.sub.2, 2.0 M/THF (0.0015 mol) was added and
the reaction mixture was stirred for 3 hours at room temperature. A
saturated aqueous NH.sub.4Cl solution was added. The organic layer
was separated, washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered and the solvent was evaporated. The
residue was purified by short open column chromatography over
silica gel (eluent: CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3) 97/3).
The product fractions were collected and the solvent was
evaporated. Yield: 0.020 g of final compound 123.
Example B10
Preparation of Final Compound 124
##STR00066##
[0221] A mixture of final compound 139 (prepared according to B1.b)
(0.001 mol) and 1H-pyrrole-2,5-dione (0.00092 mol) in EtOAc (3 mL)
was stirred for 2 days at room temperature. The solvent was
evaporated. The residue was purified by short open column
chromatography over silica gel. The product fractions were
collected and the solvent was evaporated. Yield: 0.292 g of final
compound 124.
Example B11
a. Preparation of Final Compounds 144 and 2
##STR00067##
[0223] A mixture of intermediate compound 7 (prepared according to
A3.c) (0.00058 mol), CH.sub.3NH.sub.2 (0.00586 mol) and CaO (0.100
g) in THF (20 mL) was stirred and heated at 130.degree. C. (oil
bath temperature) for 10 hours in a high-pressure Parr reactor
vessel, then the reaction mixture was cooled to room temperature
and the solids were filtered off. The organic solvent (THF) was
evaporated, then the aqueous concentrate was taken up in
CH.sub.2Cl.sub.2 and the mixture was washed with a saturated
aqueous NaHCO.sub.3 solution. The organic layer was separated,
dried (Na.sub.2SO.sub.4) and the solvent was evaporated. The
residue was purified in a manifold (vacuum) using Sep-Pak silica
cartridge. The product fractions were collected and the solvent was
evaporated to give final compound 144. Final compound 144 was
treated with oxalic acid in EtO.sub.2 and converted into the
ethanedioic acid salt. The resulting precipitate was collected and
dried in vacuo to give final compound 2.
b. Preparation of Final Compound 127
##STR00068##
[0225] A mixture of final compound 144 (prepared according to
B11.a) (0.003 mol), ethylsulfonylchloride (0.0033 mol) and
Et.sub.3N (0.0039 mol) in CH.sub.2Cl.sub.2 (50 mL) was stirred for
2 hours at room temperature. The resultant reaction mixture was
washed with a 10% aqueous NaHCO.sub.3 solution, with water, dried
(Na.sub.2SO.sub.4), filtered and the solvent evaporated under
reduced pressure. The residue was purified by short open column
chromatography over silica gel (eluent: CH.sub.2Cl.sub.2/hexane
4/1). The product fractions were collected and the solvent was
evaporated. Yield: 0.431 g of final compound 127.
Example B12
Preparation of Final Compounds 102
##STR00069##
[0227] A mixture of intermediate compound 7 (prepared according to
A3.c) (0.019 mol), piperazine (0.193 mol) and CaO (8.0 g) in THF
(50 mL) was heated for 16 hours at 120.degree. C. (oil batch
temperature) in a high-pressure Parr reaction vessel and the
resulting suspension was filtered over celite. The filtrate was
evaporated under reduced pressure and the residue was partitioned
between CH.sub.2Cl.sub.2/H.sub.2O. After extraction of the aqueous
layer, the organic layer was washed with NaHCO.sub.3, with water
and with brine, then dried (Na.sub.2SO.sub.4), filtered off and the
solvent was evaporated under reduced pressure. The residue was
purified by short open column chromatography (eluent:
CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3) 95/5). The product fractions
were collected and the solvent was evaporated. Yield: 3.7 g of
final compound 102.
Example B13
Preparation of Final Compounds 95
##STR00070##
[0229] A mixture of intermediate compound 10 (prepared according to
A4.c) (0.000212 mol), CH.sub.3NH.sub.2(0.00212 mol) and CaO (q.s.)
in THF (q.s.) was heated in a high-pressure Parr vessel for 16
hours at 140.degree. C. (oil bath temperature), then the suspension
was filtered and the filtrate was evaporated under reduced
pressure. The residue was purified by short open column
chromatography (eluent: CH.sub.2Cl.sub.2/CH.sub.3OH 98/2). The
product fractions were collected and the solvent was evaporated.
Yield: 0.072 g of final compound 95.
Example B14
Preparation of Final Compounds 131
##STR00071##
[0231] Dimethylamine (0.0010 mol) was added to a solution of
intermediate compound 27 (prepared according to A7.b) (0.001 mol)
in THF (5 mL) and the resultant reaction mixture was stirred and
refluxed for 12 hours into a high-pressure Parr reaction vessel,
then cooled and solvent was evaporated in vacuo. The residue was
purified by column chromatography over silica gel (eluent:
EtOAc/methanol 90/10). The product fractions were collected and the
solvent was evaporated. Yield: 0.11 g of final compound 131 (39%;
mp. 174-176.degree. C.).
Example B15
Preparation of Final Compound 1
##STR00072##
[0233] A mixture of intermediate compound 31 (1.13 g; 0.0037 mol),
Pd/C 10% (catalytic) in Methanol (15 mL) and EtOAc (15 mL) was
hydrogenated at rt under hydrogen pressure of 50 psi for 1 h. Then,
the catalyst was filtered off throught a celite pad and the
filtrate was evaporated in vacuo. The resulting residue was
purified by short open column chromatography (eluent:
CH.sub.2Cl.sub.2, then CH.sub.2Cl.sub.2/MeOH(NH.sub.3) 96:4). The
product fractions were collected and vacumm evaporated to give 1 g
of final compound 1 (Yield: 96%)
Example B16
Preparation of Final Compound 6
##STR00073##
[0235] Reaction under Nitrogen atmosphere. To a solution of final
compound 5 (0.2 g; 0.56 mmol) in dry THF (20 mL) at -30.degree. C.,
nButylithium (1.6 M in hexanes) was dropwise added. The mixture was
allowed to slowly warm to rt. Water was added and layers were
separated. The organic phase was dried (Na.sub.2SO.sub.4) and
vacumm concentrated, affording a residue that was purified by short
open column chromatography. The product fractions were collected
and vacumm evaporated to give final compound 6. (Yield: 10%)
[0236] Tables 1-5 list compounds of Formula (I), which were
prepared according to one of the above examples. Table 5 shown LCMS
data for a selected set of compounds.
TABLE-US-00001 TABLE 1 ##STR00074## Co. Physical No Ex. No. R.sup.1
R.sup.2 X R.sup.B data 1 B15 H H CH.sub.2 F RS-enantiomeric mixture
144 B11.a H CH.sub.3 CH.sub.2 F RS-enantiomeric mixture 2 B11.a H
CH.sub.3 CH.sub.2 F RS-enantiomeric mixture; .cndot.oxalate 3 B1.a
H CH.sub.3 CH.sub.2 F R, .cndot.HCl; m.p. 244.9.degree. C.;
.alpha.D +75.55.degree. (Na), c 0.54 4 B1.a H CH.sub.3 CH.sub.2 F
S, .cndot.HCl; m.p. 249.2.degree. C.; .alpha.D -75.55.degree. (Na),
c 0.54 139 B1.b H CH.sub.3 CH.sub.2 F R 5 B1.3 H CH.sub.3 CH.sub.2
Br RS-enantiomeric mixture 6 B16 H CH.sub.3 CH.sub.2 nBu
RS-enantiomeric mixture 7 B1.b H CH.sub.3 ##STR00075## H 2RS, 8RS 8
B1.b H CH.sub.3 ##STR00076## F 2RS, 8RS 9 B1.b H CH.sub.3
##STR00077## H 2RS, 8RS; .cndot.HCl 10 B1.b H CH.sub.3 ##STR00078##
H 2RS, 8RS; .cndot.HCl 11 B1.b H CH.sub.3 ##STR00079## H
RS-enantiomeric mixture; .cndot.oxalate 12 B2.c H CH.sub.3 O F
RS-enantiomeric mixture; .cndot.oxalate 13 B2.a H CH.sub.3 S F R*,
.cndot.oxalate; m.p. 234.4.degree. C.; .alpha.D free base
+48.1.degree. (Na), c 0.43 14 B2a H CH.sub.3 S F S*,
.cndot.oxalate; m.p. 231.5.degree. C.; .alpha.D free base
-50.0.degree. (Na), c 0.33 30 B2a H CH.sub.2CH.sub.3 CH.sub.2 F
RS-enantiomeric mixture; .cndot.oxalate 15 B2a H CH.sub.2CH.sub.3
CH.sub.2 F R*, .cndot.oxalate; m.p. 234.6.degree. C.; .alpha.D free
base -69.3.degree. (Na), c 0.39 16 B2a H CH.sub.2CH.sub.3 CH.sub.2
F S*, .cndot.oxalate; m.p. 240.7.degree. C.; .alpha.D free base
+74.5.degree. (Na), c 0.44 17 B2a H CH.sub.2CH.sub.3 CH.sub.2 Br
RS-enantiomeric mixture 18 B2a H CH.sub.2CH.sub.3 S F
RS-enantiomeric mixture; .cndot.oxalate; m.p. 240.7.degree. C.; 19
B2a H CH.sub.2CH.sub.2OH CH.sub.2 F RS-enantiomeric mixture;
.cndot.oxalate; m.p. 209.degree. C.; 20 B2a H CH.sub.2CH.sub.2OH
CH.sub.2 Br RS-enantiomeric mixture; m.p. 140.2.degree. C.; 103
B1.c --H ##STR00080## CH.sub.2 F 2S 104 B1.c --H ##STR00081##
CH.sub.2 F 2S 105 B1.c --H ##STR00082## CH.sub.2 F 2S 106 B1.c --H
##STR00083## CH.sub.2 F 2S 21 B1.b CH.sub.3 CH.sub.3 CH.sub.2 Br
RS-enantiomeric mixture 22 B5a CH.sub.3 CH.sub.3 CH.sub.2 H
RS-enantiomeric mixture; .cndot.oxalate; m.p. 172.8.degree. C.; 23
B1a CH.sub.3 CH.sub.3 CH.sub.2 H R*, .cndot.oxalate; m.p.
185.7.degree. C.; .alpha.D +39.5.degree. (Na), c 0.44 24 B1a
CH.sub.3 CH.sub.3 CH.sub.2 H S*, .cndot.oxalate; m.p. 189.6.degree.
C.; .alpha.D -39.5.degree. (Na), c 0.55 101 B5b CH.sub.3 CH.sub.3 O
H RS-enantiomeric mixture 25 B5b CH.sub.3 CH.sub.3 O H
RS-enantiomeric mixture; .cndot.oxalate 26 B2b CH.sub.3 CH.sub.3 O
F RS-enantiomeric mixture; .cndot.oxalate 100 B2b CH.sub.3 CH.sub.3
O Br RS-enantiomeric mixture 27 B2b CH.sub.3 CH.sub.3 O Br
RS-enantiomeric mixture .cndot.oxalate 28 B2a CH.sub.3 CH.sub.3 S F
RS-enantiomeric mixture; .cndot.oxalate 29 B2a CH.sub.3 CH.sub.3
N--CH.sub.3 H RS-enantiomeric mixture; .cndot.oxalate 142 B8.a
--CH.sub.3 CH.sub.2CN CH.sub.2 F 2R 31 B4 CH.sub.3
CH.sub.2CH.sub.2OH CH.sub.2 F RS-enantiomeric mixture;
.cndot.oxalate 32 B1b CH.sub.3 CH.sub.2CH.sub.2OH O F
RS-enantiomeric mixture; .cndot.trifluoroacetate 107 B9.b
--CH.sub.3 ##STR00084## CH.sub.2 F 2R; m.p. 194.7.degree. C. 108
B9.b --CH.sub.3 ##STR00085## CH.sub.2 F 2R 109 B9.b --CH.sub.3
##STR00086## CH.sub.2 F 2R-(E) 145 B9.a --CH.sub.3 ##STR00087##
CH.sub.2 F 2R-(E) 110 B9.a --CH.sub.3 ##STR00088## CH.sub.2 F
2R-(E); (1:1) Hydrochloride; m.p. 136.8.degree. C. 111 B10.b
--CH.sub.3 ##STR00089## CH.sub.2 F 2R 112 B10.b --CH.sub.3
##STR00090## CH.sub.2 F 2R 143 B9.a --CH.sub.3 ##STR00091##
CH.sub.2 F 2R 113 B9.a --CH.sub.3 ##STR00092## CH.sub.2 F 2R (1:1)
Hydrochloride; m.p. 99.3.degree. C. 146 B9.a --CH.sub.3
##STR00093## CH.sub.2 F 2R 114 B9.a --CH.sub.3 ##STR00094##
CH.sub.2 F 2R; (1:1) Hydrochloride; m.p. 123.4.degree. C. 147 B9.a
--CH.sub.3 ##STR00095## CH.sub.2 F 2R 115 B9.a --CH.sub.3
##STR00096## CH.sub.2 F 2R; (1:1) Hydrochloride; m.p. 225.3.degree.
C. 148 B9.d --CH.sub.3 ##STR00097## CH.sub.2 F 2R 116 B9.d
--CH.sub.3 ##STR00098## CH.sub.2 F 2R; (1:1) Hydrochloride; m.p.
120.8.degree. C. 149 B9.a --CH.sub.3 ##STR00099## CH.sub.2 F 2R 117
B9.a --CH.sub.3 ##STR00100## CH.sub.2 F 2R; (1:1) Hydrochloride;
m.p. 145.2.degree. C. 150 B9.d --CH.sub.3 ##STR00101## CH.sub.2 F
2R 118 B9.d --CH.sub.3 ##STR00102## CH.sub.2 F 2R; (1:1)
Hydrochloride; m.p. 181.3.degree. C. 120 B9.d --CH.sub.3
##STR00103## CH.sub.2 F 2R 119 B9.d --CH.sub.3 ##STR00104##
CH.sub.2 F 2R; (1:1) Hydrochloride; m.p. 129.9.degree. C. 120 B9.c
--CH.sub.3 ##STR00105## CH.sub.2 F 2R; m.p. 88.5.degree. C. 121
B9.c --CH.sub.3 ##STR00106## CH.sub.2 F 2R 122 B9.c --CH.sub.3
##STR00107## CH.sub.2 F 2R; m.p. 156.1.degree. C. 123 B9.d
--CH.sub.3 ##STR00108## CH.sub.2 F 2R-(E) 124 B10.a --CH.sub.3
##STR00109## CH.sub.2 F 2R--(3'RS) 125 B8.b --CH.sub.3 ##STR00110##
CH.sub.2 F 2R 126 B10.b --CH.sub.3 ##STR00111## CH.sub.2 F 2R 127
B11.b --CH.sub.3 ##STR00112## CH.sub.2 F 2RS 138 B8.c --CH.sub.3
##STR00113## CH.sub.2 F 2R
TABLE-US-00002 TABLE 2 ##STR00114## Co. Physical No Ex. No.
--NR.sup.1R.sup.2 X R.sup.B data 33 B4 ##STR00115## CH.sub.2 F
RS-enantiomeric mixture .cndot.oxalate 34 B4 ##STR00116## S F
RS-enantiomeric mixture .cndot.oxalate 35 B4 ##STR00117## CH.sub.2
F RS-enantiomeric mixture .cndot.oxalate 36 B4 ##STR00118##
CH.sub.2 F RS-enantiomeric mixture .cndot.oxalate 37 B4
##STR00119## CH.sub.2 F RS-enantiomeric mixture .cndot.oxalate 38
B4 ##STR00120## CH.sub.2 F RS-enantiomeric mixture .cndot.oxalate
39 B4 ##STR00121## CH.sub.2 F RS-enantiomeric mixture
.cndot.oxalate 40 B4 ##STR00122## CH.sub.2 F RS-enantiomeric
mixture .cndot.oxalate 43 B1.b ##STR00123## CH.sub.2 F
RS-enantiomeric mixture .cndot.oxalate 102 B1.b ##STR00124##
CH.sub.2 F RS-enantiomeric mixture 41 B4 ##STR00125## CH.sub.2 F
RS-enantiomeric mixture .cndot.oxalate 42 B1.b ##STR00126## S F
RS-enantiomeric mixture .cndot.oxalate 44 B6a ##STR00127## CH.sub.2
F RS-enantiomeric mixture .cndot.trifluoroacetate 45 B6a
##STR00128## O F RS-enantiomeric mixture .cndot.trifluoroacetate 46
B6a ##STR00129## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 47 B6a ##STR00130## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 48 B6a ##STR00131## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 49 B6a ##STR00132##
CH.sub.2 F RS-enantiomeric mixture .cndot.trifluoroacetate 50 B6a
##STR00133## O F RS-enantiomeric mixture .cndot.trifluoroacetate 51
B6a ##STR00134## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 52 B6a ##STR00135## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 53 B6a ##STR00136## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 54 B6a ##STR00137##
O F RS-enantiomeric mixture .cndot.trifluoroacetate 55 B6a
##STR00138## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 56 B6a ##STR00139## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 57 B6a ##STR00140## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 58 B6a ##STR00141##
O F RS-enantiomeric mixture .cndot.trifluoroacetate 59 B6a
##STR00142## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 60 B6a ##STR00143## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 61 B6a ##STR00144## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 62 B6a ##STR00145##
O F RS-enantiomeric mixture .cndot.trifluoroacetate 63 B6a
##STR00146## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 62 B6a ##STR00147## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 65 B6a ##STR00148## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 66 B6a ##STR00149##
O F RS-enantiomeric mixture .cndot.trifluoroacetate 67 B6a
##STR00150## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 68 B6a ##STR00151## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 69 B6a ##STR00152## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 70 B6a ##STR00153##
O F RS-enantiomeric mixture .cndot.trifluoroacetate 71 B6a
##STR00154## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 72 B6a ##STR00155## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 73 B6a ##STR00156## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 74 B6a ##STR00157##
O F RS-enantiomeric mixture .cndot.trifluoroacetate 75 B6a
##STR00158## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 76 B6a ##STR00159## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 77 B6b ##STR00160## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 78 B6b ##STR00161##
O F RS-enantiomeric mixture .cndot.trifluoroacetate 79 B6b
##STR00162## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 80 B6b ##STR00163## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 81 B6b ##STR00164## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 82 B6b ##STR00165##
O F RS-enantiomeric mixture .cndot.trifluoroacetate 83 B6b
##STR00166## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 84 B6b ##STR00167## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 85 B6b ##STR00168## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 86 B6b ##STR00169##
O F RS-enantiomeric mixture .cndot.trifluoroacetate 87 B6b
##STR00170## CH.sub.2 F RS-enantiomeric mixture
.cndot.trifluoroacetate 88 B6b ##STR00171## O F RS-enantiomeric
mixture .cndot.trifluoroacetate 89 B6b ##STR00172## CH.sub.2 F
RS-enantiomeric mixture .cndot.trifluoroacetate 90 B6b ##STR00173##
O F RS-enantiomeric mixture .cndot.trifluoroacetate
TABLE-US-00003 TABLE 3 ##STR00174## Co. Ex. Physical No No R.sup.1
R.sup.2 X B data 131 B14 --CH.sub.3 --CH.sub.3 --CH.sub.2--
##STR00175## RS 91 B14 H CH.sub.3 N-benzyl ##STR00176## RS- enanti-
omeric mixture 92 B3 H CH.sub.3 S ##STR00177## RS- enanti- omeric
mixture .cndot.oxalate 93 B3 H CH.sub.3 S ##STR00178## RS- enanti-
omeric mixture 94 B3 CH.sub.3 CH.sub.3 S ##STR00179## RS- enanti-
omeric mixture 95 B3 H CH.sub.3 S ##STR00180## RS- enanti- omeric
mixture
TABLE-US-00004 TABLE 4 ##STR00181## Co. Ex. Physical No No R.sup.A
R.sup.B data 132 B2.b 4-F H RS-enantiomeric mixture;
.cndot.oxalate; m.p. 230.5.degree. C. 96 B2b 5-F H RS-enantiomeric
mixture 133 B2.b 5-CN H RS-enantiomeric mixture; .cndot.oxalate;
m.p. 187.6.degree. C. 97 B2.b 5-F H RS-enantiomeric mixture;
.cndot.oxalate; m.p. 231.3.degree. C. 99 B2.b 5-F 10-F
RS-enantiomeric mixture; .cndot.oxalate 98 B2.b 6-F 11-F
RS-enantiomeric mixture; .cndot.oxalate 134 B2.b 6-F H
RS-enantiomeric mixture; .cndot.oxalate; m.p. 214.7.degree. C. 135
B2.b H 10-F RS-enantiomeric mixture; .cndot.oxalate 136 B2.b H 12-F
RS-enantiomeric mixture; .cndot.oxalate
TABLE-US-00005 TABLE 5 ##STR00182## Co. Ex. Physical No No. R.sup.1
R.sup.2 n R.sup.B data 140 B7.a H H 2 F 2RS enantiomeric mixture
137 B7.b --CH.sub.3 --CH.sub.3 2 F 2RS enantiomeric mixture (1:1)
.cndot.HCl; m.p. 201.1.degree. C. 141 B7.b --CH.sub.3 --CH.sub.3 2
F 2RS enantiomeric mixture
[0237] The LCMS data shown in Table 6 have been obtained by the
following method:
[0238] The HPLC gradient was supplied by a HP 1100 from Agilent
with a column heater set at 40.degree. C. Flow from the column was
passed through photodiode array (PDA) detector and then split to a
Light Scattering detector (ELSD) and to a Waters-Micromass Time of
Flight (ToF) mass spectrometer with an electrospray ionization
source operated simultaneously in positive and negative ionization
mode.
[0239] Reversed phase HPLC was carried out on a XDB-C18 cartridge
(3.5 .mu.m, 4.6.times.30 mm) from Agilent, with a flow rate of 1
ml/min. Three mobile phases (mobile phase A: 0.5 g/l
ammoniumacetate solution, mobile phase B: acetonitrile; mobile
phase C: methanol) were employed to run a gradient condition from
80% A, 10% B, 10% C to 50% B and 50% C in 6.0 min., to 100% B at
6.5 min., kept till 7.0 min and reequilibrated with 80% A, 10% B
and 10% C at 7.6 min. that was kept till 9.0 min. An injection
volume of 5 .mu.L was used.
[0240] High Resolution Mass spectra were acquired by scanning from
100 to 750 in 1 s using a dwell time of 1 s. The capillary needle
voltage was 3 kV and the source temperature was maintained at
140.degree. C. Nitrogen was used as the nebulizer gas. Cone voltage
was 30 V for both positive and negative ionization mode.
Leucine-enkephaline was the reference used for the lock spray. Data
acquisition was performed with a Waters-Micromass MassLynx-Openlynx
data system. Unless otherwise specified, the parent peak mass
corresponds to the free base+H.sup.+.
TABLE-US-00006 TABLE 6 Analytical data Retention Parent peak mass
Co. No. time (ES+) Remarks 3 3.97 296 5 4.54 356 6 6.24 334 7 4.03
292 9 4.04 292 12 3.86 298 13 4.05 314 Correspond to the free base
14 4.18 314 Correspond to the free base 15 4.11 310 16 4.08 310 17
4.68 370 19 4.11 326 ES- = 324 20 4.64 386 21 5.74 370 25 4.85 294
26 4.95 312 27 5.79 372 28 5.41 328 29 4.51 307 30 4.14 301 31 5.03
340 33 4.84 352 34 4.93 370 35 5.09 379 36 5.05 366 38 5.22 394 39
5.92 408 40 6.30 458 41 4.85 395 42 4.93 413 43 5.68 352 44 5.45
429 45 5.19 431 46 5.64 443 47 5.40 445 48 6.16 491 49 6.36 385 50
6.16 507 51 6.08 505 52 5.87 507 53 5.28 393 54 5.00 395 55 5.84
421 56 5.59 423 57 5.66 419 58 5.42 421 59 5.33 451 60 5.07 453 61
6.11 423 62 5.88 425 63 6.32 437 64 6.11 439 65 6.35 471 66 6.14
473 67 6.32 501 68 6.11 503 69 6.47 485 70 6.27 487 71 5.97 455 72
5.74 457 73 5.99 422 74 5.76 487 75 5.63 422 76 5.37 424 77 5.82
450 78 5.60 452 79 6.07 476 80 5.85 478 81 5.36 478 82 5.40 482 83
5.83 470 ES- = 468 84 5.61 472 85 5.86 488 ES- = 486 87 5.81 484 88
5.59 486 89 5.75 500 ES- = 498 90 5.55 502 ES- = 500 92 4.51 349 93
5.13 377 94 6.22 391 95 4.91 375 98 4.01 314 99 4.05 314 103 6.35
358 104 5.50 374 105 6.21 388 106 6.50 388 107 3.71 354 108 3.72
368 109 3.89 380 110 6.67 412 111 6.16 416 113 6.11 382 114 6.34
414 115 5.13 353 116 5.36 367 117 5.47 381 118 6.13 429 119 6.29
459 120 3.52 431 121 4.37 485 122 4.09 493 123 5.18 393 124 5.11
393 125 3.54 378 126 5.45 388 132 3.80 296 133 3.46 303 134 3.86
296 135 3.93 296 136 3.71 296 137 4.78 324
C. Pharmacological Example
Example C.1
In Vitro Binding Affinity for 5-HT.sub.2A and 5-HT.sub.2C
Receptors
[0241] The interaction of the compounds of Formula (I) with
5-HT.sub.2A and 5-HT.sub.2C receptors was assessed in in vitro
radioligand binding experiments. In general, a low concentration of
a radioligand with a high binding affinity for the receptor is
incubated with a sample of a tissue preparation enriched in a
particular receptor (1 to 5 mg tissue) in a buffered medium (0.2 to
5 ml). During the incubation, the radioligands bind to the
receptor. When equilibrium of binding is reached, the receptor
bound radioactivity is separated from the non-bound radioactivity,
and the receptor bound activity is counted. The interaction of the
test compounds with the receptors is assessed in competition
binding experiments. Various concentrations of the test compound
are added to the incubation mixture containing the tissue
preparation and the radioligand. Binding of the radioligand will be
inhibited by the test compound in proportion to its binding
affinity and its concentration. The affinities of the compounds for
the 5-HT.sub.2 receptors were measured by means of radioligand
binding studies conducted with: (a) human cloned 5-HT.sub.2A
receptor, expressed in L929 cells using [.sup.125I]R91150 as
radioligand and (b) human cloned 5-HT.sub.2C receptor, expressed in
CHO cells using [.sup.3H]mesulergine as radioligand.
Example C.2
In Vitro Determination of NET Reuptake Inhibition
[0242] Cortex from rat brain was collected and homogenised using an
Ultra-Turrax T25 and a Dual homogeniser in ice-cold homogenising
buffer containing Tris, NaCl and KCl (50 mM, 120 mM and 5 mM,
respectively, pH 7.4) prior to dilution to an appropriate protein
concentration optimised for specific and non-specific binding.
Binding was performed with radioligand [.sup.3H]Nixosetine (NEN,
NET-1084, specific activity .about.70 Ci/mmol) diluted in ice cold
assay buffer containing Tris, NaCl and KCl (50 mM, 300 mM and 5 mM,
respectively, pH 7.4). at a concentration of 20 nmol/L. Prepared
radioligand (50 .mu.l) was then incubated (60 min, 25.degree. C.)
with membrane preparations pre-diluted to an appropriate protein
concentration (400 .mu.l), and with 50 .mu.l of either the 10% DMSO
control, Mazindol (10.sup.-6 mol/L final concentration), or
compound of interest. Membrane-bound activity was detected by
filtration through a Packard Filtermate harvester onto GF/B
Unifilterplates, washed with ice-cold Tris-HCl buffer, containing
NaCl and KCl (50 mM, 120 mM and 4 mM; pH 7.4; 6.times.0.5 ml).
Filters were allowed to dry for 24 h before adding scintillation
fluid. Scintillation fluid was allowed to saturate filters for 24 h
before counting in a Topcount scintillation counter. Percentage
specific bound and competition binding curves were calculated using
S-Plus software (Insightful).
Example C.3
In Vitro Binding Affinity for Human D2.sub.L Receptor
[0243] Frozen membranes of human Dopamine D2.sub.L
receptor-transfected CHO cells were thawed, briefly homogenised
using an Ultra-Turrax T25 homogeniser and diluted in Tris-HCl assay
buffer containing NaCl, CaCl.sub.2, MgCl.sub.2, KCl (50, 120, 2, 1,
and 5 mM respectively, adjusted to pH 7.7 with HCl) to an
appropriate protein concentration optimised for specific and
non-specific binding. Radioligand [.sup.3H]Spiperone (NEN, specific
activity .about.70 Ci/mmol) was diluted in assay buffer at a
concentration of 2 nmol/L. Prepared radioligand (50 .mu.l), along
with 50 .mu.l of either the 10% DMSO control, Butaclamol (10.sup.-6
mol/l final concentration), or compound of interest, was then
incubated (30 min, 37.degree. C.) with 400 .mu.l of the prepared
membrane solution. Membrane-bound activity was filtered through a
Packard Filtermate harvester onto GF/B Unifilterplates and washed
with ice-cold Tris-HCl buffer (50 mM; pH 7.7; 6.times.0.5 ml).
Filters were allowed to dry before adding scintillation fluid and
counting in a Topcount scintillation counter. Percentage specific
bound and competition binding curves were calculated using S-Plus
software (Insightful).
TABLE-US-00007 TABLE 7 Pharmacological data. NET Reuptake Co. No.
h-5HT.sub.2A h-5HT.sub.2C h-D2L Inhibition 34 9.9 9.3 8.0 6.3 14
9.6 9.7 7.6 8.6 38 9.5 8.9 8.7 5.4 18 9.4 8.9 7.8 8.5 28 9.4 9.3
7.9 8.3 4 9.3 9.2 7.2 8.0 36 9.2 9.2 8.2 5.2 2 9.2 9.0 7.1 7.8 5
9.1 9.1 7.5 6.6 33 9.1 9.1 7.4 5.9 37 9.0 8.7 7.7 5.4 1 8.8 9.1 6.5
6.5 19 8.8 9.0 7.2 7.4 123 8.7 8.7 7.3 6.7 89 8.7 8.5 7.4 5.2 59
8.7 8.3 6.5 <5 31 8.6 8.8 7.4 7.4 30 8.6 8.8 7.3 8.1 134 8.5 8.8
6.2 6.0 114 8.5 8.8 6.1 7.0 125 8.5 8.6 5.9 7.1 13 8.5 8.4 6.7 8.2
85 8.5 8.3 7.0 5.3 42 8.5 8.0 8.3 <5 57 8.4 7.7 6.5 5.3 73 8.4
7.5 7.1 5.6 22 8.4 8.4 6.2 7.1 77 8.4 8.1 6.9 5.1 53 8.4 8.1 6.7
5.7 55 8.4 8.0 6.5 5.6 41 8.3 7.9 8.0 5.1 135 8.3 8.6 5.5 6.2 71
8.2 7.8 6.9 5.3 40 8.2 8.6 7.3 5.4 90 8.2 7.5 6.3 5.7 3 8.2 8.2 6.4
7.8 27 8.1 8.6 7.3 6.3 95 8.1 8.2 6.4 6.8 117 8.0 8.7 5.6 6.1 61
8.0 7.7 6.7 5.5 132 8.0 8.4 n.d. 7.2 81 8.0 7.5 6.6 <5 115 8.0
8.4 5.9 6.3 26 8.0 8.1 6.4 7.4 116 8.0 8.1 5.5 5.6 107 8.0 8.1 5.4
5.8 83 8.0 8.0 6.6 5.3 108 7.9 7.9 5.4 6.4 137 7.9 8.5 5.8 6.8 110
7.9 8.3 6.8 6.0 12 7.9 8.1 6.7 7.4 74 7.9 7.0 6.6 6.1 138 7.9 8.2
5.5 6.1 109 7.8 7.9 5.5 6.4 32 7.8 7.6 6.3 6.7 113 7.8 8.0 5.8 5.4
67 7.7 7.3 6.4 5.5 72 7.6 7.2 6.4 5.2 93 7.6 8.0 6.4 7.0 133 7.6
n.d. 5.69 6.5 119 7.5 7.6 5.1 5.3 92 7.5 7.3 6.3 6.6 84 7.5 7.3 6.0
5.8 6 7.5 8.1 6.6 5.1 8 7.5 8.0 5.7 7.4 54 7.5 7.0 5.8 5.8 11 7.4
7.7 5.8 7.6 82 7.4 6.8 5.8 5.7 131 7.4 8.1 6.7 6.1 124 7.4 7.2
<5 5.2 80 7.4 7.1 6.0 5.8 79 7.4 7.1 5.8 5.1 65 7.3 6.9 6.0 5.5
76 7.3 6.8 6.6 5.7 7 7.3 7.7 5.7 7.2 75 7.3 6.5 6.1 <5 118 7.3
8.0 6.1 5.2 25 7.2 7.7 5.9 6.6 68 7.2 6.6 6.1 5.8 51 7.1 6.7 7.0
<5 62 7.1 6.7 6.2 <5 78 7.1 7.3 5.9 5.9 45 7.1 7.0 6.1 6.0 52
7.0 6.7 6.8 6.0 64 7.0 6.6 6.2 <5 9 7.0 7.3 5.4 7.1 56 7.0 7.0
5.9 5.8 126 6.9 8.4 n.d. 5.1 66 6.9 6.5 6.1 5.9 94 6.9 7.4 6.0 5.9
47 6.8 6.7 5.9 6.4 88 6.8 7.0 5.9 5.8 111 6.7 8.4 n.d. <5 50 6.7
6.5 5.7 5.8 112 6.7 7.2 n.d. 5.1 63 6.6 6.3 5.4 <5 29 6.5 6.9
5.2 7.1 49 6.5 6.7 5.7 <5 48 6.4 6.7 5.5 <5 91 6.4 6.5 5.4
5.3 69 6.3 6.0 5.9 5.1 87 6.2 7.0 6.1 5.1 70 6.0 6.2 6.6 <5 17
n.d. 8.9 7.6 7.0 24 n.d. 8.9 6.8 7.5 20 n.d. 8.8 7.5 6.3 16 n.d.
7.9 6.5 6.8 35 n.d. 7.8 7.4 <5 99 n.d. 8.7 6.4 6.7 23 n.d. 7.8
5.8 6.2 136 7.6 8.7 5.8 7.0 43 n.d. 7.7 7.1 5.8 58 n.d. 6.8 5.8 5.8
46 n.d. 6.7 6.3 <5 96 n.d. 8.5 6.1 7.1 10 n.d. 7.6 5.8 7.3 106
8.2 7.5 <5 <5 86 n.d. 7.4 6.6 <5 21 n.d. 9.1 7.8 6.6 15
n.d. 9.1 7.4 8.5 39 n.d. 7.3 7.3 <5 44 n.d. 7.3 6.8 <5 60
n.d. 7.1 5.7 5.8 127 6.7 8.0 <5 <5 n.d. = not determined
[0244] In Table 8 is demonstrated that the activity profile for
5-HT.sub.2A/C, D2L and NET Reuptake inhibition is virtually
unchanged while the complexity of the molecule has drastically been
reduced.
TABLE-US-00008 TABLE 8 Comparative in vitro analysis of a preferred
compound according to the invention with its corresponding prior
art analogue. NET Reuptake Co. No. h-5HT.sub.2A h-5HT.sub.2C h-D2L
Inhibition 13 (Table 1, WO 8.7 9.2 8 7.8 99/19317 4 9.3 9.2 7.2
8.0
D. Composition Examples
[0245] "Active ingredient" (A.I.) as used throughout these examples
relates to a compound of Formula (I), a pharmaceutically acceptable
acid addition salt, a stereochemically isomeric form thereof or a
N-oxide form thereof.
Example D.1
Oral Solution
[0246] Methyl 4-hydroxybenzoate (9 g) and propyl 4-hydroxybenzoate
(1 g) were dissolved in boiling purified water (4 l). In 3 l of
this solution were dissolved first 2,3-dihydroxybutanedioic acid
(10 g) and thereafter A.I (20 g). The latter solution was combined
with the remaining part of the former solution and
1,2,3-propanetriol (12 l) and sorbitol 70% solution (3 l) were
added thereto. Sodium saccharin (40 g) were dissolved in water (500
ml) and raspberry (2 ml) and gooseberry essence (2 ml) were added.
The latter solution was combined with the former, water was added
q.s. to a volume of 20 l providing an oral solution comprising 5 mg
of the active ingredient per teaspoonful (5 ml). The resulting
solution was filled in suitable containers.
Example D.2
Film-Coated Tablets
Preparation of Tablet Core
[0247] A mixture of A.I. (100 g), lactose (570 g) and starch (200
g) was mixed well and thereafter humidified with a solution of
sodium dodecyl sulfate (5 g) and polyvinylpyrrolidone (10 g) in
water (200 ml). The wet powder mixture was sieved, dried and sieved
again. Then there was added microcrystalline cellulose (100 g) and
hydrogenated vegetable oil (15 g). The whole was mixed well and
compressed into tablets, giving 10.000 tablets, each containing 10
mg of the active ingredient.
Coating
[0248] To a solution of methyl cellulose (10 g) in denaturated
ethanol (75 ml) there was added a solution of ethyl cellulose (5 g)
in dichloromethane (150 ml). Then there were added dichloromethane
(75 ml) and 1,2,3-propanetriol (2.5 ml). Polyethylene glycol (10 g)
was molten and dissolved in dichloromethane (75 ml). The latter
solution was added to the former and then there were added
magnesium octadecanoate (2.5 g), polyvinylpyrrolidone (5 g) and
concentrated colour suspension (30 ml) and the whole was
homogenated. The tablet cores were coated with the thus obtained
mixture in a coating apparatus.
Example D.3
Injectable Solution
[0249] Methyl 4-hydroxybenzoate (1.8 g) and propyl
4-hydroxybenzoate (0.2 g) were dissolved in boiling water (500 ml)
for injection. After cooling to about 50.degree. C. there were
added while stirring lactic acid (4 g), propylene glycol (0.05 g)
and A.I. (4 g). The solution was cooled to room temperature and
supplemented with water for injection q.s. ad 1000 ml, giving a
solution comprising 4 mg/ml of A.I. The solution was sterilized by
filtration and filled in sterile containers.
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