U.S. patent application number 11/294602 was filed with the patent office on 2006-06-08 for phenylpiperazine derivatives with a combination of partial dopamine-d2 receptor agonism and serotonin reuptake inhibition.
This patent application is currently assigned to SOLVAY PHARMACEUTICALS B.V.. Invention is credited to Roelof W. Feenstra, Mayke B. Hesselink, Cornelis G. Kruse, Andrew C. McCreary, Maria L. Pras-Raves, Axel Stoit, Jan-Willem Terpstra, Gustaaf J.M. Van Scharrenburg, Bernard J. Van Vliet.
Application Number | 20060122189 11/294602 |
Document ID | / |
Family ID | 40635724 |
Filed Date | 2006-06-08 |
United States Patent
Application |
20060122189 |
Kind Code |
A1 |
Feenstra; Roelof W. ; et
al. |
June 8, 2006 |
Phenylpiperazine derivatives with a combination of partial
dopamine-D2 receptor agonism and serotonin reuptake inhibition
Abstract
The invention relates to a group of novel phenylpiperazine
derivatives with a dual mode of action: serotonin reuptake
inhibition and partial agonism on dopamine-D.sub.2 receptors. The
invention also relates to the use of a compound disclosed herein
for the manufacture of a medicament giving a beneficial effect. The
compounds have the general formula (1): ##STR1## wherein the
symbols have the meanings given in the specification. and
tautomers, stereoisomers and N-oxides thereof, as well as
pharmacologically acceptable salts, hydrates and solvates of said
compounds of formula (1) and its tautomers, stereoisomers and
N-oxides.
Inventors: |
Feenstra; Roelof W.; (Weesp,
NL) ; Stoit; Axel; (Weesp, NL) ; Terpstra;
Jan-Willem; (Weesp, NL) ; Pras-Raves; Maria L.;
(Weesp, NL) ; McCreary; Andrew C.; (Weesp, NL)
; Van Vliet; Bernard J.; (Weesp, NL) ; Hesselink;
Mayke B.; (Weesp, NL) ; Kruse; Cornelis G.;
(Weesp, NL) ; Van Scharrenburg; Gustaaf J.M.;
(Weesp, NL) |
Correspondence
Address: |
FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER;LLP
901 NEW YORK AVENUE, NW
WASHINGTON
DC
20001-4413
US
|
Assignee: |
SOLVAY PHARMACEUTICALS B.V.
|
Family ID: |
40635724 |
Appl. No.: |
11/294602 |
Filed: |
December 6, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60634074 |
Dec 8, 2004 |
|
|
|
Current U.S.
Class: |
514/254.02 ;
544/368 |
Current CPC
Class: |
C07D 413/12 20130101;
C07D 263/58 20130101 |
Class at
Publication: |
514/254.02 ;
544/368 |
International
Class: |
A61K 31/496 20060101
A61K031/496; C07D 413/14 20060101 C07D413/14; C07D 413/02 20060101
C07D413/02 |
Claims
1. Compounds of the general formula (1): ##STR45## wherein X.dbd.S
or O, R.sub.1 is H, (C.sub.1-C.sub.6)alkyl, CF.sub.3,
CH.sub.2CF.sub.3, OH or O--(C.sub.1-C.sub.6)alkyl R.sub.2 is H,
(C.sub.1-C.sub.6)alkyl, halogen or cyano R.sub.3 is H or
(C.sub.1-C.sub.6)alkyl R.sub.4 is H, (C.sub.1-C.sub.6)alkyl,
optionally substituted with a halogen atom T is a saturated or
unsaturated carbon chain of 2-7 atoms, wherein one carbon atom may
be replaced with a nitrogen atom optionally substituted with an
(C.sub.1-C.sub.3)alkyl, CF.sub.3 or CH.sub.2CF.sub.3 group, an
oxygen atom or a sulphur atom, which chain is optionally
substituted with one or more substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy,
halogen, cyano, trifluoromethyl, OCF.sub.3, SCF.sub.3, OCHF.sub.2
and nitro, Ar is selected from the groups: ##STR46## which Ar group
is optionally further substituted with one or more substituents
selected from the group consisting of (C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.3)alkoxy, halogen, cyano, trifluoromethyl,
OCF.sub.3, SCF.sub.3 OCHF.sub.2 and nitro, and in which Ar groups
that contain a five-membered ring, the double bond in the
five-membered ring may be saturated, and tautomers, stereoisomers
and N-oxides thereof, as well as pharmacologically acceptable
salts, hydrates and solvates of said compounds of formula (1) and
its tautomers, stereoisomers and N-oxides.
2. Compounds of the formula (1) as claimed in claim 1, wherein the
phenylpiperazine part of the molecule is selected from the group
consisting of: ##STR47## ##STR48## in which formulae the dot
represents the attachment to `T` of formula (1), and wherein the
second part of the molecule, represented by the symbols -T-Ar in
formula (1), is selected from the group consisting of: ##STR49##
##STR50## ##STR51## ##STR52## ##STR53## ##STR54## ##STR55##
##STR56## in which formulae the dot represents the attachment to
the phenylpiperazine part of the compounds of formula (1). and
tautomers, stereoisomers and N-oxides thereof, as well as
pharmacologically acceptable salts, hydrates and solvates of said
compounds of formula (1) and its tautomers, stereoisomers and
N-oxides.
3. A pharmaceutical composition comprising, in addition to a
pharmaceutically acceptable carrier and/or at least one
pharmaceutically acceptable auxiliary substance, a
pharmacologically active amount of at least one compound of claim
1, or a salt thereof, as an active ingredient.
4. A method of preparing a composition as claimed in claim 3,
characterised in that at least one compound of claims 1 or a salt
thereof, is brought into a form suitable for administration
5. A compound as claimed in claim 1, or a salt thereof, for use as
a medicament.
6. Use of a compound as claimed in claim 1 for the preparation of a
pharmaceutical composition for the treatment of CNS disorders.
7. Use as claimed in claim 6, characterized in that said disorders
are aggression, anxiety disorders, autism, vertigo, depression,
disturbances of cognition or memory, Parkinson's disease,
schizophrenia and other psychotic disorders.
8. Use as claimed in claim 6, characterized in that said disorder
is depression.
9. Use as claimed in claim 6, characterized in that said disorders
are schizophrenia and other psychotic disorders.
10. Use as claimed in claim 6, characterized in that said disorder
is Parkinson's disease.
Description
[0001] The present invention relates to a group of novel
phenylpiperazine derivatives with a dual mode of action: serotonin
reuptake inhibition and partial agonism on dopamine-D.sub.2
receptors. The invention also relates to the use of a compound
disclosed herein for the manufacture of a medicament giving a
beneficial effect. A beneficial effect is disclosed herein or
apparent to a person skilled in the art from the specification and
general knowledge in the art. The invention also relates to the use
of a compound of the invention for the manufacture of a medicament
for treating or preventing a disease or condition. More
particularly, the invention relates to a new use for the treatment
of a disease or condition disclosed herein or apparent to a person
skilled in the art from the specification and general knowledge in
the art. In embodiments of the invention specific compounds
disclosed herein are used for the manufacture of a medicament
useful in the treatment of disorders in which dopamine-D.sub.2
receptors and serotonin, reuptake sites are involved, or that can
be treated via manipulation of those targets.
[0002] Compounds with a dual action as dopamine-D.sub.2 antagonists
and serotonin reuptake inhibitors are known from WO 00/023441, WO
00/069424 and WO 01/014330. This combination of activities is
useful for the treatment of schizophrenia and other psychotic
disorders: it enables a more complete treatment of all disease
symptoms (e.g. positive symptoms and negative symptoms).
[0003] The goal of the present invention was to provide further
compounds with a dual action as partial dopamine-D.sub.2
antagonists and serotonin reuptake inhibitors.
[0004] The invention relates to a group of novel compounds of the
formula (1): ##STR2## wherein:
[0005] X.dbd.S or O,
[0006] R.sub.1 is H, (C.sub.1-C.sub.6)alkyl, CF.sub.3,
CH.sub.2CF.sub.3, OH or O--(C.sub.1-C.sub.6)alkyl
[0007] R.sub.2 is H, (C.sub.1-C.sub.6)alkyl, halogen or cyano
[0008] R.sub.3 is H or (C.sub.1-C.sub.6)alkyl
[0009] R.sub.4 is H, (C.sub.1-C.sub.6)alkyl, optionally substituted
with a halogen atom [0010] T is a saturated or unsaturated carbon
chain of 2-7 atoms, wherein one carbon atom may be replaced with a
nitrogen atom, optionally substituted with an
(C.sub.1-C.sub.3)alkyl, CF.sub.3 or CH.sub.2CF.sub.3 group, an
oxygen atom or a sulphur atom, which chain is optionally
substituted with one or more substituents selected from the group
consisting of (C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy,
halogen, cyano, trifluoromethyl, OCF.sub.3, SCF.sub.3, OCHF.sub.2
and nitro, [0011] Ar is selected from the groups: ##STR3## [0012]
which Ar group is optionally further substituted with one or more
substituents selected from the group consisting of
(C.sub.1-C.sub.3)alkyl, (C.sub.1-C.sub.3)alkoxy, halogen, cyano,
trifluoromethyl, OCF.sub.3, SCF.sub.3, OCHF.sub.2 and nitro, [0013]
and in which Ar groups that contain a five-membered ring, the
double bond in the five-membered ring may be saturated, [0014] and
tautomers, stereoisomers and N-oxides thereof, as well as
pharmacologically acceptable salts, hydrates and solvates of said
compounds of formula (1) and its tautomers, stereoisomers and
N-oxides.
[0015] In the groups `Ar`, the dot represents the attachement point
of group `T`.
[0016] In the description of the substituents the abbreviation
`alkyl(C.sub.1-3)` means `methyl, ethyl, n-propyl or
isopropyl`.
[0017] Prodrugs of the compounds mentioned above are in the scope
of the present invention. Prodrugs are therapeutic agents which are
inactive per se, but are transformed into one or more active
metabolites. Prodrugs are bioreversible derivatives of drug
molecules used to overcome some barriers to the utility of the
parent drug molecule. These barriers include, but are not limited
to, solubility, permeability, stability, presystemic metabolism and
targeting limitations (Medicinal Chemistry: Principles and
Practice, 1994, Ed.: F. D. King, p. 215; J. Stella, "Prodrugs as
therapeutics", Expert Opin. Ther. Patents, 14(3), 277-280, 2004; P.
Ettmayer et al., "Lessons learned from marketed and investigational
prodrugs", J. Med. Chem., 47, 2393-2404, 2004). Pro-drugs, i.e.
compounds which when administered to humans by any known route, are
metabolised to compounds having formula (1), belong to the
invention. In particular this relates to compounds with primary or
secondary amino or hydroxy groups. Such compounds can be reacted
with organic acids to yield compounds having formula (1) wherein an
additional group is present which is easily removed after
administration, for instance, but not limited to amidine, enamine,
a Mannich base, a hydroxyl-methylene derivative, an
O-(acyloxy-methylene carbamate) derivative, carbamate, ester, amide
or enaminone.
[0018] N-oxides of the compounds mentioned above are in the scope
of the present invention. Tertiary amines may or may not give rise
to N-oxide metabolites. The extend to what N-oxidation takes place
varies from trace amounts to a near quantitative conversion.
N-oxides may be more active than their corresponding tertiary
amines or less active. Whilst N-oxides are easily reduced to their
corresponding tertiary amines by chemical means, in the human body
this happens to varying degrees. Some N-oxides undergo nearly
quantitative reductive conversion to the corresponding tertiary
amines, in other cases the conversion is a mere trace reaction or
even completely absent. (M. H. Bickel: "The pharmacology and
Biochemistry of N-oxides", Pharmaco-logical Reviews, 21(4),
325-355, 1969).
[0019] It has been found that the compounds according to the
invention show high affinity for both the dopamine D.sub.2 receptor
and the serotonin reuptake site. The compounds show activity at
dopamine D.sub.2 receptors with varying degree of agonism. All of
the compounds show activity as inhibitors of serotonin reuptake, as
they potentiate 5-HTP induced behaviour in mice (B. L. Jacobs., `An
animal behaviour model for studying central serotonergic synapses`;
Life Sci., 1976, 19(6) 777-785).
[0020] In contrast to the use of full dopamine-D.sub.2 receptor
agonists or antagonists, the use of partial dopamine-D.sub.2
receptor agonists offers a dynamic medication that self-adjusts on
a moment-to-moment basis to the endogenous state of the patient.
Thus, it provides the desired flexible modulation of the dopamine
system and avoidance of the many adverse effects caused either by
treatment using full dopamine-D.sub.2 receptor agonists like
bromocriptine (hallucinations, nausea, vomiting, dyskinesia,
orthostatic hypotension, somnolescence) or full dopamine-D.sub.2
receptor antagonists like haloperidol (emotional blunting,
dysphoria, tardive dyskinesia). Because of these many adverse
effects, full agonists and antagonists have found only very limited
use in the therapy of depressive and anxiety disorders. Partial
dopamine-D.sub.2 receptor agonists not only show a flexible
modulation and a favourable side-effect profile, they also have a
pronounced anxiolytic profile in relevant animal models (Drugs of
the Future 2001, 26(2): 128-132).
[0021] Partial dopamine-D.sub.2 receptor agonists, according to the
present invention, are compounds that--when tested in a
concentration response range--achieve activation in the functional
cAMP cell based assay (as described below). Partial
dopamine-D.sub.2 receptor agonists will act as an agonist in cases
when the endogenous synaptic tone of dopamine is low, or in the the
presence of a full dopamine-D.sub.2 receptor antagonist, and will
act as an antagonist in cases when the endogenous synaptic tone of
dopamine is high, or in the presence of a full dopamine D.sub.2
receptor agonist. Like full agonists, partial dopamine-D.sub.2
receptor agonists in general are active in sensitized systems. They
induce contralateral turning in rats with unilateral
6-hydroxy-dopamine (6-OHDA) lesions in the substantia nigra pars
compacta. In MPTP-treated common marmosets they produce potent and
long-lasting reversal of motor symptoms (Drugs of the Future 2001,
26(2): 128-132). In contrast to full agonists, however, partial
dopamine-D.sub.2 agonists are substantially less active in
non-sensitized systems: they hardly reverse reserpine induced
hypolocomotion in rats.
[0022] For the treatment of CNS disorders involving an overactive
dopaminergic system a pharmaceutical preparation combining partial
dopamine-D.sub.2 receptor agonistic activity having low intrinsic
functional activity with serotonin reuptake inhibitory activity is
recommended. In case of a disorder involving dopamine insufficiency
a pharmaceutical preparation combining partial dopamine-D.sub.2
receptor agonistic activity with high intrinsic functional activity
and serotonin reuptake activity according to the invention has
considerable advantages.
[0023] Disorders characterized by dynamic fluctuations in dopamine
neurotransmission like bipolar depression and addiction will profit
in particular from the flexible adjustment of the dopamine system
by the partial dopamine-D.sub.2 receptor agonists in the
pharmaceutical preparation. Combining this "dopaminergic
neurotransmission stabilizing" activity with serotonin reuptake
inhibitory activity will enhance antidepressive and anxiolytic
efficacy. The compounds can be used for the treatment of affections
or diseases of the central nervous system caused by disturbances in
the dopaminergic and serotonergic systems, for example: aggression,
anxiety, disorders, autism, vertigo, depression, disturbances of
cognition or memory, Parkinson's disease, and in particular
schizophrenia and other psychotic disorders.
[0024] Pharmaceutically acceptable salts may be obtained using
standard procedures well known in the art, for example by mixing a
compound of the present invention with a suitable acid, for
instance an inorganic acid such as hydrochloric acid, or with an
organic acid.
Pharmaceutical Preparations
[0025] The compounds of the invention can be brought into forms
suitable for administration by means of usual processes using
auxiliary substances such as liquid or solid carrier material. The
pharmaceutical compositions of the invention may be administered
enterally, orally, parenterally (intramuscularly or intravenously),
rectally or locally (topically). They can be administered in the
form of solutions, powders, tablets, capsules (including
microcapsules), ointments (creams or gel) or suppositories.
Suitable excipients for such formulations are the pharmaceutically
customary liquid or solid fillers and extenders, solvents,
emulsifiers, lubricants, flavorings, colorings and/or buffer
substances. Frequently used auxiliary substances which may be
mentioned are magnesium carbonate, titanium dioxide, lactose,
mannitol and other sugars, talc, lactoprotein, gelatin, starch,
cellulose and its derivatives, animal and vegetable oils such as
fish liver oil, sunflower, groundnut or sesame oil, polyethylene
glycol and solvents such as, for example, sterile water and mono-
or polyhydric alcohols such as glycerol.
[0026] Compounds of the present invention are generally
administered as pharmaceutical compositions which are important and
novel embodiments of the invention because of the presence of the
compounds, more particularly specific compounds disclosed herein.
Types of pharmaceutical compositions that may be used include but
are not limited to tablets, chewable tablets; capsules, solutions,
parenteral solutions, suppositories, suspensions, and other types
disclosed herein or apparent to a person skilled in the art from
the specification and general knowledge in the art. In embodiments
of the invention, a pharmaceutical pack or kit is provided
comprising one or more containers filled with one or more of the
ingredients of a pharmaceutical composition of the invention.
Associated with such container(s) can be various written materials
such as instructions for use, or a notice in the form prescribed by
a governmental agency regulating the manufacture, use or sale of
pharmaceuticals products, which notice reflects approval by the
agency of manufacture, use, or sale for human or veterinary
administration.
Pharmacological Methods
In Vitro Affinity for Dopamine-D.sub.2 Receptors
[0027] Affinity of the compounds for dopamine-D.sub.2 receptors was
determined using the receptor binding assay described by 1. Creese,
R. Schneider and S. H. Snyder: "[.sup.3H]-Spiroperidol labels
dopamine receptors in rat pituitary and brain", Eur. J. Pharmacol.,
46, 377-381, 1977.
In Vitro Affinity for Serotonin Reuptake Sites
[0028] Affinity of the compounds for serotonin reuptake sites was
determined using the receptor binding assay described by E. Habert
et al.,: "Characterisation of [.sup.3H]-paroxetine binding to rat
cortical membranes", Eur. J. Pharmacol., 118, 107-114, 1985.
Inhibition of Forskolin-Induced [.sup.3H]-cAMP Accumulation
[0029] The in vitro functional activity at dopamine-D.sub.2
receptors, including the intrinsic activity (E) of the compounds of
the invention was measured by their ability to inhibit
forskolin-induced [.sup.3H]-cAMP accumulation.
[0030] Human dopamine D.sub.2,L receptors were cloned in fibroblast
cell line CHO-K1' cells and obtained from Dr. Grandy, Vollum
Institute, Portland, Oreg., USA. CHO cells were grown in a
Dulbecco's modified Eagle's medium (DMEM) culture medium,
supplemented with 10% heat-inactivated fetal calf serum, 2 mM
glutamine, 1 mM pyruvate, 5000 units/ml penicillin, 5000 .mu.g/ml
streptomycin and 200 .mu.g/ml G-418 at 37.degree. C. in 93% air/7%
CO.sub.2. For incubation with test compounds, confluent cultures
grown in 24 wells plates were used. Each condition or substance was
routinely tested in quadruplicate. Cells were loaded with 1 .mu.Ci
[.sup.3H]-adenine in 0.5 ml medium/well. After 2 hours, cultures
were washed with 0.5 ml PBS containing 1 mM of the
phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) and
incubated for 20 min with 0.5 ml PBS containing 1 mM IBMX and
forskolin with or without test compound. After aspiration the
reaction was stopped with 1 ml trichloroacetic acid 5% (w/v). The
[.sup.3H]-ATP and [.sup.3H]-cAMP formed in the cellular extract
were assayed as described by Solomon Y, Landos C, Rodbell M, 1974,
A highly selective adenylyl cyclase assay, Anal Biochem 58:541-548
and Weiss S, Sebben M, Bockaert J J, 1985, Corticotropin-peptide
regulation of intracellular cyclic AMP production in cortical
neurons in primary culture, J Neurochem 45:869-874. 0.8 ml Extract
was passed over Dowex (50WX-4 200-400 mesh) and aluminumoxide
columns, eluted with water and 0.1M imidazole (pH=7.5). Eluates
were mixed with 7 ml Insta-gel and radioactivity was counted with a
liquid scintillation counter. The conversion of [.sup.3H]-ATP into
[.sup.3H]-cAMP was expressed as the ratio in percentage
radioactivity in the cAMP fraction as compared to combined
radioactivity in both cAMP and ATP fractions, and basal activity
was subtracted to correct for spontaneous activity.
[0031] Test compounds were obtained as 10 mM stock solutions in
100% DMSO, and diluted in PBS/IBMX to final concentrations.
Typically, compounds were used in concentrations that ranged from
10.sup.-10M to 10.sup.-5M. From quadruplicate data counts, the mean
was taken as an estimate for drug-induced, receptor-mediated
effects at specified second messenger accumulation, expressed as
percentage of control values (forskolin-stimulated cAMP
accumulation, subtracted by basal activity). By using the
non-linear curve-fitting program INPLOT or the Excel-add-in XL-Fit,
mean values were plotted against drug concentration (in molar) and
a sigmoid curve (four-parameter logistic curve) was constructed.
The maximal forskolin-induced stimulated conversion is taken as
maximum value and the maximal inhibition (usually at drug
concentrations 10.sup.-4 M or 10.sup.-5 M) as minimum and these
values were fixed during the fitting process. Thus, concentrations
of the compound, causing 50% of the maximally obtained inhibition
of forskolin-induced cAMP accumulation (EC.sub.50), are averaged
over several experiments and presented as mean pEC.sub.50.+-.SEM.
Antagonist potency is assessed by co-incubating cells with a fixed
agonist concentration and specified antagonist concentrations.
Curve fitting procedures are identical to those used for estimating
EC.sub.50 values. Thus IC.sub.50 values, i.e. the concentration
that is able to achieve 50% of maximal antagonism that can be
achieved by this compound. IC.sub.50 values are corrected using a
Cheng-Prussoff equation, correcting it for agonist concentration
and EC.sub.50 values that is obtained in the same experiment. Thus,
K.sub.b=IC.sub.50/(1+[agonist]/EC.sub.50, agonist). The
corresponding pA.sub.2 value is -log (K.sub.b).
Concentration-response curve fitting allows estimation of
pEC.sub.50 values and of maximal achievable effect (intrinsic
activity or efficacy (.epsilon.). A full receptor agonist has
.epsilon.=1, a full receptor antagonist has .epsilon.=0, and a
partial receptor agonist has an intermediate intrinsic
activity.
Dosages
[0032] The affinity of the compounds of the invention for
dopamine-D.sub.2 receptors and serotonine reuptake sites was
determined as described above. From the binding affinity measured
for a given compound of formula (1), one can estimate a theoretical
lowest effective dose. At a concentration of the compound equal to
twice the measured K.sub.i-value, 100% of the receptors likely will
be occupied by the compound. Converting that concentration to mg of
compound per kg of patient yields a theoretical lowest effective
dose, assuming ideal bioavailability. Pharmacokinetic,
pharmacodynamic, and other considerations may alter the dose
actually administered to a higher or lower value. The dosage
expediently administered is 0.001-1000 mg/kg, preferably 0.1-100
mg/kg of patient's bodyweight.
Treatment
[0033] The term `treatment` as used herein refers to any treatment
of a mammalian, preferably human condition or disease, and
includes: (1) preventing the disease or condition from occurring in
a subject which may be predisposed to the disease but has not yet
been diagnosed as having it, (2) inhibiting the disease or
condition, i.e., arresting its development, (3) relieving the
disease or condition, i.e., causing regression of the condition, or
(4) relieving the conditions caused by the disease, i.e., stopping
the symptoms of the disease.
Materials and Methods
[0034] .sup.1H and .sup.13C NMR spectra were recorded on a Bruker
Avance DRX600 instrument (600 MHz), Varian UN400 instrument (400
MHz) or on a Varian VXR200 instrument (200 MHz) using DMSO-D.sub.6
or CDCl.sub.3 as solvents with tetramethylsilane as an internal
standard. Chemical shifts are given in ppm (.delta. scale)
downfield from tetramethylsilane. Peakshapes in the NMR spectra are
indicated with the symbols `q` (quartet), `dq` (double quartet),
`t` (triplet), `dt` (double triplet), `d` (doublet), `dd` (double
doublet), `s` (singlet), `bs` (broad singlet) and `m` (multiplet).
Flash chromatography was performed using silica gel 60 (0.040-0.063
mm, Merck). Column chromatography was performed using silica gel 60
(0.063-0.200 mm, Merck). Mass spectra were recorded on a Micromass
QTOF-2 instrument with MassLynx application software for
acquisition and reconstruction of the data. Exact mass measurement
was done of the quasimolecular ion [M+H].sup.+. Melting points were
recorded on a Buchi B-545 melting point apparatus.
[0035] Yields refer to isolated pure products. The preparation of
the compounds having formula (I) will now be described in more
detail in the following Examples.
EXAMPLES
[0036] The H-atom of the N-H moiety of amines I-H to X-H can be
replaced by Q in two different chemical ways, A and B, eventually
leading to the compounds of the invention which are listed in table
1 (see below.
Method A:
[0037] The compounds were prepared via the synthesis depicted in
scheme A1: an amine (from FIG. 1) was reacted with Q-X (X=leaving
group like e.g. Cl, Br, I) in e.g. acetonitrile or butyronitrile
with Et(i-Pr).sub.2N acting as a base, in some cases KI (or NaI)
was added. Et.sub.3N ran be used instead of Et(i-Pr).sub.2N.
##STR4##
Example 1
[0038] ##STR5##
[0039] Scheme A2, Step i: To a suspension of 0.6 g (2.35 mmol) of
the piperazine hydrochloride I-H.HCl in 100 ml of acetonitril were
added 0.77 g (2.35 mmol) of the iodide, 0.71 g (4.7 mmol) of NaI
and 1.39 ml (8 mmol) of DIPEA. The mixture was refluxed for 20
hours and concentrated in vacuo. The residue was taken up in
CH.sub.2Cl.sub.2 and the resulting mixture washed with water. The
organic layer was dried on Na.sub.2SO.sub.4. The drying agent was
removed by filtration and the solvent by concentration in
vacuo.
[0040] The residue was purified by flash column chromatography
(SiO.sub.2, eluent CH.sub.2Cl.sub.2/MeOH/NH.sub.4OH 960/37.5/2.5).
The product containg fractions were concentrated in vacuo leaving a
residue which was stirred in diisopropylether. The solid material
was collected by filtration, yielding 0.79 g (81%) of compound 9.
M.p.: 228-230.degree. C.
Method B:
[0041] The compounds were prepared via the synthesis depicted in
scheme B1: an amine (from FIG. 1) was alkylated by means of a
reductive alkylation. Q-OH was oxidized to the corresponding
aldehyde Q'-CHO after which reductive alkylation was performed. THF
and DCE are suitable solvents for this type of reaction.
##STR6##
Example 2
[0042] The Swern oxidation was carried out according to literature:
Anthony J. Mancuso, Daniel Swern; Synthesis, (1981) 165-184.
##STR7## Scheme B2, Step i:
[0043] A solution of oxalyl chloride (0.45 ml, 5.2 mmol) in 15 ml
DCM is placed in a three-necked round bottom flask equipped with a
thermometer and two pressure-equalizing dropping funnels
respectively containing dimethyl sulfoxide (0.74 ml, 10.4 mmol) in
3 ml DCM, and the 3-(6-chloro-indazo-1-yl)-propanol Q56-OH (1.0 g,
4.7 mmol) in 5 ml DCM under an N.sub.2 atmosphere. The dimethyl
sulfoxide is added to the stirred oxalyl chloride solution at
-50.degree. C. to -60.degree. C. The reaction mixture is stirred
for 2 minutes and the alcohol is added within 5 minutes; stirring
is continued for an additional 15 minutes. Triethylamine (3.3 ml,
23.73 mmol) is added and the reaction mixture is stirred for 15
minutes and then allowed to warm to room temperature. Water is
added and the aqueous layer is re-extracted with additional DCM.
The organic layer is washed with 0.3 N HCl, water, 5% NaHCO.sub.3,
saturated NaCl solution and dried with Na.sub.2SO.sub.4. The
filtered solution is evaporated yielding the corresponding
aldehyde.
Scheme B2, Step ii:
[0044] The crude product containing the aldehyde (from step i) is
added to a stirred solution of
3-7-piperazin-1-yl-3H-benzooxazole-2-one.2HCl (V.2HCl) (0.57 g,
2.44 mmol) and tri-ethyl amine (0.76 ml, 5.38 mmol) in 100 ml DCE.
The reaction mixture is stirred for 1 hour and NaBH(OAc).sub.3
(0.83 g, 3.91 mmol) is added. The mixture is stirred for an
additional 8 hours. Water was added and the resulting fraction
extracted with DCM (3 times). The combined organic layers were
evaporated. The crude product was purified by flash chromatography
on silica (eluent: 1.5% MeOH in DCM.fwdarw.2% MeOH in DCM) to
afford 128 as a crystalline solid in a 58% yield. Melting point:
118-120.degree. C. TABLE-US-00001 TABLE 1 examples of compounds of
the invention. Comp. L- melting nr. amine Q meth. group salt r.
.degree. C. 1 I 1 A I free base 194-196.5 2 I 2 A I free base
168-170 3 I 3 A I free base 206.5-207.5 4 I 4 A I free base
173.5-175 5 I 5 A I free base 173-176 6 I 6 A I free base 180-182 7
I 7 A I free base 211-213 8 I 8 A I free base 193-195 9 I 9 A I
free base 228-230 10 I 10 A I free base 186-188 11 I 11 A I free
base 176-178 12 I 12 A I free base 212-214 13 I 13 A I free base
183-184 14 I 14 A I HCl 225-227 15 I 15 A I HCl 255-260 16 I 16 A I
free base 143-145 17 I 17 A I free base 152-157 18 I 18 A I free
base 157-159 19 I 19 A I HCl 179-181 20 I 20 A I free base
174.5-177 21 I 21 A Cl free base 180-183 22 I 22 A I free base
206-208 23 I 23 A I free base 202-204 24 I 25 A I free base 154-156
25 I 29 A I free base amorph 26 I 30 A I free base 177-179 27 I 31
A I free base 153-156 28 I 32 A I free base 174-177 29 I 33 A Br
free base 187-190 30 I 34 A Br free base 190-192 31 I 35 A Br free
base 174-177 32 I 36 A Br free base 198-200 33 I 37 A Br free base
194-195 34 I 38 A Br free base 137-138 35 I 39 A Br free base
136-138 36 I 40 A Cl free base 121-123 37 I 41 A Br free base
133-135 38 I 42 A Br free base 135-137 39 I 43 A Cl free base
111-112 40 I 44 B free base 200-202 41 I 45 A Br free base 197-199
42 I 46 A Cl free base 162-164 43 I 47 A Br free base 204-206 44 I
48 A Cl free base 162-164 45 I 49 A Br free base 188-189 46 I 50 A
Cl free base 146-149 47 I 51 A Cl free base 109-113 48 I 52 A Br
free base 75-105 amorph 49 I 53 A Br free base 209-210 50 I 54 B
free base 201-203 51 I 55 B free base 161-162 52 I 56 B free base
203-204 53 I 57 B free base 83-86 54 I 58 B free base 172-174 55 I
59 B free base 134-137 56 I 60 A Br free base 214-6 57 I 61 A I HCl
214-6 58 I 62 A I HCl 275-7 (d) 59 I 63 A I free base NMR** 60 I 64
A Cl free base 234-6 61 II 3 A I free base 187-189 62 II 5 A I free
base 157-159 63 II 6 A I free base 154-156 64 II 8 A I free base
190-192 65 II 9 A I free base 234-236 66 II 11 A I free base
176-178 67 II 13 A I free base 236-239 68 II 15 A I free base
156-158 69 II 16 A I HCl 256-260 70 II 17 A I HCl 244-246 71 II 26
A I HCl 232-5 (d) 72 II 29 A I free base 157-158 73 II 31 A I free
base 190-1 74 II 32 A I free base 168-170 75 II 35 A Br free base
170-173 76 II 36 A Br free base 193-196 77 II 45 A Br free base
166-169 78 II 47 A Br free base 108-113 79 II 49 A Br free base
168-170 80 II 50 A Cl free base 194-7 81 II 59 B free base 153-5 82
II 61 A I free base 157-9 83 III 16 A I free base 153-154 84 IV 16
A I free base 163-5 85 V 1 A I free base 125-127 86 V 3 A I free
base 153-155 87 V 4 A I HCl 182-183 88 V 5 A I free base 113-116 89
V 6 A I free base 162-164 90 V 8 A I free base 119-121 91 V 9 A I
free base 150-152 92 V 10 A I free base 141-142 93 V 11 A I free
base 124-126 94 V 12 A I free base 184-186 95 V 13 A I HCl 107 96 V
14 A I HCl 197-199 97 V 15 A I HCl 216-218 98 V 16 A I HCl 199-201
99 V 17 A I HCl 214-218 100 V 18 A I free base 228-229 101 V 19 A I
free base 132-134 102 V 20 A I free base 138-140 103 V 22 A I free
base 143-145 104 V 23 A I free base 150-152 105 V 24 A I free base
179-181 106 V 25 A I HCl 197-199 107 V 26 A I free base 105-107 108
V 28 A I free base 146-147 109 V 31 A I free base 119-21 110 V 33 A
Br HCl >240 d 111 V 34 A Br free base 108-111 112 V 35 A Br free
base 129-132 113 V 36 A Br HCl >240 d 114 V 37 A Br free base
146-149 115 V 41 A Br free base 117-118 116 V 42 A Br free base
110-112 117 V 43 A Cl free base 167-170 118 V 45 A Br free base
111-113 119 V 46 A Cl free base 88-91 120 V 47 A Br free base
131-133 121 V 49 A Br free base 124-126 122 V 50 A Cl free base
103-105 123 V 51 A Cl free base 112-115 124 V 52 A Br free base
203-205 125 V 53 A Br HCl 262-264 126 V 54 B free base 116-118 127
V 55 B free base 104-107 128 V 56 B free base 118-120 129 V 57 A I
free base 108-112 130 V 58 B free base 102-104 131 V 59 B free base
125-128 132 V 60 A Br free base 202-3 133 V 61 A I HCl 194-7 134 V
62 A I HCl 274-6 (d) 135 V 63 A I free base NMR** 136 V 64 A Cl
free base 154-5 137 VI 16 A I free base 134-6 138 VI 31 A I free
base 125-6 139 VI 50 A Cl free base 116-8 140 VI 59 B free base
130-2 141 VII 16 A I HCl 274-276 142 VIII 16 A I free base 135-137
143 IX 3 A I free base 106-108 144 IX 6 A I free base 117-119 145
IX 49 A Br HCl 204-206 146 IX 50 A Cl free base 107-109 NMR**,
compound 59: (d, ppm) 3.36 (t, broad,
Ph--N(CH.sub.2CH.sub.2).sub.2N--) NMR**, compound 135: (d, ppm)
3.29 (t, broad, Ph--N(CH.sub.2CH.sub.2).sub.2N--)
**CDCl.sub.3/d.sup.6-DMSO = 1/4
[0045] Structures of the phehylpiperazine part of the compounds of
formula (1), herein termed `amines`, and groups `Q` are given
below. In the column `method`, the general method (A or B) is
given, and in case of method A, the next column gives the leaving
group.
[0046] The phenylpiperazine parts of the compounds of formula (1)
used in these methods are indicated as I-H to IX-H, wherein the dot
on the N-atom is the attachment point for the group Q: ##STR8##
##STR9##
[0047] The syntheses of the piperazines I-H, III-H and V-H are
described in WO97/36893. Synthesis of Amine II-H: ##STR10##
[0048] The synthesis of the starting material has been described
(patent DE487014).
Scheme II, Step i:
[0049] 30 g ((0.14 mol) of the starting material was suspended in
600 ml of MeOH. Then a small amount of Raney nickel was added after
which hydrogenation was started (atmospheric, room temperature).
After 24 hours 7.2 liters (theoretical amount 9.4 liters) of
hydrogen was absorbed. To the reaction mixture 150 ml of THF was
added and another small amount of Raney nickel. After one hour the
reaction mixture was filtered over hyflo, the residue washed with
THF. The filtrate was concentrated in vacuo, yielding 25.2 g (98%)
of the correspondig aniline.
Scheme II, Step ii:
[0050] 24.2 g (131.2 mmol) of the aniline of the previous step and
25.8 g (144.3 mmol) of bis (2-chloroethyl)amine were suspended in
675 ml of chlorobenzene. While stirring, 25 ml of solvent were
distilled off with the aid of a Dean-Stark apparatus. After removal
of the Dean-Stark apparatus, the reaction was allowed to reflux for
48 hours. When the reaction mixture had come to room temperature,
the mixture was decanted and the residue washed twice with
Et.sub.2O. Then 400 ml of MeOH were added after which the mixture
was warmed until almost all of the residue was dissolved. Then 200
ml of silica were added after which the whole was concentrated in
vacuo. Then the residue was put on top of a flash chromatography
column using DMA 0.75 as the eluent. After removal of the solvent a
residue was isolated which was suspended in about 100 ml of
acetonitrile and stirred for 4 hours. Filtration and drying yielded
17 g of the desired piperazine II-H as a free base. Synthesis of
Amine IV-H: ##STR11##
[0051] The toluene used in this experiment was degassed for three
hours prior to usage. 1.48 g (1.61 mmol) of Pd.sub.2(dba).sub.3 and
3.02 g (4.85 mmol) of BINAP were put into 400 ml of toluene after
which the mixture was stirred and heated to 105.degree. C. for 0.5
hours after which the mixture was allowed to room temperature.
Subsequently were added to the reaction mixture: 27.
Scheme IV, Step i:
[0052] 20.5 g (81.3 mmol) of dibromophenol and 20 g of potassium
carbonate were suspended in 400 ml of aceton, after which 15.7 ml
of benzylbromide were added. The reaction mixture was refluxed for
24 hours. After the mixture had reached room temperature, it was
concentrated in vacuo. Subsequently water was added and
CH.sub.2Cl.sub.2. The organic layer was filtered with a water
repellant filter, the dry filtrate concentrated in vacuo after
which it was dissolved again in 200 ml of acetonitrile.
Subsequently, 15 ml of piperidine were added after which the
temperature was raised to 60.degree. C. for one hour. The reaction
mixture was concentrated in vacuo and CH.sub.2Cl.sub.2 was added.
The latter was washed with: 1N HCl (3.times.), water, 2N NaOH, and
again water. The organic layer was filtered with a water repellant
filter, the dry filtrate concentrated in vacuo yielding 27.6 g
(99%) of the corresponding benzylated phenol.
Scheme IV, Step ii:
[0053] 6 g (80.7 mmol) of the benzylated compound (step i)
dissolved in 50 ml of toluene, 9.2 g (80.7 mmol) of the
(.alpha.,.alpha.')-dimethylpiperazine and 10.08 g (104.9 mmol) of
sodium tertbutoxide. The resulting mixture was heated at
105.degree. C. for 20 hours, after which it was allowed to reach
room temperature. The mixture was diluted with CH.sub.2Cl.sub.2
after which it was filtered over hyflo and concentrated in vacuo.
The residue was put on top of a flash chromatography column
(SiO.sub.2) using DMA 0.125. The combined product containing
fractions yielded after concentration in vacuo 7.7 g (26%) of the
almost pure phenylpiperazine.
Scheme IV, Step iii:
[0054] This step was done analogously to the procedure described in
the previous step ii (scheme IV). In this case benzylamine was used
in the Buchwald reaction. Yield: 88%.
Scheme IV, Step iv:
[0055] 7 ml (98 mmol) of acetyl chloride was added dropwise to 70
ml of cooled absolute ethanol, stirring was continued for 15
minutes. The latter solution was added to a solution of 11.5 g
(28.7 mmol) of the dibenzyl product of step iii in 250 ml of
methanol. Subsequently 1.5 g of Pd/C (10%) was added, after which
the reaction mixture was hydrogenated for 24 hours. The mixture was
filtered over hyflo, the filtrate concentrated in vacuo. The
residue containing the amino phenol HCl salt was directly used in
step v.
Scheme IV Step v:
[0056] The residue (28.7 mmol) obtained in step iv, 52 ml of DIPEA
(298 mmol), and 20.9 g (129 mmol) of CDI were added to 750 ml of
THF after which the mixture was refluxed for 20 hours under a
nitrogen atmosphere. After cooling to room temperature, the mixture
was concentrated in vacuo, to the residue CH.sub.2Cl.sub.2 and 5%
NaHCO.sub.3 were added, the whole being stirred for one hour.
Extraction with CH.sub.2Cl.sub.2 (3.times.), the water fraction was
concentrated and extracted again (CH.sub.2Cl.sub.2, 3.times.). The
combined organic fractions were concentrated in vacuo, the residue
contained a considerable amount of imidazol. The whole was solved
in 120 ml of acetonitrile after which the solution was allowed to
reach room temperature. The precipitate which formed was filtered
yielding almost pure piperazine IV. Synthesis of Amine V-H:
##STR12## Scheme V, Steps i, ii and iii:
[0057] Synthesis of V-H has been described in WO97/36893. The steps
i, ii and iii were done analogously to steps i, ii and iii in
scheme VI. Synthesis of Amine VI-H: ##STR13## Scheme VI, Step
i:
[0058] While stirring, 3.8 g (15 mmol) of piperazine II-H were
suspended in 5.48 ml (31.5 mmol) of DIPEA and the mixture was
brought to -40.degree. C. A solution of 3.14 g (14.4 mmol, 0.96 eq)
of Boc-anhydride in 30 ml of CH.sub.2Cl.sub.2 was added dropwise in
100 minutes. Stirring was continued at -40.degree. C. (1 hour),
then at -30.degree. C. (2 hours), and the reaction mixture was
allowed to come to room temperature (16 hours). Then water and some
MeOH were added after which it was extracted with CH.sub.2Cl.sub.2.
The combined organic fractions were filtered with a water repellant
filter, the dry filtrate mixed with 50 ml of silica after which the
whole was concentrated in vacuo. Then the residue was put on top of
a dry chromatography column (SiO.sub.2) using CH.sub.2Cl.sub.2/MeOH
(98/2) as the eluent. The part of the column containing the product
was cut out, and the product washed out of the column material with
CH.sub.2Cl.sub.2/MeOH (98/2) yielding 3.55 g (67%) of the desired
N-Boc II.
Scheme VI, Step ii:
[0059] 4.5 g (12.7 mmol) N-Boc II together with 5.8 g (3.3 eq) of
potassium carbonate were suspended in 100 ml of aceton. While
stirring, the reaction mixture was cooled to -10.degree. C. after
which 0.87 ml (14 mmol, 1.1 eq) of methyl iodide was added
dropwise. After 15 minutes, the reaction mixture was allowed to
reach room temperature and stirring was continued for 14 hours.
Subsequently, the reaction mixture was concentrated in vacuo, the
residue mixed with water and CH.sub.2Cl.sub.2. The water layer was
separated and extracted twice with CH.sub.2Cl.sub.2. The combined
organic layers were filtered with a water repellant filter, the dry
filtrate concentrated in vacuo yielding 4.5 g (98%) of the
corresponding N'-methylated N-Boc II.
Scheme VI, Step iii:
[0060] While stirring at -10.degree. C., 5 ml of acetyl chloride
(70.4 mmol, 5.8 eq) was added dropwise to 65 ml of ethanol. The
latter solution was added to 4.5 g (12.2 mmol) of the N'-methylated
N-Boc II isolated in step ii. The resulting mixture was stirred for
3 hours at 55.degree. C., then the reaction mixture was allowed to
reach room temperature and stirring was continued for 14 hours.
Subsequently, the mixture was concentrated in vacuo after which the
residue was suspended in di-isopropyl ether and stirred for 2
hours. The precipitate was isolated by filtration yielding 3.6 g
(97%) of piperazine VI-H.HCl. Synthesis of Amine VII-H: ##STR14##
Scheme VII, Step i:
[0061] This step was done analogously to step i in scheme IV. After
chromatograhic purification an oil containing the benzylated
product, was isolated in 88% yield. The oil solidified upon
standing.
Scheme VII, Step ii:
[0062] This step was done analogously to step ii in scheme IV.
Boc-piperazine was used in this Buchwald reaction. Yield after
chromatographic purification: 44% of a brown oil.
Scheme VII, Step iii:
[0063] This step was done analogously to the procedure described in
the previous step ii (scheme VII). In this case benzylamine was
used in the Buchwald reaction. Yield after chromatographic
purification: 73% of a brown oil.
Scheme VII, Step iv:
[0064] 11.91 g (24.3 mmol) of the dibenzylated product isolated in
previous step iii (scheme, VII) was suspended in a mixture of 110
ml of ethanol, 72 ml of water and 11 ml of acetic acid. While
stirring, 0.5 g of Pd(OH).sub.2/C was added and hydrogenation was
started for 6 days. After one day and after 3 days an additional
small amount of Pd(OH).sub.2/C was added. The reaction mixture was
filtered over hyflo, the filtrate concentrated in vacuo. The
residue was treated with toluene and concentrated in vacuo, this
procedure was repeated, leaving a dark sirup 7.9 g (88%),
containing the amino phenol.
Scheme VII, Step v:
[0065] This step (ring closure with CDI) was done analogously to
step v in scheme IV. The crude product after work up was
chromatographed (flash column, SiO.sub.2, eluent DCM/MeOH 97/3)
yielding 7.6 g of an impure brown foam. A second chromatography
(flash column, SiO.sub.2, eluent EtOAc/petroleum ether 1/2) yielded
3.3 g (42%) of pure brown foam, containing the N-Boc protected
benzoxazolinone piperazine.
Scheme VII, Step vi:
[0066] This methylation step was done analogously to the procedure
described in step ii (scheme VI). Yield: 98% of a brown foam of 97%
purity.
Scheme VII, Step vii:
[0067] This deprotection step was done analogously to the procedure
described in step iii (scheme VI). Yield: 94% of a light pink solid
of 98% purity, containing the product VII-H.HCl. Synthesis of Amine
VIII-H: ##STR15## Scheme VIII, Step i:
[0068] The starting material synthesis has been described in
EP0189612.
[0069] 4.91 g (32.7 mmol) of the anilin was suspended in 75 ml of
48% of HBr/water, while it was cooled to -5.degree. C. Subsequently
2.27 g (33 mmol) of sodium nitrite dissolved in 4 ml of water, were
added dropwise during 15 minutes. Stirring was continued at
0.degree. C. for 15 minutes.
[0070] Subsequently, the reaction mixture was added, in one time,
to a 0.degree. C. solution of 2.42 g (16.9 mmol) CuBr in 20 ml of
48% HBr/water. After 30 minutes the reaction mixture was heated to
85.degree. C. for one hour, after which it was allowed to reach
room temperature, stirring was continued for 14 hours. To the
mixture diethyl ether and water were added, after shaking the
organic layer was isolated which was washed with water. The organic
layer, together with some silica, was concentrated in vacuo, and
the residue was put on top of a flash chromatography column
(SiO.sub.2) using Et.sub.2O/petroleum ether (1/1), and later on
pure Et.sub.2O as the eluent. The combined product containing
fractions yielded after concentration in vacuo 3.3 g (47%) of the
desired corresponding bromo product.
Scheme VIII, Step ii:
[0071] This step was carried out identical to step ii in scheme VI.
Yield: 92% of the corresponding methylated bromo compound.
Scheme VIII, Step iii:
[0072] In the following order 6.82 g (29.9 mmol) of the methylated
bromo compound, 4.03 g (35.9 mmol) of the dimethyl piperazine, 13.6
g (41.9 mmol) of Cs.sub.2CO.sub.3, 1.42 g (2.99 mmol) of X-Phos
(see Huang et al., J. Am. Chem. Soc., 125(2003)6653). and 0.55 g
(0.6 mmol) of Pd.sub.2(dba).sub.3 were added to 225 ml of toluene
which was degassed for 4 hours prior to usage. While stirring and
under a nitrogen atmosphere the temperature was raised to
100.degree. C. for 20 hours, after which it was allowed to reach
room temperature. The mixture was diluted with CH.sub.2Cl.sub.2
after which it was filtered and concentrated in vacuo. The residue
was put on top of a flash chromatography column (SiO.sub.2) using
DMA 0.25. The combined product containing fractions yielded after
concentration in vacuo 0.73 g (9%) of the desired pure piperazine
VIII-H. Synthesis of Amine IX-H: ##STR16## Scheme IX, Steps i, ii
and iii:
[0073] Synthesis of I-H has been described in WO97/36893. The steps
i, ii and iii were done analogously to steps i, ii and iii in
scheme VI.
[0074] Below, the different structures of Q1 to Q64 are given:
##STR17## ##STR18## ##STR19## ##STR20## ##STR21## ##STR22##
##STR23## ##STR24##
[0075] In these formulae `Q`, the dot represents the attachment to
the phenylpiperazine part of the compounds of formula (1).
Synthesis of Q1-6: ##STR25##
[0076] All starting materials (phenols and alkynes) were prepared
according to procedures described in the literature:
[0077] Alkynes: Davison, Edwin C.; Fox, Martin E.; J. Chem. Soc.
Perkin Trans. 1; 12(2002). 1494-1514. Yu, Ming; Alonso-Alicia, M.;
Bioorg. Med. Chem.; 11 (2003)2802-2822. Phenols: Buchan; McCombie;
J. Chem. Soc.; 137 (1931) 144. Finger et al; J. Amer. Chem. Soc.;
81 (1959) 94, 95, 97. Berg; Newbery; J. Chem. Soc.; (1949)
642-645.
Scheme 1-6, Step i:
R.dbd.CN, n=2
[0078] A stirred solution of the silylated alcohol (3.35 g, 10
mmol) in 20 ml of dry THF was cooled to -70.degree. C. 2.5M n-BuLi
(4.8 ml, 12 mmol) was slowly added dropwise at such a rate that the
temperature was kept below -65.degree. C. The solution was allowed
to warm to -20.degree. C. and stirring was continued for 1 hour
during which the color of the solution changed from light to dark
yellow. The solution is again cooled to -70.degree. C. and a
solution of tert-butyldimethylsilylchloride (1.66 g, 11 mmol) in 15
ml of dry THF is slowly added dropwise in 10 minutes. The reaction
mixture was allowed to warm to room temperature and stirring was
continued for 20 h. The reaction mixture was quenched by the
addition of saturated NH.sub.4Cl and extracted 2.times. with
Et.sub.2O. The combined Et.sub.2O layers were washed with 5%
NaHCO.sub.3 (1.times.) and H.sub.2O (1.times.) and dried
(Na.sub.2SO.sub.4). The Et.sub.2O fraction was concentrated under
reduced pressure and the residue was chromatographed (SiO.sub.2)
using DMA/petroleum ether 1/5 as eluent to give 3.35 g (75%) of the
silylated alkyne as a colorless oil.
Scheme 1-6, Step ii:
[0079] A mixture of 4-cyano-2-iodophenol (1.23 g, 5 mmol),
silylated alkyne (from step i) (2.18 g, 5 mmol), LiCl (0.21 g, 5
mmol) and Na.sub.2CO.sub.3 (2.38 g, 22.5 mmol) in 20 ml DMF was
degassed by bubbling nitrogen through the solution for 2 h.
Pd(OAc).sub.2 (50 mg, 0.20 mmol) was added and the reaction mixture
was stirred for 7 hours at 100.degree. C. H.sub.2O and hexane were
added and the mixture was filtered over hyflo. After separation of
the hexane layer, the aqueous layer was extracted with hexane
(1.times.). The combined hexane layers were washed with H.sub.2O
(1.times.) and brine 1.times.). The hexane fraction was partially
evaporated under reduced pressure and 8 g of silicagel was added
and stirring was continued for 15 minutes. The silica is filtered
off and the filtrate is concentrated under reduced pressure. The
residue was chromatographed (SiO.sub.2) using Et.sub.2O/petroleum
ether 1/9 as the eluent to give 0.93 g (35%) of the benzfurane
derivative as a light yellow oil.
Scheme 1-6, Step iii:
[0080] A mixture of the cyclized compound (29.58 g, 52.17 mmol),
KF.2H.sub.2O (14.73 g, 156.51 mmol), benzyltriethylammoniumchloride
(14.26 g, 62.60 mmol) in 450 ml of CH.sub.3CN was refluxed for 4 h.
After cooling to room temperature, CH.sub.3CN was washed 2.times.
with hexane. The CH.sub.3CN fraction was evaporated under reduced
pressure. H.sub.2O was added the residue and this was extracted
twice with EtOAc. The combined organic layers were washed with
respectively H.sub.2O (1.times.) and brine (1.times.). The organic
layer was dried (Na.sub.2SO.sub.4) and concentrated in vacuo. The
residue was subjected to column chromatography (SiO2, eluent:
EtOAc/petroleum ether 1:3.fwdarw.EtOAc/petroleum ether 1:1) to
yield 9.20 g (82%) of the alcohol Q3-OH as a yellow oil.
Scheme 1-6, Step iv:
[0081] PPh.sub.3 (14.38 g, 54.84 mmol) and imidazole (3.73 g, 54.84
mmol) were dissolved in 160 ml of CH.sub.2Cl.sub.2. Iodine (13.92
g, 54.84 mmol) was added and the resulting suspension was stirred
for 20 minutes at room temperature. A solution of the alcohol
obtained at step iii (9.07 g, 42.19 mmol) in 70 ml of
CH.sub.2Cl.sub.2 was added dropwise and the reaction mixture was
stirred for 20 h at room temperature. Water was added and after
separation the H.sub.2O layer was extracted with CH.sub.2Cl.sub.2.
The combined organic layers were washed with respectively 5%
NaHSO.sub.3 solution (1.times.) and H.sub.2O (1.times.) and dried
on Na.sub.2SO.sub.4. The drying agent was removed by filtration and
the solvent by concentration in vacuo. The residue was
chromatographed (SiO.sub.2) using CH.sub.2Cl.sub.2 as the eluent to
give 12.9 g (94%) of the iodide Q3-I as a thick oil which
crystallized on standing. Synthesis of Q7-9: ##STR26##
[0082] The 5-bromobenzthiophene was prepared according to: Leclerc,
V.; Beaurain, N.; Pharm. Pharmacol. Commun., 6(2000)61-66.
Scheme 7-9, Step i:
[0083] Sodium metal (4.5 g, 195.9 mmol) was added in pieces to 260
ml of absolute EtOH. The malonic ester (116 ml, 779 mmol) was added
and the reaction mixture was stirred under a nitrogen atmosphere
for 30 minutes. The 5-bromobenzthiophene (29.5 g, 97.2 mmol) was
added as a suspension in 125 ml of absolute EtOH and stirring was
continued at reflux for 18 h. The solvent was evaporated under
reduced pressure after which 250 ml H.sub.2O and 15 g NH.sub.4Cl
were added to the residue. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (2.times.) and the combined organic layers were
dried (Water Repelling Filter) and the filtrate concentrated in
vacuo (by means of an oil pump, 8 mbar). The residue was
chromatographed (SiO.sub.2) with CH.sub.2Cl.sub.2/petroleumether
3/2 to give 23.9 g (64%) of the di-ester.
Scheme 7-9, Step ii:
[0084] This step was carried out analogous to step ii from Scheme
51.
Scheme 7-9, Step ii:
[0085] This step was carried out analogous to step iii from Scheme
51.
Scheme 7-9, Step iv:
[0086] This step was carried out analogous to step iii from scheme
10-12.
Scheme 7-9, Step v
[0087] This step was carried out analogous to step v from scheme
10-12.
Scheme 7-9, Step vi:
[0088] This step was carried out analogous to step iv from scheme
1-6.
[0089] Derivatives of Q7 and Q8 were prepared analogously to the
above described procedures. Synthesis of Q10-12: ##STR27##
[0090] All reagents were commercially available. The
5-bromobenzthiophene was prepared according to Badger et al., J.
Chem. Soc., (1957) 2624, 2628.
Scheme 10-12, Step i:
[0091] To a stirred mixture of 5-bromobenzthiophene (22.5 g, 105.6
mmol) and the acid chloride (17.4 ml, 141.3 mmol) in 135 ml benzene
at 0.degree. C., SnCl.sub.4 (43.1 ml, 368 mmol) was added in 2 h.
Stirring was continued for 4 hours at the same temperature. The
reaction mixture was poured into a mixture of 95 ml concentrated
HCl (36-38%) in ice. The reaction mixture was extracted with EtOAc
and the organic layer was washed with H.sub.2O (3.times.), 1N NaOH
(1.times.), 5% NaHCO.sub.3 and H.sub.2O (2.times.). The EtOAc
fraction was dried (MgSO.sub.4). The drying agent was removed by
filtration and the solvent by evaporation under reduced pressure.
The residue was recrystallized from 950 ml MeOH and chromatographed
with Et.sub.2O/petroleum ether 1/1 as eluent to give 23.3 g (68%)
of the acylated benzthiophene.
Scheme 10-12, Step ii:
[0092] To a stirred mixture of the acylated benzthiophene (23.3 g,
71.3 mmol) and powdered NaOH (23 g, 575 mmol) in 285 ml
diethyleneglycol, hydrazine hydrate (23 ml, 474 mmol) was added.
Stirring was continued for 2 hours at 145.degree. C. after which
additional stirring for 2 hours at 180.degree. C. was needed to
complete the conversion. The reaction mixture was poured onto ice
and acidified with concentrated HCl (36-38%). The aqueous layer was
extracted with Et.sub.2O and the organic layer was washed with
H.sub.2O (3.times.) and brine (1.times.) and dried (MgSO.sub.4).
The drying agent was removed by filtration and the solvent by
evaporation under reduced pressure yielded 19.7 g (93%) of the
acid.
Scheme 10-12, Step iii:
[0093] At -5.degree. C., 29 ml of thionyl chloride were added
dropwise in 30 minutes to 250 ml of MeOH. The mixture was stirred
for 15 minutes during which the temperature was kept between
-10.degree. C. and -5.degree. C. The acid (19.7 g, 65.9 mmol) was
added in one time to the cooled solution. The reaction mixture was
stirred for 1 hour after which is was allowed to warm to room
temperature and stirred for an additional 20 h. The reaction
mixture was concentrated in vacuo and the residue was
chromatographed (SiO.sub.2) with CH.sub.2Cl.sub.2 as the eluent to
give 20.6 g (100%) of the methyl ester.
Scheme 10-12, Step iv:
[0094] A mixture of the methyl ester (20.6 g, 65.8 mmol) and zinc
cyanide (4.64 g, 39.5 mmol) in 85 ml of dry DMF was degassed by
bubbling nitrogen through the solution for 1 h. Palladium tetrakis,
Pd(PPh.sub.3).sub.4, (3.8 g, 3.29 mmol) was added under a nitrogen
atmosphere and the reaction mixture was stirred for 16 hours at
90.degree. C. The reaction mixture was diluted with 200 ml toluene
and filtered through a pad of Hyflo. The organic layer was washed
with 5% NaHCO.sub.3 (2.times.) and brine (1.times.). The organic
layer was dried (MgSO.sub.4). The drying agent was removed by
filtration and the solvent by evaporation under reduced pressure.
The residue was chromatographed (SiO.sub.2) using
CH.sub.2Cl.sub.2/petroleum ether 3/2.fwdarw.CH.sub.2Cl.sub.2 as
eluent to give 15.6 g (92%) of the 5-cyanobenzthiophene.
Scheme 10-12, Step v:
[0095] To a stirring solution of the 5-cyanobenzthiophene (15.6 g,
60.2 mmol) in 250 ml 96% EtOH at 15.degree. C. was added sodium
borohydride (22.8 g, 602 mmol) in one time. The reaction mixture
was stirred at room temperature for 48 h. H.sub.2O was added and
the aqueous layer was extracted with Et.sub.2O (3.times.). The
combined organic layers were washed with brine (1.times.). The
Et.sub.2O fraction was dried (MgSO.sub.4). The drying agent was
removed by filtration and the solvent by evaporation under reduced
pressure. The residue was chromatographed (SiO.sub.2) with
Et.sub.2O/CH.sub.2Cl.sub.2 1/9 as eluent to give 9.2 g (66%) of the
alcohol Q12-OH.
Scheme 10-12, Step vi:
[0096] Was prepared according to the procedure described in Scheme
1-6, Step iii.
[0097] Q10-OH and Q11-OH were prepared similarly using steps i, ii,
iii and v respectively. Synthesis of Q13-20: ##STR28##
[0098] All starting materials were commercially available.
Scheme 13-20 Step i:
[0099] To a stirring solution of 3-nitro-p-tolunitrile (16.58 g,
102.3 mmol) in 55 ml DMF was added DMF-dimethylacetale (15.24 g,
128.1 mmol). The reaction mixture turned dark red and was stirred
at 110.degree. C. for 3 h. The solvent was removed under reduced
pressure and taken up in a mixture of 300 ml EtOH and 300 ml acetic
acid. The reaction mixture was heated to 60.degree. C. and iron
powder (33 g, 594 mmol) was added in portions. The reaction mixture
was refluxed for 2 hours and filtered over a pad of Hyflo.
Et.sub.2O was added to the filtrate and the acidic layer was
extracted with Et.sub.2O (1.times.). The Et.sub.2O fraction was
concentrated in vacuo. The residue was chromatographed (SiO.sub.2)
with CH.sub.2Cl.sub.2 as the eluent to give 7.02 g (48%) of a
solid, containing the 6-cyano-indole.
Scheme 13-20 Step ii:
[0100] To a stirring suspension of NaH (60%) (1.13 g, 25.96 mmol)
in 60 ml DMF under a nitrogen atmosphere was added 6-cyanoindole of
step i (3.51 g, 24.72 mmol) in portions. After stirring at room
temperature for 1 hour the 1-(dimethyl-tert.butylsilyl)-3-bromo
propane (6.30 ml, 27.29 mmol) was added dropwise at -5.degree. C.
The reaction mixture is stirred at room temperature for 20 h. 400
ml H.sub.2O and 400 ml Et.sub.2O were added. The Et.sub.2O layer
was separated and the aqueous layer was extracted 1.times. with
Et.sub.2O. The combined Et.sub.2O layers were concentrated in
vacuo. The residue was chromatographed (SiO.sub.2) with
CH.sub.2Cl.sub.2/petroleum ether 3/1 as the eluent to give 5.50 g
(71%) as a light yellow oil.
Scheme 13-20 Step iii:
[0101] Was performed analogously to step iii in scheme 1-6, and
yielded Q19-OH.
Scheme 13-20 Step iv:
[0102] The conversion of the resulting alcohols to the
corresponding iodo derivatives was performed analogously to the
procedure described in scheme 1-6 step iv.
[0103] The 6-cyano-indole derivative Q20-OH was prepared according
to the procedure described above.
[0104] The indole, 6-Fluoroindole and 6-Chloroindole were
commercially available and were further converted to the indole
derivatives Q13-18-OH according to the procedures given above.
Synthesis of Q21: ##STR29## Scheme 21 Step i:
[0105] To a stirred suspension of NaH (55%) (0.48 g, 20 mmol) in 20
ml NMP at room temperature was added dropwise a solution of
benzimidazole (1.18 g, 10 mmol) in 20 ml NMP. The reaction mixture
turned light red and hydrogen forming was observed. After stirring
at room temperature for 30 minutes 3-chlorobromopropane (1.08 ml,
11 mmol) in 10 ml NMP was added dropwise. The reaction mixture was
stirred at room temperature for 2 hours after which the reaction
mixture was heated at 100.degree. C. for 2 h. After additional
stirring at room temperature for 72 h, H.sub.2O and EtOAc were
added. The layers were separated and the aqueous layer was
extracted with EtOAc (2.times.). The combined organic layers were
washed with brine (1.times.) and dried (MgSO.sub.4). The drying
agent was removed by filtration and the solvent by evaporation
under reduced pressure to give 2.9 g of Q21-Cl (150%, still NMP
present) as an oil. This was used in coupling reactions with
amines. Synthesis of Q22-23: ##STR30##
[0106] All reagents were commercially available.
Scheme 22-23 Step i:
[0107] To a stirring solution of 2,4-difluoronitrobenzene (8 g,
50.3 mmol) in 100 ml CH.sub.3CN was added 4-aminobutanol (5.61 ml,
60.4 mmol) and DIPEA (20.9 ml, 120.7 mmol). The reaction mixture
was stirred at room temperature for 72 h. The solvent was
evaporated under reduced pressure and CH.sub.2Cl.sub.2 was added to
the residue. The CH.sub.2Cl.sub.2 fraction was washed with H.sub.2O
(2.times.), dried (by a Water Repelling Filter) and the filtrate
evaporated under reduced pressure. The residue was chromatographed
(SiO.sub.2) with Et.sub.2O as the eluent to give 9.68 g (84%) of
the amino-alkylated product.
Scheme 22-23 Step ii:
[0108] To a solution of the amino-alkylated product (from step i)
(9.68 g, 42.5 mmol) in 250 ml EtOH (96%) was added 1 g 10% Pd/C
after which the mixture was hydrogenated at room temperature (1
atm) for 3 h. The reaction mixture was filtered through a pad of
Hyflo and the black filtrate was concentrated in vacuo under
reduced pressure to give 8.42 g (100%) of the corresponding
aniline.
Scheme 22-23 Step iii:
[0109] A mixture of the aniline (from step ii) (8.42 g, 42.5 mmol)
in 25 ml formic acid (96%) was refluxed for 2.5 hours after which
it was allowed to cool to room temperature. H.sub.2O was added and
after cooling, to the reaction mixture 50 ml of 50% NaOH was added.
After stirring for 2 hours the aqueous layer was extracted with
CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2 fraction was dried (by a
Water Repelling Filter) and concentrated in vacuo under reduced
pressure. The residue was chromatographed (SiO.sub.2) with
CH.sub.2Cl.sub.2/MeOH 9:1 as the eluent to give 8.1 g (92%) of the
benzimidazole.
Scheme 22-23 Step iv:
[0110] The conversion of the resulting alcohols to the
corresponding iodo derivatives was performed according to the
procedure described in scheme 1-6 step iv. In this case
triphenylphosphine on solid support was used.
[0111] Q22-OH was prepared via the same procedure as described
above. Synthesis of Q24: ##STR31##
[0112] All reagents were commercially available.
Scheme 24 Step i:
[0113] A suspension of sodium borate tetrahydrate (32.5 g, 211.2
mmol) in 195 ml of acetic acid was heated until the temperature of
the reaction mixture was above 50.degree. C. The reaction
temperature was kept this way while 2-chloro-4-cyanoaniline (5.93
g, 38.9 mmol) was added in portions over 1 h. Stirring and heating
were continued for 2 hours on an oil bath of 62.degree. C. After
cooling to room temperature the reaction mixture was poured into 1
L icewater. The aqueous layer was extracted with Et.sub.2O
(3.times.). The combined organic layers were washed with H.sub.2O
(2.times.) and dried (MgSO.sub.4). The drying agent was removed by
filtration and the solvent by evaporation under reduced pressure.
The residue was chromatographed (SiO.sub.2) with
Et.sub.2O/petroleum ether 1/3 as eluent to give 5.27 g (74%) of the
oxidized product.
Scheme 24 Step ii:
[0114] To a stirring solution of 2-chloro-4-cyanonitrobenzene from
step i (2.48 g, 13.6 mmol) in 12 ml DMF was cooled in ice.
4-aminobutanol (5.50 ml, 59.3 mmol) was added and the reaction
mixture was slowly allowed to warm to room temperature after which
stirring was continued at room temperature for 72 h. H.sub.2O was
added and the aqueous layer was extracted with CH.sub.2Cl.sub.2
(2.times.) The combined organic layers were washed with H.sub.2O
(3.times.), dried (by a Water Repelling Filter) and evaporated
under reduced pressure. The residue was chromatographed with
Et.sub.2O/petroleum ether 4:1 as eluent to give 2.6 g (49%) of the
amino-alkylated product.
Scheme 24 Step iii:
[0115] Prepared according to step ii, in scheme 22-23.
Scheme 24 Step iv:
[0116] Prepared according step iii, in scheme 22-23.
Scheme 24 Step v:
[0117] Prepared according step iv, in scheme 22-23. Synthesis of
Q25-28: ##STR32##
[0118] All reagents were commercially available.
Scheme 25-28 Step i:
[0119] To a stirring solution of 3-nitro-p-tolunitrile (8.1 g, 50
mmol) in 30 ml DMF was added DMF-dimethylacetale (13.3 ml, 100
mmol) and the reaction mixture was stirred at 120.degree. C. for 3
h. The solvent was evaporated under reduced pressure and the
residue was taken up in CH.sub.2Cl.sub.2. The CH.sub.2Cl.sub.2
fraction was washed with H.sub.2O (2.times.), dried (by a Water
Repelling Filter). The drying agent was removed by filtration and
the solvent by evaporation under reduced pressure to give 10.6 g
(98%) of the adduct.
Scheme 25-28 Step ii:
[0120] To a stirring emulsion of the adduct (from step i) (6 g,
27.6 mmol) in 175 ml Et.sub.2O was added 8.1 g NH.sub.4Cl and 29 g
zinc granules (40 mesh). After stirring at room temperature for 2
hours 100 ml THF was added to dissolve the starting material. After
an additional stirring for 6 hours the reaction mixture was
filtered over a pad of Hyflo. Half of the resulting filtrate was
used in the next step.
Scheme 25-28 Step iii:
[0121] To the filtrate of the former step ii was added
2-bromoethanol (7.9 ml, 112 mmol), Aliquat (0.6 g, 10 mol %) and 90
ml 10% NaOH. The reaction mixture was stirred at room temperature
for 20 h. After separation of the layers, the aqueous layer was
extracted with Et.sub.2O (1.times.). The combined organic layers
were washed with H.sub.2O (4.times.) and dried (MgSO.sub.4). The
drying agent was removed by filtration and the solvent by
evaporation under reduced pressure (by means of an oil pump). The
residue was chromatographed (SiO.sub.2, eluent: CH.sub.2Cl.sub.2 4
CH.sub.2Cl.sub.2/Et.sub.2O 4:1) to give 1 g (36%) of the
corresponding alcohol Q27-OH.
Scheme 25-28 Step iv:
[0122] The conversion of the resulting alcohols to the
corresponding iodo derivatives was performed according to the
procedure described in scheme 1-6 step iv.
[0123] Q25-OH, Q26-OH and Q28-OH were prepared analogously to the
procedure described above. Synthesis of Q29: ##STR33##
[0124] The naphtylpropylalcohol was prepared according to: Searles,
J. Amer. Chem. Soc., 73 (1951) 124.
Scheme 29 Step i:
[0125] The conversion of the resulting alcohol to the corresponding
iodo derivative was performed according to the procedure described
in scheme 1-6 step iv. Synthesis of Q30: ##STR34##
[0126] 2-chloro-7-iodo-naphtalene was prepared according to the
literature (Beattie; Whitmore; J. Chem. Soc. 1934, 50, 51, 52)
Scheme 30 Step i:
[0127] A 100 ml roundbottom flask under an nitrogen atmosphere was
charged with 2-chloro-7-iodo-napthalene (11 mmol, 3.60 g),
allyl-tributyltin (13 mmol, 4.30 g, 3.96 ml),
tetrakis(triphenylphosphine)palladium(0) (0.55 mmol, 0.635 g) and
10 ml degassed benzene. The mixture was heated to relfux under a
nitrogen atmosphere and after 20 hours another portion of
tetrakis(triphenylphosphine)palladium(0) (0.55 mmol, 0.635 g) was
added. The mixture was again heated at reflux for 20 hours after
which it was allowed to cool to room temperature after which it was
poured into 70 ml of a 10% KF-solution. After 30 min stirring at
room temperature the suspension was filtered over Hyflo
Supercel.RTM.. The filtrate was washed with water, brine and dried
(Na.sub.2SO.sub.4). Column chromatography on silica gel (eluens 1/9
toluene/petroleum ether) afforded almost pure
2-allyl-7-chloro-napthalene (1.80 g, 80%).
Scheme 30 Step ii:
[0128] A 100 ml threeneck roundbottom flask under a nitrogen
atmosphere was charged with 2-allyl-7-chloro-napthalene (1.80 g,
8.9 mmol) and 12 ml of dry THF. The mixture was cooled in an
ice-bath and borane-THF (3.05 mmol, 3.05 ml 1.0 M borane in THF)
was added dropwise in about 20 minutes After the addition the
mixture was allowed to warm to room temperature and stirred for 20
hours. 3.0 N NaOH solution (2.65 mmol, 0.89 ml) was then added to
the solution and the mixture was cooled in a waterbath while adding
30% hydrogen peroxide (10.62 mmol, 1.1 ml) dropwise at such a rate
that the temperature did not exceed 30.degree. C. After the
addition the mixture was stirred for 6 hours at room
temperature.
[0129] Water and diethyl ether were added and the organic layer was
separated. The water layer was extracted again with ethyl ether and
the combined organic extracts were washed with water, brine and
dried (Na.sub.2SO.sub.4). The drying agent was removed by
filtration and the solvent by evaporation in vacua. Flash column
chromatography on silica gel (eluent: 1/99
methanol/dichloromethane) afforded
3-(7-chloro-napthalene-2-yl)-propan-1-ol (0.79 g, 40%) Q30-OH.
Scheme 30 Step iii:
[0130] The conversion of the resulting alcohol to the corresponding
iodo derivative was performed according to the procedure described
in scheme 79-84 step iii, yielding Q30-I. Synthesis of Q31:
##STR35##
[0131] The fluorobromonaphtalene was prepared according to: Adcock,
W. et al., Aust. J. Chem., 23 (1970)1921-1937.
Scheme 31 Step i:
[0132] To a stirred suspension of magnesium turnings (0.49 g, 20
mmol) and 0.1 ml 1,2-dibromoethane in 20 ml THF was added the
fluoronaphtalene (0.45 g, 2 mmol) in one time. After the start of
the grignard a solution of the fluoronaphtalene (4.06 g, 18 mmol)
in 25 ml THF was slowly added dropwise. The temperature rose during
the addition to 40.degree. C. The reaction mixture was stirred at
room temperature for 2 hours until all the magnesium had
disappeared. A freshly prepared solution from LiCl and CuCN in THF
was added dropwise at -10.degree. C. which resulted in a dark green
solution. At the same temperature was added dropwise a solution of
allyl bromide (1.9 ml, 22 mmol) in 15 ml THF. After the complete
addition the reaction mixture was stirred at -10-0.degree. C. for
30 minutes. The green color disappeared and stirring was continued
at room temperature for 20 h. The reaction mixture was poured into
200 ml of saturated NH.sub.4Cl and extracted with CH.sub.2Cl.sub.2
(3.times.). The combined organic layers were washed with brine and
dried (MgSO.sub.4). The drying agent was removed by filtration and
the solvent by evaporation under reduced pressure. The residue was
chromatographed (SiO.sub.2) using petroleum ether as eluent to give
1.65 g (44%) of the corresponding allylfluoro-naphtalene.
Scheme 31 Step ii:
[0133] To a cooled stirring solution of the allyl-fluoronaphtalene
(1.65 g, 8.8 mmol) in 10 ml THF at -5.degree. C. was slowly added
dropwise 3.05 ml 1.0 M Borane.THF-complex. After stirring for 20
minutes at the same temperature and additional stirring at room
temperature iodine (2.11 g, 8.6 mmol) was added in one time. 3.1 ml
of a freshly prepared 2.7 M solution of sodium metal in MeOH) was
slowly added dropwise (exothermic) after which the reaction mixture
is stirred at room temperature for 20 h. 75 ml NaHSO.sub.3 was
added and the aqueous layer was extracted with CH.sub.2Cl.sub.2
(3.times.). The organic layer was washed with brine (1.times.) and
dried (MgSO.sub.4). The drying agent was removed by filtration and
the solvent by evaporation under reduced pressure. The residue was
chromatographed (SiO.sub.2) using petroleum ether as eluent to give
1.25 g (46%) of the iodide Q31-I as a white solid. Synthesis of
Q32-39, Q41-42: ##STR36## Scheme 32-39, 41-42 Step i:
[0134] A mixture of KOH pellets (140 g, 2.5 mol) and 10 ml H.sub.2O
in a nickel crucible was heated to 250.degree. C. with a Bunsen
burner while being stirred with a stainless steel stirrer. The
flame is removed and 7-amino-2-naphtalenesulfonic acid sodium salt
(0.245 mol, 60.0 g) was added to the clear liquid in 3 portions.
The clear liquid changes into a thick black slurry which is again
strongly heated with a Bunsen burner. At about 280.degree. C. gas
evolved and the temperature of the mixture quickly rises to
310-320.degree. C. This temperature was maintained for 8 minutes
after which the mixture was allowed to cool to about 200.degree. C.
The thick black paste was carefully transferred to a 3 litre beaker
filled with ice. The product of 2 runs were combined and
neutralized with concentrated HCl under cooling with an ice-salt
bath. The suspension wa filtered and the black solid wa washed with
4 500 ml portions of 1.0 N HCl and discarded. The brown, clear
filtrate that is obtained was cooled in an ice-salt bath and
KOH-pellets are added until a light suspension was obtained. After
addition of a saturated NH.sub.4OAc-solution the green-grey solid
fully precipitates and was collected through filtration to obtain
7-amino-naphtalene-2-ol (27.9 g, 36%) after drying in the air.
Scheme 32-39, 41-42 Step ii:
[0135] 7-amino-naphtalene-2-ol (0.169 mol, 27.0 g) is suspended in
750 ml DCM and TEA (0.169 mol, 17.2 g, 23.6 ml) was added. The
mixture wais stirred for 30 min at room temperature after which it
was cooled to -5.degree. C. in an ice-salt bath. A solution of
p-Tosylchloride (0.17 mol, 32.4 g) in 250 ml DCM was added over a
period of 2.5 hours at -5-0.degree. C. The mixture was stirred for
10 minutes at -5-0.degree. C. after which it was allowed to warm to
room temperature and stirred for 18 hours. 1 L of H.sub.2O was
added to the mixture and the resulting suspension was filtered over
Hyflo Super Cel.RTM. and the filtrate was transferred to a
separatory funnel. After extracting the organic layer, the
water-layer was again extracted with DCM (2.times.). The combined
organic layers are washed with brine, dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to give 51.5 g of a black oil which was
purified by column chromatography on silica gel (eluens 1/1
ethylacetate/petroleum ether) to afford toluene-4-sulfonic
acid-7-amino-napthalene-2-yl-ester (12.1 g, 23%).
Scheme 32-39, 41-42 Step iii:
[0136] A 500 ml threeneck roundbottom flask made from PFA was
charged with 100 g Pyridine/HF complex (30:70% w/w) and cooled to
-10.degree. C. with an ice/EtOH bath toluene-4-sulfonic
acid-7-amino-napthalene-2-yl-ester (38.6 mmol, 12.1 g) was added in
one portion and the mixture was stirred for 10 minutes after which
a clear purple solution was obtained. This solution was cooled to
<-30.degree. C. in an dry-ice cooling bath and sodium nitrite
(42.5 mmol, 2.93 g, dried by heating at 140.degree. C. for 3 days)
was added in one portion. The dry-ice bath was replaced by a normal
ice-bath and the mixture was stirred at 0.degree. C. for 20 minutes
after which it was heated to 55-60.degree. C. on an oilbath
(evolution of nitrogen was observed). After 1.5 hours nitrogen
evolution ceased and the mixture was allowed to cool to room
temperature and poured into a large beaker filled with ice. The
mixture was transferred to a separatory funnel and extracted 3
times with DCM. The organic layers where pooled together, washed
with brine and dried (Na.sub.2SO.sub.4). Concentration in vacuo
afforded 10.4 g of a red oil which was purified by flash column
chromatography on silica gel (eluens 1/4 ethylacetate/petroleum
ether) to give toluene-4-sulfonic
acid-7-fluoro-napthalene-2-yl-ester (7.1 g, 58%)
Scheme 32-39, 41-42 Step iv:
[0137] A 500 ml roundbottom flask protected with a CaCl.sub.2-tube
was charged with toluene-4-sulfonic
acid-7-fluoro-napthalene-2-yl-ester (22.4 mmol, 7.1 g) and 200
MeOH. The suspension was heated until a clear solution was obtained
and then cooled down to room temperature in a waterbad to afford a
fine suspension. Magnesium (179 mmol, 4.36 g) was added to the
mixture which was then stirred for 4 hours at room temperature. The
brown suspension was cooled in an ice-EtOH bath and acidified with
6N HCl and then concentrated in vacua. The mixture was transferred
to a separatory funnel and extracted 3 times with ethylether. The
organic extracts are pooled together, washed with brine and dried
(Na.sub.2SO.sub.4). The drying agent was removed by filtration and
the solvent by evaporation in vacua. Flash column chromatography on
silica gel (eluens dichloromethaan) afforded unpure
7-fluoro-napthalene-2-ol (4.69 g) as an off white solid. This solid
was dissolved in DCM and extracting 3 times with 2N NaOH-solution.
The basic extracts were combined and acidified with 3N HCl while
cooling with an ice bath. White crystals precipitated from the
solution and were collected by filtration and dried in the air to
afford pure 7-fluoro-napthalene-2-ol. (3.16 g, 87%)
Scheme 38-45: 47-48, Step v:
[0138] To a stirred suspension at -5.degree. C. 0.97 g (6 mmol) of
2-hydroxy-7-fluoronaphtalene, 2.83 g (10.8 mmol) of
triphenylphosphine and 1.11 ml (12.6 mmol) of 3-bromo-1-propanol in
30 ml of toluene, was added dropwise a solution of 2.13 ml (10.8
mmol) DIAD in 5 ml toluene. The reaction mixture was allowed to
reach room temperature after which stirring was continued
overnight. The reaction mixture was concentrated in vacuo and the
residue taken up in 30 ml of diethylether. The mixture was filtered
an the filtrate concentrated in vacuo and the residue subjected to
flash column chromatography (SiO2, eluent:
CH.sub.2Cl.sub.2/petroleum ether 1/5). Yield 1.28 g (75%) of
Q37-Br.
[0139] Q32 was synthesized as Q32-I, Q33-36, Q38-39 and Q41-42
derivatives were prepared similarly to the above described
procedures (as bromides). Synthesis of Q40, Q43: ##STR37## Scheme
40, 43 Step i:
[0140] A mixture of 7-fluoro-2-naphtol (see Scheme 32-39, 41-42
step iv) (0.62 g, 3.82 mmol), the alkene (1.11 ml, 9.56 mmol) and
K.sub.2CO.sub.3 (1.58 g, 11.5 mmol) in 35 ml CH.sub.3CN was
refluxed for 3 hours after which was was cooled to room temperature
and evaporated under reduced pressure. The residue was taken up in
H.sub.2O and Et.sub.2O and extracted with Et.sub.2O (2.times.). The
combined organic layers were washed with H.sub.2O (1.times.) and
brine (1.times.) after which it was dried (Na.sub.2SO.sub.4). The
drying agent was removed by filtration and the solvent by
evaporation under reduced pressure. The residue was chromatographed
(SiO.sub.2) with CH.sub.2Cl.sub.2/petroleum ether 1/5 as eluent to
give 0.56 g (58%) of the fluoronaphthol derivative Q43-Cl as a
colorless oil. Synthesis of Q44: ##STR38## Scheme 44 Step i:
[0141] For the fluornaphtol, see Scheme 32-39, 41-42 step iv. This
Mitsunobu reaction was performed analogously to step v in scheme
32-39, 41-42.
Scheme 44 Step ii:
[0142] This step can be performed similar to step iii in scheme
1-6, and yielded Q44-OH.
Scheme 44 Step iii:
[0143] Q44-OH was oxidized following the procedure of step i in
scheme B2. The product, Q'44-C.dbd.O was used in the reductive
alkylation of amines. Synthesis of Q45-50: ##STR39##
[0144] The starting acid and reagents were commercially available.
The Cl-C4-MgBr was prepared according to: C. R. Hebd, Seances Acad.
Ser. C, 268 (1969)1152-1154.
Scheme 45-50 Step i:
[0145] To a solution of the acid (25 g, 148.8 mmol) in 140 ml
benzene was added 0.07 ml DMF after which oxalylchloride was added
all at once. Immediate foaming of the reaction mixture was
observed. The reaction mixture was stirred for at room temperature
18 hours and the solvent was removed by evaporation under reduced
pressure. Acetonitrile was added to the residue for co-evaporation
and again removed by evaporation under reduced pressure to give
27.75 g (100%).
Scheme 45-50 Step ii:
[0146] AlCl.sub.3 (27.8 g, 208 mmol) was suspended in 200 ml
1,2-dichloroethane. The mixture was cooled under a nitrogen
atmosphere to 0-5.degree. C. and a solution of the acid chloride
(27.75 g, 148.8 mmol) in 140 ml 1,2-dichloroethane was added
dropwise in 1 h. The cooling bath was removed and after stirring
for 30 min., stirring was continued for 2 hours at 70.degree. C.
After cooling to room temperature the reaction mixture was poured
into a mixture of ice and 330 ml concentrated HCl (36-38%). The
aqueous layer was extracted with CH.sub.2Cl.sub.2 and the resulting
organic layer was washed with H.sub.2O (2.times.), 5% NaHCO.sub.3
and brine. The organic layer was dried (MgSO.sub.4). The drying
agent was removed by filtration and the solvent by evaporation
under reduced pressure to give 19.02 g (85%).
Scheme 45-50 Step iii:
[0147] To a cooled solution of 0.5M cyclopropyl magnesiumbromide in
THF (100 ml, 50 mmol) at 15.degree. C. was added a solution of the
ketone (5.3 g, 35.3 mmol) in 40 ml THF. The reaction mixture was
stirred at reflux for 2 hours after which was was cooled in an ice
bath. 50 ml saturated NH.sub.4Cl was added dropwise and the aqueous
layer was extracted with Et.sub.2O. The Et.sub.2O was washed with
brine (1.times.), dried (MgSO.sub.4) and evaporated under reduced
pressure. The residue was dissolved in 85 ml acetic acid and 62 ml
of a 20% HBr solution was added. The reaction mixture was stirred
for 20 h. H.sub.2O was added and the aqueous layer was extracted
with CH.sub.2Cl.sub.2. The organic layer was further washed with
H.sub.2O (1.times.) and 5% NaHCO.sub.3 (1.times.). The organic
layer was dried (by a Water Repelling Filter) and evaporated under
reduced pressure. The residue was chromatographed with
CH.sub.2Cl.sub.2/petroleum ether 2.5/97.5 as eluent to give 4.44 g
(49%) of the indene Q49-Br.
Scheme 45-50 Step iv:
[0148] Was prepared according to the procedure as described for
step iii, yielding Q50-Cl Q45, Q46, Q47, and Q48 derivatives were
made analogously to the above described procedure. Synthesis of
Q51: ##STR40##
[0149] The starting materials were commercially available.
Scheme 51 Step i:
[0150] A mixture of the Grignard reagent (90 ml, 90 mmol) and CuI
(18 mg, 0.02 mmol) was stirred for 15 minutes after which it was
cooled in an ice bath. A solution of the di-ester (18.9 ml, 96.7
mmol) in 25 ml THF was added in 90 min and the reaction mixture
was, stirred at 0.degree. C. for 2 h. 100 ml saturated NH.sub.4Cl
was added dropwise and the aqueous layer was extracted with
Et.sub.2O. The Et.sub.2O fraction was washed with brine (1.times.)
and dried (MgSO.sub.4). The drying agent was removed by filtration
and the solvent by evaporation under reduced pressure. The residue
was chromatographed with CH.sub.2Cl.sub.2/petroleum ether 1/1 as
eluent to give 26.17 g (98%) of the adduct.
Scheme 51 Step ii:
[0151] To a stirring solution of the adduct (26.17 g, 88.4 mmol) in
222 ml EtOH was added 265 ml 10% NaOH. The reaction mixture was
refluxed for 3 hours and the solvent was evaporated under reduced
pressure. The residue was cooled in ice and acidified with
concentrated HCl (36-38%). The aqueous layer was extracted with
EtOAc. The EtOAc fraction was washed with brine (1.times.) and
dried (MgSO.sub.4). The drying agent was removed by filtration and
the solvent by evaporation under reduced pressure to give 20.9 g
(99%) of the di-acid.
Scheme 51 Step iii:
[0152] A mixture of the di-acid (20.9 g, 87.1 mmol) and Cu.sub.2O
(0.62 g, 4.34 mmol) in 600 ml CH.sub.3CN was refluxed for 16 h. The
solvent was removed by evaporation under reduced pressure and 125
ml 3N HCl was added to the residue. The aqueous layer was extracted
with EtOAc. The EtOAc fraction was washed with brine (1.times.) and
dried (MgSO.sub.4). The drying agent was removed by filtration and
the solvent by evaporation under reduced pressure to give 16.9 g
(99%) of the de-carboxylated product.
Scheme 51 Step iv:
[0153] Was prepared according to step i in scheme 45-50.
Scheme 51 Step v:
[0154] Was prepared according to step ii in scheme 45-50.
Scheme 51 Step vi:
[0155] Was prepared according to step iii in scheme 45-50, yielding
Q51-Cl. Synthesis of Q52-53: ##STR41## Scheme 52-53 Step i:
[0156] A 3 litre beaker was charged with 2-amino-5-fluoro-benzoic
acid (64 mmol, 10 g), 100 ml H.sub.2O and 110 ml concentrated HCl
and the suspension was cooled to 0.degree. C. in an ice/aceton
bath. A solution of natrium nitrite (64 mmol, 4.44 g) in 68 ml
H.sub.2O was added dropwise to the mixture while the temperature
was maintained at below 3.degree. C. After the addition was
complete the brown solution was added in portions over 20 minutes,
under a stream of sulfurdioxide, to a solution of 760 ml H.sub.2O
saturated with sulfurdioxide cooled at 0-5.degree. C. with an
ice-bath. After the addition was complete the ice-bath was removed
and the solution was allowed to warm to room temperature while the
stream of sulfurdioxide was maintained. After 1 hour the supply of
sulfurdioxide was discontinued and the solution was allowed to
stand at room temperature overnight. To the dark yellow solution
which was obtained was added 620 ml concentrated HCl and after
cooling the mixture a yellow precipitate separates which was
collected on a cooled buchner funnel. The solid was suspended in a
solution of 2 ml concentrated HCl and 200 ml H.sub.2O and the
mixture was heated to reflux. After a time the solid dissolves and
a clear solution was obtained. After 1.5 hours of reflux a
orange/brown solid has crystallized and the mixture was allowed to
cool to room temperature and was concentrated to about 50 ml in
vacuo. The solid was collected and dried in the air to afford
5-fluoro-1,2-dihydro-indazol-3-one (5.05 g, 52%)
Scheme 52-53 Step ii:
[0157] 5-fluoro-1,2-dihydro-indazol-3-one (32 mmol 5.05 g) was
suspended in 30 ml pyridine and under cooling with an ice-bath
chloroethylformiate (64 mmol, 6.94 g, 6.09 ml) was, added dropwise.
The mixture was heated to reflux for 3 hours and was then allowed
to cool to room temperature ad concentrated in vacuo to afford a
dark red oil which crystallizes after the addition of water. The
solid was filtered and dried in the air to afford the corresponding
urethane (5.52 g, 77%)
Scheme 52-53 Step iii:
[0158] To 20 ml toluene under a nitrogen atmosphere was added the
urethane derivative (from step ii) (0.45 g, 2 mmol),
3-bromopropanol (0.18 ml, 2.1 mmol), Bu.sub.3P (0.40 g, 2 mmol) and
ADDP (0.5 g, 2 mmol). After the addition of ADDP the solution
turned clear. The reaction mixture was heated at 85.degree. C. for
20 hours and cooled to room temperature. 2N NaOH and EtOAc were
added and the aqueous layer was extracted with EtOAc (2.times.).
The combined organic layers were washed with 2N NaOH (1.times.),
H.sub.2O (1.times.) and brine (1.times.) after which the EtOAc was
dried (Na.sub.2SO.sub.4) and evaporated under reduced pressure. The
residue was chromatographed with CH.sub.2Cl.sub.2/MeOH 99:1 as
eluent to give 0.22 g (32%) of the alkylated indazol-3-one.
Scheme 52-53 Step iv:
[0159] Was performed according to the procedure as described in
scheme A2, Step i.
Scheme 52-53 Step v:
[0160] A mixture of the ethyl carbamate (0.38 g, 0.79 mmol) and
K.sub.2CO.sub.3 (0.38 g, 2.74 mmol) in 21 ml of MeOH/DME/H.sub.2O
(5/1/1) was stirred at room temperature for 4 h. The reaction
mixture was further purified using a SCX-column (ion exchange
column) with 1N NH.sub.3/MeOH as eluent to rinse the product off
the column. The eluate was evaporated under reduced pressure and
the residue refluxed in 20 ml CH.sub.3CN. The suspension was
filtered by suction to give 0.28 g (86%) of the de-protected
product as a light orange solid containing compound 125 which was
later transformed into its mono HCl salt (AcCl/MeOH), 125-HCl.
[0161] The Q53 analogue can be synthesized as well, as described
above.
[0162] Compounds 48, 49 and 124 were prepared analogously to the
procedures given above. Synthesis of Q54-59: ##STR42##
[0163] The indazoles were preapared according to Christoph
Ruchardt, Volkert Hassemann; Liebigs Ann. Chem.; (1980)
908-927.
Scheme 54-59, Step i:
56; R=Cl, n=3:
[0164] NaH (55%) (2.14 g, 49.15 mmol) was suspended in 70 ml of dry
DMF under a N.sub.2 atmosphere. 6-chloro-indazole (7.5 g, 49.15
mmol) was added at room temperature. The mixture was stirred for 1
hour before cooling with an ice bath and
(3-bromo-propoxy)-tert-butyl-dimethyl-silane (11.4 ml, 49.15 mmol)
was added dropwise. After stirring for an additional 15 minutes the
mixture was allowed to reach room temperature, stirring was
continued for another 8 hours. Subsequently, the mixture was
concentrated in vacuo and the residue was dissolved in DCM, the
organic layer was then washed with water (3.times.). The organic
layer was concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (SiO.sub.2, eluent: petroleum
ether/diethyl ether 5/1 ? 4/1) to afford the N1 substituted
indazole in 61% yield.
Scheme 54-59, Step ii:
[0165] To a stirred solution of KF.2H.sub.2O (4.3 g, 45.24 mmol)
and benzyl tri-ethyl ammonium chloride (7.6 g, 33.18 mmol) in 300
ml acetonitrile, the N1 substituted indazole (from step i) (9.8 g,
30.16 mmol) was added. The mixture was warmed to reflux and stirred
for 8 hours. The solvent was evaporated and DCM was added to the
residue. The organic layer was washed with water (3.times.). De
organic layer was concentrated in vacuo. The crude product was
purified by flash chromatography on silica (eluent:
diethylether.fwdarw.1% MeOH in diethylether) to afford the
3-(indazol-1-yl)-propanol in 95% yield.
[0166] The other indazolyl alcohols were prepared analogously. In
step ii, tetrabutyl ammonium chloride in THF can be used instead of
the combination KF.2H.sub.2O/benzyl tri-ethyl ammonium
chloride.
Synthesis of Q60:
[0167] Q60-Br was synthesized analogously to the synthesis depicted
in Scheme 52-53, using bromoethanol in the Mitsunobu step iii.
Synthesis of Q61-62:
[0168] Q61-1 and Q62-1 were synthesized analogously to the
synthesis depicted in scheme 13-20, Steps ii, iii and iv.
Synthesis of Q63:
[0169] Q63-1 was synthesized as depicted in scheme 63: ##STR43##
Scheme 63, Step i:
[0170] Through a suspension containing the fluorobromonapthalene
(0.90 g, 4 mmol), tri-phenylphospine (0.21 g, 0.8 mmol),
dichlorobis(tri-phenylphospine)palladium (0.28 g, 0.4 mmol) in 15
ml Et.sub.3N, nitrogen was bubbled for 1 hour. 3-Butyn-1-ol (0.4 g,
0.45 ml, 6 mmol) was added and the mixture was heated to
40-50.degree. C. on an oilbath. After 15 minutes of stirring at
this temperature, CuI (0.15 g, 0.8 mmol) was added and the mixture
was heated at 70.degree. C. and stirred for 48 hours.
[0171] The resulting black suspension was allowed to reach room
temperature and diethyl ether and water were added. The fractions
were separated and the water layer was extracted twice with diethyl
ether. The combined organic extracts were washed with water, brine
and dried (Na.sub.2SO.sub.4). After removal of the drying agent by
filtration and solvent by concentration in vacuo, the residue was
subjected to flash chromatography (SiO.sub.2, eluent: DCM)
affording Q63-OH, 4-(2-fluoro-napthalene-7-yl)-3-butyne-1-ol (0.30
g, 1.46 mmol).
Scheme 63, Step ii:
[0172] The conversion of the alcohol of step i to the corresponding
iodo-derivative was performed according to scheme 1-6 step iv,
yielding Q63-1. Synthesis of Q64: ##STR44## Scheme 64, Step i:
[0173] A solution of Red-Al (4.47 ml of a 3.4 M solution in
toluene) in 25 ml of dry diethyl ether was cooled in an ice-bath
under nitrogen to which a solution of Q63-OH (1.90 g, 9.5 mmol) in
40 ml of diethylther (dry) was added dropwise. After the addition
was complete, the resulting mixture is stirred for 10 min at
0.degree. C. after which it was allowed to reach room temperature
and stirred for an additional 2.5 hours. The reaction mixture was
again cooled in a ice-bath and quenched by the careful addition of
50 ml of 3.6 M H.sub.2SO.sub.4. The reaction mixture was extracted
three times with diethyl ether. The combined organic extracts are
washed with water, brine, and dried Na.sub.2SO.sub.4). After
removal of the drying agent by filtration and solvent by
concentration in vacuo, the residue was subjected to flash
chromatography (SiO.sub.2, eluent: DCM) affording 1.17 g of Q64-OH,
4-(2-fluoro-naphtalene-7-yl)-3-butene-1-ol (5.8 mmol).
Scheme 64, Step ii:
[0174] 5 ml of concentrated hydrochloric acid is added to a
solution of Q64-OH (1.17 g, 5.8 mmol) in 5 ml of THF. The mixture
is stirred for 4.5 hours at room temperature after which another 2
ml of concentrated hydrochloric acid and 2 ml of THF are added.
After another 30 minutes diethyl ether and water are added and the
resulting fractions were separated. The water layer is extracted
twice with diethyl ether. The combined organic fractions are washed
with water, brine, dried (Na.sub.2SO.sub.4). After removal of the
drying agent by filtration and solvent by concentration in vacuo,
the residue was subjected to flash chromatography (SiO.sub.2,
eluent: DCM) affording 1.03 g of Q64-Cl (4.67 mmol).
[0175] The specific compounds of which the synthesis is described
above are intended to further illustrate the invention in more
detail, and therefore are not deemed to restrict the scope of the
invention in any way. Other embodiments of the invention will be
apparent to those skilled in the art from consideration of the
specification and practice of the invention disclosed herein. It is
thus intended that the specification and examples be considered as
exemplary only, with a true scope and spirit of the invention being
indicated by the claims. TABLE-US-00002 ABBREVIATIONS AcCl
acetylchloride ADDP 1,1'-(azodicarbonyl)dipiperidine CDI
carbonyldiimidazol Dba see Huang et al., J. Am. Chem. Soc.,
125(2003)6653 DCE dichloroethane DCM dichloromethane DIAD
diisopropyldiazodicarboxylate DIPE diisopropylether DIPEA
diisopropylethylamine CH.sub.2Cl.sub.2(ml) MeOH(ml) NH.sub.4OH(ml)
DMA 0.125 980 18.75 1.25 DMA 0.187 970 28.13 1.87 DMA 0.25 960 37.5
2.5 DMA 0.50 920 75.0 5.0 DMA 0.75 880 112.5 7.5 DMA 1.00 840 150.0
10.0 DMAP 4-dimethylaminopyridin DME dimethoxyethane DMF
N,N-dimethylformamide EtOH ethanol MeOH methanol MTBE
methyl(tert.)-butylether NMP N-methylpyrrolidon PA petroleum ether
TBAB tetrabutylammoniumbromide TBAC tetrabutylammoniumchloride TBAF
tetrabutylammoniumfluoride THF tetrahydrofurane XPHOS see Huang et
al., J. Am. Chem. Soc., 125(2003)6653
Example
Formulation of Compound 56 Used in Animal Studies
[0176] For oral (p.o.) administration: to the desired quantity
(0.5-5 mg) of the solid compound 56 in a glass tube, some glass
beads were added and the solid was milled by vortexing for 2
minutes. After addition of 1 ml of a solution of 1% methylcellulose
in water and 2% (v/v) of Poloxamer 188 (Lutrol F68), the compound
was suspended by vortexing for 10 minutes. The pH was adjusted to 7
with a few drops of aqueous NaOH (0.1N). Remaining particles in the
suspension were further suspended by using an ultrasonic bath.
[0177] For intraperitoneal (i.p.) administration: to the desired
quantity (0.5-15 mg) of the solid compound 56 in a glass tube, some
glass beads were added and the solid was milled by vortexing for 2
minutes. After addition of 1 ml of a solution of 1% methylcellulose
and 5% mannitol in water, the compound was suspended by vortexing
for 10 minutes. Finally the pH was adjusted to 7.
Example
Pharmacological Test Results
[0178] TABLE-US-00003 TABLE 2 In vitro affinities and functional
activity of compounds of the invention Dopamine-D.sub.2 5-HT
reuptake Dopamine-D.sub.2 binding binding cAMP accum compound
pK.sub.i pK.sub.i .epsilon. (intrinsic activity) 6 7.7 9.8 0.85 7
8.2 8.5 0.39 8 8.3 8.9 0.10 16 8.5 9.1 0.73 53 8.8 8.8 0.62 56 8.9
8.1 0.38 79 7.1 8.5 0.10 94 7.8 8.5 0.70 98 6.9 9.0 0.75 102 7.4
9.0 0.81 108 7.7 8.1 0.95 117 8.1 >9.0 0.29 135 7.2 8.7 0.45 140
7.0 7.3 0.24
[0179] Dopamine-D.sub.2 and serotonin reuptake receptor affinity
data obtained according to the protocols given above are shown in
the table below. In vitro functional activity at cloned human
dopamine D.sub.2,L receptors as measured by accumulation of
radiolabeled cAMP (potency: pEC.sub.50, intrinsic activity
.epsilon.)
* * * * *