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United States Patent |
6,228,857
|
Berg
,   et al.
|
May 8, 2001
|
Morpholinobenzamide salts
Abstract
The present invention relates to pharmaceutically acceptable salts of the
compound of formula I or solvates of said salt in which the compound of
formula I is as the (R)-enantiomer, the (S)-enantiomer or the racemate,
##STR1##
a process for their preparation, pharmaceutical formulations containing
said therapeutically active compounds and to the use of said active
compounds in therapy.
Inventors:
|
Berg; Stefan (Ekero, SE);
Sohn; Daniel (Northborough, MA)
|
Assignee:
|
AstraZeneca AB (Sodertalje, SE)
|
Appl. No.:
|
621387 |
Filed:
|
July 21, 2000 |
Foreign Application Priority Data
| Jul 02, 1997[SE] | 9702799 |
| Jan 22, 1999[SE] | 9900190 |
Intern'l Class: |
A61K 031/537.7; A61P 025/22; C07D 413/14 |
Field of Search: |
544/121
514/235.8
|
References Cited
U.S. Patent Documents
5196454 | Mar., 1993 | Crauert et al.
| |
6124283 | Sep., 2000 | Berg et al. | 514/227.
|
Foreign Patent Documents |
402923 | Dec., 1990 | EP.
| |
533266 | Mar., 1993 | EP.
| |
533267 | Mar., 1993 | EP.
| |
533268 | Mar., 1993 | EP.
| |
2273930 | Jul., 1994 | GB.
| |
9413659 | Jun., 1994 | WO.
| |
9421619 | Sep., 1994 | WO.
| |
9511243 | Apr., 1995 | WO.
| |
9734883 | Sep., 1997 | WO.
| |
Primary Examiner: Ramsuer; Robert W.
Attorney, Agent or Firm: White & Case LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of International PCT Application No.
PCT/SE00/00079 filed on Jan. 14, 2000, and which is a continuation-in-part
of U.S. application Ser. No. 09/171,577 filed on Oct. 21, 1998 (pending),
which is a 371 of PCT/SE98/01390 filed on Jul. 15, 1998.
Claims
What is clamed is:
1. A pharmaceutically acceptable salt of the compound of formula I or a
solvate of said salt in which the compound of formula I is as the
(R)-enantiomer, the (S)-enantiomer or the racemate
##STR13##
with the proviso that
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen (2S,3S)-tartrate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen (2R,3R)-tartrate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide benzenesulfonate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen 1,2-ethanedisulfonate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen maleate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen sulfate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide D-gluconate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen succinate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide methanesulfonate,
(R)-N-[5-mnethyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide hydrogen (S)-maleate,
(R)-N-[.sup.5
-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpho
linobenzamide dihydrogen citrate and
(R)-N-[.sup.5
-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpho
linobenzamide hydrochloride are excluded.
2. A pharmaceutically acceptable salt according to claim 1 in which the
compound of formula I is an (R)-enantiomer or a solvate of said salt.
3. A salt or solvate according to claim 1 which is
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide L-lactate or a solvate thereof.
4. A salt or solvate according to claim 1 which is
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzarnide L-ascorbate or a solvate thereof.
5. A salt or solvate according to claim 1 which is
(R)-N-[5-methyl-8-(4-methylpiperazin-1yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide salicylate or a solvate thereof.
6. A salt or solvate according to claim 1 which is
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide glycolate or a solvate thereof.
7. A salt or solvate according to claim 1 which is
R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide dihydrobromide or a solvate thereof.
8. A salt or solvate according to claim 1 which is
R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide monohydrobromide or a solvate thereof.
9. A salt or solvate according to claim 1 which is
R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide dihydrochloride or a solvate thereof.
10. A pharmaceutical formulation comprising as active ingredient a
therapeutically effective amount of the salt or solvate according to any
one of claims 1-9 or a combination of such salts and/or solvates,
optionally in association with diluents, excipients or inert carriers.
11. A method for the treatment of 5-hydroxytryptamine mediated disorders,
comprising administering to a patient in need of such treatment the
pharmaceutical formulation according to claim 10.
12. A method for the treatment of mood disorders, anxiety disorders,
personality disorders, obesity, anorexia, bulimia, premenstrual syndrome,
sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit,
hyperactivity disorder, migraine, memory disorders, pathological
aggression, schizophrenia, endocrine disorders, stroke, dyskinesia,
Parkinson's disease, thermoregulatory disorders, pain, hypertension,
urinary incontinence or vasospasm; or for inhibiting growth of tumors,
comprising administering to a patient in need of such treatment the
pharmaceutical formulation according to claim 10.
13. A method according to claim 12 for the treatment of major depressive
disorder.
14. A method for the treatment of disorders in the central nervous system,
comprising administering to a patient in need of such treatment a
therapeutically effective amount of a salt or solvate as defined in any
one of claims 1-9.
15. A method for the treatment of urinary incontinence or vasospasm or for
inhibiting growth of tumors, comprising administering to a patient in need
of such treatment a therapeutically effective amount of a salt or solvate
as defined in any one of claims 1-9.
16. A method according to claim 14 for the treatment of mood disorders,
anxiety disorders, personality disorders, obesity, anorexia, bulimia,
premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse,
autism, attention deficit, hyperactivity disorder, migraine, memory
disorders, pathological aggression, schizophrenia, endocrine disorders,
stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain
or hypertension.
17. A method according to claim 16 for the treatment of major depressive
disorder.
18. A method for the treatment of 5-hydroxytryptamine mediated disorders,
comprising administering to a patient in need of such treatment a
therapeutically effective amount of a salt or solvate as defined in any
one of claims 1-9.
19. A method according to claim 18 wherein the disorder is effectively
treated with a h5-HT.sub.1B antagonist.
20. A process for the preparation of the salt of the compound of formula I
or the solvate of said salt according to claim 1, comprising acylation of
a compound of formula XII,
##STR14##
with activated 4-morpholinobenzoic acid and reaction of the base with an
organic or inorganic acid to form the salt with or without a solvate.
Description
FIELD OF THE INVENTION
The present invention relates to new pharmaceutically acceptable salts of
N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-mo
rpholinobenzamide as the (R)-enantiomer, the (S)-enantiomer or the racemate
or as solvates of said salts, a process for their preparation,
pharmaceutical formulations containing said salts or solvates and to the
use of said active salts or solvates in therapy.
An object of the invention is to provide compounds for therapeutic use,
especially compounds having a selective effect at a subgroup of
5-hydroxytryptamine receptors, designated the h5-HT.sub.1B -receptor
(previously called the 5-HT.sub.1D.beta. -receptor) in mammals including
man, which compounds are easily formulated into pharmaceutical
formulations.
It is also an object of the invention to provide compounds with a
therapeutic effect after oral administration.
PRIOR ART
Different classes of piperazinyl substituted benzanilide derivatives as
5-HT.sub.1D antagonists are disclosed in inter alia EP 533266, EP 533267,
EP 533268, GB 2273930 and WO 95/11243.
WO 94/13659 discloses an extremely broad class of fused benzo compounds
having a para substituted piperidyl or piperazinyl radical in the aromatic
ring, said class or compounds is stated to bind to the 5-HT.sub.1A
receptor.
WO 94/21619 discloses a fully aromatic naphthalene ring system which may be
substituted with a piperidyl or piperazinyl group, said compounds are also
stated to be potent serotonin (5HT.sub.1) agonists and antagonists.
EP 402923 discloses 2-aminoalkyl or alkylenaromatic substituted
1,2,3,4-tetrahydronaphthalene derivatives having a further nitrogen
substitution in the 5 position in the tetraline ring, said compounds act
as dopamine agonists.
BACKGROUND OF THE INVENTION
Various central nervous system disorders such as depression, anxiety, etc.
appear to involve the disturbance of the neurotransmitters noradrenaline
(NA) and/or 5-hydroxytryptamine(5-HT), the latter also known as serotonin.
The drugs most frequently used in the treatment of depression are believed
to act by improving the neurotransmission of either or both of these
physiological agonists. It appears that the enhancement of 5-HT
neurotransmission primarily affects the depressed mood and anxiety,
whereas the enhancement of noradrenaline neurotransmission affects the
retardation symptoms occurring in depressed patients.
Serotonin, or 5-HT, activity is thought to be involved in many different
types of psychiatric disorders. For instance it is thought that an
increase in 5-HT activity is associated with anxiety, while a decrease in
5-HT release has been associated with depression. Serotonin has in
addition been implicated in such diverse conditions as eating disorders,
gastrointestinal disorders, cardiovascular regulation and sexual behavior.
The compound of formula I below in base form has an extremely low
solubility in water and a slow release rate which rate is pH dependent,
i.e. the rate is different in the stomach and the intestines. From a
pharmaceutical formulation point of view it is very difficult to dissolve
the base rapidly enough and maintain the same dissolved in the gastric
juice until a sufficient amount of substance has been absorbed.
The 5-HT Receptors
The various effects of 5-HT may be related to the fact that serotoninergic
neurons stimulate the secretion of several hormones, e.g. cortisol,
prolactin, B-endorphin, vasopressin and others. The secretion of each of
these other hormones appears to be regulated on a specific basis by
several different 5-HT (serotonin) receptor subtypes. With the aid of
molecular biology techniques, to date these receptors have been classified
as 5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-HT.sub.5, 5-HT.sub.6
and 5-HT.sub.7 with the .sup.5 -HT.sub.1 receptor further divided into the
5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1D, 5-HT.sub.1E and 5-HT.sub.1F
subtypes. Each receptor subtype is involved in a different serotonin
function and has different properties.
Regulation of the 5-HT transmission
The release of 5-HT at the nerve terminals is feedback-regulated by two
different subtypes of 5-HT receptors. Inhibitory 5-HT.sub.1A autoreceptors
are located on the cell bodies in the raphe nuclei which upon stimulation
by 5-HT decrease the impulse propagation in the 5-HT neurons and thereby
reducing the 5-HT release at the nerve terminals. Another subtype of
inhibitory 5-HT receptors is located on the 5-HT nerve terminals, the
h5-HT.sub.1B receptors (in rodents the r5-HT.sub.1B receptors) which
regulate the synaptic concentration of 5-HT by controlling the amount of
5-HT that is released. An antagonist of these terminal autoreceptors thus
increases the amount of 5-HT released by nerve impulses as has been shown
in both in vitro and in vivo experiments.
The use of an antagonist of the terminal h5-HT.sub.1B autoreceptor will
accordingly increase the synaptic 5-HT concentration and enhance the
transmission in the 5-HT system. It would thus produce an antidepressant
effect making it useful as a medication for depression.
Other localizations of h5-HT.sub.1B receptor subtype also exist. A large
part of these postsynaptic receptors appear to be located on nerve
terminals of other neuronal systems (so called heteroreceptors). Since the
h5-HT.sub.1B receptor mediates inhibitory responses an antagonist of this
receptor subtype might also increase the release of other
neurotransmitters than 5-HT.
Compounds having h5-HT.sub.1B activity may according to well known and
recognised pharmacological tests be divided into full agonists, partial
agonists and antagonists.
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide compounds having a
selective effect at the h5-HT.sub.1B receptor, preferably antagonistic
properties, as well as having a good bioavailability and which may easily
be formulated into pharmaceutical formulations. The compounds according to
the invention have surprisingly solved the above problem since they are
dissolved rapidly enough and are maintained dissolved in the gastric juice
until a sufficient amount of substance has been absorbed
Accordingly, the present invention provides pharmaceutically acceptable
salts of the compound of formula I or solvates of said salt in which the
compound of formula I is as the (R)-enantiomer, the (S)-enantiomer or the
racemate,
##STR2##
with the proviso that
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen (2S,3S)-tartrate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen (2R,3R)-tartrate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide benzenesulfonate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzarnide hydrogen 1,2-ethanedisulfonate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen maleate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzarnide hydrogen sulfate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide D-gluconate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen succinate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide methanesulfonate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrogen (S)-maleate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide dihydrogen citrate and
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide hydrochloride are excluded,
which salts possess a high selective effect at the h5-HT.sub.1B receptor,
are easily formulated into pharmaceutical formulations and also show
sufficient bioavailability after oral administration.
The preferred enantiomers are the (R)-enantiomers.
Preferred compounds are
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide L-lactate,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide dihydrobromide,
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide monohydrobromide and
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide dihydrochloride.
Both organic and inorganic acids can be employed to form non-toxic
pharmaceutically acceptable acid addition salts according to the
invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic,
hydrochloric, forrnic, hydrobromic, citric, acetic, lactic, tartaric,
dibenzoyltartaric, diacetyltartaric, palmoic, ethanedisulfonic, sulfamic,
succinic, propionic, glycolic, malic, gluconic, pyruvic, phenylacetic,
4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic,
4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic,
3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic,
hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, sulfanilic,
naphthalenesulfonic, ascorbic, cyclohexylsulfamic, fumaric, maleic and
benzoic acids. The compound of formula I can form hemi- mono-, sesqui-,
di- or trisalts or any other salt combination therein between of the above
acids, if applicable. These salts are readily prepared by methods known in
the art.
The preferred solvates of this invention are the hydrates. Other solvates
may be formed from solvents such as ethyl acetate, ethanol or acetone. The
solvates of the salts are readily prepared by methods known in the art.
Pharmaceutical Formulations
In a second aspect the present invention provides easily formulated
pharmaceutical formulations comprising as active ingredient a
therapeutically effective amount of a pharmaceutically acceptable salt of
the compound of formula I or a solvate of said salt as an enantiomer or a
racemate, or a combination of such salts and/or solvates, optionally in
association with diluents, excipients or inert carriers.
According to the present invention the compound of the invention will
normally be administered orally, rectally or by injection, in the form of
pharmaceutical formulations comprising the active ingredient either as a
pharmaceutically acceptable non-toxic acid addition salt, e.g.
hydrochlorides, hydrobromides, lactates, acetates, phosphates, sulfates,
sulfamates, citrates, tartrates, oxalates and the like or as a solvate of
such salt in a pharmaceutically acceptable dosage form. The dosage form
may be a solid, semisolid or liquid preparation. Usually the active
substance will constitute between 0.1 and 99% by weight of the
preparation, more specifically between 0.5 and 20% by weight for
preparations intended for injection and between 0.2 and 50% by weight for
preparations suitable for oral administration.
To produce pharmaceutical formulations containing the compound of the
invention in the form of dosage units for oral application, the selected
compound may be mixed with a solid excipient, e.g. lactose, saccharose,
sorbitol, mannitol, starches such as potato starch, corn starch or
amylopectin, cellulose derivatives, a binder such as gelatine or
poly-vinylpyrrolidone, and a lubricant such as magnesium stearate, calcium
stearate, polyethylene glycol, waxes, paraffin, and the like, and then
compressed into tablets. If coated tablets are required, the cores,
prepared as described above, may be coated with a concentrated sugar
solution which may contain e.g. gum arabic, gelatine, talcum, titanium
dioxide, and the like. Alternatively, the tablet can be coated with a
polymer known to the person skilled in the art, dissolved in a readily
volatile organic solvent or mixture of organic solvents. Dyestuffs may be
added to these coatings in order to readily distinguish between tablets
containing different active substances or different amounts of the active
compound.
For the preparation of soft gelatine capsules, the active substance may be
admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine
capsules may contain granules of the active substance using either the
above mentioned excipients for tablets e.g. lactose, saccharose, sorbitol,
mannitol, starches (e.g. potato starch, corn starch or amylopectin),
cellulose derivatives or gelatine. Also liquids or semisolids of the drug
can be filled into hard gelatine capsules.
Dosage units for rectal application can be solutions or suspensions or can
be prepared in the form of suppositories comprising the active substance
in a mixture with a neutral fatty base, or gelatine rectal capsules
comprising the active substance in admixture with vegetable oil or
paraffin oil. Liquid preparations for oral application may be in the form
of syrups or suspensions, for example solutions containing from about 0.1%
to about 20% by weight of the active substance herein described, the
balance being sugar and mixture of ethanol, water, glycerol and propylene
glycol. Optionally such liquid preparations may contain colouring agents,
flavouring agents, saccharin and carboxymethylcellulose as a thickening
agent or other excipients known to the person skilled in the art.
Solutions for parenteral applications by injection can be prepared in an
aqueous solution of a water-soluble pharmaceutically acceptable salt of
the active substance, preferably in a concentration of from about 0.1% to
about 10% by weight. These solutions may also contain stabilizing agents
and/or buffering agents and may conveniently be provided in various dosage
unit ampoules.
Suitable daily doses of the compound of the invention in therapeutical
treatment of humans are about 0.01-100 mg/kg bodyweight at peroral
administration and 0.001-100 mg/kg bodyweight at parenteral
administration.
The compound of the invention may be used in a combination with a 5-HT
reuptake inhibitor, such as fluoxetine, paroxetine, citalopram,
clomipramine, sertraline, alaproclate or fluvoxamin, preferably paroxetine
or citalopram. Another possible combination is to use the compound of the
invention together with a monoamine oxidase inhibitor, such as
moclobemide, tranylcypramine, brofaromide or phenelzine, preferably
moclobemide or phenelzine. Still another possible combination is the
compound of the invention together with a 5-HT.sub.1A antagonist, such as
one of the compounds disclosed in WO 96/33710, preferably
(R)-5-carbamoyl-3-(N,N-dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzop
yran.
Medical and Pharmaceutical Use
In a further aspect the present invention provides the use of the compounds
of the invention in therapy as a h5-HT.sub.1B antagonists, partial
agonists or full agonists, preferably as antagonists and the use in the
treatment of 5-hydroxytryptamine mediated disorders. Examples of such
disorders are disorders in the CNS such as mood disorders (depression,
major depressive disorder, major depressive episodes, dysthymia, seasonal
affective disorder, depressive phases of bipolar disorder), anxiety
disorders (obsessive compulsive disorder, panic disorder with/without
agoraphobia, social phobia, specific phobia, generalized anxiety disorder,
posttraumatic stress disorder), personality disorders (disorders of
impulse control, trichotellomania), obesity, anorexia, bulimia,
premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse,
autism, attention deficit, hyperactivity disorder, migraine, memory
disorders (age associated memory impairment, presenile and senile
dementia), pathological aggression, schizophrenia, endocrine disorders (e
g hyperprolactinaemia), stroke, dyskinesia, Parkinson's disease,
thermoregulation, pain, and hypertension. Other examples of
hydroxytryptamine mediated disorders are urinary incontinence, vasospasm
and growth control of tumors (e g lung carcinoma).
Methods of Preparation
The present invention also relates to processes for preparing compounds of
the nvention.
Methods of Preparation of Intermediates
(i) Benzylation of the compound of formula II, either as a racemate or as
an enantiomer,
##STR3##
to obtain a compound of formula III may be carried out by reaction with a
suitable benzylation agent e.g. a benzyl halide such as benzyl bromide or
benzyl chloride or an activated alcohol e.g. benzylesylate or benzyl
tosylate. The reaction may be carried out using a salt or the base of
compound II in a suitable solvent e.g. N,N-dimethylformamide, acetone or
acetonitrile with a suitable base e.g. NaOH, NaHCO.sub.3, K.sub.2 CO.sub.3
or a trialkylamine such as triethylamine at a temperature within the range
of +20.degree. C. to +150 .degree. C. The presence of a suitable catalyst
e.g. potassium iodide or sodium iodide, may increase the speed of the
reaction.
(ii) Demethylation of the compound of formula III
##STR4##
to obtain a compound of formula IV may be carried out by treating the
compound with an acidic reagent such as aqueous HBr, HI, HBr/CH.sub.3
COOH, BBr.sub.3, AlCl.sub.3, pyridine-HCl or with a basic nucleophilic
reagent such as CH.sub.3 C.sub.6 H.sub.4 S.sup.- or C.sub.2 H.sub.5
S.sup.- in a suitable solvent. Suitable solvents may be methylene chloride
or chloroform and the reaction may occur between -78.degree. C. and
+60.degree. C.
(iii) Conversion of the compound of formula IV to a compound of formula V
##STR5##
may be carried out by the reaction with a compound of formula VI
##STR6##
where X stands for a leaving group, e.g. a halogen such as chlorine,
bromine or iodine or an alkane- or arenesulfonyloxy group such as a
p-toluenesulfonyloxy group and R.sub.a and R.sub.b are hydrogen or a lower
alkyl group e.g. methyl. The process may be carried out with a salt of the
compound of formula IV obtained by reaction with a base such as K.sub.2
CO.sub.3, Na.sub.2 CO.sub.3, KOH, NaOH, BuLi or NaH. The reaction may be
conducted in a suitable solvent e.g. an aprotic solvent such as dioxane,
N,N-dimethylformamide, tetrahydrofuran, toluene, benzene or petroleum
ether and the reaction may occur between +20.degree. C. and +150.degree.
C.
(iv) Rearrangement of a compound of formula V to a compound of formula VII
##STR7##
may be carried out in a suitable solvent e.g. an aprotic solvent such as NN
dimethylformamide, dioxane, 1,1,3,3-tetramethylurea, tetrahydrofuran or
hexamethylphosphoric triamide with a suitable base e.g. K.sub.2 CO.sub.3,
KOH, potassium tert-butoxide or NaH at a temperature within the range of
+20.degree. C. to +150.degree. C. The presence of a cosolvent such as
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone or hexamethylphosphoric
triamide in appropriate concentration in the solvent may increase the
speed of the reaction.
(v) Hydrolysis of a compound of formula VII to a compound VIII may be
carried out under acidic conditions using acids such as H.sub.2 SO.sub.4,
HCl or HBr in a suitable solvent e.g. H.sub.2 O, ethanol, methanol or
mixtures thereof and the reaction may occur between +20.degree. C. and
+100.degree. C. or under basic conditions using bases such as NaOH or KOH
in a suitable solvent e.g. H.sub.2 O, ethanol, methanol or mixtures
thereof and the reaction may occur between +20.degree. C. and +100.degree.
C.
(vi) Conversion of compound of formula VIII to a compound of formula IX
##STR8##
may be carried out by reaction with a compound of formula X.
##STR9##
The process may be carried out in a suitable solvent e.g. an
aprotic/anhydrous solvent such as tetrahydrofuran or N,N-dimethylformamide
in the presence of a coupling reagent such as N,N'-carbonyldiimidazole and
the reaction may occur between +20.degree. C. and +130.degree. C. The
reaction is followed by the reduction of the imide with a suitable
reducing agent e.g. LiAlH.sub.4 in a suitable solvent e.g. diethyl ether
or tetrahydrofuran at a temperature between +20.degree. C. and reflux.
(vii) Halogenation of the compound of formula IX
##STR10##
to obtain a compound of formula XI may be performed by aromatic
electrophilic substitution using a suitable halogenation agent such as
Br.sub.2, Cl.sub.2, I.sub.2, ICl, or SO.sub.2 Cl.sub.2. The reaction may
be carried out using the salt or the base of the compound IX in an
appropriate solvent e.g. acetic acid, HCl/ethanol or water with or without
a suitable base e.g. alkali metal acetate such as sodium acetate and at a
reaction temperature between -20.degree. C. and room temperature.
##STR11##
(viii) Conversion of the compound of formula XI to a compound of formula
XII may be carried out by a metal-halogen exchange, in a appropriate
anhydrous solvent such as tetrahydrofuran or diethyl ether using a
suitable alkyl-lithium or metal e.g. butyllithium, lithium or magnesium
turnings, followed by treatment with methyl iodide and the reaction may be
performed at a reaction temperature within the range of -78.degree. C. to
room temperature, followed by cleavage of the benzyl groups by
hydrogenation over a suitable catalyst containing palladium, rhodium,
platinum or nickel, in a suitable solvent e.g. acetic acid or ethanol and
at a reaction temperature between +20.degree. C. and +120.degree. C.
Method of Preparation of End Product.
Another object of the invention is a process for the preparation of the
compound of the invention by acylation of a compound of formula XII,
##STR12##
with activated 4-morpholinobenzoic acid and reacting the base with an
organic or inorganic acid to form the salt with or without a solvate.
Thus, the acylation may be carried out by reacting the compound of formula
XII with the acid chloride or acid bromide of 4-morpholinobenzoic acid in
a suitable solvent such as methylene chloride or chloroform with a
suitable base e.g. trialkylamine such as triethylamine at a temperature
between -20.degree. C. and reflux temperature or by activating the
carboxylic acid function in 4-morpholinobenzoic acid with an activating
reagent such as N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide or
diphenylphosphinic chloride with or without a suitable base such as
N-methylmorpholine in a suitable solvent such as N,N-dimethylformamide or
tetrahydrofuran and the reaction may be conducted at a temperature between
+20.degree. C. and +150.degree. C.
Furthermore, the pharmaceutically acceptable salt of the compound of the
formula I may be obtained by reacting the base with the appropriate acid
in a suitable solvent such as an alcohol e.g. methanol, ethanol or
2-propanol or another suitable solvent such as water, ethyl acetate,
hexane, tetrahydrofuran, acetone, acetonitrile, chloroform or mixtures
thereof. The process may be carried out at various temperatures between
-30 and reflux. The salt formed in the above process may be formed as a
solvate.
WORKING EXAMPLES
The following examples will describe, but not limit, the invention.
Example 1
(R)-2-N,N-Dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene
To a solution of (R)-8-methoxy-2-amino-1,2,3,4-tetrahydronaphthalene
hydrochloride (24 g, 0. 11 mol) in acetonitrile (600 mL) were added
potassium carbonate (53 g, 0.39 mol), potassium iodide (catalytic amount)
and benzyl bromide (34 mL, 0.28 mol). The reaction mixture was stirred at
reflux for a period of 35 h.
After the precipitate was filtered off and the acetonitrile removed in
vacuo, the residue was partitioned between diethyl ether and water. The
organic phase was separated, dried (Na.sub.2 SO.sub.4) and evaporated in
vacuo to give a crude product which was purified on a silica gel column
using hexane/ethyl acetate, (3:1) as the eluent. Yield: 36 g (91%) of the
title compound as a white solid: mp 105-107.degree. C.; [a].sup.21.sub.D
+124.degree. (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity)
357 (100, M.sup.+).
Example 2
(R)-7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthol
(R)-2-N,N-Dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene (43 g, 0.12
mol) was dissolved in diethyl ether (800 mL) and an excess of an ethereal
HCl solution was added dropwise. The precipitate was filtered and dried in
vacuo to give a white solid. This crude product (42 g, 0.11 mol) was
dissolved in anhydrous methylene chloride (1 L) and cooled to -60.degree.
C. To the solution was boron tribromide (16 mL, 0.15 mol), dissolved in
anhydrous methylene chloride (100 mL), added dropwise. The reaction
temperature was allowed to reach -5.degree. C. and was kept there
overnight. To the ice-cooled solution was a 2 M aqueous ammonium hydroxide
solution added dropwise and the mixture was extracted, twice, with
methylene chloride. The combined organic phases were dried (Na.sub.2
SO.sub.4), filtered and the solvent removed in vacuo to give a crude
residue. Chromatography on silica (eluent: methylene chloride) gave 34 g
(93% yield) of the title compound as a viscous clear oil: [a].sup.21.sub.D
+118.degree. (c 1.5, chloroform); EIMS (70 eV) m/z (relative intensity)
343 (53, M.sup.+).
Example 3
(R)-2-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy)-2-methylpropan
amide
(R)-2-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (10 g, 29 mmol) was
stirred in anhydrous dioxane (150 mL) with sodium hydride (80% in oil,
0.96 g, 32 mmol) for 1 h. 2-Bromo-2-methylpropanamide (4.8 g, 29 mmol;
described in: Coutts, I. G. C.; Southcott, M. R. J. Chem. Soc. Perkin
Trans. 1 1990, 767-770) was added and the reaction mixture was heated at
100.degree. C. for 2.5 h. After cooling, the precipitated sodium bromide
was filtered off, the filtrate evaporated in vacuo and the residue was
partitioned between water and methylene chloride. The organic phase was
separated, dried (Na.sub.2 SO.sub.4), filtered and evaporated to give a
crude product which was purified on a silica gel column using methylene
chloride as the eluent. Yield: 9.6 g (76%) of the title compound as white
crystals: mp 125-126.degree. C.; [a].sup.21.sub.D +98.degree. (c 1.1,
chloroform); EIMS (70 eV) m/z (relative intensity) 428 (13, M.sup.+).
Example 4
(R)-N-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-2-hydroxy-2-methy
lpropanamide
To a solution of
(R)-2-(7-N,N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy)-2-methylpropa
namide (9.1 g, 21 mmol) in anhydrous
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (10 mL) and dry
N,N-dimethylformamide (100 mL) was added sodium hydride (80% in oil, 1.4
g, 47 mmol) and the reaction was heated at 130.degree. C. for 8 h. The
solution was poured into a mixture of ice and water and extracted three
times with ethyl acetate. The combined organic phases were dried (Na.sub.2
SO.sub.4), filtered and evaporated in vacuo. Chromatography on silica
(eluent: chloroform/ethanol saturated with NH.sub.3 ; 100:0.5) gave 7.6 g
(84% yield) as white crystals: mp 134-135.degree. C.; [a].sup.21.sub.D
+130.degree. (c 1.1, chloroform);
EIMS (70 eV) m/z (relative intesity) 428 (1, M.sup.+).
Example 5
(R)-2-N,N-Dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene
(R)-N-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-2-hydroxy-2-methy
lpropionamide (7.4 g, 17 mmol) was dissolved in a mixture of ethanol (200
mL) and a 20% HCl aqueous solution (300 mL) and heated to reflux for 8 h.
The ethanol was evaporated in vacuo and the remaining solution was washed
twice with diethyl ether and cooled on ice-bath. After alkalization with a
45% aqueous solution of sodium hydroxide the mixture was extracted with
methylene chloride. The combined organic phases were dried (Na.sub.2
SO.sub.4), filtered and evaporated in vacuo. Purification on a silica gel
column using chloroform as the eluent gave 3.8 g (76% yield) of the title
compound as a light-brown oil: [a].sup.21.sup.D +1240 (c 0.9, chloroform);
EIMS (70 eV) m/z (relative intensity) 342 (92, M.sup.+).
Example 6
(R)-1-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-4-N-methylpiperaz
ine-2,6-dione
1,1'-Carbonyldiimidazole (6.0 g, 37 mmol) was added to a stirred suspension
of methyliminodiacetic acid (2.7 g, 18 mmol) in anhydrous tetrahydrofuran
(250 mL). The reaction mixture was heated at reflux for 1.5 h.
(R)-2-N,N-Dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene (5.7 g, 17
mmol) was then added and stirring at reflux was continued for 17 h. An
additional amount of 1,1'-carbonyldiimidazole (2.9 g, 18 mmol) was added
and heating at reflux was continued for another 17 h. The solvent was
evaporated in vacuo and the crude product was purified on a silica gel
column using chloroform/ethanol saturated with NH.sub.3 (100:0.5) as the
eluent. Yield: 6.6 g (87%) of the title compound as an oil:
[a].sup.21.sup.D +90.degree. (c 0.52, chloroform); EIMS (70 eV) m/z
(relative intensity) 453 (8, M.sup.+).
Example 7
(R)-2-N,N-Dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphth
alene
(R)-1-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-4-methylpiperazin
e-2,6-dione (1.4 g, 3.1 mmol) was added to a suspension of lithium
aluminium hydride (0.57 g, 15 mmol) in anhydrous diethyl ether (70 mL).
The reaction mixture was heated at reflux for 7 h. The reaction was
quenched by the addition of water (0.60 mL), 15% aqueous sodium hydroxide
(0.60 mL) and again water (1.8 mL). The mixture was filtered, dried
(Na.sub.2 SO.sub.4) and evaporated in vacuo. Purification on a silica gel
column using chloroform/ethanol saturated with NH.sub.3 (100:2) as the
eluent gave 1.0 g (79% yield) of the title compound as a viscous oil:
[a].sup.21.sub.D +53.degree. (c 0.5, chloroform); EIMS (70 eV) m/z
(relative intensity) 425 (2, M.sup.+).
Example 8
(R)-5-Bromo-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahyd
ronaphthalene.
To a solution of
(R)-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronapht
halene (2.8 g, 6.5 mmol) and sodium acetate (6.8 g, 83 mmol) in acetic acid
(100 mL) was bromine (370 mL, 7.2 mmol) added in one portion and the
reaction was stirred for 5 min. The solvent was evaporated in vacuo and
the remaining solid was partitioned between water and methylene chloride
and cooled on ice-bath. The water phase was alkalized with 2 M aqueous
solution of sodium hydroxide and the phases were separated. The organic
phase was dried (Na.sub.2 SO.sub.4), filtered and evaporated in vacuo to
give a crude product which was purified on a silica gel column using
chloroforn/ethanol saturated with NH.sub.3 (100:2) as the eluent. Yield: 2
g (61%) of a viscous brown oil: EIMS (70 eV) m/z (relative intensity) 503
and 505 (0.6, M.sup.+)
Example 9
(R)-2-N,N-Dibenzylamino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetra-h
ydronaphthalene
(R)-2-N,N-Dibenzylamino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetra-hy
dronaphthalene (16 g, 0.31 mol) was dissolved in freshly distilled
tetrahydrofuran (300 mL) and cooled to -78.degree. C. under argon. To the
solution was added n-butyl lithium (19 mL, 1.6 M in hexane, 0.31 mol,)
dropwise during 45 min at a maximum temperature of -76.degree. C. The dark
green solution was stirred for an additional 20 min. A solution of methyl
iodide (1.9 mL, 0.31 mol) in freshly distilled tetrahydrofuran (10 mL) was
added dropwise during 25 min at a maximum temperature of -74.degree. C.
making the green color disappear. The reaction mixture was stirred at
-78.degree. C. for 50 min and at 0.degree. C. for 50 min. The reaction was
quenched with i-propylalcohol (3 mL) and the solvent was evaporated in
vacuo. The residue was partitioned between ethyl acetate (300 mL) and
H.sub.2 O (30 mL) and the phases were separated and the organic layer was
washed with brine (30 mL). After drying (Na.sub.2 SO.sub.4), and
evaporation of the solvent in vacuo, 15 g of a crude product was obtained.
Purification by column chromatography on silica using ethyl
acetate/triethylaamine (100:1) as the eluent afforded 11 g (82% yield) of
the title compound as a brown oil: EIMS (70 eV) m/z (relative intensity)
439 (5, M.sup.+); [a].sub.D.sup.22 +86.degree. (c 0.05, CHCl.sub.3).
Example 10
(R)-2-Amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-naphthal
ene
(R)-2-N,N-Dibenzylamino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetra-h
ydronaphthalene (28 g, 64 mmol) was dissolved in acetic acid (280 mL) and
charged into a Buchi glass autoclave (1 L). 10% Palladium on charcoal (2.8
g, containing 50% H.sub.2 O) was added. The reaction mixture was stirred
at 70.degree. C. and at 5 bar hydrogen pressure for 3.5 h. The catalyst
was filtered off and the solvent was evaporated in vacuo. The residue was
partitioned between ethyl acetate (400 mL) and water (100 mL) and cooled
on an ice-bath. The pH was adjusted to 12 by addition of aqueous NaOH
(45%) and the phases were separated. The aqueous phase was re-extracted
with ethyl acetate (2.times.100 mL) and the combined organic layer was
washed with brine (50 mL) and dried (Na.sub.2 SO.sub.4). Evaporation of
the solvent in vacuo gave 18 g (99% yield) of the title compound as a
brown oil. EIMS (70 eV) m/z (relative intensity) 259 (34, M.sup.+);
[.alpha.].sub.D.sup.22 -1.1.degree. (c 0.09, CHCl.sub.3).
Example 11
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyll-4
-morpholinobenzamide
4-Morpholinobenzoic acid (23.3 g, 113 mmol; described in: Degutis,
J.;Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064)
and 1,1'-carbonyldiimidazole (19.2 g, 118 mmol) dissolved in anhydrous
N,N-dimethylformarnide (250 mL), were stirred at 75.degree. C. for 2 h and
cooled to room temperature. To the solution was added
(R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthal
ene (27.8 g, 107 mmol) dissolved in anhydrous N,N-dimethylformamide (250
mL). The reaction mixture was stirred for 58 h giving a white slurry. The
precipitate was filtered off and dried in vacuo giving 13.3 g of a crude
product. The mother liquid was concentrated to dryness in vacuo giving 65
g of a crude material which was partitioned between CH.sub.2 Cl.sub.2 (500
mL) and H.sub.2 O(70 mL). The organic layer was washed with H.sub.2 O (70
mL) and brine (2.times.70 mL) and dried (Na.sub.2 SO.sub.4). The solvent
was evaporated in vacuo giving 40 g. The two portions were combined and
recrystallized, three times, from anhydrous methanol to give 33.6 g (70%
yield) of the title compound as white needles: mp 236-237.degree. C.; EIMS
(70 eV) m/z (relative intensity) 448 (3, M.sup.+); [.alpha.].sub.D.sup.22
-60.degree. (c 0.15, CHCl.sub.3)
Salts of
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide.
All melting points were determined using Differential Scanning Calorimetry
(DSC). The temperature scanning rate was 10.degree. C. per minute starting
from room temperature. The samples were investigated in aluminum-pans with
loose lids under nitrogen.
Example 12
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide L-Lactate.
To a warm solution of
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide (1.0 g, 2.2 mmol) in methanol (40 mL) was added
L-lactic acid (240 mg, 2.7 mmol) and the solution was allowed to cool to
room temperature. The solvent was evaporated in vacuo and the white
residue was dissolved in 2-propanol (20 mL) under heating. After addition
of diethyl ether (10 mL),
the solution was allowed to cool to room temperature. The formed
precipitate was filtered off and dried in vacuo to give 360 mg (30% yield)
of the desired product as white crystals: mp 130-140.degree. C. Anal.
Calcd. for C.sub.27 H.sub.36 N.sub.4 O.sub.2.times.C.sub.3 H.sub.6 O.sub.3
: C, 66.9; H, 7.9; N, 10.4. Found: C, 66.6; H, 7.9; N, 10.3.
Example 13
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide L-Ascorbate.
To a warm solution of
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide (1.0 g, 2.2 mmol) in methanol (30 mL) was added a
solution of L-ascorbic acid (475 mg, 2.7 mmol) in methanol (20 mL) and the
solution was allowed to cool to room temperature. About 25 mL of the
solvent was evaporated in vacuo and the remaining solution (25 mL) was
allowed to stand at room temperature for 2.5 h. The crystals were filtered
and dried in vacuo to give 1.3 gram (92% yield) of the title compound as
light grey crystals. mp 235-245.degree. C. Anal. Calcd. for C.sub.27
H.sub.36 N.sub.4 O.sub.2.times.C.sub.6 H.sub.8 O.sub.6.times.H.sub.2 O: C,
61.7; H, 7.2; N, 8.7. Found: C, 61.9; H, 7.0; N, 8.9.
Example 14
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide Salicylate.
To a boiling solution of
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide (1.0 g, 2.2 mmol) in ethanol (50 mL) was added a
solution of salicylic acid (400 mg, 2.9 mmol) in ethanol (10 mL). The
solvent was concentrated in vacuo and the remaining solution (20 mL) was
allowed to cool to room temperature. The solution was put in the freezer
over the weekend. The crystals were filtered and dried in vacuo to give
1.2 gram (86% yield) of the title compound as white crystals: mp
235-240.degree. C. Anal. Calcd. for C.sub.27 H.sub.36 N.sub.4
O.sub.2.times.C.sub.7 H.sub.6 O.sub.3 : C, 69.6; H, 7.2; N, 9.6. Found: C,
69.5; H, 7.2; N, 9.5.
Example 15
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide Glycolate.
To a hot solution of
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl)-
4-morpholinobenzamide (1.0 g, 2.2 mmol) in ethanol (50 mL) was added a hot
solution of glycolic acid (200 mg, 2.6 mmol) in ethanol (10 mL). The
solvent was concentrated in vacuo and to the remaining solution (20 mL)
was boiling ethyl acetate added until the solution was cloudy. After
boiling for a few minutes, the solution was cooled and put in the
refrigerator over night. The crystals were filtered and dried in vacuo to
give 1.0 gram (83% yield) of the title compound as white crystals. Anal.
Calcd. for C.sub.27 H.sub.36 N.sub.4 O.sub.2.times.C.sub.7 H.sub.6
O.sub.3.times.2H.sub.2 O: C, 62.1; H, 7.9; N, 10.0. Found: C, 62.7; H,
7.7; N, 9.6.
Example 16
(R)-N-15-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide Dihydrobromide
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide (2.0 g, 4.5 mmol) was dissolved in anhydrous
tetrahydrofuran (55 mL) and an ethereal HBr solution was added until the
solution was acidic. The white solid was filtered, washed with diethyl
ether and dried to give the crude solid. The crude solid was
recrystallized from absolute ethanol/ethyl acetate to give 0.78 g (29%
yield) of white transparent crystals: mp 250-265.degree. C. Anal. Calcd.
for C.sub.27 H.sub.38 Br.sub.2 N.sub.4 O.sub.2 : C, 53.1; H, 6.3;
Br, 26.2; N, 9.2. Found: C, 53.0; H, 6.4; Br, 26.3; N, 9.0.
Example 17
(R)-N-15-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4
-morpholinobenzamide Dihydrochloride
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3
,4-tetrahydro-2-naphthyl]-4-morpholinobenzamide (2.0 g, 4.5 mmol) was
dissolved in anhydrous tetrahydrofuran (55 mL) and an ethereal HCl
solution was added until the solution was acidic. The white solid was
filtered, washed with diethyl ether and dried to give a crude hygroscopic
solid. The crude solid was recrystallized, twice, from ethanol/ethyl
acetate to give 0.11 g (16% yield) of small hard white crystals. Anal.
Calcd. for C.sub.27 H.sub.38 Cl.sub.2 N.sub.4 O.sub.2 : C, 62.2; H, 7.3;
Cl, 13.6; N, 10.7. Found: C, 62.1; H, 7.4; Cl, 13.4; N, 10.8.
Example 18
(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl-1-
4-morpholinobenzamide Monohydrobromide.
Imidazole (16.3 g, 239 mmol) was dissolved in isopropanol (170 mL) and
hydrobromic acid (34% w/w in acetic acid, 49.5 mL, 218 mmol) was added
dropwise. This solution was added to a slurry of
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide (89.2 g, 198 mmol) in isopropanol (710 mL) at
40.degree. C. After the addition was complete the mixture was heated to
reflux for 3 h. After cooling to 0.degree. C. the crystals were collected
by filtration and dried at 60.degree. C. under vacuum to give 98.5 g
(93.6% yield) of crude monohydrobromide.
The crude monohydrobromide above (96.6 g, 182 mmol) was recrystallized from
95% ethanol (5% water v/v, 598 mL) and ethyl acetate (2280 mL) at
60-70.degree. C. and the slurry was slowly cooled to -10.degree. C. before
filtration. The crystals were collected by filtration and dried at
60.degree. C. under vacuum to give 87.7 g (91% yield) of slightly pink
crystals: mp 265.degree. C. (decom.). .sup.1 H NMR (300 MHz,
DMSO-d.sub.6).delta.8.24 (d, J=7.5 Hz, 1 H), 7.86 (d, J=8 Hz, 2 H),
6.92-7.08 (m, 1H), 7.01 (d, J=7.5 Hz, 1 H), 6.98 (d, J=8 Hz, 1 H), 6.86
(d, J=8 Hz, 1 H), 3.61-4.07 (m, 5 H), 2.42-3.61 (m, 16 H), 2.84 (s, 3 H),
2.00-2.20 (m, 1 H), 2.15 (s, 3 H), 1.63-1.88 (m, 1H).
Pharmacology
Electrical field stimulation of [.sup.3 H] -5-HT release from occipital
cortex of guinea pigs [.sup.3 H] -5-HT is released by electrical field
stimulation from slices of occipital cortex of guinea pigs which have been
pre-incubated with [.sup.3 H] -5-HT. This release is similar to that
caused by nerve stimulation, i.e. exocytotical release from serotonergic
nerve terminals, depending on the presence of Ca.sup.2+ in the incubation
medium. The 5-HT release is regulated at the level of the nerve terminals
by autoreceptors, in the guinea pigs (like in humans) belonging to the
h5-HT.sup.1B receptor subtype. Thus, agonists of h5-HT.sup.1B receptors
reduce the amount of [3H]-5-HT released by field stimulation whereas the
release is increased by antagonists of this receptor type. Testing
compounds with this method is accordingly a convenient screening technique
for determining the potency and functional effect of new h5-HTIB receptor
agonists and antagonists.
Methods and Materials
Buffer composition (mM) NaHCO.sub.3 (25), NaH.sub.2 PO.sub.4. H.sub.2 O
(1.2), NaCl (117), KCl(6), MgSO.sub.4.times.7H.sub.2 O(1.2), CaCl.sub.2
(1.3), EDTA Na.sub.2 (0.03). The buffer is gassed for at least 30 min
before use. The pH of the buffer is about 7.2 at room temperature but it
rises to about 7.4 at 37.degree. C.
Preparation of Occipital Cortical Slices
Guinea pigs (200-250 g) were decapitated and the whole brain was removed.
The occipital cortex was dissected and cut to slices 0.4.times.4 mm with
McIlwain chopper machine. The white part of the tissue should be removed
carefully with a tweezers before slicing. The slices were incubated in 5
ml buffer in the presence of 5 mM pargyline chloride. After incubation
with 0.1 mM [.sup.3 H]-5-HT for another 30 min the slices were transferred
to a test tube and washed three times with same volume buffer. The slices
were transferred to the superfusion chambers with a plastic pipette and
were washed for 40 min with the buffer in the presence of uptake inhibitor
citalopram 2.5 .mu.M with a flow 0.5 ml/min.
Electrical Stimulation of 5-HT Release
The superfused buffer was collected in 2 mL fractions. The slices were
stimulated by electricity with a train of pulses of frequency 3 Hz,
duration 2 ms and current 30 mA for 3 min at the 4th and 13th fractions.
The tested drugs were added from the 8th fraction to the end of
experiment.
Results
A first electrical (or K.sup.+) stimulation results in a standard amount of
[.sup.3 H]-5-HT released (S1). Between the first and a second stimulation
the h5-HT.sub.1B antagonist is added to the media which results in a dose
depending increase of the release(S.sub.2) after the second stimulation.
See FIG. 1.
The S.sub.2 /S.sub.1 ratio which is the per cent of released [.sup.3
H]-5-HT at the second stimulation (S.sub.2) divided by that of the first
stimulation (S.sub.1) was used to estimate drug effects on transmitter
release.
Solubility Determination of
(R)-N-15-Methyl-8-(4-Methylpiperazin-1-yl)-1,2,3,4-Tetrahydro-2-Naphthyl]-
4-Morpholinobenzamide and it's corresponding Salts.
Method
Excess of
(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-
4-morpholinobenzamide or it's corresponding salts was added to purified
water. The solution was agitated overnight in a water bath, kept at
25.degree. C. by using a thermostat (Julabo SW and U3, 60 strokes/min).
The saturated solution was centrifuged and filtered through a 0.45
.quadrature.m Gelman GHP Acrodisc.RTM. 13 filter, diluted and assayed by
HPLC.
Results
Solubility in Water at 25.degree. C. for the Base,
(R)-N-[5-Methyl-8-(4-Methylpiperazin-1-yl)-1,2,3,4-Tetrahydro-2-Naphthyl]-
4-Morpholinobenzamide.
0.034 mg/mL
Solubility in Water at 25.degree. C. for different salts of
(R)-N-[5-Methyl-8-(4-Methylpiperazin-1-yl)-1,2,3,4-Tetrahydro-2-Naphthyl]-
4-Morpholinobenzamide.
Salt (Example) Solubility mg/mL
L-Lactate 18.8
L-Ascorbate 4.2
Salicylate 0.29
Glycolate >23.6
Dihydrobromide 4.6
It is clear from the above comparison between the base compound and a
number of representaive salts thereof that salts of the compound according
to formula (I) to a greater extent are more soluble in water compared to
the base and thus are more suitable for preparing pharmaceutical
formulations.
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