U.S. patent application number 09/878045 was filed with the patent office on 2002-02-14 for pharmaceutical compositions containing a 4, 5-dihydro-1, 3-thiazol-2-ylamine derivative, novel derivatives and preparation thereof.
Invention is credited to Bacque, Eric, Bigot, Antony, Carry, Jean-Christophe, Damour, Dominique, Guyon, Claude, Mignani, Serge.
Application Number | 20020019427 09/878045 |
Document ID | / |
Family ID | 27248676 |
Filed Date | 2002-02-14 |
United States Patent
Application |
20020019427 |
Kind Code |
A1 |
Carry, Jean-Christophe ; et
al. |
February 14, 2002 |
Pharmaceutical compositions containing a 4, 5-dihydro-1,
3-thiazol-2-ylamine derivative, novel derivatives and preparation
thereof
Abstract
The present invention relates to pharmaceutical compositions
containing, as active principle, a
4,5-dihydro-1,3-thiazol-2-ylamine derivative of formula (I): 1 in
which R represents an --alk--S--alk--Ar radical, a phenyl radical
or a phenyl radical substituted with alkoxy or halogen, or to one
of the pharmaceutically acceptable salts thereof, to the novel
derivatives of formula (I) and to their preparation.
Inventors: |
Carry, Jean-Christophe;
(Saint Maur Des Fosses, FR) ; Damour, Dominique;
(Orly, FR) ; Guyon, Claude; (Saint Maur Des
Fosses, FR) ; Mignani, Serge; (Chatenay-Malabry,
FR) ; Bacque, Eric; (Morsang Sur Orge, FR) ;
Bigot, Antony; (Massy, FR) |
Correspondence
Address: |
AVENTIS PHARMACEUTICALS, INC.
PATENTS DEPARTMENT
ROUTE 202-206, P.O. BOX 6800
BRIDGEWATER
NJ
08807-0800
US
|
Family ID: |
27248676 |
Appl. No.: |
09/878045 |
Filed: |
June 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60231613 |
Sep 11, 2000 |
|
|
|
Current U.S.
Class: |
514/370 ;
548/193 |
Current CPC
Class: |
C07D 277/18
20130101 |
Class at
Publication: |
514/370 ;
548/193 |
International
Class: |
A61K 031/426; C07D
277/18 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 9, 2000 |
FR |
0007396 |
Claims
What is claimed is:
1. A pharmaceutical composition comprising, as active principle, a
compound of formula (I): 8wherein R represents an --alk--S--alk--Ar
radical, a phenyl radical or a phenyl radical substituted with one
or more substituents of C.sub.1-6alkoxy or halogen, and wherein Ar
represents a phenyl radical and alk represents an C.sub.1-6alkylene
radical, or a racemic mixture, an enantiomer or a diastereoisomer
thereof or mixtures thereof, or tautomer thereof or a
pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition according to claim 1, wherein R
is a phenyl radical or a phenyl radical monosubstituted with
C.sub.1-6alkoxy or halogen or a racemic mixture, an enantiomer or a
diastereoisomer thereof or mixtures thereof, or tautomer thereof or
a pharmaceutically acceptable salt thereof.
3. The pharmaceutical composition according to claim 2, wherein R
is a phenyl monosubstituted with C.sub.1-6alkoxy or halogen at
position 3 or 4.
4. The pharmaceutical composition according to claim 1 wherein the
halogen is bromine.
5. The pharmaceutical composition according to claim 2 wherein the
halogen is bromine.
6. The pharmaceutical composition according to claim 3 wherein the
halogen is bromine.
7. The pharmaceutical composition according to claim 1 wherein the
C.sub.1-6alkoxy is methoxy.
8. The pharmaceutical composition according to claim 2 wherein the
C.sub.1-6alkoxy is methoxy.
9. The pharmaceutical composition according to claim 3 wherein the
C.sub.1-6alkoxy is methoxy.
10. The pharmaceutical composition according to claim 1 wherein the
compound of formula (I) is selected from the group consisting of:
4-(3-bromophenyl) -4,5-dihydro-,3-thiazol-2-ylamine,
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine and
4-(benzylsulfanylmethyl)-4- ,5-dihydro-1,3-thiazol-2-ylamine, or a
racemic mixture, enantiomer or diastereoisomer thereof or mixtures
thereof, or tautomer thereof or a pharmaceutically acceptable salt
thereof.
11. The Pharmaceutical composition according to claim 1 wherein
compound of formula (I) is selected from the group consisting of:
(4RS)-4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4R)-4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol -2-ylamine and
(-)-(4R)-4-phenyl-4, 5-dihydro-1,3-thiazol-2-ylamine, or a tautomer
thereof or a pharmaceutically acceptable salt thereof.
12. A Compound of formula (I): 9wherein R represents an
--alk--S--alk--Ar radical, or a phenyl radical substituted with one
or more substituents of C.sub.1-6alkoxy or halogen, and wherein Ar
represents a phenyl radical and alk represents an C.sub.1-6alkylene
radical, or a racemic mixture, an enantiomer or a diastereoisomer
thereof or mixtures thereof, or tautomer thereof or a
pharmaceutically acceptable salt thereof.
13. The compound according to claim 12, which is chosen from the
following: 4-(3-bromophenyl) -4,5-dihydro-1,3-thiazol-2-ylamine,
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
4-(benzylsulfanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or a
racemic mixture, an enantiomer or a diastereoisomer thereof or a
mixture thereof, or a tautomer thereof or a pharmaceutically
acceptable salt thereof.
14. The compound of formula (I) according to claim 12, which is
chosen from the following:
(4RS)-4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-yla- mine,
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine,
(-)-(4R)-4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine, or
a tautomer thereof or a pharmaceutically acceptable salts
thereof.
15. A process for preparing a compound of formula (I): 10comprising
the step of cyclizing a derivative of formula (II): 11wherein R
represents an --alk--S--alk--Ar radical, a phenyl radical or a
phenyl radical substituted with one or more substituents Of
C.sub.1-6alkoxy or halogen, and wherein Ar represents a phenyl
radical and alk represents an C.sub.1-6alkylene radical, and
isolating the product and optionally converting it into a
pharmaceutically acceptable salt.
16. A process for preparing a compound of formula (I): 12comprising
the step of reacting a derivative of formula (III): 13with a
derivative of formula HS-alk-Ar wherein R is --CH.sub.2--S--alk-Ar,
Ar represents a phenyl radical and alk represents an
C.sub.1-6alkylene radical, X is halogen or a tosyl radical and Ra
and Rb are hydrogen atoms or protecting groups for the amine
function, and optionally, deprotecting the amine function and
isolating the product and optionally converting the product into a
pharmaceutically acceptable salt.
17. A method of preventing or treating an illness which involves an
abnormal production of nitric oxide (NO) by inducing an inducible
NO-synthase (NOS-2) comprising administering to a patient in need
thereof a therapeutically effective amount of a compound of formula
(I): 14wherein R represents an --alk--S--alk--Ar radical, a phenyl
radical or a phenyl radical substituted with one or more
substituents of C.sub.1-6alkoxy or halogen, and wherein Ar
represents a phenyl radical and alk represents an C.sub.1-6alkylene
radical, or a racemic mixture, an enantiomer or a diastereoisomer
thereof or mixtures thereof, or tautomer thereof or a
pharmaceutically acceptable salt thereof, optionally in combination
with a pharmaceutically acceptable carrier.
18. The method according to claim 17, wherein the illness is
selected from the group consisting of multiple sclerosis, cerebral,
focal or global ischemia, cerebral or spinal trauma, Parkinson's
disease, Huntington's disease, Alzheimer's disease, amyotrophic
lateral sclerosis, migraine, depression, schizophrenia, anxiety and
epilepsy.
19. The method according to claim 17, wherein the illness is caused
by inflammatory components.
20. The method according to claim 17, wherein the illness is caused
by the growth of a tumor.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/231,613, filed Sep. 11, 2000, which claims the
benefit of priority of French Patent Application No. 00/07,396,
filed Jun. 9, 2000.
[0002] The present invention relates to pharmaceutical compositions
containing, as active principle, a
4,5-dihydro-1,3-thiazol-2-ylamine derivative of formula (I): 2
[0003] or to one of the pharmaceutically acceptable salts thereof,
to the novel derivatives of formula (I) and to their
preparation.
[0004] The compounds of formula (I) are inhibitors of nitric oxide
synthase and particularly of the inducible isoform of this
enzyme.
[0005] Nitric oxide (NO) is a diffusable radical involved in many
physiological and pathological processes. It is synthesized by
oxidation of L-arginine, this reaction being catalyzed by a family
of enzymes known as nitric oxide syntheses or NO-synthases (NOSs),
which is referenced in the international enzyme nomenclature system
under the number E.C. 1.14.13.39.
[0006] Three NOS isoforms, two of which are constitutive and one
inducible, are known:
[0007] a neuronal NOS (NOS-1 or nNOS) was originally isolated and
cloned from nerve tissue in which it is a constitutive enzyme.
NOS-1 produces NO in response to various physiological stimuli such
as the activation of membrane receptors according to a mechanism
dependent on calcium and on calmodulin;
[0008] an inducible NOS (NOS-2 or iNOS) can be induced in response
to immunological stimuli such as, for example, cytokines or
bacterial antigens in various cells such as, for example,
macrophages, endothelial cells, hepatocytes, glial cells, as well
as many other types of cell. The activity of this isoform is not
regulated by calcium. Consequently, once induced, it produces large
amounts of NO over prolonged periods.
[0009] an endothelial NOS (NOS-3 or eNOS) is constitutive and
calcium/calmodulin-dependent. It was originally identified in
vascular endothelial cells, in which it generates NO in response to
physiological stimuli such as the activation of membrane
receptors.
[0010] The NO produced by the neuronal and endothelial constitutive
isoforms (NOS-1 and NOS-3) is generally involved in intercellular
signalling functions. For example, the endothelial cells which line
the inner wall of the blood vessels induce the relaxation of the
underlying smooth muscle cells via the production of NO. It thus
contributes towards regulating the arterial pressure.
[0011] The NO produced in large amount by the inducible isoform
NOS-2 is, inter alia, involved in pathological phenomena associated
with acute and chronic inflammatory processes in a large variety of
tissues and organs.
[0012] An excessive production of NO by induction of NOS-2 thus
plays a part in degenerative pathologies of the nervous system such
as, for example, multiple sclerosis, cerebral, focal or global
ischemia, cerebral or spinal trauma, Parkinson's disease,
Huntington's disease, Alzheimer's disease, amyotrophic lateral
sclerosis, migraine, depression, schizophrenia, anxiety and
epilepsy. Similarly, aside from the central nervous system, the
induction of NOS-2 is involved in numerous pathologies with
inflammatory components, such as, for example, diabetes,
atherosclerosis, myocarditis, arthritis, arthrosis, asthma,
irritable bowel syndrome, Crohn's disease, peritonitis,
gastro-esophageal reflux, uveitis, Guillain-Barre syndrome,
glomerulonephritis, lupus erythematosus and psoriasis. NOS-2 has
also been implicated in the growth of certain forms of tumors such
as, for example, epitheliomas, adenocarcinomas or sarcomas, and in
infections with Gram-positive or Gram-negative intracellular or
extracellular bacteria.
[0013] In all the situations in which an overproduction of NO is
deleterious, it thus appears to be desirable to reduce the
production of NO by administering substances capable of inhibiting
NOS-2.
[0014] Thiazoline-based NOS inhibitors are described in particular
in patent applications WO 94/12165, WO95/11231 and WO 96/14842.
[0015] The pharmaceutical compositions according to the present
invention are those containing, as active principle, a derivative
of formula (I) in which R represents an --alk--S--alk--Ar radical,
a phenyl radical or a phenyl radical substituted with alkoxy or
halogen, Ar is a phenyl radical and alk represents an alkylene
radical.
[0016] When R is a substituted phenyl it is preferably
monosubstituted, and in particular in position 3 or 4.
[0017] In the preceding definitions and in those which follow, the
alkyl, alkylene and alkoxy radicals and the alkyl and alkoxy
portions contain 1 to 6 carbon atoms in a straight or branched
chain.
[0018] The halogen atoms are bromine, chlorine, iodine and fluorine
atoms, and more particularly the bromine atom.
[0019] The alkoxy radicals are, in particular, methoxy, ethoxy and
propoxy radicals, and more preferably methoxy radicals
[0020] R preferably represents a phenyl radical, a phenyl radical
which is monosubstituted with alkoxy and more particularly with
methoxy or a halogen atom and more particularly with a bromine
atom.
[0021] The compounds of formula (I) contain one or more asymmetric
carbon atoms and can thus be in racemic form or in the form of
enantiomers and diastereoisomers; these also form part of the
invention, as well as mixtures thereof.
[0022] Moreover, the compounds of formula (I) can be in the
tautomeric form (Ia): 3
[0023] These tautomers also form part of the invention.
[0024] The preferred pharmaceutical compositions are those
containing a compound of formula (I), the racemic mixture,
enantiomers and diastereoisomers thereof, the tautomer thereof and
the pharmaceutically acceptable salts thereof chosen from the
following compounds:
[0025] 4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine
4-(benzylsulfanylmethyl)-4,5-d- ihydro-1,3-thiazol-2-ylamine.
[0026] The pharmaceutical compositions that are even more preferred
are those containing, as active principle, a compound of formula
(I), the tautomer thereof or pharmaceutically acceptable salts
thereof, chosen from the following compounds:
[0027] (4RS)-4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(-)-(4R)-4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(-)-(4R)-4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine.
[0028] The derivative of formula (I) for which R is phenyl is known
(Chem. Abst., registry Number 76999-87-6).
[0029] The other derivatives of formula (I) are novel and as such
form part of the invention.
[0030] The compounds of formula (I) that are preferred are the
following compounds:
[0031] 4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(benzylsulfanylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine the
racemic mixtures, enantiomers, diastereoisomers and mixtures
thereof, the tautomers thereof and the pharmaceutically acceptable
salts thereof.
[0032] The compounds that are even more preferred are the
following:
[0033] (4RS)-4-(3-bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
(-)-(4R)-4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine the
tautomers thereof and the pharmaceutically acceptable salts
thereof.
[0034] The compounds of formula (I) can be prepared by cyclization
of a derivative of formula: 4
[0035] in which R has the same meanings as in formula (I).
[0036] This cyclization is generally carried out using an acid such
as hydrochloric acid, in aqueous medium, at a temperature of
100.degree. C. 6N hydrochloric acid is preferably used.
[0037] The derivatives of formula (II) can be obtained according to
the reaction scheme below: 5
[0038] In these formulae, R has the same meanings as in formula
(I), Ra represents a hydrogen atom or an alkyl or alkoxycarbonyl
radical, preferably methyl, ethyl or isobutyloxycarbonyl, and Rb is
a hydrogen atom or a protecting group for the amine function such
as those described by T. W. Greene, Protective groups in Organic
Synthesis, J. Wiley-Interscience Publication (1991), and preferably
an acetyl or tert-butoxycarbonyl radical.
[0039] The reduction step a is preferably carried out using a
hydride such as sodium borohydride or lithium aluminum hydride, in
a (1-4C) aliphatic alcohol or tetrahydrofuran, at a temperature of
between 10.degree. C. and 30.degree. C., or alternatively using a
borane derivative such as the BH.sub.3-THF complex, in a solvent
such as tetrahydrofuran, at a temperature of between 0.degree. C.
and 30.degree. C.
[0040] The deprotection reaction b for the compounds for which Rb
is a protecting group for the amine function is carried out by any
deprotection method known to those skilled in the art, and in
particular those described by T. W. Greene, Protective groups in
Organic Synthesis, J. Wiley-Interscience Publication (1991). When
the protecting group is an acetyl radical, this reaction is
preferably carried out using aqueous hydrochloric acid, at a
temperature of 100.degree. C. When the protecting group is a
tert-butoxycarbonyl radical, this reaction is carried out using
hydrochloric acid in dioxane, at a temperature in the region of
20.degree. C.
[0041] Reaction c is carried out by the action of tert-butyl
isothiocyanate, in an inert solvent such as a (1-4C) aliphatic
alcohol (preferably methanol or ethanol), in the presence of a
tertiary amine such as triethylamine, at a temperature of between
20.degree. C. and the boiling point of the reaction medium.
[0042] The intermediates A are commercially available or can be
prepared by application or adaptation of the methods described in
the examples, and in particular by the following methods:
[0043] When R is phenyl substituted with halogen, the intermediate
A can be obtained from the corresponding halobenzaldehyde by the
action of potassium hydroxide and aqueous ammonia, in the presence
of lithium chloride and benzyltriethylammonium chloride, in a
solvent such as a mixture of dichloromethane, chloroform and water
at a temperature of between 0.degree. C. and 30.degree. C.,
optionally followed by an esterification by the action of a (1-4C)
aliphatic alcohol (preferably methanol or ethanol), in the presence
of an inorganic acid such as sulfuric acid, at a temperature of
between 50.degree. C. and the boiling point of the reaction medium.
When R is phenyl substituted with alkoxy, Ra is an alkyl radical
and Rb is tert-butoxycarbonyl, the intermediate A can be obtained
by alkylation of the corresponding
N-tert-butoxycarbonylhydroxyphenylglycine by the action of an alkyl
halide (for example methyl iodide), in the presence of a base such
as potassium carbonate, in an inert solvent such as
dimethylformamide, at a temperature of between 0.degree. C. and
30.degree. C.
[0044] The compounds of formula (I) for which R is a radical
--alk(1C)--S--alk--Ar may also be prepared by the action of a
derivative of formula: 6
[0045] in which X is a halogen atom and preferably iodine, or a
tosyl radical, Ra and Rb are hydrogen atoms or protecting groups
for the amine function such as those described by T. W. Greene,
Protective Groups in Organic Synthesis, J. Wiley-Interscience
Publication (1991), preferably alkoxycarbonyl or acetyl and more
particularly tert-butoxycarbonyl, with a derivative of formula
HS--alk--Ar in which Ar represents a phenyl radical and alk is an
alkylene radical (1-6C in a straight or branched chain), followed,
if necessary, by a deprotection of the amine function.
[0046] This reaction is generally carried out in the presence of a
base such as potassium carbonate, in a solvent such as acetonitrile
or dimethylformamide and preferably acetonitrile, at a temperature
of between 20.degree. C. and the boiling point of the reaction
medium.
[0047] The deprotection reaction for the compounds for which Ra or
Rb is a protecting group for the amine function is carried out by
any deprotection method known to those skilled in the art and in
particular those described by T. W. Greene, Protective Groups in
Organic Synthesis, J. Wiley-Interscience Publication (1991).
Preferably, when the protecting group is an acetyl radical, this
reaction is carried out using aqueous hydrochloric acid, at a
temperature of 100.degree. C. When the protecting group is a
tert-butoxycarbonyl radical, this reaction is carried out using
hydrochloric acid in dioxane, at a temperature in the region of
20.degree. C.
[0048] The compounds of formula (III) may themselves be obtained
according to the following reaction scheme: 7
[0049] In these formulae, Ra and Rb are a hydrogen atom or a
protecting group for the amine function such as those described by
T. W. Greene, Protective Groups in Organic Synthesis, J.
Wiley-Interscience Publication (1991), preferably alkoxycarbonyl or
acetyl and more particularly tert-butoxycarbonyl, and Ts is a tosyl
radical.
[0050] Reaction a is generally carried out by the action of
tert-butyl isothiocyanate, in an inert solvent such as an aliphatic
(1-4C) alcohol (preferably methanol or ethanol), optionally in the
presence of a tertiary amine such as triethylamine, at a
temperature of between 20.degree. C. and the boiling point of the
reaction medium.
[0051] Cyclization reaction b is generally carried out using an
acid such as hydrochloric acid, in aqueous medium, at a temperature
in the region of 100.degree. C. 6N hydrochloric acid is preferably
used.
[0052] When Ra or Rb is a tert-butoxycarbonyl group, reactions c
and g are carried out by any protection method known to those
skilled in the art and in particular those described by T. W.
Greene, Protective Groups in Organic Synthesis, J.
Wiley-Interscience Publication (1991). This reaction is preferably
carried out using di-tert-butyl dicarbonate, in the presence of a
base such as triethylamine and optionally in the presence of
4-(dimethylamino)pyridine, in a solvent such as dichloromethane and
at a temperature in the region of 20.degree. C., or alternatively
in the presence of a base such as potassium carbonate, in a solvent
such as water and at a temperature in the region of 20.degree.
C.
[0053] Reaction d is generally carried out by the action of
p-toluenesulfonyl chloride, in the presence of a tertiary amine
such as triethylamine, in an inert solvent such as dichloromethane,
at a temperature of between 20.degree. C. and the boiling point of
the reaction medium.
[0054] Reaction e is generally carried out by the action of sodium
iodide, in an inert solvent such as acetone, at a temperature of
between 20.degree. C. and the boiling point of the reaction
medium.
[0055] Reaction f is generally carried out by the action of an
allyl halide, for example allyl chloride, in an aliphatic (1-4C)
alcohol, preferably ethanol, at a temperature of between 20.degree.
C. and the boiling point of the reaction medium.
[0056] Reaction h is generally carried out by the action of iodine,
in the presence of a base such as sodium bicarbonate, in a solvent
such as dichloromethane, at a temperature of between 20.degree. C.
and the boiling point of the reaction medium.
[0057] The compounds of formula (I) are isolated and can be
purified by the usual known methods, for example by
crystallization, chromatography or extraction.
[0058] The enantiomers of the compounds of formula (I) can be
obtained by resolving the racemic mixtures, for example by
chromatography on a chiral column according to Pirckle W. H. et
al., Asymmetric Synthesis, Vol. 1, Academic Press (1983) or by
formation of salts or by synthesis from chiral precursors. The
diastereoisomers can be prepared according to the known
conventional methods (crystallization or chromatography or from
chiral precursors).
[0059] The compounds of formula (I) can optionally be converted
into addition salts with an inorganic or organic acid by the action
of such an acid in an organic solvent such as an alcohol, a ketone,
an ether or a chlorinated solvent. These salts also form part of
the invention.
[0060] Examples of pharmaceutically acceptable salts which may be
mentioned are the following salts: benzenesulfonate, hydrobromide,
hydrochloride, citrate, ethanesulfonate, fumarate, gluconate,
iodate, isethionate, maleate, methanesulfonate,
methylenebis-b-oxynaphthoate, nitrate, oxalate, pamoate, phosphate,
salicylate, succinate, sulfate, tartrate, theophyllineacetate and
p-toluenesulfonate.
[0061] The compounds of formula (I) are inhibitors of inducible
NO-synthase or type-2 NO-synthase (NOS-2) and are thus useful for
preventing and treating disorders associated with excessive NO
production, such as multiple sclerosis, cerebral, focal or global
ischemia, cerebral or spinal trauma, Parkinson's disease,
Huntington's disease, Alzheimer's disease, amyotrophic lateral
sclerosis, migraine, depression, schizophrenia, anxiety and
epilepsy, diabetes, atherosclerosis, myocarditis, arthritis,
arthrosis, asthma, irritable bowel syndrome, Crohn's disease,
peritonitis, gastro-esophageal reflux, uveitis, Guillain-Barre
syndrome, glomerulonephritis, lupus erythematosus, psoriasis, the
growth of certain forms of tumors such as, for example,
epitheliomas, adenocarcinomas or sarcomas, and infections with
Gram-positive or Gram-negative intracellular or extracellular
bacteria.
[0062] Their activity as NOS-2 inhibitors was determined by
measuring the conversion of [.sup.3H]-L-arginine into
[.sup.3H]-L-citrulline with, respectively, an NOS-2 enzymatic
fraction extracted from the lungs of rats or mice pretreated with
lipopolysaccharides (10 mg/kg i.p. 6 hours before collecting the
tissue). The compounds were incubated for 20 to 30 minutes at
37.degree. C. in the presence of 5 .mu.M of [.sup.3H]-L-arginine, 1
mM of NADPH, 15 .mu.M of tetrabiopterine, 1 .mu.M of FAD and 0.1 mM
of DTT in a HEPES buffer (50 mM, pH 6.7) containing 10 .mu.g/ml of
calmodulin. The incubation was stopped by adding cold HEPES buffer
(100 mM, pH 5.5) containing 10 mM of EGTA and 500 mg of a cationic
ion-exchange resin (AG50W-X8, counterion: Na+) to separate the
[.sup.3H]-L-arginine from the [.sup.3H]-L-citrulline. After
separation of the phases by settling for 5 min, the radioactivity
remaining in the liquid phase was measured in a scintillation
counter in the presence of a suitable scintillation liquid. The
yield for the recovery of the [.sup.3H]-L-citrulline formed was
able to be estimated using [.sup.14C-ureido]-L-citrulline as
external standard.
[0063] The activity was expressed as picomole(s) of
[.sup.3H]-L-citrulline formed per minute and per milligram of
protein contained in the reaction medium.
[0064] In this test, the IC.sub.50 value of the compounds of
formula (I) is less than or equal to 1 .mu.M.
[0065] The compounds of formula (I) are of low toxicity. Their
LD.sub.50 value is greater than 40 mg/kg via the subcutaneous route
in mice.
[0066] The examples which follow illustrate the invention.
EXAMPLE 1
(4RS)-4-(3-Bromophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0067] A suspension of 0.5 g of
N-(tert-butyl)-N'-[2-hydroxy-1-(3-bromophe- nyl)ethyl]thiourea in
3.8 cm.sup.3 of 6 N hydrochloric acid is heated with stirring at a
temperature in the region of 100.degree. C. for 5 hours 30 minutes.
The reaction medium is then cooled to a temperature in the region
of 20.degree. C. A white precipitate forms, which is filtered off
after stirring for 30 minutes. The filter cake is rinsed with
diethyl ether and then dried in an oven under reduced pressure (10
Pa) at a temperature in the region of 60.degree. C, after which it
is purified by chromatography, under an argon pressure of 50 kPa,
on a column of silica gel (particle size 40-63 .mu.; diameter 1.5
cm; height 20 cm), eluting with a dichloromethane/methanol mixture
(90/10 by volume). The fractions containing the expected product
are collected. These fractions are combined and then concentrated
under reduced pressure (5 kPa) at a temperature in the region of
40.degree. C. 0.1 g of (4RS)-4-(3-bromophenyl)
-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride is obtained in the
form of a white solid. (R.sup.f=0.26 in a 90/10 by volume
dichloromethane/methanol mixture, on a Merck 60F.sub.254R silica
plate). [.sup.1H NMR spectrum (250 MHz, d.sub.6-(CD.sub.3)SO,
.delta. in ppm): 3.45 (dd, J=14 and 8 Hz: 1H); 3.97 (dd, J=14 and
8.5 Hz: 1H); 5.42 (dd, J=8.5 and 8 Hz: 1H); from 7.35 to 7.55 (mt:
2H); from 7.55 to 7.75 (mt: 2H); from 9.10 to 10.90 (broad unres.
mult.: 1H)].
[0068] N-(tert-Butyl)-N'-[2-hydroxy-1-(3-bromophenyl)
ethyl]thiourea: A solution of 3.54 g of 2-amino
-2-(3-bromophenyl)-1-ethanol, in 20 cm.sup.3 of ethanol containing
0.18 cm.sup.3 of tert-butyl isothiocyanate is stirred at a
temperature in the region of 20.degree. C. for 5 hours. After
concentration of the reaction mass under reduced pressure (5 kPa)
at a temperature in the region of 40.degree. C., the residue
obtained is taken up in 25 cm.sup.3 of petroleum ether. The
resulting crystals are spin-filtered, washed with twice 25 cm.sup.3
of petroleum ether and then dried under reduced pressure (5 kPa) at
a temperature in the region of 20.degree. C. 4 g of N--(tert-butyl)
--N'--[2-hydroxy-1-(3-bromophenyl)et- hyl]thiourea are obtained in
the form of a white solid (R.sub.f=0.68 in a 40/5/0.5 by volume
dichloromethane/methanol/aqueous ammonia mixture, on a Merck
60F.sub.254R silica plate).
[0069] 2-Amino-2-(3-bromophenyl)-1-ethanol: A solution of 4.4 g of
ethyl 3-bromophenylglycinate in 80 cm.sup.3 of ethanol is
maintained at a temperature in the region of 20.degree. C. 0.97 g
of sodium borohydride is added portionwise with stirring and the
mixture is then stirred for 18 hours at a temperature in the region
of 20.degree. C. After concentration of the reaction medium under
reduced pressure (5 kPa) at a temperature in the region of
40.degree. C., the residue obtained is taken up in 40 cm.sup.3 of
water and then extracted with 3 times 50 cm.sup.3 of ethyl acetate.
The extracts are combined and then dried over sodium sulfate,
filtered and concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. An oil is obtained,
which is purified by chromatography under an argon pressure of 50
kPa, on a column of silica gel (particle size 40-63 .mu.; diameter
2.5 cm; height of silica 35 cm), eluting with a
dichloromethane/methanol mixture (90/10 by volume). The fractions
containing the product are collected. These fractions are combined
and then concentrated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. 2.1 g of
2-amino-2-(3-bromophenyl)-1-ethanol are obtained in the form of a
yellow solid melting at 76.degree. C.
[0070] Ethyl 3-bromophenylglycinate: A mixture of 21.3 g of
3-bromophenylglycine in 160 cm.sup.3 of 6.5 N hydrochloric ethanol
is heated with stirring for 24 hours at a temperature in the region
of 80.degree. C. The reaction medium is filtered and the filter
cake is then washed with twice 30 cm.sup.3 of ethanol. The filtrate
is concentrated under reduced pressure (5 kPa) at a temperature in
the region of 40.degree. C. An oil is obtained, which is basified
by addition of aqueous sodium carbonate solution. The mixture is
extracted with 3 times 100 cm.sup.3 of ethyl acetate. The extracts
are combined, washed with twice 100 cm.sup.3 of aqueous sodium
chloride solution, dried over sodium sulfate, filtered and then
concentrated under reduced pressure (5 kPa) at a temperature in the
region of 40.degree. C. 4.7 g of ethyl 3-bromophenylglycinate are
obtained in the form of a yellow oil. (R.sub.f=0.38 in a 90/5 by
volume dichloromethane/methanol mixture, on a Merck
60F.sub.254.sub..sup.R silica plate).
[0071] 3-Bromophenylglycine: 8.4 g of lithium chloride are
introduced into a stirred mixture, under an inert atmosphere, of
16.8 g of potassium hydroxide in 56 cm.sup.3 of 32% aqueous
ammonia, followed by addition of 2.78 g of benzyltriethylammonium
chloride predissolved in 50 cm.sup.3 of dichloromethane. The
mixture obtained is cooled to a temperature in the region of
0.degree. C., followed by addition thereto of 18.5 g of
3-bromobenzaldehyde predissolved in 50 cm.sup.3 of dichloromethane
and 12.8 cm.sup.3 of chloroform, while maintaining the mixture at a
temperature in the region of 0.degree. C. The reaction medium is
stirred for 6 hours at this temperature and then for 18 hours at a
temperature in the region of 20.degree. C. The insoluble material
is filtered off and the filtrate is then separated out after
settling has taken place. The aqueous phase is separated out,
washed with twice 50 cm.sup.3 of dichloromethane and acidified with
10 cm.sup.3 of concentrated hydrochloric acid to obtain a pH of 7.
The acidification is completed up to pH 6 by a further addition of
aqueous 1 N hydrochloric acid. The expected acid precipitates after
scratching. The mixture is stirred for 1 hour at a temperature in
the region of 5.degree. C., and is then filtered. The crystals
obtained are washed with 5 cm.sup.3 of water and dried in an oven
under reduced pressure (10 Pa) at a temperature in the region of
60.degree. C. 0.41 g of 3-bromophenylglycine is obtained in the
form of a white solid. [Infrared spectrum (KBr): 3080; 2980; 2670;
1635; 1580; 1400; 1355; 775 and 695 cm.sup.-1].
EXAMPLE 2
4-(4-Methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine oxalate
[0072] A mixture of 1.3 g of N-(tert-butyl)-N'-[1-(4-methoxyphenyl)
-2-hydroxyethyl]thiourea in 12.3 cm.sup.3 of aqueous 6 N
hydrochloric acid is heated with stirring at a temperature in the
region of 100.degree. C. for 1 hour. The dense oil which
precipitates is separated out after settling from the supernatant
hydrochloric aqueous phase. After cooling to about 20.degree. C.,
this aqueous phase is extracted with 5 cm.sup.3 of ethyl acetate
and the resulting aqueous phase is then evaporated under reduced
pressure (5 kPa) at a temperature in the region of 50.degree. C. An
oil is obtained, which is freed of its residual water by azeotropic
entrainment first with 10 cm.sup.3 of ethanol and then with 10
cm.sup.3 of diethyl ether, each repetition being followed by
concentrating under the above conditions. 6 cm.sup.3 of 1 N sodium
hydroxide are added to the oil obtained and the mixture is then
extracted with 30 cm.sup.3 of diethyl ether containing 15 cm.sup.3
of ethyl acetate. The organic phase is separated out after settling
has taken place and evaporated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. 0.1 g of oxalic acid
predissolved in 1 cm.sup.3 of acetone is added to the residue
obtained. The white precipitate formed is separated out by
filtration, washed once with acetone, twice with chloroform and
then once with ethyl acetate, and dried under reduced pressure (10
Pa) at a temperature in the region of 40.degree. C. 0.063 g of
4-(4-methoxyphenyl)-4,5-dihydro-1,3-thiazol -2-ylamine is obtained
in the form of a white solid melting at 180.degree. C. [.sup.1H NMR
spectrum (300 MHz, d.sub.6-(CD.sub.3)SO, .delta. in ppm): 3.40 (dd,
J=14 and 8.5 Hz: 1H); 3.80 (s: 3H); 3.93 (dd, J=14 and 8.5 Hz: 1H);
4.22 (unres. mult.: 2H); 3.58 (t, J=8.5 Hz: 1H); 7.00 (d, J=8.5 Hz:
2H); 7.34 (d, J=8.5 Hz: 2H)].
[0073]
N--(tert-Butyl)--N'--[1-(4-methoxyphenyl)-2-hydroxyethyl]thiourea:
The process is performed under the conditions of Example 1,
starting with 1.3 g of 2-amino -2-(4-methoxyphenyl)-1-ethanol and
1.46 cm.sup.3 of tert-butyl isothiocyanate in 12 cm.sup.3 of
absolute ethanol for 21 hours at a temperature in the region of
20.degree. C. After concentration of the reaction mass under
reduced pressure (5 kPa) at a temperature in the region of
40.degree. C., the residue obtained is taken up in 10 cm.sup.3 of
water. A crystalline precipitate forms, which is filtered off,
washed with 3 times 5 cm.sup.3 of diethyl ether and dried under
reduced pressure (10 Pa) at a temperature in the region of
40.degree. C. 1.32 g of N--(tert-butyl) --N'--[1-
(4-methoxyphenyl)-2-hydroxyethyl]thiourea are obtained in the form
of a white solid melting at 127.degree. C.
[0074] 2-Amino-2-(4-methoxyphenyl)-1-ethanol: A mixture of 3.4 g of
tert-butyl 1-(4-methoxyphenyl)-2-hydroxyethylcarbamate in 32
cm.sup.3 of methanol containing 10% by mass of anhydrous hydrogen
chloride is stirred for 1 hour at a temperature in the region of
20.degree. C. The reaction medium is concentrated under reduced
pressure (5 kPa) at a temperature in the region of 40.degree. C.
The residue is taken up in 9 cm.sup.3 of aqueous 5% sodium hydrogen
carbonate solution and the mixture is then extracted with 3 times
30 cm.sup.3 of dichloromethane. The aqueous phase is concentrated
as above and the white solid obtained is then taken up in 17
cm.sup.3 of aqueous 1 N sodium hydroxide solution. The precipitate
is extracted with 3 times 30 cm.sup.3 of dichloromethane. The
combined organic extracts are evaporated under reduced pressure (5
kPa) at a temperature in the region of 40.degree. C. The white
solid obtained is dried under reduced pressure (10 Pa) at a
temperature in the region of 40.degree. C. 1.3 g of
2-amino-2-(4-methoxyphenyl)-1-ethanol are obtained in the form of a
white solid melting at 96.degree. C.
[0075] tert-Butyl 1-(4-methoxyphenyl)-2-hydroxyethylcarbamate: 2.24
g of lithium chloride are added to a solution of 7.8 g of methyl
N-Boc-(4-methoxyphenyl)glycinate in 35 cm.sup.3 of tetrahydrofuran
cooled to a temperature of 0.degree. C., followed by portionwise
addition of 1.99 g of sodium borohydride and finally 74 cm.sup.3 of
ethanol. The temperature is allowed to return to about 20.degree.
C. and the reaction is then completed by stirring the mixture for
18 hours at this same temperature. The medium is re-cooled to about
5.degree. C. and a sufficient amount of aqueous 1 M sodium hydrogen
sulfate solution to give a pH in the region of 2 is then added
thereto. The mixture is stirred for 3 hours and is then evaporated
under reduced pressure (5 kPa) at a temperature in the region of
50.degree. C. 60 cm.sup.3 of dichloromethane and 30 cm.sup.3 of
aqueous 1 M sodium hydrogen sulfate solution are added to the
residue obtained. After stirring the mixture and then separating
out the organic phase after settling of the phases has taken place,
the aqueous phase is extracted with twice 30 cm.sup.3 of
dichloromethane. The combined organic extracts are dried over
sodium sulfate and concentrated as above. A white solid is
obtained, which is taken up in 30 cm.sup.3 of cyclohexane and
filtered. The crystals are dried under reduced pressure (10 Pa) at
a temperature in the region of 60.degree. C. 3.47 g of tert-butyl
1-(4-methoxyphenyl)-2-hydroxyethylcarbamate are obtained in the
form of a white solid melting at 130.degree. C.
[0076] Methyl N-Boc-(4-methoxyphenyl)glycinate: 10.45 g of
potassium carbonate are added to a stirred solution, cooled to a
temperature in the region of 0.degree. C., of 8.25 g of
N-Boc-(4-hydroxyphenyl)glycine in 112 cm.sup.3 of anhydrous
dimethylformamide, followed by dropwise addition of 4.7 cm.sup.3 of
methyl iodide. The mixture is stirred at a temperature in the
region of 20.degree. C. for 18 h 30 min. After addition of 280
cm.sup.3 of diethyl ether and 140 cm.sup.3 of water, the ether
phase is separated out after settling has taken place and is then
washed successively with 140 cm.sup.3 of water, 140 cm.sup.3 of
aqueous 1 M sodium hydrogen sulfate solution and 140 cm.sup.3 of
saturated sodium chloride solution. The organic phase is dried over
sodium sulfate and evaporated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. 7.88 g of methyl
N-Boc-(4-methoxyphenyl)-glycinate are obtained in the form of an
oil which crystallizes rapidly. (R.sub.f=0.28 in a 30/20 by volume
cyclohexane/diethyl ether mixture, on a Merck
60F.sub.254.sub..sup.R silica plate).
[0077] N-Boc-(4-Hydroxyphenyl)glycine: 12 g of di-tert-butyl
dicarbonate are added, at a temperature in the region of 20.degree.
C., to a stirred solution of 7.55 g of 4-hydroxyphenylglycine in
53.2 cm.sup.3 of aqueous 1 N sodium hydroxide solution and the
mixture is then stirred for 4 hours at a temperature in the region
of 15.degree. C. After leaving the reaction medium to stand for 16
hours at a temperature in the region of 20.degree. C., it is washed
with twice 30 cm.sup.3 of diethyl ether. The aqueous phase is
separated out after settling of the phases has taken place, and 73
cm.sup.3 of aqueous 1 M sodium hydrogen sulfate solution are then
added thereto with stirring. The mixture is extracted with twice
135 cm.sup.3 of dichloromethane. The organic extracts are combined,
dried over sodium sulfate and concentrated under reduced pressure
(5 kPa) at a temperature in the region of 40.degree. C. A white
foam is obtained, which is taken up in 60 cm.sup.3 of water and
spin-filtered. The solid obtained is dried under reduced pressure
(10 Pa) at a temperature in the region of 20.degree. C. 9.26 g of
N-Boc-(4-hydroxyphenyl)glycine are obtained in the form of a white
solid melting at 110.degree. C.
EXAMPLE 3
(-)-(4R)-4-(4-Methoxyphenyl)-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0078] The process is performed under the conditions of Example 1,
starting with 2.5 g of N--(tert-butyl)--N'--[(1R)
-1-(4-methoxyphenyl)-2-- hydroxyethyl]thiourea in 25 cm.sup.3 of
aqueous 6 N hydrochloric acid for 3 hours at a temperature in the
region of 100.degree. C. The reaction mass is evaporated under
reduced pressure (5 kPa) at a temperature in the region of
50.degree. C. 15 cm.sup.3 of aqueous 1 N sodium hydroxide and 5
cm.sup.3 of water are added to the residue obtained. The mixture is
extracted with 20 cm.sup.3 of ethyl acetate and the organic phase
is then concentrated as above. The product obtained is purified by
chromatography, under an argon pressure of 50 kPa, on a column of
silica gel (particle size 40-63 .mu.; mass of silica 80 g), eluting
with an ethyl acetate/methanol mixture (80/20 by volume), and
collecting about 10 cm.sup.3 fractions. Fractions 10 to 16 are
combined and then evaporated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. 0.23 g of a lacquer is
obtained, the hydrochloride of which is prepared in the following
way: the product is dissolved in 2.5 cm.sup.3 of acetone and 1
cm.sup.3 of diethyl ether, followed by addition thereto of 2
cm.sup.3 of 4.5 N hydrochloric ether. A crystalline product
precipitates. It is filtered off, washed 3 times with acetone and
then dried at a temperature in the region of 40.degree. C. under
reduced pressure (10 Pa). 0.09 g of (-)-(4R)
-4-(4-methoxyphenyl)-4,5-dihydro-1,3- -thiazol-2-ylamine
hydrochloride is obtained in the form of a white solid melting at
236.degree. C. (.alpha..sup.20.sub.D=-79.6 .+-.1.3 at a
concentration of 0.5% in methanol).
[0079]
N--(tert-Butyl)--N'--[(1R)-1-(4-methoxyphenyl)2-hydroxyethyl]thiour-
ea: The process is performed under the conditions of Example 1,
starting with 5.78 g of (2R)-2-amino-2-(4-methoxyphenyl)-1-ethanol
and 6.48 cm.sup.3 of tert-butyl isothiocyanate in 73 cm.sup.3 of
ethanol for 17 h 30 minutes at a temperature in the region of
20.degree. C. The reaction mass is evaporated under reduced
pressure (5 kPa) at a temperature in the region of 40.degree. C.
and the solid residue obtained is then ground in 45 cm.sup.3 of
water, filtered and washed with twice 20 cm.sup.3 of water and
twice 25 cm.sup.3 of diethyl ether. The crystals are dried in an
oven under reduced pressure (10 Pa) at a temperature in the region
of 45.degree. C. 4.9 g of
N--(tert-butyl)--N'--[(1R)-1-(4-methoxyphenyl)2-hy-
droxyethyl]-thiourea are obtained in the form of a white solid.
(R.sub.f=0.60 in ethyl acetate, on a Merck 60F.sub.254.sub..sup.R
silica plate).
[0080] (2R)-2-Amino-2-(4-methoxyphenyl)-1-ethanol: The process is
performed under the conditions of Example 2, starting with 12.45 g
of tert-butyl (1R)-1-(4-methoxyphenyl) -2-hydroxyethylcarbamate in
130 cm.sup.3 of 2.5 N hydrochloric methanol, with stirring for 1 h
30 minutes at a temperature in the region of 20.degree. C., and
then for 30 minutes at a temperature in the region of 30.degree. C.
The reaction mass is evaporated under reduced pressure (5 kPa) at a
temperature in the region of 40.degree. C. 61 cm.sup.3 of aqueous
5% sodium hydrogen carbonate solution are added to the residue
obtained and the mixture is then extracted with 3 times 100
cm.sup.3 of dichloromethane. The aqueous phase is separated out
after settling has taken place and is then evaporated as above. The
solid obtained is taken up in 65 cm.sup.3 of aqueous 1 N sodium
hydroxide solution and the resulting solution is reduced to 2/3 of
its volume by concentration under the above conditions. The mixture
is extracted with 3 times 100 cm.sup.3 of dichloromethane. The
extracts are combined, dried over magnesium sulfate, filtered and
evaporated under reduced pressure (5 kPa) at a temperature in the
region of 40.degree. C. The crystals obtained are dried under
reduced pressure (5 kPa) at about 20.degree. C. 5.86 g of
(2R)-2-amino-2-(4-methoxyphenyl) -1-ethanol are obtained in the
form of a white solid melting at 103.degree. C.
[0081] tert-Butyl (1R)-1-(4-methoxyphenyl)-2-hydroxyethylcarbamate:
The process is performed under the conditions of Example 2,
starting with 15.6 g of methyl N-Boc-D-(4-methoxyphenyl)glycinate
dissolved in 70 cm.sup.3 of anhydrous tetrahydrofuran, and in the
presence of 4.48 g of lithium chloride. The portionwise addition of
3.98 g of sodium borohydride is carried out at a temperature in the
region of 0.degree. C. After addition of 148 cm.sup.3 of absolute
ethanol at this same temperature, the temperature is allowed to
return to about 20.degree. C. and stirring is continued for 20
hours. After cooling the reaction mass to a temperature in the
region of 5.degree. C., 98 cm.sup.3 of aqueous 1 M sodium hydrogen
sulfate solution are added. The mixture is stirred for 3 hours and
is then evaporated under reduced pressure (5 kPa) at a temperature
in the region of 40.degree. C. The residue is taken up in 220
cm.sup.3 of dichloromethane, 70 cm.sup.3 of aqueous 1 M sodium
hydrogen sulfate solution and 30 cm.sup.3 of water. The mixture is
stirred and then the phases are allowed to separate by settling.
The organic phase is separated out and the aqueous phase is
extracted with twice 60 cm.sup.3 of dichloromethane. The organic
extracts are combined and then dried over sodium sulfate, filtered
and then evaporated under reduced pressure (5 kPa) at a temperature
in the region of 40.degree. C. A solid is obtained, which is taken
up in 50 cm.sup.3 of cyclohexane; the crystals are then
spin-filtered and dried in an over under reduced pressure (10 Pa)
at a temperature in the region of 60.degree. C. 12.47 g of
tert-butyl (1R)-1-(4-methoxyphenyl)-2-hydroxyethylcarbamate are
obtained in the form of a white solid melting at 138.degree. C.
[0082] Methyl N-Boc-D-(4-methoxyphenyl)glycinate: The process is
performed as in Example 2, starting with a solution of 30.8 g of
N-Boc-D-(4-hydroxyphenyl)-glycine in 418 cm.sup.3 of anhydrous
dimethylformamide, cooled to a temperature in the region of
0.degree. C., to which is added 17.5 cm.sup.3 of methyl iodide in
the presence of 39 g of potassium carbonate. The reaction medium is
returned to a temperature in the region of 20.degree. C. and is
then stirred for 22 hours at this same temperature. 1 liter of
diethyl ether and 500 cm.sup.3 of water are added to the mixture.
The ether phase is separated out after settling of the phases has
taken place and is washed with 500 cm.sup.3 of water and then
evaporated under reduced pressure (5 kPa) at a temperature in the
region of 40.degree. C. 31.53 g of methyl
N-Boc-D-(4-methoxyphenyl)-glyci- nate are obtained in the form of a
yellow oil which crystallizes rapidly. (R.sub.f=0.30 in 30/20
cyclohexane/diethyl ether, on a Merck 60F.sub.254.sub..sup.R silica
plate).
[0083] N-Boc-D-(4-Hydroxyphenyl)glycine: The process is performed
under the conditions of Example 2, starting with a solution of 30.2
g of D-(-)-(4-hydroxyphenyl)glycine in 213 cm.sup.3 of aqueous 1 N
sodium hydroxide solution and 48 g of di-tert-butyl dicarbonate,
stirred for 4 hours at a temperature in the region of 20.degree. C.
The reaction medium is washed with twice 120 cm.sup.3 of diethyl
ether and the aqueous phase is then separated out after settling
has taken place and 392 cm.sup.3 of aqueous 1 M sodium hydrogen
sulfate solution are added, the amount required to obtain a pH in
the region of 1. 450 cm.sup.3 of dichloromethane are added and,
after shaking the mixture, the organic phase is separated out after
settling of the phases has taken place. The aqueous phase is
extracted twice more with 450 cm of dichloromethane. The organic
extracts are combined, dried over sodium sulfate and then
concentrated under reduced pressure (5 kPa) at a temperature in the
region of 40.degree. C. A residue is obtained, which is taken up in
240 cm.sup.3 of water. The resulting crystals are spin-filtered and
then dried under reduced pressure (10 Pa) at a temperature in the
region of 40.degree. C. 9.59 g of N-Boc-D-(4-hydroxyphenyl)-glycine
are obtained in the form of a white solid. [.sup.1H NMR spectrum
(300 MHz, d.sub.6-(CD.sub.3)SO, .delta. in ppm): 1.38 (s: 9H); 4.98
(d, J=9 Hz: 1H); 6.73 (d, J=8 Hz: 2H); 7.20 (d, J=8 Hz: 2H); 7.41
(d, J=9 Hz, 1H); 9.48 (unres. mult.: 1H)].
EXAMPLE 4
(-)-(4R)-4-Phenyl-4,5-dihydro-1,3-thiazol-2-ylamine
hydrochloride
[0084] The process is performed under the conditions of Example 1,
starting with 2.4 g of N-(tert-butyl)-N'-[(1R)
-2-hydroxy-1-phenylethyl]t- hiourea in 24 cm.sup.3 of aqueous 6 N
hydrochloric acid for 1 hour 30 minutes at a temperature in the
region of 100.degree. C. After cooling the medium to a temperature
in the region of 0.degree. C., the precipitate formed is filtered
off and the filter cake is then washed with 7 cm.sup.3 of aqueous 6
N hydrochloric acid and twice 15 cm.sup.3 of diethyl ether. The
solid obtained is dried in an oven under reduced pressure (10 Pa)
at a temperature in the region of 60.degree. C. 1.6 g of
(-)-(4R)-4-phenyl-4,5-dihydro-1,3-thiazol-2-ylamine hydrochloride
are obtained in the form of a white solid melting at 260.degree. C.
(.alpha..sup.20.sub.D=-109.6 .+-.1.3 at a concentration of 1% in
methanol).
[0085] N--(tert-Butyl)--N'--[(1R)-2-hydroxy-1-phenylethyl]thiourea:
The process is performed under the conditions of Example 1,
starting with 2.74 g of (R)-(-)-2-amino-2-phenylethanol and 2.8
cm.sup.3 of tert-butyl isothiocyanate in 15 cm.sup.3 of ethanol for
20 hours at a temperature in the region of 20.degree. C. The
reaction medium is concentrated under reduced pressure (5 kPa) at a
temperature in the region of 50.degree. C. A yellow oil is
obtained, which is dissolved in 100 cm.sup.3 of ethyl acetate and
the organic solution is then washed with twice 50 cm.sup.3 of
aqueous sodium hydrogen carbonate solution and twice with aqueous
sodium chloride solution. After drying over sodium sulfate, the
organic solution is filtered and then concentrated under reduced
pressure (5 kPa) at a temperature in the region of 40.degree. C.
4.9 g of N--(tert-butyl)--N'--[(1R)-2-hydroxy
-1-phenylethyl]thiourea are obtained in the form of a yellow solid
melting at 98.degree. C.
EXAMPLE 5
(4RS)-4-Benzylsulfanylmethyl-4,5-dihydrothiazol-2-ylamine
hydrochloride
[0086] A suspension of 0.1 g of N--tert-butyl--N'--[(4RS)
-4-benzylsulfanylmethyl-4,5-dihydrothiazol-2-yl]amine in 5 cm.sup.3
of 5 N hydrochloric acid is heated at a temperature in the region
of 100.degree. C. for 2 hours. After cooling to room temperature,
the reaction mixture is concentrated under reduced pressure (1 kPa)
at a temperature in the region of 50.degree. C. The oil obtained is
slurried in 5 cm.sup.3 of diethyl ether and the solid obtained is
then filtered off and dried in a desiccator under reduced pressure
(0.1 kPa) at a temperature in the region of 40.degree. C. 0.06 g of
(4RS)-4-benzylsulfanyl-methyl -4,5-dihydrothiazol-2-ylamine
hydrochloride is obtained in the form of a cream-colored solid
[.sup.1H NMR spectrum (300 MHz, d.sub.6-(CD.sub.3) .sub.2SO,
.delta. in ppm): 2.74 (d, J=6 Hz: 2H); 3.37 (dd, J=11.5 and 5.5 Hz:
1H); 3.71 (dd, J=11.5 and 8 Hz: 1H); 3.85 (s: 2H); 4.45 (mt: 1H);
from 7.25 to 7.45 (mt: 5H); from 9.00 to 9.90 (very broad
unresolved complex: 2H); 10.03 (unresolved complex: 1H)].
[0087] N--tert-Butyl--N'--[(4RS)-4-benzylsulfanylmethyl
-4,5-dihydrothiazol-2-yl]amine: 0.28 g of potassium carbonate and
0.13 cm.sup.3 of benzyl mercaptan are added with stirring, at a
temperature in the region of 20.degree. C., to a solution of 0.39 g
of tert-butyl N-[(4RS)-4-p-toluenesulfonylmethyl-4,5-dihydrothiazol
-2-yl]-carbamate. After stirring for 40 hours at a temperature in
the region of 20.degree. C., the reaction mixture is filtered. The
filtrate is concentrated under reduced pressure (1 kPa) at a
temperature in the region of 50.degree. C. The residue obtained is
purified by chromatography under atmospheric pressure on a column
of silica gel (particle size 40-60 .mu.), eluting with a mixture of
cyclohexane/ethyl acetate (75/25 by volume) and collecting 20
cm.sup.3 fractions. The fractions containing the expected product
are combined and then concentrated under the above conditions. 11 g
of N--tert-butyl--N'--[(4RS)
-4-benzylsulfanylmethyl-4,5-dihydrothiazol- -2-yl]amine are
obtained in the form of a cream-colored lacquer [.sup.1H NMR
spectrum (300 MHz, d.sub.6-(CD.sub.3).sub.2SO, .delta. in ppm):
1.41 (s: 9H); from 2.50 to 2.70 (mt: 2H); 3.01 (dd, J=11 and 6 Hz:
1H); from 3.25 to 3.40 (mt: 1H); 3.82 (s: 2H); 4.13 (mt: 1H); from
7.20 to 7.40 (mt: 5H); from 9.40 to 9.80 (very broad unresolved
complex: 1H)].
[0088] tert-Butyl N-[(4RS)-4-p-toluenesulfonylmethyl
-4,5-dihydrothiazol-2-yl]carbamate: a solution of 0.8 g of
tert-butyl N-[(4RS)
-4-hydroxymethyl-4,5-dihydrothiazol-2-yl]carbamate, 0.76 g of
p-toluene-sulfonyl chloride and 0.56 cm.sup.3 of triethylamine in
25 cm.sup.3 of dichloromethane is stirred for 16 hours at a
temperature in the region of 20.degree. C. The solution obtained is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. The evaporation residue obtained is
purified by chromatography under atmospheric pressure on a column
of silica gel (particle size 60-200 .mu.; diameter 2 cm; height 25
cm), eluting with a mixture of cyclohexane/ethyl acetate (70/30 by
volume) and collecting 30 cm.sup.3 fractions. The fractions
containing the expected product are combined and then concentrated
under the above conditions. 0.8 g of tert-butyl
N-[(4RS)-4-p-toluenesulfonylmethyl-4,5-dihydrothiazol-2-yl]carbamate
is obtained in the form of a white solid [.sup.1H NMR spectrum (300
MHz, CDCl.sub.3, .delta. in ppm): 1.48 (s: 9H); 2.46 (s: 3H); 3.10
(dd, J=11.5 and 5.5 Hz: 1H); 3.33 (dd, J=11.5 and 8.5 Hz: 1H); 3.97
(dd, J=9.5 and 8 Hz: 1H); 4.06 (dd, J=9.5 and 4.5 Hz: 1H); 4.43
(mt: 1H); 7.36 (d, J=8 Hz: 2H); 7.80 (d, J=8 Hz: 2H); from 8.50 to
9.40 (very broad unresolved complex: 1H)].
[0089] tert-Butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydrothiazol
-2-yl]carbamate: 10 cm.sup.3 of aqueous 1 N sodium hydroxide are
added to a solution of 2 g of tert-butyl
2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(- tert-butoxycarbonyl)
-oxy]methyl-1,3-thiazolidine-3-carboxylate in 20 cm.sup.3 of
methanol, and the mixture is then stirred at a temperature in the
region of 20.degree. C. for 4 hours. The reaction mixture is
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 50.degree. C. The residue obtained is taken up in 30
cm.sup.3 of water, filtered and washed with ethyl acetate and then
with water. 0.37 g of tert-butyl N-[4-(R,S)
(hydroxymethyl)-4,5-dihydrothiazol-2-yl]c- arbamate is obtained in
the form of a white solid [mass spectrum: DCI m/z=233, MH+m/z=177
(M-C.sub.4H.sub.7)+].
[0090] tert-Butyl 2-[(tert-butoxycarbonyl)imino]-(4RS)
-4-[(tert-butoxycarbonyl)oxy]methyl-1,3-thiazolidine
-3-carboxylate: 10.91 g of di-tert-butyl dicarbonate and 2.81
cm.sup.3 of triethylamine are added to a solution of 1.98 g of
(4RS)-4-hydroxymethyl-4,5-dihydrothi- azol -2-ylamine in 20
cm.sup.3 of dichloromethane and the mixture is then stirred at a
temperature in the region of 20.degree. C. After 4 hours, a further
3 cm.sup.3 of triethylamine are added and the mixture is then
stirred for 16 hours at a temperature in the region of 20.degree.
C. 50 cm.sup.3 of water are added to the reaction mixture, the
phases are separated out after settling has taken place and the
organic phase is dried over magnesium sulfate, filtered and
concentrated under reduced pressure (1 kPa) at a temperature in the
region of 40.degree. C. 7 g of tert-butyl
2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(tert-butoxycarbonyl)
oxy]methyl-1,3-thiazolidine-3-carboxylate are obtained in the form
of an oil [mass spectrum: DCI m/z=433, MH+m/z=333
(M-C.sub.5H.sub.7O.sub.2)+].
[0091] (4RS)-4-Hydroxymethyl-4,5-dihydrothiazol-2-ylamine: a
solution of 90 g of 1-tert-butyl-3-(2-hydroxy
-1-hydroxymethylethyl)thiourea in 500 cm.sup.3 of 6 N hydrochloric
acid is stirred at a temperature in the region of 100.degree. C.
After 3 hours, the reaction mixture is cooled to about 20.degree.
C. and is then concentrated under reduced pressure (1 kPa) at a
temperature in the region of 50.degree. C. The residue obtained is
taken up in 100 cm.sup.3 of water, basified with 100 cm.sup.3 of 5
N sodium hydroxide and then concentrated as above. The oil obtained
is stirred for 20 hours at a temperature in the region of
20.degree. C. in 300 cm.sup.3 of ethanol, filtered and washed with
5 times 50 cm.sup.3 of ethanol and then with 3 times 100 cm.sup.3
of methanol. The various filtrates are combined, evaporated under
reduced pressure (1 kPa) at a temperature in the region of
40.degree. C. and then crystallized from 400 cm.sup.3 of ethanol to
give 31 g of (4RS)-4-hydroxy-methyl -4,5-dihydrothiazol-2-ylamine
in the form of a white solid melting at 122.degree. C. [Infrared
spectrum (KBr): 3311; 3164; 1648; 1601; 1349; 1051 and 982
cm.sup.-1].
[0092] 1-tert-Butyl-3-(2-hydroxy-1-hydroxymethyl-ethyl) thiourea:
30.4 cm.sup.3 of butyl isothiocyanate are added to a solution of
14.6 g of 2-amino-1,3-propanediol in 245 cm.sup.3 of ethanol, and
the mixture is then stirred at a temperature in the region of
20.degree. C. for 94 hours. The reaction medium is concentrated
under reduced pressure (5 kPa) at a temperature in the region of
40.degree. C., slurried in a mixture of 160 cm.sup.3 of petroleum
ether and 26 cm.sup.3 of ethanol, filtered and then dried in a
desiccator under reduced pressure (0.1 kPa) at a temperature in the
region of 60.degree. C. 30 g of 1-tert-butyl
-3-(2-hydroxy-1-hydroxymethylethyl)thiourea are obtained in the
form of a white solid [.sup.1H NMR spectrum (250 MHz,
d.sub.6-(CD.sub.3).sub.2SO, .delta. in ppm): 1.42 (s: 9H); 3.38
(mt: 2H); 3.54 (mt: 2H); 4.17 (unresolved complex: 1H); 4.70 (t,
J=5 Hz: 2H); 7.08 (d, J=8 Hz: 1H); 7.38 (s: 1H)].
[0093] The medicinal products according to the invention consist of
a compound of formula (I) or an isomer or tautomer or salt of such
a compound, in pure form or in the form of a composition in which
it is combined with any other pharmaceutically compatible product,
which may be inert or physiologically active. The medicinal
products according to the invention may be used orally,
parenterally, rectally or topically.
[0094] Solid compositions for oral administration which can be used
include tablets, pills, powders (gelatin capsules, cachets) or
granules. In these compositions, the active principle according to
the invention is mixed with one or more inert diluents, such as
starch, cellulose, sucrose, lactose or silica, under a stream of
argon. These compositions can also comprise substances other than
diluents, for example one or more lubricants such as magnesium
stearate or talc, a dye, a coating (dragees) or a varnish.
[0095] Liquid compositions for oral administration that can be used
include pharmaceutically acceptable solutions, suspensions,
emulsions, syrups and elixirs containing inert diluents such as
water, ethanol, glycerol, plant oils or liquid paraffin. These
compositions can comprise substances other than diluents, for
example wetting products, sweeteners, thickeners, flavorings or
stabilizers.
[0096] The sterile compositions for parenteral administration can
preferably be aqueous or non-aqueous solutions, suspensions or
emulsions. Solvents or vehicles which may be used include water,
propylene glycol, a polyethylene glycol, plant oils, in particular
olive oil, injectable organic esters, for example ethyl oleate, or
other suitable organic solvents. These compositions can also
contain adjuvants, in particular wetting agents, isotonic agents,
emulsifiers, dispersants and stabilizers. The sterilization can be
carried out in several ways, for example by aseptic filtration, by
incorporating sterilizing agents into the composition, by
irradiation or by heating. They can also be prepared in the form of
sterile solid compositions which can be dissolved at the time of
use in sterile water or any other injectable sterile medium.
[0097] The compositions for rectal administration are suppositories
or rectal capsules which contain, besides the active product,
excipients such as cocoa butter, semisynthetic glycerides or
polyethylene glycols.
[0098] Compositions for topical administration can be, for example,
creams, lotions, eye drops, mouth washes, nasal drops or
aerosols.
[0099] In human therapy, the compounds according to the invention
are particularly useful for treating and/or preventing multiple
sclerosis, cerebral, focal or global ischemia, cerebral or spinal
trauma, Parkinson's disease, Huntington's disease, Alzheimer's
disease, amyotrophic lateral sclerosis, migraine, depression,
schizophrenia, anxiety, epilepsy, diabetes, atherosclerosis,
myocarditis, arthritis, arthrosis, asthma, irritable bowel
syndrome, Crohn's disease, peritonitis, gastro-esophageal reflux,
uveitis, Guillain-Barre syndrome, glomerulonephritis, lupus
erythematosus, psoriasis, the growth of certain forms of tumors
such as, for example, epitheliomas, adenocarcinomas or sarcomas,
and in infections with Gram-positive or Gram-negative intracellular
or extracellular bacteria.
[0100] The doses depend on the desired effect, the duration of the
treatment and the route of administration used; they are generally
between 1 mg and 100 mg per day via the oral route for an adult,
with unit doses ranging from 0.5 mg to 50 mg of active
substance.
[0101] In general, the doctor will determine the appropriate dosage
as a function of the age, weight and all the other personal factors
of the individual to be treated.
[0102] The examples which follow illustrate compositions according
to the invention:
Example A
[0103] Gel capsules containing a 50 mg dose of active product and
having the composition below are prepared, according to the usual
technique:
1 Compound of formula (I) 50 mg Cellulose 18 mg Lactose 55 mg
Colloidal silica 1 mg Sodium carboxymethylstarch 10 mg Talc 10 mg
Magnesium stearate 1 mg
Example B
[0104] Tablets containing a 50 mg dose of active product and having
the composition below are prepared according to the usual
technique:
2 Compound of formula (I) 50 mg Lactose 104 mg Cellulose 40 mg
Polyvidone 10 mg Sodium carboxymethylstarch 22 mg Talc 10 mg
Magnesium stearate 2 mg Colloidal silica 2 mg Mixture of
hydroxymethylcellulose, glycerol and titanium oxide (72/3.5/24.5)
qs 1 finished film- coated tablet weighing 245 mg
Examle C
[0105] An injectable solution containing 10 mg of active product
and having the composition below is prepared:
3 Compound of formula (I) 10 mg Benzoic acid 80 mg Benzyl alcohol
0.06 ml Sodium benzoate 80 mg 95% ethanol 0.4 ml Sodium hydroxide
24 mg Propylene glycol 1.6 ml Water qs 4 ml
[0106] The present invention also relates to the use of a compound
of formula (I), the racemic mixture, enantiomers, diastereoisomers
and mixtures thereof, the tautomeric form thereof and
pharmaceutically acceptable salts thereof for the preparation of
pharmaceutical compositions for preventing and treating diseases in
which an abnormal production of nitric oxide (NO) by induction of
inducible NO-synthase (NOS-2) is involved.
[0107] The present invention also relates to the method for
preventing and treating diseases in which an abnormal production of
nitric oxide (NO) by induction of inducible NO-synthase (NOS-2 or
iNOS) is involved, by administering a compound of formula (I), the
racemic mixture, enantiomers, diastereoisomers and mixtures
thereof, the tautomer thereof and pharmaceutically acceptable salts
thereof.
* * * * *