U.S. patent application number 09/998949 was filed with the patent office on 2002-09-26 for aminothiazole derivatives, process for preparing them and pharmaceutical compositions containing them.
Invention is credited to Fontaine, Evelyne, Gully, Danielle, Roger, Pierre, Wermuth, Camille Georges.
Application Number | 20020137740 09/998949 |
Document ID | / |
Family ID | 9496466 |
Filed Date | 2002-09-26 |
United States Patent
Application |
20020137740 |
Kind Code |
A1 |
Fontaine, Evelyne ; et
al. |
September 26, 2002 |
Aminothiazole derivatives, process for preparing them and
pharmaceutical compositions containing them
Abstract
The subject of the invention is the compounds of formula: 1 in
which R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are
as defined in Claim 1. The compounds have a high affinity for the
CRF receptors.
Inventors: |
Fontaine, Evelyne;
(Castanet-Tolosan, FR) ; Gully, Danielle; (Muret,
FR) ; Roger, Pierre; (Montigny le Bretonneux, FR)
; Wermuth, Camille Georges; (Strasbourg, FR) |
Correspondence
Address: |
SANOFI-SYNTHELABO INC.
9 GREAT VALLEY PARKWAY
P.O. BOX 3026
MALVERN
PA
19355
US
|
Family ID: |
9496466 |
Appl. No.: |
09/998949 |
Filed: |
November 15, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09998949 |
Nov 15, 2001 |
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09269516 |
Apr 2, 1999 |
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6344470 |
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09269516 |
Apr 2, 1999 |
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PCT/FR97/01788 |
Oct 7, 1997 |
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Current U.S.
Class: |
514/217.1 ;
514/326; 514/370; 540/603; 546/209; 548/190 |
Current CPC
Class: |
A61P 37/06 20180101;
A61P 25/22 20180101; A61P 25/24 20180101; A61P 29/00 20180101; A61P
37/00 20180101; A61P 25/18 20180101; A61P 43/00 20180101; C07D
277/40 20130101; A61P 1/00 20180101; A61P 5/38 20180101; C07D
277/42 20130101 |
Class at
Publication: |
514/217.1 ;
514/326; 514/370; 548/190; 546/209; 540/603 |
International
Class: |
A61K 031/55; A61K
031/454; A61K 031/426; C07D 417/02 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 8, 1996 |
FR |
FR 96 12256 |
Claims
1. Compound of formula: 92in which R.sub.1 and R.sub.2, which are
identical or different, each represent independently a halogen
atom; a (C.sub.1-C.sub.5)hydroxyalkyl; a (C.sub.1-C.sub.5)alkyl; an
aralkyl in which the aryl part is a (C.sub.6-C.sub.8) and the alkyl
part is a (C.sub.1-C.sub.4); a (C.sub.1-C.sub.5)alkoxy; a
trifluoromethyl group; a nitro group; a nitrile group; a group --SR
in which R represents hydrogen, a (C.sub.1-C.sub.5)alkyl or an
aralkyl in which the aryl part is a (C.sub.6-C.sub.8) and the alkyl
part is a (C.sub.1-C.sub.4); a group --S--CO--R in which R
represents a (C.sub.1-C.sub.5)alkyl radical or an aralkyl in which
the aryl part is a (C.sub.6-C.sub.8) and the alkyl part is a
(C.sub.1-C.sub.4); a group --COORa in which Ra represents hydrogen
or a (C.sub.1-C.sub.5)alkyl; a group --CONRaRb with Ra and Rb as
defined above for Ra; a group --NRaRb with Ra and Rb as defined
above for Ra; a group --CONRcRd or --NRcRd in which Rc and Rd
constitute, with the nitrogen atom to which they are attached, a 5-
to 7-membered heterocycle; or a group --NHCO--NRaRb with Ra and Rb
as defined above for Ra; R.sub.3 represents hydrogen or is as
defined above for R.sub.1 and R.sub.2; R.sub.4 represents a
(C.sub.1-C.sub.5)alkyl; a hydroxymethyl group; a formyl group; or a
halogen atom; R.sub.5 represents a (C.sub.1-C.sub.5)alkyl; a
cycloalkylalkyl group in which the cycloalkyl is a
(C.sub.3-C.sub.7) and the alkyl is a (C.sub.1-C.sub.5); an alkenyl
of 3 to 6 carbon atoms; a (C.sub.1-C.sub.5)hydroxyalkyl; an
alkylcarbonyloxyalkyl group in which the alkyls are a
(C.sub.1-C.sub.5); or an alkynyl group of 3 to 6 carbon atoms;
R.sub.6 represents a phenyl substituted with one or more
substituents Z as defined below; a monocyclic heteroaromatic
C.sub.5-C.sub.7 group substituted with one or more radicals Z as
defined below; or a bicyclic C.sub.9-C.sub.10 group consisting of
an aromatic monocycle optionally comprising one or more heteroatoms
selected from O, N and S, condensed with a cycloalkyl group
optionally comprising in the ring one or more heteroatoms selected
from O, N and S, which bicyclic group is substituted with one or
more substituents Z as defined below and which is attached to the
nitrogen by the ring of an aromatic nature, it being understood
that R.sub.6 does not represent a substituted indan and that the
substituent Z represents a radical selected from: a halogen atom, a
nitro group, a hydroxyl group, a trifluoromethyl group, a
(C.sub.1-C.sub.5)alkyl, a (C.sub.1-C.sub.5)thioalkyl, a group
--NRaRb with Ra and Rb as defined above for Ra, a
(C.sub.1-C.sub.5)hydroxyalkyl, a (C.sub.1-C.sub.5)alkoxy, a
trifluoromethyloxy group, an alkoxyalkyl in which the alkyls are a
(C.sub.1-C.sub.5), a group --COORa with Ra as defined above, a
group --CONRaRb with Ra and Rb as defined above for Ra, a
carboxy-(C.sub.1-C.sub.5)alkyl, an alkoxycarbonylalkyl in which the
alkyls are a (C.sub.1-C.sub.5), a (C.sub.1-C.sub.5)alkylcarbonyl,
an alkylcarbonylalkyl in which the alkyls are a (C.sub.1-C.sub.5),
a morpholinocarbonyl or morpholinocarbonyl(C.sub.1-C.sub.5)alkyl
group, or a group --NRaCOORb with Ra and Rb as defined above, a
group --NHCORc in which Rc represents a (C.sub.1-C.sub.8)alkyl, a
cycloalkylcarbonyl in which the cycloalkyl is a (C.sub.3-C.sub.6),
a cycloalkylalkylcarbonyl in which the cycloalkyl is a
(C.sub.3-C.sub.6) and the alkyl a (C.sub.1-C.sub.3), a benzoyl, a
phenyl which is unsubstituted or substituted with a
(C.sub.1-C.sub.5)alkyl, with a (C.sub.1-C.sub.5)alkoxy- , with a
halogen atom, with a nitro group, with a hydroxyl group or with a
trifluoromethyl group; their stereoisomers, their addition salts,
their hydrates and/or their solvates.
2. Compound of formula (I) according to claim 1, in which R.sub.6
represents a phenyl or tetrahydronaphthyl group substituted with
one or more substituents Z as defined for (I), R.sub.1, R.sub.2,
R.sub.3, R.sub.4, and R.sub.5 also being as defined for (I), one of
their stereoisomers, one of their salts, one of their hydrates
and/or one of their solvates.
3. Compound of formula (I) according to claims 1 and 2, in which
R.sub.4 represents a methyl, R.sub.1, R.sub.2, R.sub.3 and R.sub.5
being as defined for (I), one of their stereoisomers, one of their
hydrates and/or one of their solvates.
4. Compound of formula (I) according to claim 3, in which R.sub.1
and/or R.sub.2 represents a halogen, a trifluoromethyl, a
(C.sub.1-C.sub.5)alkyl or a (C.sub.1-C.sub.5)alkoxy, R.sub.4
represents a methyl, R.sub.6 represents a phenyl at least
substituted at the 2 position with a substituent Z as defined for
(I), R.sub.3 and R.sub.5 are as defined for (I), one of their
stereoisomers, one of their salts, one of their hydrates and/or one
of their solvates.
5. Compounds of formula:
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-eth- oxycarbonyl
-2-methoxyphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro
-2-methylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-me-
thyl-2-[N-(2-trifluoromethylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxyphenyl)-N-propylamin-
o]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,6-dichlorophenyl)-
-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-di-
chlorophenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl- -2-[N-(2-chloro
-5-methylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-chloro
-5-trifluoromethylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphe- nyl)-5-methyl-2-[N-(2-chloro
-5-methoxyphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro
-2-methoxyphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-m- ethyl-2-[N-(5-chloro
-2-ethoxyphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxphenyl)-5-methyl-2-[N-(2-methoxy-5-methylphenyl)-N-pr-
opylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-dimethy-
lphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-
-(2,5-difluoromethylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyph-
enyl)-5-methyl-2-[N-(2-methoxy-5-trifluoromethylphenyl)-N-propylamino]thia-
zole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-dimethoxyphenyl)-N-pr-
opylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-
-methoxycarbonylphenyl)-N-propylamino]thiazole
4-(2,4-Dichlorophenyl)-5-me-
thyl-2-[N-(2,5-dichlorophenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-acetyl
-2-methoxyphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-m-
ethyl-2-[N-(2-(methoxy)-5-(phenyl)phenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,6-dimethoxyphenyl)-N-propyl-
amino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-6-met-
hylphenyl)-N-propylamino]thiazole
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2--
methoxy-6-methylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl-
)-5-methyl-2-[N-(5-ethyl-2-methoxyphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-bromo-2-methoxyphenyl)-N-pr-
opylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-
-o-tolylphenyl)-N-propylamino]thiazole
4-(2,4,6-Trichlorophenyl)-5-methyl--
2-[N-2,5-ditrifluoromethylphenyl)-N-propylamino]thiazole
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2,5-ditrifluoromethylphenyl)-N-prop-
ylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-n-
itrophenyl)-N-propylamino]thiazole
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2-
,6-dichloro-5-methylphenyl)-N-propylamino]thiazole
4-(2,4-Dichlorophenyl)--
5-methyl-2-[N-(2-methoxy-6-methylphenyl)-N-propylamino]thiazole
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(5-chloro-2-methylphenyl)-N-propylam-
ino]thiazole
4-(4-Chloro-2-trifluoromethylphenyl)-5-methyl-2-[N-(5-chloro--
2-methylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxy-5-methylpheny-
l)-5-methyl-2-[N-(2-methoxy-5-methylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methyl-thio-5-trifluorometh-
ylphenyl)-N-propylamino]thiazole
4-(2,4-Dichloro-5-methylphenyl)-5-methyl--
2-[N-(2-methoxy-5-methylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4,5-dimethylphenyl)-5-methyl-2-[N-(2-methoxy-5-methylphenyl)--
N-propylamino]thiazole
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-metho-
xy-5-methoxycarbonylphenyl)-N-propylamino]thiazole
4-(2-Chloro-4-methoxyph-
enyl)-5-methyl-2-[N-(5-chloro-2-methylphenyl)-N-prop-2-ynylamino]thiazole
one of their stereoisomers, one of their salts, one of their
hydrates and/or one of their solvates.
6. Process for the preparation of the compounds of formula (I)
according to claim 1, characterized in that alpha-halogenated
derivative of formula (III) 93in which R.sub.1, R.sub.2, R.sub.3
and R.sub.4 are as defined for (I) and Hal represents a halogen,
preferably bromine or chlorine, atom, is reacted either with a
thiourea (ROUTE A) of formula: 94in which R.sub.6 is as defined for
(I) in order to obtain a compound of formula (II) 95in which
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.6 are as defined for
(I) in order to then subject it to an alkylation reaction in order
to provide the compound (I), or with a thiourea (ROUTE B) of
formula 96in which R.sub.5 and R.sub.6 are as defined for (I) in
order to give directly the compound (I), and, where appropriate,
the compounds of formula (I) thus obtained are then optionally
separated into their possible stereoisomers and/or salified in
order to form the corresponding salts.
7. Use of the compounds of formula (I) according to any one of
claims 1 to 7, for the preparation of a medicament which can be
used in the treatment of diseases requiring modulation of the
action of corticopropin releasing factor.
8. Pharmaceutical composition containing, as active ingredient, at
least one compound according to any one of claims 1 to 7, in the
form of a base or in the form of a salt with a pharmaceutically
acceptable inorganic or organic acid, in combination with or mixed
with a pharmaceutically acceptable nontoxic inert excipient.
9. Pharmaceutical composition according to claim 10, in the form of
dosage units, in which the active ingredient is mixed with at least
one pharmaceutical excipient.
10. Composition according to claim 11, in which each dosage unit
contains from 0.5 to 800 mg of active ingredient.
11. Composition according to claim 12, in which each dosage unit
contains from 0.5 to 200 mg of active ingredient.
12. Pharmaceutical composition containing a compound according to
claims 1 to 7 in combination with another anxiolytic,
antidepressant or anorexigenic active ingredient.
Description
[0001] The subject of the present invention is new branched amino
derivatives of thiazole, a process for preparing them and
pharmaceutical compositions containing them. These new thiazole
derivatives are endowed with CRF (corticotropin releasing factor)
antagonizing activity and can therefore constitute active
ingredients in pharmaceutical compositions.
[0002] Corticotropin releasing factor (CRF) is a peptide whose
sequence of 41 amino acids has been characterized by Vale W. et al.
in 1981 (Science, 1981, 213, 1394-1397). CRF is the principal
endogenous factor involved in the regulation of the
hypothalamohypophyso-adrenal axis (release of the
adrenocorticotropic hormone: ACTH) and its pathologies, as well as
in the depressive syndromes which result therefrom. CRF also causes
the secretion of .beta.-endorphin, .beta.-lipotropin and
corticosterone. CRF is therefore the physiological regulator of the
secretion of the adrenocorticotropic hormone (ACTH) and more
generally of the peptides derived from pro-opiomelanocortin (POMC).
In addition to its hypothalamic localization, CRF is widely
distributed in the central nervous system, but also in
extraneuronal tissues such as the adrenal glands and the testicles.
The presence of CRF has also been demonstrated during inflammatory
processes.
[0003] Numerous animal experiments have shown that the central
administration of CRF causes various anxiogenic effects such as the
modification of behaviour in general: for example neophobia,
reduction in sexual receptivity, decrease in food consumption and
lingering sleep in rats. The intracerebroventricular injection of
CRF also increases the excitation of the noradrenergic neurons of
the locus coeruleus which is often associated, in animals, with a
state of anxiety. In rats, the central or peripheral administration
of CRF or of related peptides (for example urocortin, sauvagin)
induces, in addition to central effects such as an increase in
wakefulness and in emotional reactivity towards the surroundings,
modifications in the emptying of the stomach, in acid secretion, in
intestinal transit and in faecal excretion as well as tensional
effects. CRF is also involved in the complex regulation of the
inflammatory responses, on the one hand with a pro-inflammatory
role in certain animal models, on the other hand as inhibitor of
the effects induced by the increase in vascular permeability
following the inflammation.
[0004] The use of a peptide antagonist, alpha-helical CRF(9-41)
(ah-CRF), or of specific antibodies (Rivier J. et al., Science,
1984, 224, 889-891) has made it possible to confirm the role of
this peptide in all of these effects. These experiments have also
confirmed the important role of CRF in humans in the integration of
the complex responses observed during a physiological,
psychological or immunological stress both from the
neuroendocrinal, visceral and behavioural point of view (Morley J.
E. et al., Endocrine Review, 1987, 8, 3, 256-287; Smith M. A. et
al., Horm. Res., 1989, 31, 66-71). In addition, clinical data
militate in favour of the effective involvement of CRF in numerous
disorders resulting from a state of stress (Gulley L. R. et al., J.
Clin. Psychiatry, 1993, 54, 1, (suppl.), 16-19) for example:
[0005] the existence of the CRF-based test (i.v. administration) in
humans has made it possible to demonstrate the modification of the
ACTH response in depressive patients (Breier A. et al., Am. J.
Psychiatry, 1987, 144, 1419-1425);
[0006] the discovery of hypersecretion of endogenous CRF in certain
pathologies, for example of a high CRF level in the
cephalorachidien fluid in non medicated patients, depressed
patients or patients suffering from dementia of the Alzheimer's
disease type (Nemeroff C. B. et al., Science, 1984, 226, 4680,
1342-1343; Regul. Pept., 1989, 25, 123-130), or of a reduced
density of CRF receptors in the cortex of victims of suicide
(Nemeroff C. B. et al., Arch. Gen. Psychiatry, 1988, 45,
577-579);
[0007] the dysfunction of the CRF-dependent neurons is even
suggested in severe pathologies such as Alzheimer's disease,
Parkinson's disease, Huntingdon's chorea and amyotrophic lateral
sclerosis (De Souza, E. B., Hospital Practice, 1988, 23, 59).
[0008] The central administration of CRF in numerous animal species
produces behavioural effects similar to those obtained in man in
situations of stress. When they are repeated over time, these
effects can cause various pathologies such as fatigue,
hypertension, cardiac disorders, modification in the emptying of
the stomach, in faecal excretion (colitis, irritable colon),
modification in acid secretion, hyperglycaemia, retarded growth,
anorexia, neophobia, reproductive disorders, immunosuppression
(inflammatory processes, multiple infections and cancers) and
various neuropsychiatric disorders (depression, nervous anorexia
and anxiety).
[0009] The injection, by the intracerebroventricular route, of the
reference peptide antagonist, ah-CRF, prevents the effects obtained
either by the administration of exogenous CRF, or by the use of
stress-causing agents (ether, constraint, noise, electric shock,
alcohol withdrawal, surgery) which are capable, by themselves, of
inducing an increase in the endogenous CRF level. These results are
confirmed by the study of numerous antagonist peptide molecules
which are structurally related to CRF and which possess a prolonged
duration of action compared with ah-CRF (Rivier J. et al., J. Med.
Chem., 1993, 36, 2851-2859; Menzaghi F. et al., J. Pharmacol. Exp.
Ther., 1994, 269, 2, 564-572; Hernandez J. F. et al., J. Med.
Chem., 1993, 36, 2860-2867). Such CRF-antagonizing peptide
compounds are described, for example, in U.S. Pat. Nos. 5,109,111,
5,132,111, 5,245,009 and in Patent Applications WO 92 22576 and WO
96 19499.
[0010] In addition, preliminary studies have shown that tricyclic
antidepressants could modulate the CRF level as well as the number
of CRF receptors in the brain (Grigoriadis D. E. et al.,
Neuropsycho-pharmacolog- y, 1989, 2, 53-60). Likewise,
benzodiazepine anxiolytics are capable of reversing the effect of
CRF (Britton K. T. et al., Psychopharmacology, 1988, 94, 306),
without the mechanism of action of these substances being
completely elucidated. These results strengthen, if necessary, the
increasing need for molecules which are nonpeptide antagonists of
the CRF receptors.
[0011] It is important to also report three possible consequences
of the states of chronic stress which are immunodepression,
fertility disorders as well as the appearance of diabetes.
[0012] CRF exerts such effects by interacting with specific
membrane receptors which have been characterized in the hypophysis
and the brain of numerous species (mice, rats and humans) as well
as in the heart, the skeletal muscle (rats, mice) and in the
myometrium and the placenta during pregnancy.
[0013] A large number of 2-aminothiazole derivatives are already
known. Patent Application EP 462 264 describes 2-aminothiazole
derivatives whose tertiary amine in the 2 position comprises two
substituents each having at least one heteroatom including one
amine derivative. These compounds are antagonists of the platelet
activating factor (PAF-acether) and find applications in the
treatment of asthma, of certain allergic or inflammatory states, of
cardiovascular diseases, of hypertension and of various renal
pathologies or alternatively as contraceptive agents.
[0014] Application GB 2 022 285 describes compounds possessing an
activity which regulates the immune response and having
anti-inflammatory properties. They are thiazole derivatives which
are substituted at the 2 position with secondary amine groups.
[0015] Some 2-acylaminothiazole derivatives have been described in
Patent Application EP 432 040. These compounds are antagonists of
cholecystokinin and of gastrin.
[0016] 2-Amino-4,5-diphenylthiazole derivatives having
anti-inflammatory properties are also known (Patent Application
JP-01 75 475).
[0017] 2-Amino-4-(4-hydroxyphenyl)thiazole derivatives which are
useful as synthesis intermediates for the preparation of
2,2-diarylchromenothiazole derivatives are also known (Patent
Application EP 205 069).
[0018] 2-(N-methyl-N-benzylamino)thiazole derivatives are also
described in J. Chem. Soc. Perkin, Trans 1, 1984, 2, 147-153 and in
J. Chem. Soc. Perkin, Trans 1, 1983, 2, 341-347.
[0019] Patent Application WO 94 01423 describes 2-aminothiazole
derivatives of general formula: 2
[0020] it being possible for R.sub.3a to represent an alkyl and
R.sub.4a a substituted phenyl. These compounds, which are used as
insecticide, have no substitution at the 5 position of the
heterocycle.
[0021] Likewise, Patent Application WO 96 16650 describes compounds
of general formula: 3
[0022] in which R.sub.2b may represent a substituted phenyl,
R.sub.1b an alkyl, R.sub.3b an alkyl and R.sub.4b a sulphonyl or an
acyl; these compounds are used as antibiotics.
[0023] Patent Application EP 283 390 describes, among other
thiazole derivatives, 2-(N-alkyl-N-pyridylalkylamino)thiazole
derivatives of formula: 4
[0024] for which m is different from zero.
[0025] These derivatives, whose amine at the 2 position is
substituted with an unbranched pyridylalkyl radical, possess in
particular a central cholinergic transmission stimulating activity.
They can therefore be used as agonists of the muscarine receptors
and find applications in the treatment of memory disorders and of
senile dementia.
[0026] 2-Aminothiazole derivatives in which the amine at the 2
position is a tertiary amine having a branched alkyl or aralkyl
substituent have been described in EP 576 350 and in EP 659 747 as
having affinity for the CRF receptors. None of these compounds
have, as substituent of the tertiary amine at the 2 position of the
thiazole ring, a substituted phenyl.
[0027] U.S. Pat. No. 5,063,245 describes antagonists of CRF which
make it possible to displace in vitro the binding of CRF to its
specific receptors at a concentration close to one micromole. Since
then, numerous Patent Applications relating to nonpeptide molecules
have been published, for example Applications WO 94/13643, WO
94/13644, WO 94/13661, WO 94/13676, WO 94/13677, WO 94/10333, WO
95/00640, WO 95/10506, WO 95/13372, WO 95/33727, WO 95/33750, WO
95/34563, EP 691 128 or EP 729 758.
[0028] It has now been found that some branched amino derivatives
of thiazole, which are the subject of the present invention,
exhibit excellent affinity towards the CRF receptors. Furthermore,
given their structure, these molecules possess good dispersibility
and/or solubility in solvents and solutions commonly used in
therapy which confers pharmacological activity on them and also
allow easy preparation of oral and parenteral galenic forms.
[0029] The subject of the present invention is the compounds of
formula: 5
[0030] in which
[0031] R.sub.1 and R.sub.2, which are identical or different, each
represent independently a halogen atom; a (C.sub.1-C.sub.5)
hydroxyalkyl; a (C.sub.1-C.sub.5)alkyl; an aralkyl in which the
aryl part is a (C.sub.6-C.sub.8) and the alkyl part is a
(C.sub.1-C.sub.4); a (C.sub.1-C.sub.5)alkoxy; a trifluoromethyl
group; a nitro group; a nitrile group; a group --SR in which R
represents hydrogen, a (C.sub.1-C.sub.5)alkyl or an aralkyl in
which the aryl part is a (C.sub.6-C.sub.8) and the alkyl part is a
(C.sub.1-C.sub.4); a group --S--CO--R in which R represents a
(C.sub.1-C.sub.5)alkyl radical or an aralkyl in which the aryl part
is a (C.sub.6-C.sub.8) and the alkyl part is a (C.sub.1-C.sub.4); a
group --COORa in which Ra represents hydrogen or a
(C.sub.1-C.sub.5)alkyl; a group --CONRaRb with Ra and Rb as defined
above for Ra; a group --NRaRb with Ra and Rb as defined above for
Ra; a group --CONRcRd or --NRcRd in which Rc and Rd constitute,
with the nitrogen atom to which they are attached, a 5- to
7-membered heterocycle; or a group --NHCO--NRaRb with Ra and Rb as
defined above for Ra;
[0032] R.sub.3 represents hydrogen or is as defined above for
R.sub.1 and R.sub.2;
[0033] R.sub.4 represents a (C.sub.1-C.sub.5) alkyl; a
hydroxymethyl group; a formyl group; or a halogen atom;
[0034] R.sub.5 represents a (C.sub.1-C.sub.5)alkyl; a
cycloalkylalkyl group in which the cycloalkyl is a
(C.sub.3-C.sub.7) and the alkyl is a (C.sub.1-C.sub.5); an alkenyl
of 3 to 6 carbon atoms; a (C.sub.1-C.sub.5)hydroxyalkyl; an
alkylcarbonyloxyalkyl group in which the alkyls are a
(C.sub.1-C.sub.5); or an alkynyl group of 3 to 6 carbon atoms;
[0035] R.sub.6 represents a phenyl substituted with one or more
substituents Z as defined below; a monocyclic heteroaromatic
C.sub.5-C.sub.7 group substituted with one or more radicals Z as
defined below; or a bicyclic C.sub.9-C.sub.10 group consisting of
an aromatic monocycle optionally comprising one or more heteroatoms
selected from O, N and S, condensed with a cycloalkyl group
optionally comprising in the ring one or more heteroatoms selected
from O, N and S, which bicyclic group is substituted with one or
more substituents Z as defined below and which is attached to the
nitrogen by the ring of an aromatic nature, it being understood
that R.sub.6 does not represent a substituted indan and that the
substituent Z represents a radical selected from: a halogen atom, a
nitro group, a hydroxyl group, a trifluoromethyl group, a
(C.sub.1-C.sub.5)alkyl, a (C.sub.1-C.sub.5)thioalkyl, a group
--NRaRb with Ra and Rb as defined above for Ra, a
(C.sub.1-C.sub.5)hydroxyalkyl, a (C.sub.1-C.sub.5)alkoxy, a
trifluoromethyloxy group, an alkoxyalkyl in which the alkyls are a
(C.sub.1-C.sub.5), a group --COORa with Ra as defined above, a
group --CONRaRb with Ra and Rb as defined above for Ra, a
carboxy(C.sub.1-C.sub.5)alkyl, an alkoxycarbonylalkyl in which the
alkyls are a (C.sub.1-C.sub.5), a (C.sub.1-C.sub.5)alkylcarbonyl,
an alkylcarbonylalkyl in which the alkyls are a (C.sub.1-C.sub.5),
a morpholinocarbonyl or morpholinocarbonyl(C.sub.1-C.sub.5)alkyl
group, or a group --NRaCOORb with Ra and Rb as defined above, a
group --NHCORc in which Rc represents a (C.sub.1-C.sub.8)alkyl, a
cycloalkylcarbonyl in which the cycloalkyl is a (C.sub.3-C.sub.6),
a cycloalkylalkylcarbonyl in which the cycloalkyl is a
(C.sub.3-C.sub.6) and the alkyl a (C.sub.1-C.sub.3), a benzoyl, a
phenyl which is unsubstituted or substituted with a
(C.sub.1-C.sub.3)alkyl, with a (C.sub.1-C.sub.5)alkoxy- , with a
halogen atom, with a nitro group, with a hydroxyl group or with a
trifluoromethyl group;
[0036] their stereoisomers, their addition salts, their hydrates
and/or their solvates.
[0037] Monocyclic heteroaromatic group is understood to mean
particularly a group selected from azepinyl, pyridyl, pyrazinyl,
pyridazinyl, pyrimidyl, triazinyl, furyl and thienyl.
[0038] Examples of C.sub.9-C.sub.10 bicyclic groups are
1,2,3,4-tetrahydronaphthyl as well as groups comprising one or more
heteroatoms selected from N, O and S and represented, for example,
by 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl,
1,2,3,4-tetrahydrophthalazinyl, 1,2,3,4-tetrahydroquinazolinyl,
1,2,3,4-tetrahydroquinoxalinyl, 1,2,3,4-tetrahydrocinnolinyl,
1,2,3,4-tetrahydrobenzotriazinyl, chromanyl, isochromanyl,
indolinyl, isoindolinyl, 2,3-dihydroindazyl,
2,3-dihydrobenzoimidazolyl, 1,2-dihydrobenzotriazolyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydrobenzoisothiazolyl, 2,3-dihydrobenzothiazolyl,
2,3-dihydrobenzoisoxazolyl, 2,3-dihydrobenzoxazolyl,
1,2-dihydrobenzoxazinyl, 1,2,3,4-tetrahydropteri- dinyl,
8,9-dihydropurinyl. These bicyclic groups are substituted with one
or more substituents Z as defined above.
[0039] Examples of 5- to 7-membered heterocycles are morpholine,
piperidine or pyrrolidine.
[0040] In the present description, the alkyl groups or the alkoxy
groups are linear or branched.
[0041] Halogen atom is understood to mean a fluorine, chlorine,
bromine or iodine atom.
[0042] Advantageous compounds according to the invention are those
in which R.sub.6 represents a phenyl or tetrahydronaphthyl group
substituted with one or more substituents Z as defined for (I),
R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 also being as
defined for (I), one of their stereoisomers, one of their salts,
one of their hydrates and/or one of their solvates.
[0043] Among these compounds, there are particularly preferred the
compounds in which R.sub.4 represents a methyl, R.sub.1, R.sub.2,
R.sub.5 and R.sub.3 being as defined for (I), one of their
stereoisomers, one of their hydrates and/or one of their
solvates.
[0044] More particularly preferred among these compounds are those
in which R.sub.1 and/or R.sub.2 represents a halogen, a
trifluoromethyl, a (C.sub.1-C.sub.5)alkyl or a
(C.sub.1-C.sub.5)alkoxy, R.sub.4 represents a methyl, R.sub.6
represents a phenyl at least substituted at the 2 position with a
substituent Z as defined for (I), R.sub.3 and R.sub.5 are as
defined for (I), one of their stereoisomers, one of their salts,
one of their hydrates and/or one of their solvates.
[0045] Most particularly preferred are thus the compounds:
[0046]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-ethoxy-carbonyl-2-met-
hoxyphenyl)-N-propylamino]thiazole
[0047] 4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro
-2-methylphenyl)-N-propylamino]thiazole
[0048]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-trifluoromethylphenyl-
)-N-propylamino]thiazole
[0049]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxyphenyl)-N-prop-
ylamino]thiazole
[0050]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,6-dichlorophenyl)-N-p-
ropylamino]thiazole
[0051]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-dichlorophenyl)-N-p-
ropylamino]thiazole
[0052]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-chloro-5-methylphenyl-
)-N-propylamino]thiazole
[0053]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-chloro-5-trifluoromet-
hylphenyl)-N-propylamino]thiazole
[0054]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-chloro-5-methoxypheny-
l)-N-propylanino]thiazole
[0055]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro-2-methoxypheny-
l)-N-propylamino]thiazole
[0056]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro-2-ethoxyphenyl-
)-N-propylamino]thiazole
[0057]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-methylpheny-
l)-N-propylamino]thiazole
[0058]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-dimethylphenyl)-N-p-
ropylamino]thiazole
[0059]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-difluoromethylpheny-
l)-N-propylamino]thiazole
[0060]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-trifluorome-
thylphenyl)-N-propylamino]thiazole
[0061]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,5-dimethoxyphenyl)-N--
propylamino]thiazole
[0062]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-methoxycarb-
onylphenyl)-N-propylamino]thiazole
[0063]
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2,5-dichlorophenyl)-N-propyla-
mino]thiazole
[0064]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-acetyl-2-methoxypheny-
l)-N-propylamino]thiazole
[0065]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-(methoxy)-5-(phenyl)p-
henyl)-N-propylamino]thiazole
[0066]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2,6-dimethoxyphenyl)-N--
propylamino]thiazole
[0067]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-6-methylpheny-
l)-N-propylamino]thiazole
[0068]
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2-methoxy-6-methylphenyl)-N-p-
ropylamino]thiazole
[0069]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-ethyl-2-methoxyphenyl-
)-N-propylamino]thiazole
[0070]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-bromo-2-methoxyphenyl-
)-N-propylamino]thiazole
[0071]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-o-tolylphen-
yl)-N-propylamino]thiazole
[0072]
4-(2,4,6-Trichlorophenyl)-5-methyl-2-[N-2,5-ditrifluoromethylphenyl-
)-N-propylamino]thiazole
[0073]
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2,5-ditrifluoromethylphenyl)--
N-propylamino]thiazole
[0074]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-nitrophenyl-
)-N-propylamino]thiazole
[0075]
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2,6-dichloro-5-methylphenyl)--
N-propylamino]thiazole
[0076]
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(2-methoxy-6-methylphenyl)-N-p-
ropylamino]thiazole
[0077]
4-(2,4-Dichlorophenyl)-5-methyl-2-[N-(5-chloro-2-methylphenyl)-N-pr-
opylamino]thiazole
[0078]
4-(4-Chloro-2-trifluoromethylphenyl)-5-methyl-2-[N-(5-chloro-2-meth-
ylphenyl)-N-propylamino]thiazole
[0079]
4-(2-Chloro-4-methoxy-5-methylphenyl)-5-methyl-2-[N-(2-methoxy-5-me-
thylphenyl)-N-propylamino]thiazole
[0080]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methyl-thio-5-trifluo-
romethylphenyl)-N-propylamino]thiazole
[0081]
4-(2,4-Dichloro-5-methylphenyl)-5-methyl-2-[N-(2-methoxy-5-methylph-
enyl)-N-propylamino]thiazole
[0082]
4-(2-Chloro-4,5-dimethylphenyl)-5-methyl-2-[N-(2-methoxy-5-methylph-
enyl)-N-propylamino]thiazole
[0083]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-methooxycar-
bonylphenyl)-N-propylamino]thiazole
[0084]
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro-2-methylphenyl-
)-N-prop-2-ynylamino]thiazole one of their stereoisomers, one of
their salts, one of their hydrates and/or one of their
solvates.
[0085] The compounds of the invention in free form generally
exhibit basic properties. However, depending on the nature of the
substituents, some may exhibit acidic properties.
[0086] The salts of the compounds of formula (I) with
pharmaceutically acceptable acids or bases (when this is possible)
are the preferred salts, but those which make it possible to
isolate the compounds of formula (I), in particular to purify them
or to obtain pure isomers also form the subject of the
invention.
[0087] Among the pharmaceutically acceptable acids for the
preparation of the addition salts of the compounds of formula (I),
there may be mentioned hydrochloric, phosphoric, fumaric, citric,
oxalic, sulphuric, ascorbic, tartaric, maleic, mandelic,
methanesulphonic, lactobionic, gluconic, glucaric, succinic,
sulphonic and hydroxypropanesulphonic acids.
[0088] Among the pharmaceutically acceptable bases for the
preparation of the addition salts with the compounds of formula (I)
when these have acidic properties, there may be mentioned sodium,
potassium or ammonium hydroxide.
[0089] The compounds according to the invention as well as the
intermediates useful for their preparation are prepared according
to methods well known to persons skilled in the art, in particular
according to EP 576 350 and EP 659 747.
[0090] The following reaction scheme illustrates a process of
preparation for the synthesis of the compounds (I). 6
[0091] According to another of its features, the subject of the
present invention is also a process for the preparation of the
compounds of formula (I), characterized in that an
alpha-halogenated, preferably alpha-brominated or
alpha-chlorinated, derivative of formula (III) 7
[0092] in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as
defined for (I) and Hal represents a halogen, preferably bromine or
chlorine, atom, is reacted
[0093] either with a thiourea (ROUTE A) of formula: 8
[0094] in which R.sub.6 is as defined for (I) in order to obtain a
compound of formula (II) 9
[0095] in which R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.6 are
as defined for (I) in order to then subject it to an alkylation
reaction in order to provide the compound (I),
[0096] or with a thiourea (ROUTE B) of formula 10
[0097] in which R.sub.5 and R.sub.6 are as defined for (I) in order
to give directly the compound (I), and, where appropriate, the
compounds of formula (I) thus obtained are then optionally
separated into their possible stereoisomers and/or salified in
order to form the corresponding salts.
[0098] The alkylation reactions used in the above process are
carried out under the usual conditions known to persons skilled in
the art by the action of an appropriate alkylating agent such as,
for example, an alkyl halide in the presence of a base, preferably
sodium hydride.
[0099] The derivatives of formula (III) can be obtained from the
corresponding nonhalogenated ketones of formula 11
[0100] in which R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are as
defined for (I) either (i) by the action of bromine in an
appropriate organic solvent, such as acetic acid, carbon
tetrachloride or diethyl ether, or (ii) by the action of quaternary
ammonium tribromides according to the method described in Bull.
Chem. Soc. Japan, 1987, 60, 1159-1160 and 2667-2668, or (iii)
alternatively by the action of copper(II) bromide in an organic
solvent, such as a mixture of chloroform and ethyl acetate
according to J. Org. Chem. 1964, 29, 3451-3461. As a variant, the
compounds of formula (II) can be obtained by the action of
2-bromopropionyl bromide on a substituted benzene of formula 12
[0101] by a Friedel-Crafts reaction.
[0102] The abovementioned ketones are in general known or
commercially available products. These compounds can be prepared by
Friedel-Crafts reaction, in the presence of a Lewis acid according
to methods well known to persons skilled in the art.
[0103] The thiourea derivatives (IVa) and (IVb) are obtained from
the compounds 13
[0104] in which Prot represents a protecting group, for example
benzoyl or pivaloyl, R.sub.5 and R.sub.6 being as defined above for
(I), either by a basic treatment, preferably using ammonia, sodium
hydroxide or hydrazine at a temperature ranging from room
temperature to the reflux temperature of the reaction mixture, or
by an acidic treatment preferably using hydrochloric acid.
[0105] The compounds of formula (Va) and (Vb) are prepared by
reacting, according to known methods, an isothiocyanate, for
example a benzoyl isothiocyanate or a pivaloyl isothiocyanate, with
the corresponding amines of formula (VIa) and (VIb) 14
[0106] in which R.sub.5 and R.sub.6 are as defined for (I).
[0107] The secondary amines (VIb) are prepared from primary
amines
R.sub.6--NH.sub.2 (VIa)
[0108] either by reacting with an aldehyde of formula R'.sub.5-CHO
in which R'.sub.5 represents R.sub.5 as defined for (I) shortened
by one carbon atom in the linear alkyl part, then reducing the
imine with an alkali metal hydride, for example with NaBH.sub.4, in
an alkanol, preferably in ethanol or methanol, at room temperature,
or by reacting with an acid of formula R'.sub.5COOH which serves
both as reagent and as solvent, the aldehyde being formed in situ
during the addition of the alkali metal hydride,
[0109] or by reacting with an acid halide or an acid anhydride in
an organic solvent selected from the halogenated hydrocarbons, such
as dichloromethane, in the presence of a proton acceptor,
preferably triethylamine. The amide derived from this reaction is
then reduced with an alkali metal hydride such as AlLiH.sub.4 in
organic solvents of the diethyl ether type.
[0110] The compounds of formula (I) above also comprise those in
which one or more hydrogen or carbon atoms have been replaced by
their radioactive isotope, for example tritium or carbon-14. Such
labelled compounds are useful in research, metabolism or
pharmacokinetic work, or alternatively in biochemical tests as
receptor ligands.
[0111] The compounds of the present invention have been the subject
of biochemical and pharmacological studies. They possess highly
advantageous pharmacological properties. The compounds of the
invention displace, at concentrations less than 10 .mu.m, the
binding of CRF or of iodinated related peptides (urotensin,
sauvagin) to the specific receptors present on the membranes of
animal (rats, mice) or human brains and on cultured cells,
according to the method described by E. B. De Souza (J. Neurosci.,
1987, 7, 1, 88-100).
[0112] This is surprising and unexpected since compounds of similar
structure to that of the compounds of the invention do not
significantly displace this binding. CRF is a neuropeptide which
controls the activity of the hypothalamohypophysoadrenal axis. This
factor is responsible for stress-related endocrine and behavioural
responses.
[0113] Indeed, it has been demonstrated that CRF can modulate
behaviour like also certain functions of the autonomous nervous
system (G. F. Koob, F. E. Bloom, Fed. Proc., 1985, 44, 259; M. R.
Brown, L. A. Fisher, Fed. Proc., 1985, 44, 243). More particularly,
CRF induces the secretion of corticotropin (ACTH),
.beta.-endorphins and other peptides derived from
proopiomelanocortin (A. Tazi et al., Regul. Peptides, 1987, 18, 37;
M. R. Brown et al., Regul. Peptides, 1986, 16, 321; C. L. Williams
et al., Am. J. Physiol., 1987, G 582, 253).
[0114] The compounds of the invention may therefore be useful for
the regulation of the secretion of these endogenous substances.
They find more especially applications as active ingredients of
medicaments for reducing the response to stress (behaviour,
emotional states, gastrointestinal and cardiovascular disorders,
immune system disorders) and more generally in pathologies
involving CRF, for example psychiatric disorders, anxiety,
depression, nervous anorexia, sexual activity and fertility
disorders, Alzheimer's disease and the like.
[0115] The compounds of the invention are very stable and are
therefore thereby particularly appropriate for constituting the
active ingredient of medicaments.
[0116] The invention also extends to the pharmaceutical
compositions containing, as active ingredient, a compound of
formula (I) or one of its pharmaceutically acceptable salts,
optionally in combination with one or more inert and appropriate
excipients.
[0117] In each dosage unit, the active ingredient of formula (I) is
present in quantities suited to the daily doses envisaged. Each
dosage unit is suitably adjusted according to the dosage and the
type of administration expected, for example tablets, gelatine
capsules and the like, sachets, ampoules, syrups and the like,
drops, transdermal or transmucosal patch, such that such a dosage
unit contains 0.5 to 200 mg of active ingredient, preferably 0.5 to
800 mg which should be administered daily.
[0118] The compounds of the invention can also be used in
combination with another active ingredient useful for the desired
therapy, such as for example anxiolytics, antidepressants or
anorexigenic agents.
[0119] The compounds of formula (I) are not very toxic; their
toxicity is compatible with their use as a medicament for the
treatment of the above disorders and diseases.
[0120] The compounds of formula (I) can be formulated in
pharmaceutical compositions for administration to mammals,
including humans, for the treatment of the abovementioned
diseases.
[0121] The pharmaceutical compositions thus obtained are
advantageously provided in various forms, such as for example
injectable or oral solutions, sugar-coated tablets, plain tablets
or gelatine capsules. The pharmaceutical compositions containing,
as active ingredient, at least one compound of formula (I) or one
of its salts, are in particular useful for the treatment, for
preventive or curative purposes, of stress-related diseases and
more generally in the treatment of any pathology involving CRF,
such as for example: Cushing's disease, neuropsychiatric disorders
such as depression, anxiety, panic, obsessive-compulsive disorders,
mood disorders, behavioural disorders, aggressiveness, anorexia,
bulimia, hyperglycaemia, retarded growth, sleep disorders, epilepsy
and depressions of all types; Alzheimer's disease, Parkinson's
disease; Huntingdon's chorea; amyotrophic lateral sclerosis;
vascular, cardiac and cerebral disorders; sexual activity and
fertility disorders; immunodepression, immunosuppression,
inflammatory processes, multiple infections, rheumatoid arthritis,
osteoarthritis, uveitis, psoriasis as well as diabetes; cancers,
gastrointestinal disorders and inflammations resulting therefrom
(irritable and inflammatory colon, diarrhoea); disorders in the
perception of pain, fibromyalgias related or otherwise to sleep
disorders, fatigue, migraine; symptoms related to (alcohol)
dependency and to drug withdrawal.
[0122] The dosage can vary widely according to the patient's age,
weight and state of health, the nature and seriousness of the
condition, as well as the route of administration. This dosage
comprises the administration of one or more doses of about 0.5 mg
to 200 mg per day, preferably of about 0.5 to 800 mg per day.
[0123] In the pharmaceutical compositions of the present invention
for oral, sublingual, subcutaneous, intramuscular, intravenous,
transdermal, transmucosal, local or rectal administration, the
active ingredient may be administered in unit forms for
administration, mixed with conventional pharmaceutical carriers, to
animals and to human beings. The appropriate unit forms for
administration comprise the oral forms such as tablets, gelatine
capsules, powders, granules and oral solutions or suspensions,
forms for sublingual and oral administration, forms for
subcutaneous, intramuscular, intravenous, intranasal or intraocular
administration and forms for rectal administration.
[0124] When a solid composition in the form of tablets is prepared,
the principal active ingredient is mixed with a pharmaceutical
vehicle such as gelatin, starch, lactose, magnesium stearate, talc,
gum arabic and the like. The tablets can be coated with sucrose or
other appropriate materials or alternatively they can be treated so
that they have a prolonged or delayed activity and so that they
continuously liberate a predetermined quantity of active
ingredient.
[0125] A preparation in gelatine capsules is obtained by mixing the
active ingredient with a diluent and by pouring the mixture
obtained into soft or hard gelatine capsules.
[0126] A preparation in syrup or elixir form may contain the active
ingredient together with a sweetener, preferably calorie free,
methylparaben and propylparaben as antiseptic, as well as a
taste-enhancing agent and an appropriate colouring.
[0127] The water-dispersible powders or granules may contain the
active ingredient in the form of a mixture with dispersing agents
or wetting agents, or suspending agents, such as
polyvinylpyrrolidone, as well as with sweeteners or flavour
correctors.
[0128] For rectal administration, suppositories are used which are
prepared with binders which melt at the rectal temperature, for
example cocoa butter or polyethylene glycols.
[0129] For parenteral, intranasal or intraocular administration,
aqueous suspensions, isotonic saline solutions or sterile and
injectable solutions are used which contain pharmacologically
compatible dispersing agents and/or wetting agents, for example
propylene glycol or butylene glycol.
[0130] For transmucosal administration, the active ingredient may
be formulated in the presence of an enhancer such as a bile salt, a
hydrophilic polymer such as for example hydroxypropyl cellulose,
hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethyl
cellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone,
pectins, starches, gelatin, casein, acrylic acids, acrylic esters
and copolymers thereof, vinyl polymers or copolymers, vinyl
alcohols, alkoxy polymers, polymers of polyethylene oxide,
polyethers or mixtures thereof.
[0131] The active ingredient can also be formulated in the form of
microcapsules, optionally with one or more carriers or
additives.
[0132] The active ingredient may also be provided in the form of a
complex with a cyclodextrin, for example .alpha.-, .alpha.- or
.gamma.-cyclodextrin, 2-hydroxypropyl-.beta.-cyclodextrin or
methyl-.beta.-cyclodextrin.
[0133] The following EXAMPLES, given with no limitation being
implied, illustrate the invention.
[0134] In the PREPARATIONS, there are described the methods of
synthesis of the various intermediates which make it possible to
obtain the compounds of the invention. These intermediates are all
obtained according to methods well known to persons skilled in the
art.
[0135] The melting points were measured according to the
Micro-Kofler technique are expressed in degrees Celsius.
[0136] The proton nuclear magnetic resonance spectra (.sup.1H NMR)
of the compounds of formula (I) were recorded, depending on the
case, at 200 MHz or at 100 MHz. The chemical shifts are given in
ppm and the coupling constants in Hertz.
[0137] The compounds of the invention exhibit a percentage analysis
in accordance with theory.
[0138] The compounds of the invention which are described in TABLE
I also have NMR spectra in accordance with their structure.
PREPARATIONS
Preparation of the Ketones of Formula III
[0139] Preparation I
2-Bromo-1-(2,4-dichlorophenyl)propan-1-one (Compound 1-1)
[0140] 17.4 g of tetrabutylammonium tribromide are added to 7 g of
1-(2,4-dichlorophenyl)propan-1-one in solution in a mixture of 420
ml of dichloromethane and 140 ml of methanol, at room temperature.
After 24 hours, the reaction mixture is concentrated under vacuum.
The residue is taken up in water, extracted with ethyl acetate and
the organic phase is dried with sodium sulphate and evaporated
under vacuum; then the residue is purified on a silica gel column
with, as eluent, a cyclohexane/ethyl acetate 20/1 (v/v) mixture in
order to obtain an oil.
[0141] In the same manner, there may be obtained, using the
appropriate ketones, the following compound:
2-bromo-1-(2-chloro-4-methoxyphenyl)prop- arl-1-one (Compound
1-2)
[0142] Preparation II
2-Bromo-1-(2-chloro-4-trifluoromethylpheryl)propan-1-one (Compound
2-1)
[0143] Stage 1: At 0.degree. C., under an inert atmosphere, 63 ml
of a solution (3M) of ethylmagnesium in diethyl ether are added to
a solution of 19.5 g of 3-chloro-4-cyanobenzotrifluoride in 250 ml
of ether. After reacting for 4 hours at room temperature, the
reaction mixture is again cooled to 0.degree. C. 5 ml of
hydrochloric acid (10 N) are added. When the addition is complete,
the mixture is heated under reflux (60.degree. C.) for 1 hour.
After returning to room temperature, the aqueous phase is extracted
with ether and then with dichloromethane. The organic phases are
washed with a saturated NaCl solution before being dried over
sodium sulphate. After evaporation under vacuum, the residue is
purified on a silica gel; eluent cyclohexane/ethyl acetate 20/1
(v/v); yield=92%.
[0144] .sup.1H NMR (DMSO): 1.10(t, 3H); 2.94(q, 2H); 7.84(s, 2H);
7.92(s, 1H).
[0145] Stage 2: At room temperature, 26 g of tetrabutylammonium
tribromide are added to 11.8 g of the product obtained above in
solution in 500 ml of dichloromethane. The mixture is then heated
for 3 hours at 35-40.degree. C. Again at room temperature, the
organic phase is washed with water and then with a saturated NaCl
solution before drying it over sodium sulphate. It is evaporated
under vacuum; yield=97%.
[0146] .sup.1H NMR (CDCl.sub.3): 0.89(d, 3H); 5.16(q, 1H); 7.61(m,
2H); 7.67(m, 1H).
[0147] Preparation III
2-Bromo-1-(2,4,6-trichlorophenyl)ethan-1-one (Compound 3-1)
[0148] At 0.degree. C., under argon, to a solution of 31.1 g of
1,3,5-trichlorobenzene, there are added 15.2 ml of bromoacetyl
bromide, followed by 23.3 g of aluminium chloride in small portions
(over 2 hours). The reaction mixture is then heated for 8 hours at
80.degree. C. After returning to room temperature, it is diluted
with dichloromethane and then hydrochloric acid (1 N) is added at
0.degree. C. The aqueous phase is extracted with dichloromethane,
the organic phases are combined, washed with water and then dried
over sodium sulphate. The evaporation residue is purified on
silica; yield=70%.
[0149] .sup.1H NMR (DMSO): 4.77(s, 2H); 7.85(s, 2H).
[0150] A variant of this process consists in using a
CH.sub.2Cl.sub.2 solvent and in operating at a temperature close to
10.degree. C. Starting with 1,3-dichloro-4-methylbenzene,
2-bromo-1-(2,4-dichloro-5-methylphenyl- )ethan-1-one (Compound 3-2)
is obtained.
[0151] 2-Bromo-1-(2-chloro-4,5-dimethylphenyl)ethan-1-one (Compound
3-3) is prepared in the same manner.
Preparation of the Amines
[0152] Preparation IV
6-Amino-7-methoxy-1,2,3,4-tetrahydronaphthalene (Compound 4-1)
[0153] Stage 1: 12.0 ml of 7-methoxy-1,2,3,4-tetrahydronaphthalene
are dissolved in 100 ml of acetic anhydride and then 3.6 ml of
fuming nitric acid, dissolved in 10 ml of acetic anhydride, are
added. The reaction mixture is stirred for one hour at room
temperature.
[0154] After ice has been added, the mixture is neutralized with 10
N sodium hydroxide and extracted with ethyl acetate. The resulting
solution is dried over sodium sulphate and then evaporated to
dryness. The residue obtained is purified by chromatography on a
silica gel column eluted with an ethyl acetate/hexane 10/90 (v/v)
mixture for the separation of the two isomers. 3.3 g of the
expected product are obtained in the form of yellow crystals.
[0155] Stage 2: 3.2 g of the product obtained above are dissolved
in 60 ml of acetic acid and 30 ml of concentrated hydrochloric acid
and then 10 g of SnCl.sub.2.H.sub.2O are added and the reaction
mixture is heated under reflux for 3 hours. It is evaporated and
then the residue obtained is taken up in a saturated sodium
carbonate solution and extracted with ethyl acetate. The resulting
solution is dried over sodium sulphate and then evaporated to
dryness. 2.65 g of the expected product are obtained in the form of
crystals; yield=9,7%.
[0156] .sup.1H NMR (CDCl.sub.3: 1.74-1.80(m, 4H,
--CH.sub.2--CH.sub.2--); 2.64-2.68(m, 4H,
--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2); 3.67(m, 2H, --NH.sub.2);
3.68 (s, 3H, --OCH.sub.3); 6.46(s, 1H, H.sub.1); 6.51(s, 1H,
H.sub.4).
[0157] Preparation V
N-Propyl-2,4-dichloroaniline (Compound 5-1)
[0158] Stage 1: To a solution of 9.2 g of 2,4-dichloroaniline in
100 ml of anhydrous methylene chloride, there are added, under
argon at 0.degree. C., 9.5 ml of triethylamine followed, dropwise,
by 5.9 ml of propionyl chloride. The temperature of the reaction
mixture is then allowed to rise to room temperature. The organic
phase is washed with water and then with a saturated NaCl solution,
it is dried over sodium sulphate and evaporated to dryness under
vacuum. After solubilization of the residue obtained in
dichloromethane with the use of heat, isopropyl ether is added.
[0159] 9.6 g of the desired product are obtained in the form of
white crystals; yield=80%; m.p.=121.degree. C.
[0160] Stage 2: 50 ml of a 1 M solution of lithium aluminium
hydride in tetrahydrofuran are added slowly and under argon to 9.6
g of the product previously obtained in solution in 80 ml of
tetrahydrofuran. The reaction mixture is heated under reflux for 2
hours. At 0.degree. C., the excess lithium aluminium hydride is
carefully destroyed by addition of water and then of sodium
hydroxide. After removing the precipitate, the organic solution is
evaporated to dryness under vacuum. The residue obtained is taken
up in diethyl ether and then extracted with a 1 N solution of
hydrochloric acid. The aqueous phase is adjusted to pH=12 and
extracted with dichloromethane. The organic phase is dried over
sodium sulphate and then evaporated off. 7.5 g of the expected
product are obtained in the form of an oil; yield=84%.
[0161] .sup.1H NMR (CDCl.sub.3): 0.99(t, 2H); 1.57(m, 2H); 3.01(t,
2H); 4.27(1H); 6.4-7.2(m, 3H).
[0162] By carrying out the procedure as indicated for PREPARATION V
above, and by using, as raw materials, the appropriate primary
amines, the following are prepared:
[0163] N-Propyl-2-chloroaniline (Compound 5-2)
[0164] N-Propyl-3-chloroaniline (Compound 5-3)
[0165] N-Propyl-2-methylaniline (Compound 5-4)
[0166] N-Propyl-2-methoxyaniline (Compound 5-5)
[0167] N-Propyl-2-trifluoromethoxyaniline (Compound 5-6)
[0168] N-Propyl-2,6-dichloroaniline (Compound 5-7)
[0169] N-Propyl-2,5-dichloroaniline (Compound 5-8)
[0170] N-Propyl-2-chloro-5-trifluoromethylaniline (Compound
5-9)
[0171] N-Propyl-2-chloro-5-methoxyaniline (Compound 5-10)
[0172] N-Propyl-5-chloro-2-methoxyaniline (Compound 5-11)
[0173] N-Propyl-5-chloro-2-ethoxyaniline (Compound 5-12)
[0174] N-Propyl-2,5-dimethylaniline (Compound 5-13)
[0175] N-Propyl-2-methoxy-5-methylaniline (Compound 5-14)
[0176] N-Propyl-2-methoxy-5-trifluoromethylaniline (Compound
5-15)
[0177] N-Propyl-2,5-dimethoxyaniline (Compound 5-16)
[0178] N-Propyl-2,4,6-trichloroaniline (Compound 5-17)
[0179] N-Propyl-2,6-dimethoxyaniline (Compound 5-18)
[0180] Preparation VI
N-Propyl-5-bromo-2-methoxyaniline (Compound 6-1)
[0181] Stage 1: by carrying out the procedure according to Simada
T. (Sci. Pap. Inst. Phys. Chem. Res. Jpn., Vol. 35, No. 884, pp
365-371, 1938), 5-bromo-2-methoxy-nitrobenzene is obtained from
4-bromo-2-nitrophenol.
[0182] .sup.1H NMR (CDCl.sub.3): 3.94(s, 3H); 7.06(d, 1H); 7.64(dd,
1H); 8.23(d, 1H).
[0183] Stage 2: the product obtained above is reduced in the
presence of iron and concentrated hydrochloric acid in an
ethanol-water mixture. The 5-bromo-2-methoxyaniline obtained
undergoes acylation followed by reduction as described in
PREPARATION V.
[0184] .sup.1H NMR (CDCl.sub.3): 1.00(t, 3H), 1.66(m, 2H); 3.05(t,
2H); 3.81(s, 3H); 4.25(m, 1H); 6.55-6.74(m, 3H).
[0185] Preparation VII
N-Propyl-2-methoxy-6-methylaniline (Compound 7-1)
[0186] Stage 1: Starting with 2-methoxy-6-methylaniline,
N-propionyl-2-methoxy-6-methylaniline is obtained by following the
procedure described above (PREPARATION V, Stage 1).
[0187] .sup.1H NMR (CDCl.sub.3): 1.29(t, 3H); 2.21(s, 3H); 2.48(q,
2H); 3.78(s, 3H); 6.70-6.83(m, 3H); 7.06-7.14(m, 1H).
[0188] Stage 2: at 0.degree. C., under argon, 11.9 g of sodium
borohydride (3.5 equivalents) are added to 180 ml of a 1 M solution
in dichloromethane of titanium tetrachloride (2 equivalents). The
solution of 19 g of N-propionyl-2-methoxy-6-methylaniline in 100 ml
of dimethoxyethane is added slowly to the reaction mixture so that
the temperature of the mixture is between 5 and 15.degree. C. When
the addition is complete, the mixture is heated to around
65.degree. C. At 0.degree. C., the mixture is then hydrolyzed very
slowly and then alkalinized with the aid of sodium hydroxide. The
aqueous phase is extracted with dichloromethane.
[0189] The organic phases are washed with water and then with a
saturated NaCl solution before being dried over sodium sulphate and
evaporated under vacuum; yield=58%.
[0190] .sup.1H NMR (CDCl.sub.3): 0.95(t, 3H); 1.57(m, 2H); 2.27(s,
3H); 3.00(t, 2H); 3.77(s, 3H); 6.65-6.80(m, 3H).
[0191] Preparation VIII
N-Propyl-2-methoxy-5-methoxycarbonylaniline (Compound 8-1)
[0192] 15 g of 2-methoxy-5-methoxycarbonylaniline are dissolved in
500 ml of propionic acid under argon and at room temperature and
15.7 g of sodium borohydride are added in small portions. The
reaction mixture is stirred for 2 hours and then hydrolyzed and
alkalinized with 10 N sodium hydroxide while the temperature is
maintained below 20.degree. C. It is extracted with
dichloromethane, the organic phase is washed with a saturated NaCl
solution, dried and then evaporated under vacuum. The expected
product is obtained in the form of an oil with a quantitative
yield.
[0193] By carrying out the procedure as described for PREPARATION
VIII above, and using the appropriate primary amine, the following
are prepared:
[0194] N-Propyl-2,5-ditrifluoromethylaniline (Compound 8-2)
[0195] N-Propyl-2-chloro-5-methylaniline (Compound 8-3)
[0196] N-Propyl-2-methoxy-5-phenylaniline (Compound 8-4)
[0197] N-Propyl-5-ethyl-2-methoxyaniline (Compound 8-5)
[0198] N-Propyl-5-chloro-2,4-dimethoxyaniline (Compound 8-6)
[0199] N-Propyl-4-chloro-2,5-dimethoxyaniline (Compound 8-7)
[0200] N-Propyl-2-chloro-5-methoxy-4-methoxycarbonylaniline
(Compound 8-8)
[0201] N-Propyl-2-thiomethyl-5-trifluoromethylaniline (Compound
8-9)
[0202] N-Propyl-2-methyl-5-methoxycarbonylaniline (Compound
8-10)
Preparation of the Thioureas
[0203] Preparation IX
N-(7-Methoxy-1,2,3,4-tetrahydronaphth-6-yl)thiourea (Compound
9-1)
[0204] 1.45 g of ammonium thiocyanate are dissolved in 30 ml of
acetone and after 2.2 ml of benzoyl chloride have been added, the
reaction mixture is heated under reflux for 15 minutes. 2.6 g of
6-amino-7-methoxy-1,2,3,4-tetrahydronaphthalene (Compound 4-1)
dissolved in 20 ml of acetone are added and then the mixture is
heated under reflux for 30 minutes. It is evaporated to dryness,
the residue obtained is taken up in a minimum of ethanol, 50 ml of
30% ammonium hydroxide are added and the mixture is heated under
reflux for 20 hours. The thiourea obtained is cooled, filtered,
washed with water and then with an ethyl acetate/hexane 25/75 (v/v)
mixture. 2.8 g of the expected product are obtained in the form of
a beige powder; yield=80%.
[0205] Preparation X
N-(2,4-Dichlorophenyl)-N-propylthiourea (Compound 10-1)
[0206] Stage 1: 5.1 ml of benzoyl chloride are added under argon
and at 0.degree. C. to 3.4 g of ammonium thiocyanate in 80 ml of
anhydrous acetone and the reaction mixture is stirred for 15
minutes. 7.48 g of N-propyl-2,4-dichloroaniline (Compound 5-1) in
60 ml of anhydrous acetone are added and the reaction mixture is
stirred for 2 hours at room temperature. It is evaporated to
dryness, the residue obtained is taken up in dichloromethane,
washed with water and dried. 13.5 g of the expected product are
obtained in the form of an oil; yield=82%.
[0207] Stage 2: 3.6 ml of hydrazine are added to 13.5 g of the
product previously obtained in solution in 150 ml of methanol. The
reaction mixture is left for 12 hours at room temperature. The
methanol is evaporated off, the residue obtained is taken up in
dichloromethane and then the mixture is washed with water and
evaporated to dryness. The residue is purified by chromatography on
a silica gel column eluted with an ethyl acetate/cyclohexane 1/3
(v/v) mixture. 6.9 g of the expected product are obtained in the
form of crystals; yield=71%; m.p.=121.degree. C.
[0208] By carrying out the procedure as indicated for Stage 1 of
PREPARATION X above, and by using N-propyl
-2-methoxy-5-methoxycarbonylan- iline (Compound 8-1),
N'-benzoyl-N-(2-methoxy-5-methoxycarbonylphenyl)-N-p- ropylthiourea
(Compound 10-2) is prepared.
[0209] Preparation XI
N-(5-Chloro-2-methylphenyl)thiourea (Compound 11-1)
[0210] Stage 1: 8.9 ml of benzoyl chloride are added to a solution
of 5.9 g of ammonium thiocyanate in 130 ml of anhydrous acetone.
The reaction mixture is heated under reflux for 15 minutes and then
after cooling, 10 g of 5-chloro-2-methylaniline are added. The
reaction mixture is heated under reflux for 2 hours and the acetone
is removed by distillation under vacuum. The residue obtained is
taken up in dichloromethane. The mixture is washed with water,
dried over sodium sulphate and evaporated under vacuum. The
expected product is obtained in the form of an oil with a
quantitative yield.
[0211] Stage 2: The product obtained above is heated at 90.degree.
C. for 16 hours in the presence of 300 ml of a 5% sodium hydroxide
solution. After cooling, the reaction mixture is adjusted to pH=7
by addition of a 1 N solution of hydrochloric acid. The product
precipitates and 10.53 g of the expected product are obtained in
the form of yellow crystals; yield=74%; m.p.=137.degree. C.
[0212] Preparation XII
N-(5-Carboxy-2-methoxyphenyl)-N-propylthiourea (Compound 12-1)
[0213] The expected product is obtained from
N'-benzoyl-N-(2-methoxy-5-met- hoxycarbonylphenyl)-N-propylthiourea
(Compound 10-2) by carrying out the procedure according to
PREPARATION X and by using an excess of sodium hydroxide to obtain,
in addition to the deprotection of the thiourea, the saponification
of the ester.
[0214] By carrying out the procedure according to PREPARATIONS I to
XII above, the intermediates allowing the synthesis of the
compounds (I) according to the invention are prepared using the
appropriate starting materials.
EXAMPLE 1
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(7-methoxy-1,2,3,4-tetrahydrona-
phth-6-yl)-N-propylamino]thiazole hydrochloride
(I) R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3
[0215] 15
[0216] Stage 1: 1.4 g of
2-bromo-1-(2-chloro-4-methoxyphenyl)-propan-1-one (Compound 1-2)
are dissolved in 50 ml of methanol and then 1.3 g of
N-(7-methoxy-1,2,3,4-tetrahydronaphth-6-yl)thiourea (Compound 9-1)
are added. The reaction mixture is heated under reflux for 12
hours, it is evaporated to dryness and then the residue obtained is
taken up in a saturated sodium carbonate solution. The resulting
solution is extracted with ethyl acetate, dried over sodium
sulphate and evaporated to dryness. The residue is purified by
chromatography on a silica gel column eluted with an ethyl
acetate/hexane 25/75 (v/v) mixture. The precipitate obtained is
taken up in petroleum ether and then filtered.
[0217] 1.3 g of the expected product are obtained in the form of a
white powder (yield=62%).
[0218] .sup.1H NMR (CDCl.sub.3): 1.78-1.82(m, 4H,
--CH.sub.2--CH.sub.2); 2.24(s, 3H, --CH.sub.3); 2.73-2.75(m, 4H,
--CH.sub.2--CH.sub.2--); 3.85(s, 3H, OCH.sub.3); 3.86(s, 3H,
--OCH.sub.3); 6.58(s, 1H, H.sub.4); 6.87(dd, J=2.5, J=8.4 1H,
H.sub.5); 7.02(d, J=2.5, 1H, H.sub.3); 7.35(d, J=8.7, 1H, H.sub.6),
7.46(s, 1H, H.sub.5); 7.46(s, 1H, H.sub.1); 7.47(s, 1H,
--NH--Y.
[0219] Stage 2: 1.0 g of the product previously obtained, dissolved
in 20 ml of anhydrous dimethylformamide, is added to a suspension
of 0.17 g of sodium hydride in 20 ml of dimethylformamide. 0.44 ml
of bromopropane is added and then the reaction mixture is stirred
at room temperature for one hour. 100 ml of a saturated ammonium
chloride solution are then added, the mixture extracted with ethyl
acetate and then the organic phase washed with a saturated NaCl
solution.
[0220] It is dried over sodium sulphate and evaporated to dryness.
The residue is purified by chromatography on a silica gel column
eluted with an ethyl acetate/hexane 10/90 (v/v) mixture. 0.89 g of
the expected product is isolated in the form of a colourless oil.
The hydrochloride is obtained by adding to the product, previously
dissolved in diethyl ether, petroleum ether followed by diethyl
ether saturated with gaseous hydrochloric acid until total
precipitation of the salt is obtained; m.p.=101.degree. C.
[0221] .sup.1H NMR (CDCl.sub.3): 0.85(t, J=7.3, 3H,
--CH.sub.2--CH.sub.3); 1.46-1.57(m, 2H, --CH.sub.2--CH.sub.3);
1.72(m, 4H, --CH.sub.2--CH.sub.2--); 1.99(s, 3H, --CH.sub.3);
2.65-2.77 (m, 4H, --CH.sub.2--CH.sub.2--); 3.73-3.83(m, with at
3.78(s, 3H, --OCH.sub.3) and at 3.83(s, 3H, --OCH.sub.3); 2H,
--N--CH.sub.2--CH.sub.2); 6.96(s, 1H, H.sub.1); 7.04(dd, J=2.5,
J=8.4, 1H, H.sub.5); 7.15(s, 1H, H); 7.20(d, J=2.5, H.sub.3);
7.43(d, J=8.4, 1H, H.sub.6).
EXAMPLE 2
4-(2,4-Dichlorophenyl)-5-methyl-2[N-(2,4-dichlorophenyl)-N-propylamino]thi-
azole
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.Cl; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3
[0222] 16
[0223] To 1.07 g of N-(2,4-dichlorophenyl)-N-propyl-thiourea
(Compound 10-1) in 6 ml of ethanol, there is added 1 ml of
triethylamine followed, dropwise, by 1.3 g of
2-bromo-1-(2,4-dichlorophenyl)propan-1-one (Compound 1-1). The
reaction mixture is heated for 3 hours at 78.degree. C., it is
evaporated to dryness and then the residue is taken up in
dichioromethane. The organic phase is washed with water, dried over
sodium sulphate and evaporated to dryness under vacuum.
[0224] The residue is purified by chromatography on a silica gel
column eluted with a cyclohexane/ethyl acetate 3/1 (v/v) mixture.
1.31 g of the expected product are obtained in the form of crystals
in pentane; yield=72%; m.p.=90.degree. C.
EXAMPLE 3
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2-methoxyphenyl)-N-p-
ropylamino]thiazole
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0225] 17
[0226] By following the procedure of EXAMPLE 2 and by using
2-bromo-1-(2-chloro-4-methoxyphenyl)propan-1-one (Compound 1-2) and
N-(2-methoxy-5-carboxyphenyl)-N-propylthiourea (Compound 12-1), the
expected product is obtained in the form of white crystals;
yield=70%; m.p.=109.degree. C.
EXAMPLE 4
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-ethoxy-carbonyl-2-methoxyphe-
nyl)-N-propylamino]thiazole hydrochloride
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0227] 18
[0228] 1 g of
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2-meth-
oxyphenyl)-N-propylamino]thiazole (EXAMPLE 3) is dissolved at room
temperature and under argon in 3 ml of dimethylformamide and then
0.66 g of Cs.sub.2CO.sub.3 and 0.5 ml of ethyl iodide are added.
The reaction mixture is stirred for one hour and then diluted with
ethyl acetate. It is washed with water, dried over sodium sulphate
and evaporated to dryness. The residue is purified by
chromatography on a silica gel column eluted with a
cyclohexane/ethyl acetate 5/1 (v/v) mixture. The expected product
is obtained in the form of a colourless oil.
[0229] It is taken up in dichloromethane and a 0.1 N solution of
hydrochloric acid in isopropanol is added. After filtration, the
expected product is obtained in the hydrochloride form;
m.p.=111.degree. C.
EXAMPLE 5
4-(2-Chloro-4-methoxyphenyl)-5-methyl)-2-[N-(2-methoxy-5-morpholinocarbony-
lphenyl)-N-propylamino]thiazole
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0230] 19
[0231] 1 g of
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2-meth-
oxyphenyl)-N-propylamino]thiazole (EXAMPLE 3) is added in solution
in 19 ml of dimethylformamide, and then 0.31 ml of triethylamine
and 0.32 ml of isobutylchloroformate are added at -10.degree. C.
and under argon. The reaction mixture is stirred for 10 minutes and
0.8 ml of morpholine is added. The mixture is kept stirring for 2
hours at room temperature. The reaction mixture is then diluted in
ethyl acetate, washed with water, dried over sodium sulphate and
then evaporated under vacuum. The residue is purified by
chromatography on a silica gel column eluted with a
cyclohexane/ethyl acetate 1/1 (v/v) mixture. The expected product
is obtained in the form of a powder; m.p.=62.degree. C.
EXAMPLE 6
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-acetyl-2-methoxyphenyl)-N-pr-
opylamino]thiazole
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0232] 20
[0233] At 0.degree. C., under an inert atmosphere, 2 g of
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2-methoxyphenyl)-N--
propylamino]thiazole are dissolved in 30 ml of diethyl ether.
Methyllithium (3 equivalents) is slowly added to the ethereal
solution. When the addition is complete, the reaction mixture is
brought to room temperature. After 2 hours, it is diluted with
ethyl acetate and then hydrolyzed. The organic phase is washed with
water and then dried over sodium sulphate. After evaporation, the
residue is purified on a silica gel. The expected product is
obtained in the form of a powder; m.p.=50.degree. C.
EXAMPLE 7
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-cyclopropylcarbonyl-2-methox-
yphenyl)-N-propylamino]thiazole
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0234] 21
[0235] Starting with lithium cyclopropane and using the process of
EXAMPLE 6, the expected product is obtained in the form of a
powder; m.p.=69.degree. C.
EXAMPLE 8
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-iso-butyryl-2-methoxyphenyl)-
-N-propylamino]thiazole
(I):R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0236] 22
[0237] Stage 1: under an inert atmosphere, 6.5 g of
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2-methoxyphenyl)-N--
propylamino]thiazole are dissolved in 130 ml of dimethylformamide.
The temperature of the mixture is brought to 0.degree. C., 7.5 ml
of triethylamine are added as well as 2.8 ml of isobutyl
chloroformate (1.5 equivalents). After 15 minutes, 2.84 g of
N-methoxy-N-methylamine (2 equivalents) are added. The reaction is
practically complete in 2 hours at room temperature.
[0238] The reaction mixture is then diluted with ethyl acetate.
After several washes with water and then with a saturated NaCl
solution, the organic phase is dried over sodium sulphate. After
evaporation, the product is purified on a silica gel; eluent
dichloromethane/ethyl acetate 95/5 (v/v); yield=72%.
[0239] .sup.1H NMR (CDCl.sub.3): 0.91(t, 3H); 1.59(m, 2H); 2.04(s,
3H); 3.37(s, 3H); 3.58(s, 3H); 3.81(s, 3H); 3.85(m, 2H); 3.88(s,
3H); 6.81-6.87(dd, 1H); 6.97-7.06(m, 2H); 7.33-7.38(d, 1H);
7.78-7.82(m, 2H).
[0240] Stage 2: the solution of 650 mg of product previously
obtained under an inert atmosphere in 2 ml of tetrahydrofuran is
slowly added and at 0.degree. C. over 1.4 ml of a solution (2 M) of
isopropylmagnesium chloride in tetrahydrofuran. After a reaction
time of 2 hours at room temperature, the reaction mixture is again
cooled before being acidified with 1 N hydrochloric acid. The
aqueous phase is extracted with diethyl ether. The organic phases
are then washed with a saturated sodium bicarbonate solution and
then with a saturated sodium chloride solution.
[0241] The residue is dried over sodium sulphate, the solvent
evaporated off before being purified on a silica gel; eluent
cyclohexane (3), ethyl acetate (1). The product is obtained in
hydrochloride form; m.p.=114.degree. C.
EXAMPLE 9
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-hydroxymethyl-2-methoxypheny-
l)-N-propylamino]thiazole.
(I):R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0242] 23
[0243] At 0.degree. C., under an inert atmosphere, 1.5 g of
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2-methoxyphenyl)-N--
propylamino]thiazole are dissolved in 11 ml of tetrahydrofuran. 5
ml of a 1 M solution of lithium aluminium hydride in
tetrahydrofuran are added slowly so that the temperature of the
mixture does not exceed 10.degree. C. After 2 hours at room
temperature, the reaction mixture is cooled with the aid of an ice
bath and then hydrolyzed slowly. The crude material is alkalanized
before being filtered over sodium sulphate. After evaporation under
vacuum, the product is obtained by purification on a silica gel;
eluent: dichloromethane/ethyl acetate 95/5 (v/v); yield=87%. The
expected product is in the form of a powder; m.p.=115.degree.
C.
EXAMPLE 10
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-methoxymethylpheny-
l)-N-propylamino]thiazole hydrochloride.
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0244] 24
[0245] At 0.degree. C., under an inert atmosphere, 320 mg of
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-hydroxymethyl-2-methoxyphen-
yl)-N-propylamino]thiazole are dissolved in 0.7 ml of
dimethylformamide. 70 mg of sodium hydride (50% in oil) are added.
After 5 minutes, 0.24 ml of methyl iodide is added. After 12 hours
at room temperature, the reaction mixture is diluted with ethyl
acetate and then hydrolyzed. The organic phase is washed several
times with water before being dried over sodium sulphate. After
purification on a silica gel; the expected product is dissolved in
dichloromethane. A 0.1 N solution of hydrochloric acid in
isopropanol is then added. After evaporation under vacuum, the
expected product is obtained in hydrochloride form; m.p.=71.degree.
C.
EXAMPLE 11
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro-2-methylphenyl)-N-pro-
pylamino]thiazole hydrochloride.
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0246] 25
[0247] Stage 1: 5 g of
2-bromo-1-(2-chloro-4-methoxyphenyl)-propan-1-one (Compound 1-2)
and 4.2 ml of triethylamine in 25 ml of ethanol are added to 3 g of
N-(5-chloro-2-methylphenyl)thiourea (Compound 11-1) in 25 ml of
ethanol. The reaction mixture is heated under reflux for 2 hours
and reduced under vacuum. The residue thus obtained is taken up in
dichloromethane. The resulting solution is washed with water, dried
over sodium sulphate and evaporated off. 5.09 g of the expected
crude product are obtained.
[0248] .sup.1H NMR (CDCl.sub.3): 2.14(s, 3H); 2.23(s, 3H); 3.80(s,
3H); 6.80-7.34(m, 6H); 9.02(m, 1H).
[0249] Stage 2: 5.09 g of the crude product previously obtained are
dissolved in 70 ml of anhydrous dimethylformamide and 1.08 g of
sodium hydride are added under argon. After stirring for 15
minutes, 4.4 g of propyl iodide are added and the reaction mixture
is heated at 75.degree. C. for 2 hours. It is evaporated, the
residue obtained hydrolyzed and the aqueous phase extracted with
ethyl acetate. The organic phase is washed with a saturated NaCl
solution, dried over sodium sulphate and evaporated under vacuum.
The residue is purified by chromatography on a silica gel column,
eluted with a cyclohexane/ethyl acetate 20/1 (v/v) mixture.
[0250] The product obtained is taken up in dichloromethane and a
0.1 N solution of hydrochloric acid in isopropanol is added so as
to obtain the hydrochloride; m.p.=69.degree. C.
EXAMPLE 12
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(3,5-dimethylphenyl)-N-propylam-
ino]thiazole
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0251] 26
[0252] By carrying out the procedure according to EXAMPLE 11,
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(3,5-dimethylphenyl)-N-propyla-
mino]thiazole is obtained, with the same reagents but at room
temperature as regards the reaction temperature after introducing
propyl iodide.
[0253] The product obtained is in the form of a powder;
m.p.=40.degree. C.
EXAMPLE 13
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-o-tolylphenyl)-N-p-
ropylamino]thiazole.
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0254] 27
[0255] 1.96 g of barium hydroxide, 0.52 g of o-tolylboronic acid
and 40 mg of palladium diacetate are added in succession to 1 g of
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-bromo-2-methoxyphenyl)-N-pr-
opylamino]-thiazole, in solution in 25 ml of ethanol and 0.8 ml of
water. The reaction mixture is heated for 1 hour under reflux;
after returning to room temperature, it is filtered on Celite.
After evaporation of the solvent, the residue is taken up in
dichloromethane. The organic phase is washed with water and then
dried over sodium sulphate. The evaporation residue is purified on
silica gel; eluent dichloromethane/cyclohexane 9/1 (v/v). The
expected product is obtained in the form of a powder;
m.p.=55.degree. C.
EXAMPLE 14
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-nitrophenyl)-N-pro-
pylamino]thiazole
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0256] 28
[0257] By carrying out the procedure according to EXAMPLE 12 and by
using 2-bromo-1-(2-chloro-4-methoxyphenyl)propan-1-one (Compound
1-2) and N-(2-methoxy-5-nitrophenyl)-N-propylthiourea, the expected
product is obtained in the form of a powder; m.p.=97.degree. C.
EXAMPLE 15
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-amino-2-methoxyphenyl)-N-pro-
pylamino]thiazole.
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0258] 29
[0259] 13.5 g of
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(2-methoxy-5-n-
itrophenyl)-N-propylamino]-thiazole are dissolved in 120 ml of
methanol and then 5.3 g of iron powder and 18.5 ml of concentrated
hydrochloric acid are added. The mixture is heated under reflux for
half an hour. The methanol is evaporated under vacuum, the residue
is taken up in dichloromethane before being filtered on Celite. The
product is extracted with 1 N hydrochloric acid. The acidic phase
is then neutralized with sodium hydroxide before being extracted
with dichloromethane. After evaporation of the dichloromethane, the
crude reaction product is purified on silica gel; eluent
dichloromethane/methanol 95/5 (v/v).
[0260] The expected product is solid; m.p.=89.degree. C.
EXAMPLE 16
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-acetamido-2-methoxyphenyl1)--
N-propylamino]thiazole
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0261] 30
[0262] At 0.degree. C., under an inert atmosphere, 1 g of
4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-amino-2-methoxyphenyl)-N-pr-
opylamino]thiazole is dissolved in 3.5 ml of dichloromethane. 0.4
ml of triethylamine is added followed by 0.14 ml of acetyl bromide.
After 1 hour at room temperature, the reaction mixture is diluted
with dichloromethane. The organic phase is washed with water and
then dried over sodium sulphate. The evaporation residue is
purified on silica gel; eluent cyclohexane/ethyl acetate 1/1.
[0263] The product solidifies in pentane; yield=71%;
m.p.=171.degree. C.
EXAMPLE 17
4-(2,4,6-Trichlorophenyl)-5-methyl-2-[N-(2,5-ditrifluoromethylphenyl)-N-pr-
opylamino]thiazole
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.Cl; R.sub.3.dbd.Cl;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2CH.sub.2CH.sub.3;
[0264] 31
[0265] Stage 1: by carrying out the procedure according to EXAMPLE
2, using 2-bromo-1-(2,4,6-trichlorophenyl)-ethan-1-one (Compound
3-1) and N-(2,5-ditrifluoromethylphenyl)-N-propylthiourea,
4-(2,4,6-trichloropheny-
l)-2-[N-(2,5-ditrifluoromethylphenyl)-N-propylamino]thiazole is
obtained; yield=33%.
[0266] .sup.1H NMR (CDCl.sub.3): 0.87(t, 3H, J=3.8); 1.77(sext.,
2H, J=3.8, J=7.8); 3.88(m, 2H); 6.51(s, 1H); 7.36(s, 2H).
[0267] Stage 2: the product previously obtained is dissolved in 50
ml of dichloromethane. 0.3 ml of triethylamine is added followed by
0.11 ml of bromine. The mixture is stirred for 8 hours and a
solution of sodium thiosulphate is added. The aqueous phase is
extracted with dichloromethane. The organic phases are combined,
washed with water and dried over sodium sulphate. The evaporation
residue is purified on silica; eluent dichloromethane/cyclohexane
1/2.
[0268] .sup.1H NMR (CDCl.sub.3) 0.92(t, 3H, J=3.7); 1.73(sext., 2H,
J=3.7, J=7.7); 3.71(m, 2H); 7.38(s, 2H); 7.72(s, 1H); 7.80(d, 1H,
J=4.2); 7.96(d, 1H, J=4.2).
[0269] Stage 3: the product derived from Stage 2 (1.05 g) is
dissolved in 40 ml of tetrahydrofuran. At -70.degree. C., under an
inert atmosphere, 1.6 ml of butyllithium (1.6 M in hexane) are
added. After 20 minutes, 0.7 ml of methyl iodide (6 equivalents) is
added. The mixture, after gradually returning to room temperature,
is stirred for 3 hours. The mixture is then hydrolyzed at low
temperature. The aqueous phase is extracted with dichloromethane,
the organic phases are combined and dried over sodium sulphate. The
evaporation residue is purified on silica gel; eluent
dichloromethane/cyclohexane 1/2. The product is obtained in the
form of a powder; m.p.=88.degree. C.
[0270] By carrying out the procedure according to EXAMPLES 1 to 17
above, EXAMPLES 18 to 75, described in TABLE I below, are prepared
in the same manner:
1TABLE I 32 Example m.p.; .degree. C. number R.sub.1 R.sub.2
R.sub.3 R.sub.4 Route salt 18 Cl OCH.sub.3 H 33 B 58 HCl 19 Cl
OCH.sub.3 H 34 B 69 HCl 20 Cl OCH.sub.3 H 35 B 83 base 21 Cl
OCH.sub.3 H 36 A 172 HCl 22 Cl OCH.sub.3 H 37 B 85 base 23 Cl
OCH.sub.3 H 38 B 45 base 24 Cl OCH.sub.3 H 39 B 105 HCl 25 Cl
OCH.sub.3 H 40 B 98 base 26 Cl OCH.sub.3 H 41 B 68 HCl 27 Cl
OCH.sub.3 H 42 B 170 HCl 28 Cl OCH.sub.3 H 43 B 60 HCl 29 Cl
OCH.sub.3 H 44 B 172 HCl 30 Cl OCH.sub.3 H 45 B 65 HCl 31 Cl
OCH.sub.3 H 46 B 109 HCl 32 Cl OCH.sub.3 H 47 A 90 HCl 33 Cl
OCH.sub.3 H 48 B 47 sulphonate 34 Cl OCH.sub.3 H 49 B NMR.sup.(1)
oil 35 Cl OCH.sub.3 H 50 B NMR.sup.(2) oil 36 Cl OCH.sub.3 H 51 B
94 HCl 37 Cl OCH.sub.3 H 52 A 98 HCl 38 Cl OCH.sub.3 H 53 B 68 HCl
39 Cl OCH.sub.3 H 54 B 82 HCl 40 Cl OCH.sub.3 H 55 B 60 base 41 Cl
Cl H 56 B 85 base 42 Cl OCH.sub.3 H 57 A 91 HCl 43 Cl OCH.sub.3 H
58 B 71 base 44 Cl OCH.sub.3 H 59 B 120 base 45 Cl OCH.sub.3 H 60 B
203 HCl 46 Cl OCH.sub.3 H 61 B 109 HCl 47 Cl OCH.sub.3 H 62 B 61
base 48 Cl OCH.sub.3 H 63 B 71 base 49 Cl OCH.sub.3 H 64 B 85 base
50 Cl OCH.sub.3 H 65 B 180 base 51 Cl OCH.sub.3 H 66 B 78 HCl 52 Cl
OCH.sub.3 H 67 B 62 HCl 53 Cl OCH.sub.3 H 68 A 96 HCl 54 Cl
OCH.sub.3 H 69 A 180 HCl 55 Cl OCH.sub.3 H 70 B 80 HCl 56 Cl
OCH.sub.3 H 71 A 80 base 57 Cl OCH.sub.3 H 72 B 65 HCl 58 Cl
OCH.sub.3 H 73 B 53 base 59 Cl Cl H 74 B .sup.1H NMR.sup.(3) oil 60
Cl OCH.sub.3 H 75 A 158 HCl 61 Cl Cl H 76 A 77 base 62 Cl Cl H 77 B
79 base 63 Cl Cl H 78 A 59 HCl 64 CF.sub.3 Cl H 79 A .sup.1H
NMR.sup.(4) oil 65 Cl OCH.sub.3 H 80 A 56 HCl 66 Cl Cl 5-Cl 81 A
101 HCl 67 Cl Cl 5-Cl 82 A 96 HCl 68 Cl OCH.sub.3 5-CH.sub.3 83 B
104 base 69 Cl OCH.sub.3 H 84 B 69 HCl 70 Cl Cl 5-CH.sub.3 85 B 76
HCl 71 Cl CH.sub.3 5-CH.sub.3 86 B 79 HCl 72 Cl Cl H 87 B 166 HCl
73 Cl OCH.sub.3 H 88 B 77 HCl 74 Cl OCH.sub.3 H 89 A 96 HCl 75 Cl
Cl 5-Cl 90 A 82 HCl .sup.(1)H MNR(CDCl.sub.3): 0.89(t, 3H); 1.59(m,
2H); 2.09(s, 3H); 2.30(s, 3H); 3.80(m, 8H); 6.79-7.37(m, 6H);
.sup.(2)H MNR(CDCl.sub.3): 0.90(t, 3H); 1.77(m, 2H); 2.09(s, 3H);
3.79(m, 5H); 6.79-7.94(m, 6H); .sup.(2)H MNR(CDCl.sub.3): 0.91(t,
3H); 1.75(m, 2H); 2.09(s, 3H); 3.73(m, 2H); 7.22-7.35(m, 2H);
7.44(d, 1H); 7.67-7.74(m, 2H); 7.90-7.95(m, 1H) .sup.(2)H
MNR(CDCl.sub.3): 0.92(t, 3H); 1.66(m, 2H); 2.08(s, 3H); 2.25(s,
3H); 3.75(m, 2H); 7.25-7.28(m, 3H); 7.55(m, 2H); 7.70(m, 1H).
EXAMPLE 76
4-(2-Chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-chloro-2-methylphenyl)-N-pro-
p-2-ynylamino]thiazole hydrobromide
(I): R.sub.1.dbd.Cl; R.sub.2.dbd.OCH.sub.3; R.sub.3.dbd.H;
R.sub.4.dbd.CH.sub.3; R.sub.5.dbd.--CH.sub.2--C.ident.CH
[0271] 91
[0272] Stage 1: By carrying out the procedure according to EXAMPLE
11 but using 2-propynyl iodide in Stage 2,
4-(2-chloro-4-methoxyphenyl)-5-methyl-
-2-[N-(5-chloro-2-methylphenyl)amino]thiazole is obtained.
[0273] Stage 2: At 0.degree. C., under argon, 1.3 g of the product
obtained in Stage 1 are dissolved in 10 ml of dimethylformamide.
0.2 g of sodium hydride (50% in oil) is added. After a quarter of
an hour, 0.8 ml of an 80% solution of propargyl bromide in toluene
is added slowly. The reaction mixture is stirred. The reaction
mixture is diluted with ethyl acetate and it is hydrolyzed.
[0274] The organic phase is washed 3 times with water and then
dried over sodium sulphate. After evaporation, the product is
purified on a silica gel; eluent cyclohexane, dichloromethane/ethyl
acetate 80/20 (v/v) mixture. The hydrobromide is obtained by adding
the product previously obtained, in solution in dichloromethane, to
a 0.2 M solution of hydrobromic acid in isopropanol. After
evaporation, a white powder is obtained; m.p.=101.degree. C.
* * * * *