AU2002361313B8 - 2-amino-thiazoline derivatives and their use as inhibitors of inducible no-synthase - Google Patents
2-amino-thiazoline derivatives and their use as inhibitors of inducible no-synthase Download PDFInfo
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- AU2002361313B8 AU2002361313B8 AU2002361313A AU2002361313A AU2002361313B8 AU 2002361313 B8 AU2002361313 B8 AU 2002361313B8 AU 2002361313 A AU2002361313 A AU 2002361313A AU 2002361313 A AU2002361313 A AU 2002361313A AU 2002361313 B8 AU2002361313 B8 AU 2002361313B8
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- 229940093471 ethyl oleate Drugs 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
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- SMWNFFKPVLVOQQ-UHFFFAOYSA-N methyl 2-acetamidoprop-2-enoate Chemical compound COC(=O)C(=C)NC(C)=O SMWNFFKPVLVOQQ-UHFFFAOYSA-N 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/18—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
USE OF 2-AMINO-THIAZOLINE DERIVATIVES AS INHIBITORS OF INDUCIBLE NO-SYNTHASE The present invention relates to the use of 2-amino-thiazoline derivatives of formula x~y S X
NH
2 (i) or pharmaceutically acceptable salts thereof as inhibitors of inducible NO-synthase.
The subject of the invention is the use of 2-amino-thiazoline derivatives of formula and pharmaceutically acceptable salts thereof for the preparation of pharmaceutical compositions intended for preventing and treating diseases in which an abnormal production of nitric oxide (NO) by induction of inducible NO-synthase (NOS-2 ou iNOS) is involved, the pharmaceutical compositions containing the novel 2-amino-thiazoline derivatives and pharmaceutically acceptable salts thereof and the novel derivatives of 2-amino-thiazoline and pharmaceutically acceptable salts thereof.
Nitric oxide (NO) is a diffusable radical involved in many physiological and pathological processes. It is synthesized by oxidation of L-Arginine, a reaction catalyzed by a family of enzymes known as nitric oxide synthases or NO-Synthase (NOS), referenced in the international enzyme nomenclature under the number E.C.
1.14.13.39.
Three NOS isoforms, two of which are constitutive and one inducible, are known: a neuronal NOS (NOS-1 or nNOS) was originally isolated and cloned from nerve tissue in which it is a constitutive enzyme. The 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.
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 cells. This isoform activity is not regulated by calcium. Consequently, once induced, it produces a large amount of NO over prolonged periods.
an endothelial NOS (NOS-3 or eNOS) is constitutive and calcium/calmodulin dependent. It was originally identified in vascular endothelium cells, in which it generates NO in response to physiological stimuli such as theactivation of membrane receptors.
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 blood vessels induce the relaxation of the underlying smooth muscular cells via the production de NO. It thus contributes towards regulating the arterial pressure.
The NO produced in large amount by the inducible isoform NOS-2 is, inter alia, involved in the pathological phenomena associated with acute and chronic inflammatory processes in a large variety of tissues and organs.
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, focal or global cerebral ischemia, cerebral or spinal trauma, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, migraine, depression, schizophrenia, anxiety, epilepsy. Similarly, aside the central nervous system, the induction of NOS-2 is involved in many pathologies with inflammatory components such as, for example, diabetes, atherosclerosis, myocarditis, arthritis, arthrosis, asthma, inflammatory bowel disease, Crohn's disease, peritonitis, gastroesophageal reflux, uveitis, Guillain-Barr6 syndrome, glomerulo-nephritis, lupus erythematosus and psoriasis. The NOS-2 was also involved in the growth of certain forms of tumors such as, for example, epitheliomas, adenocarcinomas or sarcomas, and in infections with Gram-positive or Gramnegative intracellular or extracellular bacteria.
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 the NOS-2. However, given the important physiological roles played by the constitutive isoform NOS-3, in particular in regulating the arterial pressure, it is essential that the inhibition of the isoform NOS-2 has the least possible effect on the isoform NOS-3. Actually, it is known that the administration of unselective inhibitors of NOS isoforms leads to vasoconstriction and an increase in arterial pressure (Moncada, Palmer, R.M.J. and Higgs, Biosynthesis of nitric oxide from L-arginine: a pathway for the regulation of cell function and communication, Biochem. Pharmacol., 1989, 38: 1709-1715). These effects on the cardiovascular system are deleterious since they reduce the supply of nutrients to the tissues.
Consequently, the present invention relates to compounds whose inhibitory activity with respect to NOS-2 is significantly higher than their inhibitory activity with.
respect to NOS-3.
j Thiazoline-based NOS inhibitors are described in particular in patent applications W094/12165, W095/11231 and W096/14842.
The present invention relates to the use of 2-amino-thiazoline derivatives of formula in which: either Y is a methylene (CH 2 and X is chosen from the following groups: O, NH,
(C
1
-C
4 N-Alkyl, N-Bn, N-Ph, N-2-pyrimidyl, pyrimidyl, S, SO, SO 2
CH
2 or CHPh; or Y is a carboxy and X is chosen from the following groups NH, N-Ph, N-2-pyrimidyl, N-5-pyrimidyl for the preparation of medicinal products 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.
In a first embodiment of the invention there is provided a compound of formula (I)
YS
X T NH 2
(I)
wherein either Y is a methylene (CH 2 and X is chosen from the following groups O, NH, N-Alkyl(C1-C4), N-Bn, N-Ph, N(2-Py), N-2-pyrimidyl, pyrimidyl, S, SO, SO2, CH 2 or CHPh or Y is a carboxy and X is chosen from the following groups NH, N-Ph, N- N-2-pyrimidyle or wherein the (C1-C4) alkyl radicals contain 1 to 4 carbon atoms in straight or branched chain wherein abbreviations Bn, Py, Ph mean respectively benzyl, pyridyl, phenyl; the racemics, enantiomers, diastereoisomers thereof and mixtures thereof, tautomer thereof and pharmaceutically acceptable salts thereof.
In the above definitions and in those which follow, the alkyl radicals contain 1 to 4 carbon atoms in a straight or branched chain. The abbreviations Bn, Py, Ph mean respectively benzyl, pyridyl, phenyl.
The compounds of formula contain one or more asymmetric carbons and can thus be in racemic form or in the form of enantiomers and diastereoisomers; these also form a part of the invention as well as the mixtures thereof.
Moreover, the compounds of formula can be in the tautomeric form (la): N N
H
H (la) These tautomers also form a part of the invention.
Among the compounds of formula useful according to the invention, mention may be made of the following compounds: 4-(morpholin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, 4-(piperazin-1-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, and 4-(4-methyl-piperazin-1 -ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine, the racemic mixtures, enantiomers, diastereoisomers, tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
Among the compounds useful according to the invention and particularly preferred, mention may be made of the following compound: 4-(4-methyl-piperazin-l-ylmethyl)-4,5-dihydro-l,3-thiazol-2-ylamine, the racemic mixtures, enantiomers, tautomers thereof, as well as the pharmaceutically acceptable salts thereof.
The invention also relates to the pharmaceutical compositions containing, as active principle, a derivative of formula for which either Y is a methylene (CH 2 and X is chosen from the following groups: O, NH, (CI-C 4 N-Alkyl, N-Bn, N-Ph, N-(2-Py), N-2-pyrimidyl, N-5-pyrimidyl, S, SO, SO2, CH 2 or CHPh; or Y is a carbonyl and X is chosen from the following groups NH, N-Ph, N-2-pyrimidyl, N-5-pyrimidyl as well as the racemic mixtures, enantiomers, diastereoisomers, tautomer thereof, and pharmaceutically acceptable salts thereof.
The compounds of formula can be prepared by cyclization of a derivative of formula (II): X Y
(OH
/N H-CS-NH-C(CH 3 3
(II)
in which X and Y have the same meaning as in formula This cyclization is generally carried out using an acid such as hydrochloric acid, in aqueous medium, at a temperature of about 1000 C. 6N hydrochloric is generally used.
The derivatives of formula (II) can be obtained according to the following reaction schemes:
H
2 ,C NHRa x Y x I H2C= H2C ,cNH COORb
H
2
H
2
X-C
HC Y a C-N NHRa
H
2 S 2 C-CH H2 COORb
H
2 -C2 X CY
NH
2 C I I I
H
2 C N. CC..
OH
C C H C
H
2
H
2
H
2 d H2 X 'Y NHCSNHC(CH 3 3 I I I H2C ,N C C ,OH C CHC
H
2
H
2
H
2
(II)
H
2 X "CY NHRa I I I
H
2 CN .N,N OH C C H H
H
2
H
2
H
2 in these formulae X and Y have the same meanings as in formula Ra is a protecting group of the amine function such as those described by T.W. GREENE, Protective groups in Organic Synthesis, J. Wiley-Interscience Publication (1991), preferably an acetyl or tert-butyloxycarbonyl radical, and Rb is a (Ci-C 4 alkyl or alkoxycarbonyl radical, preferably methyl, ethyl or isobutyloxycarbonyl.
The reaction a is generally carried out in the presence of a Lewis acid such as the iron trichloride (III), in an inert solvent such as dichloromethane or acetonitrile, at a temperature of between 100 C and the boiling point of the reaction medium. When X represents NH, X can be protected by a protecting group of the amine function such as described by T.W. GREENE, Protective Groups in Organic Synthesis, J. Wiley- Interscience Publication (1991), preferably using a tert-butoxycarbonyl radical.
The reduction reaction b is preferably carried out in using hydride such as sodium borohydride or lithium aluminum hydride in a (Ci-C 4 aliphatic alcohol or tetrahydrofuran, at a temperature of between 00 C and 30° C.
The deprotection reaction c for the compounds in which Ra is a protecting group of 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 about 1000 C. When the protecting group is a tert-butoxycarbonyl radical, this reaction is carried out using hydrochloric acid in dioxane, at a temperature of about 200 C.
The reaction d is carried out by the action of tert-butyl isothiocyanate, in an inert solvent such as a (Ci-C 4 aliphatic alcohol (preferably methanol or ethanol), optionally in the presence of a tertiairy amine such as triethylamine, at a temperature between 200 C and the boiling point of the reaction medium.
The compounds of formula in which X represents either SO, or SO2 can be obtained by direct oxidation of the compound of formula in which X represents S.
This oxidation is carried out according to the known methods of oxidation of organosufur compounds, such as described by M. HUDLICKY, Oxidation in Organic Chemistry, ACS Monograph, 186, 252-263 (1990). For example, it is carried out by the action of af organic peracid or organic peracid salt (percarboxylic or persulfonic acid, in particular perbenzoic acid, 3-chloro-perbenzoic acid, 4-nitroperbenzoic acid, peracetic acid, pertrifluoroacetic acid, performic acid, monoperphthalic acid) or a mineral peracid or mineral peracide salt (for example, periodic or persulfuric acid), in an inert solvent such as a chlorine solvent for example, trichlorethane or dichloromethane), at a temperature of between 0° C and 200 C. The hydrogen peroxide or periodate (sodium periodate, for example), in an inert solvent such as (Ci-
C
4 aliphatic alcohol, water or a mixture of these solvents, at a temperature between 0° and 200 C can also be used. These products can also be prepared from the corresponding compounds of formula obtained according to the following reaction schemes:
H
2
S--C
H
2 C CH 2 C-N NHRa
H
2 2 C-CH
H
2 H2
C-OH
H
2
H
2
X-C
HC CH, a C-N NHRa
H
2 2
C-CH
H2
C-OH
H
2 X= S=O, SO2 b
H
2 X CH2 NHCSNHC(CH 3 3
H
2 Cc C--c OH CH H C
H
2 H2 H2 X= S=O, SO 2 X 'CH 2
NH
2
H
2 N OH H C CH C
H
2
H
2
H
2 X= S=O, SO2 The oxidation reaction a is carried out according to the known methods of oxidation of organosulfur compounds as described above.
The deprotection reaction b for the compounds in which Ra is a protecting group of the amine function is carried out by any method of deprotection known by those skilled in the art and particularly 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 about 1000 C. When the protecting group is a tert-butyloxycarbonyl radical, this reaction is carried out using an hydrochloric acid in dioxane, at a temperature of about 200 C.
The reaction c is carried out by the action of tert-butyl isothiocyanate, in an inert solvent such as a (Ci-C 4 aliphatic alcohol (preferably methanol or ethanol), optionally in the presence of a tertiary amine such as triethylamine, at a temperature of between 200 C and the boiling point of the reaction medium.
The compounds of formula are isolated and can be purified by the usual known methods, for example crystallization, chromatography or extraction.
The enantiomers of the compounds of formula 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, chromatography or from chiral precursors).
The compounds of formula can optionally be converted in addition salts with a mineral or organic acid by the 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 a part of the invention.
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-o-oxynaphtoate, nitrate, oxalate, pamoate, phosphate, salicylate, succinate, sulfate, tartrate, theophyllinacetate and p-toluenesulfonate.
The compounds of formula are inhibitors of NO-synthase inducible or NOsynthase of type 2 (NOS-2) and are thus useful for preventing and treating disorders associated with an excessive NO production such as mutiple sclerosis, focal or global cerebral 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, inflammatory bowel disease, Crohn's disease, peritonitis, gastroesophageal reflux, uveitis, Guillain-Barr6 syndrome, glomerulo-nephritis, lupus erythematosus and psoriasis, the growth of certain forms of tumors such as for example epitheliomas, adenocarcinomas or sarcomas, and in infections with Grampositive or Gram-negative intracellular or extracellular bacteria.
Their activities as inhibitors of NOS-2 and NOS-3 were determined by measuring the conversion of 3 H]-L-arginine into 3 H]-L-citrulline with, respectively, a NOS-2 enzymatic fraction extracted from the lungs of rats or mices pretreated with lipopolysaccharides (10 mg/kg i.p. 6 hours before collecting the tissue) and with a commercial preparation of recombinant bovine NOS-3. The compounds were incubated for 20 to 30 minutes at 370 C in the presence of 5 pM (for NOS-2 activity) or 10 pM (for NOS-3 activity) of 3 H]-L-arginine, 1 mM of NADPH, 15 jM of tetrabiopterine, 1 M of FAD, 0.1 mM of DTT in a HEPES buffer (50 mM, pH 6.7) containing 10 tg/ml of calmodulin and 1.25 mM of CaC12 when the NOS-3 activity was measured. The incubation was stopped by adding cold HEPES buffer (100 mM, pH 5.5) containing 10 mM EGTA and 500 mg of cationic ion-exchange resin (AG50W-X8, counter-ion Na to separate the 3 H]-L-arginine from the 3
H]-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 formed
L-[
3 H]citrulline was able to be estimated using L-[ureido- 4 C]-citrulline as external standard.
The NOS-2 or NOS-3 activity was expressed in picomole(s) of 3 H]-L-citrulline formed per minute and per milligram of protein contained in the rection medium.
In this test on the enzyme NOS-2, the IC 50 value for the compounds of formula is less than or equal to 10 /M.
The selectivity is measured by the IC 5 o NOS-3 IC5o NOS-2 ratio. This selectivity is greater than The compounds of formula are of low toxicity. Their LD 5 o is greater than mg/kg via cutaneous route in mice.
The following examples illustrate the invention.
Example 1: 4-(4-Methyl-piperazin-1 -vlmethvl)-4,5-dihvdro-thiazol-2-ylamine trichlorhydrate 11 S
NH
2 N N ,3HCI A suspension of 0.42 g de N-(tert-butyl)-N'-[2-hydroxy-l-(4-methylpiperazin-l-ylmethyl)ethyl]-thiourea in 3.9 mL of an aqueous 6N hydrochloric acid is heated at a temperature of about 1000 C for 5 hours. After cooling, the reaction medium is then concentrated under reduced pressure (2 kPa) at a temperature of about 550 C. The residue obtained is dried in an oven under vacuum (2 kPa) for 4 hours.
About 0.47 g of 4-(4-methyl-piperazin-l-ylmethyl)-4,5-dihydro-thiazol-2-ylamine, trihydrochloride are obtained in the form of a very hygroscopic off-white paste. [1H NMR spectrum (300 MHz, (CD 3 2 SO d6 with addition of a few drops of CD 3
COOD
d4. 8 in ppm): from 2.55 to 2.90 (mf, 4H); 2.80 3H); from 2.95 to 3.30 (mf, 4H); from 3.30 to 3.60 (mf, 2H); 3.40 (dd, J 11.5 and 5.5 Hz, 1H); 3.69 (dd, J 11.5 and Hz, 1H); 4.51 (mt, 1H)].
N-(tert-Butvl)-N'-r2-hvdroxv- 1 -(4-methyl-piperazin- -vlmethvl)ethvl]-thiourea
OH
To a solution of 1 g of 2-amino-3-(4-methyl-piperazinl-yl)-l-propanol hydrochloride in 20 mL of anhydre ethanol and 1.43 mL of triethylamine, about 0.78 mL of tertbutylisothiocyanate are added. The reaction mixture is stirred under inert atmosphere at a temperature of about 200 C for 42 hours then is heated at a temperature of about C for 1 hour 30 min. After cooling at a temperature of about 200 C, the reaction medium is evaporated under reduced pressure (2 kPa) at a temperature of about 300 C. The evaporating residue is taken up in 10 mL of water and 40 mL of dichloromethane. The aqueous phase is extracted with 2 times 30 mL of dichloromethane. The organic phases are collected, washed with 15 mL of water, dried over magnesium sulfate, filtered, then concentrated under reduced pressure (2 kPa) at a temperature of about 200 C. About 0.42 g of N-(tert-butyl)-N'-[2-hydroxy- 1-(4-methyl-piperazin-l-ylmethyl)ethyl]thiourea are obtained in the form of a white paste. [Infrared spectrum between lamella of KBr 3279; 3075; 2939; 2806; 1533; 1459; 1359; 1295; 1204; 1010 and 821 cm'].
2-Amino-3-(4-methvl-piperazin-1 -vl)-1-propanol chlorhydrate
OH
N NH 2
HCI
A suspension of 0.89 g of N-[2-hydroxy-l-(4-methyl-piperazin-1-ylmethyl)ethyl] acetamide in 10.3 mL of an aqueous acid solution of 6N hydrochloric acid is heated at a temperature of about 1000 C for 3 hours. After cooling at a temperature of about 600 C, the reaction medium is filtered and the filtrate is concentrated under reduced pressure (2 kPa) at a temperature of about 600 C. About 1 g of 2-amino-3-(4-methylpiperazinyl)-l-propanol, hydrochloride is obtained in the form of a tacky beigecolored paste. [Infrared spectrum (KBr) 3337; 2955; 2637; 2522; 1617; 1457; 1062; 1009 and 962 cm' 1 N-[2-Hydroxy-1 -(4-methvl-piperazin- 1-ylmethl)ethyl] acetamide
OH
O
A solution under inert atmosphere of 3.27 g of methyl (acetylamino)-3-(4-methylpiperazin-l-yl)propanoate in 100 mL of anhydrous methanol is cooled at a temperature of about 100 C, then 0.76 g of sodium borohydride are added using a spatula. The reaction medium is stirred for 5 hours at a temperature of about 200 C, then are added again 0.26 g of sodium borohydride and the stirring is carried out for 38 hours. Then, 5 mL of water is dropped into the reaction mass which is heated and concentated under reduced pressure (2 kPa) at a temperature of about 30° C. The obtained residue is taken up with dichloromethane and the insoluble matter is removed by filtration. The filtrate is concentrated under reduced pressure (2 kPa) at a temperature of about 200 C. The residue is purified by chromatography under argon pressure (60 kPa), on a column of silica gel (particle size 40-63 pm; diameter 5 cm; height 19 cm), eluting with successive mixtures of 20% dichloromethane/methanol/ aqueous ammonia (98/2/0, 95/5/0.1, 90/10/0.2, 80/20/0.25, 50/50/0.25 by volume).
The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 400 C. About 0.92 g of N-[2hydroxy-l-(4-methyl-piperazin-l-ylmethyl)ethyl] acetamide are obtained in the form of a yellow-colored liquid. [Infrared spectrum CH 2 C1 2 3621; 3429; 3352; 2944; 2803; 1657; 1513; 1460; 1284; 1050; 1011 and 816 cm- 1 2-(Acetvlamino)-3-(4-methyl-piperazin-1-yl)propanoate de methyle
NH
N N 0 To a solution of 8.57 g of methyl 2-acetamidoacrylate in 500 mL of dichloromethane stirred under inert atmosphere, about 6.65 mL of N-methylpiperazine are added, then 0.97 g of iron trichloride are added, and the mixture is stirred at a temperature of about 200 C for 66 hours. Then, 300 mL of an aqueous solution of sodium sulfate are dropped to the reaction medium while stirring the reaction mixture and the mixture filtered through Celite. After separation of the phase by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated in a vacuum oven under reduced pressure (2 kPa) at a temperature of about 40° C in order to obtain an orangecolored liquid. The aqueous phase is extracted with 3 times 150 mL of dichloromethane and all of the organic extracts are collected, dried over sodium sulfate, then concentrated under reduced pressure (2 kPa) at a temperature of about 200 C in order to obtain an yellow oil. Both of the organic extracts as described above are combined and purified by chromatography under argon pressure (50 kPa), on a column of silica gel (particle size 40-63 pm; diameter 5 cm; height 25 cm), eluting with successive mixtures of 20% dichloromethane/methanol/ aqueous ammonia (99/1/0, 97/3/0, 90/10/0.25, 80/20/0.25 by volume). The fractions containing the expected product are combined and concentrated under reduced pressure (2 kPa) at a temperature of about 300 C. About 3.3 g of methyl 2- (acetylamino)-3-(4-methyl-piperazinyl)propanoate are obtained in the form of a yellow liquid. [Infrared spectrum CC1 4 3437; 3318; 2941; 2798; 1749; 1685; 1499; 1458; 1374; 1286; 1204; 1168 and 1014 cm'] The pharmaceutical compositions according to the invention consist of a compound of formula 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.
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 (dragres) or a varnish.
Liquid compositions for oral administration which can be used include pharmaceutically acceptables 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.
The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. Solvent 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, 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 incorporing 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 The compositions for rectal administration are suppositories or rectal capsules which contain, besides the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
The compositions for topical administration can be, for example, creams, lotions, eye drops, mouth washes, nasal drops or aerosols.
In human therapy, the compounds according to the invention are particularly useful for treating and/or preventing multiple sclerosis, focal or global cerebral 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, inflammatory bowel disease, Crohn's disease, peritonitis, gastro-esophageal reflux, uveitis, Guillain-Barr6 syndrome, glomerulo-nephritis, 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 Gramnegative intracellular or extracellular bacteria.
The doses depend on the disired effect, the duration of the treatment and the route of administration used; they are generally comprised between 1mg 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.
The examples which follow illustrate compositions according to the invention EXAMPLE A Gel capsules containing 50 mg of active product and having the composition below are prepared, according to the usual technique: Compound of formula 50 mg C 18 m g L 55 m g Colloidal 1 m g Sodium 10 mg T 10 m g M agnesium 1 mg EXAMPLE B Tablets containing 50 mg of active product and having the composition below are prepared, according to the usual technique: Compound of formula 50 mg 104 m g 40 mg 10 m g Sodium carboxymethylstarch.................. 22 mg Talc 10 m g M agnesium 2 m g Colloidal 2 m g Mixture of hydroxymethylcellulose, glycerol, titanium oxide (72/3.5/24.5) q.s. 1 finished film-coated tablet weighing 245 mg EXAMPLE C An injectible solution containing 10 mg of active product having the following composition Compound of formula 10 mg Benzoic 80 mg Benzyl 0.06 m l Sodium 80 mg 95% 0.4 m l Sodium 24 mg P ropylene 1.6 m l W 4 m l 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 administration of a compound of formula the racemic mixtures, enantiomers, diastereoisomers thereof and mixtures thereof, tautomer thereof and pharmaceutically acceptable salts thereof.
Comprises/comprising and grammatical variations thereof when used in this specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.
Claims (13)
1. Compound of formula (I) x y __S N S I I NH2 (I) wherein either Y is a methylene (CH 2 and X is chosen from the following groups O, NH, N-Alkyl(C1-C4), N-Bn, N-Ph, N(2-Py), N-2-pyrimidyl, pyrimidyl, S, SO, SO 2 CH 2 or CHPh; or Y is a carboxy and X is chosen from the following groups NH, N-Ph, N- N-2-pyrimidyle or wherein the (C1-C4) alkyl radicals contain 1 to 4 carbon atoms in straight or branched chain wherein abbreviations Bn, Py, Ph mean respectively benzyl, pyridyl, phenyl; the racemics, enantiomers, diastereoisomers thereof and mixtures thereof, tautomer thereof and pharmaceutically acceptable salts thereof.
2. The compound according to claim 1, wherein the compound of formula is chosen from the following compounds:
4-(morpholin-4-ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine 4-(pyperazin-1 -ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine 4-(4-methyl-pyperazin-1 -ylmethyl)-4,5-dihydro-1,3-thiazol-2-ylamine the racemics, enantiomers, diastereoisomers thereof and mixtures thereof, tautomer thereof and pharmaceutically acceptable salts thereof. 3. The compound according to claim 1 or claim 2, wherein the compound of formula is chosen from the following compound: 4-(4-methyl-pyperazin-1 -ylmethyl)-4.5-dihydro-1.3-thiazol-2-ylamine the racemic, enantiomers, tautomers thereof as well as the pharmaceutically acceptable salts thereof. 4. A 2-amino-thiazoline derivative which is substantially as hereinbefore described with reference to Example 1. The compound according to any one of claims 1 to 4, for their application as a medicinal product.
6. A pharmaceutical composition wherein it contains, in a pharmaceutically acceptable medium, a compound defined according to any one of claims 1 to 4.
7. A pharmaceutical composition substantially as hereinbefore described with reference to any one of Examples A, B or C.
8. The medicinal product according to claim 5 wherein it contains at least one compound defined according to claims 1 to 4 for their therapeutic application in the treatment of a disease in which an abnormal production of nitric oxyde (NO) by induction of inducible NO-synthase (NOS-2) is involved.
9. The medicinal product according to claim 5 wherein it contains at least a compound defined according to claims 1 to 4 for their therapeutic application in the treatment of the Parkinson's disease. A method for the preparation of the compounds of formula as defined in claim 1, the method comprising a step of cyclizing a derivative of formula: X Y H NH-CS-NH-C(CH 3 3 wherein X and Y have the same meanings as in claim 1, and optionally converting the product into a pharmaceutically acceptable salt.
11. The method for the preparation according to claim 10 wherein the cyclization is carried out in an acid medium at a temperature of about 1000C.
12. The method for the preparation according to claim 11 wherein the acid medium is preferably 6N hydrochloric acid.
13. The method for the preparation of compounds of formula (II) as defined in claim 10 and in which X et Y have the same meaning as in claim 1, the method comprising a step of subjecting a compound of formula (Ila) X Y COORb N NH-Ra (lIa) wherein Ra is a protecting group of the amine function and Rb a protecting group of the acid function with the action of a reducting agent in order to obtain a compound of formula (Ilb) OH dNHNH-Ra (lib) which is subjected to the action of a deprotecting agent, in order to obtain a compound of formula (l1c) (Ic) which is subjected to the action of a tert-butylisothiocyanate, in order to obtain a compound of formula (II) X Y H NH-CS-NH-C(CH 3 3 (II)
14. As intermediate compounds, the compounds II. Ila. lib. Ilc as defined in claim 13, with the exception of the following: N-[2-hydroxy-1-(4-phenyl-piperazin-l-ylmethyl)ethyl] thiobenzamide methyl 2-(N-CBZ-amino)-3-morpholino-propionate boc-DL-3-(4-morpholinyl)alanine methyl ester methyl 2-acetamido-3-piperidinopropanoate methyl 2-acetamido-3-morpholinopropanoate ethyl 2-(N-benzyl-amino)-3-piperidinopropanoate ethyl 2-(N-benzyl-amino)3-morpholinopropanoate. As intermediate compounds, N/-(tert-Butyl)-N'-[2-hydroxy-1-(4-methyl- piperazin-1 -ylmethyl)ethyl]-thiourea;N-[2-Hydroxy-1 -(4-methyl-piperazin-1 ylmethyl)ethyl] acetamide; 2-(Acetylamino)-3-(4-methyl-piperazin-1 yl)propanoate of methyl.
16. A method for the treatment of a disease in which an abnormal production of nitric oxide (NO) by induction of inducible NO-synthase (NOS-2) is involved, which method comprises administering to a patient a therapeutically effective amount of a compound according to any one of claims 1 to 4 or of a pharmaceutical composition according to claim 6 or claim 7.
17. Use of a compound according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of a disease in which an abnormal production of nitric oxide (NO) by induction of inducible NO-synthase (NOS-2) is involved. AVENTIS PHARMS S.A. WATERMARK PATENT TRADE MARK ATTORNEYS P23947AU00
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FR0114510A FR2832152A1 (en) | 2001-11-09 | 2001-11-09 | New 2-amino-thiazoline derivatives having inducible NO-synthase inhibiting activity, useful for treating Parkinson's, cerebral disorders, migraines, depression, diabetes |
US35279702P | 2002-01-30 | 2002-01-30 | |
US60/352,797 | 2002-01-30 | ||
PCT/FR2002/003810 WO2003040115A1 (en) | 2001-11-09 | 2002-11-07 | 2-amino-thiazoline derivatives and their use as inhibitors of inducible no-synthase |
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