FR2478092A1 - Sulindac salts with bases e.g. di:isopropylamine or arginine - with antiinflammatory, antipyretic and analgesic activity suitable for admin. by injection - Google Patents
Sulindac salts with bases e.g. di:isopropylamine or arginine - with antiinflammatory, antipyretic and analgesic activity suitable for admin. by injection Download PDFInfo
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- FR2478092A1 FR2478092A1 FR8023162A FR8023162A FR2478092A1 FR 2478092 A1 FR2478092 A1 FR 2478092A1 FR 8023162 A FR8023162 A FR 8023162A FR 8023162 A FR8023162 A FR 8023162A FR 2478092 A1 FR2478092 A1 FR 2478092A1
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- France
- Prior art keywords
- salts
- methyl
- benzylidene
- fluoro
- base
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- 230000000202 analgesic effect Effects 0.000 title claims abstract description 6
- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 6
- 230000001754 anti-pyretic effect Effects 0.000 title claims abstract description 6
- 239000002221 antipyretic Substances 0.000 title claims abstract description 6
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical class CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 title abstract 3
- 239000004475 Arginine Substances 0.000 title 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 title 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 title 1
- 238000002347 injection Methods 0.000 title 1
- 239000007924 injection Substances 0.000 title 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 239000002253 acid Substances 0.000 claims abstract description 19
- 150000001447 alkali salts Chemical class 0.000 claims abstract description 5
- 230000007935 neutral effect Effects 0.000 claims abstract description 5
- 150000007529 inorganic bases Chemical group 0.000 claims abstract description 3
- 150000007530 organic bases Chemical group 0.000 claims abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 3
- 239000002904 solvent Substances 0.000 claims description 11
- -1 p- (methylsulfinyl) -benzylidene Chemical group 0.000 claims description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Substances CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 239000008298 dragée Substances 0.000 claims description 2
- 239000006196 drop Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- OSHVGUAPPIYWIS-UHFFFAOYSA-N piperazin-1-ium;acetate Chemical compound CC(O)=O.C1CNCCN1 OSHVGUAPPIYWIS-UHFFFAOYSA-N 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000006186 oral dosage form Substances 0.000 abstract 1
- 229960000894 sulindac Drugs 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 241001558496 Talpa caeca Species 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- MLKXDPUZXIRXEP-UHFFFAOYSA-N 2-[6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]-1-indenyl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2C1=CC1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
La présente invention concerne des sels de l'acide 5-fluoro-2-methyl-1-(p-(methylsulfinyl)-benzylidène)-indine- 3-acétique avec diverses bases organiques et minérales. Lesdits sels ont l'activité anti-inflammatoire, antipyrétique et analgésique dudit acide, mais sont formulables en formes pharmaceutiques injectables et hautement tolérées. L'invention concerne par suite également lesdites formes pharmaceutiques et un procédé pour la préparation des sels précités. The present invention relates to salts of 5-fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) -indine-3-acetic acid with various organic and mineral bases. Said salts have the anti-inflammatory, antipyretic and analgesic activity of said acid, but can be formulated in injectable pharmaceutical forms and are highly tolerated. The invention therefore also relates to said pharmaceutical forms and to a process for the preparation of the abovementioned salts.
L'acide 5-fluoro-2-méthyl-1- (p- (méthylsulfinyl) - benzylidène)-indène-3-acétique, ayant la formule structurale suivante
possède des propriétés anti-inflammatoires, antipyrétiques et analgésiques, comme mentionné, par exemple, dans les brevets de la République Fédérale Allemande Nos 2.039.426 t des U.S.A.5-fluoro-2-methyl-1- (p- (methylsulfinyl) - benzylidene) -indene-3-acetic acid, having the following structural formula
has anti-inflammatory, antipyretic and analgesic properties, as mentioned, for example, in the patents of the German Federal Republic Nos 2,039,426 t from the USA
NQs 3.654.349 et 3.647.858, ainsi que dans les publications de - Van Arman et colt., Fed. Proc. 31, 577 (1972) - Van Arman et coll., Scand. J. Rheumatol., 4, suppl. 8,
s04-01 (1975) - Rosekrans et coll., Pharmatherapeutica, 1, 52 (1976) - Hucker et coll., Drug Metab. Disp., 1, 721 (1973).NQs 3,654,349 and 3,647,858, as well as in the publications of - Van Arman et al., Fed. Proc. 31, 577 (1972) - Van Arman et al., Scand. J. Rheumatol., 4, suppl. 8,
s04-01 (1975) - Rosekrans et al., Pharmatherapeutica, 1, 52 (1976) - Hucker et al., Drug Metab. Disp., 1, 721 (1973).
La présente invention concerne ainsi, comme mentionné ci-dessus, des nouveaux dérivés de l'acide 5-fluoro-2-méthyl- l-(p-(methylsulfinyl)-benzylidene)-indene-3-acetique et, plus précisément, des sels de formule générale suivante (I)
dans laquelle B représente une base organique ou inorganique, qui peut être une "mono"- (n = 1), une t'bi"- (n = 2), une "poly"- base (n > 2) capable de réaliser une salification avec une ou plusieurs molécules de l'acide pour donner des sels neutres et basiques.The present invention thus relates, as mentioned above, to new derivatives of 5-fluoro-2-methyl-l- (p- (methylsulfinyl) -benzylidene) -indene-3-acetic acid and, more specifically, salts of the following general formula (I)
in which B represents an organic or inorganic base, which can be a "mono" - (n = 1), a t'bi "- (n = 2), a" poly "- base (n> 2) capable of producing salification with one or more molecules of the acid to give neutral and basic salts.
L'invention concerne en outre un procédé pour la préparation des sels de formule (I). Selon ledit procédé, on fait réagir 1' acide 5-fluoro-2-méthyl-1-(p-(méthylsulfinyl)- benzylidène)-indène-3-acétique avec une base B dans un solvant convenable. Comme solvants, on peut utiliser de préférence, ceux dans lesquels sont solubles l'acide ainsi que la base, tandis que le sel obtenu s'y montre peu soluble ou insoluble. D'une manière différente, on peut dissoudre l'acide et la base dans des solvants différents entre eux, tandis que le sel est peu soluble ou insoluble dans le mélange des deux solvants. En pratique, on peut utiliser des alcools inférieurs (par exemple ltéthanoD, des cétones inférieures (par exemple l'acétone), ou leurs mélanges avec de l'eau. The invention further relates to a process for the preparation of the salts of formula (I). According to said method, the 5-fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) -indene-3-acetic acid is reacted with a base B in a suitable solvent. As solvents, use may preferably be made of those in which the acid and the base are soluble, while the salt obtained is shown to be sparingly soluble or insoluble. In a different way, the acid and the base can be dissolved in solvents which are different from each other, while the salt is sparingly soluble or insoluble in the mixture of the two solvents. In practice, it is possible to use lower alcohols (for example léthanoD, lower ketones (for example acetone), or their mixtures with water.
On utilise l'acide et la base en quantités sensiblement équimolaires dans le cas de bases monoacides. The acid and the base are used in substantially equimolar amounts in the case of mono-acid bases.
Lorsque la base est bi- ou polyacide, on adopte le rapport acide/base qui conduit à des sels neutres ou basiques.When the base is bi- or polyacid, the acid / base ratio is adopted which leads to neutral or basic salts.
Beaucoup de sels (I) ont des propriétés physicochimiques nettement différentes de celles de l'acide d'origine, par exemple la solubilité dans l'eau et/ou dans des solutions physiologiques. Many salts (I) have physicochemical properties clearly different from those of the original acid, for example solubility in water and / or in physiological solutions.
Les sels de l'acide 5-fluoro-2-méthyl-1-(p-(méthyl sulfinyl)-benzylidène)-indène-3-acétique avec des bases thérapeutiquement acceptables montrent, pour des doses équimoléculaires, la même intensité d'action thérapeutique que celle de l'acide dont ils proviennent. The salts of 5-fluoro-2-methyl-1- (p- (methyl sulfinyl) -benzylidene) -indene-3-acetic acid with therapeutically acceptable bases show, for equimolecular doses, the same intensity of action therapeutic than that of the acid from which they come.
Selon la présente invention, les propriétés particulières des nouveaux sels permettent de realiser des formes pharmaceutiques qui ne pourraient pas être préparées avec l'acide seul, telles que, par exemple, les formes injectables stériles dans lesquelles le solvant principal est l'eau ou une solution physiologique. Ceci démontre par suite d'une manière évidente le progrès technique réalisé avec les sels de formule (I) ; parmi ceux-ci les sels avec des aminoacides se sont démontrés particulièrement adaptés. According to the present invention, the particular properties of the new salts make it possible to produce pharmaceutical forms which could not be prepared with the acid alone, such as, for example, sterile injectable forms in which the main solvent is water or a physiological solution. This therefore clearly demonstrates the technical progress made with the salts of formula (I); among these, the salts with amino acids have been shown to be particularly suitable.
Un grand nombre desdites-solutions (en particulier celles qui sont obtenues en salifiant l'acide avec des aminoacide s physiologiques basiques), administrées sous forme injectable, sont hautement tolérées tant localement que généralement, par les tissus des organismes chez l'animal et chez l'homme, en révélant l'action thérapeutique désirée de façon plus rapide ou plus intense par rapport à la voie orale. A large number of said solutions (in particular those obtained by salifying the acid with basic physiological amino acids), administered in injectable form, are highly tolerated both locally and generally, by the tissues of organisms in animals and in humans, by revealing the desired therapeutic action more quickly or more intensely than the oral route.
En dehors des formes pharmaceutiques injectables, un sel conforme à l'invention peut être favorablement utilisé comme principe actif dans d'autres formes pharmaceutiques solides ou liquides, telles que, par exemple, des comprimés, des granulés, des sirops, des gouttes, des dragées, avec pour avantage une meilleure tolérabilité par rapport à l'acide correspondant. Apart from the injectable pharmaceutical forms, a salt in accordance with the invention can be favorably used as active principle in other solid or liquid pharmaceutical forms, such as, for example, tablets, granules, syrups, drops, dragees, with the advantage of better tolerability compared to the corresponding acid.
Les formes pharmaceutiques injectables préparées avec l'un des nouveaux sels de l'invention peuvent être réalisées également sous forme solide et stérile, à solubiliser au moment de l'emploi à l'aide d'un solvant. The injectable pharmaceutical forms prepared with one of the new salts of the invention can also be produced in solid and sterile form, to be dissolved at the time of use using a solvent.
Les formes pharmaceutiques préparées avec lesdits sels, sont solides ou liquides et peuvent contenir, en dehors de l'eau, d'autres diluants inertes et thérapeutiquement acceptables. On peut encore leur ajouter des aromatisants, édulcorants, stabilisants, colorants ou autres composants thérapeutiquement inertes, propres à rendre la préparation pharmaceutique la mieux acceptée en thérapie. The pharmaceutical forms prepared with said salts are solid or liquid and may contain, apart from water, other inert and therapeutically acceptable diluents. It is also possible to add to them flavorings, sweeteners, stabilizers, colorings or other therapeutically inert components, capable of making the pharmaceutical preparation the most accepted in therapy.
L'invention sera maintenant illustrée ci-après par quelques exemples de préparation et les caractéristiques de quelques sels,l'invention n'étant nullement limitée à ces exemples et pouvant être mise en oeuvre selon des variantes sans pour autant s'écarter de son cadre et de son esprit. The invention will now be illustrated below by a few examples of preparation and the characteristics of some salts, the invention not being in any way limited to these examples and being able to be implemented according to variants without however departing from its scope. and his mind.
EXEMPLE 1 5-Fluoro-2-méthyl-1-(p-(méthylsulfinyl)-benzylidene)-inddne-3- acétate de diisopropylamine
Dans de l'acétone anhydre (30 ml), on dissout de l'acide 5-fluoro-2-methyl-1-(p-(méthylsulfinyl)-benzylidene)-indene- 3-acétique (1,07 g ; 3,0 m.moles). On dissout à part,de la diisopropylamine (0,31 g ; 3,0 m.moles) dans de l'acétone anhydre (6,0 ml), puis on chauffe les deux solutions (30-550C) et on les réunit encore chaudes, en les agitant. On laisse refroidir le mélange, puis on recueille le sel brut précipité, que l'on purifie par dissolution dans l'éthanol absolu (40 ml) et précipitation par adjonction d'éther éthyliqué (30 Lfll). On obtient le sel pur cristallin, jaune clair, à p.f. 180-1820C (non corrigé).EXAMPLE 1 5-Fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) -inddne-3- diisopropylamine acetate
In anhydrous acetone (30 ml), 5-fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) -indene- 3-acetic acid (1.07 g; 3) is dissolved. 0 m.moles). Separately, diisopropylamine (0.31 g; 3.0 m.moles) is dissolved in anhydrous acetone (6.0 ml), then the two solutions are heated (30-550C) and combined again hot, shaking them. The mixture is allowed to cool, then the precipitated crude salt is collected, which is purified by dissolution in absolute ethanol (40 ml) and precipitation by addition of ethyl ether (30 Lfll). The pure crystalline salt, light yellow, is obtained at mp 180-1820C (uncorrected).
Pour C26H32FNO3S (457,61) trouvé % C, 68,03 ; H, 6,95
N, 3,08 ; S, 7,11
calculé % C, 68,24 ; H, 7,05
N, 3,06 ; S, 7,01.For C26H32FNO3S (457.61) found% C, 68.03; H, 6.95
N, 3.08; S, 7.11
calculated% C, 68.24; H, 7.05
N, 3.06; S, 7.01.
EXEMPLE 2 5-Fluoro-2-méthyl-1-(p-(méthylsulfinyl)-benzylidene)-indene3-acétate de L-arginine
On dissout l'acide 5-fluoro-2-méthyl-1- (p- (méthyl- sulfinyl)-benzylidène)-indène-3-acétique (2,14 g ; 6,0 m.moles) dans de l'acétone (60 ml). On dissout à part,de la
L-arginine (1,06 g ; 6,0 m.moles) dans de l'eau distillée (18 ml). On chauffe les deux solutions à 30-550C et on les réunit, encore chaudes, en agitant. Après avoir laissé refroidir pendant quelques heures, on recueille le sel brut précipité, que l'on purifie par aissolution dans le méthanol anhydre (240 ml) et précipitation par adjonction d'éther diéthylique (20 ml). EXAMPLE 2 5-Fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) -indene3-L-arginine acetate
5-fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) -indene-3-acetic acid (2.14 g; 6.0 m.moles) is dissolved in acetone (60 ml). We dissolve separately,
L-arginine (1.06 g; 6.0 m.moles) in distilled water (18 ml). The two solutions are heated to 30-550C and are combined, still hot, with stirring. After having allowed to cool for a few hours, the precipitated crude salt is collected, which is purified by aissolution in anhydrous methanol (240 ml) and precipitation by addition of diethyl ether (20 ml).
On obtient un produit cristallisé jaune brillant, à p.f. 200-2010C (non corrigé), soluble dans l'eau. La solution aqueuse à 5 e (p:v) a un pH de 6,9 environ et un 23 (α)D23 + 6 . A brilliant yellow crystallized product is obtained, m.p. 200-2010C (not corrected), soluble in water. The 5 th (p: v) aqueous solution has a pH of about 6.9 and a 23 (α) D23 + 6.
Pour C26H31FN405S (530,64) trouvé % C, 58,90 ; H, 6,05
N, 10,60 ; S, 6,15
calculé % C, 58,85 ; H, 5,89
N, 10,56 ; S, 6,04.For C26H31FN405S (530.64) found% C, 58.90; H, 6.05
N, 10.60; S, 6.15
calculated% C, 58.85; H, 5.89
N, 10.56; S, 6.04.
EXEMPLE 3 5-Fluoro-2-méthyl-1- (p- (méthylsulfinyl) -benzylidène) -indène3-acétate de L-lysine
On dissout dans l'acétone anhydre (90 ml) de l'acide 5-fluoro-2-méthyl-1- (p- (méthylsulfinyl) -benzylidêne) - indene-3-acétique (3,20 g ; 9,0 m.moles) On prépare une autre solution d'éthanol absolu (150 ml) et de L-lysine base (1,14 g ; 9,0 m.moles). On chauffe les deux solutions limpides et on les réunit en agitant. On laisse refroidir et on recueille le sel brut sur Büchner, on le lave sur le filtre avec de l'éther diéthylique, puis on le dissout dans l'éthanol absolu (510 ml) et le précipite par adjonction d'éther diéthylique (90 ml).EXAMPLE 3 5-Fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) -indene3-L-lysine acetate
5-fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) - indene-3-acetic acid (3.20 g; 9.0 m) is dissolved in anhydrous acetone (90 ml) Another solution of absolute ethanol (150 ml) and of L-lysine base (1.14 g; 9.0 m.moles) is prepared. The two clear solutions are heated and combined with stirring. The mixture is allowed to cool and the crude salt is collected on Büchner, it is washed on the filter with diethyl ether, then it is dissolved in absolute ethanol (510 ml) and precipitated by adding diethyl ether (90 ml ).
Le sel cristallin, de couleur jaune ocre obtenu, a un p.f.The crystalline salt, ocher yellow in color obtained, has a m.p.
de 165-1670C (non corrigé) et il est extrêmement soluble dans l'eau.from 165-1670C (uncorrected) and it is extremely soluble in water.
La solution aqueuse à 5 % (p:v) a un pH de 6,6-6,8 et un (α)D24 + 6,50. The 5% aqueous solution (w: v) has a pH of 6.6-6.8 and a (α) D24 + 6.50.
Pour C26H31FN2O5S (502,62) trouvé % C, 61,98 ; H, 6,31
N, 5,61 ; S, 6t42
calculé % C, 62,13 ; H, 6,22
N, 5,57 ; S, 6,38.For C26H31FN2O5S (502.62) found% C, 61.98; H, 6.31
N, 5.61; S, 6t42
calculated% C, 62.13; H, 6.22
N, 5.57; S, 6.38.
EXEMPLE 4 5-Fluoro-2-méthyl-1-p- (méthylsulfinyl) -benzylidène) -indèfle- 3-acétate basique de pipérazine
Dans l'acétone anhydre (30 ml), on dissout 1,07 g (3,0 m.moles) d'acide 5-fluoro-2-méthyl-1- (p- (méthylsulfinyl) - benzylidène)-indène-3-acétique. On dissout à part, dans l'acétone anhydre (10 ml), 0,26 g (3,0 m.moles) de pipérazine.EXAMPLE 4 5-Fluoro-2-methyl-1-p- (methylsulfinyl) -benzylidene) -indeflea-3-basic acetate of piperazine
In anhydrous acetone (30 ml), 1.07 g (3.0 m.moles) of 5-fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) -indene-3 acid are dissolved. -acetic. Separately, in anhydrous acetone (10 ml), 0.26 g (3.0 m.moles) of piperazine is dissolved.
On chauffe les deux solutions (30-550C) et on les réunit en agitant, alors qu'elles sont encore chaudes. Après refroidissement, on recueille le sel par filtration, puis on le purifie en le cristallisant à partir d'éthanol absolu (environ 160 ml).The two solutions are heated (30-550C) and combined with stirring while they are still hot. After cooling, the salt is collected by filtration, then it is purified by crystallizing it from absolute ethanol (about 160 ml).
On obtient un sel cristallin jaune brillant à p.f. A brilliant yellow crystalline salt is obtained at m.p.
de 189-1910C (non corrigé).from 189-1910C (not corrected).
Pour C24H27FN2 3S (442,55) trouvé % C, 65,25 ; H, 6,18
N, 6,42 ; S, 7,18
calculé % C 65,14 ; H, 6,15
N, 6,33 ; S, 7,42.For C24H27FN2 3S (442.55) found% C, 65.25; H, 6.18
N, 6.42; S, 7.18
calculated% C 65.14; H, 6.15
N, 6.33; S, 7.42.
EXEMPLE 5 5-Fluoro-2-méthyl-1-(p-(méthylsulfinyl)-benzylidène)-indene3-acétate neutre de pipérazine
La préparation est identique à celle de l'Exemple 4, à l'exception que la quantité de la pipérazine dans la réaction est la moitié de la précédente (0,13 g ; 1,5 m.mole) dans 5 ml d'acétone.EXAMPLE 5 5-Fluoro-2-methyl-1- (p- (methylsulfinyl) -benzylidene) -indene3-neutral piperazine acetate
The preparation is identical to that of Example 4, except that the amount of piperazine in the reaction is half of the previous one (0.13 g; 1.5 m.mole) in 5 ml of acetone .
On obtient un sel cristallin jaune à p.f. 1930C (non corrigé). A yellow crystalline salt is obtained at m.p. 1930C (not corrected).
Pour C44H44F2N2O6S2 (798,96) trouvé % C, 66,09 ; H, 5,60 ;
N, 3,60 ; S, 8,15 ;
calculé % C, 66,15 ; H, 5,55
N, 3,51 ; S, 8,02. For C44H44F2N2O6S2 (798.96) found% C, 66.09; H, 5.60;
N, 3.60; S, 8.15;
calculated% C, 66.15; H, 5.55
N, 3.51; S, 8.02.
Claims (12)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT27822/79A IT1127274B (en) | 1979-12-04 | 1979-12-04 | SALTS OF 5-FLUORO-2-METHYL-1- (P- (METHYLSULFINYL) -BENZYLIDENE) -INDENE-3-ACETIC ACID |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2478092A1 true FR2478092A1 (en) | 1981-09-18 |
| FR2478092B1 FR2478092B1 (en) | 1983-04-01 |
Family
ID=11222398
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8023162A Granted FR2478092A1 (en) | 1979-12-04 | 1980-10-29 | Sulindac salts with bases e.g. di:isopropylamine or arginine - with antiinflammatory, antipyretic and analgesic activity suitable for admin. by injection |
Country Status (4)
| Country | Link |
|---|---|
| JP (2) | JPS5692264A (en) |
| DE (1) | DE3040737A1 (en) |
| FR (1) | FR2478092A1 (en) |
| IT (1) | IT1127274B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2685916A1 (en) * | 1992-01-04 | 1993-07-09 | Scras | MIXED INHIBITORS OF NO SYNTHASE AND CYCLOOXYGENASE, AND METHOD FOR THE PREPARATION THEREOF |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0405602A1 (en) * | 1989-06-30 | 1991-01-02 | Laboratorios Vinas S.A. | New Zinc derivatives of anti-inflammatory drugs having improved therapeutic activity |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2164489A1 (en) * | 1970-04-07 | 1973-08-03 | Merck & Co Inc | 2-methyl-1-(para-methylsulphinylbenzylidene)inden - -3-yl-acetic acid esters - anti-inflammatories, antipyretics and anal |
-
1979
- 1979-12-04 IT IT27822/79A patent/IT1127274B/en active
-
1980
- 1980-10-29 FR FR8023162A patent/FR2478092A1/en active Granted
- 1980-10-29 DE DE19803040737 patent/DE3040737A1/en not_active Ceased
- 1980-12-03 JP JP17144980A patent/JPS5692264A/en active Pending
-
1982
- 1982-03-23 JP JP57047032A patent/JPS57167958A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2164489A1 (en) * | 1970-04-07 | 1973-08-03 | Merck & Co Inc | 2-methyl-1-(para-methylsulphinylbenzylidene)inden - -3-yl-acetic acid esters - anti-inflammatories, antipyretics and anal |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2685916A1 (en) * | 1992-01-04 | 1993-07-09 | Scras | MIXED INHIBITORS OF NO SYNTHASE AND CYCLOOXYGENASE, AND METHOD FOR THE PREPARATION THEREOF |
| FR2685869A1 (en) * | 1992-01-04 | 1993-07-09 | Scras | THERAPEUTIC COMPOSITIONS BASED ON MIXED INHIBITORS OF NO SYNTHASE AND CYCLOOXYGENASE. |
| GR1001443B (en) * | 1992-01-04 | 1993-12-30 | Sod Conseils Rech Applic | Preparation process of dual inhibitors of no synthase and cyclooxygenase. |
| BE1006227A3 (en) * | 1992-01-04 | 1994-06-14 | Sod Conseils Rech Applic | Inhibitors combination of no synthase and cyclooxygenase, a process for their preparation and therapeutic compositions containing. |
| US5360925A (en) * | 1992-01-04 | 1994-11-01 | Societe De Conseils De Recherches Et D'applications Scientifiques | Dual inhibitors of no synthase and cyclooxygenase, process for their preparation and therapeutical compositions containing them |
| US5480999A (en) * | 1992-01-04 | 1996-01-02 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Dual inhibitors of NO synthase and cyclooxygenase, therapeutical compositions containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| IT1127274B (en) | 1986-05-21 |
| DE3040737A1 (en) | 1981-08-27 |
| FR2478092B1 (en) | 1983-04-01 |
| IT7927822A0 (en) | 1979-12-04 |
| JPS57167958A (en) | 1982-10-16 |
| JPS5692264A (en) | 1981-07-25 |
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