FR2564463A1 - Novel heterocyclic derivatives, processes for their preparation, medicaments containing them, which are useful especially as aldose reductase inhibitors - Google Patents

Novel heterocyclic derivatives, processes for their preparation, medicaments containing them, which are useful especially as aldose reductase inhibitors Download PDF

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FR2564463A1
FR2564463A1 FR8407791A FR8407791A FR2564463A1 FR 2564463 A1 FR2564463 A1 FR 2564463A1 FR 8407791 A FR8407791 A FR 8407791A FR 8407791 A FR8407791 A FR 8407791A FR 2564463 A1 FR2564463 A1 FR 2564463A1
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FR2564463B1 (en
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Jean-Marie Teulon
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Carpibem SA
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Carpibem SA
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Priority to IE112685A priority patent/IE58312B1/en
Priority to PH32246A priority patent/PH21118A/en
Priority to AT85400927T priority patent/ATE42297T1/en
Priority to EP85400927A priority patent/EP0162776B1/en
Priority to GR851159A priority patent/GR851159B/el
Priority to DE8585400927T priority patent/DE3569529D1/en
Priority to NZ212060A priority patent/NZ212060A/en
Priority to CA000481503A priority patent/CA1306747C/en
Priority to US06/733,685 priority patent/US4755509A/en
Priority to ZA853629A priority patent/ZA853629B/en
Priority to KR1019850003306A priority patent/KR900004320B1/en
Priority to AU42518/85A priority patent/AU586972B2/en
Priority to JP60102788A priority patent/JPH0692371B2/en
Priority to DK219685A priority patent/DK219685A/en
Priority to PT80489A priority patent/PT80489B/en
Priority to ES543266A priority patent/ES8607263A1/en
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    • C07—ORGANIC CHEMISTRY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/20—Oxygen atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract

The invention relates to novel compounds of formula which are aldose reductase inhibitors. Treatment of certain complications of diabetes.

Description

Nouveaux dérivés hétérocycliques, leurs procédés de préparation, médicaments les contenant utiles notamment comme inhibiteurs de l'aldose réductase.Novel heterocyclic derivatives, processes for their preparation, medicaments containing them, in particular as inhibitors of aldose reductase

La présente invention concerne des dérivés hétérocycliques de formule (I). Elle concerne également les procédés de préparation desdits produits et leurs applications en thérapeutique. The present invention relates to heterocyclic derivatives of formula (I). It also relates to the processes for preparing said products and their applications in therapeutics.

Les nouveaux composés selon l'invention sont choisis parmi l'ensemble constitué par les Composés de formule générale (I) :

Figure img00010001

dans laquelle
Z représente l'atome d'oxygène ou de soufre, optimalement le soufre ;
Y représente l'atome d'oxygène ou de soufre, optimalenent le soufre
Y peut, en outre, représenter l'atome d'azote notamment Si X est l'azote;
Z et Y ne peuvent représenter simultanément l'atome d'oxygène ;
X représente CH ou l'atome d'azote ;
R peut représenter l'hydrogène dans le cas où X = N ou alors un
halogène, un groupement trifluorométhyle, méthoxy, thiométhyle,
thiotrifluorométhyle, trifluorométhoxy, optimalement le fluor.The new compounds according to the invention are chosen from the group consisting of the compounds of general formula (I):
Figure img00010001

in which
Z represents the oxygen or sulfur atom, optimally sulfur;
Y represents the oxygen or sulfur atom, optimally sulfur
Y may, in addition, represent the nitrogen atom, especially Si X is nitrogen;
Z and Y can not simultaneously represent the oxygen atom;
X represents CH or the nitrogen atom;
R can represent hydrogen in the case where X = N or else a
halogen, trifluoromethyl, methoxy, thiomethyl,
thiotrifluoromethyl, trifluoromethoxy, optimally fluorine.

Les composés de formule (I) selon l'invention peuvent être synthétisés par hydrolyse en milieu basique ou acide d'esters de formule CLI)

Figure img00010002

dans laquelle R, X, Y et Z sont définis comme ci-dessus, R' étant un groupement alkyle inférieur ; on entend par "alkyle inférieur" un groupement en C1-C5 ramifié ou non. The compounds of formula (I) according to the invention can be synthesized by hydrolysis in basic or acidic medium of esters of formula CLI)
Figure img00010002

wherein R, X, Y and Z are defined as above, R 'being a lower alkyl group; "lower alkyl" is understood to mean a C 1 -C 5 branched or unbranched group.

Les composés de formule II dans lesquels
Z = S sont synthétisés à partir des dérivés dans lesquels Z = O par action de P2S5 selon des méthodes connues de l'homme de métier.The compounds of formula II in which
Z = S are synthesized from derivatives in which Z = O by P2S5 action according to methods known to those skilled in the art.

Les esters de formule II dans lesquels Z = O sont obtenus par action d'un halogénoacétate d'alkyle sur les dérivés
NH de formule III préalablement métallés à l'aide d'agents courants de métallation dans des solvants classiques pour ce type de réaction, tels que le diméthylformamide,par exemple

Figure img00020001
The esters of formula II in which Z = O are obtained by the action of an alkyl haloacetate on the derivatives
NH of formula III previously metallized using standard metallation agents in conventional solvents for this type of reaction, such as dimethylformamide, for example
Figure img00020001

Dans la formule III, R, X et Y sont définis comme ci-dessus. In formula III, R, X and Y are defined as above.

Les dérivés de formule III sont obtenus par cyclisation des aminoesters de formule IV

Figure img00020002

dans laquelle R, X et Y sont définis comme ci-dessus, R" étant un alkyle inférieur.The derivatives of formula III are obtained by cyclization of the aminoesters of formula IV
Figure img00020002

wherein R, X and Y are defined as above, R "being lower alkyl.

Les composés de formule IV sont synthétisés par hydrogénation des dérivés nitrés de formule V

Figure img00020003

dans laquelle R, X, Y et R" sont définis comme ci-dessus.The compounds of formula IV are synthesized by hydrogenation of the nitro derivatives of formula V
Figure img00020003

wherein R, X, Y and R "are defined as above.

Les dérivés de formule V sont obtenus par action, dans le cas où Y = N, d'un ester de la glycine ou,dans le cas où Y = S,d'un ester de l'acide mercaptoacétique sur les dérivés nitrés de formule VI :

Figure img00030001

et, dans le cas où Y = 0, par action d'un halogénoacétate d'alkyle sur le phénol de formule VII préalablement métallé
Figure img00030002
The derivatives of formula V are obtained by action, in the case where Y = N, of a glycine ester or, in the case where Y = S, of a mercaptoacetic acid ester on nitrated derivatives of formula VI:
Figure img00030001

and, in the case where Y = 0, by the action of an alkyl haloacetate on the phenol of formula VII previously metallated
Figure img00030002

Selon l'invention, on propose des compositions thérapeutiques utiles notamment pour le traitement des troubles péri sériques consécutifs au diabète (cataracte, neuropathie), caractérisées en ce qu'elles renferment, en association avec un excipient physiologiquement acceptable, au moins un composé de formule (I). According to the invention, therapeutic compositions are proposed which are useful in particular for the treatment of peripheral peri-serum disorders resulting from diabetes (cataract, neuropathy), characterized in that they contain, in association with a physiologically acceptable excipient, at least one compound of formula (I).

D'autres caractéristiques et avantages de l'invention seront mieux compris à la lecture qui va suivre de quelques exemples de préparation nullement limitatifs, mais donnés à titre d'illustration. Other characteristics and advantages of the invention will be better understood on reading which will follow of some examples of preparation which are in no way limitative but which are given by way of illustration.

Le tableau II ci-après donne la forme développée de certains produits. Table II below gives the developed form of certain products.

EXEMPLE 1 3-nitro 2-mercaptoacétate d'éthyle-pyridine
Formule V : R = H ; X = N ; Y = S ; R" = C2H5
On porte au reflux durant 7 h une solution de 50 g de 3-nitro 2-chloropyridine, 38 g de mercaptoacétate d'éthyle dans 400 ml méthanol contenant 30 g de bicarbonate de sodium. La solution est ensuite concentrée sous vide puis, apres refroidissement, le résidu additionné d'eau et de glace est extrait à l'éther. La phase éthérée, lavée à l'eau, est séchée et,le solvant évaporé, on récupère un résidu qui cristallise dans l'éther isopropylique. Les cristaux sont essorés et séchés et on obtient 49 g de 3-nitro 2mercaptoacétate d'éthyle-pyridine sous forme de cristaux de point de fusion 58 C. EXAMPLE 1 ethyl 3-nitro-2-mercaptoacetate-pyridine
Formula V: R = H; X = N; Y = S; R "= C2H5
A solution of 50 g of 3-nitro-2-chloropyridine, 38 g of ethyl mercaptoacetate in 400 ml of methanol containing 30 g of sodium bicarbonate is refluxed for 7 hours. The solution is then concentrated under vacuum and, after cooling, the residue, added with water and ice, is extracted with ether. The ethereal phase, washed with water, is dried and the solvent evaporated, a residue is recovered which crystallizes in isopropyl ether. The crystals are filtered off and dried and 49 g of ethyl 3-nitro-2-mercaptoacetate-pyridine are obtained in the form of crystals with a melting point of 58.degree.

EXEMPLE 2 6-chioro- 3-nitro 2-mercaptoacétate d'éthyle-pyridine
Formule V : R = C1 ; X = N ; Y = S ; R" = C2H5
Selon le mode opératoire de l'exemple 1, mais en utilisant 25 g de 2,6-dichloro 3-nitropyridine à 90 % et 14 g de mercaptoacétate d'éthyle, on obtient 32,5 g de 6-chloro3-nitro 2-mercaptoacétate d'éthyle-pyridine sous forme d'une huile utilisée brute pour l'étape ultérieure.EXAMPLE 2 6-Chioro-3-nitro-2-mercaptoacetate ethyl-pyridine
Formula V: R = C1; X = N; Y = S; R "= C2H5
According to the procedure of Example 1, but using 25 g of 90% 2,6-dichloro-3-nitropyridine and 14 g of ethyl mercaptoacetate, 32.5 g of 6-chloro-3-nitro are obtained. ethyl mercaptoacetate-pyridine as a crude used oil for the subsequent step.

EXEMPLE 3 3-nitro 2-aminoacétate d 'éthyle-pyridine
Formule V : R = H : X = N : Y = N ; R" = C2H5
On porte au reflux durant 3 h une solution de 20 g de 3-nitro 2-chloropyridine et de 32 g de glycinate d'éthyle dans 100 mld'éthanol. La solution est ensuite concentrée sous vide, et, après refroidissement puis addition d'eau et de glace, on extrait à l'éther. La phase éthérée est lavée a l'eau puis séchée et l'éther est évaporé sous vide. On récupère 28 g de 3-nitro 2-aminoacétate d'éthyle;pyridine sous forme d'une huile utilisée brute pour l'étape suivante.EXAMPLE 3 Ethyl-pyridine 3-nitro 2-aminoacetate
Formula V: R = H: X = N: Y = N; R "= C2H5
A solution of 20 g of 3-nitro-2-chloropyridine and 32 g of ethyl glycinate in 100 ml of ethanol is refluxed for 3 hours. The solution is then concentrated under vacuum, and after cooling and then adding water and ice, the mixture is extracted with ether. The ethereal phase is washed with water and then dried and the ether is evaporated under vacuum. 28 g of ethyl 3-nitro 2-aminoacetate, pyridine, are recovered in the form of a crude oil used for the next step.

EXEMPLE 4 4-trifluorométhyl 2-nitrophénylthioacétate d 'éthyle
Formule V : R = CF3 ; X F H ; Y = S ; R" = C2H5
Selon le mode opératoire de l'exemple 1, mais en utilisant 38 g de 4-trifluorométhyl 2-nitrochlorobenzène et 21,5 g de mercaptoacétate d'éthyle, on obtient, après distillation du résidu [E. (2 mmHg) = 155-1600C1, 29 g de 4-trifluorométhyl 2-nitrophénylthioacétate d'éthyle sous forme de cristaux de point de fusion 42-45oC. EXAMPLE 4 Ethyl 4-trifluoromethyl-2-nitrophenylthioacetate
Formula V: R = CF3; XFH; Y = S; R "= C2H5
According to the procedure of Example 1, but using 38 g of 4-trifluoromethyl-2-nitrochlorobenzene and 21.5 g of ethyl mercaptoacetate, after distillation of the residue [E. (2 mmHg) = 155-1600Cl, 29 g of ethyl 4-trifluoromethyl-2-nitrophenylthioacetate in the form of crystals melting point 42-45oC.

EXEMPLE 5 5-fluoro 2-nitrophénylthioacétate d 'éthyle
Formule V : R = F ; X = H ; Y = S ; R" = C H
Selon le mode opératoire de l'exemple 1, mais en utilisant 83 g de 2,4-difluoronitrobenzène et 63 g de mercaptoacétate d'éthyle, on obtient après distillation du résidu [E. (1 mmHg) = l55-l6O0C 85 g de 5-fluoro 2-nitrophénylthioacétate d'éthyle sous forme de cristaux de point de fusion 58"C. EXAMPLE 5 Ethyl 5-fluoro-2-nitrophenylthioacetate
Formula V: R = F; X = H; Y = S; R "= CH
According to the procedure of Example 1, but using 83 g of 2,4-difluoronitrobenzene and 63 g of ethyl mercaptoacetate, the residue [E. (1 mmHg) = 155 ° -16 ° C. 85 g of ethyl 5-fluoro-2-nitrophenylthioacetate in the form of crystals of mp 58 ° C.

EXEMPLE 6 4-fluoro 2-nitrophénylthioacétate d 'éthyle
Formule V : R = F ; X = H ; Y =S ; R" = C2H5
Selon le mode opératoire de l'exemple 1, mais à partir de 73 g de 2,5-difluoronitrobenzène et de 56 g de mercaptoacétate d'éthyle, on obtient après cristallisation du résidu dans le pentane 75 g de 4-fluoro 2-ntrophénylthioacétate d'éthyle sous forme de cristaux de point de fusion < (500C. EXAMPLE 6 Ethyl 4-fluoro-2-nitrophenylthioacetate
Formula V: R = F; X = H; Y = S; R "= C2H5
According to the procedure of Example 1, but starting from 73 g of 2,5-difluoronitrobenzene and 56 g of ethyl mercaptoacetate, 75 g of 4-fluoro-2-ntrophenylthioacetate are obtained after crystallization of the residue in pentane. of ethyl in the form of crystals of melting point <(500C.

EXEMPLE 7 4-fluoro -2-nitrophénoxyacétate d'éthyle
Formule V : R = F; X = H ; Y = O R" = C H
A une solution de 54,7 g de 4-fluoro 2-nitrophénol dans 400 ml d'éthanol, on ajoute goutte à goutte 14 g de soude en solution dans 30 ml d'eau. te mélange réactionnel est ensuite refroidi par un bain de glace et on additionne goutte à goutte 40 ml de chloroacétate d'éthyle. On laisse ensuite revenir d température ambiante puis on agite durant 4 h et on porte ensuite au reflux toujours sous agitation quatre nouvelles heures.EXAMPLE 7 Ethyl 4-fluoro-2-nitrophenoxyacetate
Formula V: R = F; X = H; Y = OR "= CH
To a solution of 54.7 g of 4-fluoro-2-nitrophenol in 400 ml of ethanol is added dropwise 14 g of sodium hydroxide in solution in 30 ml of water. The reaction mixture is then cooled with an ice bath and 40 ml of ethyl chloroacetate are added dropwise. It is then allowed to return to room temperature and then stirred for 4 hours and then refluxed for four more hours at reflux.

Le mélange réactionnel est ensuite concentré: sous vide, le résidu repris par l'eau et la glace est extrait à l'éther qu'on lave à l'eau, à la soude diluée puis encore à l'eau et qu'on sèche. The reaction mixture is then concentrated: under vacuum, the residue is taken up in water and the ice is extracted with ether which is washed with water, diluted sodium hydroxide then again with water and dried .

L'éther évaporé, on récupère 46 g de 4-fluoro 2-nitrophénoxyacétate d'éthyle sous forme d'une huile utilisée brute pour l'étape suivante.The ether evaporated, 46 g of ethyl 4-fluoro-2-nitrophenoxyacetate are recovered in the form of a crude oil used for the next step.

EXEMPLE 8 1H-pyrido[2.3-b][1.4]thiazine-2 (3H)-one
Formule III : R = H ; X = N ; Y = S
On hydrogène sous pression atmosphérique une solution de 49 g de 3-nitro 2-mercaptoacétate d'éthyle-pyridine préparés à l'exemple 1, en présence de nickel de Raney dans 500 ml de méthanol.EXAMPLE 8 1H-pyrido [2.3-b] [1.4] thiazine-2 (3H) -one
Formula III: R = H; X = N; Y = S
A solution of 49 g of ethyl 3-nitro-2-mercaptoacetate-pyridine prepared in Example 1 in the presence of Raney nickel in 500 ml of methanol is hydrogenated under atmospheric pressure.

Après l'absorption de la quantité théorique d'hydrogène, le catalyseur est séparé par filtration et la solution concentrée sous vide, puis le résidu repris au xylène est chauffé 16 h au reflux. Après re- froidissement, puis addition d'hexane, les cristaux formés sont essorés puis séchés. On récupère 24 g de 1H-pyrido[2,3-b][1,4]- thiazine-2 (3H)-one sous forme de cristaux de point de fusion 2070C. After absorption of the theoretical amount of hydrogen, the catalyst is filtered off and the solution concentrated in vacuo and the residue taken up in xylene is refluxed for 16 hours. After cooling, then adding hexane, the crystals formed are drained and dried. 24 g of 1H-pyrido [2,3-b] [1,4] thiazin-2 (3H) -one are recovered in the form of crystals of melting point 2070C.

EXEMPLE 9
6-chloro lH-pyrido[2 3-bl[141thiazine-2 (3H)-one
Formule III : R = C1 ; X = N ; Y = S
Selon le mode opératoire de l'exemple 9, mais å partir de 14 g de 6-chloro 3-nitro 2-mercaptoacétate d'éthylepyridine préparés å l'exemple 2, on récupère 4,1 g de 6-chloro
lH-pyrido[2,3-b][1,4]thiazine-2(3H)-one sous forme de cristaux de point de fusion 240-2450C.EXAMPLE 9
6-chloro-1H-pyrido [2,3-b] [141thiazine-2 (3H) -one
Formula III: R = C1; X = N; Y = S
According to the procedure of Example 9, but from 14 g of ethylpyridine-6-chloro-3-nitro-2-mercaptoacetate prepared in Example 2, 4.1 g of 6-chloro was recovered.
1H-pyrido [2,3-b] [1,4] thiazin-2 (3H) -one as mp 240-2450C crystals.

EXEMPLE 10 lH-pyrido[2 3-bl[1 4]pyrazine-2 (3H)-one
Formule III : R = H, X = Y = N
Selon le mode opératoire de l'exemple 9, mais à partir de 33 g de 3-nitro 2-aminoacétate d'éthyle-pyridine, préparés à l'exemple 3, on obtient 19 g de lH-pyrido[2,3-b][1,4]pyrazine-2
(3H)-one sous forme de cristaux de point de fusion 278-2820C.EXAMPLE 10 1H-pyrido [2,3-b] [1 4] pyrazine-2 (3H) -one
Formula III: R = H, X = Y = N
According to the procedure of Example 9, but starting from 33 g of ethyl 3-nitro 2-aminoacetate-pyridine, prepared in Example 3, 19 g of 1H-pyrido [2,3-b ] [1,4] pyrazine-2
(3H) -one as crystals mp 278-2820C.

EXEMPLE 11 6-trifluorométhyl 2H-l4-benzothiazine-3 (4H)-one
Formule III : R = CF3 ; X = CH ; Y = S
Selon le mode opératoire de l'exemple 9, mais à partir de 29 g de 4-trifluorométhyl 2-nitrophénylthioacétate d'éthyle préparés å l'exemple 4, on récupère 15 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 1900C.EXAMPLE 11 6-trifluoromethyl 2H-14-benzothiazine-3 (4H) -one
Formula III: R = CF3; X = CH; Y = S
According to the procedure of Example 9, but starting from 29 g of ethyl 4-trifluoromethyl-2-nitrophenylthioacetate prepared in Example 4, 15 g of 6-trifluoromethyl-2H-1,4-benzothiazine-3 are recovered. (4H) -one as 1900C melting point crystals.

EXEMPLE 12 7-fluoro 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R = F ; X = CH ; Y = S
Selon le mode opératoire de l'exemple 9, mais à. EXAMPLE 12 7-Fluoro 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R = F; X = CH; Y = S
According to the procedure of Example 9, but at.

partir de 90 g de 5-fluoro 2-nitrophénylthioacétate d'éthyle, préparés à l'exemple 5, on obtient 45 g de 7-fluoro 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 2150C.from 90 g of ethyl 5-fluoro-2-nitrophenylthioacetate, prepared in Example 5, 45 g of 7-fluoro-2H-1,4-benzothiazine-3 (4H) -one in the form of point crystals are obtained 2150C melting point.

EXEMPLE 13 6-fluoro 2H-1 4-benzothiazine-3 (4H)-one
Formule III : R = F ; X = CH ; Y = S
On hydrogène sous pression atmosphérique une solution de 75 g de 4-fluoro 2-nitrophénylthioacétate d'éthyle, préparés à l'exemple 6, en présence de nickel de Raney dans 1 litre de méthanol. EXAMPLE 13 6-Fluoro 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R = F; X = CH; Y = S
A solution of 75 g of ethyl 4-fluoro-2-nitrophenylthioacetate, prepared in Example 6, is hydrogenated under atmospheric pressure, in the presence of Raney nickel in 1 liter of methanol.

Après l'absorption de la quantitéthforique d'hydrogène, le catalyseur est séparé par filtration et la solution est concentrée sous vide puis le résidu repris par 250 ml d'eau à 500C et 60 ml d'acide chlorhydrique concentré est agité durant 30 min. Les cristaux formés sont essorés, lavés à l'eau puis au pentane et séchés. On récupère ainsi 46 g de 6-fluoro 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 1890C.After absorption of the amount of hydrogen, the catalyst is filtered off and the solution is concentrated in vacuo and the residue taken up in 250 ml of water at 50 ° C. and 60 ml of concentrated hydrochloric acid is stirred for 30 minutes. The crystals formed are drained, washed with water and then with pentane and dried. 46 g of 6-fluoro-2H-1,4-benzothiazine-3 (4H) -one are thus recovered in the form of crystals of melting point 1890C.

EXEMPLE 14 6-fluoro 2H-1,4-benzoxazine-3 (4H)-one
Formule III : R = F ; X = CH ; Y = O
On hydrogène sous pression atmosphérique une solution de 46 g de 4-fluoro 2-nitrophénoxyacétate d'éthyle, préparés a l'exemple 7, en présence de nickel de Raney dans 500 ml de méthanol.EXAMPLE 14 6-Fluoro 2H-1,4-benzoxazine-3 (4H) -one
Formula III: R = F; X = CH; Y = O
A solution of 46 g of ethyl 4-fluoro-2-nitrophenoxyacetate, prepared in Example 7, is hydrogenated under atmospheric pressure in the presence of Raney nickel in 500 ml of methanol.

Après l'absorption de la quantité théorique d'hydrogène le catalyseur est séparé par filtration et la solution est concentrée sous vide, et le résidu repris à l'éther cristallise. Les cristaux formés sont essorés, lavés à l'éther et séchés. On obtient ainsi 28 g de 6-fluoro' 2H-1,4-benzoxazine-3 (4H)-one sous forme de cristaux de point de fusion 206-2070C.After absorption of the theoretical amount of hydrogen the catalyst is filtered off and the solution is concentrated in vacuo and the residue taken up in ether crystallizes. The crystals formed are drained, washed with ether and dried. 28 g of 6-fluoro-2H-1,4-benzoxazine-3 (4H) -one are thus obtained in the form of crystals of melting point 206-2070 ° C.

EXEMPLE 15 1-acétate d'éthyle-pyrido[2.3-b](l.4]thiazine-2 (3H)-one
Formule Il: R = H; X = N; Y S; Z =0; R' = C H
Une solution de 12 g de lH-pyrido[2,3-b][l,4jthiazine-2 (311)-one dans 75 ml de diméthylformamide est ajoutée goutte à goutte à une suspension de 3,5 g d'hydrure de sodium dans 30 mi de diméthylformamide.Après la fin de l'addition, on agite durant 30 min puis on ajoute goutte à goutte 9 ml de bromoacétate d'éthyle ; quand l'addition est achevée, on agite encore durant 6 h a température ambiante, puis, apres addition d'eau et de glace, on extrait à l'éther qu'on lave soigneusement à l'eau, sèche et qu'on évapore. Le résidu obtenu cristallise dans un mélange d'éther isopropylique et d'hexane.EXAMPLE 15 1-ethyl acetate-pyrido [2.3-b] (1,4) thiazine-2 (3H) -one
Formula II: R = H; X = N; YS; Z = 0; R '= CH
A solution of 12 g of 1H-pyrido [2,3-b] [1,4thiazin-2 (311) -one in 75 ml of dimethylformamide is added dropwise to a suspension of 3.5 g of sodium hydride. in 30 ml of dimethylformamide. After the end of the addition, the mixture is stirred for 30 minutes and 9 ml of ethyl bromoacetate are then added dropwise; when the addition is complete, stirring is continued for 6 hours at room temperature, then, after addition of water and ice, extracted with ether, washed well with water, dried and evaporated. The resulting residue crystallizes from a mixture of isopropyl ether and hexane.

Les cristaux sont essorés et séchés. On obtient 9 g de l-acétate d'éthyle-pyrido[2,3-b][1,4]thiazine-2 (3H)-one sous forme de cristaux de point de fusion 830C. The crystals are dewatered and dried. 9 g of 1-ethyl acetate-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one are obtained in the form of crystals with a melting point of 830 ° C.

EXEMPLE 16 6-chloro l-acétate d'éthyle-pyridor2. 3-b C1.47thiazine-2 (3H)-one
Formule II : R = C1 ; X = N ; Y = S ; Z = 0 ; R' = C2H5
Selon le mode opératoire de l'exemple 15, mais à partir de 4,1 g de 6-chlorolH-pyrido[2,3-b][l,4]thiazine-2 (3H)-one préparés l'exemple 9, on obtient après cristallisation dans l'éther isopropylique 3,5 g de 6-chloro 1-acétate d'éthyle-pyrido[2,3b][l,4] thiazine-2 (3H)-one sous forme de cristaux de point due fusion 105 C. EXAMPLE 16 6-chloro-1-ethyl acetate-pyridor 2 3-b C1.47thiazine-2 (3H) -one
Formula II: R = C1; X = N; Y = S; Z = 0; R '= C2H5
According to the procedure of Example 15, but starting from 4.1 g of 6-chloroH-pyrido [2,3-b] [1,4] thiazin-2 (3H) -one prepared in Example 9, 3.5 g of 6-chloro-1-ethyl acetate-pyrido [2,3b] [1,4] thiazin-2 (3H) -one are obtained after crystallization from isopropyl ether in the form of crystals of dot 105 C fusion

EXEMPLE 17
Chlorhydrate de lacétate d 'éthyle-pyrido(2 3-b][1 4]pyrazine-2 (3H)-one
Formule II : R = H ; X = Y = N ; Z = O ; R' = C H
Selon le mode opératoire de l'exemple 15, mais à partir de 12 g de 1H-pyrido[2,3-b][1,4]pyrazine-2 (3H)-one préparés a l'exemple 10, on obtient par extraction au chloroforme et cristallisation dans un mélange éther-éther de pétrole la base qui a un point de fusion de 142 C. Cette base est dissoute dans un mélange acétone-méthanol et additionnée d'éther chlorhydrique jusqu'à pH acide. Les cristaux formés essorés sont lavés àltéther et séchés.On récupère ainsi 7,8 g de chlorhydrate de 1-acétate d'éthyle-pyrido[2,3-b][1,4Jpyrazine-2 (3H)-one sous forme de cristaux de point de fusion 207-2100C.EXAMPLE 17
Ethyl-pyrido (2 3-b) [1 4] pyrazine-2 (3H) -one ethyl acetate hydrochloride
Formula II: R = H; X = Y = N; Z = O; R '= CH
According to the procedure of Example 15, but from 12 g of 1H-pyrido [2,3-b] [1,4] pyrazine-2 (3H) -one prepared in Example 10, there is obtained by extraction with chloroform and crystallization in a mixture of ether and petroleum ether base which has a melting point of 142 C. This base is dissolved in an acetone-methanol mixture and added with hydrochloric ether until acidic pH. The crystals which have been dewatered are washed with ether and dried. 7.8 g of ethyl 1-acetate-pyrido [2,3-b] [1,4-pyrazine-2 (3H) -one hydrochloride are thus recovered in the form of crystals. Melting point 207-2100C.

EXEMPLE 18 6-trifluorométhyl 2H-1.4-benzothiazine-3-one 4-acétate d'éthyle
Formule II : R = CF3 ; .X = CH ; Y = S ; Z = O ; R' = C2H5
Selon le mode opératoire de l'exemple 15, mais å partir de 12 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3 (4H)-one préparés a l'exemple 11, on obtient après filtration sur gel de silice 10,5 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme d'une huile qu'on utilise telle quelle pour l'étape suivante.EXAMPLE 18 6-trifluoromethyl 2H-1,4-benzothiazin-3-one 4-ethyl acetate
Formula II: R = CF3; X = CH; Y = S; Z = O; R '= C2H5
According to the procedure of Example 15, but starting from 12 g of 6-trifluoromethyl-2H-1,4-benzothiazine-3 (4H) -one prepared in Example 11, after filtration on silica gel 10 5 g of 6-trifluoromethyl-2H-1,4-benzothiazin-3-one 4-ethyl acetate in the form of an oil which is used as it is for the next step.

EXEMPLE 19 7-fluoro 2H-1.4-benzothiazine-3-one 4-acétate d'éthyle
Formule II : R = F ; X = CH ; Y = S ; Z = 0 ; R' = C2H5
Selon le mode opératoire de l'exemple 15, mais a partir de 20 g de 7-fluoro 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 12, on obtient après cristallisation dans un mélange éther-pentane 19 g de 7-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 850C. EXAMPLE 19 7-Fluoro-2H-1,4-benzothiazin-3-one 4-ethyl acetate
Formula II: R = F; X = CH; Y = S; Z = 0; R '= C2H5
According to the procedure of Example 15, but starting from 20 g of 7-fluoro-2H-1,4-benzothiazine-3 (4H) -one prepared in Example 12, after crystallization in a mixture of ether and pentane 19 g of 7-fluoro 2H-1,4-benzothiazin-3-one 4-ethyl acetate in the form of crystals of melting point 850C.

EXEMPLE 20 7-fluoro 2H-1.4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R = F ; X = CH ; Y = Z = S ; R' = C2H5
On agite durant 15 h å température ambiante une solution de 19 g de 7-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle, préparés à l'exemple 19, dans 200 ml de chloroforme contenant 19 g de P2 S5. La solution est ensuite filtrée puis concentrée sous vide et le résidu est filtré sur silicagel. Par élution au benzène puis recristallisation des cristaux obtenus dans l'hexane, on obtient 11,2 g de 7-fluoro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 870C.EXAMPLE 20 7-Fluoro-2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R = F; X = CH; Y = Z = S; R '= C2H5
A solution of 19 g of 7-fluoro-2H-1,4-benzothiazin-3-one 4-ethyl acetate, prepared in Example 19, in 200 ml of chloroform containing 19 g, is stirred at room temperature for 15 hours. P2 S5. The solution is then filtered and concentrated in vacuo and the residue is filtered on silica gel. By elution with benzene and then recrystallization of the crystals obtained in hexane, 11.2 g of 7-fluoro-2H-1,4-benzothiazine-3-thione 4-ethyl acetate are obtained in the form of crystals of melting point 870 ° C. .

EXEMPLE 21 6-fluoro 2H-1*4-benzothiazine-3-one 4-acétate d'éthyle
Formule II : R = F ; X = CH ; Y = S ; Z = O ; R' = C2H5
Selon le mode opératoire de l'exemple 15, mais à partir de 43 g de 6-fluoro 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 13,on obtient après cristallisation dans un mélange acétone-pentane 36 g de 6-fluoro2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 800C.EXAMPLE 21 6-Fluoro-2H-1 * 4-benzothiazin-3-one 4-ethyl acetate
Formula II: R = F; X = CH; Y = S; Z = O; R '= C2H5
According to the procedure of Example 15, but starting from 43 g of 6-fluoro-2H-1,4-benzothiazine-3 (4H) -one prepared in Example 13, after crystallization in a mixture acetone- pentane 36 g of 6-fluoro2H-1,4-benzothiazin-3-one 4-ethyl acetate in the form of crystals melting point 800C.

EXEMPLE 22 6-fluoro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule Il : R = F ; X = CH ; Y = Z = S, R' = C H
Selon le mode opératoire de l'exemple 20, mais à partir de 15 g de 6-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d éthyle préparés à l'exemple 21, on obtient après filtration sur silicagel, élution au benzene et cristallisation dans le mélange éther isopropylique-pentane, 7,4 g de 6-fluoro 2H-1,4-benzothiazine3-thione 4-acétate d'éthyle sous forme de dristaux de point de fusion 66 C. EXAMPLE 22 6-Fluoro-2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R = F; X = CH; Y = Z = S, R '= CH
According to the procedure of Example 20, but from 15 g of 6-fluoro-2H-1,4-benzothiazin-3-one 4-ethyl acetate prepared in Example 21, after filtration on silica gel, benzene elution and crystallization in the isopropyl ether-pentane mixture, 7.4 g of 6-fluoro-2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of 66 m.

EXEMPLE 23 6-fluoro 2H-1.4-benzoxazine-3-on 4-acétate d'éthyle
Formule II : R = F ; X = CH ; Y = Z = 0 ; R' = C2H5
Selon le mode 'opératoire de l'exempte 15, mais à partir de 27,3 g de 6-fluoro 2H-1,4-benzoxazine-3 (4H)-one préparés à l'exemple 14, on récupère 32 g de 6-fluoro 2H-1,4-benzoxazine-3one 4-acétate d'éthyle sous forme de cristaux de point de fusion 730C. EXAMPLE 23 6-Fluoro 2H-1,4-benzoxazine-3-on 4-ethyl acetate
Formula II: R = F; X = CH; Y = Z = 0; R '= C2H5
According to the procedure of Example 15, but from 27.3 g of 6-fluoro-2H-1,4-benzoxazine-3 (4H) -one prepared in Example 14, 32 g of 2-fluoro-1,4-benzoxazin-3-yl 4-ethyl acetate in the form of crystals of melting point 730 ° C.

EXEMPLE 24 6-fluoro 2H-1,4-benzoxazine-3-thione 4-acétate d'éthyle
Formule II : R = F ; X = CH ; Y = O ; Z = S ; R' = C H
Selon le mode opératoire de l'exemple 20, mais à partir de 22 g de 6-fluoro 2H-1,4-benzoxazine-3-one 4-acétate d'éthyle préparés à l'exemple 23, on obtient après filtration sur silicagel, élution au benzène et cristallisation dans le mélange éther-pentane, 13,8 g de 6-fluoro 2H-l,4-benzoxazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 52"C. EXAMPLE 24 6-Fluoro-2H-1,4-benzoxazine-3-thione 4-ethyl acetate
Formula II: R = F; X = CH; Y = O; Z = S; R '= CH
According to the procedure of Example 20, but from 22 g of 6-fluoro-2H-1,4-benzoxazin-3-one 4-ethyl acetate prepared in Example 23, after filtration is obtained on silica gel , eluting with benzene and crystallizing from the ether-pentane mixture, 13.8 g of 6-fluoro-2H-1,4-benzoxazine-3-thione 4-ethyl acetate as crystals of melting point 52 ° C.

EXEMPLE 25 l-acide acétique-pyrido[2.3-b]thiazine-2 (3H)-one
Formule I : R = H ; X = N ; Y = S ; Z = O
On porte 10 min à 500C une solution de 9 g de l-acé- tate d'éthyle-pyridot2,3-b]thiazine-2 (3H)-one préparés à l'exemple 15 dans 30 ml de méthanol contenant 1,5 g de soude dissoute dans 20 ml d'eau. Le mélange réactionnel est ensuite traité au charbon actif, puis filtré et acidifié à froid par de l'acide chlorhydrique dilué, concentré sous vide de moitié puis additionné d'eau et de glace.EXAMPLE 25 1-acetic acid-pyrido [2.3-b] thiazine-2 (3H) -one
Formula I: R = H; X = N; Y = S; Z = O
A solution of 9 g of 1-ethyl acetate-pyridot2,3-b] thiazin-2 (3H) -one prepared in Example 15 in 30 ml of methanol containing 1.5 g is heated for 10 min at 500 ° C. g of sodium hydroxide dissolved in 20 ml of water. The reaction mixture is then treated with activated charcoal, then filtered and cold acidified with dilute hydrochloric acid, concentrated in vacuo in half and then added with water and ice.

Les cristaux formés sont essorés, lavés 2 fois avec 10 ml d'eau puis à l'acétone et séchés. On récupère ainsi 5,5 g de l-acide acétique pyrido[2,3-b]thiazine-2 (3H)-one sous forme de cristaux de point de fusion 252-255"C. The crystals formed are drained, washed twice with 10 ml of water and then with acetone and dried. 5.5 g of 1-acetic acid pyrido [2,3-b] thiazine-2 (3H) -one are thus recovered in the form of crystals of melting point 252-255 ° C.

EXEMPLE 26 6-chloro l-acide acétique-pyridor2 3-b]thiazine-2 (3H)-one Formule I : R= C1 ; X = N ; Y = S ; Z = O
Selon le mode opératoire de l'exemple 25, mais en utilisant 3,5 g de 6-chloro l-acétate d'éthyle-pyrido[2,3-bJthiazine-2
(3H)-one préparés à l'exemple 16, on obtient 2 g de 6-chloro l-acide acétique-pyrido[2,3-b]-thiazine-2 (3H)-one sous forme de cristaux de point de fusion 195-200tC. EXAMPLE 26 6-Chloro-1-acetic acid-pyridor-3-b] thiazine-2 (3H) -one Formula I: R = Cl; X = N; Y = S; Z = O
According to the procedure of Example 25, but using 3.5 g of 6-chloro-1-ethyl acetate-pyrido [2,3-b] thiazine-2
(3H) -one prepared in Example 16, 2 g of 6-chloro-1-acetic acid-pyrido [2,3-b] thiazine-2 (3H) -one are obtained in the form of melting point crystals. 195-200tC.

EXEMPLE 27
Chlorhydrate de l-acide acétique-pyrido[2.3-b][1 4Jpyrazine-2 (3H)-one
Formule I : R = H ; X = Y = N ; Z = 0
On chauffe durant 7 h au reflux une solution de 7,8 g du chlorhydrate de 1-acétate d'éthyle-pyrido[2,3-b][1,4]pyrazine- 2 (3H)-one préparés à l'exemple 17 dans 50 ml d'acide chlorhydrique 3N.EXAMPLE 27
1-acetic acid-pyrido [2,3-b] [1,4] pyrazine-2 (3H) -one hydrochloride
Formula I: R = H; X = Y = N; Z = 0
A solution of 7.8 g of 1-ethyl acetate-pyrido [2,3-b] [1,4] pyrazine-2 (3H) -one hydrochloride prepared in the example of Example 1 is heated under reflux for 7 hours. 17 in 50 ml of 3N hydrochloric acid.

Le mélange réactionnel est ensuite concentré sous vide et le résidu repris à l'acétone cristallise. Les cristaux essorés, lavés à l-'acé- tone et séchés sont recristallisés dans 1 'acide acétique. On obtient ainsi 3,6 g du chlorhydrate de l-acide acétique-pyridop2,3-b][1,4]- pyrazine-2 (3H)-one sous forme de cristaux de point de -fusion 260-2650C avec décomposition.The reaction mixture is then concentrated under vacuum and the residue taken up in acetone crystallizes. The crystals drained, washed with acetone and dried are recrystallized from acetic acid. 3.6 g of 1-acetic acid-pyridop [2,3-b] [1,4] pyrazine-2 (3H) -one hydrochloride are thus obtained in the form of mp 260-2650C crystals with decomposition.

EXEMPLE 28 6-trifluorométhol-2H-1.4-benzothiazine-3-one 4-acide acétique
Formule I : R = CF3 ; X = CH ; Y = S ; Z = O
On porte 15 min, à 60 C, une solution de 10,5 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle, préparés à l'exemple 18, dans 20 ml méthanol contenant 2 g de soude dissoute dans 10 ml d'eau. Le mélange réactionnel est ensuite traité au charbon actif puis filtré et acidifié à froid par de l'acide chlorhydrique dilué. Les cristaux obtenus alors sont essorés, lavés à l'eau puis à l'éther isopropylique et séchés. On récupère ainsi 7 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 165-1670C.EXAMPLE 28 6-trifluoromethol-2H-1,4-benzothiazin-3-one 4-acetic acid
Formula I: R = CF3; X = CH; Y = S; Z = O
A solution of 10.5 g of 6-trifluoromethyl-2H-1,4-benzothiazin-3-one 4-ethyl acetate, prepared in Example 18, in 20 ml of methanol, is heated for 15 min at 60 ° C. 2 g of sodium hydroxide dissolved in 10 ml of water. The reaction mixture is then treated with activated charcoal and then filtered and cold acidified with dilute hydrochloric acid. The crystals thus obtained are dewatered, washed with water and then with isopropyl ether and dried. 7 g of 6-trifluoromethyl-2H-1,4-benzothiazin-3-one 4-acetic acid are thus recovered in the form of crystals of melting point 165 ° -1670 ° C.

EXEMPLE 29 7-fluoro 2H-1.4-benzothiazine-3-one 4-acide acétique
Formule I : R = F ; X = CH ; Y = S ; Z = 0
Selon le mode opératoire de l'exemple 28, mais å partir de 11 g de 7-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 19, on récupère 7 g de 7-fluoro 2H1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 152-1540C.EXAMPLE 29 7-Fluoro 2H-1,4-benzothiazin-3-one 4-acetic acid
Formula I: R = F; X = CH; Y = S; Z = 0
According to the procedure of Example 28, but from 11 g of 7-fluoro-2H-1,4-benzothiazin-3-one-4-ethyl acetate prepared in Example 19, 7 g of 2-fluoro-1,4-benzothiazin-3-one 4-acetic acid in the form of crystals having a melting point of 152-1540 ° C.

EXEMPLE 30 7-fluoro 2H-l .4-benzothiazine-3-thione 4-acide acétique
Formule I : R = F ; X = CH ; Y = Z = S
On abandonne 2 jours à température ambiante une solution de 8,7 g de 7-fluoro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle, préparés à l'exemple 20, dans 100 ml de méthanol contenant 1,2 g de soude dissoute dans 15 ml d'eau. Le mélange réactionnel est ensuite concentré sous vide à froid puis dilué à l'eau qu'on extrait - l'éther. La phase aqueuse est ensuite acidifiée à froid par de
l'acide chlorhydrique dilué et extraite à l'éther. Cette phase
éthérée, lavée à l'eau, est séchée puis, après filtration, l'éther est évaporé sous vide. Le résidu obtenu cristallise dans un mélange éther-hexane.On récupère ainsi après essorage et séchage, des cristaux, 6 g de 7-fluoro 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 156-1570C.EXAMPLE 30 7-Fluoro 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R = F; X = CH; Y = Z = S
At room temperature, a solution of 8.7 g of 7-fluoro-2H-1,4-benzothiazine-3-thione 4-ethyl acetate, prepared in Example 20, in 100 ml of methanol containing 1 g. 2 g of sodium hydroxide dissolved in 15 ml of water. The reaction mixture is then concentrated under vacuum in the cold and then diluted with water which is extracted with ether. The aqueous phase is then acidified cold by
the hydrochloric acid diluted and extracted with ether. This phase
ethereal, washed with water, is dried and then, after filtration, the ether is evaporated under vacuum. The residue obtained crystallizes in an ether-hexane mixture. After extraction and drying, crystals are thus recovered. 6 g of 7-fluoro-2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of 156-1570C fusion.

EXEMPLE 31 6-fluoro 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R = F ; X = CH ; Y = S ; Z = O
Selon le mode opératoire de l'exemple 28, mais a partir de 12 g de 6-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 21, on obtient après cristallisation dans le toluène 7,5 g de 6-fluoro 2H-1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 156-157"C. EXAMPLE 31 6-Fluoro-2H-1,4-benzothiazin-3-one 4-acetic acid
Formula I: R = F; X = CH; Y = S; Z = O
According to the procedure of Example 28, but from 12 g of 6-fluoro-2H-1,4-benzothiazin-3-one 4-ethyl acetate prepared in Example 21, after crystallization in the toluene 7.5 g of 6-fluoro-2H-1,4-benzothiazin-3-one 4-acetic acid as crystals of mp 156-157 ° C.

EXEMPLE 32 6-fluoro 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R = F ; X = CH ; Y = Z = S
Selon le mode opératoire de l'exemple 30, mais à partir de 7,4 g de 6-fluoro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 22, on obtient 5,3 g de 6-fluoro 2H1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 188-1900C.EXAMPLE 32 6-Fluoro 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R = F; X = CH; Y = Z = S
According to the procedure of Example 30, but starting from 7.4 g of 6-fluoro-2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 22, 5, 3 g of 6-fluoro-2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals having a melting point 188-1900 ° C.

EXEMPLE 33 6-fluoro .2H-l.4-benzoxazîne-3-thione 4-acide acétique
Formule I : R = F ; X -- CH ; Y = O ; Z = S
Selon le mode opératoire de 1 'exemple 30, mais en utilisant 8,8 g de 6-fluoro 2H-1,4-benzoxazine-3-thione 4-acétate d'éthyle, préparés à l'exemple 24, on obtient apres filtration sur silicagel, en éluant au benzène, 1,5 g de 6-fluoro 2H-14-benzoxazine- 3-thione 4-acide acétique sous forme de cristaux de point de fusion 153-155"C.EXAMPLE 33 6-Fluoro-2H-1,4-benzoxazin-3-thione 4-acetic acid
Formula I: R = F; X - CH; Y = O; Z = S
According to the procedure of Example 30, but using 8.8 g of 6-fluoro-2H-1,4-benzoxazine-3-thione 4-ethyl acetate, prepared in Example 24, is obtained after filtration. on silica gel, eluting with benzene, 1.5 g of 6-fluoro-2H-14-benzoxazine-3-thione 4-acetic acid as crystals, m.p. 153-155 ° C.

PHAZACOLOGIE
Principe
L'activité inhibitrice de l'aldose réductase est évaluée in vitro a partir d'un homogénat de cristallin de rat comme source d'enzyme. Le substrat utilisé est le DL-glycéraldShyde qui est transformé par l'aldose réductase en glycérol, en présence de NADPH.(x)
Cette réaction est suivie par spectrophotométrie à 340 nm, en l'absence () Nicotinamide Adénine Dinucléotide PHosphate forme réduite. PHAZACOLOGIE
Principle
The inhibitory activity of aldose reductase is evaluated in vitro from a rat crystalline homogenate as an enzyme source. The substrate used is DL-glyceraldehyde, which is converted by aldose reductase to glycerol in the presence of NADPH.
This reaction is followed spectrophotometrically at 340 nm, in the absence () Nicotinamide adenine dinucleotide phosphate reduced form.

et en présence des inhibiteurs à tester, la variation de densité optique étant proportionnelle à la concentration de la coenzyme réduite.and in the presence of the inhibitors to be tested, the variation in optical density being proportional to the concentration of the reduced coenzyme.

Résultats
Les résultats figurent dans le tableau I ci-dessous et représentent pour les différents exemples le pourcentage d'inhibition de l'activité enzymatique par rapport å l'activité témoin en fonction des différentes concentrations (M.l > utilisées.Results
The results are shown in Table I below and represent for the various examples the percentage inhibition of the enzymatic activity relative to the control activity as a function of the different concentrations (Ml> used.

TABLEAU I

Figure img00130001
TABLE I
Figure img00130001

<tb> <SEP> Inhibition <SEP> par <SEP> rapport <SEP> à <SEP> l'activité <SEP> témoin, <SEP> %
<tb> Concentration <SEP> 10-4 <SEP> 10-5 <SEP> 10-6 <SEP> 10-7 <SEP> <SEP> 10-8 <SEP> 10-9 <SEP>
<tb> <SEP> (mole/litre)
<tb> <SEP> exemple <SEP> 25 <SEP> 95 <SEP> 82 <SEP> 37 <SEP> 11 <SEP> 4 <SEP> 9
<tb> <SEP> exemple <SEP> 26 <SEP> 96 <SEP> 80 <SEP> 5
<tb> <SEP> exemple <SEP> 27 <SEP> 95 <SEP> 86 <SEP> 6
<tb> <SEP> exemple <SEP> 28 <SEP> 90 <SEP> 57 <SEP> 3
<tb> <SEP> exemple <SEP> 29 <SEP> 100 <SEP> 95 <SEP> 25
<tb> <SEP> exemple <SEP> 30 <SEP> 99 <SEP> 97 <SEP> 91 <SEP> 58 <SEP> 60 <SEP> 15
<tb> <SEP> exemple <SEP> 31 <SEP> 98 <SEP> 91 <SEP> 10
<tb>
En thérapeutique humaine, les composés de formule I et éventuellement leurs sels d'addition non toxiques peuvent être administrés notamment par voie orale sous forme de gélules ou comprimés renfermant de 50 à 300 mg de principe actif.<tb><SEP> Inhibition <SEP> with <SEP> report <SEP> at <SEP> activity <SEP> control, <SEP>%
<tb> Concentration <SEP> 10-4 <SEP> 10-5 <SEP> 10-6 <SEP> 10-7 <SEP><SEP> 10-8 <SEP> 10-9 <SEP>
<tb><SEP> (mole / liter)
<tb><SEP> example <SEP> 25 <SEP> 95 <SEP> 82 <SEP> 37 <SEP> 11 <SEP> 4 <SEP> 9
<tb><SEP> example <SEP> 26 <SEP> 96 <SEP> 80 <SEP> 5
<tb><SEP> example <SEP> 27 <SEP> 95 <SEP> 86 <SEP> 6
<tb><SEP> example <SEP> 28 <SEP> 90 <SEP> 57 <SEP> 3
<tb><SEP> example <SEP> 29 <SEP> 100 <SEP> 95 <SEP> 25
<tb><SEP> example <SEP> 30 <SEP> 99 <SEP> 97 <SEP> 91 <SEP> 58 <SEP> 60 <SEP> 15
<tb><SEP> example <SEP> 31 <SEP> 98 <SEP> 91 <SEP> 10
<Tb>
In human therapy, the compounds of formula I and optionally their non-toxic addition salts may be administered especially orally in the form of capsules or tablets containing 50 to 300 mg of active ingredient.

Ces différents composés de formule I ou leurs sels d'addition non toxiques présentent une activité inhibitrice de l'aldose réductase. Ils peuvent donc être administrés avec profit pour traiter certaines complications de la maladie diabétique (cataracte et neuropathies périphériques).  These various compounds of formula I or their non-toxic addition salts have an aldose reductase inhibitory activity. They can therefore be used with advantage to treat certain complications of diabetic disease (cataracts and peripheral neuropathies).

TABLEAU II

Figure img00140001
TABLE II
Figure img00140001

<tb> <SEP> CH <SEP> COOH
<tb> Exemple <SEP> 25 <SEP> lÉ
<tb> <SEP> CH2COOH
<tb> Exemple <SEP> 26 <SEP> v <SEP> f
<tb> <SEP> Cl <SEP> NS
<tb> <SEP> CH <SEP> COOH
<tb> Exemple <SEP> 27 <SEP> t <SEP> f <SEP> , <SEP> HC1
<tb> <SEP> N
<tb> <SEP> CH <SEP> COOH
<tb> <SEP> l
<tb> <SEP> 3 <SEP> W <SEP> N <SEP> > g > O
<tb> Exemple <SEP> 28
<tb> <SEP> CH <SEP> CO0H
<tb> <SEP> v2
<tb> Exemple <SEP> 29 <SEP> FÀ
<tb> <SEP> CH <SEP> COOH
<tb> <SEP> s
<tb> Exemple <SEP> 30
<tb> <SEP> F <SEP> t <SEP> S
<tb> Exemple <SEP> 30
<tb>
TABLEAU II(suite)

Figure img00150001
<tb><SEP> CH <SEP> COOH
<tb> Example <SEP> 25 <SEP>
<tb><SEP> CH2COOH
<tb> Example <SEP> 26 <SEP> v <SEP> f
<tb><SEP> Cl <SEP> NS
<tb><SEP> CH <SEP> COOH
<tb> Example <SEP> 27 <SEP> t <SEP> f <SEP>, <SEP> HC1
<tb><SEP> N
<tb><SEP> CH <SEP> COOH
<tb><SEP>
<tb><SEP> 3 <SEP> W <SEP> N <SEP>>g> O
<tb> Example <SEP> 28
<tb><SEP> CH <SEP> CO0H
<tb><SEP> v2
<tb> Example <SEP> 29 <SEP> FÀ
<tb><SEP> CH <SEP> COOH
<tb><SEP> s
<tb> Example <SEP> 30
<tb><SEP> F <SEP> t <SEP> S
<tb> Example <SEP> 30
<Tb>
TABLE II (continued)
Figure img00150001

<tb> <SEP> CH2COOH
<tb> <SEP> FMÀ
<tb> Exemple <SEP> 31
<tb> <SEP> CH2COOH
<tb> <SEP> FEZ
<tb> Exemple <SEP> 32
<tb> <SEP> CH <SEP> COOH
<tb> <SEP> FùS
<tb> Exemple <SEP> 33
<tb> <SEP> o
<tb> <tb><SEP> CH2COOH
<tb><SEP> FMÀ
<tb> Example <SEP> 31
<tb><SEP> CH2COOH
<tb><SEP> FEZ
<tb> Example <SEP> 32
<tb><SEP> CH <SEP> COOH
<tb><SEP> FùS
<tb> Example <SEP> 33
<tb><SEP> o
<Tb>

Claims (9)

tr ifluoromé thyle, trifluorométhoxy, et leurs sels non toxiques d'addition. trluoromethyl, trifluoromethoxy, and their non-toxic addition salts. gène, un groupement trifluorométhyle, méthoxy, thiométhyle, thio gene, a group trifluoromethyl, methoxy, thiomethyl, thio R peutreprésenter l'hydrogène dans le cas où X = N ou alors un haloR can represent hydrogen in the case where X = N or a halo X représente CH ou l'atome d'azoteX represents CH or the nitrogen atom Z et Y ne peuvent représenter simultanément l'atome d'oxygène; Z and Y can not simultaneously represent the oxygen atom; Y peut, en outre, représenter l'atome d'azote notamment si X est 11 azote, Y may also represent the nitrogen atom, especially if X is nitrogen, Y représente l'atome d' oxygène ou de soufre,Y represents the oxygen or sulfur atom, Z représente l'atome d'oxygène ou de soufre,Z represents the oxygen or sulfur atom, dans laquelle in which
Figure img00160001
Figure img00160001
 REVENDICATIONS 1. Nouveaux composés, caractérisés en ce qu'ils répondent à la formule 1. New compounds, characterized in that they respond to the formula 2. Nouveaux composés selon la revendication 1, caractérisésen ce que Z représente le soufre.2. New compounds according to claim 1, characterized in that Z represents sulfur. 3. Nouveaux composés selon la revendication 1 ou 2, caractérisés en ce que Y représente le soufre.3. New compounds according to claim 1 or 2, characterized in that Y represents sulfur. 4. Nouveaux composés selon l'une quelconque des revendications 1 à 3, caractérisés en ce que R représente le fluor.4. New compounds according to any one of claims 1 to 3, characterized in that R represents fluorine. 5. Nouveau composé selon la revendication 1, caractérisé en ce qu'il répond à la formule5. New compound according to claim 1, characterized in that it meets the formula
Figure img00160002
Figure img00160002
 6. Nouveau composé selon la revendication 1, caractérisé en ce qu'il répond la formule 6. New compound according to claim 1, characterized in that it meets the formula
Figure img00160003
Figure img00160003
 7. Nouveau composé selon la revendication 1, caractérisé en ce qu'il répond a la formule 7. New compound according to claim 1, characterized in that it corresponds to the formula
Figure img00170001
Figure img00170001
 8. Procédé de préparation des nouveaux composés selon l'une quelconque des revendications 1 a 7, caractérisé en ce que l'on réalise l'hydrolyse en milieu basique cu acide d'esters de formule 8. Process for the preparation of the new compounds according to any one of claims 1 to 7, characterized in that the hydrolysis in basic medium or acid of esters of formula
Figure img00170002
Figure img00170002
 où R, X, Y et Z sont tels que définis dans l'une quelconque des revendications 1 à 7 et R' représente un radical alkyle inférieur en C1-C5, ramifié ou non. where R, X, Y and Z are as defined in any one of claims 1 to 7 and R 'represents a lower alkyl radical C1-C5, branched or unbranched. 9. Nouveaux médicaments, caractérisés en ce qu'ils contiennent au moins un composé selon l'une quelconque des revendications 1 à 8. 9. New drugs, characterized in that they contain at least one compound according to any one of claims 1 to 8.
FR8407791A 1984-05-18 1984-05-18 NOVEL HETEROCYCLIC DERIVATIVES, PROCESSES FOR THEIR PREPARATION, MEDICAMENTS CONTAINING THEM, USEFUL IN PARTICULAR AS INHIBITORS OF ALDOSE REDUCTASE Expired FR2564463B1 (en)

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IE112685A IE58312B1 (en) 1984-05-18 1985-05-06 Heterocyclic derivatives, processes for their preparation and drugs in which they are present, which are useful especially as aldose reductase inhibitors
PH32246A PH21118A (en) 1984-05-18 1985-05-09 Heterocyclic derivatives, a process for their preparation the pharmaceutical composition containing them
EP85400927A EP0162776B1 (en) 1984-05-18 1985-05-13 Heterocyclic derivatives, process for their preparation and medicaments useful as aldose reductase inhibitors containing them
GR851159A GR851159B (en) 1984-05-18 1985-05-13
DE8585400927T DE3569529D1 (en) 1984-05-18 1985-05-13 Heterocyclic derivatives, process for their preparation and medicaments useful as aldose reductase inhibitors containing them
NZ212060A NZ212060A (en) 1984-05-18 1985-05-13 Bicyclic hetrocycles and pharmaceutical derivatives
AT85400927T ATE42297T1 (en) 1984-05-18 1985-05-13 HETEROCYCLIC DERIVATIVES, PROCESSES FOR THEIR MANUFACTURE, PHARMACEUTICALS CONTAINING THEM USEFUL AS ALDOSE REDUCTAE INHIBITORS.
CA000481503A CA1306747C (en) 1984-05-18 1985-05-14 Process for the preparation of new heterocyclic derivatives which can be used especially as aldose reductase inhibitors
US06/733,685 US4755509A (en) 1984-05-18 1985-05-14 Heterocyclic aldose reductase inhibitors and methods of using them
ZA853629A ZA853629B (en) 1984-05-18 1985-05-14 New heterocyclic derivatives,the processes for their preparation and drugs in which they are present,which are useful especially as aldose reductase inhibitors
KR1019850003306A KR900004320B1 (en) 1984-05-18 1985-05-15 Process for preparation of new heterocyclic derivatives
AU42518/85A AU586972B2 (en) 1984-05-18 1985-05-15 New heterocyclic derivatives, the processes for their preparation and drugs in which they are present, which are useful especially as aldose reductase inhibitors
JP60102788A JPH0692371B2 (en) 1984-05-18 1985-05-16 Novel heterocyclic derivative, method for producing the same, and method for producing a medicine containing these and particularly useful as an aldose reductase inhibitor
DK219685A DK219685A (en) 1984-05-18 1985-05-17 HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND USE AS MEDICINAL PRODUCTS
PT80489A PT80489B (en) 1984-05-18 1985-05-17 PROCESS FOR THE PREPARATION OF NOVEL HETEROCYCLIC DERIVATIVES USEFULLY AS INNIBITORS OF ALDOSE REDUCTASE
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GB1173942A (en) * 1967-06-06 1969-12-10 Bellon Labor Sa Roger New 2,3-Dihydro-1,4-Benzoxazines
US3923709A (en) * 1974-08-30 1975-12-02 Monsanto Co 3,4-Dihydro-3-oxo-2H-1,4-benzothiazines and benzoxazines

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