FR2578542A2 - New heterocyclic derivatives, processes for their preparation, medicaments which contain them, useful especially as aldose reductase inhibitors - Google Patents

New heterocyclic derivatives, processes for their preparation, medicaments which contain them, useful especially as aldose reductase inhibitors Download PDF

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Publication number
FR2578542A2
FR2578542A2 FR8503236A FR8503236A FR2578542A2 FR 2578542 A2 FR2578542 A2 FR 2578542A2 FR 8503236 A FR8503236 A FR 8503236A FR 8503236 A FR8503236 A FR 8503236A FR 2578542 A2 FR2578542 A2 FR 2578542A2
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Prior art keywords
benzothiazine
formula
ethyl acetate
crystals
chloro
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FR8503236A
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FR2578542B2 (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 FR8503236A priority Critical patent/FR2578542B2/en
Priority to IE112685A priority patent/IE58312B1/en
Priority to PH32246A priority patent/PH21118A/en
Priority to AT85400927T priority patent/ATE42297T1/en
Priority to GR851159A priority patent/GR851159B/el
Priority to DE8585400927T priority patent/DE3569529D1/en
Priority to NZ212060A priority patent/NZ212060A/en
Priority to EP85400927A priority patent/EP0162776B1/en
Priority to CA000481503A priority patent/CA1306747C/en
Priority to US06/733,685 priority patent/US4755509A/en
Priority to AU42518/85A priority patent/AU586972B2/en
Priority to KR1019850003306A priority patent/KR900004320B1/en
Priority to JP60102788A priority patent/JPH0692371B2/en
Priority to ES543266A priority patent/ES8607263A1/en
Priority to DK219685A priority patent/DK219685A/en
Priority to PT80489A priority patent/PT80489B/en
Publication of FR2578542A2 publication Critical patent/FR2578542A2/en
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
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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
    • C07D215/36—Sulfur atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • C07D417/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/04—Ortho-condensed systems
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    • C07D513/00—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
    • 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
    • C07D513/04—Ortho-condensed systems

Abstract

New compounds of formula: Aldose reductase inhibitors. Treatment of certain complications of diabetes.

Description

Nouveaux dérivés hétérocycliques, Leurs orocédés de préparation médicaments Les contenant. utiles notamment comme inhibiteurs de L1aldose réductase. New heterocyclic derivatives, Their drug preparation procedures containing them. useful 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 therapeutic applications.

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

Figure img00010001

dans laquelle :
Z représente L'atome de soufre mais peut représenter également
l'oxygène quand Y représente le soufre ou quand X = Y = N ;
Y représente l'atome d'oxygène ou L'atome de soufre ou un
méthylène ; y peut, en outre, représenter L'atome d'azote quand
X est L'azote ;
X représente CH ou L'atome d'azote ;
R1 et R2 peuvent représenter L'hydrogène, un halogène, un groupement
trifluorométhyle, méthoxy, thiométhyle, thiotrifluorométhyle,
trifluorométhoxy ;
R3 et R4 peuvent représenter L'hydrogène, un alkyle inférieur, un
noyau phényle ou pyridyle éventuellement substitué ; on entend
par "alkyle inférieur" un groupement en C1 -C5 ramifié ou non.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 sulfur atom but can also represent
oxygen when Y represents sulfur or when X = Y = N;
Y represents the oxygen atom or the sulfur atom or a
methylene; y can, in addition, represent the nitrogen atom when
X is nitrogen;
X represents CH or the nitrogen atom;
R1 and R2 can represent Hydrogen, a halogen, a group
trifluoromethyl, methoxy, thiomethyl, thiotrifluoromethyl,
trifluoromethoxy;
R3 and R4 can represent Hydrogen, lower alkyl,
optionally substituted phenyl or pyridyl ring; we hear
by "lower alkyl" a C1-C5 group branched or not.

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

Figure img00010002

dans laquelle R1, R2, R3, R4, X, Y et Z sont définis comme ci-dessus,
R' étant un groupement alkyle inférieur. The compounds of formula (I) according to the invention can be synthesized by hydrolysis in basic or acid medium of esters of formula (II)
Figure img00010002

in which R1, R2, R3, R4, X, Y and Z are defined as above,
R 'being a lower alkyl group.

Les composés de formule II dans lesqueLs Z = S sont synthétisés à partir des dérivés dans lesquels Z = 0 par action de P2S5 ou du réactif de Lawesson ou d'un réactif de thioLation analogue seLon des méthodes connues de l'homme de métier. The compounds of formula II in which Z = S are synthesized from the derivatives in which Z = 0 by action of P2S5 or of the Lawesson reagent or of an analogous thiolating reagent according to methods known to those skilled in the art.

Les esters de formule II dans Lesquels Z = 0 sont obtenus par action d'un halogénoacétate d'alkyle sur les dérives
NH de formule III préaLablement métaLlés à L'aide d'agents courants de métallationdans des solvants classiques pour ce type de réaction, tels que le diméthylformamide, par exemple :

Figure img00020001
The esters of formula II in which Z = 0 are obtained by the action of an alkyl haloacetate on the derivatives
NH of formula III previously metallized using current metallation agents in conventional solvents for this type of reaction, such as dimethylformamide, for example:
Figure img00020001

Dans la formule III, R1, R2, R3, R4, X et Y sont définis comme cidessus.In formula III, R1, R2, R3, R4, X and Y are defined as above.

Les dérivés de formule III sont obtenus par cycLisation des aminoesters ou des aminoacides de formule IV

Figure img00020002

dans laquelle R1, R2, R3, R4, X et Y sont définis comme ci-dessus,
R" étant L'hydrogène ou un alkyle inférieur.The derivatives of formula III are obtained by cycLisation of aminoesters or amino acids of formula IV
Figure img00020002

in which R1, R2, R3, R4, X and Y are defined as above,
R "being hydrogen or lower alkyl.

Les dérivés de formule III, dans lesquels Y = S, peuvent également etre synthétisés directement par action d'un dérivé de formule V sur un halogénoacétate d'alkyle ou L'acide ou son chlorure d'acide de formule VI.

Figure img00020003
The derivatives of formula III, in which Y = S, can also be synthesized directly by the action of a derivative of formula V on an alkyl haloacetate or The acid or its acid chloride of formula VI.
Figure img00020003

Figure img00030001
Figure img00030001

Dans La formule V, R1, R2 et X sont définis comme ci-dessus ; dans la formule VI, R3 et R4 Sont définis comme ci-dessus, W represente un halogène, U représente OH, OR" ou le chlore, R" étant défini comme ci-dessus
Les dérivés de formule III dans lesquels Y = CH2 et
X = CH peuvent également être synthétisés par cyclisation à L'acide, de méthode connue en soi, par exemple Le chlorure d'aluminium, de dérivés de Formule VII :

Figure img00030002
In Formula V, R1, R2 and X are defined as above; in formula VI, R3 and R4 are defined as above, W represents a halogen, U represents OH, OR "or chlorine, R" being defined as above
The derivatives of formula III in which Y = CH2 and
X = CH can also be synthesized by acid cyclization, by a method known per se, for example aluminum chloride, of derivatives of Formula VII:
Figure img00030002

Dans la formule VII, 1' R2, R3 et R4 sont définis comme ci-dessus,
T représente L'atome de chlore ou de brome.In formula VII, 1 'R2, R3 and R4 are defined as above,
T represents the chlorine or bromine atom.

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

Figure img00030003
The compounds of formula IV are synthesized by hydrogenation of the nitro derivatives of formula VIII
Figure img00030003

dans LaquelLe R1, R2, R3, R4' X, Y et R" sont définis comme ci-dessus. in which the R1, R2, R3, R4 'X, Y and R "are defined as above.

Les dérivés de formule VIII 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 d'un acide mercaptoacétique ou de L'acide lui-meme sur les dérivés nitrés de formule IX

Figure img00030004

dans laquelle R1, R2 et X sont définis comme ci-dessus et, dans le cas oùY= 0 pour X = CH ou Y = *peuvent également être obtenus par action d'un halogénoacétate d'allyle convenablement substitué sur un dérivé de formule X préalablement métallé si nécessaire.
Figure img00040001
The derivatives of formula VIII are obtained by action, in the case where Y = N, of an ester of glycine or, in the case where Y = S, of an ester of a mercaptoacetic acid or of the acid itself. - even on the nitro derivatives of formula IX
Figure img00030004

in which R1, R2 and X are defined as above and, in the case whereY = 0 for X = CH or Y = * can also be obtained by the action of a suitably substituted allyl haloacetate on a derivative of formula X previously metallized if necessary.
Figure img00040001

Dans La formule X, R1, R2, X et Y sont définis comme ci-dessus.In Formula X, R1, R2, X and Y are defined as above.

Selon l'invention, on propose des compositions thérapeutiques utiles notamment pour le traitement des troubles périphériques consécutifs au diabète (cataracte, neuropathie), caractérisées en ce qu'elles renferment, en association avec un excipient physio
Logiquement acceptable, au moins un composé de formule I ou un de ses sels non toxiques d'addition.According to the invention, therapeutic compositions useful in particular for the treatment of peripheral disorders consecutive to diabetes are proposed (cataract, neuropathy), characterized in that they contain, in association with a physio excipient.
Logically acceptable, at least one compound of formula I or one of its non-toxic addition salts.

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'illus- tration. Other characteristics and advantages of the invention will be better understood on reading which will follow from a few examples of preparation which are in no way limitative, but given by way of illustration.

Le tabLeau Il ci-après donne la forme développée de certains produits. The table II below gives the developed form of certain products.

EXEMPLE 1 3-nitro 2-mercaptoacétate d'éthyle-pyridine
Formule VIII : R1 = R2 = R3 = R4 = H ; X = N ; Y = S ; R" = C2H5
On porte au reflux durant 7 h une solution de 50 g de 3-nitro 2-chioropyridine, 38 g de mercaptoacétate d'éthyte dans 400 ml d'éthanol contenant 30 g de bicarbonate- de sodium. La solution est ensuite concentrée sous vide puis, après refroidissement, le résidu additionnée d'eau et de glace est extrait à L'éther.EXAMPLE 1 Ethyl 3-nitro 2-mercaptoacetate-pyridine
Formula VIII: R1 = R2 = R3 = R4 = H; X = N; Y = S; R "= C2H5
A solution of 50 g of 3-nitro 2-chioropyridine, 38 g of ethyl mercaptoacetate in 400 ml of ethanol containing 30 g of sodium bicarbonate is brought to reflux for 7 h. The solution is then concentrated in vacuo then, after cooling, the residue added with water and ice is extracted with Ether.

La phase éthérée, lavée à l'eau, est séchée et, le solvant évaporé, on récupère un résidu qui cristallise dans l'éther isopropylique.The ethereal phase, washed with water, is dried and, the solvent evaporated, a residue is recovered which crystallizes from isopropyl ether.

Les cristaux sont essorés et séchés et on obtient 49 g de 3-nitro 2-mercaptoacétate d'éthyle-pyridine sous forme de cristaux de point de fusion 58 C. The crystals are drained 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 C.

EXEMPLE 2 6-chloro 3-nitro 2-mercaptoacétate d'éthyle-pyridine
Formule VIII : R1 = 6-chloro,R2 = R3 = R4 =H ; 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-chloro 3-nitro 2-mercaptoacétate d'éthyle-pyridine sous forme d'une huile utilisée brute pour
L'étape ultérieure.EXAMPLE 2 Ethyl 6-chloro 3-nitro 2-mercaptoacetate-pyridine
Formula VIII: R1 = 6-chloro, R2 = R3 = R4 = H; X = N; Y = S;
R "= C2H5
According to the procedure of Example 1, but using 25 g of 2,6-dichloro 3-nitropyridine at 90% and 14 g of ethyl mercaptoacetate, 32.5 g of 6-chloro 3-nitro 2 are obtained. - ethyl mercaptoacetate-pyridine in the form of a crude oil used for
The next step.

EXEMPLE 3 3-nitro 2-mercapto α-méthylacétique acide-pyridine
Formule VIII : R1 = R2 = R3 = H ; R4 = CH3 ; X = N ; Y = S ; R" = H
Selon Le mode opératoire de l'exemple 1, mais en utilisant 46 g de 3-nitro 2-chloropyridine et 32 g de 2-mercaptopropionique acide, on obtient, après acidification à L'acide acétique, 50 g de 3-nitro 2-mercapto α-méthylacétique acide-pyridine sous forme de cristaux de point de fusion 135 C.EXAMPLE 3 3-nitro 2-mercapto α -methylacetic acid-pyridine
Formula VIII: R1 = R2 = R3 = H; R4 = CH3; X = N; Y = S; R "= H
According to the procedure of Example 1, but using 46 g of 3-nitro 2-chloropyridine and 32 g of acid 2-mercaptopropionic, 50 g of 3-nitro 2- are obtained after acidification with acetic acid. mercapto α -methylacetic acid-pyridine in the form of crystals with a melting point of 135 C.

EXEMPLE 4 3-nitro 2-amino acétate d'éthyle-pyridine
Formule VIII : R1 = R2 = R3 = R4 = H ; X = Y = N ; R" = C2H
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 ml d'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 à 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 4 3-nitro 2-amino ethyl acetate-pyridine
Formula VIII: R1 = R2 = R3 = R4 = H; X = Y = N; R "= C2H
A solution of 20 g of 3-nitro 2-chloropyridine and 32 g of ethyl glycinate in 100 ml of ethanol is brought to reflux for 3 h. The solution is then concentrated under vacuum and, after cooling and then adding water and ice, extraction is carried out with ether. The ethereal phase is washed with water and then dried and the ether is evaporated in vacuo. 28 g of ethyl 3-nitro-2-aminoacetate-pyridine are recovered in the form of a crude oil used for the next step.

EXEMPLE 5 4-trifluorométhyl 2-nitrophénylthioacétate d'èthyle
Formule VIII : R1 = 4-CF3 ; R2 = R3 = R4 = H ; X = CH ; Y = S ;
= C2H
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
CE. (2 mmHg) = 155-160 C] 29 g de 4-trifluorométhyl 2-nitrophénylthioacétate d'éthyle sous forme de cristaux de point de fusion 42-45 C.EXAMPLE 5 Ethyl 4-trifluoromethyl 2-nitrophenylthioacetate
Formula VIII: R1 = 4-CF3; R2 = R3 = R4 = H; X = CH; Y = S;
= C2H
According to the procedure of Example 1, but using 38 g of 4-trifluoromethyl 2-nitrochlorobenzene and 21.5 g of ethyl mercaptoacetate, the residue is obtained after distillation
THIS. (2 mmHg) = 155-160 C] 29 g of ethyl 4-trifluoromethyl 2-nitrophenylthioacetate in the form of crystals with melting point 42-45 C.


EXEMPLE 6 5-fluoro 2-nitrophénylthioacétate d'éthyle
Formule VIII : R1 = 5-F ; R2 = R3 = R4 = H ; X = CH ; Y = S ;
R" = C H
Selon le mode opératoire de l'exemple I, mais en utilisant 83 g de 2,4-difluoronitrobenzène et 63 g de mercaptoacétate d'éthyle, on obtient après distillation du résidu CE. (1 mmHg) = 155-1600C 85 g de 5-fluoro 2-nitrophénylthioacétate d'éthyle sous forme de cristaux de point de fusion 58 C.
EXAMPLE 6 Ethyl 5-fluoro 2-nitrophenylthioacetate
Formula VIII: R1 = 5-F; R2 = R3 = R4 = H; X = CH; Y = S;
R "= CH
According to the procedure of Example I, but using 83 g of 2,4-difluoronitrobenzene and 63 g of ethyl mercaptoacetate, the residue EC is obtained after distillation. (1 mmHg) = 155-1600C 85 g of ethyl 5-fluoro 2-nitrophenylthioacetate in the form of crystals with a melting point of 58 C.

EXEMPLE 7 4-fluoro 2-nitrophénylthioacétate d'éthyle
Formule VIII : R1 = 4-F ; R2 = R3 = R4 = H ; X = CH ; Y = S ;
R" = C H
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-nitrophénylthioacétate d'éthyle sous forme de cristaux de point de fusion < 50 C.EXAMPLE 7 Ethyl 4-fluoro 2-nitrophenylthioacetate
Formula VIII: R1 = 4-F; R2 = R3 = R4 = H; X = CH; Y = S;
R "= CH
According to the procedure of Example 1, but from 73 g of 2,5-difluoronitrobenzene and 56 g of ethyl mercaptoacetate, after crystallization of the residue in pentane, 75 g of 4-fluoro 2-nitrophenylthioacetate is obtained. ethyl in the form of crystals with a melting point <50 C.

EXEMPLE 8 6-chloro 2-nitrophénylthioacétate d'éthyle
Formule VIII R = 6-Cl ; R = R3 = R4 = H ; X = CH ; Y = S ;
R" = C2H
Selon le mode opératoire de L'exemple 1, mais en utilisant 100 g de 2,3-dichloronitrobenzène et 63 g de mercaptoacétate d'éthyle, on obtient après filtration sur gel de silice 22,5 g de 6-chloro 2-nitrophénylthioacétate d'éthyle sous forme d'une huile utiliséé brute pour l'étape suivante.EXAMPLE 8 Ethyl 6-chloro 2-nitrophenylthioacetate
Formula VIII R = 6-Cl; R = R3 = R4 = H; X = CH; Y = S;
R "= C2H
According to the procedure of Example 1, but using 100 g of 2,3-dichloronitrobenzene and 63 g of ethyl mercaptoacetate, 22.5 g of 6-chloro 2-nitrophenylthioacetate is obtained after filtration through silica gel. ethyl in the form of a crude oil used for the next step.

EXEMPLE 9 4-méthoxy 2-nitrophénylthioacétate d'éthyle
Formule VIII : R1 = 4-0CH3 ; R2 = R3 = R4 = H ; X = CH ; Y = S ;
R" = C H
Selon le mode opératoire de L'exemple 1, mais à partir de 100 g de 2-chloro 5-méthoxynitrobenzène et de 68 g de mercaptoacétate d'éthyle, on obtient après cristallisation du résidu dans
l'éther isopropylique 55 g de 4-méthoxy 2-nitrophénylthioacétate d'éthyle sous forme de cristaux de point de fusion 75 C. EXAMPLE 9 Ethyl 4-methoxy 2-nitrophenylthioacetate
Formula VIII: R1 = 4-0CH3; R2 = R3 = R4 = H; X = CH; Y = S;
R "= CH
According to the procedure of Example 1, but starting from 100 g of 2-chloro 5-methoxynitrobenzene and 68 g of ethyl mercaptoacetate, the residue is obtained after crystallization in
isopropyl ether 55 g of ethyl 4-methoxy 2-nitrophenylthioacetate in the form of crystals with a melting point of 75 C.

EXEMPLE 10 4-trifluorométhyl 5-chloro 2-nitrophénylthioacétate d'éthyle
Formule VIII : R1 = 4-CF3 ; R2 = 5-Cl ; R3 = R4 = H ; X =CH ;
Y = S 2 R" =C2H5
Selon le mode opératoire de exemple 1, mais à partir de 50 g de 2,4-dichloro 5-trifluorométhylnitrobenzène et de 23 g de mercaptoacétate d'éthyle, on obtient 56 g de 4-trifluorométhyl 5-chloro 2-nitrophénylthioacétate d'éthyle sous forme de cristaux de point de fusion 85 C. EXAMPLE 10 Ethyl 4-trifluoromethyl 5-chloro 2-nitrophenylthioacetate
Formula VIII: R1 = 4-CF3; R2 = 5-Cl; R3 = R4 = H; X = CH;
Y = S 2 R "= C2H5
According to the procedure of Example 1, but from 50 g of 2,4-dichloro 5-trifluoromethylnitrobenzene and 23 g of ethyl mercaptoacetate, 56 g of ethyl 4-trifluoromethyl 5-chloro 2-nitrophenylthioacetate is obtained. in the form of crystals with a melting point of 85 C.

EXEMPLE 11 5-chloro 2-nitrophénylthioacétate d'éthyle
Formule VIII : R1 = 5-Cl ; R2 = R3 = R4 = H ; X - CH ; Y = S ;
R" = C2H5
Selon le mode opératoire de L'exemple 1, mais en utilisant 68,8 g de 2,4-dichloronitrobenzène et 43 g de mercaptoacétate d'éthyle, on obtient après filtration sur gel de silice 45 g de 5-chloro 2-nitrophénylthioacétate d'éthyle sous forme de cristaux de point de fusion 48-50 C
EXEMPLE 12 4-chloro 2-nitrophénylthioacétate d'éthyle
Formule VIII :R1 = 4-Cl ; R2 = R3 = R4 = H ; X = CH ; Y =
R" = C2H
Selon le mode opératoire de Exemple 1, mais en utilisant 100 g de 2,5-dichloronitrobenzène et 63 g de mercaptoacétate d'éthyle on obtient après cristallisation du résidu dans un mélange pentane éther isopropylique 52 g de 4-chloro 2-nitrophénylthioacétate sous forme de cristaux de point de fusion 52 C.EXAMPLE 11 Ethyl 5-chloro 2-nitrophenylthioacetate
Formula VIII: R1 = 5-Cl; R2 = R3 = R4 = H; X - CH; Y = S;
R "= C2H5
According to the procedure of Example 1, but using 68.8 g of 2,4-dichloronitrobenzene and 43 g of ethyl mercaptoacetate, 45 g of 5-chloro 2-nitrophenylthioacetate is obtained after filtration through silica gel. ethyl in the form of crystals with melting point 48-50 C
EXAMPLE 12 Ethyl 4-chloro 2-nitrophenylthioacetate
Formula VIII: R1 = 4-Cl; R2 = R3 = R4 = H; X = CH; Y =
R "= C2H
According to the procedure of Example 1, but using 100 g of 2,5-dichloronitrobenzene and 63 g of ethyl mercaptoacetate, 52 g of 4-chloro 2-nitrophenylthioacetate are obtained after crystallization of the residue in a pentane isopropyl ether mixture. 52 C melting point crystals

EXEMPLE 13 4-fluoro 2-nitrophénylthio &alpha;-méthylacétique acide
Formule VIII : R1 = 4 F ; R3 = CH3 ; R2 = R4 = H r X = CH ; Y = S
R" = H
Selon le mode opératoire de exemple 1e mais en utilisant 15,9 g de 2,5-difluoronitrobenzène et 11 g de 2 mercaptopropionique acide, on obtient, après acidification à l'acide acétique, 21 g de 4-fluoro 2-nitrophénylthio a-méthylacétique acide sous forme de cristaux de point de fusion 116 C.EXAMPLE 13 4-fluoro 2-nitrophenylthio &alpha; -methylacetic acid
Formula VIII: R1 = 4 F; R3 = CH3; R2 = R4 = H r X = CH; Y = S
R "= H
According to the procedure of Example 1e but using 15.9 g of 2,5-difluoronitrobenzene and 11 g of 2 acid mercaptopropionic, 21 g of 4-fluoro 2-nitrophenylthio a- are obtained, after acidification with acetic acid. methylacetic acid in the form of crystals with a melting point of 116 C.


EXEMPLE 14 4-chloro 2-nitrophénylthio &alpha;-méthylacétique acide
Formule VIII : R1 = 4-Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = S ;
R" = H
Selon le mode opératoire de L'exemple 1, mais en utilisant 38,4 g de 2,5-dichloronitrobenzène et 22 g de 2-nercaptopropionique acide1 on obtient, après acidification à l'acide acétique, 32 g de 4-chloro 2-nitrophényl ot-méthylacétique acide sous forme de cristaux de point de fusion 114 C.
EXAMPLE 14 4-chloro 2-nitrophenylthio &alpha; -methylacetic acid
Formula VIII: R1 = 4-Cl; R3 = CH3; R2 = R4 = H; X = CH; Y = S;
R "= H
According to the procedure of Example 1, but using 38.4 g of 2,5-dichloronitrobenzene and 22 g of 2-nercaptopropionic acid1, 32 g of 4-chloro 2- are obtained after acidification with acetic acid. nitrophenyl ot-methylacetic acid in the form of crystals with a melting point of 114 C.

EXEMPLE 15 4-chloro 2-nitrophénylthio &alpha;-phénylacétate d'éthyle
Formule VIII : R1 = 4-Cl ; R3 = phényl ; R2 =R4 R4 H ; X = CH ;
Y = S ; R" = C2H5
A une solution de 10,5 g de 2-nitro 4-chlorothiophénol dans 100mid'éthanol contenant 2,2 g de soude dissoute dans 10 ml d'eau, on ajoute goutte à goutte sous agitation une solution de 14 g d'a-bromophénylacétate d'éthyle dans 10 ml d'éthanol. Après la fin de l'addition, l'agitation est continuée 3 h à température ambiante puis le précipité formé est essoré, lavé par un peu d'éthanol, avec une solution aqueuse de soude 5 %.' puis à L'eau et séché.On récupère ainsi 11,5 g de 4-chloro 2-nitrophénylthio ct-phénylacétate d'éthyle sous forme de cristaux de point de fusion 112 c. EXAMPLE 15 Ethyl 4-chloro 2-nitrophenylthio &alpha; -phenylacetate
Formula VIII: R1 = 4-Cl; R3 = phenyl; R2 = R4 R4 H; X = CH;
Y = S; R "= C2H5
To a solution of 10.5 g of 2-nitro 4-chlorothiophenol in 100mid of ethanol containing 2.2 g of sodium hydroxide dissolved in 10 ml of water, a solution of 14 g of a- is added dropwise with stirring. ethyl bromophenylacetate in 10 ml of ethanol. After the end of the addition, the stirring is continued for 3 h at room temperature then the precipitate formed is drained, washed with a little ethanol, with a 5% aqueous sodium hydroxide solution. then with water and dried. 11.5 g of 4-chloro 2-nitrophenylthio ct-ethyl phenylacetate are thus recovered in the form of crystals with a melting point of 112 c.

EXEMPLE 16 5-chloro 2-nitrophénylthio &alpha;-méthylacétique acide
Formule VIII : R1 = 5-Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH : Y = S ;
R" = H
Selon le mode opératoire de l'exemple 1, mais en utilisant 100 g de 2,4-dichloronitrobenzène et 55 g de 2-mercaptopropionique acide, on obtient, après acidification à l'acide acétique et cristallisation du résidu dans un mélange éther isopropylique et pentane, 76 g de 5-chloro 2-nitrophénylthio a-methylacétique acide sous forme de cristaux de point de fusion 125 C. EXAMPLE 16 5-chloro 2-nitrophenylthio &alpha; -methylacetic acid
Formula VIII: R1 = 5-Cl; R3 = CH3; R2 = R4 = H; X = CH: Y = S;
R "= H
According to the procedure of Example 1, but using 100 g of 2,4-dichloronitrobenzene and 55 g of acid 2-mercaptopropionic, after acidification with acetic acid and crystallization of the residue, an isopropyl ether mixture is obtained and pentane, 76 g of 5-chloro 2-nitrophenylthio a-methylacetic acid in the form of crystals with a melting point of 125 C.

EXEMPLE 17 4,5-dichloro 2-nitrophénylthioacétate
Formule VIII : R1 = 4-Cl ; R2 = 5-CL; R3 = R4 = H ; X =CH ; Y = S ;
R" = C2H5
Selon le mode opératoire de l'exemple 1, mais en utilisant 93,2 g de 2,4,5-trichloronitrobenzène et 42 g de mercaptoacétate d'éthyle, on obtient après filtration sur gel de silice 68 g d'un mélange de 4,5-dichloro 2-nitrophénylthioacétate d'éthyle et de 2,5-dichloro 4-nitrophénylthioacétate d'éthyle qui est utilisé brut pour L'étape suivante.EXAMPLE 17 4,5-dichloro 2-nitrophenylthioacetate
Formula VIII: R1 = 4-Cl; R2 = 5-CL; R3 = R4 = H; X = CH; Y = S;
R "= C2H5
According to the procedure of Example 1, but using 93.2 g of 2,4,5-trichloronitrobenzene and 42 g of ethyl mercaptoacetate, 68 g of a mixture of 4 is obtained after filtration through silica gel. , Ethyl 5-dichloro 2-nitrophenylthioacetate and ethyl 2,5-dichloro 4-nitrophenylthioacetate which is used crude for the next step.

EXEMPLE 18 4-fluoro 2-nitrophénoxyacétate d'éthyle
Formule VIII : R1 = 4-F ; R2 = R3 = R4 = H ; X = CH ; Y = 0 ;
R" = C2H5
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. Le mélange réactionnel est ensuite refroidi par un bain de glace et on additionne goutte à goutte 40 ml de chloroacétate d'éthyle sous agitation. On laisse ensuite revenir à température ambiante, puis on agite durant 4 h et on porte ensuite au reflux toujours sous agitation quatre nouvelles heures.EXAMPLE 18 Ethyl 4-fluoro 2-nitrophenoxyacetate
Formula VIII: R1 = 4-F; R2 = R3 = R4 = H; X = CH; Y = 0;
R "= C2H5
To a solution of 54.7 g of 4-fluoro 2-nitrophenol in 400 ml of ethanol, 14 g of sodium hydroxide dissolved in 30 ml of water are added dropwise. The reaction mixture is then cooled by an ice bath and 40 ml of ethyl chloroacetate are added dropwise with stirring. Then allowed to return to room temperature, then stirred for 4 h and then brought to reflux still with stirring four new hours.

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 in vacuo, the residue taken up in water and the ice is extracted with ether which is washed with water, with 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 à L'étape suivante.The ether evaporated, 46 g of ethyl 4-fluoro-2-nitrophenoxyacetate are recovered in the form of a crude oil used in the next step.

EXEMPLE 19 4-fluoro 2-nitrophénylthio &alpha;-méthylacétate d'éthyle
Formule VIII : R1 = 4-F ; R3 = CH3 , R2 = R4 = H ; X = CH ; Y = S ;
R" = C2H5
On porte au reflux durant 5 h une solution de 44,3 g de 4-fluoro 2-nitrophénylthio a-méthylacétique acide préparé à
L'exemple 13 dans 300 ml d'éthanol contenant 10 ml d'acide sulfurique concentré. Le mélange réactionnel est ensuite concentré sous vide, le résidu repris à L'eau, extrait à L'éther qu'on lave avec une solution d'ammoniaque à 5 % puis essore à l'eau et qu'on sèche. EXAMPLE 19 4-fluoro 2-nitrophenylthio & ethyl ethyl acetate
Formula VIII: R1 = 4-F; R3 = CH3, R2 = R4 = H; X = CH; Y = S;
R "= C2H5
A solution of 44.3 g of 4-fluoro 2-nitrophenylthio a-methylacetic acid prepared at
Example 13 in 300 ml of ethanol containing 10 ml of concentrated sulfuric acid. The reaction mixture is then concentrated in vacuo, the residue taken up in water, extracted with ether which is washed with a 5% ammonia solution then drained with water and dried.

Après évaporation de l'éther, on récupère 46,5 g de 4-fluoro 2-nitrophénylthio ct-méthylacétate d'éthyle sous forme d'une huile qui est utilisée brute pour l'étape suivante.After evaporation of the ether, 46.5 g of 4-fluoro 2-nitrophenylthio ct-ethyl methyl acetate are recovered in the form of an oil which is used crude for the next step.


EXEMPLE 20 4-chloro 2-nitrophénylthio &alpha;-méthylacétate d'éthyle
Formule VIII : R1 = 4-Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = S ;
R" = C2H5
Selon le mode opératoire de l'exemple 19, mais à partir de 32 g de 4-chloro 2-nitrophénylthio &alpha;-méthylacétique acide préparé à l'exemple 14, on obtient 34 g de 4-chloro 2-nitrophénylthio a-méthylacétate d'éthyle sous forme d'une huile utilisée brute pour l'étape suivante.
EXAMPLE 20 Ethyl 4-chloro 2-nitrophenylthio &alpha; -methylacetate
Formula VIII: R1 = 4-Cl; R3 = CH3; R2 = R4 = H; X = CH; Y = S;
R "= C2H5
According to the procedure of Example 19, but from 32 g of 4-chloro 2-nitrophenylthio &alpha; -methylacetic acid prepared in Example 14, 34 g of 4-chloro 2-nitrophenylthio a-methylacetate are obtained. ethyl in the form of a crude oil used for the next step.

EXEMPLE 21 5-chloro 2-nitrophénylthio &alpha;-méthylacétate d'éthyle
Formule VIII : R1 = 5-CL ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = S ;
R" = C H
Selon le mode opératoire de L'exemple 19, mais à partir de 76 g de 5-chloro 2-nitrophénylthio &alpha;-méthylacétique acide préparé à
L'exemple 16, on obtient 72 g de 5-chloro 2-nitrophénylthio a-méthylacétate d'éthyle sous forme d'une huile utilisée brute pour l'étape suivante.EXAMPLE 21 Ethyl 5-chloro 2-nitrophenylthio &alpha; -methylacetate
Formula VIII: R1 = 5-CL; R3 = CH3; R2 = R4 = H; X = CH; Y = S;
R "= CH
According to the procedure of Example 19, but from 76 g of 5-chloro 2-nitrophenylthio &alpha; -methylacetic acid prepared at
Example 16, 72 g of ethyl 5-chloro-2-nitrophenylthio a-methylacetate are obtained in the form of a crude oil used for the next step.

EXEMPLE 22 1H-pyrido [2,3-b] [1,4] thiazine-2 (3H)-one
Formule III : R1 2 R2 3 R3 = R4 = 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 22 1H-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one
Formula III: R1 2 R2 3 R3 = R4 = H; X = N; Y = S
A solution of 49 g of ethyl 3-nitro-2-mercaptoacetate-pyridine prepared at atmospheric pressure is hydrogenated.
Example 1, in the presence of Nickle de Raney in 500 ml of methanol.

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 refroidissement, puis addition d'hexane, les cristaux formés sont essorés puis séchés. On récupère 24 g de 1H-pyridoC2,3-b7C1,47thiazine-2 (3H)-one sous forme de cristaux de point de fusion 207 C.After absorption of the theoretical quantity of hydrogen, the catalyst is separated by filtration and the solution concentrated under vacuum, then the residue taken up in xylene is heated for 16 h at reflux. After cooling, then addition of hexane, the crystals formed are drained and then dried. 24 g of 1H-pyridoC2,3-b7C1,47thiazine-2 (3H) -one are recovered in the form of crystals with melting point 207 C.

EXEMPLE 23 6-chloro 1H-pyrido [2,3-b][1,4] thiazine-2 (3H)-one
Formule III : R1 = 6-chloro ; R2 = R3 = R4 = H ; X = N ; Y = S
Selon le mode opératoire de L'exemple 22, mais à partir de 14 g de 6-chloro 3-nitro 2-mercaptoacétate d'éthyle-pyridine préparés à L'exemple 2, on récupère 4,1 g de 6-chLoro 1H-pyrido E213-bE1,4]thiazine-2 (3)one sous forme de cristaux de point de fusion 240-245 C.EXAMPLE 23 6-chloro 1H-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one
Formula III: R1 = 6-chloro; R2 = R3 = R4 = H; X = N; Y = S
According to the procedure of Example 22, but from 14 g of 6-chloro 3-nitro 2-ethyl mercaptoacetate-pyridine prepared in Example 2, 4.1 g of 6-chloro 1H- are recovered. pyrido E213-bE1,4] thiazine-2 (3) one as crystals with melting point 240-245 C.

EXEMPLE 24 3-méthyl 1H-pyrido [2,3-b][1,4] thiazine-2 (3H)-one
Formule III : R1 = R2 = R3 = H ; R4 = CH3 ; X = N ; Y = S
Selon le mode opératoire de l'exemple 22, mais à partir de 30 g de 3-nitro 2-mercapto &alpha;-méthylacétique acide-pyridine préparés à L'exemple 3, on récupère 16 9 de 3-méthyl 1H-pyrido [2,3-b]- [1,4] thiazine-2 (3H)-one sous forme de cristaux de point de fusion 178 C.EXAMPLE 24 3-methyl 1H-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one
Formula III: R1 = R2 = R3 = H; R4 = CH3; X = N; Y = S
According to the procedure of Example 22, but from 30 g of 3-nitro 2-mercapto &alpha; -methylacetic acid-pyridine prepared in Example 3, 16 9 of 3-methyl 1H-pyrido are recovered [2 , 3-b] - [1,4] thiazine-2 (3H) -one in the form of crystals with a melting point of 178 C.

EXEMPLE 25 1H-pyrido [2,3-b][1,4] pyrazine-2 (3H)-one
Formule III : R1 = R2 = R3 = R4 = H ; X = Y = N
Selon le mode opératoire de l'exemple 22, mais à partir de 33 g de 3-nitro 2-aminoacétate d'éthyle-pyridine, préparés à
L'exemple 4, on obtient 19 g de 1H-pyrido[2,3-b][1,4] pyrazine-2 (3H)-one sous forme de cristaux de point de fusion 278-282 C.EXAMPLE 25 1H-pyrido [2,3-b] [1,4] pyrazine-2 (3H) -one
Formula III: R1 = R2 = R3 = R4 = H; X = Y = N
According to the procedure of Example 22, but from 33 g of ethyl 3-nitro 2-aminoacetate-pyridine, prepared at
Example 4, 19 g of 1H-pyrido [2,3-b] [1,4] pyrazine-2 (3H) -one are obtained in the form of crystals with melting point 278-282 C.

EXEMPLE 26 6-trifluorométhyl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = 6-CF3 ; R2 = R3 = R4 = H ; X = CH ; Y = S
Selon le mode opératoire de l'exemple 22, mais à partir de 29 g de 4-trifluorométhyl 2-nitrophenylacétate d'éthyle préparés à L'exemple 5, on récupère 15 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 1900C. EXAMPLE 26 6-trifluoromethyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = 6-CF3; R2 = R3 = R4 = H; X = CH; Y = S
According to the procedure of Example 22, but from 29 g of ethyl 4-trifluoromethyl 2-nitrophenylacetate prepared in Example 5, 15 g of 6-trifluoromethyl 2H-1,4-benzothiazine-3 are recovered. (4H) -one in the form of crystals with a melting point of 1900C.

EXEMPLE 27 7-fluoro 2H-1,4-benzothiazine-3 (4H)-one
Formule III R1 = 7-F ; R2 = R3 = R4 = H ; X = CH ; Y = S
Selon le mode opératoire de Exemple 22, mais à partir de 90 g de 5-fluoro 2-nitrophénylthioacétate d'éthyle, préparés à l'exemple 6, on obtient 45 g de 7-fluoro 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 215 C.EXAMPLE 27 7-fluoro 2H-1,4-benzothiazine-3 (4H) -one
Formula III R1 = 7-F; R2 = R3 = R4 = H; X = CH; Y = S
According to the procedure of Example 22, but from 90 g of ethyl 5-fluoro 2-nitrophenylthioacetate, prepared in Example 6, 45 g of 7-fluoro 2H-1,4-benzothiazine-3 are obtained ( 4H) -one in the form of crystals with a melting point of 215 C.

EXEMPLE 28 6-fluoro 2H-1,4-benzothiazine-3 (4H)-one
Formule III: R1 = 6-F; R2 = R3 = R4 H; 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 7, en présence de nickel de Raney dans 1 litre de méthanol.EXAMPLE 28 6-fluoro 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = 6-F; R2 = R3 = R4 H; X = CH; Y = S
A solution of 75 g of ethyl 4-fluoro-2-nitrophenylthioacetate, prepared at atmospheric pressure, is hydrogenated.
Example 7, in the presence of Raney nickel in 1 liter of methanol.

Après l'absorption de la quantité theorique 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 50 C 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-f luoro 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 189 C.After absorption of the theoretical quantity of hydrogen, the catalyst is separated by filtration and the solution is concentrated in vacuo then the residue taken up in 250 ml of water at 50 ° C. and 60 ml of concentrated hydrochloric acid is stirred for 30 min. The crystals formed are drained, washed with water and then with pentane and dried. 46 g of 6-f luoro 2H-1,4-benzothiazine-3 (4H) -one are thus recovered in the form of crystals with a melting point of 189 C.

EXEMPLE 29 8-chloro 2H-1,4-benzothiazine-3 (4H)-one
Formule III R = 8-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = S
Selon le mode opératoire de L'exemple 28, mais en utilisant 22,5 g de 6-chloro 2-nitrophénylthioacétate d'éthyle, préparés à l'exemple 8, on obtient 12 g de 8-chloro 2H-1,4- benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 222 C.EXAMPLE 29 8-chloro 2H-1,4-benzothiazine-3 (4H) -one
Formula III R = 8-Cl; R2 = R3 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but using 22.5 g of ethyl 6-chloro 2-nitrophenylthioacetate, prepared in Example 8, 12 g of 8-chloro 2H-1,4-benzothiazine are obtained -3 (4H) -one in the form of crystals with a melting point of 222 C.

EXEMPLE 30 7-chloro 2H-1,4-benzothiazine-3 (4H)-one
FormuLe III : R1 = 7-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = S
Selon le mode opératoire de L'exemple 28, mais en utiLisant 42 g de 5-chloro 2-nitrophénylthioacétate d'éthyle, préparés à L'exemple 11, on obtient 23 g de 7-chloro 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 21Q C. EXAMPLE 30 7-chloro 2H-1,4-benzothiazine-3 (4H) -one
Form III: R1 = 7-Cl; R2 = R3 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but using 42 g of 5-chloro 2-nitrophenylthioacetate, prepared in Example 11, 23 g of 7-chloro 2H-1,4-benzothiazine-3 are obtained. (4H) -one in the form of crystals with a melting point of 21Q C.

EXEMPLE 31 6-méthoxy 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = 6-OCH3 ; R2 = R3 = R4 = H ; X = CH ; Y = S
Selon le mode opératoire de l'exemple 28, mais en utilisant 45 g de 4-méthoxy 2-nitrophénylthioacétate d'éthyle, préparés à
L'exemple 9, on obtient 27 g de 6-méthoxy 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 180-182 C.EXAMPLE 31 6-methoxy 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = 6-OCH3; R2 = R3 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but using 45 g of ethyl 4-methoxy 2-nitrophenylthioacetate, prepared at
Example 9, 27 g of 6-methoxy 2H-1,4-benzothiazine-3 (4H) -one are obtained in the form of crystals with a melting point of 180-182 C.

EXEMPLE 32 6-trifluorométhyl 7-chloro 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = 6-CF3 ; R2 = 7-Cl ; R3 = R4 = H ; X = CH; Y = S
Selon le mode opératoire de exemple 28, mais en utilisant 56 g de 4-trifluorométhyl 5-chloro 2-nitrophénylthioacétate d'éthyle, préparés à l'exemple 10, on obtient après recristallisation dans Le méthanol 30 g de 6-trifluorométhyl 7-chloro 2H-I,4benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 234-235 C.EXAMPLE 32 6-trifluoromethyl 7-chloro 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = 6-CF3; R2 = 7-Cl; R3 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but using 56 g of ethyl 4-trifluoromethyl 5-chloro 2-nitrophenylthioacetate, prepared in Example 10, 30 g of 6-trifluoromethyl 7-chloro are obtained after recrystallization from methanol. 2H-I, 4bothothiazine-3 (4H) -one in the form of crystals with melting point 234-235 C.

EXEMPLE 33 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = R2 = R3 = R4 = H ; X = CH; Y = S
On prépare une solution d'éthylate de sodium en dissolvant 4,6 g de sodium dans 200 ml d'éthanol absolu. A cette solution, on ajoute goutte à goutte 25 g d'orthoaminothiophénol puis,à la fin de l'addition, on agite durant 10 min, on refroidit par un bain de glace puis on ajoute goutte à goutte 24 ml de bromoacétate d'éthyle. Après la fin de L'addition, on agite durant 3 h à température ambiante puis on filtre le bromure de sodium formé et le filtrat est concentré sous vide.Le résidu obtenu cristallise dans L'éther. Les cristaux essorés et séchés, on obtient 23 g de 2H-1,4-benzothiazine-3 (4H)- one sous forme de cristaux de point de fusion 177 C. EXAMPLE 33 2H-1,4-Benzothiazine-3 (4H) -one
Formula III: R1 = R2 = R3 = R4 = H; X = CH; Y = S
A solution of sodium ethylate is prepared by dissolving 4.6 g of sodium in 200 ml of absolute ethanol. To this solution, 25 g of orthoaminothiophenol are added dropwise, then, at the end of the addition, the mixture is stirred for 10 min, the mixture is cooled in an ice bath and then 24 ml of ethyl bromoacetate are added dropwise . After the end of the addition, the mixture is stirred for 3 h at room temperature and then the sodium bromide formed is filtered and the filtrate is concentrated in vacuo. The residue obtained crystallizes from ether. The crystals drained and dried, 23 g of 2H-1,4-benzothiazine-3 (4H) - one are obtained in the form of crystals with melting point 177 C.

EXEMPLE 34 2-méthyl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = R2 = R3 = H ; R4 = CH3 ; X = CH ; Y = S
A une solution de 37,5 g d'orthoaminothiophénol dans 100 ml d'éthanol, on additionne une solution de 24 g de soude dissoute dans le minimum d'eau, on laisse sous agitation 10 min, on refroidit par un bain de glace puis on ajoute goutte à goutte 45,9 g d'a-bromopropionique acide en solution dans 50 ml d'éthanol. On laisse le mélange réactionnel revenir à température ambiante puis on porte au reflux durant 4 h. Après concentration sous vide, on additionne de l'eau et de l'acide chlorhydrique jusqu'à pH acide et les cristaux formés sont essorés, lavés à l'eau puis séchés.On récupère ainsi 41,7 g de 2-méthyl 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 126-127 C. EXAMPLE 34 2-methyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = R2 = R3 = H; R4 = CH3; X = CH; Y = S
To a solution of 37.5 g of orthoaminothiophenol in 100 ml of ethanol, a solution of 24 g of sodium hydroxide dissolved in the minimum of water is added, the mixture is stirred for 10 min, cooled by an ice bath and then 45.9 g of acidic α-bromopropionic acid dissolved in 50 ml of ethanol are added dropwise. The reaction mixture is allowed to return to room temperature and then brought to reflux for 4 h. After concentration in vacuo, water and hydrochloric acid are added to acidic pH and the crystals formed are drained, washed with water and then dried. 41.7 g of 2-methyl 2H- are thus recovered 1,4-Benzothiazine-3 (4H) -one as crystals with melting point 126-127 C.

EXEMPLE 35 2-phényl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = R2 = R3 = H g R4 = phényle ; X = CH ; Y = S
Selon le mode opératoire de l'exemple 34, mais en utilisant 12,5 g d'orthoaminothiophénol et 17 g d'a-chlorophénylacétique acide, on obtient 9,7 g de 2-phényl 2H-1,4-benzothiazine-3 C4H)-one sous forme de cristaux de point de fusion 194 C. EXAMPLE 35 2-phenyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = R2 = R3 = H g R4 = phenyl; X = CH; Y = S
According to the procedure of Example 34, but using 12.5 g of orthoaminothiophenol and 17 g of acidic α-chlorophenylacetic, 9.7 g of 2-phenyl 2H-1,4-benzothiazine-3 C4H are obtained. ) -one in the form of crystals with a melting point of 194 C.

EXEMPLE 36 6-chloro 2H-1,4-behzothiazine-3 (4H)-one
Formule III : R1 = 6-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = S
Selon le mode opératoire de l'exemple 28, mais en utilisant 52 g de 4-chloro 2-nitrophénylthioacétate d'éthyle, préparés à l'exemple 12, on obtient 27,3 g de 6-chloro 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 208 C.EXAMPLE 36 6-chloro 2H-1,4-behzothiazine-3 (4H) -one
Formula III: R1 = 6-Cl; R2 = R3 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but using 52 g of ethyl 4-chloro 2-nitrophenylthioacetate, prepared in Example 12, 27.3 g of 6-chloro 2H-1,4-benzothiazine are obtained. -3 (4H) -one in the form of crystals with a melting point of 208 C.

EXEMPLE 37 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = 6-F ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = S
Selon le mode opératoire de l'exemple 28, mais en utilisant 55 g de 4-fluoro 2-nitrophénylthio a-méthylacétate d'éthyle, préparés à l'exemple 19, on obtient, après recristallisation dans l'isopropanol, 31 g de 6-f luoro 2-méthyl 2H-1,4-benzothiazine-3 C4H)-one sous forme de cristaux de point de fusion 164 C.EXAMPLE 37 6-fluoro 2-methyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = 6-F; R3 = CH3; R2 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but using 55 g of 4-fluoro 2-nitrophenylthio a-ethyl methyl acetate, prepared in Example 19, 31 g of 6 are obtained, after recrystallization from isopropanol. -f luoro 2-methyl 2H-1,4-benzothiazine-3 C4H) -one in the form of crystals with melting point 164 C.

EXEMPLE 38 6-chloro 2-méthyl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = 6-Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = S
Selon le mode opératoire de l'exemple 28, mais en utilisant 34 g de 4-chloro 2-nitrophénylthio a-méthylacétate d'éthyle, préparés à
L'exemple 20, on obtient 19 g de 6-chlàro 2-méthyl 2H-1,4-benzo- thiazine-3 < 4H)-one sous forme de cristaux de point de fusion 188 C.EXAMPLE 38 6-chloro 2-methyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = 6-Cl; R3 = CH3; R2 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but using 34 g of ethyl 4-chloro 2-nitrophenylthio a-methylacetate, prepared at
Example 20, 19 g of 6-chloro 2-methyl 2H-1,4-benzothiazine-3 (4H) -one are obtained in the form of crystals with a melting point of 188 C.

EXEMPLE 39 6-chloro 2-phényl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = 6-Cl ; R3 = phényle ; R2 = R4 = H ; X = CH; Y = S
Selon le mode opératoire de l'exemple 28, mais en utilisant 11,5 g de 4-chloro 2-nitrophénylthio a-phénylacétate d'éthyle, préparés à l'exemple 15, on obtient 4 g de 6-chloro 2-phényl 2H-1,4-benzo- thiazine-3 (4H)-one sous forme de cristaux de point de fusion 216 C.EXAMPLE 39 6-chloro 2-phenyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = 6-Cl; R3 = phenyl; R2 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but using 11.5 g of ethyl 4-chloro 2-nitrophenylthio a-phenylacetate, prepared in Example 15, 4 g of 6-chloro 2-phenyl 2H are obtained. -1,4-benzothiazine-3 (4H) -one in the form of crystals with a melting point of 216 C.

EXEMPLE 40 2,2-diméthyl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = R2 = H ; R3 = R4 = CH3 ; X = CH ; Y = S
Selon le mode opératoire de l'exemple 34, mais à partir de 90 g d'orthoaminothiophénol, 28,8 g de soude et 140,4 g d'&alpha;-bromoiso- butyrate d'éthyle, on obtient 112 g de 2,2-diméthyl 2H-1,4-benzo- thiazine-3 (4H)-one sous forme de cristaux de point de fusion 155 C. EXAMPLE 40 2,2-dimethyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = R2 = H; R3 = R4 = CH3; X = CH; Y = S
According to the procedure of Example 34, but from 90 g of orthoaminothiophenol, 28.8 g of sodium hydroxide and 140.4 g of ethyl alpha-bromoiso- butyrate, 112 g of 2 are obtained, 2-dimethyl 2H-1,4-benzothiazine-3 (4H) -one in the form of crystals with a melting point of 155 C.

EXEMPLE 41 2-parachlorophényl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = R2 = R3 = H ; R4 = parachlorophényl w X = GH ;
Y=S
Selon le mode opératoire de exemple 34, mais à partir de 25 g d'orthoaminothiophénol, 8 g de soude et 55 g d'&alpha;-bromopara- chlorophénylacétate d'éthyle, on obtient 37,8 g de 2-parachlorophényl 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 198 C.EXAMPLE 41 2-parachlorophenyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = R2 = R3 = H; R4 = parachlorophenyl w X = GH;
Y = S
According to the procedure of Example 34, but from 25 g of orthoaminothiophenol, 8 g of sodium hydroxide and 55 g of ethyl alpha-bromopara-chlorophenylacetate, 37.8 g of 2-parachlorophenyl 2H-1 are obtained. , 4-benzothiazine-3 (4H) -one in the form of crystals with a melting point of 198 C.

EXEMPLE 42 2-orthochlorophényl 2H-1,4-benzothiazine-3 (4H)-one Formule III : R1 = R2 =R3 R3 = H ; = orthochlorophényl ; X = ê ;
Y=S
Selon le mode opératoire de l'exemple 34, mais à partir de 25 g d'orthoaminothiophénol, 8 g de soude et 55 g d'&alpha;-bromoorthochloro- phénylacétate d'éthyle, on obtient 37 g de 2-orthochlorophényl 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 200 C.EXAMPLE 42 2-orthochlorophenyl 2H-1,4-benzothiazine-3 (4H) -one Formula III: R1 = R2 = R3 R3 = H; = orthochlorophenyl; X = ê;
Y = S
According to the procedure of Example 34, but from 25 g of orthoaminothiophenol, 8 g of sodium hydroxide and 55 g of ethyl alpha-bromoorthochlorophenyl acetate, 37 g of 2-orthochlorophenyl 2H-1 are obtained. , 4-benzothiazine-3 (4H) -one in the form of crystals with a melting point of 200 C.

EXEMPLE 43 6,7-dichtoro 2H-1,4-benzothiazine-3 (4H)
Formule III : R1 = 6 Cl ; R2 = 7-Cl; R3 = R4 = H ; X = CH ; Y = S
Selon le mode opératoire de L'exemple 28, mais à partir du mélange de 68 g de 4,5-dichloro 2-nitrophénylthioacétate d'éthyle et de ?,5-dichloro 4-nitrophénylthioacétate d'éthyle, préparés à l'exemple 17, on obtient 4,5 g de 6,7-dichloro 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 251-253 C.EXAMPLE 43 6,7-dichtoro 2H-1,4-benzothiazine-3 (4H)
Formula III: R1 = 6 Cl; R2 = 7-Cl; R3 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but from the mixture of 68 g of 4,5-dichloro 2-nitrophenylthioacetate and ethyl ?, 5-dichloro 4-nitrophenylthioacetate, prepared in Example 17 , 4.5 g of 6,7-dichloro 2H-1,4-benzothiazine-3 (4H) -one are obtained in the form of crystals of melting point 251-253 C.

EXEMPLE 44 2-méthyl 2-(2'-pyridyl) 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = R2 = H R R3 = CH3; R4 = 2'-pyridyl ; X = CH ; Y = S
On prépare une solution d'éthylate de sodium en dissolvant 4 g de sodium dans 300 ml d'éthanol absolu. A cette solution on ajoute goutte à goutte 21,5 g d'orthoaminothiophénol puis, après la fin de l'addition, on agite durant 10 min. On refroidit par un bain de glace, puis on ajoute goutte à goutte 40 g d'&alpha;-bromo &alpha;-méthyl 2-pyridylacetate d'éthyle ; après la fin de leadditione on laisse reve- nir à température ambiante puis on continue l'agitation durant 4 h et on laisse au repos une nuit. Le précipité formé est essoré, lavé à l'eau puis à l'éthanol et séché. On récupère ainsi 25,3 g de 2-méthyl 2-(2'-pyridyl) 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 217-219 C.EXAMPLE 44 2-methyl 2- (2'-pyridyl) 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = R2 = HR R3 = CH3; R4 = 2'-pyridyl; X = CH; Y = S
A solution of sodium ethylate is prepared by dissolving 4 g of sodium in 300 ml of absolute ethanol. To this solution are added dropwise 21.5 g of orthoaminothiophenol then, after the end of the addition, the mixture is stirred for 10 min. It is cooled by an ice bath, then 40 g of ethyl &alpha; -bromo &alpha; -methyl 2-pyridylacetate are added dropwise; after the end of the addition, the mixture is allowed to return to ambient temperature then the stirring is continued for 4 hours and left to stand overnight. The precipitate formed is drained, washed with water and then with ethanol and dried. 25.3 g of 2-methyl 2- (2'-pyridyl) 2H-1,4-benzothiazine-3 (4H) -one are thus recovered in the form of crystals with melting point 217-219 C.

EXEMPLE 45 6-fluoro 2H-1,4-benzoxazine-3 (4H) one
Formule III : R1 = 6-F ; R2 Ra R4 H; X = CH ; Y = 0
On hydrogène sous pression atmosphérique une solution de 46 g de 4-fluoro 2-nitrophénoxyacétate d'éthyle, préparés à l'exempLe 18, en présence de nickel de Raney dans 500 ml de méthanol. 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 206-207 C.EXAMPLE 45 6-fluoro 2H-1,4-benzoxazine-3 (4H) one
Formula III: R1 = 6-F; R2 Ra R4 H; X = CH; Y = 0
A solution of 46 g of ethyl 4-fluoro-2-nitrophenoxyacetate, prepared in Example 18, is hydrogenated at atmospheric pressure, in the presence of Raney nickel in 500 ml of methanol. After absorption of the theoretical quantity of hydrogen, the catalyst is separated by filtration and the solution is concentrated under vacuum, 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 with melting point 206-207 C.

EXEMPLE 46 6-fluoro 3,4-dihydrocarbostyril
Formule III : R1 = 6-F ; R2 = R3 = R4 = H ; X = CH ; Y = CH2
A un mélange de 158 g de chlorure dtaluminium et 40 g de chlorure de sodium, on ajoute entre 180 et 2200C 31 g du N-(parafluorophényl) ss-chloropropionamide puis on agite le mélange réactionnel à cette température durant 30 min. Le mélangeréactionnel est ensuite détruit sur de la glace et les cristaux formés sont essorés, lavés à l'eau et séchés.On récupère ainsi après recristallisation dans l'isopropanol 14 g de 6-fluoro 3,4-dihydrocarbostyril sous forme de cristaux de point de fusion 180-181 C
EXEMPLE 47 6-chloro 3,4-dihydrocarbostyril
Formule III : R1 = 6-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = CH2
Selon le mode opératoire de l'exemple 46, mais à partir de 142,7 g de N-(parachlorophényl) ss-chloropropionamide, on récupère 66,4 g de 6-chloro 3,4-dihydrocarbostyril sous forme de cristaux de point de fusion 163-165 C après recristallisation dans l'acé- tonitri le. EXAMPLE 46 6-fluoro 3,4-dihydrocarbostyril
Formula III: R1 = 6-F; R2 = R3 = R4 = H; X = CH; Y = CH2
To a mixture of 158 g of aluminum chloride and 40 g of sodium chloride, 31 g of N- (parafluorophenyl) ss-chloropropionamide are added between 180 and 2200C, then the reaction mixture is stirred at this temperature for 30 min. The reaction mixture is then destroyed on ice and the crystals formed are wrung, washed with water and dried. This is thus recovered after recrystallization from isopropanol 14 g of 6-fluoro 3,4-dihydrocarbostyril in the form of point crystals 180-181 C
EXAMPLE 47 6-chloro 3,4-dihydrocarbostyril
Formula III: R1 = 6-Cl; R2 = R3 = R4 = H; X = CH; Y = CH2
According to the procedure of Example 46, but from 142.7 g of N- (parachlorophenyl) ss-chloropropionamide, 66.4 g of 6-chloro 3,4-dihydrocarbostyril is recovered in the form of point-point crystals melting 163-165 C after recrystallization from acetonitrile.

EXEMPLE 48 7-fluoro 3,4-dihydrocarbostyril
Formule III : R1 = 7-F ; R2 = R3 = R4 = H ; X = CH ; Y = CH2
Selon le mode opératoire de l'exemple 46, mais à partir de 90,4 g de N-(méta-fluorophényl) ss-chloropropionamide, on obtient 35,3 g de 7-fluoro 3,4-dihydrocarbostyril sous forme de cristaux de point de fusion 187-188 C après recristallisation dans l'iso- propanol.EXAMPLE 48 7-fluoro 3,4-dihydrocarbostyril
Formula III: R1 = 7-F; R2 = R3 = R4 = H; X = CH; Y = CH2
According to the procedure of Example 46, but from 90.4 g of N- (meta-fluorophenyl) ss-chloropropionamide, 35.3 g of 7-fluoro 3,4-dihydrocarbostyril are obtained in the form of crystals of melting point 187-188 C after recrystallization from isopropanol.

EXEMPLE 59 7-chloro 3,4-dihydrocarbostyril
Formule III : R1 = 7-Cl ; R2 = R3 = R4 = H; X = CH ; Y = CH2
Selon le mode opératoire de l'exemple 46, mais à partir de 133,9 g de N-(méta-chlorophényl) ss-chloropropionamide, on obtient 56 g de 7-chloro 3,4-dihydrocarbostyril sus forme de cristaux de point de fusion 160-165 C après recristallisation dans l'acétonitrile.EXAMPLE 59 7-chloro 3,4-dihydrocarbostyril
Formula III: R1 = 7-Cl; R2 = R3 = R4 = H; X = CH; Y = CH2
According to the procedure of Example 46, but from 133.9 g of N- (meta-chlorophenyl) ss-chloropropionamide, 56 g of 7-chloro 3,4-dihydrocarbostyril in the form of point-point crystals are obtained. fusion 160-165 C after recrystallization from acetonitrile.


EXEMPLE 50 2-para-fluorophénol 2H-1,4-benzothiazine-3 (4H)-one
Formule III R2 = R2 = R3 = H; R4 = para-fluorophényl ; X = CH; Y = S
Selon le mode opératoire de L'exemple 34, mais à partir de 20,7 g d'ortho-aminothiophénol, 6,7 g de soude et 43 g d'v-bromo- para-fluorophénylacétate d'éthyle, on obtient 34,7 g de 2-para-fluorophényl 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 215 C.
EXAMPLE 50 2-para-fluorophenol 2H-1,4-benzothiazine-3 (4H) -one
Formula III R2 = R2 = R3 = H; R4 = para-fluorophenyl; X = CH; Y = S
According to the procedure of Example 34, but from 20.7 g of ortho-aminothiophenol, 6.7 g of sodium hydroxide and 43 g of ethyl v-bromo-para-fluorophenylacetate, 34 is obtained, 7 g of 2-para-fluorophenyl 2H-1,4-benzothiazine-3 (4H) -one in the form of crystals with melting point 215 C.

EXEMPLE 51 2-ortho-fluorophényl 2H-1,4-benzothiazine-3 (4H
Formule III : R1 = R2 = R3 = H ; R4 = ortho-fluorophényl ; X = CH ;
Y=S
Selon le mode opératoire de l'exemple 34, mais à partir de 20,7 g d'ortho-aminothiophénol, 6,7 g de soude et 43 g d' -bromo- ortho-fluorophénylacétate d'éthyle, on obtient 33,5 g de 2-orthofluorophényl 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 177 C.EXAMPLE 51 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3 (4H
Formula III: R1 = R2 = R3 = H; R4 = ortho-fluorophenyl; X = CH;
Y = S
According to the procedure of Example 34, but from 20.7 g of ortho-aminothiophenol, 6.7 g of sodium hydroxide and 43 g of ethyl bromo-ortho-fluorophenylacetate, 33.5 g are obtained. of 2-orthofluorophenyl 2H-1,4-benzothiazine-3 (4H) -one in the form of crystals with melting point 177 C.

EXEMPLE 52 1-acétate d'éthyle-pyrido [2,3-b][1,4] thiazine-2 (3H)-one
Formule Il: R1 = R2 = R3 = R4 = H ; X = N ; Y = S ; Z = O ; R' = C2H5
Une solution de 12 g de 1H-pyrido [2,3-b][1,4] thiazine-2 (3H)-one préparés à l'exemple 22 dans 75 ml de diméthylformamide est ajoutée goutte à goutte à une suspension de 3,5 g d'hydrure de sodium dans 30 ml 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 à température ambiante, puis, après 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.Les cristaux sont essorés et séchés. On obtient 9 g de 1-acétate d'éthyle-pyrido[2,3-b][1,4] thiazine-2 (3H)-one sous forme de cristaux de point de fusion 83 C.EXAMPLE 52 1-ethyl acetate-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one
Formula II: R1 = R2 = R3 = R4 = H; X = N; Y = S; Z = O; R '= C2H5
A solution of 12 g of 1H-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one prepared in Example 22 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 min and then 9 ml of ethyl bromoacetate are added dropwise; when the addition is complete, the mixture is still stirred for 6 h at room temperature, then, after addition of water and ice, it is extracted with ether which is washed thoroughly with water, dried and evaporated . The residue obtained crystallizes from a mixture of isopropyl ether and hexane. The crystals are drained and dried. 9 g of ethyl acetate-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one are obtained in the form of crystals with a melting point of 83 C.

EXEMPLE 53 6-chloro 1-acétate d'éthyle-pyrido [2,3-b][1,4] thiazine-2 (3H)-one
Formule II : R1 = 6-Cl ; R2 = R3 = H ; X = N ; Y = S ; Z = O ; R'=C2H5
Selon de mode opératoire de l'exemple 52, mais à partir de 4,1 g de 6-chloro 1H-pyrido [2,3-b][1,4] thiazine-2 (3H)-one préparés à l'exemple 23, on obtient après cristallisation dans l'éther isopropylique 3,5 g de 6-chloro 1-acétate d'éthyle-pyrido [2,3-b][1,4]- thiazine-2 (3H))one sous forme de cristaux de point de fusion 105 C.EXAMPLE 53 6-chloro 1-ethyl acetate-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one
Formula II: R1 = 6-Cl; R2 = R3 = H; X = N; Y = S; Z = O; R '= C2H5
According to the procedure of Example 52, but using 4.1 g of 6-chloro 1H-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one prepared in Example 23, after crystallization from isopropyl ether, 3.5 g of 6-chloro 1-ethyl acetate-pyrido [2,3-b] [1,4] - thiazine-2 (3H)) one is obtained in the form 105 C melting point crystals

EXEMPLE 54 3-méthyl 1-acétate d'éthyle-pyrido [2,3-b][1,4] thiazine-2 (3H)-one
Formule II : R1 = R2 = R3 = H ; R4 = CH3 ; X = N ; Y = S ; Z = 0 ; R' = C2H5
Selon le mode opératoire de l'exemple 52, mais à partir de 15,7 g de 3-méthyl 1H-pyridoC2,3-b3tl,47thiazine-2 (3H)-one préparés à l'exemple 24, on obtient après recristallisation dans un mélange éther isopropylique-acétone 10 g de 3-méthyl 1-acétate d'éthylepyrido [2,3-b][1,4] thiazine-2 (3H)-one sous forme de cristaux de point de fusion 89 C.EXAMPLE 54 3-methyl 1-ethyl acetate-pyrido [2,3-b] [1,4] thiazine-2 (3H) -one
Formula II: R1 = R2 = R3 = H; R4 = CH3; X = N; Y = S; Z = 0; R '= C2H5
According to the procedure of Example 52, but starting from 15.7 g of 3-methyl 1H-pyridoC2,3-b3tl, 47thiazine-2 (3H) -one prepared in Example 24, one obtains after recrystallization in an isopropyl ether-acetone mixture 10 g of 3-methyl 1-ethyl acetate pyrido [2,3-b] [1,4] thiazine-2 (3H) -one in the form of crystals with a melting point of 89 C.

EXEMPLE 55
Chlorhydrate de 1-acétate d'éthyle-pyrido [2,3-b][1,4] pyrazine-2 (3H)-one
Formule Il : R1 = R2 = R3 = R4 = H ; X = Y = N ; Z = O ; R' = C H
Selon le mode opératoire de L'exemple 52, mais à partir de 12 g de 1H-pyrido [2,3-b][1,4] pyrazine-2 (3H)-one préparés à L'exemple 25, 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 addtionnée d'éther chlorhydrique jusqu'à pH acide. Les cristaux formés essorés sont lavés à l'éther et séchés. On récupère ainsi 7,8 g de chlorhydrate de 1-acétate d'éthyle-pyrido [2,3-b][1,4]- pyrazine-2 (3H)-one sous forme de cristaux de point de fusion 207-210 C.EXAMPLE 55
1-Ethyl acetate hydrochloride-pyrido [2,3-b] [1,4] pyrazine-2 (3H) -one
Formula II: R1 = R2 = R3 = R4 = H; X = Y = N; Z = O; R '= CH
According to the procedure of Example 52, but starting from 12 g of 1H-pyrido [2,3-b] [1,4] pyrazine-2 (3H) -one prepared in Example 25, we obtain by extraction with chloroform and crystallization from an ether-petroleum ether mixture, the base which has a melting point of 142 C. This base is dissolved in an acetone-methanol mixture and added with hydrochloric ether to acid pH. The drained crystals formed are washed with ether and dried. 7.8 g of 1-ethyl acetate-pyrido [2,3-b] [1,4] - pyrazine-2 (3H) -one hydrochloride are thus recovered in the form of crystals of melting point 207-210 vs.

EXEMPLE 56 6-trifluorométhyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule II : R1 = 6-CF3 ; R2 = R3 = R4 = H ; X = CH ; Y = S R
Z=O; R= C2H
Selon le mode opératoire de 18exemple 52, mais à partir de 12 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 26, on obtient, après cristallisation dans le pentane, 8 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 60 C.EXAMPLE 56 6-trifluoromethyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 6-CF3; R2 = R3 = R4 = H; X = CH; Y = SR
Z = O; R = C2H
According to the procedure of Example 18, but from 12 g of 6-trifluoromethyl 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 26, 8 g are obtained, after crystallization from pentane. of 6-trifluoromethyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with a melting point of 60 C.

EXEMPLE 57 7-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = 7-F ; R2 = R3 = R4 = H ; X = CH ; Y = S ; Z= O *
R = C2H
Selon Le mode opératoire de l'exemple 52, mais à partir de 20 g de 7-fluoro 2H-1,4-benzothiazine-3 (4H)-one préparés à
L'exemple 27, 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 85 C. EXAMPLE 57 7-fluoro 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 7-F; R2 = R3 = R4 = H; X = CH; Y = S; Z = O *
R = C2H
According to the procedure of Example 52, but starting from 20 g of 7-fluoro 2H-1,4-benzothiazine-3 (4H) -one prepared at
Example 27, 19 g of 7-fluoro 2H-1,4-benzothiazine-3-one 4-ethyl acetate are obtained, after crystallization from an ether-pentane mixture, in the form of crystals with a melting point of 85 C .

EXEMPLE 58 6-fLuoro 2H-1 4-benzothiazine-3-one 4-acétate dXethyle
Formule II : R1 = 6-F ; R2 = R3 = R4 = H ; X = CH ; Y = S ; Z = O ;
R = C2H5
Selon le mode opératoire de L'exemple 52, mais à partir de 43 g de 6-fluoro 2H"1,4-benzothiazine-3 (4H)-one préparés à L'exemple 28, on obtient après cristallisation dans un mélange acétone-pentane 36 g de 6-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 80 C. EXAMPLE 58 6-fLuoro 2H-1 4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 6-F; R2 = R3 = R4 = H; X = CH; Y = S; Z = O;
R = C2H5
According to the procedure of Example 52, but from 43 g of 6-fluoro 2H "1,4-benzothiazine-3 (4H) -one prepared in Example 28, after crystallization in an acetone mixture- pentane 36 g of 6-fluoro 2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with a melting point of 80 C.

EXEMPLE 59 8-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = 8-Cl; R2 = R3 = R4 = H X = CH = Y = S; Z = 0 ;
R = C2H5
Selon le mode opératoire de exemple 52, mais à partir de 12 g de 8-chloro 2H-1,4-benzothiazine-3 (4H)-one préparés à
L'exemple 29, on récupère 14 9 de 8-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme d'une huile qu'on peut utiliser brute pour l'étape suivante. EXAMPLE 59 8-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 8-Cl; R2 = R3 = R4 = HX = CH = Y = S; Z = 0;
R = C2H5
According to the procedure of Example 52, but from 12 g of 8-chloro 2H-1,4-benzothiazine-3 (4H) -one prepared at
In Example 29, 14 9 of 8-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate are recovered in the form of a crude oil which can be used for the next step.

EXEMPLE 60 7-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = 7-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = S ; Z = 0 ;
R' = C H
Selon le mode opératoire de L'exemple 52, mais à partir de
23 g de 7-chloro 2H-1,4-benzothiazine-3 (4H)-one préparés à
l'exemple 30, on obtient 32 g de 7-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 75-78 C.EXAMPLE 60 7-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 7-Cl; R2 = R3 = R4 = H; X = CH; Y = S; Z = 0;
R '= CH
According to the procedure of Example 52, but starting from
23 g of 7-chloro 2H-1,4-benzothiazine-3 (4H) -one prepared for
Example 30, 32 g of 7-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate are obtained in the form of crystals of melting point 75-78 C.

EXEMPLE 61 6-méthoxy 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = 6-OCH3 ; R2 = R3 = R4 = H ; X = CH ; Y = S ; Z = O ; R' = C H
Selon le mode opératoire de L'exemple 52, mais à partir de
26,9 g de 6-méthoxy 2H-1,4-benzothiazine-3 (4H)-one préparés à
l'exemple 31, on obtient après cristallisation dans l'éther
24,5 g de 6-méthoxy 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
sous forme de cristaux de point de fusion 84-870C.EXAMPLE 61 6-methoxy 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 6-OCH3; R2 = R3 = R4 = H; X = CH; Y = S; Z = O; R '= CH
According to the procedure of Example 52, but starting from
26.9 g of 6-methoxy 2H-1,4-benzothiazine-3 (4H) -one prepared at
Example 31, after crystallization from ether, is obtained
24.5 g of 6-methoxy 2H-1,4-benzothiazine-3-one 4-ethyl acetate
in the form of melting point crystals 84-870C.

EXEMPLE 62 6-trifluorométhyl 7-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = 6-CF3 ; R2 = 7-Cl ; R3 = R4 = H ; X = CH ; Y = S ;
Z =0 ; R' = C H
Selon le mode opératoire de l'exemple 52, mais à partir de 15,5 g de 6-trifluorométhyl-7-chloro 2H-1,4-benzothiazine-3 (4H)-one préparés à L'exemple 32, on obtient après cristallisation dans le pentane 13 g de 6-trifluorométhyl 2-chloro 2H-1,4-benzothiazine-3one 4-acétate d'éthyle sous forme de cristaux de point de fusion 93 C.EXAMPLE 62 6-trifluoromethyl 7-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 6-CF3; R2 = 7-Cl; R3 = R4 = H; X = CH; Y = S;
Z = 0; R '= CH
According to the procedure of Example 52, but starting from 15.5 g of 6-trifluoromethyl-7-chloro 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 32, the following is obtained crystallization from pentane 13 g of 6-trifluoromethyl 2-chloro 2H-1,4-benzothiazine-3one 4-ethyl acetate in the form of crystals with a melting point of 93 C.

EXEMPLE 63
2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule II R1 = R2 = R3 = R4 = H ; X = CH ; Y = S ; Z = O ;
R' = C H
Selon le mode opératoire de l'exemple 52, mais à partir de 23 g de 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 33, on obtient apres cristallisation dans L'éther isopropylique 21,8 g de 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 43-44 C. EXAMPLE 63
2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II R1 = R2 = R3 = R4 = H; X = CH; Y = S; Z = O;
R '= CH
According to the procedure of Example 52, but starting with 23 g of 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 33, after crystallization from isopropyl ether 21.8 is obtained. g of 2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with melting point 43-44 C.

EXEMPLE 64 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = R2 = R3 = H ; R4 = CH3 ; X = CH ; Y = S ; Z = 0 ;
R' = C H
Selon le mode opératoire de l'exemple 52, mais à partir de 34 g de 2-méthyl 2H-1,4-benzothiazine-3 (4H)-one préparés à L'exemple 34, on obtient après cristallisation dans le pentane 39,6 g de 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 70-72 C.EXAMPLE 64 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R4 = CH3; X = CH; Y = S; Z = 0;
R '= CH
According to the procedure of Example 52, but from 34 g of 2-methyl 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 34, after crystallization from pentane 39, 6 g of 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with melting point 70-72 C.

EXEMPLE 65 2-phényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule II : R1 = R2 = R3 = H ; R4 = phényle ; X = CH ; Y = S ;
Z = O R' = C H
Selon le mode opératoire de l'exemple 52@ mais à partir de 45,5 g de 2-phényl 2H 1,4-benzothiazine-3 (4H)-one préparés à l'exemple 35, on obtient 38 g de 2-phényl 2H-1,4-benzothiazine-3one 4-acétate d'éthyle sous forme d'une huile qu'on peut utiliser brute pour L'étape suivante.EXAMPLE 65 2-phenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R4 = phenyl; X = CH; Y = S;
Z = OR '= CH
According to the procedure of Example 52 @ but from 45.5 g of 2-phenyl 2H 1,4-benzothiazine-3 (4H) -one prepared in Example 35, 38 g of 2-phenyl are obtained 2H-1,4-Benzothiazine-3one 4-ethyl acetate in the form of a crude oil which can be used for the next step.

EXEMPLE 66 6-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule II : R1 = 6-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = S ; Z = 0 ; R' = C2 H5
Selon le mode opératoire de L'exemple 52, mais à partir de 27,3 g de 6-chloro 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 36, on récupère après recristallisation dans le pentane, 32 g de 6-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 720C. EXAMPLE 66 6-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 6-Cl; R2 = R3 = R4 = H; X = CH; Y = S; Z = 0; R '= C2 H5
According to the procedure of Example 52, but from 27.3 g of 6-chloro 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 36, recovery is obtained after recrystallization from pentane , 32 g of 6-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with melting point 720C.

EXEMPLE 67 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il R1 = 6-F ; R3 = CH3 ; R2 =R4 = H ; X =CH ; Y = S ;
Z = O R' = C H
Selon le mode opératoire de L'exemple 52, mais à partir de 20 g de 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 37, on obtient après cristallisation dans un mélange éther isopropylique-pentane, 13 g de 6-f luoro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 92 C. EXAMPLE 67 6-fluoro 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula Il R1 = 6-F; R3 = CH3; R2 = R4 = H; X = CH; Y = S;
Z = OR '= CH
According to the procedure of Example 52, but starting from 20 g of 6-fluoro 2-methyl 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 37, after crystallization in a isopropyl ether-pentane mixture, 13 g of 6-fluoro 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with a melting point of 92 C.

EXEMPLE 68 6-chloro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'é
Formule Il : R1 = 6-Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = S ; Z =0; R' = C H
Selon le mode opératoire de l'exemple 52, mais à partir de 19 g de 6-chloro 2-méthyl 2H-l,4-benzothiazine3 (4H)-one préparés à l'exemple 38, on récupère après cristallisation dans un mélange éther isopropylique-pentane, 24 g de 6-chloro 2-méthyl 2H-1,4benzothiazine-3-one, 4-acétate d'éthyle sous forme de cristaux de point de fusion 105 C.EXAMPLE 68 6-chloro 2-methyl 2H-1,4-benzothiazine-3-one 4-acetate
Formula II: R1 = 6-Cl; R3 = CH3; R2 = R4 = H; X = CH; Y = S; Z = 0; R '= CH
According to the procedure of Example 52, but starting from 19 g of 6-chloro 2-methyl 2H-1,4-benzothiazine3 (4H) -one prepared in Example 38, is recovered after crystallization from an ether mixture isopropyl-pentane, 24 g of 6-chloro 2-methyl 2H-1,4benzothiazine-3-one, 4-ethyl acetate in the form of crystals with a melting point of 105 C.

EXEMPLE 69 6-chloro 2-phényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = 6-Cl ; R3 = phényl ; R2 = R4 = H; X = CH ; Y = S ;
Z = O ; R = C2H5
Selon le mode opératoire de l'exemple 52, mais à partir de 6,3 g de 6-chloro 2-phényl 2H-1,4-benzothiazine-3 (4H)-one préparés à L'exemple 39, on récupère 8 g de 6-chloro 2-phényl 2H-1,4benzothiazine-3-one 4-acétate d'éthyle sous forme d'une huile qu'on peut utiliser brute pour l'étape suivante :
EXEMPLE 70 2,2-diméthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule II :R1 = R2 = H ; R3 = R4 = CH3 ; X = CH ; Y = S ; Z = 0 ;
R' = C H
Selon le mode opératoire de L'exemple 52, mais à partir de 40 g de 2,2-diméthyl 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 40, on récupère après cristallisation dans le pentane 50,1 g de 2,2-diméthyl-2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 60 C.EXAMPLE 69 6-chloro 2-phenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 6-Cl; R3 = phenyl; R2 = R4 = H; X = CH; Y = S;
Z = O; R = C2H5
According to the procedure of Example 52, but starting with 6.3 g of 6-chloro 2-phenyl 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 39, 8 g are recovered of 6-chloro 2-phenyl 2H-1,4benzothiazine-3-one 4-ethyl acetate in the form of a crude oil which can be used for the following stage:
EXAMPLE 70 2,2-dimethyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = R2 = H; R3 = R4 = CH3; X = CH; Y = S; Z = 0;
R '= CH
According to the procedure of Example 52, but using 40 g of 2,2-dimethyl 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 40, recovery is obtained after crystallization from pentane 50.1 g of 2,2-dimethyl-2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with a melting point of 60 C.

EXEMPLE 71 2-para-chlorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule II : R1 = R2 = R3 = H ; R4 = parachlorophényl ; X = CH ;
Y S; Z =0 ; R' = C H
Selon le mode opératoire de l'exemple 52, mais à partir de 37,8 g de 2-para-chlorophényl 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 41, on obtient après cristallisation dans un mélange éther isopropylique-pentane-isopropanol 25 g de 2-para chlorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 118 C.EXAMPLE 71 2-para-chlorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R4 = parachlorophenyl; X = CH;
YS; Z = 0; R '= CH
According to the procedure of Example 52, but from 37.8 g of 2-para-chlorophenyl 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 41, after crystallization in an isopropyl ether-pentane-isopropanol mixture 25 g of 2-para chlorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with a melting point of 118 C.

EXEMPLE 72 2-ortho-chlorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule II : R1 = R2 = R3 = H ; R4 = Ortho-chlorophényl ; X = CH ;
Y = S ; Z = O ; R = C2H5
Selon le mode opératoire de L'exemple 52, mais à partir de 37 g de 2-ortho-chlorophényl 2H-1,4-benzothiazine-3 (4H)-one préparès à l'exemple 42, on obtient 44,3 g de 2-ortho-chlorophényl 2H-1,4benzothiazine-3-one 4-acétate d'éthyle sous forme d'une huile qu'on peut utiliser brute pour l'étape suivante.EXAMPLE 72 2-ortho-chlorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R4 = Ortho-chlorophenyl; X = CH;
Y = S; Z = O; R = C2H5
According to the procedure of Example 52, but from 37 g of 2-ortho-chlorophenyl 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 42, 44.3 g of 2-ortho-chlorophenyl 2H-1,4benzothiazine-3-one 4-ethyl acetate in the form of a crude oil which can be used for the next step.

EXEMPLE 73 6,7-dichloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = 6 Cl , R2 = 7Cl 2 R3 = R4 = H ; X = CH; Y = S ;
Z = O ; R =C2H
Selon Le mode opératoire de l'exemple 52, mais à partir de 4,5 g de 6,7-dichloro 2H-1,4-benzothiazine-3 (4H)-one préparés à L'exemple 42, on obtient après cristallisation dans éther isopropylique 4 g de 6,7-dichloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 160 C.EXAMPLE 73 6,7-dichloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 6 Cl, R2 = 7Cl 2 R3 = R4 = H; X = CH; Y = S;
Z = O; R = C2H
According to the procedure of Example 52, but from 4.5 g of 6,7-dichloro 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 42, after crystallization in isopropyl ether 4 g of 6,7-dichloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with a melting point of 160 C.

EXEMPLE 74 2-méthyl 2-(2'-pyridyl D 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = R2 = H ; R3 = CH3 = R4 = 2'-pyridyL ; X = CH ;
Y= S ; Z = O ; $R = C2H
Selon Le mode opératoire de l'exemple 52, mais à partir de 9,5 g de 2-méthyl 2-(2-pyridyl) 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 44, on obtient 12 g de 2-méthyl 2-(2-pyridyl) 2H-1,4benzothiazine-3-one 4-acétate d'éthyle sous forme d'une huile qu'on peut utiliser brute pour l'étape suivante.EXAMPLE 74 2-methyl 2- (2'-pyridyl D 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = R2 = H; R3 = CH3 = R4 = 2'-pyridyL; X = CH;
Y = S; Z = O; $ R = C2H
According to the procedure of Example 52, but starting from 9.5 g of 2-methyl 2- (2-pyridyl) 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 44, 12 g of 2-methyl 2- (2-pyridyl) 2H-1,4-benzothiazine-3-one 4-ethyl acetate are obtained in the form of an oil which can be used crude for the following step.

EXEMPLE 75 6-fluoro 2H-1,4-benzoxazine-3-one 4-acétate d'éthyle
Formule II : R1 = 6-F ; R2 = R3 = R4 = H ; X = CH ; Y = Z = O ;
R = C2H5
Selon le mode opératoire de l'exemple 52, mais à partir de 27,3 g de 6-fluoro 2H-1,4-benzoxazine-3 (4H)-one préparés à
L'exemple 45, on récupère 32 g de 6-fluoro 2H-1,4-benzoxazine-3- one 4-acétate d'éthyle sous forme de cristaux de point de fusion 73 C.EXAMPLE 75 6-fluoro 2H-1,4-benzoxazine-3-one 4-ethyl acetate
Formula II: R1 = 6-F; R2 = R3 = R4 = H; X = CH; Y = Z = O;
R = C2H5
According to the procedure of Example 52, but from 27.3 g of 6-fluoro 2H-1,4-benzoxazine-3 (4H) -one prepared at
Example 45, 32 g of 6-fluoro 2H-1,4-benzoxazine-3-one 4-ethyl acetate are recovered in the form of crystals with a melting point of 73 C.

EXEMPLE 76 6-fluoro 3,4-dihydrocarbostyril 1-acétate d'éthyle
Formule II : R1 = 6-F ; R2 = R3 = R4 = H ; X = CH ; Y = CH2 ; Z = 0 ,
R' = C214
Selon le mode opératoire de l'exemple 52, mais à partir de 12,8 g de 6-fluoro 3,4-dihydrocarbostyril préparés à L'exemple 46, on récupère après cristallisation dans un mélange éther-pentane, 12,5 g de 6-fluoro 3,4-dihydrocarbostyril 1-acétate d'éthyle sous forme de cristaux de point de fusion 82-86 C.EXAMPLE 76 6-fluoro 3,4-dihydrocarbostyril 1-ethyl acetate
Formula II: R1 = 6-F; R2 = R3 = R4 = H; X = CH; Y = CH2; Z = 0,
R '= C214
According to the procedure of Example 52, but from 12.8 g of 6-fluoro 3,4-dihydrocarbostyril prepared in Example 46, after crystallization from an ether-pentane mixture, 12.5 g of 6-fluoro 3,4-dihydrocarbostyril 1-ethyl acetate in the form of crystals with melting point 82-86 C.

EXEMPLE 77 6-chloro 3,4-dihydrocarbostyril 1-acétate d'éthyle
Formule II : R1 = 6-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = CH2 Z = 0 ;
R' = C2H5
Selon le mode opératoire de L'exemple 52, mais à partir de 33 g de 6-chloro 3,4-dihydrocarbostyril préparés à L'exemple 47, on récupère après cristaüisation dans un mélange éther-pentane 30,7 g de 6-chLoro 3,4-dihydrocarbostyril 1-acétate d'éthyle sous forme de cristaux de point de fusion 72-75 c.EXAMPLE 77 6-chloro 3,4-dihydrocarbostyril 1-ethyl acetate
Formula II: R1 = 6-Cl; R2 = R3 = R4 = H; X = CH; Y = CH2 Z = 0;
R '= C2H5
According to the procedure of Example 52, but starting from 33 g of 6-chloro 3,4-dihydrocarbostyril prepared in Example 47, 30.7 g of 6-chloro are recovered after etching in an ether-pentane mixture 3,4-dihydrocarbostyril 1-ethyl acetate in the form of crystals with a melting point of 72-75 c.


EXEMPLE 78 7-fluoro 3,4-dihydrocarbostyril 1-acétate d'éthyle
Formule Il: R1 = 7-F ; R2 = R3 = R4 = H ; X = CH ; Y= CH2 ; Z = 0 ;
R' - C H
Selon le mode opératoire de L'exemple 52, mais à partir de 30,8 g de 7-fluoro 3,4-dihydrocarbostyril préparés à l'exemple 48, on récupère après cristatLisation dans le pentane 36,3 g de 7-fluoro 3,4- - dihydrocarbostyril 1-acétate d'éthyle sous forme de cristaux de point de fusion 75-78 C.
EXAMPLE 78 7-fluoro 3,4-dihydrocarbostyril 1-ethyl acetate
Formula II: R1 = 7-F; R2 = R3 = R4 = H; X = CH; Y = CH2; Z = 0;
R '- CH
According to the procedure of Example 52, but starting from 30.8 g of 7-fluoro 3,4-dihydrocarbostyril prepared in Example 48, after 36.4 g of 7-fluoro 3 is recovered after crystallization in pentane. , 4- - dihydrocarbostyril 1-ethyl acetate in the form of crystals with melting point 75-78 C.


EXEMPLE 79 7-chloro 3,4-dihydrocarbostyril 1-acétate d'éthyle
Formule II : R1 = 7-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = CH2 ; Z = O
R' = C2H5
Selon le mode opératoire de l'exemple 52, mais à partir de 40 g de 7-chloro 3,4-dihydrocarbostyril préparés à l'exemple 49, on récupère après cristallisation dans le mélange éther-pentane 39,8 g de 7-chloro 3,4-dihydrocarbostyril 1-acétate d'éthyle sous forme de cristaux de point de fusion 79-83 C.
EXAMPLE 79 7-chloro 3,4-dihydrocarbostyril 1-ethyl acetate
Formula II: R1 = 7-Cl; R2 = R3 = R4 = H; X = CH; Y = CH2; Z = O
R '= C2H5
According to the procedure of Example 52, but starting from 40 g of 7-chloro 3,4-dihydrocarbostyril prepared in Example 49, 39.8 g of 7-chloro is recovered after crystallization from the ether-pentane mixture. 3,4-dihydrocarbostyril 1-ethyl acetate in the form of crystals with melting point 79-83 C.


EXEMPLE 80 2-para-fluorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = R2 = R3 = H ; R4 = para-fluorophényl ; X = CH ;
Y = S ; Z = O R' = C H
Selon le mode opératoire de Exemple 52, mais à partir de 34,7 g de 2-para-fluorophényl 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 50, on obtient 35 g de 2-para-fluorophényl 2H1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme d'une huile qu'on peut utiliser brute pour l'étape suivante.
EXAMPLE 80 2-para-fluorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R4 = para-fluorophenyl; X = CH;
Y = S; Z = OR '= CH
According to the procedure of Example 52, but from 34.7 g of 2-para-fluorophenyl 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 50, 35 g of 2- para-fluorophenyl 2H1,4-benzothiazine-3-one 4-ethyl acetate in the form of a crude oil which can be used for the next step.

EXEMPLE 81 2-ortho-fluorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = R2 = R3 = H ; R4 = ortho-fluorophényl ; X = CH ;
Y = S ; Z = O ; Rs = C?H5 Selon le mode opératoire de @2 5 exemple 52, mais à partir de 33 g de 2-ortho-fluorophényl 2H-1,4-benzothiazine-3 (4H)-one préparés à l'exemple 51, on obtient 37,4 g de 2-ortho-fluorophényl2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 118 C.EXAMPLE 81 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R4 = ortho-fluorophenyl; X = CH;
Y = S; Z = O; Rs = C? H5 According to the procedure of @ 2 5 example 52, but starting from 33 g of 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3 (4H) -one prepared in example 51, we obtains 37.4 g of 2-ortho-fluorophenyl2H-1,4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with a melting point of 118 C.

EXEMPLE 82 7-chloro 2-méthyl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = 7-Cl ; R3 = CH3 R2 = R4 = H ; X = CH; Y = S
Selon le mode opératoire de l'exemple 28, mais en utilisant 72 g de 5-chloro 2-nitrophénylthio a-méthylacétate d'éthyle, préparés à l'exemple 21, on obtient 26,8 g de 7-chloro 2-méthyl 2H-1,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 200 C.EXAMPLE 82 7-chloro 2-methyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = 7-Cl; R3 = CH3 R2 = R4 = H; X = CH; Y = S
According to the procedure of Example 28, but using 72 g of ethyl 5-chloro 2-nitrophenylthio a-methylacetate, prepared in Example 21, 26.8 g of 7-chloro 2-methyl 2H are obtained. -1,4-benzothiazine-3 (4H) -one in the form of crystals with a melting point of 200 C.

EXEMPLE 83 7-chloro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle
Formule Il : R1 = 7-CL ; R3 = CH3 R2 = R4 = H ; X = CH ; Y = S ;
Z = 0 ; R' = C H
25
Selon le mode opératoire de l'exemple 52, mais à partir de 19,7 g de 7-chloro 2-méthyl 2H-1,4-benzothiazine-3 (4H)-one préparés à
l'exemple 82, on obtient après cristallisation dans l'éther 20,7 g de 7-chloro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 112-1130C. EXAMPLE 83 7-chloro 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 7-CL; R3 = CH3 R2 = R4 = H; X = CH; Y = S;
Z = 0; R '= CH
25
According to the procedure of Example 52, but from 19.7 g of 7-chloro 2-methyl 2H-1,4-benzothiazine-3 (4H) -one prepared at
Example 82, after crystallization from ether, 20.7 g of 7-chloro 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate are obtained in the form of crystals of melting point 112 -1130C.

EXEMPLE 84 7-fluoro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = 7-F ; R2 = R3 = R4 = H ; X = CH; Y = Z = S ;
R'- = C H
On agite durant 15 h à température ambiante une solution de 19 g de 7-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle, préparés à l'exemple 57, dans 200 nI de chLoroforme contenant 19 g de P2S5. La solution est ensuite filtrée puis concentrée sous vide et te résidu est filtré sur silicagel. Par élution au benzine 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 87 C.EXAMPLE 84 7-fluoro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 7-F; R2 = R3 = R4 = H; X = CH; Y = Z = S;
R'- = CH
A solution of 19 g of 7-fluoro 2H-1,4-benzothiazine-3-one 4-ethyl acetate, prepared in Example 57, in 200 nI of chloroform containing 19 g is stirred for 15 h at room temperature. of P2S5. The solution is then filtered and then concentrated in vacuo and the residue is filtered through silica gel. By elution with benzine and then recrystallization of the crystals obtained from 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 87 vs.

EXEMPLE 85 6-fluoro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = 6-F ; R2 = R3 = R4 = H ; X = CH ; Y = Z = S ;
R = C2H
Selon le mode opératoire de l'exemple 84, mais à partir de 15 g de 6-fluoro 2H-1,4benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 58, on obtient après filtration sur silicagel, élution au benzène et cristallisation dans Le mélange éther isopropylique-pentane, 7,4 g de 6-fluoro 2H-1,4-benzothiazine-3-thione 4-acé- tate d'éthyle sous forme de cristaux de point de fusion 66 C.EXAMPLE 85 6-fluoro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-F; R2 = R3 = R4 = H; X = CH; Y = Z = S;
R = C2H
According to the procedure of Example 84, but starting from 15 g of 6-fluoro 2H-1,4benzothiazine-3-one 4-ethyl acetate prepared in Example 58, after filtration on silica gel, elution is obtained with benzene and crystallization from an isopropyl ether-pentane mixture, 7.4 g of 6-fluoro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 66 C.


EXEMPLE 86 7-chloro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = 7Cl ; R2 = R3 = R4 = H ; X = CH ; Y = Z = S ;
1 2 3 4
R = C2H5
Selon le mode opératoire de l'exemple 84, mais à partir de 32 g de 7-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 60, on récupère après cristallisation dans le pentane, 20,5 g de 7-chloro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 98 C.
EXAMPLE 86 7-chloro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 7Cl; R2 = R3 = R4 = H; X = CH; Y = Z = S;
1 2 3 4
R = C2H5
According to the procedure of Example 84, but from 32 g of ethyl 7-chloro 2H-1,4-benzothiazine-3-one 4-acetate prepared in Example 60, it is recovered after crystallization from pentane, 20.5 g of 7-chloro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 98 C.

EXEMPLE 87 6-méthoxy 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = 6-OCH3 ; R2 = R3 = R4 = H ; X = CH ; Y = Z = S ;
R = C2H
Selon le mode opératoire de l'exemple 84, mais à partir de 12 g de 6-méthoxy 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 61, on récupère 8 g de 6-méthoxy 2H-1,4-benzo- thiazine-3-thione-4-acétate d'éthyle.EXAMPLE 87 6-methoxy 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-OCH3; R2 = R3 = R4 = H; X = CH; Y = Z = S;
R = C2H
According to the procedure of Example 84, but starting from 12 g of 6-methoxy 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 61, 8 g of 6 are recovered. -methoxy 2H-1,4-benzothiazine-3-thione-4-ethyl acetate.

EXEMPLE 88 6-trifluorométhyl 7-chloro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = 6-CF3 ; R2 = 7-Cl ; R3 = R4 = H ; X = CH ; Y = Z = S
R = C2H5
Selon le mode opératoire de l'exemple 84, mais à partir de 13 g de 6-trifluorométhyt 7-chloro 2H-1,4-benzothiazine- 3-one 4-acétate d'éthyle préparés à l'exemple 62, on récupère après cristallisation dans le pentane 5,1 g de 6-trifluorométhyl 7-chloro 2H-1,4-benzothiazione-3-thione 4-acétate éthyle sous forme de cristaux de point de fusion 83 C. EXAMPLE 88 6-trifluoromethyl 7-chloro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-CF3; R2 = 7-Cl; R3 = R4 = H; X = CH; Y = Z = S
R = C2H5
According to the procedure of Example 84, but from 13 g of 6-trifluoromethyt 7-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 62, it is recovered after crystallization from pentane 5.1 g of 6-trifluoromethyl 7-chloro 2H-1,4-benzothiazione-3-thione 4-ethyl acetate in the form of crystals with a melting point of 83 C.

EXEMPLE 89 2-phényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = R2 = R3 = H ; R4 = phényle ; X = CH ; Y = Z = S ;
R = C2H5
Selon le mode opératoire de l'exemple 84, mais à partir de 23 g de 2-phényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 65, on récupère 9 g de 2-phényl 2H-1,4-benzothiazine-3- thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 135 C.EXAMPLE 89 2-phenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R4 = phenyl; X = CH; Y = Z = S;
R = C2H5
According to the procedure of Example 84, but from 23 g of 2-phenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 65, 9 g of 2 are recovered. -phenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 135 C.

EXEMPLE 90 6-trifluorométhyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyl
Formule II : R1 = 6-CF3 ; R2 = R3 = R4 = H ; X = CH ; Y = Z = S ;
R' = C 2H5
Selon le mode opératoire de l'exemple 84, mais à partir de 31 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à L'exemple 36, on obtient après recristallisation dans L'isopropanol 14 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3- thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 110 C
EXEMPLE 91 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule Il : R1 = R2 = R3 = H ; R = CH3; X = CH ;Y = Z = S ;
R = C2H
On porte à 80 C durant 5 h une solution de 20 g de 2-méthyl
2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à L'exemple 64 dans 100 ml de diméthoxyéthane en présence de 20 g de réactif de
Lawesson. Le mélange réactionnel est ensuite concentré sous vide,
le résidu repris à chaud par 400 ml de cyclohexane et, après filtration, le cyclohexane est évaporé sous vide et le résidu obtenu est filtré sur gel de silice. Par élution au toluène, on récupère 11 g de 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 65.C.EXAMPLE 90 6-trifluoromethyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-CF3; R2 = R3 = R4 = H; X = CH; Y = Z = S;
R '= C 2H5
According to the procedure of Example 84, but starting from 31 g of 6-trifluoromethyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 36, after recrystallization from L is obtained 'isopropanol 14 g of 6-trifluoromethyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 110 C
EXAMPLE 91 2-methyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R = CH3; X = CH; Y = Z = S;
R = C2H
A 20 g solution of 2-methyl is brought to 80 ° C. for 5 h.
2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 64 in 100 ml of dimethoxyethane in the presence of 20 g of reagent
Lawesson. The reaction mixture is then concentrated under vacuum,
the residue taken up hot with 400 ml of cyclohexane and, after filtration, the cyclohexane is evaporated under vacuum and the residue obtained is filtered through silica gel. By elution with toluene, 11 g of 2-methyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate are recovered in the form of crystals of melting point 65.C.

EXEMPLE 92 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = R2 = R3 = R4 = H ; X = CH ; Y = Z = S ; R = C2H
Selon le mode opératoire de l'exemple 84, mais à partir de 35 g de 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à
l'exemple 63, on obtient après cristallisation dans le mélange pentane-éther isopropylique 21 g de 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 50 C.EXAMPLE 92 2H-1,4-Benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = R2 = R3 = R4 = H; X = CH; Y = Z = S; R = C2H
According to the procedure of Example 84, but starting from 35 g of 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared at
Example 63, after crystallization from the pentane-isopropyl ether mixture, 21 g of 2H-1,4-benzothiazine-3-thione 4-ethyl acetate are obtained in the form of crystals with a melting point of 50 C.

EXEMPLE 93 6-chloro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = 6-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = Z = S ;
R' = C2H5
Selon le mode opératoire de l'exemple 84, mais à partir de
23 g de 6-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 66, on obtient après cristallisation dans le mélange éther isopropylique-pentane 11,5 g de 6-chloro 2H-1,4benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 64"C. EXAMPLE 93 6-chloro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-Cl; R2 = R3 = R4 = H; X = CH; Y = Z = S;
R '= C2H5
According to the procedure of Example 84, but starting from
23 g of 6-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 66, 11.5 g of 6-chloro 2H are obtained after crystallization from the isopropyl ether-pentane mixture -1,4benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 64 "C.

EXEMPLE 94 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = 6-F ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = Z = S ;
R' = C H
Selon le mode opératoire de l'exemple 84, mais à partir de Il g de 6-fluoro 2-méthyl 2H-14-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 67, on obtient 6 g de 6-fluoro 2-méthyl 2H-1,4benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 91 C. EXAMPLE 94 6-fluoro 2-methyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-F; R3 = CH3; R2 = R4 = H; X = CH; Y = Z = S;
R '= CH
According to the procedure of Example 84, but from II g of 6-fluoro 2-methyl 2H-14-benzothiazine-3-one 4-ethyl acetate prepared in Example 67, 6 g of 6-fluoro 2-methyl 2H-1,4benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 91 C.

EXEMPLE 95 6-chloro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule Il : R1 = 6-Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH;
Y = Z =S; R' = C H
Selon le mode opératoire de l'exemple 84, mais à partir de 17 g de 6-chloro 2-méthyl 2H 1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 68, on obtient après cristallisation dans le pentane 9,5 g de 6-chloro 2-méthyl 2H 1,4-benzothiazine-3thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 55 C.EXAMPLE 95 6-chloro 2-methyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-Cl; R3 = CH3; R2 = R4 = H; X = CH;
Y = Z = S; R '= CH
According to the procedure of Example 84, but from 17 g of 6-chloro 2-methyl 2H 1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 68, after crystallization is obtained in pentane 9.5 g of 6-chloro 2-methyl 2H 1,4-benzothiazine-3thione 4-ethyl acetate in the form of crystals with a melting point of 55 C.

EXEMPLE 96 6-chloro 2-phényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule Il : R1 = 6-Cl; R3 = phényle ; R2 - R4 = H ; X = CH ;
Y = Z = S ; R = C2H
Selon le mode opératoire de l'exemple 84, mais à partir de 21 g de 6-chloro 2-phényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 69, on obtient après cristallisation dans l'éther 11 g de 6-chloro 2-phényl 2H-1,4-benzothiazine-3- thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 148 C. EXAMPLE 96 6-chloro 2-phenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-Cl; R3 = phenyl; R2 - R4 = H; X = CH;
Y = Z = S; R = C2H
According to the procedure of Example 84, but starting from 21 g of 6-chloro 2-phenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 69, the following is obtained crystallization from ether 11 g of 6-chloro 2-phenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 148 C.

EXEMPLE 97 2,2-diméthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = R2 = H ; R3 = R4 = CH3 ; X = CH ; Y = Z = S ; C2 5
Selon le mode opératoire de l'exemple 84, mais à partir de 25 g de 2,2-diméthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 70, on obtient après cristallisation dans le pentane,11,2 g de 2,2-diméthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 82-86 C.EXAMPLE 97 2,2-dimethyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = R2 = H; R3 = R4 = CH3; X = CH; Y = Z = S; C2 5
According to the procedure of Example 84, but from 25 g of 2,2-dimethyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 70, after crystallization is obtained in pentane, 11.2 g of 2,2-dimethyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals of melting point 82-86 C.

EXEMPLE 98 2-para-chlorophényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle Formule II : R1 = R2 = R3 = H ; R4=para-chlorophényl ; X = CH ;
Y = Z = S ; R' = C2H5
Selon le mode opératoire de l'exemple 84, mais à partir de 17,5 g de 2-para-chlorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 71, on obtient après cristallisation dans un mélange éther isopropylique-pentane . 11,2 g de 2-para chlorophényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 94 C.EXAMPLE 98 2-para-chlorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate Formula II: R1 = R2 = R3 = H; R4 = para-chlorophenyl; X = CH;
Y = Z = S; R '= C2H5
According to the procedure of Example 84, but starting from 17.5 g of 2-para-chlorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 71, one obtains after crystallization from an isopropyl ether-pentane mixture. 11.2 g of 2-para chlorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 94 C.

EXEMPLE 99 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule Il : R1 = 6-Cl ; R2 = 7-Cl : R3 = R4 = H ; X = CH ; Y = Z = S ;
R' = C H
Selon le mode opératoire de l'exemple 84, mais à partir de 4 g de 6,7-dichloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à L'exemple 73, on obtient après cristallisation dans le pentane 2,4 g de 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 123 C.EXAMPLE 99 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-Cl; R2 = 7-Cl: R3 = R4 = H; X = CH; Y = Z = S;
R '= CH
According to the procedure of Example 84, but from 4 g of 6,7-dichloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 73, after crystallization is obtained in pentane 2.4 g of 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals with melting point 123 C.

EXEMPLE 100 7-chloro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule Il : R1 = Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = Z = S ;
R' = C H
Selon le mode opératoire de l'exemple 84, mais à partir de 11,5 g de 7-chloro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 83, on obtient 9,2 g de 7-chloro 2méthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle. EXAMPLE 100 7-chloro 2-methyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = Cl; R3 = CH3; R2 = R4 = H; X = CH; Y = Z = S;
R '= CH
According to the procedure of Example 84, but starting from 11.5 g of 7-chloro 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 83, we obtains 9.2 g of 7-chloro 2methyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate.

EXEMPLE 101 2-ortho-chlorophényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule Il R1 = R2 = R3 = H ; R4 = ortho-chlorophényl ; X = CH ;
Y = Z S; R' = C H
Selon le mode opératoire de l'exemple 84, mais à partir de 32 g de 2-ortho-chlorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 72, on obtient après recristallisation dans l'acétonitrile 18 g de 2-ortho-chlorophényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 154 C.EXAMPLE 101 2-ortho-chlorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II R1 = R2 = R3 = H; R4 = ortho-chlorophenyl; X = CH;
Y = ZS; R '= CH
According to the procedure of Example 84, but from 32 g of 2-ortho-chlorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 72, after recrystallization is obtained in acetonitrile 18 g of 2-ortho-chlorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 154 C.

EXEMPLE 102 6-fluoro 2H-1,4-benzoxazine-3-thione 4-acétate d'éthyle
Formule Il : R1 = 6-F ; R2 = R3 = R4 = H ; X = CH ; Y = 0 ; Z = S ;
1 2 3 4
R = C2H5
Selon le mode opératoire de l'exemple 84, mais à partir de 22,9 de 6-fluoro 2H-1,4-benzoxazine-3-one 4-acétate d'éthyle préparés à l'exemple 75, on obtient après cristallisation dans le mélange éther-pentane 13,8 g de 6-fluoro 2H-1,4-benzoxazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 52 C.EXAMPLE 102 6-fluoro 2H-1,4-benzoxazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-F; R2 = R3 = R4 = H; X = CH; Y = 0; Z = S;
1 2 3 4
R = C2H5
According to the procedure of Example 84, but from 22.9 of 6-fluoro 2H-1,4-benzoxazine-3-one 4-ethyl acetate prepared in Example 75, after crystallization in the ether-pentane mixture 13.8 g of 6-fluoro 2H-1,4-benzoxazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 52 C.

EXEMPLE 103 6-fluoro 3,4-dihydroquinoline 2-thione 1-acétate d'éthyle
Formule II : R1 = 6-F ; R = R3 = R4 = H ; X = CH ; Y = CH2 ; Z = S,
R = C2H
Selon le mode opératoire de Exemple 84, mais à partir de 17 g de 6-fluoro 3,4-dihydrocarbostyril 1-acétate éthyle préparés a' l'exemple 76, on récupere 6,5 g de 6-fluoro 3,4-dihydroquinoline 2-thione 1-acétate éthyle sous forme de cristaux de point de fusion 80-82 C.EXAMPLE 103 6-fluoro 3,4-dihydroquinoline 2-thione 1-ethyl acetate
Formula II: R1 = 6-F; R = R3 = R4 = H; X = CH; Y = CH2; Z = S,
R = C2H
According to the procedure of Example 84, but from 17 g of 6-fluoro 3,4-dihydrocarbostyril 1-ethyl acetate prepared in Example 76, 6.5 g of 6-fluoro 3,4-dihydroquinoline are recovered. 2-thione 1-ethyl acetate in the form of crystals with a melting point of 80-82 C.

EXEMPLE 104 6-chloro 3,4-dihydroquinoline 2-thione 1-acétate d'éthyle
Formule II : R1 = 6-Cl ; R2 ~ R3 = R4 = H 4 X = CH ; Y = CH2 ; Z = S ;
R = C2H5
Selon le mode opératoire de l'exemple 84, mais à partir de 20 g de 6-chloro 3,4-dihydrocarbostyril 1-acétate d'éthyle préparés à l'exemple 77, on récupère 9,4 g de 6 chloro 3,4-dihydroquinoline 2-thione 1-acétate d'éthyle sous forme de cristaux de point de fusion 84-87 C.EXAMPLE 104 6-chloro 3,4-dihydroquinoline 2-thione 1-ethyl acetate
Formula II: R1 = 6-Cl; R2 ~ R3 = R4 = H 4 X = CH; Y = CH2; Z = S;
R = C2H5
According to the procedure of Example 84, but from 20 g of 6-chloro 3,4-dihydrocarbostyril 1-ethyl acetate prepared in Example 77, 9.4 g of 6 chloro 3,4 are recovered. -dihydroquinoline 2-thione 1-ethyl acetate in the form of crystals with melting point 84-87 C.

EXEMPLE 105 7-fluoro 3,4-dihydroquinoline 2-thione 1-acétate d'éthyle
Formule II : R1 = 7-F ; R2 = R3 ~ R4 = H é X = CH ; Y = CH2 ; Z = S ;
R = C2H
Selon le mode opératoire de L'exemple 84, mais à partir de 26 g de 7-fluoro 3,4-dihydrocarbostyril 1-acétate d'éthyle préparés à l'exemple 78, on récupère 15,7 g de 7-fluoro 3,4-dihydro- quinoline 2-thione 1 acétate d'éthyle sous forme de cristaux de point de fusion 76-79 C.EXAMPLE 105 7-fluoro 3,4-dihydroquinoline 2-thione 1-ethyl acetate
Formula II: R1 = 7-F; R2 = R3 ~ R4 = H é X = CH; Y = CH2; Z = S;
R = C2H
According to the procedure of Example 84, but starting from 26 g of 7-fluoro 3,4-dihydrocarbostyril 1-ethyl acetate prepared in Example 78, 15.7 g of 7-fluoro 3 are recovered, 4-dihydroquinoline 2-thione 1 ethyl acetate in the form of crystals with melting point 76-79 C.

EXEMPLE 106 7-chloro 3,4-dihydroguinoline 2-thione 1-acétate d'éthyle
Formule Il . R1 = 7-Cl ; R2 =R3 = R = H; X = CH ; Y = CH2 ; Z = S é
R = C2H5
Selon le mode opératoire de l'exemple 04, mais à partir de 25,5 g de 7-chloro 3,4-dihydrocarbostyril 1-acétate d'éthyle préparés à l'exemple 79, on récupère 12 g de 7-chloro 3,4-dihydroquinoline
2-thione 1-acétate d'éthyle sous forme de cristaux de point de
fusion 68-72 C.EXAMPLE 106 7-chloro 3,4-dihydroguinoline 2-thione 1-ethyl acetate
Formula II. R1 = 7-Cl; R2 = R3 = R = H; X = CH; Y = CH2; Z = S é
R = C2H5
According to the procedure of Example 04, but from 25.5 g of 7-chloro 3,4-dihydrocarbostyril 1-ethyl acetate prepared in Example 79, 12 g of 7-chloro 3 are recovered, 4-dihydroquinoline
2-thione 1-ethyl acetate in the form of point crystals
fusion 68-72 C.

EXEMPLE 107
3-méthyl 1-acétate d'éthyle-pyrido [2,3-b][1,4] thiazine-2 (3H)-thione
Formule II : R1 = R2 = R3 = H ; R4 3 CH3 ; X = N ; Y = Z = S ;
R' = C H
Selon le mode opératoire de L'exemple 84, mais à partir de
10 g de 3-méthyl 1-acétate d'éthyle-pyrido [2,3-b][1,4] thiazine-2
(3H)-one préparésà L'exemple 54, on récupère 3 g de 3-méthyl 1
acétate d'éthyle-pyrido [2,3-b][1,4] thiazine-2 (3H)-thione sous forme
de cristaux de point de fusion 100 C.EXAMPLE 107
3-methyl 1-ethyl acetate-pyrido [2,3-b] [1,4] thiazine-2 (3H) -thione
Formula II: R1 = R2 = R3 = H; R4 3 CH3; X = N; Y = Z = S;
R '= CH
According to the procedure of Example 84, but starting from
10 g 3-methyl 1-ethyl acetate-pyrido [2,3-b] [1,4] thiazine-2
(3H) -one prepared in Example 54, 3 g of 3-methyl 1 are recovered
ethyl acetate-pyrido [2,3-b] [1,4] thiazine-2 (3H) -thione in the form
of crystals with a melting point of 100 C.

EXEMPLE 108
2-para-fluorophényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule Il : R1 = R2 = R3 = H ; R4 = para-fluorophényl ; X -= CH ; Y = Z = S ; R' = C H
Selon le mode opératoire de l'exemple 84, mais à partir de
23 g de 2-para-fluorophényl 2H-1,4-benzothiazine-3-one 4-acétate
d'éthyle préparés à L'exemple 80, on récupère 17 9 de 2-para-fluoro
phényl-2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle.EXAMPLE 108
2-para-fluorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R4 = para-fluorophenyl; X - = CH; Y = Z = S; R '= CH
According to the procedure of Example 84, but starting from
23 g of 2-para-fluorophenyl 2H-1,4-benzothiazine-3-one 4-acetate
of ethyl prepared in Example 80, 17 9 of 2-para-fluoro are recovered
phenyl-2H-1,4-benzothiazine-3-thione 4-ethyl acetate.

EXEMPLE 109 2-ortho-fluorophényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule Il : R1 = R2 = R3 = H ; R4 = ortho-fluorophényl ; X = CH ; Y = Z =S; R' = C H
Selon le mode opératoire de l'exemple 84, mais à partir de 25 g de 2-ortho-fluorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 81, on récupère 19 g de 2-ortho-fluorophényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 174"C. EXAMPLE 109 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = R2 = R3 = H; R4 = ortho-fluorophenyl; X = CH; Y = Z = S; R '= CH
According to the procedure of Example 84, but from 25 g of 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 81, 19 g are recovered. of 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals with a melting point of 174 "C.

EXEMPLE 110 1-acide acétique-pyrido [2,3-b] thiazine-2 (3H)-one
Formule I : R1 = R2 = R3 = R4 = H ; X = N ; Y = S ; Z = O
On porte 10 min à 500C une solution de 9 g de 1-acétate d'éthylepyrido [2,3-b] thiazine-2 (3H)-one préparés à L'exemple 52 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. Les cristaux formés sont essorés, lavés 2 fois avec 10 ml d'eau puis à L'acétone et séchés.EXAMPLE 110 1-acetic acid-pyrido [2,3-b] thiazine-2 (3H) -one
Formula I: R1 = R2 = R3 = R4 = H; X = N; Y = S; Z = O
A solution of 9 g of 1-ethyl acetatepyrido [2,3-b] thiazine-2 (3H) -one prepared in Example 52 in 30 ml of methanol containing 1.5 g of is brought to 500 ° C. soda dissolved in 20 ml of water. The reaction mixture is then treated with activated carbon; then filtered and acidified cold with dilute hydrochloric acid, concentrated in vacuo by half then added with water and ice. The crystals formed are drained, washed twice with 10 ml of water then with acetone and dried.

On récupère ainsi 5,5 g de 1-acide acétique-pyridoC2,3-b7thiazine-2 (3H)-one sous forme de cristaux de point de fusion 252-255 C.5.5 g of 1-acetic acid-pyridoC2,3-b7thiazine-2 (3H) -one are thus recovered in the form of crystals of melting point 252-255 C.

EXEMPLE 111 6-chloro 1-acide acétique-pyrido [2,3-b] thiazine-2 (3H)-one
Formule I : R1 = 6-Cl ; R2 = R3 = R4 = H ; X = N ; Y = S ; Z = 0
Selon le mode opératoire de l'exemple 110, mais en utilisant 3,5 g de 6-chloro 1-acétate d'éthyle-pyrido [2,3-b] thiazine-2 (3H)-one préparés à L'exemple 53, on obtient 2 g de 6-chloro 1-acide acétique-pyridoE2,3-b3thiazine-2 (3H)-one sous forme de cristaux de point de fusion 195-200 C.EXAMPLE 111 6-chloro 1-acetic acid-pyrido [2,3-b] thiazine-2 (3H) -one
Formula I: R1 = 6-Cl; R2 = R3 = R4 = H; X = N; Y = S; Z = 0
According to the procedure of Example 110, but using 3.5 g of 6-chloro 1-ethyl acetate-pyrido [2,3-b] thiazine-2 (3H) -one prepared in Example 53 , 2 g of 6-chloro 1-acetic acid-pyridoE2,3-b3thiazine-2 (3H) -one are obtained in the form of crystals with melting point 195-200 C.

EXEMPLE 112 3-méthyl 1-acide acétique-pyrido [2,3-b]-thiazine-2 (3H)-one
Formule I : R1 = R2 = R3 = H ; R4 = CH3 ; X = N ; Y = S ; Z = O
Selon le mode opératoire de l'exemple 110, mais en utilisant 7 g de 3-méthyl 1-acétate d'éthyle-pyrido [2,3-b]thiazine-2 (3H)one préparés à l'exemple 54, on récupère 3 g de 3-méthyl 1-acide acétique-pyrido [2,3-b]-thiazine-2 (3H)one sous forme. de cristaux de point de fusion 189-190 C.EXAMPLE 112 3-methyl 1-acetic acid-pyrido [2,3-b] -thiazine-2 (3H) -one
Formula I: R1 = R2 = R3 = H; R4 = CH3; X = N; Y = S; Z = O
According to the procedure of Example 110, but using 7 g of 3-methyl 1-ethyl acetate-pyrido [2,3-b] thiazine-2 (3H) one prepared in Example 54, one recovers 3 g of 3-methyl 1-acetic acid-pyrido [2,3-b] -thiazine-2 (3H) one in form. of melting point crystals 189-190 C.

EXEMPLE 113 3-méthyl 1-acide acétique-pyrido [2,3-b]-thiazine-2 (3H)-thion
Formule I : R1 = R2 = R3 = H ; R R4 CH3 ; X = N ; Y = Z = S
On laisse sous agitation durant 24 h une solution de 3 g de 3-méthyl 1-acétate d'éthyle-pyrido [2,3-b][1,4] thiazine-2 (3H)-thione préparés à l'exemple 107 dans 25 ml de tétrahydrofuranne et 25 ml d'éthanol contenant 0,5 g de soude dissoute dans 10 ml d'eau.EXAMPLE 113 3-methyl 1-acetic acid-pyrido [2,3-b] -thiazine-2 (3H) -thion
Formula I: R1 = R2 = R3 = H; R R4 CH3; X = N; Y = Z = S
A solution of 3 g of 3-methyl 1-ethyl acetate-pyrido [2,3-b] [1,4] thiazine-2 (3H) -thione prepared in Example 107 is left stirring for 24 h. in 25 ml of tetrahydrofuran and 25 ml of ethanol containing 0.5 g of sodium hydroxide dissolved in 10 ml of water.

Le mélange est ensuite concentré sous vide, sans chauffer, puis, après addition d'eau, les neutres sont extraits à l'éther. La phase aqueuse est acidifiée à froid par de l'acide acétique et les produits organiques extraits au chloroforme. La phase chloroformique séchée, le chloroforme évaporé, le résidu obtenu. cristallise dans
l'éther. Les cristaux sont essorés, lavés avec un peu d'éther et séchés. On récupère ainsi 1 g de 3-méthyl 1-acide acétique-pyrido
E2,3-b-thiazine-2 (3H)-thione sous forme de cristaux de point de
fusion 196-198 C. The mixture is then concentrated under vacuum, without heating, then, after addition of water, the neutrals are extracted with ether. The aqueous phase is acidified cold with acetic acid and the organic products extracted with chloroform. The dried chloroform phase, the chloroform evaporated, the residue obtained. crystallizes in
ether. The crystals are wrung out, washed with a little ether and dried. 1 g of 3-methyl 1-acetic acid-pyrido is thus recovered
E2,3-b-thiazine-2 (3H) -thione in the form of point crystals
fusion 196-198 C.

EXEMPLE 114
Chlorhydrate de 1-acide acétique-pyrido [2,3-b][1,4]pyrazine-2 (3H)-one
Formule I : R1 = R2 = R3 = R4 = H ; X = Y = N ; Z = O
On chauffe durant 7 h au reflux une solution de 7,8 g de chlorhydrate de 1-acétate d'éthyle-pyrido [2,3-b][1,4]pyrazine- 2 (3H)-one préparés à l'exemple 55, dans 50 ml d'acide chlorhydrique 3N. Le mélange réactionnel est ensuite concentré sous vide et le résidu repris à l'acétone cristallise. Les cristaux essorés, lavés à l'acétone et séchés sont recristallisés dans l'acide acétique.EXAMPLE 114
1-acetic acid-pyrido hydrochloride [2,3-b] [1,4] pyrazine-2 (3H) -one
Formula I: R1 = R2 = R3 = R4 = H; X = Y = N; Z = O
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 is heated for 7 h at reflux. 55, in 50 ml of 3N hydrochloric acid. The reaction mixture is then concentrated in vacuo and the residue taken up in acetone crystallizes. The crystals drained, washed with acetone and dried are recrystallized from acetic acid.

On obtient ainsi 3,6 g du chlorhydrate de 1-acide acétique-pyrido [2,3-b][1,4]pyrazine-2 (3H)-one sous forme de cristaux de point de fusion 260-265 C avec décomposition.3.6 g of 1-acetic acid-pyrido hydrochloride [2,3-b] [1,4] pyrazine-2 (3H) -one are thus obtained in the form of crystals of melting point 260-265 C with decomposition .

EXEMPLE 115 6-trifluorométhyl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = 6-CF3 ; R2 = R3 = R4 = H ; 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'éthyte préparés à l'exemple 56, dans 20 ml d'éthanol 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 165-167 C.EXAMPLE 115 6-trifluoromethyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 6-CF3; R2 = R3 = R4 = H; X = CH; Y = S = Z = O
A solution of 10.5 g of 6-trifluoromethyl 2H-1, 4-benzothiazine-3-one 4-ethyl acetate prepared in Example 56, in 20 ml of ethanol containing 2 is heated to 60 ° C. g of sodium hydroxide dissolved in 10 ml of water. The reaction mixture is then treated with active carbon then filtered and acidified in the cold with dilute hydrochloric acid. The crystals obtained are then drained, washed with water and then with isopropyl ether and dried. 7 g of 6-trifluoromethyl 2H-1,4-benzothiazine-3-one 4-acetic acid are thus recovered in the form of crystals with melting point 165-167 C.


EXEMPLE 116 7-fluoro 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = 7-F ; R2 = R3 = R4 = H ; X = CH ; Y = S ; Z = O
Selon le mode opératoire de l'exemple 115, mais à partir de 11 g de 7-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 57, on récupère 7 g de 7-fluoro 2H1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 152-154 C.
EXAMPLE 116 7-fluoro 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 7-F; R2 = R3 = R4 = H; X = CH; Y = S; Z = O
According to the procedure of Example 115, but starting from 11 g of 7-fluoro 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 57, 7 g of 7 are recovered. -fluoro 2H1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 152-154 C.

EXEMPLE 117 7-fluoro 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 7-F; R2 = R3 = R4 = H; Y = 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 84, 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 à l'éther. La phase aqueuse est ensuite acidifiée à froid par de l'acide chlorhydrique dilue 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 156-157 C.EXAMPLE 117 7-fluoro 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 7-F; R2 = R3 = R4 = H; Y = CH: Y = Z = S
A solution of 8.7 g of 7-fluoro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate, prepared in Example 84, in 100 ml of methanol containing 1 is left at room temperature for 2 days at room temperature. , 2 g of sodium hydroxide dissolved in 15 ml of water. The reaction mixture is then concentrated under cold vacuum and then diluted with water which is extracted with ether. The aqueous phase is then acidified cold with dilute hydrochloric acid and extracted with ether. This ethereal phase, washed with water, is dried then, after filtration, the ether is evaporated under vacuum. The residue obtained crystallizes in an ether-hexane mixture. 6 g of 7-fluoro 2H-1,4-benzothiazine-3-thione 4-acetic acid are thus recovered, after spinning and drying the crystals, in the form of crystals with melting point 156-157 C.

EXEMPLE 118 6-fluoro 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = 6-F ; R2 = R3 = R4 = H ; X =CH ; V = S ; Z =O
Selon le mode opératoire de l'exemple 115, mais à partir de 12 g de 6-fluoro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle prépares à exemple 58, 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 118 6-fluoro 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 6-F; R2 = R3 = R4 = H; X = CH; V = S; Z = O
According to the procedure of Example 115, but starting from 12 g of 6-fluoro 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 58, after crystallization from toluene 7 is obtained , 5 g of 6-fluoro 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 156-157 C.

EXEMPLE 119 6-fluoro 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 6-F ; R2 = R3 = R4 = H ; X = CH ; Y = Z = S
Selon le mode opératoire de l'exemple 117, mais à partir de 7,4 g de 6-fluoro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 85, on obtient 5,3 g de 6-fluoro 2H-1,4- benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 188-190 C.EXAMPLE 119 6-fluoro 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 6-F; R2 = R3 = R4 = H; X = CH; Y = Z = S
According to the procedure of Example 117, but starting from 7.4 g of 6-fluoro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 85, 5 is obtained, 3 g of 6-fluoro 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals of melting point 188-190 C.

EXEMPLE 120 8-chloro 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = 8-Cl ; R2 = R3 = R4 = H; X = CH ; Y = S ; Z = Q
Selon le mode opératoire de l'exemple 115, mais à partir de de 14 g de 8-chloro 2H-1,4-benzothiazine-3-one 4-acétate éthyle préparés à l'exemple 59, on obtient 7,5 g de 8-chloro 2H-1,4- benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 175-177 C. EXAMPLE 120 8-chloro 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 8-Cl; R2 = R3 = R4 = H; X = CH; Y = S; Z = Q
According to the procedure of Example 115, but starting from 14 g of 8-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 59, 7.5 g of 8-chloro 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with a melting point of 175-177 C.

EXEMPLE 121 7-chloro 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = 7-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = S ; Z =0
Selon le mode opératoire de L'exempte 115, mais à partir de 14,3 g de 7-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 60, on récupère 8,5 g de 7-chîoro 2H 1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 188-190 C. EXAMPLE 121 7-chloro 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 7-Cl; R2 = R3 = R4 = H; X = CH; Y = S; Z = 0
According to the procedure of Example 115, but starting with 14.3 g of 7-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 60, 8 is recovered, 5 g of 7-chloro 2H 1,4-benzothiazine-3-one 4-acetic acid in the form of crystals of melting point 188-190 C.

EXEMPLE 122 6-méthoxy 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = 6-OCH3 ; R2 = R3 = R4 = H ; X = CH ; Y = S ; Z = O
Selon le mode opératoire de l'exemple 115, mais à partir de 17 g de 6-méthoxy 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 61, on récupère après recristallisation dans l'acétonitrile 8,6 g de 6-méthoxy 2H-1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 152-155 C.EXAMPLE 122 6-methoxy 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 6-OCH3; R2 = R3 = R4 = H; X = CH; Y = S; Z = O
According to the procedure of Example 115, but starting from 17 g of ethyl 6-methoxy 2H-1,4-benzothiazine-3-one 4-acetate prepared in Example 61, recovery is obtained after recrystallization from l acetonitrile 8.6 g of 6-methoxy 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 152-155 C.

EXEMPLE 123 6-trifluorométhyl 7-chloro 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = 6-CF3 ; R2 = 7-CI ; R3 = R4 = H ; X = CH ; Y = S ;
Z = O
Selon le mode opératoire de L'exempte 115, mais à partir de 6 g de 6-trifluorométhyl 7-chtoro 2H-1,4-benzothiazine-3- one 4-acétate d'éthyle préparés à l'exemple 62, on récupère 4,3 g de 6-trifluorométhyl 7-chloro 2H-1 ,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 157-159 C.EXAMPLE 123 6-trifluoromethyl 7-chloro 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 6-CF3; R2 = 7-CI; R3 = R4 = H; X = CH; Y = S;
Z = O
According to the operating procedure of Example 115, but from 6 g of 6-trifluoromethyl 7-chtoro 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 62, 4 is recovered. , 3 g of 6-trifluoromethyl 7-chloro 2H-1, 4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 157-159 C.

EXEMPLE 124 2H-1,4-benzothiazine-3-one 4-acide acétique Formule I R = R2 = R3 = R4 = H ; X = CH ; Y = S ; Z = 0
Selon le mode opératoire de L'exemple 115, mais à partir de 14 g de 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à L'exemple 63, on récupère 10 g de 2N-1,4-benzothiazine-3- one 4-acide acétique sous forme de cristaux de point de fusion 152-154 C.EXAMPLE 124 2H-1,4-Benzothiazine-3-one 4-acetic acid Formula IR = R2 = R3 = R4 = H; X = CH; Y = S; Z = 0
According to the procedure of Example 115, but from 14 g of 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 63, 10 g of 2N-1 are recovered, 4-benzothiazine-3- one 4-acetic acid in the form of crystals with melting point 152-154 C.

EXEMPLE 125 2-méthyl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = R2 = R3 = H ; R4 = CH3 ; X = CH ; Y = S ; Z = O
Selon le mode opératoire de l'exemple 115, mais à partir de 13 g de 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 64, on obtient 8 g de 2-méthyl 2H-1,4benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 113-115 C.EXAMPLE 125 2-methyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = R2 = R3 = H; R4 = CH3; X = CH; Y = S; Z = O
According to the procedure of Example 115, but starting with 13 g of 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 64, 8 g of 2 are obtained. -methyl 2H-1,4benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 113-115 C.

EXEMPLE 126 2-phényl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = R2 = R2 = R3 = H ; R4 - phényl ; X = CH ; Y = S ; Z = O
Selon le mode opératoire de l'exemple 115, mais à partir de 15 g de 2-phényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 65, on obtient 7,8 g de 2-phényl 2H-1,4- benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 155-1570C.EXAMPLE 126 2-phenyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = R2 = R2 = R3 = H; R4 - phenyl; X = CH; Y = S; Z = O
According to the procedure of Example 115, but starting from 15 g of 2-phenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 65, 7.8 g are obtained of 2-phenyl 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals of melting point 155-1570C.

EXEMPLE 127 7-chloro 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 7-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = Z = S
Selon le mode opératoire de l'exemple 117, mais à partir de 20,5 g de 7-chloro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 86, on obtient 8 g de 7-chloro 2H 1,4-benzothiazine-3-thione. 4-acide acétique sous forme de cristaux de point de fusion 181-183 C.EXAMPLE 127 7-chloro 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 7-Cl; R2 = R3 = R4 = H; X = CH; Y = Z = S
According to the procedure of Example 117, but starting with 20.5 g of 7-chloro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 86, 8 g are obtained of 7-chloro 2H 1,4-benzothiazine-3-thione. 4-acetic acid in the form of crystals with a melting point of 181-183 C.

EXEMPLE 128 6-méthoxy 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 6-OCH3 ; R2 = R3 = R4 = H ; X = CH ; Y = Z = S
Selon le mode opératoire de l'exemple 117, mais à partir de 8 g de 6-méthoxy 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 87, on récupère 5,5 g de 6-méthoxy 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 163-165 C.EXAMPLE 128 6-methoxy 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 6-OCH3; R2 = R3 = R4 = H; X = CH; Y = Z = S
According to the procedure of Example 117, but starting from 8 g of 6-methoxy 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 87, 5.5 g are recovered. of 6-methoxy 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 163-165 C.

EXEMPLE 129 6-trifluorométhyl loro 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 6-CF3 ; R2 = 7-Cl ; R3 = R4 = H ; X = H ; Y = Z = S
Selon le mode opératoire de l'exemple 117, mais à partir de 5,1 g de 6-trifluorométhyl 7-chloro 2H-1,4-benzothiazine-3thione 4-acétate d'éthyle préparés à l'exemple 88, on obtient 3,5 g de 6-trifluorométhyl 7-chLoro 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 170-172 C.EXAMPLE 129 6-trifluoromethyl loro 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 6-CF3; R2 = 7-Cl; R3 = R4 = H; X = H; Y = Z = S
According to the procedure of Example 117, but starting from 5.1 g of 6-trifluoromethyl 7-chloro 2H-1,4-benzothiazine-3thione 4-ethyl acetate prepared in Example 88, 3 are obtained , 5 g of 6-trifluoromethyl 7-chLoro 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 170-172 C.

EXEMPLE 130 2-phényl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = R2 = R3 = H ; R4 = phényle ; X = Ch ; Y = Z = S
Selon le mode opératoire de l'exemple 117, mais à partir de 9 g de 2-phényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à L'exemple 89, on obtient 4,2 g de 2-phényl 2H1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 182-184 C.EXAMPLE 130 2-phenyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = R2 = R3 = H; R4 = phenyl; X = Ch; Y = Z = S
According to the procedure of Example 117, but from 9 g of 2-phenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 89, 4.2 g are obtained of 2-phenyl 2H1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 182-184 C.

EXEMPLE 131 6-trifluorométhyl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 6-CF3 ; R2 = R3 = R4 = H ; X = CH ; Y = Z = S
Selon Le mode opératoire de l'exemple 117, mais à partir de 14 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 90, on récupère 5,5 g de 6-trifluorométhyl 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 163-165 C.EXAMPLE 131 6-trifluoromethyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 6-CF3; R2 = R3 = R4 = H; X = CH; Y = Z = S
According to the procedure of Example 117, but from 14 g of 6-trifluoromethyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 90, 5.5 g are recovered. of 6-trifluoromethyl 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 163-165 C.

EXEMPLE 132 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = R2 = R3 = H ; R4 = CH3 ; X = CH ; Y = Z = S
Selon le mode opératoire de l'exemple 117, mais à partir de 11 g de 2-méthyt 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyhle préparés à L'exemple 91, on obtient 4,5 g de 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 128-131 C.EXAMPLE 132 2-methyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = R2 = R3 = H; R4 = CH3; X = CH; Y = Z = S
According to the procedure of Example 117, but starting with 11 g of 2-methyt 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 91, 4.5 g are obtained of 2-methyl 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 128-131 C.

EXEMPLE 133 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = R2 = R3 = R4 = H ; X = CH ; Y = Z =S
Selon le mode opératoire de L'exemple 117, mais à partir de 21 g de 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 92, on récupère 9 g de 2H-1,4-benzothiazine-3thione 4-acide acétique sous forme de cristaux de point de fusion 187-188 C. EXAMPLE 133 2H-1,4-Benzothiazine-3-thione 4-acetic acid
Formula I: R1 = R2 = R3 = R4 = H; X = CH; Y = Z = S
According to the procedure of Example 117, but starting from 21 g of 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 92, 9 g of 2H-1 are recovered, 4-benzothiazine-3thione 4-acetic acid in the form of crystals with melting point 187-188 C.

EXEMPLE 134 6-chloro 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = 6-Cl ; R2 = R3 = R4 = H ; X = CH ; Y = S ; Z = O
Selon te mode opératoire de exemple 115, mais à partir de 9 g de 6-chloro 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 66, on obtient 5,5 g de 6-chloro 2H1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 151-153 C.EXAMPLE 134 6-chloro 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 6-Cl; R2 = R3 = R4 = H; X = CH; Y = S; Z = O
According to the procedure of Example 115, but from 9 g of 6-chloro 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 66, 5.5 g of 6 are obtained. -chloro 2H1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 151-153 C.

EXEMPLE 135 6-chloro 2H-1,4-benzothiazine 3-thione 4-acide acétique
Formule I : R1 = ó-Cl ; R2 = R3 = R4 =H H ; X = CH ; Y = Z = S
Selon te mode opératoire de l'exemple 117, mais à partir de 11 g de 6-chloro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à L'exemple 93, on récupère 5,2 g de 6-chloro 2H1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 186-188 C
EXEMPLE 136 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétique acide
Formule I :R1 = 6-F ; R3 = CH3 ; R2 = R4 = H ; X = CH E Y = S ; Z = O
Selon le mode opératoire de l'exemple 115, mais à partir de 10 g de 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle péparés à l'exemple 67, on récupère 6,5 g de 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétique acide sous forme de cristaux de point de fusion 139-141 C.EXAMPLE 135 6-chloro 2H-1,4-benzothiazine 3-thione 4-acetic acid
Formula I: R1 = ó-Cl; R2 = R3 = R4 = HH; X = CH; Y = Z = S
According to the procedure of Example 117, but starting from 11 g of 6-chloro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 93, 5.2 g are recovered. of 6-chloro 2H1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 186-188 C
EXAMPLE 136 6-fluoro 2-methyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 6-F; R3 = CH3; R2 = R4 = H; X = CH EY = S; Z = O
According to the procedure of Example 115, but starting from 10 g of 6-fluoro 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 67, 6 is recovered. , 5 g of 6-fluoro 2-methyl 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 139-141 C.


EXEMPLE 137 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétique acide
Formule I : R1 = 6-F ; R3 CH3 ; R2 = R4 = H S X = CH ; Y = Z=S
Selon le mode opératoire de l'exempte 117, mais à partir de 6 g de 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 94, on obtient 3 g de 6-fluoro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétique acide sous forme de cristaux de point de fusion 138-140 C.
EXAMPLE 137 6-fluoro 2-methyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 6-F; R3 CH3; R2 = R4 = HSX = CH; Y = Z = S
According to the procedure of Example 117, but starting from 6 g of 6-fluoro 2-methyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 94, 3 are obtained g of 6-fluoro 2-methyl 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 138-140 C.

EXEMPLE 138 6-chloro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétique acide
Formule I : R1 = 6-Cl ; R3 = CH3 ; R2 = R4 = H e X = CH E Y = S g Z = O
Selon le mode opératoire de l'exemple 115, mais à partir de 7 g de 6-chloro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à L'exemple 68, on obtient 4,9 g de 6-chtoro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétique acide sous forme de cristaux de point de fusion 129-131 C.EXAMPLE 138 6-chloro 2-methyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 6-Cl; R3 = CH3; R2 = R4 = H e X = CH EY = S g Z = O
According to the procedure of Example 115, but from 7 g of 6-chloro 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 68, 4 are obtained , 9 g of 6-chtoro 2-methyl 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 129-131 C.


EXEMPLE 139 6-chloro 2-phényl 2H-1,4-benzothiazine-3-one 4-acétique acide
Formule : : R1 = 6-Ct ; R3 = phényle ; R2 = RA = H ; X = CH ; Y=S;Z=O
Selon te mode opératoire de L'exemple 115, mais à partir de 8 g de 6-chloro 2-phényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 69, on récupère 5,3 g de 6-chloro 2-phényl 2H-1,4-benzothiazine-3-one 4-acétique acide sous forme de cristaux de point de fusion 169-170 c.
EXAMPLE 139 6-chloro 2-phenyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula:: R1 = 6-Ct; R3 = phenyl; R2 = RA = H; X = CH; Y = S; Z = O
According to the procedure of Example 115, but starting from 8 g of 6-chloro 2-phenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 69, 5 is recovered. , 3 g of 6-chloro 2-phenyl 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with a melting point 169-170 c.

EXEMPLE 140 6-chloro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétique acide
Formule I : R1 = 6-Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = Z = S
Selon le mode opératoire de l'exemple 117, mais à partir de 9 g de 6-chîoro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 95, on récupère 4,5 g de 6-chloro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétique acide sous forme de cristaux de point de fusion 126-128 C.EXAMPLE 140 6-chloro 2-methyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 6-Cl; R3 = CH3; R2 = R4 = H; X = CH; Y = Z = S
According to the procedure of Example 117, but from 9 g of 6-chloro 2-methyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 95, 4 is recovered. , 5 g of 6-chloro 2-methyl 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 126-128 C.


EXEMPLE 141 2,2-diméthyl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I R1 = R2 = H ; R3 = R4 = CH3 ; X = CH ; Y = S ; Z = O
Selon le mode opératoire de L'exemple 115, mais à partir de 15 g de 2,2-diméthyl 2H-1,4-benzothiazine-3-one4acétate d'éthyle préparés à l'exemple 70, on obtient 12 g de 2,2-diméthyl 2H-1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 114-116 C.
EXAMPLE 141 2,2-dimethyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I R1 = R2 = H; R3 = R4 = CH3; X = CH; Y = S; Z = O
According to the procedure of Example 115, but from 15 g of 2,2-dimethyl 2H-1,4-benzothiazine-3-one4acetate ethyl prepared in Example 70, 12 g of 2 are obtained, 2-dimethyl 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with a melting point of 114-116 C.


EXEMPLE 142 6-chloro 2-phényl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 6-CI ; R3 = phényle ; R2 = R4 = H ; X = CH ; Y = Z = S
Selon le mode opératoire de L'exemple 117, mais en utilisant Il g de 6-chloro 2-phényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 96, on récupère 4,5 g de 6-chtoro 2-phényl 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 199-2010C.
EXAMPLE 142 6-chloro 2-phenyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 6-CI; R3 = phenyl; R2 = R4 = H; X = CH; Y = Z = S
According to the procedure of Example 117, but using II g of 6-chloro 2-phenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 96, 4 is recovered, 5 g of 6-chtoro 2-phenyl 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 199-2010C.

EXEMPLE 143 2-para-chlorophényl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = R2 = R3 = H; R4 =para-chlorophényle g X = CH ; Y = S ; Z=O
Selon le mode opératoire de l'exemple 115, mais à partir de 7 g de 2-para-chlorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 71, on récupère 5 g de 2-para-chlorophényl 2H-1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 138-140 C.EXAMPLE 143 2-para-chlorophenyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = R2 = R3 = H; R4 = para-chlorophenyl g X = CH; Y = S; Z = O
According to the procedure of Example 115, but from 7 g of 2-para-chlorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 71, 5 g are recovered. of 2-para-chlorophenyl 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 138-140 C.


EXEMPLE 144 2-ortho-chlorophényl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I: R1 = R2 = R3 = H; R4 = ortho-chlorophényl ; X = CH;
Y =S;Z=O
Selon le mode opératoire de l'exemple 115, mais à partir de 10 g de 2-orthochlorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 72, on obtient 6,3 g de 2ortho-chlorophényl 2H-1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 164-165 C.
EXAMPLE 144 2-ortho-chlorophenyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = R2 = R3 = H; R4 = ortho-chlorophenyl; X = CH;
Y = S; Z = O
According to the procedure of Example 115, but starting from 10 g of 2-orthochlorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 72, 6.3 g are obtained of 2ortho-chlorophenyl 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 164-165 C.

EXEMPLE 145 7-chloro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = 7-Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = S ; Z = O
Selon le mode opératoire de l'exemple 115, mais à partir de 7,2 g de 7-chloro 2-méthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle, préparés à l'exemple 83, on récupère 3,2 g de 7-chloro 2-méthyl 2H-1,4-benzothizine-3-one 4-acide acétique sous forme de cristaux de point'de fusion 117-119 C.EXAMPLE 145 7-chloro 2-methyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 7-Cl; R3 = CH3; R2 = R4 = H; X = CH; Y = S; Z = O
According to the procedure of Example 115, but using 7.2 g of 7-chloro 2-methyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate, prepared in Example 83, 3.2 g of 7-chloro 2-methyl 2H-1,4-benzothizine-3-one 4-acetic acid are recovered in the form of crystals with a melting point of 117-119 C.

EXEMPLE 146 2,2-diméthyl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule F : R1 = R2 = H ; R3 = R4 = Ch3 ; X = CH ; Y = Z = S
Selon le mode opératoire de l'exemple 117, mais à partir de 11,2 g de 2,2-diméthyl 2Hrî,4-benzothiazine-3-thione 4acétate d'éthyle préparés à l'exemple 97, on obtient 5,8 g de 2,2diméthyl 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 176-178 C. EXAMPLE 146 2,2-dimethyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula F: R1 = R2 = H; R3 = R4 = Ch3; X = CH; Y = Z = S
According to the procedure of Example 117, but starting with 11.2 g of 2,2-dimethyl 2Hri, 4-benzothiazine-3-thione 4 ethyl acetate prepared in Example 97, 5.8 g are obtained 2,2dimethyl 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 176-178 C.

EXEMPLE 147 2-para-chlorophényl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = R2 = R3 = H ; R4 = para-chlorophényle ; X = CH ;
Y=Z=S
Selon le mode opératoire de L'exemple 117, mais à partir de 11,2 g de 2-para-chlorophényl 2H-1,4-benzothiazine-3- thione 4-acétate d'éthyle préparés à l'exemple 98, on obtient 5,9 g de 2-para-chlorophényl 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 173-174
EXEMPLE148 2-ortho-chlorophényl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I R1 = R2 = R3 = H ; R4 = ortho-chlorophényl ;X = CH ;
Y=Z=S
Selon le mode opératoire de l'exemple 117, mais à partir de 18 g de 2-orthochlorophenyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle synthétisés à l'exemple 101, on récupère 8,2 g de 2-ortho-chlorophényl 2H-1 ,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 179-181 C.EXAMPLE 147 2-para-chlorophenyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = R2 = R3 = H; R4 = para-chlorophenyl; X = CH;
Y = Z = S
According to the procedure of Example 117, but from 11.2 g of 2-para-chlorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 98, one obtains 5.9 g of 2-para-chlorophenyl 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 173-174
EXAMPLE 148 2-ortho-chlorophenyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I R1 = R2 = R3 = H; R4 = ortho-chlorophenyl; X = CH;
Y = Z = S
According to the procedure of Example 117, but starting from 18 g of 2-orthochlorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate synthesized in Example 101, 8.2 g are recovered. of 2-ortho-chlorophenyl 2H-1, 4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 179-181 C.

EXEMPLE 149 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 6-CI ; R2 = 7-Cl ; R3 = R4 H = H ; X = CH ;
Y=Z=S
Selon le mode opératoire de L'exemple 117, mais à partir de 2,4 g de 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 99, on obtient 1 g de 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 185-187 C.EXAMPLE 149 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 6-CI; R2 = 7-Cl; R3 = R4 H = H; X = CH;
Y = Z = S
According to the procedure of Example 117, but starting with 2.4 g of 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 99, one obtains 1 g of 6,7-dichloro 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 185-187 C.


EXEMPLE 150 7-chloro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 7-Cl ; R3 = CH3 ; R2 = R4 = H ; X = CH ; Y = Z = S
Selon le mode opératoire de L'exemple 117, mais à partir de 9,2 g de 7-chloro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à l'exemple 100, on obtient 5 g de 7-chloro 2-méthyl 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 136-138 C.
EXAMPLE 150 7-chloro 2-methyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 7-Cl; R3 = CH3; R2 = R4 = H; X = CH; Y = Z = S
According to the procedure of Example 117, but starting from 9.2 g of 7-chloro 2-methyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 100, we obtains 5 g of 7-chloro 2-methyl 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 136-138 C.

EXEMPLE 151 2-méthyl 2-(2'-pyridyl) 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = R2 = H ; R3 = CH3 ; R4=2'-pyridyl ; X = CH ;
Y = S ; Z = O
Selon le mode opératoire de L'exemple 115, mais à partir de 12 g de 2-méthyl 2-(2'-pyridyl) 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 74 et en neutralisant à la fin de la saponification par l'acide acétique au lieu de l'acide chlorhydrique, on obtient 5,6 g de 2-méthyl 2-(2'-pyridyl) 2H-1,4- benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 194-196 C.EXAMPLE 151 2-methyl 2- (2'-pyridyl) 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = R2 = H; R3 = CH3; R4 = 2'-pyridyl; X = CH;
Y = S; Z = O
According to the procedure of Example 115, but from 12 g of 2-methyl 2- (2'-pyridyl) 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 74 and by neutralizing at the end of the saponification with acetic acid instead of hydrochloric acid, 5.6 g of 2-methyl 2- (2'-pyridyl) 2H-1,4-benzothiazine-3 are obtained -one 4-acetic acid in the form of melting point crystals 194-196 C.

EXEMPLE 152 6-fluoro 2H-1,4-benzoxazine-3-thione 4-acide acétique
Formule I : R1 = 6-F ; R2 = R3 = R4 = H ; X = CH ; Y = O ; Z = S
Selon le mode opératoire de l'exemple 117, mais en utilisant 8, g de 6-f luoro 2H-1,4-benzoxazine-3-thione 4-acétate d'éthyle préparés à l'exemple 102, on obtient après filtration sur gel de silice en éluant au benzène, 1,5 g de 6-fluoro 2H-1,4- benzoxazine-3-thione 4-acide acétique sous forme de cristaux de.EXAMPLE 152 6-fluoro 2H-1,4-benzoxazine-3-thione 4-acetic acid
Formula I: R1 = 6-F; R2 = R3 = R4 = H; X = CH; Y = O; Z = S
According to the procedure of Example 117, but using 8 g of 6-fluoro 2H-1,4-benzoxazine-3-thione 4-ethyl acetate prepared in Example 102, after filtration through silica gel, eluting with benzene, 1.5 g of 6-fluoro 2H-1,4-benzoxazine-3-thione 4-acetic acid in the form of crystals.

point de fusion 153-155 C.melting point 153-155 C.

EXEMPLE 153 6-fluoro 3,4-dihydroquinoline 2-thione 1-acide acétique
Formule I : R1 = 6-F ; R2 = R3 = R4 = H ; X = CH ; V=CH2 : Z = S
Selon le mode opératoire de L'exemple 117, mais en utilisant 6,5 g de 6-fluoro 3,4-dihydroquinoline 2-thione 1-acétate d'éthyle préparés à l'exemple 103, on obtient après recristallisation dans l'acétonitrile 2,9 g de 6-fluoro 3,4-dihydroquinoline 2-thione acide acétique sous forme de cristaux de point de fusion 177-180 C.EXAMPLE 153 6-fluoro 3,4-dihydroquinoline 2-thione 1-acetic acid
Formula I: R1 = 6-F; R2 = R3 = R4 = H; X = CH; V = CH2: Z = S
According to the procedure of Example 117, but using 6.5 g of 6-fluoro 3,4-dihydroquinoline 2-thione 1-ethyl acetate prepared in Example 103, one obtains after recrystallization from acetonitrile 2.9 g of 6-fluoro 3,4-dihydroquinoline 2-thione acetic acid in the form of crystals with melting point 177-180 C.

EXEMPLE 154 6-chloro 3,4-dihydroquinoline 2-thione 1-acide acétique
Formule I : R1 = 6-Cl ; R2 = R3 =R4 = H ; X = CH g Y = CH2 ; Z = S
Selon le mode opératoire de l'exemple 117, mais en utilisant 9,4 g de 6-chloro 3,4-dihydroquinoline 2-thione 1-acétate d'éthyle préparés à l'exemple 104, on récupère 3,5 g de 6-chLoro 3,4-dihydroquinoline 2-thione 1-acide acétique sous forme de cristaux de. point de fusion 165 C. EXAMPLE 154 6-chloro 3,4-dihydroquinoline 2-thione 1-acetic acid
Formula I: R1 = 6-Cl; R2 = R3 = R4 = H; X = CH g Y = CH2; Z = S
According to the procedure of Example 117, but using 9.4 g of 6-chloro 3,4-dihydroquinoline 2-thione 1-ethyl acetate prepared in Example 104, 3.5 g of 6 are recovered. -chLoro 3,4-dihydroquinoline 2-thione 1-acetic acid in the form of crystals. melting point 165 C.

EXEMPLE 155 7-fluoro 3,4-dihydroquinoline 2-thione 1-acide acétique
FormuLe I : R1 = 7-F ; R2 = R3 = R4 = H ; X = CH ; Y = CH2 ; Z = S
Selon le mode opératoire de L'exemple 117, mais en utilisant 15,7 g de 7-fluoro 3,4-dihydroquinotine 2-thione 1-acétate d'éthyle préparés à L'exempLe 105, on récupère 5,8 g de 7-fluoro 3,4-dihydroquinoline 2-thione 1-acide acétique sous forme de cristaux de point de fusion 154-156 C.EXAMPLE 155 7-fluoro 3,4-dihydroquinoline 2-thione 1-acetic acid
FormuLe I: R1 = 7-F; R2 = R3 = R4 = H; X = CH; Y = CH2; Z = S
According to the procedure of Example 117, but using 15.7 g of 7-fluoro 3,4-dihydroquinotine 2-thione 1-ethyl acetate prepared in Example 105, 5.8 g of 7 are recovered. -fluoro 3,4-dihydroquinoline 2-thione 1-acetic acid in the form of crystals of melting point 154-156 C.

EXEMPLE 156 7-chloro 3,4-dihydroquinoline 2-thione 1-acide acétique
Formule I : R1 = 7-CI ; R2 = R3 = R4 = H ; X = CH ; Y = CH2 = Z = S
Selon le mode opératoire de l'exemple 117, mais en partant de 12 g de 7-chloro 3,4-dihydroquinoline 2-thione 1-acétate d'éthyle préparés à Exemple 106, on récupère après recristaLlisation dans un mélange toluène-acétonitrile 4 g de 7-chLoro 3,4-dihydroquinoline 2-thione 1-acide acétique sous forme de cristaux de point de fusion 148-155 C.EXAMPLE 156 7-chloro 3,4-dihydroquinoline 2-thione 1-acetic acid
Formula I: R1 = 7-CI; R2 = R3 = R4 = H; X = CH; Y = CH2 = Z = S
According to the procedure of Example 117, but starting from 12 g of 7-chloro 3,4-dihydroquinoline 2-thione 1-ethyl acetate prepared in Example 106, it is recovered after recrystallization from a toluene-acetonitrile 4 mixture. g of 7-chLoro 3,4-dihydroquinoline 2-thione 1-acetic acid in the form of crystals with a melting point of 148-155 C.

EXEMPLE 157 2-para-fluorophényl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 = R2 = R3 = H ; R4 = para-fluorophényle ; X = CH ; Y=S ; Z=O
Selon le mode opératoire del'exemple 115, mais en partant de 12 g de 2-para-fluorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à L'exemple 80, on récupère 7 g de 2para-fluorophényl 2H-1,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 140-141 C.EXAMPLE 157 2-para-fluorophenyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = R2 = R3 = H; R4 = para-fluorophenyl; X = CH; Y = S; Z = O
According to the procedure of Example 115, but starting from 12 g of 2-para-fluorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 80, 7 g of 2para-fluorophenyl 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 140-141 C.

EXEMPLE 158 2-ortho-fluorophényl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : = R2 = R3 = H ; R4 = ortho-fluorophényl ; X = CH ; Y=S;Z=O
Selon le mode opératoire de l'exemple 115, mais en partant de 12 g de 2-ortho-fluorophényl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle préparés à l'exemple 81, on obtient 10,2 g de 2-ortho-fluorophényl 2H-1 ,4-benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 162-163 C. EXAMPLE 158 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: = R2 = R3 = H; R4 = ortho-fluorophenyl; X = CH; Y = S; Z = O
According to the procedure of Example 115, but starting with 12 g of 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate prepared in Example 81, 10 are obtained, 2 g of 2-ortho-fluorophenyl 2H-1, 4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 162-163 C.

EXEMPLE 159 2-para-fluorophényl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = R2 = R3 ; H ; R4 = para-fluorophényl ; X = CH ;
Y=Z=S
Selon le mode opératoire de L'exemple 117, mais à partir de 12 g de 2-para-fîuorophényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle préparés à L'exemple 108, on obtient après cris- tallisation dans un mélange d'éther isopropylique et de pentane 4,2 g de 2-para-fluorophényl 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 160-161 C.EXAMPLE 159 2-para-fluorophenyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = R2 = R3; H; R4 = para-fluorophenyl; X = CH;
Y = Z = S
According to the procedure of Example 117, but from 12 g of 2-para-fiorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 108, one obtains after shouting - tallization in a mixture of isopropyl ether and pentane 4.2 g of 2-para-fluorophenyl 2H-1,4-benzothiazine-3-thione 4-acetic acid in the form of crystals with melting point 160-161 C.

EXEMPLE 160 2-ortho-fluorophényl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = R2 = R3 = H ; R4 = ortho-fluorophényle ; X = CH ;
Y=Z=S
Selon le mode opératoire de l'exemple 117, mais à partir de 19 g de 2-ortho-fluorophényl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle obtenus à L'exemple 109, on récupère après cris tallisation dans un mélange d'éther isopropylique et de pentane 7 g de 2-ortho-fluorophényl 2H-1t4-benzothiazine-3thione 4-acide acétique sous forme de cristaux de point de fusion 180-182 C.EXAMPLE 160 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = R2 = R3 = H; R4 = ortho-fluorophenyl; X = CH;
Y = Z = S
According to the procedure of Example 117, but from 19 g of 2-ortho-fluorophenyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate obtained in Example 109, recovery is obtained after shouting tallization in a mixture of isopropyl ether and pentane 7 g of 2-ortho-fluorophenyl 2H-1t4-benzothiazine-3thione 4-acetic acid in the form of crystals with melting point 180-182 C.


EXEMPLE 161 4-fluoro 2-nitrophénylthio &alpha;,&alpha;'-diméthyl acétique acide
Formule VIII : R1 = 4-F; R3 = R4 = CH3 R2 = H ; X = CH ; Y = S ;
R" = H
Selon te mode opératoire de L'exemple 1, mais en utilisant 48 g de 2,5-difluoronitrobenzène et 36,2 g d'&alpha;-mercapto- isobutyrique acide, on obtient après acidification à L'acide acétique, extraction à l'éther et cristallisation du résidu dans un mélange éther isopropylique et pentane 37,4 g de 4-fluoro 2-nitrophénylthio &alpha;,&alpha;'-diméthyl acétique acide sous forme de cristaux de point de fusion 104 C.
EXAMPLE 161 4-fluoro 2-nitrophenylthio &alpha;,&alpha;'- dimethyl acetic acid
Formula VIII: R1 = 4-F; R3 = R4 = CH3 R2 = H; X = CH; Y = S;
R "= H
According to the procedure of Example 1, but using 48 g of 2,5-difluoronitrobenzene and 36.2 g of alpha-mercapto-isobutyric acid, after acidification with acetic acid, extraction with ether and crystallization of the residue in a mixture of isopropyl ether and pentane 37.4 g of 4-fluoro 2-nitrophenylthio &alpha;,&alpha;'- dimethyl acetic acid in the form of crystals with melting point 104 C.

EXEMPLE 162 4-fluoro 2-nitrophénylthio &alpha;,&alpha;'-diméthyl acétate d'éthyle
Formule VIII : R1 = 4-F; R3 = R4 = CH3 ; R2 = H ; X X = CH ; Y = S;
R" = C2H5
Selon le mode opér atoire de l'exemple 19, mais à partir de 37,4 g de 4-fluoro 2-nitrophénylthio &alpha;,&alpha;'-diméthyl acétique acide, préparés à l'exemple 161, on obtient 38,5 g de 4-fluoro 2-nitrophénylthio a,a'-diméthyl acétate d'éthyle sous forme d'une huile utilisée brute pour L'étape suivante.EXAMPLE 162 4-fluoro 2-nitrophenylthio &alpha;,&alpha;'- dimethyl ethyl acetate
Formula VIII: R1 = 4-F; R3 = R4 = CH3; R2 = H; XX = CH; Y = S;
R "= C2H5
According to the operating method of Example 19, but from 37.4 g of 4-fluoro 2-nitrophenylthio &alpha;,&alpha;'- dimethyl acetic acid, prepared in Example 161, 38.5 g are obtained. of 4-fluoro 2-nitrophenylthio a, a'-dimethyl ethyl acetate in the form of a crude oil used for the following stage.

EXEMPLE 163 6-fluoro 2,2-diméthyl 2H-1,4-benzothiazine-3 (4H)-one
Formule III : R1 = 6-F ; R3 = R4 = CH3 ; R2 = H ; X = CH ; Y = S
Selon le mode opératoire de L'exemple 28, mais en utilisant 38,5 g de 4-fluoro 2-nitrophénylthio a,a'-diméthyl acétate d'éthyle, préparésà L'exemple 162, on obtient 18,5 g de 6-fluoro 2,2-diméthyl 2H-,4-benzothiazine-3 (4H)-one sous forme de cristaux de point de fusion 176 C.EXAMPLE 163 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3 (4H) -one
Formula III: R1 = 6-F; R3 = R4 = CH3; R2 = H; X = CH; Y = S
According to the procedure of Example 28, but using 38.5 g of 4-fluoro 2-nitrophenylthio a, a'-dimethyl ethyl acetate, prepared in Example 162, 18.5 g of 6- are obtained. fluoro 2,2-dimethyl 2H-, 4-benzothiazine-3 (4H) -one in the form of crystals with melting point 176 C.

EXEMPLE 164 6-fluoro 2,2-diméthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthy
Formule II : R1 = 6-F ; R3 = R4 = CH3 ; R2 = H ; X = CH ; Y = S ;
Z = 0 ; R' = C2H5
Selon le mode opératoire de l'exemple 52, mais à partir de 18,5 g de 6-fluoro 2,2-diméthyl 2H-1,4-benzothiazine-3 (4H)-one préparés à Exemple 163, on obtient 25 g de 6-ftuoro 2,2-diméthyl 2H-1 ,4-benzothiazine-3-one 4-acétate d'éthyle sous forme de cristaux de point de fusion 78 C.EXAMPLE 164 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate
Formula II: R1 = 6-F; R3 = R4 = CH3; R2 = H; X = CH; Y = S;
Z = 0; R '= C2H5
According to the procedure of Example 52, but from 18.5 g of 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3 (4H) -one prepared in Example 163, 25 g are obtained of 6-ftuoro 2,2-dimethyl 2H-1, 4-benzothiazine-3-one 4-ethyl acetate in the form of crystals with melting point 78 C.

EXEMPLE 165 6-fluoro 2,3-diméthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle
Formule II : R1 = 6-F ; R3 = R4 = CH3 ; R2 = H ; X = CH ; Y = Z = S
R = C2H
Selon le mode opératoire de l'exemple 84, mais à partir de 18 g de 6-fluoro 2,2-diméthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle, préparésà l'exemple 164, on obtient après filtration sur gel de silice en éluant au toluène et après cristallisation dans le pentane 8 g de 6-fluoro 2,2-diméthyl 2H-1,4-benzothiazine-3-thione 4-acétate d'éthyle sous forme de cristaux de point de fusion 60-62 C.EXAMPLE 165 6-fluoro 2,3-dimethyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate
Formula II: R1 = 6-F; R3 = R4 = CH3; R2 = H; X = CH; Y = Z = S
R = C2H
According to the procedure of Example 84, but starting from 18 g of 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate, prepared in Example 164, obtained after filtration on silica gel, eluting with toluene and after crystallization from pentane 8 g of 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate in the form of crystals of melting point 60-62 C.

EXEMPLE 166 6-fluoro 2,2-diméthyl 2H-1,4-benzothiazine-3-one 4-acide acétique
Formule I : R1 =6-F; R3 = R4 = CH3 ; R2 = H ; X = CH ; Y = S ; Z = O
Selon Le mode opératoire de L'exempte 115, mais à partir de 7 g de 6-fluoro 2,2-diméthyl 2H-1,4-benzothiazine-3-one 4-acétate d'éthyle, exemple 164: on obtient après recristallisation dans Le tétrachlorure de carbone 4 g de 6-fluoro 2,2-diméthyl 2H-1,4- benzothiazine-3-one 4-acide acétique sous forme de cristaux de point de fusion 137-138 C.EXAMPLE 166 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3-one 4-acetic acid
Formula I: R1 = 6-F; R3 = R4 = CH3; R2 = H; X = CH; Y = S; Z = O
According to the procedure of Example 115, but from 7 g of 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3-one 4-ethyl acetate, example 164: after recrystallization is obtained in Carbon tetrachloride 4 g of 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3-one 4-acetic acid in the form of crystals with melting point 137-138 C.

EXEMPLE 167 6-fluoro 2,3-diméthyl 2H-1,4-benzothiazine-3-thione 4-acide acétique
Formule I : R1 = 6-F ; R3 = Rz = CH3 g R2 = H ; X = CH ; Y = Z = S
Selon le mode opératoire de l'exemple 117, mais à partir de 7,8 g de 6-fluoro 2,2-diméthyl 2H-1,4-benzothiazine-3-thione 4-acetate d'éthyle préparé à l'exemple 165, on récupère 5,8 g de 6-fluoro 2,2-diméthyl 2H-1,4-benzothiazine-3-thione 4-acide acétique sous forme de cristaux de point de fusion 171-1720C. EXAMPLE 167 6-fluoro 2,3-dimethyl 2H-1,4-benzothiazine-3-thione 4-acetic acid
Formula I: R1 = 6-F; R3 = Rz = CH3 g R2 = H; X = CH; Y = Z = S
According to the procedure of Example 117, but from 7.8 g of 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3-thione 4-ethyl acetate prepared in Example 165 , 5.8 g of 6-fluoro 2,2-dimethyl 2H-1,4-benzothiazine-3-thione 4-acetic acid are recovered in the form of crystals with melting point 171-1720C.

PHARMACOLOGIE
Principe
L'activité inhibitrice de L'aldose réductase est évaluée in vitro à partir d'un homogènat de cristallin de rat utilisé comme source d'enzyme Le substrat utilisé est le DL-glycéraldéhyde qui est transformé par l'aldose réductase en glycérol, en présence de
NADPH (*). Cette reaction est suivie par spectrophotométrie à 340 nm, en L'absence et en présence des inhibiteurs à tester, la variation de densité optique étant proportionnelle à l'oxydation du coenzyme réduit.PHARMACOLOGY
Principle
The inhibitory activity of aldose reductase is evaluated in vitro from a rat crystalline homogenate used as an enzyme source. The substrate used is DL-glyceraldehyde which is transformed by aldose reductase into glycerol, in the presence of
NADPH (*). This reaction is followed by spectrophotometry at 340 nm, in the absence and in the presence of the inhibitors to be tested, the variation in optical density being proportional to the oxidation of the reduced coenzyme.

Résultats
Les résultats figurent dans le tableau I ci-dessous et représentent pour différents exemples le pourcentage dsinhibition de l'activité enzymatique par rapport à Inactivité témoin en fonction des différentes concentrations (N.l-1) utilisées.Pour les dérivés les plus actifs, la concentration inhibitrice 50 a été déterminée TABLEAU I
Inhibition par rapport à l'activité
témoin, z CISO
nm/l (**)
Concentration 10-4 10-5 10-6 10-7 10-8 10-9 (mole/litre)
Exemple 110 95 82 37 Il 4 9
Exemple 111 96 80 5
Exemple 114 95 86 6
Exemple 115 90 57 3
TABLEAU I (suite)
Inhibition par rapport à L'activité
témoin, % CI50
nm/l (**)
Concentration 10-4 10-5 10-6 10-7 10-8 10-0 (mole/litre)
Exemple 116 100 95 25
Exemple 117 100 100 65 5 82 + 1
Exemple 118 98 91 10
ExempLe 119 100 98 67 22 46 + 2
Exemple 121 97 92 16
Exemple 123 97 81 0
Exemple 124 97 86 10
Exemple 125 99 91 12
Exemple 127 98 93 28
Exemple 129 74 25 5
Exemple 130 99 95 17
Exemple 132 95 92 16 42 + 13@
Exemple 133 98 69 18 54 * 5
Exemple 136 95 30 11
Exemple 137 94 80 13
Exemple 151 96 73 16
Exemple 152 100 99 54 86 + 4
ExempLe 154 94 56 29 91 + 15
(*) Nicotinamide Adénine Dinucléotide PHosphate forme réduite
(**) n = moyenne de 3 déterminations (***) n = moyenne de 2 déterminations
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.Results
The results are shown in Table I below and represent for different examples the percentage inhibition of the enzymatic activity relative to the control inactivity as a function of the different concentrations (Nl-1) used. For the most active derivatives, the inhibitory concentration 50 has been determined TABLE I
Inhibition from activity
witness, z CISO
nm / l (**)
Concentration 10-4 10-5 10-6 10-7 10-8 10-9 (mole / liter)
Example 110 95 82 37 Il 4 9
Example 111 96 80 5
Example 114 95 86 6
Example 115 90 57 3
TABLE I (continued)
Inhibition from Activity
control,% CI50
nm / l (**)
Concentration 10-4 10-5 10-6 10-7 10-8 10-0 (mole / liter)
Example 116 100 95 25
Example 117 100 100 65 5 82 + 1
Example 118 98 91 10
EXAMPLE 119 100 98 67 22 46 + 2
Example 121 97 92 16
Example 123 97 81 0
Example 124 97 86 10
Example 125 99 91 12
Example 127 98 93 28
Example 129 74 25 5
Example 130 99 95 17
Example 132 95 92 16 42 + 13 @
Example 133 98 69 18 54 * 5
Example 136 95 30 11
Example 137 94 80 13
Example 151 96 73 16
Example 152 100 99 54 86 + 4
EXAMPLE 154 94 56 29 91 + 15
(*) Nicotinamide Adenine Dinucleotide PHosphate reduced form
(**) n = average of 3 determinations (***) n = average of 2 determinations
In human therapy, the compounds of formula I and optionally their non-toxic addition salts can be administered, in particular orally, in the form of capsules or tablets containing from 50 to 300 mg of active principle.

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

Les produits des différents exemples décrits sont peu toxiques dans la mesure où les doses létales 50, déterminées chez le rat par voie orale, sont toutes supérieures à 300 mg.kg-1.  The products of the various examples described are not very toxic since the lethal doses 50, determined in the oral rat, are all greater than 300 mg.kg-1.

IABLEAU II
Exemple 110

Figure img00490001
LEAD II
Example 110
Figure img00490001

Code 5155-01
Exemple 111

Figure img00490002
Code 5155-01
Example 111
Figure img00490002

Code 5155-02
Exemple 112

Figure img00490003
Code 5155-02
Example 112
Figure img00490003

Code 5155-06
Exemple 113

Figure img00490004
Code 5155-06
Example 113
Figure img00490004

Code 5155-07
Exemple 114

Figure img00490005
Code 5155-07
Example 114
Figure img00490005

Code 515503
Exemple 115

Figure img00490006
Code 515503
Example 115
Figure img00490006

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Exemple 116

Figure img00490007
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Example 116
Figure img00490007

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TABLEAU II (suite 1)
Exemple 117

Figure img00500001
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TABLE II (continued 1)
Example 117
Figure img00500001

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Exemple 118

Figure img00500002
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Example 118
Figure img00500002

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Exemple 119

Figure img00500003
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Example 119
Figure img00500003

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Exemple 120

Figure img00500004
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Example 120
Figure img00500004

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Exemple 121

Figure img00500005
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Example 121
Figure img00500005

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Exemple 122

Figure img00500006
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Example 122
Figure img00500006

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ExempLe 123

Figure img00500007
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EXAMPLE 123
Figure img00500007

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Exemple 124

Figure img00510001
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Example 124
Figure img00510001

Code 5180-18
Exemple 125

Figure img00510002
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Example 125
Figure img00510002

Code 5180-19
Exemple 126

Figure img00510003
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Example 126
Figure img00510003

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Exempte 127

Figure img00510004
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Free 127
Figure img00510004

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Exemple 128

Figure img00510005
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Example 128
Figure img00510005

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Exemple 129

Figure img00510006
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Example 129
Figure img00510006

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Exemple 130

Figure img00520001
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Example 130
Figure img00520001

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Exemple 131

Figure img00520002
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Example 131
Figure img00520002

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Exemple 132

Figure img00520003
Code 5180-25
Example 132
Figure img00520003

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Exemple 133

Figure img00520004
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Example 133
Figure img00520004

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Exemple 134

Figure img00520005
Code 5180-27
Example 134
Figure img00520005

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Exemple 135

Figure img00520006
Code 5180-28
Example 135
Figure img00520006

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Exemple 136

Figure img00520007
Code 5180-29
Example 136
Figure img00520007

Code 5180-30
Exemple 137

Figure img00530001
Code 5180-30
Example 137
Figure img00530001

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ExempLe 138

Figure img00530002
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EXAMPLE 138
Figure img00530002

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Exemple 139 #
Code 5180-33
ExempLe 140

Figure img00530003
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Example 139 #
Code 5180-33
EXAMPLE 140
Figure img00530003

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Exemple 141

Figure img00530004
Code 5180-34
Example 141
Figure img00530004

Code 5180-35
Exemple 142

Figure img00530005
Code 5180-35
Example 142
Figure img00530005

Code 5180-36
Exemple 143

Figure img00530006
Code 5180-36
Example 143
Figure img00530006

Code 5180-37
Exemple 144

Figure img00540001
Code 5180-37
Example 144
Figure img00540001

Code 5180-38
Exemple 145

Figure img00540002
Code 5180-38
Example 145
Figure img00540002

Code 5180-39
Exemple í46

Figure img00540003
Code 5180-39
Example í46
Figure img00540003

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Exemple 147

Figure img00540004
Code 5180-40
Example 147
Figure img00540004

Code 5180-41
Exemple 149

Figure img00540005
Code 5180-41
Example 149
Figure img00540005

Code 5180-42
Exemple 150

Figure img00540006
Code 5180-42
Example 150
Figure img00540006

Code 5180-43
Exemple 148

Figure img00550001
Code 5180-43
Example 148
Figure img00550001

Code 5180-44
Exemple 157

Figure img00550002
Code 5180-44
Example 157
Figure img00550002

Code 5180-45
Exemple 158

Figure img00550003
Code 5180-45
Example 158
Figure img00550003

Code 5180-46
Exemple 159

Figure img00550004
Code 5180-46
Example 159
Figure img00550004

Code 5180-47
Exemple 160

Figure img00550005
Code 5180-47
Example 160
Figure img00550005

Code 5180-48
Exemple 151

Figure img00550006
Code 5180-48
Example 151
Figure img00550006

Code 5177-01
Exemple 152

Figure img00560001
Code 5177-01
Example 152
Figure img00560001

Code 5180-13
Exemple 153

Figure img00560002
Code 5180-13
Example 153
Figure img00560002

Code 5204-04
Exemple 154

Figure img00560003
Code 5204-04
Example 154
Figure img00560003

Code 5204-05
Exemple 155

Figure img00560004
Code 5204-05
Example 155
Figure img00560004

Code 5204-07
Exemple 156

Figure img00560005
Code 5204-07
Example 156
Figure img00560005

Code 5204-08
Exemple 166

Figure img00560006
Code 5204-08
Example 166
Figure img00560006

Code 5180-49
Exemple 167

Figure img00560007
Code 5180-49
Example 167
Figure img00560007

Code 5180-50 Code 5180-50

Claims (15)

inférieur", on entend une chaîne en C -C ramifiée ou non ; et leurs sels non toxiques d'addition. lower "means a branched or unbranched C -C chain; and their non-toxic addition salts. noyau phényle ou pyridyle éventuellement substitué ; par "alkyle optionally substituted phenyl or pyridyl ring; by "alkyl R3 et R4 peuvent représenter L'hydrogène, un alkyle inférieur, unR3 and R4 can represent Hydrogen, lower alkyl, fluorométhoxy ; fluoromethoxy; trifluorométhyle, méthoxy, thiométhyle, thiotrifluorométhylev  trifluoromethyl, methoxy, thiomethyl, thiotrifluoromethylv R1 et R2 peuvent représenter L'hydrogène, un halogène, un groupeR1 and R2 can represent Hydrogen, a halogen, a group X représente CH ou l'atome d'azote;X represents CH or the nitrogen atom; Y peut en outre représenter l'atome d'azote quand X est L'azote ; Y can also represent the nitrogen atom when X is nitrogen; Y représente L'atome d'oxygène ou l'atome de soufre ou un méthylène ;Y represents the oxygen atom or the sulfur atom or a methylene; quand Y représente le soufre ou quand X = Y = N ; when Y represents sulfur or when X = Y = N; Z représente l'atome de soufre, mais peut représenter également l'oxygèneZ represents the sulfur atom, but can also represent oxygen dans laquelle in which
Figure img00570001
Figure img00570001
 REVENDICATIONS 1. Nouveaux composés, caractérisés en ce qu'ils répondent à la formule : CLAIMS 1. New compounds, characterized in that they correspond to the formula: 2. Nouveaux composés selon la revendication 1, caractérisés en cc 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, caractérises 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@ 3, caractérisés en ce que R1 = H et R2 représente le fluor.4. New compounds according to any one of claims 1 @ 3, characterized in that R1 = H and R2 represents fluorine.
Figure img00570002
Figure img00570002
 5. Nouveaux composés selon L'une quelconque des revendications @ @@ caractérisés en ce que R3 = H et R4 représente un méthyle ou un phén@@@ 5. New compounds according to any one of claims @ @@ characterized in that R3 = H and R4 represents a methyl or a phen @@@ 6. Nouveau composé selon la revendication 1, caractérisé en ce qu'il répond à la formule6. New compound according to claim 1, characterized in that it corresponds to the formula 7. Nouveau composé selon la revendication 1, caractérisé en ce qu'iL répond à la formule  7. New compound according to claim 1, characterized in that iL corresponds to the formula
Figure img00580001
Figure img00580001
 8. Nouveau composé selon la revendication 1, caractérise en ce qu'il répond à la formule 8. New compound according to claim 1, characterized in that it corresponds to the formula
Figure img00580002
Figure img00580002
 9. Nouveau composé selon la revendication 1, caractérise en ce qu'iL répond à la formule : 9. New compound according to claim 1, characterized in that iL corresponds to the formula:
Figure img00580003
Figure img00580003
 10. Nouveau composé selon la revendication 1, caractérisé en ce qu'il répond à la formule 10. New compound according to claim 1, characterized in that it corresponds to the formula
Figure img00580004
Figure img00580004
 11. Nouveau composé selon la revendication 1, caractérise en ce qu'iL répond à La formule 11. New compound according to claim 1, characterized in that iL corresponds to the formula
Figure img00580005
Figure img00580005
 12. Nouveau composé selon la revendication 1, caractérisé en ce qu'il répond à la formule  12. New compound according to claim 1, characterized in that it corresponds to the formula
Figure img00590001
Figure img00590001
 13. Nouveau composé se Ion la revendication 1, caractérisé en ce qu'il repond à la formule 13. New compound according to claim 1, characterized in that it corresponds to the formula
Figure img00590002
Figure img00590002
 14. Procédé de préparation des nouveaux composés selon L'une quelconque des revendications 1 à 13, caractérisé en ce que l'on réalise l'hydrolyse en milieu basique ou acide d'esters de formule : 14. Process for the preparation of the new compounds according to any one of claims 1 to 13, characterized in that the hydrolysis is carried out in basic or acidic medium of esters of formula:
Figure img00590003
Figure img00590003
 où R1, R2, R3, R4, X, Y et Z sont tels que définis dans L'une quelconque des revendications 1 à 13 et R' représente un radical alkyle inférieur en C1-C5 ramifié ou non. where R1, R2, R3, R4, X, Y and Z are as defined in any one of Claims 1 to 13 and R 'represents a branched or unbranched C1-C5 lower alkyl radical. 15. Nouveaux médicaments, caractérisés en ce qu'ils contiennent au moins un compose selon l'une quelconque des revendications 1 à 14. 15. New drugs, characterized in that they contain at least one compound according to any one of claims 1 to 14.
FR8503236A 1984-05-18 1985-03-05 NOVEL HETEROCYCLIC DERIVATIVES, PROCESSES FOR THEIR PREPARATION, MEDICAMENTS CONTAINING THEM, USEFUL IN PARTICULAR AS INHIBITORS OF ALDOSE REDUCTASE Expired FR2578542B2 (en)

Priority Applications (16)

Application Number Priority Date Filing Date Title
FR8503236A FR2578542B2 (en) 1985-03-05 1985-03-05 NOVEL HETEROCYCLIC DERIVATIVES, PROCESSES FOR THEIR PREPARATION, MEDICAMENTS CONTAINING THEM, USEFUL IN PARTICULAR AS INHIBITORS OF ALDOSE REDUCTASE
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
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
EP85400927A EP0162776B1 (en) 1984-05-18 1985-05-13 Heterocyclic derivatives, process for their preparation and medicaments useful as aldose reductase inhibitors containing them
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
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
KR1019850003306A KR900004320B1 (en) 1984-05-18 1985-05-15 Process for preparation of new heterocyclic derivatives
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
ES543266A ES8607263A1 (en) 1984-05-18 1985-05-17 Heterocyclic derivatives, process for their preparation and medicaments useful as aldose reductase inhibitors containing them.
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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FR8503236A FR2578542B2 (en) 1985-03-05 1985-03-05 NOVEL HETEROCYCLIC DERIVATIVES, PROCESSES FOR THEIR PREPARATION, MEDICAMENTS CONTAINING THEM, USEFUL IN PARTICULAR AS INHIBITORS OF ALDOSE REDUCTASE

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FR2578542B2 FR2578542B2 (en) 1987-08-28

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