CS248726B2

CS248726B2 - Process for the production of ether precursors of anti-inflammatory oxicams

Info

Publication number: CS248726B2
Application number: CS1000284A
Authority: CS
Inventors: Anthony Marat
Original assignee: Pfizer
Priority date: 1983-12-21
Filing date: 1984-12-19
Publication date: 1987-02-12
Also published as: SU1503682A3; JPS60156688A; ZA849926B; IN162323B; JPH0246036B2

Abstract

Vynález popisuje způsob výroby enoletherových derivátů oxicamů (1,1-dioxidů N- -heteroaryl-4-hydroxy-2-methyl-2H-l,2- -ibenzothiazin-3-karboxamidů a N-heteroaryI-4-hydroxy-2-methyl-2H-thieno [ 2,3-e ] - -l,2-thiazin-3-karboxamidů). Tyto ethery jsou cenné jako prekursory těchto nesteroidních protizánětlivých činidel, která jsou obecně známa pod označením „oxicamy“. Tyto oxicamy (včetně enolesterů) a jejich použitelnost jako protizánětlivých činidel jsou popsány v amerických patentových spisech 3 591 584, 3 787 324, 3 822 258, 4 180 662 a 4 309 427, v belgickém patentovém spisu č. 895 712 a v publikované evropské přihlášce vynálezu č. 85 866. Dříve popsané enolethery oxicamů (viz americký patentový spis č. 3 892 740) nevykazují protizánětlivou účinnost jako sloučeniny podle vynálezu. Vynález zahrnuje enoletherové prekursory protizánětlivých oxicamů, obecného vzorce I v němž W znamená benzoskupinuThe invention describes a process for the preparation of enol ether derivatives of oxicams (1,1-dioxides of N- -heteroaryl-4-hydroxy-2-methyl-2H-l,2- -ibenzothiazine-3-carboxamides and N-heteroaryl-4-hydroxy-2-methyl-2H-thieno [2,3-e] - -l,2-thiazine-3-carboxamides). These ethers are valuable as precursors of these nonsteroidal anti-inflammatory agents, which are generally known under the name "oxicams". These oxicams (including enol esters) and their utility as anti-inflammatory agents are described in U.S. Patents 3,591,584, 3,787,324, 3,822,258, 4,180,662 and 4,309,427, Belgian Patent No. 895,712 and Published European Patent Application No. 85,866. The previously described enol ethers of oxicams (see U.S. Patent No. 3,892,740) do not exhibit the anti-inflammatory activity of the compounds of the invention. The invention includes enol ether precursors of anti-inflammatory oxicams of formula I wherein W is benzo

Description

CZECHOSLOVAK SOCIALIST REPUBLIC (19) DESCRIPTION OF THE INVENTION 248726 (11) (®2) (22) Registered 19 12 84 (51) Int. Cl.4 C 07 D 417/12 C 07 D 513/04 C 07 D 279 / 0.2 JEB (21) (PV 10002-84) A 61 K 31/54 PROJECT FOR INVENTIONS (32) (31) (33) Right Advantages from 21 12 83 (563902) United States (40) Published 12 OB 86 (45) Published 15 03 88 A DISCOVERY (72)

Author of the invention MARFAT ANTHONY, GROTON, CONNECTICUT (SP.) (73)

Patent holder PFIZER INC., NEW YORK, NY (54) Method for the production of ether precursors of anti-inflammatory oxicam 1

The present invention provides a process for the preparation of enol ether derivatives of oxicams (1,1-dioxides of N-heteroaryl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamides and N-heteroaryl-4-hydroxy -2-methyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamides). These ethers are valuable as precursors of these non-steroidal anti-inflammatory agents, commonly known as "oxicams".

These oxicams (including enol esters) and their usefulness as anti-inflammatory agents are described in U.S. Pat. Nos. 3,591,584, 3,787,324, 3,822,258.4,180,662, and 4,309,427, in the Belgian Patent Application. No. 895,712 and European Patent Application 85,866. The previously described enol ethers of oxicam (U.S. Pat. No. 3,892,740) do not exhibit anti-inflammatory activity as compounds of the invention.

The invention encompasses enol ether prodrugs of anti-inflammatory oxicam, formula I

wherein W is benzo

248728 248726 6

3 or 2,3-thieno-CHo (G) R represents the remainder of the formula

-CH — O — C — R 3 R 2 (A) fit —CH — O — C — OR 3

(B) CD) / A (ε)

wherein n is 2, 3 or 4, R 2 is hydrogen, methyl or phenyl, R 4 and R 5 are each independently hydrogen or alkyl of 1 to 3 carbon atoms, R 3 is C 1 -C 10 alkyl, cycloalkyl C 3 -C 7, phenyl or benzyl, which may each be substituted with the radical OR 6 or OR 6 and R 6 is C 1 -C 3 alkyl. Preferred compounds of the invention are derivatives of piroxicam of formula I wherein W is benzo and R is 2-pyridyl, and especially those wherein R 1 is 1- (propionyloxy) ethyl (the remainder of Formula A, in wherein R 2 is methyl and R 3 is ethyl, 1- (cyclopropylcarbonyloxy) ethyl (the remainder of formula A wherein R 2 is methyl and R 3 is cyclopropyl), 1- (benzoyloxy) ethyl ( the remainder of formula A wherein R 2 is a methyl group and R 3 is a phenyl group, 1- (2-methyl-2-methoxycarbonylpropionyloxy) methyl group [the radical of formula A wherein R 2 is hydrogen and R 3 is C (CH 3) 2 COOCH 3], 1- (ethoxycarbonyl-oxy) ethyl (residue of formula B wherein R 2 is methyl and R 3 is ethyl), 1- (benzyloxycarbonyl-oxy) ethyl (residue of formula B wherein R 2 is methyl and R 3 benzyl), 1- (cyclohexyloxycarbo nyloxy) ethyl (the remainder of Formula B wherein R 2 is methyl and R 3 is cyclohexyl, 1- (decyloxycarbonyloxy) ethyl (radical of formula B wherein R 2 is methyl and R 3 is cyclohexyl), 1- ( decyloxycarbonyloxy) ethyl (the radical of formula B wherein R 2 is methyl and R 3 is n-decyl), 2- (7-butyrolactonyl) (radical of formula E wherein n is 2), 5- (2 -oxo-2,5-dihydrofuryl) (radical of formula C wherein R 4 and R 5 are hydrogen), 1- (4-methyl-2-oxo-1,3-dioxol-5-yl) a methyl group (residue of formula 248C in which R6 is methyl) or 3-phthalidyl (residue of formula F). Further preferred are those compounds which, as symbol R1, contain 1- (ethoxycarbonyloxy) ethyl, corresponding to formula I wherein W represents 2,3-thieno and R is 2-pyridyl, or Formula I wherein W is benzo and R is 6-methyl-2-pyridyl, 6-chloro-2-pyridyl or 5-methyl-3-isoxazolyl; ethyl or 1- (propionyloxy) ethyl groups, in accordance with the general formula I in which W represents; benzo and R is 6-methyl-2-pyridyl. In the present case, the term "prodrugs" refers to those prodrugs from which the drug is released by a certain metabolic process, such as in vivo hydrolysis. Γ26 6

Pharmaceutical formulations suitable for administration to mammals comprise an anti-inflammatory amount of a compound of Formula I. The method of treating inflammatory diseases of a mammal is to administer an anti-inflammatory effective amount of a compound of Formula I. Although the compounds described herein may be administered by all conventional application routes including topical application, is a preferred mode of administration for oral administration; After absorption in the gastrointestinal tract, the compounds of the invention are hydrolyzed in vivo by the above-mentioned anti-inflammatory drugs. Since the compounds of the invention are not acidic in character, the time during which the gastrointestinal tract is exposed to the acid-reactive oxicam is minimized.

The compounds of formula (I) are generally readily prepared by a nucleophilic substitution reaction, as follows:

In this scheme, W, R and R 1 are as defined above and X is a nucleophilically exchangeable group such as a halo (chlorine, bromine or iodine) atom or a sulfonic acid ester residue (e.g., mesylate or tosylate residue).

The oxicam salt required may be prepared in advance or more conveniently prepared by use of at least one equivalent of the base. The reaction is carried out in an inert solvent, preferably a substantially anhydrous inert solvent. A particularly suitable reaction system is an excess of potassium carbonate as a base in acetone. like a diversion. Preferred X is chlorine or bromine, and, if desired, up to three or more equivalents of anhydrous sodium iodide may be added to accelerate the reaction. The excess of the reagent of formula R1 is not critical to the reaction, but this excess is generally used to complete the reaction in a shorter time. The rate of reaction also greatly depends on the character of the radical X (for example, iodide reacts more rapidly than bromide and more rapidly than chloride) and on the radical R1 (e.g., the more branched radical XCHCH3OCCH3)

II o reacts more slowly than the residue XCH2OOCH3).

II o hu; in general, temperatures in the range of 50 ° C to 100 ° C can be used successfully. When using potassium carbonate as a base and acetone as a solvent, the reaction is carried out particularly boiling under reflux. The course of the above-described reactions is efficiently followed by thin layer chromatography to determine the reaction time required to complete the reaction, while avoiding unnecessary heating of the reaction mixture and unnecessarily long reaction times, which may result in larger quantities of by-products and reduced yields.

The oxicams required as starting materials can be obtained by methods well known in the art (see, for example, the above literature review of oxic-248726 moss). The necessary reagents of the general formula RxX are either commercially available or can be prepared by known methods or by methods detailed in detail below.

The anti-inflammatory activity of the oxicamido derivatives of formula I is also evaluated by known methods such as rat paw edema test, rat adjuvant arthritis test, or phenylbenzoquinone induced cramping test, as previously used to assess basic oxicam. the assays are described in the above-cited publications and in the literature on this subject. '

The oxicam precursors of the present invention are generally administered, based on the number of moles, in the same amount and with the same frequency as the known oxicams from which they are removed. However, the non-acidic nature of the compounds of the invention generally permits oral administration of higher doses in the event that the dosages are needed to control the inflammation.

The oxicam precursors of the present invention can also be formulated into dosage forms and applied in the same manner as known oxicams, the dosage forms and delivery routes described in the literature cited above. A preferred mode of administration is the administration of an oral formulation, which utilizes the characteristic advantages of the compounds of the present invention - that is, their non-acidic character.

The invention is illustrated by the following non-limiting Examples. Example 1 4- (5- (2-oxo-2,5-dihydrofuryl) oxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1 , 1-dioxide

3.00 g (9.06 mmol) of 2-methyl-N- (2-pyridyl) -4-hydroxy-2H-1,2 were introduced into a round bottom flask equipped with a reflux condenser and a mechanical stirrer. -benzo-thiazine-3-carboxamide-1,1-dioxide (piroxica-mu), 2.50 g (18.1 mmol) of potassium carbonate, 1.77 g (10.8 mmol) of 2-oxo-5 -bromo-2,5-dihydrofuran (Elming et al., Acta.Chem. Scand. 6, 566 (1952)) and 45 ml of acetone. The heterogeneous reaction mixture was heated to reflux under nitrogen. After 10 minutes, the dark brown mixture was removed from the heating bath and the acetone was evaporated. The brown-colored residue was stirred with 200 ml of water and 200 ml of methylene chloride. The organic layer was separated and the aqueous layer was extracted with additional 200 mL of methylene chloride. The combined organic extracts were washed with 200 mL of water, 200 mL of brine, dried over Na2 SO4 and concentrated in vacuo to give a brownish oily residue which was chromatographed on a silica gel column eluted with 2: 8 ethyl acetate / CH2 Cl2. 6 g (6.29 mmol, 69.4% yield) of a yellow solid which had Rf 0.42 on thin layer chromatography in ethyl acetate-methylene chloride (2: 8). Recrystallization from toluene / hexane yields an oil which crystallizes upon cooling. 520 mg of pale yellow crystals are obtained, m.p. 142-143 ° C. IR (KBr) 1778, 1689 cm -1. 1 H-NMR (CDCl 3) δ: 3.10 (s, 3H), 6.28 to 6.37 (m, 1H), 6.45 to 6.52 (m, 1H), 7.10 to 7.19 (m) (1H), 7.59-7.95 (m, 5H), 8.02-8.11 (m, 1H), 8.26-8.41 (m, 2H), 9.20 (bs, 1H).

Mass spectrum: C 19 H 16 N 3 O 6 S requires m / e (M + + H) 414.0 767, found 414.0 794.

Analysis: for C 19 H 15 N 3 O & S calculated: 55.20% C, 3.66% H, 10.16% N, found: 55.04% C, 3.73% H, 9.91% N. the signal shapes in NMR spectra are indicated by the abbreviations below: s = singletd = dublett = triplet = multiplet = broad signal Example 2 4- [(2-butyrolactonyl) oxy] -2-methyl-N- (2- pyridyl) 2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer was charged 9.00 g (27.2 mmol) of piroxicam, 7.50 g (54.3 mmol) of potassium carbonate, 13.45. g (81.5 mmol) of α-bromo-γ-butyllactone and 60 ml of acetone, and the heterogeneous mixture is heated to reflux under nitrogen. After 20 hours, thin layer chromatography (ethyl acetate-methylene chloride 1: 4) indicated complete consumption of the starting material. The reaction mixture was concentrated in vacuo at room temperature, the residue was stirred with water (500 ml) and extracted twice with 500 ml of methylene chloride each time. The combined organic extracts were washed with 300 ml of brine, dried over sulfuric acid. sodium sulfate and concentrated in vacuo to give a brown oily residue which was chromatographed on a silica gel column using ethyl acetate / methylene chloride (1: 3) as eluent. A pale brown solid is obtained which upon recrystallization from isopropyl alcohol yields 3.36 g (29.8%) of an off-white solid, m.p. IR (KBr): 1785, 1690 cm < -1 > H-NMR (CDCl3, [delta]: 2.54 (m, 2Hj, 3.12 (s, 3H, 4.20 (double d, J = 7); 9 Hz, J = 2.0 Hz, 1H), 4.47 [m, 1H], 4.81 (t, J = 6.0 Hz, 1H j, 7.13 (m, 1H), 7.78 (m, m); 3H), 7.94 (m, 1H), 8.17 (m, 1H), 8.34 (m, 1H), 9.34 (bs, 1H).

Mass Spectrum: m / e = 330 (M @ + - Gd1 O11).

Analysis: for C 19 H 17 N 3 O & S calculated: 54.93% C, 4.12% H, 10.12% N, found. 54.04% G, 4.08% II, 10.21% N. PTitelad 3- 4- [(4-methyl-2-oxo-1,3-dioxol-5-yl) -methyloxy] -12-methyl- N- (2-pyridyl-2H, 2-benzothiazine-3-carboxamide-11β-dioxide)

A round bottom flask equipped with a reflux condenser and a mechanical stirrer was charged with 5.00 g (15.1 mmol of piroxicam, 4.20 g (30.2 mmol of potassium carbonate, 4.37 g (22%)). 6 mmol of 5-bromomethyl-4-methyl-2-oxo-1,3-dioxole (prepared according to European Patent Application No. 39,477) and 60 ml of acetone, and the heterogeneous reaction mixture was refluxed under nitrogen for 20 minutes under nitrogen. Thin layer chromatography (ethyl acetate / methylene chloride 1: 4, UV detection) showed no piroxicam, the acetone was evaporated in vacuo and the brown residue was triturated with 200 mL of water and 200 mL of methylene chloride. and the aqueous layer is extracted with an additional 200 ml of methylene chloride, the combined organic extracts are washed with 200 ml of 10 ml of water and 200 ml of sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. a brown oily residue which forms a solid silica gel column chromatography (using ethyl acetate / methylene chloride (1: 4) as eluent), collecting all fractions; whose thin layer chromatogram contains a Rj of 0.30. From these fractions, a yellow solid was obtained which upon recrystallization from hot toluene yielded 3.08 g (6.95 mmol, 46.9%) of a white crystalline solid, m.p. 157-158 ° C. IR (KBr): 1836, 1824, 1671 cm @ 1 H-NMR (CDCl3, .delta. [Delta]: 1.95 (s, 3H, 3.13 (s, 3H, 4.79 (s, 2H), 7.10-7.21 (m, 1H), 7.70-7.99 (m) 5H, 8/27 to 8.42 (m, 2H, 9.45 (bs, 1H).

Mass spectrum: for C15H12N3O4S, m / e = 330.0553, found 330.0567; for C5H5O3 calculated m / e - 113.0243, found 113.0244.

Analysis calculated for: C20H17N3O7S: C, 54.17; H, 3.86; N, 9.48. Found: C, 54.52; H, 3.93; 3 -talidyloxy) -2-methyl-N- (2-pyridyl) -4H-2H-benzothiazine-5-carboxamide · D-Oxidazole;

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer, 3.00 g (9.1 mmol of piroxicam, 2.50 g: (18.21 mmol of potassium carbonate, 2.51 g) are introduced. g; (11) 3 mmol-3-bromophthalide (prepared according to British Patent No. 1,304,672) and 45 ml of acetone, and the heterogeneous reaction mixture is heated to reflux under a nitrogen atmosphere. The solvent was evaporated in vacuo and the brown residue was triturated with 200 mL of water and 200 mL of methylene chloride, the organic layer was separated and the aqueous layer was extracted with further 2001 mL of methylene chloride, and the organic extracts were washed with 200 mL of water and 200 mL of sodium chloride solution. dried over sodium sulfate and concentrated in vacuo to a brown oily residue (248726.112) which was chromatographed on a silica gel column using ethyl acetate / methylene chloride (1: 9) as the eluent to give a foamy solid. This is precipitated in hot toluene in the form of pure white crystals within a few seconds. The yield was 3.42 g (7.38 mmol, 81.5%). The product melted at 151-152 ° C. IR (KBr) 1785, 1688 cm -1. H-NMR (CDCl3): 3.13 (singlet, 3H), 6.97 (s, 1H), 7.07-7.35 (m, 1H), 7.58-8.18 (m 9H), 8.30 to 8.44 (m, 2H), 9.18 (bs, 1H).

Mass spectrum: C 23 H 17 N 3 O 6 S requires m / e = 463.0855, found 463.0871.

Analysis calculated for C23H17N3O & S: 59.61% C, 3.70% H, 9.07% N, found: 59.75% C, 3.76% H, 8.73% N. Example 5 4- (1- (pr opionyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer, 2.00 g (6.0 mmol) of piroxicam, 1.67 g (12.1 mmol) of potassium carbonate, 2.50 g (18.1 g) were charged. and (30 ml of acetone) and the heterogeneous reaction mixture is heated to reflux in a nitrogen atmosphere. After 24 hours, 4.52 g (30.2 mmol) of anhydrous sodium iodide was added and refluxing continued for 0.5 hours. The Acer ton is evaporated in vacuo to a brown residue which is stirred with 200 ml of water and 200 ml of methylene chloride. The combined organic extracts are washed with 200 ml of water and 200 ml of brine, dried over sodium sulfate and concentrated in vacuo to give a brown oil which is chromatographed on a silica gel column using ethyl acetate. and methylene chloride (1: 9) as eluent. 1.17 g (2.7 mmol, 44.9%) of a yellow solid is obtained which, after crystallization from isopropyl alcohol, yields 998 mg of pure white crystals, mp 156-158 ° C. IR (KBr): 1748, 1677 cm -1. @ 1 H-NMR (CDCl3, .delta <5): 0.98 (t, J = 7 Hz, 3H), 1.73 (d, J = 6 Hz, 3H), 2.10 to 2.39 (m, 2H), 3.13 (s, 3H ), 6.41 (quartet, J = 6 Hz, 1H), 7.07 to 7.17 (m, 1H), 7.63 to 7.95 (m, 5H), 8.31 to 8.41 ( m, 2H), 9.57 [bs, 1H].

Mass spectrum: for C 20 H 21 N 3 O 6 S calculated m / e = 431.1157, found 431.1092.

Analysis: for C20H21N3O6S: C, 55.68; H, 4.91; N, 9.47. Found: C, 55.91; H, 5.04; [(1-benzyloxycarbonyl) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer was charged 3.00 g (9.1 mmol) of piroxicam, 2.50 g (18.1 mmol) of potassium carbonate, 5.56 g (27.2). and (45 ml) acetone, and the heterogeneous reaction mixture is refluxed under nitrogen. Sodium iodide (4.52 g, 30.2 mmol) was added after 20 h and reflux was continued for a further 8 h. The title compound was isolated by chromatography as described above. There were obtained 3.24 g (6.4 mmol, 70.2%) of a white foamy product which crystallized from a toluene / hexane mixture at 120 to 122 ° C. IR (KBr): 1761, 1680 cm -1. 1 H-NMR (CDCl 3, δ): 1.75 (d, J = 6 Hz, 3H), 3.12 (s, 3H), 5.02 (d, J = 1 Hz, 2H), 6.41 (quartet, J = 6 Hz, 1H), 7.03 to 7.14 (m, 1H), 7.14 to 7.30 (m, 5H), 7.62 to 7.97 (m, 5H), 8, 25-8.38 (m, 2H), 9.38 (bs, 1H). 2 4 8 7 2'8 13

Mass Spectrum:

for C29H23N3O7S calculated m / e = 509.1 257, found 509.1 163.

Analysis calculated for C25H23N3O7S: 58.93% C, 4.55% H, 8.25% N, found: 59.01% C, 4.53% H, 8.32% N. Example 7 4- [1- (propoxycarbonyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

In analogy to Example 6, 3.00 g (9.1 mmol) of piroxicane were reacted with 4.52 g (27.2 mmol) of α-chloroethylpropyl carbonate to give the title compound. 5 mmol, 83.0%) of a yellow foamy substance which upon crystallization from isopropyl alcohol yields 3.00 g of a white crystalline product which melts at 150 DEG-151 DEG C. IR (KBr): 1,760, 1,678 cm @ -1. 1 H-NMR (CDCl 3): 0.84 (t, J = 7 Hz, 3H), 1.46-1.65 (m, 2H), 1.75 (d, J = 6 Hz) , 3Ή), 3.11 (s, 3H), 3.97 (t, J = 7 Hz, 2H), 6.35 (quartet, J = 6 Hz, 1H), 7.04 to 7.16 (m (1H), 7.62-7.97 (m, 5H), 8.30-8.41 (m, 2Ή), 9.40 (bs, 1H).

Mass spectrum: for C 21 H 23 N 3 O 7 S calculated m / e = 461.1 264, found 461.1 260.

Analysis calculated for C21H23N3O7S: 54.66% C, 5.02% H, 9.11% N, found: 5.5% C, 5.13% H, 9.19% N. Example 8 4- [ 1- (cyclohexyloxycarbonyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

By analogy to Example 6se, 3.00 g (9.1 mmol) of piroxicam are converted to the title compound by reaction with 5.37 g (26.1 mmol) of α-chloroethyl-cyclohexyl carbonate. 3.85 g (7.7 mmol, 84.7%) of a pale yellow foam which, after crystallization from sesoluol and hexane, yields 2.45 g of white crystals, m.p. 14.2-144 DEG C. IR (KBr) 1749, 1682 cm @ -1. @ 1 H-NMR (CDCl3, d): 0.99-1.93 ('Hm, 10H), 1.76 (d, J = 6 Hz, 3H), 3.11 (s). , 3H), 4.40 - 4.58 (br m, 1H), 6.36 (quartet, J = '6 Hz, 1Ή), 7.06 - 7.18 (m, 111), 7.62 - 7.97 ( m, 5H], 8.32-8.43 (m, 2H), 9.40 (bs, 111).

Mass spectrum: for pro24Η27Κ [3θ78 calculated exactly m / e = 501 1576 found 501.1613

Analysis: for C21H27N3O7S: 57, N: 47.3%, 5; 43%, 8.38%, found: 57.37% G, 5.38 ° / o H, 8.27% N. Example 9 4- (1- (decyloxycarbonyloxy) ethoxy) ] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

In an analogous manner to that of Example 6, 3.00 g (9.1 mmol) of piroxicam are reacted with 4.79 g (18.1 mmol) of α-chloroethyl decyl carbonate to give the title compound. After chromatography, 4.46 g (8.0 mmol, 88.0%) of a white foamy compound are obtained which, after crystallization from isopropanol, yields a white crystalline product, m.p. 84-86 ° C. IR (KBr, 1764, 1679 cm -1). 1 H-NMR (CDCl 3, δ): 0.89 (t, J = 7 Hz, 3Ή), 1.09-1.41 (m, 14H), 1.41-1.60 (br, 2H), 1.75 (d, J = 6Hz, 3Ή), 3.11 (s, 3H), 4.00 (t, J = 7Hz, 2H) , 6.36 (quartet, J = 6 Hz, III), 7.07-7.17 (m, 1H), 7.63-7.96 (m, 5H), 8.30-8.40 (m, 211), 9.40 (bs, 1H) 248726 16

1S

Mass Spectrum:

for C28H37N3O7S calculated m / e = 559.2352 found 559.2346

Analysis calculated for C28H37N3O7S: C, 60.09; H, 6.66; N, 7.51 Found: C, 60.10; H, 6.67; N, 7.49. Example 10 4- [1 - (isopropoxycarbonyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer, 3.00 g (9.1 mmol) of piroxicam, 2.50 g (18.1 mmol) of potassium carbonate, 3.02 g (18.1 g) were introduced. mmol) of α-chloroethyl isopropyl carbonate and 45 ml of acetone, and the heterogeneous reaction mixture is heated to reflux under nitrogen. After 24 hours, 4.52 g (30.2 mmol) of anhydrous sodium iodide was added and the reflux condenser was continued for an additional 72 hours. Chromatography afforded 1.76 g (3.8 mmol, 42.1%) of the title compound as a white foam which gave 1.27 g of white crystals after crystallization from isopropyl alcohol, m.p. 180-181 ° C. IC (KBr): 1761, 1675 cm 4. 1 H-NMR (CDCl 3): 1.13 (d, J = 7 Hz, 3H), 1.16 (d, J = 7 Hz, 3H), 1.77 (d, J = 6 Hz, 3H) 3.10 (s, 3H), 4.57-4.88 (m, 1H), 6.37 (quartet, J = 6 Hz, 1H), 7.06-7.17 (m, 1H), 7 62-8.04 (m, 5H), 8.31-8.50 (m, 2H), 9.50 (bs, 1H).

Mass Spectrum:

for C 21 H 23 N 3 O 7 S calculated m / e = 461.1257, found 461.1295

Analysis calculated for: C21H23N3O7S: C, 54.66; H, 5.02; N, 9.11. Found: C, 54.56; H, 5.02; N, 9.03. - (methoxycarbonyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

The procedure is analogous to that described in Example 6 except that the reaction mixture is boiled under a reflux condenser for 1 hour before the addition of sodium iodide. In this way, 2.00 g (6.0 mmol) of piroxicam and 2.50 g (18.1 mmol) of α-chloroethyl methyl carbonate are converted to the title compound which is chromatographed as a yellow solid which upon crystallization from isopropyl the alcohol gives 660 mg (1.5 mmol, 25.0%) of the product, m.p. 150-151 ° C. IR (KBr): 1757, 1677 cm -1. 1 H-NMR (CDCl 3): 1.75 (d, J = 6 Hz, 3H), 3.12 (s, 3H), 3.65 (s, 3H), 6.35 (quartet, J = 6 Hz) (1H), 7.07-7.18 (m, 1H), 7.65-7.95 (m, 5H), 8.30-8.42 (m, 2H), 9.42 (bs, 1H).

Mass Spectrum:

accurately calculated m / e = 433.0944 found 433.1004 for C 19 H 19 N 3 O 7 S

% C, 52.29;% H, 9.63;% H, 1 P, 7P, TI; P, 52.18;% H, 4.41;% N, 9.61. Example 12 4- (1- (ethoxycarbonyloxy) ethoxy] -2-methyl-N- (6-methyl-2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-one dioxide

In an analogous manner to Example 6, 1.0 g (2.89 mmol) of N- (6-methyl-2-pyridyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3- converting the carboxamide-1,1-dioxide and 1.18 ml (1.32 g), 8.67 mmol) of α-chloroethyl ethylcarbonate to the crude title compound resulting in a yellow oil decomposition which remained at the heat will solidify the room. After chromatography on a silica gel column using methylene chloride / ethyl acetate (8: 2) as the eluent, 1.15 g (86.2%) of a slightly yellow solid is obtained which, after 248726 of 17 recrystallization from isopropyl alcohol, yields 1: 2. 1 g of white crystals, m.p. 156-157 ° C. IR (KBr) 1765, 1680 cm -1. 1 H-NMR (CDCl 3 values [Delta]: 1.18 (t, J = 7 Hz, 3H), 1.75 (d, J = 6 Hz, 3H), 2.50 (s, 3H), 3.12 (s, 3H), 4.08 (quartet, J = 7 Hz, 2H), 6.34 (quartet, J = 6 Hz, 1H), 6.96 (d, J = 6.5 Hz, 1H), 7.60 - 7.80 ( m, 3H), 7.85-7.95 (m, 2H), 8.15 (d, J = 8 Hz, 1H), 9.28 (bs, 1H).

Mass spectrum: C21H23N3SO7 calculated exactly m / e = 461.1257 found 461.1348

Analysis calculated for: C21H23N3SO7: 54.60% C, 5.02% H, 9.11% N, found 54.35 ° C, 5.00% H, 9.04% N. Example 13 4- (1 - (ethoxycarbonyloxy) ethoxy] -2-methyl-N- (2-pyridyl-2H-thieno [2,3-e] -1,2-thiazine-3-carboxamido-1,1-dioxide)

In an analogous manner to Example 12, 0.15 g (0.445 mmol) of 4-hydroxy-2-methyl-N- (2-pyridyl) -2H-thieno [2,3-e] -1,2-thiazine Converting the 3-carboxamide-1,1-dioxide by reaction with 0.182 ml (1.134 mmol) of α-chloroethyl ethyl carbonate to the title compound. Chromatography gave 0.19 g (94%) of a pale yellow foam which crystallized from toluene containing a small amount of hexane to give 0.15 g of a white crystalline product, mp 121-123 ° C. IC (KBr) 1775, 1683 cm -1. @ 1 H-NMR (CDCl3, .delta <5}: 1.18 (t, J = 7 Hz, 3H), 1.77 (d, J = 6 Hz, 3H), 3.17 (s, 3H), 4.10 (quartet, J = 7) Hz, 2H), 6.55 (quartet, J = 6 Hz, 1H), 7.05-7.18 (m, 1H), 7.40 (d, J = 6.7 Hz, 1H), 7, 64 (d, J = 6.7 Hz, 1H), 7.71-7.82 (m, 1H), 8.28-8.41 (m, 2H), 9.20 (bs, 1H). 18

Mass spectrum: C18H17N5O7S2 calculated exactly m / e = 453.0664 found 453.0664

Analysis calculated for C18H17N3O7S2: 47.67% C, 4.22% H, 9.27% N, η q1 o * 7 p η n · 47.65θ / ο C, 4.17% H, 9, 21% N. Example 14 4- (1- (Ethoxycarbonyloxy) ethoxy] -2-methyl-N- (6-chloro-2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1.1 -dioxide

In an analogous manner to Example 6, 0.20 g (0.547 mmol) of N- (6-chloro-2-pyridyl) -4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide of 1,1-dioxide by reaction with 0.225 ml (0.25 g, 1.65 mmol) of α-chloroethyl ethyl carbonate into the title compound. Chromatography gave 0.22 g (83.6%) of a white crystalline solid which, after recrystallization from isopropanol, gave 0.20 g of white crystals, m.p. 161-162.5 ° C. IR (KBr) 1770, 1690 cm -1. 1 H-NMR (CDCl 3): 1.19 (t, J = 7 Hz, 3H), 1.76 (d, J = 6 Hz, 3H), 3.08 (s, 3H), 4.09 (quartet, J = 7 Hz, 2H), 6.34 (quartet, J = 6 Hz, 1H), 7.16 (d,) = 7.5 Hz, 1H), 7.66-7.91 (m , 3H), 7.81-7.96 (m, 2H), 8.30 (d, J = 7.5 Hz, 1H), 9.39 (bs, 1H).

Mass Spectrum:

for C 20 H 20 N 3 O 7 S calculated m / e = 483.0681 found 483.0538

Analysis calculated for: C20H20N3O7S: C, 49.85; H, 4.18; N, 8.72 Found: C, 49.72; H, 4.07; N, 8.73. - (hexyloxycarbonyloxy) ethoxy) -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

Analogous to Example 248726 19 20 11, 3.00 g (9.1 mmol) of piroxicam and 2.85 g (13.6 mmol) of α-chloroethyl hexyl carbonate are converted to the title compound which is isolated by chromatography as a yellow solid. which, after crystallization from a mixture of isopropyl alcohol and hexane, yielded 280 mg (0.5 mmol, 6.1%) of the desired compound, m.p. 86-87 ° C. IR (KBr): 1764, 1678 cm @ -1. @ 1 H-NMR (CDCl3) .delta. 0.87 (t, J = 7 Hz, 3H), 1.05-1.39 (m, 6H), 1.41-1.60 (m, 2H) , 1.75 (d, J = 6 Hz, 3H), 3.10 (s, 3H), 4.00 (t, J = 7 Hz, 2H), 6.36 (quartet, J = 6 Hz, 1H) ), 7.06-7.17 (m, 1H), 7.63-7.86 (m, 5H), 8.31-8.42 (m, 2H), 9.39 (bs, 1H).

Mass Spectrum:

for C24H29N3O7S calculated m / e = 503.1737 found 503.1761

Analysis calculated for C24H29N3O7S: C, 57.24; H, 5.80; N, 8.34. Found: C, 57.32; H, 5.77; N, 8.39. - (ethoxycarbonyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer, 10.0 g (30.2 mmol) of piroxicam, 8.35 g (60.4 mmol) of potassium carbonate, 12.35 ml (13.81 g, 90%) are charged. 6 mmol) of α-chloroethyl ethylcarbonate and 350 ml of acetone, and the heterogeneous reaction mixture is refluxed under nitrogen. After 19 hours, 22.6 g (150.7 mmol) of anhydrous sodium iodide are added and the reflux is continued for 5 hours. The acetone was evaporated in vacuo. The brown residue was stirred with 250 ml of water and 250 ml of methylene chloride. The organic layer was separated and the aqueous layer was extracted with 250 ml of methylene chloride. The combined organic phases were washed with 250 ml of brine and 250 ml of brine, dried over Na2 SO4 and concentrated in vacuo to give a brown oil which was chromatographed on silica gel using ethyl acetate / methylene chloride (1: 9). ) as an eluting agent. There were obtained 10.67 g (79.0%) of a pale yellow foamy solid which, after recrystallization from toluene, gave 9.50 g of pure white crystals, m.p. IC (KBr): 1757, 1676 cm -1. 1 H-NMR (CDCl 3): 1.16 (t, J = 7.5 Hz, 3H), 1.76 (d, J = 5 Hz, 3H), 3.11 (s, 3H), 4.07 (quartet, J = 7.5 Hz, 2H), 6.35 (quartet, J = 5 Hz, 1H), 7.11 (m, 1H), 7.67-7.80 (m, 3H), 7.86-7 93 (m, 2H); 8.36 (m, 2H); 9.40 (bs, 1H).

Mass Spectrum:

for C20H11N3O7S calculated m / e = 447.1108 found 447.1164

Analysis calculated for: C20H21N3O7S: C, 53.68; H, 4.73; N, 9.39; N, λ, 107, N, 53.87; Example 17 4- (1- (ethoxycarbonyloxy) ethoxy] -2-methyl-N- (5-methyl-3-isoxazolyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

In an analogous manner to Example 16, 0.5 g (1.49 mmol) of N- (5-methyl-3-isoxazolyl) -4-hydroxy-2-methyl-1,2-benzothiazine-3- Carboxamide-1,1-dioxide (isoxicam) and 0.61 mL (0.67 g, 4.46 mmol) of α-chloroethyl-ethyl carbonate are converted to the title compound. Chromatography gave 0.61 g (91%) of the product as a white foamy solid which was homogeneous by thin layer chromatography. This product affords 0.52 g of a white crystalline solid by crystallization from isopropyl alcohol, m.p. 158-159 ° C. IR (KBr) 1750, 1690 cm @ -1. @ 1 H-NMR (CDCl3) .delta. 1.20 (t, J = 7.0 Hz, 3H), 1.75 (d, J = 6.0 Hz, 3H), 2.47 (s, 3H) , 3.08 (s, 3H), 4.10 (quartet, J = 7.0 Hz, 2H), 6.34 (quartet, J = 6.0 Hz, 1H), 6.83 (s, 1H) ,

24872S 21 7.77-7.97 (m, 4H), 9.45 (bs, 1H).

Mass Spectrum:

accurately calculated m / e = 451.1059 found 451.1101

Analysis calculated for C 19 H 21 N 3 O 8 S: C, 50.55; H, 4.69; N, 9.31. Found: C, 50.21; H, 4.61; N, 9.15. - (butoxycarbonyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

In an analogous manner to Example 6se, 3.00 g (9.1 mmol) of piroxicam and 5.30 g (29.3 mmol) of α-chloroethyl butyl carbonate were converted to 600 mg (1.3 mmol, 13.9%) of the compound shown in The title compound is obtained in the form of a yellow solid which, after recrystallization from isopropyl alcohol, gives 325 mg of white crystals, m.p. 132-133 ° C. IR (KBr) 1758, 1681 cm -1. 1 H-NMR (CDCl 3): 0.87 (t, J = 7 Hz, 3H), 1.18-1.35 (m, 2H), 1.42-1.58 (m, 2H), 1.76 (d, J = 6 Hz, 3H), 3.11 (s, 3H), 4.01 (t, J = 7 Hz, 2H), 6.35 (quartet, J = 6 Hz, 1H) , 7.05-7.15 (m, 1H), 7.65-7.82 (m, 3H), 7.82-7.95 (m, 2H), 8.30-8.40 (m, 2H), 9.39 (bs, 1H).

Mass Spectrum:

for C22H25N5O7S calculated exactly m / e = 475.1413 found 475.1425

Analysis: for C22H25N3O7S: C, 55.57; H, 5.30; N, 8.84; C, 55.51; C, 5.24; N, 8.64. - (1- (octyloxycarbonyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide 22

In an analogous manner to Example 11, 3.00 g (9.1 mmol) of piroxicam and 3.25 g (13.6 mmol) of α-chloroethyl octyl carbonate were converted to the title compound which was chromatographed as a white solid. This product provided crystallization from isopropyl alcohol of 3.5 g (6.6 mmol, 72.7%) of white crystals, m.p. 93-94 ° C. IR (KBr): 1763, 1678 cm -1. @ 1 H-NMR (CDCl3, .delta.): 0.88 (t, J = 7 Hz, 3H), 1.10-1.39 (m, 10H), 1.53 (b, 2H), 1.75 (d, 2H); J = 6 Hz, 3H), 3.10 (s, 3H), 3.99 (t, J = 7Hz, 2H), 6.36 (quartet, J = 6Hz, 1H), 7.04-7.15 (m (1H), 7.61-7.96 (m, 5H), 8.27-8.41 (m, 2H), 9.40 (bs, 1H).

Mass spectrum;

accurately calculated m / e = 531.2044 found 531.2100

% C, 58.74;% H, 7.90;% C, 58.65; H, 6.24; N, 7.78. [1- (Butyryloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

In an analogous manner to Example 6, 2.00 g (6.0 mmol) of piroxicam and 2.75 g (18.1 mmol) of α-chloroethyl butyrate were converted to the title compound which resulted in chromatography as a white solid. This product, after recrystallization from isopropyl alcohol, gave 1.07 g (2.41 mmol, 40.0%) of white crystals, m.p. 151-152 ° C. IR (KBr): 1755, 1678 cm -1. 1 H-NMR (CDCl 3, m / z) Δ: 0.81 (t, J = 7Hz, 3H), 1.37-1.58 (m, 2H), 1.72 (d, J = 6Hz, 3H), 2.05-2.31 (m, 2H), 3.12 (s, 3H), 6.39 (quartet, J = 6 Hz, 1H), 7.07-7.18 (m, 1H), 248726 24 23 7.63-7 95 (m, 5H), 8.30 - 8.41 (m, 2H), 9.55 (bs, 1H).

Mass spectrum: for C 17 H 16 N 3 O 4 Calculated (M-C 4 H 7 O 2) m / e = 358.0865 found 358.0839

H, 5.20; N, 9.43; N, 1070ΪΊ, 56.62; C, 5.16; H, 9.43; Example 21 4- [1- (Acetyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

In an analogous manner to Example 5, 2.00 g (6.0 mmol) of piroxicam and 2.22 g (18.1 mmol) of α-chloroethyl acetate were converted to the title compound. Chromatography gave 1.17 g (2.8 mmol, 46.4%) of a yellow solid which crystallized from isopropanol to give 1.08 g of white crystals, m.p. 161-162 ° C. IR (KBr): 1755, 1677 cm -1. 1 H-NMR (CDCl 3, δ): 1.72 (d, J = 6 Hz, 3H), 1.95 (s, 3H), 3 13 (s, 3H), 6.39 (quartet, J = 6 Hz, 1H), 7.07-7.18 (m, 1H), 7.65-7.96 (m, 5H), 8, 30-8.42 (m, 2H), 9.52 (bs, 1H).

Mass spectrum: for C 17 H 15 N 3 O 5 Calculated (M + - C 2 H 4 O m / e = 373.0738 found 373.0678

% C, 54.67; H, 4.59; N, 10.07. Found: C, 54.60; H, 4.54; N, 10.10. (1- (hexanoyloxy) ethoxy) -2-methyl-N- (2-pyridyl) -2H-1,2-toensothiazine-3-carboxamide-1,1-dioxide

In an analogous manner to Example 11, 2.00 g (6.0 mmol) of piroxicam and 3.51 g (19.6 mmol) of α-chloroethyl hexanoate were converted to the title compound resolving after yellow oil chromatography. which, after crystallization from toluene / hexane, yields 1.21 g (2.5 mmol, 42.1 DEG) of product, m.p. 62 DEG-65 DEG. IR (KBr): 1755, 1676 cm @ -1. @ 1 H-NMR (CDCl3, .delta Δ: 0.81 (t, J = 7 Hz, 3H), 1.00-1.30 (m, 4H), 1.35-1.53 (m, 2H), 1.73 (d, 4H) J = 6 Hz, 3H), 2.08-2.32 (m, 2H), 3.12 (s, 3H), 6.39 (quartet, J = 6 Hz, 1H), 7.05-7.32 ( m, 1H), 7.57-7.95 (m, 5H), 8.30-8.43 (m, 2H), 9.58 (bs, 1H).

Mass spectrum: for C 23 H 28 N 3 O 6 Calculated (M + + H) m / e = 474.1703 found 474.1645

Analysis calculated for: C23H27N3O6S: C, 58.34; H, 5.75; N, 8.87. Found: 58.48; C, 5.79; H, 8.93; N. EXAMPLE 23 4- (1- (cyclopropyloxycarbonyl) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide 1,1,1 dioxide

In an analogous manner to Example 6, 3.00 g (9.1 mmol) of piroxicam and 4.03 g (27.2 mmol) of cyclopropanecarboxylic acid α-chloroethyl ester were converted to the title compound. 3.51 g (7.0 mmol, 87.3%) of a white foamy product are obtained, which after crystallization from toluene yields 1.90 g of white crystals, m.p. IR (KBr): 1735, 1680 cm @ -1. @ 1 H-NMR (CDCl3) .delta. 0.70-0.97 (m, 4H), 1.37-1.50 (m, 1H) ), 1.72 (d, J = 6 Hz, 3H), 3.11 (s, 3H), 6.40 (quartet, J = 6 Hz, 1H), 7.07-7.17 (m, 1H), 7.63-7.97 (m, 5H), 248726 25 8.29-8.42 (m, 2H), 9.54 (bs, 1H).

Mass spectrum: for C 21 H 22 N 3 O 6 Calculated (M + + H) m / e = 444.1235 found 444.1013

Analysis calculated for C21H21N3O6S: C, 56.88; H, 4.77; N, 9.48. Found: C, 56.55; H, 4.70; N, 9.41. - (benzyloxy) ethoxy] -2-methyl-N - (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

In an analogous manner to Example 6, 3.00 g (9.1 mmol) of piroxicam and 5.00 g (27.0 mmol) of α-chloroethyl benzoate were converted to the title compound by chromatography as a yellow oil which gave crystallization from isopropyl alcohol 3.41 g of pure white crystals (7.1 mmol, 78.5%), m.p. 151-152 ° C. IR (KBr) 1748, 1681 cm -1. 1 H-NMR (CDCl 3): 1.83 (d, J = 6 Hz, 3H), 3.09 (s, 3H), 6.68 (quartet, J = 6 Hz, 1H), 7.07 - 7.17 (m, 1H), 7.23-7.34 (m, 2H), 7.43-7.55 (m, 1H), 7.63-8.00 (m, 7H), 8, 27-8.40 (m, 2H), 9.54 (bs, 1H).

Mass spectrum: C 24 H 21 N 3 O 6 S calculated m / e = 479.1157 found 479.1062

Analysis calculated for C24H21N3O6S: 60.12% C, 4.41% H, 8.76% N, found: 60.10% C, 4.49% H, 8.83% N. Example 25 4- (1 - (octanoyloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer was charged 3.00 g (9.1 mmol) of piroxicam, 26 2.50 g (18.1 mmol) of potassium carbonate, 5.6 g (27%). 0 mmol) of α-chloroethyl octanoate and 45 ml of acetone, and the heterogeneous reaction mixture is refluxed under nitrogen for reflux. After one hour, 4.52 g (30.2 mmol) of sodium iodide was added and refluxing continued for 72 hours. After chromatography, the title compound is isolated as described in Example 5 in the form of a white lignite, which is separated from the toluene / hexane mixture in an oily form, but this oil crystallizes. 2.19 g of white crystals (4.4 mmol, 48.2%), m.p. 90 DEG-91 DEG C., are collected in two portions. IR (KBr) 1766, 1675 cm -1. Ή-ΝΜΡ (deuterochloroform, values S: 0.85 (t, J = 7 Hz, 3H), 1.02-1.34 (m, 8H), 1.45 (d, quintet, 2H), 1.73 (d, J) = 6 Hz, 1H), 7.06-7.17 (m, 1H), 7.63-7.95 (m, 5H), 8.30-8.42 (m, 2H), 9.56 ( ss, 1H).

Mass Spectrum: for C 25 H 27 N 3 O 5 S calculated (M + - C 2 H 4 O) m / e = 457.1429 found 457.1700

Analysis calculated for: C25H31N3O8S: C, 59.86; H, 6.23; N, 8.38 Found: C, 59.99; H, 6.11; N, 8.35. 2-methoxycarbonyl-2-methylpropionyloxy) methoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide

To a dry round bottom flask equipped with a reflux condenser and a mechanical stirrer, 1.50 g (4.53 mmol) of piroxicam, 1.24 g (9.98 mmol) of potassium carbonate, 1.48 g (5%) are introduced. , 17 mmol) of iodomethyl-methyl-2,2-dimethylmalonate and 15 ml of dry acetone. The heterogeneous reaction mixture was heated under reflux for 3 hours under nitrogen and the title compound was isolated by chromatography as in Example 5. 0.95 g (43.2%) of a light yellow solid was obtained, which after recrystallization from toluene and hexane gave pale yellow crystals and m.p. 112-114 ° C. IR (KBr) 1690, 1680 cm -1. 248726 27H-NMR (CDCl3): 1.28 (s, 6H), 3.11 (s, 3H), 7.70-7.88 (m, 4H), 7.89-7.99 (dd, J). = 8 Hz, J = 4 Hz, 1H), 7.30-7.44 (m, 2H), 9.42 (s, 1H).

Mass Spectrum:

for C 22 H 23 N 3 O 6 S calculated m / e = 489.1205 found 489.1230

Analysis calculated for: C22H23N3O3S: C, 53.99; H, 4.74; N, 8.58. Found: C, 54.30; H, 4.86; N, 8.57. Example 27 4- (Octanoyloxy) methoxy -2-methyl-N - (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a round bottom flask fitted with a reflux condenser and a mechanical stirrer, 1.00 g (3.0 mmol) of piroxicam, 840 mg (6.0 mmol) of potassium carbonate, 870 mg (4.5 mmol) of chloromethyl- octanoate and 15 ml acetone, and the heterogeneous reaction mixture is heated to reflux under nitrogen. After 6 hours, a further 250 mg (0.75 mmol) of chloromethyl octanoate and 210 mg (1.5 mmol) of potassium carbonate are added and refluxing is continued for another hour. After chromatography, the title compound is isolated as in Example 5 in the form of a yellow foamy substance which is removed from the toluene / hexane mixture as an oil which crystallizes upon cooling. There were obtained 690 mg (1.4 mmol, 47%) of white crystals, m.p. 98-99 ° C. IR (KBr) 1766, 1683 cm -1. @ 1 H-NMR (CDCl3, .delta Δ: 0.87 (t, J = 8 Hz, 3H), 1.02-1.48 (m, 10H), 2.19 (t, J = 6 Hz, 2H), 3.12 (s, 3H ), 5.70 (s, 2H), 7.08-7.17 (m, 1H), 7.67-7.98 (m, 5H), 8.30-8.45 (m, 2H), 9.32 ( ss, 1H).

Mass spectrum: for C 24 H 30 N 3 O 6 Calculated (M + -I) H / m = 488.1859 found 488.1794 28

Analysis calculated for: C24H29N3O6S: C, 59.12; H, 6.00; N, 8.26; Example 28 4- (heptanoyl) methoxy-2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

By analogous procedure to Example 2, 2.00 g (6.0 mmol) of piroxicam and 1.20 g (66.4 mmol) of chloromethyl-heptanoate were converted to the title compound, which was chromatographed as a yellow oil. An attempt was made to recrystallize toluene / hexane to give an oily material which, after cooling, yielded 1.01 g (2.13 mmol, 35.3%) of pure white crystals, m.p. 98-99 ° C. IR (KBr): 1778, 1688 cm -1. 1 H-NMR (CDCl 3): 0.85 (t, J = 6 Hz, 3H), 1.05-1.47 (m, 8H), 2.20 (t, J = 6 Hz, 2H) 3.13 (s, 3H), 5.69 (s, 2H), 7.06-7.17 (m, 1H), 7.68-8.00 (m, 5H), 8.30-8 42 (m, 2H), 9.33 (bs, 1H).

Mass Spectrum:

for C 23 H 27 N 3 O 6 S calculated m / e = 473.1820 found 473.1644

Analysis calculated for: C23H27N3O6S: 58.34 .delta. C, 5.75 θ / ο H, 8.87% N, ηπ1Ρ7ΡΐΊΠ '58.39% C, 5.74% H, 8.99% N. Example 29 4- (pivaloyloxy) methoxy-2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

By analogy to Example 5se, 2.00 g (6.0 mmol) of piroxicam and 2.61 mL (2.73 g, 16.1 mmol) of chloromethyl pivalate are converted to the title compound which yields after chromatography. 1.78 g (66.2%) as a white foam. Crystallization from a mixture of toluene and hexane gave 1.56 g of pure white crystals, m.p. 132-133 ° C. IR (KBr): 1,757, 1,672 cm @ -1. 1 H-NMR (CDCl 3): 1.03 (s, 9H), 3.12 (s, 3H), 5.74 (s, 2H), 7.08-7.17 (m, 1H), 7.68 - 7.87 (m, 4H), 7.92 - 7.99 (m, 1H), 8.30 - 8.43 (m, 2H), 9.48 (bs, 1H).

Mass Spectrum:

for C 21 H 23 N 3 O 6 S calculated m / e = 445.1313 found 445.1352

Analysis calculated for: C21H23N3O6S: C, 56.62; H, 5.20; N, 9.43. Found: C, 56.63; H, 5.18; N, 9.47. Example 30 4- (Benzoyloxy) methoxy-2 -methyl-N - (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

By analogous procedure to Example 6, 3.33 g (10.1 mmol) of piroxicam and 4.29 g (25.0 mmol) of chloromethyl benzoate were converted to the title compound. Chromatography gave 2.3 g (4.9 mmol, 48.9%) of a white foamy product which melted at 149-150 ° C after crystallization from isopropyl alcohol. IR (KBr): 1745, 1687 cm @ -1. 1 H-NMR (CDCl 3): 3.07 (s, 3H), 5.89 (s, 2H), 6.97-7.08 (m, 1H), 7.19-7.35 (m (2H), 7.35-7.63 (m, 2H), 7.63-7.99 (m, 6H), 8.22-8.35 (m, 2H), 9.22 (bs, 1H) )

Mass Spectrum:

for C 23 H 19 N 3 O 6 S calculated m / e = 465.1001 found 465.1051

Analysis calculated for C23H19N3O6S: C, 59.35; H, 4.11; N, 9.03. Found: C, 59.46; H, 4.10; N, 9.01. - (isobutyryloxy) ethoxy] -2-methyl-N- (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

In an analogous manner to Example 6se, 3.00 g (9.1 mmol) of piroxicam and 4.10 g (27.2 mmol) of α-chloroethyl isobutyrate were converted to the title compound, yielding 3.50 g after chromatography. (7.9 mmol, 86.7%) as a white foam. This product melted at 151 DEG-153 DEG C. after crystallization from isopropyl alcohol and hexane. IR (KBr): 1751, 1680 cm -1. @ 1 H-NMR (CDCl3, .delta.): 0.98 (d, J = 1 Hz, 3H), 1.03 (d, J = 1 Hz, 3H), 1.73 (d, J = 6 Hz, 3H) ), 3.11 (s, 3H), 6.36 (quartet, J = 6 Hz, 1H), 7.07-7.17 (m, 1H), 7.63-7.95 (m, 5H) 8.32 - 8.42 (m, 2H), 9.65 (bs, 1H).

Mass Spectrum:

for C21H23N3O & S accurately calculated m / e = 445.1313 found 445.1240

Analysis calculated for: C21H23N3O6S: C, 56.62; H, 5.20; N, 9.43. Found: C, 56.19; H, 5.06; N, 9.37. 32 4- (Butyryloxy) methoxy-2-methyl-N - (2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer was charged 1.00 g (3.0 mmol) of piroxicam, 0.84 g (6.1 mmol) of potassium carbonate, 0.45 g (3.3%) (3.3%). of chloromethyl butyrate and 15 ml of acetone, and the heterogeneous reaction mixture is heated to reflux with a reflux condenser under nitrogen. After 24 hours, the acetone was evaporated in vacuo and the yellow solid was stirred with 100 ml of water and 100 ml of methylene chloride. The organic layer was separated and the aqueous layer was extracted with an additional 100 mL of methylene chloride.

The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate and concentrated in vacuo to give a yellow oil (248726 31 32), eluting with silica gel column eluting with 1: 9 ethyl acetate: ethylene chloride The reagents give 260 mg of a yellow oil which turns white foam into the vacuum. Yield: 0.60 mmol, corresponding to 20.2%. In an attempt to crystallize from toluene / hexane, an oily material is obtained which upon cooling yields pure white crystals. Combination of the first and second portions yielded 86 mg of white crystals, m.p. 202-204 ° C. IR (KBr): 1770, 1688 cm @ -1. @ 1 H-NMR (CDCl3, .delta. <5): 0.79 (t, J = 7 Hz, 3H), 1.35-1.53 (m, 2H), 2.18 (t, J = 7 Hz, 2H), 3.12 (s). 3.75 (s, 2H); 7.05-7.18 (m, 1H); 7.65-7.88 (m, 4H); 7.88-7.99 (m, 1H); 8.28 to 8.42 (m, 2H), 9.32 (bs, 1H).

Mass spectrum: for C 20 H 21 N 3 O 6 S calculated m / e = 431.1151, found 431.1106.

Analysis calculated for: C 20 H 21 N 3 O 6 S: C, 55.68; H, 4.91; N, 9.74. Found: C, 55.28; H, 4.93; N, 9.75. acetoxy) ethoxy] -2-methyl-N - (6-methyl-2-pyridyl) -2H, 1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer was charged 1.50 g (4.34 mmol) of N- (6-methyl-2-pyridyl) -4-hydroxy-2-methyl-2H -1,2-benzothiazine-3-carboxamide 1,1-dioxide, 1.20 g (8.69 mmol) of potassium carbonate, 1.60 g (13.03 mmol) N-chloroethyl acetate and 150 ml acetone , and the heterogeneous reaction mixture is heated to reflux under nitrogen. After 24 hours, 2.60 g (17.37 mmol) of sodium iodide are added and refluxing is continued for 6 hours. The acetone is evaporated off under vacuum and the yellow residue is stirred with 300 ml of water and 300 ml of methylene chloride. The organic layer is separated and the aqueous layer is extracted with another 100 ml of methylene chloride. The combined organic extracts were washed with 300 mL of water and 200 mL of brine, dried over sodium sulfate, and concentrated in vacuo. Chromatography of the yellow solid on a silica gel column using ethyl acetate / methylene chloride (1: 9) as eluent gave 1.64 g (3.80 mmol, 87.3%) of a white solid which crystallized from isopropyl ether. the alcohol gives 1.50 g of the title compound as white crystals, m.p. 190-191 ° C. IR (KBr) 1770, 1682 cm -1. 1 H-NMR (CDCl 3): 1.72 (d, J = 6 Hz, 3H), 1.94 (s, 3H), 2.50 (s, 3H), 3.12 (s, 3H) ), 6.39 (quartet, J = 6 Hz, 1H), 6.96 (d, J = 6 Hz, 1H), 7.59 to 7.95 (m, 5H), 8.15 (d, J = 6 Hz, 1H), 9.39 (bs, 1H).

Mass spectrum: for C 18 H 17 N 3 O 5 Calculated (M - C 2 H 4 O) m / e = 387.0 894, found 387.0 900.

Analysis: for C20H21N3O6S: C, 55.68; H, 4.91; N, 9.74. Found: C, 55.51; H, 4.91; N, 9.70. Example 34 4- [1 - (pr opionyloxy) ethoxy] -2-methyl-N- (6-methyl-2-pyridyl) -2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide

To a round bottom flask equipped with a reflux condenser and a mechanical stirrer was charged 1.50 g (4.34 mmol) of 2-methyl-N- (6-methyl-2-pyridyl) -4-hydroxy-2H- 1,2-benzothiazine-3-carboxamide-1,1-dioxide, 1.20gram (8.69 mmol) of potassium carbonate, 1.78 g (13.03 mmol) of N-chloroethyl propionate and 150 ml of acetone and the heterogeneous reaction mixture is heated to reflux under nitrogen. After 24 hours, iodide (2.60 g, 17.4 mmol) was added and the mixture was refluxed for a further 6 hours. The acetone was evaporated in vacuo and the yellow residue was stirred with 300 ml of water and 300 ml of methylene chloride. The organic layer was separated and the aqueous layer was extracted with additional methylene chloride. The combined organic extracts were washed with 300 ml of water and 200 ml of sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. Chromatography of the solid residue on a silica gel column using 1: 9 mixture of ethyl acetate and methylene chloride yielded 1.65 g (3.70 mmol, 85.3%) of a white solid (248725 33 34) which upon crystallization from isopropyl alcohol to give 1.55 of the title compound as white crystals, m.p. 174-175 ° C. IR (KBr): 1770, 1683 cm -1, 1 H-NMR (CDCl 3, δ): 0.97 (t, J = 7 Hz, 3H), 1.71 (d, J = 6 Hz) , 3H), 2.10-2.38 (m, 2H), 2.49 (s, 3H), 3.11 (5H), 6.39 (quartet, J = 6 Hz, 1H), 6.96 (d) , J = 6 Hz, 1H), 7.59-7.69 (m, 5H), 8.13 (d, J = 6 Hz, 1H), 9.45 (bs, 1H).

Mass spectrum: C19H19N5O5S calculated exactly (M-C2H4O) m / e = 401.150, found 401.1125.

Analysis calculated for: C21H23N3O6S: C, 56.62; H, 5.20; N, 9.43. Found: C, 56.21; H, 5.17; N, 9.31. octyl carbonate To a solution of 6.42 g (49.3 mmol) of dryhon-octanol and 3.90 g (49.3 mmol) of pyridine in 75 ml of anhydrous ether was added 7.00 g (49.3 mmol) at 0 ° C. ) and - chloroethyl chloroformate (prepared according to U.S. Pat. No. 1426,717). The mixture was stirred vigorously at 25 ° C for 3 hours, then filtered, the filtrate concentrated in vacuo and distilled. 8.1 g (34.2 mmol, 69.4%) of the title compound are obtained in the form of a clear oil boiling at 102 DEG-107 DEG C./0.2 mm Hg. 1 H-NMR (CDCl 3) δ 0.44-2.03 (m, 15H), 1.60 (d, J = 6 Hz, 3H), 3.94 (t, J = 7 Hz, 2H), 6 , 18 (quartet, J = 6 Hz, 1H). Preparation 2 α-chloroethyl hexyl carbonate

In an analogous manner to that described above, 5.04 g (49.3 mmol) of n-hexanol was converted to the title compound. Distillation at 78-81 QC / 400 Pa gave 8.82 g (38.9 mmol, 79.0%) of the product as a clear oil. 1 H-NMR (CDCl 3, δ): 0.50-2.18 (m, 11H), 1.81 (d, J = 6 Hz, 3H), 4.15 (t, J = 7 Hz, 2H) , 6.36 (quartet, J = 6 Hz, 1H). Preparation 3 α-Chloroethyl propyl carbonate

By analogous procedure to Preparation 1, 2.95 g (49.0 mmol) of dry 1-propanol are converted to the title compound. Distillation at 43-45 ° C / 667 Pa yields 6.75 g (40.5 mmol, 82.7%) of the product as a clear oil (1 H-NMR (CDCl 3, δ): 0.95 (t , J = 7Hz, 3H), 1.33-1.95 (m, 2H), 1.80 (d, J = 6Hz, 3H), 4.10 (t, J = 7Hz, 2H), 6.41 ( quartet, J = 6 Hz, 1H) Preparation 4 α-chloroethyl decyl carbonate

In an analogous manner to that described above, 7.75 g (49.0 mmol) of n-decyl alcohol are converted to the title compound. By distillation at 110-117 ° C / 200 Pa, a 10.5 gram (39.7 mmol, 81.0%) product was obtained as a clear oil. 1 H-NMR (CDCl 3, δ): 0.46 to 2.17 (b, 19H), 1.85 (d, J = 6 Hz, 3H), 4.20 (t, J = 7 Hz, 2H) ), 6.42 (quartet, J = 6 Hz, 1H). Preparation 5 α-Chloroethyl benzyl carbonate

5.30 g (49.0 mmol) of benzyl alcohol are converted to the title compound in an analogous manner to that described above. By distillation at 111 to 113 qC / 400 Pa, 8.3 g (38.7 mmol, 79.0%) of the product are obtained in the form of a clear oil.

@ 1 H-NMR (CDCl3, m / z) S: 1.75 (d, J = 6 Hz, 3H), 5.17 (s, 2H), 6.41 (quartet, J = 6 Hz, 1H), 6.80-7.28 (m, 5H ). Preparation 6 α-Chloroethyl isopropyl carbonate

In an analogous manner to the preparation of 1, 2.95 g (49.0 mmol) of isopropyl alcohol is converted to the title compound. Distillation at 57 to 59 ° C / 1333 Pa gives 33 5.04 g (30.3 mmol, 61%). 8%) of the product as a clear oil. @ 1 H-NMR (CDCl3, .delta.): 1.35 (d, J = 7 Hz, 6H), 1.82 (d, J = 6 Hz, 3H), 4.52-5.17 (m, 1H) ., 6.40 (quartet, J = 6 Hz, 1H). Preparation 7 α-Chloroethylcyclohexyl carbonate

4.90 g (49.0 mmol) of cyclohexylalcohol are converted to the title compound in an analogous manner to the preparation of 1.90 g (40.4 mmol, 82.4) by distillation at 73-77 QC / 133 Pa. %) of the product in the form of a clear oil. @ 1 H-NMR (CDCl3, .delta .: 0.80-2.30 (br, 10H), 1.83 (d, J = 6 Hz, 3H), 4.40-5.00 (brm, 1H), 6.42 ( quartet, J = -6 Hz, 1H) Preparation of 8 α-chloroethyl methylcarbonate

In an analogous manner to the preparation 1, 1.6 g (30.0 mmol) of methanol were converted to the title compound. The distillation at 35 to 45 GC / 1467 Pa yields 3.5 g <(25.3 mmol, 50.6%) product in the form of a clear oil. 1 H-NMR (CDCl 3, δ): 1.90 (d, J = 6 Hz, 3H), 3.95 (s, 3H), 6.48 (quartet, J = 6 Hz, 1H). Preparation 9 α-Chloroethyl butyl carbonate

In an analogous manner to the preparation 1, 3.65 g (49.3 mmol) of n-butanil is converted to the title compound. Distillation at 60-62 [deg.] C / 667 Pa gave 5.2 g (28.8 mmol, 58.4%) of the product as a clear oil. 1 H-NMR (CDCl 3) δ 0.50-1.90 (m, 7H), 1.80 (d, J = 6 Hz, 3H), 4.20 (t, J = 7 Hz, 2H), 6.40 (quartet, J = 6Hz, 1H). Preparation 10 Chloromethyl butyrate 38.54 g (113.5 mmol) of tetra-butylaninium hydrogen sulfate with 9.53 g (113.5 mmol) of sodium bicarbonate are mixed in 225 rolls in a single cylinder beaker. After a total of 38 foaming has ceased, 675 ml of chloroform and a lever of 12.30 g (118.5 ram) of sodiumunybutyrate are first added to the solution with stirring. The resulting two-phase system is stirred for 15 minutes, then the organic layer is separated, the aqueous layer is combined with 325 ml of chloroform, combined the organic extracts were dried over sodium sulfate and evaporated in a vacuum to a thick solid, which was taken up in 650 ml of acetone. A solution of 20.0 g (118.5 g / ml) is rapidly added to this solution with stirring at room temperature iododWL-methane in 25 ml of acetone and stirring is continued for 0.5 hours. Acetone is evaporated in vacuo and the white solid residue is chromatographed on a silica gel column using methylene chloride / hexane (9: 1) as eluent. Fractions were collected which, according to the low tungsten thin layer (the same solvent system, spraying with light culmination and heating at least polarized> Rf = 0.60. Fractional fractions yielded 3.00 g) (22 (0)). mmol, 19.4%) chloromethyl butyrate as a pale yellow oil. 1 H-NMR (CDCl 3, δ): 0.80 (t, J = 7 Hz, 23 H), 1.45 (sextet, J = 7 (bz, 2H), 2.16 (t, J = 7 Hz, 2H), 5.77 (s, 2H).

Chloromethyl-heptanoate

In an analogous manner to the preceding preparation, the tert-heptanoate was converted to the crude title compound. This product will give you the chromatography to rise! sulfuric acid, using a mixture of StereoOh d® & N-tetrafluoromethylchloride hexane as the buffer and the fractions collected by thin layer chromatography on a mixture of equal parts of ethylene chloride and hexane (detection by bromocresol greening) <a href="http://www.free.fr/home.html] IRf (0(831 1,20 g !Ρ6,·7 mmtíl, 12j5'%()-Shr. 2.00 (m, 1H, 2.40 (t, 2H), 5.78 (s, 2H) Preparation of 12-Chloromethyl benzoate

In an analogous manner to that in Preparation 10, 29.97 g of sodium benzoate (208 .mu.mol) are converted to the crude title compound in the form of a thick (solidified solid on standing). 248726 37 38 layer (hexane-methylene chloride 3: 2, UV detection) contains two contact spots (Rf 0.65 and 0.75) and start a large spot, the solid prepared above is mixed with a large amount of hexane and filtered. The thin-layer filtrate contains only less polar products, the chromatogram of the solid only the salt remaining at the start, and the filtrate is concentrated in vacuo to a yellow oil which is chromatographed on silica gel using hexane / methylene chloride. (3: 2) The fractions containing the least polar spot (R (0.75) were combined and concentrated to give 4.29 g (25.2 mmol, 12.0%) of chloromethyl benzoate in 1 H-NMR (de-chloroform, values α): 5.95 (s, 2H), 7.15-7.61 (m, 3H), 7.85-8.18 (m, 2H). Preparation 13

Chloromethyl octanoate

In an analogous manner to the preparation 10, 11.52 g (69.3 mmol) of sodium octanoate was converted to the crude title compound as a yellow solid. This material was chromatographed on silica gel using methylene chloride / hexane (1: 1) as the eluent, collecting fractions which were chromatographed on a thin layer (same solvent system, bromocresol spray). green and warming) contained at least a polar spot of Rf 0.61. From these fractions, 2.25 g (11.7 mmol, 17.0%) of chloromethyl octanoate was obtained as a pale yellow oil. @ 1 H-NMR (.delta. hydrochloride, .alpha.): 0.65-1.96 (m, 13H), 2.35 (t, J = 7 Hz, 2H), 5.76 (s, 2H). Preparation 14a-chloroethyl acetate

21.33 ml (23.55 g, 300 mmol) of freshly distilled acetyl chloride are added to a three-necked round-bottomed flask containing 1 g of zinc chloride anhydrous, and the turbid heterogeneous mixture is stirred at room temperature under nitrogen for 15 minutes. 16.18 ml (12.73 g, 289 mmol) of acetaldehyde are added thereto at a rate such that the temperature does not exceed 0 ° C. The orange-colored solution was allowed to warm to room temperature and then subjected to distillation at 27-32 ° C / 2.3 kPa to give 27.1 g (221 mmol, 76.5%) of the title compound as a colorless oil. Yippee. @ 1 H-NMR (de-chloroform, .delta.): 1.79 (d, J = 7 Hz, 3H), 2.10 (s, 3H), 6.49 (quartet, J = 7 Hz, 1H). Preparation 15a-chloroethyl benzoate

In an analogous manner to the previous preparation, 58.0 ml (70.3 g, 500 mmol) of freshly distilled benzoyl chloride are not reacted with 27.9 ml (22.0 g, 500 mmol) of acetaldehyde, which is added at such an acceleration rate, so that the reaction temperature does not exceed 5 ° C during addition. After the addition was complete, the orange-colored solution was allowed to warm to room temperature and 100 mL of water and 100 mL of methylene chloride were added. The pH is adjusted to 7.0, the organic layer is isolated, washed with 100 ml of brine and 100 ml of brine, dried over sodium sulfate and concentrated in vacuo. 83.0 g of a dark brown oleaginous material are obtained which, according to the @ 1 H-NMR spectrum, contains less than 0.5% hexanoyl chloride in the product mixture. The thin layer chromatograph of this material (dichloromethane) contained two UV-visible spots, Rf 0.60 and 0.65. 10.0 g of the oil-like material prepared above are chromatographed on silica gel using methylene chloride as the eluent. 7.3 g of the title compound is obtained, which is the least polar component of Rf 0.65. @ 1 H-NMR (.delta <1): 1.88 (d, J = 6 Hz, 3H), 6.78 (quartet, J = 6 Hz, 1H), 7.15-7.70 (m, 3H), 7.70-8.20 (m, 2H). Preparation 16 α-Chloroethyl propionate

In an analogous manner to the preparation 14, 21.72 ml (23.13 g, 250 mmol) of distilled propionyl chloride was converted to the title compound. Distillation at 40-45 ° C / 2.27 kPa gave 9.0 g (65.9mmol, 26.4%) of the desired product as a colorless oil. 1 H-NMR (de-chloroform, α-values): 1.15 (t, J = 7 Hz, 3H), 1.76 (d, J = 6, 3H), 2.24 (quartet, J = 7 Hz, 2H), 6.50 (quartet, J = 6 Hz, 1H). Preparation 17 α-Chloroethyl cyclopropanecarboxylate

By the same procedure as in the preparation

Claims

20.70 g (198 mmol) of freshly-precipitated cycloprapanecarboxylic acid chloride is converted to 20.38 g (137 mmol, 69.3%) of the compound. in the title, resulting in a light green oil. 1 H-NMR (CDCl 3, δ): 0.64-1.16 (m, 4H), 1.32-1.86 (m, 1H); 1.82 (d, J = 6 Hz, 3H), 6.55 (quartet, J = 6 Hz, 1H): Preparation of 18 α-chloroethyl isobutyrate 30.08 g (289 mmol) of freshly distilled isobutyryl chloride. converted to the title compound, yielding 33.7 g (224 mmol, 77.5%) as a pale green oil. 20 (d, J = 7 Hz, 6H); 1.80 (cl, J = 6, 3H), 2.53 (quintet, J = 7 Hz, 1H-), 6.50 (quartet, J = 6 Hz, 1 H) Example 19a-chloroethyl hexanoate In an analogous manner to Preparation 17, 35.1 ml (24 g, 185 mmol) of distilled hexanoyl chloride is converted into the salt. the resulting title compound, resulting in a light green oil-yield of > 19 $ -g (126 mmol, 68.1%), 401 x H 1 NH 2 (deuterochloroal; (mpllHUl) 76? (d ',: J = 6sHz, 3H ·)) 2.86r (ts J; = 7 <ΉΖ,' -, 2Η); 6.58? (quartet) Ji = By analogy to the same procedure as in preparation? 14: 25 $ ®: .inl; (28,641 ^ 250 $ nmm0il? Fresh * distilled ') hutyrylchlaride. To do this, you can see the list of things that are listed in the following section: Qesttláeíipřf'35 * .až ', 45 55'ád iádádádaaaaaaaaa55555555555555aa 5ád5555555555555555555 produktu produktu produktu produktu 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 1 H4N > MR: (deteorWorophore; 5) 1: 0.93 (t, J = 7 Hz, 3H), 1.16-2.00 (m, 2H), 1.75 (d, J = 6 2.30 (t, J = 7 Hz, 3H), 6.50 (quartet, J 1 = 6'Hz, 1H, 1H). Example 21a-chloroethyl octanoate! Analogous; procedure®® ”as.» in preparation; 171'a »-43 $> ml (4-13484 gy 2556md / phthalate distilled octannylchloridium is converted to the distillate; m / z is dissolved in a light green oil in a yield of 44 g); (214inunoll-8339s%), hi-NMR (dteteroiliterof, values * 6?): 0.513-1.199 '(m; 13H), 1176? (d; J - = - 6 Hz, '3H ·),' 2 $ 0T (ie J? = - 7? H?; 2H)), 6; 49M Quartet; p = 6¾ 1W SUB

A process for the preparation of ether precursors of anti-inflammatory-active oxioam, general formula I of the invention

wherein W represents benzo or 2,3-thienosuccin R represents the radical of formula acR-V denotes the radical: formula A).

248726 41 —CH — O — C — R I II r 2 o (A) —CH — O-C-OR 3 I II r 2 o (B) 42

wherein n is 2, 3 or 4, R 2 is hydrogen, methyl or phenyl, R 4 and R 5 are each independently hydrogen or methyl, R 3 is C 1 -C 10 alkyl, cycloalkyl is 3 to 7 carbon atoms, phenyl or benzyl, optionally substituted with OR6 or OCOR6 and R6 is a C1-3 alkyl group, characterized in that the seanionic salt of formula 11 wherein R and W are as defined above does not react with a compound of formula R 4 X wherein R 1 is as defined above and X is a nucleophilically replaceable group.

2. A process according to claim 1 wherein the corresponding starting materials are used to form compounds of formula I wherein R is a radical of formula (I).

R 1 is as defined above and W is benzo.

3. A process according to claim 2, wherein the corresponding starting materials are used to produce the compounds of clause 2, wherein R and W are as defined in (2) and R1 is a radical of formula (CH-O-C-R3-I). R 2 O wherein R 2 and R 3 are as defined above.

4. A process according to claim 3, wherein the corresponding starting materials are used to form compounds of formula (I) according to (3), wherein R2 is methyl and R3 is methyl, and the remaining general symbols are as defined in (3).

5. The process of claim 2 wherein the corresponding starting materials are used to produce the compounds of clause 2 wherein R and W are as defined in 2a. R1 is -CH-O-C-OR3. R 2 O wherein R 2 and R 3 are as defined above.

6. A process according to claim 5, wherein the corresponding starting material is used to form the compound of formula (S) wherein R @ 2 is methyl and R @ 3 is ethyl.

7. The process of claim 1 wherein the corresponding starting materials are used to form a compound of formula I wherein R is a radical

C1 R1 represents the radical II-CH-O-C-O-C2H5 GH3 and W represents a benzo group.

8. A process as claimed in claim 1, wherein the corresponding starting materials are used to form a compound of formula I wherein R is a radical

26 44 -O-CH-O-C-C 2 -C 5 H 3 CH 3 and W is benzo.

9. A process according to claim 1 wherein the corresponding starting materials are used to form a compound of formula I wherein R is a radical

R 1 is a radical O-CH-O-C-O-G 2 H 5 CH 3 and W is 2,3-thieno.

10. A process according to claim 1, wherein the starting materials of the formula R @ 1 X in which X is halogen and R @ 1 is as defined above. R1 is the remainder of the residue