DE2412138A1 - ACYLDER DERIVATIVES OF 4-HYDROXY-2H-1-BENZOTHIOPYRAN-3-CARBOXAMIDE-1,1-DIOXIDES - Google Patents

Description

PATENTANWÄLTE HENKEL - KERN - FEiLER - I1ÄNZEL - MÜLLER

D1PL.-ING.

DR. PHIL.

DIPL.-ING.

xJR. R £ K. WaT.

DI-> L.-ING.

TELEX: 05 29 802 HNKL D TELEPHONE: (08 11) 66 31 97, 66 30 9t-92 TELEGRAMS: ELLIPSOID MUNICH

EDUARD-SCHMID-STRASSE 2 D-8000 MUNICH 90

Warner-Lambert Company Morris Plains, N.J., V.St.A.

BAVARIAN MORTGAGE AND EXCHANGE BANK MUNICH NO. 318 - 85 HL POSTSCHECK: MCHN 162147 - 80 »

1 -3. HRZ. 187%

Aoyl derivatives of 4-hydroxy-2H-l-benzothiopyran-3-carboxamide-1,1-dioxides

The invention relates to acyl derivatives of 4-hydroxy-2H-1-benzothiopyran-3-carboxamide-1,1-dioxides of the general formulas:

CONB

II -

III

wherein R, land Rp for hydrogen or halogen atoms or Alkyl, aryl, aralkyl, alkoxy, cyano, nitro or trifluoromethyl radicals.

Dr.f./ek.

• 409841/1008

The compounds of the invention are useful as anti-inflammatory agents for administration Mammals such as cats, dogs, monkeys and the like., As well as People. For example, if you use experimental animals, such as rats, in a dose of 25 to 200 mg / kg orally or are administered intraperitoneally, they can be previously administered by an injection of an irritant, e.g. carrageenin, caused swelling in the paws (of the test animals) subside.

The compounds of the invention are useful in inflammation of smooth or soft tissue, e.g., in rheumatic Mammalian arthritis, indicated. Here, a total dose of 25 to 200 mg / kg daily in several individual doses recommended by oral administration or by injection. However, this dosage may vary depending on weight, age, The sex and species of the mammal to be treated or Patients can be varied.

For administration, the compounds according to the invention with pharmaceutical diluents or extenders, such as lactose, blended and then in suitable administration forms, like tablets. On the other hand, with the help of a sterile vehicle, e.g. water, they can be in an injectable form or a suspension suitable for parenteral administration.

The compounds according to the invention are prepared according to the following reaction scheme:

409841/1008

2. COCl ₂ or R ₃ OCCl

XV

The radical R ^ ₅ in the given reaction scheme denotes an alkyl or aryl radical.

In the preparation of the compounds according to the invention, one compound of the formula I is first used in succession treated with a base such as sodium hydride and an acid chloride in a solvent such as dimethylformamide, whereby a monoacyl derivative of the formula II is formed. The diacyl derivatives of formula III are by heating with a compound of formula I obtained with an acid anhydride.

The cyclic derivatives of Formula IV form as a result an internal diacylation reaction. This is running

40 9841 / 1UG8

ORIGINAL INSPECTED

when reacting a compound of the formula I with a base, such as sodium hydride, and then adding either phosgene (COCIp) or an alkyl or aralkyl

It

ehloroformiats (IUOCCl) in a solvent such as dimethylformamide, away.

The preparation of compounds of the formula I is described in DT-OS 2,226,298.

In the formulas given, the radicals R, Rp and R, alkyl or alkoxy radicals can contain 1 to 7 carbon atoms and are, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl or heptyl radicals or their isomers or methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy or heptoxy radicals or their isomers. If the radicals R 1, Rp and R ^ are aryl radicals, these can mean 6 to 8 carbon atoms and, for example, consist of phenyl or tolyl radicals. If the radicals R ₁ and R _{2 are} aralkyl radicals, these can consist of aryl radicals of the definition given which are substituted by alkyl radicals of the definition given.

The following examples are intended to illustrate the invention in more detail.

example 1

Preparation of 4-hydroxy-2H-1-benzothiopyran-J-carboxanilide acetate-1,1-dioxide the formula

OCOCH ₃

09841 / 1U08 - 5 _

A slurry, cooled to a temperature of 5 ° C., of 0.044 mol of sodium hydride in 30 ml of dimethylformamide was slowly with a solution of 12.6 g (0.4 mol) of 4-hydroxy-2H-1-benzothiopyran-3-carboxanilide-1,1-dioxide over a period of 15 minutes added in 30 ml of dimethylformamide. After the gas formation had ceased, a solution of 3 * 4 ml of acetyl chloride was used added in 10 ml of dimethylformamide, whereupon the resulting reaction mixture for 1.5 hours at room temperature was stirred. The reaction mixture was then poured into ice water containing excess hydrochloric acid. The precipitate which separated out was filtered off and dissolved in dichloromethane. The solution obtained Was washed with water, dried and evaporated to dryness. The resulting solid residue was recrystallized from methanol, with a yield of 55% 7.8 g of the desired product with a melting point of

152.5 to 154.5 ^O C and an IR spectrum ^ ¹ ^ ⁰¹ at 3300,

<< max

1680 and 1660 cm "was obtained.

An elementary analysis of the compound C ₁ QH ₁₁ -NO ₁ -S obtained gave the following values:

Calculated: C 60.49 H 4.23 N 3.92 S 8.97 Found: C 60.71 H 4.37 N 3.64 S 9 * 03

Example 2

Preparation of N-acetyl-4-hydroxy-2H-l-benzothiopyran-3-carboxanilide acetate-l, l-dioxide the formula:

OCOCH ₃ COCH ₃

ccL // \

- 6 409841/11) 08

A mixture of 10 g of 4- ^ rdroxy-2H-l-benzothiopyran-3-earboxanilid-l, l-dioxide, 20 ml acetic anhydride and 2 ml pyridine were heated on a steam bath for 5 minutes, then cooled to room temperature and diluted with ether. The precipitate formed was recrystallized from acetic acid, whereby 5 g of the desired product with a melting point of 188 ° to 192 ° C (with decomposition; "the Compound began to darken at a temperature of 180 ° C

zu] BECfär3i) and an IR spectrum ^ i ^ £ ^o1 at 1775 and 1715 ι max

a "with missing NH band were obtained.

El Tie elemental ^{analysis of the compound C} 20 ^H 17 ^N0 6 ^{S obtained} gave the following values:

Calculated: C. 60, 14th H 4.29 N 3.51 S. • 8th, 03 Found: C. 60, 18th H 4.40 N 3.49 S. 8th, 07 Example 3

Preparation of 3,4-dihydro-3-phenyl-2H, 5H-l-benzothiopyrano- * 4-eJ / l, 3joxazin-2, 4-dione-6,6-dioxide of the formula:

- 7 409841 / 1Ü08

A cooled and stirred slurry of 0.022 mol of sodium hydride in 50 ml of dimethylformamide was slowly added to a solution of 6.3 g (0.02 mol) of 4-hydroxy-N-phenyl-2H-1-benzothiopyran-3-carboxamide-1.1 -dioxide added in 100 ml of dimethylformamide. After the gas formation had ceased, a solution of 3 × 6 g of hexyl chloroformate in 25 ml of dimethylformamide was slowly added while stirring. The obtained reaction mixture was stirred at room temperature for 1 hour and then poured into ice water containing excess hydrochloric acid. The gummy precipitate which separated out was filtered off and dissolved in diehlomethane. The resulting solution was washed thoroughly with water, dried and evaporated to dryness, whereupon the resulting residue was dissolved in 600 ml of methanol. Concentration to a volume of 400 ml and cooling gave 3 * 7 g of the desired product with a melting point of 208 ° up to 209.5 ° C. It gave a negative ferric chloride test and was insoluble in dilute / sodium hydroxide solution. The IR spectrum ν ^ £ ^o1 was 1780, 17OO (sh) and

1 IIlcLX.

1680 cm.

An elemental analysis of the compound C ₁₇ H ₁₁ NO-S gave the following values:

Calculated: C 59.82 H 3.25 N 4.10 S 9.39 Found: C 59.5 ^ H 3.16 N 4.09 S 9.18

409841 / 1UÜ8

Claims (4)

Claims 1. Acyl derivatives of ^ hydroxy-SH-l-benzothiopyran-J-carboxamide-l, l-dioxides of the formulas IV wherein R ₁ and R_ represent hydrogen or halogen atoms or alkyl, aryl, aralkyl, alkoxy, cyano, nitro or trifluoromethyl radicals. 2. ^ -Hydroxy-QH-1-benzothiopyran ^ -carboxanilide acetate-1,1-dioxide. 3. N-Acetyl- ^{^} ^ -hydroxy-2H-1-benzothippyran-3-carboxanilide acetate-1,1-dioxide. 409841 / 1Ü 0 8 4. 3 * 4-Dihydro-3-phenyl-2H, 5H-1-benzothiopyrano- [3,4-e | - £ 1,3] oxazine-2,4-dione-6,6-dioxide. 409841/1008