US3835156A

US3835156A - Acyl derivatives of 4-hydroxy-2h-1-benzothiopyran-3-carboxamide 1,1-dioxide

Info

Publication number: US3835156A
Application number: US00344380A
Authority: US
Inventors: H Zinnes; N Lindo
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 1973-03-23
Filing date: 1973-03-23
Publication date: 1974-09-10
Anticipated expiration: 1991-09-10
Also published as: DK578375A; FR2222101B1; AU6703874A; GB1407185A; DK578275A; DE2412138A1; FR2222101A1; AU472179B2; DK133949C; DK133949B; CA1019737A

Abstract

Acyl derivatives of 4-hydroxy-2H-1-benzothiopyran-3-carboxamide 1,1-dioxide having the following structural formulas are disclosed:

WHEREIN R1 and R2 are hydrogen, alkyl, aryl, aralkyl, alkoxy, halogen, cyano, nitro, trifluoromethyl, and the like. These compounds are useful as anti-inflammatory agents.

Description

United States Patent [191 Zinnes et al.

[ ACYL DERIVATIVES OF 4-HYDROXY-2H-l-BENZOTHIOPYRAN-3- CARBOXAMIDE 1,1-DIOXIDE [75] Inventors: Harold Zinnes, Rockaway; Neil A.

Lindo, Chatham, both of NJ.

[73] Assignee: Warner-Lambert Company, Morris Plaines, NJ.

[22] Filed: Mar. 23, 1973 [21] Appl. No.: 344,380

[52] U.S. Cl. 260/327 TH, 260/244 R, 424/275,

424/248 [51] Int. Cl. A61k 27/00, C07d 65/08 [58] Field of Search 260/327 TH [56] References Cited UNITED STATES PATENTS 3,769,292 l0/l973 Zinnes et al. 260/294.8 C

Primary ExaminerHenry R. Jiles Assistant Examiner-C. M. S. Jaisle Attorney, Agent, or Firm-Albert H. Graddis; Frank S. Chow 11] 3,835,156 [451 Sept. 10, 1974 wherein R and R are hydrogen, alkyl, aryl, aralkyl, alkoxy, halogen, cyano, nitro, trifluoromethyl, and the like.

These compounds are useful as anti-inflammatory agents.

3 Claims, No Drawings ACYL DERIVATIVES OF such as water for injection and compounded into sus- 4-l-IYDROXY-2H-l-BENZOTHIOPYRAN-3- pensions suitable for parenteral administration.

CARBOXAMIDE 1, l-DIOXIDE According to the present invention, the above compounds are produced by the following reaction scheme:

(H) (|)II R1 00113 R2 2. B30001 R2 I II (Ri': so Z The present invention relates to acyl derivatives of a z 4-hydroxy-2l-I- l -benzothiopyran-3-carboxamide l l dioxide having the following structural formulas: 0

1. NaH l =0 CONH- I l R2 R1 2. COCzor R2 S02 ll) S02 IV 0 ll wherein R is alkyl or aryl.

a bit, Referring now to the above scheme, a compound of l structure I is successivel treated with a base such as con y R2 R sodium hydride and an acid chloride in a solvent such 1 as dimethylformamide to form a monoacyl derivative so; of formula II. Diacyl derivatives such as III are formed In by heating I with an acid anhydride. 0 The cyclic derivatives of formula IV are formed as a ll result of an internal diacylation reaction. This is 0 achieved by the treatment of I with a base such as so- I :0 R1 dium hydride followed by the addition of either phosgene (COCl or an alkylor aralkylchloroformate so. "(5 .59 1.) IV in a solvent such as dimethylformamide.

The starting material I is prepared as described in cowherein R and R are hydrogen, alkyl, aryl, aralkyl, pending application Ser. No. 163,076 filed July 15, alkoxy, halogen, cyano, nitro, trifluoromethyl, and the 1971, now abandoned.

like. In the above definitions for R,, R and R alkyl and The compounds of this invention are useful as antialkoxy have 1 to 7 carbon atoms such as methyl, inflammatory agents for mammals, i.e. cats, dogs, monethyl, propyl, isopropyl and the like, aryl has 6 to 8 keys and the like. For example, when they are adminiscarbon atoms such as phenyl or tolyl, and aralkyl is tered orally or intraperitoneally to laboratory animals aryl as defined substituted by an alkyl group as defined. such as rats, at a dose of 25-200 mg/kg, they reduce the swelling in the paw which has been previously induced To further illustrate the practice of this invention, the by injection of an irritant such as carrageenin. following examples are included:

These compounds are indicated in conditions where the soft tissues are inflamed, such as rheumatoid arthri EXAMPLE 1 tis in mammals. A dose of 25-200 mg/kg in several di- 000cm vided doses daily orally or by injection is recom- A mended. This dose regimen may be varied depending C0NHCBH5 on the weight, age, sex, and the species of the mammal J being treated.

In order to use these compounds, they are formulated 2 .W M with pharmaceutical diluents such as lactose and com- 4-Hydroxy-2H-l-benzothiopyran-3-carboxanilide acpounded into dosage forms such as tablets. Alternaetate l,l-Dioxide. A slurry of 0.044 mol of sodium hytively, they can be formulated with a sterile vehicle dride in 30 ml of dimethylformamide was cooled to 5 and a solution of 12.6 g (0.4 mol) of 4-hydroxy-2H-1- benzothiopyran-3-carboxanilide 1 1 -dioxide in 30 m1 of dimethylformamide was slowly added over a 15 minute period. When gas evolution had ceased, a solution of 3.4 ml of acetyl chloride in 10 ml of dimethylformamide was added and the reaction mixture was stirred at room temperature for 1.5 hr. It was poured into ice water containing excess hydrochloric acid and the resulting precipitate was collected and dissolved in dichloromethane. The solution was washed with water, dried, and evaporated to dryness. The solid residue was recrystallized from methanol to give 7.8 g (55%) of product; mp 152.5154.5. 1r:

W 3300, 1680, 1660 cm".

Anal. Calcd for C I-1 N 8: 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 O C OCH:

COCHa AFO L v l775, 1715 cm, absence of NH band.

EXAMPLE 3 0 N aHs 3 ,4-Dihydro-3-phe nyl-2H,5 H- 1 -benzothiopyrano- [3,4-e][1,3]oxazine-2,4-dione 6,6-dioxide. To a cooled, stirred slurry of 0.022 mol of sodium hydride in 50 ml of dimethylformamide was slowly added a solution of 6.3 g (0.02 mol) of 4-hydroxy-N-phenyl-2H-lbenzothiopyran-3-carboxamide 1,1-dioxide in 100 ml of dimethylformamide. When gas evolution had ceased, a solution of 3.6 g of hexylchloroformate in 25 ml of dimethylformamide was added slowly with cooling. The mixture was stirred at room temperature for 1 hour and poured into ice-water containing excess hydrochloric acid. The resulting gummy precipitate was collected and dissolved in dichloromethane. The solution was washed well with water, dried, evaporated to dryness, and the residue was dissolved in 600 ml of methanol. Concentration to a volume of 400 ml and cooling gave 3.7 g of product; mp 208209.5. It gave a negative ferric chloride test and was insoluble in dilute aqueous sodium hydroxide.

O O Ra III in which R and R are hydrogen, alkyl of 1 to 7 carbon atoms, aryl of 6 to 8 carbon atoms, aralkyl in which alkyl is as defined and substituted by an alkyl group as defined, alkoxy of l to 7 carbon atoms, halogen, cyano, nitro and trifluoromethyl.

2. 4-Hydroxy-2H-1-benzothiopyran-3-carboxanilide acetate 1,1-dioxide.

3. N-Acetyl-4-hydroxy-2H- 1 -benzothiopyran-3- carboxanilide acetate 1 1 -dioxide.

Claims

2. 4-Hydroxy-2H-1-benzothiopyran-3-carboxanilide acetate 1,1-dioxide.
3. N-Acetyl-4-hydroxy-2H-1-benzothiopyran-3-carboxanilide acetate 1,1-dioxide.