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Publication numberUS3787324 A
Publication typeGrant
Publication dateJan 22, 1974
Filing dateMar 1, 1971
Priority dateMar 1, 1971
Also published asCA978187A1, DE2208351A1, DE2208351B2, US3816628, US3822258, USRE29836
Publication numberUS 3787324 A, US 3787324A, US-A-3787324, US3787324 A, US3787324A
InventorsM Schwartz, J Shavel, H Zinnes
Original AssigneeWarner Lambert Co
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,dioxides and process for their production
US 3787324 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

nited States Patent [191 Zinnes et a].

[ Jan. 22, 1974 Inventors: Harold Zinnes, Rocka Martin L. Schwartz, Gillette; John Shave], Jr., Mendham,

all of NJ.

[73] Assignee: Warner-Lambert Company,

lxl orris Plains, NJ. i

Mar. 1, 1971 [21] Appl. No.: 119,967

[52] 11.8. CI. 260/243 R, 424/246 [51] Int. Cl C07d 93/02 [58] Field of Search 260/243 R [56] References Cited UNITED STATES PATENTS 1/1970 Rasmussen 260/243 3/1970 Rasmussen 260/243 Primary Examiner-John M. Ford Attorney-Albert H. Graddis, Frank S. Chow, Neil D. Edwards, and Anne M. Kelly [5 7] ABSTRACT Compounds having the following structural formula are disclosed:

wherein R is hydrogen or methyl and R and R are hydrogen or alkyl. These compounds are useful as antiinflammatory agents, antipyretics, analgesics.

4 Claims, No Drawings 1 n 4-HYDROXY-3-(3-ISOXAZOLOCARBAMYL)-2H- 1,2-BENZOTHIAZINE l, DIOXIDES AND PROCESS FOR THEIR PRODUCTION The present invention relates to 4-Hydroxy-3-(.3-.

isoxazolocarbamyl)-2l-l-1 ,Z-benzothiazine 1 1- Dioxides having the following structural formula:

wherein R, is hydrogen or methyland R and R are hydrogen or alkyl having from one to seven carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like.

The compounds of this invention are useful as antiinflammatory agents, antipyretics, and analgesics in several mammalian species. When administeredorally to rats at a dose of -200 mg./kg., they are able to cause reduction in swelling of the paw induced by injection into the footpads of an irritant such as carrageenin.

'Therapeutically orprophylactically administered orally at a dose of -200 mg./kg., the compounds inhibit adjuvant induced polyarthritis in the rat. Oral doses of -100 mg./kg. are sufficient to inhibit yeast induced hyperthermia in the rat. At oral doses of 25-200 mg./kg. they exhibit a significant analgesic effect as determined by the phenylquinone writhing procedure in mice.

Generally speaking, these compounds are indicated in conditions such as pain resultingfrom arthritis, bursitis and the like. A daily dosage regimen of about 0.5 grams to about 2 grams in several divided doses is recommended for a mammal weighing about 70 kg. body weight to relieve the pain and swelling associated with these conditions. These compounds are administered either orally or by injection.

In order to use these compounds, they are formulated into dosage forms such as tablets or syrups by blending with an inert pharmaceutical carrier such as lactose-or simple syrup by methods well known to the pharmacists art. For injectionable dosage forms, they are formulated with vehicles such as water, peanut oil, sesame Generally speaking, starting compound is refluxed with 3-aminoisoxazole ill in an inert solvent such as xylene. In a preferred embodiment of the present invention, the reactants are refluxed in the presence of a molecular sieve which promote the desired reaction by removing the alcohol which is formed as a by-product. The use of molecular sieves results in a more convenient and practical process in that lengthy distillation to remove the alcohol is no longer required. Typically the reaction is carried out in a Soxhlet apparatus with the molecular sieves contained in the thimble.

Examples of the molecular sieves, which can be used in this process, are commercially available molecular sieves under the trade name Linde type 4A molecular sieve from Matheson Coleman & Bell Company. See also Fieser & Fieser, Reagents for Organic Synthesis, Vol. 1.

The starting material II are known compounds and they are prepared in accordance with the description in' US. Pat; No. 3,501,466.

Starting compound 3-aminoisoxazole is prepared in accordance with the description in Chem. Pharm. Bull. 14, 1277 (1966); The starting compound 3-amino-5- methylisoxazole is commercially available from Hoffmann-La Roche. It is prepared in accordance with the description set forth in the Netherlands Pat; No. 6,511,924, issued Mar. 15, 1966.

The corresponding salts with metal or with amine are prepared by treating the above compounds with the desiredbase e.g., sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, pyrrolidine and the like by conventional procedures.

In order to further illustrate the practice of this invention, the following examples are included. All temperatures are givenin degrees centigrade.

EXAMPLE 1 4-Hydroxy-3-(5-methyl-3-isoxazolocarbamyl)-2- methyl-21L l ,2-benzothiazine l l -Dioxide A mixture of 40.5 g (0.15 3-carbethoxy-4-hydroxy- 2-methyl-2H-l,2-ben2othiazine 1,1-dioxide, 20.6 g (0.21 mole) of 3-amino-5-methylisoxazole, and 2500 ml of xylene was refluxed for 24 hr in a Soxholet apparatus, the thimble of which contained 60 g of Linde type 4A molecular sieve. The mixture was cooled to 25 and the resulting crystalline precipitate was collected and washed. with ether to give 44 g of crude product. Re-crystallization from 1600 ml of 1,4-dioxan gave 34.7 of material, mp 265271 dec.

Al'lal. Calcd for C14H13N305S: C, H, N, 12.53; S, 9.56. Found: C, 50.33; H, 3.88; N, 12.30; S, 9.49.

The corresponding sodium salt was prepared by treating the above compound with sodium hydroxide which has the following structural formula:

mole) of its 0 ENE-3* NCH! \OL ELAMPLE ll CONH NCH:

4-Hydroxy-3-( 3-isoxazo1ocarbamy1)-2-methyl-2H- 1 ,2- benzothiazine 1 1 -Dioxide A mixture of 4.15 g (0.0155 mole) of 3-carbethoxy- 4-hydroxy-2-methy1-2H-l ,2-benzothiazine 1 1 -dioxide, 1.3 g. (0.0155 mole) of 3-aminoisoxazole, and 500 ml of xylene was refluxed for 24 hr in a Soxholet apparatus, the thimble of which contained g of Linde 4A molecular sieve. The mixture was cooled to 25 and the resulting crystalline precipitate was collected and washed with ether to give 3.2 g of product, mp. 235-240 dec. Recrystallization from 175 ml of ethyl acetate gave 1.6 g of material, mp. 237-240 dec.

Anal. Calcd for C H N O S: C, 48.60; H, 3.45; N, 13.08; S, 9.98. Found: C, 48.77; H, 3.44; N, 12.86; S, 9.85.

. EXAMPLE 111 4-1-1ydroxy-3-(5-methyl-3-isoxazolocarbamyl)-2H-1 ,2- benzothiazine 1 ,1 -Dioxide A mixture of 15.3 g (0.06 mole) of 3-carbethoxy-4- hydroxy-2-methyl-2H-l ,2-benzothiazine 1 1 -dioxide, 5.9 g (0.06 mole) of 3-amino-5-methy1isoxazole, and 800 ml of xylene was refluxed for 24 hr. in a Soxholet apparatus, the thimble of which contained 20 g of Linde type 4A molecular sieve. The mixture was cooled to 25 and the resulting precipitate was collected and washed with ether to give 11.5 g of crude product, mp. 242248 dec. Recrystallization from 300 m1 of 1,4-dioxan gave 1 1.2 g of crystalline product, mp. 254257 dec.

Anal. Calcd for C H N O Sf C, 48.60; H, 3.45; N, 13.08; S, 9.98. Found: C, 48.67; H, 3.44; N, 12.91; S, 10.23.

We claim:

1. A compound of the formula:

SO; I

wherein R is liydrog en or rnethyl and R and R are benzothiazine 1 ,1 -Dioxide.

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3957772 *May 21, 1975May 18, 1976Warner-Lambert CompanyProcess for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2h-1,2-benzothiazine 1,1-dioxide
US3987038 *May 21, 1975Oct 19, 1976Warner-Lambert CompanyProcess for the preparation of {1-[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanone S,S-dioxide
US4551452 *May 2, 1984Nov 5, 1985Pfizer Inc.Anti-inflammatory 2-methyl-2H-1,2-benzo-(or -thieno-)thiazine-3-carboxamide 1,1-dioxide derivatives, compositions, and method of use therefor
US4656265 *Jun 21, 1984Apr 7, 1987Pfizer Inc.Cyclic prodrugs of antiinflammatory oxicams
US4829062 *May 16, 1986May 9, 1989Pfizer Inc.Benzothiazine dioxide derivatives
US5308839 *Sep 4, 1992May 3, 1994The Research Foundation Of State University Of New YorkComposition comprising non-steroidal anti-inflammatory agent tenidap and effectively non-antibacterial tetracycline
US5321017 *Aug 12, 1991Jun 14, 1994The Research Foundation Of State University Of New YorkComposition comprising fluriprofen and effectively non-antibacterial tetracycline to reduce bone loss
US5459135 *Feb 23, 1994Oct 17, 1995The Research Foundation Of State University Of New YorkComposition comprising indomethacin [non-steroidal anti-inflammatory agent] and effectively non-antibacterial tetracycline to reduce bone loss
EP0208404A2May 27, 1986Jan 14, 1987Pfizer Inc.Benzothiazine dioxide derivatives
WO2008044095A1Oct 11, 2006Apr 17, 2008Techfields Biochem Co LtdPositively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate
Classifications
U.S. Classification544/49
International ClassificationC07D417/12, A01N43/72
Cooperative ClassificationA01N43/72, C07D417/12
European ClassificationA01N43/72, C07D417/12