US3816628A - 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides to treat inflammatory fever and pain conditions - Google Patents

4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides to treat inflammatory fever and pain conditions Download PDF

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US3816628A
US3816628A US00333821A US33382173A US3816628A US 3816628 A US3816628 A US 3816628A US 00333821 A US00333821 A US 00333821A US 33382173 A US33382173 A US 33382173A US 3816628 A US3816628 A US 3816628A
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benzothiazine
hydroxy
isoxazolocarbamyl
dioxides
compounds
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M Schwartz
J Shavel
H Zinnes
W Lake
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Priority to AU39038/72A priority patent/AU456075B2/en
Priority to GB783872A priority patent/GB1323283A/en
Priority to DE19722208351 priority patent/DE2208351C3/en
Priority to FR7206659A priority patent/FR2128371B1/fr
Priority to CA135,876A priority patent/CA978187A/en
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Priority to US00333821A priority patent/US3816628A/en
Priority to US00356026A priority patent/US3822258A/en
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Priority to US05/840,929 priority patent/USRE29836E/en
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D417/12—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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms

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  • R is hydrogen or methyl and R and R are hydrogen or alkyl. These compounds are useful as antiinflammatory agents, antipyretics, analgesics.
  • the present invention relates to 4-hydroxy-3-(3-isoxazolocarbamyl)-2H-1,2-benzothiazine 1,1-dioxides having the following structural formula:
  • R is hydrogen or methyl and R and R are hydrogen or alkyl having from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like.
  • the present invention also includes within its scope the corresponding alkali metal, alkaline earth and amine salts.
  • the compounds of this invention are useful as antiinfiammatory agents, antipyretics, and analgesics in several mammalian species.
  • rats When administered orally to rats at a dose of 10-200 mg./kg., they are able to cause reduction in swelling of the paw induced by injection into the foot pads of an irritant such as carrageenin.
  • Therapeutically or prophylactically administered orally at a dose of -200 mg./kg. the compounds inhibit adjuvant induced polyarthritis in the rat.
  • Oral doses of 25-100 mg./kg. are sufiicient to inhibit yeast induced hyperthermia in the rat.
  • these compounds are indicated in conditions such as pain resulting from 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.
  • the above compounds are prepared by a reaction scheme as follows:
  • starting compound II is refluxed with 3-aminoisoxazole III in an inert solvent such as xylene.
  • 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.
  • 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.
  • the reaction is carried out in a Soxhlet apparatusus with the molecular sieves contained in the thimble.
  • 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 U.S. Pat. No. 3,501,466.
  • the corresponding salts with metal or with amine are prepared by treating the above compounds with the desired base e.g. sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, pyrrolidine and the like by conventional procedures.
  • the desired base e.g. sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, pyrrolidine and the like by conventional procedures.
  • EXAMPLE 1 4-hydroxy-3-(S-methyl-3-isoxazolocarbamyl) 2 methyl- 2H-1,2-benzothiazine 1,1-dioxide
  • the corresponding sodium salt was prepared by treating the above compound with sodium hydroxide which has the following structural formula:
  • the sodium salt after recrystallization from ethanol has M.P. 270-272 dec.
  • Claim 1 A process for alleviating inflammatory fever or painful conditions in a mammalian host which comprises administering to said mammal an effective amount of a compound of the formula:
  • R is hydrogen or methyl and R and R are hydrogen or alkyl having 1 to 7 carbon atoms or an alkali metal, alkaline earth and amine salt.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

COMPOUNDS HAVING THE FOLLOWING STRUCTURAL FORMULA ARE DISCLOSED.

2-R1,3-((4-R2,5-R3-ISOXAZOL-3-YL)-NH-CO-),4-HO-2H-1,2-

BENZOTHIAZINE 1,1-DIOXIDE

WHEREIN R1 IS HYDROGEN OR METHYL AND R2, AND R3 ARE HYDROGEN OR ALKYL. THESE COMPOUNDS ARE USEFUL AS ANTIINFLAMMATORY AGENTS, ANTIPYRETICS, ANALGESICS.

Description

United States Patent U.S. Cl. 424-246 1 Claim ABSTRACT OF THE DISCLOSURE 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.
This application is a divisional of application Ser. No. 119,967 filed Mar. 1, 1971 and now U.S. Pat. No. 3,787,324.
The present invention relates to 4-hydroxy-3-(3-isoxazolocarbamyl)-2H-1,2-benzothiazine 1,1-dioxides having the following structural formula:
O -ENH i *3: N-Rr ll L so 0 I wherein R is hydrogen or methyl and R and R are hydrogen or alkyl having from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like.
The present invention also includes within its scope the corresponding alkali metal, alkaline earth and amine salts.
The compounds of this invention are useful as antiinfiammatory agents, antipyretics, and analgesics in several mammalian species. When administered orally to rats at a dose of 10-200 mg./kg., they are able to cause reduction in swelling of the paw induced by injection into the foot pads of an irritant such as carrageenin. Therapeutically or prophylactically administered orally at a dose of -200 mg./kg., the compounds inhibit adjuvant induced polyarthritis in the rat. Oral doses of 25-100 mg./kg. are sufiicient to inhibit yeast induced hyperthermia in the rat. At oral doses of 25-200 mg./kg. they exhibit a significant analgesic etiect as determined by the phenylquinone writhing procedure in mice.
Generally speaking, these compounds are indicated in conditions such as pain resulting from 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.
3,816,628 Patented June 11, 1974 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 oil, and the like. In these dosage forms, the active ingredient is from about 0.5 grams to 1 gram per dosage unit.
According to the present invention, the above compounds are prepared by a reaction scheme as follows:
Generally speaking, starting compound II is refluxed with 3-aminoisoxazole III 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 aparatus 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 U.S. 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 Hoffman-La Roche. It is prepared in accordance with the description set forth in the Netherlands Pat. No. 6511924, issued Mar. 15, 1966.
The corresponding salts with metal or with amine are prepared by treating the above compounds with the desired base 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 given in degrees centigrade.
EXAMPLE 1 4-hydroxy-3-(S-methyl-3-isoxazolocarbamyl) 2 methyl- 2H-1,2-benzothiazine 1,1-dioxide A mixture of 40.5 g. (0.15 mole) of 3-carbethoxy-4- hydroxy 2 methyl 2H 1,2 benzothiazine 1,1-dioxide, 20.6 g. (0.21 mole) of 3-amino-S-methylisoxazole, and 2500 ml. of xylene as refluxed for 24 hr. in a Soxhlet 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-
3 crystallization from 1600 ml. of 1,4-dioxan gave 34.7 of material, M.P. 26527 1 dec.
Anal.--Calcd. for C H N O S: C, 50.14; H, 3.91; 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:
k" G 'iiNH NCHI CH \6. 0
The sodium salt after recrystallization from ethanol has M.P. 270-272 dec.
Anal.Calcd. for C H N O SNa: C, 47.06; H, 3.39; N, 11.76; S, 8.97. Found: C, 47.09; H, 3.69; N, 11.50; S, 8.81.
EXAMPLE II 0 ONH-| 9"" i i so, 0
4-hydroxy-3-(3-isoxazolocarbamyl)-2-methy1- 2H-l,2-benzothiazine1,1-dioxide A mixture of 4.15 g. (0.0155 mole) of 3-carbethoxy-4 hydroxy-Z-methyl-ZH-l,Z-benzothiazine 1,1-dioxide, 1.3 g. (0.0155 mole) of S-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 and the resulting crystalline precipitate was collected and washed with ether to give 3.2 g. of product, M.P. 235240 dec. Recrystallization from 175 ml. of ethyl acetate gave 1.6 g. of material, M.P. 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.
4 EXAMPLE m 4-hydroxy-3- (5 -methyl-3 -isoxazolocarbamyl) 2H-1,2-benzothiazine 1,1-di0xide A mixture of 15.3 g. (0.06 mole) of 3-carbethoxy-4- hydroxy-Z-methyl-ZH-1,2-benzothiazine 1,1-dioxide, 5.9 g. (0.06 mole) of 3-amino-5-methylisoxazole, and 800 ml. of xylene as refluxed for 24 hr. in a Soxhlet 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, M.P. 242-248" dec. Recrystallization from 300 ml. of 1,4dioxan gave 11.2 g. of crystalline product, M.P. 254257 dec.
Anal.-Calcd. for C H N O S: 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:
Claim 1. A process for alleviating inflammatory fever or painful conditions in a mammalian host which comprises administering to said mammal an effective amount of a compound of the formula:
wherein R is hydrogen or methyl and R and R are hydrogen or alkyl having 1 to 7 carbon atoms or an alkali metal, alkaline earth and amine salt.
References Cited UNITED STATES PATENTS 3,492,298 1/1970 Rasmussen 260243 3,501,466 3/1970 Rasmussen 260243 STANLEY I. FRIEDMAN, Examiner
US00333821A 1971-03-01 1973-02-20 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides to treat inflammatory fever and pain conditions Expired - Lifetime US3816628A (en)

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Application Number Priority Date Filing Date Title
US00119967A US3787324A (en) 1971-03-01 1971-03-01 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,dioxides and process for their production
AU39038/72A AU456075B2 (en) 1971-03-01 1972-02-16 4-hydroxy-3-[3-isoxazolocarbamyl]-2h-1,2-benzothiazine 1, 1-dioxides and process for their production
GB783872A GB1323283A (en) 1971-03-01 1972-02-21 Benzothiazine 1,1, dioxide derivatives
DE19722208351 DE2208351C3 (en) 1971-03-01 1972-02-22 4-Hydroxy-3- (3-isoxazolocarbamoyl) -2H-1,2-benzothiazine-1,1-dioxides and process for their preparation
FR7206659A FR2128371B1 (en) 1971-03-01 1972-02-28
CA135,876A CA978187A (en) 1971-03-01 1972-02-29 4-hydroxy-3-(3-isoxazolocarbanyl)-2h-1,2-benzothiazine 1,1-dioxides and process for their production
US00333821A US3816628A (en) 1971-03-01 1973-02-20 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides to treat inflammatory fever and pain conditions
US00356026A US3822258A (en) 1971-03-01 1973-04-30 4-hydroxy-3-(3-isoxazolylcarbamoyl)-2h-1,2-benzothiazine 1,1-dioxides and process for their production
US05/840,929 USRE29836E (en) 1971-03-01 1977-10-11 4-Hydroxy-3-(3-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-dioxides and process for their production

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US11996771A 1971-03-01 1971-03-01
US00333821A US3816628A (en) 1971-03-01 1973-02-20 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides to treat inflammatory fever and pain conditions
US00356026A US3822258A (en) 1971-03-01 1973-04-30 4-hydroxy-3-(3-isoxazolylcarbamoyl)-2h-1,2-benzothiazine 1,1-dioxides and process for their production

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US00119967A Expired - Lifetime US3787324A (en) 1971-03-01 1971-03-01 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,dioxides and process for their production
US00333821A Expired - Lifetime US3816628A (en) 1971-03-01 1973-02-20 4-hydroxy-3-(3-isoxazolocarbamyl)-2h-1,2-benzothiazine 1,1-dioxides to treat inflammatory fever and pain conditions
US00356026A Expired - Lifetime US3822258A (en) 1971-03-01 1973-04-30 4-hydroxy-3-(3-isoxazolylcarbamoyl)-2h-1,2-benzothiazine 1,1-dioxides and process for their production
US05/840,929 Expired - Lifetime USRE29836E (en) 1971-03-01 1977-10-11 4-Hydroxy-3-(3-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-dioxides and process for their production

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US05/840,929 Expired - Lifetime USRE29836E (en) 1971-03-01 1977-10-11 4-Hydroxy-3-(3-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-dioxides and process for their production

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US3868367A (en) * 1974-04-11 1975-02-25 Warner Lambert Co 4-Hydroxy-3-(5-isoxazolylcarbamoyl)-2H-1,2-benzothiazine 1,1-dioxides
US3957772A (en) * 1975-05-21 1976-05-18 Warner-Lambert Company Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2h-1,2-benzothiazine 1,1-dioxide
US3987038A (en) * 1975-05-21 1976-10-19 Warner-Lambert Company Process 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
US4024136A (en) * 1975-06-20 1977-05-17 Warner-Lambert Company Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide
LU78009A1 (en) 1977-08-22 1979-05-23 Hoffmann La Roche METHOD FOR PRODUCING THIAZINE DERIVATIVES
AU518216B2 (en) 1977-09-06 1981-09-17 Hafslund Nycomed Pharma Aktiengesellschaft Thienothiazine derivatives
US4474955A (en) * 1981-06-17 1984-10-02 Vincenzo Iannella Process for preparing 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-[N-(2-pyridinyl)carboxamide]-1,1-dioxide, and its phosphoric ester
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US5308839A (en) * 1989-12-04 1994-05-03 The Research Foundation Of State University Of New York Composition comprising non-steroidal anti-inflammatory agent tenidap and effectively non-antibacterial tetracycline
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US20090221703A1 (en) 2006-07-09 2009-09-03 Chongxi Yu High penetration composition and uses thereof
US20090238763A1 (en) 2006-07-09 2009-09-24 Chongxi Yu High penetration compositions and uses thereof
CN101522692A (en) 2006-10-11 2009-09-02 于崇曦 Positively charged water-soluble prodrugs of oxicams and related compounds with very high skin penetration rate
CA2691446C (en) * 2007-06-04 2021-07-06 Techfields Inc Pro-drugs of nsaias with very high skin and membranes penetration rates and their new medicinal uses
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US4289879A (en) * 1980-09-29 1981-09-15 Pfizer Inc. Synthetic method and intermediate for piroxicam

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US3822258A (en) 1974-07-02
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FR2128371B1 (en) 1975-10-10
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US3787324A (en) 1974-01-22
AU3903872A (en) 1973-08-23
CA978187A (en) 1975-11-18
AU456075B2 (en) 1972-11-21
DE2208351B2 (en) 1976-09-16
FR2128371A1 (en) 1972-10-20

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