US3048519A - Benzenesulfonamido-halo-pyrimidines: antibacterials - Google Patents
Benzenesulfonamido-halo-pyrimidines: antibacterials Download PDFInfo
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- US3048519A US3048519A US90245A US9024561A US3048519A US 3048519 A US3048519 A US 3048519A US 90245 A US90245 A US 90245A US 9024561 A US9024561 A US 9024561A US 3048519 A US3048519 A US 3048519A
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- iodopyrimidine
- infection
- sulfanilamido
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- sulfa
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/69—Benzenesulfonamido-pyrimidines
Definitions
- This invention relates to new compositions of matter. More particularly, it relates to therapeutic compositions of substituted benzenesulfonamido-iodopyrimidines and a carrier.
- sulfa drugs In the development of sulfa drugs, sulfapyridine and sulfathiazole were found to be active but also somewhat toxic. Other sulfa drugs were developed which were more active, such as sulfadiazine and sulfamethazine. To avoid the requirement of dosage every four hours day and night, more slowly excreted sulfa drugs have been sought. The desirable feature of slow excretion of sulfa drugs is commonly called persistence of activity. The persistent or long-acting sulfa drugs most commonly used now are 3-sulfanilamido-6-methoxypyridazine and 4-sulfanilnols, acetone, Water, etc. These compounds are ordinarily purified by dissolving in aqueous alkali and neutralizing the resulting solution with aqueous acid.
- 2-sulfanilamido-S-iodopyrimidine would have high activity and persistence of said activity when closely related compounds such as, for example, 2- sulfanilamido-5-bromopyrimidine and 2-sulfanilamido-5- chloropyrimidine do not possess these properties.
- Single oral dosage in mice shows that the latter drugs are toxic to the extent of being about sixty times more toxic than the iodo derivative and, in addition, are less active and less persistent.
- the amount of single doses or daily doses to be given v would vary with the size of the man or animal to be treated but should be such as to give a proportionate dosage of '1 to 500 mg./kg. per body weight. In terms of total weight of drug, this is usually from about 0.01 g. to 10.00 g. per dosage unit. In larger animals, obviously, larger dosage units may be desirable.
- compositions containing 2-sulfanilamido- 5-iodopyrimidine, 2-(p-acetamidobenzenesulfonamido)-5- iodopyrimidine and 2-(p-nitrobenzenesulfonamido)-5- iodopyrimidine are effective antibacterial agents against infection with Staphylococcus aureus, a commonly-used test organism and with many other organisms as shown hereinafter.
- the new compositions containing 2-(pacetamidobenzenesulfonamido)-5-iodopyrimidine show the best activity when used in a prophylactic fashion, e.g. oral dosage six to twenty-four hours before infection.
- compositions of the present invention containing 2-sulfanilamido-S-iodopyrimidine or 2-(p-nitrobenzenesulfonamido)-5-iodopyrirnidine when tested against a number of infections where the standard infection is given to mice and the infected mice are treated by drug diet for seven days followed by a holding period of seven days, the following Table HI illustrates the results obtained with the present compositions against various infections when compared to sulfadiazine.
- N o'rE Rel ative activities based on median effective doses against the various infections shown above. The standard infection given at 0 day; drug diet from 1 to +6 days; holding period 14 days after infection.
- Table I illustrates the re
- the unexpected high activity of the present compositions such as 2-sulfanilamido-5-iodopyrimidine when tested along with the commonly used sulfa drugs shows the great superiority of the present compositions over known sulfa drugs.
- These tests were conducted in mice and the infection used was Streptococcus pyogenes and Staphylococcus aureus. A summary of these tests is shown in the following Table IV.
- the infection is Streptococcus pj/ogenes, beta hemolytic strain 0203; 0.5 ml. of a 1:100,000 broth dilution of a 5 hour blood-broth culture was given intraperitoneally.
- the treatment single subcutaneous dose of 500 mg./kg. contained in 0.5 ml. of 0.2% aqueous agar; at time of infection (0 hours) or before infection (e.g 48 hours signifies 48 hours before infection).
- Controls 120 of 120 untreated infected mice were dead within 2 days after infection.
- the infection is Staphylococcus aureus, strain Smith: 0.5 m1. of a 1:100 broth dilution of a 5 hour blood-broth culture was given intraperitoneally. Treatment was a single Subcutaneous dose of 500 mg./kg. contained in 0.5 ml of 0.2% aqueous agar at time of infection (0 hours) or before infection as lndicated 1n hours (eg. 24, etc). Controls: 137 of 140 untreated infected mice were dead within 2 days after infection.
- the sulfa drugs 2-sulfanilamido-5-iodopyrimidine, 2- p-acetamidobenzenesulfonamido)-5-iodopyrimidine and 2-(p-nitrobenzenesulfonamido)-5-iodopyrimidine can be combined with a carrier and dispensed in any of the usual dosage unit forms of pharmaceutical preparations; for example, tablets, capsules, pills, suspension, as a power or in any other desirable form in therapeutic quantities hereinbefore given.
- the therapeutic agents may be combined with binders such as gum t-ragacanth, acacia, corn starch, gelatin etc.
- a disintegrating agent such as, for example, corn starch, potato starch, alginic acid or the like.
- a lubricant such as stearic acid, magnesium stearate or talc along with sweetening agents such as saccharin.
- sweetening agents such as saccharin.
- Flavoring agents may also be used such as peppermint, oil of Wintergreen or cherry flavor.
- Larger tablets usually referred to as oblets of from 1-10 g. can be used in veterinary medicines. In the preparation of capsules, fillers such as enumerated above for tablets can also be used.
- compositions when used in the form of suspensions or solutions may be combined with aqueous sugar or sorbitol type vehicle including a viscosity control agent such as Veegum (magnesium aluminum silicate), methocel or carboxymethylcellulose and a suitable perservative such as sodium benzoate or parabens (methyl and propyl p-hydroxybenzoic acid salts).
- a viscosity control agent such as Veegum (magnesium aluminum silicate), methocel or carboxymethylcellulose
- a suitable perservative such as sodium benzoate or parabens (methyl and propyl p-hydroxybenzoic acid salts).
- colorings, fiavorings and buffers can also be included to produce a more pharmaceutically elegant preparation. It is also well-known in pharmaceutical practice to use a propylene glycol type larger quantities from which single doses are withdrawn at the time of use.
- the new compositions may be combined with edible carriers such as feed stuffs and so forth.
- a method of maintaining persistence of activity useful in the treatment of ani-tbacterial infections which comprises administering in dosage unit form from 1 mg. to 500 mg./kg. of body weight of a sulfa drug selected from the group consisting of 2-sulfanilarnido-5-iodopyrimidine, 2-(p-acctamidobenzenesulfonamido)-5-iodopyrimidine and 2-(p-nitrobenzenesulfonamido)-S-iodopyrimidine and an edible carrier.
- a sulfa drug selected from the group consisting of 2-sulfanilarnido-5-iodopyrimidine, 2-(p-acctamidobenzenesulfonamido)-5-iodopyrimidine and 2-(p-nitrobenzenesulfonamido)-S-iodopyrimidine and an edible carrier.
- a method of maintaining persistence of acitvity against bacterial infections which comprises introducing into the alimentary tract of animals having a bacterial infection, a therapeutic composition comprising from 1 mg. to 500 rug/kg. of body weight of 2-sulfanilamido-5- iodopyrimidine and an edible carrier.
- a method of maintaining persistence of activity against bacterial infections which comprises parenterally administering into animals having a bacterial infection, a therapeutic composition comprising from 1 mg. to 500 mg./kg. of body weight of 2-sulfanilarnido-S-iodopyrimidine and a parenteral vehicle.
- a method of maintaining persistence of activity against bacterial infections which comprises parenterally administering into animals having a bacterial infection, a therapeutic composition comprising from 1 mg. to 500 mg./kg. of body weight of 2-(p-acetamidobenzenesulfonamido)-5-idodopyrimidine and a parenteral vehicle.
- a method of maintaining persistence of activity against bacterial infections which comprises parenterally administering into animals having a bacterial infection, a therapeutic composition comprising from 1 mg. to 500 mg./kg. of body weight of 2-(p-nitrobenzenesulfonamido)-5-iodopyrimidine and a parenteral vehicle.
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent l 3,048,519 BENZENESULFONAMIDO-HALO-PYRWINES: ANTEBACTERIALS James L. Fedrick, Pearl River, and Gunnar S. Rodin,
New City, N.Y., and Robert G. Shepherd, Ridgewood, N.J., assignors to American Cyanamid Company, New York, N.Y., a corporation of Maine No Drawing. Filed Feb. 20, 1961, Ser. No. 90,245 Claims. (Cl. 167-515) This invention relates to new compositions of matter. More particularly, it relates to therapeutic compositions of substituted benzenesulfonamido-iodopyrimidines and a carrier.
In the development of sulfa drugs, sulfapyridine and sulfathiazole were found to be active but also somewhat toxic. Other sulfa drugs were developed which were more active, such as sulfadiazine and sulfamethazine. To avoid the requirement of dosage every four hours day and night, more slowly excreted sulfa drugs have been sought. The desirable feature of slow excretion of sulfa drugs is commonly called persistence of activity. The persistent or long-acting sulfa drugs most commonly used now are 3-sulfanilamido-6-methoxypyridazine and 4-sulfanilnols, acetone, Water, etc. These compounds are ordinarily purified by dissolving in aqueous alkali and neutralizing the resulting solution with aqueous acid.
It is unexpected that 2-sulfanilamido-S-iodopyrimidine would have high activity and persistence of said activity when closely related compounds such as, for example, 2- sulfanilamido-5-bromopyrimidine and 2-sulfanilamido-5- chloropyrimidine do not possess these properties. Single oral dosage in mice shows that the latter drugs are toxic to the extent of being about sixty times more toxic than the iodo derivative and, in addition, are less active and less persistent. The high activity of 2-(p-nitrobenzenesulfonainido)-5-iodopyrimidine and of 2-(p-acetamidobenzenesulfonamido)-5 iodopyrimidine is unexpected since it is well known [H. J. White et al., J. Pharmacol. 72, 112-122 (1941)], that such compounds are generally inactive. amido-S-iodopyrimidine, are so slowly excreted that they can be effectively used for prophylactic action using infrequent dosages such as one dose per week. The present compositions are unusual in also giving extremely good antibacterial activity both orally and subcutaneously.
The amount of single doses or daily doses to be given v would vary with the size of the man or animal to be treated but should be such as to give a proportionate dosage of '1 to 500 mg./kg. per body weight. In terms of total weight of drug, this is usually from about 0.01 g. to 10.00 g. per dosage unit. In larger animals, obviously, larger dosage units may be desirable.
Experiments carried out using a single oral dose of various sulfa drugs 24 hours before infection with Staphylococcus aureus shows that 2-sulfanilamido-5-iodopyrimidine and 2-(p-nitrobenzenesulfonamido)-5-iodopyrimidine are greatly superior to the commonly used These substances, and in particular 2-sulfanil- 3,048,519 Patented Aug. 7, 1962 sulfa drugs. suits obtained.
TABLE I The Efiect of Single Oral Doses Given 24 Hours Before Infection With Staphylococcus aureus, Strain Smith Median efiec- Sulfa drug tive doses,
rug/kg.
Sulfadiazine l Inactive 3-su1fanilamido-G-methoxypyridazine 880 4-suIianilan1id0-2,G-dimethoxypyrinn 1 Inactive 2-sultanilamido-5-iodopyrimidine 320 2-(p-nitrobenzene sulfonamido)-5-iodopyrimidine 290 1 Inactive at the highest dose (1,280 mg./kg.)
The present compositions containing 2-sulfanilamido- 5-iodopyrimidine, 2-(p-acetamidobenzenesulfonamido)-5- iodopyrimidine and 2-(p-nitrobenzenesulfonamido)-5- iodopyrimidine are effective antibacterial agents against infection with Staphylococcus aureus, a commonly-used test organism and with many other organisms as shown hereinafter. The new compositions containing 2-(pacetamidobenzenesulfonamido)-5-iodopyrimidine show the best activity when used in a prophylactic fashion, e.g. oral dosage six to twenty-four hours before infection.
TABLE II Prophylactic Treatment of Staphylococcus aureus Infection Treatment Rcgaive Drug Percent an renal Single survival oral dose on 14th potency day 320 100 160 S0 75 40 20 D0 20 15 2-(pacetamidobenzenesultonamido)- fi-iodopyrimidine a. 320 D 50 8O 10 40 5 2O 0 1 Treatment with the single oral doses shown six hours before infection of mice.
The compositions of the present invention containing 2-sulfanilamido-S-iodopyrimidine or 2-(p-nitrobenzenesulfonamido)-5-iodopyrirnidine when tested against a number of infections where the standard infection is given to mice and the infected mice are treated by drug diet for seven days followed by a holding period of seven days, the following Table HI illustrates the results obtained with the present compositions against various infections when compared to sulfadiazine.
N o'rE. Rel ative activities based on median effective doses against the various infections shown above. The standard infection given at 0 day; drug diet from 1 to +6 days; holding period 14 days after infection.
The following Table I illustrates the re The unexpected high activity of the present compositions such as 2-sulfanilamido-5-iodopyrimidine when tested along with the commonly used sulfa drugs shows the great superiority of the present compositions over known sulfa drugs. These tests were conducted in mice and the infection used was Streptococcus pyogenes and Staphylococcus aureus. A summary of these tests is shown in the following Table IV.
TABLE IV Percentage Survival of Infected Mice Treated With Various Sulfa Drugs Treated with- Hour of dosing 2-sulfa- 2-su1fa- 3,4-dlmethyle-sulfanil- 2,6-dimethoxy 3-sulfanilrelative to ni1amido-5- nilamido fi-sulfanilarmdo-l-phenyl 4-sulfanilarnldoG-rnethoxy infection iodopyrimidine, pyrimidine, amido pyrazole, amido pyridazine,
percent percent lsoxazole, percent pyrimidine, percent percent percent Group L- O 100 93 0 40 100 55 Group I -24 100 37 0 30 0 Group III -48 90 7 0 0 0 0 Group IV 72 90 7 Group V -96 70 0 In the above experiment the infection is Streptococcus pj/ogenes, beta hemolytic strain 0203; 0.5 ml. of a 1:100,000 broth dilution of a 5 hour blood-broth culture was given intraperitoneally. The treatment: single subcutaneous dose of 500 mg./kg. contained in 0.5 ml. of 0.2% aqueous agar; at time of infection (0 hours) or before infection (e.g 48 hours signifies 48 hours before infection). Controls: 120 of 120 untreated infected mice were dead within 2 days after infection.
Treated with Hour of dosing 2-sulfa- 2-sulfa- 3,4-d1rnethylfi-sulfanil- 2,6-dlmethoxy 3-sulfanilrelative to nilamido-onilamido s-sulfanilamido-l-phenyl 4-sulfanilamido-e-methoxy infection iodopyrimidme, pyrimidine, amide pyrazole, amide pyridazine,
percent percent isoxazole, percent pyrimidine, percent percent percent Group I 0 100 100 90 95 100 95 Group II 24 100 100 0 30 85 20 Group III 48 100 55 0 0 10 Group IV 72 100 0 0 0 0 Group V 96 95 10 0 0 0 0 In the above experiment the infection is Staphylococcus aureus, strain Smith: 0.5 m1. of a 1:100 broth dilution of a 5 hour blood-broth culture was given intraperitoneally. Treatment was a single Subcutaneous dose of 500 mg./kg. contained in 0.5 ml of 0.2% aqueous agar at time of infection (0 hours) or before infection as lndicated 1n hours (eg. 24, etc). Controls: 137 of 140 untreated infected mice were dead within 2 days after infection.
The sulfa drugs 2-sulfanilamido-5-iodopyrimidine, 2- p-acetamidobenzenesulfonamido)-5-iodopyrimidine and 2-(p-nitrobenzenesulfonamido)-5-iodopyrimidine can be combined with a carrier and dispensed in any of the usual dosage unit forms of pharmaceutical preparations; for example, tablets, capsules, pills, suspension, as a power or in any other desirable form in therapeutic quantities hereinbefore given. In the preparation of tablets, for example, the therapeutic agents may be combined with binders such as gum t-ragacanth, acacia, corn starch, gelatin etc. It is also usually desirable to have present a disintegrating agent such as, for example, corn starch, potato starch, alginic acid or the like. Also desirable usually is a lubricant such as stearic acid, magnesium stearate or talc along with sweetening agents such as saccharin. Flavoring agents may also be used such as peppermint, oil of Wintergreen or cherry flavor. Larger tablets usually referred to as oblets of from 1-10 g. can be used in veterinary medicines. In the preparation of capsules, fillers such as enumerated above for tablets can also be used. The compositions when used in the form of suspensions or solutions may be combined with aqueous sugar or sorbitol type vehicle including a viscosity control agent such as Veegum (magnesium aluminum silicate), methocel or carboxymethylcellulose and a suitable perservative such as sodium benzoate or parabens (methyl and propyl p-hydroxybenzoic acid salts). In these liquid preparations, colorings, fiavorings and buffers can also be included to produce a more pharmaceutically elegant preparation. It is also well-known in pharmaceutical practice to use a propylene glycol type larger quantities from which single doses are withdrawn at the time of use.
For use in veterinary medicine, the new compositions may be combined with edible carriers such as feed stuffs and so forth.
We claim:
1. A method of maintaining persistence of activity useful in the treatment of ani-tbacterial infections which comprises administering in dosage unit form from 1 mg. to 500 mg./kg. of body weight of a sulfa drug selected from the group consisting of 2-sulfanilarnido-5-iodopyrimidine, 2-(p-acctamidobenzenesulfonamido)-5-iodopyrimidine and 2-(p-nitrobenzenesulfonamido)-S-iodopyrimidine and an edible carrier.
2. A method of maintaining persistence of acitvity against bacterial infections which comprises introducing into the alimentary tract of animals having a bacterial infection, a therapeutic composition comprising from 1 mg. to 500 rug/kg. of body weight of 2-sulfanilamido-5- iodopyrimidine and an edible carrier.
3. A method of maintaining persistence of activity against bacterial infections which comprises parenterally administering into animals having a bacterial infection, a therapeutic composition comprising from 1 mg. to 500 mg./kg. of body weight of 2-sulfanilarnido-S-iodopyrimidine and a parenteral vehicle.
4. A method of maintaining persistence of activity against bacterial infections which comprises parenterally administering into animals having a bacterial infection, a therapeutic composition comprising from 1 mg. to 500 mg./kg. of body weight of 2-(p-acetamidobenzenesulfonamido)-5-idodopyrimidine and a parenteral vehicle. 5. A method of maintaining persistence of activity against bacterial infections which comprises parenterally administering into animals having a bacterial infection, a therapeutic composition comprising from 1 mg. to 500 mg./kg. of body weight of 2-(p-nitrobenzenesulfonamido)-5-iodopyrimidine and a parenteral vehicle.
References Cited in the file of this patent Shepherd: Chemical Abstracts, vol. 42, page 3409b, 1948, abs. of JACS, v01. 70, pp. 157-160, 1948.
English et al.: JACS, v01. 68, March 1946, page 5 453-458.
English et al.: JACS, vol. 68, June 1946, pages 1039-1049.
Claims (1)
1. A METHOD OF MAINTAINIG PERSISTENCE OF ACTIVITY USEFUL IN THE TREATMENT OF ANITBACTERIAL INFECTIONS WHICH COMPRISES ADMINISTERING IN DOSAGE UNIT FORM FROM 1 MG. TO 500 MG/KG OF BODY WEIGHT OF A SULFA DRUG SELECTED FROM THE GROUP CONSISTING OF 2-SULFANILAMIDO-5-IODOPYRIMIDINE, 2-(P-ACETAMIDOBENZENESULFONAMIDO)-5-IODOPYRIMIDINE AND 2-(P-NITROBENZENESULFONAMIDO)-5-IODOPYRIMIDINE AND AN EDIBLE CARRIER.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US90245A US3048519A (en) | 1961-02-20 | 1961-02-20 | Benzenesulfonamido-halo-pyrimidines: antibacterials |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US90245A US3048519A (en) | 1961-02-20 | 1961-02-20 | Benzenesulfonamido-halo-pyrimidines: antibacterials |
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| US3048519A true US3048519A (en) | 1962-08-07 |
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| US90245A Expired - Lifetime US3048519A (en) | 1961-02-20 | 1961-02-20 | Benzenesulfonamido-halo-pyrimidines: antibacterials |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3144448A (en) * | 1964-08-11 | Isoxazole derivatives of sulfanilamide | ||
| US3334302A (en) * | 1962-07-02 | 1967-08-01 | Snc Science Union Et Cie Soc F | Dicyclic sulfonylurea compounds |
-
1961
- 1961-02-20 US US90245A patent/US3048519A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3144448A (en) * | 1964-08-11 | Isoxazole derivatives of sulfanilamide | ||
| US3334302A (en) * | 1962-07-02 | 1967-08-01 | Snc Science Union Et Cie Soc F | Dicyclic sulfonylurea compounds |
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