Claims
- 1. A compound of the formula ##STR18## wherein each ##STR19## group is located anywhere on the carbon ring with the proviso that one group cannot be ortho to the other group;
- R is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms, phenyl, and a pharmaceutically acceptable metal or amine cation;
- X and Y are the same or different and are selected from the group consisting of hydrogen, alkyl from one through four carbon atoms, phenyl, alkoxy from one through three carbon atoms, nitro, amino, trifluoromethyl, halogen, cyano, and ##STR20## wherein D is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms, and a pharmaceutically acceptable metal or amine cation with the proviso that when R is hydrogen or a pharmaceutically acceptable metal or amine cation, then D is the same as R and when R is alkyl from one through six carbon atoms or phenyl, then D is alkyl from one through six carbon atoms, phenyl or hydrogen; with the overall proviso that at least one of X and Y is cyano; or a pharmaceutically acceptable acid addition salt thereof.
- 2. A compound in accordance with claim 1 wherein R is selected from the group consisting of hydrogen, alkyl of from one through four carbon atoms, and a pharmaceutically acceptable metal or amine cation;
- X and Y are the same or different and are selected from the group consisting of hydrogen, alkyl from one through four carbon atoms, phenyl, alkoxy from one through three carbon atoms, nitro, trifluoromethyl, halogen, cyano, and ##STR21## wherein when D is alkyl, the upper limit of carbon atoms is four.
- 3. A compound in accordance with claim 2 wherein the ##STR22## groups are located at the 2 and 6 positions or the 3 and 5 positions; R is selected from the group consisting of hydrogen and a pharmaceutically acceptable metal or amine cation.
- 4. A compound in accordance with claim 3 wherein X is hydrogen and Y is cyano.
- 5. A compound in accordance with claim 4 with the proviso that Y is located at the 4-position.
- 6. A compound in accordance with claim 5 wherein the ##STR23## groups are located at the 2 and 6 positions.
- 7. A compound in accordance with claim 1 wherein the ##STR24## groups are at the 2 and 6 positions of ##STR25## R is selected from the group consisting of hydrogen, alkyl of one to three carbon atoms, inclusive, and a pharmaceutically acceptable metal or amine cation and X and Y are hydrogen.
- 8. A compound in accordance with claim 1 wherein the ##STR26## groups are at the 2 and 5 positions of ##STR27## R is selected from the group consisting of hydrogen, alkyl from one to three carbon atoms, inclusive, and a pharmaceutically acceptable metal or amine cation and X and Y are hydrogen.
- 9. A compound in accordance with claim 7 where R is selected from the group consisting of hydrogen and tris-(hydroxymethyl)methylammonium.
- 10. A compound in accordance with claim 8 where R is selected from the group consisting of hydrogen and tris-(hydroxymethyl)methylammonium.
- 11. A compound in accordance with claim 4 wherein the structure is ##STR28## or a pharmaceutically acceptable acid addition salt thereof.
- 12. A compound in accordance with claim 5 wherein the structure is ##STR29## or a pharmaceutically acceptable acid addition salt thereof.
- 13. A compound in accordance with claim 6 wherein the structure is ##STR30## or a pharmaceutically acceptable acid addition salt thereof.
- 14. A compound in accordance with claim 1 wherein the ##STR31## groups are located at the 2 and 6 positions.
- 15. A compound in accordance with claim 2 wherein the ##STR32## groups are located at the 2 and 6 positions.
- 16. A compound in accordance with claim 3 wherein the ##STR33## groups are located at the 2 and 6 positions.
- 17. A compound in accordance with claim 4 wherein the ##STR34## groups are located at the 2 and 6 positions.
- 18. A pharmaceutical composition which comprises an anti-bronchial asthma, allergic rhinitis, food allergy, or urticaria effective amount of a compound selected from the group consisting of ##STR35## wherein each ##STR36## group is located anywhere on the carbon ring with the proviso that one group cannot be ortho to the other group;
- R is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms, phenyl, and a pharmaceutically acceptable metal or amine cation;
- X and Y are the same or different and are selected from the group consisting of hydrogen, alkyl from one through four carbon atoms, phenyl, alkoxy from one through three carbon atoms, nitro, amino, trifluoromethyl, halogen, cyano, and ##STR37## wherein D is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms, and a pharmaceutically acceptable metal or amine cation with the proviso that when R is hydrogen or a pharmaceutically acceptable metal or amine cation, then D is the same as R; and when R is alkyl or phenyl, then D is selected from the group consisting of alkyl, phenyl and hydrogen; with the proviso that at least one of X and Y is cyano; or a pharmaceutically acceptable acid addition salt thereof
- in association with a pharmaceutical carrier.
- 19. A composition in accordance with claim 18 wherein the ##STR38## groups are located at the 2 and 6 positions; R is selected from the group consisting of hydrogen and a pharmaceutically acceptable metal or amine cation;
- X is hydrogen, Y is at the 4-position and is cyano.
- 20. A composition in accordance with claim 19 wherein the structure is ##STR39## or a pharmaceutically acceptable acid addition salt thereof.
- 21. A composition in accordance with claim 18 wherein the composition is suitable for administration orally, parenterally, or by inhalation.
- 22. A composition in accordance with claim 19 wherein the composition is suitable for administration orally, parenterally, or by inhalation.
- 23. A composition in accordance with claim 20 wherein the composition is suitable for administration orally, parenterally, or by inhalation.
- 24. A method for prophylactically treating bronchial asthma, allergic rhinitis, food allergy or urticaria in mammals in need of said treatment which comprises administering compound selected from the group consisting of ##STR40## wherein each ##STR41## group is located anywhere on the carbon ring with the proviso that one group cannot be ortho to the other group;
- R is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms, phenyl, and a pharmaceutically acceptable metal or amine cation;
- X and Y are the same or different and are selected from the group consisting of hydrogen, alkyl from one through four carbon atoms, phenyl, alkoxy from one through three carbon atoms, nitro, amino, trifluoromethyl, halogen, cyano, and ##STR42## wherein D is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms, and a pharmaceutically acceptable metal or amine cation with the proviso that when R is hydrogen or a pharmaceutically acceptable metal or amine cation, then D is the same as R; and when R is alkyl or phenyl, then D is selected from the group consisting of alkyl, phenyl, and hydrogen; with the proviso that at least one of X and Y is cyano; or a pharmaceutically acceptable acid addition salt thereof, in an amount effective to prevent the symptoms of said asthma, rhinitis, food allergy or urticaria, in association with a pharmaceutical carrier.
- 25. A method in accordance with claim 24 wherein the ##STR43## groups are located at the 2 and 6 positions; R is selected from the group consisting of hydrogen and a pharmaceutically acceptable metal or amine cation;
- X is hydrogen, Y is at the 4-position and is cyano.
- 26. A method in accordance with claim 25 wherein the chemical structure administered is ##STR44## or a pharmaceutically acceptable acid addition salt thereof.
- 27. A method in accordance with claim 24 wherein the administration is oral, parenteral, or by inhalation.
- 28. A method in accordance with claim 25 wherein the administration is oral, parenteral, or by inhalation.
- 29. A method in accordance with claim 26 wherein the administration is oral, parenteral, or by inhalation.
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of our copending application Ser. No. 563,919, filed on Mar. 31, 1975, issued as U.S. Pat. No. 3,963,660, which is a continuation-in-part application of our application Ser. No. 403,677, filed Oct. 4, 1973, and now abandoned.
It has now been discovered that novel compounds of Figure I are useful in the prophylactic treatment of sensitized humans and animals for allergy and all anaphylactic reactions of a reagin or non-reagin mediated nature. The compounds are formulated with pharmaceutical carriers for oral, parenteral, inhalation or rectal means of administration.
In accordance with this invention there are provided compounds represented by (I), and hereafter referred to as Group A: ##STR2## wherein each ##STR3## is located anywhere on the carbon ring with the proviso that one group cannot be ortho to the other group;
R is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms, phenyl, and a pharmaceutically acceptable metal or amine cation;
X and Y can be the same or different and are selected from the group consisting of hydrogen, alkyl from one through four carbon atoms, phenyl, alkoxy from one through three carbon atoms, nitro, amino, trifluoromethyl, halogen, cyano and ##STR4## wherein D is selected from the group consisting of hydrogen, alkyl from one through six carbon atoms and a pharmaceutically acceptable metal or amine cation with the proviso that when R is hydrogen or a pharmaceutically acceptable metal or amine cation, then D is the same as R, and when R is alkyl from one through six carbon atoms or phenyl, then D is alkyl from one through six carbon atoms, phenyl or hydrogen; and pharmaceutically acceptable acid addition salts thereof.
A preferred group of compounds, hereafter referred to as Group B, are where R is selected from the group consisting of hydrogen, alkyl of from one through four carbon atoms, and a pharmaceutically acceptable metal or amine cation;
X and Y are the same or different and are selected from the group consisting of hydrogen, alkyl of from one through four carbon atoms, phenyl, alkoxy of from one through three carbon atoms, nitro, trifluoromethyl, halogen, cyano, and ##STR5## wherein D is defined as in Group A, with the proviso that when D is alkyl, the upper carbon number limitation is four.
A more preferred group of compounds, hereinafter referred to as Group C, are compounds wherein the ##STR6## groups are located at the 2 and 6 positions or the 3 and 5 positions;
R is selected from the group consisting of hydrogen and a pharmaceutically acceptable metal or amine cation.
X and Y are as defined in Group B.
A still more preferred group of compounds, hereinafter referred to as Group D, are compounds wherein the location of ##STR7## and R are as defined as in Group C, X is hydrogen and Y is selected from the group consisting of hydrogen, alkyl of from one through four carbon atoms, alkoxy of from one through three carbon atoms, nitro, trifluoromethyl, halogen, cyano, and ##STR8## wherein D is defined as in Group B.
A further group of compounds, hereinafter referred to as Group E, are compounds wherein the location of ##STR9## R, X and Y are defined as in Group D with the proviso that Y is limited to the 4 position.
A still further group of compounds, hereinafter referred to as Group F, are compounds wherein R, X and Y are defined as in Group E and the location of the ##STR10## groups are at the 2 and 6 positions.
A further group of compounds hereinafter referred to as Group G are compounds wherein the location of the ##STR11## group, R, X and Y are defined as in Group F with the proviso that halogen is fluoro, chloro, and bromo.
A still further group of compounds are compounds of successive Groups D, E, F and G, with the proviso that the nucleus to which the ##STR12## and the X and Y groups are attached is ##STR13## and its pharmaceutically acceptable acid addition salts.
As employed in the above disclosure and throughout the specification, the term "halogen" includes fluoro, chloro, bromo and iodo. The term "alkyl" includes methyl, ethyl, propyl and isopropyl when limited to three carbon atoms, n-butyl and isomers thereof when limited to four carbon atoms, n-pentyl and n-hexyl and isomers thereof when limited to six carbon atoms. The term "pharmaceutically acceptable metal" includes alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium and other acceptable metals such as aluminum. The term "amine cation" includes all pharmaceutically acceptable cations from amines such as ammonia, tris-(hydroxymethyl)-aminomethane (THAM), D-threo-2-amino-1-p-nitrophenyl-1,3-propanediol, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, 2-amino-2-methyl-1,3-propanediol and 2,2-bis(hydroxymethyl)-2,2',2"-nitrolotriethanol and further amines including H.sub.2 NR', HNR'.sub.2, and NR'.sub.3, wherein R' is selected from the group consisting of alkyl from one to three carbon atoms, inclusive, and --CH.sub.2 CH.sub.2 OH.
Pharmaceutically acceptable acid addition salts refer to the salts which can be prepared at the nitrogen of the pyridine ring. Illustrative of these salts are hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, oxalic, cyclohexanesulfamic, salicylic, and the like.
The compounds of this invention can be prepared by methods known to the art. The appropriately substituted diaminopyridines (II) are suitable starting materials. These compounds are reacted with an alkyl oxalyl halide, preferably ethyl oxalyl chloride (IIIa), in a suitable solvent and base to form the dioxamate (IV). An alternative method of preparing the dioxamate is to react (II) with a dialkyl oxalate, preferably diethyl oxalate (IIIb) in neat solution or with an additional solvent, if necessary, at a temperature ranging from about 25.degree. C. to about reflux temperature of the system: ##STR14##
At this point of the synthetic pathway, the oxamate can be transesterified to other esters and/or converted to the diacid by hydrolysis and thence to the metal or amine salts by standard methods.
The N-oxide derivative of the pyridylyl dioxamic acid ester or salt can be readily prepared by oxidation of the diester with an oxidizing agent, such as m-chloroperoxybenzoid acid.
The appropriately X and Y substituted diaminopyridine starting materials are prepared by conventional substitution means well known in the art. These means depend somewhat upon the substituent itself, the placement of the substituent and the placement of the oxamic group.
The particular ##STR15## substituents can be prepared by converting the corresponding diamino or dinitro pyridinecarboxylic acid, for example, to the ester, amide, etc., by standard methods. This can be done prior to the preparation of the dioxamate from the substituted diamino starting material.
Illustrative examples of starting materials of (II) are below. ##STR16##
An additional route of preparing the starting materials, (II), for example, is by reacting a substituted dihalopyridine, for example, dichloropyridine (V) with ammonia under pressure and elevated temperature to produce the substituted diaminopyridine starting material (II) ##STR17##
Once starting material II is prepared, it is reacted with an alkyl oxalyl halide or dialkyl oxalate. When using an alkyl oxalyl halide, reaction is carried out in base and solvent at standard conditions. Examples of suitable solvents are dimethylformamide (DMF), dioxane, and tetrahydrofuran. Appropriate bases include triethylamine, N-methylmorpholine, dimethylpiperazine, and N-methylpiperidine. When the dialkyl oxalate is employed, the starting material II or its substituted analogue is heated together with the dialkyl oxalate or an additional solvent such as a xylene or diphenyl ether if desired, thereby forming the dioxamate. The temperature is from about 25.degree. C. to the reflux temperature of the system, preferably temperature between about 100.degree. C. and reflux temperature of the system.
The dioxamate is then readily converted to the dioxamic acid by using dilute base such as sodium hydroxide, potassium hydroxide or potassium carbonate at temperatures ranging from about 25.degree. to about 100.degree. C., followed by addition of acid. The alkaline metal salts of the oxamate may be soluble in aqueous medium or relatively insoluble. If soluble in aqueous medium, the pH is adjusted with acid and the resulting precipitate is collected. If the alkaline metal salt is insoluble in aqueous medium, the precipitate per se can be collected and then heated in aqueous acid to an appropriate temperature, collecting the mixture, and isolating the desired diacid. The acid can then be easily converted to the metal or amine salt by contacting the diacid with two equivalents of the desired amine or metal hydroxide and heating in a sufficient amount of water to effect solubilization. The crystalline salts can be precipitated by the addition of an organic solvent, for example, methanol.
An illustrative list of compounds of this invention are the dioxamic acids prepared from the starting materials of Table I by methods of this application, and can be considered as being made and stated under the title "Table II".
The dioxamic acids of Table II are converted to pharmaceutically acceptable salts, e.g., metal and amine cations, and particularly the tris(hydroxymethyl)methylammonium salt by standard methods.
The dioxamic acids of Table II are converted into compounds where R is alkyl of from one through six carbon atoms and phenyl by standard methods.
The compounds of Table IV are converted to pyridyl N-oxide oxamates by standard means.
The compounds of Table V are converted to pyridyl N-oxide dioxamic acids by standard means.
The dioxamic acids of Table VI are converted to pharmaceutically acceptable salts, e.g., metal and amine cations, and particularly the tris(hydroxymethyl)methylammonium salt by standard methods.
Tables II through VII are not rendered in the same manner as Table I for the purpose of brevity. However, the same scoping is intended.
US Referenced Citations (4)
Divisions (1)
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Number |
Date |
Country |
| Parent |
563919 |
Mar 1975 |
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Continuation in Parts (1)
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| Parent |
403677 |
Oct 1973 |
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Patent Grant
4038398
