Claims
- 1. A member of the class consisting of amido compounds of the formula ##SPC28## and pharmaceutically acceptable salts thereof; wherein R is hydrogen or methyl; R.sub.3 is phenyl, p-hydroxyphenyl; 2-thienyl and cyclohexa-1,4-dien-1-yl and R.sub.5 is a lower alkyl group of from 1 to 6 carbon atoms, cyclohexyl, benzyl, phenyl and halophenyl wherein halo represents chlorine, fluorine, bromine or iodo, X is hydrogen, chlorine or bromine; Y is hydrogen or bromine and n is two or three with the provisio that when n is three R.sub.5 is methyl.
- 2. A compound according to claim 1 which is N-[6-[p-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin and pharmaceutically-acceptable salts thereof.
- 3. A compound according to claim 1 which is N-[6-[p-(4-ethyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-ampicillin and pharmaceutically-acceptable salts thereof.
- 4. A compound according to claim 1 which is N-[6-[p-(4-n-propyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin and pharmaceutically-acceptable salts thereof.
- 5. A compound according to claim 1 which is N-[6-[p-[3-chloro-4-(4-methyl-1-piperazinyl)]phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin and pharmaceutically-acceptable salts thereof.
- 6. A compound according to claim 1 which is N-[6-[m-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-ampicillin and pharmaceutically-acceptable salts thereof.
- 7. A compound according to claim 1 which is N-[6-[p-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-amoxicillin and pharmaceutically-acceptable salts thereof.
- 8. A compound according to claim 1 which is N-[6-[p-(4-methyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-epicillin and pharmaceutically-acceptable salts thereof.
- 9. A compound according to claim 1 which is N-[6-[p-(4-benzyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinyl]-ampicillin and pharmaceutically-acceptable salts thereof.
- 10. A compound according to claim 1 which is N-[6-[p-(4-cyclohexyl-1-piperazinyl)phenyl]-1,2-dihydro-2-oxonicotinyl]ampicillin and pharmaceutically-acceptable salts thereof.
SUMMARY AND DETAILED DESCRIPTION
This application is a Continuation-in-Part of copending application, Ser. No. 434,763, filed Jan. 21, 1974 now abandoned.
The present invention relates to novel chemical compounds that are useful as pharmacological agents and to methods for their production. More particularly, the invention relates to novel organic amide compounds having the formulae ##SPC1##
The preferred compounds being those wherein R is hydrogen; R.sub.1 and R.sub.2 are ethyl or R.sub.1 R.sub.2 N taken together is 4-R.sub.5 -1-piperazino wherein R.sub.5 is a straight or branched lower alkyl group of from one to six carbon atoms or benzyl and R.sub.3 is phenyl or p-hydroxyphenyl. The most preferred compounds are those wherein the R.sub.1 R.sub.2 N group is m-diethylamino and p-(4-methyl-1-piperazino).
In accordance with the invention the foregoing amide compounds having the formula ##SPC2## and pharmaceutically acceptable salts thereof wherein R, R.sub.1, R.sub.2, R.sub.1 R.sub.2 N, R.sub.3, R.sub.4, X and Y are as previously defined are produced by reacting a compound of the formulae ##SPC3##
The reactants are normally employed in approximate equimolar quantities, although an excess of either (okonicotinic acid compound or amino acid compound) can be used if desired. The reaction can be carried out in any of a number of unreactive solvents. When using a silylated derivative for the reaction the solvent should be anhydrous and may include tertiary amides (such as N,N-dimethylacetamide, dimethylformamide, and N-methyl-2-pyrrolidinone), ethers (such as dioxane, tetrahydrofuran, and 1,2-dimethoxyethane), chlorinated hydrocarbons (such as chloroform and dichloromethane), and mixtures of these. In addition to any of these solvents, when using the penicillin and cephalosporin type compounds in the free acid or salt form, aqueous solutions may be used for acylation with an acid halide or mixed anhydride under normal Schotten-Baumann conditions. The duration and temperature of the reaction are not critical. Temperatures in the range from -30.degree. to +30.degree.C are commonly used for reaction times ranging from a few hours up to a day or more. The product may be isolated in any suitable way as the free acid or as a salt by appropriate adjustment of the pH.
The 6-[(substituted amino)phenyl]-1,2-dihydro-2-oxonicotinic acid compounds and their reactive derivatives which are required as starting materials in the foregoing process can be prepared according to any of a variety of methods as illustrated in greater detail hereinafter
A compound of the formula ##SPC5##
In addition, the fluoro atom may be activated for easier removal, especially if it is in the meta position by the presence of a nitro group.
Thus, a compound of the formula ##SPC8##
The nitro group is removed by catalytically reducing the nitro group to an amino group, then treating a salt of the resultant amine with sodium nitrite followed by water.
A method for preparing halo substituted starting materials relies on reacting a compound of the formula ##SPC11##
The compound of the formula ##SPC13##
The above compounds in turn are reacted with 2-cyanoacetamide or N-methyl-2-cyanoacetamide in the presence of piperidine acetate to give the following nitrile ##SPC15##
The above nitrile wherein X.sub.3 is hydrogen and Y is hydrogen or bromine may also be prepared by reacting a compound of the formula ##SPC16##
The nitriles prepared by the above procedures are converted to the desired 6-[(substituted amino)phenyl]-1,2-dihydro-2-oxonicotinic acid by conversion of the cyano group to a carboxyl group utilizing an aqueous solution of a strong base.
The 6-[(substituted amino)phenyl]-1,2-dihydro-2-oxonicotinic acid may be converted to its acid chloride utilizing thionyl chloride, its mixed anhydride utilizing ethyl chloroformate, its pentachlorophenyl ester by esterification with pentachlorophenol and its imidazolide by reacting the acid with 1,1'-carbonyldiimidazole.
The silylated amino acid starting materials can be prepared by reacting an amino acid of the formulae ##SPC17##
Also in accordance with the invention, the compounds of this invention may be produced by reacting a free amino acid of the formulae ##SPC18##
Some examples of reactive derivatives of the D-N-(1,2-dihydro-2-oxonicotinyl)-2-substituted glycine compounds suitable for the reaction are the acid halides, the imidazolide, mixed anhydrides (especially those formed from an alkyl chloroformate such as ethyl chloroformate and isobutyl chloroformate), and activated esters such as the pentachlorophenyl ester. Since racemization is more likely with the acid halide, the other forms are generally preferred. The reactants are normally employed in approximate equimolar quantities, although an excess of either (oxonicotinic acid compound or amino acid compound) can be used if desired. The reaction can be carried out in any of a number of unreactive solvents. When using the silylated derivative for the reaction the solvent should be anhydrous and may include tertiary amides (such as N,N-dimethylacetamide, dimethylformamide, and N-methyl-2-pyrrolidinone), ethers (such as dioxane, tetrahydrofuran, and 1,2-dimethoxyethane), chlorinated hydrocarbons (such as chloroform and dichloromethane), and mixtures of these. In addition to any of these solvents, 6-aminopenicillanic acid and 7-amino-3R.sub.4 CH.sub.2 ceph-3-em-4 carboxylic acid may be reacted with an acid chloride or mixed anhydride in the free acid or salt form using aqueous solutions under normal Schotten-Baumann conditions. The duration and temperature of the reaction are not critical. Temperatures in the range from -30.degree. to +30.degree. C. are commonly used for reaction times ranging from a few hours up to a day or more. The product may be isolated in any suitable way as the free acid or as a salt by appropriate adjustment of the pH.
The N-[6-[(substituted amino)phenyl]-1,2-dihydro-2-oxonicotinyl]-2substituted glycines and their reactive derivatives which are required as starting materials in the foregoing process can be prepared by methods illustrated in greater detail hereinafter.
The desired N-[6-[(substituted amino)phenyl]-1,2-dihydro-2-oxonicotinyl)-2-substituted glycine may be prepared by reacting the corresponding 6-[(substituted amino)phenyl]-1,2-dihydro-2-oxonicotinyl chloride with the appropriate D-N-(trimethylsilyl)-2-substituted glycine, trimethylsilyl ester in the presence of triethylamine followed by hydrolysis.
The silylated amino acid starting materials can be prepared by reacting an anhydrous compound of the formulae ##SPC20##
Compounds of this invention having the formulae ##SPC21##
While chemical reduction procedures may be employed, a catalytic procedure is preferred. Of the numerous noble metal catalysts that may be used, palladium on a barium sulfate (about 20 percent palladium) support is preferred. The ratio of catalyst to nitro compound is not critical and may vary from about 1 percent to about 50 percent. Standard hydrogenation solvents may be employed such as tetrahydrofuran, water, ethanol or mixtures thereof. The reaction is generally conducted at temperatures of from about 0.degree. to 45.degree., preferrably at room temperature and at pressures of from about atmospheric pressure to pressure of over 100 pounds per square inch, preferably 50 pounds per square inch. The reaction is carried out until hydrogen uptake is complete.
The nitro containing starting materials are prepared by the earlier described methods.
Lastly, compounds of the formula ##SPC23##
A polar solvent which is inert to the mercuric perchlorate, such as water, is generally employed. Temperatures of from room temperature to 80.degree. and times of from fifteen minutes to twenty-four hours are generally used with a shorter time period being used when carrying out the reaction at a higher temperature.
The necessary starting material of the formula ##SPC25##
The free acids of the invention form carboxylate salts with any of a variety of inorganic and organic bases. Pharmaceutically-acceptable carboxylate salts are formed by reacting the free acids with such bases as sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium 2-ethylhexanoate, potassium hydroxide, potassium carbonate, potassium 2-ethylhexanoate, calcium hydroxide, ethylamine, 2-hydroxyethylamine, and procaine. Preferred carboxylate salt forms are the alkali metal salts. The carboxylate salts are converted to the free acids by acidification. The free acids and their carboxylate salts usually differ somewhat in solubility properties but, in general, are otherwise equivalent for the purposes of the invention. In addition, the compounds of the invention can exist in the form of an acid-addition salt. Pharmaceutically-acceptable salts are formed by reaction of the free base or a carboxylate salt with any of a number of inorganic and organic acids, including hydrochloric, sulfuric, nitric, phosphoric, acetic, benzoic, citric, maleic, malic, tartaric, succinic, gluconic, ascorbic, sulfamic, pamoic, methanesulfonic, benzenesulfonic, and related acids.
The compounds of the invention can exist in anhydrous form, as well as in solvated, including hydrated, forms. In general, the hydrated forms and the solvated forms with pharmaceutically-acceptable solvents are equivalent to the anhydrous or unsolvated forms for the purposes of the invention.
The compounds of the invention are new chemical compounds that are used as pharmacological agents and especially as broad spectrum antibacterial agents. They are active in vitro against strains of both gram-positive and gram-negative bacteria. The activity of the compounds is illustrated by the results shown in the table for the following preferred compounds.
Thus, the compounds of this invention and their non-toxic pharmaceutically-acceptable salts are highly useful as broad spectrum antibiotics in mammals when administered in amounts ranging from about 5 mg. to about 100 mg. per kg. of body weight per day. A preferred dosage regimen for optimum results would be from about 10 mg. to about 50 mg. per kg. of body weight per day, and such dosage units are employed that a total of from about 700 mg. to about 3,500 mg. of active ingredient for a subject of about 70 kg. body weight are administered in a 24 hour period.
While the compounds of this invention may be administered orally in the form of tablets, capsules, syrups, etc., (for treating infections of the alimentary tract) the preferred route of administration is parenterally for treating systemic infections.
In the present invention the term "pharmaceutical composition" is defined as a finished pharmaceutical that may be administered directly or a pharmaceutical which water is added to prior to use in order to form a satisfactory product for administration. The pharmaceutical compositions to be employed parenterally are generally supplied in a dry, sterile form having about 50 mg. to about 1000 mg. of active compound per vial. The vial may also contain other active ingredients, buffers, salts, etc. The sterile material in the vial is dissolved in water for injection at the time of use.
The invention is illustrated by the following examples.
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
|
3433784 |
Long et al. |
Mar 1969 |
|
|
3864329 |
Tobiki et al. |
Feb 1975 |
|
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 799,202 |
Jan 1973 |
BE |
| 7,303,660 |
Jan 1973 |
NL |
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
434763 |
Jan 1974 |
|
Patent Grant
3954734
