Claims
- 1. A compound having the formula ##STR53## wherein R.sub.1 and R.sub.2 are each independently hydrogen or alkyl of 1 to 4 carbon atoms, or R.sub.1 and R.sub.2 together with the carbon atom to which they are attached form a cycloalkyl ring;
- R.sub.3 is hydrogen or alkyl;
- R.sub.4 is hydrogen or alkyl, and R.sub.5 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, ##STR54## or together R.sub.4 and R.sub.5 are .dbd.CH-Y.sub.7 ; wherein Y.sub.1 is hydrogen, alkyl, phenyl, substituted phenyl, methylcarbonyl, trifluoromethylcarbonyl, phenylcarbonyl, (substituted phenyl)carbonyl, carboxymethyl, methylsulfonyl, phenylsulfonyl, (substituted phenyl)sulfonyl, aminocarbonyl, aminocarbonylamino, aminoethyl, hydroxy, alkoxy, amino, alkyamino, dialkyamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, 1-pyrrolidinyl or 1-piperidinyl; Y.sub.2 is hydrogen, alkyl, phenyl, substituted phenyl, alkoxy, formyl, carbonyl, aminocarbonyl, aminothiocarbonyl, methylaminocarbonyl, methylaminothiocarbonyl, trifluoromethyl, phenylmethyl, (substituted phenyl)methyl, phenyloxymethyl, (substituted phenyl)oxymethyl, cyanomethyl, hydroxmethyl, alkoxymethyl, aminomethyl, methylcarbonylaminomethyl, aminocarbonylaminomethyl, methylsulfonylaminomethyl, carboxymethyl, aminocarbonylmethyl, alkoxycarbonylmethyl, hydroxyaminocarbonylmethyl, or azidomethyl;
- Y.sub.3 is amino, alkyl, alkylthio, carboxythio, alkoxycarbonylthio or aminocarbonylthio;
- Y.sub.4 is alkyl, amino, hydroxyamino, alkoxyamino, methylcarbonylamino, or phenylcarbonylamino;
- Y.sub.5 is hydrogen or alkyl;
- Y.sub.6 is hydrogen, alkyl, carboxymethyl, or aminocarbonylmethyl; and
- Y.sub.7 is phenyl or substituted phenyl;
- wherein
- the terms "alkyl" and "alkoxy" refer to groups having 1 to 10 carbon atoms;
- the term "cycloalkyl" refers to cycloalkyl groups having 3, 4, 5, 6 or 7 carbon atoms;
- the term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or carboxyl groups.
- 2. A compound in accordance with claim 1 wherein R.sub.3 and R.sub.4 are each hydrogen.
- 3. A compound in accordance with claim 2 wherein R.sub.1 and R.sub.2 are each methyl.
- 4. A compound in accordance with claim 1 wherein R.sub.1 and R.sub.2 are each methyl.
BACKGROUND OF THE INVENTION
This is a division of application Ser. No. 658,849, filed Oct. 9, 1984, now U.S. Pat. No. 4,610,824, issued Sept. 9, 1986.
U.S. Pat. No. 4,252,802, issued Feb. 24, 1981, describes cephalosporin antibiotics having a 7-acylamino group of the formula ##STR3## wherein R.sub.a and R.sub.b are each independently hydrogen or methyl, R.sub.c is hydrogen, alkyl, phenyl or alkyl; and n is 1, 2, 3, or 4. The cephalosporins described by the reference are antibacterial agents.
United Kingdom patent application No. 2071650, published Sept 23, 1981, describes monocyclic .beta.-lactam antibiotics having a sulfonic acid salt substituent in the 1-position of the .beta.-lactam nucleus and an acylamino substituent in the 3-position of the .beta.-lactam nucleus.
Compounds having the formula ##STR4## and pharmaceutically acceptable salts thereof, have antibacterial activity. In formula I, and throughout the specification, the symbols are as defined below.
Listed below are definitions of various terms used to describe .beta.-lactams of this invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as a part of a larger group.
The terms "alkyl" and "alkoxy" refer to both straight and branched chain groups. Those groups having 1 to 10 carbon atoms are preferred.
The term "cycloalkyl" refers to cycloalkyl groups having 3, 4, 5, 6 or 7 carbon atoms.
The term "substituted alkyl" refers to alkyl groups substituted with one, or more, azido, amino (--NH.sub.2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy, phenyloxy, (substituted phenyl)oxy, R.sub.x -oxy, mercapto, alkylthio, phenylthio, (substituted phenyl)thio, alkylsulfinyl, or alkylsulfonyl groups.
The terms "alkanoyl", "alkenyl", and "alkynyl" refer both to straight and branched chain groups. Those groups having 2 to 10 carbon atoms are preferred.
The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine.
The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino (--NH.sub.2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1 to 4 carbon atoms), alkoxy (of 1 to 4 carbon atoms), or carboxyl groups.
The expression "a 4, 5, 6, or 7-membered heterocycle" (referred to as "R.sub.x ") refers to substituted and unsubstituted, aromatic and non-aromatic groups containing one or more nitrogen, oxygen or sulfur atoms. Exemplary substituents are oxo (.dbd.0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl of 1 to 4 carbons, alkoxy of 1 to 4 carbons, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylideneamino ##STR11## and substituted alkyl groups (wherein the alkyl group has 1 to 4 carbons). One type of "4,5,6 or 7-membered heterocycle" is the "heteroaryl" group. The term "heteroaryl" refers to those 4,5,6 or 7-membered heterocycles which are aromatic. Exemplary heteroaryl groups are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl, triazinyl, and tetrazolyl. Exemplary nonaromatic heterocycles (i.e., fully or partially saturated heterocyclic groups) are substituted and unsubstituted azetinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihyrothiazolyl and hexahydroazepinyl. Exemplary of the substituted 4,5,6 or 7-membered heterocycles are 1-alkyl-3-azetinyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-benzylimino-2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl (or substituted phenyl)-2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo-1-imidazolidinyl, 3-(2-aminoethyl)-2-oxo-1-imidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3-[(alkoxycarbonyl)amino]-2-oxo-1-imidazolidinyl, 3-[2-[ (alkoxycarbonyl)-amino]ethyl]-2-oxo-1-imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydrofuranyl, 2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl, and 4-phenyl-2,3-dioxo-1-piperazinyl.
The term "substituted amino" refers to a group having the formula --NZ.sub.1 Z.sub.2 wherein Z.sub.1 is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl, and Z.sub.2 is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, hydroxy, cyano, alkoxy, phenylalkoxy, or amino (--NH.sub.2).
The terms "salt" and "salts", when used to describe the .beta.-lactams of this invention, refer to basic salts formed with inorganic and organic bases. Such salts include ammonium salts, alkali metal salts like sodium and potassium salts, alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, e.g., dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine salts, salts with amino acids like arginine, lysine and the like. Pharmaceutically acceptable salts are preferred.
Salts of an azetidinone-1-sulfonic acid are formed by reacting the free acid form of the sulfonate with one or more equivalents of an appropriate base providing the desired cation in water or in a solvent mixture containing water. The salt is isolated by removal of solvent in vacuo, or, in the case of water, by lyophilization. The free acid of the sulfonate is formed by treating an azetidinone-1-sulfonic acid salt with an insoluble sulfonic acid such as a cation exchange resin in the hydrogen form (e.g. a polystyrene sulfonic acid resin like Dowex 50).
Alternatively, salts may be formed by cation interchange. A salt of a .beta.-lactam compound soluble in organic solvent is combined with a salt containing the desired cation, also soluble in the same solvent system. The solvent system is chosen so that the formed salt is much less soluble than either of the added salts and thus precipitates from the medium and is collected.
The .beta.-lactams of formula I, and pharmaceutically acceptable salts thereof, have activity against gram-negative organisms. The compounds of this invention can be used as agents to combat bacterial infections (including urinary tract infections and respiratory infections) in mammalian species, such as domesticated animals (e.g., dogs, cats, cows, horses, and the like) and humans.
For combating bacterial infections in mammals, a compound of this invention can be administered to a mammal in need thereof in an amount of about 1.4 mg/kg/day to about 350 mg/kg/day, preferably about 14 mg/kg/day to about 100 mg/kg/day. All modes of administration which have been used in the past to deliver penicillins and cephalosporins to the site of the infection are also contemplated for use with .beta.-lactams of this invention. Such methods of administration include oral, intravenous, intramuscular, and as a suppository.
The compounds of this invention can be prepared using a variety of procedures. One method utilizes as a starting material the known monocyclic .beta.-lactam antibiotics having the formula ##STR12## and salts thereof. Compounds of formula II are described in the literature; see, for example, United Kingdom patent application No. 2071650, published Sept. 23, 1981. Reaction of a compound of formula II with a hydrazide having the formula ##STR13## or a salt thereof, in the presence of a coupling agent, yields the desired products of formula I. If the starting material of formula II is an inner salt (--SO.sub.3 H in the 1-position), it is preferable to first treat the compound with one equivalent of a base (e.g., tributylamine or trioctylamine) to form the salt of the sulfonic acid. Preferably, the reaction is run in the presence of a substance capable of forming a reactive intermediate in situ, such as N-hydroxybenzotriazole and/or a catalyst such as dimethylaminopyridine, using a coupling agent such as dicyclohexylcarbodiimide. Exemplary solvents which can be used for the reaction are dimethylformamide, tetrahydrofuran, dichloromethane or mixtures thereof.
Alternatively, the comounds of this invention can be prepared by acylating a compound having the formula ##STR14## or a salt thereof, with a carboxylic acid having the formula ##STR15## Well-known acylation procedures can be used for the reaction. Exemplary techniques include the use of a carboxylic acid of formula V or a corresponding carboxylic acid halide or carboxylic acid anhydride. The reaction with a carboxylic acid proceeds most readily in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming a reactive intermediate is situ such as N--hydroxybenzotriazole or N-hydroxysuccinimide.
Compounds of formula V are novel compounds, and as such, form an integral part of this invention. They can be prepared by reacting (2-amino-4-thiazolyl)glyoxylic acid, which has the formula ##STR16## with a compound having the formula ##STR17## or a salt thereof. The reaction proceeds best in water and in mixtures of water and organic solvents, such as methanol, ethanol, tetrahydrofuran or dioxane.
Reactants of formula VII can be prepared by reacting a compound having the formula ##STR18## with hydrazide having the formula ##STR19## to yield the corresponding compound having the formula ##STR20## If an acid reactant of formula VIII is used, a suitable coupling agent, such as dicyclohexylcarbodiimide, should be present. Alternatiely, an acid of formula VIII can be activated by formation of mixed anhydride. If an acid halide derivative of formula IX is used, a suitable base should be present. The hydrazides of formula X can be deprotected using standard methodology to yeild the desired reactants of formula VII. Exemplary deprotecting agents are hydrazine and methylhydrazine.
Hydrazine derivatives of formula II, and methods for their preparation, are well known in the literature. Reviews of their synthesis can be found in Smith, "The Chemistry of Open-Chain Organic Nitrogen Compounds", Vols. I and II, Benjamin, Inc., New York, Amsterdam, 1966; Muller, "Methoden der Organischen Chemie" (Houben-Weyl), Vol. 10/2, Georg Thieme Verlag Stuttgart, 1967; Sandler and Karo, "Organic Functional Group Preparations", Vol. 1, Academic Press, New York, 1968; and Timberlake and Stowell, "The Chemistry of Hydrazo, Azo, and Azoxy Groups", ed. S. Patai, part 1, Interscience, New York, 1975.
Reactants of formula IV are described in United Kingdom patent application No. 2071650, published Sept. 23, 1981.
The compounds of this invention (both the pharmaceutical products of formula I and the intermediates of formula V) contain an imino group ##STR21## and can exist as syn or anti isomers or as mixtures of both. All of these isomeric forms are within the scope of this invention. The syn isomers are preferred, however, because that isomeric form has superior activity.
Whether the pharmaceutical products of formula I are prepared from a starting compound of formula II or from a starting compound of formula V, the isomerism of the starting material will determine the isomerism of the product. In preparing a compound of formula V, the ratio of syn/anti will depend on the reaction conditions. If the reaction of compounds of formula VI and VII is run at room temperature, the ratio of syn/anti will be favorable to the obtaining of the syn isomer. Lowering the reaction temperature increases the ratio of syn/anti, but slows the reaction. Raising the reaction temperature decreases the ratio of syn/anti, but speeds the reaction. Separation of the syn and anti isomers can be accomplished using fractional crystallization.
Alternative methodology for preparing the compounds of this invention will be apparent to the practitioner of this ivention. For example, those compounds of formula I wherein R.sub.4 and R.sub.5 are .dbd.CH--Y.sub.7 can be prepared by reacting the corresponding compound of formula I wherein R.sub.4 and R.sub.5 are each hydrogen with the appropriate benzaldehyde.
US Referenced Citations (3)
| Number |
Name |
Date |
Kind |
|
4252802 |
Denzel et al. |
Feb 1981 |
|
|
4487937 |
Heymes |
Dec 1984 |
|
|
4525473 |
Aburaki et al. |
Jun 1985 |
|
Foreign Referenced Citations (2)
| Number |
Date |
Country |
| 0162394 |
May 1985 |
EPX |
| 2071650 |
Sep 1981 |
GBX |
Divisions (1)
|
Number |
Date |
Country |
| Parent |
658849 |
Oct 1984 |
|
Patent Grant
4680409
