The present invention relates to a cephem prodrug having formula III or formula IV:

The present invention relates to novel cephalosporin antibiotics and their methods of production and use, as well as prodrugs thereof. These compounds exhibit antibiotic activity against a wide spectrum of organisms, including organisms which are resistant to conventional xcex2-lactam antibiotics.
The following review of the background of the invention is merely provided to aid in the understanding of the present invention and neither it nor any of the references cited within it are admitted to be prior art to the present invention.
Over the past three decades a large variety of antibiotics has become available for clinical use. One class of antibiotics which has seen remarkable growth are the cephalosporins, over 70 of which have entered clinical use for the treatment of bacterial infections in mammals since 1965. The cephalosporins exhibit their antibacterial activity by inhibiting bacterial peptidoglycan biosynthesis, and have been extremely effective in treating a wide variety of bacterial infections. Cephalosporins that are said to have antibacterial activity are described in U.S. Pat. No. 3,992,377 and U.S. Pat. No. 4,256,739.
Unfortunately, the wide-spread and indiscriminant use of these antibiotics has led to a rapid increase in the number of bacterial strains which are resistant to these compounds. Most importantly, this resistance has emerged among clinically important microorganisms which threaten to limit the utility of presently available cephalosporin antibiotics. In particular, resistant strains of Salmonella, S. pneumonœ, Enterobacteriaceoe, Staphylococcus aureus, and Pseudomonas have emerged which threaten to undo many of the strides made in reducing mortality and morbidity from bacterial infections.
Bacterial resistance to cephalosporins follows three major pathways: (a) the development of xcex2-lactamases capable of inactivating the xcex2-lactam ring of the cephalosporin; (b) decreased cephalosporin penetration into the bacteria due to changes in bacterial cell wall composition; and (c) poor binding to penicillin-binding proteins (PBPs). The latter pathway is especially important, as the binding of xcex2-lactams to PBPs is essential for inhibiting bacterial cell-wall biosynthesis. Certain Gram-positive bacteria, namely methicillin-resistant Staphylococcus aureus (xe2x80x9cMRSAxe2x80x9d) and Enterococci are highly resistant to xcex2-lactam antibiotics. Resistance in MRSA is due to the presence of high levels of an unusual PBP, PBP2a, which is insensitive, or binds poorly, to xcex2-lactam antibiotics. The activity of xcex2-lactam antibiotics against PBP2a-containing organisms has been shown to correlate well with the binding affinity of the antibiotic to PBP2a. Currently, the glycopeptides vancomycin and teicoplanin are primarily used for MRSA bacteremia. The quinolone antibacterials and some carbapenems, such as imipenem, have been reported to be active against a few MRSA strains, but their use is restricted due to emerging resistant MRSA strains.
Experimental compounds which may possess utility as anti-MRSA or anti-enterococcal bactericides include the glycylcyclines (see, e.g., P.-E. Sum et al., J. Med. Chem., 37, (1994)), FK-037 (see, e.g., H. Ohki et al., J. Antibiotics, 46:359-361 (1993)), RP-59,500 (see, e.g., S. K. Spangler et al., Antimicro. Agents Chemother., 36:856-9 (1992)), the everninomycin complex (see, e.g., W. E. Sanders et al., Antimicro. Agents Chemother., 6: 232-8 (1974)), the 2-(biaryl)carbapenems (see, e.g., U.S. Pat. No. 5,025,006), 3-(benzothiazolylthio)cephems (see, e.g., EP Application No. 527686), 3-(thiazolylthio)carbacephems (see, e.g., R. J. Ternansky et al., J. Med. Chem., 36:1971 (1993) and U.S. Pat. No. 5,077,287) and arbekacin (S. Kondo, et al. J. Antibiotics 46:531 (1993).
Recent advances in the compounds, compositions and methods useful for treating infections in mammals arising from xcex2-lactam antibiotic resistant bacteria are described in commonly owned International Application No. PCT/US95/03976 and U.S. patent applications Ser. No. 08/222,262, filed Apr. 1, 1994; Ser. No. 08/369,798, filed Jan. 6, 1995; Ser. Nos. 08/413,713, 08/413,714, 08/415,065, 08/413,712, 08/415,064, and Ser. No. 08/415,069, all of which were filed on Mar. 29, 1995; Ser. No. 08/455,969, filed May 31, 1995; Ser. No. 08/457,673, filed Jun. 1, 1995; Ser. Nos. 08/940,508 and 08/937,812, both of which were filed Sep. 29, 1997; Ser. Nos. 08/730,041, 08/730,039, 08/728,232, 08/430,042, 08/728,233, and 08/730,040, all of which were filed Oct. 1, 1996; and Ser. No. 08/842,915, filed Apr. 17, 1997; all of which are incorporated herein by reference in their entirety, including any drawings.
The present invention includes compounds, compositions and methods effective to treat infections in mammals arising from xcex2-lactam antibiotic resistant bacteria. Preferred compounds will have a minimum inhibitory concentration (MIC) that is less that 50%, more preferably less than 10%, and most preferably less than 1% of the MIC of cefotaxime or imipenem for a beta-lactam resistant organism, preferably a methicillin-resistant Staphylococcal organism. Other preferred compounds will be able to prevent or reduce mortality in mice infected with the beta-lactam resistant organism to a greater extent than cefotaxime or imipenem.
Compounds from the class of 7-acylamino-3-heteroarylthio-3-cephem carboxylic acids of this invention have higher chemical reactivity and lower stability towards chemical or enzymatic decomposition than other cephalosporin compounds known in the art. Without wishing to be bound by any particular theory of operation of the invention, it is believed that this is due to an unusual type of substitution at the 3-position of the cephalosporin system. One aspect of the present invention features certain compounds from the class of 7-acylamino-3-heteroarylthio-3-cephem carboxylic acids which display an unexpected advantage over other compounds of this class, by virtue of lowered susceptibility to decomposition by enzymes present in mammalian serum. Compounds having this property are described below, and data is presented showing their improved stability in mammalian serum. In addition to this increased stability, there is also an improvement in pharmacokinetic parameters of such compounds and especially a lowered clearance of such compounds from the body. Pharmacological data demonstrating this lowered clearance is shown below, as well as improved efficacy in an animal model of infection due to this lowered clearance. One aspect of the present invention features certain compounds from the class of 7-acylamino-3-heteroarylthio-3-cephem carboxylic, acids which combine the above mentioned improved characteristics of increased stability in mammalian serum and lowered clearance with low binding to human serum proteins.
In one aspect the invention features compounds of Formula I or II:
or a pharmaceutically acceptable salt thereof, where
R1 is selected from the group consisting of optionally substituted aryl and optionally substituted heterocycle,
where the heterocycle is selected from the group consisting of pyridyl, thiadiazolyl, and thiazolyl; and
where the aryl and heterocycle are each independently and optionally substituted with substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, and carboxamido;
R2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted aralkyl, and trialkylsilyl;
where the alkyl, alkenyl, and aryl are each independently and optionally substituted with substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, and carboxamido;
R11 is selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted amino,
where the alkyl, alkoxy, and amino are each independently and optionally substituted with substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, and carboxamido;
alk1 and alk2 are alkylene groups;
p is 0 or 1;
R99 is selected from the group consisting of NH, sulfur, SO, and SO2;
q is 0 or 1;
r is 0 or 1;
R12 is selected from the group consisting of xe2x80x94NR21R22, xe2x80x94NR23xe2x80x94C(xe2x95x90NR24)xe2x80x94NR25R26, xe2x80x94C(xe2x95x90NR27)xe2x80x94NR28R29, and xe2x80x94NR30xe2x80x94CH(xe2x95x90NR31)
where R21xe2x80x94R31 are each independently and optionally selected from the group consisting of hydrogen and alkyl;
A, B, D, L, E, G, and J are each independently nitrogen or carbon,
where the specific juxtaposition of groups A, B, D, and L forms a heterocyclic group selected from the group consisting of
and where the specific juxtaposition of groups E, G, and J forms a heterocyclic group selected from the group consisting of
The specific juxtaposition of groups A, B, D, and L or E, G, and J may also form a heterocyclic group, which when connected to the sulfur linkage forms a group as shown below.
It is understood that a ring of a compound of the invention may be substituted by two specific unidentical substituents, each of which is described by the generic formula [(alk1)p(R99)q(alk2)rR12], as defined herein. Similarly, a ring of a compound of the invention may be substituted by two or three specific unidentical substituents, each of which is described by the generic formula R11, as defined herein.
In preferred embodiments, R1 in formula I or II is an optionally substituted heterocycle. This heterocycle may be optionally substituted with one or more substituents selected from the group consisting of halogen and amino. More preferably, R1 is selected from the group consisting of 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl, and 2-aminopyrid-6-yl.
In these and other preferred embodiments, alk1 and alk2 in the above structures are each independently selected from the group consisting of methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), propylene (xe2x80x94CH2CH2CH2xe2x80x94), and butylene (xe2x80x94CH2CH2CH2CH2xe2x80x94). Furthermore, R99 is sulfur or NH. In more preferred embodiments, R11 is selected from the group consisting of hydrogen, methyl, methoxy, hydroxy, NH2, and chloro.
Preferably, R21-R23 are each independently and optionally selected from the group consisting of hydrogen and methyl. R12 is preferably selected from the group consisting of xe2x80x94NH2, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2, xe2x80x94C(xe2x95x90NH)xe2x80x94NH2, and xe2x80x94NHCH(xe2x95x90NH).
In preferred embodiments, the specific juxtaposition of groups A, B, D, and L forms
Furthermore, the specific juxtaposition of groups E, G, and J preferably forms
In these and other preferred embodiments, the invention features compounds of formula I or II, where the compound is selected from the group consisting of
Cmpd 1. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxylamino)acetamido-3-(2-aminoethylthio-1,3,4-thiadiazol-5-ylthio)-3-cephem-4-carboxylic acid,
Cmpd 2. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxylamino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-methyl-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 3. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-amino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 4. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-1,3-thiazol-2-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 5. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-methoxy-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 6. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyridazin-6-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 7. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyridazin-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 8. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyrimidin-4-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 9. (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)-pyridazin-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 10. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(2-aminoethylthiomethyl-1,3,4-thiadiazol-5-ylthio)-3-cephem-4-carboxylic acid,
Cmpd 11. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-aminoethylthio-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 12. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)-1,2,4-thiadiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 13. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 14. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 15. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthlomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 16. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-aminoethylamino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 17. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 18. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 19. (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)-acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 20. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 21. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 22. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-(2-aminoethylthio-1,3,4-thiadiazol-5-ylthio)-3-cephem-4-carboxylic acid,
Cmpd 23. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 24. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 25. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-guanidinoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 26. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxylamino)acetamido]-3-[4-(2-guanidinoethylthiomethyl)-2-amino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 27. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 28. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 29. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-chloro-4-(2-aminoethylthiomethyl)-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid.
The structures of these compounds are shown below in Section II.
In more preferred embodiments, the compound of formula I or II is selected from the group consisting of
Cmpd 3. (7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-amino-1,3-thiazol]-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 13. (7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 14. (7R)-7[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 15. (7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 17. (7R)-7[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 20. (7R)-7[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 23. (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 25. (7R)-7[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-guanidinoethylthlomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid, and
Cmpd 27. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid.
In even more preferred embodiments, the compound of formula I or II is selected from the group consisting of
Cmpd 3. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-amino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 13. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 17. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid,
Cmpd 21. (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid, and
Cmpd 27. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid.
It is understood that the above-named compounds may be synthesized, purified, and used in their neutral form, as the above names suggest, or as pharmaceutically acceptable salts. The pharmaceutically acceptable salt comprises the above compounds in their charged form, either as cations or anions, along with a counterion. Preferred pharmaceutically acceptable salts include (1) inorganic salts such as sodium, potassium, chloride, bromide, iodide, nitrate, phosphate or sulfate; (2) carboxylate salts such as acetate, propionate, butyrate, maleate, or fumarate; (3) alkylsulfonates such as methanesulfonate, ethanesulfonate, 2-hydroxyethylsulfonate, n-propylsulfonate or isopropylsulfonate; and (4) hydroxycarboxylates such as lactate, malate, and citrate. Generally, pharmaceutically acceptable salts may be obtained by reacting any one of the compounds of the invention with an organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable salts may also be obtained by reacting any one of the compounds of the invention with an organic or inorganic base, such as benzathene, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procain, and the hydroxide, alkoxide, carbonate, bicarbonate, sulfate, bisulfate, amide, alkylamide, or dialkylamide salts of the following metal cations: lithium, sodium, potassium, magnesium, calcium, aluminum, and zinc.
As explained herein, the compounds of the invention have biological activity. The invention features a compound of formula I or II which is active against methicillin-resistant Staphylococci, as demonstrated by a lower minimum inhibitory concentration than methicillin, where the bacteria are selected from the group consisting of S. aureus Col (MethR)(lacxe2x88x92), S. aureus 76 (MethR)(lac+), S. aureus ATCC 33593 (MethR), S. aureus Spain #356 (MethR), and S. haemolyticus 05 (MethR).
In another embodiment, the present invention provides for compositions comprising an amount of a compound of formula I or II effective to treat bacterial infections in mammals arising from bacteria resistant to xcex2-lactam antibiotics.
In still another embodiment, the present invention includes methods for treating a bacterial infection in a mammal arising from bacteria resistant to xcex2-lactam antibiotics, or a, mammal suffering from a methicillin-resistant Staphylococcal bacterial infection, comprising administering to such mammal a therapeutically effective amount of a compound of formula I or II. Of course, the compounds of the present invention also have utility in compositions and methods to treat mammals infected with bacteria that are sensitive to conventional xcex2-lactam antibiotics. Thus, the invention also features an antibacterial composition for treating a methicillin-resistant Staphylococcal bacterial infection, comprising a therapeutically effective amount of a compound of formula I or II in a pharmaceutically acceptable carrier or diluent.
In another aspect, the invention features a method of synthesizing a compound of formula I or II, comprising the step of combining a first reactant and a second reactant under conditions that are suitable for the synthesis, where the first reactant is a compound of formula
where
R1 is selected from the group consisting of optionally substituted aryl and optionally substituted heterocycle,
where the heterocycle is selected from the group consisting of pyridyl, thiadiazolyl, and thiazolyl; and
where the aryl and heterocycle are each independently and optionally substituted with substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, and carboxamido;
R2 is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted aralkyl, and trialkylsilyl;
where the alkyl, alkenyl, and aryl are each independently and optionally substituted with substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, carboxyl; oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, and carboxamido;
Rxe2x80x32 is selected from the group consisting of p-toluenesulfonate, methanesulfonate, trifluoromethanesulfonate, fluorosulfonate, chloro, bromo, and (Rxe2x80x32O)2POxe2x80x94,
Rxe2x80x32 is selected from the group consisting of hydrogen and alkyl;
R4 is a protecting group selected from the group consisting of benzyl, p-nitrobenzyl, o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, xcex2-(trimethylsilyl)ethyl, benzyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, benzhydryl, and 3,3-dimethylallyl;
the second reactant is a compound of formula MSR3, where
M is hydrogen or a cationic group;
R3 is selected from the group consisting of
xe2x80x83where
R11 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkoxy, and optionally substituted amino,
where the alkyl, alkoxy, and amino are each independently and optionally substituted with substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, and carboxamido;
alk1 and alk2 are alkylene groups;
p is 0 or 1;
R99 is selected from the group consisting of NH, sulfur, SO, and SO2;
q is 0 or 1;
r is 0 or 1;
R12 is selected from the group consisting of xe2x80x94NR21R22, xe2x80x94NR23xe2x80x94C(xe2x95x90NR24)xe2x80x94NR25R26, xe2x80x94C(xe2x95x90NR27)xe2x80x94NR28R29 and xe2x80x94NR30xe2x80x94CH(xe2x95x90NR31)
where R21-R31 are each independently and optionally selected from the group consisting of hydrogen and alkyl;
A, B, D, L, E, G, and J are each independently nitrogen or carbon,
where the specific juxtaposition of groups A, B, D, and L forms a heterocyclic group selected from the group consisting of
and where the specific juxtaposition of groups E, G, and J forms a heterocyclic group selected from the group consisting of
As mentioned above, M may be hydrogen or a cationic group. Cationic groups may be selected from monovalent metal cations, such as, sodium and potassium, or divalent metal cations, such as magnesium and calcium. Other cationic groups, such as, tetra-alkylammonium groups, may also be used.
In another aspect the invention relates to a compound of formula III or formula IV
or a pharmaceutically acceptable salt thereof,
where
Rxe2x80x21 is selected from the group consisting of hydrogen and xe2x80x94C(O)CH(NH2)CH3; and
Rxe2x80x22 is hydrogen or an acyl group that is cleaved by an enzyme found in mammals, as defined herein;
A, B, L, G, E, and J are each independently nitrogen or carbon,
where the specific juxtaposition of groups A, B, and L forms a heterocyclic group selected from the group consisting of
where the specific juxtaposition of groups E, G, and J forms a heterocyclic group selected from the group consisting of
provided that the group xe2x80x94CH2xe2x80x94Sxe2x80x94CH2CH2NHRxe2x80x22 is attached only to a carbon atom of said heterocyclic group;
Q is selected from the group consisting of nitrogen and xe2x80x94CX, wherein X is selected from the group consisting of hydrogen and chlorine.
Preferably, Rxe2x80x22 is selected from the group consisting of hydrogen, xe2x80x94C(O)xe2x80x94R88, xe2x80x94C(O)xe2x80x94OR89, xe2x80x94C(O)xe2x80x94CH(NHRxe2x80x23)-alk4, and
where
Rxe2x80x23 is selected from the group consisting of hydrogen, xe2x80x94C(O)xe2x80x94OR89, and xe2x80x94C(O)xe2x80x94CH(NH2)-alk4;
alk4 is selected from the group consisting of hydrogen, and optionally substituted alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, phenyl, xe2x80x94COOH, xe2x80x94C(O)xe2x80x94OR89, xe2x80x94C(O)NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, and
R89 is selected from the group consisting of benzhydryl, t-butyl, allyl, p-nitrobenzyl, benzyl, p- or o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, xcex2-(trimethylsilyl)ethyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, and 3,3-dimethylallyl.
More preferably, the compound of formula III, above, is the compound set forth in formula V,
or a pharmaceutically acceptable salt thereof,
where
Rxe2x80x21 is selected from the group consisting of hydrogen and xe2x80x94C(O)CH(NH2)CH3; and
Rxe2x80x22 is hydrogen or an acyl group that is cleaved by an enzyme found in mammals, as defined herein.
Preferably, Rxe2x80x22 is selected from the group consisting of hydrogen, xe2x80x94C(O)xe2x80x94R88, xe2x80x94C(O)xe2x80x94OR89, xe2x80x94C(O)xe2x80x94CH(NHRxe2x80x23)-alk4, and
wherein
Rxe2x80x23 is selected from the group consisting of hydrogen, xe2x80x94C(O)xe2x80x94OR89, and xe2x80x94C(O)xe2x80x94CH(2)-alk4;
alk4 is selected from the group consisting of hydrogen, and optionally substituted alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from the group consisting of hydrogen, phenyl, xe2x80x94COOH, xe2x80x94C(O)xe2x80x94OR89, C(O)NH2, xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, and
R89 is selected from the group consisting of benzhydryl, t-butyl, allyl, p-nitrobenzyl, benzyl, p- or o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, xcex2-(trimethylsilyl)ethyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, and 3,3-dimethylallyl.
In other preferred embodiments Rxe2x80x23 is selected from the group consisting of hydrogen, methyl, and xe2x80x94C(O)xe2x80x94CH(NH2)CH3. Furthermore, alk4 is selected from the group consisting of hydrogen, xe2x80x94CH3, xe2x80x94CH(CH3)2, xe2x80x94CH2OH, xe2x80x94CH2NH2, xe2x80x94CH2CH2NH2, xe2x80x94CH2CH2CH2NH2, xe2x80x94CH2CH2CH2CH2NH2, xe2x80x94CH2COOH, xe2x80x94CH2CH2COOH, xe2x80x94CH2xe2x80x94C(O)NH2, xe2x80x94CH2CH2xe2x80x94C(O)NH2, and
In more preferred embodiments, the invention s a compound of formula III, where the compound is selected from the group consisting of
Cmpd 17. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-aminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-A. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-ornithylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-B. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-prolylaminoethylthiomethyl]pyrid-3-ylthio)-3-cephem-4-carboxylic acid,
Cmpd 17-C. (7R)-7-[(Z)-2-(5-N-(L)-alanylamino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)-acetamido]-3-{2-[2-aminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-D. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L,L)-alanylalanylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-E. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-glycylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-F. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-aspartylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-G. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-alanylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-H. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-(Nxcex1-methyl)alanylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-I. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-histidylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-J. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-valylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-K. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-asparagylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-L. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-lysylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-M. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-serylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-N. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-glutaminylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-O. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-(5-methyl-1,3-dioxolan-4-en-2-on-4-yl)methoxycarbonyl)aminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, and
Cmpd 17-P. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-(2-N-(L)-pyroglutamylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid.
In even more preferred embodiments, the invention features a compound of formula III, where the compound is selected from the group consisting of
Cmpd 17-A. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-ornithylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-D. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L,L)-alanylalanylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-F. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-aspartylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-G. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-alanylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-L. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-lysylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid,
Cmpd 17-N. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-glutaminylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid, and
Cmpd 17-O. (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-(5-methyl-1,3-dioxolan-4-en-2-on-4-yl)methoxycarbonyl)aminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid.
In another aspect, the invention provides for a heteroaryl compound, or a salt thereof, selected from the group consisting of
3-triphenylmethylthio-2-hydroxymethylpyridine,
3-triphenylmethylthio-2-chloromethylpyridine,
3-triphenylmethylthio-2-chloromethylpyridine hydrochloride,
3-triphenylmethylthio-2-[2-N-(t-butoxycarbonyl)aminoethylthiomethyl)]pyridine,
2-(2-aminoethylthiomethyl)-3-mercaptopyridine,
bis(2-(2-aminoethylthiomethyl)pyrid-3-yl)disulfide,
and the compound of the following formula:
where Rxe2x80x22 is as defined herein.
In another aspect, the invention relates to a compound selected from the group consisting of
7-amino-3-chloro-3-cephem-4-carboxylate, t-butyl ester,
(7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(triphenylmethoxyimino)acetamido-3-chloro-3-cephem-4-carboxylate, t-butyl ester,
and the compound of the following formula:
where Rxe2x80x22 and R89 are as defined herein.
In a further aspect, the invention relates to a method of synthesizing a compound of formula VI
comprising reacting a compound of formula VII with an amine-N-oxide,
where:
R66 is selected from the group comprising of hydrogen, alkyl, benzyl, xe2x80x94C(O)xe2x80x94R68,
where R68 is selected from the group consisting of hydrogen, alkyl, aryl, alkoxyl, and aryloxy;
R67 is alkyl or benzyl; and
the amine-N-oxide is selected from the group consisting of trialkylamine-N-oxide and pyridine-N-oxide.
Preferably, R66 is benzyl or xe2x80x94C(O)xe2x80x94OCH2CH3; R67 is methyl or benzyl; and the amine-N-oxide is selected from the group consisting of trimethylamine-N-oxide, N-methylmorpholine-N-oxide, and pyridine-N-oxide.
In another aspect, the invention relates to a compound of formula VIII
where
R1 is selected from the group consisting of optionally substituted aryl and optionally substituted heterocycle,
where the heterocycle is selected from the group consisting of pyridyl, thiadiazolyl, and thiazolyl; and
where the aryl and heterocycle are each independently and optionally substituted with substituents selected from the group consisting of hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, and carboxamido;
R4 is a protecting group selected from the group consisting of benzyl, p-nitrobenzyl, o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, xcex2-(trimethylsilyl)ethyl, benzyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, benzhydryl, and 3,3-dimethylallyl; and
X3 is selected from the group consisting of xe2x80x94OP(O)xe2x80x94(O-phenyl)2, and xe2x80x94OP(O)xe2x80x94Cl2.
Preferably, R1 is 5-amino-1,2,4-thiadiazol-3-yl and R4 is trityl.
The summary of the invention described above is non-limiting and other features and advantages of the invention will be apparent from the following description of the preferred embodiments, and from the claims.
As used herein, the term xe2x80x9calkylxe2x80x9d denotes a branched, unbranched, or cyclic hydrocarbon group, preferably containing between one and six, more preferably one and four, carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and 2-methylpentyl. These groups may be optionally substituted with one or more functional groups which are attached commonly to such chains, such as hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and optionally substituted isothioureido, amidino, guanidino, and the like to form alkyl groups such as trifluoromethyl, 3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl, 4-cyanobutyl, 2-guanidinoethyl, 3-N,Nxe2x80x2-dimethylisothiouroniumpropyl, and the like.
The term xe2x80x9calkylenexe2x80x9d refers to a straight chain or branched chain of carbon atoms, all bearing hydrogen atoms so that there are no unsaturated carbon atoms in the chain, where the chain is substituted with a chemical group other than hydrogen at two ends. Thus, the xe2x80x94CH2xe2x80x94 group (known as methylene), the xe2x80x94CH2CH2xe2x80x94 group (known as ethylene), the, xe2x80x94CH2CH2CH2xe2x80x94 group (known as propylene), and xe2x80x94CH2CH(CH3)CH2xe2x80x94 (known as isopropylene) are examples without limitation of alkylene groups.
The term xe2x80x9calkenylxe2x80x9d denotes an alkyl group as defined above having at least one double bond, e.g., allyl, 3-hydroxy-2-buten-1-yl, 1-methyl-2-propen-1-yl and the like.
The term xe2x80x9carylxe2x80x9d denotes a chain of carbon atoms which form at least one aromatic ring having preferably between about 6-14 carbon atoms, such as phenyl, naphthyl, indenyl, and the like, and which may be substituted with one or more functional groups which are attached commonly to such chains, such as, hydroxyl, bromo, fluoro, chloro, iodo, mercapto, cyano, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form aryl groups such as biphenyl, iodobiphenyl, methoxybiphenyl, anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl, methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl, trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl, amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenyl, imidazolylmethylphenyl, cyanophenyl, pyridylphenyl, pyrrolylphenyl, pyrazolylphenyl, triazolylphenyl, tetrazolylphenyl and the like.
The term xe2x80x9cheterocyclexe2x80x9d denotes a chain of carbon and at least one non-carbon atoms which together form one or more aromatic or non-aromatic rings having preferably between about 5-14 atoms, such as, furyl, thienyl, imidazolyl, indolyl, pyridyl, thiadiazolyl, thiazolyl, piperazinyl, dibenzfuranyl, dibenzthienyl. These rings may be optionally substituted with one or more functional groups which are attached commonly to such rings, such as, hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio, cyano, alkylthio, heterocycle, aryl, heteroaryl, carboxyl, oxo, alkoxycarbonyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the like to form rings such as, 2-aminothiazol-4-yl, 2-amino-5-chlorothiazol-4-yl, 5-amino-1,2,4-thiadiazol-3-yl, 2,3-dioxopiperazinyl, 4-alkylpiperazinyl, 2-iodo-3-dibenzfuranyl and 3-hydroxy-4-dibenzthienyl and the like.
The term xe2x80x9cheteroaromaticxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d (HetAr) denotes an aromatic heterocycle as defined above.
The term xe2x80x9cheterotricyclexe2x80x9d denotes an aromatic heterocyclic substituent as defined above which comprises three aromatic rings.
The term xe2x80x9cheterocyclecarbonylxe2x80x9d denotes the group xe2x80x94C(O)Het, where Het is heterocycle as defined above.
The term xe2x80x9calkoxylxe2x80x9d denotes the group xe2x80x94OR, where R is alkyl as defined above, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy, trifluoromethoxy, 3-hydroxyhexyloxy, 2-carboxypropyloxy, 2-fluoroethoxy, carboxymethoxy and cyanobutyloxy and the like.
The term xe2x80x9calkylthioxe2x80x9d denotes the group xe2x80x94SR, where R is alkyl as defined above, such as methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, sec-butylthio, iso-butylthio, tert-butylthio, trifluoromethythio, 3-hydroxyhexylthio, 2-carboxypropylthio, 2-fluoroethylthio, carboxymethylthio and cyanobutylthio and the like.
The term xe2x80x9cacylxe2x80x9d denotes groups xe2x80x94C(O)R, where R is hydrogen or alkyl as defined above, such as formyl, acetyl, propionyl, or butyryl.
The term xe2x80x9caryloxyxe2x80x9d denotes groups xe2x80x94OAr, where Ar is an aryl group as defined above.
The term xe2x80x9caralkylxe2x80x9d denotes groups xe2x80x94RAr, where R is alkyl and Ar is aryl, both as defined above. The term encompasses groups where the R group is substituted with one or more aryl groups. Examples of aralkyl groups include, but are not limited to, benzyl, diphenylmethyl, and triphenylmethyl.
The term xe2x80x9cheteroaralkylxe2x80x9d denotes groups xe2x80x94RHetAr where R is alkylene as defined above and HetAr is heteroaryl as defined above.
The term xe2x80x9ctrialkylsilylxe2x80x9d denotes the group RRxe2x80x2Rxe2x80x3Sixe2x80x94, where R, Rxe2x80x2 and Rxe2x80x3 are alkyl as defined above.
The term xe2x80x9ctrialkylammoniumxe2x80x9d denotes the group [RRxe2x80x2Rxe2x80x3Nxe2x80x94]+, where R, Rxe2x80x2 and Rxe2x80x3 are alkyl as defined above.
The term xe2x80x9caminoxe2x80x9d denotes the group NRRxe2x80x2, where R and Rxe2x80x2 may independently be alkyl, aryl or acyl as defined above, or hydrogen.
The term xe2x80x9ccarboxamidoxe2x80x9d denotes the group xe2x80x94C(O)NRRxe2x80x2, where R and Rxe2x80x2 may independently be alkyl, aryl or acyl as defined above, or hydrogen.
The term xe2x80x9cxcex2-lactam resistant bacteriaxe2x80x9d refers to bacteria against which a xcex2-lactam antibiotic has a minimum inhibitory concentration (MIC) of greater than 32 mg/mL.
The term xe2x80x9cmethicillin-resistant bacteriaxe2x80x9d refers to bacteria that are resistant to methicillin. Examples of such bacteria are provided in Table 1 and are identified MethR. The term xe2x80x9cmethicillin sensitive bacteriaxe2x80x9d refers to bacteria that are sensitive to methicillin. Examples of such bacteria are provided in Table 1 and are identified MethS.
A xe2x80x9cprodrugxe2x80x9d refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of the present invention which is administered as an ester (the xe2x80x9cprodrugxe2x80x9d) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
The present invention provides compounds, methods and compositions effective to treat bacterial infections, and, especially, infections arising from bacteria which have developed resistance to conventional xcex2-lactam antibiotics. The present invention also provides compounds, methods and compositions effective to treat bacterial infections arising from bacteria which have developed resistance to conventional cephalosporin antibiotics.
It is understood to those skilled in the art that the compounds of the present invention can be prepared or be present as their pharmaceutically acceptable salts or as salts that may not be pharmaceutically acceptable. Such salts are within the scope and contemplation of the claims of the present invention. Such salts can exist as the combination of the compounds of the present invention and acids or bases. These acids may include trifluoroacetic acid, hydrochloric acid, methanesulfonic acid, and other organic or inorganic acids. The bases may include benzathene, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procain, and the hydroxide, alkoxide, carbonate, bicarbonate, sulfate, bisulfate, amide, alkylamide, or dialkylamide salts of the following metal cations: lithium, sodium, potasium, magnesium, calcium, aluminum, and zinc and other organic or inorganic bases. These salts may exist as a combination of one or more equivalents of acid or base per compound or one or more equivalents of compound per acid or base.
The names and structures of some of the compounds of the invention are shown below.
Cmpd 1 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(2-aminoethylthio-1,3,4-thiadiazol-5-ylthio)-3-cephem-4-carboxylic acid
Cmpd 2 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-methyl-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid
Cmpd 3 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-amino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid
Cmpd 4 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-1,3-thiazol-2-ylthio]-3-cephem-4-carboxylic acid
Cmpd 5 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-methoxy-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid
Cmpd 6 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyridazin-6-ylthio]-3-cephem-4-carboxylic acid
Cmpd 7 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyridazin-3-ylthio]-3-cephem-4-carboxylic acid
Cmpd 8 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthio)-pyrimidin-4-ylthio]-3-cephem-4-carboxylic acid
Cmpd 9 (7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)-pyridazin-3-ylthio]-3-cephem-4-carboxylic acid
Cmpd 10 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-(2-aminoethylthiomethyl-1,3,4-thiadiazol-5-ylthio)-3-cephem-4-carboxylic acid
Cmpd 11 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-aminoethylthio-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid
Cmpd 12 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)-1,2,4-thiadiazol-5-ylthio]-3-cephem-4-carboxylic acid
Cmpd 13 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid
Cmpd 14 (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid
Cmpd 15 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-guanidinoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid
Cmpd 16 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-2-aminoethylamino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid
Cmpd 17 (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[2-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid
Cmpd 18 (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid
Cmpd 19 (7R)-7-[(Z)-2-(5-aminothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid
Cmpd 20 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid
Cmpd 21 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid
Cmpd 22 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-(2-aminoethylthio-1,3,4-thiadiazol-5-ylthio)-3-cephem-4-carboxylic acid
Cmpd 23 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid
Cmpd 24 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-aminoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid
Cmpd 25 (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[3-(2-guanidinoethylthiomethyl)pyrid-4-ylthio]-3-cephem-4-carboxylic acid
Cmpd 26 (7R)-7-[(Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-guanidinoethylthiomethyl)-2-amino-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid
Cmpd 27 (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid
Cmpd 28 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[4-(2-aminoethylthiomethyl)pyrid-3-ylthio]-3-cephem-4-carboxylic acid
Cmpd 29 (7R)-7-[(Z)-2-(2-aminopyrid-6-yl)-2-(hydroxyimino)acetamido]-3-[2-chloro-4-(2-aminoethylthiomethyl)-1,3-thiazol-5-ylthio]-3-cephem-4-carboxylic acid
The compounds of the present invention may be readily prepared in accordance with the following schemes. However, it will be appreciated that other synthetic pathways for forming the compounds of the invention are available and that the following is offered merely by way of example, and not limitation. It will be further recognized that various protecting and deprotecting strategies will be employed which are standard in the art (see, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 2nd Ed., John Wiley and Sons, New York, N.Y., 1991). Those of skill in the art will recognize that the selection of any particular protecting group (e.g., a carboxyl protecting group) will depend on the stability of the protected moiety with respect to subsequent reaction conditions.
Generally, the synthesis of the cephalosporins of the present invention may be achieved using well-known methods and readily available materials (see, e.g., March; Larock, COMPREHENSIVE ORGANIC TRANSFORMATIONS (VCH Publishers, 1989); and G. I. Georg, THE ORGANIC CHEMISTRY OF xcex2-LACTAMS, (VCH 1992), each of which is incorporated herein by reference).
Cephalosporin intermediates bearing an appropriate acylamino substituent R1 and carboxyl protecting group R2 and leaving group Rxe2x80x31 can be reacted with a heterocyclic thiol, displacing Rxe2x80x31.
In the above structures, Rxe2x80x31 is a leaving group, which may be selected from the group consisting of p-toluenesulfonate, methylsulfonate, fluorosulfonate, chloro, bromo, and (Rxe2x80x32O)2POxe2x80x94, where Rxe2x80x32 is selected from the group consisting of hydrogen and alkyl, as defined herein; and
R2 is a carboxyl protecting group, which may be selected from the group consisting of p-methoxybenzyl, benzhydryl, t-butyl, allyl, and p-nitrobenzyl. Those skilled in the art realize that other suitable leaving groups or carboxyl protecting groups may be used in place of those mentioned here for Rxe2x80x31 and R2, respectively. For example, the carboxyl protecting group R2 may be those protecting groups amenable to reductive cleavage, such as benzyl, p- or o-nitrobenzyl, 2,2,2-trichloroethyl, allyl, cinnamyl, benzhydryl, 2-chloroallyl and the like. Alternatively, R2 may be a protecting group amenable to acidic cleavage, such as t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, xcex2-(trimethylsilyl)ethyl, benzyl, 4- or 2-methoxybenzyl, 2,4-dimethoxybenzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, methoxymethyl, benzhydryl, or 3,3-dimethylallyl. Preferred protecting groups are t-butyl, p-methoxybenzyl, p-nitrobenzyl, allyl and benzhydryl. Such groups may be attached to the unprotected carboxyl group of the cephalosporin starting material using known reagents and techniques, such as those described in Greene and Wuts.
The above reaction may be carried out at room temperature, at temperatures higher than room temperature, or at temperatures lower than room temperature. The reaction is preferably carried out in the range of about xe2x88x9278xc2x0 C. to about 50xc2x0 C., more preferably in the range of about xe2x88x9210xc2x0 C. to about 40xc2x0 C., and most preferably in the range of about 0xc2x0 C. to room temperature. xe2x80x9cRoom temperaturexe2x80x9d is generally in the range of about 20xc2x0 C. to about 25xc2x0 C. By xe2x80x9caboutxe2x80x9d a certain temperature it is meant that the temperature range is preferably within 10xc2x0 C. of the listed temperature, more preferably within 5xc2x0 C. of the listed temperature, and most preferably within 2xc2x0 C. of the listed temperature. Therefore, by way of example, by xe2x80x9cabout 40xc2x0 C.xe2x80x9d it is meant that the temperature range is preferably 40xc2x110xc2x0 C., more preferably 40xc2x15xc2x0 C., and most preferably 40xc2x12xc2x0 C.
The reaction can also be carried out with or without an external base. If a base is used, the base is preferably a nitrogen base, an organic base, or an inorganic base. xe2x80x9cNitrogen basesxe2x80x9d are commonly used in the art and are selected from acyclic and cyclic amines. Examples of nitrogen bases include, but are not limited to, ammonia, methylamine, trimethylamine, triethylamine, aniline, 1,8-diazabicyclo[5.4.0]undec-7-ene, diisopropylethylamine, pyrrolidine, piperidine, and pyridine or substituted pyridine (e.g., 2,6-di-tert-butylpyridine). xe2x80x9cOrganic basesxe2x80x9d are bases that contain carbon atoms. Examples of organic bases include, but are not limited to, carbonate, bicarbonate, acetate, and formate anions. xe2x80x9cInorganic basesxe2x80x9d are bases that do not contain any carbon atoms. Examples of inorganic bases include, but are not limited to, hydroxide, phosphate, bisulfate, hydrosulfide, and amide anions. Those skilled in the art know which nitrogen base or inorganic base would match the requirements of the reaction conditions. In certain embodiments of the invention, the base used may be pyrrolidine or piperidine. In other embodiments the base may be the hydroxide, carbonate, bicarbonate or anion, preferably used as the sodium or potassium salt.
The solvent in which the reaction is carried out may be a homogeneous solvent system, in which case no phase transfer catalyst is used. In other cases, the solvent may, be a heterogeneous solvent system, in which case a phase transfer catalyst is used. By xe2x80x9chomogeneous solvent systemxe2x80x9d it is meant a solvent system which uses one or more solvents that are fully miscible, and therefore, form one phase. The solvents in a homogeneous solvent system are all other hydrophobic or hydrophilic. By xe2x80x9cheterogeneous solvent systemxe2x80x9d it is meant a solvent system which uses two or more solvents that are not fully miscible, and therefore, form more than one phase, usually two phases consisting of an aqueous phase and an organic phase. Some of the solvents in a heterogeneous solvent system are hydrophobic while others are hydrophilic.
If a heterogeneous solvent system is used, then the reaction may be carried out in the presence of a phase transfer catalyst. Those skilled in the art can select a suitable phase transfer catalyst by knowing the reaction conditions or by further experimentation. Common phase transfer catalysts include, but are not limited to, quaternary ammonium salts.
Manipulation of the 7-acyl substituent can be performed after the thio-linked heterocyclic substituent is attached to the cephalosporin:
In the above scheme R1, R2, R3, and R4 are as defined herein. Rxe2x80x27 is preferably selected from the group consisting of alkyl and aryl, as those terms are defined herein. Rxe2x80x27 is more preferably selected from the group consisting of phenyl, tert-butyl, and benzyl. Zxe2x80x2 is preferably selected from the group consisting of methylene (xe2x80x94CH2xe2x80x94), oxygen, sulfur, and xe2x80x94NHxe2x80x94. More preferably, Zxe2x80x2 is selected from the group consisting of methylene and oxygen. X3 in the above scheme is preferably selected from the group consisting of xe2x80x94OP(O)xe2x80x94(O-phenyl)2, and xe2x80x94OP(O)xe2x80x94Cl2.
Alternatively, the displacement of the leaving group at the 3-position of cephalosporin can be performed at the stage of the 7-amino intermediate and then followed by acylation of the amine with appropriate acylating reagent:
In the above scheme R1, R2, R3, R4, and X3 are as defined herein.
Finally, the one-step or multi-step deprotection of the fully assembled cephalosporin, removing protecting group R2, and other protecting groups present at substituents R3, Z, and R7 using conditions appropriate for the removal of all protecting groups is used for obtaining the biologically active cephalosporin.
The substituent R1 in all of the above schemes may be any of the groups described above and are either available commercially (e.g., from Aldrich, Milwaukee, Wis.) or can be formed using known techniques and starting materials (see, e.g., March; Larock). These groups can be substituted for those present on the starting material by variety of well known techniques (see, e.g., Barrett, J. C. S. Perkin I, 1629 (1979) or Chauvette, J. Org. Chem. 36:1259 (1971), both of which are incorporated herein by reference), such as by transamination of an existing substituent for the desired substituent, or hydrolytic removal of the existing substituent followed by reaction with a suitably reactive form of desired substituent, such as an acyl chloride. Again, the appropriate reagents and techniques will be apparent to those of skill in the art.
Side chains on C-7 and C-3 of the cephem core are synthesized by the procedures described below. These procedures are modified from the procedures found in chemical literature, in particular, Tatsuda, K. et al., Bull. Chem. Soc. Jpn., 1994, 67, 1701-1707; Csendes, B. et al., Journal of Antibiotics, 1983, 36, 1020; Memoli, K. A., Tetrahedron Lett, 1996, 37, 3617; and Bjoork, P., et al., J. Heterocyc. Chem, 1995, 32 (3), 751.
The following diagrams depict the synthetic schemes for the side chains.
b. C-3 Side Chain Synthesis (Memoli, et al., Route):
As shown below, 3-mercapto-2-hydroxymethylpyridine is synthesized using the Memoli, et al., route.
The product of the above synthesis can be used to synthesize the C-3 side chains for the compounds of the present invention, using the synthetic schemes shown below.
Or the following alternative pathway.
Some of the cephalosporin compounds of the invention can be synthesized using the scheme shown below.
According to this invention, a therapeutically or pharmaceutically effective amount of a cephalosporin and particularly, a compound of Formula I, II or III, is administered to a mammal suffering from a methicillin-resistant bacterial infection (or other xcex2-lactam resistant bacterial infections, such as vancomycin-resistant or ampicillin-resistant infections), especially resistant S. aureus, in an amount effective to at least partially relieve the infection. Especially important are infections resulting from strains having similar activity to strains such as S. aureus Col (MethR)(lacxe2x88x92), S. aureus 76 (MethR) (lac+), E. fœcium ATCC 35667, or E. fœcalis ATCC 29212. Again, such compounds are also effective against bacteria sensitive to methicillin, vancomycin, and/or ampicillin and therefore have utility in such compositions and methods.
The compositions containing the compound(s) of the invention can be administered for prophylactic and/or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from an infection, as described above, in an amount sufficient to cure or at least partially arrest the symptoms of the infection. An amount adequate to accomplish this is defined as xe2x80x9ctherapeutically effective amount or dose.xe2x80x9d Amounts effective for this use will depend on the severity and course of the infection, previous therapy, the patient""s health status and response to the drugs, and the judgment of the treating physician. In prophylactic applications, compositions containing the compounds of the invention are administered to a patient susceptible to or otherwise at risk of a particular infection. Such an amount is defined to be a xe2x80x9cprophylactically effective amount or dose.xe2x80x9d In this use, the precise amounts again depend on the patient""s state of health, weight, and the like.
Once improvement of the patient""s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment can cease. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of the disease symptoms.
In general, a suitable effective dose of the compound of the invention will be in the range of 0.1 to 1000 milligram (mg) per recipient per day, preferably in the range of 1 to 100 mg per day. The desired dosage is preferably presented in one, two, three, four or more subdoses administered at appropriate intervals throughout the day. These subdoses can be administered as unit dosage forms, for example, containing 5 to 1000 mg, preferably 10 to 100 mg of active ingredient per unit dosage form. Preferably, the compounds of the invention will be administered in amounts of between about 2.0 mg/kg to 250 mg/kg of patient body weight, between about one to four times per day.
While it is possible to administer the active ingredient of this invention alone, it is preferable to present it as part of a pharmaceutical formulation. The formulations of the present invention comprise at least one compound or inhibitor of this invention in a therapeutically or pharmaceutically effective dose together with one or more pharmaceutically or therapeutically acceptable carriers. Solid carriers include, e.g., starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, and optionally other therapeutic ingredients. Liquid carriers include, e.g., sterile water, polyethylene glycols, non-ionic surfactants, and edible oils such as corn, peanut and sesame oils. In addition, various adjuvants such as are commonly used in the art may be included. For example: flavoring agents, coloring agents, preservatives, and antioxidants, e.g., vitamin E, ascorbic acid, BHT and BHA. Various other considerations are described, e.g., in Gilman et al. (eds) (1990) Goodman and Gilman""s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press; and Remington""s supra. Methods for administration are discussed therein, e.g., for oral, intravenous, intraperitoneal, or intramuscular administration, and others. Pharmaceutically acceptable carriers will include water, saline, buffers, and other compounds described, e.g., in the MERCK INDEX, Merck and Co., Rahway, N.J. Generally, preferred routes of administration are intravenous and intraperitoneal.
These pharmacological agents can be in a variety of forms. These include, for example, solid, semi-solid and liquid dosage forms, such as tablets, pills, powders, liquid solutions or suspensions, liposomes, injectable and infusible solutions. The preferred form depends on the intended mode of administration and therapeutic application. Generally, a pharmacologically acceptable salt of the compound will be used to simplify preparation of the composition. Preferred salts include sodium, potassium, arginine, glycine, alanine, threonine, and lysine. These are prepared, preferably, in water suitably mixed with a surfactant such as hydroxypropylcellulose.
Depending on the specific conditions being treated, such agents may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in Remington""s Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, Pa. (1990). Suitable routes may include oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular subcutaneous, intramedullary injections, as well an intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. just to name a few.
For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks"" solution, Ringer""s solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
Some of the compounds of the invention can be used as prodrugs. As explained above, a prodrug is an agent that is converted to the parent drug in vivo. The prodrugs of the present invention have the unusual and surprising characteristic of being more soluble than the parent compound at or near physiological pH. These prodrugs are converted to the parent compound in the body of the mammal that has received the prodrug. As can be seen from the structures of these prodrugs, a substituent either on C-5 of the thiadiazole group, or on C-2 of the pyridyl group can by cleaved by hydrolysis or enzymatic action in order to afford the parent compound. For instance, the amide group on the C-2 side chain of the pyridyl group of compounds 17-A, 17-B, 17-D -17-Q or the amide group on the C-5 side chain of the thiadiazole group of compound 17-C can be hydrolyzed and form an amine side chain, which is the parent compound 17.
The names and the structures of some of the prodrugs of the invention are shown below.
Cmpd 17-A (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-ornithylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-B (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-prolylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-C (7R)-7-[(Z)-2-(5-N-(L)-alanylamino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-aminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-D (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L,L)-alanylalanylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-E (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-glycylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-F (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-aspartylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-G (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-alanylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-H (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-(Nxcex1-methyl)alanylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-I (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-y)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-histidylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-J (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-valylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-K (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-asparagylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-L (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-lysylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-M (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-serylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-N (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-N-(L)-glutaminylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-O (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-[2-(5-methyl-1,3-dioxolan-4-en-2-on-4-yl)methoxycarbonyl)aminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Cmpd 17-P (7R)-7-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(hydroxyimino)acetamido]-3-{2-(2-N-(L)-pyroglutamylaminoethylthiomethyl]pyrid-3-ylthio}-3-cephem-4-carboxylic acid
Thus, it will be appreciated that the compounds, methods and compositions of the invention are effective against various xcex2-lactam resistant strains of bacteria which pose an increasing health risk to society.

7-acylamino-3-heteroarylthio-3-cephem carboxylic acid antibiotics and prodrugs thereof

Abstract: or a pharmaceutically acceptable salt thereof, wherein Rxe2x80x21 is selected from the group consisting of hydrogen and xe2x80x94C(O)CH(NH2)CH3 and Rxe2x80x22 is selected from the group consisting of hydrogen and an acyl group that is cleaved by an enzyme found in mammals, with the proviso that, when either Rxe2x80x21 or Rxe2x80x22 is hydrogen, the other is not. A, B, L, G, E, and J are each independently nitrogen or carbon such that the respective rings are selected from the group consisting of

Abstract: provided that the group xe2x80x94CH2xe2x80x94Sxe2x80x94CH2CH2NHRxe2x80x22 is attached only to a carbon atom of said heterocyclic group, and Q is selected from the group consisting of nitrogen and xe2x80x94CX, wherein X is selected from the group consisting of hydrogen and chlorine.


A valve structure for treating a patient suffering from obstructive sleep apnea is provided. The valve structure is connected to an air flow generator and is connected to a mask that covers at least the nostrils of a patient. The valve structure includes an inlet pressure port attached to the air flow generator and an expiration valve that includes an expiratory membrane, a primary seat and a secondary seat. During inspiration, the expiratory membrane forms a seal with the primary seat, and during expiration, the expiratory membrane forms a seal with the secondary seat.

Obstructive sleep apnea (OSA) is a common medical disorder that can be quite serious. It has been reported that approximately one in twenty-two Americans (about 12,000,000 people) suffer from OSA, and many cases go undiagnosed. Chronic fatigue has long been recognized as the hallmark of OSA, but more recently, large clinical studies have shown a strong link between OSA, strokes and death.
Obstructive sleep apnea is a condition in which the flow of air pauses or decreases during breathing while one is asleep because the airway has become narrowed, blocked, or floppy. (See FIG. 1A of published patent application US20140246025 A1 to Cragg et al., published Sep. 4, 2014, which is incorporated herein by reference, illustrating an airway during normal breathing, and FIG. 1B therein illustrating the airway A during OSA.) A pause in breathing is called an apnea episode, while a decrease in airflow during breathing is called a hypopnea episode. Almost everyone has brief apnea or hypopnea episodes while they sleep. In OSA, however, apnea episodes occur more frequently and last longer than in the general population. OSA has become an increasingly costly medical condition in recent years, as the disorder is more prevalent in obese people, and obesity has become significantly more prevalent. Unfortunately, the currently available options for treating OSA are not ideal.
A person with OSA usually begins snoring heavily soon after falling asleep. Often, the snoring gets louder. The snoring is then interrupted by a long silent period, during which there is no breathing. This is followed by a loud snort and gasp, as the person attempts to breathe. This pattern repeats. Many people wake up unrefreshed in the morning and feel sleepy or drowsy throughout the day. This is called excessive daytime sleepiness (EDS). People with sleep apnea may act grumpy or irritable, be forgetful, fall asleep while working, reading, or watching TV, feel sleepy or even fall asleep while driving, or have hard-to-treat headaches. OSA sufferers may also experience depression that becomes worse, hyperactive behavior (especially in children), or leg swelling (if severe).
The most widely used therapy for OSA is Continuous Positive Airway Pressure (CPAP). As shown in FIG. 2 of US20140246025 A1 to Cragg et al., a CPAP system 10 typically consists of a mask 12a-12c fitting in or over the nose or nose and mouth, an air pressurizing console 14, and a tube 16 connecting the two (typically a six-foot long hose with a 20 mm diameter bore). CPAP works by pressurizing the upper airway throughout the breathing cycle, essentially inflating the airway to keep it open and thus creating what is sometimes referred to as a "pneumatic splint." This flow is set at a pressure that has been predetermined through medical testing to be appropriate to create a pneumatic splint in the user's airway. This prevents airway collapse and allows the user to breathe without obstruction. Because the masks 12a-12c typically leak air, CPAP systems have to provide an airflow rate of up to 200 liters per minute (approximate figure based on unpublished data). The high airflow rate is needed for multiple reasons. First, all the air needed for breathing must come through the hose. Second, conventional masks have an intended leak built in for the purpose of constant "CO2 washout." Third, these systems achieve the required pressure by using a high airflow rate to generate a back-pressure at the mask end where the air is leaking out. Unfortunately, this high flow rate makes breathing feel quite uncomfortable for many users and requires a relatively large, noisy pressurizing console 14. Additionally, the high required flow rates of CPAP often cause discomfort during exhalation due to increased resistance, as well as nasal dryness, dry mouth, ear pain, rhinitis, abdominal bloating and headaches.
The overwhelming shortcoming of CPAP is poor user compliance. Over half of all users who try CPAP stop using it. Users dislike the side effects mentioned above, as well as having to wear an uncomfortable, claustrophobic mask, being tethered to a pressurizing console, the noise of the console, traveling with a bulky device, and a loss of personal space in bed.
Many CPAP devices and alternatives to CPAP have been developed, but all have significant shortcomings. Less invasive attempts at OSA treatment, such as behavior modification, sleep positioning and removable splints to be worn in the mouth, rarely work. A number of different surgical approaches for treating OSA have also been tried, some of which are still in use. For example, Uvulopalatopharyngoplasty (UPPP) and Laser Assisted Uvula Palatoplasty (LAUP) are currently used. Surgical approaches, however, are often quite invasive and not always effective at treating OSA.
One alternative approach to OSA treatment is to provide a pneumatic splint during the expiratory portion of the respiratory cycle by producing a partial blockage in the nose or mouth, thus slowing the release of air during expiration and increasing positive pressure in the airway. The simplest way to form an expiratory pneumatic splint, pursing the lips, has been shown to open the upper airway and improve breathing in emphysema users. This type of maneuver is generically labeled Expiratory Positive Airway Pressure (EPAP).
Ventus Medical, Inc. (http://www.proventtherapy.com/ventus_medical) has developed a removable nasal EPAP device to produce such a pneumatic splint during exhalation (the Provent® Sleep Apnea Therapy). (See, for example, published patent application US20060150978 A1 to Doshi et al., published Jul. 13, 2006, which is incorporated herein by reference.) This device restricts exhalation by forcing expired air through several small orifices attached to the nose. This is labeled a Fixed Orifice Resistor (FOR). Shortcomings of this therapy are that 1) the fixed hole exhalation valve does not have a capped maximum pressure, 2) the pressure increases immediately upon exhalation and therefore makes it difficult to exhale, and 3) with no assistance of additional pressure from an external source, if the user has an apneic event there is no 'rescue pressure'—i.e., the flow supplied by the blower box. A further disadvantage is that the Provent® device or any FOR restricts expiratory airflow using a fixed hole for resistance. This leads to an uncomfortable spike in nasal pressure at the beginning of expiration when airflow is highest and a less efficacious decrease in nasal pressure at the end of expiration when airflow is lowest. Another shortcoming of the Provent® device is that it produces the pneumatic splint only during exhalation—i.e., there is no increased pressure during inhalation.
In addition, the device is not effective in mouth breathers or users who become mouth breathers when resistance is added to the nasal passages. Thus, the Provent® device is useful only in moderate cases of OSA that do not convert to mouth breathing.
Although snoring is not as severe a condition as OSA, it does affect lives adversely. Snoring can adversely affect sleep quality and can make sleeping with a spouse or other partner difficult. Although many snoring therapies have been tried, including Breathe Right® Nasal Strips and more invasive approaches in more severe cases, no ideal solution has been found.
Therefore, it would be advantageous to have improved systems, devices and methods for treating OSA and snoring. Ideally, such systems, devices and methods would be less cumbersome than currently available CPAP systems, to improve user compliance. Also ideally, such systems, devices and methods would provide some of the advantages of an expiratory pneumatic splint. At least some of these objectives were met by the embodiments described in US20140246025 A1 to Cragg et al., previously incorporated herein by reference (herein sometimes referred to as "Cragg '025").
Cragg '025 utilized a novel system of valves to allow inspiration of air supplied via the hose and also from inlets in the mask that take in room air. In various example embodiments, Cragg '025 provided variable resistance to expiratory air flow using a resistive mechanism other than the infused external air that increases over the course of expiration, thus providing an easier, more comfortable start to expiration while maintaining airway pressure toward the end of expiration (e.g., by decreasing resistance to expiratory flow when intranasal pressure reaches a threshold pressure and/or by gradually increasing resistance to expiratory air flow until intranasal pressure reaches the threshold pressure). Another improvement in various embodiments of Cragg '025 was that lower air flow rates were used (e.g., less than or equal to 20 L/min), while still supplying the desired therapeutic pressure (e.g., between about 4 cmH2O and 20 cmH2O), thus requiring less power and smaller device components than traditional CPAP and reducing side effects. Still another improvement of Cragg '025 was a less cumbersome, more form-fitting mask that reduced air leaks and was more comfortable to wear than prior CPAP masks and eliminated the need for high flow rates because there was no need to compensate for air leaks. Accordingly, the devices described therein could be used in connection with a small diameter hose (e.g., having a diameter of less than or equal to about 15 mm), thus decreasing the bulkiness of the system.
While Cragg '025 was an important improvement over the state of the art, it required and relied upon a special system of protruding valves that had to be pre-adjusted or set to suit each user. It would be advantageous to improve upon the system of Cragg '025 by making the system simpler and more compact in design, simpler to use, and more robust.

Sleep apnea treatment system and improvements thereto


An object of the invention is to provide an organic electroluminescent element with high luminance and long half life and a display employing the organic EL element.

As an emission type electronic displaying device, there is an electroluminescence device (ELD). As elements constituting the ELD, there is an inorganic electroluminescence element or an organic electroluminescent element (hereinafter referred to also as organic EL element). The inorganic electroluminescent element has been used for a plane-shaped light source, but a high voltage alternating current has been required to drive the element.
An organic electro-luminescent element has a structure in which a light emission layer containing a light emission compound is arranged between a cathode and an anode, and an electron and a hole were injected into the light emission layer and recombined to form an exciton. The element emits light, utilizing light (fluorescent light or phosphorescent light) generated by inactivation of the exciton, and the element can emit light by applying a relatively low voltage of from several volts to several decade volts. The element has a wide viewing angle and a high visuality since the element is of-self light emission type. Further, the element is a thin, complete solid element, and therefore, the element is noted from the viewpoint of space saving and portability.
An organic EL element for practical use is required which efficiently emits light with high luminance at a lower power. For example, there are disclosed an element with long lifetime emitting light with high luminance in which stilbene derivatives, distyrylarylene derivatives or tristyrylarylene derivatives are doped with a slight amount of a fluorescent compound (see, for example, Japanese Patent No. 3093796), an element which comprises an organic light emission layer containing an 8-hydroxyquinoline aluminum complex as a host compound doped with a slight amount of a fluorescent compound (see, for example, Japanese Patent O.P.I. Publication No. 63-264692), and an element which comprises an organic light emission layer containing an 8-hydroxyquinoline aluminum complex as a host compound doped with a quinacridone type dye (see, for example Japanese Patent O.P.I. Publication No. 3-255190).
When light emitted through excited singlet state is used in the element disclosed in the above patent documents, the upper limit of the external quantum efficiency (ηnext) is considered to be at most 5%, as the generation ratio of singlet excited species to triplet excited species is 1:3, that is, the generation probability of excited species capable of emitting light is 25%, and further, external light emission efficiency is 20%.
Since an organic EL element, employing phosphorescence through the excited triplet, was reported by Prinston University (for example, see M. A. Baldo et al., Nature, 395, p. 151-154 (1998), study on materials emitting phosphorescence at room temperature has been actively made (for example, see M. A. Baldo et al., Nature, 403, 17, p. 750-753 (2000) or U.S. Pat. No. 6,097,147).
As the upper limit of the internal quantum efficiency of the excited triplet is 100%, the light emission efficiency of the exited triplet is theoretically four times that of the excited singlet. Accordingly, light emission employing the excited triplet exhibits the same performance as a cold cathode tube, and can be applied to illumination.
For example, many kinds of heavy metal complexes such as iridium complexes has been synthesized and studied (for example, see S. Lamansky et al., J. Am. Chem. Soc., 123, 4304 (2001)).
An example employing tris(2-phenylpyridine)iridium as a dopant has been studied (for example, see M. A. Baldo et al., Nature, 403, 17, p. 750-753 (2000)).
Further, an example employing as a dopant L2Ir (acac) (in which L represents a ligand) such as (ppy)2Ir (acac) (for example, see M. E. Thompson et al., The 10th International Workshop on Inorganic and Organic Electroluminescence (EL′ 00, Hamamatsu)), or employing as a dopant tris(2-p-tolylpyridine)iridium {Ir(ptpy)3}, tris(benzo-[h]-quinoline)iridium {Ir(bzq)3}, or Ir(bzq)2ClP (Bu)3 has been studied (for example, see Moon-Jae Youn. Og, Tetsuo Tsutsui et al., The 10th International Workshop on Inorganic and Organic Electroluminescence (EL′ 00, Hamamatsu)).
A hole transporting material is used as a host of a phosphorescent compound in order to increase emission efficiency (see, for example, Ikai et al., The 10th International Workshop on Inorganic and Organic Electroluminescence (EL′ 00, Hamamatsu)).
Various kinds of electron transporting materials are used as a host of a phosphorescent compound, and further doped with a new iridium complex (for example, see non-patent document 4 below). High emission efficiency is obtained by incorporation of a hole blocking layer (for example, see Moon-Jae Youn. Og, Tetsuo Tsutsui et al., The 10th International Workshop on Inorganic and Organic Electroluminescence (EL′ 00, Hamamatsu)).
An external qauntum efficiency of around 20%, which is theoretically a threshold value, is attained in green light emission, but a sufficient emission efficiency is not attained in another color light, where there is room to be improved. An organic EL element for practical use is required which efficiently emits light with high luminance at a lower power.
In order to solve the problems described above, many kinds of compounds as described above have been proposed, and carbazole derivatives have been studied among them. For example, N-phenylcarbazole derivatives as an electron transporting material are disclosed in Japanese Patent O.P.I. Publication No. 8-60144, and biscarbazole derivatives as a hole injecting material in which two carbazole rings are connected through a vinylene group are disclosed in Japanese Patent O.P.I. Publication No. 5-194943. A phosphorescence emitting element employing a polymer having a carbazole nucleus is proposed in Japanese Patent O.P.I. Publication No. 2001-257076, and a compound in which an aryl group bonds to carbazole at its N position is proposed in Japanese Patent O.P.I. Publication No. 2002-100476. However, an organic electroluminescent element employing these compounds disclosed in these documents does not solve all of quantum efficiency, emission luminance, and durability, problems to be solved for practical use.

This patent is subject to a terminal disclaimer.

Organic electroluminescent element and display

Abstract: An organic electroluminescent element comprising a component layer including at least one light emission layer capable of emitting phosphorescence, wherein the component layer contains at least one specific carbazole derivative.


An image processing apparatus processes image data including first data corresponding to an output color of an output device and a plurality of second data of respective spot colors. The image processing apparatus includes a conversion section and a storage section. The conversion section calculates a device color value for a spot color or a spot color combination among the spot colors, referring to a first table, to generate a second table. In the second table, spot color identification information on the spot color or the spot color combination is correlated with the device color value. The conversion section also generates third data based on the plurality of second data. In the third data, each pixel is represented by the spot color identification information. The storage section stores the first data, the second table and the third data.

1. Field of the Invention
The present invention relates to an image processing apparatus, an image processing method and a recording medium.
2. Description of the Related Art
These days, in the production printing market, an MFP (Multi Function Peripheral) is often used as a POD (Print On Demand) solution instead of an offset printer. This is because the MFP is strong in small-lot production of various products and short-run production. In general, in an MFP, colors are reproduced by using cyan (C), magenta (M), yellow (Y) and black (K) color materials (toners). The C, M, Y and K are so-called process colors. In raster image processing to generate image data (CMYK data) from a print job, colors are converted into device-dependent CMYK values (device color values) by using an ICC (International Color Consortium) profile to perform printing. On the other hand, in offset printing, printing is sometimes performed by using color (spot color) ink. The colors (spot colors) are different from the process colors. The spot color ink (spot colors) varies depending on ink manufacturers, and hence there are thousands of kinds of spot color ink.
In POD printing, in general, documents are created with RGB or CMYK. However, logos, marks or the like of organizations are sometimes specified by spot colors. Therefore, it has been important for MPFs too to deal with spot colors not only for proofs but also for commercial printing. In order to deal with spot colors, Japanese Patent Application Laid-Open Publication No. 2005-223695 and Japanese Patent Application Laid-Open Publication No. 2005-278074 propose performing color conversion on image data for printing including spot colors, referring to a spot color table in which spot color names are respectively correlated with values of converted colors. According to the publications, when printing is performed, each spot color is converted into a CMYK value by using the spot color table, and the CMYK value is combined with a CMYK value outputted to a printer.
Furthermore, in a workflow of POD, so-called job storage/editing function and reprint function are important. With the functions, image data on which raster image processing and/or color conversion are already performed is temporarily stored in an MFP; trial printing to check an output setting, colors and image positions as a final check before printing is performed; setting change and/or some adjustment (color adjustment) are performed as needed; and then the printing (reprinting) is performed.
However, in such a case where reprinting is performed after spot color adjustment is performed (a spot color table is changed), conventionally, it is necessary to re-send a print job and/or to re-perform raster image processing, and/or it is necessary to store a plurality of spot color data of respective spot colors in addition to normal CMYK data when image data is stored in an MFP, and to combine the plurality of spot color data with the CMYK data when printing (reprinting) is performed. Thus, conventional methods require a large storage region to store data and/or much time to perform processing.

Image processing apparatus, image processing method and recording medium

Konica Minolta Business Technologies, Inc.


A rotary electric machine includes a stator having stator windings; and a rotor rotatably disposed in the stator, said rotor having a rotor core provided with a plurality of magnets and a plurality of magnetic auxiliary salient poles formed between poles of the magnets. In this rotary electric machine: a magnetic air gap is provided in an axial direction of the rotor in a position shifted in a circumferential direction from a q axis passing through a center of the magnetic auxiliary salient pole within the magnetic auxiliary salient pole; and an amount of shifting the magnetic air gap from the q axis in the circumferential direction differs according to a position of the magnetic air gap in the axial direction so as to cancel torque pulsation in energization caused due to the magnetic air gap.

1. Field of the Invention
The present invention relates to a rotary electric machine, and an electric vehicle including the same.
2. Description of the Related Art
Drive motors used for electric vehicles or hybrid vehicles are required to output large power. Thus, permanent magnet type motors using a sintered magnet made of rare earth material for holding large energy is generally used. An embedded magnet type motor among the permanent magnet type motors is used as the drive motor which can satisfy requirements, including low-speed and large-torque output, and a wide range of rotation speeds.
Torque pulsation of the motor causes noise or vibration. In particular, the torque pulsation on the low-speed side of the electric vehicle disadvantageously deteriorates ride quality. In a conventional motor, a permanent magnet is generally skewed so as to reduce cogging torque. Instead of skewing the permanent magnet, JP-A-2005-176424 has proposed that a rotary electric machine is provided with slots on the outer peripheral side of the embedded magnet or the outer peripheral surface of a pole piece so as to reduce the cogging torque such that the slot is formed to be shifted in the direction of rotation as viewed from the direction of a rotation axis.
The occurrence of torque pulsation in a rotary electric machine is caused by the cogging torque due to a magnetic circuit for allowing a magnetic flux generated from a permanent magnet provided in a rotor to pass through a stator and then to return to the rotor again, and by a rotating magnetic flux generated by a current of the stator. The above-mentioned JP-A-176424/2005 relates to a technique for reducing the cogging torque as mentioned above.
The invention is directed to reduction of the pulsation due to the rotating magnetic flux generated by the stator current as mentioned above.
When the method disclosed in the above-mentioned JP-A-176424/2005 is intended to be used for reducing torque pulsation due to the stator current, which is to be solved by the invention, the appropriate reduction of the cogging torque becomes very difficult. That is, the method disclosed in JP-A-176424/2005 is designed to reduce the cogging torque. When the concept of this method is intended to be further applied so as to reduce the torque pulsation due to the stator current, the inherent cogging torque cannot be appropriately reduced.
General techniques proposed for reducing torque pulsation have the same influence on both of the cogging torque and the torque pulsation due to the stator current. As a result, in order to reduce both torque pulsations, it is necessary to handle the rotary electric machine taking into consideration the influence on both. This makes it difficult to easily solve both pulsations.
The inventors have thought that the entire torque pulsation can be more easily reduced and adjusted if the torque pulsation due to the stator current can be reduced by a structure or way which has little influence on the cogging torque. For example, when the cogging torque can be reduced and additionally the torque pulsation due to the stator current can also be reduced, the entire torque pulsation can be easily reduced.

Rotary electric machine with air gaps configured to cancel torque pulsations


During testing of an integrated circuit (IC), a channel masking capability is used for masking out unknown or unpredictable (X) values from being compressed into a signature register. The approach provides flexibility to allow for masking of unknown values, while avoiding many of the problems caused by over-masking of known values. The circuitry added to the design to allow for masking is reasonably small, and provides an effective way of masking unknown values during the testing process.

Compression of test pattern response data into signatures is a well-established technique that has been used for decades, especially for logic built-in self-test (LBIST). More recently, it has been used as part of a more general approach for test data compression, in order to save data volume and test time.
One problem with compressing test responses into signatures is dealing with circuits that produce unknown responses. An unknown response, if allowed to be captured into a signature register, will re-circulate, quickly making the final signature unpredictable. If just a single unknown value is captured, it is possible to predict two possible signatures, either of which could be assumed to be a non-defective response. However, when multiple unknown values are captured into a signature, the number of possible good signatures grows exponentially, and it quickly becomes impractical to predict all possible good response signatures.
One approach to dealing with unknown response values is to prevent the unknown values from being captured into the signature registers. One way of doing this is to provide a mechanism to mask out the unknown values before they are captured into the signature registers.
However, the conventional methods lack the capability to mask out the specific channel bits containing unpredictable or unknown values. Without this flexibility, predictable values may be unnecessarily masked, in order to ensure the masking of the unpredictable values. When masking out the predictable values, over-masking occurs, and reduces the effectiveness of the test patterns. For example, faults targeted by the test patterns may not be detected if the channel bit used to observe the fault's effect is masked due to over-masking.

Channel masking during integrated circuit testing