6,7-disubstituted-4-aminopyridoÝ2,3-d¨pyrimidine compounds

Pyrrolidines as inhibitors of neuraminidases

Nöraminidazların inhibitörleri olarak pirolidinler.

6,7-disubstituted-4-aminopyrido{2,3-d}pyrimidine compounds

Pyrrolidines as inhibitors of neuraminidases

6,7-ikameli-4-aminopirido[2,3,-D]Pirimidin bileşikleri.

Inhibiting Transient Receptor Potential Ion Channel TRPA1

This disclosure describes a novel compounds and pharmaceutical compositions for inhibiting the TRPA1 ion channel and/or medical conditions related to TRPA1, such as pain. 1. A method for treating or ameliorating pain, comprising intravenously administering to an animal or human an effective amount of a pharmaceutical composition comprising a compound of Formula (Ia), or a pharmaceutically acceptable salt thereof: This patent application is a continuation of U.S. patent application Ser. No. 13/571,288, filed Aug. 9, 2012, which claims priority to U.S. provisional patent application Ser. No. 61/521,705, filed Aug. 9, 2011. The contents of these applications are incorporated herein by reference in their entireties.The present disclosure relates to compounds and methods for treating pain, for example by inhibiting the Transient Receptor Potential A1 ion channel (TRPA1).TRPA1 is a non-selective cation channel related to pain sensation in humans. TRPA1 is found in sensory neurons and functions as a signal transduction receptor linking inflammation to pain. Activation of TRPA1 can cause pain by inducing firing of nociceptive neurons and driving central sensitization in the spinal cord. TRPA1 stimulation can also increase firing of sensory neurons, leading to the release of pro-inflammatory neuropeptides such as NK-A, substance P and CGRP (which induce vasodilation and help recruit immune cells). A variety of endogenous reactive compounds produced during inflammation activate TRPA1 (including 4-hydroxynonenal released during liposome peroxidation; cyclopentane prostaglandins synthesized by COX enzymes; hydrogen peroxide produced by oxidative stress). TRPA1 can also be activated by a variety of stimuli, including natural products (e.g., allyl isothiocyanate, or AITC), environmental irritants (e.g., acrolein), amphipathic molecules (e.g., trinitrophenol and chlorpromazine) and pharmacological agents. Activation of TRPA1 also sensitizes TRPA1 to cold. Furthermore, a gain-of- ...

1,2,4-OXADIAZOLE AND 1,2,4-THIADIAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 4. A pharmaceutical composition comprising a compound of and at least 1 β-lactam antibiotic or a pharmaceutically acceptable salt thereof.5. A method of treating a bacterial infection comprising administering to a subject in need thereof a therapeutically-effective amount of the pharmaceutical composition according to .6. A method of treating a bacterial infection comprising administering to a subject in need thereof claim 1 , a therapeutically-effective amount of a β-lactam antibiotic in conjunction with a compound of .7. (canceled)8. (canceled)9. The pharmaceutical composition of wherein the β-lactam antibiotic is selected from the group consisting of: a cephalosporin claim 4 , a carbapenem and a monobactam.10. The method of wherein the β-lactam antibiotic is selected from the group consisting of: a cephalosporin claim 6 , a carbapenem and a monobactam.11. The pharmaceutical composition of wherein the cephalosporin is Ceftolozane.12. The method of wherein the cephalosporin is Ceftolozane.13. (canceled)14. (canceled)15. (canceled)16. The method of wherein the β-lactam antibiotic is a monobactam.17. The method of claim 6 , wherein the bacterial infection is caused by bacteria that produce a Class A claim 6 , Class C or Class D β-lactamase.18. (canceled)19AcinetobacterAcinetobacter baumannii, CitrobacterEnterobacterEscherichiaEscherichia coli, Haemophilus influenzae, Morganella morganii, Pseudomonas aeruginosa, KlebsiellaKlebsiella pneumoniae, EnterobacterEnterobacter cloacae, Enterobacter aerogenes PasteurellaProteusProteus mirabilis, SerratiaSerratia marcescensProvidencia. The method of wherein the bacterial infections is caused by a bacteria selected from spp. ...

1,3,4-OXADIAZOLE AND 1,3,4-THIADIAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 2. A pharmaceutical composition comprising a compound of and at least 1 β-lactam antibiotic.3. The pharmaceutical composition of wherein the β-lactam antibiotic is a cephalosporin.4. The pharmaceutical composition of wherein the cephalosporin is Ceftolozane.5. The pharmaceutical composition of wherein the β-lactam antibiotic is a carbapenem.6. The pharmaceutical composition of wherein the β-lactam antibiotic is a monobactam.7. A method of treating or preventing a bacterial infection comprising administering to a subject in need thereof a therapeutically-effective amount of the pharmaceutical composition according to .8. A method of treating a bacterial infection comprising administering to a subject in need thereof claim 1 , a therapeutically-effective amount of a β-lactam antibiotic in conjunction with a compound of .9. The method of wherein the β-lactam antibiotic is a cephalosporin.10. The method of wherein the cephalosporin is Ceftolozane.11. The method of wherein the β-lactam antibiotic is a carbapenem.12. The method of wherein the β-lactam antibiotic is a monobactam.13. The method of wherein the bacterial infection is caused by bacteria that produce a class A claim 8 , class C or class D β-lactamase.14. The method of wherein the bacterial infection is caused by bacteria that produce a class A or class C β-lactamase.15AcinetobacterAcinetobacter baumannii, CitrobacterEscherichiaEscherichia coli, Haemophilus influenzae, Morganella morganii, Pseudomonas aeruginosa, KlebsiellaKlebsiella pneumoniae, EnterobacterEnterobacter cloacaeEnterobacter aerogenes PasteurellaProteusProteus mirabilis, Serratia spp, Serratia marcescensProvidencia. The method of wherein the ...

1,3,4-OXADIAZOLE AND 1,3,4-THIADIAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 2. A pharmaceutical composition comprising a compound of and at least 1 β-lactam antibiotic.3. The pharmaceutical composition of wherein the β-lactam antibiotic is a cephalosporin.4. The pharmaceutical composition of wherein the cephalosporin is Ceftolozane.5. The pharmaceutical composition of wherein the β-lactam antibiotic is a carbapenem.6. The pharmaceutical composition of wherein the β-lactam antibiotic is a monobactam.7. A method of treating or preventing a bacterial infection comprising administering to a subject in need thereof a therapeutically-effective amount of the pharmaceutical composition according to .8. A method of treating a bacterial infection comprising administering to a subject in need thereof claim 1 , a therapeutically-effective amount of a β-lactam antibiotic in conjunction with a compound of .9. The method of wherein the β-lactam antibiotic is a cephalosporin.10. The method of wherein the cephalosporin is Ceftolozane.11. The method of wherein the β-lactam antibiotic is a carbapenem.12. The method of wherein the β-lactam antibiotic is a monobactam.13. The method of wherein the bacterial infection is caused by bacteria that produce a class A claim 8 , class C or class D β-lactamase.14. The method of wherein the bacterial infection is caused by bacteria that produce a class A or class C β-lactamase.15AcinetobacterAcinetobacter baumannii, CitrobacterEscherichiaEscherichia coli, Haemophilus influenzae, Morganella morganii, Pseudomonas aeruginosa, KlebsiellaKlebsiella pneumoniae, EnterobacterEnterobacter cloacaeEnterobacter aerogenes, PasteurellaProteusProteus mirabilis, Serratia spp, Serratia marcescensProvidencia. The method of wherein the ...

1,3,4-oxadiazole and 1,3,4-thiadiazole beta-lactamase inhibitors

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

1,3,4-OXADIAZOLE AND 1,3,4-THIADIAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

BETA-LACTAMASE INHIBITORS

Aryl substituted diazabicyclooctanes (DBO) compounds that inhibit β-lactamases of class A, class C or class D and potentiate β-lactam antibiotics are disclosed. In particular, this disclosure provides DBO compounds that, when used in the disclosed Synergy MIC Assay with a β-lactam antibiotic at a fixed concentration have an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains. 2. The compound of wherein the β-lactamase is selected from a KPC claim 1 , CTX-M claim 1 , SHV or AmpC β-lactamase3. The compound of wherein the β-lactamase is an OXA β-lactamase4. The compound of wherein the OXA β-lactamase is OXA-15. This application claims priority to U.S. Provisional Application No. 61/618,119, filed Mar. 30, 2012, incorporated herein by reference, and U.S. Provisional Application No. 61/792,672, filed Mar. 15, 2013, also incorporated herein by reference. This application is also related to U.S. patent application Ser. Nos. 13/853,443, 13/853,498 and 13/853,506, filed Mar. 29, 2013, the contents of which are incorporated herein by reference in their entirety.This invention is directed to β-lactamase inhibitors (BLI) or compositions comprising β-lactamase inhibitors.Bacterial resistance to β-lactam antibiotics is most commonly mediated by inactivation by β-lactamases. There is an urgent need for novel BLIs that are effective in inhibiting β-lactamases thus, slowing or preventing the degradation of the β-lactam antibiotic and restoring β-lactam antibiotic susceptibility to β-lactamase producing bacteria.Aryl substituted diazabicyclooctanes (DBO) compounds that potentiate (i.e make more potent) β-lactam antibiotics are disclosed. In particular, this invention provides DBO compounds that inhibit β-lactamases of class A, C and D, such as KPC-2, CTX-M-15, SHV-12 and P99 AmpC and potentiate a β-lactam antibiotic as evidenced by the Synergy MIC (sMIC) assay described in Example 23. Unexpectedly, many of these compounds are better inhibitors ...

1,3,4-OXADIAZOLE AND 1,3,4-THIADIAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 2. A pharmaceutical composition comprising a compound of and at least 1 β-lactam antibiotic.3. The pharmaceutical composition of wherein the β-lactam antibiotic is a cephalosporin.4. The pharmaceutical composition of wherein the cephalosporin is Ceftolozane.5. The pharmaceutical composition of wherein the β-lactam antibiotic is a carbapenem.6. The pharmaceutical composition of wherein the β-lactam antibiotic is a monobactam.7. A method of treating or preventing a bacterial infection comprising administering to a subject in need thereof a therapeutically-effective amount of the pharmaceutical composition according to .8. A method of treating a bacterial infection comprising administering to a subject in need thereof claim 1 , a therapeutically-effective amount of a β-lactam antibiotic in conjunction with a compound of .9. The method of wherein the β-lactam antibiotic is a cephalosporin.10. The method of wherein the cephalosporin is Ceftolozane.11. The method of wherein the β-lactam antibiotic is a carbapenem.12. The method of wherein the β-lactam antibiotic is a monobactam.13. The method of wherein the bacterial infection is caused by bacteria that produce a class A claim 8 , class C or class D β-lactamase.14. The method of wherein the bacterial infection is caused by bacteria that produce a class A or class C β-lactamase.15AcinetobacterAcinetobacter baumannii, CitrobacterEscherichiaEscherichia coli, Haemophilus influenzae, Morganella morganii, Pseudomonas aeruginosa, KlebsiellaKlebsiella pneumoniae, EnterobacterEnterobacter cloacaeEnterobacter aerogenes PasteurellaProteusProteus mirabilis, SerratiaSerratia marcescensProvidencia. The method of wherein the bacterial ...

ISOXAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 1. (canceled)3. A pharmaceutical composition comprising a compound of and at least 1 β-lactam antibiotic or a pharmaceutically acceptable salt thereof.4. The pharmaceutical composition of wherein the β-lactam antibiotic is a cephalosporin.5. The pharmaceutical composition of wherein the cephalosporin is Ceftolozane.6. (canceled)7. (canceled)8. (canceled)9. A method of treating a bacterial infection comprising administering to a subject in need thereof claim 2 , a therapeutically-effective amount of a β-lactam antibiotic in conjunction with a compound of .10. The method of wherein the β-lactam antibiotic is a cephalosporin.11. The method of wherein the cephalosporin is Ceftolozane.12. The method of wherein the β-lactam antibiotic is a carbapenem.13. The method of wherein the β-lactam antibiotic is a monobactam.14. (canceled)15. (canceled)16. (canceled)17. (canceled)18. (canceled)19. (canceled)20. (canceled)21. (canceled)22. (canceled)23. (canceled)24. (canceled)25. (canceled)26. (canceled)27. (canceled)28. (canceled)29. (canceled)30. (canceled)31. A method of inhibiting β-lactamase comprising administering to a subject a compound of .32. (canceled)39. A pharmaceutical composition comprising a compound of and Ceftolozane.40. A pharmaceutical composition comprising a compound of and Ceftolozane.41. A method of treating or preventing a bacterial infection comprising administering to a subject in need thereof a therapeutically-effective amount of the pharmaceutical composition according to .42. A method of treating or preventing a bacterial infection comprising administering to a subject in need thereof a therapeutically-effective amount of the pharmaceutical composition ...

Cephalosporin compound

The cephalosporin compound of formula (I) is disclosed, which exhibits antibiotic activity against Gram-negative (e.g., Pseudomonas aeruginosa ) and Gram-positive (e.g., methicillin-resistant Staphylococcus aureus ) bacteria. Methods of manufacturing the compound of formula (I), and uses of the compound in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

1,3,4-oxadiazole and 1,3,4-thiadiazole beta-lactamase inhibitors

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

1,2,4-oxadiazole and 1,2,4-thiadiazole beta-lactamase inhibitors

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

1,3,4-OXADIAZOLE AND 1,3,4-THIADIAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 121.-. (canceled)23. A method of treating or preventing a bacterial infection comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to .24. The method of wherein the bacterial infection is caused by bacteria that produce a class A claim 23 , class C or class D β-lactamase.25AcinetobacterAcinetobacter baumannii, CitrobacterEscherichiaEscherichia coli, Haemophilus influenzae, Morganella morganii, Pseudomonas aeruginosa, KlebsiellaKlebsiella pneumoniae, EnterobacterEnterobacter cloacae, Enterobacter aerogenes, PasteurellaProteusProteus mirabilis, SerratiaSerratia marcescensProvidencia. The method of wherein the bacterial infection is caused by bacteria selected from spp. claim 24 , spp. claim 24 , spp. claim 24 , spp. claim 24 , spp. claim 24 , spp. claim 24 , spp. claim 24 , spp. claim 24 , claim 24 , and spp.26. The method of wherein the bacterial infection is caused by bacteria that produce a KPC-2 or KPC-3 β-lactamase.27. The method of wherein the bacterial infection is caused by bacteria that produce an OXA-15 β-lactamase.28. The method of wherein the bacterial infection is caused by β-lactam resistant bacteria.29. The method of wherein the aztreonam and the compound of formula (I) are administered together in a single composition.31. A method of treating or preventing a bacterial infection comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to .32. The method of wherein the bacterial infection is caused by bacteria that produce a class A claim 31 , class C or class D β-lactamase.33AcinetobacterAcinetobacter ...

1,2,4-oxadiazole and 1,2,4-thiadiazole beta-lactamase inhibitors

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

Beta-lactamase inhibitors

Aryl substituted diazabicyclooctanes (DBO) compounds that inhibit β-lactamases of class A, class C or class D and potentiate β-lactam antibiotics are disclosed. In particular, this disclosure provides DBO compounds that, when used in the disclosed Synergy MIC Assay with a β-lactam antibiotic at a fixed concentration have an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains.

ISOXAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 150-. (canceled) This application claims priority to U.S. Provisional Application No. 61/618,127, filed Mar. 30, 2012, and U.S. Provisional Application No. 61/790,248, filed Mar. 15, 2013. The entire contents of these applications are incorporated herein by reference in their entireties.This disclosure is directed to β-lactamase inhibitors (BLIs) which are effective as inhibitors of β-lactamases and, when used in combination with β-lactam antibiotics are useful in the treatment of bacterial infections. The compounds when combined with a β-lactam antibiotic are effective in treating infections caused by bacteria that are resistant to β-lactam antibiotics due to the presence of β-lactamases. Pharmaceutical compositions comprising such compounds, methods of using such compounds, and processes for preparing such compounds are also disclosed.Bacterial resistance to β-lactam antibiotics, especially in Gram-negative bacteria, is most commonly mediated by β-lactamases. β-lactamases are enzymes that catalyze the hydrolysis of the β-lactam ring, which inactivates the antibacterial activity of the β-lactam antibiotic and allows the bacteria to become resistant. Inhibition of the β-lactamase with a BLI slows or prevents degradation of the β-lactam antibiotic and restores β-lactam antibiotic susceptibility to β-lactamase producing bacteria. Many of these β-lactamases are not effectively inhibited by BLIs currently on the market rendering the β-lactam antibiotics ineffective in treating bacteria that produce these β-lactamases. There is an urgent need for novel BLIs that inhibit β-lactamases that are not effectively inhibited by the current clinical BLIs (e.g. KPC, class C and ...

ISOXAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 150.-. (canceled) This application claims priority to U.S. Provisional Application No. 61/618,127, filed Mar. 30, 2012, and U.S. Provisional Application No. 61/790,248, filed Mar. 15, 2013. The entire contents of these applications are incorporated herein by reference in their entireties.This disclosure is directed to β-lactamase inhibitors (BLIs) which are effective as inhibitors of β-lactamases and, when used in combination with β-lactam antibiotics are useful in the treatment of bacterial infections. The compounds when combined with a β-lactam antibiotic are effective in treating infections caused by bacteria that are resistant to β-lactam antibiotics due to the presence of β-lactamases. Pharmaceutical compositions comprising such compounds, methods of using such compounds, and processes for preparing such compounds are also disclosed.Bacterial resistance to β-lactam antibiotics, especially in Gram-negative bacteria, is most commonly mediated by β-lactamases. β-lactamases are enzymes that catalyze the hydrolysis of the β-lactam ring, which inactivates the antibacterial activity of the β-lactam antibiotic and allows the bacteria to become resistant. Inhibition of the β-lactamase with a BLI slows or prevents degradation of the β-lactam antibiotic and restores β-lactam antibiotic susceptibility to β-lactamase producing bacteria. Many of these β-lactamases are not effectively inhibited by BLIs currently on the market rendering the β-lactam antibiotics ineffective in treating bacteria that produce these β-lactamases. There is an urgent need for novel BLIs that inhibit β-lactamases that are not effectively inhibited by the current clinical BLIs (e.g. KPC, class C and ...

INHIBITING TRPA1 FOR THE TREATMENT OF ASTHMA

This disclosure describes novel compounds and pharmaceutical compositions for inhibiting the TRPA1 ion channel and/or medical conditions related to TRPA1, such as asthma. 2. The method of claim 1 , wherein the compound of Formula (Ia) is in the form of a hydrochloride salt.3. The method of claim 1 , wherein the pharmaceutical composition is administered by inhalation.4. The method of claim 1 , wherein method is for the treatment of human asthma.5. The method of claim 4 , wherein the human asthma is selected from the group consisting of: cold induced asthma claim 4 , exercise-induced asthma claim 4 , allergy-induced asthma claim 4 , and occupational asthma.6. The method of claim 1 , wherein the pharmaceutical composition is administered as an aerosol.7. The method of claim 1 , wherein the pharmaceutical composition is administered at a dose of about 0.5-25 mg/kg.8. The method of claim 1 , wherein the pharmaceutical composition is administered at a dose of about 5-10 mg/kg.9. The method of claim 1 , wherein the pharmaceutical composition is administered in a unit dosage form that comprises about 200 mg-1600 mg of a compound of Formula (I).10. The method of claim 1 , wherein the pharmaceutical composition is administered in a unit dosage form that comprises about 200 mg claim 1 , 400 mg claim 1 , 800 mg claim 1 , 1200 mg or 1600 mg of a compound of Formula (I).11. The method of claim 6 , wherein the pharmaceutical composition is administered as droplets of about 5 mm or less in diameter.12. The method of claim 1 , wherein the pharmaceutical composition is administered using metered dose aerosol dispenser containing the pharmaceutical composition.13. The method of claim 1 , wherein the pharmaceutical composition is administered using a metered dose inhaler claim 1 , a dry powder inhaler or an air-jet nebulizer.14. The method of claim 1 , wherein the pharmaceutical composition is administered with a pH in the range of about 4.5 to 5.5.16. The method of claim 15 , wherein ...

BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 183-. (canceled)86. A pharmaceutical composition comprising a compound of and at least 1 β-lactam antibiotic.87. The pharmaceutical composition of wherein the β-lactam antibiotic is a cephalosporin.88. The pharmaceutical composition of wherein the β-lactam antibiotic is a carbapenem.89. The pharmaceutical composition of wherein the β-lactam antibiotic is a monobactam. This disclosure is directed to β-lactamase inhibitors (BLIs) which are effective as inhibitors of β-lactamases and, when used in combination with β-lactam antibiotics are useful in the treatment of bacterial infections. The compounds when combined with a β-lactam antibiotic are effective in treating infections caused by bacteria that are resistant to β-lactam antibiotics due to the presence of β-lactamases. Pharmaceutical compositions comprising such compounds, methods of using such compounds, and processes for preparing such compounds are also disclosed.Bacterial resistance to β-lactam antibiotics, especially in Gram-negative bacteria, is most commonly mediated by β-lactamases. β-lactamases are enzymes that catalyze the hydrolysis of the β-lactam ring, which inactivates the antibacterial activity of the β-lactam antibiotic and allows the bacteria to become resistant. Inhibition of the β-lactamase with a BLI slows or prevents degradation of the β-lactam antibiotic and restores β-lactam antibiotic susceptibility to β-lactamase producing bacteria. Many of these β-lactamases are not effectively inhibited by BLIs currently on the market rendering the β-lactam antibiotics ineffective in treating bacteria that produce these β-lactamases. There is an urgent need for novel BLIs that inhibit β-lactamases that ...

Beta-lactamase inhibitors

Aryl substituted diazabicyclooctanes (DBO) compounds that inhibit β-lactamases of class A, class C or class D and potentiate β-lactam antibiotics are disclosed. In particular, this disclosure provides DBO compounds that, when used in the disclosed Synergy MIC Assay with a β-lactam antibiotic at a fixed concentration have an MIC of 8 μg/mL or less against one or more isogenic β-lactamase expressing bacterial strains

ISOXAZOLE BETA-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed. 150-. (canceled)52. The composition of claim 51 , wherein the composition is formulated for intravenous delivery upon reconstitution.53. The composition of claim 51 , wherein the composition is in a unit dosage form comprising 100-1000 mg of the compound of formula (CCC).54. The composition of claim 51 , wherein the composition is in a unit dosage form comprising ceftolozane and the compound of formula (CCC) in a ratio between 1:4 and 8:1.55. The unit dosage form of comprising 100-1000 mg of the compound of formula (CCC).56. The composition of claim 51 , wherein the composition is a reconstituted composition obtained by a process comprising dissolving a composition comprising the ceftolozane and the compound of formula (CCC) in a pharmaceutically appropriate carrier to obtain the reconstituted composition.58. The method of claim 57 , wherein the composition is formulated for intravenous delivery upon reconstitution.59. The method of claim 57 , wherein the pharmaceutical composition is administered in three equal doses per day.60. The method of claim 57 , wherein the therapeutically effective amount comprises 100-1000 mg of the compound of formula (CCC) per unit dose.61. The method of claim 57 , wherein the therapeutically effective amount comprises ceftolozane and the compound of formula (CCC) in a ratio between 1:4 and 8:1.62. The method of claim 57 , wherein:a. the therapeutically effective amount comprises ceftolozane and the compound of formula (CCC) in a ratio of 1:4 to 8:1;b. the therapeutically effective amount comprises 100-1000 mg of the compound of formula (CCC) per unit dose; andc. the pharmaceutical composition is administered in three equal doses per day ...

Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome

The present invention relates to compounds of Formula (I) which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.

Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome

The present invention relates to compounds of formula (I); Pharmaceutical compositions and methods that are useful in the treatment or prevention of metabolic diseases or conditions are also provided.

Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome

The present invention is directed to compounds of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or combination thereof, wherein Y is selected from the group consisting of-CRxRy-, -C(O)-, -O-, -N(H)-, -N(alkyl)- and -S-; wherein each of Rx and Ry is independently selected from the group consisting of hydrogen. alkyl, hydroxyalkyl, and haloalkyl; or Rx and Ry together with the carbon to which they are attached form a monocyclic cycloalkyl or heterocycle ring, Ar1 is selected from the group consisting of phenyl and a monocyclic, five or six- membered heteroaryl, Ar3 is phenyl or monocyclic heteroaryl, wherein Ar3 is substituted with 1, 2, 3 or 4 substituents Ar2 is a group of formula (a), (b), (c), (d), or (e); wherein R is hydrogen, cycloalkyj, alkyl or haloalkyl, Z1, Z2, Z3 and Z4 are C(R101), or one or two of Z1, Z2, Z3 and Z4 is N and the others are C(R101); Z5, Z6 and Z7 are C(102). or one or two of Z5, Z6 and Z7 are N, and the others are C(R102), Z is selected from the group consisting of -OR5, -alkylenyl-OR5, -N(R6)(R7) and -alkylenyI-N(R6)(R7), which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.

5,6,7-trisubstituted-4-aminopyridol(2,3-d)pyrimidine compounds

Acetyl-CoA carboxylase (ACC) inhibitors and their use in diabetes, obesity and metabolic syndrome

The present invention relates to compounds of formula (I), which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.

Inhibitors of neuraminidases

Enantiomerically enriched compounds having the absolute stereochemistry of the formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof, which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

Pyrrolidines as inhibitors of neuraminidases

Disclosed are compounds of formula (I) which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome

The present invention relates to compounds of formula (I) which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.

5,6,7-trisubstituted-4-aminopyrido [2,3-D] pyrimidine

Isoxazole .beta.-lactamase inhibitors

ß-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D ß-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

Tricyclic macrolide antibacterial compounds

Antibacterial compounds having formula (I) and salts, prodrugs, and salts of prodrugs thereof, processes for making the compounds and intermediates used in the processes, compositions containing the compounds, and methods for prophylaxis or treatment of bacterial infections using the compounds are disclosed.

Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome

NEURAMINIDASE INHIBITORS

Un compuesto enriquecido enantioméricamente CARACTERIZADO PORQUE tiene la estereoquímica absoluta de la fórmula: <EMI FILE="00079306_1" ID="1" IMF=JPEG >o una sal, un éster o una prodroga aceptable para uso farmacéutico de los mismosdonde R1 se selecciona del grupo formado por (a) -CO2H, (b) -CH2CO2H, (c) -SO3H, (d) -CH2SO3H, (e) -SO2H, (f) -CH2SO2H, (g) -PO3H2, (h) -CH2PO3H2, (i) -PO2H, o) -CH2PO2H, (k) tetrazolilo, (l) -CH2-tetrazolilo, (m) -C(=O)-NH-S(O)2-R11, (n) -CH2C(=O)-NH-S(O)2-R11, (o) -SO2N(T-R11)R12 y (p) -CH2SO2N(T-R11)R12donde T se selecciona del grupo formado por (i) un enlace, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v) -C(O)NR36, (vi) -C(=S)O-, (vii) -C(=S)S- y (viii) -C(=S)NR36-,R11 se selecciona del grupo formado por(i) C1-C12-alquilo, (ii) C2-C12 -alquenilo, (iii) cicloalquilo, (iv) (cicloalquil)alquilo, (v) (cicloalquil)alquenilo, (vi) cicloalquenilo, (vii) (cicloalquenil)alquilo, (viii) (cicloalquenil)alquenilo, (ix) arilo, (x) (aril)alquilo, (xi) (aril)alquenilo, (xii) heterocíclico, (xiii) alquilo(heterocíclico) y (xiv) alquenilo(heterocíclico); y R12 y R36 se selecionan independiente entre sí, del grupo formado - 2 -(i) hidrógeno, (ii) C1-C12-alquilo, (iii) C1-C12-alquenilo, (iv) cicloalquilo (v) (cicloalquil)alquilo, (vi) (cicloalquil)alquenilo, (vii) cicloalquenilo, (viii) (cicloalquenil)alquilo, (ix) (cicloalquenil)alquenilo, (x) arilo, (xi) (aril)alquilo, (xii) (aril)alquenilo, (xiii) heterocíclico, (xiv) alquilo (heterocíclico) y (xv) alquenilo(heterocíclico)X se selecciona del grupo formado por (a -C(=O)-N(R*)-, (b)-N(R*)-C(=O)-, (c)-C(=S)-N(R*)-, (d) -N(R*)-C(=S)-, (e)-N(R*)-SO2-, y M -SO2-N(R*)-, donde R* es hidrógeno, C1-C3-alquilo inferior o ciclopropilo, R2 se selecciona del grupo formado por (a) hidrógeno, (b) C1-C6-alquilo, (C) C2-C6-alquenilo, (d) C3C6 cicloalquilo, (e) C5-C6-cicloalquenilo, (f) halo-C1-C6-alquilo y (g) halo-C2-C6-alquenilo; o R2-X es <EMI FILE="00079306_2" ID="2" ...

6,7-disubstituted-4-aminopyrido [2,3-D] pyrimidine

ISOXAZOLE β-LACTAMASE INHIBITORS

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidine compounds

Pyrrolidines as inhibitors of neuraminidases

1,3,4-oxadiazole and 1,3,4-thiadiazole β-lactamase inhibitors

β-Lactamase inhibitor compounds (BLIs) are disclosed, including compounds that have activity against class A, class C or class D β-lactamases. Methods of manufacturing the BLIs, and uses of the compounds in the preparation of pharmaceutical compositions and antibacterial applications are also disclosed.

Pyrrolidine derivatives, their preparation and their use as inhibitors of neuraminidases

Enantiomerically enriched compounds having the absolute stereochemistry of the formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof, which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

Inhibitors of neuraminidases

Disclosed are compounds of the formula: which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome

The present invention relates to compounds of Formula (I) which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.

COMPOUNDS 5,6,7-TRISUSTITUIDOS-4-AMINOPIRIDO [2,3-D] PIRIMI- DINA

Un compuesto o una de sus sales o amidas farmacéuticamenteaceptables, que tienen la fórmula (I):DondeR1 y R2 son independientemente H, alquilo C1 -C6 arilalquilo o acilo, o pueden tomarse en conjunto con el átomo de nitrógeno al cual se adhieren para formar un anillo de 5 a 7 miembros, que contiene opcionalmente de 1 a 3 heteroátomos adicionales que se seleccionan a partir de N, O ó S,R3 , R4 y R5 se seleccionan independientemente a partir del alquilo C1 -C6 , alquenilo C2 -C6 , alquinilo C2 -C6 , cicloalquilo C3 -C6 , arilo, arilalquilo, heteroarilo o un grupo heterocíclico y las líneas punteadas que indican un doble enlace opcionalmente presente. A compound or a pharmaceutically acceptable salt or amide thereof, having the formula (I): Where R.sub.1 and R.sub.2 are independently H, C.sub.1 -C.sub.6 arylalkyl or acyl, or may be taken together with the nitrogen atom to which they adhere to form a 5-7 membered ring, optionally containing 1-3 additional heteroatoms that are selected from N, O, or S, R3, R4, and R5 are independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, aryl, arylalkyl, heteroaryl or a heterocyclic group and the dotted lines indicating an optionally present double bond.

Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome

The present invention relates to compounds of formula (I), wherein R1 is selected from the group consisting of hydrogen, cycloalkyl, alkyl and haloalkyl; Y is selected from the group consisting of -(CR4aR-4b)m-, -C(O)-, -O-, -N(H)-, -N(alkyl)- and -S-; wherein m is 1, 2 or 3; Ar3 is phenyl or monocyclic heteroaryl; wherein Ar3 is substituted with 1, 2 or 3 or 4 substituents. Ar1 is selected from the group consisting of phenyl and a monocyclic, five or six- membered heteroaryl; Ar2 is a monocyclic five membered heteroaryl, wherein each Ar2 is independently unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of alkyl, alkenyl, halogen, -CN, -NO2, hydroxy, alkoxy, -NH2, -N(H)(alkyl), -N(alkyl)2. -C(O)OH, -C(O)Oalkyl, -C(O)H, -C(O)alkyl, and haloalkyl; Z is selected from the group consisting of -OR9a, -alkylenyl-OR9a, -NR6R99b; and -alkylenyl-NR6R9b; which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type U diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.

Novel acetyl-coa carboxylase (acc) inhibitors and their use in diabetes, obesity and metabolic syndrome

The present invention is directed to compounds of formula (I), or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or combination thereof, wherein Y is selected from the group consisting of-CRxRy-, -C(O)-, -O-, -N(H)-, -N(alkyl)- and -S-; wherein each of Rx and Ry is independently selected from the group consisting of hydrogen. alkyl, hydroxyalkyl, and haloalkyl; or Rx and Ry together with the carbon to which they are attached form a monocyclic cycloalkyl or heterocycle ring, Ar1 is selected from the group consisting of phenyl and a monocyclic, five or six- membered heteroaryl, Ar3 is phenyl or monocyclic heteroaryl, wherein Ar3 is substituted with 1, 2, 3 or 4 substituents Ar2 is a group of formula (a), (b), (c), (d), or (e); wherein R is hydrogen, cycloalkyj, alkyl or haloalkyl, Z1, Z2, Z3 and Z4 are C(R101), or one or two of Z1, Z2, Z3 and Z4 is N and the others are C(R101); Z5, Z6 and Z7 are C(102). or one or two of Z5, Z6 and Z7 are N, and the others are C(R102), Z is selected from the group consisting of -OR5, -alkylenyl-OR5, -N(R6)(R7) and -alkylenyI-N(R6)(R7), which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.

TRANS-2,6-, 3,6- AND 4,6-DIAZA-5,6,6a,7,8,12b-HEXAHYDROBENZO[C]PHENANTHRENE COMPOUNDS AS DOPAMINE AGONISTS

A tetracyclic compound of formula (1) wherein A and the atoms to which it is attached comprise a pyridine ring selected from: (a), and (b), wherein R?1, R2 and R3¿ are specifically defined, which compounds are useful in the treatment of dopamine-related neurological, psychological and cardiovascular disorders as well as in the treatment of substance abuse and other addictive behavior disorders, cognitive impairment and attention deficit disorder, and methods for the preparation thereof.

Antibacterial compounds

Bacterial protein synthesis-inhibiting compounds having formula (I) and salts, prodrugs, and salts of prodrugs thereof, processes for making the compounds and intermediates in the processes, compositions containing the compounds, and methods of using the compounds are disclosed.