Benzimidazole tetrahydropyran derivatives

Benzimidazole hexahydrofuro[3,2-b]furan derivatives

The novel benzimidazole hexahydrofuro[3,2-B]furan derivatives of the present invention are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

Iminothiadiazine dioxides containing a thioamide, amidine, or amide oxime group as BACE inhibitors, compositions, and their use

In its many embodiments, the present invention provides certain C2-ring-substituted iminothiadiazine compounds, or a tautomers thereof, and pharmaceutically acceptable salts of said compounds and said tautomers. The novel compounds of the invention are as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed.

Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Benzimidazole tetrahydrofuran derivatives

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

Thrombin inhibitors

Compounds of the invention, which may be useful in inhibiting thrombin and associated thrombotic occlusions, have the following structure: or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; R is a heterocycle, —(CR8R9)1-2NH2, or —(CR8R9)1-2OH, wherein R8and R9, each time in which they occur, are independently H, C1-6alkyl, —CH2F, —CHF2, CF3or —CH2OH; W is a) —CHR1R2, where R1is —C(CH3)3, and R2is —(CH2)1-2OH, b) a 5- or 6-membered unsubstituted or substituted heterocycle having 1 or 2 heteroatoms selected from N and O, wherein substituted heterocycle is substituted with R3, c) a 9- or 10-membered unsubstituted or substituted heterocycle having 1 or 2 heteroatoms selected from N, O and S, wherein substituted heterocycle is mono-substituted with R3, or disubstituted with R3and R4, or d) a 3-, 4-, or 5-membered carbocyclic ring which is unsubstituted, mono-substituted with R3, di-substituted with R3and R4, or tri-substituted with R3, R4and R5; R3is —CF3, —COOH, —COOR7, —C( ...

ANTIDIABETIC TRICYCLIC COMPOUNDS

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia. 4. The compound according to wherein n is 1; or a pharmaceutically acceptable salt thereof.5. The compound according to wherein Ris hydrogen; or a pharmaceutically acceptable salt thereof.6. The compound according to wherein X is oxygen; or a pharmaceutically acceptable salt thereof.7. The compound according to whereinT is selected from the group consisting of: CH and N;U is selected from the group consisting of: CH and N;V is selected from the group consisting of: CH and N; andW is selected from the group consisting of: CH and N,provided that one of T, U, V and W is N;or a pharmaceutically acceptable salt thereof.8. The compound according to wherein T is CH; U is CH; V is N; and W is CH; or a pharmaceutically acceptable salt thereof.9. The compound according to whereinA is a bicyclic aryl ring,{'sup': a', 'a', '8, 'sub': 1-6', '1-6, 'wherein each bicyclic aryl ring is unsubstituted or substituted with one to six substituents selected from R, and wherein two Rsubstituents together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring, or a 3-6 membered cycloheteroalkyl ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, and NR, and wherein each 3-6 membered cycloalkyl and each 3-6 membered cycloheteroalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from: —Calkyl, —O—Calkyl, halogen and OH;'}or a ...

Antidiabetic tricyclic compounds

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

Azabenzimidazole tetrahydrofuran derivatives

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

Aminocyclohexanes as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminocyclohexanes which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DPP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

ANTIDIABETIC TRICYCLIC COMPOUNDS

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents

Novel compounds of structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

SUBSTITUTED AMINOPIPERIDINES AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OF DIABETES

The present invention is directed to novel substituted aminopiperidines of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-ÏV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. 2. The compound of wherein Ar is optionally substituted with one to three substituents independently selected from the group consisting of fluorine claim 1 , chlorine claim 1 , bromine claim 1 , methyl claim 1 , trifluoromethyl claim 1 , and trifluoromethoxy.3. The compound of wherein Ar is 2 claim 2 ,5-difluorophenyl or 2 claim 2 ,4 claim 2 ,5-trifluorophenyl.4. The compound of wherein Rand Rare both hydrogen.6. The compound of wherein Ris hydrogen.8. The compound of wherein Ris hydrogen.9. The compound of wherein Ris selected from the group consisting of:hydrogen,{'sub': '1-6', 'Calkyl, wherein alkyl is optionally substituted with hydroxy or one to five fluorines,'}{'sub': 2', '1-6, '—SOCalkyl, and'}{'sub': 2', '3-6, '—SOCcycloalkyl,'}wherein alkyl and cycloalkyl are optionally substituted with one to five fluorines.10. The compound of wherein Ris selected from the group consisting of hydrogen claim 9 , —SOCalkyl claim 9 , and —SOcyclopropyl.16. The compound of wherein Ris hydrogen claim 15 , and Ris selected from the group consisting of hydrogen claim 15 , —SOCalkyl claim 15 , and —SOcyclopropyl.20. The compound of wherein Ris hydrogen claim 19 , and Ris selected from the group consisting of hydrogen claim 19 , —SOCalkyl claim 19 , and —SOcyclopropyl.21. The compound of wherein each Ris independently selected from the group consisting ofhydrogen;cyano;{'sub': '1-6', 'Calkyl, wherein alkyl is optionally ...

SUBSTITUTED AMINOTETRAHYDROTHIOPYRANS AND DERIVATIVES THEREOF AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OF DIABETES

The present invention is directed to novel substituted aminotetrahydrothiopyrans and derivatives thereof of structural formula (I) which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. 2. The compound of wherein Ar is optionally substituted with one to three substituents independently selected from the group consisting of fluorine claim 1 , chlorine claim 1 , bromine claim 1 , methyl claim 1 , trifluoromethyl claim 1 , and trifluoromethoxy.3. The compound of wherein Ar is 2 claim 2 ,5-difluorophenyl or 2 claim 2 ,4 claim 2 ,5-trifluorophenyl.4. The compound of wherein R claim 1 , Rand Rare each hydrogen.6. The compound of wherein Ris hydrogen claim 5 , cyano claim 5 , or —C(O)NH.8. The compound of wherein Ris hydrogen claim 7 , cyano claim 7 , or —C(O)NH.10. The compound of wherein Ris selected from the group consisting of hydrogen claim 9 , —SOCalkyl claim 9 , —SOcyclopropyl claim 9 , and Calkyl wherein alkyl is optionally substituted with hydroxy or one to three fluorines.13. The compound of wherein r is 0.16. The compound of wherein r is 0.18. The compound of wherein Ris hydrogen claim 17 , and Ris selected from the group consisting of hydrogen claim 17 , —SOCalkyl claim 17 , —SOcyclopropyl claim 17 , and Calkyl wherein alkyl is optionally substituted with hydroxy or one to three fluorines.2025-. (canceled)26. A pharmaceutical composition which comprises a compound of and a pharmaceutically acceptable carrier.2728-. (canceled) The present invention relates to novel substituted aminotetrahydrothiopyrans and derivatives thereof which are inhibitors of ...

NOVEL CYCLIC AZABENZIMIDAZOLE DERIVATIVES USEFUL AS ANTI-DIABETIC AGENTS

Novel compounds of structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension. 2. The compound according to wherein:{'sup': '3', 'T is selected from the group consisting of: CR, N and N-oxide;'}{'sup': '1', 'U is selected from the group consisting of: CR, N and N-oxide;'}{'sup': '2', 'V is selected from the group consisting of: CR, N and N-oxide;'}{'sup': '4', 'W is selected from the group consisting of: CR, N and N-oxide,'}provided that at least one of T, U, V and W is N or N-oxide; [{'sub': '2', '(1) —CH—,'}, '(2) —CHF—,', {'sub': '2', '(3) —CF—,'}, '(4) —S—,', '(5) —O—,', {'sub': '2', '(6) —O—CH—,'}, '(7) —NH—,', '(8) —C(O)—,', '(9) —NHC(O)—,', '(10) —C(O)NH—,', {'sub': '2', '(11) —NHSO—,'}, {'sub': '2', '(12) —SONH—, and'}, {'sub': '2', '(13) —CO—,'}], 'X is absent or selected from{'sub': 2', '2', '1-6', '2', '2', '1-6', '1-6', '2', '1-6', '2', '2', '1-6', '1-6', '2, 'wherein each CHis unsubstituted or substituted with 1 or 2 substituents selected from: hydroxy, halogen, NH, Calkyl, COH, COCalkyl, COCalkyl, phenyl and —CH-phenyl, and wherein each NH is unsubstituted or substituted with 1 substituent selected from: Calkyl, COH, COCalkyl, COCalkyl, phenyl and —CH-phenyl;'} [{'sub': '3-10', '(1) Ccycloalkyl,'}, {'sub': '3-10', '(2) Ccycloalkenyl,'}, {'sub': '2-10', '(3) Ccycloheteroalkyl,'}, {'sub': '2-10', '(4) Ccycloheteroalkenyl,'}, '(5) aryl, and', '(6) heteroaryl,, 'Y is selected from{'sup': 'b', 'wherein cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from R;'} (1) oxo,', '(2) —CN,', {'sub': '3', '(3) —CF,'}, {'sub': '1-6', '(4) —Calkyl,'}, {'sub': 2', 't, '(5) —(CH)- ...

AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. 125-. (canceled) The present invention relates to novel substituted aminotetrahydropyrans which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-4 inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of ...

SUBSTITUTED SEVEN-MEMBERED HETEROCYCLIC COMPOUNDS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OF DIABETES

The present invention is directed to novel amino-substituted seven-membered heterocyclic compounds of structural formula (I) which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. 2. The compound of wherein Ar is optionally substituted with one to three substituents independently selected from the group consisting of fluorine claim 1 , chlorine claim 1 , bromine claim 1 , methyl claim 1 , trifluoromethyl claim 1 , and trifluoromethoxy.3. The compound of wherein Ar is 2 claim 2 ,5-difluorophenyl or 2 claim 2 ,4 claim 2 ,5-trifluorophenyl.4. The compound of wherein R claim 1 , Rand Rare each hydrogen.11. The compound of wherein Ris selected from the group consisting of:hydrogen;cyano;{'sub': '2', 'CONH;'}{'sub': '1-3', 'Calkyl, wherein alkyl is optionally substituted with one to five fluorines; and'}{'sub': 3-5', '1-4, 'Ccycloalkyl, wherein cycloalkyl is optionally substituted with one to three substituents independently selected from halogen, hydroxy, and Calkyl, wherein alkyl is optionally substituted with one to five fluorines.'}12. The compound of wherein Ris selected from the group consisting of:hydrogen;phenyl;heteroaryl;{'sub': '3-6', 'Ccycloalkyl;'}{'sub': 2', '1-3, 'SOCalkyl;'}{'sub': 2', '1-3, 'CH2SOCalkyl;'}{'sub': 2', '3-6, 'SOCcycloalkyl; and'}{'sub': 1-5', '1-6', '1-6, 'Calkyl; wherein each alkyl residue is optionally substituted with one to five substituents independently selected from fluorine and hydroxy and wherein phenyl, heteroaryl, and each cycloalkyl residue are optionally substituted with one to five substituents independently selected ...

AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. 125-. (canceled)27. The method of claim 26 , wherein the a sodium-glucose transporter (SGLT) inhibitor is a sodium-glucose transporter 2 (SGLT-2) inhibitor. The present invention relates to novel substituted aminotetrahydropyrans which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-4 inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary ...

NOVEL CRYSTALLINE FORMS OF A DIPEPTIDYL PEPTIDASE-IV INHIBITOR

Novel crystalline forms of (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine are potent inhibitors of dipeptidyl peptidase-IV and are useful for the treatment of non-insulin dependent (Type 2) diabetes mellitus. The invention also relates to pharmaceutical compositions containing these novel forms, processes to prepare these forms and their pharmaceutical compositions as well as uses thereof for the treatment of Type 2 diabetes. 2. Crystalline (2R claim 1 ,3S claim 1 ,5R)-2-(2 claim 1 ,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2 claim 1 ,6-dihydropyrrolo[3 claim 1 ,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine (Form I) of characterized by having at least four peaks in its powder X-ray diffraction pattern selected from the group consisting of 10.3±0.1 2θ claim 1 , 12.7±0.1 2θ claim 1 , 14.6±0.1 2θ claim 1 , 16.1±0.1 2θ claim 1 , 17.8±0.1 2θ claim 1 , 19.2±0.1 2θ claim 1 , 22.2±0.1 2θ claim 1 , 24.1±0.1 2θ and 26.9±0.1 2θ.3. The crystalline form of claim characterized by the following four peaks in its powder X-ray diffraction pattern 17.8±0.1 2θ claim 1 , 19.2±0.1 2θ claim 1 , 22.2±0.1 2θ and 24.1+0.1 2θ.4. The crystalline form of further characterized by the differential scanning calorimetric (DSC) curve of or further characterized by the thermogravimetric analysis (TGA) curve of .5. The crystalline form of further characterized by the nuclear magnetic resonance (NMR) spectra of or further characterized by the IR spectra of .6. Crystalline (2R claim 1 ,3S claim 1 ,5R)-2-(2 claim 1 ,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2 claim 1 ,6-dihydropyrrolo[3 claim 1 ,4-c]pyrazol-5 (4H)-yl]tetrahydro-2H-pyran-3-amine (Form II) of characterized by having at least four peaks in its powder X-ray diffraction pattern selected from the group consisting of 7.5±0.1 2θ claim 1 , 15.0±0.1 2θ claim 1 , 16.2±0.1 2θ claim 1 , 20.9±0.1 2θ claim 1 , 22.0±0.1 2θ claim 1 , 27.0±0.1 2θ claim 1 , 27.6±0.1 2θ claim 1 , ...

Dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted dihydropyrrolopyrazoles of structural Formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

PREPARATION AND USE OF BICYCLIC HIMBACINE DERIVATIVES AS PAR-1 RECEPTOR ANTAGONISTS

The present invention relates to bicyclic himbacine derivatives of the formula or a pharmaceutically acceptable salt thereof, wherein: X is —O—, —N(R), —C(R)(R) or —C(O)—; and Y is —O—, —N(R), —C(R)(R) or —C(O)— and the remaining variables are described herein. The compounds of the invention are effective inhibitors of the PAR-1 receptor. The inventive compounds may be used for the treatment or prophylaxis of disease states such as ACS, secondary prevention of myocardial infarction or stroke, or PAD. 4. The compound as defined in or a pharmaceutically acceptable salt thereof wherein:{'sup': '17', 'W is an optionally mono- or di substituted phenyl wherein the optional substituents are halogen, —CN, alkyl, haloalkoxy or R-heteroaryl;'}{'sup': 10', '11, 'Rand Rare both halogen;'}{'sup': 3', '12', '26', '25', '26', '12', '17', '17', '17', '17', '17, 'sub': 3', '2, 'Ris H, Nhalogen; —OH, alkoxy, —C(O)OR, —C(O)N(H)(R), —N(R)(R), —SOR, R-alkyl, R-cycloalkyl, R-phenyl, R-heterocycloalkyl, or R-heteroaryl;'}{'sup': '12', 'sub': '2', 'Ris H, alkyl cycloalkyl, optionally substituted phenyl or optionally substituted heteroaryl and the optional substituents are halogen, alkyl, —CN, —NH, —N(H)(alkyl) or —N(alkyl)(alkyl).'}{'sup': 17', '12, 'sub': 2', '2, 'Ris 1 to 3 substituents and is independently H; halogen; —CN; —OH, alkoxy; —C(O)OR; —NH; —N(H)(alkyl); —N(alkyl)(alkyl); optionally substituted phenyl; optionally substituted heteroaryl, wherein the optional substituents are halogen, alkyl, NH; —N(H)(alkyl); —N(alkyl)(alkyl) or phenyl;'}{'sup': '25', 'Ris H or alkyl;'}{'sup': '22', 'Ris H, alkyl, hydroxyalkyl or cycloalkyl; and'}{'sup': 26', '17', '12', '22, 'sub': '2', 'Ris H, —OH; alkyl; R-alkyl; cycloalkyl; —C(O)R; cycloalkyl; phenyl, heterocycloalkyl or heteroaryl; —C(S)N(H)(alkyl); —C(S)N(H)(cycloalkyl); —S(O)alkyl or —C(O)N(H)(R).'}6. The compound as defined in or a pharmaceutically acceptable salt thereof claim 5 , wherein{'sup': '10', 'Ris halogen;'}{'sup': '11', 'Ris ...

THROMBIN INHIBITORS

Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: (I) or a pharmaceutically acceptable salt thereof, wherein Q is CH, NR, O, S, S(O) or S(O), wherein Ris H, Calkyl, aryl, or Ccycloalkyl; Ris a heterocycle or —(CRR)1-2NH2, wherein Rand R, each time in which they occur, are independently H, Calkyl, —CHF, —CHF, CFor —CHOH; Ris OH, NHor NHSOCH; and Ris Calkyl. 3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris tetrazole or —CHNH.4. A compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein Ris —CHNH.5. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris OH.6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris —C(CH).7. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris H or CH.8. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris H.9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein Ris H.11. A compound of claim 1 , or pharmaceutically acceptable salt thereof claim 1 , which is(2S)—N-[2-(aminomethyl)-5-chlorobenzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]piperidine-2-carboxamide,(2S)—N-[2-(aminomethyl)-5-chlorobenzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]piperazine-2-carboxamide,(2S)—N-[2-(aminomethyl)-5-chlorobenzyl]-1-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]-4-methylpiperazine-2-carboxamide,(3 S)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]morpholine-3-carboxamide,(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide,(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3-carboxamide 1-oxide, or(3R)—N-[2-(aminomethyl)-5-chlorobenzyl]-4-[(2R)-2-hydroxy-3,3-dimethylbutanoyl]thiomorpholine-3- ...

Heterocyclic cgrp receptor antagonists

The present invention is directed to heterocyclic compounds which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

PYRIDINE CGRP RECEPTOR ANTAGONISTS

The present invention is directed to pyridine derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved. 2) The compound of wherein{'sup': '1', 'claim-text': (1) hydrogen,', {'sub': 1-6', '1-6, 'sup': b', 'c, '(2) —Calkyl, which is optionally substituted with 1-7 substituents each independently selected from the group consisting of halo, hydroxy, —O—Calkyl, and —NRR,'}, '(3) halo,', '(4) hydroxy,', {'sub': '1-6', '(5) —O—Calkyl, which is optionally substituted with 1-6 halo,'}, '(6) —CN or', {'sup': b', 'c, '(7) —NRR,'}], 'Ris selected from{'sup': 2a', '2b, 'claim-text': (1) hydrogen,', {'sub': 1-6', '1-6, '(2) —Calkyl, which is optionally substituted with 1-7 substituents each independently selected from the group consisting of halo, hydroxy and —O—Calkyl,'}, '(3) halo,', {'sup': 'a', '(4) —OR,'}, '(5) —CN and', {'sup': b', 'c, '(6) —NRR;'}], 'Rand Rare independently selected from the group consisting of{'sup': '3', 'claim-text': (1) hydrogen,', {'sub': 1-6', '1-6, '(2) —Calkyl, which is optionally substituted with 1-7 substituents each independently selected from the group consisting of halo, hydroxy and —O—Calkyl,'}, '(3) halo,', {'sup': 'a', '(4) —ORor'}, '(5) —CN,, 'Ris selected from{'sup': 4a', '4b, 'claim-text': (1) hydrogen,', {'sub': 1-6', '1-6, '(2) —Calkyl, which is optionally substituted with 1-7 substituents each independently selected from the group consisting of halo, hydroxy and —O—Calkyl,'}, '(3) halo,', {'sup': 'a', '(4) —OR,'}, '(5) —CN and', {'sup': b', 'c, '(6) —NRR;'}], 'Rand Rare independently selected from the group consisting of{'sup': '5', 'claim-text': (1) hydrogen or', {'sub': 1-6', '1-6, '(2) —Calkyl, which is optionally substituted with 1 ...

NOVEL CRYSTALLINE FORMS OF A DIPEPTIDYL PEPTIDASE-IV INHIBITORS

Novel crystalline forms of (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine are potent inhibitors of dipeptidyl peptidase-IV and are useful for the treatment of non-insulin dependent (Type 2) diabetes mellitus. The invention also relates to pharmaceutical compositions containing these novel forms, processes to prepare these forms and their pharmaceutical compositions as well as uses thereof for the treatment of Type 2 diabetes. 1. (canceled)2. (canceled)3. (canceled)5. The crystalline form of further characterized by the IR spectra of .6. (canceled)7. (canceled)9. The crystalline form of further characterized by the IR spectra of .10. (canceled)11. (canceled)13. (canceled)14. (canceled)16. (canceled)17. (canceled)18. (canceled)19. (canceled)20. (canceled)21. The crystalline form of claim 4 , further characterized by a thermogravimetric analysis (TGA) thermogram characterized by weight loss of about 0.02113% from about 24.57° C. to about 175.21° C.22. The crystalline form of claim 8 , further characterized by a thermogravimetric analysis (TGA) curve of .23. The crystalline form of claim 12 , further characterized by a thermogravimetric analysis (TGA) characterized by weight loss of about 0.5132% from about 140.08° C. to about 173.85° C.24. The crystalline form of claim 15 , further characterized by a thermogravimetric analysis (TGA) curve of .25. The crystalline form of claim 4 , further characterized by a by the nuclear magnetic resonance (NMR) spectra chemical shifts at 128.9±0.2 claim 4 , 124.3±0.2 claim 4 , 119.0±0.2 claim 4 , 48.6±0.2 and 42.6±0.2 ppm.26. The crystalline form of claim 8 , further characterized by a by the nuclear magnetic resonance (NMR) spectrum comprising chemical shifts at 132.1±0.2 claim 8 , 127.5±0.2 claim 8 , 116.9±0.2 claim 8 , 73.5±0.2 and 42.2±0.2 ppm. The present invention relates to novel crystalline forms of a dipeptidyl peptidase-IV inhibitor. More ...

SPIROLACTAM CGRP RECEPTOR ANTAGONISTS

The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved. 5. The compound of wherein Ais a bond claim 1 , Ais a bond claim 1 , and pharmaceutically acceptable salts thereof.6. The compound of wherein{'sup': '5', 'Ais a bond,'}{'sup': '6', 'claim-text': (1) —O—,', {'sup': 6a', '6b, '(2) —CRR—,'}, {'sup': '6a', '(3) —CRH, or'}, {'sub': '2', '(4) —CH—,'}], 'Ais selected from{'sup': '7', 'claim-text': (1) —O—,', {'sup': 6a', '6b, '(2) —CRR—,'}, {'sup': '6a', '(3) —CRH,'}, {'sub': '2', '(4) —CH—, or'}, '(5) a bond,, 'Ais selected from{'sup': '8', 'claim-text': (1) —O—,', {'sup': 6a', '6b, '(2) —CRR—,'}, {'sup': '6a', '(3) —CRH, or'}, {'sub': '2', '(4) —CH—,'}], 'Ais selected from{'sup': 6', '7', '8, 'claim-text': [{'sup': 6a', '6b, '(1) —CRR—,'}, {'sup': '6a', '(2) —CRH—, or'}, '(3) —O—,, 'wherein at least one of A, A, and Ais selected fromand pharmaceutically acceptable salts thereof.7. The compound of wherein Gis —C(R)═ claim 5 , Gis —C(R)═ claim 5 , Gis —N═ or —(N—O)═; and pharmaceutically acceptable salts thereof.8. The compound of wherein Gis —C(R)═ claim 5 , Gis —C(R)═ claim 5 , G3 is C(R)═ claim 5 , and pharmaceutically acceptable salts thereof.9. The compound of wherein{'sup': 3a', '3b, 'J is ═C(R)—, Y is ═C(R)—,'}{'sup': 3a', '3b, 'claim-text': (1) hydrogen,', {'sub': '1-4', 'claim-text': (a) halo,', {'sup': 'a', '(b) —OR,'}, {'sub': '3-6', '(c) —Ccycloalkyl,'}, (i) halo,', {'sup': 'a', '(ii) —OR,'}, '(iii) —CN, and', {'sub': '1-6', '(iv) Calkyl, which is optionally substituted with 1-6 halo,'}], '(d) phenyl or heterocycle, wherein said heterocycle is selected from: imidazolyl, oxazolyl, pyridyl, pyrimidinyl, ...

AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OF DIABETES

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. 125-. (canceled) The present invention relates to novel substituted aminotetrahydropyrans which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-4 inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of ...

AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. 125-. (canceled) The present invention relates to novel substituted aminotetrahydropyrans which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-4 inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of ...

TREATING DIABETES WITH DIPEPTIDYL PEPTIDASE-IV INHIBITORS

The present invention is directed to novel substituted dihydropyrrolopyrazoles of structural Formula I which are inhibitors of the dipeptidyl peptidase-N enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase IV enzyme is involved. 2. The compound of wherein Rand Rare fluorine.3. The compound of wherein Rand Rare fluorine.4. The compound of wherein Y is —N—.5. The compound of wherein Y is —CHR—.6. The compound of wherein Y is —CH—.7. The compound of wherein Rtaken together with Rform (CH).8. The compound of wherein Rtaken together with Rform (CH).9. The compound of wherein Z is —N—.10. The compound of wherein Z is —CH—.11. The compound of wherein X is —NH—.12. The compound of wherein X is —CHR—.13. The compound of wherein Z is —N— claim 1 , X is —CNR— and Rand Rtaken together form a pyrimidine.14. The compound of wherein Ris SONH claim 1 , SONH(Calkyl) claim 1 , SON(Calkyl)or SONHCcycloalkyl.17. The compound of claim 1 , wherein R claim 1 , R claim 1 , Rand Rare not simultaneously hydrogen.19. A pharmaceutical composition which comprises a compound of and a pharmaceutically acceptable carrier.20. A method of treating a condition selected from the group consisting of insulin resistance claim 1 , hyperglycemia claim 1 , and Type 2 diabetes comprising administering a compound of to a mammal in need thereof.21. (canceled) The present invention relates to substituted dihydropyrrolopyrazoles which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-4 inhibitors”) and which maybe useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 ...

NOVEL BENZIMIDAZOLE TETRAHYDROPYRAN DERIVATIVES

Novel compounds described herein are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPKactivated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension. 2. The compound according to wherein T is CR; U is CR; V is CR; and W is CR claim 1 , wherein Ris hydrogen or halogen; or a pharmaceutically acceptable salt thereof.3. The compound according to wherein T is CR; U is CR; V is CR; and W is CR claim 1 , wherein Ris hydrogen or halogen; and Ris halogen; or a pharmaceutically acceptable salt thereof.4. The compound according to claim 1 , wherein T is CR; U is CR; V is CR; and W is CR claim 1 , wherein Ris hydrogen or halogen; Ris halogen; and Ris hydrogen; or a pharmaceutically acceptable salt thereof.5. The compound according to claim 1 , wherein X is —O—; or a pharmaceutically acceptable salt thereof.8. The compound according to claim 1 , wherein Z is NR; or a pharmaceutically acceptable salt thereof.12. The compound according to claim 1 , wherein each Ris independently selected from: aryl-aryl claim 1 , wherein each aryl is unsubstituted or substituted with 1 claim 1 , 2 claim 1 , 3 or 4 substituents independently selected from R claim 1 , and Ris halogen;or a pharmaceutically acceptable salt thereof.13. The compound according to claim 1 , wherein Ris hydrogen or halogen; Ris hydrogen; and Ris hydrogen; or a pharmaceutically acceptable salt thereof.14. The compound according to claim 1 , wherein Ris hydrogen or F; Ris hydrogen; and Ris hydrogen; or a pharmaceutically acceptable salt thereof.18. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.19. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and ...

NOVEL AZABENZIMIDAZOLE TETRAHYDROFURAN DERIVATIVES

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension. 2. The compound according to wherein one of T claim 1 , V and W is N or N-oxide claim 1 , and U is —CR—; or a pharmaceutically acceptable salt thereof.3. The compound according to wherein T is N or N-oxide; U is —CR—; V is —CR—; and W is —CR—; or a pharmaceutically acceptable salt thereof.4. The compound according to wherein T is N; U is —CR—; V is —CR—; and W is —CR—; or a pharmaceutically acceptable salt thereof.5. The compound according to claim 1 , wherein X is —O—; or a pharmaceutically acceptable salt thereof.8. The compound according to claim 1 , wherein Z is NR; or a pharmaceutically acceptable salt thereof.9. The compound according to claim 1 ,{'sup': 1', '2, 'claim-text': (1) halogen,', {'sub': 2', 'p, '(2) —(CH)aryl-aryl, and'}, {'sub': 2', 'p, '(3) —(CH)aryl-heteroaryl,'}], 'wherein each Rand Ris independently selected from{'sub': 2', '3', '2', '1-6', '1-6', '1-6', '1-6', '2, 'sup': a', '1', '2, 'wherein each CHis unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF, —OH, —NH, —Calkyl, —OCalkyl, —NHCalkyl, and —N(Calkyl), and wherein each aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R, provided that at least one of and only one of Rand Ris halogen;'}or a pharmaceutically acceptable salt thereof.10. The compound according to claims 1 ,{'sup': '1', 'claim-text': [{'sub': 2', 'p, '(1) —(CH)aryl-aryl, and'}, {'sub': 2', 'p, '(2) —(CH)aryl-heteroaryl,'}], 'wherein each Ris independently selected from{'sub': 2', '3', '2', '1-6', '1-6', '1-6', '1-6', '2, 'sup': 'a', 'wherein each CHis ...

ALIPHATIC SPIROLACTAM CGRP RECEPTOR ANTAGONISTS

The present invention is directed to aliphatic spirolactam derivatives which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical\compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved. 5. The compound of wherein{'sup': '1', 'claim-text': (1) a bond,', {'sup': e', 'f, '(2) —CRR—, or'}, {'sup': 'b', '(3) —N(R)—,'}], 'Ais selected from{'sup': '2', 'claim-text': [{'sup': e', 'f, '(1) —CRR—,'}, {'sup': 'b', '(2) —N(R)—,'}, '(3) —O—,', {'sup': g', 'h, '(4) —C(R)═C(R)—, or'}, '(5) a bond,, 'Ais selected from{'sup': 2', '3', 'g', 'h, 'wherein Acannot be a bond unless Ais —C(R)═C(R)— or —C≡C—;'}{'sup': '3', 'claim-text': [{'sup': e', 'f, '(1) —CRR—,'}, {'sub': 'v', '(2) —S(O)—,'}, {'sup': g', 'h, '(3) —C(R)═C(R)—, and'}, '(4) —C≡C—;, 'Ais selected fromand pharmaceutically acceptable salts thereof.6. The compound of wherein Aand Aare each a bond; Aand Aare each —CRR— claim 4 , and pharmaceutically acceptable salts thereof.7. The compound of wherein Gis —C(R)═ claim 5 , Gis —C(R)═ claim 5 , Gis —N═ or —(N—O)═; and pharmaceutically acceptable salts thereof.8. The compound of wherein Gis —C(R)═ claim 5 , Gis —C(R)═ claim 5 , Gis C(R)═ claim 5 , and pharmaceutically acceptable salts thereof.11. The compound of whereinJ is —N(R)—, and Y is —C(═O)—;and pharmaceutically acceptable salts thereof.13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.14. Use of a pharmaceutical composition of claim 13 , for the manufacture of a medicament for the treatment of a migraine. CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and ...

AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. 125-. (canceled) The present invention relates to novel substituted aminotetrahydropyrans which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-4 inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of ...

NOVEL AZABENZIMIDAZOLE TETRAHYDROPYRAN DERIVATIVES

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPKactivated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension. 2. The compound according to wherein one of T claim 1 , V and W is N or N-oxide claim 1 , and U is —CR—; or a pharmaceutically acceptable salt thereof.3. The compound according to wherein T is N or N-oxide; U is —CR—; V is —CR—; and W is —CR—; or a pharmaceutically acceptable salt thereof.4. The compound according to wherein T is N; U is —CR—; V is —CR—; and W is —CR—; or a pharmaceutically acceptable salt thereof.5. The compound according to claims 1 ,wherein X is —O—; or a pharmaceutically acceptable salt thereof.8. The compound according to claim 1 , wherein Z is NR; or a pharmaceutically acceptable salt thereof.13. The compound according to claim 1 , wherein Ris hydrogen or absent; Ris hydrogen; and Ris hydrogen; or a pharmaceutically acceptable salt thereof.14. The compound according to claim 1 , wherein Ris hydrogen or absent; Ris hydrogen; Ris hydrogen; and Ris halogen; or a pharmaceutically acceptable salt thereof.18. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.19. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a compound selected from simvastatin claim 1 , ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.20. (canceled)21. (canceled)22. (canceled)23. (canceled)24. A method of treating or preventing a disorder claim 1 , condition or disease that is responsive to the activation of AMP-activated protein kinase in a patient in need thereof comprising administration of a therapeutically effective ...

ANTIDIABETIC TRICYCLIC COMPOUNDS

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslip idemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia. 8. The compound according to wherein Ris —Calkyl claim 1 , wherein each —Calkyl is substituted with one claim 1 , two or three substituents selected from halogen; or a pharmaceutically acceptable salt thereof.9. The compound according to wherein Ris F; or a pharmaceutically acceptable salt thereof.11. The compound according to wherein Ris OCalkyl claim 1 , wherein —Calkyl is substituted with one substituent selected from R; or a pharmaceutically acceptable salt thereof.21. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.2224-. (canceled)25. A method of treating or preventing a disorder claim 1 , condition or disease that is responsive to the agonism of the G-protein-coupled receptor 40 in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.26. A method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.27. A pharmaceutical composition comprising{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(1) a compound of or a pharmaceutically acceptable salt thereof;'} (a) PPAR gamma agonists and ...

Novel benzimidazole tetrahydrofuran derivatives

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

NOVEL BENZIMIDAZOLE HEXAHYDROFURO[3,2-B]FURAN DERIVATIVES

The novel benzimidazole hexahydrofuro[3,2-B]furan derivatives of the present invention are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension. 2. The compound according to wherein T is CR; U is CR; V is CR; and W is CR claim 1 , wherein Ris hydrogen or halogen; or a pharmaceutically acceptable salt thereof.3. The compound according to wherein T is CR; U is CR; V is CR; and W is CR claim 1 , wherein Ris hydrogen or halogen; and Ris halogen; or a pharmaceutically acceptable salt thereof.4. The compound according to claim 1 , wherein T is CR; U is CR; V is CR; and W is CR claim 1 , wherein Ris hydrogen or halogen; Ris halogen; and Ris hydrogen; or a pharmaceutically acceptable salt thereof.5. The compound according to claim 1 , wherein X is —O—; or a pharmaceutically acceptable salt thereof.9. The compound according to claim 1 , wherein Z is NR; or a pharmaceutically acceptable salt thereof.10. The compound according to claim 1 , each Rand Ris independently selected from:(1) halogen,{'sub': 2', 'p', '2-10, '(2) —(CH)aryl-Ccycloheteroalkyl,'}{'sub': 2', 'p, '(3) —(CH)aryl-aryl, and'}{'sub': 2', 'p, '(4) —(CH)aryl-heteroaryl,'}{'sub': 2', '3', '2', '1-6', '1-6', '1-6', '1-6', '2, 'sup': a', '1', '2, 'wherein each CHis unsubstituted or substituted with 1 or 2 substituents selected from: halogen, CF, —OH, —NH, —Calkyl, —OCalkyl, —NHCalkyl, and —N(Calkyl), and wherein each cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from R, provided that at least one of and only one of Rand Ris halogen; or a pharmaceutically acceptable salt thereof.'}11. The compound according to claim 1 , wherein each Ris independently selected from:{'sub ...

TREATING DIABETES WITH DIPEPTIDYL PEPTIDASE-IV INHIBITORS

The present invention is directed to novel substituted dihydropyrrolopyrazoles of structural Formula I which are inhibitors of the dipeptidyl peptidase-N enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase IV enzyme is involved. 2. The compound of wherein Rand Rare fluorine.3. The compound of wherein Rand Rare fluorine.4. The compound of wherein Ris taken together with Rto form a cyclohexyl and tetrahydropyran claim 1 , wherein the cyclohexyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of Calkyl claim 1 , halogen and Calkoxy.5. The compound of wherein the Ris selected from the group consisting of hydrogen claim 1 , SOCH claim 1 , and SOcyclopropyl.6. The compound of wherein Ris taken with the carbon it is attached to and forms a Ccycloalkyl claim 1 , wherein the Ccycloalkyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of —OH and flourine.7. The compound of wherein Ris heterocycle claim 1 , wherein the heterocycle is furan.8. The compound of claim wherein Ris taken with Rand forms a Ccycloalkyl or phenyl.9. The compound of wherein Ris taken with the carbon it is attached to and forms a hetrocycle.10. The compound wherein Ris taken with Rand forms a heterocycle.11. The compound of wherein Ris taken with the carbon it is attached to and forms a heterocycle claim 1 , wherein the heterocycle is imidazolidine-2 claim 1 ,4-dione.12. The compound of wherein Ris hydrogen.13. The compound of wherein Ris hydrogen.14. The compound of wherein Ris taken together with Rto form a 5-7 membered heterocycle wherein the heterocycle is unsubstituted or ...

NOVEL AZABENZIMIDAZOLE HEXAHYDROFURO[E,2-B]FURAN DERIVATIVES

Novel compounds of the structural formula (I) are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension. 3. The compound according to wherein T is N or N-oxide; U is —CR—; V is —CR—; and W is —CR—; or a pharmaceutically acceptable salt thereof.4. The compound according to wherein T is N; U is —CR—; V is —CR—; and W is —CR—; or a pharmaceutically acceptable salt thereof.6. The compound according to claim 1 , wherein X is —O—; or a pharmaceutically acceptable salt thereof.9. The compound according to claim 1 , wherein Z is NR; or a pharmaceutically acceptable salt thereof.13. The compound according to claim 1 , wherein Ris hydrogen or absent; Ris hydrogen; and Ris selected from: hydrogen claim 1 , —Calkyl and —(CH)OH; or a pharmaceutically acceptable salt thereof.14. The compound according to claim 1 , wherein Ris hydrogen or absent; Ris hydrogen; and Ris hydrogen; or a pharmaceutically acceptable salt thereof.15. The compound according to claim 1 , wherein Ris hydrogen or absent; Ris hydrogen; Ris hydrogen; and Ris halogen; or a pharmaceutically acceptable salt thereof.19. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.20. A composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a compound selected from simvastatin claim 1 , ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.21. (canceled)22. (canceled)23. (canceled)24. (canceled)25. A method of treating or preventing a disorder claim 1 , condition or disease that is responsive to the activation of AMP-activated protein kinase in a patient in need thereof comprising ...

Thrombin Inhibitors

Compounds of the invention, which may be useful in inhibiting thrombin and associated thrombotic occlusions, have the following structure: or a pharmaceutically acceptable salt thereof, wherein m is 0 or 1; R is a heterocycle, —(CR 8 R 9 ) 1-2 NH 2 , or —(CR 8 R 9 ) 1-2 OH, wherein R 8 and R 9 , each time in which they occur, are independently H, C 1-6 alkyl, —CH 2 F, —CHF 2 , CF 3 or —CH 2 OH; W is a) —CHR 1 R 2 , where R 1 is —C(CH 3 ) 3 , and R 2 is —(CH 2 ) 1-2 OH, b) a 5- or 6-membered unsubstituted or substituted heterocycle having 1 or 2 heteroatoms selected from N and O, wherein substituted heterocycle is substituted with R 3 , c) a 9- or 10-membered unsubstituted or substituted heterocycle having 1 or 2 heteroatoms selected from N, O and S, wherein substituted heterocycle is mono-substituted with R 3 , or disubstituted with R 3 and R 4 , or d) a 3-, 4-, or 5-membered carbocyclic ring which is unsubstituted, mono-substituted with R 3 , di-substituted with R 3 and R 4 , or tri-substituted with R 3 , R 4 and R 5 ; R 3 is —CF 3 , —COOH, —COOR 7 , —C(O)R 6 , —CH(OH)R 6 , —CH 2 R 6 , R 6 , =O, halogen, R 7 , —OH, —NH 2 , or —NHSO 2 R 7 ; and R 10 is H or C 1-6 alkyl.

CHROMANE MONOBACTAM COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS

The present invention relates to monobactam compounds of Formula (I) and pharmaceutically acceptable salts thereof. The present invention also relates to compositions which comprise a monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic. 2. A compound of whereinT, U and V are each CH;or a pharmaceutically acceptable salt thereof.3. The compound of whereinW is O;or a pharmaceutically acceptable salt thereof.4. The compound of wherein{'sup': '3', 'Q is CR; and'}{'sup': '3', 'Ris hydrogen;'}or a pharmaceutically acceptable salt thereof.5. The compound of wherein{'sub': '2', 'X is CH;'}or a pharmaceutically acceptable salt thereof.6. The compound of wherein{'sub': '2', 'Y is O or CH; and'}{'sub': '2', 'Z is O or CH;'}or a pharmaceutically acceptable salt thereof.7. The compound of wherein{'sub': '2', 'Y is CH; and'}Z is O;or a pharmaceutically acceptable salt thereof.8. The compound of wherein Rand Rare independently selected from:1) hydrogen,{'sub': 1', '8, '2) —C-Calkyl, and'}{'sup': 'e', '3) —C(O)OR,'}{'sub': 1', '8, 'sup': 'a', 'wherein —C-Calkyl is unsubstituted or substituted with one to three R,'}{'sup': 1', 'e', '2', 'e, 'provided that if Ris —C(O)OR, then Ris not —C(O)OR;'}or a pharmaceutically acceptable salt thereof.9. The compound of wherein{'sup': 1', '2, 'claim-text': [{'sub': 1', '8, '1) —C-Calkyl, and'}, {'sup': 'e', '2) —C(O)OR,'}], 'Rand Rare independently selected from'}{'sup': 1', 'e', '2', '2', 'e', '1, 'sub': 1', '8', '1', '8, 'provided if Ris —C(O)OR, then Ris —C-Calkyl, and if Ris —C(O)OR, then Ris —C-Calkyl; or a pharmaceutically acceptable salt thereof.'}10. The compound of wherein{'sup': ...

NOVEL TRICYCLIC COMPOUNDS AS INHIBITORS OF MUTANT IDH ENZYMES

The present invention is directed to tricyclic compounds of formula (I), (Ia) or (Ib) which are inhibitors of one or more mutant IDH enzymes. The present invention is also directed to uses of these tricyclic compounds in the potential treatment or prevention of cancers in which one or more mutant IDH enzymes are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such cancers. 2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein each occurrence of a heterocyclyl is independently selected from the group consisting of: 2-azabicyclo[2.2.2]octanyl claim 1 , 8-azabicyclo[3.2.1]octanyl claim 1 , 2-azaspiro[3.3]heptanyl claim 1 , azaindolyl claim 1 , 1 claim 1 ,6-diazaspiro[3.3]heptanyl claim 1 , 2 claim 1 ,3-dihydro-1 claim 1 ,4-dioxinyl claim 1 , 1 claim 1 ,4-dioxanyl claim 1 , hexahydro-3 claim 1 ,6-epiminofuro[3 claim 1 ,2-b]furanyl claim 1 , hexahydro-1H-furo[3 claim 1 ,4-c]pyrrolyl claim 1 , imidazolyl claim 1 , isoxazolyl claim 1 , morpholinyl claim 1 , 2-oxa-5-azabicyclo[2.2.1]heptanyl claim 1 , 6-oxa-3-azabicyclo[3.1.1]heptanyl claim 1 , 6-oxa-2-azaspiro[3.5]nonanyl claim 1 , 2-oxa-5-azabicyclo[2.2.2]octanyl claim 1 , 3-oxa-8-azabicyclo[3.2.1]octanyl claim 1 , 8-oxa-3-azabicyclo[3.2.1]octanyl claim 1 , 1-oxa-8-azaspiro[4.5]decanyl claim 1 , 6-oxa-2-azaspiro[3.4]octanyl claim 1 , 3-oxa-1 claim 1 ,7-diazaspiro[4.4]nonanyl claim 1 , 3 claim 1 ,9-dioxa-7-azabicyclo[3.3.1]nonanyl claim 1 , oxazolidinyl claim 1 , piperazinyl claim 1 , piperidinyl claim 1 , pyrazolyl claim 1 , pyridazinyl claim 1 , pyridinyl claim 1 , pyrimidinyl claim 1 , pyrrolidinyl claim 1 , pyrrolyl claim 1 , tetrahydrofuranyl and tetrahydropyranyl.3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , wherein:{'sup': 1', '2', '1', '2, 'sub': 1-6', '1-6', '2', '3', '2', '1-4, 'A ...

AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OF DIABETES

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. 125-. (canceled) The present invention relates to novel substituted aminotetrahydropyrans which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-4 inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of ...

IMINOTHIADIAZINE DIOXIDES CONTAINING A THIOAMIDE, AMIDINE, OR AMIDE OXIME GROUP AS BACE INHIBITORS, COMPOSITIONS, AND THEIR USE

In its many embodiments, the present invention provides certain C2-ring-substituted iminothiadiazine compounds, or a tautomers thereof, and pharmaceutically acceptable salts of said compounds and said tautomers. The novel compounds of the invention are as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed. 2. A compound of claim 1 , or a tautomer thereof claim 1 , or a pharmaceutically acceptable salt of said compound or said tautomer claim 1 , wherein:{'sup': '1', 'sub': 2', '2', '3, 'Ris selected from the group consisting of H, methyl, ethyl, cyclopropyl, —CH-cyclopropyl, and —CHOCH.'}3. A compound of claim 2 , or a tautomer thereof claim 2 , or a pharmaceutically acceptable salt of said compound or said tautomer claim 2 , wherein:{'sup': '4', 'sub': '2', 'Ris selected from the group consisting of methyl and —CHF; and'}{'sup': 2', '3, 'one of Rand Ris H and the other is selected from the group consisting of H and methyl.'}4. A compound of claim 3 , or a tautomer thereof claim 3 , or a pharmaceutically acceptable salt of said compound or said tautomer claim 3 , wherein:{'sup': 1', '10', '10, 'Lis selected from the group consisting of —C(S)NH— and —C(NR)NH—, wherein Ris selected from the group consisting of H and —OMe.'}5. A compound of claim 4 , or a tautomer thereof claim 4 , or a pharmaceutically acceptable salt of said compound or said tautomer claim 4 , wherein:ring A is selected from the group consisting of phenyl, pyridazinyl, pyridyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl;m is 0, 1, or 2; and{'sup': 'A', 'sub': 5', '3', '3', '2', '3', '2', '3', '2', '2', '3', '3', '2', '3', '2', '2', '3', '2, 'each R(when present) is independently selected from the ...

BIARYL MONOBACTAM COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF BACTERIAL INFECTIONS

The present invention relates to biaryl monobactam compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, Z, A, Q, M, W, Rand Rare as defined herein. The present invention also relates to compositions which comprise a biaryl monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic. 4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein Rand Rare independently hydrogen claim 3 , C-Calkyl claim 3 , tetrazolyl claim 3 , oxadiazolonyl or —C(O)OR; and Ris hydrogen.5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein X is N.6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein X is CR.8. The compound of any of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein Ais HetC or a 5- to 6-membered monocyclic aromatic ring with 1 claim 2 , 2 claim 2 , or 3 ring atoms independently selected from N claim 2 , N as a quaternary salt claim 2 , O and S claim 2 , optionally substituted with one to four R.10. The compound of any of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein M is —(CH)Ror R.11. The compound of any of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein M is C-Calkyl substituted with —NRR.12. The compound of any of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein Rand Rare methyl claim 2 , or Ris methyl and Ris hydrogen.14. A trifluoroacetic acid salt of the compound of .15. A trifluoroacetic acid salt of the compound of .16. A pharmaceutical composition comprising a ...

BIARYL MONOBACTAM COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF BACTERIAL INFECTIONS

The present invention relates to biaryl monobactam compounds of Formula I 4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof claim 3 , wherein Rand Rare independently hydrogen claim 3 , C-Calkyl claim 3 , tetrazolyl claim 3 , oxadiazolonyl or —C(O)OR; and Ris hydrogen.5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein X is N.6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein X is CR.8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein Ais HetC or a 5- to 6-membered monocyclic aromatic ring with 1 claim 2 , 2 claim 2 , or 3 ring atoms independently selected from N claim 2 , N as a quaternary salt claim 2 , O and S claim 2 , optionally substituted with one to four R.9. (canceled)10. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein M is —(CH)Ror R.11. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein M is C-Calkyl substituted with —NRR.12. The compound of claim 2 , or a pharmaceutically acceptable salt thereof claim 2 , wherein Rand Rare methyl claim 2 , or Ris methyl and Ris hydrogen.14. A trifluoroacetic acid salt of the compound of .15. A trifluoroacetic acid salt of the compound of .16. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof claim 1 , and a pharmaceutically acceptable carrier.17. A pharmaceutical composition according to claim 16 , which further comprises a therapeutically effective amount of a beta-lactamase inhibitor compound.18. A pharmaceutical composition according to claim 17 , wherein the beta-lactamase inhibitor compound is selected from the group consisting of relebactam claim 17 , tazobactam claim 17 , clavulanic acid claim 17 , sulbactam claim 17 , and avibactam.19. A method for treating a bacterial infection ...

Biaryl monobactam compounds and methods of use thereof for the treatment of bacterial infections

The present invention relates to biaryl monobactam compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, Z, A1, Q, A2, M, W, RX and Rz are as defined herein. The present invention also relates to compositions which comprise a biaryl monobactam compound of the invention or a pharmaceutically acceptable salt therof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic.

Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme ('DP-IV inhibitors') and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

AMINOTETRAHYDROPYRANES AS DIPEPTIDYLPEPTIDASE-IV INHIBITORS TREATMENT OR PREVENTION OF DIABETES

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

New 5-(pyrrol-2-oyl)-1,2-dihydro-3h-pyrrolo(1,2-a)pyrrole derivatives as anti-inflammatory and analgesic agents

Epibatidine and derivatives thereof as nicotine cholinergic receptor agonists

The present invention provides methods of treatment utilizing pharmaceutical compositions comprising an effective nicotine agonist amount of epibatidine (1) or a synthetic 7-azabicyclo[2.2.1]-heptane or heptene derivative thereof, and a pharmaceutically acceptable earner, excipient or diluent.

Novel crystalline forms of a dipeptidyl peptidase-iv inhibitor.

Las nuevas formas cristalinas de (2R,3S,5R)-2-(2,5-Difluorofenil)- 5-[2-(metilsulfonil)-2,6-dihid ropirrolo[3,4-c]pirazol-5(4H)-il]te trahidro2H-piran-3-amina son potentes inhibidores de la dipeptidil peptidasa-IV y son útiles para el tratamiento de la diabetes mellitus no insulinodependiente (Tipo 2); la presente invención también se refiere a composiciones farmacéuticas que contienen estas nuevas formas, a los procedimientos para preparar estas formas y a sus composiciones farmacéuticas así como a los usos de las mismas para el tratamiento de la diabetes de Tipo 2.

Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminocyclohexanes which are inhibitors of the dipeptidyl peptidase-IV enzyme ("DPP-IV inhibitors") and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved. Compounds of the invention include the compound of formula I (see formula I)

Preparation and use of bicyclic himbacine derivatives as PAR-1 receptor antagonists

The present invention relates to bicyclic himbacine derivatives of the formula or a pharmaceutically acceptable salt thereof, wherein: X is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)—; and Y is —O—, —N(R), —C(R 8 )(R 9 ) or —C(O)— and the remaining variables are described herein. The compounds of the invention are effective inhibitors of the PAR-1 receptor. The inventive compounds may be used for the treatment or prophylaxis of disease states such as ACS, secondary prevention of myocardial infarction or stroke, or PAD.

Novel cholesterol lowering compounds

2109523 9220336 PCTABScor01 Disclosed herein are compounds of structural formula (I) which are useful as cholesterol lowering agents. These compounds are also useful as inhibitors of squalene synthetase, inhibitors of fungal growth, inhibitors of farnesyl-protein transferase and farnesylation of the oncogene protein Ras. These compounds are also useful in the treatment of cancer.

Novel crystalline forms of a dipeptidyl peptidase-iv inhibitor

Novel crystalline forms of (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine are potent inhibitors of dipeptidyl peptidase-IV and are useful for the treatment of non-insulin dependent (Type 2) diabetes mellitus. The invention also relates to pharmaceutical compositions containing these novel forms, processes to prepare these forms and their pharmaceutical compositions as well as uses thereof for the treatment of Type 2 diabetes.

Chromane monobactam compounds for the treatment of bacterial infections

The present invention relates to monobactam compounds of Formula (I) and pharmaceutically acceptable salts thereof. The present invention also relates to compositions which comprise a monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic.

Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula (I) which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

New 5-(pyrrol-2-oyl)-1,2-dihydro-3h-pyrrolo(1,2-a)pyrrole derivatives as anti-inflammatory and analgesic agents

Aminotetrahydropyrans as dipeptidyl peptidase IV inhibitors for the treatment or prevention of diabetes

Foreliggende oppfinnelse er rettet mot nye, substituerte aminotetra-hydropyraner med strukturformel (I) som er inhibitorer av enzymet dipeptidylpeptidase-IV og som er anvendbare for behandling eller forebyggelse av sykdommer i hvilke dipeptidylpeptidase-IV-enzymet inngår, f.eks. diabetes, fortrinnsvis type 2 diabetes. Oppfinnelsen er også rettet mot farmasøytiske preparater som omfatter disse forbindelsene og anvendelse av disse forbindelsene og preparatene for forebyggelse eller behandling av sykdommer i hvilke enzymet dipeptidylpeptidase-IV inngår.

(Pyrimidinyl) (phenyl) substituted fused heteroaryl p38 inhibiting and pkg kinase inhibiting compounds

Compounds of formula (I) and pharmaceutically acceptable salts thereof are useful in the treatment of cytokine mediated diseases such as arthritis and in the treatment and/or prevention of protozoal diseases such as coccidiosis.

Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders

New 5-(pyrrol-2-oyl)-1,2-dihydro-3h-pyrrolo(1,2-a)pyrrole derivatives as anti-inflammatory and analgesic agents

Antiprotozoal imidazopyridine compounds

Compounds described by the Formula (I) or (II): or pharmaceutically acceptable salts, or N-oxides thereof. The compounds are useful for the treatment and prevention of protozoal diseases in mammals and birds. A method for controlling coccidiosis in poultry comprises administering an effective amount of the compound alone, or in combination with one or more anticoccidieal agent(s). A composition for controlling coccidiosis in poultry comprises the compound alone, or in combination with one or more anticoccidial agent(s). Methods for the treatment and prevention of mammalian protozoal diseases, such as, for example, toxoplasmosis, malaria. African typanosomiasis, Chagas disease, and opportunistic infections comprise administering the compound alone, or in combination with one or more antiprotozoal agent(s).

Aminocyclohexanes as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminocyclohexanes which are inhibitors of the dipeptidyl peptidase-IV enzyme ('DPP-IV inhibitors') and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Novel tricyclic compounds as inhibitors of mutant idh enzymes

The present invention is directed to tricyclic compounds of formula (I) which are inhibitors of one or more mutant IDH enzymes: (I). The present invention is also directed to uses of the tricyclic compounds described herein in the potential treatment or prevention of cancers in which one or more mutant IDH enzymes are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such cancers.

Aminocyclohexanes as dipeptidyl peptidase-IV inhibitors for the treatment of diabetes

The present invention is directed to novel substituted aminocyclohexanes which are inhibitors of the dipeptidyl peptidase-IV enzyme (“DPP-IV inhibitors”) and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Thrombin inhibitors

Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof, wherein Q is CH 2 , NR 4 , O, S, S(O) or S(O 2 ), wherein R 4 is H, C 1-6 alkyl, aryl, or C 3-8 cycloalkyl; R 1 is a heterocycle or —(CR 5 R 6 ) 1-2 NH 2 , wherein R 5 and R 6 , each time in which they occur, are independently H, C 1-6 alkyl, —CH 2 F, —CHF 2 , CF 3 or —CH 2 OH; R 2 is OH, NH 2 or NHSO 2 CH 3 ; R 3 is C 1-6 alkyl.

2,5 - diaryl tetrahydrofurans and 2-aryl-5-cyclo tetrahydrofurans and analogs thereof as paf antogonists

Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

Novel cholesterol lowering compounds

Disclosed herein are compounds of structural formula (I) which are useful as cholesterol lowering agents. These compounds are also useful as inhibitors of squalene synthetase, inhibitors of fungal growth, inhibitors of farnesyl-protein transferase and farnesylation of the oncogene protein Ras. These compounds are also useful in the treatment of cancer.

Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents

Novel compounds of structural formula (I) are activators of AMP-protein kinase and are useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention are useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

Compounds and Methods for the Treatment of Cardiovascular, Inflammatory and Immune Disorders

Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

DERIVATIVES OF DIARIL PIPERIDIL PIRROL AS ANTIPROTOZOAR AGENTS.

Un compuesto de Fórmula I o una sal farmacéuticamente aceptable del mismo en el que: R1 es 1) alquilo-C1-10, 2) alquenilo-C2-10, 3) alquinilo-C2-10, 4) Cy, 5) Cy-alquilo-C1-10; 6) Cy-alquenilo-C2-10, 7) Cy-alquinilo-C2-10, en el que alquilo, alquenilo y alquinilo están opcionalmente sustituidos por de uno a cuatro sustituyentes seleccionados independientemente de Ra; y Cy está opcionalmente sustituido por de uno a cuatro sustituyentes seleccionados independientemente de Rb; R2 y R3 son independientemente 1) hidrógeno, o 2) un grupo seleccionado de R1; o R2 y R3 junto con los átomos a los que están unidos forman un anillo de 4 a 7 miembros que contiene de 0 a 2 heteroátomos adicionales seleccionados independientemente entre oxígeno, azufre y nitrógeno, en los que dicho anillo puede estar aislado o benzo-fusionado, y opcionalmente sustituido por de uno a cuatro sustituyentes seleccionados independientemente de Rb. A compound of Formula I or a pharmaceutically acceptable salt thereof wherein: R1 is 1) C1-10 alkyl, 2) C2-10 alkenyl, 3) C2-10 alkynyl, 4) Cy, 5) Cy- C1-10 alkyl; 6) Cy-C2-10 alkenyl, 7) Cy-C2-10 alkynyl, wherein alkyl, alkenyl and alkynyl are optionally substituted by one to four substituents independently selected from Ra; and Cy is optionally substituted by one to four substituents independently selected from Rb; R2 and R3 are independently 1) hydrogen, or 2) a group selected from R1; or R2 and R3 together with the atoms to which they are attached form a 4 to 7 member ring containing 0 to 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen, in which said ring can be isolated or benzo-fused , and optionally substituted by one to four substituents independently selected from Rb.

Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted dihydropyrrolopyrazoles of structural Formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Biaryl monobactam compounds for the treatment of bacterial infections

Thrombin inhibitors

Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Novel benzimidazole hexahydrofuro[3,2-b]furan derivatives

The novel benzimidazole hexahydrofuro[3,2-B]furan derivatives of the present invention are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPK-activated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

Spirolactam cgrp receptor antagonists

The present invention is directed to spirolactam analogues which are antagonists of CGRP receptors and useful in the treatment or prevention of diseases in which CGRP is involved, such as migraine. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved.

Novel crystalline forms of a dipeptidyl peptidase-iv inhibitor

Novel crystalline forms of (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine are potent inhibitors of dipeptidyl peptidase-IV and are useful for the treatment of non-insulin dependent (Type 2) diabetes mellitus. The invention also relates to pharmaceutical compositions containing these novel forms, processes to prepare these forms and their pharmaceutical compositions as well as uses thereof for the treatment of Type 2 diabetes.

Bace inhibitors of iminothiadiazine dioxides

In its many embodiments, the present invention provides certain C2-ring-substituted iminothiadiazine compounds, or a tautomers thereof, and pharmaceutically acceptable salts of said compounds and said tautomers. The novel compounds of the invention are as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer's disease, are also disclosed.

CONNECTIONS AND METHODS FOR TREATING CARDIOVASCULAR, INFLAMMATIONAL AND IMMUNE DISEASES

Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

Disclosed are aminotetrahydropyran compounds of formula (I), wherein the substituents are as described within the specification. An example of a compound of formula (I) includes (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine. Further disclosed is a pharmaceutical composition which comprises a compound of formula (I) and a pharmaceutically acceptable carrier, and the use of a compound of formula (I) in the manufacture of a medicament for use in treating a condition selected from the group consisting of insulin resistance, hyperglycemia, and Type 2 diabetes.

Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Thrombin inhibitors

Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: (I) or a pharmaceutically acceptable salt thereof, wherein Q is CH 2 , NR 4 , O, S, S(O) or S(O 2 ), wherein R 4 is H, C 1-6 alkyl, aryl, or C 3-8 cycloalkyl; R 1 is a heterocycle or -(CR 5 R 6 )1-2NH2, wherein R 5 and R 6 , each time in which they occur, are independently H, C 1-6 alkyl, -CH 2 F,-CHF 2 , CF 3 or -CH 2 OH; R 2 is OH, NH 2 or NHSO 2 CH 3 ; and R 3 is C 1-6 alkyl.

Compounds and methods for the treatment of cardiovascular, inflammatory and immune disorders

2,5-Diaryl tetrahydrofurans, 2,5-diaryl tetrahydrothiophenes, 1,3-diaryl cyclopentanes are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i,e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. Also disclosed is a method to treat disorders mediated by PAF and/or leukotrienes that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutically acceptable carrier, to a patient in need of such therapy.

Thrombin inhibitors

Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: (I) or a pharmaceutically acceptable salt thereof, wherein Q is CH2, NR4, O, S, S(O) or S(O2), wherein R4 is H, C1-6 alkyl, aryl, or C3-8 cycloalkyl; R1 is a heterocycle or -(CR5R6)1-2NH2, wherein R5 and R6, each time in which they occur, are independently H, C1-6 alkyl, -CH2F,-CHF2, CF3 or -CH2OH; R2 is OH, NH2 or NHSO2CH3; and R3 is C1-6 alkyl.

COMPOUND, TRIFLUOROACETIC ACID SALT, PHARMACEUTICAL COMPOSITION, METHOD FOR TREATING A BACTERIAL INFECTION, AND, USE OF A COMPOUND

A presente invenção refere-se a compostos de biaril monobactama de Fórmula I e sais farmaceuticamente aceitáveis dos mesmos, em que X, Y, Z, Al, Q, A2, M, W, Rx e Rz são como aqui definidos. A presente invenção também se refere a composições que compreendem um composto de biaril monobactama da invenção ou um sal farmaceuticamente aceitável dos mesmos, e um carreador farmaceuticamente aceitável. A invenção refere-se ainda a métodos para tratar uma infecção bacteriana compreendendo administrar ao paciente uma quantidade terapeuticamente eficaz de um composto da invenção, isoladamente ou em combinação com uma quantidade terapeuticamente eficaz de um segundo antibiótico de beta-lactama. The present invention relates to biaryl monobactam compounds of Formula I and pharmaceutically acceptable salts thereof, wherein X, Y, Z, Al, Q, A2, M, W, Rx and Rz are as defined herein. The present invention also relates to compositions comprising a biaryl monobactam compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates to methods of treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic.

Antiprotozoal imidazopyridine compounds

Compounds described by the Formula (I): (I) or pharmaceutically acceptable salts, or N-oxides thereof. The compounds are useful for the treatment and prevention of protozoal diseases in mammals and birds. A method for controlling coccidiosis in poultry comprises administering an effective amount of the compound alone, or in combination with one or more anticoccidial agent(s). A composition for controlling coccidiosis in poultry comprises the compound alone, or in combination with one or more anticoccidial agent(s). Methods for the treatment and prevention of mammalian protozoal diseases, such as, for example, toxoplasmosis, malaria, African trypanosomiasis, Chagas disease, and opportunistic infections comprise administering the compound alone, or in combination with one or more antiprotozoal agent(s).

Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes

The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

Novel benzimidazole tetrahydropyran derivatives

Novel compounds described herein are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPKactivated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

Novel benzimidazole tetrahydrofuran derivatives

MONOBACTAM CHROMAN COMPOUNDS FOR THE TREATMENT OF BACTERIAL INFECTIONS

Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

Zaragozic acid derivatives

This invention is directed to compounds of formula (I) which are novel C3- or C5-acyl sulfonamide, carboxamic acid or tetrazolyl analogs of the Zaragozic acids. These compounds inhibit the enzyme squalene synthase and are useful as cholesterol lowering agents.

New 2,5-diaryl tetrahydrofurans and analogs thereof as paf antagonists

A class of 2,5-diaryl tetrahydrofuran derivatives are PAF antagonists and are therefore useful in the treatment of various diseases including prevention of platelet aggregation, hypotension, inflammation, asthma, lung edema, adult respiratory distress syndrome, various shock syndromes, cardiovascular disorders and other related skeletal-muscular disorders.

Cholesterol-lowering agents

This invention relates to compounds of structural formula (I): ##STR1## which are squalene synthase inhibitors and thus useful as cholesterol lowering agents and antifungal agents. These compounds are also inhibitors of farnesyl protein transferass and farnesylation of the oncogene protein Ras and thus useful in treating cancer.

Aminocyclohexanes as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

Trans-2-(3,4,5-trimethoxyphenyl)-5-(5,6-dimethoxy-3-pyridyl)-tetrahydrothiophene, a PAF-antagonist.

2,5-Diaryl tetrahydrothiophenes of formula: < CHEM > or a sulfoxide or sulfone thereof are disclosed wherein R and R<1> independently are (a) hydrogen (b) lower alkyl or cycloalkyl of l-6 carbon atoms (c) haloloweralkyl (d) halo (e) COOH (f) CONR<2>R<3> wherein R<2> and R<3> independently represent C1-6 alkyl and hydrogen (g) COOR<2> (h) loweralkenyl (i) COR<2> (j) -CH2OR<2> (k) loweralkynyl (l) -CH2NR<2>R<3> (m) -CH2SR<2> (n) =O or (o) -OR<2> Ar and Arl are the same or different from each other and are (a) phenyl or substituted phenyl of formula < CHEM > where R<4>-R<8> independently represent H, RO-, RS-, R<2>SO, R<2>SO2-, CF3O-, CF3S-, CF3SO-, CF3SO2-, R<2>R<3>N-, -NR<2>-COR<3>, -OCONH2, -OCH2CO2R<2>, -SO2NR<2>R<3>, -CO2R<2>, CONR<2>R<3>, -CR<2>R<3>R<4>, -NR<2>SO2R<3>, COR<2>, NO2, or CN or R<4>-R<5>, R<5>-R<6>, R<6>-R<7> and R<7>-R<8> are joined together forming a bridge (b) pyrryl or substituted pyrryl (c) furyl or substituted furyl (d) pyridyl or substituted pyridyl (e) thiophene or substituted thiophene (f) cyclohexyl or substituted cyclohexyl or (g) pyrimidyl or substituted pyrimidyl salts thereof. These compounds are found to be leukotriene inhibitors and potent and specific PAF (Platelet Activating Factor) antagonists.

Biologically active compounds and process therefor

Disclosed herein are compounds of structural formula (I), and a process for making compounds of formula (I) involving selective saponification of the C-4 ester using Lewis acids such as thionyl chloride, tin (IV) chloride or hydrogen fluoride. The compounds of formula (I) are useful as cholesterol lowering agents.

Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity

Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

The present invention is directed to compounds which are inhibitors of the dipeptidyl peptidase-IV enzyme ('DP-IV inhibitors') and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

5-(2,3-Dihydro-1H-pyrrolizin-5-oyl)-2-alkanoic or carboxylic acids and analogs as anti-inflammatory and analgesic agents

New 5-(2,3-dihydro-1H-pyrrolizin-5-oyl)-, 5-(2,3-dihydro-1H-pyrrolo[2,1-b]thiazol-5-oyl)-, 5-(2,3-dihydro-1H-pyrrolo[2,1-b]imidazol-5-oyl)-, and 5-(2,3-dihydro-1H-pyrrolo[2,1-b]oxazol-5-oyl)-pyrrole-2-alkanoic acid derivatives have been prepared. They are found to be effective inhibitors of platelet aggregation and are analgesic and anti-inflammatory agents with low ulcerogenic side effects.