EP1244628A1 - Substituted 8-arylquinoline phosphodiesterase-4 inhibitors - Google Patents
Substituted 8-arylquinoline phosphodiesterase-4 inhibitorsInfo
- Publication number
- EP1244628A1 EP1244628A1 EP00986937A EP00986937A EP1244628A1 EP 1244628 A1 EP1244628 A1 EP 1244628A1 EP 00986937 A EP00986937 A EP 00986937A EP 00986937 A EP00986937 A EP 00986937A EP 1244628 A1 EP1244628 A1 EP 1244628A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- c6alkyl
- phenyl
- aryl
- methylsulfonyl
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Definitions
- the present invention is directed to compounds that are substituted 8- arylquinolines.
- this invention is directed to substituted 8-arylquinolines which are phosphodiesterase-4 inhibitors wherein the aryl group at the 8-position contains a substituent substituted-alkenyl group.
- Hormones are compounds that variously affect cellular activity. In many respects, hormones act as messengers to trigger specific cellular responses and activities. Many effects produced by hormones, however, are not caused by the singular effect of just the hormone. Instead, the hormone first binds to a receptor, thereby triggering the release of a second compound that goes on to affect the cellular activity. In this scenario, the hormone is known as the first messenger while the second compound is called the second messenger.
- Cyclic adenosine monophosphate (adenosine 3', 5 '-cyclic monophosphate, "cAMP” or “cyclic AMP”) is known as a second messenger for hormones including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin.
- cAMP mediates cellular responses to hormones.
- Cyclic AMP also mediates cellular responses to various neurotransmitters .
- PDE Phosphodiesterases
- PDE4 Phosphodiesterases
- A.H.Cook, et al., J.Chem. Soc, 413-417(1943) describes gamma- pyridylquinolines.
- Other quinoline compounds are described in Kei Manabe et al., J. Org. Chem., 58(24):6692-6700( 993); Kei Manabe et al., J.Am. Chem. Soc. ,
- 5,780,478 describes PDE4 inhibitors that are tetra- substituted phenyl derivatives.
- International Patent Publication WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors.
- U.S. Patent No. 5,633,257 describes PDE4 inhibitors that are cyclo(alkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.
- the present invention is directed to novel substituted 8-arylquinolines that are PDE4 inhibitors, wherein the aryl group at the 8-position is substituted by a substituted-alkenyl group.
- This invention also provides a pharmaceutical composition which includes an effective amount of the novel substituted 8-arylquinpline and a pharmaceutically acceptable carrier.
- This invention further provides a method of treatment in mammals of, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn' s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft
- Fig. 1 is a chemical schematic drawing of the general structure of the compounds of the present invention.
- Fig. 2 is a graph of Counts against °Theta for an X-ray Powder Diffraction of the Form A polymorph of the benzenesulfonic acid salt of 6-[l-methyl- l-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-l,2,4-oxadiazol-5-yl]-2-[4- (methylsulfonyl)phenyl]ethenyl]phenyl]quinoline.
- Fig. 3 is a graph of Counts against °Theta for an X-ray Powder Diffraction of the Form B polymorph of the benzenesulfonic acid salt of 6-[l-methyl- l-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-l,2,4-oxadiazol-5-yl]-2-[4- (methylsulfonyl)phenyl]ethenyl]phenyl]quinoline.
- Fig. 4 is a comparison of the X-ray Powder Diffractions of the Form A polymorph (bottom trace) and the Form B (upper trace) of the benzenesulfonic acid salt of 6-[l-methyl-l-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-l,2,4-oxadiazol-5- yl]-2-[4-(methylsulfonyl)phenyl]ethenyl]phenyl]quinoline.
- Fig. 5 is a graph of the distinguishing feature peaks of the X-ray Powder Diffraction of the Form A polymorph of the benzenesulfonic acid salt of 6-[l- methyl-l-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-l,2,4-oxadiazol-5-yl]-2-[4- (methylsulfonyl)phenyl]ethenyl]phenyl]quinoline.
- Fig. 5 is a graph of the distinguishing feature peaks of the X-ray Powder Diffraction of the Form A polymorph of the benzenesulfonic acid salt of 6-[l- methyl-l-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-l,2,4-oxadiazol-5-yl]-2-[4- (methylsulfonyl)phenyl]ethenyl]phenyl
- 6 is a graph of the distinguishing feature peaks of the X-ray Powder Diffraction of the Form B polymorph of the benzenesulfonic acid salt of 6-[l- methyl-l-(methylsulfonyl)ethyl]-8-[3-[(E)-2-[3-methyl-l,2,4-oxadiazol-5-yl]-2-[4- (methylsulfonyl)phenyl]ethenyl]phenyl]quinoline.
- a compound of this invention is represented by Formula (I):
- Si, S2, and S3 are independently H, -OH, halogen, -C ⁇ -C6alkyl, -NO2, -CN, or -C ⁇ -C6alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; Ri is a H, OH, halogen, carbonyl, or -Ci-Cgalkyl, -cycloC3-C6alkyl,
- each substituent is independently a halogen, -OH, -CN, -C ⁇ -C6alkyl, -cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(Co-C6alkyl), -C(O)-aryloxy, -C ⁇ -C6alkoxy, -(Co-C6alkyi ⁇ Co-C6alkyl)amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO n -(Ci-C6alkyl);
- A is CH, C-ester, or C-R4;
- R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -C ⁇ -C6alkyl, heterocycloC3_6alkyl, -Ci-C ⁇ alkoxy, carbonyl, carbamoyl, -C(O)OH, -(C ⁇ -C6alkyl)-SOn-(C ⁇ -C 6 alkyl), -C(O)N(Co-C 6 alkyl)(Co-C6alkyl), or -C ⁇ -C6alkylacylamino group, wherein any of the groups is optionally substituted with
- each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(Ci-C6alkyl), -SOrr(aryl), aryloxy, -heteroaryloxy, Cl-C6alkoxy, N-oxide,
- R4 is an aryl, -Ci-C ⁇ alkyl, heteroaryl, -CN, carbonyl, carbamoyl, -(C ⁇ -C6alkyl)-SO n -(C ⁇ -C6alkyl), -C(O)N(Co-C6alkyl)(Co-C6alkyl), or -C ⁇ -C6alkylacylamino group, wherein any of the groups is optionally substituted with
- substituents wherein each substituent is independently a carbonyl, -CN, halogen, -C(O)(Co-C6alkyl), -C(O)O(Co-C6alkyl), -C ⁇ -C6alkyl, -SO n -(Ci-C6alkyl), -OH, C ⁇ -C6alkoxy, or -(Co-C6alkyl)(Co-C6alkyl)amino, group; n is independently 0, 1, or 2; and
- R2 or R3 may optionally be joined to R4 by a bond to form a ring.
- Si, S2, and S3 are independently H, -OH, halogen, -Ci-C ⁇ alkyl, -NO2, -CN, or -Ci-C ⁇ alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; Rl is a H, OH, halogen, carbonyl, or -C ⁇ -C6alkyl, -cycloC3-C6alkyl,
- A is CH
- R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -Ci-C6alkyl, heterocyloC3-.6alkyl, -C ⁇ -C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(C ⁇ -C6alkyl)-SO n -(C ⁇ -C6alkyl), -C(O)N(Co-C6alkyl)(Co-C6alkyl), or
- each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(C ⁇ -C6alkyl), -SO n -(aryl), -aryloxy, -heteroaryloxy, Ci-C ⁇ alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
- Si, S2, and S3 are independently H, -OH, halogen, -Ci-C6alkyl, -NO2, -CN, or -Ci-C ⁇ alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a -Ci-C6alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(C ⁇ -C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO n -(C ⁇ -C6alkyl), -(Co-C6alkyl)(Co-C6alkyl)amino;
- A is CH
- R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -C ⁇ -C6alkyl, heterocyloC3_6alkyl,-C ⁇ -C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(C ⁇ -C6alkyl)-SO n -(C ⁇ -C6alkyl), -C(O)N(Co-C6alkyl)(Co-C6alkyl), or -Ci-C ⁇ alkylacylamino group, wherein any of the groups is optionally substituted with
- each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -Ci-C6alkyl, -SO n -(C ⁇ -C6alkyl), -SO n -(aryl), -O-aryl, -O-heteroaryl, C ⁇ -C6alkoxy, N-oxide,
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
- Si, S2, and S3 are independently H, -OH, halogen, -Ci-C ⁇ alkyl, -NO2, -CN, or -Ci-C ⁇ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a -cycloC3-C6alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(Co-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO -(Ci-C6alkyl);
- A is CH
- R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -Ci-C6alkyl, heterocyloC3_6alkyl,-Ci-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(Ci-C6alkyl)-SOn-(C ⁇ -C 6 alkyl), -C(O)N(Co-C6alkyl)(Co-C 6 alkyl), or -C ⁇ -C6alkylacylamino group, wherein any of the groups is optionally substituted with
- each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -Ci-C6alkyl, -SO n -(Ci-C6alkyl), -SO n -(aryl), -O-aryl, -O-heteroaryl, C ⁇ -C6alkoxy, N-oxide,
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
- Si, S2, and S3 are independently H, -OH, halogen, -Ci-C6alkyl, -NO2, -CN, or -C ⁇ -C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a -Ci-C ⁇ alkenyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(Co-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO n -(C ⁇ -C6alkyl);
- A is CH
- R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -Ci-C ⁇ alkyl, heterocyloC3_6alkyl,-C ⁇ -C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(C ⁇ -C6alkyl)-SO n -(Ci-C6alkyl), -C(O)N(Co-C6alkyl)(Co-C6alkyl), or -Ci-C6alkylacylamino group, wherein any of the groups is optionally substituted with
- each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(C ⁇ -C6alkyl), -SO n -(aryl), -O-aryl, -O-heteroaryl, C ⁇ -C6alkoxy, N-oxide,
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein Si, S2, and S3 are independently H, -OH, halogen, -Ci-C ⁇ alkyl, -NO2, -CN, or -C ⁇ -C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a heteroaryl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3- C ⁇ alkyl), -C(O)-O-(Co-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO n -(Ci-C6alkyl);
- A is CH
- R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -Ci-C6alkyl, heterocyloC3_6alkyl,-Ci-C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(C ⁇ -C6alkyl)-SO n -(C ⁇ -C6alkyl), -C(O)N(Co-C6alkyl)(Co-C6alkyl), or -Ci-C ⁇ alkylacylamino group, wherein any of the groups is optionally substituted with
- each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -Ci-C6alkyl, -SO n -(C ⁇ -C6alkyl), -SOrr(aryl), -aryloxy, -O-heteroaryl, C -C ⁇ alkoxy, N-oxide,
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein Si, S2, and S3 are independently H, -OH, halogen, -C ⁇ -C6alkyl,
- alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a an -amino, -Ci-C ⁇ alkylamino, or -(C ⁇ -C6alkyi ⁇ C ⁇ -C6alkyl)amino group, wherein any of the groups is optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(Co-C6alkyl), -C(O)-O-aryl, alkoxy, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO n -(Ci-C6alkyl);
- A is CH;
- R2 and R3 independently is an aryl, heteroaryl, H, halogen, -CN, -Ci-C6alkyl, heterocyloC3_6alkyl,-C ⁇ -C6alkoxy, carbonyl, carbamoyl, -C(O)OH, -(C ⁇ -C6alkyl)-SO n -(C ⁇ -C6alkyl), -C(O)N(Co-C6alkyl)(Co-C6alkyl), or -C ⁇ -C6alkylacylamino group, wherein any of the groups is optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -Ci-C ⁇ alkyl.
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein Si, S2, and S3 are independently H, -OH, halogen, -Ci-C6alkyl, -NO2, -CN, or -Ci-Cgalkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; Rl is a -C ⁇ -C6alkyl, -cycloC3-C6alkyl, -C ⁇ -C6alkenyl, -C ⁇ -C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -Ci-C6alkylamino, -(C ⁇ -C6alkyl)(Ci-C6alkyl)amino, -Ci-C6alkyl(
- R2 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(C ⁇ -C6alkyl), -SO n -(aryl), -aryloxy, -O-heteroaryl, Ci- C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(Co-C6alkyi ⁇ Co-C6alkyl)amino, -C(O)-N(Co-C6alkyl)(Co-C6alkyl) • substituent group, wherein each substituent group independently is optionally substituted with -OH, C ⁇ -C6alkoxy, -C ⁇
- R3 is a heteroaryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(Ci-C6alkyl), -SO n -(aryl), -aryloxy, -O-heteroaryl, C ⁇ -C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(Co-C6alkyl)(Co-C6alkyl)amino, -C(O)-N(Co-C6alkyl)(Co-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C ⁇ -C6alkoxy, -
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
- Si, S2, and S3 are independently H, -OH, halogen, -Ci-C ⁇ alkyl, -NO2, -CN, or -Ci-C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a halogen, carbonyl, -C ⁇ -C6alkyl, -cycloC3-C6alkyl, -C ⁇ -C6alkenyl, -C ⁇ -C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C ⁇ -C6alkylamino, -(C ⁇ -C6alkyl)(C ⁇ -C6alkyl)amino, -Ci-C6alkyl(oxy)C ⁇ -C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SO n NH(aryl), -SO n NH(heteroaryl), -SO n NH(C ⁇ -C6alkyl), -C(O)N(Co-C6alkyl)(C()-C6alkyl), -NH-SO
- R2 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -Ci-C6alkyl, -SO n -(C ⁇ -C6alkyl), -SO n -(aryl), -aryloxy, -O-heteroaryl, Ci- C ⁇ alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(Co-C6alkyi ⁇ Co-C6alkyl)amino, -C(O)-N(Co-C6alkyl)(Co-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C ⁇ -C6alkoxy, -Ci-
- R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -Ci-C6alkyl, -SO n -(C ⁇ -C6alkyl), -SO n -(aryl), -aryloxy, -O-heteroaryl, Ci- C ⁇ alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(Co-C6alkyi ⁇ Co-C6alkyl)amino, -C(O)-N(Co-C6alkyl)(Co-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C ⁇ -C6alkoxy, -Ci-
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein Si, S2, and S3 are independently H, -OH, halogen, -Ci-C6alkyl,
- alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a halogen, carbonyl, -Ci-C6alkyl, -cycloC3-C6alkyl, -C ⁇ -C6alkenyl, -C ⁇ -C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -Ci-C6alkylamino, -(Ci-C6alkyl)(C ⁇ -C6alkyl)amino, -C ⁇ -C6alkyl(oxy)C ⁇ -C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SO n NH(aryl), -SO n NH(heteroaryl), -SO n NH(C ⁇ -C6alkyl), -C(O)N(Co-C6alkyl)(Co-C 6 alkyl), -NH-SOn-
- A is CH
- R2 is a carbonyl, optionally substituted with 1 substituent, wherein the substituent is an, aryl, heteroaryl, -C(O)OH, carbonyl, -Ci-C ⁇ alkyl, -O-aryl,
- R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(C ⁇ -C6alkyl), -SO n -(aryl), -aryloxy, -O-heteroaryl, Ci- C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(Co-C6alkyl)(Co-C6alkyl)amino, -C(O)-N(Co-C6alkyl)(Co-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C ⁇ -C6alkoxy, -Ci
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein Si, S2, and S3 are independently H, -OH, halogen, -Ci-C6alkyl,
- alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a halogen, carbonyl, -Ci-C6alkyl, -cycloC3-C6alkyl, -C ⁇ -C6alkenyl, -Ci-C ⁇ alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C ⁇ -C6alkylamino, -(C ⁇ -C6alkyl)(Ci-C6alkyl)amino, -Ci-C6alkyl(oxy)C ⁇ -C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SO n NH(aryl), -SO n NH(heteroaryl), -SO n NH(C i-C6alkyl), -C(O)N(Co-C6alkyl)(Co-C6alkyl), -NH-SO
- A is CH;
- R2 is a carbamoyl, optionally substituted with 1-2 substituents, wherein each substituent is independently a carbonyl, -CN, -Ci-C ⁇ alkyl, -SO n -(C ⁇ - C6alkyl), -O-aryl, -O-heteroaryl, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -Ci-C6alkyl(amino) substituent group, wherein each substituent group independently is optionally substituted with -OH, -O(C ⁇ -C6alkyl), -O(aryl), -COOH, -COO(C ⁇ -C6alkyl), halogen, -NO2, -CN, or
- R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl,
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
- Si, S2, and S3 are independently H, -OH, halogen, -C ⁇ -C6alkyl, -NO2, -CN, or -Ci-C ⁇ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a halogen, carbonyl, -C ⁇ -C6alkyl, -cycloC3-C6alkyl, -Ci-C6alkenyl, -C -C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C ⁇ -C6alkylamino, -(Ci-C6alkyl)(C ⁇ -C6alkyl)amino, -C ⁇ -C6alkyl(oxy)C ⁇ -C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SO n NH(aryl), -SO n NH(heteroaryl),
- A is CH
- R2 and R3 are each independently an aryl, optionally substituted, connected to each other by a thio, oxy, or (C ⁇ -C4alkyl) bridge to form a fused three ring system; and n is independently 0, 1, or 2.
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein Si, S2, and S3 are independently H, -OH, halogen, -Ci-C ⁇ alkyl, -NO2, -CN, or -C ⁇ -C6alkoxy;
- Rl is a halogen, carbonyl, -C ⁇ -C6alkyl, -cycloC3-C6alkyl, -Ci-C ⁇ alkenyl, -C ⁇ -C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -Ci-C6alkylamino, -(C ⁇ -C6alkyl)(C ⁇ -C6alkyl)amino, -C ⁇ -C6alkyl(oxy)C ⁇ -C6alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SO n NH(aryl), -SO n NH(heteroaryl), -SO n NH(C ⁇ -C6alkyl), -C(O)N(C ⁇ -C6alkyl)(Co-C6alkyl), -NH-SO
- A is CH
- R2 is a -(C ⁇ -C6alkyl)-SO n -(C ⁇ -C6alkyl), optionally substituted with 1-5 substituents, wherein each substituent is independently a halogen, -NO2, -COOH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(C ⁇ -C6alkyl), -O-aryl, -O-heteroaryl, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -C ⁇ -C6alkyl(amino) substituent group, wherein each substituent group independently is optionally substituted with -OH, -O(Ci-C6alkyl), -O(aryl), -COOH, -COO(C ⁇ -C6alkyl), halogen, -NO2, -CN, or -C(
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein
- Si, S2, and S3 are independently H, -OH, halogen, -Ci-C ⁇ alkyl, -NO2, -CN, or -C ⁇ -C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a halogen, carbonyl, -C ⁇ -C6alkyl, -cycloC3-C6alkyl, -C ⁇ -C6alkenyl, -C ⁇ -C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C ⁇ -C6alkylamino, -(C ⁇ -C6alkyl)(C ⁇ -C6alkyl)amino, -C ⁇ -C6alkyl(oxy)C ⁇ -C6alkyl, -C(O)NH(
- A is CH
- R2 is a -C(O)N-(Co-C6alkyl)(Co-C6alkyl), optionally substituted with 1-5 substituents, wherein each substituent is independently a halogen, -NO2, -COOH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(C ⁇ -C6alkyl), aryloxy, -heteroaryloxy, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -C ⁇ -C6alkyl(amino) substituent group, wherein each substituent group independently is optionally substituted with -OH, -O(Ci-C6alkyl), -O(aryl), -COOH, -COO(Ci-C6alkyl), halogen, -NO2, -CN, or -C(O)-N(
- Si, S2, and S3 are independently H, -OH, halogen, -Ci-C6alkyl, -NO2, -CN, or -Ci-C ⁇ alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH;
- Rl is a halogen, carbonyl, -Ci-C6alkyl, -cycloC3-C6alkyl, -C ⁇ -C6alkenyl, -Ci-C6alkoxy, aryl, heteroaryl, -CN, -heterocycloC3-C6alkyl, -amino, -C 1 -C6alkylamino, -(C 1 -C6alkyl)(C 1 -C6alkyl)amino, -C 1 -C6alkyl(oxy)C 1 -C ⁇ alkyl, -C(O)NH(aryl), -C(O)NH(heteroaryl), -SO n NH(aryl), -SO n NH(heteroaryl), -SO n NH(heteroaryl),
- A is CH
- R2 is -CN;
- R3 is an aryl, optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(C ⁇ -C6alkyl), -SO n -(aryl), -aryloxy, -O-heteroaryl, - C ⁇ alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(Co-C6alkyi ⁇ Co-C6alkyl)amino, -C(O)-N(Co-C6alkyl)(Co-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C ⁇ -C6
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein Si, S2, and S3 are independently H, -OH, halogen, -C ⁇ -C6alkyl, -NO2, -CN, or -Ci-C6alkoxy, wherein said alkyl and alkoxy groups are optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen or OH; Ri is -Ci-C ⁇ alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -Ci-C6alkyl, -cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(Co-C6alkyl), -C(O)-aryloxy, -Ci-C ⁇ alkoxy, -(Co
- A is CH
- R2 and R3 each independently is an aryl or heteroaryl, wherein each is optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(C ⁇ -C6alkyl), -SO n -(aryl), aryloxy, -heteroaryloxy, C ⁇ -C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(Co-C6alkyl)(Co-C6alkyl)amino, -C(O)-N(Co-C6alkyl)(Co-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -OH, C
- R2 and R3 may be optionally connected by a thio, oxy, or (Ci-C4alkyl) bridge to form a fused three ring system; and n is independently 0, 1, or 2;
- a compound of this invention is represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein Si, S2, and S3 are each H;
- Rl is -Ci-C ⁇ alkyl, optionally substituted with 1-5 substituents; wherein each substituent is independently a halogen, -OH, -CN, -Ci-C6alkyl, -cycloC3-C6alkyl, -C(O)(heterocycloC3-C6alkyl), -C(O)-O-(Co-C6alkyl), -C(O)-aryloxy, -Ci-C ⁇ alkoxy, -(Co-C6alkyl)(Co-C6alkyl)amino, cycloalkyloxy, acyl, acyloxy, -cycloC3-C6alkyl, heterocycloC3-C6alkyl, aryl, heteroaryl, carbonyl, carbamoyl, or -SO n -(C ⁇ -C6alkyl);
- A is CH, R2 and R3 each independently is an aryl or heteroaryl, wherein each is optionally substituted with 1-5 substituents, wherein each substituent is independently an aryl, heteroaryl, halogen, -NO2, -C(O)OH, carbonyl, -CN, -C ⁇ -C6alkyl, -SO n -(Ci-C6alkyl), -SO n -(aryl), aryloxy, -heteroaryloxy, Ci-C6alkoxy, N-oxide, -C(O)-heterocycloC3-C6alkyl, -NH-cycloC3-C6alkyl, amino, -OH, or -(Co-C6alkyl)(Co-C6alkyl)amino, -C(O)-N(Co-C6alkyl)(Co-C6alkyl) substituent group, wherein each substituent group independently is optionally substituted with -
- alkyl as well as other groups having the prefix “alk” such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chains which may be linear or branched or combinations thereof.
- alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like.
- alkenyl alkynyl and other like terms include carbon chains containing at least one unsaturated C-C bond.
- cycloalkyl means carbocycles containing no heteroatoms, and includes mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems.
- fused ring systems can include one ring that is partially or fully unsaturated such as a benzene ring to form fused ring systems such as benzofused carbocycles.
- Cycloalkyl includes such fused ring systems as spirofused ring systems.
- cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl, 1,2,3,4- tetrahydronaphalene and the like.
- cycloalkenyl means carbocycles containing no heteroatoms and at least one non-aromatic C-C double bond, and include mono-, bi- and tricyclic partially saturated carbocycles, as well as benzofused cycloalkenes.
- Examples of cycloalkenyl examples include cyclohexenyl, indenyl, and the like.
- cycloalkyloxy unless specifically stated otherwise includes a cycloalkyl group connected to the oxy connecting atom.
- alkoxy unless specifically stated otherwise includes an alkyl group connected to the oxy connecting atom.
- aryl unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl.
- aryloxy unless specifically stated otherwise includes multiple ring systems as well as single ring systems such as, for example, phenyl or naphthyl, connected through the oxy connecting atom to the connecting site.
- Co-C6alkyl includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms.
- An alkyl with no carbon atoms is a hydrogen atom substituent or a direct bond - depending on whether the alkyl is a terminus or a bridging moiety.
- hetero unless specifically stated otherwise includes one or more O, S, or N atoms.
- heterocycloalkyl and heteroaryl include ring systems that contain one or more O, S, or N atoms in the ring, including mixtures of such atoms.
- the hetero atoms replace ring carbon atoms.
- a heterocycloC5alkyl is a five membered ring containing from 5 to no carbon atoms.
- heteroaryl examples include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.
- heteroaryloxy unless specifically stated otherwise describes a heteroaryl group connected through an oxy connecting atom to the connecting site.
- heteroaryl(C 1 - 6 )alkyl examples include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and qui
- heterocycloC -7 alkyl examples include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrolidin-2-one, piperidin-2-one, and thiomorpholinyl.
- Examples of aryl(C 1-6 )alkyl include, for example, phenyl(C 1-6 )alkyl, and naphthyl(C 1-6 )alkyl.
- Examples of heterocycloC -7 alkylcarbonyl(C 1-6 )alkyl include, for example, azetidinyl carbonyl(C 1-6 )alkyl, pyrrolidinyl carbonyl(C 1 - 6 )alkyl, piperidinyl carbonyl(C 1-6 )alkyl, piperazinyl carbonyl(C 1 _ 6 )alkyl, morpholinyl carbonyl(C 1 - 6 )alkyl, and thiomorpholinyl carbonyl(C 1-6 )alkyl.
- amine unless specifically stated otherwise includes primary, secondary and tertiary amines.
- carbamoyl is used to include -NHC(O)OC ⁇ -C4alkyl, and -OC(O)NHC ⁇ -C4alkyl.
- halogen includes fluorine, chlorine, bromine and iodine atoms.
- optionally substituted is intended to include both substituted and unsubstituted.
- optionally substituted aryl could represent a pentafluorophenyl or a phenyl ring.
- the substitution can be made at any of the groups.
- substituted aryl(C 1-6 )alkyl includes substitution on the aryl group as well as substitution on the alkyl group.
- Compounds described herein contain one or more double bonds and may thus give rise to cis/trans isomers as well as other conformational isomers.
- the present invention includes all such possible isomers as well as mixtures of such isomers.
- Compounds described herein can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers.
- the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
- the above Formula I is shown without a definitive stereochemistry at certain positions.
- the present invention includes all stereoisomers of Formula I and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.
- salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
- the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases.
- Salts derived from such inorganic bases include aluminum, ammonium, calcium, copper (ic and ous), ferric, ferrous, lithium, magnesium, manganese (ic and ous), potassium, sodium, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, as well as cyclic amines and substituted amines such as naturally occurring and synthesized substituted amines.
- Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ion exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanoI, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N- ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethyl
- the compound of the present invention When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
- Particularly preferred are benzenesulfonic, citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
- compositions of the present invention comprise a compound represented by Formula I (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
- additional therapeutic ingredients include, for example, i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) HI receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COX-2 selective inhibitors, vii) statins, viii) non-steroidal anti- inflammatory drugs ("NSAID”), and ix) M2/M3 antagonists.
- NSAID non-steroidal anti- inflammatory drugs
- compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
- the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
- Creams, ointments, jellies, solutions, or suspensions containing the compound of Formula I can be employed for topical use. Mouth washes and gargles are included within the scope of topical use for the purposes of this invention.
- Dosage levels from about O.OOlmg/kg to about 140mg/kg of body weight per day are useful in the treatment of conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn' s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid
- inflammation may be effectively treated by the administration of from about O.Olmg to 50mg of the compound per kilogram of body weight per day, or alternatively about 0.5mg to about 2.5g per patient per day.
- PDE4 inhibiting compounds of this invention can be administered at prophylactically effective dosage levels to prevent the above-recited conditions.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a formulation intended for the oral administration to humans may conveniently contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
- Unit dosage forms will generally contain between from about O.Olmg to about lOOOmg of the active ingredient, typically O.Olmg, 0.05mg, 0.25mg, lmg, 5mg, 25mg, 50mg, lOOmg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or lOOOmg.
- the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
- the compounds represented by Formula I, or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
- compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
- the compound represented by Formula I, or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices.
- the compositions may be prepared by any of the methods of pharmacy.
- such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients.
- the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
- compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I.
- the compounds of Formula I, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
- the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
- solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
- liquid carriers are sugar syrup, peanut oil, olive oil, and water.
- gaseous carriers include carbon dioxide and nitrogen.
- any convenient pharmaceutical media may be employed.
- water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
- carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets.
- tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
- tablets may be coated by standard aqueous or nonaqueous techniques
- a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
- Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
- Each tablet preferably contains from about 0. Img to about 500mg of the active ingredient and each cachet or capsule preferably containing from about O.lmg to about 500mg of the active ingredient.
- compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
- a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
- compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
- the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
- the final injectable form must be sterile and must be effectively fluid for easy syringability.
- the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
- compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound represented by Formula I of this invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
- compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in moulds.
- the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives, (including anti-oxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives, (including anti-oxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives, (including anti-oxidants) and the like.
- additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives, (including anti-oxidants) and the like.
- other adjuvants can be included to render the formulation isotonic with the blood
- another aspect of the invention is the treatment in mammals of, for example, asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), eosinophilic granuloma, psoriasis and other benign or malignant proliferative skin diseases, endotoxic shock (and associated conditions such as laminitis and colic in horses), septic shock, ulcerative colitis, Crohn' s disease, reperfusion injury of the myocardium and brain, inflammatory arthritis, osteoporosis, chronic glomerulonephritis, atopic dermatitis, urticaria, adult respiratory distress syndrome, infant respiratory distress syndrome, chronic obstructive pulmonary disease in animals, diabetes insipidus, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, arterial restenosis, atherosclerosis, neurogenic inflammation, pain, cough, rheumatoid arthritis, ankylosing spondylitis, transplant rejection and graft
- the compound of this invention can be utilized in combination with other therapeutic compounds.
- the combinations of the PDE4 inhibiting compound of this invention can be advantageously used in combination with i) Leukotriene receptor antagonists, ii) Leukotriene biosynthesis inhibitors, iii) COX-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii) corticosteroids, viii) HI (histamine) receptor antagonists and ix) beta 2 adrenoceptor agonist.
- the compound of this invention can be formed as a metabolite in the mammalian system.
- Example 19 (5- ⁇ (E)-2-(3 - ⁇ 6- [ 1 -methyl- 1 -(methylsulf onyl)ethyl] - 8-quinolinyl ⁇ phenyl)- 1 - [4- (methylsulfonyl)phenyl]ethenyl ⁇ -l,2,4-oxadiazol-3-yl)methanol:
- the present invention includes prodrugs that form PDE4 inhibitors in vivo as a metabolite after administering such prodrugs to a mammal. Further, this invention includes a method of treatment by a step of administering a prodrug to form in vivo an effective amount of a PDE4 inhibitor described by Formula I.
- the abbreviations used herein have the following tabulated meanings. Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.
- Whole blood provides a protein and cell-rich milieu appropriate for the study of biochemical efficacy of anti-inflammatory compounds such as PDE4- selective inhibitors.
- Normal non-stimulated human blood does not contain detectable levels of TNF- ⁇ and LTB4.
- activated monocytes Upon stimulation with LPS, activated monocytes express and secrete TNF- ⁇ up to 8 hours and plasma levels remain stable for 24 hours.
- LTB4 synthesis is also sensitive to levels of intracellular cAMP and can be completely inhibited by PDE4-selective inhibitors.
- the blood was then challenged with either lO ⁇ L of PBS (blank) or 10/ ⁇ L of fMLP (l ⁇ M final concentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37°C.
- the blood samples were centrifuged at 1500xg for 10 minutes at 4°C to obtain plasma.
- a 50 ⁇ L aliquot of plasma was mixed with 200/ L methanol for protein precipitation and centrifuged as above.
- the supernatant was assayed for LTB4 using an enzyme immunoassay kit (#520111 from Cayman Chemical Co., Ann
- TNF- ⁇ was assayed in diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, NI) according to manufacturer's procedure.
- the IC50 values of Examples 1-42 generally ranged from 0.04 ⁇ M to 8.71 ⁇ M.
- BAL bronchial alveolar lavages
- the reaction was initiated by the addition of lOmL of human recombinant PDE4 (the amount was controlled so that -10% product was formed in lOmin.). The reaction was stopped after lOmin. by the addition of Img of PDE-SPA beads
- IC50 value was approximated with a non-linear regression fit using the standard 4-parameter/multiple binding sites equation from a ten point ti tration.
- the IC50 values of Examples 1-42 were determined with lOOnM cAMP using the purified GST fusion protein of the human recombinant phosphodiesterase IVa (met-248) produced from a baculovirus/Sf-9 expression system.
- the IC50 values of Examples 1-42 generally ranged from 0.14nM to 10.24nM, although one example had an IC50 value of 109nM.
- Polymorphism may result in isolation of materials with different melting points in some preparations.
- the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. Yields are given for illustration only.
- NMR data is in the form of delta (6) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz, 400 MHz or 500 MHz using the indicated solvent.
- TMS tetramethylsilane
- Conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.
- the alcohol intermediate II may be prepared by the reaction of an aryl or heteroaryl metallic species III such as an organomagnesium halide with 4-(methylthio)benzaldehyde (A) in an organic solvent such as THF.
- the alcohol intermediate II may also be prepared by treatment an aryl or heteroaryl hydride or bromide IV with a base or an organometallic such as n-butyllithium in an organic solvent such as THF, followed by 4-(methylthio)benzaldehyde.
- the alcohol intermediate II may also be prepared by the following chemical transformations: 1) Treatment of an aryl or heteroaryl dihydride, halide-hydride or dihalide V with a base or an organometallic such as n-butyllithium in an organic solvent such as THF, followed by an electrophile such as acetone or 4-(methylthio)benzaldehyde; 2) Subsequent treatment with a base or an organometallic such as ⁇ -butyllithium in an organic solvent such as THF, followed by an electrophile such as acetone or 4-(methylthio)benzaldehyde, where the first or the second transformation must use 4-(methylthio)benzaldehyde as the electrophile.
- the sulfone-alcohol VI may be prepared by the oxidation of the sulfide- alcohol II with an oxidizing agent such as oxone in a solvent such as a mixture of THF/MeOH/H 2 ⁇ .
- the ketones VII and VIII may be prepared by the oxidation of the alcohols II and VI, respectively, with an oxidizing agent such as MnO 2 in a solvent such as CH 2 C1 2 .
- the sulfone-ketone VIII may also be prepared by the oxidation of the sulfide-ketone VII with an oxidizing agent such as oxone in a solvent such as a mixture of THF/MeOH/H 2 O.
- Ketone Kl (4-Fluorophenyl) [4-(methylsulf onyl)]phenyl ketone
- Step 1 (4-Fluorophenyl)[4-methylthio)phenyl]ketone
- 4-fluorophenylmagnesium bromide 1.0M in THF, 19.7ml, 19.7mmol
- Step 2 (4-Fluorophenyl)[4-(methylsulfonyl)phenyl]ketone
- the (4-Fluorophenyl)[4- methylthio)phenyl]ketone - from the present step 1 (2.0g, 8.1mmol) in
- Ketone K2 ( 1 -Methyl- lH-imidazol-2-yl) [4-methylthio)phenyl]ketone Ketone K2 was prepared by the following procedure. Step 1: (1 -Methyl- lH-imidazol-2-yl)[4-(methylthio)phenyl]methanol
- N-methylimidazole (lO.Og, 122mmol) in 500mL THF at -78°C was added n-butyllithium (2.5M in hexanes, 48.7ml, 118mmol) dropwise and the resulting solution was stirred at -78°C for 30min.
- 4-(Methylthio)benzaldehyde 14.73ml, HOmmol was then added at -78°C and the mixture was stirred until completion by TLC, and quenched with NH C1 (sat). The mixture was then diluted with EtOAc, extracted and washed (NaHCO 3 (sat.), brine).
- Step 2 (1 -Methyl- lH-imidazol-2-yl)[4-(methylthio)phenyl]ketone
- EtOAc 250ml
- CH 2 C1 2 250ml
- MnO 2 140g, 1.66mol
- Ketone K3 was prepared by the following procedure.
- Step 3 (4-Methylsulfonyl)(phenyl)ketone To a solution of (4-Methylthio)(phenyl)ketone from the present step 2
- Ketone K4 ( 1 ,3-Thiazol-2-yl) [4-(methylthio)phenyl]ketone
- Ketone K4 was prepared by the following procedure. Step 1: (l,3-Thiazol-2-yl)[4-(methylthio)phenyl]methanol To a -78°C solution of thiazole (5.0g, 58.7mmol) in THF (250ml) was added n-butyllithium (2.5M in hexanes, 23.5ml, 58.7mmol) dropwise and the resulting solution was stirred at -78°C for lOmin. 4-(Methylthio)benzaldehyde (7.1ml, 53.4mmol) was then added at -78°C. The resulting mixture was stirred until completion, and quenched with a saturated aqueous solution of NBUC1.
- Step 2 (l,3-Thiazol-2-yl)[4-(methylthio)phenyl]ketone
- EtOAc 250ml
- MnO 2 70g, 843mmol
- Ketone K5 (l,3-Thiazol-2-yl)[4-(methylsulfonyl)phenyl]ketone
- Ketone K5 was prepared by the following procedure. To a solution of K4 (l,3-Thiazol-2-yl)[4-(methylthio)phenyl]ketone (8.2g, 34.7mmol) in
- Ketone K6 [5-(l-Hydroxy-l-Methylethyl)-l,3-thiazol-2-yl][4-(methylsulfonyl)phenyl]ketone
- Step 1 [5-(l-Hydroxy-l-Methylethyl)-l,3-thiazol-2-yl][4- (methylthio)phenyl]ketone
- n-butyllithium (2.3M in hexanes, 5.3ml, 12.3mmol) was added dropwise and the resulting solution was stirred at 25°C for lOmin and quenched with acetone (3.0ml). The mixture was then diluted with EtOAc and HCl 10%, extracted and washed (NaHCO 3 (sat.), brine). The organic phase was dried over MgSO and concentrated. The residue was then treated with MnO 2 (20.4g, 235mmol) in CH 2 C1 2 (250ml) and the reaction was stirred at r.t. overnight. The resulting mixture was then filtered through a plug of silica (EtOAc).
- Ketone K7 (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]ketone
- Ketone K7 was prepared by the following procedure.
- Step 1 (6-Methyl-3-pyridinyl)[4-(methylthio)phenyl]methanol
- 3-bromo-6-methylpyridine 738mg, l.leq
- 4-(thiomethyl)benzaldehyde 738mg, l.leq
- the solution was warmed to rt.
- NH 4 CI (sat.) was added, then water and EtOAc.
- the organic phase was separated, dried over MgSO 4 , and concentrated.
- the (6-Methyl-3-pyridinyl)[4-(methylthio)phenyl]methanol was obtained by precipitation with ether/hexane and was used without further purification for the next step.
- Step 2 (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]methanol Following the procedure of step 2 of ketone Kl above but substituting the sulfide (6-Methyl-3-pyridinyl)[4-(methylthio)phenyl]methanol from the present step 1 for (4-fluorophenyl)[4-(methylthio)phenyl]ketone as the starting material, (6- Methyl-3-pyridinyl) [4-(methylsulfonyl)phenyl]methanol was obtained.
- Step 3 (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]ketone Following the procedure of step 2 of ketone K2 above but substituting the (6-Methyl-3-pyridinyl)[4-(methylsulfonyl)phenyl]methanol from the present step 2 for (l-methyl-lH-imidazol-2-yl)[4-(methylthio)phenyl]methanol as the starting material, ketone K7 was obtained.
- Ketone K8 (5-Methyl-2-pyridinyl) [4-(methylsulf onyl)phenyl]ketone
- Ketone K8 was prepared by following the procedure described for ketone K7 but substituting 2-bromo-5-methylpyridine for 3-bromo-6-methylpyridine.
- Ketone K9 was prepared by following the procedure described for ketone K7 but substituting 4-bromothioanisole for 3-bromo-6-methylpyridine and using twice the amount of Oxone in the sulfide-oxidation step.
- Ketone K10 (2-Pyridinyl) [4-(methylsulfonyl)phenyl]ketone Ketone K10 was prepared by following the procedure described for ketone K7 but substituting 2-bromopyridine for 3-bromo-6-methylpyridine.
- step 2 of ketone Kl substituting the sulfide - that is, [5-(l-Hydroxy-l-methylethyl)-2-pyridinyl][4- (methylthio)phenyl]methanol - from the present step 1 for (4-fluorophenyl)[4- (methylthio)phenyl]ketone as the starting material, [5-(l -Hydroxy- l-methylethyl)-2- pyridinyl] [4-(methylsulfonyl)phenyl]methanol was obtained.
- the aryl bromides IX and X may be prepared by treatment of the benzyl phosphonium bromide XI with a base such as t-BuOK or LiHMDS in an organic solvent such as THF, followed by the addition of the ketone VII or VIII to the reaction mixture.
- the sulfide in IX may be converted to the sulfone X by treatment with oxone in a solvent such as a mixture of THF/MeOH/ ⁇ 2 O.
- the boronate ester XII can be prepared by heating the aryl bromide X with pinacol diborane in the presence of a base such as KOAc and a catalyst such as PdCl 2 (dppf) in a solvent such as DMF.
- Boronate Bl was prepared by the following procedure.
- Step 1 (E/Z)-2-(3-Bromophenyl)-l-(l-methyl-lH-imidazol-2-yl)-l-[4- (methylthio)phenyl]ethene
- 3-bromobenzyl)(triphenyl)phosphonium bromide (10.2g, 19.9mmol) in THF (200mL) and CH 3 CN (50mL) at 25°C was added t-BuOK (1.0M in THF, 19.9mL, 19.9mmol) dropwise and the resulting red solution was stirred at r.t. for 20min.
- To this resulting ylide was then added at 25°C the ketone K2 (4.4g, 18.9mmol).
- Step 2 (E)-2-(3 -Bromophenyl)- 1 -( 1 -methyl- 1 H-imidazol-2-yl)- 1 - [4- (methylsulfonyl)phenyl]ethene
- Step 3 Pinacol 3- ⁇ (E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4- (methylsulfonyl)phenyl]ethenyl Jphenylboronate
- Step 1 (E/Z)-2-(3-Bromophenyl)-l-(l,3-thiazol-2-yl)-l-[4- (methylthio)phenyl]ethene
- Step 2 (E/Z)-2-(3-Bromophenyl)-l-(l,3-thiazol-2-yl)-l-[4- (methylsulf onyl)phenyl] ethene
- a solution of the sulfide - that is, (E/Z)-2-(3-Bromophenyl)-l-(l,3- thiazol-2-yl)-l-[4-(methylthio)phenyl]ethene - from present step 1 (24.8g, 63.9mmol) in THF/MeOH/H2 ⁇ (600/300/300 ml) was added Oxone (78.5g, 128mmol). The resulting reaction mixture was stirred at r.t.
- Step 3 Pinacol 3- ⁇ (E/Z)-2-(l,3-thiazol-2-yl)-2-[4-
- Step 2 Pinacol 3- ⁇ (E)-2-(5-methyl-2-pyridinyl)-2-[4- (methylsulf onyl)phenyl] ethenyl ⁇ phenylboronate
- step 3 for boronate Bl but substituting the bromide (E)-2-(3-Bromophenyl)-l-(5-methyl-2-pyridinyl)-l-[4- (methylsulfonyl)phenyl] ethylene from present step 1 for (E)-2-(3-Bromophenyl)-l-(l- methyl-lH-imidazol-2-yl)-l-[4-(methylsulfonyl)phenyl]ethene as the starting material, boronate B3 was obtained.
- Boronate B4 was prepared by the following procedure.
- Step 1 (E)-2-(3-Bromophenyl)-l-[5-(l-hydroxy-l-methylethyl)-2- pyridinyl] - 1 - [4-(methylsulf onyl)phenyl]ethene
- (E)-2-(3- Bromophenyl)- 1 - [5 -( 1 -hydroxy- 1 -methylethyl)-2-pyridinyl] - 1 - [4- (methylsulfonyl)phenyljethene was obtained after separation of the isomers by flash chromatography.
- Step 2 Pinacol 3- ⁇ (E)-2-(5-(l-hydroxy-l-methylethyl)-2-pyridinyl)-2- [4-(methylsulfonyl)phenyl]ethenyl ⁇ phenylboronate
- the nitrile intermediate Xllla may be prepared by the alkylation of 4-methoxyphenol with chloroacetonitrile in the presence of a base such as potassium carbonate in a solvent such as acetone.
- the amide-oxime XIV may be prepared by treatment of the nitrile XIII with hydroxyl amine in a solvent such as methanol in the presence of a base such as sodium acetate.
- Formation of the oxadizole XVI may be achieved by activation of the arylacetic acid XV with carbonyldiimidazole in a solvent such as DMF followed by the addition of the amide- oxime XIV and subsequent heating of the reaction mixture.
- condensation of the aldehyde XVII by heating with the arylacetic acid XV in the presence of a base such as piperidine in a solvent such as toluene produces the unsaturated acid XVIIIa.
- Formation of the acid chloride of XVIIIa in situ by treatment with thionyl chloride and a base such as triethylamine in a solvent such as toluene is followed by the addition of an amine to the reaction mixture to yield the amide XVIIIb.
- the oxadiazole-ethene XVIIIc may be formed by heating OXl with XVII in the presence of a base such as piperidine in a solvent such as toluene.
- Aryl Bromide ABI was prepared by the following procedure. To a solution of 3-bromobenzaldehyde (12.9g, 70mmol) in toluene (lOOmL) was added 4- (methylsulfonyl)phenylacetic acid (15g, 70mmol) and piperidine (2mL). After overnight refluxing, the mixture was cooled down to r.t. To the slurry thus formed, toluene was added (10 mL) . Filtration gave (E)-3-(3-Bromophenyl)-2-[4- (methylsulfonyl)phenyl]-2-propenoic acid as a white solid.
- Aryl Bromide AB2 was prepared by the following procedure. To a solution of ABI (24.9g, 65mmol) in toluene (250mL) was added thionyl chloride (14.3mL, 196mmol) and triethylamine (34mL, 245mmol). After stirring at r.t. for 0.5h., isopropyl amine (28mL, 327mmol) was added. After a further 2h at r.t., the mixture was cooled to 0°C and was neutralised with saturated NF1 4 CI solution, then extracted with EtOAc. The organic extracts were washed (H 2 O, brine), dried (MgSO 4 ), filtered and concentrated.
- Aryl Bromide AB3 was prepared by following the procedure described for aryl bromide AB2 but substituting ammonium hydroxide for isopropyl amine as the starting material.
- Aryl Bromide AB4 (E)-N-(t-Butyl)-3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenamide
- Aryl Bromide AB4 was prepared by following the procedure described for aryl bromide AB2 but substituting t-butyl amine for isopropyl amine as the starting material.
- Step 2 (Scheme 4): (E)-l-(3-Bromophenyl)-2-(3-methyl-l,2,4- oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl]ethene To a solution of 3-bromobenzaldehyde (2.2g, 11.9mmol) in toluene
- treatment of the bromomethyl compound XIX with a nucleophile such as sodium methanesulfinate or potassium cyanide in a solvent such as DMF or a mixture of DMF and water can be used to produce the compounds XXa.
- the compound XXb may be prepared by treatment of XXa with a base such as potassium t-butoxide (1.1 equivalents) in a solvent such as THF followed by the addition of the resulting mixture into a solution of methyl iodide in a solvent such as THF.
- the compound XXc may be prepared by treatment of XXb with a base such as potassium t-butoxide (1.1 equivalents) in a solvent such as THF followed by the addition of the resulting mixture into a solution of methyl iodide in a solvent such as THF.
- a base such as potassium t-butoxide (1.3 equivalents) and methyl iodide (1.6 equivalents) in a solvent such as THF, followed by an additional amount of methyl iodide (1.6 equivalents) and an additional amount of the same base (1.0 equivalents).
- 6-bromomethyl-8-bromoquinoline 60g, 200mmol
- sodium methanesulfinate 27.6g, 270mmol
- Bromoquinoline Q2 was prepared by the following procedure. To a solution of bromoquinoline Ql (16. Ig, 54mmol) in THF (500mL) at -78°C, was added potassium t-butoxide (59mL, IN in THF). After 0.5h at -78°C, the resulting mixture was stirred at 0°C for 45min and then transferred by canula dropwise into a solution of Mel (16.7mL , 268.3mmol) in THF (160mL).
- Bromoquinoline Q3 was prepared by the following procedure. To a solution of bromoquinoline Q2 (15.7g, 50mmol) in THF (500mL) at -78°C, was added potassium t-butoxide (55mL, IN in THF). After stirring 0.5h at -78°C, the resulting mixture was stirred at 0°C for 45min and then transfered dropwise into a solution of Mel (15.6mL, 250mmol) in THF (40mL) at 0°C.
- 6-cyanomethyl-8-bromoquinoline Bromoquinoline Q4 was prepared by the following procedure. DMF (lOmL) and H 2 O (5mL) were added to 6-bromomethyl-8-bromoquinoline (3g, lOmmol) (described in International Patent Publication WO 94/22852) and potassium cyanide (1.6g, 25mmol). After heating at 100°C for 1 hour, the resulting mixture was quenched with H 2 O (lOOmL) and extracted with EtOAc. The organic extracts were washed (H 2 O, brine), dried (MgSO ), filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 3:1) yielded 6-cyanomethyl-8-bromoquinoline.
- Bromoquinoline Q5 was prepared by the following procedure. To a solution of bromoquinoline Q4 (3g, 12.1mmol) in THF (lOOmL) at -78°C, was added Mel (1.7mL, 27mmol) followed by potassium t-butoxide (27mL, 27mmol). After 2h at -78°C, the mixture was warmed to 0°C and was neutralised with saturated NFJ CI solution then extracted with EtOAc. The organic extracts were washed (H 2 O, brine), dried (MgSO ), filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 3:1) yielded 6-[l-methyl-l-cyanoethyl]-8-bromoquinoline.
- the arylquinolines of the formula XXII may be prepared by coupling bromoquinoline XX with the boronic acid XXI by heating in the presence of a catalyst such as Pd(PPh ) 4 and a base such as sodium carbonate (aqueous) in a solvent such as a DME.
- the alcohol XXII may be converted to the bromide XXIII by treatment with HBr (aq) in a solvent such as acetic acid.
- the alcohol XXII may be converted to the methyl sulfonate ester XXIV by methanesulfonyl chloride in the presence of a base such as triethylamine in a solvent such as dichloromethane.
- the benzyl phosphorous reagents XXV may be prepared either by heating XXIII in the presence of PPh 3 in a solvent such as acetonitrile or by treating XXIII or XXIV with diethylphosphite and a base such as potassium t-butoxide in a solvent such as THF.
- Benzylphosphonium Bromide PI was prepared by the following procedure.
- Benzylphosphonate P2 was prepared by the following procedure. The bromomethyl compound from from step 2 above of the synthesis of PI (11.34g, leq) was dissolved in THF (170mL). Diethylphosphite (3.87mL, 1.05eq) was added and the solution was cooled down to 0°C. Next, t-BuOK (3.87mL, IN in THF) was added slowly. The reaction was stirred 2h and the quenched by addition of NILC sat), water and EtOAc. The organic phase was separated and washed with brine, dried over MgSO and concentrated. Purification by flash chromatography on silica gel (hexane:EtOAc, 1/9) gave Diethyl 3-(6-isopropyl-8-quinolinyl)benzylphosphonate as a clear oil.
- Step 3 Diethyl 3-[6-(l-cyano-l-methylethyl)-8- quinolinyl]benzylphosphonate
- diethylphosphite 2.5mL, 18mmol
- THF lOOmL
- IM potassium t-butoxide
- the compound XXVI may be obtained by adding a solution of the ketone VII in a solvent such as THF to a mixture of the benzylphosphorous reagent XXV and a base such as potassium t-butoxide in a solvent such as THF.
- the compounds corresponding to the formula I may then be prepared by treating XXVI with oxone in a mixture of solvents such as THF/MeOH/water.
- the compounds of formula I may be prepared by reacting the ketone VIII with XXV in the presence of a base such as potassium t- butoxide in a solvent such as THF.
- compounds corresponding to the formula I may be prepared by in situ conversion of the aryl bromide XVIII to the corresponding boronate ester by heating with diboron pinacol ester, a catalyst such as [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base such as potassium acetate in a solvent such as DMF, followed by the addition of the bromoquinoline XX, an additional amount of the same catalyst, an additional amount of a base such as sodium carbonate (aqueous) and an additional period of heating.
- a catalyst such as [1,1'- bis(diphenylphosphino)-ferrocene]dichloropalladium(II) and a base such as potassium acetate in a solvent such as DMF
- the aldehyde XXVII may be prepared by heating the bromoquinoline XX, 3- formylbenzeneboronic acid, a catalyst such as Pd(PPh 3 ) and a base such as sodium carbonate (aqueous) in a solvent such as DME.
- the aldehyde XXVII may be converted to Example 18 by heating with XVI in the presence of a base such as piperidine in a solvent such as toluene.
- Example 19 may be obtained by treatment of Example 18 with cerric ammonium nitrate ("CAN") in a mixture of solvents such as acetonitrile/water.
- CAN cerric ammonium nitrate
- the aldehyde XXVII may be converted to the unsaturated acid XXVIII by heating with XV and a base such as piperidine in a solvent such as toluene.
- the acid XXVIII may then be converted to the amide I (Example 27, 28 and 29) by treatment with a coupling system such as EDCI, HOBt, and an amine in a solvent such as DMF.
- Scheme 10 describes how compounds of formula I may be obtained by coupling the bromoquinoline XX with the boronate ester XII in the presence of a catalyst such as Pd(OAc) 2 , PPh 3 , and a base such as sodium carbonate (aqueous) in a solvent such as n-propanol.
- a catalyst such as Pd(OAc) 2 , PPh 3
- a base such as sodium carbonate (aqueous) in a solvent such as n-propanol.
- Examples 1 and 2 were prepared by the following procedure. To a mixture of benzylphosphonate P2 (330mg, 0.83mmol) and ketone K3 (200mg,
- Example 1 was the less polar Z-isomer and Example 2 was the more polar E-isomer.
- Example 1 NMR 1H (400MHz, Acetone-_? 6 ) d 8.79 (q, IH), 8.28 (q, IH), 7.94 (d, 2H), 7.73 (d, IH), 7.6-7.1 (m, 14H), 3.14 (m, IH), 2.97 (s, 3H), 1.34 (d, 6H).
- Example 3 was prepared by the following procedure. To a suspension of the benzylphosphonium bromide PI (320mg, 0.531mmol) in 2.5mL THF at -78°C was added t-BuOK (l.OM in THF, 0.55mL, 0.55mmol) dropwise and the resulting red solution was stirred 30min at 0°C . To this ylide at -78°C was then added ketone K5 (122mg, 0.455mmol) in 2mL of THF dropwise. The mixture was warmed to r.t., then stired for lh, quenched with a NH 4 CI (sat.) and diluted with EtOAc. The organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. Flash chromatography (Silica cartridge, Hex/EtOAc 10 to 100% in 20min) yielded Example 3 (1.5 to 1 mixture of isomers).
- Example 4 was prepared by the following procedure.
- Step 1 6-isopropyl-8-(3- ⁇ (E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4- (methylthio)phenyl] ethenyl ⁇ phenyl)quinoline
- Step 2 6-isopro ⁇ yl-8-(3- ⁇ (E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4- (methylsulf onyl)phenyl] ethenyl ⁇ phenyl)quinoline
- Examples 5 and 6 were prepared by the following procedure. Following the procedure for Example 1 but substituting the ketone Kl for K3 as the starting material, and purification by flash chromatography (50%EtOAc/50%Hexanes) yielded Examples 5 and 6.
- Example 7 was prepared by following the procedure for Example 1 but substituting the ketone K6 for K3 as the starting material. Purification by flash chromatography (100%EtOAc) yielded Example 7 as a mixture of isomers.
- Example 8 was prepared by following the procedure for Example 1 but substituting the ketone K6 for K3 and the benzyl phosponate P3 for P2 as the starting materials. Purification by flash chromatography (20%CH 2 Cl 2 /80%EtOAc) yielded Example 8 as a mixture of isomers.
- Step 1 2-methyl-2-[8-(3- ⁇ (E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4- (methylthio)phenyl]ethenyl ⁇ phenyl)-6-quinolinyl]propanenitrile was prepared by following the procedure for Example 1 but substituting the ketone K2 for K3 and the benzyl phosphonate P3 for P2 as the starting materials.
- Step 2 2-methyl-2-[8-(3- ⁇ (E)-2-(l-methyl-lH-imidazol-2-yl)-2-[4-
- Example 9 was prepared by following the procedure used for the preparation of the boronate Bl (step 2 of Scheme 2) but substituting the sulfide obtained in present step 1 for (E/Z)-2-(3- Bromophenyl)- 1-( 1 -methyl- lH-imidazol-2-yl)- 1 - [4-(methylthio)phenyl]ethene as the starting material.
- Example 9 was obtained after purification by flash chromatography (97%EtOAc/3%Et 3 N).
- Example 10 was prepared by the following procedure. A mixture of bromoquinoline Q2 (105mg, 0.33mmol), boronate B2 (236mg, 0.5 lmmol), Na 2 CO 3 (2M, 0.65mL, 1.3mmol), Pd(OAc) 2 (6.3mg, 0.028mmol) and PPh 3 (28mg, 0.1 lmmol) in 4mL of n-propanol was stirred at 90°C for 2h. The mixture was cooled to r.t., diluted with EtOAc, washed with brine, dried over Na 2 SO 4 , filtered and concentrated.
- Example 10 Single isomer as a white solid.
- NMR 1H 400MHz, Acetone-t 6 ) d 8.89 (dd, IH), 8.39 (dd, IH), 8.07 (d, IH), 8.03 (d, 2H), 7.94 (s, IH), 7.86 (d, IH), 7.71-7.68 (m, 3H) 7.62-7.60 (m, 2H), 7.55 (dd, IH), 7.45 (s, IH) 7.34 (t, IH), 7.18 (d, IH), 4.67 (q, IH), 3.04 (s, 3H), 2.86 (s, 3H) 1.88 (s,3H)
- Example 11 was prepared by following the procedure described in Example 10 but substituting bromoquinoline Q3 for Q2 and using boronate B2. Flash chromatography (Tol/ Acetone; 9/1) and stirring in EtO Ac/Hex yielded Example 11 (single isomer) as a white solid.
- Example 12 was prepared following the procedure described in Example 10 using the bromoquinoline Q2 but substituting the boronate Bl for boronate B2. Flash chromatography (95%CH 2 Cl 2 /5%EtOH) yielded the Example 12 compound.
- Example 13 was prepared following the procedure described in Example 10 but substituting the bromoquinoline Q3 for Q2 and substituting the boronate Bl for boronate B2. Flash chromatography (95%EtO Ac/5% Et 3 N) produced Example 13 (single isomer) as a foam.
- Example 15 Examples 14 and 15 were prepared by the following procedure. A solution of the aryl bromide AB5 (249mg, 0.57mmol), diboron pinacol ester (167mg, 0.66mmol), [l,r-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (12mg, 0.015mmol) and potassium acetate (176mg, 1.8mmol) in DMF (N,N- Dimethylformamide) (lOmL) was degassed and stirred at 80°C for 3h.
- DMF N,N- Dimethylformamide
- Example 14 can be made by the following procedure: Step 1. Skraup Reaction
- the mixture was cooled to 70-90°C and diluted with water. The solution was then cooled to about 20°C, and neutralized with aqueous NaOH and sodium bicarbonate. MTBE (methyl t-butyl ether) was added and the mixture was filtered and the phases were separated (the product was in the MTBE layer).
- MTBE methyl t-butyl ether
- Step 2 Bromination
- the MTBE solution from step 1 was solvent switched to chlorobenzene. After filtered through Silica gel and partially concentrated, N- bromosuccinimide (NBS, 0.6-0.8 equiv) and 2,2'-azobisisobutylnitrile (AIBN, 0.01- 0.1 equiv) were added. The degassed mixture was heated at 55-85°C. The resulting mixture was diluted with cyclohexane. Additional NBS (0.3-0.5 equiv) and AIBN (0.01-0.05 equiv) were added. The degassed mixture was heated at about 55-85°C until reaction completed. The mixture was cooled at 10-40°C and diluted with cyclohexane and aged. The solid was isolated by filtration.
- NBS N- bromosuccinimide
- AIBN 2,2'-azobisisobutylnitrile
- Step 4 Methylation A solution of the sulfone (product from the previous step, 1 equiv) in DMF was cooled to about -10 to 0°C. Sodium t-butoxide ( ⁇ 1 equiv) was added . A solution of methyl iodide/DMF solution ( ⁇ 1 equiv of Mel) was added slowly while maintaining temperature at about -10 to 0°C.
- Step 6 Oxadiazole To the mixture of hydroxy benzotriazole (“HOBt”) hydrate (1-1.5 equiv), 4-methylsulfonylphenylacetic acid (1 equiv) in acetonitrile was added EDC hydrochioride (1-1.5 equiv). The slurry was aged at about 20-30°C for 30min.
- HOBt hydroxy benzotriazole
- EDC hydrochioride 1-1.5 equiv
- N-OH compounds such as N-hydroxyphthalimide, 2- hydroxypyridine N-oxide, N-hydroxysuccinimide, can also be used to replace HOBt.
- carbodiimides such as dicyclohexylcarbodiimide and diisopropylcarbodiimide can be used to replace EDC hydrochioride (ethyl dimethylaminopropylcarbodiimide hydrochioride).
- Example 16 Example 17 Examples 16 and 17 were prepared following the procedure described previously for Examples 14 and 15 but substituting the aryl bromide AB2 for AB5 and the bromoquinoline Q5 for Q3 as the starting materials. Examples 16 and 17 were obtained as a 4:1 mixture.
- Example 18 was prepared by the following procedure.
- Step 2 (4-methoxyphenoxy)acetamide oxime
- 4-methoxyphenoxy)acetamide oxime A mixture of the (4-methoxyphenoxy) acetonitrile product (5.0g, 3 lmmol) from step 1, hydroxylamine hydrochioride (4.3g, 62mmol) and sodium acetate (5.1g, 62mmol) in MeOH (lOOmL) was stirred at r.t. for 2h. The resulting mixture was filtered on
- Step 4 3- ⁇ 6-[l-methyl-l-(methylsulfonyl)ethyl]-8- quinolinyl ⁇ benzaldehyde
- Step 5 8-(3- ⁇ (E)-2- ⁇ 3-[(4-methoxyphenoxy)methyl]-l,2,4-oxadiazol- 5-yl ⁇ -2-[4-(methylsulfonyl)phenyl]ethenyl ⁇ phenyl)-6-[l-methyl-l- (methylsulf onyl)ethyl] quinoline
- Example 18 A mixture of the product from present step 4 (150mg, 0.42mmol), the oxadiazole OX2 from present step 3 above (175mg, 0.47mmol) and piperidine (O.lrnL, l.Ommol) in toluene (0.6mL) was heated at 120°C for 3h. The mixture was purified by flash chromatography (Hex:EtOAc, 3:2 to 1:4) to yield Example 18 as a foam.
- Example 19 was prepared by the following procedure. To a solution of the Example 18 compound (250mg, 0.35mmol) in acetonitrile:water (4:1, 8 mL) was added CAN (330mg, 0.62mmol) in two portions at r.t. After 3h at r.t., the mixture was diluted with saturated NaHCO 3 solution, diluted with water and extracted with EtOAc. The organic extracts were washed (H2O), (brine), dried (MgSO 4 ), filtered and concentrated.
- Example 20 was prepared by following the procedure described above for Examples 14 and 15 but substituting the aryl bromide AB2 for AB5, and using the bromoquinoline Q3, as the starting materials.
- Example 21 was prepared by following the procedure described above for Examples 14 and 15 but substituting the aryl bromide ABI for AB5 and the bromoquinoline Q5 for Q3 as the starting materials.
- Example 22 was prepared by following the procedure described for Examples 14 and 15 using the aryl bromide AB5 and substituting the bromoquinoline Q5 for Q3 as the starting materials.
- Example 23 was prepared by following the procedure described above for Examples 14 and 15 but substituting the aryl bromide AB3 for AB5 and the bromoquinoline Q5 for Q3 as the starting materials, the title compound was obtained.
- Example 24 was prepared by following the procedure described for Examples 14 and 15 but substituting, the aryl bromide AB4 for AB5 and the bromoquinoline Q5 for Q3 as the starting materials.
- Example 25 was prepared by following the procedure described for Examples 14 and 15 but substituting the aryl bromide ABI for AB5, and 5-isopropyl- 8-bromoquinoline (described in International Patent Publication WO9422852) for Q3, as the starting materials.
- Example 26 was prepared by following the procedure described for Examples 14 and 15 using the aryl bromide AB5, and substituting 5-isopropyl-8- bromoquinoline (described in International Patent Publication O9422852) for Q3 as the starting materials.
- Step 1 (E)-3-(3- ⁇ 6-[l-methyl-l-(methylsulfonyl)ethyl]-8- quinolinyl ⁇ phenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid
- Step 2 (E)-3-(3- ⁇ 6-[l-methyl-l-(methylsulfonyl)ethyl]-8- quinolinyl ⁇ phenyl)-2-[4-(methylsulfonyl)phenyl]-l-(l-pyrrolidinyl)-2-propen-l-one
- Example 28 was prepared by following the procedure for step 2 of Example 27 but substituting cyclopropyl amine for pyrrolidine, thus yielding a white solid.
- Example 29 was prepared as a white solid by following the procedure for step 2 of Example 27 but substituting t-butyl amine amine for pyrrolidine.
- Example 30 was prepared by the following procedure. To a mixture of the benzylphosphonate P2 (lOOmg, 0.25mmol), 4,4-dichlorobenzophenone (63mg, 0.25mmol),) in THF (2mL) at r.t. was added potassium t-butoxide (IM, THF, 0.35mL, 0.35mmol). After lh at r.t., the mixture was diluted with water/NEL t Cl and extracted with EtOAc. The organic extracts were washed (H 2 O), (brine), dried (MgSO 4 ), filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 8:2) yielded Example 30 as a white foam.
- IM potassium t-butoxide
- Example 32 Examples 31 and 32 were prepared by followmg the procedure described for Example 30 but substituting the ketone K7 for 4,4 - dichlorobenzophenone and using the benzylphosphonate P2 as the starting materials.
- Examples 33 and 34 were prepared by following the procedure described for Example 30 but substituting the ketone K8 for 4,4 - dichlorobenzophenone and using the benzylphosphonate P2 as the starting materials.
- Example 35 was prepared by following the procedure described for Example 30 but substituting the ketone K9 for 4,4-dichlorobenzophenone and using the benzylphosphonate P2 as the starting materials.
- Example 37 Examples 36 and 37 were prepared by following the procedure described for Example 30 but substituting the ketone K8 for 4,4 - dichlorobenzophenone and substituting the benzylphosphonate P3 for P2 as the starting materials.
- Example 38 was prepared by following the procedure described for Example 30 but substituting the ketone K9 for 4,4 '-dichlorobenzophenone and substituting the benzylphosphonate P3 for P2 as the starting materials.
- Example 39 was prepared by following the procedure described for Example 30 but substituting the ketone K10 for 4,4 -dichlorobenzophenone and substituting the benzylphosphonate P3 for P2 as the starting materials.
- Examples 41 and 42 were prepared by following the procedure described in Example 10 but substituting bromoquinoline Q3 for Q2 and substituting boronate B3 for boronate B2.
- Example 42 was prepared by following the procedure described in Example 10 but substituting bromoquinoline Q3 for Q2 and substituting boronate B4 for boronate B2.
- Example 43 was prepared following the procedure described previously for Examples 14 and 15 but substituting the aryl bromide AB6 for AB5 and the bromoquinoline Q5 for Q3 as the starting materials.
- salts are often desirable. Examples of such salts are described below:
- Salts of the compounds of this invention that are basic may be prepared in several ways:
- SULFURIC ACID SALT OF THE EXAMPLE 14 COMPOUND The sulfuric acid salt of the example 14 compound was prepared by dissolving the compound (1.00 equiv) in refluxing ethyl acetate. After cooling to room temperature, sulfuric acid (1.04 equiv) was added slowly, while stirring. The resulting suspension was stirred a further 40 minutes and the solid was isolated by filtration and washed with ethyl acetate to give the sulfuric acid salt of the example 14 compound.
- the methanesulfonic acid salt of the example 14 compound was prepared by dissolving the compound (1.0 equiv) in refluxing ethyl acetate. After cooling to room temperature, methanesulfonic acid (1.1 equiv) was added slowly, while stirring. The resulting suspension was stirred, allowed to concentrate by evaporation and the solid was isolated by filtration and washed with ether to give the methanesulfonic acid salt of the example 14 compound.
- the p-toluenesulfonic acid salt of the example 14 compound was prepared by dissolving the compound (1.0 equiv) in refluxing ethyl acetate. After cooling to room temperature, p-toluenesulfonic acid (1.1 equiv) in ethyl acetate was added slowly. The solution was concentrated and the suspension was aged with stirring and periodic sonication at room temperature for 3 days. The solid was then isolated by filtration and washed with ethyl acetate to give the p-toluenesulfonic acid salt of the example 14 compound), mp 184-185 °C.
- 2-NAPHTHALENESULFONIC ACID SALT OF THE EXAMPLE 14 COMPOUND The 2-naphthalenesulfonic acid salt of the example 14 compound was prepared by dissolving the compound (1.0 equiv) in refluxing ethyl acetate. After cooling to room temperature, 2-naphthalenesulfonic acid (1.1 equiv) in ethyl acetate was added slowly, followed by ethanol. Toluene was then added to the solution, followed by concentration. More toluene was then added and the suspension was aged with stirring and periodic sonication at room temperature for 24h. The solid was then isolated by filtration and washed with toluene to give the 2-naphthalenesulfonic acid salt of the example 14 compound, mp 202-204 °C.
- the hydrochioride salt of the example 43 compound was prepared by dissolving the compound (1.0 equiv) in ethyl acetate with heating and sonication. After cooling the solution to room temperature, HCl in 1,4-dioxane (4M, 1.0 equiv) was added while stirring. The suspension was stirred for a further 5 minutes and the solid was isolated by filtration to give the mono-hydrochloride salt of the example 43 compound.
- XRPD X-ray Powder Diffraction
- Example 14 compound (1 equiv) in a mixture of isopropyl acetate (i-PrOAc) and methanol (1:1) was added benzenesulfonic acid (1- 1.2 equiv).
- benzenesulfonic acid (1- 1.2 equiv).
- Other esters may be used in place of i-PrOAc and other alcohols such as ethanol or propanol may be used in place of methanol.
- the mixture was aged at 20 - 50 °C until the solids dissolved.
- the resulting solution was filtered and distilled while the volume was maintained by addition of a 9: 1 (v/v) mixture of i- PrOAc/methanol.
- the product crystallized during the distillation.
- the XRPD Spectrogram for the Form B is shown in Fig. 2.
- the identifying peaks are tabulated below and shown in Fig. 5.
- the spectra are compared in Fig. 3 with the identifying peaks pointed out by arrows.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Communicable Diseases (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US17152299P | 1999-12-22 | 1999-12-22 | |
US171522P | 1999-12-22 | ||
PCT/CA2000/001559 WO2001046151A1 (en) | 1999-12-22 | 2000-12-20 | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1244628A1 true EP1244628A1 (en) | 2002-10-02 |
Family
ID=22624050
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00986937A Withdrawn EP1244628A1 (en) | 1999-12-22 | 2000-12-20 | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors |
Country Status (32)
Country | Link |
---|---|
EP (1) | EP1244628A1 (hu) |
JP (1) | JP3782011B2 (hu) |
KR (1) | KR20020082839A (hu) |
CN (1) | CN1221534C (hu) |
AR (1) | AR029214A1 (hu) |
AU (1) | AU778531B2 (hu) |
BG (1) | BG65403B1 (hu) |
BR (1) | BR0016651A (hu) |
CA (1) | CA2393749C (hu) |
CO (1) | CO5261613A1 (hu) |
CZ (1) | CZ20022171A3 (hu) |
DZ (1) | DZ3244A1 (hu) |
EA (1) | EA004747B1 (hu) |
EE (1) | EE200200342A (hu) |
GE (1) | GEP20053626B (hu) |
HK (1) | HK1057560A1 (hu) |
HR (1) | HRP20020545A2 (hu) |
HU (1) | HUP0203896A3 (hu) |
IL (1) | IL150114A0 (hu) |
IS (1) | IS6413A (hu) |
MX (1) | MXPA02006329A (hu) |
MY (1) | MY134008A (hu) |
NO (1) | NO20023013L (hu) |
NZ (1) | NZ520258A (hu) |
PE (1) | PE20010989A1 (hu) |
PL (1) | PL355752A1 (hu) |
SK (1) | SK8972002A3 (hu) |
TW (1) | TWI280240B (hu) |
UA (1) | UA74815C2 (hu) |
WO (1) | WO2001046151A1 (hu) |
YU (1) | YU47102A (hu) |
ZA (1) | ZA200204862B (hu) |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7776315B2 (en) | 2000-10-31 | 2010-08-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Pharmaceutical compositions based on anticholinergics and additional active ingredients |
DE10110772A1 (de) * | 2001-03-07 | 2002-09-12 | Boehringer Ingelheim Pharma | Neue Arzneimittelkompositionen auf der Basis von Anticholinergika und PDE-IV-Inhibitoren |
EA005864B1 (ru) * | 2000-12-20 | 2005-06-30 | Мерк Энд Ко., Инк. | Способ получения замещенного бензолсульфоната 8-арилхинолиния |
US6740666B2 (en) * | 2000-12-20 | 2004-05-25 | Merck & Co., Inc. | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors |
DE60204463T2 (de) | 2001-06-27 | 2006-05-18 | Merck Frosst Canada & Co, Kirkland | Substituierte 8-Arylchinoline als PDE4-Hemmer |
US7009055B2 (en) * | 2001-07-24 | 2006-03-07 | Merck & Co., Inc. | Preparation of Sulfonyl quinoline |
PL205927B1 (pl) * | 2001-09-19 | 2010-06-30 | Nycomed Gmbh | Kompozycja farmaceutyczna zawierająca inhibitor PDE - roflumilast i antagonistę receptora leukotrienowego - montelukast, sposób wytwarzania tej kompozycji, produkt farmaceutyczny i zestaw zawierający te związki oraz zastosowanie kompozycji i produktu farmaceutycznego |
ATE432261T1 (de) * | 2002-03-18 | 2009-06-15 | Merck Frosst Canada Ltd | Pde4-inhibitoren mit heterobrückensubstituiertem 8-arylchinolin |
NZ542407A (en) * | 2003-03-05 | 2008-08-29 | Celgene Corp | Diphenylethylene compounds and uses thereof |
JP2007530594A (ja) * | 2004-03-25 | 2007-11-01 | シンタ ファーマシューティカルズ コーポレーション | 炎症及び免疫に関連する用途に用いられるアクリロニトリル誘導体 |
JP2008545389A (ja) * | 2005-05-19 | 2008-12-18 | シナージェンズ バイオサイエンス リミティド | 肺機能及び肺障害の評価のための方法及び組成物 |
RS53461B (en) | 2006-07-05 | 2014-12-31 | Takeda Gmbh | COMBINATION OF HMG-COA REDUCTASE INHIBITOR OR SIMVASTATIN WITH PHOSPHODIESTERASE 4 INHIBITOR AS A ROFLUMILAST FOR THE TREATMENT OF INFLAMMATORY PULMONARY DISEASES |
MX2009000148A (es) * | 2006-07-07 | 2009-10-26 | Kalypsys Inc | Inhibidores heteroaril biciclicos de fosfodiesterasa 4. |
US20080103105A1 (en) * | 2006-09-22 | 2008-05-01 | Braincells, Inc. | HMG CoA REDUCTASE MEDIATED MODULATION OF NEUROGENESIS |
WO2008099210A2 (en) | 2007-02-12 | 2008-08-21 | Merck & Co., Inc. | Piperazine derivatives for treatment of ad and related conditions |
WO2009128057A2 (en) | 2008-04-18 | 2009-10-22 | UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN et al | Psycho-pharmaceuticals |
EP2533780B1 (en) | 2010-02-12 | 2017-08-23 | AskAt Inc. | 5-ht4 receptor agonists for the treatment of dementia |
EP2741777B1 (en) | 2011-08-12 | 2017-01-18 | INSERM - Institut National de la Santé et de la Recherche Médicale | Methods and pharmaceutical compositions for treatment of pulmonary hypertension |
US20140328893A1 (en) | 2011-10-11 | 2014-11-06 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Nutlin compounds for use in the treatment of pulmonary hypertension |
JP2020532551A (ja) * | 2017-09-03 | 2020-11-12 | アンジオン バイオメディカ コーポレーション | Rho関連コイルドコイルキナーゼ(ROCK)阻害剤としてのビニルヘテロ環 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9226830D0 (en) * | 1992-12-23 | 1993-02-17 | Celltech Ltd | Chemical compounds |
US5455252A (en) * | 1993-03-31 | 1995-10-03 | Syntex (U.S.A.) Inc. | Optionally substituted 6,8-quinolines |
US6245774B1 (en) * | 1994-06-21 | 2001-06-12 | Celltech Therapeutics Limited | Tri-substituted phenyl or pyridine derivatives |
JPH11209350A (ja) * | 1998-01-26 | 1999-08-03 | Eisai Co Ltd | 含窒素複素環誘導体およびその医薬 |
-
2000
- 2000-12-19 MY MYPI20005965A patent/MY134008A/en unknown
- 2000-12-20 AU AU23362/01A patent/AU778531B2/en not_active Ceased
- 2000-12-20 CO CO00096650A patent/CO5261613A1/es not_active Application Discontinuation
- 2000-12-20 UA UA2002076108A patent/UA74815C2/uk unknown
- 2000-12-20 BR BR0016651-0A patent/BR0016651A/pt not_active IP Right Cessation
- 2000-12-20 CN CNB00818951XA patent/CN1221534C/zh not_active Expired - Fee Related
- 2000-12-20 DZ DZ003244A patent/DZ3244A1/fr active
- 2000-12-20 EA EA200200702A patent/EA004747B1/ru not_active IP Right Cessation
- 2000-12-20 GE GE4903A patent/GEP20053626B/en unknown
- 2000-12-20 PL PL00355752A patent/PL355752A1/xx not_active IP Right Cessation
- 2000-12-20 EP EP00986937A patent/EP1244628A1/en not_active Withdrawn
- 2000-12-20 IL IL15011400A patent/IL150114A0/xx unknown
- 2000-12-20 SK SK897-2002A patent/SK8972002A3/sk not_active Application Discontinuation
- 2000-12-20 JP JP2001547062A patent/JP3782011B2/ja not_active Expired - Fee Related
- 2000-12-20 KR KR1020027008079A patent/KR20020082839A/ko not_active Application Discontinuation
- 2000-12-20 CZ CZ20022171A patent/CZ20022171A3/cs unknown
- 2000-12-20 EE EEP200200342A patent/EE200200342A/xx unknown
- 2000-12-20 MX MXPA02006329A patent/MXPA02006329A/es not_active Application Discontinuation
- 2000-12-20 YU YU47102A patent/YU47102A/sh unknown
- 2000-12-20 HU HU0203896A patent/HUP0203896A3/hu unknown
- 2000-12-20 NZ NZ520258A patent/NZ520258A/en unknown
- 2000-12-20 WO PCT/CA2000/001559 patent/WO2001046151A1/en active IP Right Grant
- 2000-12-20 CA CA002393749A patent/CA2393749C/en not_active Expired - Fee Related
- 2000-12-21 TW TW089127506A patent/TWI280240B/zh not_active IP Right Cessation
- 2000-12-21 AR ARP000106867A patent/AR029214A1/es not_active Application Discontinuation
- 2000-12-22 PE PE2000001396A patent/PE20010989A1/es not_active Application Discontinuation
-
2002
- 2002-06-11 IS IS6413A patent/IS6413A/is unknown
- 2002-06-18 ZA ZA200204862A patent/ZA200204862B/en unknown
- 2002-06-19 BG BG106840A patent/BG65403B1/bg unknown
- 2002-06-21 HR HR20020545A patent/HRP20020545A2/hr not_active Application Discontinuation
- 2002-06-21 NO NO20023013A patent/NO20023013L/no unknown
-
2004
- 2004-01-26 HK HK04100511A patent/HK1057560A1/xx not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
See references of WO0146151A1 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6743802B2 (en) | Alkyne-aryl phosphodiesterase-4 inhibitors | |
US6410563B1 (en) | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors | |
WO2001046151A1 (en) | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors | |
EP1363635B1 (en) | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors | |
WO2004005258A1 (en) | Di-aryl-substituted-ethane pyridone pde4 inhibitors | |
AU2002322940A1 (en) | Alkyne-aryl phosphodiesterase-4 inhibitors | |
AU2001297603A1 (en) | Substituted 8-arylquinoline phosphodiesterase-4 inhibitors | |
US6399636B2 (en) | Tri-aryl-substituted-ethane PDE4 inhibitors | |
WO2003002118A1 (en) | Substituted 8-arylquinoline pde4 inhibitors | |
AU2002344885A1 (en) | Substituted 8-arylquinoline PDE4 Inhibitors | |
EP1635829A1 (en) | 8-(3-biaryl)phenylquinoline phosphodiesterase-4-inhibitors | |
US6639077B2 (en) | Tri-aryl-substituted-ethane PDE4 inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20020722 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
AX | Request for extension of the european patent |
Free format text: AL PAYMENT 20020722;LT PAYMENT 20020722;LV PAYMENT 20020722;MK PAYMENT 20020722;RO PAYMENT 20020722;SI PAYMENT 20020722 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: MERCK FROSST CANADA LTD. |
|
17Q | First examination report despatched |
Effective date: 20081216 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20100728 |