WO2008140781A1 - Spiro compounds for treatment of inflammatory disorders - Google Patents
Spiro compounds for treatment of inflammatory disorders Download PDFInfo
- Publication number
- WO2008140781A1 WO2008140781A1 PCT/US2008/005996 US2008005996W WO2008140781A1 WO 2008140781 A1 WO2008140781 A1 WO 2008140781A1 US 2008005996 W US2008005996 W US 2008005996W WO 2008140781 A1 WO2008140781 A1 WO 2008140781A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- group
- hydroxy
- carboxy
- alkenyl
- Prior art date
Links
- 0 *C(*)(C1)c2c(*)c(O*)c(*)c(*)c2*C1(CC1(*)*)*c(c(*)c2*)c1c(*)c2OI Chemical compound *C(*)(C1)c2c(*)c(O*)c(*)c(*)c2*C1(CC1(*)*)*c(c(*)c2*)c1c(*)c2OI 0.000 description 5
- JZJOVGJUMSCETN-UHFFFAOYSA-N CC(C)(C1)c(cc(c(C)c2)O)c2OC1(CC(C)(C)c1c2)Oc1cc(C)c2OCCC[n]1cncc1 Chemical compound CC(C)(C1)c(cc(c(C)c2)O)c2OC1(CC(C)(C)c1c2)Oc1cc(C)c2OCCC[n]1cncc1 JZJOVGJUMSCETN-UHFFFAOYSA-N 0.000 description 1
- ZLWAYLPYOFCQHU-WFFHQLTOSA-N CC(C)(C1)c(cc(c(C)c2)O)c2OC1(CC1(C)C)Oc(cc2C)c1cc2OC[C@H](CO)O Chemical compound CC(C)(C1)c(cc(c(C)c2)O)c2OC1(CC1(C)C)Oc(cc2C)c1cc2OC[C@H](CO)O ZLWAYLPYOFCQHU-WFFHQLTOSA-N 0.000 description 1
- ILWCRASDENNGGD-UYAFCKSNSA-N C[C@H](CC[C@H]1C(C)(C)c2ccccc2)C[C@H]1OC(COc(cc1C(C)(C)C2)c(C)cc1OC2(CC1(C)C)Oc(cc2C)c1cc2O)=O Chemical compound C[C@H](CC[C@H]1C(C)(C)c2ccccc2)C[C@H]1OC(COc(cc1C(C)(C)C2)c(C)cc1OC2(CC1(C)C)Oc(cc2C)c1cc2O)=O ILWCRASDENNGGD-UYAFCKSNSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- 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
- A61P11/02—Nasal agents, e.g. decongestants
-
- 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
- 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
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- 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
-
- 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
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- 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
-
- 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
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- A61P7/06—Antianaemics
-
- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention is in the area of methods and compositions for the treatment and prophylaxis of inflammatory disorders and, in particular, for the treatment or prophylaxis of respiratory inflammatory diseases such as asthma.
- chronic inflammation is involved in diseases as diverse as allergy, anemia, aortic valve stenosis, arthritis, atherosclerosis, cancer, heart valve dysfunction, obesity, diabetes, congestive heart failure, digestive system diseases, and Alzheimer's disease (Brouqui et al. 1994; Devaux et al. 1997; De Keyser et al. 1998).
- Chronic inflammation inevitably causes tissue damage and is accompanied by simultaneous attempts at healing and repair.
- the exact nature, extent and time course of chronic inflammation is variable, and depends on a balance between the causative agent and the attempts of the body to remove it.
- Disorders associated with inflammation are debilitating to individuals suffering from them and cost billions in reduced productivity and increased medical expenses.
- Asthma is one of the most common chronic health conditions and is on the rise due to irritants such as pollution and chronic exposure to indoor allergens such as cigarette smoke, cockroaches, dust mites, mold, animals, pollen, cold air, exercise, stress, and respiratory infections.
- Asthma and related respiratory disorders such as chronic obstructive pulmonary disease (COPD) are chronic or recurring inflammatory conditions in which the airway develops increased responsiveness to various stimuli, characterized by bronchial hyper- responsiveness, inflammation, increased mucus production, and intermittent airway obstruction.
- COPD chronic obstructive pulmonary disease
- Coronary heart disease (CHD) remains the leading cause of death in the industrialized countries.
- Cardiovascular disease has been linked to several causative factors, which include hypercholesterolemia, hyperlipidemia, and the expression of VCAM-I in vascular endothelial cells.
- the primary cause of CHD is atherosclerosis, a disease characterized by the deposition of lipids in the arterial vessel wall, resulting in a narrowing of the vessel passages and ultimately hardening the vascular system, which is likely mediated by the expression of certain inflammatory cytokines and VCAM-I.
- Atherosclerosis as manifested in its major clinical complication, ischemic heart disease, continues to be a major cause of death in industrialized countries.
- Atherosclerosis can begin with local injury to the arterial endothelium followed by proliferation of arterial smooth muscle cells from the medial layer to the intimal layer along the deposition of lipid and accumulation of foam cells in the lesion. As the atherosclerotic plaque develops it progressively occludes more and more of the affected blood vessel and can eventually lead to ischaemia or infarction.
- vascular endothelial cells that are chronically exposed to higher than normal levels of polyunsaturated fatty acids or their oxidized counterparts can initiate an immune response that is not normal and which is out of proportion to the threat presented, leading to a diseased state.
- the oversensitization of vascular endothelial cells to PUFAs and ox-PUFAs can accelerate the formation, for example, of atherosclerotic plaque.
- cytokines include the IL-6 and IL-8 families. Regulation of these and other related cytokines can be a strategy when overstimmulation of the immune responses leads to adverse events.
- Cytokines are produced predominantly by activated immune cells such as microglia and are involved in the amplification of inflammatory reactions. These include IL-I, IL-6, TNF- ⁇ , and TGF- ⁇ .
- a spiro compound is a bicyclic organic compound with rings connected through just one atom.
- the rings can be different in nature or identical.
- the connecting atom is also called the spiroatom, most often a quaternary carbon ("spiro carbon").
- Some spiro compounds exhibit axial chirality. Spiroatoms can be centers of chirality even when they lack the four different substituents normally observed in chirality.
- the priority is determined by a slight modification of the CEP system assigning a higher priority to one ring extension and a lower priority to an extension in the other ring.
- rings are dissimilar the regular rules apply.
- Spiro forms of lactones and oxazines are frequently used as leuco dyes, frequently displaying chromism - reversible change between their colorless and color form.
- Spiroketals or spiroacetals
- Spiroketals are substructures in many naturally occurring substances, including insects, microbes, plants, fungi, and marine organisms (F. Perron and K.F. Albizati, Chem. Rev. 1989, 89, pp. 1617-1661).
- Most naturally occurring spiroketal compounds include one of the substructures (A) 1,7-Dioxaspiro[5.5]undecane, (B) 1,6- Dioxaspiro[4.5]decane, or (C) 1,7-Dioxaspiro[4.4]nonane.
- Reveromycin A is a naturally occurring spiroketal compound isolated from the soil actinomycete genus Streptomyces sp. Reveromycin A is known to inhibits bone resorption in vitro and in vivo by inducing apoptosis specifically in ostesoclasts, suggesting that RM-A might be useful in the treatment of bone disorders, including osteoporosis.
- Reveromycin A is also known to have antifungal and antiproliferative properties. (Takahashi, H. et al. (1992) J. Antibiot.
- reveromycin A includes a [6,6] spiroketal core.
- the enantioselective sysnthesis of the spiroketal core of reveromycin A has recently been achieved. (K. Drouet, et al., Org. Lett. 2000, Vol. 2., No. 2, pp. 207-210).
- Spongistatin is a potent tubulin depolymerizing natural product isolated from an Eastern Indian Ocean sponge in the genus Spongia. (Bai et al. MoI Pharmacol.1993; 44: 757- 766).
- X 1 , X 2 , and X 3 are the same or different, and are each independently O, C, or
- R 22 represents an alkyl, alkenyl, aryl, alkoxy, alkenoxy, or aryloxy group
- R 23 and R 24 each represent a hydrogen, halogen, alkyl, alkenyl, or alkoxy group
- R 1 represents an alkyl, alkenyl, cycloalkyl, aryl, heterocyclic, R 25 CO-, R 26 SO 2 -, or R 27 NHCO- group
- R 2 represents a hydrogen, alkyl, alkenyl, R 25 CO-, R 26 SO 2 - or R 27 NHCO- group
- R 25 , R 26 and R 27 each represent an alkyl, alkenyl, cycloalkyl, aryl, or heterocyclic group.
- Ri represents an alkyl, alkenyl, alkoxyl, alkenoxyl or aryloxyl group
- R 2 and R 3 individually represent hydrogen, halogen, alkyl, alkenyl or alkoxyl group
- R represents an alkyl, alkenyl, cycloalkyl, aryl, heterocyclic, R 6 CO-, R 7 SO 2 - or R 8 NHCO-
- R' is hydrogen, R 6 CO-, R 7 SO 2 - or R 8 NHCO-
- R 6 , R 7 and R 8 individually represent an alkyl, alkenyl, cycloalkyl, aryl or heterocyclic; and, the respective above-mentioned groups may be substituted by halogen, alkyl, aryl, aryloxyl, cyano, acyloxyl, carboalkoxyl, acyl, sulfamoyl, hydroxyl, nitro or amino group.
- R' represents R 6 CO-, R 7 SO
- R 22 and R 22 which may be the same or different and are each hydrogen, alkyl, alkenyl, cycloalkyl, aryl, a heterocyclic, -CO-V, -SO2 -V or -CONH-V wherein V is an alkyl of 1-20 carbons, alkoxy of 1-20 carbons, aryloxy, alkyloxycarbonyl, or aryloxycarbonyl; R 23 is an alkyl of 1-20 carbons, alkenyl of 2-20 carbons, aryl, alkoxy of 1- 20 carbons, or aryloxy; when both R 22 or R 22 and R 23 are alkyl, R 22 or R 22 and R 23 may be fused to form a 5- to 7-membered ring; X and Y each represent a hydrogen, halogen, alkyl of 1-20 carbons, alkoxy of 1-20 carbons, alkenyl, aryl or aryloxy.
- R 1 A , R 4A and R 5 A which may be the same or different, each represents a hydrogen, alkyl, aryl, alkenyl, aralkyl, alkoxy, aryloxy, alkenoxy, aralkoxy, alkylthio, arylthio, halogen, hydroxy, amino, acylamino, diacylamino, sulfonamide, alkylamino, dialkylamino, arylamino, heterocyclic amino, sulfo, arylsulfonyl, arylsulfinyl, acyloxy, acyl, alkoxycarbonyl, , and Ri 4A represents a hydrogen, alkyl, aryl, aralkyl, alkenyl, acyl, or sulfonyl group.
- Ari is (un)substituted fused of spiro polycyclic cycloalkyl, heterocycloalkyl, aryl or heteroaryl group
- Ri is (un)substituted aryl, cycloalkyl, heterocycloalkyl, alkyl, alkenyl, etc.
- Z is O, S, SO 2 , or NR 2
- V is SO, S, or C
- X is O, N, or S
- Y is O, or NR 2
- R 2 is H, alkyl or alkoxy.
- spiroketal compounds are useful in the treatment or prophylaxis of inflammatory conditions.
- compounds described below are useful for treating respiratory inflammation such as found in asthma as well as other inflammatory disorders such as atherosclerosis or arthritis.
- compounds, pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprising administering to a host in need thereof a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided:
- compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprising administering to a host in need thereof a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided:
- Y and Z are independently O, S(O) q , Se(O) q or N(R . 1 1 3 J ) ⁇ ;
- each q is independently 0, 1 or 2;
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl and -OR 14 , wherein all may be optionally substituted by a hydroxy group;
- R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, and C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by a hydroxy group;
- R 11 and R 12 are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, carboxy, alkoxy, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR 14 R 15 , oxo, cyano, alkoxycarbonyl, -OR 16 , -C(O)R 16 , -C(O)-NH 2 , -C(O)-N(H)R 14 , -C(O)-N(H)OR 14 , -C(O)- NR 14 R 15 , -NR 15 C
- each n is independently O, 1, or 2;
- R 13 is independently selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, alkoxy, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
- R 14 and R 15 are independently selected from the group consisting of hydrogen, Cj-C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, alkoxy heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16 ;
- R 14 and R 15 taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
- R 16 is independently selected from the group consisting of Ci-C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy;
- R 1 ' and R 12 are heteroaryl, R 1 ' and R 12 cannot be 2-furyl.
- the pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprises administering to a host in need thereof a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof wherein R 11 is hydrogen.
- compounds, pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprising administering to a host in need thereof a compound of Formula FI, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided:
- Y* and Z* are independently O, S(O) q , Se(O) q or N(R 13* );
- each q is independently 0, 1 or 2;
- R 1 * , R 2* , R 3* , R 4* , R 5* and R 6* are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, C]-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl and -OR 14* , wherein all may be optionally substituted by a hydroxy group;
- R 7* , R 8* , R 9* and R 10* are independently selected from the group consisting of hydrogen, halo, Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, and C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by a hydroxy group;
- R 12* is selected from the group consisting of Ci-C 6 straight alkyl, hydroxy-Ci-C 6 straight alkyl, polyhydroxy-Ci -C 6 straight alkyl, carboxy-Q -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13* )-Ci -C 6 straight alkyl, (C(O)NHR 13* )-C 3 -C 6 branched alkyl, (C(O)NHR 13* )-C 2 -C 6 alkenyl, (C(O)NHR 13* )-C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl
- each n is independently 0, 1, or 2;
- R 13* is selected from the group consisting of hydrogen, hydroxy, Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -Cg cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
- R 14* and R 15* are independently selected from the group consisting of hydrogen, Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16* ;
- R 14* and R 15* taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
- R 16* is independently selected from the group consisting OfCi-C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
- the inflammatory disorder is a respiratory disorder.
- the inflammatory disorder is asthma or COPD.
- the inflammatory disorder is a cardiovascular disorder.
- Cardiovascular inflammatory disorders include atherosclerosis, post-angioplasty, restenosis, coronary artery diseases, angina, and other cardiovascular diseases.
- the disorder is a non-cardiovascular inflammatory disorder such as rheumatoid and osteoarthritis, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, eczematous dermatitis, Kaposi's sarcoma, multiple sclerosis or is diabetes.
- the compounds disclosed herein can be selected to treat inflammatory conditions that are mediated by mononuclear leucocytes.
- the compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.
- Inflammatory disorders include, but are not limited to asthma, atherosclerosis, post- angioplasty, restenosis, coronary artery diseases, angina, as well as other cardiovascular and noncardiovascular inflammatory diseases such as rheumatoid and osteoarthritis, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, eczematous dermatitis, Kaposi's sarcoma, multiple sclerosis, or proliferative disorders of smooth muscle cells or diabetes.
- compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprising administering to a host in need thereof a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided:
- Y and Z are independently O, S(O) q , Se(O) q or N(R » 1 1 J 3) ⁇ ;
- each q is independently 0, 1 or 2;
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, CpC 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl and -OR 14 , wherein all may be optionally substituted by a hydroxy group;
- R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of hydrogen, halo, Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, and C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by a hydroxy group;
- R 11 and R 12 are independently selected from the group consisting of hydrogen, Ci-C 6 straight alkyl, Ci -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, carboxy, alkoxy, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR 14 R 15 , oxo, cyano, alkoxycarbonyl, -OR 16 , -C(O)R 16 , -C(O)-NH 2 , -C(O)-N(H)R 14 , -C(O)-N(H)OR 14 , -C(O)- NR 14 R 15 , -NR 15 C(O)
- R 11 and R 12 are independently selected from the group consisting of hydrogen, aryl, heteroaryl and heterocycle, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, alkoxy, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR 14 R 15 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 16 , -C(O)R 16 , -C(O)-NH 2 , -C(O)-N(H)R 14 , -C(O)-N(H)OR 14 , -C(O)-NR 14 R 15 , -NR 15 C(O)R 14 , - NR 15 C(O)NR 14 R 15 , -OC(O)NR 14 R 15 , -NR
- each n is independently O, 1, or 2;
- R 13 is independently selected from the group consisting of hydrogen, hydroxy, Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, alkoxy, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
- R 14 and R 15 are independently selected from the group consisting of hydrogen, Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, alkoxy heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16 ;
- R 14 and R 15 taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
- R 16 is independently selected from the group consisting Of Ci-C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy;
- the pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprises administering to a host in need thereof a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof wherein R 11 is hydrogen.
- Y and Z are independently O or S(O) q . In another embodiment, Y and Z are independently O or S(O) q and q is 0. In another embodiment, Y and Z are each O. In another embodiment, Y and Z are each S(O) q and q is 0. In another embodiment, Y and Z are each Se(O) q and q is 0. In another embodiment, Y and Z are each N(R 13 ). In a subembodiment, R 13 is H or C 1 -C 6 straight or branched alkyl.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, Ci-C 4 straight alkyl, Ci-C 4 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cyclic alkyl, aryl and -OR 14 , wherein all may be optionally substituted by a hydroxy group.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, C 1 -C 4 straight alkyl, Ci-C 4 branched alkyl, C 2 -C 6 alkenyl, and C 3 -C 6 cyclic alkyl.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, halo, Ci-C 4 straight alkyl, and in particular, H or methyl.
- R 1 , R 3 , R 4 and R 6 are hydrogen; and R 2 , R 5 are Q- C 4 straight or branched alkyl, for example, methyl, ethyl, propyl, isopropyl, w-butyl, t-butyl, or 5-butyl.
- R 1 , R 3 , R 4 and R 6 are hydrogen; and R 2 and R 5 are Ci- C 4 straight alkyl, Ci-C 4 branched alkyl, or C 2 -C 6 alkenyl, wherein all may be optionally substituted by one or more halo groups.
- R 1 , R 3 , R 4 and R 6 are hydrogen; and R 2 and R 5 are methyl.
- R , R , R 9 and R 10 are independently selected from the group consisting of hydrogen, halo, C 1 -C 4 straight alkyl and C 1 -C 4 branched alkyl; wherein all may be optionally substituted by a hydroxy group.
- R 7 , R 8 , R 9 and R 10 are independently selected from the group consisting of Ci-C 4 straight or branched alkyl, for example, methyl, ethyl, propyl, isopropyl, H-butyl, t-butyl, or s-butyl.
- R 7 , R 8 , R 9 and R 10 are methyl.
- R 1 is hydrogen. In another embodiment, both R 1 ' and R 12 are hydrogen. In another embodiment, at least one of R 11 and R 12 is not hydrogen.
- R 1 is C 1 -C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, or C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of acyl, hydroxy, Ci-C 4 alkoxy, heterocyclic, heteroaryl, aryl, amino, -NR 14 R 15 , oxo, cyano, alkoxycarbonyl, -OR 16 , -C(O)R 16 , -C(O)-NH 2 , -C(O)- N(H)R 14 , -C(O)-N(H)OR 14 , -C(O)-NR 14 R 15 , -NR 15 C(O)R 14 , -NR 15 C(O)NR 14 R 15 , -OC(O)NR 14 R 15 , -NR 15 C(O)OR 16 , -S(O)
- R 12 is C]-C 6 straight alkyl, Ci -C 6 branched alkyl, optionally substituted by one or more hydroxy, heteroaryl, or alkoxycarbonyl.
- R 12 is Cj-C 4 straight alkyl, Ci-C 4 branched alkyl, optionally substituted by one or more hydroxy, heteroaryl, or alkoxycarbonyl.
- R 12 is Ci-C 4 straight alkyl, Ci-C 4 branched alkyl, substituted by one or more hydroxy groups.
- R 12 is Ci-C 4 straight alkyl, Ci-C 4 branched alkyl, substituted by one or more heteroaryl which may be optionally substituted.
- R 12 is Ci-C 4 straight alkyl, Ci-C 4 branched alkyl, substituted by one or more pyrrolyl, pyrazolyl or imidazolyl, which may be optionally substituted.
- R 12 is Ci-C 4 straight alkyl, C]-C 4 branched alkyl substituted by one or more alkoxycarbonyl.
- R 12 is Ci-C 6 straight alkyl, Ci -C 6 branched alkyl, substituted by carboxy, for example, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 2- carboxypropyl, 3-carboxypropyl, 1-carboxyisopropyl, 2-carboxyisopropyl, l-carboxy- «- butyl, 2-carboxy-n-butyl, 3-carboxy-n-butyl, 4-carboxy-n-butyl, or 2-carboxy-t-butyl.
- R 12 is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2- hydroxy-2,2-dimethylethyl, 2-hydroxy-l,l-dimethylethyl, 1-hydroxypropyl, 2- hydroxypropyl, 3-hydroxypropyl, 1-hydroxyisopropyl, 2-hydroxyisopropyl, 1 -hydroxy-n- butyl, 2-hydroxy-n-butyl, 3-hydroxy-n-butyl, 4-hydroxy- «-butyl, or 2-hydroxy-/-butyl.
- R 12 is 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, 2,3- dihydroxypropyl, 1,3-dihydroxypropyl, 1,2-dihydroxyisopropyl, 1,2-dihydroxy-n-butyl, 1,3- dihydroxy-n-butyl, 1 ,4-dihydroxy-H-butyl, 2,3-dihydroxy-n-butyl, 2,4-dihydroxy- «-butyl, or 3 ,4-dihydroxy-n -butyl .
- R 12 is 1,2,3-trihydroxy-w-butyl, 1,2,4-trihydroxy- ⁇ i-butyl, 1,3,4-trihydroxy-n-butyl, or 2,3,4-trihydroxy-H-butyl.
- R 12 is Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, substituted by a substituted or unubstituted heteroaryl or heterocycle, for example, pyrazole, imidazole, methyl-pyrazole, dimethylpyrazole, 3-hydroxymethyl-5-methyl-pyrazole, 5-hydroxymethyl- 3-methyl-pyrazole.
- R 12 is optionally substituted C 2 -C 6 alkenyl, for example, ethenyl, propenyl, 1-butenyl, 2-butenyl or 3-butenyl.
- R 12 is selected from the group consisting of aryl, heteroaryl and heterocycle, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, alkoxy, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR 14 R 15 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 16 , -C(O)R 16 , -C(O)-NH 2 , -C(O)- N(H)R 14 , -C(O)-N(H)OR 14 , -C(O)-NR 14 R 15 , -NR 15 C(O)R 14 , -NR 15 C(O)NR 14 R 15 , -OC(O)NR 14 R 15 , -NR 15 C(
- R 12 is selected from the group consisting of aryl, heteroaryl and heterocycle, wherein all may be optionally substituted by one or more independently selected from the group consisting of alkyl, acyl, hydroxy, hydroxyalkyl, alkoxy, carboxy, carboxyalkyl, or alkoxycarbonyl.
- R 12 is a pyrrolyl, pyrazolyl or imidazolyl group, all of which may be optionally substituted.
- the compound is selected from the group consisting of:
- the pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprises administering to a host in need thereof one enantiomer or one stereoisomer of a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof.
- the compounds are present as enantiomers.
- the compound is present as a racemic mixture.
- the enantiomer can be named by the configuration at the chiral center, such as R or S.
- the compound is present as a racemic mixture of R- and S- enantiomers.
- the compound is present as a mixture of two enantiomers.
- the mixture has an enantiomeric excess in R.
- the mixture has an enantiomeric excess in S.
- the compound is in an enantiomeric excess of the R- or S- enantiomer.
- the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the single enantiomer.
- the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the R enantiomer.
- the enantiomeric excess can be 51 % or more, such as 51 % or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the S enantiomer.
- the compound is substantially in the form of a single enantiomer. In some embodiments, the compound is present substantially in the form of the R enantiomer. In some embodiments, the compound is present substantially in the form of the S enantiomer.
- the phrase "substantially in the form of a single enantiomer" is intended to mean at least 70% or more in the form of a single enantiomer, for example 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in either the R or S enantiomer.
- the enantiomer can be named by the direction in which it rotates the plane of polarized light. If it rotates the light clockwise as seen by the viewer towards whom the light is traveling, the isomer can be labeled (+) and if it rotates the light counterclockwise, the isomer can be labeled (-).
- the compound is present as a racemic mixture of (+) and (-) isomers. In certain embodiments, the compound is present as a mixture of two isomers. In one embodiment, the mixture has an excess in (+). In one embodiment, the mixture has an excess in (-). In certain other embodiments, the compound is in an excess of the (+) or (-) isomer.
- the isomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the (+) isomer.
- the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the (-) isomer.
- the compound is substantially in the form of a single optical isomer. In some embodiments, the compound is present substantially in the form of the (+) isomer. In other embodiments, the compound is present substantially in the form of the (-) isomer.
- the phrase "substantially in the form of a single optical isomer” is intended to mean at least 70% or more in the form of a single isomer, for example 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of either the (+) or (-) isomer.
- the compound has two or more chiral or stereogenic carbons, hi certain embodiments, the compound is a compound of Formula I wherein R 12 comprises a substituent with one or more chiral or stereogenic carbons. hi certain embodiments the compound of any of the foregoing formula or embodiments, is a diastereomer. In certain embodiments, the compound is substantially in the form of one diastereomer. In certain embodiments, the compound is substantially in the form of two diastereomers.
- the pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprises administering to a host in need thereof one diastereomer of a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof.
- the pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprises administering to a host in need thereof one diastereomer, or a mixture of two or more diastereomers, of a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof.
- the compounds are present as diastereomers.
- the compound is present as a mixture of diastereomers.
- the diastereomers can be named by the configuration at each of the chiral centers, such as (R,R) or (R,S).
- the compound is present as a mixture of two diastereomers.
- the compound is present as a mixture of four diastereomers.
- the compound is present as a mixture of two or more diastereomers. In one embodiment, the mixture has one diastereomer in excess.
- the compound is substantially in the form of one diastereomer.
- the phrase "substantially in the form of one diastereomer” is intended to mean at least 70% or more in the form of the diastereomer, for example 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more.
- the compound of any of the foregoing formula or embodiments is a diastereomer.
- the pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprises administering to a host in need thereof one diastereomer of a compound of Formula I, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof.
- compounds, pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma, comprising administering to a host in need thereof a compound of Formula II, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided:
- Y* and Z* are independently O, S(O) q , Se(O) q or N(R 1 1 3 3 * ); each q is independently 0, 1 or 2;
- R 1* , R 2* , R 3* , R 4* , R 5* and R 6* are independently selected from the group consisting of hydrogen, halo, C 1 -C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl and -OR 14* , wherein all may be optionally substituted by a hydroxy group;
- R 7* , R 8* , R 9* and R are independently selected from the group consisting of hydrogen, halo, Cj-C 6 straight alkyl, Cj-C 6 branched alkyl, and C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by a hydroxy group;
- R 12* is selected from the group consisting of C J -C 6 straight alkyl, hydroxy-Ci-C 6 straight alkyl, polyhydroxy-Cj-C 6 straight alkyl, carboxy-Cj-C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13* )-Ci -C 6 straight alkyl, (C(O)NHR 13* )-C 3 -C 6 branched alkyl, (C(O)NHR 13* )-C 2 -C 6 alkenyl, (C(O)NHR 13* )-C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alky
- each n is independently 0, 1, or 2;
- R 13* is selected from the group consisting of hydrogen, hydroxy, Cj-C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
- R 14* and R 15* are independently selected from the group consisting of hydrogen, Cj-C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16* ;
- R 14* and R 15* taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
- R 16* is independently selected from the group consisting Of Cj-C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
- the compound is a compound of formula II wherein R 1 * , R 2* , R 3* , R 4* , R 5* and R 6 are independently selected from the group consisting of hydrogen, halo, Ci- C 4 straight alkyl, Ci-C 4 branched alkyl, C 2 -C 6 alkenyl, aryl and -OR 14* .
- R 7* , R 8* , R 9* and R 10* are independently selected from the group consisting of hydrogen, halo, Ci-C 4 straight alkyl, and Ci-C 4 branched alkyl.
- Y * and Z * are independently O or S(O) q . In another embodiment, Y * and Z * are independently O or S(O) q and q is 0. In another embodiment, Y * and Z * are each O. In another embodiment, Y * and Z * are each S(O) q and q is 0. In another embodiment, Y * and Z * are each Se(O) q and q is 0. In another embodiment, Y * and Z * are each N(R > 13 ⁇ ). In another embodiment, R » 13 is H or C]-C 6 straight or branched alkyl.
- compounds, pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprising administering to a host in need thereof a compound of Formula III, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided:
- R 1 ** , R 2** , R 3** , R 4** , R 5** and R 6** are independently selected from the group consisting of hydrogen, halo, Q-C 4 straight alkyl, Ci-C 4 branched alkyl, C 2 -C 6 alkenyl, aryl and -OR 14 ";
- R 12** is selected from the group consisting OfCi-C 6 straight alkyl, hydroxy-Ci-C 6 straight alkyl, polyhydroxy-Q -C 6 straight alkyl, carboxy-Ci -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13** )-Ci-C 6 straight alkyl, (C(O)NHR 13 ")-C 3 -C 6 branched alkyl, (C(O)NHR 13 ")-C 2 -C 6 alkenyl, (C(O)NHR 13** )-C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, al
- each n is independently O, 1, or 2;
- R 13** is selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
- R 14** and R 15** are independently selected from the group consisting of hydrogen, Ci- C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, , heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16 ;
- R 14** and R 15** taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
- R 16** is independently selected from the group consisting of Cj-C 6 straight alkyl, Ci- C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
- compounds, pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprising administering to a host in need thereof a compound of Formula FV, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided:
- R 12a is selected from the group consisting of carboxy-d -C 6 straight alkyl, carboxy-C 3 - C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13a )-Ci -C 6 straight alkyl, (C(O)NHR 13a )-C 3 -C 6 branched alkyl, (C(O)NHR 13a )-C 2 -C 6 alkenyl, (C(O)NHR 13a )-C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, ary
- R 12a is selected from the group consisting of Ci-C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-Cj -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -0R 16a , -C(0)R 16a , -C(O)-
- R 13a is selected from the group consisting of hydrogen, hydroxy, Cj-C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
- R 14a andR 15a are independently selected from the group consisting of hydrogen, C]-C 6 straight alkyl, Cj-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16a ;
- R 14a andR 15a taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzo fused ring;
- R 16a is selected from the group consisting OfC 1 -C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
- the compound of Formula IV is a compound wherein R 12a is selected from the group consisting of carboxy-Ci -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13a )-Ci -C 6 straight alkyl, (C(O)NHR 13a )-C 3 -C 6 branched alkyl, (C(O)NHR 13a )-C 3 -C 8 cyclic alkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, -NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbon
- R 12a is selected from the group consisting of Ci -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-Ci-C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, -NR 14a R 15a , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 16a , - C(O)R 16a , -C(O)-NH 2 , -C(O)-N
- R 13a is selected from the group consisting of hydrogen, hydroxy, heterocyclic and heteroaryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
- R 14a andR 15a are independently selected from the group consisting of hydrogen, C]-C 6 straight alkyl, Ci -C 6 branched alkyl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16a ; and
- R 16a is independently selected from the group consisting of Cj-C 4 straight alkyl, Ci-C 4 branched alkyl, heterocyclic and heteroaryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
- the compound of Formula IV is a compound wherein R 12a is selected from the group consisting of carboxy-C]-C 4 straight alkyl, carboxy-C 3 -C 6 branched alkyl, (C(O)NHR 13a )-Ci -C 4 straight alkyl and (C(O)NHR 13a )-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, oxo, cyano, and alkoxycarbonyl; and
- R 13a is selected from the group consisting of hydrogen, hydroxy, heterocyclic and heteroaryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy.
- the compound of Formula IV is a compound wherein R 12a is selected from the group consisting of carboxy-Ci-C 4 straight alkyl and carboxy-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
- the compound of Formula IV is a compound wherein R 12a is selected from the group consisting of Ci -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-Ci -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, oxo, cyano, and alkoxycarbonyl; and
- R 13a is selected from the group consisting of hydrogen, hydroxy, heterocyclic and heteroaryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy.
- the compound of Formula IV is a compound wherein R 12a is selected from the group consisting of hydroxy-d-C 4 straight alkyl and hydroxy-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
- the compound of Formula IV is a compound wherein R 12a is selected from the group consisting Of C 1 -C 4 straight alkyl and C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
- compounds, pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma, comprising administering to a host in need thereof a compound of Formula V, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided:
- R 12b is selected from the group consisting of carboxy-Q -C 6 straight alkyl, carboxy- C 3 -C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13b )-Ci- C 6 straight alkyl, (C(O)NHR 13b )-C 3 -C 6 branched alkyl, (C(O)NHR 13b )-C 2 -C 6 alkenyl, (C(O)NHR 13b )-C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl
- R 12b is selected from the group consisting of C 1 -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-d-C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR 14b R 15b , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 16b , -C(O)R 16b , -C(O)
- each n is independently O, 1, or 2;
- R 13b is selected from the group consisting of hydrogen, hydroxy, C]-C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
- R 14b andR 15b are independently selected from the group consisting of hydrogen, Ci-C 6 straight alkyl, Ci -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16b ;
- R 14b andR 15b taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
- R 16b is selected from the group consisting of Ci -C 6 straight alkyl, Ci -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
- the compound of Formula IV is a compound wherein R is selected from the group consisting of carboxy-Ci-C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13b )-Ci -C 6 straight alkyl, (C(O)NHR 13b )-C 3 -C 6 branched alkyl, (C(O)NHR 13b )-C 3 -C 8 cyclic alkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, -NR 14b R 15b , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl,
- R 12b is selected from the group consisting Of Ci-C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-Ci-C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, -NR 1 ⁇ R 15 ⁇ oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -0R 16b , - C(O)R 16b , -C(O)-NH 2 , -C(0)-N(H
- R 14b andR 15b are independently selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, C]-C 6 branched alkyl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16b ; and
- R 16b is independently selected from the group consisting OfCj-C 4 straight alkyl, C]-C 4 branched alkyl, heterocyclic and heteroaryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
- the compound of Formula V is a compound wherein R 12b is selected from the group consisting of carboxy-Ci-C 4 straight alkyl, carboxy-C 3 -C 6 branched alkyl, (C(O)NHR 13b )-C, -C 4 straight alkyl and (C(O)NHR 13b )-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, oxo, cyano, and alkoxycarbonyl; and
- R 13b is selected from the group consisting of hydrogen, hydroxy, heterocyclic and heteroaryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy.
- the compound of Formula V is a compound wherein R 12b is selected from the group consisting of carboxy-Ci-C 4 straight alkyl and carboxy-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
- the compound of Formula V is a compound wherein R 12b is selected from the group consisting of C ! -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-Q -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, oxo, cyano, and alkoxycarbonyl; and
- R 13b is selected from the group consisting of hydrogen, hydroxy, heterocyclic and heteroaryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy.
- the compound of Formula V is a compound wherein R 12b is selected from the group consisting of hydroxy-Ci-C 4 straight alkyl and hydroxy-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
- the compound of Formula V is a compound wherein R 12b is selected from the group consisting of Ci-C 4 straight alkyl and C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
- compounds, pharmaceutical compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprising administering to a host in need thereof a compound of Formula VI, or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof are provided:
- R 12c is selected from the group consisting of carboxy-Ci -C 6 straight alkyl, carboxy-C 3 - C 6 branched alkyl, carboxy-C 2 -C 6 alkenyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13 ⁇ -C 1 -C 6 straight alkyl, (C(O)NHR 13c )-C 3 -C 6 branched alkyl, (C(O)NHR 13c )-C 2 -C 6 alkenyl, (C(O)NHR 13c )-C 3 -C 8 cyclic alkyl, heteroaralkyl, heterocyclicalkyl, and aralkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, ary
- R 12c is selected from the group consisting of C 1 -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-d -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR 14c R 15c , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -0R 16c , -C(0)R 16c , -C(O)
- each n is independently O, 1, or 2;
- R 13c is selected from the group consisting of hydrogen, hydroxy, C 1 -C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, heterocyclic, heteroaryl and aryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy;
- R 1 ⁇ andR 15c are selected from the group consisting of hydrogen, C 1 -C 6 straight alkyl, Ci-C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl; aryl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16c ;
- R 14c andR 15c taken together may form a 4- to 12-membered monocyclic, bicyclic, tricyclic or benzofused ring;
- R 16c is independently selected from the group consisting of Ci-C 6 straight alkyl, C 1 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl; heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
- the compound of Formula VI is a compound wherein R 12c is selected from the group consisting of carboxy-Q -C 6 straight alkyl, carboxy-C 3 -C 6 branched alkyl, carboxy-C 3 -C 8 cyclic alkyl, (C(O)NHR 13c )-C, -C 6 straight alkyl, (C(O)NHR 13c )-C 3 -C 6 branched alkyl, (C(O)NHR 13c )-C 3 -C 8 cyclic alkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, -NR 14c R 15c , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbony
- R 12c is selected from the group consisting of Ci -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-C]-C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, -NR 14c R 15c , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -0R 16c , - C(O)R 16c , -C(O)-NH 2 , -C(0)-N(
- R I4c andR 15c are independently selected from the group consisting of hydrogen, Ci-C 6 straight alkyl, C 1 -C 6 branched alkyl, heteroaryl, heterocycle, and acyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 16b ; and
- R 16c is independently selected from the group consisting of Ci-C 4 straight alkyl, C 1 -C 4 branched alkyl, heterocyclic and heteroaryl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, cyano, and carboxy.
- the compound of Formula VI is a compound wherein R 12c is selected from the group consisting of carboxy-Q-Q straight alkyl, carboxy-C 3 -C 6 branched alkyl, (C(O)NHR 13c )-C r C 4 straight alkyl and (C(O)NHR 13c )-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, oxo, cyano, and alkoxycarbonyl; and
- R 13c is selected from the group consisting of hydrogen, hydroxy, heterocyclic and heteroaryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy.
- the compound of Formula VI is a compound wherein R 12c is selected from the group consisting of carboxy-Ci-C4 straight alkyl and carboxy-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
- the compound of Formula VI is a compound wherein R 12c is selected from the group consisting of Ci -C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-Ci -C 6 straight alkyl, hydroxy-C 3 -C ⁇ branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, oxo, cyano, and alkoxycarbonyl; and
- R 13c is selected from the group consisting of hydrogen, hydroxy, heterocyclic and heteroaryl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, oxo, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, cyano, amino, aminoalkyl, and carboxy.
- the compound of Formula VI is a compound wherein R 12c is selected from the group consisting of hydroxy-Ci-C 4 straight alkyl and hydroxy-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
- the compound of Formula VI is a compound wherein R 12c is selected from the group consisting Of C 1 -C 4 straight alkyl and C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, and amino.
- a compound of any one of Formula II, III, IV, V or VI is a compound wherein R 12* , R 12** , R 12a , R 12b or R 12c is selected from the group consisting of carboxy-Ci-C 4 straight alkyl, carboxy-C 3 -C 6 branched alkyl, (C(O)NHR 13 )-Ci -C 4 straight alkyl and (C(O)NHR 13 )-C 3 -C 6 branched alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, aminoalkyl, oxo, cyano, and alkoxycarbonyl.
- the substituents are independently selected from lower alkyl, acyl, hydroxy, hydroxyalkyl and alkoxycarbonyl.
- a compound of any one of Formula II, III, IV, V or VI is a compound wherein R 12* , R 12 ", R 12a , R 12b or R 12c is selected from the group consisting of C 1 - C 6 straight alkyl, C 3 -C 6 branched alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cyclic alkyl, hydroxy-Ci-C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 -C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxy
- R 12 , R 12* , R 12 ", R 12a , R 12b or R 12c is selected from the group consisting of hydroxy-Ci -C 6 straight alkyl, hydroxy-C 3 -C 6 branched alkyl, hydroxy-C 2 - C 6 alkenyl, hydroxy-C 3 -C 8 cyclic alkyl, wherein all may be optionally substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, oxo, cyano, carboxy, carboxyalkyl, and alkoxycarbonyl.
- R 12 , R 12* , R 12 ", R 12a , R 12b or R 12c is Ci-C 4 branched alkyl, optionally substituted by one or more hydroxy, cyano and heteroaryl.
- R 12 , R 12* , R 12** , R 12a , R 12b or R 12c is selected from the group consisting of hydrogen, cyanomethyl, tetrazolylmethyl, imidazolylethyl, hydroxymethyl, 2-methyl-2- hydroxypropyl, and hydroxyethyl.
- R 12 , R 12* , R 12** , R 12a , R 12b or R 12c is selected from the group consisting of hydrogen, hydroxymethyl, 2-methyl-2- hydroxypropyl, and hydroxyethyl.
- R 12 , R 12* , R 12** , R 12a , R 12b or R I2c is unsubstituted heteroaryl.
- R 12 , R 12* , R 12 ", R 12a , R 12b or R 12c is heteroaryl, substituted with one substituent.
- R 12 , R 12* , R 12** , R 12a , R 12b or R 12c is heteroaryl substituted with more than one substituent.
- substituents on R 12 , R 12* , R 12** , R 12a , R 12b or R 12c are selected from alkyl, hydroxyalkyl, carboxy and carboxyalkyl.
- R 12 , R 12* , R 12 ", R 12a , R 12b or R 12c is selected from the group consisting of furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, , triazolyl, tetrazolyl, oxazolyl, imidazolyl, isooxazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazinyl, benzimidazolyl, tetrahydrobenzimidazolyl, benzofuryl, benzothienyl, benzothiazolyl, benzopyrazolyl, indolyl, benzotriazolyl, benzoxazolyl, benzoisoxazolyl, benzoisothiazolyl, benzopyridyl, benzopyridazinyl, benzopyrimidin
- R 12 , R 12* , R 12** , R 12a , R 12b or R 12c is selected from the group consisting of furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl and imidazolyl, wherein all may be substituted by one or more independently selected from the group consisting of fluoro, chloro, trifluoromethyl, methyl, hydroxymethyl, 2-methyl-2-hydroxyethyl, amino, and carboxy.
- R 12 , R 12* , R 12 ", R 12a , R 12b or R 12c is pyrrolyl or imidazolyl, wherein all may be substituted by one or more independently selected from the group consisting of methyl, hydroxymethyl, 2-methyl-2-hydroxyethyl, and carboxy.
- the compound is
- the compound is or a pharmaceutically acceptable salt, ester, prodrug or derivative thereof.
- compositions and methods of treatment or prophylaxis of an inflammatory condition comprises administering to a host in need thereof a compound
- the compound is any pharmaceutically acceptable salt, ester, prodrug or derivative thereof.
- the compound is
- the compound is any pharmaceutically acceptable salt, ester, prodrug or derivative thereof.
- the compound is
- compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprises administering to a host in need thereof a compound
- compositions and methods of treatment or prophylaxis of an inflammatory condition, and in particular asthma comprises administering to a host in need thereof a compound
- compositions and methods of treatment or prophylaxis of an inflammatory condition comprises administering to a host in need thereof a compound
- compounds of the invention are as defined below in Table A: Table A.
- compounds of the invention are as defined below in Table B: Table B.
- compounds of the invention are as defined below in Table C: Table C.
- the compounds are present as enantiomers.
- the compound is present as a racemic mixture.
- the enantiomer can be named by the configuration at the chiral center, such as R or S.
- the compound is present as a racemic mixture of R- and S- enantiomers.
- the compound is present as a mixture of two enantiomers.
- the mixture has an enantiomeric excess in R.
- the mixture has an enantiomeric excess in S. hi certain other embodiments, the compound is in an enantiomeric excess of the R- or S- enantiomer.
- the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the single enantiomer.
- the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the R enantiomer.
- the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the S enantiomer.
- the compound is substantially in the form of a single enantiomer.
- the compound is present substantially in the form of the R enantiomer.
- the compound is present substantially in the form of the S enantiomer.
- the phrase "substantially in the form of a single enantiomer" is intended to mean at least 70% or more in the form of a single enantiomer, for example 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in either the R or S enantiomer.
- the enantiomer can be named by the direction in which it rotates the plane of polarized light. If it rotates the light clockwise as seen by the viewer towards whom the light is traveling, the isomer can be labeled (+) and if it rotates the light counterclockwise, the isomer can be labeled (-).
- the compound is present as a racemic mixture of (+) and (-) isomers.
- the compound is present as a mixture of two isomers, hi one embodiment, the mixture has an excess in (+). hi one embodiment, the mixture has an excess in (-). hi certain other embodiments, the compound is in an excess of the (+) or (-) isomer.
- the isomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the (+) isomer.
- the enantiomeric excess can be 51% or more, such as 51% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more in the (-) isomer.
- the compound is substantially in the form of a single optical isomer, hi some embodiments, the compound is present substantially in the form of the (+) isomer, hi other embodiments, the compound is present substantially in the form of the (-) isomer.
- the phrase "substantially in the form of a single optical isomer” is intended to mean at least 70% or more in the form of a single isomer, for example 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% or more of either the (+) or (-) isomer.
- a term in the specification is identified as a range (i.e. C M alkyl), the range independently refers to each element of the range.
- Ci -4 alkyl means, independently, Ci, C 2 , C 3 or C 4 alkyl.
- substituents when one or more substituents are referred to as being "independently selected from” a group, this means that each substituent can be any element of that group, and any combination of these groups can be separated from the group.
- R 1 and R 2 can be independently selected from X, Y and Z, this separately includes the groups R 1 is X and R 2 is X; R 1 is X and R 2 is Y; R 1 is X and R 2 is Z; R 1 is Y and R 2 is X; R 1 is Y and R 2 is Y; R 1 is Y and R 2 is Z; R 1 is Z and R 2 is X; R 1 is Z and R 2 is Y; and R 1 is Z and R 2 is Z.
- alkyl refers to a saturated straight, branched, or cyclic (also identified as cycloalkyl), primary, secondary, or tertiary hydrocarbon, including but not limited to those of Ci to C 6 .
- alkyl groups are methyl, ethyl, propyl, wopropyl, cyclopropyl, butyl, secbutyl, isobutyl, tertbutyl, cyclobutyl, 1-methylbutyl, 1,1-dimethylpropyl, pentyl, cyclopentyl, isopentyl, neopentyl, cyclopentyl, hexyl, isohexyl, and cyclohexyl.
- the alkyl group can be unsubstituted or substituted with one or more moieties selected from the group consisting of alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, thio, sulfonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, thioether, oxime, or any other viable functional group that does not inhibit the pharmacological activity of this compound, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
- alkyl may be optionally substituted by one or more halo, hydroxy, heterocyclic, heteroaryl, carboxy, -NRR , alkoxycarbonyl, -NRC(O)R , - NRC(O)NRR ' , -NRC(O)OR ' , -OC(O)NRR ' , -OR, -C(O)R, -S(O) n -R, -C(O)-NRR ' , and/or cyano.
- the alkyl may be optionally substituted by one or more halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NRR , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, , -OR, - C(O)R, -C(O)-NH 2 , -C(O)-N(H)R, -C(O)-NRR ' , -NRC(O)R ' , -NRC(O)OR , -S(O) n -R, -S(O) 2 - NH 2 , -S(O) 2 -N(H)R and/or -S(O) 2 -NRR ' , wherein R and R' are each independently selected from an alkyl,
- lower alkyl refers to a Ci to C 5 saturated or unsaturated straight, branched carbon chain such as methyl, ethyl, isopropyl, n-butyl, tert- butyl, n-pentyl, sec-pentyl, 3-methylpentyl, and the like, or if appropriate, a cyclic (for example, cyclopropyl) alkyl group.
- halo or halogen refers to chloro, bromo, iodo, or fluoro.
- heteroaryl or “heteroaromatic,” refers to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
- heterocyclic refers to a non-aromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
- heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole
- the heteroaromatic or heterocyclic group can be optionally substituted with one or more substituent selected from halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, dialkylamino.
- the heteroaromatic can be partially or totally hydrogenated as desired.
- Nonlimiting examples include dihydropyridine and tetrahydrobenzimidazole.
- the heteroaryl may be optionally substituted by one or more halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NRR , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, , -OR, -C(O)R, -C(O)-NH 2 , -C(O)-N(H)R, -C(O)-NRR ' , -NRC(O)R , - NRC(O)OR ' , -S(O) n -R, -S(O) 2 -NH 2 , -S(O) 2 -N(H)R and/or -S(O) 2 -NRR ' , wherein R and R' are each independently selected from an alkyl, aryl
- Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t- butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl.
- aryl refers to a carbon based aromatic ring, including phenyl, biphenyl, or naphthyl.
- the aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, acyl, amino, halo, alkylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991.
- the aryl group is optionally substituted by one or more halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NRR , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR, -C(O)R, -C(O)-NH 2 , -C(O)-N(H)R, -C(O)-NRR ' , - NRC(O)R ' , -NRC(O)OR ' , -S(O) n -R, -S(O) 2 -NH 2 , -S(O) 2 -N(H)R and/or -S(O) 2 -NRR ' , wherein R and R' are each independently selected from an alkyl, ary
- alkyl refers to an aryl group as defined above linked to the molecule through an alkyl group as defined above.
- alkaryl unless otherwise specified, refers to an alkyl group as defind above linked to the molecule through an aryl group as defined above.
- acyloxyalkyl alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylaminoalkyl, alkylthioalkyl, amidoalkyl, aminoalkyl, carboxyalkyl, dialkylaminoalkyl, haloalkyl, heteroaralkyl, heterocyclicalkyl, hydroxyalkyl, sulfonamidoalkyl, sulfonylalkyl and thioalkyl are named in a similar manner.
- alkoxy refers to a moiety of the structure -O- alkyl, wherein alkyl is as defined above.
- acyl refers to a group of the formula -C(O)R wherein R is an alkyl, aryl, alkaryl or aralkyl group, or substituted alkyl, aryl, aralkyl or alkaryl.
- alkenyl means a monovalent, unbranched or branched hydrocarbon chain having one or more double bonds therein.
- the double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group.
- Suitable alkenyl groups include, but are not limited to (C2-C8)alkenyl groups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4- (2-methyl-3-butene)-pentenyl.
- An alkenyl group can be unsubstituted or substituted with one or two suitable substituents.
- amino indicates presence of -NH 2 .
- thio indicates the presence of a sulfur group.
- the prefix thio- denotes that there is at least one extra sulfur atom added to the chemical.
- the prefix 'thio- 1 can also be placed before the name of a compound to mean that an oxygen atom in the compound has been replaced by a sulfur atom.
- thiol is typically used to indicate the presence of -SH, in instances in which the sulfur atom would be have improper valance a radical if the hydrogen is improperly designated, the terms 'thio' and 'thiol' are used interchangeably, unless otherwise indicated.
- amido indicates a group -NH-C(O)-R.
- salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxico logical effects.
- Nonlimiting examples of such salts are (a) acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalcturonic acid; (b) base addition salts formed with metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium, and the like, or with a
- quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula -NR + A " , wherein R is as defined above and A is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
- R is as defined above and A is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate
- protected refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent its further reaction or for other purposes.
- oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis.
- stereoisomers refers to isomeric molecules whose atomic connectivity is the same but whose atomic arrangement in space is different.
- enantiomers refers to compounds that are stereoisomers that are nonsuperimposable complete mirror images of each other. Enantiomers have, when present in a symmetric environment, identical chemical and physical properties except for their ability to rotate plane-polarized light by equal amounts but in opposite directions.
- racemic refers to a mixture of equal parts of an optically active isomer and its enantiomer.
- diastereomers refers to a pair stereoisomers that are not mirror images of each other and one or more stereogenic centers differ between the two stereoisomers, or one or more chiral centers have opposite configurations between the two stereoisomers.
- the compounds of the invention can generally be administered to a host at risk of, or suffering from, an inflammatory condition.
- the compounds are administered for the treatment or prophylaxis of an inflammatory disorder.
- the inflammatory disorder is a respiratory disorder.
- the inflammatory disorder is asthma or COPD.
- the inflammatory disorder is a cardiovascular disorder.
- the inflammatory condition is mediated by known cytokines such as IL-6 or IL-8.
- the inflammatory condition is unrelated to levels of any particular cytokines, such as IL-6 or IL-8.
- Certain of the compounds of the invention are useful in the treatment of inflammatory respiratory conditions, such as asthma, independently of their effect on inflammatory cytokines related to chemotaxis or antibody-mediated immune responses.
- Cytokines are small secreted proteins which mediate and regulate immunity, inflammation, and hematopoiesis. They must be produced de novo in response to an immune stimulus. They generally (although not always) act over short distances and short time spans and at very low concentration. They act by binding to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter its behavior (gene expression). Responses to cytokines include increasing or decreasing expression of membrane proteins (including cytokine receptors), proliferation, and secretion of effector molecules.
- Cytokines are redundant in their activity, meaning similar functions can be stimulated by different cytokines.
- the largest group of cytokines stimulates immune cell proliferation and differentiation. This group includes Interleukin 1 (EL-I), which activates T cells; IL-2, which stimulates proliferation of antigen- activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; Interferon gamma (IFN ⁇ ), which activates macrophages; and IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF), which stimulate hematopoiesis.
- EL-I Interleukin 1
- IL-2 which stimulates proliferation of antigen- activated T and B cells
- IL-4, IL-5, and IL-6 which stimulate proliferation and differentiation of B cells
- IFN ⁇ Interferon gamma
- IL-6 is generally produced by monocytes, macrophages, Th2 cells and stromal cells. It acts on activated B cells to differentiate into plasma cells, plasma cells to induce antibody secretion, stem cells to induce differentiation, and on various other cells to induce acute inflammatory responses.
- IL-8 produced by macrophages and endothelial cells generally acts on neutrophils to induce chemotaxis.
- inflammatory disorders include, but are not limited to, respiratory disorders (including asthma, COPD, chronic bronchitis and cystic fibrosis); cardiovascular related disorders (including atherosclerosis, post-angioplasty, restenosis, coronary artery diseases and angina); inflammatory diseases of the joints (including rheumatoid and osteoarthritis); skin disorders (including dermatitis, eczematous dermatitis and psoriasis); post transplantation late and chronic solid organ rejection; multiple sclerosis; autoimmune conditions (including systemic lupus erythematosus, dermatomyositis, polymyositis, Sjogren's syndrome, polymyalgia rheumatica, temporal arteritis, Behcet's disease, Guillain Barre, Wegener's granulomatosus, polyarteritis nodosa); inflammatory neuropathies (including inflammatory polyneuropathies); vasculitis (including Churg-StroStr
- Respiratory disorders that may be prevented or treated include a disease or disorder of the respiratory system that can affect any part of the respiratory tract. These conditions range from life threatening to mild. Certain diseases cause respiratory symptoms although the diseases are initially caused by an infection, such as a cold virus, bronchitis, pneumonia and tuberculosis. Other disorders are caused by irritation of the lung tissue, such as, for example, by an allergen. These disorders include hay fever and other respiratory allergies and asthma. In certain embodiments, the host is at risk of or suffering from a disorder of the lower airway.
- bronchitis simple and mucopurulent chronic bronchitis
- unspecified chronic bronchitis including chronic bronchitis NOS, chronic tracheitis and chronic tracheobronchitis
- emphysema other chronic obstructive pulmonary disease
- asthma status asthmaticus
- bronchiectasis include chronic bronchitis NOS, chronic tracheitis and chronic tracheobronchitis, emphysema, other chronic obstructive pulmonary disease, asthma, status asthmaticus and bronchiectasis.
- bronchi and bronchioles are typically temporarily constricted and inflamed.
- Other disorders typically involving lung irritants include emphysema, which can result from multiple factors including: smog, cigarette smoke, infection, and a genetic predisposition to the condition, laryngitis, lung cancer, respiratory distress syndrome (RDS), which refers to a group of symptoms that indicate severe malfunctioning of the lungs affecting adults and infants and specifically Adult respiratory distress syndrome (ARDS).
- RDS respiratory distress syndrome
- ARDS Adult respiratory distress syndrome
- asthmatic condition marked by recurrent attacks of paroxysmal dyspnea (i.e., "reversible obstructive airway passage disease") with wheezing due to spasmodic contraction of the bronchi (so called “bronchospasm”).
- Asthmatic conditions which may be treated or even prevented in accordance with this invention include allergic asthma and bronchial allergy characterized by manifestations in sensitized persons provoked by a variety of factors including exercise, especially vigorous exercise ("exercise-induced bronchospasm"), irritant particles (pollen, dust, cotton, cat dander) as well as mild to moderate asthma, chronic asthma, severe chronic asthma, severe and unstable asthma, nocturnal asthma, and psychologic stresses.
- Other respiratory disorders include allergic and non-allergic rhinitis as well as non- malignant proliferative and/or inflammatory disease of the airway passages and lungs.
- Allergic rhinitis means generally any allergic reaction of the nasal mucosa and includes hay fever (seasonal allergic rhinitis) and perennial rhinitis (non-seasonal allergic rhinitis) which are characterized by seasonal or perennial sneezing, rhinorrhea, nasal congestion, pruritis and eye itching, redness and tearing.
- Non-allergic rhinitis means eosinophilic nonallergic rhinitis which is found in patients with negative skin tests and those who have numerous eosinophils in their nasal secretions.
- Non-malignant prolifertive and/or inflammatory diseases of the airway passages or lungs means one or more of (1) alveolitis, such as extrinsic allergic alveolitis, and drug toxicity such as caused by, e.g. cytotoxic and/or alkylating agents; (2) vasculitis such as Wegener's granulomatosis, allergic granulomatosis, pulmonary hemangiomatosis and idiopathic pulmonary fibrosis, chronic eosinophilic pneumonia, eosinophilic granuloma and sarcoidoses.
- alveolitis such as extrinsic allergic alveolitis
- drug toxicity such as caused by, e.g. cytotoxic and/or alkylating agents
- vasculitis such as Wegener's granulomatosis, allergic granulomatosis, pulmonary hemangiomatosis and idiopathic pulmonary fibrosis, chronic eosinophilic
- the use of the compounds of the invention reduces symptoms of these disorders, including cough, shortness of breath, chest pain, wheezing, cyanosis, finger clubbing, stridor (a crowing sound when breathing), hemoptysis (coughing up of blood), and respiratory failure.
- the use of these compounds may reduce respiratory acidosis , due to a failure by the lungs to remove carbon dioxide.
- the use of the compounds improve lung function.
- the compounds of the invention are administered to a patient suffering from a cardiovascular disorder related to inflammation.
- cardiovascular disorder related to inflammation include, but are not limited to, atherosclerosis, post-angioplasty restenosis, coronary artery diseases and angina.
- cardiovascular disorders are a class of diseases that involve the heart and/or blood vessels (arteries and veins). While the term technically refers to any disease that affects the cardiovascular system, it is usually used to refer to those related to atherosclerosis (arterial disease).
- Cardiovascular inflammatory disorders include atherosclerosis, post-angioplasty, restenosis, coronary artery diseases, angina, and other cardiovascular diseases, hi certain embodiments the disorder is a non-cardiovascular inflammatory disorder such as rheumatoid and osteoarthritis, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, eczematous dermatitis, Kaposi's sarcoma, or multiple sclerosis.
- the compounds disclosed herein can be selected to treat antiinflammatory conditions that are mediated by mononuclear leucocytes.
- the compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.
- unstable atherosclerotic plaque is a result of multiple factors but is commonly characterized by an infiltrate of inflammatory cells.
- Medical research strongly supports a role for inflammation in the pathogenesis, progression, and disruption of atherosclerotic plaque.
- Clinical studies have demonstrated systemic markers of inflammation to be strong predictors of clinical events, and specific treatments of atherosclerosis and its risk factors have been associated with reductions in inflammatory markers.
- the majority of cardiovascular events occur at sites of "nonsignificant" stenosis, as inflammation can lead to instability and rupture of these smaller atherosclerotic plaques, which are more numerous than the "significant," flow- limiting plaques.
- direct visualization of inflammatory cells within plaques is a predictor of unstable coronary disease.
- the source of inflammation is uncertain; various infectious agents have been proposed as a stimulator of this inflammatory process.
- Smooth muscle cell proliferation is also implicated both in chronic cardiovascular pathologies such as atherosclerosis, and more directly in, for example, post-angioplasty restenosis .
- Atherosclerosis vascular diseases including Raynaud's syndrome, thromboangiitis obliterans (Buerger) and other specified peripheral vascular diseases such as intermittent claudication.
- peripheral vascular diseases including Raynaud's syndrome, thromboangiitis obliterans (Buerger) and other specified peripheral vascular diseases such as intermittent claudication.
- Chronic inflammation is a risk factor for many proliferative disorders.
- airway smooth muscle mass increases due to the coordinated increase in size (hypertrophy) and number (hyperplasia) of airway smooth muscle cells.
- Myocyte migration may also serve to regulate airway smooth muscle mass.
- chronic cellular inflammation and airway wall remodelling with subepithelial fibrosis and airway smooth muscle (ASM) cell hyperplasia are features of chronic asthma.
- vascular smooth muscle, and immune cells are stimulated in cardiovascular disorders.
- inflammation is a risk factor in development of cancers, including colon cancer, and data from experimental and observational studies suggest that inflammation acts early in the carcinogenic pathway of colorectal cancer, possibly promoting the progression of colorectal adenomas to adenocarcinoma (Tangrea et al. Non-steroidal anti-inflammatory drug use is associated with reduction in the recurrence of advanced and non-advanced colorectal adenomas. Cancer Causes Control 2003; 14:403-11; Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 2004;4:l 1-22; O'Byrne et al. Chronic immune activation and inflammation as the cause of malignancy.
- COX-2 cyclooxygenase 2
- COX-2 mRNA and protein are present in both colorectal adenomas and adenocarcinomas, and thus support a role of inflammation early in the carcinogenic pathway of colorectal cancer.
- the compounds of the invention may be administered for the treatment or prophylaxis of an inflammatory disorder or the joints or connective tissue.
- disorders include rheumatoid arthritis, lupus erythematosus, Sjogren's syndrome, scleroderma (systemic sclerosis), dermatomyositis, polychondritis, polymyositis, polymyalgia rheumatica, osteoarthritis, septic arthritis, fibromyalgia, gout, pseudogout, spondyloarthropathies, such as ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthropathy, enteropathic spondylitis and reactive arthropathy, vasculitis, such as polyarteritis nodosa, Henoch-Sch ⁇ nlein purpura, serum sickness, Wegener's granulomatosis, giant cell arteritis, temporal arteritis,
- autoimmune conditions such as acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitisis, antiphospholipid antibody syndrome, autoimmune hepatitis, Coeliac disease, Crohn's disease, diabetes mellitus, Graves' disease, Guillain-Barre syndrome, Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's Disease, lupus erythematosus, multiple sclerosis, Mmyasthenia gravis, opsoclonus myoclonus syndrome, optic neuritis, Ord's thyroiditis, pemphigus, pernicious anaemia, primary biliary cirrhosis, Reiter's syndrome, Sjogren's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia and Wegener's granulomatosis.
- certain inflammtory skin disorders are treated or prevented, such as dermatitis, eczematous dermatitis and psoriasis.
- dermatitis eczematous dermatitis
- psoriasis a broad category that includes many conditions, ranging in severity from mild itching to serious medical health complications.
- Other conditions that are inflammatory skin disorders include eczema generally, acne and rosacea.
- the disorder to be treated is selected from post transplantation late and chronic solid organ rejection; multiple sclerosis; autoimmune conditions (including systemic lupus erythematosus, dermatomyositis, polymyositis, inflammatory neuropathies (Guillain Barre, inflammatory polyneuropathies), vasculitis (Wegener's granulomatosus, polyarteritis nodosa), and rare disorders such as polymyalgia rheumatica, temporal arteritis, Sjogren's syndrome, Bechet's disease, Churg- Strauss syndrome, and Takayasu's arteritis).
- autoimmune conditions including systemic lupus erythematosus, dermatomyositis, polymyositis, inflammatory neuropathies (Guillain Barre, inflammatory polyneuropathies), vasculitis (Wegener's granulomatosus, polyarteritis nodosa), and
- Methods and pharmaceutical compositions are provided for the treatment or prophylaxis or delay of onset of diabetes, pre-diabetes and related disorders.
- Related disorders of diabetes includes, but is not limited to, hyperglycemia, abnormal glucose homeostasis, insulin resistance, Syndrome X, metabolic disorders, diabetic dyslipidemia.
- the disease to be treated or prevented is type 2 diabetes.
- the chronic overabundance of glucose associated with diabetes damages the body's blood vessels and can lead to many related disorders.
- high glucose levels in the blood plasma can lead higher than normal amounts of particular hemoglobin, HbAIc.
- Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality.
- diabetes Often abnormal glucose homeostasis is associated with obesity, hypertension, and alterations of the lipid, lipoprotein and apolipoprotein metabolism, as well as other metabolic and hemodynamic disease.
- Patients with type 2 diabetes mellitus have a significantly increased risk of macrovascular and microvascular complications, including atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, microangiopathy, kidney disorders or failure, kidney and nerve damage, cardiac disease, diabetic retinopathy and other ocular disorders, including blindness. In extreme cases, diabetes can result in the amputation of limbs and death.
- Other conditions related to diabetes reported by the CDC include: nervous system diseases, which often includes impaired sensation or pain in the feet or hands, slowed digestion of food in the stomach, carpal tunnel syndrome, and other nerve problems, periodontal disease, which is a type of gum disease that can lead to tooth loss, complications of pregnancy, including congenital malformations and death of the fetus, and other complications such as diabetic ketoacidosis and hyperosmolar nonketotic coma.
- syndrome X A patient having this syndrome is characterized as having three or more symptoms selected from the following group of five symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low high-density lipoprotein cholesterol (HDL); (4) high blood pressure; and (5) elevated fasting glucose, which may be in the range characteristic of Type 2 diabetes if the patient is also diabetic.
- Each of these symptoms is defined in the recently released Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670.
- the compound is provided to a host to promote depletion of bile salts.
- Bile salts are steroids with detergent properties which are used to emulsify lipids in foodstuff passing through the intestine to enable fat digestion and absorption through the intestinal wall. They are secreted from the liver stored in the gall bladder and passed through the bile duct into the intestine when food is passing through.
- the most abundant of the bile salts in humans are cholate and deoxycholate, and they are normally conjugated with either glycine or taurine to give glycocholate or taurocholate respectively.
- Depletion of bile salts, including cholate and deoxycholate force the liver to reabsorb cholesterol to make new bile.
- patients at risk for developing diabetes are prophylactically treated to prevent onset.
- Patients with diabetes or at risk for developing diabetes can be identified through several risk factors.
- One of the key risk factors is age and obesity.
- patients who are 45 years or older and overweight is at risk of developing diabetes.
- Additional risk factors for type 2 diabetes include a family history, ethnicity (Alaska Native, American Indian, African American, Hispanic/Latino, Asian American, or Pacific Islander is at higher risk), having had gestational diabetes or giving birth to a baby weighing more than 9 pounds, previous history of high blood pressure or blood pressure of 140/90 mm Hg or higher, cholesterol levels not normal (including HDL below 35 mg/dL, or triglyceride level above 250 mg/dL), being fairly inactive (less than three times per week exercise), diagnosis of polycystic ovary syndrome, any test showing impaired glucose tolerance (IGT) or impaired fasting glucose (EFG), clinical conditions associated with insulin resistance, such as acanthosis nigricans, or a history of cardiovascular disease. Tests to be conducted can include a fasting blood glucose test or an oral glucose tolerance test.
- Glucose levels of approximately 100-126 mg/dl in a fasting plasma glucose test (FPG) or approximately 140-200 mg/dl in the oral glucose tolerance test (OGTT) indicate prediabetes.
- Levels of greater than or equal to 126 mg/dl in the FPG or greater than or equal to 200 mg/dl in the OGTT indicate diabetes.
- Symptoms of diabetes include increased thirst, increased hunger, fatigue, increased urination, especially at night, weight loss, blurred vision, sores that do not heal.
- Mammals, and specifically humans, suffering from an inflammatory disorder can be treated by either targeted or systemic administration, via oral, inhalation, topical, trans- or sub-mucosal, subcutaneous, parenteral, intramuscular, intravenous or transdermal administration of a composition comprising an effective amount of the compounds described herein or a pharmaceutically acceptable salt, ester or prodrug thereof, optionally in a pharmaceutically acceptable carrier.
- the compounds or composition is typically administered by oral administration.
- compounds can be administered by inhalation, hi another embodiment, the compound is administered transdermally (for example via a slow release patch), or topically.
- the compound is administered subcutaneously, intravenously, intraperitoneally, intramuscularly, parenterally, or submucosally. In any of these embodiments, the compound is administered in an effective dosage range to treat the target condition.
- compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
- the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules.
- Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
- a dosage unit such as a tablets, pills, capsules, troches and the like
- these can contain any of the following ingredients, or compounds of a similar nature: a binder (such as microcrystalline cellulose, gum tragacanth or gelatin); an excipient (such as starch or lactose), a disintegrating agent (such as alginic acid, Primogel, or corn starch); a lubricant (such as magnesium stearate or Sterotes); a glidant (such as colloidal silicon dioxide); a sweetening agent (such as sucrose or saccharin); and/or a flavoring agent (such as peppermint, methyl salicylate, or orange flavoring).
- a binder such as microcrystalline cellulose, gum tragacanth or gelatin
- an excipient such as starch or lactose
- a disintegrating agent such as alginic acid, Primogel, or corn starch
- a lubricant such as magnesium stearate or Sterotes
- dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier (such as a fatty oil), hi addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents.
- a liquid carrier such as a fatty oil
- the compound or its salts can also be administered orally as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
- a syrup may contain, in addition to the active compounds, a sweetening agent (such as sucrose, saccharine, etc.) and preservatives, dyes and colorings and flavors.
- the compounds of the invention may be also administered in specific, measured amounts in the form of an aqueous suspension by use of a pump spray bottle.
- the aqueous suspension compositions of the present invention may be prepared by admixing the compounds with water and other pharmaceutically acceptable excipients.
- the aqueous suspension compositions according to the present invention may contain, inter alia, water, auxiliaries and/or one or more of the excipients, such as: suspending agents, e.g., microcrystalline cellulose, sodium carboxymethylcellulose, hydroxpropyl-methyl cellulose; humectants, e.g.
- glycerin and propylene glycol e.g., citric acid, sodium citrate, phosphoric acid, sodium phospate as well as mixtures of citrate and phosphate buffers; surfactants, e.g. Polysorbate 80; and antimicrobial preservatives, e.g., benzalkonium chloride, phenylethyl alcohol and potassium sorbate.
- acids, bases or buffer substances for adjusting the pH e.g., citric acid, sodium citrate, phosphoric acid, sodium phospate as well as mixtures of citrate and phosphate buffers
- surfactants e.g. Polysorbate 80
- antimicrobial preservatives e.g., benzalkonium chloride, phenylethyl alcohol and potassium sorbate.
- the compounds of the invention are in the form of an inhaled dosage.
- the compounds may be in the form of an aerosol suspension, a dry powder or liquid particle form.
- the compounds may be prepared for delivery as a nasal spray or in an inhaler, such as a metered dose inhaler.
- Pressurized metered- dose inhalers (“MDI") generally deliver aerosolized particles suspended in chlorofluorocarbon propellants such as CFC-11, CFC- 12, or the non-chlorofluorocarbons or alternate propellants such as the fluorocarbons, HFC- 134A or HFC-227 with or without surfactants and suitable bridging agents.
- Dry-powder inhalers can also be used, either breath activated or delivered by air or gas pressure such as the dry-powder inhaler disclosed in the Schering Corporation International Patent Application No. PCT/US92/05225, published 7 Jan. 1993 as well as the TurbuhalerTM (available from Astra Pharmaceutical Products, Inc.) or the RotahalerTM (available from Allen & Hanburys) which may be used to deliver the aerosolized particles as a finely milled powder in large aggregates either alone or in combination with some pharmaceutically acceptable carrier e.g. lactose; and nebulizers.
- some pharmaceutically acceptable carrier e.g. lactose
- lactose lactose
- nebulizers e.g. nebulizers.
- Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include at least some of the following components: a sterile diluent (such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents); antibacterial agents (such as benzyl alcohol or methyl parabens); antioxidants (such as ascorbic acid or sodium bisulfite); chelating agents (such as ethylenediaminetetraacetic acid); buffers (such as acetates, citrates or phosphates); and/or agents for the adjustment of tonicity (such as sodium chloride or dextrose).
- the pH of the solution or suspension can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
- a parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
- Suitable vehicles or carriers for topical application can be prepared by conventional techniques, such as lotions, suspensions, ointments, creams, gels, tinctures, sprays, powders, pastes, slow-release transdermal patches, suppositories for application to rectal, vaginal, nasal or oral mucosa.
- thickening agents include petrolatum, beeswax, xanthan gum, or polyethylene, humectants such as sorbitol, emollients such as mineral oil, lanolin and its derivatives, or squalene.
- carriers can be physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
- physiological saline bacteriostatic water
- Cremophor ELTM BASF, Parsippany, NJ
- PBS phosphate buffered saline
- the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
- a controlled release formulation including implants and microencapsulated delivery systems.
- Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
- Liposomal suspensions including liposomes targeted to infected cells with monoclonal antibodies to viral antigens
- liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the compound is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
- appropriate lipid(s) such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol
- the compound is administered for a sufficient time period to alleviate the undesired symptoms and the clinical signs associated with the condition being treated, hi one embodiment, the compounds are administered less than three times daily. In one embodiment, the compounds are administered in one or two doses daily. In one embodiment, the compounds are administered once daily, hi some embodiments, the compounds are administered in a single oral dosage once a day.
- the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutic amount of compound in vivo in the absence of serious toxic effects.
- An effective dose can be readily determined by the use of conventional techniques and by observing results obtained under analogous circumstances, hi determining the effective dose, a number of factors are considered including, but not limited to: the species of patient; its size, age, and general health; the specific disease involved; the degree of involvement or the.severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; and the use of concomitant medication.
- Typical systemic dosages for the herein described conditions are those ranging from 0.01 mg/kg to 1500 mg/kg of body weight per day as a single daily dose or divided daily doses.
- Preferred dosages for the described conditions range from 0.5-1500 mg per day.
- a more particularly preferred dosage for the desired conditions ranges from 5-750 mg per day.
- Typical dosages can also range from 0.01 to 1500, 0.02 to 1000, 0.2 to 500, 0.02 to 200, 0.05 to 100, 0.05 to 50, 0.075 to 50, 0.1 to 50, 0.5 to 50, 1 to 50, 2 to 50, 5 to 50, 10 to 50, 25 to 50, 25 to 75, 25 to 100, 100 to 150, or 150 or more mg/kg/day, as a single daily dose or divided daily doses.
- the daily dose is between 10 and 500 mg/day.
- the dose is between about 10 and 400 mg/day, or between about 10 and 300 mg/day, or between about 20 and 300 mg/day, or between about 30 and 300 mg/day, or between about 40 and 300 mg/day, or between about 50 and 300 mg/day, or between about 60 and 300 mg/day, or between about 70 and 300 mg/day, or between about 80 and 300 mg/day, or between about 90 and 300 mg/day, or between about 100 and 300 mg/day, or about 200 mg/day.
- the compounds are given in doses of between about 1 to about 5, about 5 to about 10, about 10 to about 25 or about 25 to about 50 mg/kg. Typical dosages for topical application are those ranging from 0.001 to 100% by weight of the active compound.
- the concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
- the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
- the compound can also be mixed with other active materials which do not impair the desired action, or with materials that supplement the desired action.
- the active compounds can be administered in conjunction, i.e. combination or alternation, with other medications used in the treatment of respiratory disorders, hi another embodiment, the compounds can be administered in conjunction (combination or alternation) with other medications used in treatment or prophylaxis of inflammatory conditions, hi certain embodiments, the combination can be synergistic.
- the compounds can be administered in combination or alternation with drugs typically useful for treatment or prevention of respiratory conditions such as asthma, such as certain anti-inflammatory drugs and bronchodilators.
- drugs typically useful for treatment or prevention of respiratory conditions such as asthma, such as certain anti-inflammatory drugs and bronchodilators.
- Corticosteroids inhaled and oral
- mast cell stabilizers and the leukotriene modifier drugs are typically a useful antiinflammatory medication for people suffering from asthma. These drugs reduce swelling and mucus production in the airways.
- Bronchodilators typically relieve the symptoms of asthma by relaxing the muscle bands that tighten around the airways. This action rapidly opens the airways, letting more air come in and out of the lungs. Bronchodilators also help clear mucus from the lungs.
- Inhaled corticosteroids typically used compounds include inhaled corticosteroids, which prevent rather than relieve symptoms.
- Inhaled corticosteroids include: Advair (a combination medication that includes a corticosteroid (fluticasone) plus a long acting bronchodilator drug (in this case a ⁇ -2 adrenergic receptor agonist, salmeterol)), aerobid (flunisolide), azmacort (triamcinolone), flovent (fluticasone), methylprednisolone, prednisone, pulmicort or serevent diskus (salmeterol powder), theophylline, qvar, and xopenex (levalbuterol), Inhaled corticosteroids come in three forms: the metered dose inhaler (MDI), dry powder inhaler (DPI) and nebulizer solutions.
- MDI metered dose inhaler
- DPI dry powder inhaler
- nebulizer solutions
- Systemic steroids include: methylprednisolone (Medrol, Methylpred, Solu-Medrol), prednisone (Deltasone) and prednisolone (Prelone, Pediapred, Orapred).
- Mast Cell Stabilizers include Intal and Tilade, which work by preventing the release of irritating and inflammatory substances from mast cells.
- Leukotriene modifiers include accolate and singular and accolate (zafirlukast), singulair (montelukast) and zyflo (zileuton).
- the compounds can be administered in combination with nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac.
- the compound can also be administered with corticosteriods. Any of the compounds described herein for combination or alternation therapy can be administered as any prodrug that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound.
- Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts"), and a compound which has been alkylated or acylated at an appropriate position.
- physiologically acceptable salts alternatively referred to as "physiologically acceptable salts”
- the modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound.
- the active compounds can be administered in conjunction with medications used in the treatment or prophylaxis of conditions associated with cardiovascular disease.
- these compounds include lipid lowering agents, such as statins, probucol and nicotinic acid; platelet aggregation inhibitors such as aspirin; antithrombotic agents such as Coumadin; calcium channel blockers such as varapamil, diltiazem, and nifedipine; angiotensin converting enzyme (ACE) inhibitors such as captopril and enalopril, and ⁇ -blockers such as propanalol, terbutalol, and labetalol.
- lipid lowering agents such as statins, probucol and nicotinic acid
- platelet aggregation inhibitors such as aspirin
- antithrombotic agents such as Coumadin
- calcium channel blockers such as varapamil, diltiazem, and nifedipine
- the compounds can also be administered in combination with nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac.
- nonsteroidal antiinflammatories such as ibuprofen, indomethacin, fenoprofen, mefenamic acid, flufenamic acid, sulindac.
- the compound can also be administered, for example, with corticosteriods.
- the compounds are administered in combination or alternation with ACE (angiotensin-converting enzyme) inhibitors.
- ACE angiotensin-converting enzyme
- Nonlimiting examples are captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), quinapril (Accupril), ramipril (Altace), benazepril (Lotensin) and fosinopril (Monopril).
- the compounds are administered in combination or alternation with beta blockers.
- Nonlimiting examples are atenolol (Tenormin), carvedilol (Coreg), labetolol (Normodyne), metoprolol (Lopressor, Toprol) and propanolol (Inderal).
- the compounds are administered in combination or alternation with blood thinners such as aspirin or warfarin (Coumadin) or calcium channel blockers such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor), nifedipine (Adalat, Procardia), nicardipine (Cardene) or verapamil (Calan).
- the compounds are administered in combination or alternation with a statin.
- Nonlimiting examples of currently used statins are lovastatin (Mevacor, Altocor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor).
- the compounds can also be administered in combination or alternation with compounds that are generally used for treatment of skin inflammatory conditions, such as Acitretin , Alclometasone dipropionate , Allantoin / Coal tar extract / Hydrocortisone , Alphaderm , Alphosyl HC , Asmanex , Benzalkonium chloride / Dimeticone 350 / Hydrocortisone / Nystatin , Betacap , Betamethasone dipropionate , Betamethasone dipropionate / Calcipotriol hydrate , Betamethasone dipropionate / Salicylic acid , Betamethasone Valerate , Betamethasone Valerate / Clioquinol , Betamethasone Valerate / Fusidic Acid , Betamethasone valerate / Neomycin sulphate , Betnovate , Betnovate-C , Betnovate-N , Bettamousse , Calcipotriol , Calcipotriol
- any of the compounds described herein for combination or alternation therapy can be administered as any prodrug that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound.
- Nonlimiting examples are the pharmaceutically acceptable salts (alternatively referred to as "physiologically acceptable salts"), and a compound which has been alkylated or acylated at an appropriate position.
- physiologically acceptable salts alternatively referred to as "physiologically acceptable salts”
- the modifications can affect the biological activity of the compound, in some cases increasing the activity over the parent compound. This can easily be assessed by preparing the derivative and testing its ability to inhibit the expression of VCAM-I according to known methods.
- Y, Z independently O, S, Se
- Step 1 A compound of formula Al and a compound of formula A2 are reacted in a an organic solvent, for example acetone, in the presence of an acid catalyst such as sulfuric acid, hydrochloric acid, glacial acetic acid, and the like, to yield compound of formula A3.
- a an organic solvent for example acetone
- an acid catalyst such as sulfuric acid, hydrochloric acid, glacial acetic acid, and the like
- Step 2 Compound of formula A3 can be separated into pure (>95% e.e.) enantiomers, A4 and A5 by HPLC, SFC, and the like, using a chiral stationary phase such as Whelk-O, ChiralPak AD, ChiralPak OD, and the like, with an alcoholic solvent such as methanol, ethanol, isopropanol, and the like, or a mixture of alcoholic solvents, as the eluant.
- a chiral stationary phase such as Whelk-O, ChiralPak AD, ChiralPak OD, and the like
- an alcoholic solvent such as methanol, ethanol, isopropanol, and the like, or a mixture of alcoholic solvents, as the eluant.
- compound of formula A3 can be resolved into enantiomers, A4 and A5 by forming a diastereomeric salt with a chiral amine such as brucine, quinine, cinchonine, ephedrine, alpha-methylbenzylamine, and the like, in a crystallization solvent such as water, methanol, ethanol, acetonitrile, ethylene glycol, and the like, or a mixture of crystallization cosolvents, comprising of water, methanol, ethanol, acetonitrile, ethylene glycol, and the like.
- a chiral amine such as brucine, quinine, cinchonine, ephedrine, alpha-methylbenzylamine, and the like
- a crystallization solvent such as water, methanol, ethanol, acetonitrile, ethylene glycol, and the like, or a mixture of crystallization cosolvents, comprising of water, methanol, ethanol,
- hydrolysis of ester substituents on R 12 in A3, A4 and A5 can be carried out under basic conditions, for example, by treatment with aqueous solutions of sodium hydroxide or potassium hydroxide in an alcoholic solvent such as 2-methoxy-ethanol, ethanol, or methanol, or an ethereal solvent such as THF, 1,4-dioxane, and the like, at a temperature range of about ambient temperature to 150 0 C.
- an alcoholic solvent such as 2-methoxy-ethanol, ethanol, or methanol
- an ethereal solvent such as THF, 1,4-dioxane, and the like
- Step 1 Compound of formula Bl is alkylated with a suitably substituted alkylating reagent in the presence of an organic base such as diisopropylethylamine, pyridine, potassium tert-butoxide, benzylmagnesium halide, triethylamine, and the like, or an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate and the like, in an organic solvent such as THF, 1,4-dioxane, dichloromethane, toluene, DMF, and the like, at a temperature range of about 20-80 0 C to yield the compound of formula B2.
- an organic base such as diisopropylethylamine, pyridine, potassium tert-butoxide, benzylmagnesium halide, triethylamine, and the like
- an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate and the like
- organic solvent such as THF, 1,4-d
- Step 2 Compound of formula B2 is separated into pure (>95% e.e.) enantiomers, B3 and B4 by HPLC, SFC, and the like, using a chiral stationary phase such as Whelk-0, ChiralPak AD, ChiralPak OD, and the like, with an alcoholic solvent such as methanol, ethanol, and the like, as the eluant.
- a chiral stationary phase such as Whelk-0, ChiralPak AD, ChiralPak OD, and the like
- an alcoholic solvent such as methanol, ethanol, and the like
- compound of formula B2 can be resolved by forming a diastereomeric salt with a chiral amine such as brucine, quinine, cinchonine, ephedrine, alpha- methylbenzylamine, and the like, in a crystallization solvent such as water, methanol, ethanol, acetonitrile, ethylene glycol, and the like.
- a chiral amine such as brucine, quinine, cinchonine, ephedrine, alpha- methylbenzylamine, and the like
- Step 3 Hydrolysis of ester substituents on R 12 in B3 or B4 can be carried out under basic conditions, for example, by treatment with aqueous solutions of sodium hydroxide, potassium hydroxide, and the like, in an alcoholic solvent such as 2-methoxyethanol, ethanol, methanol, and the like, at a temperature range from about ambient temperature to 150 0 C.
- an alcoholic solvent such as 2-methoxyethanol, ethanol, methanol, and the like
- reduction of ester substituents on R 12 in B3 or B4 can be carried out under reductive conditions, for example, by treatment with lithium aluminum hydride in an ethereal solvent such as THF or diethylether at a temperature range of about 0 0 C to 70 0 C, or sodium borohydride in an alcoholic solvent such as ethanol, methanol, and the like, at a temperature range of about ambient temperature to 80 0 C.
- an ethereal solvent such as THF or diethylether
- sodium borohydride in an alcoholic solvent such as ethanol, methanol, and the like
- addition of alkyl groups can be carried out, for example, by treatment with an alkyl magnesium halide, where the halide is chloride, bromide, iodide or by treatment with an alkyl lithium reagent in an ethereal solvent such as THF, diethylether, and the like, at a temperature range of about 0 0 C to 70 0 C.
- an alkyl magnesium halide where the halide is chloride, bromide, iodide
- an alkyl lithium reagent in an ethereal solvent such as THF, diethylether, and the like
- Step 1 Compound of formula Bl is separated into pure (>95% e.e.) enantiomers, Cl and C2 by HPLC, SFC, and the like, using a chiral stationary phase such as Whelk-O, ChiralPak AD, ChiralPak OD, and the like, with an alcoholic solvent such as methanol, ethanol, and the like, as the eluant.
- a chiral stationary phase such as Whelk-O, ChiralPak AD, ChiralPak OD, and the like
- an alcoholic solvent such as methanol, ethanol, and the like
- Step 2 Compounds of formula Cl and C2 can be independently alkylated with a suitably substituted alkylating reagent in the presence of an organic base such as diisopropylethylamine, pyridine, potassium tert-butoxide, benzylmagnesium halide, triethylamine, and the like, or an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate and the like, in an organic solvent such as THF, 1,4-dioxane, dichloromethane, toluene, DMF, and the like, at a temperature range of about 20-80 0 C to yield the compound of formula B3 and B4, respectively.
- an organic base such as diisopropylethylamine, pyridine, potassium tert-butoxide, benzylmagnesium halide, triethylamine, and the like
- an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate and the like
- hydrolysis of of ester substituents on R 12 in B3 or B4 can be carried out under basic conditions, for example, by treatment with aqueous solutions of sodium hydroxide, potassium hydroxide, and the like, in an alcoholic solvent such as 2- methoxyethanol, ethanol, methanol, and the like, at a temperature range from about ambient temperature to 150 0 C.
- alcoholic solvent such as 2- methoxyethanol, ethanol, methanol, and the like
- reduction of ester substituents on R 12 in B3 or B4 can be carried out under reductive conditions, for example, by treatment with lithium aluminum hydride in an ethereal solvent such as TFfF or diethylether at a temperature range of about 0 0 C to 70 0 C, or sodium borohydride in an alcoholic solvent such as ethanol, methanol, and the like, at a temperature range of about ambient temperature to 80 0 C.
- an ethereal solvent such as TFfF or diethylether
- sodium borohydride in an alcoholic solvent such as ethanol, methanol, and the like, at a temperature range of about ambient temperature to 80 0 C.
- addition of alkyl groups can be carried out, for example, by treatment with an alkyl magnesium halide, where the halide is chloride, bromide, iodide or by treatment with an alkyl lithium reagent in an ethereal solvent such as THF, diethylether, and the like, at a temperature range of about 0 0 C to 70 0 C.
- an alkyl magnesium halide where the halide is chloride, bromide, iodide
- an alkyl lithium reagent in an ethereal solvent such as THF, diethylether, and the like
- the brown oil obtained was dissolved in 500 mL of THF and cooled to 0 °C. To this solution was added a solution of lithium aluminum hydride (50 mL, 1.0 M in THF). The resultant slurry was stirred at room temperature for 72 h. The reaction mixture was carefully quenched with saturated Rochelle's salt solution and stirred for 1 h. It was filtered and the filtrate was concentrated to a crude oil, which was dissolved in dichloromethane and washed with water. The layers were separated and the organic layer was concentrated and subjected to silica gel chromatography (hexanes/EtOAc, 2:1) to afford 4.29 g (26%) of the title compound as a white solid, m.p.
- the faster-eluting enantiomer was identified based on optical rotation, NMR and X-ray as (+)- (i?)-(6 '-hydroxy-4,4,4 ',4 ',7,7 '-hexamethyl-2,2 '-spirobi-chroman-6-yloxy)-dimethylacetic acid ethyl ester as a white solid, mp 166-167 0 C.
- (+)-(i?)-(6 '-hydroxy-4,4,4 ',4 ',7,7 '-hexamethyl-2,2 '-spirobichroman-6- yloxy)-dimethylacetic acid ethyl ester (Ex. 9a, 1.03 g) in 12 mL of THF and 6 mL of EtOH at room temperature was added 2 mL of 50% aq. NaOH (Aldrich). This mixture was heated to 75 °C for 4.25 h. The reaction mixture was diluted with H 2 O and washed with Et 2 O. The aqueous layer was acidified to pH 1 with 6 N HCl and extracted three times with Et 2 O.
- the slower-eluting enantiomer was identified based on optical rotation, NMR and X-ray as (-)-(iS)-(6 -hydroxy-4,4,4 ',4 ',7,7 '-hexamethyl-2,2 -spirobi-chroman-6-yloxy)-dimethylacetic acid ethyl ester as a white solid, mp 166-167 0 C.
- the reaction mixture was acidified to pH 5 with 3 N HCl.
- the solution was concentrated and extracted with dichloromethane.
- the combined organic extracts were washed with brine and water.
- the crude product was purified via silica gel chromatography with 1 :1 hexanes/ethyl acetate as the eluant to afford 0.35 g (25%) of the title compound as a white solid, mp 173-174 °C.
- the title compound was purchased from TCI America.
- the slower-eluting enantiomer exhibited a negative optical rotation.
- f-BuOK 0.1183 g, 1.63 mmol
- the mixture was heated to 40 °C and stirred for 15 minutes.
- Ethyl 2-bromoisobutyrate 0.3 mL, 2.04 mmol
- the reaction mixture was stirred at 40 0 C for 1 hour.
- the mixture was diluted with 8 mL of a 1:1 mixture of methyl tert-butyl ether and hexanes. NaOH (8 mL, 0.5 N) was added and the mixture was stirred for 15 minutes.
- (+)-(R)-6,6'-Dihydroxy-4,4,4',4',7,7'-hexamethyl-2,2'-spirobichroman ( ⁇ )-6,6'-Dihydroxy-4,4,4',4',7,7'-hexamethyl-2,2'-spirobichroman (from TCI America, 20 g) was separated via SFC (supercritical fluid chromatography) on a Chiralpak OD (250 mm x 30 mm) column running (88/22 v/v CO 2 /EtOH) isocratic with a flow rate of 180 mL/min (220 run) to afford two separate enantiomers (9 g each).
- the faster-eluting enantiomer (a white powder) showed a positive optical rotation. Based on the correlation study on the slower-eluting enantiomer (Ex.
- Example 30 Protocol for testing compounds in a mouse model of asthma
- mice Male 5-6 week old Balb/CJ mice were obtained from Jackson Laboratories (Bar Harbor, ME). All experimental animals were used in accordance to Institutional Animal Care and Use Committee of AtheroGenics, Inc. Mice were sensitized by administering an intraperitoneal injection of 20 ⁇ g of ovalbumin (Calbiochem, La Jolla, Ca) adsorbed in 2 mg of alum (Imject Alum; Pierce, Rockford, 111) on day 0 and 14. A group of mice received saline and served as negative control animals.
- ovalbumin Calbiochem, La Jolla, Ca
- mice were challenged by aerosol exposure to ovalbumin (1% [wt/vol]) for 25 minutes on 3 consecutive days (days 28, 29, and 30) in a plexiglas exposure chamber coupled to an Aeroneb nebulizer (Buxco Electronics, Wilmington, NC).
- Experimental compounds were dissolved in Glycofurol/PEG 300/Tween (35%/55%/10%) (Sigma-aldrich; Milwaukee, WI).
- Animals were dosed orally with either test compound or vehicle (6 ml/kg dosing volume) on days 26 - 32 of study. Compound or vehicle was administered 2 hour before the aerosol challenge on days 28, 29, and 30 and 1 hour before airway reactivity measurement on day 32.
- Methacholine-induced airway reactivity was assessed on day 32. Methacholine was administered in increasing concentrations (0.375, 0.77, 1.5, 3, 6, 12, 25, and 50 mg/ml) to unrestrained mice. Increases in airway resistance to Methacholine were determined as enhanced pause, (Penh) values, during and after the exposure (6-minute total analysis time). Mice were then humanely euthanized with an overdose of ketamine/xylazine and plasma samples collected for determination of drug levels. The data is presented as the % inhibition of the PenH vs McH dose AUC compared with the vehicle control.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Physical Education & Sports Medicine (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Endocrinology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Biomedical Technology (AREA)
- Transplantation (AREA)
- Neurosurgery (AREA)
- Ophthalmology & Optometry (AREA)
- Otolaryngology (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2008800238436A CN101795677B (en) | 2007-05-09 | 2008-05-09 | Spiro compounds for treatment of inflammatory disorders |
CA002686604A CA2686604A1 (en) | 2007-05-09 | 2008-05-09 | Spiro compounds for treatment of inflammatory disorders |
JP2010507478A JP2010526812A (en) | 2007-05-09 | 2008-05-09 | Spiro compounds for the treatment of inflammatory diseases |
AU2008251836A AU2008251836A1 (en) | 2007-05-09 | 2008-05-09 | Spiro compounds for treatment of inflammatory disorders |
EP08754326A EP2155178A4 (en) | 2007-05-09 | 2008-05-09 | Spiro compounds for treatment of inflammatory disorders |
BRPI0811557A BRPI0811557A2 (en) | 2007-05-09 | 2008-05-09 | compound, pharmaceutical composition, method of treatment or prophylaxis of an inflammatory condition. |
IL201899A IL201899A0 (en) | 2007-05-09 | 2009-11-03 | Spiro compounds for treatment of inflammatory disorders |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US92847707P | 2007-05-09 | 2007-05-09 | |
US60/928,477 | 2007-05-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2008140781A1 true WO2008140781A1 (en) | 2008-11-20 |
Family
ID=39970103
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2008/005996 WO2008140781A1 (en) | 2007-05-09 | 2008-05-09 | Spiro compounds for treatment of inflammatory disorders |
Country Status (10)
Country | Link |
---|---|
US (1) | US20080280974A1 (en) |
EP (1) | EP2155178A4 (en) |
JP (1) | JP2010526812A (en) |
CN (1) | CN101795677B (en) |
AU (1) | AU2008251836A1 (en) |
BR (1) | BRPI0811557A2 (en) |
CA (1) | CA2686604A1 (en) |
IL (1) | IL201899A0 (en) |
WO (1) | WO2008140781A1 (en) |
ZA (1) | ZA200908724B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111362963A (en) * | 2020-04-14 | 2020-07-03 | 吉林大学 | Diamine monomer containing spiropyran structure, preparation method and application thereof, polyimide, preparation method and application thereof |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7439241B2 (en) * | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
CN107105773B (en) * | 2014-12-25 | 2021-02-05 | 富特姆控股第一有限公司 | Electronic cigarette liquid detection and measurement system |
SG10201609131YA (en) | 2016-11-01 | 2018-06-28 | Xylonix Ip Holdings Pte Ltd | Zinc-pga compositions and methods for treating cancer |
SG10201708886RA (en) * | 2017-10-30 | 2019-05-30 | Xylonix Ip Holdings Pte Ltd | α-PGA-ZINC COMPOSITIONS AND METHODS FOR TREATING CANCER |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5278014A (en) * | 1991-06-21 | 1994-01-11 | Konica Corporation | Electrophotographic photoreceptor |
WO1996020197A1 (en) * | 1994-12-23 | 1996-07-04 | Merck Sharp & Dohme Limited | Spiroketal derivatives, compositions containing them and their use as therapeutic agents |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS603174B2 (en) * | 1976-10-30 | 1985-01-26 | コニカ株式会社 | Color photographic materials containing pigments and color inhibitors |
JPS5320327A (en) * | 1976-08-09 | 1978-02-24 | Konishiroku Photo Ind Co Ltd | Color photographic material containing dye image antifading agent |
JPS57202539A (en) * | 1981-06-08 | 1982-12-11 | Fuji Photo Film Co Ltd | Filled polymer latex composition |
US4522811A (en) * | 1982-07-08 | 1985-06-11 | Syntex (U.S.A.) Inc. | Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides |
DE3564871D1 (en) * | 1984-05-22 | 1988-10-13 | Konishiroku Photo Ind | Silver halide color photographic material |
US4952470A (en) * | 1986-07-10 | 1990-08-28 | Konica Corporation | Electrophotographic photosensitive member |
US6335364B1 (en) * | 1998-06-29 | 2002-01-01 | Parker Hughes Institute | Synthetic spiroketal pyranes as potent anti-cancer agents |
JP4542831B2 (en) * | 2004-06-11 | 2010-09-15 | 富士フイルムファインケミカルズ株式会社 | Method for producing arylamine |
CN1313085C (en) * | 2005-06-23 | 2007-05-02 | 中国人民解放军第二军医大学 | Application of total hypone of radix cynanchi bungei and hypnone for preparing medicine for treating gastrointestinal tract diseases |
-
2008
- 2008-05-09 AU AU2008251836A patent/AU2008251836A1/en not_active Abandoned
- 2008-05-09 CA CA002686604A patent/CA2686604A1/en not_active Abandoned
- 2008-05-09 US US12/151,919 patent/US20080280974A1/en not_active Abandoned
- 2008-05-09 EP EP08754326A patent/EP2155178A4/en not_active Withdrawn
- 2008-05-09 CN CN2008800238436A patent/CN101795677B/en not_active Expired - Fee Related
- 2008-05-09 BR BRPI0811557A patent/BRPI0811557A2/en not_active IP Right Cessation
- 2008-05-09 WO PCT/US2008/005996 patent/WO2008140781A1/en active Application Filing
- 2008-05-09 JP JP2010507478A patent/JP2010526812A/en not_active Withdrawn
-
2009
- 2009-11-03 IL IL201899A patent/IL201899A0/en unknown
- 2009-12-08 ZA ZA200908724A patent/ZA200908724B/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5278014A (en) * | 1991-06-21 | 1994-01-11 | Konica Corporation | Electrophotographic photoreceptor |
WO1996020197A1 (en) * | 1994-12-23 | 1996-07-04 | Merck Sharp & Dohme Limited | Spiroketal derivatives, compositions containing them and their use as therapeutic agents |
Non-Patent Citations (1)
Title |
---|
See also references of EP2155178A4 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111362963A (en) * | 2020-04-14 | 2020-07-03 | 吉林大学 | Diamine monomer containing spiropyran structure, preparation method and application thereof, polyimide, preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN101795677A (en) | 2010-08-04 |
CA2686604A1 (en) | 2008-11-20 |
BRPI0811557A2 (en) | 2019-09-24 |
IL201899A0 (en) | 2010-06-16 |
CN101795677B (en) | 2012-11-14 |
US20080280974A1 (en) | 2008-11-13 |
EP2155178A4 (en) | 2011-11-16 |
ZA200908724B (en) | 2010-08-25 |
EP2155178A1 (en) | 2010-02-24 |
AU2008251836A1 (en) | 2008-11-20 |
JP2010526812A (en) | 2010-08-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7897776B2 (en) | Sulfonamide containing compounds for treatment of inflammatory disorders | |
RU2495043C2 (en) | New phosphodiesterase inhibitors | |
EP2435416B1 (en) | Tetrahydropyranochromene gamma secretase inhibitors | |
CZ302629B6 (en) | Triazolo [4,5-d] pyrimidine derivative, process for its preparation and pharmaceutical composition containing thereof | |
JP6781148B2 (en) | Hydroxysteroid compounds, their intermediates, their preparation methods, compositions and uses | |
AU2010303822A1 (en) | Novel TRPA1 antagonists | |
EP2155178A1 (en) | Spiro compounds for treatment of inflammatory disorders | |
JP6461080B2 (en) | Dual SGLT1 / SGLT2 inhibitor | |
WO2006041800A2 (en) | 5-phenoxyalkoxypsoralens and methods for selective inhibition of the voltage gated kv1.3 potassium channel | |
EP3209658A1 (en) | Diterpenoid derivatives and methods of use thereof | |
WO2011003058A1 (en) | Prostacyclin derivatives | |
EP1315732A2 (en) | Radicicol and monocillin and their analogues and uses thereof | |
ES2934361T3 (en) | Indolizine derivatives and application thereof in medicine | |
JPH083163A (en) | Condensed pyridine derivative | |
RU2686675C1 (en) | Taxane compounds and also the production method and use thereof | |
CN116490190A (en) | Polycyclic cap-dependent endonuclease inhibitors for treating or preventing influenza | |
JPH01258667A (en) | Hyperlipemia treatment composition | |
JPH0412273B2 (en) | ||
US7151116B2 (en) | Apoptolidin analogs and derivatives for inducing apoptosis in transformed cells | |
EP3551632A1 (en) | Substituted pyrazoloazepin-4-ones and their use as phosphodiesterase inhibitors | |
JPH083040A (en) | Antiviral agent containing benzodithiin derivative as active ingredient | |
JP6853982B2 (en) | Tocotrienol derivatives, pharmaceutical compositions and uses in 5-lipoxygenase-related diseases | |
WO2012135669A1 (en) | Nitrogen ring containing compounds for treatment of inflammatory disorders | |
RU2022964C1 (en) | Derivatives of pyrazolo(3,4-b)pyridine | |
TWI432439B (en) | Novel phosphodiesterase inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200880023843.6 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08754326 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2686604 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2010507478 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008251836 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 8017/DELNP/2009 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008754326 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2008251836 Country of ref document: AU Date of ref document: 20080509 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: PI0811557 Country of ref document: BR Kind code of ref document: A2 Effective date: 20091106 |