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WO2012135669A1 - Composés contenant un cycle azoté pour le traitement de troubles inflammatoires - Google Patents

Composés contenant un cycle azoté pour le traitement de troubles inflammatoires Download PDF

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WO2012135669A1
WO2012135669A1 PCT/US2012/031535 US2012031535W WO2012135669A1 WO 2012135669 A1 WO2012135669 A1 WO 2012135669A1 US 2012031535 W US2012031535 W US 2012031535W WO 2012135669 A1 WO2012135669 A1 WO 2012135669A1
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alkyl
group
butyl
heteroaryl
hydroxyalkyl
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M. David Weingarten
Charles Q. Meng
James A. Sikorski
Kimberly J. WORSENCROFT
Zhihong Ye
Jr. Jacob E. SIMPSON
Liming Ni
Cynthia Clark
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54—Sulfur atoms
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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) Am J Med. 97:451-8; Devaux et al. (1997) Eur Heart J. 18:470-9.; De Keyser et al. (1998) Rheum Dis Clin North Am. 24:785). 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 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-1 on 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-1.
  • 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 with 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.
  • PUFAs polyunsaturated fatty acids
  • ox-PUFAs vascular endothelial cells
  • 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.
  • the IL-6 family all act through receptors sharing a common gpl30 subunit and includes interleukin-6, interleukin-11, ciliary neurotrophic factor, LIF, oncostatin M and cardiotrophin-1.
  • IL-6 is a pleiotropic cytokine that plays an important role in host defense by regulating immune and inflammatory responses. Produced by activated T cells, monocytes, fibroblasts, endothelial cells and keratinocytes, IL-6 has diverse biological functions. IL-6 acts in synergy with IL-1 and TNF-alpha in many immune responses, including T-cell activation. In particular, IL-6 is the primary inducer of the acute-phase response in liver.
  • IL-6 also enhances the differentiation of B-cells and their consequent production of immunoglobulin. It also synergizes with IL-3 in megakaryocyte development and platelet production, induces expression of hepatic acute-phase proteins, and regulates bone metabolism. Glucocorticoid synthesis is also enhanced by IL-6. Unlike IL-1, IL-2 and TNF-a, IL-6 does not induce cytokine expression; its main effects, therefore, are to augment the responses of immune cells to other cytokines.
  • IL-8 is a chemokine, an interleukin that belongs to an ever- expanding family of proteins that exert chemoattractant activity to leukocytes and fibroblasts.
  • IL-8 is produced by monocytes, neutrophils, and NK cells and is chemoattractant for neutrophils, basophils and T-cells.
  • IL-8 activates neutrophils to degranulate.
  • Probucol contains two hydroxyl groups and can be modified to form mono-substituted or di-substituted derivatives.
  • Mono-esters and ethers of probucol have been reported to be useful in the treatment of inflammatory diseases such as rheumatoid arthritis, osteoarthritis, asthma, and dermatitis. Methods for treating transplant rejection using mono-substituted derivatives of probucol also have been reported. See U.S. Patent Publication No. 2004/138147.
  • U.S. Patent No. 5,262,439 to Parthasarathy discloses analogs of probucol with increased water solubility in which one or both of the hydroxyl groups are replaced with ester groups that increase the water solubility of the compound.
  • a series of French patents disclose that certain probucol derivatives are hypocholesterolemic and hypolipemic agents: Fr 2168137 (bis 4hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxy alkanoic esters of probucol); Fr 2140769 (benzofuryloxyalkanoic acid derivatives of probucol); Fr 2134810 (bis-(3-alkyl-5-t-alkyl-4-thiazole-5-carboxy)phenylthio)alkanes; FR 2133024 (bis-(4 nicotinoyloxyphenylthio)-propanes; and Fr 2130975 (bis(4- phenoxyalkanoyloxy)pheny
  • European Patent Application No. 348 203 discloses phenolic thioethers which inhibit the denaturation of LDL and the incorporation of LDL by macrophages. Hydroxamic acid derivatives of these compounds are disclosed in European Patent Application No. 405 788 and are alleged as useful for the treatment of arteriosclerosis, ulcer, inflammation and allergy. Carbamoyl and cyano derivatives of the phenolic thioethers are disclosed in U.S. Patent No. 4,954,514 to Kita, et al. U.S. Patent No. 6,121,319 and corresponding WO 98/51662 and US Patent No.
  • R a , 3 ⁇ 4, R c , and R ⁇ are independently any group that does not adversely affect the desired properties of the molecule, including hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkaryl, substituted alkaryl, aralkyl, or substituted aralkyl; and Z is (i) a substituted or unsubstituted carbohydrate, (ii) a substituted or unsubstituted alditol, (iii) CMO alkyl or substituted CMO alkyl, terminated by sulfonic acid, (iv) Ci-i 0 alkyl or substituted CMO alkyl, terminated by phosphonic acid, (v) substituted or unsubstituted CMO alkyl-O-C(O)-Ci.i 0 alkyl, (vi) straight chained polyhydroxylated C 3 -i 0 alkyl; (vii) -
  • Meng et al. discloses a series of phenolic inhibitors of TNF-inducible expression of VCAM-1 with concurrent antioxidant and lipid-modulating properties.
  • the compounds disclosed have demonstrated efficacies in animal models of atherosclerosis and
  • Ri represents an alkyl group having 1-8 carbon atoms or the like
  • R 2 represents a hydrogen atom, an alkyl group having 1-8 carbon atoms, an alkylcarbonyl group having 2-8 carbon atoms or the like
  • R 3 and R4 may be the same or different and represent alkyl groups having 1-8 carbon atoms or the like.
  • n 1, 2, 3, or 4
  • m
  • X represents O, S or CH 2
  • Rj represents hydrogen or tertiary butyl or lower alkyl of from one to six carbon atoms, inclusive
  • R 2 represents tertiary butyl or lower alkyl of from one to six carbon atoms
  • R 3 represents hydrogen or alkyl or aryl or mixed alkyl/aryl, containing a total of 5 to 25 carbon atoms.
  • piperidine-containing 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, or for treatment or prevention of diabetes.
  • compounds, pharmaceutical compositions and methods of treatment of inflammatory disorders including administration of a compound of Formula I, or its pharmaceutically acceptable salt, ester, derivative or prodrug, are provided:
  • R ! , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, Ci-C 6 branched alkyl, C1-C6 cyclic alkyl, hydroxyalkyi, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, and alkaryl;
  • X and Y can be the same or different and are independently a saturated Ci-C 6 straight alkyl
  • W is selected from the group consisting of R 5 , R 5 -OH, R 5 -C(0)OH, -C(0)-R 5 , -C(O)- N(H)-R 5 , -C(0)-NR 5 R 6 , -C(0)-N(H)-C(0)-R 5 , and -C(0)-N(H)-S(0) 2 -R 5 ;
  • Z is selected from the group consisting of R 7 , R 7 -OH, R 7 -C(0)OH, -C(0)-R 7 , -C(O)- N(H)-R 7 , -C(0)-NR 7 R 8 , -C(0)-N(H)-C(0)-R 7 , and -C(0)-N(H)-S(0) 2 -R 7 ;
  • Q is selected from the group consisting of R 9 , R 9 -OH, R 9 -C(0)OH, -OH, -OR 9 , -C(O)- R 9 , -C(0)-OR 9 , -C(0)-C(0)-OR 9 , -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH 2 , -C(0)-N(H)-R 9 , - C(0)-NR R 10 , -C(0)-N(H)-C(0)-R 9 , -C(0)-N(H)-S(0) 2 -R 9 , -S(0) 2 -R 9 , and -C(0)-H;
  • R 5 , R 7 and R 9 are the same or different and are independently selected from the group consisting of hydrogen, Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Ci-C 8 cyclic alkyl, hydroxyalkyi, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, and heterocyclicalkyl;
  • R 6 , R 8 and R 10 are the same or different and are independently selected from the group consisting of hydrogen, Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, Ci-C 6 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl;
  • each option for R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X, Y, W, Z, Q may be optionally substituted by one or more substituents independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR U R 12 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 6 , -C(0)R 6 , -C(0)-NH 2 , -C(0)-N(H)R u , -C(0)-NR n R 12 , - S(0) n -R 6 , -S(0) 2 -NH 2 , -S(0) 2 -N(H)R n and
  • R 5 and R 6 taken together or R 7 and R 8 taken together or R 9 and R 10 taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be 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 n R 12 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 11 , - C(0)R n , -CCO ⁇ NH ⁇ -C ⁇ -N ⁇ -C ⁇ -NR 11 ⁇ 2 , -S(0) n -R n , -S(0) 2 -NH 2 , -S(0) 2 - N(H)R n and -S(0) 2 -NR n R 12 ;
  • R 11 and R 1 are independently selected from the group consisting of alkyl, alkenyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more
  • alkyl independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, and carboxy;
  • R 11 andR 12 taken together form a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
  • n 0, 1 or 2;
  • R 1 , R 2 , R 3 , and R 4 are independently selected from C] -C6 straight alkyl or Ci-C 6 branched alkyl. In a more particular embodiment, R 1 , R 2 , R 3 , and R 4 are tert-butyl.
  • X and Y can be the same or different and are independently selected from -CH 2 - or -CH 2 -CH 2 -.
  • one of W and Z is not hydrogen.
  • W is hydrogen.
  • Z and Q are not hydrogen.
  • W is hydrogen and Z is selected from the group consisting of 7 , -C(0)-R 7 , -C(0)-N(H)-R 7 , C(0)-NR 7 R 8 , -C(O)- N(H)-C(0)-R 7 , and -C(0)-N(H)-S(0) 2 -R 7 .
  • compounds, pharmaceutical compositions and methods of treatment of inflammatory disorders including administration of a compound of Formula II, or its pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative or prodrug, are provided:
  • Zi is selected from the group consisting of Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Ci-C 8 cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl,
  • Qi is selected from the group consisting of Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Ci-C 8 cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl,
  • R 7* and R 9* are the same or different and are independently selected from the group consisting of hydrogen, Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Q-C 8 cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, and heterocyclicalkyl;
  • R 6* , R 8* and R 10* are the same or different and are independently selected from the group consisting of hydrogen, Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, C C6 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl;
  • each option for R 6* , R 7* , R 8* , R 9* , R 10* , Z ls Qi may be optionally substituted by one or more substituents independently selected from the group wherein all may be 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 U * R 12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 6* , - C(0)R 6* , -C(0)-NH 2, -C(0)-N(H)R 11* , -C(0)-NR n *R 12i , -S(0) n -R 6* , -S(0) 2 -NH 2 , -S(0) 2 - N(H)R U*
  • R 7* and R 8* taken together or R 9* and R 10* taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be 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 n* R 12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 1 1* , - C(0)R n * , -C(0)-NH 2, -C(0)-N(H)R n * , -C(0)-NR u * R 12* , -S(0) 2 -NH 2 , -S(0) 2 - N(H)R n * and -S(0) 2 -NR n * R 12* ;
  • n 0, 1 or 2;
  • R 11 * and R 12 * are independently selected from the group consisting of alkyl, alkenyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more
  • alkyl independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, and carboxy;
  • Zi is selected from the group consisting of Ci-C 6 straight alkyl, C -C6 branched alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,
  • carboxyalkyl alkoxycarbonylalkyl, heteroaralkyl, heterocyclicalkyl, -C(0)-R 7* , and -C(O)- NR 7* R 8* , wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, cyano, and carboxy.
  • Qi is selected from the group consisting of Q-C6 straight alkyl, C ⁇ - Ce branched alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, carboxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocycle, -C(0)-R 9 *, -C(0)-OR 9 *, -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH 2 , -C(0)-N(H)-R 9 *, -C(0)-NR 9 *R 10 *, and -S(0) 2 -R 9 *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 *.
  • R 7 *and R 9 * are the same or different and are independently selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 *.
  • Zi is selected from the group consisting of C1-C6 straight alkyl, Q- C(, branched alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, cyano, and carboxy.
  • Q can be selected from the group consisting of C1-C6 straight alkyl, Ci-C 6 branched alkyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, heterocycle, -C(0)-R 9 *, -C(O)- OR 9 *, -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH 2 , -C(0)-N(H)-R 9 *, and -S(0) 2 -R 9 *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 *.
  • R 9 * can be selected from the group consisting of Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 *; and R 6 * can be independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, C1-C6 branched alkyl, Q-C6 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic,
  • Z ⁇ is selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl and carboxy.
  • Q is selected from the group consisting of -C6 straight alkyl, Ci-C 6 branched alkyl, hydroxyalkyl, carboxyalkyl, heteroaryl, heterocycle, -C(0)-R 9 *, -C(0)-OR 9 *, -C(O)- C(0)-OH, -C(0)-OH, -C(0)-NH 2 , -C(0)-N(H)-R 9 *, and -S(0) 2 -R 9 *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 *.
  • R 9 * is selected from the group consisting of Ci-C 6 straight alkyl, Ci-C 6 branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6* and R 6 * is independently selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, and alk
  • Zi is selected from the group consisting of C1-C4 straight alkyl, and C1 -C4 branched alkyl, wherein all may be substituted by one or more independently selected from hydroxy or carboxy.
  • Qi can be selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl, hydroxyalkyl, carboxyalkyl, heteroaryl, -C(0)-R 9 *, and -S(0) 2 -R 9 *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, heteroaryl, carboxy, and carboxyalkyl.
  • R 9 * can be selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl,
  • hydroxyalkyl, carboxyalkyl, and heteroaryl wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, heteroaryl, carboxy, and carboxyalkyl.
  • Z ⁇ is selected from the group consisting of methyl, ethyl, and propyl, wherein all may be substituted by one or more independently selected from hydroxy or carboxy.
  • Qi is selected from the group consisting of 2- hydroxyethyl, 3-hydroxypropyl, carboxymethyl, -C(0)-R 9 *, and -S(0) 2 -R 9 *.
  • R 9 * is selected from pyrrolyl or imidazolyl, wherein all may be substituted by one or more independently selected from the group consisting of methyl, hydroxymethyl, and carboxy.
  • 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.
  • Cardiovascular inflammatory disorders include atherosclerosis, post-angioplasty, restenosis, coronary artery diseases, agina, 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, 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.
  • the compounds reduce the levels of one or more
  • the compounds reduce the levels of IL-6. In other embodiments, the compounds reduce levels of IL-8. In certain embodiments, therefore, the compounds can be administered in individuals at risk for or in need of treatment for an inflammatory disorder mediated by a cytokine, such as IL-6 or IL-8.
  • a cytokine such as IL-6 or IL-8.
  • a pharmaceutical composition comprising a compound of Formula I or II, a pharmaceutically acceptable carrier, is provided.
  • the pharmaceutical composition is for the treatment or prophylaxis of an inflammatory disorder.
  • a method for the treatment or prophylaxis of an inflammatory disorder comprising administering an effective amount of a compound of Formula I or II to a host in need thereof, is provided.
  • a use of a compound of Formula I or II in the manufacture of a medicament for the treatment or prophylaxis of an inflammatory disorder is provided.
  • 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, as well as proliferative disorders of smooth muscle cells.
  • the compounds for treatment or propylaxis of inflammatory disorders are a compound of Formula I, or its pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative or prodrug:
  • R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, C1-C6 branched alkyl, Ci-C 6 cyclic alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, and alkaryl, all of which may be optionally substituted by one or more substituent independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR n R 12 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 6 , -C(0)R 6 , -C(0)-NH 2 , -C(0)-N(H)R 11 , -C(0)-
  • X and Y can be the same or different and are independently a saturated C1-C6 straight alkyl optionally substituted by one or more substituent independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR n R 12 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 6 , -C(0)R 6 , -C(0)-NH 2 , -C(0)-N(H)R 11 > -C(0)-NR 11 R 12 , - S(0) n -R 6 , -S(0) 2 -NH 2 , -S(0) 2 -N(H)R u and -S(0) 2 -NR n R 12 ; W is selected from the group consisting of R 5 , R5-OH, R 5
  • Z is selected from the group consisting of R 7 , R 7 -OH, R 7 -C(0)OH, -C(0)-R 7 , -C(O)- N(H)-R 7 , -C(0)-NR 7 R 8 , -C(0)-N(H)-C(0)-R 7 , and -C(0)-N(H)-S(0) 2 -R 7 , 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 n R 12 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 6 , -C(0)R 6 , -C(0)-NH 2, -C(0)-N(H)R n ; -C(0)-NR
  • Q is selected from the group consisting of R 9 , R 9 -OH, R 9 -C(0)OH, -OH, -OR 9 , -C(O)- R 9 , -C(0)-OR 9 , -C(0)-C(0)-OR 9 , -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH 2 , -C(0)-N(H)-R 9 , - C(0)-NR 9 R 10 , -C(0)-N(H)-C(0)-R 9 , -C(0)-N(H)-S(0) 2 -R 9 , -S(0) 2 -R 9 , and -C(0)-H, wherein all may be 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
  • R 5 , R 7 and R 9 are the same or different and are independently selected from the group consisting of hydrogen, Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Ci-C 8 cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy,
  • R 6 , R 8 and R 10 are the same or different and are independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, C1-C6 branched alkyl, Ci-C 6 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be substituted by one or more
  • R 5 and R 6 taken together or R 7 and R 8 taken together or R 9 and R 10 taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be 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 U R 12 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 11 , - C(0)R n , -C(0)-NH 2 , -C(0)-N(H)R n , -C(0)-NR n R 12 , -S(0) n -R n , -S(0) 2 -NH 2 , -S(0) 2 - N(H)R n and -S(0) 2 -NR
  • R 11 and R 12 are independently selected from the group consisting of alkyl, alkenyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more
  • alkyl independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, and carboxy;
  • R 1 1 and R 12 taken together form a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring;
  • n 0, 1 or 2;
  • R 1 , R 2 , R 3 , and R 4 are independently selected from Ci-C 6 straight alkyl or Ci-C 6 branched alkyl. In a more particular embodiment, R 1 , R 2 , R 3 , and R 4 are tert-butyl.
  • X and Y can be the same or different and are independently selected from -CH 2 - or -CH 2 -CH 2 -. In one embodiment, X and Y are the same. In another embodiment, X and Y are different.
  • one of W and Z is not hydrogen.
  • W is hydrogen.
  • Z is not hydrogen.
  • Z and Q are not hydrogen.
  • Z and W are both not hydrogen.
  • W is hydrogen and Z is selected from the group consisting of R 7 , -C(0)-R 7 , -C(0)-N(H)-R 7 , C(0)-NR 7 R 8 , -C(0)-N(H)-C(0)-R 7 , and -C(O)- N(H)-S(0) 2 -R 7 .
  • compounds, pharmaceutical compositions and methods of treatment of inflammatory disorders including administration of a compound of Formula II, or its pharmaceutically acceptable salt, ester, pharmaceutically acceptable derivative or prodrug, are provided:
  • Zi is selected from the group consisting of Ci-C 8 straight alkyl, Q-Cg branched alkyl, Ci-C 8 cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl,
  • Qi is selected from the group consisting of Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Ci-C 8 cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl,
  • R 7* and R 9* are the same or different and are independently selected from the group consisting of hydrogen, Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Ci-C 8 cyclic alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, acyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycle, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxy
  • R , R and R are the same or different and are independently selected from the group consisting of hydrogen, Ci-Ce straight alkyl, C1-C6 branched alkyl, Ci-Ce cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be 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 U* R 12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 11* , -C(0)R n* , -C(0)- NHz.
  • R 7* and R 8* taken together or R 9* and R 10* taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be 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 n* R 12* , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 11* , - C(0)R n* , -C(0)-NH 2 , -C(0)-N(H)R u *, -C(0)-NR u* R 12* , -S(0) n -R n* , -S(0) 2 -NH 2 , -S(0) 2 - N(H)R n* and -S
  • n 0, 1 or 2;
  • R andR l are independently selected from the group consisting of alkyl, alkenyl, heterocyclic, heteroaryl and aryl, wherein all may be substituted by one or more
  • alkyl independently selected from the group consisting of halo, alkyl, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, and carboxy;
  • R 11* andR 12* taken together form a 4- to 12-membered monocyclic, bicylic, tricyclic or benzofused ring.
  • Zi is selected from the group consisting of C1-C6 straight alkyl, C1-C branched alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl,
  • carboxyalkyl alkoxycarbonylalkyl, heteroaralkyl, heterocyclicalkyl, -C(0)-R 7 *, and -C(O)- NR 7 *R 8 *, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, cyano, and carboxy.
  • Qi is selected from the group consisting of C1-C6 straight alkyl, C Ce branched alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, carboxyalkyl, aryl, heteroaryl, heteroaralkyl, heterocycle, -C(0)-R 9 *, -C(0)-OR 9 *, -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH 2 , -C(0)-N(H)-R 9* , -C(0)-NR 9* R 10* , and -S(0) 2 -R 9* , wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 *.
  • R 7 *and R 9* are the same or different and are independently selected from the group consisting of C1-C6 straight alkyl, Ci-C 6 branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6* .
  • R 6 * and R 8 * are the same or different and are independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, Q-C6 branched alkyl, Ci-C 6 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, and alkoxycarbonyl.
  • R and R taken together or R and R taken together form a 4- to 12-membered saturated or unsaturated heterocyclic or carbocyclic ring, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, oxo, carboxy, and carboxyalkyl.
  • Zi is selected from the group consisting of Ci-Ce straight alkyl, Q- C 6 branched alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl, cyano, and carboxy.
  • Q can be selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, heterocycle, -C(0)-R , -C(O)- OR 9 *, -C(0)-C(0)-OH, -C(0)-OH, -C(0)-NH 2 , -C(0)-N(H)-R 9* , and -S(0) 2 -R 9 *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 *.
  • R 9 * can be selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 *; and R 6 * can be independently selected from the group consisting of hydrogen, C1-C6 straight alkyl, C1-C6 branched alkyl, C1-C6 cyclic alkyl, aryl, heteroaryl, heterocycle, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl,
  • Zi is selected from the group consisting of C1-C6 straight alkyl, C1-C branched alkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be substituted by one or more independently selected from the group consisting of alkyl, hydroxy, hydroxyalkyl and carboxy.
  • Q is selected from the group consisting of C1-C6 straight alkyl, C1-C6 branched alkyl, hydroxyalkyl, carboxyalkyl, heteroaryl, heterocycle, -C(0)-R 9 *, -C(0)-OR 9 *, -C(O)- C(0)-OH, -C(0)-OH, -C(0)-NH 2 , -C(0)-N(H)-R 9 *, and -S(0) 2 -R 9* , wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 *.
  • R 9 * is selected from the group consisting of Ci-C 6 straight alkyl, C1-C6 branched alkyl, acyl, hydroxyalkyl, carboxyalkyl, aryl, heteroaryl, and heterocycle, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, and -OR 6 * and R 6 * is independently selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl, and acyl, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, amino, oxo, cyano, carboxy, carboxyalkyl, and al
  • Zi is selected from the group consisting of C1-C4 straight alkyl, and C1 -C4 branched alkyl, wherein all may be substituted by one or more independently selected from hydroxy or carboxy.
  • Qi can be selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl, hydroxyalkyl, carboxyalkyl, heteroaryl, -C(0)-R 9 *, and -S(0)2-R 9 *, wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, heteroaryl, carboxy, and carboxyalkyl.
  • R can be selected from the group consisting of C1-C4 straight alkyl, C1-C4 branched alkyl,
  • hydroxyalkyl, carboxyalkyl, and heteroaryl wherein all may be substituted by one or more independently selected from the group consisting of halo, lower alkyl, hydroxyalkyl, heterocyclic, heteroaryl, carboxy, and carboxyalkyl.
  • Z ⁇ is selected from the group consisting of methyl, ethyl, and propyl, wherein all may be substituted by one or more independently selected from hydroxy or carboxy.
  • Qi is selected from the group consisting of 2- hydroxyethyl, 3-hydroxypropyl, carboxymethyl, -C(0)-R 9 *, and -S(0) 2 -R 9 *.
  • R 9 * is selected from pyrrolyl or imidazolyl, wherein all may be substituted by one or more independently selected from the group consisting of methyl, hydroxymethyl, and carboxy.
  • Zi is hydroxyalkyl, optionally substituted or terminated with carboxy.
  • Q or Qi is selected from the group consisting of hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl,
  • Q is selected from -OR 9 *, -C(0)-R 9* , and -C(0)-OR 9 *.
  • R 9 * can be substituted or unsubstituted Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Ci-C 8 cyclic alkyl, hydroxyalkyl or alkoxyalkyl.
  • Oj is -S(0) 2 -R 9 *.
  • R 9 * can be a heterocycle or heteroaromatic ring.
  • R 9 * is a nitrogen containing heterocycle or heteroaromatic.
  • R is a nitrogen containing heteroaromatic.
  • R 9* is selected from pyrrolyl or imidazolyl.
  • R 9* is further substituted.
  • R 9* is substituted with for example with alkyl, carboxy or -C(0)R 6* .
  • R 9* is substituted with more than one substituent.
  • R 9* is substituted with at least one carboxy.
  • R9* is substituted with at least one alkyl, optionally substituted with hydroxyl and/or carboxy.
  • R 9* is substituted with at least one carboxy and at least one alkyl.
  • R 9* is selected from the group consisting of hydrogen, substituted or unsubstituted Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Ci-C 8 cyclic alkyl, hydroxyalkyl, alkoxyalkyl, acyl, heteroaralkyl, and heterocyclicalkyl, wherein all may be 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 R , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR , - C(0)R 6* , -C(0)-NH 2j -C(0)-N(H)R u* ; -C(0)-NR u* R 12* , -S(0) n -R 6
  • Qi can be selected from Ci-C 8 straight alkyl, Ci-C 8 branched alkyl, Ci-C 8 cyclic alkyl, haloalkyl, thioalkyl, alkylthioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, amidoalkyl, aryl, aralkyl, -OH, - C(0)-C(0)-OR 9* , -C(0)-C(0)-OH, - C(0)-NH 2 , -C(0)-N(H)-R 9* , -C(0)-N(H)-C(0)-R 9* , -C(0)-N(H)-S(0) 2 -R 9* and -C(0)-H, wherein all may be substituted by one or more independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalky
  • Qi is selected from hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, acyloxyalkyl, sulfonylalkyl, sulfonamidoalkyl, heteroaryl, heteroaralkyl, heterocycle, heterocyclicalkyl, -OR 9* , -C(0)-R 9* , -C(0)-OR 9* , - C(0)-OH, -C(0)-NR 9* R 10* and -S(0) 2 -R 9* and Z, is selected from Ci-C 6 straight alkyl, C C 6 branched alkyl, and hydroxyalkyl, optionally substituted by one or more substituents independently selected from hydroxy or carboxy.
  • compounds of the invention are as defined below in Table I:
  • the compound is as shown in Table III:
  • the compound is as shown in Table VI:
  • C 1 -4 alkyl Whenever a term in the specification is identified as a range (i.e. C 1 -4 alkyl), the range independently refers to each element of the range.
  • C 1-4 alkyl means, independently, Q, C 2 , C3 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, z ' sopropyl, 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, imine, sulfonic acid, sulfate, sulfonyl, sulfanyl, sulfinyl, sulfamoyl, ester, carboxylic acid, amide, thioether, oxime, carbamate, heterocyclic, heteroaryl, 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 Group
  • lower alkyl refers to a Ci to C5 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 independently selected from the group consisting of halo, alkyl, lower alkyl, alkenyl, cycloalkyl, acyl, hydroxy, hydroxyalkyl, heterocyclic, heteroaryl, aryl, amino, aminoalkyl, -NR n R 12 , oxo, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, -OR 6 , -C(0)R 6 , - C(0)-NH 2 , -C(0)-N(H)R 11 , -C(0)-NR 11 R 12 , -S(0) n -R 6 , -S(0) 2 -NH 2 , -S(0) 2 -N(H)R n , -S(0) 2 - NR n R 12 , haloalkyl, alkoxy, carboxyl derivatives, amido, alkylamino, dialkylamino.
  • the heteroaromatic can be partially or totally hydrogenated as desired.
  • dihydropyridine can be used in place of pyridine.
  • Functional oxygen and nitrogen groups on the heteroaryl group can be protected as necessary or desired.
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t- butyldimethylsilyl, and i-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, alkyl, hydroxyalkyl, carboxy, carboxyalkyl, or oxo, 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 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 defmd 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(0)R' or "alkyl-oxy", 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 -N3 ⁇ 4.
  • 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-' can also be placed before the name of a ompoundto 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.
  • pharmaceutically acceptable salt refers to salts or complexes that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological 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,
  • inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • 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
  • 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 cation formed from ammonia, ⁇ , ⁇ -dibenzylethylenediamine, D-glucosamine, tetraethylammonium, or ethylenediamine; or
  • 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.
  • 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 disorder is a respiratory disorder.
  • 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 (IL-1), 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 (IFND), which activates macrophages; and IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF), which stimulate IL-1 and differentiation.
  • IL-1 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
  • Interferon gamma IFND
  • IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF) which stimulate
  • IL-6 is generally produced by monocytes, macrophages, Th2 cells and stromal cells. It acts on activated B cells to differente 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, 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, Chu
  • 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.
  • 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.
  • a 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, agina, 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, 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.
  • 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: 11-22; 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.
  • 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-Schonlein purpura, serum sickness, Wegener's granulomatosis, giant cell arteritis, temporal arteritis, Takayasu's arteritis, Behcet's syndrome, Kawasaki's disease (mucocutaneous lymph node syndrome) and Buerger's disease (thromboangiitis obliterans).
  • 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
  • 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, HbAlc.
  • Persistent or uncontrolled hyperglycemia that occurs with diabetes is associated with increased and premature morbidity and mortality.
  • 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 macro vascular 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.
  • 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
  • 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.
  • 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 (IFG), 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.
  • 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
  • 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). In 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; 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; and antimicrobial preservatives, e.g., benzalkonium chloride, phenylethyl alcohol and potassium sorbate.
  • humectants e.g. glycerin and propylene glycol
  • 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., benz
  • 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-chlorofiuorocarbons 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. PCT7US92/05225, 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. In one embodiment, the compounds are administered less than three times daily. In one
  • the compounds are administered in one or two doses daily. In one embodiment, the compounds are administered once daily. In 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. In 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. In another embodiment, 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. In one embodiment, 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.
  • the compounds can be administered in conjunction (combination or alternation) with other medications used in treatment or prophylaxis of inflammatory conditions.
  • 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 anti-inflammatory 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
  • 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
  • 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
  • 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. 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 /
  • 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 /
  • Betamethasone dipropionate Hydrocortisone / Nystatin , Betacap , Betamethasone dipropionate , Betamethasone dipropionate / Calcipotriol hydrate , Betamethasone dipropionate / Salicylic acid ,
  • Betamethasone Valerate Betamethasone Valerate , Betamethasone Valerate / Clioquinol , Betamethasone Valerate / Fusidic Acid , Betamethasone valerate / Neomycin sulphate , Betnovate , Betnovate-C , Betnovate-N , Bettamousse , Calcipotriol , Calcipotriol hydrate , Calcitriol , Calmurid HC , Canesten HC , Chlorquinaldol / Hydrocortisone Butyrate , Ciclosporin , Clarelux , Clioquinol / Hydrocortisone , Clobetasol propionate , Clobetasol propionate / Neomycin sulphate / Nystatin , Clobetasone butyrate , Clobetasone butyrate / Nystatin / Oxytetracycline calcium , Clotrimazole / Hydrocortisone ,
  • 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-1 according to known methods.
  • Step 1 Approximately two equivalents of a 2,6-dialkyl-4-mercaptophenol, for example 2,6-di-tert-butyl-4-mercaptophenol, and about one equivalent of a 4-oxo-piperidine- 1-carboxylalkyl or a 4-oxo-piperidine-l-carboxylic acid alkyl ester, for example, 4-oxo- piperidine-l-carboxylic acid ethyl ester, are combined with an organic solvent or a polar solvent or a protic solvent, for example methanol.
  • a 2,6-dialkyl-4-mercaptophenol for example 2,6-di-tert-butyl-4-mercaptophenol
  • 4-oxo-piperidine- 1-carboxylalkyl or a 4-oxo-piperidine-l-carboxylic acid alkyl ester for example, 4-oxo- piperidine-l-carboxylic acid ethyl ester
  • the concentration of the 2,6-di-alkyl-4- mercaptophenol and 4-oxo-piperidine-l-carboxylic acid alkyl ester in the solvent is approximately 0.1 to 10 M, for example, about 1 M.
  • the solution is heated, for example, to about 45°C, and stirred, for example, for 20 hours.
  • An acid is added during or at the start of the reaction.
  • HC1 gas which can be generated by the addition of concentrated sulfuric acid to NaCl, can be bubbled through the solution for about 2 h. Stirring is then continued for example, for 18 h or until after a solid has formed.
  • the slurry is cooled, for example, to 0°C and stirred, for example, for an additional 1 h.
  • the solid is isolated, for example by filtration, and can be washed, for example with a small amount of cold methanol, and dried, for example in vacuo.
  • the product is a 4,4-bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylalkyl compound or a 4,4-bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine- 1 -carboxylic acid alkyl ester compound, for example, 4,4- bis-(3,5-di-ier?-butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester.
  • Step 2 The 4,4-bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester is hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in an alcohol such as 2-methoxyethanol.
  • the mixture may be heated and stirred under an inert atmosphere, for example to 120°C for 18 h under N 2 gas.
  • the reaction mixture is subsequently cooled, for example to ambient temperature and the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield a 4,4-bis-(3,5-dialkyl-4- hydroxylphenylsulfanyl)piperidine compound, for example 4,4-bis-(3,5-di-ter/-butyl-4- hydroxylphenylsulfanyl)piperidine.
  • Step 3 The 4,4-bis-(3,5-dialkyl-4-hydroxylphenylsulfanyl)piperidine compound, for example 4,4-bis-(3,5-di-feri-butyl-4-hydroxylphenylsulfanyl)piperidine, is reacted with one or more equivalents of a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as N,N-diisopropylethylamine, in an anhydrous organic solvent, for example tetrahydrofuran.
  • a bromoacetic acid ester such as ethyl bromoacetate
  • an amine base such as N,N-diisopropylethylamine
  • the [4,4-bis-(3,5-di-1 ⁇ 2ri-butyl-4-hydroxyphenylsulfanyl)piperidin- l-yl]acetic acid alkyl ester product may be isolated by extraction.
  • the reaction mixture is concentrated in vacuo, the residue is taken up in an organic solvent such as ethyl acetate, washed, for example with water and brine, dried with a drying agent such as sodium sulfate, filtered and reduced to dryness.
  • Step 4 The ester of Step 3 can be hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in a solvent such as tetrahydrofuran.
  • the mixture may be heated and stirred, for example to 60°C for 6 h.
  • the pH of the solution is adjusted, for example to about 5 or less with the addition of an acid, such as HC1.
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4,4-Bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]acetic acid, for example [4,4-Bis-(3,5-di-te -butyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]acetic acid.
  • the product can be further purified by chromatography or recrystallization.
  • the 4,4-bis-(3,5-dialkyl-4- hydroxylphenylsulfanyl)piperidine compound for example 4,4-bis-(3,5-di-/er/-butyl-4- hydroxylphenylsulfanyl)piperidine
  • an alkali metal carbonate for example potassium carbonate
  • an organic anhydride for example succinic anhydride
  • an anhydrous organic solvent for example dimethylformamide
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4,4-Bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l- yl]carboxyalkyl-l-one compound, for example [4,4-Bis-(3,5-di-teri-butyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]-4-oxo-butyric acid.
  • the product can be further purified by chromatography or recrystallization.
  • the [4,4-Bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]carboxyalkyl-l-one compound product can optionally be converted to a [4,4-Bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]hydroxyalkyl-l-one compound by reacting the [4,4- Bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]carboxyalkyl-l-one compound, for example [4,4-Bis-(3 ,5-di-/ert-butyl-4-hydroxyphenylsulfanyl)piperidin- 1 -yl]-4-oxo-butyric acid, with an excess of borane, for example 1.0 M borane/tetrahydrofuran solution, in an organic solvent such as tetrahydrofuran.
  • the mixture is stirred at, for example, ambient temperature for two hours, and quenched with water.
  • the product can be isolated for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4,4-Bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l- yl]hydroxyalkyl-l-one compound, for example, [4,4-Bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]-4-hydroxy-butan-l-one.
  • the product can be further purified by chromatography or recrystallization.
  • the 4,4-bis-(3,5-dialkyl-4- hydroxylphenylsulfanyl)piperidine compound for example 4,4-bis-(3,5-di-fer/'-butyl-4- hydroxylphenylsulfanyl)piperidine
  • an amine base for example N,N- diisopropylethylamine
  • an anhydrous organic solvent for example tetrahydrofuran
  • a trialkylacetyl chloride for example trimethylacetyl chloride
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate and/or in vacuo.
  • the residue may be triturated, for example with an organic solvent such as hexanes, and dried, for example in vacuo.
  • the product is a [4,4-Bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]alkyl-l-one compound, for example [4,4-Bis-(3,5-di- 1 ⁇ 2ri-butyl-4-hydroxyphenylsulfanyl)piperidin- 1 -yl] -2,2-dimethyl-propan- 1 -one.
  • the 4,4-bis-(3,5-dialkyl-4- hydroxylphenylsulfanyl)piperidine compound for example 4,4-bis-(3,5-di-ier/-butyl-4- hydroxylphenylsulfanyl)piperidine
  • an amine base for example N ⁇ V-diisopropylethylamine
  • an organic solvent for example tetrahydrofuran
  • a halosulfonylalkyl or halosulfonylaryl compound for example methyl (5- chlorosulfonyl)-l -methyl- lH-pyrrole-2-carboxy late or ethyl 4-(chlorosulfonyl)-3,5-dimethyl- lH-pyrrole-2-carboxylate or methyl-5-(chlorosulfonyl)-2-furoate, is added to the reaction mixture.
  • the solution is stirred, for example at ambient temperature for 2 hours, and quenched, for example with an acid such as HC1, and optionally, diluted with water.
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate and/or in vacuo.
  • the residue may be triturated, for example with an organic solvent such as hexanes, and dried, for example in vacuo.
  • the product is a [4,4-bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]-(alkyl or aryl)- sulfonyl compound.
  • the product may be further purified by chromatography or
  • Step 1 A 4,4-bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester compound, for example, 4,4-bis-(3,5-di-1 ⁇ 2rt-butyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester, is combined with one or more equivalents of an alkali metal carbonate, for example potassium carbonate, and a haloalkyl or haloalcohol, for example 2-bromoethanol or 2-bromopropanol, in an anhydrous organic solvent, for example dimethylformamide.
  • an alkali metal carbonate for example potassium carbonate
  • a haloalkyl or haloalcohol for example 2-bromoethanol or 2-bromopropanol
  • the mixture is heated, for example to 80 °C for 100 hours, and quenched, for example with water.
  • the product can be isolated for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to isolate the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester, for example 4-[3,5-Di-1 ⁇ 2r - butyl-4-(2-hydroxyethoxy)phenylsulfanyl]-4-(3,5-di-teri-butyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester or 4-(3,5-di-fert-butyl-4- hydroxyphenylsulfanyl)-4-[3,5-di-terf-butyl-4-(3-hydroxy- propoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester or 4- ⁇ 4-
  • 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester for example 4- ⁇ 4-(3,5-di- 1 ⁇ 2rr-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-ieri-butyl-4-(3-hydroxy- propoxy)phenylsulfanyl]piperidin-l-yl ⁇ -4-oxo-butyric acid methyl ester, can be hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in a solvent such as tetrahydrofuran.
  • a solvent such as tetrahydrofuran
  • the mixture may be heated and stirred, for example to 60 °C for 6 h.
  • the pH of the solution is adjusted, for example to about 5 or less with the addition of an acid, such as HC1.
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo.
  • the product can be further purified by chromatography or recrystallization.
  • Step 1 Approximately two equivalents of a 2,6-dialkyl-4-mercaptophenol, for example 2,6-di-1 ⁇ 2r/-butyl-4-mercaptophenol, and about one equivalent of a 4-oxo-piperidine- 1-carboxylalkyl or a 4-oxo-piperidine-l-carboxylic acid alkyl ester, for example, 4-oxo- piperidine-l-carboxylic acid ethyl ester, are combined with an organic solvent or a polar solvent or a protic solvent, for example methanol.
  • a 2,6-dialkyl-4-mercaptophenol for example 2,6-di-1 ⁇ 2r/-butyl-4-mercaptophenol
  • 4-oxo-piperidine- 1-carboxylalkyl or a 4-oxo-piperidine-l-carboxylic acid alkyl ester for example, 4-oxo- piperidine-l-carboxylic acid ethyl ester
  • the concentration of the 2,6-di-alkyl-4- mercaptophenol and 4-oxo-piperidine-l-carboxylic acid alkyl ester in the solvent is approximately 0.1 to 10 M, for example, about 1 M.
  • the solution is heated, for example, to about 45 °C, and stirred, for example, for 20 hours.
  • An acid is added during or at the start of the reaction.
  • HC1 gas which can be generated by the addition of concentrated sulfuric acid to NaCl, can be bubbled through the solution for about 2 h. Stirring is then continued for example, for 18 h or until after a solid has formed.
  • the slurry is cooled, for example, to 0 °C and stirred, for example, for an additional 1 h.
  • the solid is isolated, for example by filtration, and can be washed, for example with a small amount of cold methanol, and dried, for example in vacuo.
  • the compound is a 4,4-bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylalkyl compound or a 4,4-bis-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester compound, for example, 4,4- bis-(3,5-di-ierf-butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester.
  • Step 2 A 4,4-bis-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester compound, for example, 4,4-bis-(3,5-di-tert-butyl-4- hydroxyphenylsulfanyl)piperidine- 1 -carboxylic acid ethyl ester, is combined with one or more equivalents of an alkali metal carbonate, for example potassium carbonate, and a haloalkyl or haloalcohol, for example 2-bromoethanol or 2-bromopropanol, in an anhydrous organic solvent, for example dimethylformamide.
  • an alkali metal carbonate for example potassium carbonate
  • a haloalkyl or haloalcohol for example 2-bromoethanol or 2-bromopropanol
  • the mixture is heated, for example to 80 °C for 100 hours, and quenched, for example with water.
  • the product can be isolated for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to produce the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l -carboxylic acid alkyl ester, for example 4-[3,5-Di-/er - butyl-4-(2-hydroxyethoxy)phenylsulfanyl]-4-(3,5-di-1 ⁇ 2r ⁇ -butyl-4- hydroxyphenylsulfanyI)piperidine-l -carboxylic acid ethyl ester or 4-(3,5-di-1 ⁇ 2r/-butyl-4- hydroxyphenylsulfanyl)-4-[3,5-di-tert-butyl-4-(3-hydroxy- propoxy)phenylsulfanyl]piperidine-l -carboxylic acid ethyl este
  • 4- [3 , 5 -dialkyl-4-(alkoxy)pheny lsulfany 1] -4-(3 , 5 -dialkyl-4- hydroxyphenylsulfanyl)piperidine-l -carboxylic acid alkyl ester for example 4- ⁇ 4-(3,5-di- feri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-ier/-butyl-4-(3-hydroxy- propoxy)phenylsulfanyl]piperidin-l-yl ⁇ -4-oxo-butyric acid methyl ester, can be hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in a solvent such as tetrahydrofuran.
  • a solvent such as tetrahydrofuran
  • the mixture may be heated and stirred, for example to 60 °C for 6 h.
  • the pH of the solution is adjusted, for example to about 5 or less with the addition of an acid, such as HC1.
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo.
  • the product can be further purified by chromatography or recrystallization.
  • a 4- [3 , 5 -dialky l-4-(hydroxyalkoxy)pheny lsulfanyl]-4-(3 , 5 -dialky 1-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester for example the 4-(3,5-di- 1 ⁇ 2ri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di- er?-butyl-4-(3-hydroxy- propoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester, can be used in the preparation of a 4- ⁇ 3, 5 -dialky 1 -4-[(pyrazol-l-yl)alkoxy]-phenylsulfanyl ⁇ -4-(3,5-dialkyl -4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester, for example 4- ⁇ 3,
  • methanesulfonylchloride in the presence of a base, for example an amine base such as N,N- diisopropylethylamine, in an organic solvent, for example methylene chloride.
  • a base for example an amine base such as N,N- diisopropylethylamine
  • organic solvent for example methylene chloride.
  • the product is isolated by, for example, extraction, then combined with an anhydrous organic solvent, such as dimethylformamide, and a pyrazole compound, such as (5-methyl-2H-pyrazol-3-yl)- methanol.
  • an alkyl metal hydride such as sodium hydride, or other hydride reagent or alkyl lithium reagent, is added to the reaction mixture. The reaction is quenched, if necessary, and the product is isolated, for example by extraction.
  • Step 1 The 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine-l-carboxylic acid alkyl ester is hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in an alcohol such as 2-methoxyethanol.
  • the mixture may be heated and stirred under an inert atmosphere, for example to 120 °C for 18 h under N 2 gas.
  • the reaction mixture is subsequently cooled, for example to ambient temperature and the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield a 4-[3,5- dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine compound.
  • Step 2 The 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidine compound is reacted with one or more equivalents of a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as N ⁇ V-diisopropylethylamine, in an anhydrous organic solvent, for example tefrahydrofuran.
  • a bromoacetic acid ester such as ethyl bromoacetate
  • an amine base such as N ⁇ V-diisopropylethylamine
  • the [4,4-bis-(3,5-di-/ert-butyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]acetic acid alkyl ester product may be isolated by extraction.
  • the reaction mixture is concentrated in vacuo, the residue is taken up in an organic solvent such as ethyl acetate, washed, for example with water and brine, dried with a drying agent such as sodium sulfate, filtered and reduced to dryness.
  • Step 3 The ester of Step 3 can be hydrolyzed under basic conditions, for example, by treatment with an excess of IN sodium hydroxide in a solvent such as tetrahydrofuran.
  • the mixture may be heated and stirred, for example to 60 °C for 6 h.
  • the pH of the solution is adjusted, for example to about 5 or less with the addition of an acid, such as HCl.
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4-[3,5-dialkyl-4- (alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]acetic acid compound.
  • the product can be further purified by chromatography or recrystallization.
  • the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5- dialkyl-4-hydroxyphenylsulfanyl)piperidine compound is reacted with one or more equivalents of an alkali metal carbonate, for example potassium carbonate, and an organic anhydride, for example succinic anhydride, in an anhydrous organic solvent, for example dimethylformamide.
  • an alkali metal carbonate for example potassium carbonate
  • an organic anhydride for example succinic anhydride
  • anhydrous organic solvent for example dimethylformamide
  • the mixture is stirred at, for example, ambient temperature for two hours, and quenched with water and acidified to a pH of about 5 or less with an acid, for example, HCl.
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4-[3,5-dialkyl-4- (alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l- yl]carboxyalkyl-l-one compound.
  • the product can be further purified by chromatography or recrystallization.
  • the [4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]carboxyalkyl-l-one compound product can optionally be converted to a [4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4- hydroxyphenylsulfanyl)piperidin-l-yl]hydroxyalkyl-l-one compound by reacting the [4-[3,5- dialky l-4-(alkoxy)pheny lsulfany 1] -4-(3 , 5 -dialkyl-4-hydroxypheny lsulfany l)piperidin- 1 - yl]carboxyalkyl-l-one compound with an excess of borane, for example 1.0 M
  • borane/tetrahydrofuran solution in an organic solvent such as tetrahydrofuran.
  • the mixture is stirred at, for example, ambient temperature for two hours, and quenched with water.
  • the product can be isolated for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example with acid and water and brine, and dried, for example with a drying agent such as sodium sulfate.
  • the volume of the extracts can be reduced in vacuo and/or dried in vacuo to yield the [4-[3,5-dialkyl-4- (alkoxy)phenylsulfanyl]-4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l- yl]hydroxyalkyl-l-one compound.
  • the product can be further purified by chromatography or recrystallization.
  • the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]- 4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine compound is reacted with an amine base, for example N ⁇ N-diisopropylethylamine, in an anhydrous organic solvent, for example tetrahydrofuran, a trialkylacetyl chloride, for example trimethylacetyl chloride, is added to the reaction mixture.
  • the solution is stirred, for example at ambient temperature for 1 hour, and quenched, for example with water.
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate and/or in vacuo.
  • the residue may be triturated, for example with an organic solvent such as hexanes, and dried, for example in vacuo.
  • the product is a [4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]- 4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]alkyl-l-one compound.
  • the 4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]- 4-(3,5-dialkyl-4-hydroxyphenylsulfanyl)piperidine compound is reacted with one or more equivalents of an amine base, for example N,N-diisopropylethylamine, in an organic solvent, for example tetrahydrofuran, and a halosulfonylalkyl or halosulfonylaryl compound, for example methyl (5-chlorosulfonyl)-l -methyl- lH-pyrrole-2-carboxylate or ethyl 4- (chlorosulfonyl)-3,5-dimethyl-lH-pyrrole-2-carboxylate or methyl-5-(chlorosulfonyl)-2- furoate, is added to the reaction mixture.
  • an amine base for example N,N-diisopropylethylamine
  • an organic solvent
  • the solution is stirred, for example at ambient temperature for 2 hours, and quenched, for example with an acid such as HC1, and optionally, diluted with water.
  • the product is isolated, for example by extraction with an organic solvent, for example ethyl acetate.
  • the extracts can be washed, for example water and brine, and dried, for example with a drying agent such as sodium sulfate and/or in vacuo.
  • the residue may be triturated, for example with an organic solvent such as hexanes, and dried, for example in vacuo.
  • the product is a [4-[3,5-dialkyl-4-(alkoxy)phenylsulfanyl]-4-(3,5- dialkyl-4-hydroxyphenylsulfanyl)piperidin-l-yl]-(alkyl or aryl)-sulfonyl compound.
  • the product may be further purified by chromatography or recrystallization.
  • Ex. lc A 100 mL round bottom flask was charged with 4,4-bis-(3,5-di-1 ⁇ 2rt-butyl-4- hydroxylphenylsulfanyl)piperidine (Ex. lb, 0.50 g, 0.90 mmol), 20 mL of anhydrous THF, N,N-diisopropylethylamine (0.35 g, 2.7 mmol) and ethyl bromoacetate (0.17 g, 1.0 mmol). After the resultant mixture was stirred at ambient temperature for 2 h the starting material was consumed. The reaction mixture was concentrated under reduced pressure.
  • Example 3 4-[3,5-Di-teri-butyl-4-(2-hydroxyethoxy)phenylsulfanyl]-4-(3,5-di-teri-butyl- 4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester
  • Example 7 l- ⁇ 4-(3,5-Di-tert-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-tert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidin-l-yl ⁇ -2,2-dimethylpropan-l-one
  • Example 8 l-[4,4-Bis-(3,5-di-tert-butyl-4-hydroxyphenylsuIfanyl)piperidin-l-yl]-4- hydroxy-butan-l-one
  • Example 9 4- ⁇ 4-(3,5-Di-tert-butyI-4-hydroxyphenylsulfanyl)-4-[3,5-di-tert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidin-l-yl ⁇ -4-oxo-butyric acid
  • Ex. 9a A 500 mL round bottom flask was charged with 4,4-bis-(3,5-di-?erf-butyl-4- hydroxylphenylsulfanyl)piperidine (Ex. lb, 12.6 g, 22.6 mmol), 150 mL of anhydrous THF and N,N-diisopropylethylamine (5.8 g, 45.2 mmol). Methyl-4-chloro-4-oxobutyrate (3.6 g, 23.7 mmol) was slowly added and the resulting solution was stirred at ambient temperature for 2 h. The reaction was quenched with water and the layers were separated.
  • Ex. 9b A 200 mL round bottom flask was charged with 4-[4,4-bis-(3,5-di-ter?-butyl-4- hydroxylphenylsulfanyl)piperidin-l-yl]-4-oxobutyric acid methyl ester (Ex. 9a, 9.9 g, 14.7 mmol), 50 mL of anhydrous DMF and potassium carbonate (8.1 g, 58.8 mmol). 1- Bromopropanol was added and the mixture was stirred at 85 °C for 3 h. After cooling to ambient temperature, the reaction was quenched with water and extracted with ethyl acetate (3 x 100 mL).
  • Ex. 10a 4-(3,5-Di-ier ⁇ -butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-teri-butyl-4-(3- hydroxypropoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester (Ex. 4, 18.0 g, 25.3 mmol) was charged to a 500 mL round bottom flask containing 300 mL of anhydrous CH2CI2 and N,N-diisopropylethylamine (3.9 g, 30.4 mmol). Methanesulfonyl chloride (3.0 g, 26.7 mmol) was slowly added to the solution.
  • Example 12 Ethyl 2-(4-(3,5-di-tert-butyl-4-hydroxyphenylthio)-4-((4-(3- hydroxypropoxy)-3,5-di-tert-butylphenyl)sulfanyl)piperidin-l-yl)acetate
  • Example 13 ⁇ 4-(3,5-Di-tert-butyl-4-hydroxy-phenyIsulfanyl)-4-[3,5-di-tert-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl ⁇ -acetic acid
  • Example 15 l- ⁇ 4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di-tert-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl ⁇ -2-imidazol-l-yl-ethanone
  • the aqueous layer was extracted with ethyl acetate (3 x 150 mL) and the combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel chromatography (EtOAc/hexanes, 0-5% gradient). The fractions containing the product were concentrated under reduced pressure to dryness and dried in vacuo (15.3 g, 30%).
  • the reaction was partitioned using water/ethyl acetate and the aqueous layer was extracted with additional ethyl acetate (3 x 50 mL). The combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by silica gel chromatography (EtOAc/hexanes, 0-20% gradient). The fractions containing the product were concentrated to dryness and dried in vacuo to yield the title compound (0.54 g,
  • the reaction was partitioned using water/ethyl acetate and the aqueous layer was extracted with additional ethyl acetate (3 x 50 mL). The combined organics were washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by silica gel chromatography (EtOAc/hexanes, 0-20% gradient). The fractions containing the product were concentrated to dryness and dried in vacuo to yield the title compound (0.50 g, 54%), mp 109-11 1 °C (dec).
  • the reaction was partitioned using water/ethyl acetate and the aqueous layer was extracted with additional ethyl acetate (3 x 50 mL). The combined organics were washed with saturated sodium bicarbonate solution, water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was absorbed onto silica gel and purified by silica gel chromatography (MeOH/CH 2 Cl 2 , 0-10% gradient). The fractions containing the product were concentrated to dryness and dried in vacuo to yield the title compound (0.50 g,
  • the pale yellow solution was concentrated under to an oil, which was diluted with 5 mL of anhydrous THF and charged to 100 mL round bottom flask containing 2,6-di-1 ⁇ 2ri-butyl-4-[4-(3,5-di-1 ⁇ 2r/-butyl-4-methoxy-phenylsulfanyl)-piperidin-4-ylsulfanyl]- phenol (Ex. 17, 0.86 g, 1.51 mmol), 20 mL of anhydrous THF and diisopropylethylamine (0.78 g, 6.0 mmol). The resulting dark red solution was stirred at ambient temperature for 1 h.
  • Example 23 [4-(3,5-Di-teri-butyI-4-hydroxy-phenyIsulfanyI)-4-(3,5-di-feri-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-pyrazin-2-yl-methanone
  • Example 27 [4-(3,5-Di-te/*i-butyl-4-hydroxy-phenylsu]fanyl)-4-(3,5-di-iert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-[l-(4-trifluoromethyl-pyrimidin-2-yl)- piperidin-4-yl] -methanone
  • reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with IN HC1, water, brine and dried over sodium sulfate. After concentrating under reduced pressure, the residue was absorbed onto silica gel and purified by silica gel chromatography (EtOAc/hexanes, 10%-50% gradient). The fractions containing the product were concentrated to dryness under reduced pressure and dried in vacuo (0.55 g, 51%), mp 107-1 10 °C.
  • the reaction was quenched with water and extracted with ethyl acetate (3 x 50 mL). The combined organics were washed with IN HC1, water, brine and dried over sodium sulfate. The filtrate was concentrated under reduced pressure. The residue absorbed onto silica gel and purified by silica gel chromatography (EtOAc/hexanes, 10%-50% gradient). The fractions containing the product were concentrated to dryness under reduced pressure and dried in vacuo (0.54g, 54%), mp 116-120 °C. !
  • the reaction mixture was diluted with water (15 mL) and ethyl acetate (30 mL). The organic portion was washed with IN HC1, saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a yellow oil.
  • the crude material was purified by silica gel chromatography (10% EtOAc in hexanes) to provide 0.62 g (72%) of [4-(3,5-di-rer/-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-fer?-butyl-4-methoxy- phenylsulfanyl)-piperidin-l-yl]-acetic acid as a white solid, mp 93 °C.
  • Example 30 l-[4-(3,5-di-ieri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-hydroxy-ethanone
  • the reaction mixture was diluted with water (15 mL) and ethyl acetate (30 mL). The organic portion was washed with IN HCl, saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a yellow oil.
  • the crude material was purified by silica gel chromatography (40% EtOAc in hexanes) to provide 0.67 g (72%) of acetic acid 2-[4-(3,5-di-ier/-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di- eri-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-oxo-ethyl ester as a white solid, mp 118 °C.
  • Example 31 l-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-pyrrolidin-l-yl-ethanone
  • the reaction mixture was diluted with water (15 mL) and ethyl acetate (30 mL). The organic portion was washed with IN HCl, saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to a yellow oil.
  • the crude material was purified by silica gel chromatography (30% EtOAc in hexanes) to provide 1.32 g (81%) of 2-chloro-l-[4-(3,5-di-1 ⁇ 2r -butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-1 ⁇ 2r/-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-ethanone as an off white solid, mp 87 °C.
  • the reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (2 x 15 mL). The organic portion was dried over sodium sulfate and concentrated to a beige oil. The crude material was purified by silica gel chromatography (3% MeOH in dichloromethane) to provide 0.36 g (58%) of the title compound as an off white solid, mp 93 °C.
  • Example 32 l-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-teri-butyI-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-imidazol-l-yI-ethanone
  • the reaction mixture was diluted with an aqueous solution of saturated ammonium chloride (20 mL) and extracted with ethyl acetate (2 15 mL). The organic was washed with 1:1 water:brine solution, dried over Na 2 S0 4 , filtered, concentrated to a brown oil. The crude material was purified by silica gel chromatography (3% MeOH in dichloromethane) to provide 0.31 g (51%) of the title compound as an off white solid, mp 116 °C.
  • Example 33 1- [4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-te *i-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-morpholin-4-yl-ethanone
  • the reaction mixture was quenched with 0.5N HCl and extracted with EtOAc.
  • the organic was washed with saturated sodium bicarbonate, 1 : 1 watenbrine solution, dried over Na 2 S04, filtered, concentrated, and dried.
  • the crude material was purified by silica gel chromatography (3% EtOAc in hexanes) to provide 0.51 g (82%) of the title compound as an off white solid, mp 173 °C.
  • Example 36 l- ⁇ 2-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-oxo-ethyl ⁇ -piperidine-4-carboxylic acid
  • the resulting mixture was stirred at rt and HPLC indicated that the reaction was complete after 18 h.
  • the reaction was acidified to a pH of 3 with 0.5N HCl and extracted with EtOAc (20 mL). The organic portion was washed with water, dried over sodium sulfate and concentrated to an off white foam.
  • the crude material was purified by silica gel chromatography (5% MeOH in dichloromethane). NMR analysis indicated that the material was the salt form; therefore, the isolated product was dissolved in EtOAc and diluted with water. The pH of the mixture was adjusted to 6 with IN HCl.
  • Example 37 4-[4-(3,5-Di-fe/-i-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-ie *i-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-4-oxo-butyric acid
  • Example 38 l-[4-(3,5-Di-tert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-teri'-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-(4-hydroxy-piperidin-l-yl)-ethanone
  • Example 39 l-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-fe/'i-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-(4-hydroxymethyl-piperidin-l-yl)-ethanone
  • the reaction mixture was quenched with 0.5N HCl and extracted with EtOAc.
  • the organic was washed with saturated sodium bicarbonate, 1 :1 watenbrine solution, dried over Na 2 S0 4 , filtered, concentrated, and dried.
  • the crude material was purified by silica gel chromatography (5% MeOH in dichloromethane) to provide 0.41 g (84%) of the title compound as a white solid, mp 110 °C.
  • Example 40 4,4-Bis-(3,5-di-ter/-butyl-4-methoxy-phenylsulfanyl)-piperidine-l- carboxylic acid ethyl ester
  • Ex. 41b In a 100 mL round bottom flask 4,4-bis-(3,5-di-ter/-butyl-4-methoxy- phenylsulfanyl)-piperidine (Ex. 41a, 1.0 g, 1.71 mmol) was combined with anhydrous THF (43 mL) and DIPEA (0.89 mL, 5.12 mmol) and the resulting mixture was treated with bromoacetic acid ethyl ester (0.21 mL, 1.89 mmol). HPLC indicated that the reaction was complete after 18 h. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (30 mL).
  • Example 42 l-[4-(3,5-Di-iert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-tert-butyl-4- methoxy-phenylsulfanyl)-piperidm-l-yl]-2-(2-hydroxymethyl-pyrrolidin-l-yl)-ethanone
  • Example 43 l- ⁇ 2-[4-(3,5-Di-1 ⁇ 2ri'-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-tert-butyI-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-2-oxo-ethyl ⁇ -pyrrolidine-2-carboxylic acid
  • the reaction mixture was concentrated to dryness and diluted with water (10 mL) and EtOAc (25 mL). This mix was acidified to a pH of 2 with IN HCl. The organic portion was collected, washed with 1 :1 water:brine solution, dried over sodium sulfate, concentrated, and dried. The crude material was purified by silica gel chromatography (10%-30% MeOH in dichloromethane) to provide 0.30 g (80%) of the title compound as an off white solid, mp 232 °C.
  • reaction mixture was concentrate in vacuo to provide 0.50 g (100%) of (S)-(+)-2,2-dimethyl-5-oxo-l,3-dioxolane- 4-acetic chloride as an off white solid.
  • the material was carried forward without any further purification.
  • Example 46 l-[4-(3,5-Di-teri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-tert-butyl-4- methoxy-phenylsulfanyl)-piperidin-l-yI]-4-hydroxy-butan-l-one
  • Example 48 l- ⁇ 4-(3,5-Di-fe i-butyl-4-hydroxy-phenylsulfanyl)-4-[3,5-di-1 ⁇ 2ri-butyl-4-(3- hydroxy-propoxy)-phenylsulfanyl]-piperidin-l-yl ⁇ -4-hydroxy-butan-l-one
  • Example 49 4-(3,5-Di-fert-butyl-4-hydroxyphenylsuIfanyl)-4- [3,5-di-fert-butyl-4-(3- pyrazol-l-yl-propoxy)phenylsulfanyl]piperidine-l-carboxylic acid ethyl ester
  • the reaction was acidified with IN HCl and partitioned between H 2 0 (50 mL) and EtOAc (50 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 30 mL). The combined organic cuts were washed with a saturated NaHC0 3 solution (1 x 30 mL), 50% aqueous brine solution (1 x 30 mL), brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 51 l- ⁇ 4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-tert-butyl-4-(3- pyrazol-l-yl-propoxy)phenylsulfanyl]piperidin-l-yl ⁇ -2-hydroxyethanone
  • the reaction was quenched with saturated ammonium chloride (3 mL) and partitioned between H 2 0 (15 mL) and EtOAc (15 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 15 mL). The combined organic cuts were washed with a 50% brine solution (1 x 50 mL), brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 52 ⁇ 4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyI)-4-[3,5-di-teri-butyl-4-(3- pyrazol-l-yI-propoxy)phenylsuIfanyl]piperidin-l-yI ⁇ acetic acid
  • the reaction was quenched with saturated ammonium chloride (3 mL) and partitioned between H 2 0 (15 mL) and EtOAc (15 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 15 mL). The combined organic cuts were washed with a 50% brine solution (1 x 50 mL), brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • the reaction was acidified with IN HC1 and partitioned between H 2 0 (15 mL) and EtOAc (15 mL). The layers were cut and the aqueous layer was extracted with EtOAc (2 x 15 mL). The combined organic cuts were washed with a 50% brine solution (1 x 20 mL), brine (1 x 20 mL), dried over Na 2 S0 , and concentrated under reduced pressure. The crude foam was taken up in hexanes and stirred for 2 h at rt and the resulting precipitate was collected and rinsed with fresh hexanes to afford 0.32 g (95%) of the title compound as an off-white solid, mp 140-143 °C.
  • TBAF (1.44 mL, 1.44 mmol, 1.0 M in THF) was added to the reaction and allowed to stir at rt for 30 min.
  • the reaction was partitioned between H 2 0 (25 mL) and EtOAc (25 mL). The layers were cut and the aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic cuts were washed with a 50% brine solution (1 x 50 mL), brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 54 l-(2- ⁇ 4-(3,5-Di-tert-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-teri-butyl-4- (3-pyrazoI-l-ylpropoxy)phenylsulfanyl]piperidin-l-yl ⁇ -2-oxoethyl)-lH-pyrazole-4- carboxylic acid
  • the reaction was quenched with saturated ammonium chloride (5 mL) and partitioned between H 2 0 (75 mL) and EtOAc (75 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with a 50% brine solution (1 x 50 mL), brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 55 4- [4-(3,5-Di-tert-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-teri-butyl-4- methoxy-phenylsulfanyl)-piperidine-l-carbonyl]-3-ethyl-5-methyl-lH-pyrrole-2- carboxylic acid ethyl ester
  • Example 56 4-[4-(3,5-Di-te7-/-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-teri-butyl-4- methoxy-phenylsulfanyl)piperidine-l-carbonyl]-3-ethyl-5-methyI-lH-pyrrole-2- carboxylic acid
  • Example 57 4-[3,5-Di-tert-butyl-4-(3-carboxy-3-hydroxypropoxy)phenylsulfanyl]-4- (3,5-di-ieri-butyl-4-hydroxyphenylsuIfanyl)piperidine-l-carboxylic acid ethyl ester
  • reaction mixture was concentrated under reduced pressure, redissolved in CH 2 CI 2 , and purified by silica gel chromatography (EtOAc/hexane, 1 :5) to afford a mixture (5.05 g) containing 4- ⁇ 3,5-di-teri- butyl-4-[2-(S)-(2,2-dimethyl-5-oxo-[l,3]-dioxolan-4-yl)ethoxy]-phenylsulfanyl ⁇ -4-(3,5-di- 1 ⁇ 2ri-butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester (85% HPLC) and unreacted starting carbamate.
  • Example 58 4-[3,5-Di-teri-butyl-4-((5 ⁇ -3,4-dihydroxybutoxy)phenylsulfanyl]-4-(3,5-di- teri-butyl-4-hydroxyphenylsulfanyl)piperidine-l-carboxylic acid ethyl ester
  • Example 59 4- ⁇ 2,6-Di-tert-butyl-4-[4-(3,5-di-ieri-butyl-4- hydroxyphenylsulfany ⁇ piperidin ⁇ -ylsulfanyll-phenoxyJbutane- ⁇ -l ⁇ -diol
  • the combined organic extracts were washed with a saturated NaHC0 3 solution, a 10% brine solution, dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • the material was purified by silica gel chromatography (0-10% MeOH/CH 2 Cl 2 ) to afford 0.50 g (58%) of the title compound as a white fluffy foam. !
  • Example 61 4- ⁇ 2,6-Di-teri-butyl-4-[4-(3,5-di-teri-butyl-4-hydroxyphenylsulfanyl)-l-(2- hydroxyacetyl)-piperidin-4-ylsulfanyl]phenoxy ⁇ -(S)-2-hydroxybutyric acid
  • Example 62 [4-[3,5-Di-teri-butyl-4-(4-hydroxybutoxy)phenylsulfanyl]-4-(3,5-di-tert- butyl-4-hydroxy-phenylsulfanyl)piperidin-l-yI] acetic acid
  • Example 66 l-[4-[3,5-Di-fe -i-butyl-4-(4-hydroxy-butoxy)-phenylsulfanyl]-4-(3,5-di-ieri- butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-4-hydroxy-butan-l-one
  • Ex. 67b To a mixture of l-(2-bromoethyl)-lH-pyrazole-3,5-dicarboxylic acid diethyl ester (Ex. 67a, 0.47 g, 1.49 mmol), 2 C0 3 (0.62 g, 4.46 mmol) and KI (0.49 g, 2.97 mmol) in DMF (20 mL) was added 2,6-di-1 ⁇ 2rt-butyl-4-[4-(3,5-di-1 ⁇ 2rt-butyl-4-methoxy- phenylsulfanyl)-piperidin-4-ylsulfanyl]-phenol (Ex. 17, 1.70 g, 2.97 mmol).
  • reaction mixture was allowed to stir at 120 °C for 3 h and poured into water.
  • the resulting aqueous mixture was extracted with EtOAc/z ' -PrOH (4/1, v/v).
  • the combined organic solution was washed with 0.5M HCl, a saturated NaHC0 3 solution, a 10% brine solution, dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 69 5- ⁇ 4-(3,5-Di-feri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-teri-butyl-4-(3- hydroxy-propoxy)phenylsulfanyI]piperidine-l-suIfonyl ⁇ -l-methyHH-pyrrole-2- carboxylic acid
  • Example 70 [4-(3,5-Di-ieri-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-tert-butyl-4- methoxy-phenylsulfanyl)piperidin-l-yl] acetic acid ethyl ester
  • Example 71 2-[4-(3,5-Di-tert-butyl-4-hydroxyphenylsulfanyl)-4-(3,5-di-fe , i-butyl-4- methoxy-phenylsulfanyl)piperidin-l-yl]acetamide
  • Example 72 3-[4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-fe *i-butyl-4- methoxy-phenylsulfanyl)piperidin-l-yl]-3-oxo-propionic acid
  • the reaction was quenched with 0.5N HCl (50 mL) and diluted with EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with saturated NaHC0 3 solution (1 x 50 mL), brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 73 3- ⁇ 4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-tert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-sulfonyl ⁇ thiophene-2-carboxylic acid
  • the reaction was quenched with IN HCl (50 mL) and diluted with H 2 0 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 74 4- ⁇ 4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-te/*i-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-suIfonyl ⁇ -3,5-dimethyl-lH-pyrrole-2- carboxylic acid
  • Example 75 5- ⁇ 4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-iert-butyl-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-sulfonyl ⁇ furan-2-carboxylic acid
  • the reaction was quenched with IN HC1 (50 mL) and diluted with 3 ⁇ 40 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 76 5- ⁇ 4-(3,5-Di-teri-butyl-4-hydroxyphenyIsulfanyl)-4-[3,5-di-teri-butyI-4-(3- hydroxy-propoxy)phenylsulfanyl]piperidine-l-sulfonyl ⁇ 4-methylthiophene-2-carboxylic acid
  • the reaction was quenched with IN HC1 (50 mL) and diluted with 3 ⁇ 40 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Example 77 4- ⁇ 4-(3,5-Di-teri-butyl-4-hydroxyphenylsulfanyl)-4-[3,5-di-te/-i-butyl-4-(3- hydroxy-propoxy)phenylsuIfanyl]piperidine-l-sulfonyl ⁇ -2,5-dimethylfuran-3-carboxylic acid
  • Methyl-4-(chlorosulfonyl)-2,5-dimethyl-3- furoate (0.30 g, 1.2 mmol) was added to the reaction and the resulting solution was stirred at rt for 1 h.
  • the reaction was quenched with IN HCl (50 mL) and diluted with H 2 0 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na 2 S0 4 , and concentrated under reduced pressure.
  • Methyl-5-(chlorosulfonyl)-4-methoxy- thiophene-3-carboxylate (0.33 g, 1.2 mmol) was added to the reaction and the resulting solution was stirred at rt for 2 h.
  • the reaction was quenched with IN HC1 (50 mL) and diluted with H 2 0 (50 mL) and EtOAc (100 mL). The layers were cut and the aqueous layer was extracted with EtOAc (1 x 50 mL). The combined organic cuts were washed with brine (1 x 50 mL), dried over Na 2 SC> 4 , and concentrated under reduced pressure.
  • Example 80 4-(3,5-Di-teri-butyl-4-carboxymethoxy-phenylsulfanyl)-4-(3,5-di-teri-butyl- 4-hydroxy-phenylsulfanyI)-piperidine-l-carboxylic acid ethyl ester
  • Example 81 l-[4,4-Bis-(3,5-di-feri-butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-2- imidazol-l-yl-ethanone
  • Example 82 l-[4,4-Bis-(3,5-di-3 ⁇ 4 i-butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yl]-2- pyrrolidin-l-yl-ethanone
  • Example 83 l-[4,4-Bis-(3,5-di-tei-i-butyl-4-hydroxy-phenylsulfanyl)-piperidin-l-yI]-2- hydroxy-ethanone
  • Example 84 ⁇ 2,6-Di-teri-butyl-4-[4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-l-(2- hydroxy-acetyl)-piperidin-4-ylsulfanyl]-phenoxy ⁇ -acetic acid
  • Ex. 89a 5-[4-(3,5-Di-feri-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-feri-butyl-4-methoxy- phenylsulfanyl)-piperidine-l-sulfonyl]-l -methyl- lH-pyrrole-2-carboxylic acid methyl ester was prepared in an analogous fashion as Ex. 85 using 5-chlorosulfonyl-l -methyl- lH-pyrrole- 2-carboxylic acid methyl ester; white foam in 58% yield.
  • the combined organic phase was washed with brine, dried over MgS0 4 , and concentrated to give a colorless oil which was recrystallized from CH 2 Cl 2 :hexanes to give 0.36 g (82%) of the title compound as a white solid, mp 128-135 °C. !
  • Example 90 [4-(3,5-Di-iert-butyl-4-hydroxy-phenylsulfanyl)-4-(3,5-di-teri-butyI-4- methoxy-phenylsulfanyl)-piperidin-l-yl]-oxo-acetic acid

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Abstract

L'invention concerne des composés, des compositions pharmaceutiques et des méthodes de traitement de troubles inflammatoires, comprenant un composé de formule I, ou son sel de qualité pharmaceutique, son ester, son dérivé ou promédicament de qualité pharmaceutique, où R1, R2, R3, R4, X, Y, W, Z et Q sont tels que définis dans la description.
PCT/US2012/031535 2011-04-01 2012-03-30 Composés contenant un cycle azoté pour le traitement de troubles inflammatoires Ceased WO2012135669A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991001124A1 (fr) * 1989-07-14 1991-02-07 Biodor U.S. Holding Nouveaux agents antiviraux
WO2003099788A1 (fr) * 2002-05-28 2003-12-04 Nippon Chemiphar Co., Ltd. Derives de piperidine
WO2005030721A1 (fr) * 2003-09-30 2005-04-07 Nippon Chemiphar Co., Ltd. Derive de piperidine
JP2009286712A (ja) * 2008-05-28 2009-12-10 Hyks Laboratories Kk スピロキノン化合物及び医薬組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991001124A1 (fr) * 1989-07-14 1991-02-07 Biodor U.S. Holding Nouveaux agents antiviraux
WO2003099788A1 (fr) * 2002-05-28 2003-12-04 Nippon Chemiphar Co., Ltd. Derives de piperidine
WO2005030721A1 (fr) * 2003-09-30 2005-04-07 Nippon Chemiphar Co., Ltd. Derive de piperidine
JP2009286712A (ja) * 2008-05-28 2009-12-10 Hyks Laboratories Kk スピロキノン化合物及び医薬組成物

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