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"Antiinflammatory Agents"

Abstract: The present invention relates to novel azabicyclo derivatives as anti-inflammatory agents. The compounds provided herein can be useful for inhibition and prevention of inflammation and associated pathologies including inflammatory and autoimmune diseases such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis. Also provided herein are pharmacological compositions containing compounds provided herein and associated methods of treating sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis, and other inflammatory and/or autoimmune disorders, using the compounds.

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Patent Information

Application #
Filing Date
19 June 2007
Publication Number
33/2007
Publication Type
INA
Invention Field
BIOTECHNOLOGY
Status
Email
Parent Application

Applicants

RANBAXY LABORATORIES LIMITED
12 FLOOR,DEVIKA TOWER, 6, NEHRU PLACE, NEW DELHI-110019, INDIA

Inventors

1. VENKATA P PALLE,
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA.
2. RAKESH KUMAR SINGH
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA.
3. SANJAY MALHOTRA,
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA.
4. YOGESH BHASKARRAO WAMAN
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA.
5. ASHEANI VERMA
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA.
6. ABHIJIT RAY,
ALL INDIAN NATIONALS,OF RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA.
7. GEETA SHARMA
RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR-18, UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA.

Specification

Field of the Invention The present invention relates to novel azabicyclo derivatives as anti-inflammatory agents. The compounds provided herein can be useful for inhibition and prevention of inflammation and associated pathologies including inflammatory and autoimmune diseases such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis. Also provided herein are pharmacological compositions containing compounds provided herein and associated methods of treating sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis, and other inflammatory and/or autoimmune disorders, using the compounds. Background of the Invention During the last decade, studies have focused on the roles played by cytokines, a unique class of intercellular regulatory proteins, in the pathogenesis of many diseases. Cytokines play a role in initiating, maintaining, and regulating immunological and inflammatory processes. Advances in our understanding of their role in immune and inflammatory disorders have led to the development of cytokine-based therapies, that is, therapies that aim to modulate the activity of specific cytokines. Today, drugs that block inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-a), are being introduced to the market. Elevated levels of proinflammatory cytokines viz TNF-a and IL-lα are associated with the pathogenesis of many immune mediated inflammatory disorders like sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis. Inflammation is regulated by pro- and anti-inflammatory mediators, which include cytokines, eicosanoids, nitric oxide, and reactive oxygen species. The role of these inflammatory mediators in the pathogenesis of both chronic and acute inflammatory diseases is documented. Until a few year s ago, inflammatory disorders were treated primarily with relatively non-selective anti-inflammatory agents, such as corticosteroids and various non-steroidal anti-inflammatory drugs. In recent years, novel therapies have been developed that specifically interfere with the action of selected pro-inflammatory mediators, such as TNFcc and PGE2. These specific anti-inflammatory therapies have been used for the treatment of rheumatoid arthritis, inflammatory bowel disease, and several other inflammatory diseases. The protein-based therapies that inhibit the activities of tumour-necrosis factor-α (TNF-α), including etanercept (Enbrel; Amgen/Wyeth), infliximab (Remicade; Centocor), and adalimumab (Humira; Abbott), have been used for the treatment of autoimmune diseases such as rheumatoid arthritis. However, current injectable therapies have associated limitations and risks, including the potential for increased malignancies and infections and increased congestive heart failure. Studies in rodent models have provided evidence that targeting specific pathways involved in TNF-α activities are effective approaches to interrupting the pro-inflammatory process. Oral small molecules that regulate these pathways could be the next significant advancement in the treatment of chronic inflammatory diseases when used either as a monotherapy or in combination with the current injectables. Studies have now established that the pathogenesis of inflammatory diseases utilizes cytokine-mediated communication between endothelial cells, infiltrating leukocytes, resident macrophages, mast cells, epithelial cells and osteoclasts. The p38 mitogen activated protein kinase (p38MAPK) regulates cytokine levels and therefore plays a central role in both the cellular infiltration and activation responses associated with inflammatory diseases. The p38 MAPK is a member of a large family of MAPK's whose signaling pathways also include the extracellular regulated kinases (ERK) & the c-jun N terminal kinases (INK). MAP kinases are Serine Threonine Kinases that transduce environmental stimuli to the nucleus and they themselves are activated by upstream MAPK kinases by phosphorylation on both Tyrosine and Threonine residues. The MAPK pathways are involved in alterations in cell physiology resulting from a variety of stimuli and control cell death, cell cycle machinery, gene transcription and protein translation. p38α MAPK was first identified as a tyrosine phosphorylated protein in LPS (Lipopolysaccharide) stimulated macrophages. The human p38a MAPK was identified as a target of pyridinyl imidazole compounds (cytokine suppressive anti-inflammatory drugs) that were known to block TNF-a and IL-1 release from LPS stimulated monocytes. After the cloning of first p38MAPK (p38a), additional members of the p38MAPK family were cloned by homology, including the p38ot, p38p and p38y. The p38 pathway controls the activity of multiple transcription factors and the expression of many genes. There is ample evidence implicating a role for p38 in inflammatory processes mediated by IL-1 and TNF-a. Further, p38 inhibitors have been shown to effectively block both TNFa and IL-1 biosynthesis by LPS stimulated human monocytes. In addition, p38MAPk also plays a role in the production of IL-4, IL-6, IL-8 and IL-12. p38MAPk is also critical for cell response to certain cytokines. Treatment of human neutrophils with GM-CSF, TNF-a or TGF-a results in p38 activation. GM-CSF and TNF-a are potent enhancers of neutrophil respiratory activity suggesting a role for p38MAPk in respiratory burst. p38 has also been implicated in the induction of cyclooxygenase-2 (COX-2) in LPS-induced monocytes. COX-2 enzyme is the key enzyme in the production of prostaglandins from arachidonic acid. Inhibitors of p38MAP kinase are also expected to inhibit COX-2 expression. Accordingly, inhibitors of cytokine synthesis would be expected to be effective in disorders currently treated with NSAID's. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease. Compounds which modulate release of one or more of the aforementioned inflammatory cytokines can be useful in treating diseases associated with the release of these cytokines. PCT Application WO 01/44258 discloses bone-targeting groups described as useful for treating a variety of disorders and conditions. PCT Application WO 02/18380, and U.S. Patent Nos. 6,518276 and US 6,506,749 disclose 7-oxopyridopyrimidines said to be inhibitors of cell proliferation. PCT Application WO 03/057165 describes the compositions and methods for prevention and treatment of amyloid-p-peptide related disorders. U.S. Patent No. 6,316,464 discloses compounds as possible p-38 kinase inhibitors. U.S. Patent No. 6,451,804 discloses heteroalkylamino-substituted bicyclic nitrogen heterocycles. U.S. Patent No. 6,696,566 discloses 6-substituted pyrido-pyrimidines described as useful for the treatment of p-38 mediated disorders. U.S. Patent No. 6,479,507 discloses p-38 kinase inhibitors. U.S. Application 2003/0153586 discloses 7-oxo-pyridopyridopyrimidines said to be useful for the treatment of p-38 mediated disorders. U.S. Patent No. 6,630,485 discloses p-38 kinase inhibitors, pharmaceutical compositions containing them, method for their use, and methods for preparing these compounds. Summary of the Invention Azabicyclo derivatives, which can be used for the for inhibition and prevention of inflammation and associated pathologies such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis are provided herein. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides of these compounds having the same type of activity are also provided. Pharmaceutical compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, which may be used for the treatment of inflammatory and autoimmune diseases such as such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis are also provided. Other aspects will be set forth in accompanying description which follows and in part will be apparent from the description or may be learnt by the practice of the invention. In accordance with one aspect, there is provided a compound having the structure of Formula I (Formula Removed) and its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers diastereomers, N-oxides, polymorphs, metabolite. R1 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl. When Rm is oxygen or sulphur, R2 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl. When Rm is -NH, -N-acyl, -N(CN), -N(NO2), -C(R3)2 or -CH(NO2), R2 can be hydroxy, alkoxy, aryloxy, -CHO, -CN, alkyl, alkenyl, alkynyl, cycloalkyl, carboxy, halogen, aryl, aralkyl, acyl, heteroaryl, heterocyclyl, -SO2R5, -COORe, -C(=O)NRxRy, -NRxRy or -OC(=O)NRxRy, -NHC(=O)RX. The symbol — represents a single bond or a double bond. RS can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroarylalkyl or heterocyclylalkyl. can be ^~J (wherein ^—^ represents a cyclic ring having 4 or 5 carbon atoms, k is an integer selected from 0-2, M is O or N, and T is -(CH2)n-, -CH(Q)CH2-, -CH2CH(Q)CH2-, -CH(Q)-, -CH2-O-CH2-, -CH2-NH-CH2-). Rz can be no atom (when M is oxygen), hydrogen or Ru (wherein Ru can be hydroxy, alkoxy, aryloxy, -CHO, -CN, alkyl, alkenyl, alkynyl, cycloalkyl, carboxy, halogen, aryl, aralkyl, acyl, heteroaryl, heterocyclyl, -SO2R5, -COOR6, -C(=O)NRxRy, -NRxRy or -OC(=O)NRxRy or -NHC(=0)RX). n can be an integer selected from 0-3 (wherein when n is zero then T represents a direct bond). R5 can be alkyl, alkenyl, alkynyl, cycloalkyl, -NRpRq (wherein Rp and Rq, can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl, or Rp and Rq may also together join to form a heterocyclyl ring), aryl, aralkyl, heteroaryl, heterocyclyl, heterocyclylalkyl or heteroarylalkyl. R6 can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroarylalkyl or heterocyclylalkyl. Rx and Ry can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, -SO2Rs (wherein RS is the same as defined above), heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl. Q can be alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, aralkyl, heteroarylalkyl or heterocyclylalkyl. In accordance with a second aspect, there are provided methods for the treatment of mammal suffering from inflammation and associated pathologies. In accordance with a third aspect, there are provided methods for the treatment of mammal suffering from inflammatory diseases and associated pathologies including sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis. In accordance with a fourth aspect, there are provided pharmaceutical compositions containing the compounds, and which may also contain pharmaceutically acceptable carriers or diluents, which may be used for the treatment of inflammatory and autoimmune diseases such as such as sepsis, rheumatoid arthritis, inflammatory bowel disease, type-1 diabetes, asthma, chronic obstructive pulmonary disorder, organ transplant rejection and psoriasis. In accordance with a fifth aspect, there are provided processes for the preparation of compounds disclosed herein. In accordance with a sixth aspect, the compounds disclosed herein are screened as p38 kinase inhibitors. The following definitions apply to terms as used herein: The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, -NHC(=O)Rf, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq,, -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NRfRq {wherein Rf and Rq are independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, or -SC^Re (wherein Re is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1 -3 substituents selected from alkyl, carboxy, -NRfRq, -C(=O)NRfRq, -OC(=O) NRfRq, -NHC(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CFs, cyano, and -SC^Re, (wherein Re are the same as defined earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NRa-{wherein Ra is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORf (wherein Rf is the same as defined earlier), SOaRe (where Rg is as defined earlier), or -C(=O)NRfRq (wherein Rf and Rq are as defined earlier)}. Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, -NRfRq, -C (=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier) hydroxy, alkoxy, halogen, CFs, cyano, and -SC^Re (where Re is same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above. The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl groups may be substituted further with one or more substituents selected from alkyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC (=O)Rf, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, s alkoxyamino, nitro, or SC^Re (wherein Re are is same as defined earlier). Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF3, cyano, -NRfRq, -C(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier) and -SO2Re( where Re is same as defined earlier). The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NHC(=0)Rt -NRfRq, -NHC(=O)NRfRq, -C(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), or -SOaRe (wherein Re is as defined earlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CFs, -NRfRq, -C(=0)NRfRq, -NHC(=O)NRfRq,-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), cyano, or -SOaRe (where Re is same as defined earlier). The term "cycloalkyl," unless otherwise specified, refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, which may optionally contain one or more olefinic bonds, unless otherwise constrained by the definition. Such cycloalkyl groups can include, for example, single ring structures, including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and the like, or multiple ring structures, including adamantanyl, and bicyclo [2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, -NRfRq, -NHC (=O) NRfRq, -NHC (-O) Rf, -C (=O) NRfRq, -O-C (=O)NRfRq (wherein Rf and Rq are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or SOa-Re (wherein Re is same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq , -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), cyano or -SOaRe (where Re is same as defined earlier). The term "alkoxy" denotes the group O-alkyl, wherein alkyl is the same as defined above. The term "aryl," unless otherwise specified, refers to carbocyclic aromatic groups, for example, phenyl, biphenyl or napthyl ring and the like, optionally substituted with 1 to 3 substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF3, cyano, nitro, COORe (wherein Re is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=O)Rf, -NRfRq, -C(=O)NRfRq, -NHC(=O)NRfRq, -O-C(=O)NRfRq (wherein Rf and Rq are the same as defined earlier), -SO2R6 (wherein Re is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or amino carbonyl amino. The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O,NorS. The term "aralkyl," unless otherwise specified, refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined below. Examples of aralkyl groups include benzyl, ethylphenyl and the like. The term "aralkenyl," unless otherwise specified, refers to alkenyl-aryl linked through alkenyl (wherein alkenyl is as defined above) portion and the alkenyl portion contains 1 to 6 carbon atoms and aryl is as defined below. The term "aryloxy" denotes the group O-aryl, wherein aryl is as defined above. The term "carboxy," as defined herein, refers to -C(=O)OH. The term "heteroaryl," unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having from 8 to 10 ring atoms, with one or more heteroatom(s) independently selected from N, O or S optionally substituted with 1 to 4 substituent(s) selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl, -NRfRq, CH=NOH, -(CH2)wC(=O)Rg {wherein w is an integer from 0-4 and Rg is hydrogen, hydroxy, ORf, NRfRq, -NHORZ or -NHOH}, -C(=O)NRfRq and -NHC(=O)NRfRq , -SO2R6, -O-C(=O)NRfRq, -O-C(=O)Rf, -O-C(=O)ORf (wherein Re, Rf and Rq are as defined earlier, and Rz is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, the substituents are attached to a ring atom,;'. e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, and the like. The term 'heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, aralkyl, cyano, nitro, oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)Rf, -O-C(=:O)ORf; -C(=0)NRfRq, S02R6, -0-C(0)NRfRq, -NHC(=O)NRfRq, -NRfRq (wherein R6, Rf and Rq are as defined earlier) or guanidine. Heterocyclyl can optionally include rings having one or more double bonds. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl or piperazinyl. "Heteroarylalkyl" refers to alkyl-heteroaryl group linked through alkyl portion, wherein the alkyl and heteroaryl are as defined earlier. "Heterocyclylalkyl" refers to alkyl-heterocyclyl group linked through alkyl portion, wherein the alkyl and heterocyclyl are as defined earlier. "Acyl" refers to -C(=O)R" wherein R" is selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl. "Alkylcarbonyl" refers to -C(=O)R", wherein R" is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl. "Alkylcarboxy" refers to -O-C(=O)R", wherein R" is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl. "Amine," unless otherwise specified, refers to -NH2. "Substituted amine," unless otherwise specified, refers to -N (Rk)2, wherein each Rk independently is selected from hydrogen {provided that both Rk groups are not hydrogen (defined as "amino")}, alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl, acyl, SOaRe (wherein Re is as defined above), -C(=O)NRfRq , NHC(=O)NRfRq, or -NHC(=O)ORf (wherein Rf and Rq are as defined earlier). "Thiocarbonyl" refers to -C(=S)H. "Substituted thiocarbonyl" refers to-C(=S)R", wherein R" is selected from alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl, amine or substituted amine. Unless otherwise constrained by the definition, all substituents optionally may be substituted further by 1-3 substituents selected from alkyl, aralkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF3, cyano, -C(=T)NRfRq, -O(C=O)NRfRq (wherein Rf, Rq and T are the same as defined earlier) and -OC(=T)NRfRq,, -SO2R6 (where Re is the same as defined earlier). The term "leaving group" refers to groups that exhibit or potentially exhibit the properties of being labile under the synthetic conditions and also, of being readily separated from synthetic products under defined conditions. Examples of leaving groups include, but are not limited to, halogen (e.g., F, Cl, Br, I), Inflates, tosylate, mesylates, alkoxy, thioalkoxy, or hydroxy radicals and the like. The term "protecting groups" refers to moieties that prevent chemical reaction at a location of a molecule intended to be left unaffected during chemical modification of such molecule. Unless otherwise specified, protecting groups may be used on groups, such as hydroxy, amino, or carboxy. Examples of protecting groups are found in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd Ed., John Wiley and Sons, New York, N.Y., which is incorporated herein by reference. The species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule. The term "pharmaceutically acceptable salts" refers to derivatives of compounds that can be modified by forming their corresponding acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acids salts of basic residues (such as amines), or alkali or organic salts of acidic residues (such as carboxylic acids), and the like. Detailed Description of the Invention The compounds provided herein may be prepared by techniques well known in the art and familiar to a practitioner skilled in art. In addition, the compounds provided herein may be prepared by processes as described herein, such processes not being the only means by which the compounds described may be synthesised. Further, the various synthetic steps described herein may be performed in alternate sequences in order to give the desired compounds. (Formula Removed) The compounds of Formulae XI, XIa, Xlb, VIIIc, VIIId, VIIIe, XII, Xllb and XIIc may be prepared by following the reaction sequence as depicted in Scheme I. Thus, a compound of Formula II [wherein hal is halogen (Cl, Br or I)] can be reacted with a compound of Formula III (wherein Rd is hydrogen, optionally substituted alkyl, cycloalkyl or aryl give a compound of Formula IV, which can undergo reduction to give a compound of Formula V, which can be further oxidized to give a compound of Formula VI, which can be reacted with an ester of Formula VII (wherein R' is alkyl and RI is the same as defined earlier) to give a compound of Formula VIII, Path a: which can be oxidized to give a compound of Formula IX, which can be reacted with a compound of Formula X [wherein Rp is alkyl, aralkyl, -C(=O)NRxRy (wherein Rx and Rx is the same as defined earlier) or —C(=O)OCH2C6H5 and T & k are the same as defined earlier], to give a compound of Formula XI, which can undergo deprotection (when Rp is aralkyl, -C(=O)NRxRy, -C(=O)OCH2C6H5) to give a compound of Formula XII. The compound of Formula XI can be N-alkylated with a compound of Formula hal-substituted alkyl (wherein hal is Br, Cl, or I) to give a compound of Formula XIa, which can be hydrolyzed to give a compound of Formula Xlb. The compound of Formula XII can be reacted with a compound of Formula Xlla (wherein Rx and Ry are the same as defined earlier) to give a compound of Formula Xllb, which undergoes hydrolysis (when Rx is hydrogen and Ry is ) to give a compound of Formula XIIc. Path b: which can undergo N-derivatization (when Rd is hydrogen) with a compound of Formula °T°V U" (wherein U" is hal-substituted alkyl, -OH(CH2)kN(diethyl), "°^H>W wherein n' is an integer from 1-2, -OH(CH2)kmorpholine wherein k is the same a s defined earlier or HO

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1 4732-delnp-2007-abstract.pdf 2011-08-21
1 4732-delnp-2007-form-2.pdf 2011-08-21
2 4732-delnp-2007-claims.pdf 2011-08-21
2 4732-delnp-2007-form-1.pdf 2011-08-21
3 4732-delnp-2007-correspondence others.pdf 2011-08-21
3 4732-delnp-2007-description (complete).pdf 2011-08-21
4 4732-delnp-2007-correspondence others.pdf 2011-08-21
4 4732-delnp-2007-description (complete).pdf 2011-08-21
5 4732-delnp-2007-claims.pdf 2011-08-21
5 4732-delnp-2007-form-1.pdf 2011-08-21
6 4732-delnp-2007-abstract.pdf 2011-08-21
6 4732-delnp-2007-form-2.pdf 2011-08-21