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"Inhibitors Of Phosphodiesterase Type Iv"

Abstract: The present invention relates to catechol derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV. Compounds disclosed herein can be useful in the treatment of CNS disorders, inflammatory diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn"s disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans. Processes for the preparation of disclosed compounds are provided, as well as pharmaceutical compositions containing the disclosed compounds, and their use as phosphodiesterase (PDE) type IV inhibitors.

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Patent Information

Application #
Filing Date
22 September 2006
Publication Number
14/2008
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

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

Inventors

1. SONALI RUDRA
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
2. NIDHI GUPTA
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
3. LALIT KUMAR BAREGAMA
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
4. RITU AGARWAL
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
5. VINAYAK VASANTRAO KHAIRNAR
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
6. SASWATI CHAKLADAR
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
7. MANDADAPU RAGHU RAMAIAH
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
8. NAGARAJAN MUTHUKAMAL
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
9. SARALA BALACHANDEAN
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
10. SARIKA RAMNANI
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
11. VENKATA P PALLE
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
12. SUNANDA G. DASTIDAR
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
13. ABHIJIT RAY
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA
14. LALITHA VIJAYKRISHNAN
RANBAXY LABORATORIES LIMITED PLOT NO-20 SECTOR-18 UDYOG VIHAR INDUSTRIAL AREA, GURGAON-122001, HARYANA, INDIA

Specification

INHIBITORS OF PHOSPHODIESTERASE TYPE-IV FIELD OF THE INVENTION The present invention relates to catechol derivatives, which can be used as selective inhibitors of phosphodiesterase (PDE) type IV. Compounds disclosed herein can be useful in the treatment of CNS disorders, inflammatory diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans. Processes for the preparation of disclosed compounds are provided, as well as pharmaceutical compositions containing the disclosed compounds, and their use as phosphodiesterase (PDE) type IV inhibitors. BACKGROUND OF THE INVENTION It is known that cyclic adenosine-3',5'-monophosphate (cAMP) exhibits an important role of acting as an intracellular secondary messenger (E.W. Sutherland, and T.W. Roll, Pharmacol.Rev,1960,12, 265). Its intracellular hydrolysis to adenosine 5'-monophosphate (AMP) causes number of inflammatory conditions which are not limited to psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis. The most important role in the control of cAMP (as well as of cGMP) levels is played by cyclic nucleotide phosphodiesterases (PDE) which represent a biochemically and functionally, highly variable superfamily of the enzyme. Eleven distinct families of phosphodiesterases with more than 25 gene products are currently recognized. Although PDE I, PDE II, PDE III, PDE IV, and PDE VII all use cAMP as a substrate, only the PDE IV and PDE VII types are highly selective for hydrolysis of cAMP. Inhibitors of PDE, particularly the PDE IV inhibitors, such as rolipram or Ro-1724 are therefore known as cAMP-enhancers. Immune cells contain type IV and type III PDE, the PDE IV type being prevalent in human mononuclear cells. Thus the inhibition of phosphodiesterase type IV has been a target for modulation and, accordingly, for therapeutic intervention in a range of disease processes. Studies have shown that administering PDE4 inhibitors can have a restorative effect on memory loss in animal models, including those of Alzheimer's disease (Expert Opin. Ther. Targets (2005) 9(6): 1283-1305; Drug Discovery Today, vol. 10, number 22, November 2005). The potential importance of subtypes of PDE4 in terms of development of new inhibitors of PDE4 has recently emerged. In PDE4B-deficient mice, but not those lacking PDE4D, there is a profound reduction in the ability of LPS to generate TNFa from stimulated peripheral blood leukocytes (Jin and Conti, 2002). It would appear that development of more specific PDE4B inhibitors may be useful, since the PDE4B knock-out mice showed reduced duration of xylazine/ketamine-triggered anaesthesia which is used as a surrogate marker for emesis in mice, which do not usually demonstrate vomiting (Robichaud et al., 2002, J. Clin. Invest. 110:1045). The initial observation that xanthine derivatives, theophylline and caffeine inhibit the hydrolysis of cAMP led to the discovery of the required hydrolytic activity in the cyclic nucleotide phosphodiesterase (PDE) enzymes. More recently, distinct classes of PDEs have been recognized (J.A. Bervo and D.H. Reifsnyder, TIPS, 1990, 11,150), and their selective inhibition has led to improved drug therapy (CD. Nicholus, R.A. Challiss and M. Shahid, TIPS, 1991, 12, 19). Thus it was recognized that inhibition of PDE IV could lead to inhibition of inflammatory mediator release (M.W. Verghese et. al, J. Mol. Cell. Cardiol., 1989,12 (Suppl.II), S 61). WO 2004046095 discloses certain aryl acylthiourea derivative and related compounds, which possess antiviral activity. WO 00/35891 discloses certain morpholinone and morpholine derivative, which are selective antagonists for human α1a receptor. WO 2004050024 deals with 3-aminopyrrolidine derivatives and their use as modulators of chemokine receptors. WO 2005/21515 discloses spiro compounds used as phosphodiesterase inhibitors. WO2005/051931 discloses phosphodiesterase inhibitors. SUMMARY OF INVENTION The present invention provides catechol derivatives, which can be used for the treatment of CNS disorders, inflammatory diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans, and the processes for the synthesis of these compounds. 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, which may also contain pharmaceutically acceptable carriers or diluents, can be used for CNS disorders, inflammatory diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans. The present invention encompasses a compound having the structure of Formula I, (Formula Removed) its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers or N-oxides wherein when X is oxygen: Ri can be: hydrogen; alkyl; heterocyclyl; -(CH2)1-4OR/, provided that R2 is also (CH2)M OR' (wherein R' can be alkyl, alkenyl, alkynyl, (un)saturated cycloalkyl, aryl, heterocyclyl or heteroaryl); -C(=O)NRxRy provided that R2 is also -C(=O)NRxRy [wherein RX and Ry can be hydrogen, alkyl, alkenyl of three to six carbon atoms, alkynyl of three to six carbon atoms, cycloalkyl, -SO2R5 (wherein R5 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alkaryl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl), aryl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, and heterocyclylalkyl]; -(CH2)m-C(=O)R3 (wherein m is an integer in the range of 0-2 and R3 represents optionally substituted Rp or Rq, wherein Rp is heterocyclyl or heteroaryl ring wherein the said rings are attached to (CH2)mC(=O) through N, and Rq is heterocyclyl or heteroaryl ring wherein the said rings are attached to -(CH2)mC(=O) through C). R2 can be: -(CH2)mC(=O)R3 (wherein m and R3 are the same as defined earlier); -(CH2)MOR', provided R\ is also (CH2)1-4OR' (wherein R' is same as defined earlier); -C(=O)NRxRy provided R1 is also -C(=O)NRxRy (wherein RX and Ry are same as defined earlier), or R1 and R2 may together form optionally substituted cycloalkyl or heterocyclyl ring wherein the substituents of such a joint R1-R2 ring(s) can be oxo, alkyl, alkenyl, alkynyl, halogen (F, CI, Br, I), nitro, -NH2, -C(=O)NRxRy (wherein RX and Ry are the same as defined earlier), -NHCOOR6 (wherein R6 is alkyl, alkenyl, alkynyl, cycloalkyl, alkaryl, heteroarylalkyl or heterocyclylalkyl), cyano, hydroxy, alkoxy, or substituted amino. R4 can be: hydrogen; alkyl; -OR5 (wherein R5 is the same as defined earlier); halogen (F, CI, Br, I); -NH2, substituted amino; cyano; carboxy; or -C(=O)NRxRy (wherein RX and Ry are the same as defined above), or R2 and R4 may together form optionally substituted 4-12 membered (un)saturated monocyclic or bicyclic ring system fused to ring B having 0-4 heteroatom(s) selected from N, O and S with the proviso that R2 and R4 together does not form -CH2-O-CH2-O-CH2-, wherein the substituents can be one or more of alkyl, halogen (F, CI, Br, I), hydroxy, alkoxy, -NH2 or substituted amino. R7 can be hydrogen, alkyl, alkenyl, alkynyl, -OR5 (wherein R5 is the same as defined earlier), halogen (F, CI, Br, I), cyano, -NH2 or substituted amino. Xi and X2 can be hydrogen, alkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl, -(CH2)gC(=O)NRxRy or -, -S(O)mRs (where R5 is the same as defined above and m is 0,1 or 2). The compounds of the present invention can be used for treating CNS disorders, inflammatory diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans. In accordance with yet another aspect, there are provided processes for the preparation of the compounds as described herein. DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention may be prepared by techniques well known in the art. In addition, the compounds of the present invention may be prepared following a reaction sequence as depicted below. (Formula Removed) The compounds of Formula VI can be prepared by following the procedure as depicted in Scheme I. The reaction comprises deprotecting a compound of Formula la [wherein * refers to chiral centre (racemic or R or S isomer); V is alkyl and VI is cycloalkyl] to give a compound of Formula II, which can be reacted with a compound of Formula III (wherein hal is Br, CI or I; Ryy can be alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)gCOOR3 or -, -S(O)mRs (where R5 is the same as defined above and m is 0,1 or 2). The compounds of the present invention can be used for treating CNS disorders, inflammatory diseases such as, AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease (COPD), psoriasis, allergic rhinitis, shock, atopic dermatitis, Crohn's disease, adult respiratory distress syndrome (ARDS), eosinophilic granuloma, allergic conjunctivitis, osteoarthritis, ulcerative colitis and other inflammatory diseases especially in humans. In accordance with yet another aspect, there are provided processes for the preparation of the compounds as described herein. DETAILED DESCRIPTION OF THE INVENTION The compounds of the present invention may be prepared by techniques well known in the art. In addition, the compounds of the present invention may be prepared following a reaction sequence as depicted below. (Formula Removed) The compounds of Formula VI can be prepared by following the procedure as depicted in Scheme I. The reaction comprises deprotecting a compound of Formula la [wherein * refers to chiral centre (racemic or R or S isomer); V is alkyl and VI is cycloalkyl] to give a compound of Formula II, which can be reacted with a compound of Formula III (wherein hal is Br, CI or I; Ryy can be alkyl, cycloalkyl, alkaryl, heteroaryl, heterocyclyl, heteroarylalkyl, heterocyclylalkyl, -(CH2)gCOOR3 or -

Documents

Application Documents

# Name Date
1 2097-del-2006-abstract.pdf 2011-08-21
1 2097-del-2006-form-2.pdf 2011-08-21
2 2097-del-2006-claims.pdf 2011-08-21
2 2097-del-2006-form-1.pdf 2011-08-21
3 2097-del-2006-correspondence-others.pdf 2011-08-21
3 2097-del-2006-description (complete).pdf 2011-08-21
4 2097-del-2006-correspondence-others.pdf 2011-08-21
4 2097-del-2006-description (complete).pdf 2011-08-21
5 2097-del-2006-claims.pdf 2011-08-21
5 2097-del-2006-form-1.pdf 2011-08-21
6 2097-del-2006-abstract.pdf 2011-08-21
6 2097-del-2006-form-2.pdf 2011-08-21