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WO2009071705A1 - Nouveaux composés utiles pour le traitement de maladies dégénératives et inflammatoires - Google Patents

Nouveaux composés utiles pour le traitement de maladies dégénératives et inflammatoires Download PDF

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Publication number
WO2009071705A1
WO2009071705A1 PCT/EP2008/067046 EP2008067046W WO2009071705A1 WO 2009071705 A1 WO2009071705 A1 WO 2009071705A1 EP 2008067046 W EP2008067046 W EP 2008067046W WO 2009071705 A1 WO2009071705 A1 WO 2009071705A1
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substituted
compound according
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methyl
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Graeme James Dykes
Stephen Robert Fletcher
Nuria Merayo Merayo
Benoit Antoine Schmitt
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Galapagos NV
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Galapagos NV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders

Definitions

  • the present invention relates to compounds that are inhibitors of PDElA, a phosphodiesterase that is involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation.
  • Cartilage is an avascular tissue of which chondrocytes are the main cellular component.
  • the chondrocytes in normal articular cartilage occupy approximately 5% of the tissue volume, while the extra-cellular matrix makes up the remaining 95% of the tissue.
  • the chondrocytes secrete the components of the matrix, mainly proteoglycans and collagens, which in turn supply the chondrocytes with an environment suitable for their survival under mechanical stress.
  • collagen type II together with the protein collagen type IX, is arranged in solid fibril-like structures, which provide cartilage with great mechanical strength.
  • the proteoglycans can absorb water and are responsible for the resilient and shock absorbing properties of the cartilage.
  • cartilage degradation is caused by the secretion of proteases (e.g. collagenases) by inflamed tissues (the inflamed synovium for example).
  • cartilage degradation can also be the result of an injury of the cartilage, due to an accident or surgery, or exaggerated loading or 'wear and tear'.
  • the ability of cartilage tissue to regenerate after such insults is limited. Chondrocytes in injured cartilage often display reduced cartilage synthesizing (anabolic) activity and/or increased cartilage degrading (catabolic) activity.
  • Rheumatoid arthritis is a chronic joint degenerative disease, characterized by inflammation and destruction of the joint structures. When the disease is unchecked, it leads to substantial disability and pain due to loss of joint functionality and even premature death. The aim of an RA therapy, therefore, is not to slow down the disease but to attain remission in order to stop the joint destruction. Besides the severity of the disease outcome, the high prevalence of RA ( ⁇ 0.8% of adults are affected worldwide) means a high socio-economic impact. (For reviews on RA, we refer to Smolen and Steiner (2003); Lee and Weinblatt (2001); Choy and Panayi (2001); O'Dell (2004) and Firestein (2003)).
  • Osteoarthritis also referred to as OA, or wear-and-tear arthritis
  • OA wear-and-tear arthritis
  • the disease mainly affects hands and weight-bearing joints such as knees, hips and spines. This process thins the cartilage.
  • grade I osteoarthritis When the surface area has disappeared due to the thinning, a grade I osteoarthritis is reached; when the tangential surface area has disappeared, grade II osteoarthritis is reached.
  • grade II osteoarthritis There are further levels of degeneration and destruction, which affect the deep and the calcified cartilage layers that border with the subchondral bone.
  • the clinical manifestations of the development of the osteoarthritis condition include: increased volume of the joint, pain, crepitation and functional disability that, lead to pain and reduced mobility of the joints. When disease further develops, pain at rest emerges. If the condition persists without correction and/or therapy, the joint is destroyed leading to disability. Replacement surgery with total prosthesis is then required.
  • Osteoarthritis is difficult to treat. At present, no cure is available and treatment focuses on relieving pain and preventing the affected joint from becoming deformed. Common treatments include the use of non-steroidal anti-inflammatory drugs (NSAID 's). Although the dietary supplements as chondroitin and glucosamine sulphate have been advocated as safe and effective options for the treatment of osteoarthritis, a recent clinical trial revealed that both treatments did not reduce pain associated to osteoarthritis. (Clegg et al, 2006). Taken together, no disease modifying osteoarthritic drugs are available.
  • NSAID 's non-steroidal anti-inflammatory drugs
  • chondral cellular material is taken from the patient, sent to a laboratory where it is expanded. The material is then implanted in the damaged tissues to cover the tissue's defects.
  • Another treatment includes the intra-articular instillation of Hylan G-F 20 (Synvisc,
  • Hyalgan, Artz etc. a substance that improves temporarily the rheology of the synovial fluid, producing an almost immediate sensation of free movement and a marked reduction of pain.
  • Other reported methods include application of tendinous, periosteal, fascial, muscular or perichondral grafts; implantation of fibrin or cultured chondrocytes; implantation of synthetic matrices, such as collagen, carbon fiber; administration of electromagnetic fields. All of these have reported minimal and incomplete effects, resulting in a poor quality tissue that can neither support the weighted load nor allow the restoration of an articular function with normal movement.
  • Stimulation of the anabolic processes, blocking catabolic processes, or a combination of these two, may result in stabilization of the cartilage, and perhaps even reversion of the damage, and therefore prevent further progression of the disease.
  • Various triggers may stimulate anabolic stimulation of chondrocytes.
  • Insulin- like growth factor-I IGF-I is the predominant anabolic growth factor in synovial fluid and stimulates the synthesis of both proteoglycans and collagen.
  • BMP bone morphogenetic protein
  • TGF-b human transforming growth factor-b
  • Adenosine 3', 5'-cyclic monophosphate (cyclic AMP or cAMP) and guanosine 3', 5'- cyclic monophosphate (cyclic GMP or cGMP) are key second messenger molecules in cells which are synthesized by guanylyl and adenylyl cyclases. These molecules, by playing a role as 'relay' on signal transduction pathways, are key in controlling normal and pathological cell responses. Cyclic nucleotide phosphodiesterases (PDE's) are enzymes that hydrolyse cyclic nucleotides and thereby control the cellular levels of these second messenger molecules. Because of their key role in cellular signaling, PDE's are considered new therapeutic targets.
  • PDE's are enzymes that hydrolyse cyclic nucleotides and thereby control the cellular levels of these second messenger molecules. Because of their key role in cellular signaling, PDE's are considered new therapeutic targets.
  • PDE4 and PDE5 are accepted approaches for the treatment of asthma/chronic obstructive pulmonary disease and erectile dysfunction, respectively.
  • pharmaceutical industry has recently deployed a lot of efforts to develop PDE4 inhibitors (e.g. Cilomilast) and PDE5 inhibitors (e.g. sildenafil), some of which are marketed.
  • PDEl enzymes Another feature of PDEl enzymes is their dual substrate specificity as they have the capacity to hydrolyse both cAMP and cGMP (Zhang et al., 2004).
  • the generation of transgenic animals represents the best tool for the understanding of the specific physiological role of individual PDEs.
  • a PDElB knockout mouse has been generated and characterized.
  • PDE1B(-/-) mice showed exaggerated hyperactivity after acute D- methamphetamine administration.
  • PDE1B(-/-) and PDE1B(+/-) mice demonstrated spatial-learning deficits.
  • the current therapies are not satisfactory and therefore there remains a need to identify further compounds that may be of use in the treatment of degenerative joint diseases, e.g. osteoarthritis, rheumatoid arthritis and osteoporosis.
  • the present invention therefore provides compounds, methods for their manufacture and a pharmaceutical comprising a compound of the invention together with a suitable pharmaceutical carrier.
  • the present invention also provides for the use of a compound of the invention in the preparation of a medicament for the treatment of degenerative joint diseases.
  • the present invention is based on the discovery that inhibitors of PDElA are useful for the treatment of diseases involving cartilage degradation, joint degradation and/or inflammation, for example osteoarthritis.
  • the present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for treating diseases involving cartilage degradation, joint degradation and/or inflammation by administering a compound of the invention.
  • the present invention relates to compounds having anti-inflammatory properties, according to formula (I):
  • CyI is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl
  • R 1 is H, substituted or unsubstituted alkyl
  • Cy2 is substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl
  • R 4 is H, or alkyl; and ml is 0, 1, 2, 3, or 4; provided that when CyI is heterocycloalkyl and the heterocycloalkyl group is joined to -(CH 2 )ml- via a N atom of heterocycloalkyl group then ml is 2, 3 or 4; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or isotopic variants thereof, stereoisomers or tautomers thereof.
  • R 1 is alkyl. In another embodiment R 1 is Me.
  • Cy2 is substituted or unsubstituted aryl. In another embodiment Cy2 is substituted or unsubstituted heteroaryl.
  • R 4 is alkyl.
  • Another aspect of this invention relates to the use of the present compound in a therapeutic method, a pharmaceutical composition, and the manufacture of such composition, useful for the treatment of a disease involving inflammation, and in particular, a disease characteristic of abnormal PDElA activity.
  • This invention also relates to processes for the preparation of the present compounds.
  • Figure 1 Shows the mechanism of the primary screening assay using the cAMP dynamic htrf kit from Cisbio.
  • analogue means one analogue or more than one analogue.
  • 'Acyl' or 'Alkanoyl' refers to a radical -C(O)R 20 , where R 20 is hydrogen, Ci-C 8 alkyl, C 3 -
  • Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl.
  • Exemplary 'acyl' groups are -C(O)H, -C(O)-Ci-C 8 alkyl, -C(O)-(CH 2 ) t (C 6 -Ci 0 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 X(C 3 -Ci 0 cycloalkyl), and -C(O)-(CH 2 ) t (4- 10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.
  • 'Substituted Acyl' or 'Substituted Alkanoyl' refers to a radical -C(O)R 21 , wherein R 21 is independently
  • Ci-C 8 alkyl substituted with halo or hydroxy; or • C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C 1 -C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'Acylamino' refers to a radical -NR 22 C(O)R 23 , where R 22 is hydrogen, Ci-C 8 alkyl, C 3 -
  • Exemplary 'acylamino' include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.
  • Exemplary 'acylamino' groups are -NR 21 C(O)-Ci-C 8 alkyl, -NR 2r C(O)-(CH 2 ) t (C 6 -Ci 0 aryl), -NR 2r C(O)-(CH 2 ) t (5-10 membered heteroaryl), -NR 2r C(O)-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -NR 21 C(O)-(CH 2 ) ⁇ - 10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R 21 independently represents H or Ci-C 8 alkyl.
  • 'Substituted Acylamino' refers to a radical -NR 24 C(O)R 25 , wherein:
  • R 24 is independently
  • R 25 is independently
  • alkoxy' refers to the group -OR 26 where R 26 is Ci-C 8 alkyl.
  • Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.
  • Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.
  • Substituted alkoxy' refers to an alkoxy group substituted with one or more of those groups recited in the definition of "substituted” herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -Ci 0 aryl, -O- aryl, carboxyl, cyano, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thio-0-aryl, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl- S(O) 2 -.
  • Exemplary 'substituted alkoxy' groups are -0-(CH 2 )t(C 6 -Cio aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -O-(CH 2 ) t (4- 10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • Particular exemplary 'substituted alkoxy' groups are OCF 3 , OCH 2 CF 3 , OCH 2 Ph, OCH 2 -cyclopropyl, OCH 2 CH 2 OH, OCH 2 CH 2 NMe 2 .
  • Alkoxycarbonyl' refers to a radical -C(O)-OR 27 where R 27 represents an Ci-C 8 alkyl, C 3 -
  • alkoxycarbonyl groups are C(O)O-Ci-Cg alkyl, -C(O)O- (CH 2 WC 6 -CiO aryl), -C(O)O-(CH 2 ) t (5-10 membered heteroaryl), -C(O)O-(CH 2 WC 3 -Ci 0 cycloalkyl), and -C(O)O-(CH 2 ) t (4- 10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.
  • 'Substituted Alkoxycarbonyl' refers to a radical -C(O)-OR 28 where R 28 represents:
  • '-O-arylcarbonyl' refers to a radical -C(O)-OR 29 where R 29 represents an C 6 -Ci 0 aryl, as defined herein.
  • R 29 represents an C 6 -Ci 0 aryl, as defined herein.
  • Exemplary "-O-arylcarbonyl” groups is -C(O)O-(C 6 -Ci 0 aryl).
  • Substituted -O-arylcarbonyl' refers to a radical -C(O)-OR 30 where R 30 represents a
  • Hetero-O-arylcarbonyl' refers to a radical -C(O)-OR 31 where R 31 represents a 5-10 membered heteroaryl, as defined herein
  • Hetero-O-arylcarbonyl refers to a radical -C(O)-OR 32 where R 32 represents a:
  • 'Alkyl' means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms.
  • Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms.
  • Exemplary straight chained groups include methyl, ethyl n-propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso-butyl, t-butyl and isoamyl.
  • Substituted alkyl' refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of "substituted” herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (- O-acyl or -OC(O)R 20 ), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH- C(O)-OR 27 ), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(O)-NR 2 ), aminocarbonylamino (-NR -C(O)-NR 2 ), aminocarbonyloxy (-O-C(O)-NR 2) , aminosulfonyl
  • 'substituted alkyl' refers to a Ci-C 8 alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR " SO 2 R “ , -SO 2 NR “ R “ , -C(O)R “ , -C(O)OR “ , -OC(O)R “ , - NR '” C(O)R “ , -C(O)NR R “ , -NR “ R “ , or -(CR '” R “” ) m OR " ; wherein each R " is independently selected from H, Ci-C 8 alkyl, -(CH 2 XC 6 -Ci 0 aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 XC 3 -Ci 0 cycloalkyl), and -(CH 2 ) t (4- 10
  • 'Amino' refers to the radical -NH 2 .
  • 'Substituted amino' refers to an amino group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to the group -N(R 33 ) 2 where each R is independently selected from:
  • Ci-C 8 alkyl substituted with halo or hydroxy
  • -N(R 33 ) 2 is an amino group.
  • exemplary 'substituted amino' groups are -NR 33' -C r C 8 alkyl, -NR 33' -(CH 2 ) t (C 6 -Ci 0 aryl), -NR 33' -(CH 2 ) t (5-10 membered heteroaryl), -NR 33' -(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -NR 33' -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R 33 independently represents H or Ci- C 8 alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstitute
  • substituted amino includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below.
  • 'Alkylamino' refers to the group -NHR 34 , wherein R 34 is Ci-C 8 alkyl.
  • Substituted Alkylamino' refers to the group -NHR 35 , wherein R 35 is Ci-C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • Alkylarylamino' refers to the group -NR 36 R 37 , wherein R 36 is C 6 -Ci 0 aryl and R 37 is C r
  • Substituted Alkylarylamino' refers to the group -NR 38 R 39 , wherein R 38 is C 6 -Ci 0 aryl and
  • R 39 is Ci-C 8 alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, cyano, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'Arylamino' means a radical -NHR 40 where R 40 is selected from C 6 -Ci 0 aryl and 5-10 membered heteroaryl as defined herein.
  • Substituted Arylamino' refers to the group -NHR 41 , wherein R 41 is independently selected from C 6 -Ci 0 aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, cyano, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'Dialkylamino' refers to the group -NR 42 R 43 , wherein each of R 42 and R 43 are independently selected from Ci-C 8 alkyl.
  • 'Substituted Dialkylamino' refers to the group -NR 44 R 45 , wherein each of R 44 and R 45 are independently selected from Ci-C 8 alkyl; and the alkyl group is independently substituted with halo, hydroxy, Cs-Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted C r4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'Diarylamino' refers to the group -NR 46 R 47 , wherein each of R 46 and R 47 are independently selected from C 6 -Ci 0 aryl.
  • Aminosulfonyl or “Sulfonamide” refers to the radical -S(O 2 )NH 2 .
  • Substituted aminosulfonyl or “substituted sulfonamide” refers to a radical such as -
  • each R 48 is independently selected from:
  • Ci-C 8 alkyl C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • 'Aralkyl' or 'arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.
  • 'Substituted Aralkyl' or 'substituted arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of any aryl group present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, cyano, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually 6 to 10. Where the aryl group is a monocyclic ring system it preferentially contains 6 carbon atoms.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene.
  • Particularly aryl groups include phenyl
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent.
  • 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, Ci-Cg alkyl, Ci-Cg haloalkyl, Ci-Cg haloalkoxy, cyano, hydroxy, Ci-C 8 alkoxy, and amino.
  • R 49 and R 50 may be hydrogen and at least one of R 49 and R 50 is each independently selected from Ci-Cg alkyl, 4-10 membered heterocycloalkyl, alkanoyl, Ci-Cg alkoxy, hetero-O-aryl, alkylamino, arylamino, heteroarylamino, NR 51 COR 52 , NR 51 SOR 52 NR 51 SO 2 R 52 , COOalkyl,
  • COOaryl CONR 51 R 52 , CONR 51 OR 52 , NR 51 R 52 , SO 2 NR 51 R 52 , S-alkyl, SOalkyl, S0 2 alkyl, Saryl, SOaryl,
  • R 49 and R 50 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S.
  • R 51 , and R 52 are independently hydrogen, Q-Cg alkyl, Ci-C 4 haloalkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, substituted aryl, 5-10 membered heteroaryl.
  • Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.
  • Substituted Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, cyano, unsubstituted Ci-C 4 alkoxy, unsubstituted Cr 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'Azido' refers to the radical -N 3 .
  • Carbamoyl or amido' refers to the radical -C(O)NH 2 .
  • 'Substituted Carbamoyl or substituted amido' refers to the radical -C(O)N(R 53 ) 2 wherein each R 53 is independently
  • Ci-C 8 alkyl C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • Exemplary 'Substituted Amido / Carbamoyl' groups are -C(O) NR 53' -C r C 8 alkyl, -C(O)NR 53' - (CH 2 X(C 6 -Ci 0 aryl), -C(O)N 53' -(CH 2 ) t (5-10 membered heteroaryl), -C(O)NR 53' -(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -C(O)NR 53 -(CH 2 ) t (4- 10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R 53 independently represents H or Ci-C 8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted C 1 -C 4 al
  • 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • 'Substituted cycloalkyl' refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent.
  • 'Cyano' refers to the radical -CN.
  • 'Halo' or 'halogen' refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.
  • Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings.
  • Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole.
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • Examples of representative aryl having hetero atoms containing substitution include the following:
  • each W is selected from C(R 54 ) 2 , NR 54 , O and S; and each Y is selected from carbonyl, NR 54 , O and S; and R 54 is independently hydrogen, Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl.
  • heteroaryls include the following: wherein each Y is selected from carbonyl, N, NR 55 , O and S; and R 55 is independently hydrogen, Ci-Cg alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl.
  • R 55 is independently hydrogen, Ci-Cg alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, and 5-10 membered heteroaryl.
  • the term 'heterocycloalkyl' refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1 -piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.
  • thiomorpholine and its S-oxide and S,S-dioxide particularly thiomorpholine
  • Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine.
  • heterocycloalkyl groups are shown in the following illustrative examples:
  • each W is selected from CR 56 , C(R 56 ) 2 , NR 56 , O and S; and each Y is selected from NR 56 , O and S; and R 56 is independently hydrogen, Ci-Cg alkyl, C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -CiO aryl, 5-10 membered heteroaryl,
  • These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy (-O-acyl or - OC(O)R 20 ), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (-NR -alkoxycarbonyl or -NH-C(O)-OR 27 ), amino, substituted amino, aminocarbonyl (amido or -C(O)-NR 2 ), aminocarbonylamino (-NR -C(O)- NR 2
  • 'Nitro' refers to the radical -NO 2 .
  • 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.
  • substituent group or groups are selected from: halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR " SO 2 R “ , -SO 2 NR R “ , -C(O)R “ , -C(O)OR “ , -OC(O)R “ , - NR '" C(O)R “ , -C(O)NR R “ , -NR “ R “ , -(CR “' R “' ) m OR " , wherein, each R " is independently selected from H, Ci-C 8 alkyl, -(CH 2 ) t (C 6 -Ci 0 aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and - (CH 2 ) t (4-10 membered heterocycloalkyl), wherein
  • any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • Each R independently represents H or Ci-C 6 alkyl.
  • Substituted sulfanyl refers to the group -SR 61 , wherein R 61 is selected from:
  • Ci-C 8 alkyl C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • Exemplary 'substituted sulfanyl' groups are -S-(Ci-C 8 alkyl) and -S-(C 3 -Ci 0 cycloalkyl),
  • t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C 4 haloalkyl, unsubstituted Ci-C 4 hydroxyalkyl, or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • 'substituted sulfanyl' includes the groups 'alkylsulfanyl' or 'alkylthio', 'substituted alkylthio' or 'substituted alkylsulfanyl', 'cycloalkylsulfanyl' or 'cycloalkylthio', 'substituted cycloalkylsulfanyl' or 'substituted cycloalkylthio', 'arylsulfanyl' or 'arylthio' and 'heteroarylsulfanyl' or 'heteroarylthio' as defined below.
  • 'Alkylthio' or 'Alkylsulfanyl' refers to a radical -SR 62 where R 62 is a Ci-C 8 alkyl or group as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio and butylthio.
  • 'Substituted Alkylthio'or 'substituted alkylsulfanyl' refers to the group -SR 63 where R 63 is a Ci-C 8 alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylthio' or 'Cycloalkylsulfanyl' refers to a radical -SR 64 where R 64 is a C 3 -Ci 0 cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylthio, cyclohexylthio, and cyclopentylthio.
  • 'Substituted cycloalkylthio' or 'substituted cycloalkylsulfanyl' refers to the group -SR 65 where R 65 is a C 3 -Ci 0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylthio' or 'Arylsulfanyl' refers to a radical -SR 66 where R 66 is a C 6 -Ci 0 aryl group as defined herein.
  • 'Heteroarylthio' or 'Heteroarylsulfanyl' refers to a radical -SR 67 where R 67 is a 5-10 membered heteroaryl group as defined herein.
  • Substituted sulfmyl' refers to the group -S(O)R 68 , wherein R 68 is selected from:
  • Ci-Cg alkyl C3-C 1 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • Exemplary 'substituted sulfmyl' groups are -S(O)-(Ci-C 8 alkyl) and -S(O)-(C 3 -Ci 0 cycloalkyl), -S(O)-(CH 2 ) t (C 6 -Ci 0 aryl), -S(O)-(CH 2 ) t (5-10 membered heteroaryl), -S(O)-(CH 2 ) t (C 3 -Ci 0 cycloalkyl), and -S(O)-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy, unsubstituted Ci-C
  • Ci-C 4 hydroxyalkyl or unsubstituted Ci-C 4 haloalkoxy or hydroxy.
  • substituted sulfmyl includes the groups 'alkylsulfinyl', 'substituted alkylsulfinyl', 'cycloalkylsulfinyl', 'substituted cycloalkylsulfinyl', 'arylsulfinyl' and 'heteroarylsulfinyl' as defined herein.
  • Alkylsulfinyl refers to a radical -S(O)R 69 where R 69 is a Ci-C 8 alkyl group as defined herein.
  • Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.
  • Substituted Alkylsulfinyl refers to a radical -S(O)R 70 where R 70 is a C r C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfinyl' refers to a radical -S(O)R 71 where R 71 is a C 3 -Ci 0 cycloalkyl or group as defined herein.
  • Representative examples include, but are not limited to, cyclopropylsulfinyl, cyclohexylsulfinyl, and cyclopentylsulfinyl.
  • cycloalkylsulfinyl refers to the group -S(O)R 72 where R 72 is a C 3 -Ci 0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylsulfinyl' refers to a radical -S(O)R 73 where R 73 is a C 6 -Ci 0 aryl group as defined herein.
  • Heteroarylsulfinyl' refers to a radical -S(O)R 74 where R 74 is a 5-10 membered heteroaryl group as defined herein.
  • Substituted sulfonyl' refers to the group -S(O) 2 R 75 , wherein R 75 is selected from: • Ci-C 8 alkyl, C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • Exemplary 'substituted sulfonyl' groups are -S(O) 2 -(Ci-C 8 alkyl) and -S(O) 2 -(C 3 -Ci 0 cycloalkyl), -S(O) 2 -(CH 2 ) t (C 6 -Ci 0 aryl), -S(O) 2 -(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -(CH 2 WC 3 -Ci 0 cycloalkyl), and -S(O) 2 -(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C 4 alkyl, halo, unsubstituted Ci-C 4 alkoxy,
  • substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.
  • Alkylsulfonyl refers to a radical -S(O) 2 R 76 where R 76 is an Ci-C 8 alkyl group as defined herein.
  • Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.
  • Substituted Alkylsulfonyl refers to a radical -S(O) 2 R 77 where R 77 is an Q-C 8 alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Cycloalkylsulfonyl' refers to a radical -S(O) 2 R 78 where R 78 is a C 3 -Ci 0 cycloalkyl or group as defined herein.
  • Representative examples include, but are not limited to, cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclopentylsulfonyl.
  • cycloalkylsulfonyl refers to the group -S(O) 2 R 79 where R 79 is a C 3 -Ci 0 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.
  • 'Arylsulfonyl' refers to a radical -S(O) 2 R 80 where R 80 is an C 6 -Ci 0 aryl group as defined herein.
  • Heteroarylsulfonyl refers to a radical -S(O) 2 R 81 where R 81 is an 5-10 membered heteroaryl group as defined herein.
  • 'Sulfo' or 'sulfonic acid' refers to a radical such as -SO 3 H.
  • 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(O) 2 OR 82 , wherein R 82 is selected from:
  • Ci-C 8 alkyl C 3 -Ci 0 cycloalkyl, 4-10 membered heterocycloalkyl, C 6 -Ci 0 aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or
  • Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(O) 2 -O-(Ci-C 8 alkyl) and -S(O) 2 -O-(C 3 -Ci 0 cycloalkyl), -S(O) 2 -O-(CH 2 WC 6 -Ci 0 aryl), -S(O) 2 -O-(CH 2 ) t (5-10 membered heteroaryl), -S(O) 2 -O-(CH 2 X(C 3 -Ci 0 cycloalkyl), and -S(O) 2 -O-(CH 2 ) t (4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 al
  • 'Thiol' refers to the group -SH.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • [00112] 'Pharmaceutically acceptable means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.
  • 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts.
  • such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • 'Pharmaceutically acceptable vehicle refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • 'Prodrugs' refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated.
  • Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.
  • 'Subject' includes humans.
  • the terms 'human', 'patient' and 'subject' are used interchangeably herein.
  • 'Therapeutically effective amount means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the "therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.
  • 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease.
  • prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.
  • 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof).
  • 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject.
  • 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • "treating" or "treatment” relates to slowing the progression of the disease.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci to C 8 alkyl, C 2 -C 8 alkenyl, aryl, C 7 - Ci 2 substituted aryl, and C 7 -Co arylalkyl esters of the compounds of the invention.
  • the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon- 13 ( 13 C), nitrogen- 15 ( 15 N), or the like.
  • the following atoms, where present, may vary, so that for example, any hydrogen may be 2 HIO, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon- 14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.
  • 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H).
  • enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base.
  • Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • R R
  • S S
  • the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof.
  • the methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.
  • the compounds of the present invention may be described generally as pyrazolo[4,3- d]pyrimidin-7(6H)-ones substituted in the 5-position.
  • the present invention relates to compounds having anti-inflammatory properties, according to formula (I):
  • CyI is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
  • R 1 is H, substituted or unsubstituted alkyl;
  • Cy2 is substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl
  • R 4 is H, or alkyl
  • ml is 0, 1, 2, 3, or 4; provided that when CyI is heterocycloalkyl and the heterocycloalkyl group is joined to -(CH 2 )ml- via a N atom of heterocycloalkyl group then ml is 2, 3 or 4; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof or isotopic variants thereof, stereoisomers or tautomers thereof.
  • R 1 is alkyl. In another embodiment R 1 is Me.
  • Cy2 is substituted or unsubstituted aryl. In another embodiment Cy2 is substituted or unsubstituted heteroaryl.
  • R 1 is H or alkyl.
  • R 1 is Me
  • Cy2 is substituted or unsubstituted aryl or heteroaryl.
  • Cy2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl.
  • Cy2 is substituted or unsubstituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, and oxazolyl.
  • R 4 is alkyl.
  • R 4 is Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, n-pentyl, CH 2 CH(Me)Me, CH 2 CH 2 -t-Bu, CH 2 CH(Me)CH 2 Me, CH 2 CH(Et)CH 2 Me, or
  • ml is 0, 1 or 2. In another embodiment, ml is 1 or 2. In yet another embodiment ml is 1.
  • Ak is as described for formula Ia; Cy2 is substituted or unsubstituted aryl or heteroaryl; and R 4 is alkyl.
  • Cy2 is phenyl unsubstituted or phenyl substituted with alkyl, haloalkyl, halo, alkoxy, amino, aminoalkyl, cyano, hydroxyl, or haloalkoxy.
  • Cy2 is phenyl substituted with Me, CF 3 , OMe, Cl, F, CN, OH, or OCF 3 .
  • Cy2 is pyridyl unsubstituted or pyridyl substituted with alkyl, haloalkyl, halo, alkoxy, amino, aminoalkyl, cyano, hydroxyl, or haloalkoxy.
  • Cy2 is pyridyl substituted with Me, CF 3 , OMe, Cl, F, CN, OH, or OCF 3 .
  • Cy2 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, and oxazolyl.
  • R 4 is alkyl.
  • R 4 is Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, n-pentyl, CH 2 CH(Me)Me, CH 2 CH 2 -t-Bu,
  • R 4 is n-
  • Ak is Me, Et, n-Pr, i-Pr, n-
  • Ak is n-Pr.
  • each of R 4 , and Ak is n-Pr.
  • CyI is substituted or unsubstituted aryl.
  • ml is 1 or 2.
  • the compound is according to formulae Ilia or IHb:
  • Ar is substituted or unsubstituted phenyl
  • Cy2 is aryl or heteroaryl
  • R 4 is alkyl
  • Ar is unsubstituted phenyl.
  • Ar is phenyl substituted with one or more groups selected from alkyl, halo, haloalkyl, and alkoxy. [00161] In another embodiment Ar is phenyl substituted with one or more groups selected from
  • Ar is phenyl substituted with cycloalkyl, heterocycloalkyl, aryl or heteroaryl.
  • Ar is phenyl substituted piperidinyl, piperazinyl, and morpholinyl.
  • Ar is phenyl substituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, and oxazolyl.
  • Ar is phenyl substituted pyridyl, and pyrimidinyl.
  • Cy2 and R 4 are as described for formula Ilia; and each of R 3b and R 3c is independently H, alkyl, halo, haloalkyl, or alkoxy. [00167] In one embodiment, with respect to compounds of formula IVa, one of R 3b and R 3c is Me,
  • R 3b is H; and R 3c is Me,
  • R 3b is Me, F, Cl, CF 3 ,
  • both R 3b and R 3c are independently F, Cl, OMe, CF 3 , or OEt. In another embodiment, both R 3b and R 3c are Cl. In another embodiment, both R 3b and R 3c are F. In another embodiment, both R 3b and R 3c are OMe. In another embodiment, both R 3b and R 3c are CF 3 .
  • R 3b is substituted or unsubstituted aryl, heterocycloalkyl or heteroaryl.
  • R 3b is selected from substituted or unsubstituted piperidinyl, piperazinyl, and morpholinyl.
  • R 3b is selected from substituted or unsubstituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, and oxazolyl.
  • R 3b is selected from substituted or unsubstituted pyridyl, and pyrimidinyl.
  • the compound is according to formulae Va, Vb, Vc, Vd, Ve, Vf, Vg, or Vh:
  • CyI is substituted or unsubstituted heteroaryl.
  • the compound is according to formulae Via or VIb:
  • HetAr is substituted or unsubstituted heteroaryl
  • R 4 is alkyl
  • HetAr is unsubstituted pyridyl.
  • HetAr is pyridyl substituted with one or more groups selected from alkyl, halo, haloalkyl, and alkoxy.
  • HetAr is pyridyl substituted with cycloalkyl, heterocycloalkyl, aryl or heteroaryl.
  • the compound is according to formula Vila or VIIb: wherein:
  • Cy2 and R 4 are as described for formula Via; and each of R 3b and R 3c is independently H, alkyl, halo, haloalkyl, or alkoxy.
  • R 3c is Me, F, Cl, CF 3 , OMe, or OEt and the other is H.
  • R 3c are independently F, Cl, OMe, CF 3 , or OEt.
  • R 3b is substituted or unsubstituted aryl, heterocycloalkyl or heteroaryl.
  • R 3b is selected from substituted or unsubstituted piperidinyl, piperazinyl, and morpholinyl.
  • R 3b is selected from substituted or unsubstituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, and oxazolyl.
  • R 3b is selected from substituted or unsubstituted pyridyl, and pyrimidinyl.
  • the compound is according to formula IXa, IXb, IXc, IXd, IXe, IXf, IXg, or IXh: wherein Cy2 and R 4 are as described for formula Via.
  • the compound is according to formula Xa, Xb, Xc, Xd, Xe, Xf, Xg, or Xh:
  • HetAr is selected from substituted or unsubstituted pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, and oxazolyl.
  • HetAr is selected from pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, and oxazolyl; substituted with one or more groups selected from Ci-Ce alkyl, halo, haloalkyl, and phenyl.
  • the HetAr is mono substituted and the substitution is selected from Ph, Me, CF 3 , and halo.
  • the HetAr is di substituted and the substitution is selected from Ph, Me and CF 3 .
  • the compound is according to formulae XIa, XIb, XIc, XId, or XIe:
  • Cy2 and R are as as described for formula Via; and R is H, alkyl or haloalkyl.
  • Cy2 is phenyl unsubstituted or phenyl substituted with alkyl, haloalkyl, halo, alkoxy, amino, aminoalkyl, cyano, hydroxyl, or haloalkoxy.
  • Cy2 is phenyl substituted with Me, CF 3 , OMe, Cl, F, CN, OH, or OCF 3 .
  • Cy2 is pyridyl unsubstituted or pyridyl substituted with alkyl, haloalkyl, halo, alkoxy, amino, aminoalkyl, cyano, hydroxyl, or haloalkoxy.
  • Cy2 is pyridyl substituted with Me, CF 3 , OMe, Cl, F, CN, OH, or OCF 3 .
  • Cy2 is pyrazolyl, imidazolyl, thiophen, or pyrrolyl.
  • R 4 is Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, n-pentyl, CH 2 CH(Me)Me, CH 2 CH 2 -t-Bu, CH 2 CH(Me)CH 2 Me, CH 2 CH(Et)CH 2 Me, or
  • Cy2 is sublstituted phenyl and R 4 is n-Pr.
  • the compound is selected from 5-(dipropylamino)- 1 -methyl-3-phenyl- lH-pyrazolo[4,3-d]pyrimidin-7(6H)-one;
  • a compound for use according to the invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. It will be understood by a person of skill in the art that the present invention includes both the racemic mixture and each enantiomer in isolated form. A compound according to an embodiment of the invention may be in trans or cis form.
  • the present invention also extends to a prodrug of a compound according to an embodiment of the invention such as an ester or amide thereof.
  • a prodrug is a compound that may be converted under physiological conditions or by solvolysis to a compound according to an embodiment of the invention or to a pharmaceutically acceptable salt of a compound according to an embodiment of the invention.
  • a prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention.
  • 'Pharmaceutically acceptable prodrugs' refers to those prodrugs of the compounds useful in the present invention, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients with undue toxicity, irritation, allergic response commensurate with a reasonable benefit/risk ratio, and effective for their intended use of the compounds of the invention.
  • the term 'prodrug' means a compound that is transformed in vivo to yield an effective compound useful in the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • the compounds bearing metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group, thus, such compounds act as prodrugs.
  • a thorough discussion is provided in Design of Prodrugs, H. Bundgard, ed., Elsevier (1985); Methods in Enzymology; K. Widder et al, Ed., Academic Press, 42, 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgard, ed., Chapter 5; "Design and Applications of Prodrugs” 113-191 (1991); Advanced Drug Delivery Reviews, H.
  • compositions suitable for administration to a patient in need thereof typically comprise at least one compound of the invention and at least one pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include solid carriers such as lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia or the like; and liquids such as vegetable oils, arachis oil and sterile water, or the like, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • compositions are not to be construed as limiting.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include 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 agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • compositions suitable for injectable use include sterile aqueous solutions
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, 'chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a compound according to an embodiment of the invention) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • active compound e.g., a compound according to an embodiment of the invention
  • dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the particular methods of preparation are vacuum drying and freeze-drying which yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. [00209] Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like 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; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • 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.
  • 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) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • a compound according to an embodiment of the invention may be provided as a salt, preferably as a pharmaceutically acceptable salt of compounds of formula I or Formulae Ia-Ih.
  • pharmaceutically acceptable salts of these compounds include those derived from organic acids such as acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulphonic acid, benzenesulphonic acid and/>-toluenesulphonic acid, mineral acids such as hydrochloric and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, />-toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases.
  • suitable inorganic bases for the formation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases.
  • bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are nontoxic and strong enough to form salts.
  • Such organic bases are already well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N- methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.
  • amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N- methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-
  • Salts of compounds according to an embodiment of the invention may be prepared in a conventional manner using methods well known in the art.
  • Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds according to the first or second aspects of the invention in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid.
  • a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution e.g. by evaporation.
  • the compounds of this invention may also exist in solvated or hydrated forms.
  • a compound of the invention is admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.
  • a compound of the invention is admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).
  • a compound of the invention (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water may then added to produce a total volume of 5 mL.
  • a compound of the invention may be admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press. Formulation 5 - Injection
  • a compound of the invention is dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) are melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals.
  • the present invention relates also to a method of treatment or prevention of osteoarthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of compound of the invention.
  • the present invention relates also to a method of treatment or prevention of osteoarthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of an inhibitor of PDElA according to Formula I.
  • the present invention relates also to a method of treatment or prevention of osteoarthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of an inhibitor of PDElA according to Formulae Ia-Ib.
  • Another aspect of the present method invention relates to a method of treatment or prophylaxis of a condition characterized by abnormal PDElA activity, which comprises administering a therapeutically effective amount of a PDElA inhibiting compound according to Formula I or Formulae Ia-
  • a further aspect of the present method invention is a method of treatment or prophylaxis of a disease involving degradation of cartilage, which comprises administering a therapeutically effective a compound according to Formula I or Formulae Ia-Ib.
  • a special embodiment of the present method invention is a method of treatment or prevention of OA, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to Formula I or Formulae Ia-Ib.
  • This invention also relates to the use of the present compounds in the manufacture of a medicament for treatment or prophylaxis of a condition prevented, ameliorated or eliminated by administration of an inhibitor of PDElA which is a compound of the invention, or a condition selected from diseases involving inflammation, most particularly for the treatment of diseases selected from osteoarthritis, rheumatoid arthritis and osteoporosis.
  • an inhibitor of PDElA which is a compound of the invention, or a condition selected from diseases involving inflammation, most particularly for the treatment of diseases selected from osteoarthritis, rheumatoid arthritis and osteoporosis.
  • Administration of the compound of the present invention to the subject patient includes both self-administration and administration by another person.
  • the patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions affected by a disturbance in bone metabolism.
  • the compound of the present invention may be delivered to the subject patient orally, transdermally, via inhalation, injection, nasally, rectally or via a sustained release formulation.
  • a particular regimen of the present method comprises the administration to a subject in suffering from a disease condition characterized by a disturbance in bone and/or cartilage metabolism, of an effective PDEIA-inhibiting amount of a compound of the present invention for a period of time sufficient to reduce the abnormal levels of bone and/or cartilage degradation in the patient, and particularly terminate, the self-perpetuating processes responsible for said degradation.
  • a special embodiment of the method comprises administering of an effective PDElA inhibiting amount of a compound of the present invention to a subject patient suffering from or susceptible to the development of osteoarthritis, for a period of time sufficient to reduce or prevent, respectively, collagen and bone degradation in the joints of said patient, and particularly terminate, the self-perpetuating processes responsible for said degradation.
  • Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 ZED 50 .
  • Particular compounds are those that exhibit large therapeutic indices. While compounds that exhibit toxic side effects may be used, care should be taken to design a delivery system that targets such compounds to the site of affected tissue in order to minimize potential damage to uninfected cells and, thereby, reduce side effects.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies particularly within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • IC 50 i.e., the concentration of the test compound which achieves a half-maximal inhibition of symptoms
  • levels in plasma may be measured, for example, by high performance liquid chromatography.
  • a particular therapeutically effective amount of the compound of the present invention to administer to a subject patient is about 0.1 mg/kg to about 10 mg/kg administered from once to three times a day.
  • an effective regimen of the present method may administer about 5 mg to about 1000 mg of said compound of the present invention from once to three times a day.
  • the specific dose level for any particular subject patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular inflammatory condition. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with particular doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds of this invention When used to prevent the onset of a condition related to bone and/or cartilage degradation the compounds of this invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those who have been identified by genetic testing or screening to be particularly susceptible to developing said condition.
  • the compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other compounds that demonstrate the same or a similar therapeutic activity and that are determined to safe and efficacious for such combined administration.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or particular process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; however, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • pyrazolo[4,3-d]pyrimidinones compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or particular process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [00246] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • the white precipitate obtained via this method may be collected by filtration and dried to give 3-bromo-l- methyl-3a,7a-dihydro-lH-pyrazolo[4,3-d]pyrimidine-5,7-diol as a brown solid.
  • the white solid obtained is collected by filtration and dried to afford 3-bromo-5-dipropylamino-l-methyl- 3a,7a-dihydro-lH-pyrazolo[4,3-d]pyrimidin-7-ol as a light yellow solid.
  • the method is a competitive immunoassay between native cAMP and the cAMP labeled with XL665.
  • the tracer binding is visualized by a monoclonal antibody against cAMP, labeled with
  • the specific signal i.e. energy transfer
  • concentration of cAMP in the sample see Figure 1.
  • the reaction buffer is Tris 2OmM pH 7.4, 4 ⁇ g/mLl calmodulin, 3mM MgCl 2 , 1.5mM CaCl 2 , 0.2mg/mL BSA and 0.001% Brij-35 .
  • the reaction is stopped by the addition of lO ⁇ L labelled cAMP-XL665 and 10 ⁇ L anti-cAMP-Cryptate. After 1 hour incubation at room temperature, the readout is performed on the Envision (excitation 360nm; emission donor 615nm; emission acceptor 665nm).
  • PDElA hydrolyses cAMP into 5'AMP; this low cAMP concentration will result in a high signal. A PDElA inhibitor will result in a decrease of the signal.
  • Phosphodiesterase Assay Kit from Biomol, a colorimetric, non-radioactive assay.
  • the basis for the assay is the cleavage of cAMP by PDElA.
  • the 5'AMP is further cleaved into the nucleoside and phosphate by the enzyme 5 '-nucleotidase (catnr KI-307).
  • the phosphate released due to enzymatic cleavage is quantified using BIOMOL GREENTM reagent (catnr AK-111) in a modified Malachite Green assay 1 ' 2 .
  • BIOMOL GREENTM reagent catnr AK-111
  • the reaction buffer is Tris 2OmM pH 7.4, 4 ⁇ g/mL calmodulin, 3mM MgCl 2 , 1.5mM CaCl 2 , 0.2mg/mL BSA and 0.001% Brij-35. After an incubation of 45 minutes at 37°C, the reaction is stopped by the addition of 50 ⁇ L BIOMOL GREENTM reagent. After 30 minutes incubation at room temperature, the readout is performed on the Envision
  • a cellular PDElA assay was developed in order to determine PDElA inhibitor activity on cAMP levels in forskolin (NHK477) stimulated HEK293 cells transiently transfected with PDElA with HTRF® (Homogeneous Time- Resolved Fluorescence) cAMP dynamic 2 bulk kit (from Cisbio).
  • HEK 293T are routinely maintained in Dulbecco's Modified Eagle's Medium (DMEM) containing 10% heat inactivated fetal calf serum, 100 U/mL Penicillin and 100 ⁇ g/ml Streptomycin.
  • DMEM Dulbecco's Modified Eagle's Medium
  • 70 % confluent HEK 293T are used for reverse transfection that involves simultaneously transfecting and plating cells.
  • 60 000 cells are transiently transfected with lOOng of pcDNA3.1(+)PDElA DNA using 0.2 ⁇ L Jet-PEI (Polyplus) as transfection reagent per well for 96 well plate format.
  • Transfected cells are seeded in poly-D-lysine coated 96-well plates. After overnight incubation at 37°C, 10% CO 2 , transfection medium is removed and lOO ⁇ L of cell culture medium are added.
  • Htrf reagents are added to 20 ⁇ L diluted cell lysate: lO ⁇ L cAMP-d2 (cAMP labelled with d2 dye), then lO ⁇ L anti cAMP-Cryptate (monoclonal antibody against cAMP, labeled with cryptate).
  • the plates are incubated at room temperature for 1 hour and read on the Envision ((excitation 360nm; emission donor 615nm; emission acceptor 665nm). Results are calculated from the 665nm / 615nm ratio and expressed in Delta F% as described by manufacturer.
  • Appropriate positive and negative control may be selected by a person of skill in the art and used to calculate z' and PIN values.
  • the compounds of the invention are more potent against PDElA than against other PDE isoforms.
  • the compounds are 2 fold more potent against PDElA than against one or more of the other isoforms.
  • the compounds of the invention are 5 fold, particularly 10-fold, particularly 20-fold more potent against PDElA than against one or more of the other isoforms of PDE.
  • the compounds of the invention are more potent against PDElA than against at least one of PDElB, PDE2A, PDE4A or PDE5A.
  • the compounds are more potent against PDElA than against at least two of PDElB, PDE2A, PDE4A or PDE5A.
  • the compounds are more potent against PDElA than against all of the other PDE isoforms.
  • Methods for testing the selectivity of the compounds against a range of PDE isoforms will be familiar to those of skill in the art, and for example, may measure comparative IC 5 O values or percentage inhibition values at a set concentration. Typical methods are described below. [00295] To test the selectivity of the compounds against a panel of PDE' s, lysate derived from transiently transfected HEK293 cells (transfected with PDE5A, PDElB, PDE2A or PDE4A for 48h) is used as the enzyme source.
  • the dose response of compounds on PDE5A lysate is performed using the cGMP bulk htrf kit from Cisbio (catnr 62GM2PEC).
  • the principle of this kit is based on the HTRF® technology (Homogeneous Time-Resolved Fluorescence).
  • the method is based on the competition between native cGMP and the cGMP labeled with d2.
  • the tracer binding is visualized by a monoclonal antibody against cGMP, labeled with Cryptate.
  • the specific signal i.e. energy transfer
  • PDE5A hydrolyses cGMP into 5'GMP; the decrease in cGMP concentration upon PDE5A activity will result in an increased signal.
  • a PDE5A inhibitor will cause a decrease of this signal.
  • reaction buffer consists of Tris 2OmM pH 7.4, 3mM MgCl 2 , 1.5mM CaCl 2 , 0.2mg/mL BSA and 0.001% Brij-35. After an incubation of 25 minutes at room temperature, the reaction is stopped by the addition of lO ⁇ L labeled cGMP-d2 and 10 ⁇ L anti-cGMP- Cryptate. After 1 hour incubation at room temperature, the readout is performed on the Envision (excitation 360nm; emission donor 615nm; emission acceptor 665nm).
  • PDE2A and PDE4A lysates an assay using the cAMP dynamic 2 bulk htrf kit from Cisbio (catnr 62AM4PEC) is used.
  • the principle of this kit is based on the HTRF® technology (Homogeneous Time-Resolved Fluorescence).
  • the method is based on the competition between native cAMP and the cAMP labeled with d2.
  • the tracer binding is visualized by a monoclonal antibody against cAMP, labeled with Cryptate.
  • the specific signal i.e. energy transfer
  • a mixture is made of 1 O ⁇ L with PDE IB, PDE2A or PDE4A lysate, 10OnM cAMP and the compound (5OnM in a final concentration of 1% DMSO) in a black 384- plate.
  • the reaction buffer is Tris 2OmM pH 7.4, 37.5 U/ml calmodulin, 3mM MgCl 2 , 1.5mM CaCl 2 , 0.2mg/mL BSA and 0.001% Brij-35 .
  • the reaction is stopped by the addition of 5 ⁇ L labelled cAMP-d2 and 5 ⁇ L anti-cAMP-Cryptate. After 1 hour incubation at room temperature, the readout is performed on the Envision (excitation 360nm; emission donor 615nm; emission acceptor 665nm).
  • PDElB, PDE2A and PDE4A hydrolyse cAMP into 5'AMP; this decrease in cAMP concentration will result in an increase in signal.
  • a PDElA, PDE2A or PDE4A inhibitor will result in a decrease of this signal.
  • 1% DMSO (100% inhibition) may be used as a positive control, lysate with 1% DMSO
  • the positive and negative control are used to calculate z' and PIN values.
  • All compounds may be screened at a single concentration of 5OnM.
  • the hit criteria is set at PIN 50 (50% inhibition).
  • the mouse embryonic cell line ATDC5 is a cell line that can be induced to a chondrogenic fate by certain culturing conditions such as high cell density or certain growth factors.
  • Anabolic compounds can be tested in this cell line for their capacity to induce or enhance the chondrogenic differentiation by measuring a typical chondrocyte markers such as collagen type II, alpha- 1 (col2 ⁇ l), a major constituent of normal cartilage.
  • ATDC5 cells are seeded in 384 well plates and 3 days after plating treated with compounds. Col2 ⁇ l deposition is determined 14 days after the start of the infection.
  • FK506 was described to induce chondrogenic differentiation in ATDC5 cells and increase collagen II production (Nishigaki et al., 2002, Eur J Pharmacol. FK506 induces chondrogenic differentiation of clonal mouse embryonic carcinoma cells, ATDC5). Assay description
  • ATDC5 cells are seeded on day 0 at 1000 cells/well in 50 ⁇ L of DMEM/F12
  • Up-regulation of Col2al is read at day 13: The medium is removed with a VacuSafe; 50 ⁇ L ice-cold MeOH is added and removed immediately by inverting the plate; 50 ⁇ L of ice-cold MeOH is added to fix the cells, and plates are incubated for 20 min at -20 0 C; MeOH is removed and plates are air- dried for 20 min, followed by 2x washing with 80 ⁇ l of phosphate buffered saline (PBS); 75 ⁇ L of blocking buffer (0.1% casein in PBS) is added and plates are incubated for at least 2 h at room temperature (RT). After the incubation the blocking buffer is removed; cells are washed with 25 ⁇ L of
  • EC buffer (20 mM sodium phosphate, 2mM EDTA, 400 mM NaCl, 0.2% BSA, 0.05% CHAPS, 0.4% casein, 0.05% NaN3, pH 7) and 35 ⁇ L of the primary antibody (Collagen II Ab-2, Neomarkers MS-235-P) diluted 1/400 in buffer C (20 mM sodium phosphate, 2 mM EDTA, 400 mM NaCl, 1% BSA, pH 7) is added; plates are incubated overnight at 4°C.
  • the primary antibody is removed; cells are washed once with 80 ⁇ L of PBST (0.5% Tween 20 in PBS) and once with 80 ⁇ Ll PBS; 35 ⁇ L of the secondary antibody (Goat-anti-mouse Immunoglobulins/HRP. DAKO, P0477; diluted 1/2000 in buffer C) is added; plates are incubated at RT for at least 45min but no longer than 1 h. After this incubation, the secondary antibody is removed and cells are washed twice with 80 ⁇ L PBST and once with 80 ⁇ L PBS;
  • PDE nucleotide phosphodiesterase

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Abstract

La présente invention concerne des composés qui sont des inhibiteurs de la PDElA, une phosphodiestérase qui est impliquée dans la modulation de la dégradation des cartilages, l'arthrose et des maladies impliquant ladite dégradation et/ou inflammation, et en particulier, un composé de formule (Ia) ou (Ib) ou un sel, hydrate, solvate ou promédicament de celui acceptable sur le plan pharmaceutique ou des variants isotopiques de celui-ci, des stéréoisomères ou des tautomères de celui-ci. L'invention concerne également des compositions, notamment des compositions pharmaceutiques, et des utilisations correspondantes de celles-ci, ainsi que des méthodes prophylactiques et thérapeutiques faisant intervenir lesdites compositions.
PCT/EP2008/067046 2007-12-07 2008-12-08 Nouveaux composés utiles pour le traitement de maladies dégénératives et inflammatoires Ceased WO2009071705A1 (fr)

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CN111212839A (zh) * 2017-09-15 2020-05-29 艾杜罗生物科技公司 吡唑并嘧啶酮化合物及其用途

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EP0201188A2 (fr) * 1985-04-05 1986-12-17 Warner-Lambert Company Pyrazolo[4,3-d]pyrimidine-7-ones substituées en 5, leur procédé de préparation et compositions pharmaceutiques les contenant
US5294612A (en) * 1992-03-30 1994-03-15 Sterling Winthrop Inc. 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof
WO2008055959A1 (fr) * 2006-11-09 2008-05-15 Galapagos N.V. Nouveaux composés utilisés dans le traitement de maladies dégénératives et inflammatoires
WO2008071650A2 (fr) * 2006-12-11 2008-06-19 Galapagos N.V. Nouveaux composés utiles dans le traitement de maladies dégénératives et inflammatoires

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EP0201188A2 (fr) * 1985-04-05 1986-12-17 Warner-Lambert Company Pyrazolo[4,3-d]pyrimidine-7-ones substituées en 5, leur procédé de préparation et compositions pharmaceutiques les contenant
US5294612A (en) * 1992-03-30 1994-03-15 Sterling Winthrop Inc. 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof
WO2008055959A1 (fr) * 2006-11-09 2008-05-15 Galapagos N.V. Nouveaux composés utilisés dans le traitement de maladies dégénératives et inflammatoires
WO2008071650A2 (fr) * 2006-12-11 2008-06-19 Galapagos N.V. Nouveaux composés utiles dans le traitement de maladies dégénératives et inflammatoires

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111212839A (zh) * 2017-09-15 2020-05-29 艾杜罗生物科技公司 吡唑并嘧啶酮化合物及其用途

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