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WO2010059836A1 - Composés bicycliques substitués à pont aza pour maladie cardiovasculaire et du système nerveux central - Google Patents

Composés bicycliques substitués à pont aza pour maladie cardiovasculaire et du système nerveux central Download PDF

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Publication number
WO2010059836A1
WO2010059836A1 PCT/US2009/065162 US2009065162W WO2010059836A1 WO 2010059836 A1 WO2010059836 A1 WO 2010059836A1 US 2009065162 W US2009065162 W US 2009065162W WO 2010059836 A1 WO2010059836 A1 WO 2010059836A1
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nhc
compound according
optionally substituted
alkyl
nitrogen
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PCT/US2009/065162
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English (en)
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Jasbir Singh
Mark E. Gurney
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Decode Genetics Ehf
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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
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention relates to substituted imidazopyridines, pyrazolotriazinones, triazolopyridines, pyrazolopyridines and pyrazolopyrimidines that are useful for treating stroke, myocardial infarct, and cardiovascular inflammatory conditions, to pharmaceutical compositions comprising these compounds, and to methods for the treatment of stroke, myocardial infarct, and cardiovascular inflammatory conditions in a mammal.
  • PDE4 is the major cAMP-metabolizing enzyme found in inflammatory and immune cells.
  • PDE4 inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, COPD and rhinitis. They suppress the release of cytokines and other inflammatory signals and inhibit the production of reactive oxygen species.
  • a large number of PDE4 inhibitors have been developed for a variety of clinical indications (Torphy and Page. 2000. TIPS 21, 157-159; Burnouf and Pruniaux. 2002. Curr. Pharm. Design 8, 1255-1296; Lipworth. 2005. Lancet 365, 167-175).
  • PDE4 inhibitors have been in development as a novel anti- inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications.
  • COPD chronic obstructive pulmonary disease
  • PDE4 inhibitors of various structural classes including cilomilast, filaminast, lirimilast, piclamilast, tofimilast has been discontinued due to lack of efficacy.
  • a primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given.
  • the compounds of the present invention are non-competitive inhibitors of cAMP while being gene- specific inhibitors (PDE4D), and, based on the target rationale and in vitro potency, a person of skill in the art would expect the compounds to be useful as anti- inflammatory agents for the treatment, amelioration or prevention of inflammatory diseases and of complications arising therefrom.
  • PDE4D gene- specific inhibitors
  • P is chosen from nitrogen and carbon
  • Q is chosen from nitrogen and carbon, with the provisos that one of P or Q must be nitrogen, but P and Q cannot both be nitrogen;
  • R 1 is selected from hydrogen, (Ci-C 6 ) alkyl, haloalkyl, -CONHR 5 , lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR 2 and -OCONH 2 ;
  • W is nitrogen or CR 2 ;
  • R 2 is selected from hydrogen, (Ci-C 6 ) alkyl, haloalkyl and optionally substituted heterocyclyl;
  • Y is CR 3 or nitrogen
  • R 3 is selected from hydrogen, fluoro, hydroxyl and -OR 10 ;
  • R 10 is selected from (Ci-C 6 ) alkyl optionally substituted with fluoro;
  • X is selected from CR 4 , nitrogen and N + O " ;
  • R 4 is selected from hydrogen, (Ci-C 6 ) alkyl, halogen, amino, alkoxy and hydroxyl;
  • R 5 is selected from hydrogen and (Ci-C 6 ) alkyl
  • R 8 and R 9 are independently selected from hydrogen, (Ci-C 6 ) alkyl, (Ci-C 6 ) hydroxyalkyl, (Cs-C 6 ) carbocyclyl and a 3- to 6-membered heterocyclyl; or R 8 and R 9 together form a 4-6 membered ring which optionally contains a heteroatom selected from -O-, -NR 5 and S(O) 0-2 ; or R 8 and R 9 together form an oxo group;
  • Z is selected from -O-, -S(O) 0-2 , -NH-, -CH 2 - and a direct bond;
  • Cy 1 is selected from optionally substituted (Cs-C 6 ) carbocyclyl and optionally substituted heterocyclyl;
  • Cy 2 is selected from optionally substituted aryl and optionally substituted heteroaryl
  • M is chosen from -CH 2 -, -CH 2 CH 2 -, -O-, -S(O) 0-2 , -OCH 2 , -CH 2 O, -CONH, -CONHCH 2 , -NHCO and -NHSO 2 .
  • composition comprising a compound as described herein, and a pharmaceutically acceptable carrier, excipient or diluent therefore.
  • the invention relates to methods for the treatment or prophylaxis of a disease or condition mediated by phosphodiesterase-4.
  • the methods comprise administering to a mammal a therapeutically effective amount of a compound having the general formula of formula I or II above.
  • the disease or condition may be related to allergic, acute or chronic inflammation.
  • the disease may be, for example, atherosclerosis, thrombosis, stroke, acute coronary syndrome, stable angina, peripheral vascular disease, critical leg ischemia, intermittent claudication, abdominal aortic aneurysm or myocardial infarction.
  • Selective PDE4 inhibitors of the invention are useful in improving cognition and thus useful for treating learning disorders, memory loss and other cognitive dysfunctions.
  • Selective PDE4 inhibitors of the invention are also useful for treating asthma and Chronic Obstructive Pulmonary Disease (COPD).
  • COPD Chronic Obstructive Pulmonary Disease
  • Compounds of the invention, which inhibit tumor growth and metastases, also find utility in the treatment and prevention of cancer, including esophageal cancer, brain cancer, pancreatic cancer, and colon cancer.
  • Selective PDE4 inhibitors of the invention are also thought to be useful for treating or preventing schizophrenia or Huntington's disease, bone loss, depression, anxiety, bladder inflammation, bladder pain and bladder overactivity.
  • the invention relates to compounds of formula I or formula II
  • P is nitrogen and Q is carbon.
  • Y is CR 3 .
  • X is CR 4 .
  • X is nitrogen.
  • W is CR 2 .
  • W is nitrogen.
  • P is carbon and Q is nitrogen.
  • W is CR 2 .
  • X is CR 4 .
  • X is nitrogen.
  • Y is CR .
  • Y is nitrogen.
  • P is carbon and Q is nitrogen.
  • W can be nitrogen.
  • W is CR 2 .
  • cores include imidazolopyridines, triazolopyridines, pyrazolotriazinones and imidazolopyrazines:
  • pyrazolopyridines examples include pyrazolopyrimidines:
  • R 2 is selected from hydrogen and (Ci-C 6 ) alkyl, and in some embodiments, R 2 is hydrogen.
  • X is CR 4 . In other embodiments, X is nitrogen.
  • R 1 is selected from hydrogen and (Ci-C 6 ) alkyl. In some embodiments, R 1 is methyl.
  • Z is a direct bond. In yet other embodiments, Z is selected from -O- and -S(O) 0-2 . In further embodiments, Z is -CH 2 -. In still other embodiments, Cy l is selected from optionally substituted aryl and heteroaryl.
  • Cy 2 is selected from optionally substituted aryl and heteroaryl. In yet other embodiments, Cy 1 and Cy 2 are both optionally substituted phenyl.
  • R 8 and R 9 are each independently selected from hydrogen and (Ci-C 6 ) alkyl. In further embodiments, R 8 and R 9 together form an oxo group. In still other embodiments, R 8 and R 9 together form a 4-6 membered ring, and this ring may optionally contain a heteroatom. In one embodiment, this heteroatom may be oxygen. In another embodiment, the heteroatom may be NR 5 . In still other embodiments, the heteroatom may be -S-, -S(O)- or -S(O) 2 -.
  • Z is a direct bond.
  • M is -CH 2 -.
  • M is -CONH-.
  • Cy 1 is selected from optionally substituted aryl and an optionally substituted 5- or 6-membered ring nitrogen heterocycle.
  • Cy 1 is selected from optionally substituted phenyl and an optionally substituted 5- or 6-membered ring nitrogen heterocycle.
  • Cy 1 is selected from optionally substituted phenyl, pyridinyl, morpholin-4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl.
  • Cy 2 is selected from optionally substituted phenyl and an optionally substituted 5- or 6-membered ring nitrogen heterocycle.
  • Yet other embodiments include compounds in which Cy 2 is selected from phenyl, 3-chlorophenyl, 3-nitrophenyl, 3- bromophenyl, 3-acetylphenyl, 3-trichloromethylphenyl and 3-methylthiophenyl.
  • Cy 2 is selected from phenyl and 3-chlorophenyl.
  • Cy 1 is selected from phenyl and pyridinyl, each of which is optionally substituted with a substituent chosen from (1) hydrogen, halogen, halo alky 1, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxy alky It hio, alkoxycarbonylaminoalkyl, carboxy alky lcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, amino carbonylalkyl, cyano, acetoxy, nitro, amino,
  • Cy 1 is selected from phenyl and pyridinyl, each of which is optionally substituted with a substituent chosen from -CH 3 , -CH 2 CF 3 , -CF 3 , -CHO, -COOH, -CN, halogen, -OH, , -OEt, -C(K))NH 2 , -C(K))NHEt, -C(K))NMe 2 -COOCH3, -COOEt, -CH 2 NHC(K))NH 2 , -CH(CH 3 )NHC(K))NH 2 , -CH 2 NHC(K))H, -CH 2 NHC(K))CH 3 , -CH 2 C(K))NH 2 , -CH 2 COOH, -CH 2 COOEt, -CH 2 NHC(K))OEt, -CH 2 NHC(K)O-C 6 H 5
  • Cy 1 is selected from phenyl and pyridinyl, each of which is substituted with a monocyclic heterocycle, and the monocyclic heterocycle is optionally substituted with a substituent chosen from the foregoing list.
  • An example of the embodiment in which Cy 1 is a pyridinyl substituted with a monocyclic heterocycle substituted with a carboxylic acid is found in example D-25 below:
  • W is CR and R is selected from
  • R > 2 is J is selected from O, S, S(O), SO 2 , NH and NCH 3 and L is C or N. In some of these embodiments, R 2 is hydrogen.
  • R 4 is hydrogen. In other embodiments, R 3 is hydrogen.
  • R 1 is selected from hydrogen and (Ci-C 6 ) alkyl. In some of these compounds, R 1 is methyl. In other embodiments, X is CH. In yet other embodiments, X is CF. Still other embodiments include compounds in which Cy l is selected from optionally substituted phenyl, pyridinyl, morpholin-4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl. In other embodiments of the invention, Cy 1 is phenyl optionally substituted with a substituent selected from amino, urea, alkylurea, -
  • NHCO 2 (C i-C 6 )alkyl azeditine acid, azeditine amide, an d J n further embodiments, Cy 2 is optionally substituted phenyl. In yet other embodiments, Z is a direct bond. In some embodiments, M is -CH 2 -.
  • R 1 is selected from hydrogen and (Ci-C 6 ) alkyl;
  • X is CH;
  • Cy 1 is selected from optionally substituted phenyl, pyridinyl, morpholin- 4-yl, piperazin-1-yl, piperidiny-1-yl, imidazol-1-yl, pyrazol-1-yl, and pyrazol-5-yl;
  • Cy 2 is optionally substituted phenyl;
  • Z is a direct bond; and M is -CH 2 -.
  • the compounds are of formula (A)
  • Cy 1 is selected from optionally substituted (Cs-C 6 ) carbocyclyl and optionally substituted heterocyclyl;
  • Cy 2 is selected from optionally substituted aryl and optionally substituted heteroaryl
  • R 1 is selected from hydrogen, (Ci-C 6 ) alkyl, haloalkyl, -CONHR 5 , lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR 2 and -OCONH 2 ;
  • R 2 is selected from hydrogen, (Ci-C 6 ) alkyl, haloalkyl and optionally substituted heterocyclyl;
  • R 3 is selected from hydrogen, fluoro, hydroxyl and -OR 10 ;
  • R 10 is selected from (Ci-C 6 ) alkyl optionally substituted with fluoro;
  • R 4 is selected from hydrogen, (Ci-C 6 ) alkyl, halogen, amino, alkoxy and hydroxyl;
  • M is chosen from -CH 2 -, -CH 2 CH 2 -, -O-, -S(O) 0-2 , -OCH 2 , -CH 2 O, -CONH, -CONHCH 2 , -
  • Cy l is selected from optionally substituted phenyl, pyridinyl, morpholinyl, piperazinyl, piperidinyl, imidazolyl, pyrazolyl, oxazolidinyl, pyrrolidinyl, thiazolyl and benzo[c][l,2,5]oxadiazolyl.
  • the compounds are of formula (A) wherein
  • Cy 1 is selected from optionally substituted aryl and an optionally substituted 5- or 6-membered ring nitrogen heterocycle;
  • Cy 2 is selected from optionally substituted phenyl and an optionally substituted 5- or 6- membered ring nitrogen heterocycle;
  • R 1 is selected from hydrogen and (Ci-C 6 ) alkyl
  • R 2 is selected from hydrogen, methyl, and wherein J is selected from O, S(0)o-2, NH and NCH 3 and L is selected from C and N
  • R 3 is hydrogen
  • R 4 is hydrogen
  • M is -CH 2 -.
  • the compounds are of formula (A) wherein Cy 1 is selected from phenyl and pyridinyl, each of which is optionally substituted with a substituent chosen from halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, carboxy alky lcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)a
  • Cy 2 is selected from phenyl and 3-chlorophenyl.
  • the compound is selected from the following (Table 1): [0029] Table 1.
  • the compound is represented by the following (Table 2): [0031] Table 2.
  • PDE4 inhibitors have been shown to be effective therapeutic agents in clinical studies. For example, administration of cilomilast and roflumilast (PDE4 inhibitors) to patients suffering from asthma and COPD showed initially excellent results, although the effect of cilomilast disappeared on long-term trial [Lipworth, Lancet 365. 167-175 (2005)]. L- 454,560, a selective PDE4 inhibitor has been shown to improve learning in a rat model in vivo [Huang et al. Biochemical Pharmacology 73, 1971-1981 (2007)]. This suggests that selective PDE4 inhibitors will be useful in treating learning disorders, memory loss (e.g. Alzheimer's disease) and other cognitive dysfunctions. Selective PDE4 inhibitors (e.g.
  • rolipram are also useful for treating bone loss [Yao et al., J.Musculoskelet.Neuronal Interact. 7, 119-130 (2007)].
  • a PDE4 inhibitor, YM976 was shown to ameliorate the effects of experimentally- induced interstitial cystitis in rats, resulting in a decrease in the frequency of urination and an increase in the volume of urine at each time of urination [Kitta et al., BJU Int. 102. 1472-1476 (2008)].
  • PDE4 inhibitor IC485
  • IC485 Another PDE4 inhibitor, IC485, was shown to be equally efficacious as tolteradine tartrate, a marketed drug for treating overactive bladder, in a rodent model of obstructive bladder [Kaiho et al. BJU Int. 101, 615-20 (2008)]. These findings suggest that PDE4 inhibitors will be useful in treating symptoms of bladder inflammation, such as overactivity and pain. [0034] Furthermore, the compounds, compositions and methods of the present invention are useful in treating cancer. Phosphodiesterase activity has been shown to be associated with hematological malignancies [Lerner et al., BiochemJ. 393, 21-41 (2006); Ogawa et al, Blood 99, 3390-3397 (2002)].
  • Alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl. When not otherwise restricted, the term refers to alkyl of 20 or fewer carbons. Lower alkyl refers to alkyl groups of 1, 2, 3, 4, 5 and 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl and alkylene groups are those of Ci 0 or below (e.g.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of 3, 4, 5, 6, 7, and 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.
  • C 1 to C 20 Hydrocarbon (e.g. C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 ) includes alkyl, cycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl.
  • phenylene refers to ortho, meta or para residues of the formulae:
  • Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • carbocycle (or “carbocyclyl”) is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
  • carbocycle refers to such systems as cyclopropane, benzene and cyclohexene;
  • C 8 - Ci 2 carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • Carbocycle not otherwise limited, refers to monocycles, bicycles and polycycles.
  • Alkoxy or alkoxyl refers to groups of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons.
  • alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is bonded to the atom, chain or ring from which the methylenedioxy or ethylenedioxy group is pendant so as to form a ring.
  • phenyl substituted by alkoxy may be, for example,
  • Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9- trioxadecyl and the like.
  • the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 1196, but without the restriction of Tfl27(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds). It does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
  • thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons have been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
  • Acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched or cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, propionyl, isobutyryl, ⁇ -butoxycarbonyl, benzoyl, benzyloxycarbonyl and the like.
  • Lower- acyl refers to groups containing one to four carbons.
  • the double bonded oxygen when referred to as a substituent itself, is called "oxo".
  • Aryl and heteroaryl refer to aromatic or heteroaromatic rings, respectively, as substituents.
  • Aryl and heteroaryl mean (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S.
  • Aromatic 6, 7, 8, 9, 10, 11, 12, 13 and 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5, 6, 7, 8, 9 and 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • aryl refers to residues in which one or more rings are aromatic, but not all need be.
  • Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. This is in contradistinction to alkylaryl, in which an aryl residue is attached to the parent structure through alkyl (e.g. a p-tolyl residue).
  • Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
  • Heterocyclylalkyl refers to a substituent in which a heterocyclyl residue is attached to the parent structure through alkyl. Examples include morpholinoethyl and pyrrolidinylmethyl.
  • heterocycle means a monocyclic, bicyclic or tricyclic residue with 1 to 13 carbon atoms and 1 to 4 heteroatoms chosen from the group consisting of nitrogen, oxygen and sulfur.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • a heterocycle may be non-aromatic or aromatic.
  • the heterocycle may be fused to an aromatic hydrocarbon radical.
  • Suitable examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3- triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, 1,3,5-tria
  • a nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms. Examples include piperidine, piperazine, morpholine, pyrrolidine and thiomorpholine. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic; examples include pyridine, pyrrole and thiazole.
  • heterocyclyl residues additionally include piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxo-pyrrolidinyl, 2-oxoazepinyl, azepinyl, 4-piperidinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadia
  • An oxygen heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygens, as well as other heteroatoms.
  • a sulphur heterocycle is a heterocycle containing at least one sulphur in the ring; it may contain additional sulphurs, as well as other heteroatoms.
  • a nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.
  • substituted alkyl, aryl, cycloalkyl, heterocyclyl, etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with a specified radical.
  • acyl alkoxyalkyl, benzenesulfonyl, cyano, carbonyl, nitro, amino, hydroxyalkyl, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, acylamino, diacylamino, acylaminoalkyl, acylaminoalkoxy,
  • Haloakyl refers to an alkyl group in which one or more hydrogens are replaced by halogen, for example, trifluoromethyl, trifluoromethoxy, trichloroethyl, and difluoromethyl.
  • Oxo is also included among the substituents referred to in "optionally substituted”; it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl).
  • 1, 2 or 3 hydrogen atoms are replaced with a specified radical.
  • Additional substituents that are considered within the scope of the term are the are the residues of amino acids, amino acid amides, protected residues of aminoacids and their amides, and N-methylated (mono- or di-, as appropriate) amino acids and amino acid amides.
  • a residue of an amino acid, amino acid amide refers to an amino acid etc. minus the functional groups that are considered part of the bond to the parent structure.
  • Fragment A illustrated below:
  • halogen means fluorine, chlorine, bromine or iodine.
  • haloalkyl and haloalkoxy mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms.
  • prodrug refers to a compound that is made more active in vivo. Commonly the conversion of prodrug to drug occurs by enzymatic processes in the liver or blood of the mammal. Many of the compounds of the invention may be chemically modified without absorption into the systemic circulation, and in those cases, activation in vivo may come about by chemical action (as in the acid-catalyzed cleavage in the stomach) or through the intermediacy of enzymes and microflora in the gastrointestinal GI tract.
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, iodine and chlorine include 3 H, 14 C, 35 S, 18 F, 32 P, 33 P, 125 I, and 36 Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Radiolabeled compounds described herein and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radio labeled reagent.
  • PDE4 inhibitors have been shown to be effective therapeutic agents in clinical studies. For example, administration of cilomilast and roflumilast (PDE4 inhibitors) to patients suffering from asthma and COPD showed initially excellent results, although the effect of cilomilast disappeared on long-term trial [Lipworth, Lancet 365, 167-175 (2005)]. L-454,560, a selective PDE4 inhibitor has been shown to improve learning in a rat model in vivo [Huang et al. Biochemical Pharmacology 73. 1971-1981 (2007)]. This suggests that selective PDE4 inhibitors will be useful in treating learning disorders, memory loss (e.g. Alzheimer's disease) and other cognitive dysfunctions.
  • memory loss e.g. Alzheimer's disease
  • Rolipram a selective PDE4 inhibitor has been shown to improve the outcome in two separate studies in mice in vivo in models accepted by persons of skill in the art as predictive of utility in schizophrenia [Kanes et al., Neuroscience 144. 239-246 (2007); Davis and Gould, Behav.Neurosci. 119. 595-602 (2005)]. Rolipram has also been shown to exhibit a neuroprotective effect in a rat model of Huntington's disease [DeMarch et al. Neurobiol.Dis. 25, 266-273 (2007)]. Selective PDE4 inhibitors (e.g. rolipram) are also useful for treating bone loss [Yao et al., J.Musculoskelet.Neuronal Interact. 7. 119-130 (2007)].
  • the compounds, compositions and methods of the present invention are useful in treating cancer.
  • Phosphodiesterase activity has been shown to be associated with hematological malignancies [Lerner et al., BiochemJ. 393. 21-41 (2006); Ogawa et al., Blood 99. 3390-3397 (2002)].
  • the compounds may also be administered to overcome cognitive impairment induced by one or more of the following agents, alcohol, amphetamine, antipsychotic medication, anti-retroviral therapy, MDMA ( 3,4-methylenedioxy-N- methylamphetamine, cannabis, cocaine, delta-9 tetrahydrocannabinol, dexamphetamine, haloperidol, heroin and other opiates, ketamine and metamphetamine.
  • MDMA 3,4-methylenedioxy-N- methylamphetamine
  • cannabis cocaine, delta-9 tetrahydrocannabinol, dexamphetamine, haloperidol, heroin and other opiates, ketamine and metamphetamine.
  • the compounds, compositions and methods of the present invention may be employed as imaging agents and in other ways for diagnosis and/or treatment.
  • immobilization of compounds of the invention on solid support could be of utility for affinity purification and modification of compounds of the invention with chemically active groups may be used for protein labeling.
  • cholinesterase inhibitors e.g. tacrine, huperzine, donepezil
  • NMDA antagonists e.g. lanicemine, remacemide, neramexane, memantine
  • calpain inhibitors e.g. CEP-3122
  • antioxidants e.g. vitamin E, coenzyme QlO
  • agents that have shown clinical efficacy but whose mechanism is unclear e.g. dimebon).
  • Compounds of formula I or formula II may also be administered together with one or more of the following agents to improve cognition: amisulpride, atomoxetine, bromocryptine, buspirone, caffeine, chlorpromazine, clonidine, clozapine, diazepam, flumazenil, fluoxetine, galantamine, guanfacine, methylphenidate, idazoxan, modafinil, olanzapine, paroxetine, pergolide, phenserine, quetiapine, risperidone, rivastigmine, SGS742 and sulpiride.
  • the terms "methods of treating or preventing” mean amelioration, prevention or relief from the symptoms and/or effects associated with lipid disorders.
  • preventing refers to administering a medicament beforehand to forestall or obtund an acute episode or, in the case of a chronic condition to diminish the likelihood or seriousness of the condition.
  • prevent is not an absolute term.
  • reference to “treatment” of a patient is intended to include prophylaxis.
  • mammal is used in its dictionary sense.
  • the term “mammal” includes, for example, mice, hamsters, rats, cows, sheep, pigs, goats, and horses, monkeys, dogs (e.g., Canis familiaris), cats, rabbits, guinea pigs, and primates, including humans.
  • the cognitive impairment to be treated may arise from one or more of the following disorders, which may not in themselves be necessarily associated with PDE4 abnormality: acute pain, AD/HD - Attention deficit hyperactivity disorder, AIDS dementia complex, alcoholism, amphetamine addiction, amygdalo-hippocampectomy, anorexia nervosa, anterior parietal damage, antisocial behavior, antisocial personality disorder, anxiety, autism, basal ganglia lesions, bipolar disorder, borderline personality disorder, camptocormia, capgras syndrome, carcinoid syndrome, carotid endarterectomy surgery, chronic drug misuse, chronic fatigue syndrome, chronic occupational solvent encephalopathy, chronic pain, brain ischemia, coronary artery bypass surgery, critical illness requiring intensive care, dementia Alzheimer- type (DAT), dementia Lewy Body type, dementia of frontal type, dementia caused by ischemia, dental pain, developmental dyslexia, diabetes, dorsolateral frontal cortical compression, Down's Syndrome, drug abuse, dysexecutive syndrome,
  • Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms.
  • Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
  • a compound As used herein, and as would be understood by the person of skill in the art, the recitation of "a compound” is intended to include salts, solvates and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio.
  • a compound as described herein, including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se is provided as the salt form.
  • the salt is a hydrochloride salt.
  • solvate refers to a compound in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19 th Ed. (1995) volume 1, page 176-177.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, carbonic, citric, ethanedisulfonic, ethanesulfonic, ethylenediaminetetraacetic, fumaric, glucoheptonic, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, hydroxynaphthoic, isethionic, lactic, lactobionic, laurylsulfonic, maleic, malic, mandelic, methanesulfonic, mucic, naphthylenesulfonic, nitric, pamoic, pantothenic, phosphoric, polygalacturonic, salicylic, stearic, succinic, sulfuric, tannic, tartaric acid, teoclatic, p- toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, arginine, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • enantiomeric excess is related to the older term “optical purity” in that both are measures of the same phenomenon.
  • the value of ee will be a number from 0 to 100, zero being racemic and 100 being pure, single enantiomer.
  • a compound which in the past might have been called 98% optically pure is now more precisely described as 96% ee; in other words, a 90% ee reflects the presence of 95% of one enantiomer and 5% of the other in the material in question.
  • a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • Me, Et, Ph, Tf, Ts and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, toluenesulfonyl and methanesulfonyl respectively.
  • a comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled “Standard List of Abbreviations" is incorporated herein by reference.
  • a pharmaceutical composition comprising a compound of formula I or formula II or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of formula I or formula II or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the carrier, which constitutes one or more accessory ingredients.
  • active ingredient a compound of formula I or formula II or a pharmaceutically acceptable salt or solvate thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier” also encompasses controlled release means.
  • compositions may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must be compatible with the compound of formula I or formula II to insure the stability of the formulation.
  • the composition may contain other additives as needed, including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.
  • additives including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino
  • excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, disintegrants, lubricants, anti-microbial agents, and coating agents.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of formula I or formula II which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
  • a dosage unit (e.g. an oral dosage unit) can include from, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g.
  • the agents can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasaly (including using a cannula), or by other routes.
  • the agents can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, e.g. WO 97/11682) via a liposomal formulation (see, e.g., EP 736299,WO 99/59550 and WO 97/13500), via formulations described in WO 03/094886 or in some other form.
  • a micellar formulation see, e.g. WO 97/11682
  • a liposomal formulation see, e.g., EP 736299,WO 99/59550 and WO 97/13500
  • the agents can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3: 115)).
  • the agents can be administered locally, for example, at the site of injury to an injured blood vessel.
  • the agents can be coated on a stent.
  • the agents can be administered using high-velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. 20020061336.
  • WO 00/45792 An example of a transdermal formulation containing plaster and the absorption promoter dimethylisosorbide can be found in WO 89/04179.
  • WO 96/11705 provides formulations suitable for transdermal administration.
  • the agents can be administered in the form a suppository or by other vaginal or rectal means.
  • the agents can be administered in a transmembrane formulation as described in WO 90/07923.
  • the agents can be administered non-invasively via the dehydrated particles described in U.S. 6,485,706.
  • the agent can be administered in an enteric-coated drug formulation as described in WO 02/49621.
  • the agents can be administered intranasaly using the formulation described in U.S. 5,179,079. Formulations suitable for parenteral injection are described in WO 00/62759. The agents can be administered using the casein formulation described in U.S. 20030206939 and WO 00/06108. The agents can be administered using the particulate formulations described in U.S. 20020034536.
  • the agents can be administered by pulmonary route utilizing several techniques including but not limited to intratracheal instillation (delivery of solution into the lungs by syringe), intratracheal delivery of liposomes, insufflation (administration of powder formulation by syringe or any other similar device into the lungs) and aerosol inhalation.
  • Aerosols e.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder inhalers (DPIs)
  • MDIs metered-dose inhalers
  • DPIs dry-Powder inhalers
  • Aerosol formulations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium and can be placed into pressurized acceptable propellants, such as hydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114), propane, nitrogen, and the like.
  • HFAs hydrofluoroalkanes
  • HFA-134a and HFA-227 or a mixture thereof
  • dichlorodifluoromethane or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114
  • propane nitrogen, and the like.
  • Pulmonary formulations may include permeation enhancers such as fatty acids, and saccharides, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion. Pulmonary formulations may also include surfactants which include but are not limited to bile salts and those described in U.S.
  • the surfactants described in U.S. 6,524,557 e.g., a C 8 -Ci 6 fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation.
  • dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-Powder inhaler.
  • Absorption enhancers which can be added to dry powder formulations of the present invention include those described in U.S. 6,632,456.
  • WO 02/080884 describes new methods for the surface modification of powders. Aerosol formulations may include U.S.
  • Pulmonary formulations containing stable glassy state powder are described in U.S. 20020141945 and U.S. 6,309,671.
  • Other aerosol formulations are described in EP 1338272A1 WO 90/09781, U. S. 5,348,730, U.S. 6,436,367, WO 91/04011, and U.S. 6,294,153 and U.S. 6,290,987 describes a liposomal based formulation that can be administered via aerosol or other means.
  • Powder formulations for inhalation are described in U.S. 20030053960 and WO 01/60341.
  • the agents can be administered intranasally as described in U.S. 20010038824.
  • Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer.
  • Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles.
  • More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy.
  • Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington.
  • the agent can be incorporated into a liposome to improve half-life.
  • the agent can also be conjugated to polyethylene glycol (PEG) chains.
  • PEG polyethylene glycol
  • Methods for pegylation and additional formulations containing PEG-conjugates i.e. PEG-based hydrogels, PEG modified liposomes
  • the agent can be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International).
  • the agents can be delivered transmucosally (i.e. across a mucosal surface such as the vagina, eye or nose) using formulations such as that described in U.S. 5,204,108.
  • the agents can be formulated in microcapsules as described in WO 88/01165.
  • the agent can be administered intra-orally using the formulations described in U.S. 20020055496, WO 00/47203, and U.S. 6,495,120.
  • the agent can be delivered using nanoemulsion formulations described in WO 01/91728A2.
  • compounds of formula I or formula II may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • Tables 1 and 2 above list compounds representative of embodiments of the invention. Processes for obtaining compounds of formula I or formula II are presented below. Other compounds of formula I or formula II may be prepared in analogous fashion to those whose synthesis is exemplified herein. The procedures below illustrate such methods.
  • the substituent at C8 can be introduced either before formation of the bicyclic core (S2) by Suzuki/Stille reaction allowing C-C bond formatting chemistries.
  • the intermediate S3 could be reacted by Buchwald or Cu mediated chemistries to for ether/amine linked C 8 substituent (S7).
  • the substituent at the C-6 position can be introduced by a wide variety of approaches.
  • Y is an alkyl, ester, nitrile
  • S6/S7 containing alcohol alkyl halide (W)
  • W alkyl halide
  • the carbonate or -CH2-Br (W, S6/S7) upon reaction via organometallic coupling protocols (e.g.
  • the alcohol can be converted to a primary or secondary amine.
  • the W as acid or amine thus allows formation of amide, reverse amide, sulfonamide from acylation /sulfonation chemistries or diverse amine via reductive amine chemistry approaches.
  • the substituents containing additional functions groups allow subsequent elaboration by standard chemistries outlines above depending upon the functional groups introduced at C6. These strategies allow incorporation of acyclic, heterocyclic or heteroaryl derived substituents at the C6 / C8 position of the imidazo[l,2-a]pyridine/ imidazo[l,2-a]pyrazine core.
  • pyrozolo[l,5-a]pyridine S14
  • S12 2,4-substituted pyridine
  • S13 N-amination of 2,4-disubstituted pyridine (S12) by O-2-mesitylenesulfonyl hydroxyamine provides intermediate (S13).
  • Subsequent 1,3-dipolar cycloaddition with methyl propiolate furnish the pyrozolo[l,5-a]pyridine (S 14), which can subsequently be transformed into the decarboxylated product (S 15) under acidic conditions.
  • Formation of the key intermediate pyrazolo[l,5-a]pyrimidine (S21) can be obtained from the pyrazole starting material (S 18). Reaction of pyrazole (S 18) with methyl chloroformate and subsequent bromination with NBS give intermediate bromomethyl pyrazole (S20). Nucleophilic substitution of tosylmethyl isocyanide (TosMIC) on the bromomethyl pyrazole (S20) followed by intramolecular transfer of the methoxycarbonyl group followed by cyclization and 1 ,2-elimination of p-toluenesulfinic acid to afford the pyrazolo[l,5-a] pyrimidine intermediate (S21) analogous to Mendiola, J.
  • TosMIC tosylmethyl isocyanide
  • substitution at C-6 position can be obtained via the ester group at C-6 position by similar approaches described above for Gl analogs.
  • the introduction of the substitutions at C-8 position to form a C-C bond can be accomplished by metal assisted cross coupling reactions.
  • the key intermediate pyrazolo[l,5-a]pyrimidine (S26) can be also obtained from S25.
  • the intermediate S25 in turn can be obtained from S18 via bromination and subsequent conversion to the ketone S24. Reaction of S25 with an orthoformate would then provide S26.
  • the final substituent can be introduced as part of formation of S24; in such case cyclization of S25 to S26 directly would yield the desired analogs. [0090] Scheme 5.
  • Formation of the key intermediate pyrazolo[l,5-a]pyrimidine can be obtained via cyclization reaction of the pyrazole starting material (S27) with acetoacetic acid ethyl ester (or ⁇ -keto esters).
  • S27 pyrazole starting material
  • acetoacetic acid ethyl ester or ⁇ -keto esters
  • a large number of starting materials of the general structure S27 are commercial available or can be prepared by published procedures.
  • the -OH group in S28 can convert to chloride or bromide (S29) which can form C-C link substitutions in S30 via organometallic coupling protocols (e.g. Suzuki, Stille reaction).
  • compounds of the formula G6-b can be prepared from the intermediate 2,3-disubstituted-5,6-dihydro-pyrazolo[l,5-d][l,2,4]triazine-4,7-dione (S27). Cyclization of S25 with coupling reagents (such as CDI, triphosgene etc) afford S27, which can subsequently N-alkylation with Hetl/Arl/Rl-halide at N-5 position to provide (S28). The substitutions at C-7 position in compounds G6-b can be obtained by displacement of halogen (Cl or F) of S29 with hydroxyl, amine or thiol containing heterocyclic/aryls.
  • coupling reagents such as CDI, triphosgene etc
  • Stepl 6-Amino-5-(3-chloro-phenyl)-nicotinic acid methyl ester (2).
  • methyl 6-amino-5-bromonicotinate Ig, 4.33 mmole
  • 40 ml toluene 10 ml ethanol
  • 20 ml water 1.37g, 13 mmole sodium carbonate
  • 3-chlorophenyl boronic acid 740mg, 4.73 mmole
  • the solution was degassed for 10 min. under argon, then the palladium tetrakis (500mg, 10%) was added. Reaction mixture was heated at 100 0 C for 6 hours.
  • Step 2 8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridine-6-carboxylic acid methyl ester (3).
  • Step 3 [8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-yl]-methanol (4).
  • anhydrous THF was added at 0 0 C LiBH4 (2M in THF, 2 ml). Reaction mixture was stirred at RT for 3 days. Mixture was quenched with saturated solution of NH4C1, then extracted several times with ethylacetate.
  • Step 4 Carbonic acid 8-(3-chloro-phenyl)-imidazo[l,2-a]pyridin-6-ylmethyl ester (5).
  • pyridine 80 ul, 0.96 mmole
  • the mixture was cooled to 0 0 C and methylchloro formate was added slowly (65uL, 0.81 mmole). Reaction mixture was stirred at room temperature for 3 days.
  • Step 5 4-[8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-ylmethyl]-phenylamine (D- 01).
  • the reaction was diluted with ethyl acetate (10 mL), washed with saturated ammonium chloride (10 mL), the aqueous wash back extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined. The organic solution was washed with brine (15 mL) and the solvent removed under vacuum. The crude material was purified by silica gel thin layer preparatory chromatography eluting with 7.5 % acetone in dichloromethanes to give D-04 PR231 (15.1 mg, 18% yield) as a yellow gum.
  • 6-ylmethyl]-phenyl ⁇ -urea D-05: A reaction mixture of compound 14 (60 mg crude, 0.2 mmol), 4-ureidophenylboronic acid pinacol ester (52 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol), K3PO4 (84 mg, 0.4 mmole) in DME (6 mL), ethanol (1.5 mL) and water (1.5 ml) was stirred at 65 0 C for 2 hours and then cooled to room temperature.
  • Methods of the invention parallel the compositions and formulations.
  • the methods comprise administering to a patient in need of treatment a therapeutically effective amount of a compound according to the invention.
  • the present invention also provides a method for inhibiting phosphodiesterase 4.
  • In-vitro assay for PDE4 enzymes The in-vitro activity of PDE4 enzymes and the in-vitro potency of therapeutic agents described in the present invention was measured using a real-time, enzyme-coupled spectrophotometric assay. By using three different coupling enzymes, the product of the PDE4 reaction is coupled to the oxidation of the reduced form ⁇ -nicotinamide adenine dinucleotide (NADH), which dissipation can be monitored spectrophotmetrically at 340 nM.
  • NADH ⁇ -nicotinamide adenine dinucleotide
  • Buffer A containing 50 mM Tris, pH 8.0, 16 mM MgCl 2 and 80 mM KCl is prepared and stored at room temperature.
  • Buffer B containing 50 mM Tris, pH 8.0 is prepared and stored at toom temperature.
  • Stock solutions of the following reagents are prepared in Buffer B and stored at -20 0 C: Adenosine-5 '-triphosphate (ATP), cyclic adenosine-5 '-monophosphate (cAMP), phosphoenolpyruvate (PEP) and NADH.
  • ATP Adenosine-5 '-triphosphate
  • cAMP cyclic adenosine-5 '-monophosphate
  • PEP phosphoenolpyruvate
  • An assay mix is prepared by mixing Buffer A, trichloroethylphosphine (TCEP), ATP, PEP, NADH, myokinase (MK), pyruvate kinase (PK), lactate dehydroganese (LDH) and PDE4 to a final volume of 20 mL, which is enough for a single 96-well assay plate.
  • Assay mix 180 ⁇ L
  • test article (10 ⁇ L ) in 1 : 1 DMSO/H 2 O mixture is pre-incubated at room temperature for 10 min. The enzymatic reaction is initiated by addition of c AMP (10 ⁇ L).
  • Final concentration of all components in the assay (200 ⁇ L/well) are as follows: 10 mM MgCl 2 , 50 mM KCl, 5 mM TCEP, 2.5% DMSO, 0.4 mM NADH, 1 mM PEP, 0.04 mM ATP, 5 units MK, 1 unit PK, 1 unit LDH and appropriate amount of PDE4.
  • Reaction progress curves are monitored in a plate reader capable of measuring light absorbance at 340 nM. A decrease in light absorbance at 340 nm is due to oxidation of NADH.
  • Positive controls containing no test article and negative controls containing no test article and no cAMP are included on every assay plate. Reaction rates are determined from the slopes of the linear portions of the progress curves. All data is percent normalized with respect to controls and presented as percent inhibition.
  • A-E are based on IC 50 in the assay described above.
  • the activity of PDE4 inhibitors decribed in the present invention was also measured using in an ex- vivo assay measuring leukotriene E4 (LTE4) in human whole blood after Sephadex stimulation.
  • LTE4 leukotriene E4
  • the anti- inflammatory activity of therapeutic agents of the present invention is demonstrated by the inhibition of eosinophil activation as measured by sephadex bead stimulated LTE4 production in whole human blood.
  • 356 ⁇ l of heparinized human whole blood (Vacutainer tube #6480) is added to wells of a 96 well plate.

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Abstract

L'invention porte sur des imidazopyridines, pyrazolotriazinones, triazolopyridines, pyrazolopyridines et pyrazolopyrimidines substituées qui sont utiles pour le traitement d’un accident vasculaire cérébral, d’un infarctus du myocarde et d’états inflammatoires cardiovasculaires, ainsi que sur des compositions pharmaceutiques comportant ces composés et sur des procédés pour le traitement d’un accident vasculaire cérébral, d’un infarctus du myocarde et d’états inflammatoires cardiovasculaires chez un mammifère. Les composés ont la formule générale I (I) ou II (II) où Cy1 et Cy2 sont des carbocycles ou des hétérocycles.
PCT/US2009/065162 2008-11-20 2009-11-19 Composés bicycliques substitués à pont aza pour maladie cardiovasculaire et du système nerveux central WO2010059836A1 (fr)

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