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  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/04—Ortho- or peri-condensed ring systems
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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

• This invention relates to novel arylindenopyridines and their therapeutic and prophylactic uses. Disorders treated and/or prevented using these compounds include inflammatory and AIDS-related disorders.
• PDE phosphodiesterases
• These diseases include conditions such as hypersensitivity, allergy, arthritis, asthma, bee sting, animal bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma, premature labor, a urinary tract disorder, inflammatory bowel disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular disease, gastrointestinal motility disorder, and psoriasis.
• PDE1 family are activated by calcium-calmodulin; its members include PDE1A and PDE1 B, which preferentially hydrolyze cGMP, and PDE1 C which exhibits a high affinity for both cAMP and cGMP.
• PDE2 family is characterized as being specifically stimulated by cGMP.
• PDE2A is specifically inhibited by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA).
• Enzymes in the PDE3 family e.g. PDE3A, PDE3B
• PDE4 e.g.
• PDE4A, PDE4B, PDE4C, PDE4D is a cAMP specific PDE present in T-cells, which is involved in inflammatory responses.
• a PDE3 and/or PDE4 inhibitor would be predicted to have utility in the following disorders: autoimmune disorders (e.g. arthritis), inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, and psoriasis.
• a PDE5 (e.g. PDE5A) inhibitor would be useful for the treatment of the following disorders: cardiovascular disease and erectile dysfunction.
• the photoreceptor PDE6 e.g. PDE6A, PDE6B, PDE6C
• PDE8 family exhibits high affinity for hydrolysis of both cAMP and cGMP but relatively low sensitivity to enzyme inhibitors specific for other PDE families.
• Phosphodiesterase 7 is a cyclic nucleotide phosphodiesterase that is specific for cyclic adenosine monophosphate (cAMP). PDE7 catalyzes the conversion of cAMP to adenosine monophosphate (AMP) by hydrolyzing the 3'-phosphodiester bond of cAMP. By regulating this conversion, PDE7 allows for non-uniform intracellular distribution of cAMP and thus controls the activation of distinct kinase signalling pathways. PDE7A is primarily expressed in T- cells, and it has been shown that induction of PDE7A is required for T-cell activation (Li, L; Yee, C; Beavo, J.A.
• PDE7A activation is necessary for T-cell activation, small molecule inhibitors of PDE7 would be useful as immunosuppressants.
• An inhibitor of PDE7A would be predicted to have immunosuppressive effects with utility in therapeutic areas such as organ transplantation, autoimmune disorders (e.g. arthritis), HIV/AIDS, inflammatory bowel disease, asthma, allergies and psoriasis.
• This invention provides a compound having the structure of Formula I
• Ri is selected from the group consisting of:
• R 5 is selected from H, optionally substituted C ⁇ _ 8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C 1 - 8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR 20 R 2 ⁇ wherein R 2 o and R 2 ⁇ are independently selected from the group consisting of hydrogen, C- ⁇ - 8 straight or branched chain alkyl, C 3 . 7 cycloalkyl, benzyl, aryl, or heteroaryl or NR 2 oR2i taken together form a heterocycle or heteroaryl;
• R 6 is selected from H, optionally substituted C ⁇ -8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C ⁇ -8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R 2 o and R 2 ⁇ are independently selected from the group consisting of hydrogen, C ⁇ -8 straight or branched chain alkyl, C 3- cycloalkyl, benzyl, aryl, or heteroaryl or NR20R2 1 taken together form a heterocycle or heteroaryl; (iii) cyano;
• R 7 and R 8 are independently selected from H, C ⁇ _ 8 straight or branched chain alkyl, C 3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or R 7 and
• R 3 is from one to four groups independently selected from the group consisting of:
• R is selected from the group consisting of (i) hydrogen, (ii) C-1-3 straight or branched chain alkyl, (iii) benzyl and (iv) -NR ⁇ 3 R-
• X is selected from S and O;
• the invention is directed to compounds of Formula l wherein R-i, R 3 and R 4 are as described above and R 2 is - NR 15 R 16 wherein R15 and R 16 are independently selected from hydrogen, optionally substituted C ⁇ -8 straight or branched chain alkyl, arylalkyl, C 3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R- ⁇ 5 and R 16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R 2 is NHR-I ⁇ , Ri is not -COOR ⁇ where Re is ethyl.
• This invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
• This invention further provides a method of treating a subject having a disorder ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
• this invention provides a method of preventing a disorder ameliorated by reducing PDE activity in appropriate cells in a subject, comprising administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.
• Compounds of Formula I are potent small molecule phosphodiesterase inhibitors that have demonstrated potency for inhibition of PDE7, PDE5, and PDE4. Some of the compounds of this invention are potent small molecule PDE7 inhibitors which have also demonstrated good selectivity against PDE5 and PDE4.
• Preferred embodiments for Ri are COOR ⁇ , wherein Re is selected from H, optionally substituted C ⁇ -8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl.
• RQ is H, or C- t -s straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.
• R 2 are optionally substituted aryl and optionally substituted heteroaryl.
• Preferred substituents are from one to three members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro.
• R 2 is optionally substituted
• R 2 is optionally substituted with from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro.
• R 2 is-
• Preferred substituents for R 3 include: (i) hydrogen, halo, C-
• R ⁇ and Rn are independently selected from H, C -8 straight or branched chain alkyl, arylC ⁇ -8 alkyl,
• R 12 is selected from hydrogen or alkyl and R- 13 is selected from hydrogen, alkyl, substituted alkyl, C ⁇ - 3 alkoxyI, carboxyC ⁇ -8 alkyl, aryl, arylalkyl, R 30 R 31 N (CH 2 ) P -, R 3 oR 3 iNCO(CH 2 )p-, heteroaryl and heterocyclyl or R- ⁇ 2 and R 13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein , R 30 and R 31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.
• R 3 is selected from the group consisting of
• alkyl(CO)NH- alkyl(CO)NH-, NH 2 , and NO 2 .
• R 4 include hydrogen, C 1 - 3 straight or branched chain alkyl, particularly methyl, and amino.
• Ri is COOR ⁇ and R 2 is selected from the group consisting of substituted phenyl, and substituted naphthyl or R 2 is NRi5Ri6-
• Ri is COOR 6 where R 6 is alkyl, R 2 is substituted phenyl or naphthyl or R 2 is NR ⁇ 5 R ⁇ 6 , and R 3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:
• alkyl(CO)NH- and R 4 is selected from hydrogen, C 1 - 3 straight or branched chain alkyl, particularly methyl, and amino.
• the compound is selected from the group of compounds shown in Table 1 hereinafter.
• the compound is selected from the following compounds:
• the instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts.
• salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2- naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.
• This invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.
• Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline.
• Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
• non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
• Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
• Oral carriers can be elixirs, syrups, capsules, tablets and the like.
• the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
• Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
• Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
• This invention further provides a method of treating a subject having a condition ameliorated by reducing PDE activity in appropriate cells, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.
• the disorder is an inflammatory disorder.
• the disorder is an AIDS-related disorder.
• disorders treatable by the instant pharmaceutical composition include, without limitation, organ transplantation, autoimmune disorders (e.g. arthritis), immune challenge such as a bee sting, inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, cardiovascular disorder, erectile dysfunction, allergies, and psoriasis.
• the disorder is rheumatoid arthritis.
• the term "subject” includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by reducing PDE activity in appropriate cells.
• the subject is a human.
• the subject is a human.
• appropriate cells include, by way of example, cells which display PDE activity. Specific examples of appropriate cells include, without limitation, T-Iymphocytes, muscle cells, neuro cells, adipose tissue cells, monocytes, macrophages, fibroblasts.
• Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art.
• the instant compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously.
• the instant pharmaceutical composition is administered orally.
• administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.
• a “therapeutically effective dose” of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder.
• a “prophylactically effective dose” of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder's onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition.
• the effective dose for administering the pharmaceutical composition to a human for example, can be determined mathematically from the results of animal studies.
• the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of the instant pharmaceutical composition. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily.
• infusion doses range from about 1.0 ⁇ g/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days.
• the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.
• This invention still further provides a method of preventing an inflammatory response in a subject, comprising administering to the subject a prophylactically effective amount of the instant pharmaceutical composition either preceding or subsequent to an event anticipated to cause the inflammatory response in the subject.
• the event is an insect sting or an animal bite.
• Alkyl shall mean straight, cyclic and branched-chain alkyl. Unless otherwise stated, the alkyl group will contain 1-20 carbon atoms. Unless otherwise stated, the alkyl group may be optionally substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, C ⁇ -C 8 -alkyl, C ⁇ -C 8 -alkoxyl, CrC 8 -alkylthio, C ⁇ -C 8 -alkyl-amino, di(CrC 8 -aIkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C ⁇ -C 8 - alkyl-CO-O-, C-i-C 8 -alkyl-CO-NH-, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl,
• Alkoxy shall mean -O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.
• Halogen shall mean fluorine, chlorine, bromine or iodine; "PH” or “Ph” shall mean phenyl; “Ac” shall mean acyl; “Bn” shall mean benzyl.
• acyl as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group.
• Ac as used herein, whether used alone or as part of a substituent group, means acetyl.
• Aryl or “Ar,” whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2- naphthyl and the like.
• the carbocyclic aromatic radical may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, CrC 8 -alkyl, C ⁇ -C 8 -alkoxyl, C-i-C 8 - alkylthio, C ⁇ -C 8 -alkyl-amino, di(C ⁇ -C 8 -alkyl)amino, (mono-, di-, t -, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C ⁇ -C 8 -alkyl-CO-O-, C C 8 -alkyl- CO-NH-, or carboxamide.
• Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like.
• Ph or "PH" denotes phenyl.
• heteroaryl refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon.
• the radical may be joined to the rest of the molecule via any of the ring atoms.
• heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2- oxazepinyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzof
• the heteroaryl group may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C-i-Cs-alkyl, C-i-C 8 - alkoxyl, CrC 8 -aIkyIthio, C ⁇ -C 8 -alkyl-amino, di(C ⁇ -C 8 -alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C ⁇ -C 8 -aIkyl-CO-O-, C ⁇ -C 8 -alkyl-CO-NH-, or carboxamide.
• Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1 H-quinoline.
• heterocycle refers to an optionally substituted, fully or partially saturated cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring.
• Each ring of the heterocyclic group containing a heteroatom may have 1 , 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized.
• the nitrogen atoms may optionally be quatemized.
• the heterocyclic group may be attached at any heteroatom or carbon atom.
• Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1 ,3-dioxolane; dioxanyl; thietanyl;
• bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo- quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.
• Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted- heteroaryl, or a second substituted-heterocycle to give, for example, a 4- pyrazol-1 -yl-phenyl or 4-pyridin-2-yl-phenyl.
• Designated numbers of carbon atoms e.g., C ⁇ -8 ) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
• the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such- solvates are also intended to be encompassed within the scope of this invention.
• Some of the compounds of the present invention may have trans and cis isomers.
• these isomers may be separated by conventional techniques such as preparative chromatography.
• the compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers.
• the non-racemic forms may be obtained by either synthesis or resolution.
• the compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation.
• the compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.
• Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the following general schemes.
• the products of some schemes can be used as intermediates to produce more than one of the instant compounds.
• the choice of intermediates to be used to produce subsequent compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.
• Benzylidenes 2 may be obtained by known methods (Bullington, J.L;
• Hantzsch reaction of the benzylidene compounds with enamines 3 can be performed in refluxing acetic acid (Petrow ef al., supra). When the desired enamines are not available, alternate Hantzsch conditions may be utilized which involve adding ammonium acetate to the reaction.
• the resulting dihydropyridines 4 are oxidized with chromium trioxide to obtain the desired pyridines 1 (Petrow ef al, supra).
• the substitution pattern on the fused aromatic ring (R 3 ) leads to a mixture of regioisomers, the products can be separated by column chromatography.
• R 2 is an alkyl group
• another modification of the Hantzsch may be performed which uses three components (Bocker, R.H.; Buengerich, P. J. Med. Chem. 1986, 29, 1596).
• R 2 is an alkyl group it is also necessary to perform the oxidation with DDQ or MnO 2 instead of chromium (VI) oxide (Vanden Eynde, J.J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51 , 6511 ).
• the cyanoethyl esters 5 are prepared as described above.
• the esters are converted to the carboxylic acids by treatment with sodium hydroxide in acetone and water (Ogawa, T.; Matsumoto, K.; Yokoo, C; Hatayama, K.; Kitamura, K. J. Chem. Soc, Perkin Trans. 1 1993, 525).
• the corresponding amides can then be obtained from the acids using standard means.
• the dihydropyridine lactones 9 can be synthesized from benzylidenes 8 (Zimmer, H.; Hillstrom, W.W.; Schmidt, J.C.; Seemuth, P.D.; Vogeli, R. J. Org. Chem. 1978, 43, 1541 ) and 1 ,3-indanedione, as shown in Scheme 5, and the corresponding pyridine is then obtained by oxidation with manganese dioxide.
• the amines 11 are obtained from the corresponding nitro compounds 10 by reduction with tin (II) chloride (Scheme 6). Reaction of the amines with acetyl chloride provide the amides 12.
• an alkyl chain with a carboxylic acid at the terminal end can also be added to the amines 11.
• reaction with either succinic anhydride (Omuaru, V.O.T.; Indian J. Chem., Sect B. 1998, 37, 814) or ⁇ -propiolactone (Bradley, G.; Clark, J.; Kemick, W. J. Chem. Soc, Perkin Trans. 1 1972, 2019) can provide the corresponding carboxylic acids 13.
• These carboxylic acids are then converted to the hydroxamic acids 14 by treatment with ethyl chloroformate and hydroxylamine (Reddy, A.S.; Kumar, M.S.; Reddy, G.R. Tetrahedron Lett. 2000, 41 , 6285).
• the amines 11 can also be treated with glycolic acid to afford alcohols 15 (Jursic, B.S.; Zdravkovski, Z. Synthetic Comm. 1993, 23, 2761 ) as shown in Scheme 8.
• the aminoindenopyridines 11 may also be treated with chloroacetylchloride followed by amines to provide the more elaborate amines 16 (Weissman, S.A.; Lewis, S.; Askin, D.; Volante, R.P.; Reider, P.J. Tetrahedron Lett. 1998, 39, 7459). Where R 6 is a hydroxyethyl group, the compounds can be further converted to piperazinones 17.
• the 4-aminoindenopyridines 18 can be synthesized from the 4- chloroindenopyridines 19 using a known procedure (Gorlitzer, K.; Herbig, S.; Walter, R.D. Pharmazie 1997, 504) or via palladium catalyzed coupling (Scheme 10).
• the assay of phosphodiesterase activity follows the homogeneous SPA (scintillation proximity assay) format under the principle that linear nucleotides preferentially bind yttrium silicate beads in the presence of zinc sulfate.
• SPA sintillation proximity assay
• the enzyme converts radioactively tagged cyclic nucleotides (reaction substrate) to linear nucleotides (reaction product) which are selectively captured via ion chelation on a scintillant-containing bead.
• Radiolabeled product bound to the bead surface results in energy transfer to the bead scintillant and generation of a quantifiable signal. Unbound radiolabel fails to achieve close proximity to the scintillant and therefore does not generate any signal.
• enzyme was diluted in PDE buffer (50mM pH 7.4 Tris, 8.3mM MgCI 2 , 1.7mM EGTA) with 0.1 % ovalbumin such that the final signaknoise (enzyme:no enzyme) ratio is 5-10.
• Substrate (2,8- 3 H-cAMP or 8- 3 H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4, 5, 7A) buffer to 1 nCi per ⁇ l (or 1 ⁇ Ci/ml).
• PDE 50mM pH 7.4 Tris, 8.3mM MgCI 2 , 1.7mM EGTA
• ovalbumin such that the final signaknoise (enzyme:no enzyme) ratio is 5-10.
• Substrate (2,8- 3 H-cAMP or 8- 3 H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4, 5, 7A) buffer to 1 nCi per ⁇ l (or 1 ⁇ C
• Test compounds were diluted in 100% DMSO to a concentration 20x final assay concentration. DMSO vehicle alone was added to uninhibited control wells. Inhibition (%) was calculated as follows:
• Nonspecific binding the mean of CPM of the substrate + buffer
• Total Binding (TB) the mean of the enzyme + substrate + DMSO wells
• the IC 50 values were calculated using the Deltagraph 4-parameter curve-fitting program.
• the IC 50 and % Inhibition data on PDE 4, 5, and 7A are listed for the indicated compounds in Table 2 below.

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