US20060009481A1 - Arylindenopyridines and related therapeutic and prophylactic methods - Google Patents

Arylindenopyridines and related therapeutic and prophylactic methods Download PDF

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US20060009481A1
US20060009481A1 US11/196,154 US19615405A US2006009481A1 US 20060009481 A1 US20060009481 A1 US 20060009481A1 US 19615405 A US19615405 A US 19615405A US 2006009481 A1 US2006009481 A1 US 2006009481A1
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heteroaryl
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Geoffrey Heintzelman
Kristin Averill
John Dodd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—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
    • 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
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • R 2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C 3-7 cycloalkyl;
  • R 1 is COOR 6 where R 6 is alkyl, R 2 is substituted phenyl or naphthyl or R 2 is NR 15 R 16 , and R 3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae: and R 4 is selected from hydrogen, C 1-3 straight or branched chain alkyl, particularly methyl, and amino.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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 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. TABLE 2 Ia MS IC 20 ( ⁇ M)/% inh. @ ⁇ M No.

Abstract

This invention provides novel arylindenopyridines of the formula:
Figure US20060009481A1-20060112-C00001
 and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by reducing PDE activity in appropriate cells. This invention also provides therapeutic and prophylactic methods using the instant pharmaceutical compositions.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit under 35 U.S.C. § 119(e) of provisional application Ser. No. 60/284,465, filed on Apr. 18, 2001 which is incorporated herein by reference.
    • FIELD OF THE INVENTION
  • 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.
    • BACKGROUND OF THE INVENTION
  • There are eleven known families of phosphodiesterases (PDE) widely distributed in many cell types and tissues. In their nomenclature, the number indicating the family is followed by a capital letter that indicates a distinct gene. A PDE inhibitor increases the concentration of cAMP in tissue cells, and hence, is useful in the prophylaxis or treatment of various diseases caused by the decrease in cAMP level which is induced by the abnormal metabolism of cAMP. 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.
  • Among known phosphodiesterases today, PDE1 family are activated by calcium-calmodulin; its members include PDE1A and PDE1B, which preferentially hydrolyze cGMP, and PDE1C 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) are specifically inhibited by cGMP. 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) enzymes specifically hydrolyze cGMP. 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 (PDE7A, PDE7B) 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. Science 1999, 283, 848). Since 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.
  • Few potent inhibitors of PDE7 have been reported. Most inhibitors of other phosphodiesterases have IC50's for PDE7 in the 100 μM range. Recently, Martinez, et al. (J. Med. Chem. 2000, 43, 683) reported a series of PDE7 inhibitors, among which the two best compounds have PDE7 IC50's of 8 and 13 μM. However, these compounds were only 2-3 times selective for PDE7 over PDE4 and PDE3.
  • Finally, the following compounds have been disclosed, and some of them are reported to show antimicrobial activity against strains such as Plasmodium falciparum, Candida albicans and Staphylococcus aureus (Gorlitzer, K.; Herbig, S.; Walter, R. D. Pharmazie 1997, 504):
    Figure US20060009481A1-20060112-C00002
    • SUMMARY OF THE INVENTION
  • This invention provides a compound having the structure of Formula I
    Figure US20060009481A1-20060112-C00003
  • or a pharmaceutically acceptable salt thereof, wherein
  • (a) R1 is selected from the group consisting of:
      • (i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 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 C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
      • (ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 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 C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
      • (iii) cyano;
      • (iv) a lactone or lactam formed with R4;
      • (v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 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 R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;
  • (b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C3-7 cycloalkyl;
  • (c) R3 is from one to four groups independently selected from the group consisting of:
      • (i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl;
      • (ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
      • (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyalkyl, R30R13N (CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,
        • wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;
  • (c) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;
      • wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and
  • (e) X is selected from S and O;
  • with the proviso that when R4 is isopropyl, then R3 is not halogen.
  • In an alternative embodiment, the invention is directed to compounds of Formula I wherein R1, R3 and R4 are as described above and R2 is —NR15R16 wherein R15 and R16 are independently selected from hydrogen, optionally substituted C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R15 and R16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R2 is NHR16, R1 is not —COOR6 where R6 is ethyl.
  • This invention also provides 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.
  • Finally, 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.
    • DETAILED DESCRIPTION OF THE INVENTION
  • 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 R1 are COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl. Preferably R6 is H, or C1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.
  • Preferred embodiments for R2 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. Preferably, R2 is optionally substituted phenyl or napthyl or R2 is
    Figure US20060009481A1-20060112-C00004
    optionally substituted with from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro. In another embodiment of the instant compound, R2 is —NR15R16.
  • Preferred substituents for R3 include:
      • (i) hydrogen, halo, C1-8 straight or branched chain alkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, and hydroxy;
      • (ii) —NR10R11 wherein R10and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylC1-8alkyl, C3-7 cycloalkyl, carboxyC1-8alkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
      • (iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyC1-8alkyl, aryl, arylalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein , R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.
        Particularly, R3 is selected from the group consisting of
        Figure US20060009481A1-20060112-C00005
  • Preferred embodiments for R4 include hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, and amino.
  • In a further embodiment of the instant compound, R1 is COOR6 and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl or R2 is NR15R16.
  • More particularly, R1 is COOR6 where R6 is alkyl, R2 is substituted phenyl or naphthyl or R2 is NR15R16, and R3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:
    Figure US20060009481A1-20060112-C00006
    and R4 is selected from hydrogen, C1-3 straight or branched chain alkyl, particularly methyl, and amino.
  • In a preferred embodiment, the compound is selected from the group of compounds shown in Table 1 hereinafter.
  • More preferably, the compound is selected from the following compounds:
    Figure US20060009481A1-20060112-C00007
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester
  • Figure US20060009481A1-20060112-C00008
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo- 1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
  • Figure US20060009481A1-20060112-C00009
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-( 1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
  • Figure US20060009481A1-20060112-C00010
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00011
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00012
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
  • Figure US20060009481A1-20060112-C00013
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00014
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00015
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00016
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00017
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00018
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00019
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00020
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy- 1-oxopropyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00021
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-1-oxopropyl)amino]-2-methyl-4-(4-methyl- 1-naphthalenyl)-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00022
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[4-(hydroxyamino)- 1,4-dioxobutyl]amino]-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00023
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)amino]acetyl]amino]-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00024
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(4-carboxy-1-oxobutyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00025
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-methyl-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00026
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-, methyl ester
  • Figure US20060009481A1-20060112-C00027
    • 5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-, methyl ester
  • The instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts. Examples of such 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 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. Examples of 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.
  • In one embodiment, the disorder is an inflammatory disorder. In another embodiment, the disorder is an AIDS-related disorder. Examples of disorders treacle 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. In the preferred embodiment, the disorder is rheumatoid arthritis.
  • As used herein, the term “subject” includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by reducing PDE activity in appropriate cells. In a preferred embodiment, the subject is a human. In a more preferred embodiment, the subject is a human.
  • As used herein, “appropriate cells” include, by way of example, cells which display PDE activity. Specific examples of appropriate cells include, without limitation, T-lymphocytes, 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. In the preferred embodiment, the instant pharmaceutical composition is administered orally. Additionally, 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.
  • As used herein, 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.
  • In one embodiment, 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. In yet another embodiment, infusion doses range from about 1.0 μg/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. In a further embodiment, for topical administration, 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. In the preferred embodiment, the event is an insect sting or an animal bite.
    • DEFINITIONS AND NOMENCLATURE
  • Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
  • As used herein, the following chemical terms shall have the meanings as set forth in the following paragraphs: “independently”, when in reference to chemical substituents, shall mean that when more than one substituent exists, the substituents may be the same or different;.
  • “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, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl(c1-c8)alkyl, heterocyclyl, and heteroaryl.
  • “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.
  • The term “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. The term “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, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO—O—, C1-C8-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.
  • Whether used alone or as part of a substituent group, “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. Exemplary 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, benzofurazanyl, benzothiopyranyl, indazolyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl, and furyl. 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, C1-C8-alkyl, C1-C8-alkoxyl, C1-C8-alkylthio, C1-C8-alkyl-amino, di(C1-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C1-C8-alkyl-CO—O—, C1-C8-alkyl-CO—NH—, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.
  • The terms “heterocycle,” “heterocyclic,” and “heterocyclo” refer 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 quaternized. 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; thiiranyl; and the like. Exemplary 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., C1-8) 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.
  • Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
  • Where the compounds according to this invention have at least one stereogenic center, they 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. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, 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.
  • This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims which follow thereafter. Additionally, throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
    • EXPERIMENTAL DETAILS
  • I. General Synthetic Schemes
  • 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.
    Figure US20060009481A1-20060112-C00028
  • Procedures described in Scheme 1, wherein R3a, R3b, R3c, and R3d are independently any R3 group, and R1, R2, R3, and R4 are as described above, can be used to prepare compounds of the invention wherein X is O.
  • Benzylidenes 2 may be obtained by known methods (Bullington, J. L; Cameron, J. C.; Davis, J. E.; Dodd, J. H.; Harris, C. A.; Henry, J. R.; Pellegrino-Gensey, J. L.; Rupert, K. C.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 1998, 8, 2489; Petrow, V.; Saper, J.; Sturgeon, B. J. Chem. Soc. 1949, 2134). Hantzsch reaction of the benzylidene compounds with enamines 3 can be performed in refluxing acetic acid (Petrow et 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 et al., supra). In cases where the substitution pattern on the fused aromatic ring (R3) leads to a mixture of regioisomers, the products can be separated by column chromatography.
  • In some cases, especially where R2 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). Where R2 is an alkyl group it is also necessary to perform the oxidation with DDQ or MnO2 instead of chromium (VI) oxide (Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van Haverbeke, Y. Tetrahedron 1995, 51, 6511).
    Figure US20060009481A1-20060112-C00029
  • In order to obtain the corresponding carboxylic acids and amides, 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.
    Figure US20060009481A1-20060112-C00030
  • The procedure for making compounds where R4 is NH2 may be slightly modified. These compounds are prepared in one step from the benzylidenes 2 and alkyl amidinoacetate (Kobayashi, T.; Inoue, T.; Kita, Z.; Yoshiya, H.; Nishino, S.; Oizumi, K.; Kimura, T. Chem. Pharm. Bull. 1995, 43, 788) as depicted in Scheme 4 wherein R is R5 or R6 as described above.
    Figure US20060009481A1-20060112-C00031
  • 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.
    Figure US20060009481A1-20060112-C00032
  • Representative schemes to modify substituents on the fused aromatic ring are shown below. 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.
    Figure US20060009481A1-20060112-C00033
  • In accordance with Scheme 7 wherein Y is O, and n is an integer from 1-3, an alkyl chain with a carboxylic acid at the terminal end can also be added to the amines 11. For example, reaction with either succinic anhydride (Omuaru, V. O. T.; Indian J. Chem., Sect B. 1998, 37, 814) or β-propiolactone (Bradley, G.; Clark, J.; Kernick, 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).
    Figure US20060009481A1-20060112-C00034
  • 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.
    Figure US20060009481A1-20060112-C00035
  • As shown in Scheme 9, 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 R6 is a hydroxyethyl group, the compounds can be further converted to piperazinones 17.
    Figure US20060009481A1-20060112-C00036
  • 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).
    Figure US20060009481A1-20060112-C00037
    II. Specific Compound Syntheses
  • Specific compounds which are representative of this invention can be prepared as per the following examples. No attempt has been made to optimize the yields obtained in these reactions. Based on the following, however, one skilled in the art would know how to increase yields through routine variations in reaction times, temperatures, solvents and/or reagents.
  • The products of certain syntheses can be used as intermediates to produce more than one of the instant compounds. In those cases, the choice of intermediates to be used to produce compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.
    • EXAMPLE 1 Hantzsch Condensation to Form Dihydropyridine 4 (R1═COOMe; R2=3,5-dimethylphenyl; R3b,c═Cl; R3a,b═H; R4=Me)
  • To a refluxing solution of benzylidene 2 (0.500 g, 1.5 mmol) in acetic acid (10 mL) was added methyl-3-aminocrotonate (0.695 g, 6.0 mmol). The reaction was heated to reflux for 20 minutes, then water was added until a precipitate started to form. The reaction was cooled to room temperature. The mixture was filtered and washed with water to obtain 0.354 g (55%) of a red solid. MS m/z 450 (M++23), 428 (M++1).
    • EXAMPLE 2 Alternate Hantzsch Conditions to Form Dihydropyridine 4 (R1═CO2Me; R2=2,4-dimethylphenyl; R3═H; R4=Et)
  • To a refluxing solution of benzylidene 2 (1.00 g, 3.82 mmol) in acetic acid (12 Ml) was added methyl propionylacetate (1.98 g, 15.2 mmol) and ammonium acetate (1.17 g, 15.2 mmol). The reaction was heated for 20 min and then cooled to room temperature. No product precipitated from the solution, so the reaction was heated to reflux and then water was added until a solid began to precipitate. After cooling to room temperature, the mixture was filtered and the red solid washed with water to yield 1.29 g (90%) of product. MS m/z 396 (M++23), 374 (M++1).
    • EXAMPLE 3 Oxidation of Dihydropyridine 4 to Pyridine 1 (R1═COOMe; R2=3,5-dimethylphenyl; R3b,c═Cl; R3a,d═H; R 4=Me)
  • To a refluxing solution of dihydropyridine 4 (0.250 g, 0.58 mmol) in acetic acid (10 mL) was added a solution of chromium (VI) oxide (0.584 g, 0.58 mmol) in 1 mL water. After 30 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to give 0.199 g (81%) of a yellow solid. MS m/z 448 (M++23), 426 (M++1).
    • EXAMPLE 4 Oxidation of Dihydropyridine 4 to Pyridine 1 (R1═COOMe; R2=(4-methyl)-1-naphthyl; R3b,c═H, NO2/NO2, H; R=Me)
  • To a refluxing suspension of regioisomeric dihydropyridines 4 (3.59 g, 8.16 mmol) in acetic acid (40 mL) was added a solution of chromium (VI) oxide (0.816 g, 8.16 mmol) in 3 mL water. After 20 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and allowed to stand overnight. The mixture was filtered and washed with water to yield the mixture of regioisomers as a yellow solid. The products were purified by column chromatography eluting with hexanes:ethyl acetate to yield 1.303 g (37%) of pyridine 1 (R3b═NO2; R3c═H) and 0.765 g (21%) of its regioisomer (R3b═H: R3c═NO2). MS m/z 461 (M++23), 439 (M++1).
    • EXAMPLE 5 Alternate Three Component Hantzsch Reaction to Form Dihydropyridine 4 (R1═CO2Me; R2=cyclohexyl; R3═H; R4=Me)
  • Cyclohexane carboxaldehyde (2.0 g, 17.8 mmol), 1,3-indandione (2.6 g, 17.8 mmol), methylacetoacetate (2.0 g, 17.8 mmol), and ammonium hydroxide (1 mL) were refluxed in 8 mL of methanol for 1.5 hours. The temperature was lowered to approximately 50° C. and the reaction was stirred overnight. The reaction was cooled to room temperature, filtered and the solid washed with water. The residue was then dissolved in hot ethanol and filtered while hot. The filtrate was concentrated to yield 4.1 g (68%) of the product which was used without purification. MS m/z 336 (M−−1).
    • EXAMPLE 6 DDQ Oxidation of Dihydropyridine 4 (R1═CO2Me; R2=cyclohexyl; R3═H; R4=Me)
  • To a solution of dihydropyridine 4 (2.50 g, 7.40 mmol) in 15 mL of dichloromethane was added 2,3-dichloro-3,6-dicyano-1,4-benzoquinone (1.70 g, 7.40 mmol). The reaction was stirred at room temperature for four hours. The mixture was filtered and the residue was washed with dichloromethane. After the filtrate was concentrated, the residue was purified by column chromatography eluting with ethyl acetate: hexanes to yield 0.565 g (23%) of a yellow solid. MS m/z 358 (M++23), 336 (M++1).
    • EXAMPLE 7 MnO2 Oxidation of Dihydropyridine 4 (R1═CO2Me; R2=4-(dimethylamino)phenyl; R3═H; R4=Me)
  • To a solution of dihydropyridine 4 (0.50 g, 1.3 mmol) in 10 mL of dichloromethane was added manganese dioxide (2.5 g, 28.7 mmol). The reaction was stirred at room temperature overnight before filtering and washing with dichloromethane. The filtrate was concentrated to yield 0.43 g (88%) of orange solid 1. MS m/z 395 (M++23), 373 (M++1).
    • EXAMPLE 8 Cleavage of Carboxylic Ester 5 (R2=2,4-dimethylphenyl; R3═H; R4=Me)
  • To a suspension of ester 5 (2.75 g, 6.94 mmol) in acetone (50 mL) was added aqueous 1 M NaOH (100 mL). After stirring at room temperature for 24 hours, the reaction mixture was diluted with 100 mL of water and washed with dichloromethane (2×100 mL). The aqueous layer was cooled to 0° C. and acidified with concentrated HCl. The mixture was filtered and washed with water to yield 1.84 g (77%) yellow solid 6. MS m/z 366 (M++23), 343 (M++1).
    • EXAMPLE 9 Preparation of Amide 7 (R2=2,4-dimethylphenyl; R3═H; R4=Me; R5═H; R6=Me)
  • A solution of carboxylic acid 6 (0.337 g, 0.98 mmol) in thionyl chloride (10 mL) was heated at reflux for 1 hour. The solution was cooled and concentrated in vacuo. The residue was diluted with CCl4 and concentrated to remove the residual thionyl chloride. The residue was then dissolved in THF (3.5 mL) and added to a 0° C. solution of methylamine (1.47 mL of 2.0 M solution in THF, 2.94 mmol) in 6.5 mL THF. The reaction was warmed to room temperature and stirred overnight. The mixture was poured into water, filtered, washed with water and dried to yield 0.263 g (75%) of tan solid. MS m/z 357 (M++1).
    • EXAMPLE 10 Preparation of Pyridine 1 (R1═CO2Et; R2=4-nitrophenyl; R3═H; R4═NH2)
  • To a refluxing solution of benzylidene 2 (1.05 g, 3.76 mmol) in 10 mL of acetic acid was added ethyl amidinoacetate acetic acid salt (0.720 g, 3.76 mmol). The resulting solution was heated at reflux overnight. After cooling to room temperature, the resulting precipitate was removed by filtration and washed with water. This impure residue was heated in a minimal amount of ethanol and then filtered to yield 0.527 g (35%) of a yellow solid. MS m/z 412 (M++23), 390 (M++1).
    • EXAMPLE11 Hantzsch Condensation of Benzylidene 8 (R2=3-methoxyphenyl) and 1,3-indandione)
  • The benzylidene 8 (2.00 g, 9.2 mmol), 1,3-indandione (1.34 g, 0.2 mmmol) and ammonium acetate (2.83 g, 36.7 mmol) were added to 30 mL of ethanol and heated to reflux overnight. The reaction mixture was cooled to room temperature and diluted with ethanol. A yellow precipitate was collected by filtration, washed with ethanol, and dried under vacuum to yield 1.98 g (63%) of the dihydropyridine 9. MS m/z 346 (M++1).
    • EXAMPLE 12 Reduction to Prepare Amine 11 (R1═CO2Me; R2=4-methylnaphthyl; R4=Me)
  • To a refluxing suspension of pyridine 10 (0.862 g, 1.97 mmol) in 35 mL of ethanol was added a solution of tin (II) chloride dihydrate (1.33 g, 5.90 mmol) in 6 mL of 1:1 ethanol: concentrated HCl. The resulting solution was heated at reflux overnight. Water was added until a precipitate started to form and the reaction was cooled to room temperature. The mixture was then filtered and washed with water. After drying, the residue was purified by column chromatography eluting with hexanes: ethyl acetate to yield 0.551 g (69%) of an orange solid. MS m/z 431 (M++23), 409 (M++1).
    • EXAMPLE 13 Acetylation of Amine 11 (R1═CO2Et; R2=3,4-methylenedioxyphenyl; R4=Me)
  • To a solution of amine 11 (0.070 g, 0.174 mmol) in 15 mL of dichloromethane was added triethylamine (0.026 g, 0.261 mmol) and acetyl chloride (0.015 g, 0.192 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with water and then extracted with dichloromethane (3×35 mL). The combined organics were washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography eluting with hexanes: ethyl acetate to yield 0.054 g (70%) of amide 12. MS m/z 467 (M++23), 445 (M++1).
    • EXAMPLE 14 Preparation of Carboxylic Acid 13 (R1═CO2Me; R2=3.5-dimethylphenyl; R4=Me; Y═O; n=2)
  • To a suspension of amine 11 (0.079 g, 0.212 mmol) in 5 mL of benzene was added succinic anhydride (0.021 g, 0.212 mmol). After heating at reflux for 24 hours, the reaction mixture was filtered and washed with benzene. The residue was dried under high vacuum and then washed with ether to remove the excess succinic anhydride. This yielded 0.063 g (63%) of carboxylic acid 13. MS m/z 473 (M++1).
    • EXAMPLE 15 Preparation of Carboxylic Acid 13 (R1═CO2Me; R2=3,5-dimethylphenyl; R4=Me; Y═H2; n=1)
  • To a refluxing solution of amine 11 (0.078 g, 0.210 mmol) in 5 mL of acetonitrile was added β-propiolactone (0.015 g, 0.210 mmol). The reaction was heated to reflux for 72 hours before cooling to room temperature. The reaction mixture was concentrated. The residue was mixed with 10% aqueous sodium hydroxide and washed sequentially with ether and ethyl acetate. The aqueous layer was acidified with concentrated HCl and extracted with dichloromethane (2×25 mL). The combined organics were dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography eluting with 5% MeOH in dichloromethane to yield 0.020 g (21%) of an orange solid. MS m/z 467 (M++23), 445 (M++1).
    • EXAMPLE 16 Preparation of Hydroxamic Acid 14 (R1═CO2Me; R2=(4-methyl)-1-naphthyl; Y═O; n=2; R4=Me)
  • To a 0° C. suspension of carboxylic acid 13 (0.054 g, 0.106 mmol) in 10 mL of diethyl ether was added triethylamine (0.014 g, 0.138 mmol) and then ethyl chloroformate (0.014 g, 0.127 mmol). The mixture was stirred at 0° C. for 30 minutes and them warmed to room temperature. A solution of hydroxylamine (0.159 mmol) in methanol was added and the reaction was stirred overnight at room temperature. The mixture was filtered and the residue was washed with ether and dried under vacuum to yield 0.030 g (54%) of a yellow solid. MS m/z 524 (M++1).
    • EXAMPLE 17 Preparation of Amide 15 (R1═CO2Me; R2=3,5-dimethylphenyl; R4=Me)
  • A mixture of amine 11 (0.201 g, 0.54 mmol) and glycolic acid (0.049 g, 0.65 mmol) was heated at 120-160° C. for 30 minutes. During heating, more glycolic acid was added to ensure that excess reagent was present. Once the starting material was consumed, the reaction was cooled to room temperature, and diluted with dichloromethane. The resulting mixture was extracted with 20% NaOH, followed by 10% HCl, and finally water. The combined organics were concentrated and triturated with ether. Purification by column chromatography eluting with ethyl acetate: hexanes yielded 0.012 g (5%) of a yellow solid. MS m/z 453 (M++23), 431 (M++1).
    • EXAMPLE 18 Preparation of Amide 16 (R1═CO2Me; R2=3,5-dimethylphenyl; R4=Me; NR6R7=morpholino)
  • To a 0° C. mixture of amine 11 (0.123 g, 0.331 mmol) in 2 mL of 20% aqueous NaHCO3 and 3 mL of ethyl acetate was added chloroacetyl chloride (0.047 g, 0.413 mmol). The reaction was warmed to room temperature and stirred for 45 minutes. The mixture was poured into a separatory funnel and the aqueous layer was removed. The organic layer containing the crude chloroamide was used without purification. To the ethyl acetate solution was added morpholine (0.086 g, 0.992 mmol) and the reaction was heated to approx. 65° C. overnight. The reaction was diluted with water and cooled to room temperature. After extraction with ethyl acetate (3×25 mL), the combined organics were washed with brine, dried over MgSO4 and concentrated to yield 0.130 g (79%) of a yellow solid. MS m/z 522 (M++23), 500 (M++1).
    • EXAMPLE 19 Preparation of piperazinone 17 (R1═CO2Me; R2=3,5-dimethylphenyl; R4=Me; R7═H)
  • To a 0° C. solution of amide 16 (R6═CH2CH2OH) (0.093 g, 0.20 mmol), tri n-butylphosphine (0.055 g, 0.27 mmol) in 0.35 mL ethyl acetate was slowly added di-tert-butyl azodicarboxylate (0.062 g, 0.27 mmol) in 0.20 mL ethyl acetate. The reaction was allowed to stand for 15 minutes and then heated to 40° C. overnight. 4.2 M ethanolic HCl was added dropwise. The mixture was cooled to 0° C. and allowed to stand for 2 hours. The mixture was filtered and washed with cold ethyl acetate. Purification by column chromatography with 1-5% MeOH in CH2Cl2 yielded 0.011 (12%) of a white solid. MS m/z 478 (M++23), 456 (M++1).
    • EXAMPLE 20 Preparation of 4-Aminoindenopyridine 19 (R1═CO2Me; R4=Me; R6=Me; R7=phenyl)
  • To a solution of 4-chloroindenopyridine 18 (0.069 g, 0.240 mmol) in 10 mL of 2-ethoxyethanol was added N-methylaniline (0.026 g, 0.240 mmol). The reaction was heated at reflux for 96 hours. After cooling to room temperature, the solution was concentrated. The residue was purified by column chromatography eluting with hexanes: ethyl acetate to yield 0.029 g (34%) of an orange solid. MS m/z 359 (M++1).
    • EXAMPLE 21 Preparation of 4-Aminoindenopyridine 19 (R1═CO2Me; R4=Me; R6═H; R7=cyclopentyl) by Palladium Catalyzed Coupling
  • A mixture of 4-chloroindenopyridine 18 (0.100 g, 0.347 mmol), cyclopentylamine (0.035 g, 0.416 mmol), palladium (II) acetate (0.004 g, 0.0017 mmol), 2-(di-t-butylphosphino)biphenyl (0.010 g, 0.0035 mmol), and cesium carbonate (0.124 g, 0.382 mmol) in 10 mL of dioxane was heated at reflux overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×35 mL). The combined organics were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography eluting with ethyl acetate: hexanes. The purified oil was dissolved in ether and cooled to 0° C. To this solution was slowly added 1.0 M HCl in ether. The resulting precipitate was isolated by filtration, washed with ether, and dried under vacuum to yield 0.032 g (25%) of a yellow solid. MS m/z 359 (M++23), 337 (M++1).
  • Following the general synthetic procedures outlined above and in Examples 1-21, the compounds of Table 1 below were prepared.
    TABLE 1
    Figure US20060009481A1-20060112-C00038
    No. R1 R2 R3a R3b R3c R3d R4 MS (M + 1)
    1 CN
    Figure US20060009481A1-20060112-C00039
         		H H H H Me 341
    C7H5O2
    2 CO2Et
    Figure US20060009481A1-20060112-C00040
         		H H H H Me 388
    C7H5O2
    3 CO2t-Bu
    Figure US20060009481A1-20060112-C00041
         		H H H H Me 416
    C7H5O2
    4 CO2t-Bu
    Figure US20060009481A1-20060112-C00042
         		H H H H Me 432
    C8H9O2
    5 CO2Et
    Figure US20060009481A1-20060112-C00043
         		H H H H Me 389
    C6H4NO2
    6 CO2H
    Figure US20060009481A1-20060112-C00044
         		H H H H Me 360
    C7H5O2
    7 CO2Et
    Figure US20060009481A1-20060112-C00045
         		H H H H Me 480
    C14H13O2
    8 CO2Et
    Figure US20060009481A1-20060112-C00046
         		H H H H Me 482
    C8H8BrO2
    9 CO2Et
    Figure US20060009481A1-20060112-C00047
         		H H H H Me 424
    C11H9O
    10 CO2H
    Figure US20060009481A1-20060112-C00048
         		H H H H Me 376
    C8H9O2
    11 CO2Et Ph H H H H Me 344
    12 CO2Et
    Figure US20060009481A1-20060112-C00049
         		H H H H Me 374
    C7H7O
    13 CO2Et
    Figure US20060009481A1-20060112-C00050
         		H H H H Me 434
    C9H11O3
    14 CO2Et
    Figure US20060009481A1-20060112-C00051
         		H H H H Me 454
    C6H4BrO2
    15 CO2Bn
    Figure US20060009481A1-20060112-C00052
         		H H H H Me 450
    C7H5O2
    16
    Figure US20060009481A1-20060112-C00053
    Figure US20060009481A1-20060112-C00054
         		H H H H Me 507
    C11H14NO2 C7H5O2
    17 CO2Me
    Figure US20060009481A1-20060112-C00055
         		H H H H Me 390
    C8H9O2
    18 CO2Me
    Figure US20060009481A1-20060112-C00056
         		H H H H Me 374
    C7H5O2
    19 CO2Et
    Figure US20060009481A1-20060112-C00057
         		H H H H Me 404
    C8H9O2
    20 CO2Et
    Figure US20060009481A1-20060112-C00058
         		H H H H Me 404
    C8H9O2
    21 CO2Et
    Figure US20060009481A1-20060112-C00059
         		H H H H Me 454
    C7H6BrO
    22 CO2Et
    Figure US20060009481A1-20060112-C00060
         		H H H H NH2 411 (M + 23)
    C7H5O2
    23 CO2Et
    Figure US20060009481A1-20060112-C00061
         		H H H H Me 388
    C7H5O2
    25 CO2Et
    Figure US20060009481A1-20060112-C00062
         		H H H H NH2 405
    C8H9O2
    26 CO2Et
    Figure US20060009481A1-20060112-C00063
         		H H H H NH2 390
    C6H4NO2
    27 CO2Et Ph H H H H NH2 345
    28 CO2Et
    Figure US20060009481A1-20060112-C00064
         		H H H H Me 402
    C9H11O
    29 CO2Et
    Figure US20060009481A1-20060112-C00065
         		H H H H Me 483
    C8H8BrO2
    30 CO2Me Ph H H H H Me 330
    31 CO2Et
    Figure US20060009481A1-20060112-C00066
         		H H H H Me 402
    C8H7O2
    32 CO2Et
    Figure US20060009481A1-20060112-C00067
         		H NO2 H H Me 433
    C7H5O2
    33
    Figure US20060009481A1-20060112-C00068
    Figure US20060009481A1-20060112-C00069
         		H H H H Me 413
    C4H4NO2 C7H5O2
    34 CO2Et
    Figure US20060009481A1-20060112-C00070
         		H H H H Me 433
    C7H4NO4
    35 CO2Et
    Figure US20060009481A1-20060112-C00071
         		H H NO2 H Me 433
    C7H5O2
    36 CO2Me
    Figure US20060009481A1-20060112-C00072
         		H H H H Me 398
    C7H4F3
    37 CO2Et
    Figure US20060009481A1-20060112-C00073
         		H H NH2 H Me 403
    C7H5O2
    38 CONH2
    Figure US20060009481A1-20060112-C00074
         		H H H H Me 359
    C7H5O2
    39 CO2Et
    Figure US20060009481A1-20060112-C00075
         		H H H H Me 372
    C8H9
    40 CO2Et
    Figure US20060009481A1-20060112-C00076
         		H NH2 H H Me 403
    C7H5O2
    41 CO2Et
    Figure US20060009481A1-20060112-C00077
         		H H H H Me 334
    C4H3O
    42 CO2Et 2-Thienyl H H H H Me 350
    43 CO2Me
    Figure US20060009481A1-20060112-C00078
         		H H H H Me 358
    C8H9
    44 CO2Me
    Figure US20060009481A1-20060112-C00079
         		H H H H Me 388
    C8H7O2
    45 CO2Me
    Figure US20060009481A1-20060112-C00080
         		H H H H Me 419
    C7H4NO4
    46 CO2Me
    Figure US20060009481A1-20060112-C00081
         		H H H H Me 388
    C9H11O
    47 CO2Me 4-Pyridyl H H H H Me 331
    48 CO2Me
    Figure US20060009481A1-20060112-C00082
         		H H H H Me 374
    C7H5O2
    49 CO2Me
    Figure US20060009481A1-20060112-C00083
         		H H H H Me 454
    C7H4BrO2
    50 CO2Me
    Figure US20060009481A1-20060112-C00084
         		H H H H Me 439
    C7H6BrO
    51 CO2Me
    Figure US20060009481A1-20060112-C00085
         		H H H H Me 358
    C8H9
    52 CO2Et
    Figure US20060009481A1-20060112-C00086
         		H H H H Me 372
    C8H9
    53 CO2Me
    Figure US20060009481A1-20060112-C00087
         		H H H H Me 410
    C11H9O
    54 CO2Me
    Figure US20060009481A1-20060112-C00088
         		H H H H Me 375
    C6H4NO2
    55 CO2Et
    Figure US20060009481A1-20060112-C00089
         		H NHAc H H Me 445
    C7H5O2
    56 CO2Et
    Figure US20060009481A1-20060112-C00090
         		H H NHAc H Me 445
    C7H5O2
    57 CO2Et
    Figure US20060009481A1-20060112-C00091
         		H H H H Me 358
    C7H7
    58 CO2Et
    Figure US20060009481A1-20060112-C00092
         		H H H H Me 358
    C7H7
    59 CO2Et
    Figure US20060009481A1-20060112-C00093
         		H H H H Me 358
    C7H7
    60 CO2Et
    Figure US20060009481A1-20060112-C00094
         		H NO2 H H Me 457
    C7H4F3
    61 CO2Et
    Figure US20060009481A1-20060112-C00095
         		H H NO2 H Me 457
    C7H4F3
    62 CO2Me
    Figure US20060009481A1-20060112-C00096
         		H H H H Me 344
    C7H7
    63 CO2Et
    Figure US20060009481A1-20060112-C00097
         		H NH2 H H Me 427
    C7H4F3
    64 CO2Et
    Figure US20060009481A1-20060112-C00098
         		H H NH2 H Me 427
    C7H4F3
    65 CO2Me
    Figure US20060009481A1-20060112-C00099
         		H H H H Me 466
    C8H3F6
    66 CO2Me
    Figure US20060009481A1-20060112-C00100
         		H H H H Me 344
    C7H7
    67 CO2Me
    Figure US20060009481A1-20060112-C00101
         		H H H H Me 344
    C7H7
    68 CO2Me
    Figure US20060009481A1-20060112-C00102
         		H NO2 H H Me 443
    C7H4F3
    69 CO2Me
    Figure US20060009481A1-20060112-C00103
         		H H NO2 H Me 443
    C7H4F3
    70 CO2Et
    Figure US20060009481A1-20060112-C00104
         		H H H H i-Pr 400
    C8H9
    71 CO2Me
    Figure US20060009481A1-20060112-C00105
         		H NH2 H H Me 413
    C7H4F3
    72 CO2Me
    Figure US20060009481A1-20060112-C00106
         		H H H H Me 399
    C6H3Cl2
    73 CO2Me
    Figure US20060009481A1-20060112-C00107
         		H H H H Et 372
    C8H9
    74 CO2Me
    Figure US20060009481A1-20060112-C00108
         		H H H H Me 398
    C7H4F3
    75 CO2Me
    Figure US20060009481A1-20060112-C00109
         		H H H H Me 394
    C11H9
    76 CO2Me
    Figure US20060009481A1-20060112-C00110
         		H H H H Me 372
    C9H11
    77 CO2Me
    Figure US20060009481A1-20060112-C00111
         		H NO2 H H Me 403
    C8H9
    78 CO2Me
    Figure US20060009481A1-20060112-C00112
         		H H NO2 H Me 403
    C8H9
    79 CO2Me
    Figure US20060009481A1-20060112-C00113
         		H H H H Me 394
    C11H9
    80 CO2Me
    Figure US20060009481A1-20060112-C00114
         		H NHAc H H Me 455
    C7H4F3
    81 CO2Me
    Figure US20060009481A1-20060112-C00115
         		H H H H Me 488
    C6H3Br2
    82 CO2Me
    Figure US20060009481A1-20060112-C00116
         		H NH2 H H Me 373
    C8H9
    83 CO2Me
    Figure US20060009481A1-20060112-C00117
         		H H NH2 H Me 373
    C8H9
    84 CO2Me
    Figure US20060009481A1-20060112-C00118
         		H H H H Me 362
    C7H6F
    85 CO2Me
    Figure US20060009481A1-20060112-C00119
         		H H H H Me 431
    C6H4Br
    86 CO2Me
    Figure US20060009481A1-20060112-C00120
         		H H H H Me 380
    C10H7
    87 CO2Me
    Figure US20060009481A1-20060112-C00121
         		H NO2 H H Me 439
    C11H9
    88 CO2Me
    Figure US20060009481A1-20060112-C00122
         		H H NO2 H Me 439
    C11H9
    89 CO2Me
    Figure US20060009481A1-20060112-C00123
         		H H H H Me 430
    C14H9
    90 CO2Me
    Figure US20060009481A1-20060112-C00124
         		H NH2 H H Me 409
    C11H9
    91 CO2Me
    Figure US20060009481A1-20060112-C00125
         		H H NH2 H Me 409
    C11H9
    92
    Figure US20060009481A1-20060112-C00126
    Figure US20060009481A1-20060112-C00127
         		H H H H Me 397
    C4H4NO2 C8H9
    93 CN
    Figure US20060009481A1-20060112-C00128
         		H H H H Me 325
    C8H9
    94 CO2Me
    Figure US20060009481A1-20060112-C00129
         		H H H H NH2 359
    C8H9
    95 CO2Me
    Figure US20060009481A1-20060112-C00130
         		H H H H NH2 395
    C11H9
    96 CO2H
    Figure US20060009481A1-20060112-C00131
         		H H H H Me 344
    C8H9
    97
    Figure US20060009481A1-20060112-C00132
    Figure US20060009481A1-20060112-C00133
         		H H H H Me 433
    C4H4NO2 C11H9
    98 CN
    Figure US20060009481A1-20060112-C00134
         		H H H H Me 361
    C11H9
    99
    Figure US20060009481A1-20060112-C00135
    Figure US20060009481A1-20060112-C00136
         		H H H H C2H2O2 358
    C2H2O2 C7H5O2
    100
    Figure US20060009481A1-20060112-C00137
    Figure US20060009481A1-20060112-C00138
         		H H H H C2H2O2 357
    C2H2O2/ C 8H10N
    101
    Figure US20060009481A1-20060112-C00139
         		Ph H H H H C2H2O2 314
    C2H2O2
    102
    Figure US20060009481A1-20060112-C00140
    Figure US20060009481A1-20060112-C00141
         		H H H H C2H2O2 361
    C2H2O2 C6H6NO2
    103
    Figure US20060009481A1-20060112-C00142
    Figure US20060009481A1-20060112-C00143
         		H H H H C2H2O2 364
    C2H2O2 C10H7
    104
    Figure US20060009481A1-20060112-C00144
    Figure US20060009481A1-20060112-C00145
         		H H H H C2H2O2 342
    C2H2O2 C8H9
    105 CO2H
    Figure US20060009481A1-20060112-C00146
         		H H H H Me 380
    C11H9
    106 CONH2
    Figure US20060009481A1-20060112-C00147
         		H H H H Me 343
    C8H9
    107 CONHMe
    Figure US20060009481A1-20060112-C00148
         		H H H H Me 357
    C8H9
    108 CONMe2
    Figure US20060009481A1-20060112-C00149
         		H H H H Me 371
    C8H9
    109
    Figure US20060009481A1-20060112-C00150
    Figure US20060009481A1-20060112-C00151
         		H H H H C2H2O2 378
    C2H2O2 C11H9
    110
    Figure US20060009481A1-20060112-C00152
    Figure US20060009481A1-20060112-C00153
         		H H H H C2H2O2 328
    C2H2O2 C7H7
    111
    Figure US20060009481A1-20060112-C00154
    Figure US20060009481A1-20060112-C00155
         		H H H H C2H2O2 356
    C2H2O2 C9H11
    112
    Figure US20060009481A1-20060112-C00156
    Figure US20060009481A1-20060112-C00157
         		H H H H C2H2O2 328
    C2H2O2 C7H7
    113 CO2Me
    Figure US20060009481A1-20060112-C00158
         		H H H H Me 375
    C6H4NO2
    114
    Figure US20060009481A1-20060112-C00159
    Figure US20060009481A1-20060112-C00160
         		H H H H C2H2O2 328
    C2H2O2 C7H7
    115 CO2Me
    Figure US20060009481A1-20060112-C00161
         		H H H H Me 373
    C8H10N
    116 CONH2
    Figure US20060009481A1-20060112-C00162
         		H H H H Me 379
    C11H9
    117
    Figure US20060009481A1-20060112-C00163
    Figure US20060009481A1-20060112-C00164
         		H H H H C2H2O2 365
    C2H2O2 C9H6N
    118 CO2Me
    Figure US20060009481A1-20060112-C00165
         		H H H H Me 375
    C6H4NO2
    119 CONHMe
    Figure US20060009481A1-20060112-C00166
         		H H H H Me 393
    C11H9
    120 CONMe2
    Figure US20060009481A1-20060112-C00167
         		H H H H Me 407
    C11H9
    121 CO2Me
    Figure US20060009481A1-20060112-C00168
         		H H H H Me 381
    C9H6N
    122 CO2Me
    Figure US20060009481A1-20060112-C00169
         		H Cl Cl H Me 463
    C11H9
    123 CO2Me
    Figure US20060009481A1-20060112-C00170
         		H Cl Cl H Me 427
    C8H9
    124 CO2Me
    Figure US20060009481A1-20060112-C00171
         		H H H H Me 381
    C9H6N
    125 CO2Et
    Figure US20060009481A1-20060112-C00172
         		H H H H Me 408
    C11H9
    126 CO2Me
    Figure US20060009481A1-20060112-C00173
         		H Cl Cl H Me 555
    C6H3Br2
    127 CO2Me
    Figure US20060009481A1-20060112-C00174
         		Cl H H Cl Me 427
    C8H9
    128 CO2Me
    Figure US20060009481A1-20060112-C00175
         		H H H H Me 421
    C7H6NO4
    129 CO2Me
    Figure US20060009481A1-20060112-C00176
         		Cl H H Cl Me 558
    C6H3Br2
    130 CO2Me
    Figure US20060009481A1-20060112-C00177
         		H H H H Me 345
    C6H6N
    131 CO2Et
    Figure US20060009481A1-20060112-C00178
         		H Cl Cl H Me 477
    C11H9
    132 CO2Me
    Figure US20060009481A1-20060112-C00179
         		H H H H Me 503
    C6H4Br2N
    133 Ac
    Figure US20060009481A1-20060112-C00180
         		H H H H Me 472
    C6H3Br2
    134 Ac
    Figure US20060009481A1-20060112-C00181
         		H H H H Me 342
    C8H9
    135 CO2Me
    Figure US20060009481A1-20060112-C00182
         		H H H H Me 331
    C5H4N
    136
    Figure US20060009481A1-20060112-C00183
    Figure US20060009481A1-20060112-C00184
         		H H H H Me 527
    C4H4NO2 C6H3Br2
    137
    Figure US20060009481A1-20060112-C00185
    Figure US20060009481A1-20060112-C00186
         		H H H H Me 397
    C4H4NO2 C8H9
    138 CO2Me OH
    Figure US20060009481A1-20060112-C00187
         		H H H H Me 362
    C6H5O2
    139 CO2H
    Figure US20060009481A1-20060112-C00188
         		H H H H Me 474
    C6H3Br2
    140 CO2H
    Figure US20060009481A1-20060112-C00189
         		H H H H Me 344
    C8H9
    141 CO2Me
    Figure US20060009481A1-20060112-C00190
         		H H H H Me 346
    C6H5O
    142 CO2Me
    Figure US20060009481A1-20060112-C00191
         		H H H H Me 380
    C10H7
    143 CO2Me
    Figure US20060009481A1-20060112-C00192
         		H H H H Me 486
    C16H25O
    144 CO2Me
    Figure US20060009481A1-20060112-C00193
         		H H H H Me 436
    C13H11O
    145 CO2Me
    Figure US20060009481A1-20060112-C00194
         		H H H H Me 518
    C7H5Br2O
    146
    Figure US20060009481A1-20060112-C00195
    Figure US20060009481A1-20060112-C00196
         		H H H H Me 557
    C4H4NO2 C7H5Br2O
    147
    Figure US20060009481A1-20060112-C00197
    Figure US20060009481A1-20060112-C00198
         		H Cl Cl H Me 466
    C4H4NO2 C8H9
    148 CO2Et —NHPh H H H H Me 359
    149 CO2Me
    Figure US20060009481A1-20060112-C00199
         		H H H H Me 360
    C7H7O
    150 CO2Me
    Figure US20060009481A1-20060112-C00200
         		H H H H Me 504
    C6H3Br2O
    151
    Figure US20060009481A1-20060112-C00201
    Figure US20060009481A1-20060112-C00202
         		H H H H Me 420
    C4H4NO2 C9H6N
    152 C3H5O3
    Figure US20060009481A1-20060112-C00203
         		H H H H Me 534
    C6H3Br2O
    153
    Figure US20060009481A1-20060112-C00204
    Figure US20060009481A1-20060112-C00205
         		H H H H Me 385
    C4H4NO2 C6H5O
    154
    Figure US20060009481A1-20060112-C00206
    Figure US20060009481A1-20060112-C00207
         		H H H H Me 373
    C2H4NO2 C8H9
    155
    Figure US20060009481A1-20060112-C00208
    Figure US20060009481A1-20060112-C00209
         		H H NO2 H Me 574
    C4H4NO2 C6H3Br2
    156 CO2Me
    Figure US20060009481A1-20060112-C00210
         		H Br H H Me 473
    C11H9
    157 CO2Me
    Figure US20060009481A1-20060112-C00211
         		H H Br H Me 473
    C11H9
    158
    Figure US20060009481A1-20060112-C00212
    Figure US20060009481A1-20060112-C00213
         		H Cl Cl H Me 489
    C4H4NO2 C9H6N
    159
    Figure US20060009481A1-20060112-C00214
    Figure US20060009481A1-20060112-C00215
         		H H NO2 H Me 590
    C4H4NO2 C6H3Br2O
    160
    Figure US20060009481A1-20060112-C00216
    Figure US20060009481A1-20060112-C00217
         		H H H H Me 411
    C3H5O3 C9H6N
    161 CO2Me
    Figure US20060009481A1-20060112-C00218
         		H Br H H Me 436
    C8H9
    162 CO2Me
    Figure US20060009481A1-20060112-C00219
         		H H Br H Me 438
    C8H9
    163 CO2Me
    Figure US20060009481A1-20060112-C00220
         		H Br Br H Me 516
    C8H9
    164
    Figure US20060009481A1-20060112-C00221
    Figure US20060009481A1-20060112-C00222
         		H Cl Cl H Me 597
    C4H4NO2 C6H3Br2
    165
    Figure US20060009481A1-20060112-C00223
    Figure US20060009481A1-20060112-C00224
         		H Cl Cl H Me 480
    C3H5O3 C9H6N
    166 CO2Me
    Figure US20060009481A1-20060112-C00225
         		H Br Br H Me 552
    C11H9
    167 CO2Et
    Figure US20060009481A1-20060112-C00226
         		H Br Br H Me 530
    C8H9
    168 CO2Me
    Figure US20060009481A1-20060112-C00227
         		F H H F Me 540
    C6H3Br2O
    169 CO2Me
    Figure US20060009481A1-20060112-C00228
         		H H NO2 H Me 551
    C6H3Br2O
    170 CO2Me
    Figure US20060009481A1-20060112-C00229
         		H Cl Cl H Me 573
    C6H3Br2O
    171
    Figure US20060009481A1-20060112-C00230
    Figure US20060009481A1-20060112-C00231
         		H H NO2 H Me 444
    C4H4NO2 C8H9
    172
    Figure US20060009481A1-20060112-C00232
    Figure US20060009481A1-20060112-C00233
         		H NO2 H H Me 444
    C4H4NO2 C8H9
    173 CO2Me
    Figure US20060009481A1-20060112-C00234
         		F H H F Me 394
    C8H9
    174
    Figure US20060009481A1-20060112-C00235
    Figure US20060009481A1-20060112-C00236
         		F H H F Me 433
    C4H4NO2 C8H9
    175 CO2Me
    Figure US20060009481A1-20060112-C00237
         		H Br Br H Me 548
    C8H9O2
    176 CO2Me
    Figure US20060009481A1-20060112-C00238
         		H H H H Me 355
    C7H4N
    177 CO2Me
    Figure US20060009481A1-20060112-C00239
         		H NO2 H H Me 421
    C8H9O
    178 CO2Me
    Figure US20060009481A1-20060112-C00240
         		H H NO2 H Me 453 (M + 23)
    C8H9O
    179 CO2Me
    Figure US20060009481A1-20060112-C00241
         		H Cl Cl H Me 443
    C8H9O
    180 CN
    Figure US20060009481A1-20060112-C00242
         		H H H H Me 341
    C8H9O
    181 CO2Me
    Figure US20060009481A1-20060112-C00243
         		H H H H Me 598
    C6H3I2O
    182 CO2Me
    Figure US20060009481A1-20060112-C00244
         		H Cl Cl H Me 435
    C6H3F2
    183 CO2Et
    Figure US20060009481A1-20060112-C00245
         		H H H H Me 387
    C8H10N
    184 CO2Et
    Figure US20060009481A1-20060112-C00246
         		H H H H Me 373
    C7H8N
    185 CO2Me
    Figure US20060009481A1-20060112-C00247
         		H H H H Me 612
    C7H5I2O
    186 CO2Et
    Figure US20060009481A1-20060112-C00248
         		H H H H Me 410
    C9H7N2
    187 CO2Me
    Figure US20060009481A1-20060112-C00249
         		H H NO2 H Me 345
    C6H3I2O
    188 CO2Me
    Figure US20060009481A1-20060112-C00250
         		H Cl Cl H Me 668
    C6H3I2O
    189 CO2Me
    Figure US20060009481A1-20060112-C00251
         		H H NO2 H Me 413
    C6H3F2
    190 CO2H
    Figure US20060009481A1-20060112-C00252
         		H Cl Cl H Me 544
    C6H3Br2
    191 CN
    Figure US20060009481A1-20060112-C00253
         		H H H H Me 565
    C6H3I2O
    192 CO2Me
    Figure US20060009481A1-20060112-C00254
         		H Br H H Me 606 (M + 23)
    C6H3Br2O
    193 CO2Me
    Figure US20060009481A1-20060112-C00255
         		H H Br H Me 584
    C6H3Br2O
    194 CO2Et
    Figure US20060009481A1-20060112-C00256
         		H H H H Me 373
    C7H8N
    195 CO2Et
    Figure US20060009481A1-20060112-C00257
         		H H H H Me 427
    C6H4Cl2N
    196 CO2Et
    Figure US20060009481A1-20060112-C00258
         		H Cl Cl H Me 587
    C6H3Br2O
    197 CO2Et
    Figure US20060009481A1-20060112-C00259
         		H H H H Me 437
    C6H5BrN
    198 CO2Et
    Figure US20060009481A1-20060112-C00260
         		H H H H Me 389
    C7H8NO
    199 CO2Et
    Figure US20060009481A1-20060112-C00261
         		H H H H Me 612
    C6H3I2O
    200 CO2Et
    Figure US20060009481A1-20060112-C00262
         		H Cl Cl H Me 449
    C6H3F2
    201 CO2Me
    Figure US20060009481A1-20060112-C00263
         		H Cl Cl H Me 450
    C9H6N
    202 CO2Me
    Figure US20060009481A1-20060112-C00264
         		H Cl Cl H Me 465
    C7H5F2O
    203 CO2Me
    Figure US20060009481A1-20060112-C00265
         		H H H H Me 396
    C7H5F2O
    204 CO2Me
    Figure US20060009481A1-20060112-C00266
         		H
    Figure US20060009481A1-20060112-C00267
         		H H Me 473
    C8H9 C4H6NO3
    205 CO2Me
    Figure US20060009481A1-20060112-C00268
         		H H H H Me 345
    C6H6N
    206 CO2Me
    Figure US20060009481A1-20060112-C00269
         		H H H H Me 359
    C7H8N
    207 CO2Me
    Figure US20060009481A1-20060112-C00270
         		H Cl Cl H Me 444
    C6H4NO2
    208 CO2Me
    Figure US20060009481A1-20060112-C00271
         		H H H H Me 355
    C7H4N
    209 CO2H
    Figure US20060009481A1-20060112-C00272
         		H H H H Me 366
    C10H7
    210 CO2Me
    Figure US20060009481A1-20060112-C00273
         		H Cl Cl H Me 444
    C6H4NO2
    211 CO2Me
    Figure US20060009481A1-20060112-C00274
         		H Cl Cl H Me 430
    C7H6F
    212 CO2Me
    Figure US20060009481A1-20060112-C00275
         		H H H H Me 416
    C7H3F4
    213 CO2Me
    Figure US20060009481A1-20060112-C00276
         		H Cl Cl H Me 430
    C7H6F
    214 CO2Me
    Figure US20060009481A1-20060112-C00277
         		H H H H Me 413
    C6H4Cl2N
    215 CO2Me
    Figure US20060009481A1-20060112-C00278
         		H OMe OMe H Me 418
    C8H9
    216 CO2Me
    Figure US20060009481A1-20060112-C00279
         		H OMe OMe H Me 454
    C11H9
    217 CO2Me
    Figure US20060009481A1-20060112-C00280
         		H H H H Me 362
    C7H6F
    218 CO2Me
    Figure US20060009481A1-20060112-C00281
         		H
    Figure US20060009481A1-20060112-C00282
         		H H Me 445
    C8H9 C3H6NO2
    219 CO2Me
    Figure US20060009481A1-20060112-C00283
         		H H H H Me 35
    C7H8N
    220 CO2Me —NHPh H H H H Me 345
    221 CO2Me
    Figure US20060009481A1-20060112-C00284
         		H H H H Me 423
    C6H5BrN
    222 CO2Me 2-Pyridyl H H H H Me 353 (M + 23)
    223 CO2Me
    Figure US20060009481A1-20060112-C00285
         		H OMe OMe H Me 459
    C6H3Cl2
    224 CO2Me
    Figure US20060009481A1-20060112-C00286
         		H Cl Cl H Me 485
    C7H3F4
    225 CO2Me
    Figure US20060009481A1-20060112-C00287
         		H H H H Me 345
    C6H6N
    226 CO2Me
    Figure US20060009481A1-20060112-C00288
         		H H NO2 H Me 420
    C6H4NO2
    227 CO2Me
    Figure US20060009481A1-20060112-C00289
         		H H NO2 H Me 420
    C6H4NO2
    228 CO2Me
    Figure US20060009481A1-20060112-C00290
         		H H H H Me 359
    C7H8N
    229 CO2Me
    Figure US20060009481A1-20060112-C00291
         		H H H H Me 396
    C9H7N2
    230 CO2Me
    Figure US20060009481A1-20060112-C00292
         		H OH OH H Me 426
    C11H9
    231 CO2Me
    Figure US20060009481A1-20060112-C00293
         		H H F H Me 376
    C8H9
    232 CO2Me
    Figure US20060009481A1-20060112-C00294
         		H H NO2 H Me 461
    C7H3F4
    233 CO2Me
    Figure US20060009481A1-20060112-C00295
         		H Cl Cl H Me 468
    C10H6F
    234 CO2Me
    Figure US20060009481A1-20060112-C00296
         		H H H H Me 373
    C8H10N
    235 CO2Me
    Figure US20060009481A1-20060112-C00297
         		H H H H Me 375
    C7H8NO
    236 CO2Me
    Figure US20060009481A1-20060112-C00298
         		H NO2 H H Me 443
    C10H6F
    237 CO2Me
    Figure US20060009481A1-20060112-C00299
         		H H NO2 H Me 443
    C10H6F
    238 CO2Me
    Figure US20060009481A1-20060112-C00300
         		H H H H Me 398
    C10H6F
    239 CO2Me
    Figure US20060009481A1-20060112-C00301
         		H Cl Cl H Me 491
    C12H12N
    240 CO2Me
    Figure US20060009481A1-20060112-C00302
         		H
    Figure US20060009481A1-20060112-C00303
         		H H Me 509
    C11H9 H C4H6NO3
    241 CO2Me
    Figure US20060009481A1-20060112-C00304
         		H H
    Figure US20060009481A1-20060112-C00305
         		H Me 473
    C8H9 C4H6NO3
    242 CO2Me
    Figure US20060009481A1-20060112-C00306
         		H H
    Figure US20060009481A1-20060112-C00307
         		H Me 509
    C11H9 C4H6NO3
    243 CO2Me
    Figure US20060009481A1-20060112-C00308
         		H H H H Me 310
    C4H9
    244 CO2Me
    Figure US20060009481A1-20060112-C00309
         		H
    Figure US20060009481A1-20060112-C00310
         		H H Me 524
    C11H9 C4H7N2O3
    245 CO2Me
    Figure US20060009481A1-20060112-C00311
         		H H
    Figure US20060009481A1-20060112-C00312
         		H Me 488
    C8H9 C4H7N2O3
    246 CO2Me
    Figure US20060009481A1-20060112-C00313
         		H H H H Me 308
    C4H7
    247 CO2Me i-Pr H H H H Me 296
    248 CO2Me
    Figure US20060009481A1-20060112-C00314
         		H H H H Me 336
    Cyclohexyl
    249 CO2Me Me H H H H Me 268
    250 CO2Me
    Figure US20060009481A1-20060112-C00315
         		H H
    Figure US20060009481A1-20060112-C00316
         		H Me 474
    C8H9 C4H9N2O2
    251 CO2Me
    Figure US20060009481A1-20060112-C00317
         		H H
    Figure US20060009481A1-20060112-C00318
         		H Me 487
    C8H9 C5H8NO3
    252 CO2Me N- Morpholino H H H H Me 339
    253 CO2Me
    Figure US20060009481A1-20060112-C00319
         		H H H H Me 337
    C5H10N
    254 CO2Me
    Figure US20060009481A1-20060112-C00320
         		H H
    Figure US20060009481A1-20060112-C00321
         		H Me 488
    C8H9 C5H11N2O2
    255 CO2Me
    Figure US20060009481A1-20060112-C00322
         		H
    Figure US20060009481A1-20060112-C00323
         		H H Me 474
    C8H9 C4H9N2O2
    256 CO2Me
    Figure US20060009481A1-20060112-C00324
         		H
    Figure US20060009481A1-20060112-C00325
         		H H Me 456
    C8H9 C4H7N2O
    257 CO2Me
    Figure US20060009481A1-20060112-C00326
         		H
    Figure US20060009481A1-20060112-C00327
         		H H Me 431
    C8H9 C2H4NO2
    258 CO2Me
    Figure US20060009481A1-20060112-C00328
         		H
    Figure US20060009481A1-20060112-C00329
         		H H Me 500
    C8H9 C6H11N2O2
    259 CO2Me
    Figure US20060009481A1-20060112-C00330
         		H
    Figure US20060009481A1-20060112-C00331
         		H H Me 499
    C8H9 C6H12N3O
    260 CO2Me
    Figure US20060009481A1-20060112-C00332
         		H
    Figure US20060009481A1-20060112-C00333
         		H H Me 481
    C8H9 C5H6N3O
    261 CO2Me
    Figure US20060009481A1-20060112-C00334
         		H H
    Figure US20060009481A1-20060112-C00335
         		H Me 500
    C8H9 C6H11N2O2
    262 CO2Me
    Figure US20060009481A1-20060112-C00336
         		H H
    Figure US20060009481A1-20060112-C00337
         		H Me 499
    C8H9 C6H12N3O
    263 CO2Me
    Figure US20060009481A1-20060112-C00338
         		H H
    Figure US20060009481A1-20060112-C00339
         		H Me 431
    C8H9 C2H4NO2

    III. Biological Assays and Activity
  • 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.
  • In this 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.
  • Specifically, enzyme was diluted in PDE buffer (50 mM pH 7.4 Tris, 8.3 mM MgCl2, 1.7 mM EGTA) with 0.1% ovalbumin such that the final signal:noise (enzyme:no enzyme) ratio is 5-10. Substrate (2,8-3H-cAMP or 8-3H-cGMP, purchased from Amersham Pharmacia) was diluted in PDE (4, 5, 7A) buffer to 1 nCi per μl (or 1 gCi/ml). For each test well, 48 μl of enzyme was mixed with 47 μl substrate and 5 μl test compound (or DMSO) in a white Packard plate, followed by shaking to mix and incubation for 15 minutes at room temperature. A 50 μl aliquot of evenly suspended yttrium silicate SPA beads in zinc sulfate was added to each well to terminate the reaction and capture the product. The plate was sealed using Topseal-S (Packard) sheets, and the beads were allowed to settle by gravity for 15-20 minutes prior to counting on a Packard TopCount scintillation counter using a 3H glass program with color quench correction. Output was in color quench-corrected dpm.
  • Test compounds were diluted in 100% DMSO to a concentration 20× final assay concentration. DMSO vehicle alone was added to uninhibited control wells. Inhibition (%) was calculated as follows: Nonspecific ⁢   ⁢ binding ⁢   ⁢ ( NSB ) = the ⁢   ⁢ mean ⁢   ⁢ of ⁢   ⁢ CPM ⁢   ⁢ of ⁢   ⁢ the ⁢   ⁢ substrate + buffer + DMSO ⁢   ⁢ wells Total ⁢   ⁢ Binding ⁢   ⁢ ( TB ) = the ⁢   ⁢ mean ⁢   ⁢ of ⁢   ⁢ the ⁢   ⁢ enzyme + substrate + DMSO ⁢   ⁢ wells % ⁢   ⁢ Inhibition ⁢   ⁢ listed ⁢   ⁢ in ⁢   ⁢ Table ⁢   ⁢ 1 = ( 1 - ( Sample ⁢   ⁢ CPM - NSB ) TB - NSB ) × 100
  • The IC50 values were calculated using the Deltagraph 4-parameter curve-fitting program. The IC50 and % Inhibition data on PDE 4, 5, and 7A are listed for the indicated compounds in Table 2 below.
    TABLE 2
    Ia
    Figure US20060009481A1-20060112-C00340
    MS IC20 (μM)/% inh. @ μM
    No. R1 R2 R3a R3b R3c R3d R4 (M + 1) PDE7A PDE4 PDE5
    6 CO2H
    Figure US20060009481A1-20060112-C00341
         		H H H H Me 360 45% @20 49% @5
    51 CO2Me
    Figure US20060009481A1-20060112-C00342
         		H H H H Me 358 0.055 0.353 2.7
    56 CO2Et
    Figure US20060009481A1-20060112-C00343
         		H H NHAc H Me 445 0.074 0.333 2.5
    70 CO2Et
    Figure US20060009481A1-20060112-C00344
         		H H H H i-Pr 400 2.11
    73 CO2Me
    Figure US20060009481A1-20060112-C00345
         		H H H H Et 372 1.54 0.998
    82 CO2Me
    Figure US20060009481A1-20060112-C00346
         		H NH2 H H Me 373 0.021 0.204 1.11, 0.864
    90 CO2Me
    Figure US20060009481A1-20060112-C00347
         		H NH2 H H Me 409 0.005 0.237, 0.172 2.33
    98 CN
    Figure US20060009481A1-20060112-C00348
         		H H H H Me 361 1.13
    119 CONHMe
    Figure US20060009481A1-20060112-C00349
         		H H H H Me 393 0.658 41% @20
    133 Ac
    Figure US20060009481A1-20060112-C00350
         		H H H H Me 472 1.54
    134 Ac
    Figure US20060009481A1-20060112-C00351
         		H H H H Me 342 1.14
    169 CO2Me
    Figure US20060009481A1-20060112-C00352
         		H H NO2 H Me 551 0.0053 0.184
    170 CO2Me
    Figure US20060009481A1-20060112-C00353
         		H Cl Cl H Me 573 0.0087 0.557
    190 CO2H
    Figure US20060009481A1-20060112-C00354
         		H Cl Cl H Me 544 5.9
    191 CN
    Figure US20060009481A1-20060112-C00355
         		H H H H Me 565 0.593
    197 CO2Et
    Figure US20060009481A1-20060112-C00356
         		H H H H Me 437 0.728 69% @5 0.362
    219 CO2Me
    Figure US20060009481A1-20060112-C00357
         		H H H H Me 359 0.964 61% @5 1.1
    220 CO2Me —NHPh H H H H Me 345 0.084 1.8 0.637
    241 CO2Me
    Figure US20060009481A1-20060112-C00358
         		H H
    Figure US20060009481A1-20060112-C00359
         		H Me 473 0.0035 0.954 0.183
    242 CO2Me
    Figure US20060009481A1-20060112-C00360
         		H H
    Figure US20060009481A1-20060112-C00361
         		H Me 509 0.0038 0.782 0.141
    243 CO2Me
    Figure US20060009481A1-20060112-C00362
         		H H H H Me 310 2.6
    245 CO2Me
    Figure US20060009481A1-20060112-C00363
         		H H
    Figure US20060009481A1-20060112-C00364
         		H Me 488 0.0053 0.875 0.185
    248 CO2Me
    Figure US20060009481A1-20060112-C00365
         		H H H H Me 336 0.783 0.171 0.649
    250 CO2Me
    Figure US20060009481A1-20060112-C00366
         		H H
    Figure US20060009481A1-20060112-C00367
         		H Me 474 0.0074 0.684 2.4
    251 CO2Me
    Figure US20060009481A1-20060112-C00368
         		H H
    Figure US20060009481A1-20060112-C00369
         		H Me 487 0.0054 0.754 0.26
    253 CO2Me
    Figure US20060009481A1-20060112-C00370
         		H H H H Me 337 0.905 0.85 0.303
    254 CO2Me
    Figure US20060009481A1-20060112-C00371
         		H H
    Figure US20060009481A1-20060112-C00372
         		H Me 488 0.0067 0.664 0.765
    261 CO2Me
    Figure US20060009481A1-20060112-C00373
         		H H
    Figure US20060009481A1-20060112-C00374
         		H Me 500 0.0063 0.477 0.63
    262 CO2Me
    Figure US20060009481A1-20060112-C00375
         		H H
    Figure US20060009481A1-20060112-C00376
         		H Me 499 0.008 0.702 3.7

Claims (15)

1. A compound having the structure
Figure US20060009481A1-20060112-C00377
wherein
(a) R1 is selected from the group consisting of:
(i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 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 C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
(ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 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 C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
(iii) cyano;
(iv) a lactone or lactam formed with R4;
(v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 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 R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;
(b) R2 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C3-7 cycloalkyl; or R2 is
Figure US20060009481A1-20060112-C00378
(c) R3 is from one to four groups independently selected from the group consisting of:
(i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl;
(ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
(iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3 alkoxyl, carboxyalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein , R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6,
(d) R4 is selected from the group consisting of (i) hydrogen, (ii) C1-3 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;
wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and
(e) X is selected from S and O;
with the proviso that when R4 is isopropyl, then R3 is not halogen, and with the proviso that one or more of R1, R2, R3 or R4 comprses heteroaryl or heterocycle and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
2. The compound of claim 1, wherein R1 is COOR6, wherein R6 is selected from H, optionally substituted C1-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl.
3. The compound of claim 2, wherein R6 is selected from H, or C1-8 straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.
4. The compound of claim 1, wherein R2 is selected from optionally substituted aryl and optionally substituted heteroaryl.
5. The compound of claim 4 wherein the aryl or heteroaryl groups are substituted with one to five members selected from the group consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano, and nitro.
6. The compound of claim 4 wherein, R2 is optionally substituted phenyl or napthyl or R2 is
Figure US20060009481A1-20060112-C00379
optionally substituted, wherein the optional substituents are from one to three members selected from the group consisting of halogen, alkyl, hydroxy, cyano, and nitro.
7. The compound of claim 1 wherein R3 is selected from:
(i) hydrogen, halo, C1-8 straight or branched chain alkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, and hydroxy;
(ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylC1-8alkyl, C3-7 cycloalkyl, carboxyC1-8alkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
(iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyC1-8alkyl, aryl, arylalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6.
8. The compound of claim 7, wherein R3 is selected from the group consisting of:
Figure US20060009481A1-20060112-C00380
9. The compound of claim 1 wherein R4 is selected from hydrogen, and C1-3 straight or branched chain alkyl.
10. The compound of claim 9, wherein R4 is selected from methyl and amino.
11. The compound of claim 1 wherein R1 is COOR6 and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl.
12. The compound of claim 1 wherein R1 is COOR6 where R6 is alkyl, R2 is substituted phenyl or naphthyl, and R3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:
Figure US20060009481A1-20060112-C00381
and R4 is selected from hydrogen, C1-3 straight or branched chain alkyl and amino and X is Oxygen.
13. A compound having the structure:
Figure US20060009481A1-20060112-C00382
wherein
(a) R1 is selected from the group consisting of:
(i) —COR5, wherein R5 is selected from H, optionally substituted C1-8 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 C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
(ii) COOR6, wherein R6 is selected from H, optionally substituted C1-8 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 C1-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R21 taken together form a heterocycle or heteroaryl;
(iii) cyano;
(iv) a lactone or lactam formed with R4;
(v) —CONR7R8 wherein R7 and R8 are independently selected from H, C1-8 straight or branched chain alkyl, C3-7 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 R7 and R8 taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group;
(b) R2 is —NR15R16 wherein R15 and R16 are independently selected from hydrogen, optionally substituted C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R15 and R16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R2 is NHR16, R1 is not —COOR6 where R6 is ethyl;
(c) R3 is from one to four groups independently selected from the group consisting of:
(i) hydrogen, halo, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, aryl, heteroaryl, and heterocyclyl;
(ii) —NR10R11 wherein R10 and R11 are independently selected from H, C1-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group;
(iii) —NR12COR13 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C1-3alkoxyl, carboxyalkyl, R30R31N (CH2)p—, R30R31NCO(CH2)p—, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R31 are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl;
(d) R4 is selected from the group consisting of (i) hydrogen, (ii) C13 straight or branched chain alkyl, (iii) benzyl and (iv) —NR13R14, wherein R13 and R14 are independently selected from hydrogen and C1-6 alkyl;
wherein the C1-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C1-8 alkoxy, cyano, C1-4 carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C1-8 carboxylate, amino, NR13R14, aryl and heteroaryl; and
(e) X is selected from S and O;
with the proviso that one or more of R1, R2, R3 or R4 comprises heteroaryl or heterocycle and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
14. The compound of claim 13, wherein R1 is COOR6 wherein R6 is alkyl, R2 is NR6R7, and R3 is selected from the group consisting of
Figure US20060009481A1-20060112-C00383
halogen, and hydrogen, and R4 is selected from hydrogen, C1-3 straight or branched chain alkyl and amino and X is Oxygen.
15-47. (canceled)
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