EP1385843A1 - Arylindenopyridines with pde inhibiting activity - Google Patents

Arylindenopyridines with pde inhibiting activity

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Publication number
EP1385843A1
EP1385843A1 EP02725675A EP02725675A EP1385843A1 EP 1385843 A1 EP1385843 A1 EP 1385843A1 EP 02725675 A EP02725675 A EP 02725675A EP 02725675 A EP02725675 A EP 02725675A EP 1385843 A1 EP1385843 A1 EP 1385843A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
heteroaryl
aryl
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02725675A
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German (de)
French (fr)
Inventor
Geoffrey R. Heintzelman
Kristin M. Averill
John H. Dodd
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceuticals Inc
Original Assignee
Ortho McNeil Pharmaceutical Inc
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Filing date
Publication date
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Publication of EP1385843A1 publication Critical patent/EP1385843A1/en
Withdrawn legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P15/06—Antiabortive agents; Labour repressants
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • C07D401/04—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
    • 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

Definitions

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

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Abstract

This invention provides novel arylindenopyridines of the formula (I), 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

ARYLINDENOPYRIDINES WITH PDE INHIBITING ACTIVITY.
Cross-Reference to Related Applications
This application claims the benefit under 35 U.S.C. § 119(e) of provisional application Serial No. 60/284,465, filed on April 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 PDE1 B, which preferentially hydrolyze cGMP, and PDE1 C which exhibits a high affinity for both cAMP and cGMP. PDE2 family is characterized as being specifically stimulated by cGMP. PDE2A is specifically inhibited by erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA). Enzymes in the PDE3 family (e.g. PDE3A, PDE3B) 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 IC5o'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):
Summary of the Invention
This invention provides a compound having the structure of Formula I
Formula I
or a pharmaceutically acceptable salt thereof, wherein (a) Ri is selected from the group consisting of:
(i) -COR5, wherein R5 is selected from H, optionally substituted Cι_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 NR20R2ι wherein R2o and R2ι are independently selected from the group consisting of hydrogen, C-ι-8 straight or branched chain alkyl, C3.7 cycloalkyl, benzyl, aryl, or heteroaryl or NR2oR2i taken together form a heterocycle or heteroaryl;
(ii) COOR6, wherein R6 is selected from H, optionally substituted Cι-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 Cι-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R2o and R2ι are independently selected from the group consisting of hydrogen, Cι-8 straight or branched chain alkyl, C3- 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, Cι_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, C-ι-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, Cι-4 carboalkoxy, trifluoromethyl, Cι-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, Cι-8 carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) -NR10Rn wherein R10 and R-H are independently selected from H, Cι_8 straight or branched chain alkyl, arylalkyl, C3_ 7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or Rio and R-M taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) -NR12COR-|3 wherein R12 is selected from hydrogen or alkyl and R-ι3 is selected from hydrogen, alkyl, substituted alkyl, Cι-3alkoxyl, carboxyalkyl, R30R3iN (CH2)p__, R3oR3iNCO(CH2)p-, aryl, arylalkyl, heteroaryl and heterocyclyl or Rι2 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein , R30 and R3ι 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) R is selected from the group consisting of (i) hydrogen, (ii) C-1-3 straight or branched chain alkyl, (iii) benzyl and (iv) -NRι3R-|4) wherein R13 and Rι are independently selected from hydrogen and C-ι-6 alkyl; wherein the Cι-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3- cycloalkyl, Cι-8 alkoxy, cyano, Cι- carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, Cι-8 carboxylate, amino, NRι3R-ι , 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 l wherein R-i, R3 and R4 are as described above and R2 is - NR15R16 wherein R15 and R16 are independently selected from hydrogen, optionally substituted Cι-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or R-ι5and R16 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R2 is NHR-IΘ, Ri is not -COORδ where Re 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 Ri are COORβ, wherein Re is selected from H, optionally substituted Cι-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl. Preferably RQ is H, or C-t-s straight or branched chain alkyl which may be optionally substituted with a substituent selected from CN and hydroxy.
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 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-
Preferred substituents for R3 include: (i) hydrogen, halo, C-|.8 straight or branched chain alkyl, Cι-8 alkoxy, cyano, C-ι-4 carboalkoxy, trifluoromethyl, Cι-8 alkylsulfonyl, halogen, nitro, and hydroxy;
(ii) -NR10R11 wherein R^ and Rn are independently selected from H, C -8 straight or branched chain alkyl, arylCι-8alkyl,
C3- cycloalkyl, carboxyCι-8alkyl, aryl, heteroaryl, and heterocyclyl or R-io and Rn taken together with the nitrogen form a heteroaryl or heterocyclyl group;
(iii) -NRι2COR-ι3 wherein R12 is selected from hydrogen or alkyl and R-13 is selected from hydrogen, alkyl, substituted alkyl, Cι-3alkoxyI, carboxyCι-8alkyl, aryl, arylalkyl, R30R31N (CH2)P-, R3oR3iNCO(CH2)p-, heteroaryl and heterocyclyl or R-ι2 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
, alkyl(CO)NH-, NH2, and NO2.
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, Ri is COORδ and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl or R2 is NRi5Ri6-
More particularly, Ri is COOR6 where R6 is alkyl, R2 is substituted phenyl or naphthyl or R2 is NRι5Rι6, and R3 is selected from the group consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:
, alkyl(CO)NH- 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:
Compound 22 H-indeno[1 ,2-ib]pyridine-3-carboxylic acid, 2-amino-4-( ,3- benzodioxol-5-yl)-5-oxo-, ethyl ester
Compound 24 H-indeno[1 ,2-j ]pyridine-3-carboxylic acid, 4-(6-bromo-1 ,3- benzodioxol-5-yl)-2-methyI-5-oxo-, ethyl ester
Compound 40 H-indeno[1 ,2-b]pyridine-3-carboxylic acid, 7-amino-4-(1 ,3- benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
Compound 49 H-indeno[1 ,2-j ]pyridine-3-carboxyIic acid, 4-(6-bromo-1 ,3- benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester
Compound 51 H-indeno[1 ,2-j ]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyI)-2-methyl-
5-oxo-, methyl ester
Compound 56 5H-indeno[1 ,2- _>]pyridine-3-carboxylic acid, 8-(acetylamino)-4-(1 ,3- benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
Compound 67 5H-indeno[1 ,2-j ]pyridine-3-carboxylic acid, 2-methyl-4-(3- methylphenyl)-5-oxo-, methyl ester
Compound 82
5/-/-indeno[1 ,2-ι ]pyridine-3-carboxylic acid, 7-amino-4-(3,5- dimethylphenyl)-2-methyl-5-oxo-, methyl ester
Compound 90 H-indeno[1 ,2-b]pyridine-3-carboxylic acid, 7-amino-2-methyl-4-(4- methyl-1-naphthalenyI)-5-oxo-, methyl ester
Compound 169 5H-indeno[1 ,2-£>]pyridine-3-carboxylic acid, 4-(3,5-dibromo-4- hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl ester
Compound 170 5H-indeno[1 ,2-j ]pyridine-3-carboxylic acid, 7,8-dichloro-4-(3,5- dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl ester
Compound 192 5H-indeno[1 ,2-ι ]pyridine-3-carboxylic acid, 7-bromo-4-(3,5-dibromo-4- hydroxyphenyl)-2-methyl-5-oxo-, methyl ester
Compound 193 5H-indeno[1 ,2-j ]pyridine-3-carboxylic acid, 8-bromo-4-(3,5-dibromo-4- hydroxyphenyl)-2-methyl-5-oxo-, methyl ester
Compound 241
5H-indeno[1 ,2-j ]pyridine-3-carboxylic acid, 8-[(3-carboxy-1- oxopropyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
Compound 242
5H-indeno[1 ,2-jb]pyridine-3-carboxylic acid, 8-[(3-carboxy-1 - oxopropyl)amino]-2-methyl-4-(4-methyl-1 -naphthalenyl)-5-oxo-, methyl ester
Compound 245 5H-indeno[1 ,2-ι ]pyridine-3-carboxyIic acid, 4-(3,5-dimethylphenyl)-8- [[4-(hydroxyamino)-1 ,4-dioxobutyl]amino]-2-methyl-5-oxo-, methyl ester
Compound 250 5H-indeno[1 ,2- ]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)~8- [[[(2-hydroxyethyl)amino]acetyl]amino]-2-methyl-5-oxo-, methyl ester
Compound 251 5H-indeno[1 ,2-j ]pyridine-3-carboxylic acid, 8-[(4-carboxy-1- oxobutyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
Compound 254
5H-indeno[1 ,2-£.]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-8-
[[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-methyl-5-oxo-, methyl ester
Compound 261 5H-indeno[1 ,2-j ]pyridine-3-carboxylic acid, 4-(3,5-dimethylphenyl)-2- methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-, methyl ester
Compound 262 5H-indeno[1 ,2-/)]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 treatable by the instant pharmaceutical composition include, without limitation, organ transplantation, autoimmune disorders (e.g. arthritis), immune challenge such as a bee sting, inflammatory bowel disease, bronchial disorders (e.g. asthma), HIV/AIDS, cardiovascular disorder, erectile dysfunction, allergies, and psoriasis. 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-Iymphocytes, muscle cells, neuro cells, adipose tissue cells, monocytes, macrophages, fibroblasts.
Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art. The instant compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. 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, Cι-C8-alkyl, Cι-C8-alkoxyl, CrC8-alkylthio, Cι-C8-alkyl-amino, di(CrC8-aIkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, Cι-C8- alkyl-CO-O-, C-i-C8-alkyl-CO-NH-, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl(cι-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, CrC8-alkyl, Cι-C8-alkoxyl, C-i-C8- alkylthio, Cι-C8-alkyl-amino, di(Cι-C8-alkyl)amino, (mono-, di-, t -, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, Cι-C8-alkyl-CO-O-, C 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, C-i-Cs-alkyl, C-i-C8- alkoxyl, CrC8-aIkyIthio, Cι-C8-alkyl-amino, di(Cι-C8-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, Cι-C8-aIkyl-CO-O-, Cι-C8-alkyl-CO-NH-, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1 H-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 quatemized. The heterocyclic group may be attached at any heteroatom or carbon atom.
Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1 ,3-dioxolane; dioxanyl; thietanyl; 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., Cι-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.
Scheme 1
Procedures described in Scheme 1 , wherein R3a, R3b, R3c, and R3cι are independently any R3 group, and R-i, 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 ef al., supra). When the desired enamines are not available, alternate Hantzsch conditions may be utilized which involve adding ammonium acetate to the reaction. The resulting dihydropyridines 4 are oxidized with chromium trioxide to obtain the desired pyridines 1 (Petrow ef al, supra). 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 ).
Scheme 2
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. Scheme 3
The procedure for making compounds where R 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.
Scheme 4
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. Scheme 5
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.
Scheme 6
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.; Kemick, W. J. Chem. Soc, Perkin Trans. 1 1972, 2019) can provide the corresponding carboxylic acids 13. These carboxylic acids are then converted to the hydroxamic acids 14 by treatment with ethyl chloroformate and hydroxylamine (Reddy, A.S.; Kumar, M.S.; Reddy, G.R. Tetrahedron Lett. 2000, 41 , 6285). Scheme 7
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.
Scheme 8
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. Scheme 9
1) CICOCH2CI
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).
Scheme 10
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 Dihvdropyridine 4
(Ri = COOMe: R? = 3,5-dimethylphenyl; R^ = Cl; R ^ = 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 Dihvdropyridine 4 (Ri = CO?Me; R? = 2.4-dimethylphenyl; Ra = 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 Dihvdropyridine 4 to Pyridine 1
(Ri = COOMe; R? = 3.5-dimethylphenyl; Rah,r. = Cl: R^ = H; R4 = 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 Dihvdropyridine 4 to Pyridine 1 (Rι=COOMe; R?=(4-methyl)-1 -naphthyl; R3h f. =H. NO?/NO?. 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 1.303g (37%) of pyridine 1 (R3b = NO2; R3c = H) and 0.765 g (21%) of its regioisomer (R3b = H: R3c = N02). MS m/z 461 (M++23), 439 (M++1 ).
EXAMPLE 5
Alternate Three Component Hantzsch Reaction to Form Dihvdropyridine 4 (Ri = CO?Me; R? = cvclohexyl; 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 Dihvdropyridine 4 - (Ri = CO?Me: R? = cvclohexyl: Ra = 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 MnO Oxidation of Dihvdropyridine 4 (Ri = CO?Me; R? = 4-(dimethylamino)phenyl; Ra = 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 0.43g (88%) of orange solid 1. MS m/z 395 (M++23), 373 (M++1 ).
EXAMPLE 8 Cleavage of Carboxylic Ester 5 (R? = 2,4-dimethylphenyl; Ra = 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 x 100 mL). The aqueous layer was cooled to 0°C and acidified with concentrated HCI. 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 (R? = 2,4-dimethylphenyl; Ra = H: R4 = Me: RR = H: RQ = 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 CCI4 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 0.263g (75%) of tan solid. MS m/z 357 (M++1).
EXAMPLE 10 Preparation of Pyridine 1 (Ri = CO?Et: R? = 4-nitrophenyl; Ra = H; R4 = NH?)
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 0.527g (35%) of a yellow solid. MS m/z 412 (M++23), 390 (M++1 ). EXAMPLE 11
Hantzsch Condensation of Benzylidene 8 (R? = 3-methoxyphenyl) and 1 ,3-indandione)
The benzylidene 8 (2.00g, 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 (Ri = CO?Me: R? = 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 HCI. 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
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 x 35 mL). The combined organics were washed with brine, dried over MgS0 , 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 (Ri = CO?Me: R? = 3.5-dimethylphenyl; R = 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 (Ri = CO?Me; R? = 3,5-dimethylphenyl; R4 = Me: Y = Hg: 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 HCI and extracted with dichloromethane (2 x 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 (Ri = CO?Me; 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
(Ri = COgMe: R? = 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% HCI, 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 (Ri = CO?Me; R? = 3.5-dimethylphenyl; R4 = Me; NRβR7 = 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 x 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 (Ri = CO?Me: R? = 3.5-dimethylphenyl; R4 = Me; R = 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-ferf-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 HCI 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 CH2CI2 yielded 0.011 (12%) of a white solid. MS m/z 478 (M++23), 456 (M++1).
EXAMPLE 20
Preparation of 4-Aminoindenopyridine 19 (Ri = CO2Me; R = Me; RQ = Me: R7 = phenyl)
To a solution of 4-chIoroindenopyridine 18 (0.069 g, 0.240 mmol) in 10 mL of 2-ethoxyethanoI 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 (Ri = CO?Me; R = Me; RR = H; R7 = cvclopentyl) 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 (0.01 Og, 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 x 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 HCI 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
la
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 (50mM pH 7.4 Tris, 8.3mM MgCI2, 1.7mM EGTA) with 0.1 % ovalbumin such that the final signaknoise (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 μCi/ml). For each test well, 48μl of enzyme was mixed with 47μl substrate and 5μl test compound (or DMSO) in a white Packard plate, followed by shaking to mix and incubation for 15 minutes at room temperature. A 50μl 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 20x 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 - HSB)) X 100
TB-NSB
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

Claims

CLAIMSWhat is claimed is:
1. A compound having the structure
Formula I
wherein
(a) Ri is selected from the group consisting of:
(i) -COR5, wherein R5 is selected from H, optionally substituted C-ι_8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C-i-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR2oR2i wherein R2o and R2ι are independently selected from the group consisting of hydrogen, C-i-s straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR2oR2i taken together form a heterocycle or heteroaryl;
(ii) COORβ, wherein RΘ is selected from H, optionally substituted Cι_8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C-ι-8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR2oR2i wherein R2o and R21 are independently selected from the group consisting of hydrogen, Cι-8 straight or branched chain alkyl, C3-7 cycloalkyl, benzyl, aryl, or heteroaryl or NR20R2ι taken together form a heterocycle or heteroaryl; (iii) cyano;
(iv) a lactone or lactam formed with R4; (v) -CONR R8 wherein R and R8 are independently selected from H, C-ι-8 straight or branched chain alkyl, C3- 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, C-i-8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C1-8 alkoxy, cyano, Cι- carboalkoxy, trifluoromethyl, C1-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, Cι-8 carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) -NR10R11 wherein R-io and R-n are independently selected from H, C-i-s straight or branched chain alkyl, arylalkyl, C3- cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R10 and R-n taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) -NRι2CORι3 wherein R-ι2 is selected from hydrogen or alkyl and ι3 is selected from hydrogen, alkyl, substituted alkyl, Cι-3alkoxyl, carboxyalkyl, R3o 3iN (CH2)P-, R3oR3iNCO(CH2)p-, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R13 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein , R3o 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) C-i-3 straight or branched chain alkyl, (iii) benzyl and (iv) -NRι3Rι4, wherein R13 and R-i4 are independently selected from hydrogen and Ci_6 alkyl; wherein the Cι-3alkyl and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, Cι-8 alkoxy, cyano, C-i- carboalkoxy, trifluoromethyl, Ci-8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, Cι-8 carboxylate, amino, NR13Rι4, 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 the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
2. The compound of Claim 1 , wherein Ri is COORβ. wherein RQ is selected from H, optionally substituted Cι-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 Cι-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 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, C-ι-8 straight or branched chain alkyl, Cι-8 alkoxy, cyano, C-i-4 carboalkoxy, trifluoromethyl, Cι-8 alkylsulfonyl, halogen, nitro, and hydroxy; (ii) -NR10R11 wherein R-io and Rn are independently selected from
H, Ci-8 straight or branched chain alkyl, arylCι.8alkyl, C3- cycloalkyl, carboxyCι-8alkyl, aryl, heteroaryl, and heterocyclyl or R-io and R11 taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) -NR-i2CORi3 wherein R-ι2 is selected from hydrogen or alkyl and
R-i3 is selected from hydrogen, alkyl, substituted alkyl, Cι_ 3alkoxyl, carboxyCι-8alkyl, aryl, arylalkyl, R30R3iN (CH2)P-, R3oR3iNCO(CH2)p-, heteroaryl and heterocyclyl or R-ι2 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:
, alkyl(CO)NH- NH2, and NO2.
9. The compound of claim 1 wherein R is selected from hydrogen, and C-ι-3 straight or branched chain alkyl.
10. The compound of claim 9, wherein R is selected from methyl and amino.
11. The compound of claim 1 wherein R-i is COORβ and R2 is selected from the group consisting of substituted phenyl, and substituted naphthyl.
12. The compound of claim 1 wherein R-i is COORβ 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:
, alkyl(CO)NH- and R4 is selected from hydrogen, Cι_3 straight or branched chain alkyl and amino and X is Oxygen.
13. A compound having the structure:
Formula
wherein
(a) R-i is selected from the group consisting of:
(i) -COR5, wherein R5 is selected from H, optionally substituted C-i-s 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 Cι_8 alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R2o and R21 are independently selected from the group consisting of hydrogen, C-ι-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 Re is selected from H, optionally substituted Cι-8 straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C-i-β alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR20R21 wherein R2o 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 NR2QR2I 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, C-i-s 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 R-i6 are independently selected from hydrogen, optionally substituted C-|.8 straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or Risand R-ι6 taken together with the nitrogen form a heteroaryl or heterocyclyl group; with the proviso that when R2 is NHR-ι6, Ri is not -COOR6 where Re is ethyl;
(c) R3 is from one to four groups independently selected from the group consisting of:
(i) hydrogen, halo, C-i-s straight or branched chain alkyl, arylalkyl, C3-7 cycloalkyl, C-ι-8 alkoxy, cyano, Cι_4 carboalkoxy, trifluoromethyl, C-i.8 alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C-ι.8 carboxylate, aryl, heteroaryl, and heterocyclyl; (ii) -NR10R11 wherein R-io and Ru are independently selected from H, C-ι-8 straight or branched chain alkyl, arylalkyl, C3-
7 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R-|0 and Ru taken together with the nitrogen form a heteroaryl or heterocyclyl group; (iii) -NRι2CORi3 wherein R12 is selected from hydrogen or alkyl and R13 is selected from hydrogen, alkyl, substituted alkyl, C-i-3alkoxyl, carboxyalkyl, R30R3ιN (CH2)P-, R3oR3iNCO(CH2)p-, aryl, arylalkyl, heteroaryl and heterocyclyl or R12 and R-ι3 taken together with the carbonyl form a carbonyl containing heterocyclyl group, wherein, R30 and R3ι 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) C-ι.3 straight or branched chain alkyl, (iii) benzyl and (iv) -NR 3R14, wherein R13 and Ru are independently selected from hydrogen and Cι-6 alkyl; wherein the Chalky! and benzyl groups are optionally substituted with one or more groups selected from C3-7 cycloalkyl, C-ι.8 alkoxy, cyano, C-i- carboalkoxy, trifluoromethyl, C-i-s alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C-i-s carboxylate, amino, NR-13R14, aryl and heteroaryl; and
(e) X is selected from S and O; and the pharmaceutically acceptable salts, esters and pro-drug forms thereof.
14. The compound of Claim 13, wherein R-i is COOR6 wherein R6 is alkyl, R2 is NR6R7) and R3 is selected from the group consisting of
, alkyl(CO)NH-, NH2, NO2, halogen, and hydrogen, and R is selected from hydrogen, C-1-3 straight or branched chain alkyl and amino and X is Oxygen.
15. The compound of Claim 1 , which is 5H-indeno[1 ,2-j ]pyridine-3- carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyi-5-oxo-, methyl ester.
16. The compound of Claim 1 , which is 5H-indeno[1 ,2-j ]pyridine-3- carboxylic acid, 8-(acetylamino)-4-(1 ,3-benzodioxol-5-yl)-2-methyl-5-
0x0-, ethyl ester.
17. The compound of Claim 1 , which is 5H-indeno[1 ,2-jb]pyridine-3- carboxylic acid, 7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester.
18. The compound of Claim 1 , which is 5H-indeno[1 ,2- j]pyridine-3- carboxylic acid, 7-amino-2-methyl-4-(4-methyl-1 -naphthalenyl)-5-oxo-, methyl ester.
19. The compound of Claim 1 , which is 5H-indeno[1 ,2-j ]pyridine-3- carboxylic acid, 4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5- oxo-, methyl ester.
20. The compound of Claim 1 , which is 5H-indeno[1 ,2-jb]pyridine-3- carboxylic acid, 7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2- methyl-5-oxo-, methyl ester.
21. The compound of Claim 1 , which is 5/-/-indeno[1 ,2- ]pyridine-3- carboxylic acid, 8-[(3-carboxy-1-oxopropyI)amino]-4-(3,5- dimethylphenyl)-2-methyl-5-oxo-, methyl ester.
22. The compound of Claim 1 , which is 5H-indeno[1 ,2-jb]pyridine-3- carboxylic acid, 8-[(3-carboxy-1 ~oxopropyl)amino]-2-methyl-4-(4- methyl-1-naphthalenyl)-5-oxo-, methyl ester.
23. The compound of Claim 1 , which is 5H-indeno[1 ,2-ι ]pyridine-3- carboxylic acid, 4-(3,5-dimethylphenyl)-8-[[4-(hydroxyamino)-1 ,4- dioxobutyl]amino]-2-methyl-5-oxo-, methyl ester.
24. The compound of Claim 1 , which is 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.
25. The compound of Claim 1 , which is 5H-indeno[1 ,2-j ]pyridine-3- carboxylic acid, 8-[(4-carboxy-1-oxobutyl)amino]-4-(3,5- dimethylphenyl)-2-methyl-5-oxo-, methyl ester.
26. The compound of Claim 1 , which is 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.
27. The compound of Claim 1 , which is 5H-indeno[1 ,2-jb]pyridine-3- carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-8-[(4- morpholinylacetyl)amino]-5-oxo-, methyl ester.
28. The compound of Claim 1 , which is 5H-indeno[1 ,2-j ]pyridine-3- carboxylic acid, 4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1- piperazinylacetyl)amino]-, methyl ester.
29. The compound of Claim 1 , which is 5H-indeno[1 ,2-j ]pyridine-3- carboxylic acid, 2-amino-4-(1 ,3-benzodioxol-5-yl)-5-oxo-, ethyl ester.
30. The compound of Claim 1 , which is 5H-indeno[1 ,2-j ]pyridine-3- carboxylic acid, 4-(6-bromo-1 ,3-benzodioxol-5-yl)-2-methyi-5-oxo-, ethyl ester.
31. The compound of Claim 1 , which is 5 -/-indeno[1 ,2-ιb]pyridine-3- carboxylic acid, 7-amino-4-(1 ,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester.
32. The compound of Claim 1 , which is 5H-indeno[1 ,2-j ]pyridine-3- carboxylic acid, 4-(6-bromo-1 ,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester.
33. The compound of Claim 1 , which is 5 -/-indeno[1 ,2-j ]pyridine-3- carboxylic acid, 2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester.
34. The compound of Claim 1 , which is 5H-indeno[1 ,2π ]pyridine-3- carboxylic acid, 7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5- oxo-, methyl ester.
35. The compound of Claim 1 , which is 5H-indeno[1 ,2π ]pyridine-3- carboxylic acid, 8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5- oxo-„ methyl ester.
36. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
37. A pharmaceutical composition comprising the compound of claim 13 and a pharmaceutically acceptable carrier.
38. 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 compound of claim 1 or 13.
39. 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 or 13 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by reducing PDE activity in appropriate cells in the subject.
40. The method of claim 38 or 39 comprising administering to the subject a therapeutically or prophylactically effective dose of pharmaceutical composition of Claim 36 or 37.
41. A method of inhibiting PDE activity in a subject, which comprises contacting one or more T-cells with a therapeutically effective dose of the compound of claim 1 or 13.
42 The method of claim 38, 39 or 41 , wherein the disorder is selected from the group consisting of transplant-related disorders, inflammatory- related disorders, AIDS-related disorders, vascular diseases, and erectile dysfunction.
43. The method of claim 38, wherein the disorder is selected from the group consisting of 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.
44. A method of artificially modifying an animal, comprising administering to the animal's T-cells a compound of claim 1 or 13.
45. A method of claim 44 wherein the animal is a mammal.
46. A method of claim 45 wherein the animal is selected from the group consisting of mouse, rat, rabbit, and guinea pig.
47. 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 a compound having the structure of Formula I wherein R4 is C-i-8 straight or branched chain alkyl and X is O.
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