WO2008024494A2 - Pharmacokinetically improved compounds - Google Patents

Pharmacokinetically improved compounds Download PDF

Info

Publication number
WO2008024494A2
WO2008024494A2 PCT/US2007/018784 US2007018784W WO2008024494A2 WO 2008024494 A2 WO2008024494 A2 WO 2008024494A2 US 2007018784 W US2007018784 W US 2007018784W WO 2008024494 A2 WO2008024494 A2 WO 2008024494A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
alkynyl
alkenyl
aralkyl
Prior art date
Application number
PCT/US2007/018784
Other languages
French (fr)
Other versions
WO2008024494A3 (en
WO2008024494A9 (en
Inventor
Stewart Campbell
David Duffy
Michael Grogan
Steven Kates
Emanuele Ostuni
Olivier Schueller
Paul Sweetnam
Original Assignee
Surface Logix, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to JP2009525652A priority Critical patent/JP2010501577A/en
Priority to EP07837341.2A priority patent/EP2061322B1/en
Priority to AU2007287024A priority patent/AU2007287024A1/en
Priority to MX2009002073A priority patent/MX2009002073A/en
Priority to CA002661483A priority patent/CA2661483A1/en
Priority to BRPI0716571-4A priority patent/BRPI0716571A2/en
Priority to ES07837341.2T priority patent/ES2548759T3/en
Priority to US12/438,504 priority patent/US20100324037A1/en
Application filed by Surface Logix, Inc. filed Critical Surface Logix, Inc.
Publication of WO2008024494A2 publication Critical patent/WO2008024494A2/en
Publication of WO2008024494A3 publication Critical patent/WO2008024494A3/en
Priority to IL197224A priority patent/IL197224A0/en
Priority to NO20090896A priority patent/NO20090896L/en
Publication of WO2008024494A9 publication Critical patent/WO2008024494A9/en
Priority to US13/708,420 priority patent/US8853394B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • 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
    • 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
    • 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
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/08—Six-membered rings

Definitions

  • cGMP-specific PDE cyclic guanosine 3',5'- monophosphate specific phosphodiesterase
  • PDE5 Type 5 cGMP-specific phosphodiesterase
  • an inhibitor of PDE5 may be indicated in the restoration or maintenance of endothelial and cardiovascular health and treatment of cardiovascular disorders, including but not limited to hypertension, cerebrovascular disorders, and disorders of the urogenital system, particularly erectile disfunction.
  • Vardenafil marketed under the trade name Levitra ® is a potent and selective inhibitor of PDE5 and is currently indicated for the treatment of erectile dysfunction. There is a present need to improve the pharmacokinetic properties of PDE5 inhibitors.
  • Pegylation the process of the conjugating or linking of biomolecules and drug delivery systems, e.g. liposomes, proteins, enzymes, drugs, nanoparticles, with polyethylene glycol, is a known method for altering pharmacokinetics by improving the circulating half- life of protein and liposomal pharmaceuticals.
  • Pegylayted drugs have a large molecular weight polyethylene glycol (PEG) shell around the drug which protects the drug from enzymatic degradation, and allows the drug to cross the gut, i.e.
  • pegylated proteins for example, have improved pharmacokinetics due to decreased hydrolysis and a longer circulating half-life.
  • Anticancer agents have a suboptimal pharmacokinetic profile that requires prolonged or repetitive administration of the drug.
  • Pegylated anticancer agents e.g.
  • pegfilgrastim a pegylated filgrastim
  • Pegylated liposomal doxorubicin another chemotherapeutic agent
  • pegylated drugs permit reduced dosing schedules, e.g. a fixed dose rather than a weight based dose.
  • the present invention relates to 2-phenyl substituted imidazotriazinone compounds with a sarcosine functional group having improved non-specific binding characteristics and pharmacokinetic properties.
  • the sarcosine unit serves to decrease protein binding, thereby increasing the amount of free form of the compound.
  • the functional residues which are attached to a compound differ in their chemical structure from the groups used in PEG techniques, e.g. the functional residue may be an ethylene glycol derivative, the functional residues are of a significantly smaller molecular weight, e.g. approximately MW of 100 daltons compared to 5000 daltons or more used in standard pegylation. Accordingly, the chemical or biological activity of compounds comprising the functional residues of the present invention is not altered due to less steric hindrance and greater drug accessibility to the target site(s) of the compound.
  • R 1 is lower alkyl
  • R 2 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
  • R 3 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
  • A is N or C-H
  • B is N, C-H, C-(SO 2 -R 4 ), or C-CO-R 4 ;
  • D is N, C-H, C-(SO 2 -R 4 ) or C-CO-R 4 ;
  • E is N or C-H; C-CO-R 4 ;
  • R 4 is a group having the formula: -NH-R 41 , -N(R 42 XR 43 ),
  • R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, -(CH 2 ) fl -N(H)(R 51 ) and -(CH 2 ) fl -N(R 52 )(R 53 );
  • R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R and R are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
  • R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl
  • R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH 2 (O-alkyl)-alkyl-O-alkyl, -(CH 2 ) fl -N(H)(R 51 ) and -(CH 2 ) fl -N(R 52 )(R 53 );
  • R 44 is selected from is selected from the group consisting of -(CH 2 VC(O)-(CH 2 ⁇ OR 11 , -(CH 2 ) r -C(O)-(CH 2 ),N(R 12 )(R 13 ), and -(CH 2 ) r O-(CH 2 VC(O)R 14 , each R 1 ' is independently selected from H, alkyl
  • each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl
  • 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O-C 2 -C 6 alkyl.
  • the present invention includes pharmaceutical compositions comprising the compounds of the invention and a pharmaceutically acceptable carrier and/or diluents.
  • the present invention includes pharmaceutical compositions comprising a substantially pure compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, and a pharmaceutically acceptable excipient and/or diluents.
  • the present invention also includes methods of treating erectile dysfunction, comprising administering to a human or animal an effective amount of compounds of the invention.
  • the compounds of the invention provide improved pharmacokinetic properties over the prior 2-phenyl substituted imidazoloatriazinone compounds by modifying the nonspecific in vivo protein binding of the compounds.
  • the pharmacokinetically improved compounds of the invention preferably allow a minimum effective amount of the compound to be administered to achieve the desired therapeutic effect of the unbound compound, thereby reducing the dosage amount (and may improve patient compliance).
  • the present invention provides a compound of the formula
  • R 1 isJower alkyl
  • R 2 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
  • R 3 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
  • A is N or C-H;
  • B is N, C-H, C-(SO 2 -R 4 ), or C-CO-R 4 ;
  • D is N, C-H, C-(SO 2 -R 4 ) or C-CO-R 4 ;
  • E is N or C-H; wherein only one of A, B or E may be N, and one of B or D is C-(SO 2 -R 4 ) or
  • R 4 is a group having the formula: -NH-R 41 , -N(R 42 XR 43 ),
  • R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, -(CH 2 ) n -N(H)(R 51 ) and -(CH 2 ) fl -N(R 52 )(R 53 );
  • R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, group, a is 1 to 6;
  • R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl
  • R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH 2 (O-alkyl)-alkyl-O-alkyl, -(CH 2 ) fl -N(H)(R 51 ) and -(CH 2 ) a -N(R 52 )(R 53 ); R 44 is selected from is selected from the group consisting of
  • each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and
  • each R 24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
  • R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is 0 to 6; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O-C 2 -C 6 alkyl.
  • R 1 is lower alkyl
  • R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with and alkylthio;
  • R 4 is a group having the formula:
  • R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, -(CH 2 VN(H)(R 51 ) and -(CH 2 ) fl -N(R 52 )(R 53 );
  • R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
  • R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl
  • R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH 2 (O-alkyl)-alkyl-O-alkyl, -(CH 2 VN(H)(R 51 ) and -(CH 2 ) fl -N(R 52 )(R 53 ); R 44 is selected from is selected from the group consisting of
  • each R 1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl
  • R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R 14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is 0 to 6;
  • 5 is 0 to 6; is selected from is selected from the group consisting of
  • each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-
  • 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O-C 2 -C 6 alkyl.
  • R 4 is a group having the formula:
  • R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, -(CH 2 ) fl -N(H)(R 51 ) and -(CH 2 VN(R 52 XR 53 );
  • R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, group, a is 1 to 6;
  • R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl
  • R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H, C 2 -C 6 alkyl-CH(O-alkyl)(O-alkyl), C 2 -C 6 alkyl-CH 2 (O-alkyl)-alkyl-O-alkyl, -(CH 2 VN(H)(R 51 ) and -(CH 2 ) ⁇ -N(R 52 )(R 53 ); R 44 is selected from is selected from the group consisting of
  • each R 11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R
  • each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and
  • R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is O to 6; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O-C 2 -C 6 alkyl.
  • R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted carbonyl, and alkylthio;
  • R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, -(CH 2 ) ⁇ -N(H)(R 51 ) and -(CH 2 ) fl -N(R 52 )(R 53 );
  • R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
  • R 52 and R 53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
  • R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
  • R 41 is selected from C 3 -C 6 alkyl, C 2 -C 3 alkyl-OH, -(CH 2 ) fl -N(H)(R 51 ) and -(CH 2 ) fl -N(R 52 )(R 53 );
  • R 51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
  • R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
  • R 1 is lower alkyl
  • R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
  • R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl
  • R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H,
  • R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6. [0020] In another preferred embodiment of the present invention, there is provided a compound having the formula:
  • R 42 is selected from alkyl, and C 2 -C 6 alkyl-O-alkyl
  • R 43 is selected from alkyl, C 2 -C 6 alkyl-NH-alkyl, C 2 -C 6 alkyl-O-alkyl, alkyl-CO 2 H,
  • R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 22 and R 23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
  • R 1 is lower alkyl
  • R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
  • R 44 is selected from is selected from the group consisting of
  • each R 1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkyl-O-aryl, alkenyl, alkyl-O-aryl, alkenyl, alkyl-O-aryl, alkenyl, alkyl-O-aryl, alkenyl, alkyl-O-aryl, alkenyl, alky
  • R 1 is lower alkyl
  • R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
  • R 44 is selected from is selected from the group consisting of
  • each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a
  • R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R 14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is 0 to 6; s is 0 to 6.
  • R 44 is selected from is selected from the group consisting of -(CH 2 ) r -C(O)-(CH 2 ),OR n , -(CH 2 VC(O)-(CH 2 ⁇ N(R 12 XR 13 ), and -(CH 2 ) r O-(CH 2 VC(O)R 14 , each R 1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R 12 and R 13 may be taken together with the nitrogen to which they
  • R 1 is lower alkyl
  • R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
  • R 45 is selected from is selected from the group consisting of
  • each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alky
  • R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is O to 6; v is 1 to 6; w is O to 6.
  • each R 21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl,
  • R 25 and R 26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO 2 , oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is O to 6; v is 1 to 6; and w is O to 6.
  • R 1 is lower alkyl
  • R 2 and R 3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO 2 , amino, acylamino, amido, carbonyl, and alkylthio;
  • R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O-C 2 -C 6 alkyl.
  • R 46 are both selected from C 2 -C 6 alkyl-OH, and C 2 -C 6 alkyl-O-C 2 -C 6 alkyl.
  • the substituent R 4 modulates the pharmacokinetic and/or pharmacodynamic profile of the compound and may result in improved pharmacokinetic properties compared to the unmodified, i.e. parent compound.
  • the active agent has improved physicochemical properties, pharmacokinetics, metabolism, or toxicity profile.
  • the active agent has superior solubility, lower IC 5O , and/or is substantially less protein bound in vivo compared to the compound lacking the at least one functional residue.
  • inhibitors and activators of proteins and enzymes e.g., phosphodiesterases such as PDE5, PDEl, PDE3 and PDE6, kinases, growth factor receptors, and proteases).
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen.
  • Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Most preferred are nitrogen or oxygen.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups each having up to 20 carbon atoms.
  • a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., C 1 -Ci O for straight chain, C 3 -C 10 for branched chain), and more preferably 6 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to six carbons, and more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls. hi preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sul
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, aryls and/or heterocyclic groups.
  • heterocyclyl or “heterocyclic group” refer to 3- to 10-membered ring structures, more preferably 5- or 6-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles.
  • Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, ox
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • polycyclyl or “polycyclic group” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each- of the rings of the polycyelic group can be substituted with such substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • nitro means -NO 2 ;
  • halogen designates -
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
  • R, R 1 and R" each independently represent a group permitted by the rules of valence, preferably H, alkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocyclic groups.
  • acylamino is art-recognized and refers to a moiety that can be represented by the general formula:
  • R and R' are as defined above.
  • amido is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula: f? R V
  • R, R' are as defined above.
  • Preferred embodiments of the amide will not include imides which may be unstable.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur
  • R and R' are as defined above.
  • alkoxyl refers to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • sulfonyl refers to a moiety that can be represented by the general formula:
  • R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • sulfoxido refers to a moiety that can be represented by the general formula:
  • R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl. attached thereto.
  • exemplary "selenoethers" which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and -Se-(CH2) m -R7, m and R7 being defined above.
  • Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e.g. alkyl, m, n, R, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • Table 1-3 summarizes certain biological and pharmacological properties of the above-described modified compounds of A.
  • Table 3 includes selectivity index against several PDEs.
  • the protein binding, permeability, and solubility of the above-described compounds are set forth in Table 2.
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • the compounds of the present invention may act as inhibitors of one or more phosphodiesterases, including, for example PDEl, PDE2 and PDE5.
  • the compounds of the present invention can be employed in pharmaceuticals for maintenance or restoration of endothelial health and cardiovascular health and for treatment of conditions relating to the inhibition of phosphodiesterases, particularly PDE5.
  • the compounds of the invention may be used for the treatment of cardiovascular disorders, including but not limited to hypertension, cerebrovascular disorders, and disorders of the urogenital system, treating cardiovascular disorders, hypertension, isolated systolic hypertension (ISH), pulmonary hypertension, acute heart failure, chronic heart failure, ischemic heart diesase (including, but not limited to chronic angina), peripheral arterial disease, pre-eclampsia, Raynaud's Disease, endothelial disfunction / pre -hypertension, chronic obstructive pulmonary disease (COPD), Meniere's disease, neuropathic pain in diabetes, cerebrovascular disorders, disorders of the urogenital system, benign prostatic hypertrophy, erectile disfunction, and female sexual dysfunction comprising administering to a human or animal an effective amount of any of the above compounds.
  • ISH isolated systolic hypertension
  • pulmonary hypertension including, but not limited to chronic angina
  • ischemic heart diesase including, but not limited to chronic angina
  • the compounds of the present invention which have been modified by the attachment thereto of at least one residue of the formula C provide modified pharmacokinetic properties, including modified nonspecific in vivo protein binding. Such optimal pharmacokinetic properties do not compromise either the selectivity or the potency of the modified compound.
  • the modification of protein binding is based on surface technology, i.e. the preparation and screening of surfaces for their ability to resist adsorption of proteins from solution.
  • Surfaces which are resistant to adsorption of proteins from solution are known to one of skill in the art as "protein resistant" surfaces.
  • Functional groups may be screened to identify the group(s) present in protein resistant surfaces, as described in e.g., Chapman et al. Surveying for Surfaces that Resist the Adsorption of Proteins, J. Am. Chem. Soc. 2000, 122:8303-8304; Ostuni et al.
  • protein binding is assessed by measuring the capacity of molecules of the invention to bind to one or more human serum components or mimics thereof.
  • serum components including, but not limited to serum proteins, and preferably human serum proteins.
  • Candidate residues can be screened directly by attaching them to a solid support and testing the support for protein resistance.
  • candidate residues are incorporated into, or linked to molecules of pharmaceutical interest.
  • Such compounds may be synthesized on a solid support, or bound to a solid support after synthesis.
  • immobilized candidate functional residues or molecules incorporating such residues are tested for their ability to bind serum components.
  • the serum components can be labeled with a signaling moiety for detection, or a labeled secondary reagent that binds to such serum components can be used.
  • Protein resistant surfaces which are resistant to adsorption of proteins from solution are known as "protein resistant" surfaces. Functional groups may be screened to identify the group(s) present in protein resistant surfaces, as described in e.g., Chapman et al. Surveying for Surfaces that Resist the Adsorption of Proteins, J. Am. Chem. Soc. 2000, 122:8303-8304; Ostuni et al. A Survey of Structure-Property Relationships of Surfaces that Resist the Adsorption of Protein, Langmuir 2001, 17:5605-5620; Holmlin, et al.
  • a suitable chemical skeleton or backbone of a known biologically or chemically active compound to which the functional residue may be attached by either substitution of functional group of the active compound or by replacement of a nonessential functional group of the active compound.
  • a piperazine group on a compound will indicate that such group may be either replaced or substituted with an functional residue.
  • a medicinal chemist will recognize other suitable groups on known active compounds which may be replaced or substituted with at least one functional residue.
  • a combinatorial library of compounds may be generated as described infra, wherein the compounds are modified compounds comprising a conjugate of an active site of the compound (an essential backbone of a compound having a particular desired activity), e.g. a different functional residue attached thereto, e.g. residues having formula C, wherein each R group is selected from the various groups described herein.
  • a library may be used to screen a plurality of different functional residues for improved pharmacokinetic and/or pharmacodynamic properties including non-specific protein binding of the modified compound.
  • the solid support itself is chosen or modified to minimize its interaction with the serum components.
  • examples of such supports and assay systems are described in International Application WO 02/48676, WO 03/12392, WO 03/18854, WO 03/54515, herein incorporated by reference.
  • the molecules of the invention may be mixed with one or more serum components in liquid phase, and the amount of unbound molecules determined.
  • test compounds can be mixed with one or more serum components in liquid phase, and the unbound molecules determined.
  • molecules having reduced protein binding are identified as follows: a self-assembled monolayer of thiol molecules terminated with anhydride groups is formed at a gold surface. A set of small molecules with amine groups at one end, and groups that are designed to resist binding to albumin, for example, at the other end are then attached to the surface via reaction between the amine and anhydride. The set of molecules are spotted onto spatially distinct regions on the gold surface to create an array of molecules that might resist protein binding. This array is then exposed to a solution containing albumin that is fluorescently labeled. After a suitable incubation period, the gold surface is washed and scanned on a fluorescent scanner.
  • the immobilized chemical groups that bound to albumin will be identified by the presence of a fluorescent signal; groups that resist albumin binding will have low fluorescence in that part of the array. If a fluorescent protein is not available then antibodies against the protein of interest in combination with fluorescent secondary antibodies can be used to detect protein binding to the chemical groups. If an antibody is not available then a labeless detection method such as surface plasmon resonance (SPR) or MALDI mass spectrometry can be used to identify the providing kinetic information on the binding of protein to the chemical groups.
  • SPR surface plasmon resonance
  • MALDI mass spectrometry can be used to identify the providing kinetic information on the binding of protein to the chemical groups.
  • albumin any protein of pharmacokinetic interest can be tested for binding potential.
  • blood proteins that bind small molecules such as ⁇ -acid glycoprotein (AAG, AGP) and lipoproteins, could be exposed to the array and protein binding detected.
  • AAG ⁇ -acid glycoprotein
  • AGP ⁇ -acid glycoprotein
  • chemical groups can be identified that resist binding to P-glycoprotein (PGP) and therefore have the potential to reduce efflux when appended to a small molecule therapeutic. This is particularly important for development of anti-cancer drugs provide effective treatment where multiple drug resistance (MDR) has developed.
  • PGP P-glycoprotein
  • the method could also be used to identify chemical groups that resist binding to proteins such as thrombin, anti-thrombin, and Factor Xa and therefore have the potential to control coagulation.
  • This method would also be useful for identifying groups that improve therapeutics that are designed as supplemental or replacement therapies where protein binding and PK properties are very important, e.g., hormones and their binding proteins, and steroids and their binding proteins such as testosterone and sex hormone binding globulin (SHBG).
  • SHBG testosterone and sex hormone binding globulin
  • a self-assembled monolayer of thiol molecules terminated with maleimide groups is formed at a gold surface.
  • a set of small molecules with thiol groups at one end, and groups that are hydrophilic at the other end are then attached to the surface via reaction between the thiol and maleimide.
  • the set of molecules are spotted onto spatially distinct regions on the gold surface to create an array of molecules that might increase the solubility of a small molecule. Droplets of both polar (e.g., water) and hydrophobic (e.g., octanol) liquids are then placed onto each element of the array.
  • the contact angles of the two liquids on each element are then measured at each element of the array using a goniometer.
  • the wettability of a particular liquid at a surface by a droplet when viewed from above (high contact angle will yield droplets of small area; low contact angles cover greater areas).
  • the contact angle of a liquid on a surface presenting a chemical group is inversely proportional to the miscibility of that chemical group with that liquid (solvent).
  • a chemical group for which water has a high contact angle when it is presented at the surface such as methyl (CH 3 )
  • CH 3 methyl
  • a chemical group for which water has a low contact angle when it is presented at the surface such as carboxyl (COOH)
  • COOH carboxyl
  • Sets of chemical groups can therefore be screened rapidly using contact angles on surfaces to identify groups that improve solubility or reduce hydrophilicity. This approach can be used to evaluate the effect on solubility of chemical groups used according to the invention.
  • a common parameter for the ability of a small molecule to cross the lipid membrane of a cell is logP where P is the partition coefficient of the compound between octanol and water.
  • P is the partition coefficient of the compound between octanol and water.
  • the pH dependence of the solubility of small molecules can be addressed in this method by measuring the contact angles of solutions at different pHs.
  • the parameter equivalent to logP in this case is logD, where D is the distribution coefficient, defined as the ratio of the sum of the concentrations of all species of the compound in octanol to the sum of the concentrations of all species of the compound in water at various pHs.
  • D is the distribution coefficient, defined as the ratio of the sum of the concentrations of all species of the compound in octanol to the sum of the concentrations of all species of the compound in water at various pHs.
  • Contact angles measured at different pHs therefore offer the possibility of an equivalent measure to logD.
  • the brain is one of the most difficult tissues for small molecules to penetrate.
  • the neurovascular junctions are tight and contain very few active transporters that are mostly responsible for clearing small molecules out of the brain.
  • the paracellular route (between cell junctions) is not available to small molecules, but only the transcellular route is (through cell membranes).
  • molecules to target the brain such as benzodiazepines, are hydrophobic to allow them to penetrate cell membranes.
  • the instant vinvention is compatible with the search for chemical groups that confer protein resistant and alleviate the common problem of excessive protein binding associated with molecules such as the benzodiazepines; this requires high dosing to account for the large percentage of binding to serum proteins.
  • the approaches described earlier for the identification of binders of PGP will be of help to optimize molecules for improved residence time in the brain.
  • monolayers of Caco-2 intestinal epithelial cells can be used to evaluate active transport of substances between the intestine and the bloodstream. When plated on a surface which allows the flow of material from apical to basolateral and vice versa, such cells form a biological membrane which can be used to simulate physiological absorption and bioavailability.
  • mouse brain capillary endothelial cell (MBEC) lines have been established to evaluate active transport in and out of the central nervous system.
  • Another example of such cells is HT29 human colon carcinoma cells.
  • monolayers expressing particular transporter proteins can be established using transfected cells. For example, Sasaki et al (2002) J. Biol. Chem. 8:6497 used a double-transfected Madin-Darby canine kidney cell monolayer to study transport of organic anions.
  • Alternatives to cell monolayers may of course be utilized to examine permeability.
  • Alternatives typically comprise a biological structure capable of active transport and include, but are not limited to, organs of the digestive tract obtained from lab animals and reconstituted organs or membranes created in vitro from cells seeded in an artificial matrix.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds of the present invention, including but not limited to the compounds described above and those shown in the Figures, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets
  • terapéuticaally-effective amount means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub- population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment, e.g. reasonable side effects applicable to any medical treatment.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • manufacturing aid e.g., lubricant, talc magnesium, calcium or zinc the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydrox
  • certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).
  • nontoxic salts or quaternary ammonium salts of the compounds e.g., from nontoxic organic or inorganic acids.
  • nontoxic organic or inorganic acids include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
  • the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases.
  • pharmaceutically-acceptable salts refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethyl enediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra).
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl propyl gallate, alpha-tocopherol, and the like
  • metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs, hi addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfum
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • peripheral administration and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • a compound of the present invention While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
  • the compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
  • the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin, lungs, or mucous membranes; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue
  • treatment is intended to encompass also prophylaxis, therapy and cure.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general. with pharmaceutically acceptable carriers and can also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides.
  • Conjunctive therapy thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutical effects of the first administered one is not entirely disappeared when the subsequent is administered.
  • the addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration.
  • an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed.
  • feed premixes and complete rations are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or “Livestock Feeds and Feeding” O and B books, Corvallis, Ore., U.S.A., 1977).
  • microemulsification technology to improve bioavailability of some lipophilic (water insoluble) pharmaceutical agents.
  • examples include Trimetrine (Dordunoo, S. K., et al., Drug Development and Industrial Pharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C, et al., J Pharm Sci 80(7), 712-714, 1991).
  • microemulsification provides enhanced bioavailability by preferentially directing absorption to the lymphatic system instead of the circulatory system, which thereby bypasses the liver, and prevents destruction of the compounds in the hepatobiliary circulation.
  • the formulations contain micelles formed from a compound of the present invention and at least one amphiphilic carrier, in which the micelles have an average diameter of less than about 100 nm. More preferred embodiments provide micelles having an average diameter less than about 50 nm, and even more preferred less than about 20 nm.
  • amphiphilic carriers While all suitable amphiphilic carriers are contemplated, the presently preferred carriers are generally those that have Generally-Recognized-as-Safe (GRAS) status, and that can both solubilize the compound of the present invention and microemulsify it at a later stage when the solution comes into a contact with a complex water phase (such as one found in human gastro-intestinal tract).
  • GRAS Generally-Recognized-as-Safe
  • amphiphilic ingredients that satisfy these requirements have HLB (hydrophilic to lipophilic balance) values of 2-20, and their structures contain straight chain aliphatic radicals in the range of C-6 to C-20. Examples are polyethylene-glycolized fatty glycerides and polyethylene glycols.
  • Particularly preferred amphiphilic carriers are saturated and monounsaturated polyethyleneglycolyzed fatty acid glycerides, such as those obtained from fully or partially hydrogenated various vegetable oils.
  • oils may advantageously consist of tri-. di- and mono-fatty acid glycerides and di- and mono-polyethyleneglycol esters of the corresponding fatty acids, with a particularly preferred fatty acid composition including capric acid 4-10, capric acid 3-9, lauric acid 40-50, myristic acid 14-24, palmitic acid 4-14 and stearic acid 5- 15%.
  • amphiphilic carriers includes partially esterified sorbitan and/or sorbitol, with saturated or mono-unsaturated fatty acids (SPAN-series) or corresponding ethoxylated analogs (TWEEN-series).
  • SPAN-series saturated or mono-unsaturated fatty acids
  • TWEEN-series corresponding ethoxylated analogs
  • amphiphilic carriers are particularly contemplated, including Gelucire-series, Labrafil, Labrasol, or Lauroglycol (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di- oleate, PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc (produced and distributed by a number of companies in USA and worldwide).
  • Hydrophilic polymers suitable for use in the present invention are those which are readily water-soluble, can be covalently attached to a vesicle-forming lipid, and which are tolerated in vivo without toxic effects (i.e., are biocompatible).
  • Suitable polymers include termed polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol.
  • Preferred polymers are those having a molecular weight of from about 100 or 120 daltons up to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons.
  • the polymer is polyethyleneglycol having a molecular weight of from about 100 to about 5,000 daltons, and more preferably having a molecular weight of from about 300 to about 5,000 daltons. In a particularly preferred embodiment, the polymer is polyethyleneglycol of 750 daltons (PEG(750)).
  • the polymers used in the present invention have a significantly smaller molecular weight, approximately 100 daltons, compared to the large MW of 5000 daltons or greater that used in standard pegylation techniques. Polymers may also be defined by the number of monomers therein; a preferred embodiment of the present invention utilizes polymers of at least about three monomers, such PEG polymers consisting of three monomers (approximately 150 daltons).
  • hydrophilic polymers which may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.
  • a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co- caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.
  • a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and
  • the release characteristics of a formulation of the present invention depend on the encapsulating material, the concentration of encapsulated drug, and the presence of release modifiers.
  • release can be manipulated to be pH dependent, for example, using a pH sensitive coating that releases only at a low pH, as in the stomach, or a higher pH, passage through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach, followed by later release in the intestine. Release can also be manipulated by inclusion of salts or pore forming agents, which can increase water uptake or release of drug by diffusion from the capsule. Excipients which modify the solubility of the drug can also be used to control the release rate.
  • Agents which enhance degradation of the matrix or release from the matrix can also be incorporated. They can be added to the drug, added as a separate phase (i.e., as particulates), or can be co-dissolved in the polymer phase depending on the compound. In all cases the amount should be between 0.1 and thirty percent (w/w polymer).
  • Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate, and zinc hydroxide, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine and surfactants such as Tween.RTM. and Pluronic.RTM..
  • Pore forming agents which add microstructure to the matrices i.e., water soluble compounds such as inorganic salts and sugars
  • the range should be between one and thirty percent (w/w polymer).
  • Uptake can also be manipulated by altering residence time of the particles in the gut. This can be achieved, for example, by coating the particle with, or selecting as the encapsulating material, a mucosal adhesive polymer.
  • a mucosal adhesive polymer examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (as used herein, polyacrylates refers to polymers including acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates).
  • the subject compounds may be synthesized using the methods of combinatorial synthesis described in this section.
  • Combinatorial libraries of the compounds may be used for the screening of pharmaceutical, agrochemical or other biological or medically-related activity or material-related qualities.
  • a combinatorial library for the purposes of the present invention is a mixture of chemically related compounds which may be screened together for a desired property; said libraries may be in solution or covalently greatly reduces and simplifies the number of screening processes which need to be carried out. Screening for the appropriate biological, pharmaceutical, agrochemical or physical property may be done by conventional methods.
  • Diversity in a library can be created at a variety of different levels.
  • the substrate aryl groups used in a combinatorial approach can be diverse in terms of the core aryl moiety, e.g., a variegation in terms of the ring structure, and/or can be varied with respect to the other substituents.
  • a library of substituted diversomers can be synthesized using the subject reactions adapted to the techniques described in the Still et al. PCT publication WO 94/08051, e.g., being linked to a polymer bead by a hydrolyzable or photolyzable group, e.g., located at one of the positions of substrate.
  • the library is synthesized on a set of beads, each bead including a set of tags identifying the particular diversomer on that bead.
  • the beads can be dispersed on the surface of a permeable membrane, and the diversomers released from the beads by lysis of the bead linker.
  • the diversomer from each bead will diffuse across the membrane to an assay zone, where it will interact with an enzyme assay.
  • sensitivity of techniques such as mass spectrometry (MS), e.g., which can be used to characterize sub-femtomolar amounts of a compound, and to directly determine the chemical constitution of a compound selected from a combinatorial library. For instance, where the library is provided on an insoluble support matrix, discrete populations of compounds can be first released from the support and characterized by MS.
  • MS mass spectrometry
  • MS techniques as MALDI can be used to release a compound from the matrix, particularly where a labile bond is used originally to tether the compound to the matrix.
  • a bead selected from a library can be irradiated in a MALDI step in order to release the diversomer from the matrix, and ionize the diversomer for MS analysis.
  • the libraries of the subject method can take the multipin library format.
  • Geysen and co-workers introduced a method for generating compound libraries by a parallel synthesis on polyacrylic acid-grated polyethylene pins arrayed in the microtitre plate format.
  • the Geysen technique can be used to synthesize and screen thousands of compounds per week using the multipin method, and the tethered compounds may be reused in many assays.
  • Appropriate linker moieties can also been appended to the pins so that the compounds may be cleaved from the supports after synthesis for assessment of purity and further evaluation (c.f, Bray et al. (1990) Tetrahedron Lett 31:5811-5814; Valerio et al. (1991) Anal Biochem 197:168-177; Bray et al. (1991) Tetrahedron Lett 32:6163-6166).
  • a variegated library of compounds can be provided on a set of beads utilizing the strategy of divide-couple-recombine (see, e.g., Houghten (1985) PNAS 82:5131-5135; and U.S. Patents 4,631,211; 5,440,016; 5,480,971).
  • the beads are divided into separate groups equal to the number of different substituents to be added at a particular position in the library, the different substituents coupled in separate reactions, and the beads recombined into one pool for the next iteration.
  • a scheme of combinatorial synthesis in which the identity of a compound is given by its locations on a synthesis substrate is termed a spatially-addressable synthesis.
  • the combinatorial process is carried out by controlling the addition of a chemical reagent to specific locations on a solid support (Dower et al. (1991) Annu Rep Med Chem 26:271-280; Fodor, S.P.A. (1991) Science 251 :767; Pirrung et al. (1992) U.S. Patent No. 5,143,854; Jacobs et al. (1994) Trends Biotechnol 12:19-26).
  • the spatial resolution of photolithography affords miniaturization. This technique can be carried out through the use protection/deprotection reactions with photolabile protecting groups.
  • a synthesis substrate is prepared for coupling through the covalent attachment of photolabile nitroveratryloxycarbonyl (NVOC) protected amino linkers or other photolabile linkers.
  • Light is used to selectively activate a specified region of the synthesis support for coupling. Removal of the photolabile protecting groups by light (deprotection) results in activation of selected areas. After activation, the first of a set of amino acid analogs, each bearing a photolabile protecting group on the amino terminus, is exposed to the entire surface. Coupling only occurs in regions that were addressed by light in the preceding step. The reaction is stopped, the plates washed, and the substrate is again illuminated through a second mask, activating a different region for reaction with a second protected building block.
  • NVOC photolabile nitroveratryloxycarbonyl
  • the pattern of masks and the sequence of reactants define the products and their locations. Since this process utilizes photolithography techniques, the number of compounds that can be synthesized is limited only by the number of synthesis sites that can be addressed with appropriate resolution. The position of each compound is precisely known; hence, its interactions with other molecules can be directly assessed. [00155] In a light-directed chemical synthesis, the products depend on the pattern of illumination and on the order of addition of reactants. By varying the lithographic patterns, many different sets of test compounds can be synthesized simultaneously; this characteristic leads to the generation of many different masking strategies.
  • the subject method utilizes a compound library provided with an encoded tagging system.
  • a recent improvement in the identification of active compounds from combinatorial libraries employs chemical indexing systems using tags that uniquely encode the reaction steps a given bead has undergone and, by inference, the structure it carries.
  • this approach mimics phage display libraries, where activity derives from expressed peptides, but the structures of the active peptides are deduced from the corresponding genomic DNA sequence.
  • the first encoding of synthetic combinatorial libraries employed DNA as the code.
  • a variety of other forms of encoding have been reported, including encoding with sequenceable bio-oligomers (e.g., oligonucleotides and peptides), and binary encoding with additional non-sequenceable tags.
  • a combinatorial library of nominally I ⁇ ( 823,543) peptides composed of all combinations of Arg, GIn, Phe, Lys, VaI, D-VaI and Thr (three-letter amino acid code), each of which was encoded by a specific dinucleotide (TA, TC, CT, AT, TT, CA and AC, respectively), was prepared by a series of alternating rounds of peptide and oligonucleotide synthesis on solid support.
  • the amine linking functionality on the bead was specifically differentiated toward peptide or oligonucleotide synthesis by simultaneously preincubating the beads with reagents that generate protected OH groups for oligonucleotide synthesis and protected NH2 groups for peptide synthesis (here, in a ratio of 1 :20).
  • the tags each consisted of 69-mers, 14 units of which carried the code.
  • the bead-bound library was incubated with a fluorescently labeled antibody, and beads containing bound antibody that fluoresced strongly were harvested by fluorescence-activated cell sorting (FACS).
  • the DNA tags were amplified by PCR and sequenced, and the predicted peptides were subject method, where the oligonucleotide sequence of the tag identifies the sequential combinatorial reactions that a particular bead underwent, and therefore provides the identity of the compound on the bead.
  • the method requires careful choice of orthogonal sets of protecting groups required for alternating co-synthesis of the tag and the library member.
  • chemical lability of the tag particularly the phosphate and sugar anomeric linkages, may limit the choice of reagents and conditions that can be employed for the synthesis of non-oligomeric libraries.
  • the libraries employ linkers permitting selective detachment of the test compound library member for assay.
  • Peptides have also been employed as tagging molecules for combinatorial libraries.
  • Two exemplary approaches are described in the art, both of which employ branched linkers to solid phase upon which coding and ligand strands are alternately elaborated.
  • orthogonality in synthesis is achieved by employing acid-labile protection for the coding strand and base-labile protection for the compound strand.
  • branched linkers are employed so that the coding unit and the test compound can both be attached to the same functional group on the resin.
  • a cleavable linker can be placed between the branch point and the bead so that cleavage releases a molecule containing both code and the compound (Ptek et al. (1991) Tetrahedron Lett 32:3891-3894).
  • the cleavable linker can be placed so that the test compound can be selectively separated from the bead, leaving the code behind. This last construct is particularly valuable because it permits screening of the test compound without potential interference of the coding groups.
  • tags can accurately predict the peptide structure.
  • non-sequencable electrophoric tagging molecules that are used as a binary code (Ohlmeyer et al. (1993) PNAS 90:10922-10926).
  • Exemplary tags are haloaromatic alkyl ethers that are detectable as their trimethylsilyl ethers at less than femtomolar levels by electron capture gas chromatography (ECGC).
  • the tags were bound to about 1% of the available amine groups of a peptide library via a photocleavable o-nitrobenzyl linker. This approach is convenient when preparing combinatorial libraries of peptide-like or other amine-containing molecules.
  • a more versatile system has, however, been developed that permits encoding of essentially any combinatorial library.
  • the compound would be attached to the solid support via the photocleavable linker and the tag is attached through a catechol ether linker via carbene insertion into the bead matrix (Nestler et al. (1994) J Org Chem 59:4723-4724).
  • This orthogonal attachment strategy permits the selective detachment of library members for assay in solution and subsequent decoding by ECGC after oxidative detachment of the tag sets.
  • Both libraries were constructed using an orthogonal attachment strategy in which the library member was linked to the solid support by a photolabile linker and the tags were attached through a linker cleavable only by vigorous oxidation. Because the library members can be repetitively partially photoeluted from the solid support, library members can be utilized in multiple assays. Successive photoelution also permits a very high throughput iterative screening strategy: first, multiple beads are placed in 96-well microtiter plates; second, compounds are partially detached and transferred to assay plates; third, a metal binding assay identifies the active wells; fourth, the corresponding beads are rearrayed singly structures are decoded.
  • the compound IA is treated with the amine, HNR'R", in methylene chloride or in a mixture of methylene chloride and methanol (9:1), and triethylamine.
  • the reaction mixture is stirred at room temperature.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Endocrinology (AREA)
  • Plant Pathology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Reproductive Health (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Vascular Medicine (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

A compound of formula (A) having improved non-specific binding characteristics and pharmacokinetic properties is provided or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof.

Description

PHARMACOKINETICALLY IMPROVED COMPOUNDS
Background of the Invention
[0001] The physiological and clinical effects of inhibitors of cyclic guanosine 3',5'- monophosphate specific phosphodiesterase (cGMP-specific PDE) suggest that such inhibitors have utility in a variety of disease states in which modulation of smooth muscle, renal, hemostatic, inflammatory, and/or endocrine function is desired. Type 5 cGMP-specific phosphodiesterase (PDE5) is the major cGMP hydrolyzing enzyme in vascular smooth muscle. Thus, an inhibitor of PDE5 may be indicated in the restoration or maintenance of endothelial and cardiovascular health and treatment of cardiovascular disorders, including but not limited to hypertension, cerebrovascular disorders, and disorders of the urogenital system, particularly erectile disfunction.
[0002] Pharmaceutical products that provide selective inhibition of PDE5 are currently available. Vardenafil, marketed under the trade name Levitra® is a potent and selective inhibitor of PDE5 and is currently indicated for the treatment of erectile dysfunction. There is a present need to improve the pharmacokinetic properties of PDE5 inhibitors.
[0003] The development of a new pharmaceutical agent requires careful optimization of the chemical and biological properties of a lead compound. For example, a successful drug candidate must be safe and effective for its intended use. Further, the compound must possess desired pharmacokinetic and pharmacodynamic profiles. This arduous development process usually requires extensive experimentation. In many cases, the process for determining the optimal compound can often require preparation of thousands of structurally similar compounds.
[0004] Among the properties that can limit the utility of a potential pharmaceutical agent is the degree to which the compound is complexed to proteins in vivo. If a high percentage of the compound present in vivo is non-specifically bound, for example by components of blood and blood plasma, this leaves only a very small amount of free compound available to tissue to perform its therapeutic function. Thus, binding of the large dosage of compound to achieve the desired therapeutic effect.
[0005] Traditional approaches have sought to alter pharmacokinetic properties
[0006] Pegylation, the process of the conjugating or linking of biomolecules and drug delivery systems, e.g. liposomes, proteins, enzymes, drugs, nanoparticles, with polyethylene glycol, is a known method for altering pharmacokinetics by improving the circulating half- life of protein and liposomal pharmaceuticals. (See, Bhadra et al. Pharmazie 2002 Jan; 5791):5-29) Pegylayted drugs have a large molecular weight polyethylene glycol (PEG) shell around the drug which protects the drug from enzymatic degradation, and allows the drug to cross the gut, i.e. provides oral availability and also acts as a shield to prevent recognition of the pegylated drug by cells of the immune system and protects the drug from renal clearance, (see, Molineux, Cancer Treat Rev. 2002 Apr, 28 Suppl A: 13-16) As a result, pegylated proteins, for example, have improved pharmacokinetics due to decreased hydrolysis and a longer circulating half-life. Anticancer agents have a suboptimal pharmacokinetic profile that requires prolonged or repetitive administration of the drug. Pegylated anticancer agents, e.g. pegfilgrastim, a pegylated filgrastim, have been shown to maintain drug efficacy and patient tolerability that are at least equivalent to those of unmodified filgrastim with only one administration per chemotherapy cycle, (see, Crawford, Cancer Treat Rev. 2002 Apr; 28 Suppl A: 7-11) Pegylated liposomal doxorubicin, another chemotherapeutic agent, has been found to be more effective and less cardiotoxic than the unpegylated or liposome- encapsulated doxorubicin. (See, Crawford, 2002) In addition to improved pharmacokinetics, pegylated drugs permit reduced dosing schedules, e.g. a fixed dose rather than a weight based dose. (See, Yowell and Blackwell, Cancer Treat Rev. 2002 Apr; 28 Suppl A:3-6) Since the PEG size, its geometry and attachment site of the pegylated therapeutic agent, e.g. proteins, determine the drug pharmacokinetics, therapeutic agents must be designed on a protein-by- protein basis. (See, Harris et al. Clin. Pharmacokinet. 2001, 40(7):539-551) A shortcoming of pegylated agents is potential reduced drug activity at the target site due to steric hindrance of the large PEG molecule. PEG molecule size is more of a concern in small molecules than with proteins. [0007] The present invention relates to 2-phenyl substituted imidazotriazinone compounds with a sarcosine functional group having improved non-specific binding characteristics and pharmacokinetic properties. The sarcosine unit serves to decrease protein binding, thereby increasing the amount of free form of the compound. The functional residues which are attached to a compound differ in their chemical structure from the groups used in PEG techniques, e.g. the functional residue may be an ethylene glycol derivative, the functional residues are of a significantly smaller molecular weight, e.g. approximately MW of 100 daltons compared to 5000 daltons or more used in standard pegylation. Accordingly, the chemical or biological activity of compounds comprising the functional residues of the present invention is not altered due to less steric hindrance and greater drug accessibility to the target site(s) of the compound.
[0008] A compound of formula A having improved non-specific binding characteristics and pharmacokinetic properties is provided:
Figure imgf000004_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1 is lower alkyl; R2 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
R3 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
A is N or C-H;
B is N, C-H, C-(SO2-R4), or C-CO-R4;
D is N, C-H, C-(SO2-R4) or C-CO-R4;
E is N or C-H; C-CO-R4;
R4 is a group having the formula: -NH-R41, -N(R42XR43),
Figure imgf000005_0001
-N(R46)2;
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)fl-N(H)(R51) and -(CH2)fl-N(R52)(R53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R and R are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
R42 is selected from alkyl, and C2-C6alkyl-O-alkyl;
R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H, C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl, -(CH2)fl-N(H)(R51) and -(CH2)fl-N(R52)(R53); R44 is selected from is selected from the group consisting of
Figure imgf000005_0002
-(CH2VC(O)-(CH2^OR11, -(CH2)r-C(O)-(CH2),N(R12)(R13), and -(CH2)rO-(CH2VC(O)R14, each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is 0 to 6; s is 0 to 6; is selected from is selected from the group consisting of
-(CH2)V-N(R25)(R26), -(CH2)V-N(R21)-(CH2)VV-C(O)R24, -(CH2)V-C(O)R24, -(CH2VC(O)-(CH2)^OR21, -(CH2VC(O)(CH2VN(R22XR23), -(CH2)V-O-(CH2)W-C(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to
7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
[0009] The present invention includes pharmaceutical compositions comprising the compounds of the invention and a pharmaceutically acceptable carrier and/or diluents.
[0010] The present invention includes pharmaceutical compositions comprising a substantially pure compound of the invention, or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, and a pharmaceutically acceptable excipient and/or diluents.
[0011] The present invention also includes methods of treating erectile dysfunction, comprising administering to a human or animal an effective amount of compounds of the invention.
Detailed Description
[0012] The compounds of the invention provide improved pharmacokinetic properties over the prior 2-phenyl substituted imidazoloatriazinone compounds by modifying the nonspecific in vivo protein binding of the compounds. The pharmacokinetically improved compounds of the invention preferably allow a minimum effective amount of the compound to be administered to achieve the desired therapeutic effect of the unbound compound, thereby reducing the dosage amount (and may improve patient compliance).
[0013] In one embodiment, the present invention provides a compound of the formula
A:
Figure imgf000007_0001
(A) R1 isJower alkyl;
R2 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio; R3 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio; A is N or C-H;
B is N, C-H, C-(SO2-R4), or C-CO-R4; D is N, C-H, C-(SO2-R4) or C-CO-R4; E is N or C-H; wherein only one of A, B or E may be N, and one of B or D is C-(SO2-R4) or
C-CO-R4;
R4 is a group having the formula: -NH-R41, -N(R42XR43),
Figure imgf000008_0001
-N(R46)2;
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)n-N(H)(R51) and -(CH2)fl-N(R52)(R53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R52 and R53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, group, a is 1 to 6;
R42 is selected from alkyl, and C2-C6alkyl-O-alkyl;
R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H, C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl, -(CH2)fl-N(H)(R51) and -(CH2)a-N(R52)(R53); R44 is selected from is selected from the group consisting of
-(CH2)9-N(R12)(R13), -(CH2VN(R11J-(CH2)AO)R14, -(CH2J9-C(O)R14, -(CH2VC(O)-(CH2U)R11, -(CH2>-C(O)-(CH2)5N(R12)(R13), and -(CH2)rO-(CH2VC(O)R14, each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O- aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is O to 6; s is O to 6; R45 is selected from is selected from the group consisting of
-(CH2VN(R25XR26), -(CH2)V-N(R2V(CH2)Vv-C(O)R24^(CH2)V-C(O)R24, -(CH2VC(O)-(CH2)WOR21, -(CH2VC(O)(CH2VN(R22XR23), -(CH2)V-O-(CH2)W-C(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, . alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is 0 to 6; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
[0014] In a preferred embodiment of the present invention, there is provided a compound of the formula A1
Figure imgf000010_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with and alkylthio;
R4 is a group having the formula:
-NH-R41,
-N(R42XR43),
Figure imgf000011_0001
-N(R46)2;
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2VN(H)(R51) and -(CH2)fl-N(R52)(R53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R52 and R53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
R42 is selected from alkyl, and C2-C6alkyl-O-alkyl;
R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H, C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl, -(CH2VN(H)(R51) and -(CH2)fl-N(R52)(R53); R44 is selected from is selected from the group consisting of
-(CH2VN(R12XR13), -(CH2VN(R1 ')-(CH2),C(O)R14, -(CH2)^-C(O)R14, -(CH2VC(O)-(CH2)^OR11, -(CH2VC(O)-(CH2^N(R12XR13), and -(CH2)rO-(CH2VC(O)R14, each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a
10 λ 1X heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is 0 to 6;
5 is 0 to 6; is selected from is selected from the group consisting of
-(CH2)V-N(R25)(R26), -(CH2)V-N(R21)-(CH2VC(O)R24, -(CH2)V-C(O)R24, -(CH2VC(OMCH2^OR21, -(CH2)rC(O)(CH2)w-N(R22)(R23), -(CH2)V-O-(CH2)W-C(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to
7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
[0015] In another preferred embodiment of the present invention, there is provided a compound of the formula B:
Figure imgf000013_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R4 is a group having the formula:
-NH-R41,
-N(R42XR43),
Figure imgf000013_0002
-N(R46)2;
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)fl-N(H)(R51) and -(CH2VN(R52XR53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R52 and R53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, group, a is 1 to 6;
R42 is selected from alkyl, and C2-C6alkyl-O-alkyl;
R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H, C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl, -(CH2VN(H)(R51) and -(CH2)α-N(R52)(R53); R44 is selected from is selected from the group consisting of
-(CH2VN(R12XR13), -(CH2VN(R1
Figure imgf000014_0001
-(CH2VC(O)-(CH2)^OR11, -(CH2VC(O)-(CH2)SN(R12XR13), and -(CH2)X)-(CH2VC(O)R14, each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O- aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is O to 6; s is O to 6; R45 is selected from is selected from the group consisting of
-(CH2)V-N(R25)(R26), -(CH2)V-N(R21)-(CH2)W-C(O)R24, -(CH2)V-C(O)R24,
-(CH2)rC(O)-(CH2)vvOR21, -(CH2VC(O)(CH2)ιv-N(R22)(R23),
-(CH2VO-(CH2VC(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is O to 6; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
[0016] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000015_0001
wherein, or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted carbonyl, and alkylthio;
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)Λ-N(H)(R51) and -(CH2)fl-N(R52)(R53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R52 and R53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
[0017] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000016_0001
wherein,
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)fl-N(H)(R51) and -(CH2)fl-N(R52)(R53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
[0018] Representative compounds of the formula B2 are provided below:
Figure imgf000017_0001
Figure imgf000018_0001
[0019] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000018_0002
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1 is lower alkyl; R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
R42 is selected from alkyl, and C2-C6alkyl-O-alkyl; R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H,
C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl,
-(CH2)n-N(H)(R51) and -(CH2)a-N(R52)(R53);
R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6. [0020] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000019_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R42 is selected from alkyl, and C2-C6alkyl-O-alkyl; R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H,
C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl,
-(CH2VN(H)(R51) and -(CH2)fl-N(R52)(R53);
R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
[0021] Representative compounds of the formula C2 are provided below:
Figure imgf000019_0002
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000021_0001
[0022] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000021_0002
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio; R44 is selected from is selected from the group consisting of
-(CH2VN(R12XR13), -(CH2V-N(R11)-(CH2),C(O)R14, -(CH2)9-C(O)R14, -(CH2)r-C(O)-(CH2),ORπ, -(CH2)r-C(O)-(CH2),N(R12)(R13), and -(CH2),.O-(CH2),-C(O)R14, each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is 0 to 6; s is 0 to 6; and x is 1 or 2.
[0023] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000022_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio; R44 is selected from is selected from the group consisting of
-(CH2VN(R12XR13), -(CH2V-N(R1
Figure imgf000022_0002
-(CH2)r-C(O)-(CH2)5ORu, -(CH2)r-C(O)-(CH2),N(R12)(R13), and
-(CH2)rO-(CH2)rC(O)R14, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a
1 9 1 1X heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is 0 to 6; s is 0 to 6.
[0024] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000023_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R44 is selected from is selected from the group consisting of
Figure imgf000023_0002
-(CH2)r-C(O)-(CH2),ORn, -(CH2VC(O)-(CH2^N(R12XR13), and -(CH2)rO-(CH2VC(O)R14, each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is 0 to 6; s is 0 to 6.
[0025] A representative compound of the formula D3 are provided below:
Figure imgf000024_0001
[0026] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000024_0002
(E1) R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
R45 is selected from is selected from the group consisting of
-(CH2)V-N(R25)(R26), -(CH2)V-N(R21)-(CH2)W-C(O)R24, -(CH2VC(O)R24, -(CH2VC(OMCH2)V1OR21, -(CH2VC(O)(CH2VN(R22XR23), -(CH2)V-O-(CH2)W-C(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is O to 6; v is 1 to 6; w is O to 6.
[0027] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000026_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R45 is selected from is selected from the group consisting of
-(CH2)V-N(R25)(R26), -(CH2)V-N(R21)-(CH2)M,-C(O)R24, -(CH2VC(O)R24, -(CH2)rC(O)-(CH2)wOR21, -(CH2VC(OXCH2V-N(R22XR23), -(CH2VO-(CH2V-C(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is O to 6; v is 1 to 6; and w is O to 6.
[0028] Representative compounds of the formula E2 are provided below:
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000028_0002
[0029] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000029_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
[0030] In another preferred embodiment of the present invention, there is provided a compound having the formula:
Figure imgf000029_0002
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
[0031] It is believed that the substituent R4 modulates the pharmacokinetic and/or pharmacodynamic profile of the compound and may result in improved pharmacokinetic properties compared to the unmodified, i.e. parent compound. In certain embodiments, the active agent has improved physicochemical properties, pharmacokinetics, metabolism, or toxicity profile. In a preferred embodiment, the active agent has superior solubility, lower IC5O, and/or is substantially less protein bound in vivo compared to the compound lacking the at least one functional residue. inhibitors and activators of proteins and enzymes (e.g., phosphodiesterases such as PDE5, PDEl, PDE3 and PDE6, kinases, growth factor receptors, and proteases).
[0033] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium. Most preferred are nitrogen or oxygen.
[0034] The term "alkyl" refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups each having up to 20 carbon atoms. In preferred embodiments, a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., C1-CiO for straight chain, C3-C10 for branched chain), and more preferably 6 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
[0035] Unless the number of carbons is otherwise specified, "lower alkyl" as used herein means an alkyl group, as defined above, but having from one to six carbons, and more preferably from one to six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths. Preferred alkyl groups are lower alkyls. hi preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
[0036] The term "aralkyl", as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
[0037] The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
[0038] The term "aryl" as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, the ring structure may also be referred to as "aryl heterocycles" or "heteroaromatics." The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, aryls and/or heterocyclic groups.
[0039] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 5- or 6-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclic groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
[0040] The terms "polycyclyl" or "polycyclic group" refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings. Each- of the rings of the polycyelic group can be substituted with such substituents as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
[0041] As used herein, the term "nitro" means -NO2; the term "halogen" designates -
F, -Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO2-.
[0042] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
Figure imgf000032_0001
wherein R, R1 and R" each independently represent a group permitted by the rules of valence, preferably H, alkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocyclic groups.
[0043] The term "acylamino" is art-recognized and refers to a moiety that can be represented by the general formula:
Figure imgf000032_0002
wherein R and R' are as defined above.
[0044] The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula: f? R V
wherein R, R' are as defined above. Preferred embodiments of the amide will not include imides which may be unstable.
[0045] The term "alkylthio" refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In preferred embodiments, the "alkylthio" moiety is represented by above. Representative alkylthio groups include methylthio, ethyl thio, and the like.
[0046] The term "carbonyl" is art recognized and includes such moieties as can be represented by the general formula:
Figure imgf000033_0001
wherein X is a bond or represents an oxygen or a sulfur, and R and R' are as defined above.
[0047] The terms "alkoxyl" or "alkoxy" as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
[0048] The term "sulfonate" is art recognized and includes a moiety that can be represented by the general formula:
O Il S-OR41
Il
O
in which R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
[0049] The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
[0050] The term "sulfate" is art recognized and includes a moiety that can be represented by the general formula: 0-S-OR41
Il
O in which R41 is as defined above.
[0051] The term "sulfonylamino" is art recognized and includes a moiety that can be represented by the general formula:
O Il N— S-R
Il O
R
[0052] The term "sulfamoyl" is art-recognized and includes a moiety that can be represented by the general formula:
O
Il /R S-N
Il \
O R -
[0053] The term "sulfonyl", as used herein, refers to a moiety that can be represented by the general formula:
O Il S R44
O
in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
[0054] The term "sulfoxido" as used herein, refers to a moiety that can be represented by the general formula:
O I l
-S-R44
in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl. attached thereto. Exemplary "selenoethers" which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and -Se-(CH2)m-R7, m and R7 being defined above.
[0056] Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
[0057] As used herein, the definition of each expression, e.g. alkyl, m, n, R, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
[0058] It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
[0059] As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
[0060] The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T. W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991).
[0061] Table 1-3 summarizes certain biological and pharmacological properties of the above-described modified compounds of A. Table 3 includes selectivity index against several PDEs. The protein binding, permeability, and solubility of the above-described compounds are set forth in Table 2.
[0062] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included in this invention.
[0063] In addition, if, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
[0064] The compounds of the present invention may act as inhibitors of one or more phosphodiesterases, including, for example PDEl, PDE2 and PDE5. The compounds of the present invention can be employed in pharmaceuticals for maintenance or restoration of endothelial health and cardiovascular health and for treatment of conditions relating to the inhibition of phosphodiesterases, particularly PDE5. For example, the compounds of the invention may be used for the treatment of cardiovascular disorders, including but not limited to hypertension, cerebrovascular disorders, and disorders of the urogenital system, treating cardiovascular disorders, hypertension, isolated systolic hypertension (ISH), pulmonary hypertension, acute heart failure, chronic heart failure, ischemic heart diesase (including, but not limited to chronic angina), peripheral arterial disease, pre-eclampsia, Raynaud's Disease, endothelial disfunction / pre -hypertension, chronic obstructive pulmonary disease (COPD), Meniere's disease, neuropathic pain in diabetes, cerebrovascular disorders, disorders of the urogenital system, benign prostatic hypertrophy, erectile disfunction, and female sexual dysfunction comprising administering to a human or animal an effective amount of any of the above compounds.
[0065] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
[0066] The compounds of the present invention which have been modified by the attachment thereto of at least one residue of the formula C provide modified pharmacokinetic properties, including modified nonspecific in vivo protein binding. Such optimal pharmacokinetic properties do not compromise either the selectivity or the potency of the modified compound.
[0067] The modification of protein binding is based on surface technology, i.e. the preparation and screening of surfaces for their ability to resist adsorption of proteins from solution. Surfaces which are resistant to adsorption of proteins from solution are known to one of skill in the art as "protein resistant" surfaces. Functional groups may be screened to identify the group(s) present in protein resistant surfaces, as described in e.g., Chapman et al. Surveying for Surfaces that Resist the Adsorption of Proteins, J. Am. Chem. Soc. 2000, 122:8303-8304; Ostuni et al. A Survey of Structure-Property Relationships of Surfaces that Resist the Adsorption of Protein, Langmuir 2001, 17:5605-5620; Holmlin, et al. Zwitterionic SAMs that Resist Nonspecific Adsorption of Protein from Aqueous Buffer, Langmuir 2001, 17:2841-2850; and Ostuni et al. Self-Assembled Monolayers that Resist the Adsorption of Proteins and the Adhesion of Bacterial and Mammalian Cells, Langmuir 2001, 17:6336-6343.
[0068] In general, protein binding is assessed by measuring the capacity of molecules of the invention to bind to one or more human serum components or mimics thereof. In one comprising such residues for their ability to resist adsorption of serum components, including, but not limited to serum proteins, and preferably human serum proteins. Candidate residues can be screened directly by attaching them to a solid support and testing the support for protein resistance. Alternatively, candidate residues are incorporated into, or linked to molecules of pharmaceutical interest. Such compounds may be synthesized on a solid support, or bound to a solid support after synthesis. In a non-limiting example of a direct binding assay, immobilized candidate functional residues or molecules incorporating such residues are tested for their ability to bind serum components. The serum components can be labeled with a signaling moiety for detection, or a labeled secondary reagent that binds to such serum components can be used.
[0069] Surfaces which are resistant to adsorption of proteins from solution are known as "protein resistant" surfaces. Functional groups may be screened to identify the group(s) present in protein resistant surfaces, as described in e.g., Chapman et al. Surveying for Surfaces that Resist the Adsorption of Proteins, J. Am. Chem. Soc. 2000, 122:8303-8304; Ostuni et al. A Survey of Structure-Property Relationships of Surfaces that Resist the Adsorption of Protein, Langmuir 2001, 17:5605-5620; Holmlin, et al. Zwitterionic SAMs that Resist Nonspecific Adsorption of Protein from Aqueous Buffer, Langmuir 2001, 17:2841- 2850; and Ostuni et al. Self-Assembled Monolayers that Resist the Adsorption of Proteins and the Adhesion of Bacterial and Mammalian Cells, Langmuir 2001, 17:6336-6343.
[0070] Upon identification of a functional residue which provides such protein resistance, one of skill in the art will readily determine a suitable chemical skeleton or backbone of a known biologically or chemically active compound to which the functional residue may be attached by either substitution of functional group of the active compound or by replacement of a nonessential functional group of the active compound. For example, as discussed above, the presence of a piperazine group on a compound will indicate that such group may be either replaced or substituted with an functional residue. One of skill in the art, e.g. a medicinal chemist, will recognize other suitable groups on known active compounds which may be replaced or substituted with at least one functional residue. Accordingly, a combinatorial library of compounds, may be generated as described infra, wherein the compounds are modified compounds comprising a conjugate of an active site of the compound (an essential backbone of a compound having a particular desired activity), e.g. a different functional residue attached thereto, e.g. residues having formula C, wherein each R group is selected from the various groups described herein. Accordingly, a library may be used to screen a plurality of different functional residues for improved pharmacokinetic and/or pharmacodynamic properties including non-specific protein binding of the modified compound.
[0071] In preferred embodiments, the solid support itself is chosen or modified to minimize its interaction with the serum components. Examples of such supports and assay systems are described in International Application WO 02/48676, WO 03/12392, WO 03/18854, WO 03/54515, herein incorporated by reference. Alternatively, the molecules of the invention may be mixed with one or more serum components in liquid phase, and the amount of unbound molecules determined.
[0072] A direct binding analysis can also be preformed in liquid phase. For example, test compounds can be mixed with one or more serum components in liquid phase, and the unbound molecules determined.
[0073] In an example of a preferred embodiment, molecules having reduced protein binding are identified as follows: a self-assembled monolayer of thiol molecules terminated with anhydride groups is formed at a gold surface. A set of small molecules with amine groups at one end, and groups that are designed to resist binding to albumin, for example, at the other end are then attached to the surface via reaction between the amine and anhydride. The set of molecules are spotted onto spatially distinct regions on the gold surface to create an array of molecules that might resist protein binding. This array is then exposed to a solution containing albumin that is fluorescently labeled. After a suitable incubation period, the gold surface is washed and scanned on a fluorescent scanner. The immobilized chemical groups that bound to albumin will be identified by the presence of a fluorescent signal; groups that resist albumin binding will have low fluorescence in that part of the array. If a fluorescent protein is not available then antibodies against the protein of interest in combination with fluorescent secondary antibodies can be used to detect protein binding to the chemical groups. If an antibody is not available then a labeless detection method such as surface plasmon resonance (SPR) or MALDI mass spectrometry can be used to identify the providing kinetic information on the binding of protein to the chemical groups.
[0074] The use of this system is not limited to albumin; any protein of pharmacokinetic interest can be tested for binding potential. For example, blood proteins that bind small molecules, such as α-acid glycoprotein (AAG, AGP) and lipoproteins, could be exposed to the array and protein binding detected.
[0075] In an embodiment of the invention, chemical groups can be identified that resist binding to P-glycoprotein (PGP) and therefore have the potential to reduce efflux when appended to a small molecule therapeutic. This is particularly important for development of anti-cancer drugs provide effective treatment where multiple drug resistance (MDR) has developed.
[0076] The method could also be used to identify chemical groups that resist binding to proteins such as thrombin, anti-thrombin, and Factor Xa and therefore have the potential to control coagulation.
[0077] This method would also be useful for identifying groups that improve therapeutics that are designed as supplemental or replacement therapies where protein binding and PK properties are very important, e.g., hormones and their binding proteins, and steroids and their binding proteins such as testosterone and sex hormone binding globulin (SHBG).
[0078] The following describes a surface-based method for identifying groups that can improve the solubility of small molecules. A self-assembled monolayer of thiol molecules terminated with maleimide groups is formed at a gold surface. A set of small molecules with thiol groups at one end, and groups that are hydrophilic at the other end are then attached to the surface via reaction between the thiol and maleimide. The set of molecules are spotted onto spatially distinct regions on the gold surface to create an array of molecules that might increase the solubility of a small molecule. Droplets of both polar (e.g., water) and hydrophobic (e.g., octanol) liquids are then placed onto each element of the array. The contact angles of the two liquids on each element are then measured at each element of the array using a goniometer. Alternatively, the wettability of a particular liquid at a surface by a droplet when viewed from above (high contact angle will yield droplets of small area; low contact angles cover greater areas). The contact angle of a liquid on a surface presenting a chemical group is inversely proportional to the miscibility of that chemical group with that liquid (solvent). For example, a chemical group for which water has a high contact angle when it is presented at the surface, such as methyl (CH3), has low miscibility with water, i.e., it will tend to reduce the solubility of a small molecule. Conversely, a chemical group for which water has a low contact angle when it is presented at the surface, such as carboxyl (COOH), has high miscibility with water, i.e., it will tend to increase the solubility of a small molecule. Sets of chemical groups can therefore be screened rapidly using contact angles on surfaces to identify groups that improve solubility or reduce hydrophilicity. This approach can be used to evaluate the effect on solubility of chemical groups used according to the invention.
[0079] A common parameter for the ability of a small molecule to cross the lipid membrane of a cell is logP where P is the partition coefficient of the compound between octanol and water. The relative contact angle of a surface presenting chemical groups for octanol and water therefore offers a rapid, empirical method for ranking large sets of chemical groups for their potential effect on the logP of a compound.
[0080] The pH dependence of the solubility of small molecules can be addressed in this method by measuring the contact angles of solutions at different pHs. The parameter equivalent to logP in this case is logD, where D is the distribution coefficient, defined as the ratio of the sum of the concentrations of all species of the compound in octanol to the sum of the concentrations of all species of the compound in water at various pHs. Contact angles measured at different pHs therefore offer the possibility of an equivalent measure to logD.
[0081] It will also be useful to screen candidate compounds for their capacity to be actively transported across cell membranes and cells, or for their resistance to such transport. For example, it is well known that pharmaceutically useful anti-cancer molecules may be limited in their effectiveness due to active transport out of target tumor cells. Similarly, monolayers of brain capillary endothelial cells have been observed to unidirectionally transport vincristine from basal side to apical side, effectively preventing the anti-cancer agent from entering the central nervous system. In some instances, chemical groups of value enhancing passive or active transport towards their site of action, and/or inhibiting transport from the site of action.
[0082] The brain is one of the most difficult tissues for small molecules to penetrate.
The neurovascular junctions are tight and contain very few active transporters that are mostly responsible for clearing small molecules out of the brain. The paracellular route (between cell junctions) is not available to small molecules, but only the transcellular route is (through cell membranes). Classically, molecules to target the brain, such as benzodiazepines, are hydrophobic to allow them to penetrate cell membranes. The instant vinvention is compatible with the search for chemical groups that confer protein resistant and alleviate the common problem of excessive protein binding associated with molecules such as the benzodiazepines; this requires high dosing to account for the large percentage of binding to serum proteins. The approaches described earlier for the identification of binders of PGP will be of help to optimize molecules for improved residence time in the brain.
[0083] Several model systems are available, employing monolayers of various cell types, for evaluation of active transport of pharmaceutically active substances. For example, monolayers of Caco-2 intestinal epithelial cells can be used to evaluate active transport of substances between the intestine and the bloodstream. When plated on a surface which allows the flow of material from apical to basolateral and vice versa, such cells form a biological membrane which can be used to simulate physiological absorption and bioavailability. In another example, mouse brain capillary endothelial cell (MBEC) lines have been established to evaluate active transport in and out of the central nervous system. Another example of such cells is HT29 human colon carcinoma cells. Further, monolayers expressing particular transporter proteins can be established using transfected cells. For example, Sasaki et al (2002) J. Biol. Chem. 8:6497 used a double-transfected Madin-Darby canine kidney cell monolayer to study transport of organic anions.
[0084] Alternatives to cell monolayers may of course be utilized to examine permeability. Alternatives typically comprise a biological structure capable of active transport and include, but are not limited to, organs of the digestive tract obtained from lab animals and reconstituted organs or membranes created in vitro from cells seeded in an artificial matrix. [0085] In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the compounds of the present invention, including but not limited to the compounds described above and those shown in the Figures, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
[0086] The phrase "therapeutically-effective amount" as used herein means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub- population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment, e.g. reasonable side effects applicable to any medical treatment.
[0087] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
[0088] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and/or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.
[0089] As set out above, certain embodiments of the present compounds may contain a basic functional group, such as amino or alkylamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term "pharmaceutically-acceptable salts" in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the invention in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19). conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from nontoxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.
[0091] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term "pharmaceutically-acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically-acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethyl enediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra).
[0092] Wetting agents, emulsifϊers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
[0093] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
[0094] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
[0095] In certain embodiments, a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention. In certain embodiments, an aforementioned formulation renders orally bioavailable a compound of the present invention.
[0096] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. A compound of the present invention may also be administered as a bolus, electuary or paste.
[0098] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
[0099] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
[00100] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
[00101] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs, hi addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
[00103] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[00104] Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
[00105] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
[00106] Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
[00107] The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [00108] Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
[00109] Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
[00110] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.
[00111] Pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
[00112] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as use of surfactants.
[00113] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[00114] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
[00115] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
[00116] When the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier. [00117] The preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
[00118] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
[00119] The phrases "systemic administration," "administered systemically,"
"peripheral administration" and "administered peripherally" as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
[00120] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
[00121] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically- acceptable dosage forms by conventional methods known to those of skill in the art. compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
[00123] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
[00124] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
[00125] In general, a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient, when used for the indicated analgesic effects, will range from about 0.0001 to about 100 mg per kilogram of body weight per day.
[00126] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day. [00127] While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
[00128] The compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
[00129] In another aspect, the present invention provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of one or more of the subject compounds, as described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension; (3) topical application, for example, as a cream, ointment or spray applied to the skin, lungs, or mucous membranes; or (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually or buccally; (6) ocularly; (7) transdermally; or (8) nasally.
[00130] The term "treatment" is intended to encompass also prophylaxis, therapy and cure.
[00131] The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general. with pharmaceutically acceptable carriers and can also be administered in conjunction with antimicrobial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Conjunctive therapy, thus includes sequential, simultaneous and separate administration of the active compound in a way that the therapeutical effects of the first administered one is not entirely disappeared when the subsequent is administered.
[00133] The addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration.
[00134] Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed. The way in which such feed premixes and complete rations can be prepared and administered are described in reference books (such as "Applied Animal Nutrition", W.H. Freedman and CO., San Francisco, U.S.A., 1969 or "Livestock Feeds and Feeding" O and B books, Corvallis, Ore., U.S.A., 1977).
[00135] Recently, the pharmaceutical industry introduced microemulsification technology to improve bioavailability of some lipophilic (water insoluble) pharmaceutical agents. Examples include Trimetrine (Dordunoo, S. K., et al., Drug Development and Industrial Pharmacy, 17(12), 1685-1713, 1991 and REV 5901 (Sheen, P. C, et al., J Pharm Sci 80(7), 712-714, 1991). Among other things, microemulsification provides enhanced bioavailability by preferentially directing absorption to the lymphatic system instead of the circulatory system, which thereby bypasses the liver, and prevents destruction of the compounds in the hepatobiliary circulation.
[00136] In one aspect of invention, the formulations contain micelles formed from a compound of the present invention and at least one amphiphilic carrier, in which the micelles have an average diameter of less than about 100 nm. More preferred embodiments provide micelles having an average diameter less than about 50 nm, and even more preferred less than about 20 nm.
[00137] While all suitable amphiphilic carriers are contemplated, the presently preferred carriers are generally those that have Generally-Recognized-as-Safe (GRAS) status, and that can both solubilize the compound of the present invention and microemulsify it at a later stage when the solution comes into a contact with a complex water phase (such as one found in human gastro-intestinal tract). Usually, amphiphilic ingredients that satisfy these requirements have HLB (hydrophilic to lipophilic balance) values of 2-20, and their structures contain straight chain aliphatic radicals in the range of C-6 to C-20. Examples are polyethylene-glycolized fatty glycerides and polyethylene glycols.
[00138] Particularly preferred amphiphilic carriers are saturated and monounsaturated polyethyleneglycolyzed fatty acid glycerides, such as those obtained from fully or partially hydrogenated various vegetable oils. Such oils may advantageously consist of tri-. di- and mono-fatty acid glycerides and di- and mono-polyethyleneglycol esters of the corresponding fatty acids, with a particularly preferred fatty acid composition including capric acid 4-10, capric acid 3-9, lauric acid 40-50, myristic acid 14-24, palmitic acid 4-14 and stearic acid 5- 15%. Another useful class of amphiphilic carriers includes partially esterified sorbitan and/or sorbitol, with saturated or mono-unsaturated fatty acids (SPAN-series) or corresponding ethoxylated analogs (TWEEN-series).
[00139] Commercially available amphiphilic carriers are particularly contemplated, including Gelucire-series, Labrafil, Labrasol, or Lauroglycol (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-mono-oleate, PEG-di- oleate, PEG-mono-laurate and di-laurate, Lecithin, Polysorbate 80, etc (produced and distributed by a number of companies in USA and worldwide).
[00140] Hydrophilic polymers suitable for use in the present invention are those which are readily water-soluble, can be covalently attached to a vesicle-forming lipid, and which are tolerated in vivo without toxic effects (i.e., are biocompatible). Suitable polymers include termed polyglycolide), a polylactic-polyglycolic acid copolymer, and polyvinyl alcohol. Preferred polymers are those having a molecular weight of from about 100 or 120 daltons up to about 5,000 or 10,000 daltons, and more preferably from about 300 daltons to about 5,000 daltons. In a particularly preferred embodiment, the polymer is polyethyleneglycol having a molecular weight of from about 100 to about 5,000 daltons, and more preferably having a molecular weight of from about 300 to about 5,000 daltons. In a particularly preferred embodiment, the polymer is polyethyleneglycol of 750 daltons (PEG(750)). The polymers used in the present invention have a significantly smaller molecular weight, approximately 100 daltons, compared to the large MW of 5000 daltons or greater that used in standard pegylation techniques. Polymers may also be defined by the number of monomers therein; a preferred embodiment of the present invention utilizes polymers of at least about three monomers, such PEG polymers consisting of three monomers (approximately 150 daltons).
[00141] Other hydrophilic polymers which may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.
[00142] In certain embodiments, a formulation of the present invention comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co- caprolactone), polysaccharides, proteins, polyhyaluronic acids, polycyanoacrylates, and blends, mixtures, or copolymers thereof.
[00143] The release characteristics of a formulation of the present invention depend on the encapsulating material, the concentration of encapsulated drug, and the presence of release modifiers. For example, release can be manipulated to be pH dependent, for example, using a pH sensitive coating that releases only at a low pH, as in the stomach, or a higher pH, passage through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach, followed by later release in the intestine. Release can also be manipulated by inclusion of salts or pore forming agents, which can increase water uptake or release of drug by diffusion from the capsule. Excipients which modify the solubility of the drug can also be used to control the release rate. Agents which enhance degradation of the matrix or release from the matrix can also be incorporated. They can be added to the drug, added as a separate phase (i.e., as particulates), or can be co-dissolved in the polymer phase depending on the compound. In all cases the amount should be between 0.1 and thirty percent (w/w polymer). Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate, and zinc hydroxide, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine and surfactants such as Tween.RTM. and Pluronic.RTM.. Pore forming agents which add microstructure to the matrices (i.e., water soluble compounds such as inorganic salts and sugars) are added as particulates. The range should be between one and thirty percent (w/w polymer).
[00144] Uptake can also be manipulated by altering residence time of the particles in the gut. This can be achieved, for example, by coating the particle with, or selecting as the encapsulating material, a mucosal adhesive polymer. Examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (as used herein, polyacrylates refers to polymers including acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates).
[00145] The subject compounds may be synthesized using the methods of combinatorial synthesis described in this section. Combinatorial libraries of the compounds may be used for the screening of pharmaceutical, agrochemical or other biological or medically-related activity or material-related qualities. A combinatorial library for the purposes of the present invention is a mixture of chemically related compounds which may be screened together for a desired property; said libraries may be in solution or covalently greatly reduces and simplifies the number of screening processes which need to be carried out. Screening for the appropriate biological, pharmaceutical, agrochemical or physical property may be done by conventional methods.
[00146] Diversity in a library can be created at a variety of different levels. For instance, the substrate aryl groups used in a combinatorial approach can be diverse in terms of the core aryl moiety, e.g., a variegation in terms of the ring structure, and/or can be varied with respect to the other substituents.
[00147] A variety of techniques are available in the art for generating combinatorial libraries of small organic molecules. See, for example, Blondelle et al. (1995) Trends Anal. Chem. 14:83; the Affymax U.S. Patents 5,359,115 and 5,362,899: the Ellman U.S. Patent 5,288,514: the Still et al. PCT publication WO 94/08051; Chen et al. (1994) JACS 116:2661: Kerr et al. (1993) JACS 115:252; PCT publications WO92/10092, WO93/09668 and WO91/07087; and the Lerner et al. PCT publication WO93/20242). Accordingly, a variety of libraries on the order of about 16 to 1,000,000 or more diversomers can be synthesized and screened for a particular activity or property.
[00148] In an exemplary embodiment, a library of substituted diversomers can be synthesized using the subject reactions adapted to the techniques described in the Still et al. PCT publication WO 94/08051, e.g., being linked to a polymer bead by a hydrolyzable or photolyzable group, e.g., located at one of the positions of substrate. According to the Still et al. technique, the library is synthesized on a set of beads, each bead including a set of tags identifying the particular diversomer on that bead. In one embodiment, which is particularly suitable for discovering enzyme inhibitors, the beads can be dispersed on the surface of a permeable membrane, and the diversomers released from the beads by lysis of the bead linker. The diversomer from each bead will diffuse across the membrane to an assay zone, where it will interact with an enzyme assay. Detailed descriptions of a number of combinatorial methodologies are provided below. sensitivity of techniques such as mass spectrometry (MS), e.g., which can be used to characterize sub-femtomolar amounts of a compound, and to directly determine the chemical constitution of a compound selected from a combinatorial library. For instance, where the library is provided on an insoluble support matrix, discrete populations of compounds can be first released from the support and characterized by MS. hi other embodiments, as part of the MS sample preparation technique, such MS techniques as MALDI can be used to release a compound from the matrix, particularly where a labile bond is used originally to tether the compound to the matrix. For instance, a bead selected from a library can be irradiated in a MALDI step in order to release the diversomer from the matrix, and ionize the diversomer for MS analysis.
[00150] The libraries of the subject method can take the multipin library format.
Briefly, Geysen and co-workers (Geysen et al. (1984) PNAS 81:3998-4002) introduced a method for generating compound libraries by a parallel synthesis on polyacrylic acid-grated polyethylene pins arrayed in the microtitre plate format. The Geysen technique can be used to synthesize and screen thousands of compounds per week using the multipin method, and the tethered compounds may be reused in many assays. Appropriate linker moieties can also been appended to the pins so that the compounds may be cleaved from the supports after synthesis for assessment of purity and further evaluation (c.f, Bray et al. (1990) Tetrahedron Lett 31:5811-5814; Valerio et al. (1991) Anal Biochem 197:168-177; Bray et al. (1991) Tetrahedron Lett 32:6163-6166).
[00151] In yet another embodiment, a variegated library of compounds can be provided on a set of beads utilizing the strategy of divide-couple-recombine (see, e.g., Houghten (1985) PNAS 82:5131-5135; and U.S. Patents 4,631,211; 5,440,016; 5,480,971). Briefly, as the name implies, at each synthesis step where degeneracy is introduced into the library, the beads are divided into separate groups equal to the number of different substituents to be added at a particular position in the library, the different substituents coupled in separate reactions, and the beads recombined into one pool for the next iteration. using an analogous approach to the so-called "tea bag" method first developed by Houghten, where compound synthesis occurs on resin sealed inside porous polypropylene bags (Houghten et al. (1986) PNAS 82:5131-5135). Substituents are coupled to the compound- bearing resins by placing the bags in appropriate reaction solutions, while all common steps such as resin washing and deprotection are performed simultaneously in one reaction vessel. At the end of the synthesis, each bag contains a single compound.
[00153] A scheme of combinatorial synthesis in which the identity of a compound is given by its locations on a synthesis substrate is termed a spatially-addressable synthesis. In one embodiment, the combinatorial process is carried out by controlling the addition of a chemical reagent to specific locations on a solid support (Dower et al. (1991) Annu Rep Med Chem 26:271-280; Fodor, S.P.A. (1991) Science 251 :767; Pirrung et al. (1992) U.S. Patent No. 5,143,854; Jacobs et al. (1994) Trends Biotechnol 12:19-26). The spatial resolution of photolithography affords miniaturization. This technique can be carried out through the use protection/deprotection reactions with photolabile protecting groups.
[00154] The key points of this technology are illustrated in Gallop et al. (1994) J Med
Chem 37: 1233-1251. A synthesis substrate is prepared for coupling through the covalent attachment of photolabile nitroveratryloxycarbonyl (NVOC) protected amino linkers or other photolabile linkers. Light is used to selectively activate a specified region of the synthesis support for coupling. Removal of the photolabile protecting groups by light (deprotection) results in activation of selected areas. After activation, the first of a set of amino acid analogs, each bearing a photolabile protecting group on the amino terminus, is exposed to the entire surface. Coupling only occurs in regions that were addressed by light in the preceding step. The reaction is stopped, the plates washed, and the substrate is again illuminated through a second mask, activating a different region for reaction with a second protected building block. The pattern of masks and the sequence of reactants define the products and their locations. Since this process utilizes photolithography techniques, the number of compounds that can be synthesized is limited only by the number of synthesis sites that can be addressed with appropriate resolution. The position of each compound is precisely known; hence, its interactions with other molecules can be directly assessed. [00155] In a light-directed chemical synthesis, the products depend on the pattern of illumination and on the order of addition of reactants. By varying the lithographic patterns, many different sets of test compounds can be synthesized simultaneously; this characteristic leads to the generation of many different masking strategies.
[00156] hi yet another embodiment, the subject method utilizes a compound library provided with an encoded tagging system. A recent improvement in the identification of active compounds from combinatorial libraries employs chemical indexing systems using tags that uniquely encode the reaction steps a given bead has undergone and, by inference, the structure it carries. Conceptually, this approach mimics phage display libraries, where activity derives from expressed peptides, but the structures of the active peptides are deduced from the corresponding genomic DNA sequence. The first encoding of synthetic combinatorial libraries employed DNA as the code. A variety of other forms of encoding have been reported, including encoding with sequenceable bio-oligomers (e.g., oligonucleotides and peptides), and binary encoding with additional non-sequenceable tags.
[00157] The principle of using oligonucleotides to encode combinatorial synthetic libraries was described in 1992 (Brenner et al. (1992) PNAS 89:5381-5383), and an example of such a library appeared the following year (Needles et al. (1993) PNAS 90:10700-10704).
A combinatorial library of nominally I^ (= 823,543) peptides composed of all combinations of Arg, GIn, Phe, Lys, VaI, D-VaI and Thr (three-letter amino acid code), each of which was encoded by a specific dinucleotide (TA, TC, CT, AT, TT, CA and AC, respectively), was prepared by a series of alternating rounds of peptide and oligonucleotide synthesis on solid support. In this work, the amine linking functionality on the bead was specifically differentiated toward peptide or oligonucleotide synthesis by simultaneously preincubating the beads with reagents that generate protected OH groups for oligonucleotide synthesis and protected NH2 groups for peptide synthesis (here, in a ratio of 1 :20). When complete, the tags each consisted of 69-mers, 14 units of which carried the code. The bead-bound library was incubated with a fluorescently labeled antibody, and beads containing bound antibody that fluoresced strongly were harvested by fluorescence-activated cell sorting (FACS). The DNA tags were amplified by PCR and sequenced, and the predicted peptides were subject method, where the oligonucleotide sequence of the tag identifies the sequential combinatorial reactions that a particular bead underwent, and therefore provides the identity of the compound on the bead.
[00158] The use of oligonucleotide tags permits exquisitely sensitive tag analysis.
Even so, the method requires careful choice of orthogonal sets of protecting groups required for alternating co-synthesis of the tag and the library member. Furthermore, the chemical lability of the tag, particularly the phosphate and sugar anomeric linkages, may limit the choice of reagents and conditions that can be employed for the synthesis of non-oligomeric libraries. In preferred embodiments, the libraries employ linkers permitting selective detachment of the test compound library member for assay.
[00159] Peptides have also been employed as tagging molecules for combinatorial libraries. Two exemplary approaches are described in the art, both of which employ branched linkers to solid phase upon which coding and ligand strands are alternately elaborated. In the first approach (Kerr JM et al. (1993) J Am Chem Soc 115:2529-2531). orthogonality in synthesis is achieved by employing acid-labile protection for the coding strand and base-labile protection for the compound strand.
[00160] In an alternative approach (Nikolaiev et al. (1993) Pept Res 6:161-170). branched linkers are employed so that the coding unit and the test compound can both be attached to the same functional group on the resin. In one embodiment, a cleavable linker can be placed between the branch point and the bead so that cleavage releases a molecule containing both code and the compound (Ptek et al. (1991) Tetrahedron Lett 32:3891-3894). In another embodiment, the cleavable linker can be placed so that the test compound can be selectively separated from the bead, leaving the code behind. This last construct is particularly valuable because it permits screening of the test compound without potential interference of the coding groups. Examples in the art of independent cleavage and sequencing of peptide library members and their corresponding tags has confirmed that the tags can accurately predict the peptide structure. non-sequencable electrophoric tagging molecules that are used as a binary code (Ohlmeyer et al. (1993) PNAS 90:10922-10926). Exemplary tags are haloaromatic alkyl ethers that are detectable as their trimethylsilyl ethers at less than femtomolar levels by electron capture gas chromatography (ECGC). Variations in the length of the alkyl chain, as well as the nature and position of the aromatic halide substituents, permit the synthesis of at least 40 such tags, which in principle can encode 2^0 (e.g., upwards of 10^) different molecules. In the original report (Ohlmeyer et al., supra) the tags were bound to about 1% of the available amine groups of a peptide library via a photocleavable o-nitrobenzyl linker. This approach is convenient when preparing combinatorial libraries of peptide-like or other amine-containing molecules. A more versatile system has, however, been developed that permits encoding of essentially any combinatorial library. Here, the compound would be attached to the solid support via the photocleavable linker and the tag is attached through a catechol ether linker via carbene insertion into the bead matrix (Nestler et al. (1994) J Org Chem 59:4723-4724). This orthogonal attachment strategy permits the selective detachment of library members for assay in solution and subsequent decoding by ECGC after oxidative detachment of the tag sets.
[00162] Although several amide-linked libraries in the art employ binary encoding with the electrophoric tags attached to amine groups, attaching these tags directly to the bead matrix provides far greater versatility in the structures that can be prepared in encoded combinatorial libraries. Attached in this way, the tags and their linker are nearly as unreactive as the bead matrix itself. Two binary-encoded combinatorial libraries have been reported where the electrophoric tags are attached directly to the solid phase (Ohlmeyer et al. (1995) PNAS 92:6027-6031) and provide guidance for generating the subject compound library. Both libraries were constructed using an orthogonal attachment strategy in which the library member was linked to the solid support by a photolabile linker and the tags were attached through a linker cleavable only by vigorous oxidation. Because the library members can be repetitively partially photoeluted from the solid support, library members can be utilized in multiple assays. Successive photoelution also permits a very high throughput iterative screening strategy: first, multiple beads are placed in 96-well microtiter plates; second, compounds are partially detached and transferred to assay plates; third, a metal binding assay identifies the active wells; fourth, the corresponding beads are rearrayed singly structures are decoded.
EXAMPLES
[00163] The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.
General Process:
Figure imgf000065_0001
IA IB
[00164] The compound IA is treated with the amine, HNR'R", in methylene chloride or in a mixture of methylene chloride and methanol (9:1), and triethylamine. The reaction mixture is stirred at room temperature.
[00165] To the reaction solution is added methylene chloride and water, and the layers are separated. The aqueous layer is extracted with methylene chloride. The combined organic layers are washed with 10% citric acid, water and brine and dried over sodium sulfate. For products having basic substituents (amines, etc.) saturated sodium bicarbonate solution may be substituted for the 10% citric acid. The dried organic portion is concentrated in vacuo is optionally purified by flash chromatography or by recrystalization.
Example 1
Figure imgf000066_0001
Compound 1 M.W. (calculated): 545.66 M.W. (mass spec): 546.2
Example 2
Figure imgf000066_0002
Compound 2 M.W. (calculated): 462.57 M.W. (mass spec): 463.2
Figure imgf000067_0001
Compound 3 M.W. (calculated): 461.59 M.W. (mass spec): 462.2
Example 4
Figure imgf000067_0002
Compound 4 M.W. (calculated): 435.50 M.W. (mass spec): 436.2
Example 5
Compound 5 M.W. (calculated): 463.56 M.W. (mass spec): 464.3
Figure imgf000068_0001
Compound 6 M.W. (calculated): 479.56 M.W. (mass spec): 480.3
Example 7
Figure imgf000068_0002
Compound 7 M.W. (calculated): 507.61 M.W. (mass spec): 508.3
Example 8
Figure imgf000069_0001
Compound 8 M. W. (calculated): 419.50 M.W. (mass spec): 420.4
Example 9
Figure imgf000069_0002
Compound 9 M.W. (calculated): 477.58 M.W. (mass spec): 478.4
Example 10
Figure imgf000069_0003
Compound 10 M.W. (calculated): 535.66 M.W. (mass spec): 536.4
Figure imgf000070_0001
Compound 11 M.W. (calculated): 565.14 M.W. (mass spec): 566.1
Example 12
Figure imgf000070_0002
Compound 12 M.W. (calculated): 463.51 M.W. (mass spec): 462.2
Example 13
Figure imgf000070_0003
Compound 13 M.W. (calculated): 516.62 M.W. (mass spec): 517.16
Figure imgf000071_0001
Compound 14 M.W. (calculated): 506.58 M.W. (mass spec): 507.15
Example 15
Figure imgf000071_0002
Compound 15 M.W. (calculated): 573.72 M.W. (mass spec): 574.3
Figure imgf000072_0001
Compound 16 M.W. (calculated): 545.66 M.W. (mass spec): 546.13
Example 17
Figure imgf000072_0002
Compound 17 M.W. (calculated): 493.58 M.W. (mass spec): 494.11
Example 18
Figure imgf000073_0001
Compound 18 M.W. (calculated): 559.69 M. W. (mass spec): 560.18
Example 19
Figure imgf000073_0002
Compound 19 M.W. (calculated): 558.66 M.W. (mass spec): 559.17
Figure imgf000074_0001
Compound 20 M.W. (calculated): 516.62 M.W. (mass spec): 517.29
Example 21
Figure imgf000074_0002
Compound 21 M.W. (calculated): 573.72
Example 22
Figure imgf000074_0003
Compound 22 M.W. (calculated): 587.7 M.W. (mass spec): 588.3
Figure imgf000075_0001
Compound 23 M.W. (calculated): 433.55 M.W. (mass spec): 434.3
Example 24
Figure imgf000075_0002
Compound 24 M.W. (calculated): 587.7 M.W. (mass spec): 588.3
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
[00166] All of the patents and publications cited herein are hereby incorporated by reference in their entireties.
Equivalents
[00167] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

1. A compound of the formula A:
Figure imgf000080_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1 is lower alkyl; R2 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio; R3 is selected from lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio; A is N or C-H;
B is N, C-H, C-(SO2-R4), or C-CO-R4; D is N, C-H, C-(SO2-R4) or C-CO-R4; E is N or C-H; wherein only one of A, B or E may be N, and one of B or D is C-(SO2-R4) or
C-CO-R4;
R4 is a group having the formula: -NH-R41, -N(R42)(R43),
Figure imgf000080_0002
-N(R46)2;
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)Λ-N(H)(R51) and
-(CH2VN(R52XR53); alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R52 and R53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
R42 is selected from alkyl, and C2-C6alkyl-O-alkyl;
R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H, C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl, -(CH2)fl-N(H)(R51) and -(CH2)fl-N(R52)(R53); R44 is selected from is selected from the group consisting of
Figure imgf000081_0001
-(CH2VC(O)R14, -(CH2VC(O)-(CH2U)R11, -(CH2)r-C(O)-(CH2),N(R12)(R13), and -(CH2)rO-(CH2VC(O)R14, each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is O to 6; s is O to 6; R45 is selected from is selected from the group consisting of -(CH2)PC(O)-(CH2)VvOR21, -(CH2)rC(O)(CH2)w-N(R22)(R23), -(CH2)V-O-(CH2VC(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to
7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is O to 6; v is 1 to 6; w is O to 6; x is 1 or 2; y is 1 or 2; and R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
2. A compound of claim 1 , having the formula A1 :
Figure imgf000082_0001
(A1) R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
R4 is a group having the formula:
-NH-R41,
-N(R42)(R43),
Figure imgf000083_0001
-N(R46)2;
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2VN(H)(R51) and -(CH2)fl-N(R52)(R53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R52 and R53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
R42 is selected from alkyl, and C2-C6alkyl-O-alkyl;
R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H, C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl, -(CH2)α-N(H)(R51) and -(CH2)fl-N(R52)(R53); R44 is selected from is selected from the group consisting of
-(CH2VN(R12XR13), -(CH2VN(R1
Figure imgf000083_0002
-(CH2VC(O)-(CH2U)R11, -(CH2VC(O)-(CH2^N(R12XR13), and each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is 0 to 6; s is 0 to 6; is selected from is selected from the group consisting of
-(CH2)V-N(R25)(R26), -(CH2)V-N(R21)-(CH2)VV-C(O)R24, -(CH2)V-C(O)R24, -(CH2VC(O)-(CH2VOR21, -(CH2VC(OXCH2VN(R22XR23), -(CH2VO-(CH2V-C(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is 0 to 6; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and
R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
3. The compound of claim 2, having the formula A2:
Figure imgf000085_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R4 is a group having the formula:
-NH-R41,
-N(R42)(R43),
Figure imgf000085_0002
,46Λ
-N(JO2;
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)fl-N(H)(R51) and -(CH2VN(R52XR53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R52 and R53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
R42 is selected from alkyl, and C2-C6alkyl-O-alkyl;
R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H, C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl, -(CH2)^-N(H)(R51) and -(CH2)fl-N(R52)(R53); R44 is selected from is selected from the group consisting of
Figure imgf000086_0001
-(CH2VC(O)-(CH2)^OR11, -(CH2VC(O)-(CH2)SN(R12XR13), and -(CH2MHCH2VC(O)R14, each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is O to 6; 5 is O to 6; R45 is selected from is selected from the group consisting of
-(CH2)V-N(R25)(R26), -(CH2)V-N(R21)-(CH2)W-C(O)R24, -(CH2)V-C(O)R24, -(CH2)PC(O)-(CH2VOR21, -(CH2VC(O)(CH2VN(R22XR23), -(CH2VO-(CH2VC(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, group; each R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -0-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is 0 to 6; v is 1 to 6; w is 0 to 6; x is 1 or 2; y is 1 or 2; and R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
4. The compound of claim 1 , having the formula B1 :
Figure imgf000087_0001
wherein, or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1 is lower alkyl; wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)fl-N(H)(R51) and -(CH2)Λ-N(R52)(R53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;
R52 and R53 are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
5. The compound of claim 4, having the formula B2:
Figure imgf000088_0001
wherein,
R41 is selected from C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)a-N(H)(R51) and -(CH2VN(R52XR53);
R51 is selected from alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, a is 1 to 6;
R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
6. The compound of claim 1, the having a structure selected from:
Figure imgf000089_0001
Figure imgf000089_0002
Figure imgf000090_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
R42 is selected from alkyl, and C2-C6alkyl-O-alkyl; R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H,
C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl,
-(CH2VN(H)(R51) and -(CH2)fl-N(R52)(R53);
R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R and R may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
8. The compound of claim 7 having the formula C2:
Figure imgf000090_0002
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R43 is selected from alkyl, C2-C6alkyl-NH-alkyl, C2-C6alkyl-O-alkyl, alkyl-CO2H, C2-C6alkyl-CH(O-alkyl)(O-alkyl), C2-C6alkyl-CH2(O-alkyl)-alkyl-O-alkyl, -(CH2)fl-N(H)(R51) and -(CH2)fl-N(R52)(R53);
OO O-X
R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; and v is 1 to 6.
9. The compound of claim 1, the having a structure selected from:
Figure imgf000091_0001
Figure imgf000091_0002
Figure imgf000091_0003
Figure imgf000092_0001
Figure imgf000092_0002
10. The compound of claim 1, having the formula D)
Figure imgf000093_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio;
R44 is selected from is selected from the group consisting of
-(CH2VN(R12XR13), -(CH2VN(R1 ')-(CH2),C(O)R14, -(CH2)^-C(O)R14, -(CH2VC(O)-(CH2^OR11, -(CH2VC(O)-(CH2)5N(R12)(R13), and -(CH2)rO-(CH2VC(O)R14, each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is O to 6; s is O to 6; and x is 1 or 2.
11. The compound of claim 10 having the formula D2:
Figure imgf000094_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio; R44 is selected from is selected from the group consisting of
-(CH2VN(R12XR13), -(CH2V-N(R1 ')-(CH2),C(O)R14, -(CH2)^-C(O)R14, -(CH2VC(O)-(CH2VOR11, -(CH2VC(O)-(CH2VN(R12XR13), and -(CH2VO-(CH2V-C(O)R14, each R11 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; 9 is 1 to 6: r is O to 6; 5 is O to 6.
12. The compound of claim 11 having the formula D3:
Figure imgf000095_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R44 is selected from is selected from the group consisting of
-(CH2VN(R12XR13), -(CH2VN(R1
Figure imgf000095_0002
-(CH2VC(O)-(CH2)Z)R11, -(CH2VC(O)-(CH2)SN(R12XR13), and -(CH2V)-(CH2VC(O)R14, each R1 ' is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R12 and R13 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12 and R13 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; each R14 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; q is 1 to 6: r is O to 6;
5 is O to 6.
13. The compound of claim 12, the having a structure:
Figure imgf000096_0001
14. The compound of claim 1 having the formula E1:
Figure imgf000096_0002
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkylthio; R45 is selected from is selected from the group consisting of
-(CH2)V-N(R25)(R26), -(CH2)V-N(R21)-(CH2)W-C(O)R24, -(CH2VC(O)R24,
-(CH2VC(OMCH2VOR21 , -(CH2VC(O)(CH2VN(R22XR23),
-(CH2VO-(CH2V-C(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R and R are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl,
-O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is 0 to 6; v is 1 to 6; and w is 0 to 6.
15. The compound of claim 14 having the formula E2:
Figure imgf000097_0001
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R45 is selected from is selected from the group consisting of
-(CH2)V-N(R25)(R26), -(CH2)V-N(R21)-(CH2)VV-C(O)R24, -(CH2)V-C(O)R24, -(CH2VC(O)-(CH2^OR21, -(CH2VC(O)(CH2V-N(R22)^23), -(CH2)V-O-(CH2)Vv-C(O)R24; each R21 is independently selected from H, alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R22 and R23 are independently selected from H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22 and R23 may be taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, each R24 is independently selected from H, alkyl, -OH, -O-alkyl, -O-aryl,
-O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;
R25 and R26 taken together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group; t is 0 to 6; v is 1 to 6; and w is 0 to 6.
16. The compound of claim 1, having a structure selected from:
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
17. The compound of claim 1 having the formula:
Figure imgf000100_0002
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein
R1 is lower alkyl;
R2 and R3 are independently selected from lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, carbonyl, and alkyl thio;
R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl.
18. The compound of claim 17 having the formula:
Figure imgf000100_0003
or pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R46 are both selected from C2-C6alkyl-OH, and C2-C6alkyl-O-C2-C6alkyl. administering a therapeutically effective amount of a compound according to claims 1-18 in combination with a pharmaceutically acceptable excipient to a patient suffering from erectile disfunction.
20. A method of treating cardiovascular disorders comprising: administering a therapeutically effective amount of a compound according to claims 1-18 in combination with a pharmaceutically acceptable excipient to a patient suffering from a cardiovascular disorder.
21. The method of claim 20, wherein the cardiovascular disorder is hypertension.
PCT/US2007/018784 2006-08-24 2007-08-23 Pharmacokinetically improved compounds WO2008024494A2 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
ES07837341.2T ES2548759T3 (en) 2006-08-24 2007-08-23 Pharmacokinetically Enhanced Compounds
AU2007287024A AU2007287024A1 (en) 2006-08-24 2007-08-23 Pharmacokinetically improved compounds
MX2009002073A MX2009002073A (en) 2006-08-24 2007-08-23 Pharmacokinetically improved compounds.
CA002661483A CA2661483A1 (en) 2006-08-24 2007-08-23 Pharmacokinetically improved 2-phenyl-substituted imidazotriazinone derivatives and their use
BRPI0716571-4A BRPI0716571A2 (en) 2006-08-24 2007-08-23 PHARMACEUTICALLY OPTIMIZED COMPOUNDS
JP2009525652A JP2010501577A (en) 2006-08-24 2007-08-23 Compounds with improved pharmacokinetics
US12/438,504 US20100324037A1 (en) 2006-08-24 2007-08-23 Pharmacokinetically improved compounds
EP07837341.2A EP2061322B1 (en) 2006-08-24 2007-08-23 Pharmacokinetically improved compounds
IL197224A IL197224A0 (en) 2006-08-24 2009-02-24 Pharmacokinetically improved compounds
NO20090896A NO20090896L (en) 2006-08-24 2009-02-26 Pharmacokinetically improved compounds
US13/708,420 US8853394B2 (en) 2006-08-24 2012-12-07 Pharmacokinetically improved compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US84030606P 2006-08-24 2006-08-24
US60/840,306 2006-08-24

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US12/438,504 A-371-Of-International US20100324037A1 (en) 2006-08-24 2007-08-23 Pharmacokinetically improved compounds
US13/708,420 Continuation US8853394B2 (en) 2006-08-24 2012-12-07 Pharmacokinetically improved compounds

Publications (3)

Publication Number Publication Date
WO2008024494A2 true WO2008024494A2 (en) 2008-02-28
WO2008024494A3 WO2008024494A3 (en) 2008-04-10
WO2008024494A9 WO2008024494A9 (en) 2009-04-02

Family

ID=39107450

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/018784 WO2008024494A2 (en) 2006-08-24 2007-08-23 Pharmacokinetically improved compounds

Country Status (15)

Country Link
US (2) US20100324037A1 (en)
EP (2) EP2061322B1 (en)
JP (2) JP2010501577A (en)
KR (1) KR20090042863A (en)
CN (1) CN101528042A (en)
AU (1) AU2007287024A1 (en)
BR (1) BRPI0716571A2 (en)
CA (1) CA2661483A1 (en)
ES (1) ES2548759T3 (en)
IL (1) IL197224A0 (en)
MX (1) MX2009002073A (en)
NO (1) NO20090896L (en)
TW (1) TW200826944A (en)
WO (1) WO2008024494A2 (en)
ZA (1) ZA200901462B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014131855A1 (en) * 2013-03-01 2014-09-04 Fundación Para La Investigación Médica Aplicada Novel compounds as dual inhibitors of phosphodiesterases and histone deacetylases
WO2016147659A1 (en) * 2015-03-16 2016-09-22 Sumitomo Dainippon Pharma Co., Ltd. Bicyclic imidazolo derivative

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CR9465A (en) 2005-03-25 2008-06-19 Surface Logix Inc PHARMACOCINETICALLY IMPROVED COMPOUNDS
CN114085225A (en) * 2021-06-04 2022-02-25 广东西捷药业有限公司 Vardenafil analogue and synthetic method and application thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015715A1 (en) 2004-08-06 2006-02-16 Bayer Healthcare Ag Novel uses of 2-phenyl-substituted imidazotriazinone derivatives

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4631211A (en) * 1985-03-25 1986-12-23 Scripps Clinic & Research Foundation Means for sequential solid phase organic synthesis and methods using the same
US5143854A (en) 1989-06-07 1992-09-01 Affymax Technologies N.V. Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof
AU6886791A (en) 1989-11-13 1991-06-13 Affymax Technologies N.V. Spatially-addressable immobilization of anti-ligands on surfaces
EP0562025B1 (en) 1990-12-06 2001-02-07 Affymetrix, Inc. (a Delaware Corporation) Compounds and their use in a binary synthesis strategy
JP3939338B2 (en) 1991-11-22 2007-07-04 アフィメトリックス， インコーポレイテッド Combinatorial strategies for polymer synthesis.
US5359115A (en) * 1992-03-26 1994-10-25 Affymax Technologies, N.V. Methods for the synthesis of phosphonate esters
US5573905A (en) 1992-03-30 1996-11-12 The Scripps Research Institute Encoded combinatorial chemical libraries
JP2857540B2 (en) 1992-06-22 1999-02-17 ファナック株式会社 CAD / CAM method and apparatus for automatically re-creating a cutter path
US5288514A (en) * 1992-09-14 1994-02-22 The Regents Of The University Of California Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support
AU686579B2 (en) 1992-10-01 1998-02-12 Cold Spring Harbor Laboratory Complex combinatorial chemical libraries encoded with tags
US5480971A (en) * 1993-06-17 1996-01-02 Houghten Pharmaceuticals, Inc. Peralkylated oligopeptide mixtures
US5440016A (en) * 1993-06-18 1995-08-08 Torrey Pines Institute For Molecular Studies Peptides of the formula (KFmoc) ZZZ and their uses
US5362899A (en) * 1993-09-09 1994-11-08 Affymax Technologies, N.V. Chiral synthesis of alpha-aminophosponic acids
PT1049695E (en) * 1997-11-12 2002-07-31 Bayer Ag IMIDAZOTRIAZINONES 2-PHENYL SUBSTITUTED AS PHOSPHODIESTERASE INHIBITORS
DE19827640A1 (en) * 1998-06-20 1999-12-23 Bayer Ag New imidazotriazine derivatives useful as smooth muscle relaxants for treating e.g. cardiovascular disorders, cerebrovascular disorders, or erectile dysfunction
US6451807B1 (en) * 1999-04-30 2002-09-17 Lilly Icos, Llc. Methods of treating sexual dysfunction in an individual suffering from a retinal disease, class 1 congestive heart failure, or myocardial infarction using a PDE5 inhibitor
KR20020062770A (en) * 1999-12-24 2002-07-29 바이엘 악티엔게젤샤프트 Imidazo 1,3,5 triazinones and the Use Thereof
US6699665B1 (en) 2000-11-08 2004-03-02 Surface Logix, Inc. Multiple array system for integrating bioarrays
DE10107639A1 (en) * 2001-02-15 2002-08-22 Bayer Ag 2-alkoxyphenyl substituted imidazotriazinones
AU2002327385A1 (en) 2001-07-27 2003-02-17 Surface Logix, Inc. Resealable and sealable devices for biochemical assays
CA2458844A1 (en) 2001-08-27 2003-03-06 Surface Logix, Inc. Immobilization of biological molecules onto surfaces coated with monolayers
DE10162435A1 (en) 2001-12-19 2003-07-17 Joerg Lahann Process for the production of surface coatings which reduce the adsorption of proteins or the adhesion of bacteria and / or cells
KR20050004195A (en) * 2002-05-23 2005-01-12 화이자 인코포레이티드 Novel Combination
CA2598270A1 (en) * 2005-02-18 2006-08-24 Surface Logix, Inc. Methods of making pharmacokinetically improved compounds comprising functional residues or groups and pharmaceutical compositions comprising said compounds
CR9465A (en) * 2005-03-25 2008-06-19 Surface Logix Inc PHARMACOCINETICALLY IMPROVED COMPOUNDS

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006015715A1 (en) 2004-08-06 2006-02-16 Bayer Healthcare Ag Novel uses of 2-phenyl-substituted imidazotriazinone derivatives

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BHADRA ET AL., PHARMAZIE, January 2002 (2002-01-01)
CRAWFORD, CANCER TREAT REV., vol. 28, no. A, April 2002 (2002-04-01), pages 7 - 11
HARRIS ET AL., CLIN. PHARMACOKINET., vol. 40, no. 7, 2001, pages 539 - 551
MOLINEUX, CANCER TREAT REV., vol. 28, no. A, April 2002 (2002-04-01), pages 13 - 16
See also references of EP2061322A4
YOWELL; BLACKWELL, CANCER TREAT REV., vol. 28, no. A, April 2002 (2002-04-01), pages 3 - 6

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014131855A1 (en) * 2013-03-01 2014-09-04 Fundación Para La Investigación Médica Aplicada Novel compounds as dual inhibitors of phosphodiesterases and histone deacetylases
US9573956B2 (en) 2013-03-01 2017-02-21 Fundación Para La Investigación Médica Aplicada Compounds as dual inhibitors of phosphodiesterases and histone deacetylases
WO2016147659A1 (en) * 2015-03-16 2016-09-22 Sumitomo Dainippon Pharma Co., Ltd. Bicyclic imidazolo derivative

Also Published As

Publication number Publication date
AU2007287024A1 (en) 2008-02-28
JP2010501577A (en) 2010-01-21
US8853394B2 (en) 2014-10-07
IL197224A0 (en) 2009-12-24
KR20090042863A (en) 2009-04-30
WO2008024494A3 (en) 2008-04-10
US20130096114A1 (en) 2013-04-18
ES2548759T3 (en) 2015-10-20
MX2009002073A (en) 2009-05-25
EP2705753A1 (en) 2014-03-12
WO2008024494A9 (en) 2009-04-02
ZA200901462B (en) 2010-07-28
BRPI0716571A2 (en) 2013-11-05
EP2061322A2 (en) 2009-05-27
EP2061322A4 (en) 2011-01-05
CN101528042A (en) 2009-09-09
EP2061322B1 (en) 2015-07-01
CA2661483A1 (en) 2008-02-28
TW200826944A (en) 2008-07-01
US20100324037A1 (en) 2010-12-23
NO20090896L (en) 2009-03-09
JP2014055136A (en) 2014-03-27

Similar Documents

Publication Publication Date Title
US10570123B2 (en) Pharmacokinetically improved compounds
US6599940B2 (en) Synthesis of 2-hydroxymethylglutamic acid and congeners thereof
US8853394B2 (en) Pharmacokinetically improved compounds
AU2006213985B2 (en) Pharmacokinetically improved compounds
US20110172422A1 (en) Methods of Making Pharmacokinetically Improved Compounds Comprising Functional Residues or Groups and Pharmaceutical Compositions Comprising Said Compounds

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200780039772.4

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07837341

Country of ref document: EP

Kind code of ref document: A2

WWE Wipo information: entry into national phase

Ref document number: 2661483

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2009525652

Country of ref document: JP

Ref document number: 197224

Country of ref document: IL

Ref document number: MX/A/2009/002073

Country of ref document: MX

Ref document number: 12009500365

Country of ref document: PH

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2007287024

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1020097005834

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 1889/DELNP/2009

Country of ref document: IN

NENP Non-entry into the national phase

Ref country code: RU

WWE Wipo information: entry into national phase

Ref document number: A200902506

Country of ref document: UA

Ref document number: 2007837341

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2007287024

Country of ref document: AU

Date of ref document: 20070823

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 12438504

Country of ref document: US

ENP Entry into the national phase

Ref document number: PI0716571

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20090225