WO1999010365A2 - 5',5'-linked oligomers having anti-thrombin activity - Google Patents

5',5'-linked oligomers having anti-thrombin activity Download PDF

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Publication number
WO1999010365A2
WO1999010365A2 PCT/US1998/017913 US9817913W WO9910365A2 WO 1999010365 A2 WO1999010365 A2 WO 1999010365A2 US 9817913 W US9817913 W US 9817913W WO 9910365 A2 WO9910365 A2 WO 9910365A2
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compound
groups
typically
compounds
acid
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PCT/US1998/017913
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French (fr)
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WO1999010365A3 (en
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Norbert W. Bischofberger
Chris A. Buhr
Joseph P. Dougherty
Brian C. Froehler
Arnold J. Gutierrez
Gong-Xin He
Regan G. Shea
Sundaramoorthi Swaminathan
Matthew A. Williams
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Gilead Sciences, Inc.
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Priority to AU92104/98A priority Critical patent/AU9210498A/en
Publication of WO1999010365A2 publication Critical patent/WO1999010365A2/en
Publication of WO1999010365A3 publication Critical patent/WO1999010365A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen

Definitions

  • the thrombin binding aptamer GS 522 is described in PCT US92/01383 and U.S. Patent Application Serial No. 08/484,192.
  • the structure of GS 522 is 5'-GGTTGGTGTGGTTGG-3'.
  • the present invention is directed to compounds wherein two oligomers (5'-GGTTGG-3') are linked in a 5', 5' manner via a synthetic linking moiety.
  • a principal object of the invention is inhibition of thrombin.
  • an object is inhibition of thrombin's pro-coagulation activity.
  • An additional object of the invention is to provide thrombin inhibitors that possess elevated potency, that exhibit clinically acceptable toxicity profiles and have other desirable pharmacologic properties.
  • Another object is to provide improved and less costly methods for synthesis of thrombin inhibitors.
  • An additional object is to provide compositions useful in preparing polymers, surfactants or immunogens and for use in other industrial processes and articles.
  • R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
  • R 2 is R 1 wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R groups;
  • R 3 is F, Br, Cl, I, -CN, or N 3 ;
  • R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R groups;
  • R 5 is R 3 , -N0 2 , -OR 6 , -N(R 6 ) , -SR 6 , -S(0)R 6 , -S(0) 2 R 6 , -SOR 6 , -S(0)OR 6 , -S(0) 2 OR 6 , -SN(R 6 ) 2 , -S(0)N(R 6 ) 2 , -S(0) 2 N(R 6 ) 2 , -C(0)R 6 , -C(0)OR 6 , -OC(0)R 6 , -OC(0)OR 6 , -OC(0)OR 6 , -OC(0)N(R 6 ) 2 , -N(R 6 )(C(0)R 6 ), -N(R 6 )(C(0)OR 6 ), -C(0)N(R 6 ) 2 , -C(NR 6 )(N(R 6 ) 2 ), -N(R 6 )C(N(R 6 ))(N(R 6 ) 2
  • R is alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms; R is R wherein each said alkylene, alkenylene and alkynylene is independently substituted with 0 to 3 R groups;
  • R 9 is R 6 or -R 8 W 5 ; each R 10 is independently selected from H or R 2 ; each R 11 is independently selected from H, R 2 or R 3 ; each R is independently selected from H, R or R , wherein when
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 5 groups; each X is independently selected from R 12 , 3'-G-, 3'-GG-, 3'-TGG-,
  • each X and R 13 are -OH; and each R 10 , R 11 and R 12 are H.
  • Another embodiment of the invention is directed to compounds of having formula (VI) or (VII): wherein R 10 , R 11 , R 12 , R 13 and X are defined above.
  • Another embodiment of the invention is directed to compositions comprising a compound of the invention and a pharmaceutically- acceptable carrier.
  • Another embodiment of the invention is directed to methods of detecting the presence or absence of thrombin comprising contacting a sample suspected of containing thrombin with a compound of the invention.
  • compositions of the Invention will employ, unless otherwise indicated, conventional techniques of chemistry, molecular biology, biochemistry, protein chemistry, and recombinant DNA technology, which are within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Oligonucleotide Synthesis (M.J. Gait ed. 1984); Nucleic Acid Hybridization (B.D. Hames & S.J. Higgins eds. 1984); Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989); and the series Methods in Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.).
  • the compounds of this invention exclude compounds heretofore known. With respect to the United States, the compounds or compositions herein exclude compounds that are anticipated under 35 USC ⁇ 102 or obvious under 35 USC ⁇ 103. In particular, the claims herein shall be construed as excluding the compounds which are anticipated by or not possessing novelty over Gupta, V.S., et al., "J. Med. Chem.”, 18(10):973-976, 1975.
  • each X and R 13 are -OH; and each R 10 , R 11 and R 12 are H.
  • each X and R 13 are -OH; and each R 10 , R 11 and R 12 are H.
  • One embodiment of the invention is directed to compounds of formula (I), (II), (III), (IV) or (V):
  • R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms. Typically, R is an alkyl of 1, 2, 3, 4, 5 or 6 carbon atoms, alkenyl of 2, 3, 4, 5 or 6 carbon atoms or alkynyl of 2, 3, 4, 5 or
  • R is alkyl of 1 to 4 carbon atoms, alkenyl of
  • R is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms or alkynyl of 2 to 3 carbon atoms.
  • Alkyl as used herein, unless stated to the contrary, is C ⁇ -C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.
  • Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n- propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n- butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH3, 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-buty
  • Alkynyl as used herein, unless stated to the contrary, is C2-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Alkynyl is typically ethynyl (-C ⁇ CH), 1-prop-l-ynyl (-C ⁇ CCH3), l-prop-2- ynyl (-CH2C ⁇ CH), 1-but-l-ynyl (-C ⁇ CCH2CH3), l-but-2-ynyl (-CH2C ⁇ CCH3), l-but-3-ynyl (-CH2CH2C ⁇ CH), 2-but-3-ynyl (CH(CH3)C ⁇ CH), 1-pent-l-ynyl (-C ⁇ CCH2CH2CH3), l-pent-2-ynyl (-CH2C ⁇ CCH2CH3), l-pent-3-ynyl (-CH2CH2C ⁇ CCH3) or l-pent-4-y
  • R 2 is R 1 wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R 3 groups.
  • R 3 is defined below.
  • R is R wherein each said alkyl, alkenyl and alkynyl is
  • each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2 R 3 groups, still more typically, 0 to 1 R 3 groups.
  • R 3 is F, Br, Cl, I, -CN, or N 3 .
  • R 3 is F, Br, Cl, -CN, or N 3 .
  • R 3 is F, Br, Cl or N3. Still more typically, R 3 is F or N3.
  • R is F
  • R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R 5 groups.
  • R 5 is defined be!
  • R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 R groups. More typica
  • each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2 R groups, still more typically, 0 to 1 R groups.
  • R 5 is R 3 , -N0 2 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -S(0)R 6 , -S(0) 2 R 6 , -SOR 6 , -S(0)OR 6 , -S(0) 2 OR 6 , -SN(R 6 ) 2 , -S(0)N(R 6 ) 2 , -S(0) 2 N(R 6 ) 2 , -C(0)R 6 , -C(0)OR 6 , -OC(0)R 6 , -OC(0)OR 6 , -OC(0)OR 6 , -OC(0)N(R 6 ) 2 , -N(R 6 )(C(0)R 6 ), -N(R 6 )(C(0)OR 6 ), -C(0)N(R 6 ) 2 , -C(NR 6 )(N(R 6 ) 2 ), -N(R 6 )C(N(R 6 ))(N(R 6 )
  • R 5 is F, Br, Cl, I, -CN, N 3 , -N0 2 , -OR 6 , -N(R 6 ) , -SR 6 , -S(0)R 6 , -S(0) R 6 , -S(0) 2 N(R 6 ) 2 , -C(0)R 6 , -C(0)OR 6 , -OC(0)R 6 , -OC(0)OR 6 , -OC(0)N(R 6 ) 2 , -N(R 6 )(C(0)R 6 , -C(0)N(R 6 ) 2 , -C(NR 6 )(N(R 6 ) 2 ), -N(R 6 )C(N(R 6 )(N(R 6 ) 2 ),
  • R 5 is F, Br, Cl, N 3 , -N0 2 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -S(0) 2 R 6 , -S(0) 2 N(R 6 ) 2 ,
  • R 5 is F, N 3 , -N0 2 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -S(0) 2 N(R 6 ) 2 , -C(0)R 6 , -C(0)OR 6 , -OC(0)R 6 , -OC(0)N(R 6 ) 2 , -N(R 6 )(C(0)R 6 , -OP(0)(OR 6 ) 2 , or -OP(S)(OR 6 ) 2 .
  • R 5 is F, N 3 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -C(0)R 6 , -C(0)OR 6 , or -OP(0)(OR 6 ) 2 .
  • R E is a protecting group as defined below.
  • R is H or R , more typically, H.
  • R is alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms.
  • R 7 's are of 1, 2, 3, 4, 5 or 6 carbon atoms when alkylene and of 2, 3, 4, 5 or 6 carbon atoms when alkenylene or alkynylene.
  • Each of the typical R 1 groups is a typical R 7 group with the proviso that one of the hydrogen atoms of the described R 1 group is removed to form the open valence to a carbon atom through which the second bond to the R 7 is attached.
  • R is R wherein each said alkylene, alkenylene and alkynylene is 8 7 independently substituted with 0 to 3 R groups. Typically R is R wherein each said alkylene, alkenylene and alkynylene is independently substituted with 0, 1, 2 or 3 R 3 groups. More typically, R 8 is R 7 wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2
  • R 3 groups still more typically, 0 to 1 R groups.
  • R* R 9 is R 6 or -R 8 W 5 .
  • W 5 is defined below.
  • R 9 is -R 8 W 5 .
  • R 9 is -(CR 10 2)mlW 5 ; wherein ml is an integer of 1 to 6, typically, 1, 2, 3, 4, 5 or 6, more typically 2
  • R is defined below. More typically, R is -(CH )mlW 5 . More typically yet, R 9 is -(CH 2 ) m 2W 5a ; wherein m2 is 1, 2 or 3, and W 5a is a monocyclic (saturated, monounsaturated, diunsaturated or aromatic) carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I, -CN, N 3 , -NO2,
  • Each R 10 is independently selected from H or R 2.
  • Each of the preferred embodiments of R is a preferred embodiment in the context of R 10 .
  • each R 10 is H.
  • Each R is independently selected from H, R or R .
  • R is
  • R 3 is H or R 3.
  • R is H.
  • Each R is independently selected from H, R or R . Typically, R is H or R 3. Each of the preferred embodiments of R 3 is a preferred
  • Each R 13 is independently selected from H, R 4 , R 5 , R 9 , -OR 9 , -N(R 9 ) 2 , -SR 9 , -S(0)R 9 , -S(0) 2 R 9 , -SOR 9 , -S(0)OR 9 , -S(0) 2 OR 9 , -SN(R 9 ) 2 , -S(0)N(R 9 ) 2 , -S(0) 2 N(R 9 ) 2 , -C(0)R 9 , -C(0)OR 9 , -OC(0)R 9 , -OC(0)OR 9 , -OC(0)N(R 9 ) 2 , -N(R 9 )(C(0)R 9 ), -N(R 9 )(C(0)OR 9 ), -C(0)N(R 9 ) 2 , -C(NR 9 )(N(R 9 ) 2 ), or -N(R 9 )C(N(R 9 ))(N(R 9 )
  • R is F, N 3 , -OR , -N(R 6 ) 2 , -SR 6 , -C(0)R 6 , -C(0)OR 6 , -OP(0)(OR 6 ) 2 or -OC(0)N(R 9 ) 2 .
  • R 13 is -OR 6 or -OC(0)N(R 6 )(R 8 W 5 ).
  • R 13 is -OR 10 or -OC(0)N(H)( (CR 10 2) m iW 5 ); wherein ml is an integer of 1-6, typically, 1, 2, 3, 4, 5 or 6, more typically 2 to 4, still more typically 2 or 3.
  • R 13 is -OH or -OC(0)N(R 6 )((CH 2 ) m 2W 5a ); wherein m2 is 1, 2 or 3, and W 5a is a monocyclic, saturated, monounsaturated, diunsaturated or aromatic carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I,
  • R 13 is -OH, in another R 13 is -OC(0)N(H)((CH 2 )2Ph).
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 5 groups.
  • W 5 carbocycles and heterocycles are stable chemical structures. Such structures are isolatable in measurable yield, with measurable purity, from reaction mixtures at temperatures from -78°C to 200°C.
  • W 5 is a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. More typically, W 5 has 3 to 10 ring atoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6 ring atoms.
  • the W 5 rings are saturated when containing 3 ring atoms, saturated or monounsaturated when containing 4 ring atoms, saturated, or mono- or diunsaturated when containing 5 ring atoms, and saturated, mono- or diunsaturated, or aromatic when containing 6 ring atoms.
  • Unsaturation of the W 5 rings include internal and external unsaturation wherein the external incorporates a ring atom.
  • W 5 When W 5 is carbocyclic, it is typically a 3 to 7 carbon monocycle or a 7 to 12 carbon atom bicycle. More typically, W 5 monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. W 5 bicyclic carbocycles typically have 7 to 12 ring atoms arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, still more typically, 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, 1-cy clone x-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
  • a W 5 heterocycle is typically a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). More typically, W 5 heterocyclic monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S), still more typically, 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W 5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system, still more typically, 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
  • W 5 heterocycles are selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, or pyrrolyl.
  • heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and "J. Am. Chem. Soc", 82:5566 (1960).
  • heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2- pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • W a is a monocyclic (saturated, monounsaturated, diunsaturated or aromatic) carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I, -CN, N 3 , -N0 2 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -S(0)R 6 , -S(0) 2 R 6 ,
  • W 5 optionally is selected from the group consisting of:
  • W is phenyl (Ph) substituted with 0 to 2 groups seleceted from F, N 3 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -C(0)R 6 , -C(0)OR 6 , or -OP(0)(OR ) . More typically of this embodiment is phenyl substituted with 0 to 1 groups selected from F, -OH, -SH or -NH2.
  • Each X is independently selected from R 12 , 3'-G-, 3'-GG-, 3'-TGG-, 3'-TTGG-, 3'-GTTGG-, or 3'-GGTTGG-; wherein when X is R 5 then R 5 is not
  • X is R 12 it is selected F, Br, Cl, I, -CN, N 3 , -NO2, -OR 6 , -N(R 6 ) 2 , -SR 6 , -S(0)R 6 , -S(0) 2 R 6 , -S(0) 2 N(R 6 ) 2 , -C(0)R 6 , -C(0)OR 6 , -OC(0)R 6 , -OC(0)N(R 6 ) 2 , -N(R 6 )(C(0)R 6 , -C(0)N(R 6 ) 2 , -C(NR 6 )(N(R 6 ) 2 ),
  • X is F, N 3 , -N0 2 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -S(0) 2 N(R 6 ) 2 , -C(0)R 6 , -C(0)OR 6 , -OC(0)R 6 ,
  • X is F, N 3 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -C(0)R 6 , -C(0)OR 6 , or -OP(0)(OR 6 ) 2 .
  • X is most typically -OH or -OP(0)(OR 6 ) 2 .
  • X is 3'-G-, 3'-GG-, 3'-TGG-, 3'-TTGG-,
  • Oligomers and modified oligomers in this context contain guanosine or modified guanosine (G), or thymidine or modified thymidine (T).
  • G guanosine
  • T modified thymidine
  • guanosine, modified guanosine, thymidine or modified thymidine include the conventional nucleosides and deoxynucleosides formed from the corresponding bases or modified bases of guanine or thymine.
  • uracil is considered a modified thymine in this context.
  • Oligomer is generic to polydeoxyribonucleotides (containing 2'-deoxy-D-ribose or modified forms thereof), i.e., DNA, to polyribonucleotides (containing D-ribose or modified forms thereof), i.e., RNA, and to any other type of polynucleotide which is an N-glycoside or C-glycoside of a purine or pyrimidine base, or modified purine or pyrimidine base or abasic nucleotides.
  • nucleoside or “nucleotide” is similarly generic to ribonucleosides or ribonucleotides, deoxyribonucleosides or deoxyribonucleotides, or to any other nucleoside which is an N-glycoside or C-glycoside of a purine or pyrimidine base, or modified purine or pyrimidine base.
  • the stereochemistry of the sugar carbons may be other than that of D-ribose in one or more residues.
  • analogs where the ribose or deoxyribose moiety is replaced by an alternate structure such as the 6-membered morpholino ring described in U.S.
  • Nucleoside and “nucleotide” include those moieties which contain not only the natively found purine and pyrimidine bases T, G and U, but also modified or analogous forms thereof. Modifications include alkylated purines or pyrimidines, acylated purines or pyrimidines, or other heterocycles. Such “analogous purines” and “analogous pyrimidines” are those generally known in the art, many of which are used as chemotherapeutic agents.
  • An exemplary but not exhaustive list includes 5-(carboxyhydroxylmethyl) uracil, 5-fluorouracil, 7-deazaguanine, 5-bromouracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyl uracil, dihydrouracil, 1-methylpseudouracil, 1-methylguanine, 2,2-dimethylguanine, 2-methylguanine, 7-methylguanine, 5-methylaminomethyl uracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,
  • 5'-methoxycarbonylmethyluracil 5-methoxyuracil, uracil-5-oxyacetic acid methyl ester, pseudouracil, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, N-uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, queosine, 5-propyluracil, 5-ethyluracil, 5-butyluracil, 5-pentyluracil, and 2,6-diaminopurine.
  • nucleotide residues which are devoid of a purine or a pyrimidine base may also be included in the oligomers of the invention and in the methods for their preparation.
  • sugar residues in the oligonucleotides of the invention may also be other than conventional ribose and deoxyribose residues.
  • substitution at the 2'-position of the furanose residue is particularly important with regard to enhanced nuclease stability.
  • Oligonucleotides may contain analogous forms of ribose or deoxyribose sugars that are generally known in the art.
  • An exemplary, but not exhaustive list includes 2' substituted sugars such as 2'-0-methyl-, 2'-0-alkyl, 2'-0-allyl, 2'-S-alkyl, 2'-S-allyl, 2'-fluoro-, 2'-halo, or 2'- azido-ribose, carbocyclic sugar analogs, -anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside, ethyl riboside or propyl riboside.
  • Substitute linkages per se also are known for the replacement of the entire phosphoribosyl linkage of conventional oligonucleotides. These include for example morpholino-carbamates (Stirchak, "NAR” 17:6129, 1989), peptides (Nielsen et al., "Science” 254:1497, 1991; U.S.S.N. 07/892,902 and 07/894, 397), riboacetal linkages (PCT 92/10793) and morpholino-based linkages disclosed in U.S. patent Nos. 5,521,063 and 5,185,144.
  • PRT is a protecting group.
  • protecting groups are prodrug moieties.
  • Typical PRT groups include R ⁇ a, R ⁇ b and R ⁇ c wherein: R6a is an ether- or ester-forming group;
  • R ⁇ b is a protecting group for amino or the residue of a carboxyl- containing compound
  • R ⁇ c is the residue of an amino-containing compound.
  • R and R having R ⁇ a , R ⁇ b and R ⁇ c include, by way of example and not limitation, -OR6a -N(R 10 )(R b) -N(R6b)2, "SR6a, -S(0)OR6a, -S(0) 2 OR6a, -C(0)R6 C , -C(0)OR6a, -N(R6 b )(C(O)Rl0), -N(R 6b )(C(O)ORl0, -C(O)N(R 6b )(Rl0), -C(0)N(R6 b ) 2 , -C(N(R 6 b))(N(RlO)2), -C(N(RlO))(N(RlO)(R 6b )), -C(N(R 6 b))(N(RlO)(R 6b )), -C(N(Rl0))(N(Rl0))
  • Groups R ⁇ a and R b are not critical functionalities and may vary widely. When not H, their function is to serve as intermediates for the parental drug substance. This does not mean that they are biologically inactive. On the contrary, a principal function of these groups is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs are absorbed more effectively than the parental drug they in fact often possess greater potency in vivo than the parental drug. When not hydrogen, R6a and R6b are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting pro- functionality products, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
  • chemical intermediates it is not particularly important that the resulting pro- functionality products, e.g. alcohols, be physiologically acceptable, although in general it is more
  • R6a is an ether- or ester-forming group.
  • "Ether-forming group” means a group which is capable of forming a stable, covalent bond between the parental molecule and a group having the formula:
  • Va is a tetravalent atom typically selected from C and Si
  • Vb is a trivalent atom typically selected from B, Al, N, and P, more typically N and P
  • Vc is a divalent atom typically selected from O, S, and Se, more typically O or S
  • Vi is a group bonded to Va, Vb or Vc by a stable, single covalent bond, typically Vi is H, R 2 , W 5 , or -R 8 W 5 , still more typically H or R 2
  • V3 is a group bonded to Va by a stable, triple covalent bond, typically V3 is ⁇ C(V ⁇
  • Ester-forming group means a group which is capable of forming a stable, covalent bond between the parental molecule and a group having the formula:
  • V a , V , and Vi are as described above;
  • Vd is a pentavalent atom typically selected from P and N;
  • V e is a hexavalent atom typically S;
  • Protecting groups for -OH functions are embodiments of "ether- or ester-forming groups”.
  • ether- or ester-forming groups that are capable of functioning as protecting groups in the synthetic schemes set forth herein.
  • some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed under R ⁇ c below.
  • R ⁇ c is capable of protecting hydroxyl or thio groups such that hydrolysis from the parental molecule yields hydroxyl or thio.
  • R ⁇ a In its ester-forming role, R ⁇ a typically is bound to any acidic group such as, by way of example and not limitation, a -CO2H or -C(S)OH group, thereby resulting in -C ⁇ 2R ⁇ a- R ⁇ a for example is deduced from the enumerated ester groups of WO 95/07920.
  • acidic group such as, by way of example and not limitation, a -CO2H or -C(S)OH group, thereby resulting in -C ⁇ 2R ⁇ a- R ⁇ a for example is deduced from the enumerated ester groups of WO 95/07920.
  • Rfo include
  • C 3 -C ⁇ 2 heterocyle (described above) or C6-C12 aryl.
  • aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5- isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5- pyrimidinyl, C 3 -Ci2 heterocycle or C6-C 1 2 aryl substituted with halo, Ri, Rl-
  • O-C1-C12 alkylene C 1 -C12 alkoxy, CN, NO2, OH, carboxy, carboxyester, thiol, thioester, C1-C12 haloalkyl (1-6 halogen atoms), C2-C12 alkenyl or C2-C12 alkynyl.
  • Such groups include 2-, 3- and 4-alkoxyphenyl (C ⁇ -C ⁇ 2 alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy- 4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6- hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and 4- dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4- halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4- chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,
  • C4 - C8 esters of 2-carboxyphenyl and C 1 -C 4 alkylene-C 3 -C 6 aryl (including benzyl, -CH 2 -pyrrolyl, -CH 2 - thienyl, -CH 2 -imidazolyl, -CH 2 -oxazolyl, -CH 2 -isoxazolyl, -CH 2 -thiazolyl,
  • alkoxy ethyl [C ⁇ -C 6 alkyl including -CH 2 -CH 2 -0-CH 3 (methoxy ethyl)]; alkyl substituted by any of the groups set forth above for aryl, in particular OH or by 1 to 3 halo atoms (including -CH 3/ -CH(CH 3 ) 2 , - CH ⁇ ,
  • -N-2-propylmorpholino, 2,3-dihydro-6- hydroxyindene, sesamol, catechol monoester, -CH 2 -C(0)-N(R 1 ) 2 , -CH2- S(0)(R l ), -CH 2 -S(0) 2 (R 1 ), -CH2-CH(OC(0)CH 2 R 1 )-CH2(OC(0)CH 2 R 1 ), cholesteryl, enolpyruvate (HOOC-C( CH 2 )-), glycerol; a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9 monosaccharide residues); triglycerides such as -D- ⁇ -diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C6-26, C 6 - 1 8 or C ⁇ -io fatty acids such as linoleic, lauri
  • hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in WO94/21604, or with isopropyl.
  • Table A lists examples of R ⁇ a ester moieties that for example can be bonded via oxygen to -C(0)0- and -P(0)(0-) 2 groups.
  • R6c amidates also are shown, which are bound directly to -C(O)- or -P(0)2- Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N ,N- dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsC0 3 , N,N-dimethylaniline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone).
  • esters of structures 5-7, 11, 12, 21, and 23- 26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
  • # - chiral center is (R), (S) or racemate.
  • R6a also includes "double ester” forming profunctionalities such as
  • R 3 7 and R3 are bulky groups such as branched alkyl, ortho- substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms.
  • An example is the pivaloyloxymethyl group.
  • R& a groups are alkylacyloxymethyl esters and their derivatives, including -CH(CH 2 CH2 ⁇ CH3)OC(0)C(CH 3 ) 3 ,
  • the ester typically chosen is one heretofore used for antibiotic drugs, in particular the cyclic carbonates, double esters, or the phthalidyl, aryl or alkyl esters.
  • R6 &/ R ⁇ c and R6b groups optionally are used to prevent side reactions with the protected group during synthetic procedures, so they function as protecting groups (PRT) during synthesis.
  • PRT protecting groups
  • the PRT groups do not need to be, and generally are not, the same if the compound is substituted with multiple PRT. In general, PRT will be used to protect carboxyl, hydroxyl or amino groups.
  • the R(_ a protected acidic group is an ester of the acidic group and Rfa is the residue of a hydroxyl-containing functionality.
  • an R6c amino compound is used to protect the acid functionality.
  • the residues of suitable hydroxyl or amino- containing functionalities are set forth above or are found in WO 95/07920.
  • the residues of amino acids, amino acid esters, polypeptides, or aryl alcohols are described on pages 11-18 and related text of WO 95/07920 as groups LI or L2.
  • WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
  • Typical R ⁇ a esters for protecting Wi acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication.
  • Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R 31 or R 35 ), the table on page 105, and pages 21-23 (as R).
  • esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and /or alkylestercarboxy-substituted aryl or alkylaryl, especially phenyl, ortho- ethoxyphenyl, or C1-C4 alkylestercarboxyphenyl (salicylate C ⁇ -C ⁇ 2 alkylesters).
  • the protected acidic groups Wi are useful as prodrugs for oral administration. However, it is not essential that the Wi acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route.
  • the compounds of the invention having protected groups in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydrolytic cleavage in vivo to yield the free acid.
  • One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
  • Typical R a hydroxy protecting groups described in Greene include Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, ⁇ -
  • Methoxycrotonate Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate)); Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2- Trichloroethyl, 2-(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl, 2- (Triphenylphosphonio)ethyl, Isobutyl, Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S- Benzyl Thiocarbonate, 4-Ethoxy-l-naphthyl, Methyl Dithiocarbonate); Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobut
  • Miscellaneous Esters (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4- (1,1,3,3 tetramethylbutyl)phenoxyacetate, 2,4-Bis(l,l- dimethylpropyl)phenoxyacetate, Chorodiphenylacetate, Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate), o- (Methoxycarbonyl)benzoate, p-poly-Benzoate, ⁇ -Naphthoate, Nitrate, Alkyl N,N,N ',N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate, Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate
  • R ⁇ a hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, trialkylsilyl ethers, tosylates and acetates.
  • Typical 1,2-diol protecting groups are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-f-Butylethylidene, 1-Phenylethylidene, (4- Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene, 3,4- Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1- Methoxyethylidene, 1-Ethoxy
  • 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals.
  • R ⁇ is Ci-C ⁇ alkyl.
  • R is H, a protecting group for amino or the residue of a carboxyl- containing compound, in particular H, -C(0)R 4 , an amino acid, a polypeptide or a protecting group not -C(0)R 4 , amino acid or polypeptide.
  • R6b is an amino acid or polypeptide it has the structure Rl5NHCH(Ri6)C(0)-, where R15 is H, an amino acid or polypeptide residue, or R 5 , and Ri ⁇ is defined below.
  • Rl6 is lower alkyl or lower alkyl ( -C ⁇ ) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C6-C7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate.
  • R ⁇ 6 is generally the side group of a naturally-occurring amino acid such as H, -CH 3 , -CH(CH 3 ) 2 , -CH -CH(CH 3 )2, -CHCH 3 -CH 2 -CH 3 , -CH 2 -C ⁇ H 5 , -CH2CH2-S-CHS, -CH 2 OH, -CH(OH)-CH 3 , -CH 2 -SH, -CH2-C6H4OH, -CH 2 -CO-NH2, -CH2-CH2-CO-NH2, -CH2-COOH, -CH 2 -CH 2 -COOH, -(CH 2 )4-NH 2 and -(CH 2 ) 3 -NH-C(NH 2 )-NH 2 .
  • a naturally-occurring amino acid such as H, -CH 3 , -CH(CH 3 ) 2 , -CH -CH(CH 3 )2, -CHCH 3 -CH 2
  • Ri ⁇ also includes l-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
  • R ⁇ b are residues of carboxylic acids for the most part, but any of the typical amino protecting groups described by Greene at pages 315-385 are useful.
  • N-N Derivatives N-nitro, N-nitroso, N-oxide
  • N-P Derivatives N-diphenylphosphinyl, N-dimethylthiophosphinyl, N- diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl
  • N-Si Derivatives N-S Derivatives
  • N-S Derivatives N-Sulfenyl Derivatives (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4- dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N-2-nitro-4- methoxybenzenesulfenyl, N-triphenyl
  • R ⁇ c is the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHS02R , NHC(0)R 4 , -N(R )2, NH2 or -NH(R )(H), whereby for example the carboxyl or phosphonic acid groups are reacted with the amine to form an amide, as in -C(0)R6c, -P(0)(R6c)2 or -P(0)(OH)(R6 C ).
  • R ⁇ c has the structure Rl7C(0)CH(R ⁇ 6 )NH-, where R i is OH, OR ⁇ a, OR5, an amino acid or a polypeptide residue.
  • Amino acids are low molecular weight compounds, on the order of less than about 1,000 MW, that contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man. Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Of particular interest are hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent.
  • Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline.
  • R ⁇ b and R ⁇ c are single amino acid residues or polypeptides they usually are substituted at R 4 and/or R .
  • R 4 and/or R Generally, only one of any site in the parental molecule is amidated with an amino acid as described herein, although it is within the scope of this invention to introduce amino acids at more than one permitted site.
  • a carboxyl group is amidated with an amino acid.
  • the ⁇ -amino or ⁇ -carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the parental functionalities, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates as described further below).
  • carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g. by R ⁇ a, esterified with R 5 or amidated with R ⁇ c- Similarly, the amino side chains Ri ⁇ optionally will be blocked with R ⁇ b or substituted with R 5 .
  • esters or amide bonds with side chain amino or carboxyl groups like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH ⁇ 3) or basic (pH >10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
  • the esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups.
  • the free acid or base of the parental compound for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures.
  • any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used.
  • D isomers are useful.
  • L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.
  • R ⁇ b and R ⁇ c examples include the following:
  • Aminopolycarboxylic acids e.g., aspartic acid, ⁇ -hydroxyaspartic acid, glutamic acid, ⁇ -hydroxyglutamic acid, ⁇ -methylaspartic acid, ⁇ - methylglutamic acid, ⁇ , ⁇ -dimethylaspartic acid, ⁇ -hydroxyglutamic acid, ⁇ , ⁇ - dihydroxyglutamic acid, ⁇ -phenylglutamic acid, ⁇ -methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid and 2- aminosebacic acid;
  • Amino acid amides such as glutamine and asparagine
  • Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine, ⁇ -aminoalanine, ⁇ -aminobutyrine, ornithine, citruline, homoarginine, homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;
  • Diaminodicarboxylic acids such as ⁇ , ⁇ '-diaminosuccinic acid, ⁇ , ⁇ '- diaminoglutaric acid, ⁇ , ⁇ '-diaminoadipic acid, ⁇ , ⁇ '-diaminopimelic acid, ⁇ , ⁇ '-diamino- ⁇ -hydroxypimelic acid, ⁇ , ⁇ '-diaminosuberic acid, ⁇ , ⁇ '- diaminoazelaic acid, and ⁇ , ⁇ '-diaminosebacic acid;
  • Imino acids such as proline, hydroxyproline, allohydroxyproline, ⁇ - methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2- carboxylic acid;
  • a mono- or di-alkyl (typically Ci - Cs branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, ⁇ -methylserine, ⁇ -amino- ⁇ -methyl- ⁇ - hydroxyvaleric acid, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ - methyl- ⁇ -hydroxycaproic acid, isovaline, ⁇ -methylglutamic acid, ⁇ - aminoisobutyric acid, ⁇ -aminodiethylacetic acid, ⁇ -aminodiisopropylacetic acid, ⁇ -aminodi-n-propylace
  • Aliphatic ⁇ -amino- ⁇ -hydroxy acids such as serine, ⁇ -hydroxyleucine, ⁇ -hydroxynorleucine, ⁇ -hydroxynorvaline, and ⁇ -amino- ⁇ -hydroxystearic acid; ⁇ - Amino, ⁇ -, ⁇ -, ⁇ - or ⁇ -hydroxy acids such as homoserine, ⁇ - hydroxynorvaline, ⁇ -hydroxynorvaline and epsilon-hydroxynorleucine residues; canavine and canaline; ⁇ -hydroxyornithine;
  • 2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid
  • ⁇ - Amino- ⁇ -thiols such as penicillamine, ⁇ -thiolnorvaline or ⁇ - thiolbutyrine
  • cysteine Other sulfur containing amino acid residues including cysteine; homocystine, ⁇ -phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
  • Phenylalanine, tryptophan and ring-substituted ⁇ amino acids such as the phenyl- or cyclohexylamino acids ⁇ -aminophenylacetic acid, ⁇ - aminocyclohexylacetic acid and ⁇ -amino- ⁇ -cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dicloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5-nitro- and p- nitro-phenylalanine); furyl-, thienyl-, pyridy
  • Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond.
  • Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
  • polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
  • Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound.
  • the conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it. Accordingly, the polypeptide or protein may not need to be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final product conjugate should be immunogenic in at least one of such animals.
  • the polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom.
  • Such cleavage sites are flanked by enzymatic recognition structures, e.g. a particular sequence of residues recognized by a peptidolytic enzyme.
  • Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases.
  • Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences.
  • Such enzymes and their substrate requirements in general are well known.
  • a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its ⁇ -amino group to the phosphorus or carbon atoms of the compounds herein.
  • the protected group is phosphonate it is expected that this peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond.
  • Suitable dipeptidyl groups are AA, AR, AN, AD, AC, AE, AQ, AG, AH, Al, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, C
  • Tripeptide residues are also useful as R ⁇ b or R ⁇ c- When Wi is phosphonate, the sequence -X4-pro-X5- (where X4 is any amino acid residue and X5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond.
  • the carboxy group of X5 optionally is esterified with benzyl.
  • Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types.
  • Dipeptides and tripeptides lacking an ⁇ -amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., "Pharm Res.” 9:969-978 (1992).
  • Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds.
  • Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be utilized in the amidate compounds of this invention.
  • Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N (EC 3.4.11.2).
  • di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine.
  • tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A (EC 3.4.11.7)
  • di- or tripeptides lacking amino acid residues on the N- terminal side of hydrophobic amino acids are poor substrates for endopeptidase 24.11 (EC 3.4.24.11)
  • peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P (EC 3.4.17).
  • Another embodiment of the invention is directed to compounds of having formula (VI), (VII), (VIII), (IX) or (X):
  • Preferred embodiments of the invention include compounds of the formula (VI).
  • Alternative preferred embodiments of the invention include compounds of the formula (VII).
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 and X are freely combinable into typical embodiments of the invention. All combinations of the typical, ordinary or preferred embodiments of the above variables are contemplated to be within the scope of the present invention. All that is required to derive such embodiments is that combination of those typical, ordinary or preferred embodiments of the above identified variables. To avoid redundancy in this disclosure, each of these intended embodiments will not be listed. However, two such embodiments are set forth by way of example and not limitation.
  • R 1 is alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms;
  • each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2 R groups;
  • R 3 is F, Br, Cl, -CN, or N 3 ;
  • R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2 R groups;
  • R 5 is F, Br, Cl, I, -CN, N 3 , -N0 2 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -S(0)R 6 ,
  • R 6 is H or PRT;
  • R is alkylene of 1 to 4 carbon atoms, alkenylene of 2 to 4 carbon atoms or alkynylene of 2 to 4 carbon atoms;
  • R 8 is R 7 wherein each said alkylene, alkenylene and alkynylene is independently substituted with 0 to 2 R groups;
  • R 9 is R 6; each R 10 , R 11 , R 12 is as defined above;
  • R 13 is -OR 10 or -OC(0)N(H)( (CR 10 2 ) m lW 5 ); wherein ml is an integer of 1 to 6 and W is as defined above; and
  • X is -OR 6 or 3'-GGTTGG-, wherein R 6 is as defined above.
  • R 1 is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms or alkynyl of 2 to 3 carbon atoms;
  • R 2 is R 1 wherein each said alkyl, alkenyl and alkynyl is
  • R 3 is F, Br, Cl or N 3 ;
  • R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 1 R groups;
  • R 5 is F, N 3 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -C(0)R 6 , -C(0)OR 6 , or -OP(0)(OR 6 ) 2 ;
  • R 6 is H
  • R is alkylene of 1 to 3 carbon atoms, alkenylene of 2 to 3 carbon atoms or alkynylene of 2 to 3 carbon atoms;
  • R is R wherein each said alkylene, alkenylene and alkynylene is independently substituted with 0 to 1 R groups;
  • R is -(CH 2 ) m2 W ; wherein m2 is 1, 2 or 3, and W is a monocyclic, saturated, monounsaturated, diunsaturated or aromatic carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I, -CN, N 3 , -N0 2 , -OR 6 , -N(R 6 ) 2 , -SR 6 , -S(0)R 6 , -S(0) 2 R 6 , -S(0) 2 N(R 6 ) 2 , -C(0)R 6 , -C(0)OR 6 , -OC(0)R 6 , -OC(0)N(R 6 ) 2 , -N(R 6 )(C(0)R 6 , -C(0)N(R 6 ) 2 , -C(NR 6 )(N(R 6 ) 2 ), -N(R 6 )C(N(R 6 ))
  • each R 10 , R 11 , R 12 is as defined above;
  • R 13 is -OH or -OC(0)N(R 6 )((CH 2 ) m2 W 5a ); wherein m2 is 1, 2 or 3, and W 5a is a monocyclic, saturated, monounsaturated, diunsaturated or aromatic carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I, -CN, N 3 , -N0 2 ,
  • compositions comprising a compound of of the invention and a pharmaceutically- acceptable carrier.
  • Another embodiment of the invention is directed to methods of detecting the presence or absence of thrombin comprising contacting a sample suspected of containing thrombin with a compound of the invention.
  • Another embodiment of the invention is directed to methods of inhibiting the activity of thrombin comprising contacting a sample suspected of containing thrombin with a compound of the invention.
  • Another embodiment of the invention is directed to methods of inhibiting the activity of thrombin in a host comprising administering to the host a therapeutically effective amount of a compound of the invention.
  • Two exemplary embodiments of the invention are depicted below:
  • the compounds of the invention are enriched or resolved optical isomers at any or all asymmetric atoms.
  • the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
  • racemic and diasteromeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
  • One or more of the following enumerated methods are used to prepare the enantiomerically enriched or pure isomers herein.
  • the methods are listed in approximately their order of preference, i.e., one ordinarily should employ stereospecific synthesis from chriral precursors before chromatographic resolution before spontaneous crystallization.
  • Stereospecific synthesis is described in the examples. Methods of this type conveniently are used when the appropriate chiral starting material is available and reaction steps are chosen do not result in undesired racemization at chiral sites.
  • One advantage of stereospecific synthesis is that it does not produce undesired enantiomers that must be removed from the final product, thereby lowering overall synthetic yield.
  • those skilled in the art would understand what starting materials and reaction conditions should be used to obtain the desired enantiomerically enriched or pure isomers by stereospecific synthesis. If an unexpected racemization occurs in a method thought to be stereospecific then one needs only to use one of the following separation methods to obtain the desired product.
  • a suitable stereospecific synthesis cannot be empirically designed or determined with routine experimentation then those skilled in the art would turn to other methods.
  • One method of general utility is chromotographic resolution of enantiomers on chiral chromatography resins. These resins are packed in columns, commonly called Pirkle columns, and are commercially available. The columns contain a chiral stationary phase. The racemate is placed in solution and loaded onto the column, and thereafter separated by HPLC. See for example, Proceedings Chromatographic Society - International Symposium on Chiral Separations, Sept. 3-4, 1987. Examples of chiral columns that could be used to screen for the optimal separation technique would include Diacel
  • Another method entails converting the enantiomers in the mixture to diasteriomers with chiral auxiliaries and then separting the conjugates by ordinary column chromatography. This is a very suitable method, particularly when the embodiment contains free carboxyl, amino or hydroxyl that will form a salt or covalent bond to a chiral auxiliary.
  • Chirally pure amino acids, organic acids or organosulfonic acids are all worthwhile exploring as chiral auxiliaries, all of which are well known in the art. Salts with such auxiliaries can be formed, or they can be covalently (but reversibly) bonded to the functional group.
  • pure D or L amino acids can be used to amidate the carboxyl group of embodiments of this invention and then separated by chromatography.
  • Enzymatic resolution is another method of potential value.
  • one prepares covalent derivatives of the enantiomers in the racemic mixture, generally lower alkyl esters (for example of carboxyl), and then exposes the derivative to enzymatic cleavage, generally hydrolysis.
  • an enzyme must be chosen that is capable of stereospecific cleavage, so it is frequently necessary to routinely screen several enzymes. If esters are to be cleaved, then one selects a group of esterases, phosphatases, and Upases and determines their activity on the derivative. Typical esterases are from liver, pancreas or other animal organs, and include porcine liver esterase.
  • the enatiomeric mixture separates from solution or a melt as a conglomerate, i.e., a mixture of enantiomerically-pure crystals, then the crystals can be mechanically separated, thereby producing the enantiomerically enriched preparation.
  • This method is not practical for large scale preparations and is of no value for true racemic compounds.
  • Asymmetric synthesis is another technique for achieving enantiomeric enrichment. For example, a chiral protecting group is reacted with the group to be protected and the reaction mixture allowed to equilibrate. If the reaction is enantiomerically specific then the product will be enriched in that enantiomer.
  • the compounds of the invention can also exist as tautomeric isomers in certain cases.
  • ene-amine tautomers can exist for imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • each compound is depicted as a substituted nucleus in which the nucleus is designated by capital letter and each substituent is designated in order by lower case letter or number.
  • Table 1 is a schedule of nuclei. Each nucleus is given a alphabetical designation from Table 1, and this designation appears first in each compound name.
  • Tables 2-8 list the selected Qi, Q 2 , Q 3 , Q4 Q ⁇ , Q ⁇ and Q7 substituents, again by letter or number designation.
  • each named compound will be depicted by a capital letter designating the nucleus from Table 1, followed by a number designating the Qi substituent, a lower case letter designating the Q 2 substituent, a number designating the Q 3 substituent, a lower case letter designating the Q 4 substituent, a number designating the Q5 substituent, a lower case letter designating the Q ⁇ substituent, and a number designating the Q7.
  • the compound of Example 14 is represented by A.7.a.8.a.l.a.l. Q1-Q7, it should be understood, do not represent groups or atoms but are simply connectivity designations.
  • A.l.a.l.l.l.l.c.l A.l.a.l.l.l.c.2; A.l.a.l.l.l.d.l; A.l.a.l.l.l.d.2; A.l.a.l.l.l.e.l; A.l.a.l.l.l.e.2; A.l.a.l.l.l.f.l; A.l.a.l.l.l.f.2; A.l.a.l.l.l.g.l; A.l.a.l.l.l.g.2;
  • A.l.a.2.a.l.f.l A.l.a.2.a.l.f.2; A.l.a.2.a.l.g.l; A.l.a.2.a.l.g.2; A.l.a.2.b.l.a.l;
  • A.l.a.8.b.l.d.l A.l.a.8.b.l.d.2; A.l.a.8.b.l.e.l; A.l.a.8.b.l.e.2; A.l.a. ⁇ .b.l.f.l; A.l.a.8.b.l.f.2; A.l.a. ⁇ .b.l.g.l; A.l.a. ⁇ .b.l.g.2; A.l.a.8.f.l.a.l; A.l.a.8.f.l.a.l; A.l.a.8.f.l.a.2;
  • A.l.a. ⁇ .l.l.c.l A.l.a. ⁇ .l.l.c.2; A.l.a. ⁇ .l.l.d.l; A.l.a.8.1.1.d.2; A.l.a. ⁇ .l.l.e.l;
  • A.2.a.l.a.l.f.l A.2.a.l.a.l.f.2; A.2.a.l.a.l.g.l; A.2.a.l.a.l.g.2; A.2.a.l.b.l.a.l; A.2.a.l.b.l.a.2; A.2.a.l.b.l.b.l; A.2.a.l.b.l.b.l; A.2.a.l.b.l.b.2; A.2.a.l.b.l.c.l; A.2.a.l.b.l.c.2;
  • A.2.a.l.b.l.d.l A.2.a.l.b.l.d.2; A.2.a.l.b.l.e.l; A.2.a.l.b.l.e.2; A.2.a.l.b.l.f.l;
  • A.2.a.l.f.l.g.l A.2.a.l.f.l.g.2; A.2.a.l.h.l.a.l; A.2.a.l.h.l.a.2; A.2.a.l.h.l.b.l;
  • A.2.a.2.a.l.a.l A.2.a.2.a.l.a.2; A.2.a.2.a.l.b.l; A.2.a.2.a.l.b.2; A.2.a.2.a.l.c.l;
  • A.2.a.2.a.l.f.l A.2.a.2.a.l.f.2; A.2.a.2.a.l.g.l; A.2.a.2.a.l.g.2; A.2.a.2.b.l.a.l; A.2.a.2.b.l.a.2; A.2.a.2.b.l.b.l; A.2.a.2.b.l.b.2; A.2.a.2.b.l.b.2; A.2.a.2.b.l.c.l; A.2.a.2.b.l.c.2;
  • A.2.a.2.b.l.d.l A.2.a.2.b.l.d.2; A.2.a.2.b.l.e.l; A.2.a.2.b.l.e.2; A.2.a.2.b.l.f.l;
  • A.2.a.8.a.l.a.l A.2.a. ⁇ .a.l.a.2; A.2.a. ⁇ .a.l.b.l; A.2.a.8.a.l.b.2; A.2.a.8.a.l.c.l;
  • A.2.a. ⁇ .a.l.f.l A.2.a.8.a.l.f.2; A.2.a. ⁇ .a.l.g.l; A.2.a. ⁇ .a.l.g.2; A.2.a. ⁇ .b.l.a.l;
  • A.2.a. ⁇ .l.l.c.l A.2.a. ⁇ .l.l.c.2; A.2.a.8.1.1.d.l; A.2.a. ⁇ .l.l.d.2; A.2.a. ⁇ .l.l.e.l;
  • A.8.a.l.a.l.f.l A.8.a.l.a.l.f.2; A.8.a.l.a.l.g.l; A.8.a.l.a.l.g.2; A. ⁇ .a.l.b.l.a.l;
  • A. ⁇ .a.l.b.l.d.l A. ⁇ .a.l.b.l.d.2; A. ⁇ .a.l.b.l.e.l; A. ⁇ .a.l.b.l.e.2; A. ⁇ .a.l.b.l.f.l; A. ⁇ .a.l.b.l.f.2; A. ⁇ .a.l.b.l.f.2; A. ⁇ .a.l.b.l.g.l; A. ⁇ .a.l.b.l.g.2; A. ⁇ .a.l.f.l.a.l; A.8.a.l.f.l.a.2;
  • A. ⁇ .a.l.l.l.c.l A. ⁇ .a.l.l.l.c.2; A. ⁇ .a.l.l.l.d.l; A. ⁇ .a.l.l.l.d.2; A. ⁇ .a.l.l.e.l;
  • A.8.a.2.a.l.a.l A. ⁇ .a.2.a.l.a.2; A. ⁇ .a.2.a.l.b.l; A. ⁇ .a.2.a.l.b.2; A. ⁇ .a.2.a.l.c.l;
  • A. ⁇ .a.2.b.l.d.l A. ⁇ .a.2.b.l.d.2; A. ⁇ .a.2.b.l.e.l; A. ⁇ .a.2.b.l.e.2; A. ⁇ .a.2.b.l.f.l;
  • A. ⁇ .a.2.f.l.g.l A. ⁇ .a.2.f.l.g.2; A. ⁇ .a.2.h.l.a.l; A. ⁇ .a.2.h.l.a.2; A.8.a.2.h.l.b.l;
  • A. ⁇ .a. ⁇ .a.l.a.l A. ⁇ .a. ⁇ .a.l.a.2; A. ⁇ .a. ⁇ .a.l.b.l; A.8.a.8.a.l.b.2; A. ⁇ .a. ⁇ .a.l.c.l;
  • A. ⁇ .a. ⁇ .a.l.f.l A. ⁇ .a. ⁇ .a.l.f.2; A. ⁇ .a. ⁇ .a.l.g.l; A. ⁇ .a. ⁇ .a.l.g.2; A. ⁇ .a. ⁇ .b.l.a.l; A. ⁇ .a. ⁇ .b.l.a.2; A. ⁇ .a. ⁇ .b.l.b.l; A. ⁇ .a. ⁇ .b.l.b.l; A. ⁇ .a. ⁇ .b.l.b.2; A. ⁇ .a. ⁇ .b.l.b.2; A. ⁇ .a. ⁇ .b.l.c.l; A.8.a.8.b.l.c.2;
  • A. ⁇ .a. ⁇ .b.l.d.l A. ⁇ .a. ⁇ .b.l.d.2; A.8.a.8.b.l.e.l; A. ⁇ .a. ⁇ .b.l.e.2; A. ⁇ .a. ⁇ .b.l.f.l;
  • A.10.a.l.a.l.c.l A.lO.a.l.a.l.c.2; A.lO.a.l.a.l.d.l; A.10.a.l.a.l.d.2;
  • A.10.a.2.b.l.a.l A.10.a.2.b.l.a.2; A.10.a.2.b.l.b.l; A.10.a.2.b.l.b.2; A.10.a.2.b.l.c.l; A.10.a.2.b.l.c.2; A.10.a.2.b.l.d.l; A.10.a.2.b.l.d.2;
  • A.10.a.8.f.l.a.l A.10.a. ⁇ .f.l.a.2; A.lO.a. ⁇ .f.l.b.l; A.10.a. ⁇ .f.l.b.2; A.10.a.8.f.l.c.l;
  • A.12.a.l.l.l.a.l A.12.a.l.l.l.a.2; A.12.a.l.l.l.b.l; A.12.a.l.l.l.b.2; A.12.a.l.l.l.c.l; A.12.a.l.l.l.c.2; A.12.a.l.l.l.d.l; A.12.a.l.l.l.d.2; A.12.a.l.l.l.e.l; A.12.a.l.l.l.e.2;
  • A.12.a.l.l.l.f.l A.12.a.l.l.l.f.2; A.12.a.l.l.l.g.l; A.12.a.l.l.l.g.2; A.12.a.2.a.l.a.l;
  • A.12.a. ⁇ .f.l.a.l A.12.a. ⁇ .f.l.a.2; A.12.a. ⁇ .f.l.b.l; A.12.a. ⁇ .f.l.b.2; A.12.a. ⁇ .f.l.c.l; A.12.a. ⁇ .f.l.c.2; A.12.a. ⁇ .f.l.d.l; A.12.a. ⁇ .f.l.d.2; A.12.a. ⁇ .f.l.e.l; A.12.a. ⁇ .f.l.e.2;
  • A.12.a.8.f.l.f.l A.12.a. ⁇ .f.l.f.2; A.12.a. ⁇ .f.l.g.l; A.12.a. ⁇ .f.l.g.2; A.12.a. ⁇ .h.l.a.l;
  • A.14.a.l.l.l.f.l A.14.a.l.l.l.f.2; A.14.a.l.l.l.g.l; A.14.a.l.l.l.g.2; A.14.a.2.a.l.a.l;
  • A.14.a.2.b.l.c.l A.14.a.2.b.l.c.2; A.14.a.2.b.l.d.l; A.14.a.2.b.l.d.2;
  • A.15.a.l.a.l.a.l A.15.a.l.a.l.a.2; A.15.a.l.a.l.b.l; A.15.a.l.a.l.b.2; A.15.a.l.a.l.c.l; A.15.a.l.a.l.c.2; A.15.a.l.a.l.d.l; A.15.a.l.a.l.d.2;
  • A.15.a.l.l.l.a.l A.15.a.l.l.l.a.2; A.15.a.l.l.l.b.l; A.15.a.l.l.l.b.2; A.15.a.l.l.c.l;
  • A.15.a.l.l.l.f.l A.15.a.l.l.l.f.2; A.15.a.l.l.l.g.l; A.15.a.l.l.l.g.2; A.15.a.2.a.l.a.l;
  • A.15.a.2.b.l.a.l A.15.a.2.b.l.a.2; A.15.a.2.b.l.b.l; A.15.a.2.b.l.b.2;
  • A.15.a.2.b.l.c.l A.15.a.2.b.l.c.2; A.15.a.2.b.l.d.l; A.15.a.2.b.l.d.2;
  • A.15.a.2.f.l.c.l A.15.a.2.f.l.c.2; A.15.a.2.f.l.d.l; A.15.a.2.f.l.d.2; A.15.a.2.f.l.e.l;
  • A.15.a.2.h.l.c.l A.15.a.2.h.l.c.2; A.15.a.2.h.l.d.l; A.15.a.2.h.l.d.2; A.15.a.2.h.l.e.l; A.15.a.2.h.l.e.2; A.15.a.2.h.l.f.l; A.15.a.2.h.l.f.2;
  • A.15.a.2.1.1.b.l A.15.a.2.1.1.b.2; A.15.a.2.1.1.c.l; A.15.a.2.1.1.c.2; A.15.a.2.1.1.d.l;
  • A.15.a.8.f.l.a.l A.15.a. ⁇ .f.l.a.2; A.15.a. ⁇ .f.l.b.l; A.15.a. ⁇ .f.l.b.2; A.15.a. ⁇ .f.l.c.l;
  • A.15.a. ⁇ .f.l.f.l A.15.a.8.f.l.f.2; A.15.a. ⁇ .f.l.g.l; A.15.a. ⁇ .f.l.g.2; A.15.a. ⁇ .h.l.a.l;
  • A.15.a.8.1.1.c.l A.15.a. ⁇ .l.l.c.2; A.15.a.8.1.1.d.l; A.15.a.8.1.1.d.2; A.15.a.8.1.1.e.l;
  • A.16.a.l.h.l.f.l A.16.a.l.h.l.f.2; A.l ⁇ .a.l.h.l.g.l; A.16.a.l.h.l.g.2;
  • A.16.a.2.b.l.c.l A.16.a.2.b.l.c.2; A.16.a.2.b.l.d.l; A.16.a.2.b.l.d.2; A.16.a.2.b.l.e.l; A.16.a.2.b.l.e.2; A.16.a.2.b.l.f.l; A.16.a.2.b.l.f.2; A.16.a.2.b.l.g.l;
  • A.16.a.2.h.l.a.l A.16.a.2.h.l.a.2; A.16.a.2.h.l.b.l; A.16.a.2.h.l.b.2; A.16.a.2.h.l.c.l; A.16.a.2.h.l.c.2; A.16.a.2.h.l.d.l; A.16.a.2.h.l.d.2;
  • A.16.a. ⁇ .f.l.f.l A.16.a. ⁇ .f.l.f.2; A.l ⁇ .a. ⁇ .f.l.g.l; A.16.a. ⁇ .f.l.g.2; A.l ⁇ .a. ⁇ .h.l.a.l; A.16.a.8.h.l.a.2; A.16.a.8.h.l.b.l; A.16.a.8.h.l.b.2; A.l ⁇ .a. ⁇ .h.l.c.l;
  • A.17.a.l.h.l.f.l A.17.a.l.h.l.f.2; A.17.a.l.h.l.g.l; A.17.a.l.h.l.g.2;
  • A.17.a.2.b.l.a.l A.17.a.2.b.l.a.2; A.17.a.2.b.l.b.l; A.17.a.2.b.l.b.2; A.17.a.2.b.l.c.l; A.17.a.2.b.l.c.2; A.17.a.2.b.l.d.l; A.17.a.2.b.l.d.2;
  • A.17.a. ⁇ .f.l.a.l A.17.a. ⁇ .f.l.a.2; A.17.a. ⁇ .f.l.b.l; A.17.a. ⁇ .f.l.b.2; A.17.a. ⁇ .f.l.c.l;
  • A.18.a.l.l.l.a.l A.18.a.l.l.l.a.2; A.l ⁇ .a.l.l.l.b.l; A.l ⁇ .a.l.l.l.b.2; A.l ⁇ .a.l.l.l.c.l; A.l ⁇ .a.l.l.l.c.2; A.l ⁇ .a.l.l.l.c.2; A.l ⁇ .a.l.l.l.c.2; A.l ⁇ .a.l.l.l.d.l; A.l ⁇ .a.l.l.l.d.2; A.l ⁇ .a.l.l.l.e.l; A.l ⁇ .a.l.l.e.2;
  • A.l ⁇ .a.2.b.l.c.l A.l ⁇ .a.2.b.l.c.2; A.l ⁇ .a.2.b.l.d.l; A.l ⁇ .a.2.b.l.d.2;
  • A.18.a. ⁇ .f.l.f.l A.18.a.8.f.l.f.2; A.l ⁇ .a. ⁇ .f.l.g.l; A.18.a.8.f.l.g.2; A.l ⁇ .a.8.h.l.a.l;
  • A.l ⁇ .a. ⁇ .l.l.c.l A.l ⁇ .a. ⁇ .l.l.c.2; A.l ⁇ .a. ⁇ .l.l.d.l; A.l ⁇ .a.8.1.1.d.2; A.18.a.8.1.1.e.l;
  • A.19.a.l.l.l.f.l A.19.a.l.l.l.f.2; A.19.a.l.l.l.g.l; A.19.a.l.l.l.g.2; A.19.a.2.a.l.a.l;
  • A.19.a. ⁇ .f.l.f.l A.19.a. ⁇ .f.l.f.2; A.19.a. ⁇ .f.l.g.l; A.19.a. ⁇ .f.l.g.2; A.19.a. ⁇ .h.l.a.l;
  • A.20.a.l.a.l.a.l A.20.a.l.a.l.a.l; A.20.a.l.a.l.a.2; A.20.a.l.a.l.b.l; A.20.a.l.a.l.b.2; A.20.a.l.a.l.c.l; A.20.a.l.a.l.c.2; A.20.a.l.a.l.c.2; A.20.a.l.a.l.d.l; A.20.a.l.a.l.d.2;
  • A.20.a.l.h.l.d.l A.20.a.l.h.l.d.2; A.20.a.l.h.l.e.l; A.20.a.l.h.l.e.2; A.20.a.l.h.l.f.l; A.20.a.l.h.l.f.2; A.20.a.l.h.l.g.l; A.20.a.l.h.l.g.2;
  • A.20.a.l.l.l.a.l A.20.a.l.l.l.a.2; A.20.a.l.l.l.b.l; A.20.a.l.l.l.b.2; A.20.a.l.l.l.c.l;
  • A.20.a.l.l.l.f.l A.20.a.l.l.l.f.2; A.20.a.l.l.l.g.l; A.20.a.l.l.l.g.2; A.20.a.2.a.l.a.l;
  • A.20.a.2.b.l.a.l A.20.a.2.b.l.a.2; A.20.a.2.b.l.b.l; A.20.a.2.b.l.b.2;
  • A.20.a.2.b.l.c.l A.20.a.2.b.l.c.2; A.20.a.2.b.l.d.l; A.20.a.2.b.l.d.2;
  • A.20.a.2.f.l.c.l A.20.a.2.f.l.c.2; A.20.a.2.f.l.d.l; A.20.a.2.f.l.d.2; A.20.a.2.f.l.e.l;
  • A.20.a.2.h.l.c.l A.20.a.2.h.l.c.2; A.20.a.2.h.l.d.l; A.20.a.2.h.l.d.2; A.20.a.2.h.l.e.l; A.20.a.2.h.l.e.2; A.20.a.2.h.l.f.l; A.20.a.2.h.l.f.2;
  • A.20.a.2.h.l.g.l A.20.a.2.h.l.g.2; A.20.a.2.1.1.a.l; A.20.a.2.1.1.a.2;
  • A.20.a.2.1.1.b.l A.20.a.2.1.1.b.2; A.20.a.2.1.1.c.l; A.20.a.2.1.1.c.2; A.20.a.2.1.1.d.l;
  • A.20.a. ⁇ .f.l.a.l A.20.a. ⁇ .f.l.a.2; A.20.a. ⁇ .f.l.b.l; A.20.a. ⁇ .f.l.b.2; A.20.a.8.f.l.c.l;
  • A.20.a. ⁇ .f.l.f.l A.20.a. ⁇ .f.l.f.2; A.20.a. ⁇ .f.l.g.l; A.20.a. ⁇ .f.l.g.2; A.20.a. ⁇ .h.l.a.l;
  • A.20.a.8.1.1.c.l A.20.a.8.1.1.c.2; A.20.a. ⁇ .l.l.d.l; A.20.a. ⁇ .l.l.d.2; A.20.a. ⁇ .l.l.e.l;
  • A.21.a.l.h.l.f.l A.21.a.l.h.l.f.2; A.21.a.l.h.l.g.l; A.21.a.l.h.l.g.2;
  • A.21.a.2.b.l.c.l A.21.a.2.b.l.c.2; A.21.a.2.b.l.d.l; A.21.a.2.b.l.d.2; A.21.a.2.b.l.e.l; A.21.a.2.b.l.e.2; A.21.a.2.b.l.f.l; A.21.a.2.b.l.f.2; A.21.a.2.b.l.g.l;
  • A.21.a.2.h.l.a.l A.21.a.2.h.l.a.2; A.21.a.2.h.l.b.l; A.21.a.2.h.l.b.2; A.21.a.2.h.l.c.l; A.21.a.2.h.l.c.2; A.21.a.2.h.l.d.l; A.21.a.2.h.l.d.2;
  • A.22.a.l.a.l.a.l A.22.a.l.a.l.a.2; A.22.a.l.a.l.b.l; A.22.a.l.a.l.b.2; A.22.a.l.a.l.c.l; A.22.a.l.a.l.c.2; A.22.a.l.a.l.d.l; A.22.a.l.a.l.d.2;
  • A.22.a.2.b.l.a.l A.22.a.2.b.l.a.2; A.22.a.2.b.l.b.l; A.22.a.2.b.l.b.2; A.22.a.2.b.l.c.l; A.22.a.2.b.l.c.2; A.22.a.2.b.l.d.l; A.22.a.2.b.l.d.2;
  • B.l.a.2.a.l.f.l B.l.a.2.a.l.f.2; B.l.a.2.a.l.g.l; B.l.a.2.a.l.g.2; B.l.a.2.b.l.a.l;
  • B.l.a. ⁇ .a.l.f.l B.l.a. ⁇ .a.l.f.2; B.l.a. ⁇ .a.l.g.l; B.l.a. ⁇ .a.l.g.2; B.l.a. ⁇ .b.l.a.l;
  • B.l.a. ⁇ .b.l.d.l B.l.a. ⁇ .b.l.d.2; B.l.a. ⁇ .b.l.e.l; B.l.a. ⁇ .b.l.e.2; B.l.a. ⁇ .b.l.f.l;
  • B.2.a.2.a.l.a.l B.2.a.2.a.l.a.2; B.2.a.2.a.l.b.l; B.2.a.2.a.l.b.2; B.2.a.2.a.l.c.l;
  • B.2.a.2.a.l.f.l B.2.a.2.a.l.f.2; B.2.a.2.a.l.g.l; B.2.a.2.a.l.g.2; B.2.a.2.b.l.a.l;
  • B.2.a. ⁇ .a.l.f.l B.2.a. ⁇ .a.l.f.2; B.2.a. ⁇ .a.l.g.l; B.2.a. ⁇ .a.l.g.2; B.2.a. ⁇ .b.l.a.l;
  • B.2.a. ⁇ .b.l.d.l B.2.a. ⁇ .b.l.d.2; B.2.a. ⁇ .b.l.e.l; B.2.a. ⁇ .b.l.e.2; B.2.a. ⁇ .b.l.f.l; B.2.a. ⁇ .b.l.f.2; B.2.a. ⁇ .b.l.g.l; B.2.a.8.b.l.g.2; B.2.a.8.f.l.a.l; B.2.a.8.f.l.a.l; B.2.a.8.f.l.a.2;
  • B.2.a.8.f.l.g.l B.2.a.8.f.l.g.2; B.2.a.8.h.l.a.l; B.2.a. ⁇ .h.l.a.2; B.2.a. ⁇ .h.l.b.l;
  • B. ⁇ .a. ⁇ .a.l.f.l B. ⁇ .a. ⁇ .a.l.f.2; B. ⁇ .a. ⁇ .a.l.g.l; B. ⁇ .a. ⁇ .a.l.g.2; B. ⁇ .a. ⁇ .b.l.a.l;
  • B.10.a.2.1.1.f.l B.10.a.2.1.1.f.2; B.10.a.2.1.1.g.l; B.10.a.2.1.1.g.2; B.lO.a. ⁇ .a.l.a.l;
  • B.14.a.l.a.l.f.l B.14.a.l.a.l.f.2; B.14.a.l.a.l.g.l; B.14.a.l.a.l.g.2; B.14.a.l.b.l.a.l;

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Abstract

Novel compounds are described. The compounds generally comprise two oligomers (5'-GGTTGG-3') are linked in a 5',5' manner via a synthetic linking moiety. Pharmaceutical compositions comprising the inhibitors of the invention are also described. Methods of inhibiting thrombin in samples suspected of containing thrombin are also described. Antigenic materials, polymers, antibodies, conjugates of the compounds of the invention with labels, and assay methods for detecting thrombin activity are also described.

Description

5', 5'-Linked Oligomers Having Anti-Thrombin Activity
Background of the Invention
Field of the Invention
The thrombin binding aptamer GS 522 is described in PCT US92/01383 and U.S. Patent Application Serial No. 08/484,192. The structure of GS 522 is 5'-GGTTGGTGTGGTTGG-3'. The present invention is directed to compounds wherein two oligomers (5'-GGTTGG-3') are linked in a 5', 5' manner via a synthetic linking moiety.
Brief Description of Related Art The thrombin binding aptamer GS 522 is described in PCT US92/01383 and U.S. Patent Application Serial No. 08/484,192. Gupta, V.S., et al.; "J. Med. Chem.", 18(10):973-976, 1975, discloses 5- mercaptomethyl-2'-deoxyuride and its formation of a disulfide linked dimer.
U.S. Patent Nos. 5,399,676, March 21, 1995, and 5,527,899, June 18, 1996, describe 5', 5' linked oligomers wherein the linking group is a synthetic linker moiety.
Objects of the Invention A principal object of the invention is inhibition of thrombin. In particular, an object is inhibition of thrombin's pro-coagulation activity. An additional object of the invention is to provide thrombin inhibitors that possess elevated potency, that exhibit clinically acceptable toxicity profiles and have other desirable pharmacologic properties.
Another object is to provide improved and less costly methods for synthesis of thrombin inhibitors. An additional object is to provide compositions useful in preparing polymers, surfactants or immunogens and for use in other industrial processes and articles.
These and other objects will be readily apparent to the ordinary artisan from consideration of the invention as set forth herein as a whole.
Summary of the Invention One embodiment the invention is directed to compounds of the formula (I), (II), (III), (IV) or (V):
Figure imgf000004_0001
Figure imgf000005_0001
(iv)
Figure imgf000005_0002
wherein: R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
R 2 is R 1 wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R groups; R3 is F, Br, Cl, I, -CN, or N3; R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R groups;
R5 is R3, -N02, -OR6, -N(R6) , -SR6, -S(0)R6, -S(0)2R6, -SOR6, -S(0)OR6, -S(0)2OR6, -SN(R6)2, -S(0)N(R6)2, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)OR6, -OC(0)N(R6)2, -N(R6)(C(0)R6), -N(R6)(C(0)OR6), -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6) / -OP(S)(OR6)2, =0, =S, or =N(R6); R6 is H, PRT or R2;
R is alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms; R is R wherein each said alkylene, alkenylene and alkynylene is independently substituted with 0 to 3 R groups;
R9 is R6 or -R8W5; each R 10 is independently selected from H or R 2 ; each R 11 is independently selected from H, R 2 or R 3 ; each R is independently selected from H, R or R , wherein when
R12 is R5 then R5 is not =0, =S, or =N(R6); each R13 is independently selected from H, R4, R5, R9, -OR9, -N(R9)2,
-SR9, -S(0)R9, -S(0)2R9, -SOR9, -S(0)OR9, -S(0)2OR9, -SN(R9)2, -S(0)N(R9)2,
-S(0)2N(R9)2, -C(0)R9, -C(0)OR9, -OC(0)R9, -OC(0)OR9, -OC(0)N(R9)2, -N(R9)(C(0)R9), -N(R9)(C(0)OR9), -C(0)N(R9)2, -C(NR9)(N(R9)2), or
-N(R9)C(N(R9))(N(R9)2, wherein when R13 is R5 then R5 is not =0, =S, or
=N(R6);
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R5 groups; each X is independently selected from R12, 3'-G-, 3'-GG-, 3'-TGG-,
3'-TTGG-, 3'-GTTGG-, or 3'-GGTTGG-; and the salts, solvates, resolved enantiomers or purified diastereomers thereof; provided that the compound of formula (VI) is excluded
Figure imgf000006_0001
wherein: each X and R13 are -OH; and each R10, R11 and R12 are H.
Another embodiment of the invention is directed to compounds of having formula (VI) or (VII):
Figure imgf000007_0001
wherein R10, R11, R12, R13 and X are defined above. Another embodiment of the invention is directed to compositions comprising a compound of the invention and a pharmaceutically- acceptable carrier.
Another embodiment of the invention is directed to methods of detecting the presence or absence of thrombin comprising contacting a sample suspected of containing thrombin with a compound of the invention.
Another embodiment of the invention is directed to methods of inhibiting the activity of thrombin comprising contacting a sample suspected of containing thrombin with a compound of the invention. Another embodiment of the invention is directed to methods of inhibiting the activity of thrombin in a host comprising administering to the host a therapeutically effective amount of a compound of the invention. Detailed Description
Compositions of the Invention. The practice of the present invention will employ, unless otherwise indicated, conventional techniques of chemistry, molecular biology, biochemistry, protein chemistry, and recombinant DNA technology, which are within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Oligonucleotide Synthesis (M.J. Gait ed. 1984); Nucleic Acid Hybridization (B.D. Hames & S.J. Higgins eds. 1984); Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989); and the series Methods in Enzymology (S. Colowick and N. Kaplan eds., Academic Press, Inc.).
The compounds of this invention exclude compounds heretofore known. With respect to the United States, the compounds or compositions herein exclude compounds that are anticipated under 35 USC §102 or obvious under 35 USC §103. In particular, the claims herein shall be construed as excluding the compounds which are anticipated by or not possessing novelty over Gupta, V.S., et al., "J. Med. Chem.", 18(10):973-976, 1975.
In particular, excluded from the invention is a compound of formula (VI)
Figure imgf000008_0001
wherein: each X and R13 are -OH; and each R10, R11 and R12 are H. Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "R10" or "X", then it will be understood that the groups may be the same or different, i.e., each group is independently selected.
One embodiment of the invention is directed to compounds of formula (I), (II), (III), (IV) or (V):
Figure imgf000009_0001
Figure imgf000010_0001
R1
_ R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms. Typically, R is an alkyl of 1, 2, 3, 4, 5 or 6 carbon atoms, alkenyl of 2, 3, 4, 5 or 6 carbon atoms or alkynyl of 2, 3, 4, 5 or
6 carbon atoms. More typically, R is alkyl of 1 to 4 carbon atoms, alkenyl of
2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms. Still more typically
R is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms or alkynyl of 2 to 3 carbon atoms. "Alkyl" as used herein, unless stated to the contrary, is Cχ-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n- propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n- butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l- butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3)-
"Alkenyl" as used herein, unless stated to the contrary, is C2-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Alkenyl is typically ethenyl (-CH=CH2), 1-prop-l-enyl (-CH=CHCH3), l-prop-2-enyl (-CH2CH=CH2), 2-prop-l-enyl (-C(=CH2)(CH3)), 1-but-l-enyl (-CH=CHCH2CH3), l-but-2-enyl (-CH2CH=CHCH3), l-but-3-enyl (-CH2CH2CH=CH2), 2-methyl-l-prop-l-enyl (-CH=C(CH3)2), 2-methyl-l- prop-2-enyl (-CH2C(=CH2)(CH3)), 2-but-l-enyl (-C(=CH2)CH2CH3), 2-but-2- enyl (-C(CH3)=CHCH3), 2-but-3-enyl (-CH(CH3)CH=CH2), 1-pent-l-enyl (-C=CHCH2CH2CH3), l-pent-2-enyl (-CHCH=CHCH2CH3), l-pent-3-enyl (-CHCH2CH=CHCH3), l-pent-4-enyl (-CHCH2CH2CH=CH2), 2-pent-l-enyl (-C(=CH2)CH2CH2CH3), 2-pent-2-enyl (-C(CH3)=CH2CH2CH3), 2-pent-3- enyl (-CH(CH3)CH=CHCH3), 2-pent-4-enyl (-CH(CH3)CH2CH=CH2) or 3-methyl-l-but-2-enyl (-CH2CH=C(CH3)2. "Alkynyl" as used herein, unless stated to the contrary, is C2-C6 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Alkynyl is typically ethynyl (-C≡CH), 1-prop-l-ynyl (-C≡CCH3), l-prop-2- ynyl (-CH2C≡CH), 1-but-l-ynyl (-C≡CCH2CH3), l-but-2-ynyl (-CH2C≡CCH3), l-but-3-ynyl (-CH2CH2C≡CH), 2-but-3-ynyl (CH(CH3)C≡CH), 1-pent-l-ynyl (-C≡CCH2CH2CH3), l-pent-2-ynyl (-CH2C≡CCH2CH3), l-pent-3-ynyl (-CH2CH2C≡CCH3) or l-pent-4-ynyl (-CH2CH2CH2C≡CH.)
R2
R 2 is R 1 wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R 3 groups. R 3 is defined below.
2 1
Typically R is R wherein each said alkyl, alkenyl and alkynyl is
3 independently substituted with 0, 1, 2 or 3 R groups. More typica R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2 R 3 groups, still more typically, 0 to 1 R 3 groups.
R
R3 is F, Br, Cl, I, -CN, or N3. Typically, R3 is F, Br, Cl, -CN, or N3.
More, typically, R 3 is F, Br, Cl or N3. Still more typically, R 3 is F or N3.
3
More typically yet, R is F.
R*
R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R 5 groups. R 5 is defined be!
Typically R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0, 1, 2 or 3 R groups. More typica
R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2 R groups, still more typically, 0 to 1 R groups.
R5
R5 is R3, -N02, -OR6, -N(R6)2, -SR6, -S(0)R6, -S(0)2R6, -SOR6, -S(0)OR6, -S(0)2OR6, -SN(R6)2, -S(0)N(R6)2, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)OR6, -OC(0)N(R6)2, -N(R6)(C(0)R6), -N(R6)(C(0)OR6), -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6)2, =0, =S, or =N(R6). R6 is defined below In the context of the present application, "=0" denotes a double bonded oxygen atom (oxo), and "=S" and "=N(R6)" denote the sulfur and nitrogen analogs. Typically R5 is F, Br, Cl, I, -CN, N3, -N02, -OR6, -N(R6) , -SR6, -S(0)R6, -S(0) R6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)OR6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6)2, or =0. More typically R5 is F, Br, Cl, N3, -N02, -OR6, -N(R6)2, -SR6, -S(0)2R6, -S(0)2N(R6)2,
-C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -OP(0)(OR6)2, -OP(S)(OR6)2, or =0. Still more typically R5 is F, N3, -N02, -OR6, -N(R6)2, -SR6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -OP(0)(OR6)2, or -OP(S)(OR6)2. More typically yet, R5 is F, N3, -OR6, -N(R6)2, -SR6, -C(0)R6, -C(0)OR6, or -OP(0)(OR6)2.
RE
Figure imgf000012_0001
. PRT is a protecting group as defined below. Typically, R is H or R , more typically, H.
RZ n
R is alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms. As defined above for R , R7's are of 1, 2, 3, 4, 5 or 6 carbon atoms when alkylene and of 2, 3, 4, 5 or 6 carbon atoms when alkenylene or alkynylene. Each of the typical R1 groups is a typical R7 group with the proviso that one of the hydrogen atoms of the described R1 group is removed to form the open valence to a carbon atom through which the second bond to the R7 is attached. R£
8 7
R is R wherein each said alkylene, alkenylene and alkynylene is 8 7 independently substituted with 0 to 3 R groups. Typically R is R wherein each said alkylene, alkenylene and alkynylene is independently substituted with 0, 1, 2 or 3 R 3 groups. More typically, R 8 is R 7 wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2
R 3 groups, still more typically, 0 to 1 R groups.
R* R9 is R6 or -R8W5. W5 is defined below. Each of the preferred embodiments of R , R and W are preferred in embodiments in the context of R9. Typically, R9 is -R8W5. More typically, R9 is -(CR102)mlW5; wherein ml is an integer of 1 to 6, typically, 1, 2, 3, 4, 5 or 6, more typically 2
10 9 to 4, still more typically 2 or 3. R is defined below. More typically, R is -(CH )mlW5. More typically yet, R9 is -(CH2)m2W5a; wherein m2 is 1, 2 or 3, and W 5a is a monocyclic (saturated, monounsaturated, diunsaturated or aromatic) carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I, -CN, N3, -NO2,
-OR6, -N(R6)2, -SR6, -S(0)R6, -S(0)2R6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -C(NR6)(N(R6)2),
-N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6)2, typically substitued with 0 or 1 groups selected from F, N3, -OR6, -N(R6)2, -SR6, -C(0)R6,
-C(0)OR6, or -OP(0)(OR6)2.
R 1X1
Each R 10 is independently selected from H or R 2. Each of the preferred embodiments of R is a preferred embodiment in the context of R10. Typically, each R10 is H.
R 11
11 2 3 11
Each R is independently selected from H, R or R . Typically, R is
H or R 3. Each of the preferred embodiments of R 3 is a preferred embodiment in the context of R . More typically, R is H.
R 11
1 9 ^ 1
Each R is independently selected from H, R or R . Typically, R is H or R 3. Each of the preferred embodiments of R 3 is a preferred
19 19 *ϊ embodiment in the context of R . R is not a divalent R group (i.e. =0, =S, or =N(R6)). More typically, R12 is H.
R1*
Each R13 is independently selected from H, R4, R5, R9, -OR9, -N(R9)2, -SR9, -S(0)R9, -S(0)2R9, -SOR9, -S(0)OR9, -S(0)2OR9, -SN(R9)2, -S(0)N(R9)2, -S(0)2N(R9)2, -C(0)R9, -C(0)OR9, -OC(0)R9, -OC(0)OR9, -OC(0)N(R9)2, -N(R9)(C(0)R9), -N(R9)(C(0)OR9), -C(0)N(R9)2, -C(NR9)(N(R9)2), or -N(R9)C(N(R9))(N(R9)2, wherein when R13 is R5 then R5 is not =0, =S, or =N(R6). Typically, R13 is F, Br, Cl, I, -CN, N3, -N02, -OR6, -N(R6)2, -SR6, -S(0)R6, -S(0)2R6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6)2, or =0, -OR9, -N(R9)2, -SR9, -S(0)R9, -S(0)2R9, -SOR9, -S(0)OR9, -S(0)2OR9, -SN(R9)2, -S(0)N(R9)2, -S(0)2N(R9)2, -C(0)R9, -C(0)OR9, -OC(0)R9, -OC(0)N(R9)2, -N(R9)(C(0)R9),
-N(R9)(C(0)OR9), -C(0)N(R9)2, -C(NR9)(N(R9)2), or -N(R9)C(N(R9))(N(R9)2.
Each of the preferred embodiments of R 6 and R 9 are preferred in
•i 1 y embodiments in the context of R . More typically, R is F, N3, -OR , -N(R6)2, -SR6, -C(0)R6, -C(0)OR6, -OP(0)(OR6)2 or -OC(0)N(R9)2. Still more typically, R13 is -OR6 or -OC(0)N(R6)(R8W5). More typically still, R13 is -OR10 or -OC(0)N(H)( (CR102)miW5); wherein ml is an integer of 1-6, typically, 1, 2, 3, 4, 5 or 6, more typically 2 to 4, still more typically 2 or 3.
More typically yet, R13 is -OH or -OC(0)N(R6)((CH2)m2W5a); wherein m2 is 1, 2 or 3, and W 5a is a monocyclic, saturated, monounsaturated, diunsaturated or aromatic carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I,
-CN, N3, -N02, -OR6, -N(R6)2, -SR6, -S(0)R6, -S(0)2R6, -S(0)2N(R6)2,
-C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6) , -N(R6)(C(0)R6, -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6) , typically substitued with 0 or 1 groups selected from F, N3,
Figure imgf000014_0001
-SR6, -C(0)R6, -C(0)OR6, or -OP(0)(OR6) . In one embodiment, R13 is -OH, in another R13 is -OC(0)N(H)((CH2)2Ph).
W?
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R5 groups.
W5 carbocycles and heterocycles are stable chemical structures. Such structures are isolatable in measurable yield, with measurable purity, from reaction mixtures at temperatures from -78°C to 200°C. Typically, W5 is a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. More typically, W5 has 3 to 10 ring atoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6 ring atoms. The W5 rings are saturated when containing 3 ring atoms, saturated or monounsaturated when containing 4 ring atoms, saturated, or mono- or diunsaturated when containing 5 ring atoms, and saturated, mono- or diunsaturated, or aromatic when containing 6 ring atoms. Unsaturation of the W5 rings include internal and external unsaturation wherein the external incorporates a ring atom.
When W5 is carbocyclic, it is typically a 3 to 7 carbon monocycle or a 7 to 12 carbon atom bicycle. More typically, W5 monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. W5 bicyclic carbocycles typically have 7 to 12 ring atoms arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, still more typically, 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, 1-cy clone x-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
A W5 heterocycle is typically a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). More typically, W5 heterocyclic monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S), still more typically, 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). W5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system, still more typically, 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system. Typically W5 heterocycles are selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, or pyrrolyl.
More typically, the heterocycle of W5 is bonded through a carbon atom or nitrogen atom thereof. Stable covalent bonds are chemically stable structures as described above. Exemplary "Heterocycle" as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and "J. Am. Chem. Soc", 82:5566 (1960).
Examples of heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-l,2,5-thiadiazinyl, 2H,6H- 1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H- indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, and isatinoyl.
By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2- pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,
3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β- carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
One embodiment of W is W a. W a is a monocyclic (saturated, monounsaturated, diunsaturated or aromatic) carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I, -CN, N3, -N02, -OR6, -N(R6)2, -SR6, -S(0)R6, -S(0)2R6,
-S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6)2, typically substitued with 0 or 1 groups selected from F, N3, -OR6, -N(R6)2, -SR6, -C(0)R6, -C(0)OR6, or -OP(0)(OR6)2. W5 optionally is selected from the group consisting of:
Figure imgf000018_0001
Another embodiment of W is phenyl (Ph) substituted with 0 to 2 groups seleceted from F, N3, -OR6, -N(R6)2, -SR6, -C(0)R6, -C(0)OR6, or -OP(0)(OR ) . More typically of this embodiment is phenyl substituted with 0 to 1 groups selected from F, -OH, -SH or -NH2.
Each X is independently selected from R12, 3'-G-, 3'-GG-, 3'-TGG-, 3'-TTGG-, 3'-GTTGG-, or 3'-GGTTGG-; wherein when X is R5 then R5 is not
=0, =S, or
Figure imgf000018_0002
are preferred embodiments in the context of X.
Ordinarily when X is R12 it is selected F, Br, Cl, I, -CN, N3, -NO2, -OR6, -N(R6)2, -SR6, -S(0)R6, -S(0)2R6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -C(NR6)(N(R6)2),
-N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6)2, or =0. More typically X is F, Br, Cl, N3, -N02, -OR6, -N(R6)2, -SR6, -S(0) R6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -OP(0)(OR6)2, -OP(S)(OR6)2, or =0. Still more typically X is F, N3, -N02, -OR6, -N(R6)2, -SR6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6,
-OC(0)N(R6)2, -N(R6)(C(0)R6, -OP(0)(OR6)2, or -OP(S)(OR6)2. More typically yet, X is F, N3, -OR6, -N(R6)2, -SR6, -C(0)R6, -C(0)OR6, or -OP(0)(OR6)2. In this embodiment, X is most typically -OH or -OP(0)(OR6)2. In another embodiment, X is 3'-G-, 3'-GG-, 3'-TGG-, 3'-TTGG-,
3'-GTTGG-, or 3'-GGTTGG-. Each of these is a guanosine, modified guanosine, oligomer or modified oligomer linked in the conventional sense through its 5' end. Oligomers and modified oligomers in this context contain guanosine or modified guanosine (G), or thymidine or modified thymidine (T). Within this embodiment, guanosine, modified guanosine, thymidine or modified thymidine include the conventional nucleosides and deoxynucleosides formed from the corresponding bases or modified bases of guanine or thymine. In particular, uracil is considered a modified thymine in this context.
A typical group of nucleosides suitable for use herein are disclosed in PCT US92/01383 and U.S. Patent Application Serial No. 08/484,192, both of which are incorporated herein by reference. In particular those portions describing modified bases and linkages, including the examples, are incorporated herein by reference at this location.
"Oligonucleotide" or "oligomer" is generic to polydeoxyribonucleotides (containing 2'-deoxy-D-ribose or modified forms thereof), i.e., DNA, to polyribonucleotides (containing D-ribose or modified forms thereof), i.e., RNA, and to any other type of polynucleotide which is an N-glycoside or C-glycoside of a purine or pyrimidine base, or modified purine or pyrimidine base or abasic nucleotides. The term "nucleoside" or "nucleotide" is similarly generic to ribonucleosides or ribonucleotides, deoxyribonucleosides or deoxyribonucleotides, or to any other nucleoside which is an N-glycoside or C-glycoside of a purine or pyrimidine base, or modified purine or pyrimidine base. Thus, the stereochemistry of the sugar carbons may be other than that of D-ribose in one or more residues. Also included are analogs where the ribose or deoxyribose moiety is replaced by an alternate structure such as the 6-membered morpholino ring described in U.S. patent number 5,034,506 or where an acyclic structure serves as a scaffold that positions the base analogs described herein in a manner that permits efficient binding to target nucleic acid sequences or other targets. Elements ordinarily found in oligomers, such as the furanose ring or the phosphodiester linkage may be replaced with any suitable functionally equivalent element. As the anomer binds to targets in a manner similar to that for the anomers, one or more nucleotides may contain this linkage or a domain thereof. (Praseuth, D., et al, Proc Natl Acad Sci (USA) (1988)
85:1349-1353). Modifications in the sugar moiety, for example, wherein one or more of the hydroxyl groups are replaced with halogen, aliphatic groups, or functionalized as ethers, amines, and the like, are also included.
"Nucleoside" and "nucleotide" include those moieties which contain not only the natively found purine and pyrimidine bases T, G and U, but also modified or analogous forms thereof. Modifications include alkylated purines or pyrimidines, acylated purines or pyrimidines, or other heterocycles. Such "analogous purines" and "analogous pyrimidines" are those generally known in the art, many of which are used as chemotherapeutic agents. An exemplary but not exhaustive list includes 5-(carboxyhydroxylmethyl) uracil, 5-fluorouracil, 7-deazaguanine, 5-bromouracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyl uracil, dihydrouracil, 1-methylpseudouracil, 1-methylguanine, 2,2-dimethylguanine, 2-methylguanine, 7-methylguanine, 5-methylaminomethyl uracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine,
5'-methoxycarbonylmethyluracil, 5-methoxyuracil, uracil-5-oxyacetic acid methyl ester, pseudouracil, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, N-uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, queosine, 5-propyluracil, 5-ethyluracil, 5-butyluracil, 5-pentyluracil, and 2,6-diaminopurine.
In addition to the modified bases above, nucleotide residues which are devoid of a purine or a pyrimidine base may also be included in the oligomers of the invention and in the methods for their preparation.
The sugar residues in the oligonucleotides of the invention may also be other than conventional ribose and deoxyribose residues. In particular, substitution at the 2'-position of the furanose residue is particularly important with regard to enhanced nuclease stability.
Oligonucleotides may contain analogous forms of ribose or deoxyribose sugars that are generally known in the art. An exemplary, but not exhaustive list includes 2' substituted sugars such as 2'-0-methyl-, 2'-0-alkyl, 2'-0-allyl, 2'-S-alkyl, 2'-S-allyl, 2'-fluoro-, 2'-halo, or 2'- azido-ribose, carbocyclic sugar analogs, -anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs and abasic nucleoside analogs such as methyl riboside, ethyl riboside or propyl riboside.
Although the conventional sugars and bases will be used in applying the method of the invention, substitution of analogous forms of sugars, purines and pyrimidines can be advantageous in designing the final product. Additional techniques, such as methods of synthesis of 2'- modified sugars or carbocyclic sugar analogs, are described in Sproat, B.S. et al., "Nucl Acid Res" 19:733-738, 1991; Cotten, M. et al., "Nuc Acid Res" 19:2629-2635, 1991; Hobbs, J. et al., "Biochemistry" 12:5138-5145, 1973; and Perbost, M. et al, "Biochem Biophys Res.Comm" 165:742-747, 1989 (carbocyclics).
"Substitute linkages" are well-known from the prior literature. They include for example phosphorodithioates (Marshal, "Science"
259:1564, 1993), phosphorothioates and alkylphosphonates (Kibler-Herzog, "Nucleic Acids Research" [hereafter "NAR"] 19:2979, 1991; PCT 92/01020; EP 288,163; Fig. 12-1), phosphoroamidates (Froehler, "NAR" 16:4831, 1988), 3'- NH phosphoramidates (Schultz, "NAR" 24:2966, 1996; Gryaznov, "J. Am. Chem. Soc." [hereafter "JACS"] 116:3143, 1994; Chen, "NAR" 23:2661, 1995; Gryaznov, Proc. Natl. Acad. Sci. USA 92:5798, 1995), phosphotriesters (Marcus-Sekura, "NAR" 15:5749, 1987), boranophosphates (Sood, "JACS" 112:9000, 1991), 3'-0-5'-S-phosphorothioates (Mag, "NAR" 19:1437, 1991), 3'-S-5'-0-phosphorothioates (Kyle, Biochemistry 31:3012, 1992), 3'-CH2-5'- O-phosphonates (Heinemann, "NAR" 19:427, 1991), 3'-NH-5'-0- phosphonates (Mag, "Tet. Ltt." 33:7323, 1992), sulfonates and sulfonamides (Reynolds, "JOC" 57:2983, 1992), sulfones (Huie, "JOC" 57:4519, 1992), sulfoxides (Huang, "JOC" 56:3869, 1991), sulfides (Schneider, "Tet Ltt." 30:335, 1989), sulfamates, ketals and formacetals (Matteucci, "JACS" 113:7767, 1991, PCT 92/03385 and PCT 90/06110), 3'-thioformacetals (Jones, "JOC" 58:2983, 1993), 5'-S-thioethers (Kawai, "Nucleosides and Nucleotides" 10:1485, 1991), carbonates (Gait, "J. Chem. Soc. Perkin Trans 1" 1389, 1979), carbamates (Stirchak "JOC" 52:4202, 1987), hydroxylamines (Vasseur, "JACS" 114:4006, 1992), methylamine (methylimines) and methyleneoxy (methylimino) (Debart, "Bioorg. Med. Chem. Lett." 2:1479, 1992) and amino (PCT 91/06855). Also of interest are hydrazino and siloxane (U.S. Patent 5,214,134) linkages and thionotriester linkages (WO 96/29337).
Substitute linkages per se also are known for the replacement of the entire phosphoribosyl linkage of conventional oligonucleotides. These include for example morpholino-carbamates (Stirchak, "NAR" 17:6129, 1989), peptides (Nielsen et al., "Science" 254:1497, 1991; U.S.S.N. 07/892,902 and 07/894, 397), riboacetal linkages (PCT 92/10793) and morpholino-based linkages disclosed in U.S. patent Nos. 5,521,063 and 5,185,144.
Additional disclosure of substitute linkages is found in PCT 91/08213, 90/15065, 91/15500, 92/20702, 92/20822, 92/20823, 92/04294, 89/12060 and 91/03680; Mertes, "J. Med. Chem." 12:154, 1969; Mungall, "JOC" 42:703, 1977; Wang, "Tet Lett" 32:7385, 1991; Stirchak, "NAR" 17:6129, 1989; Hewitt, "Nucleosides and Nucleotides" 11:1661, 1992; Van Aerschot, "Agnew Chem. Int. Ed. Engl. 34:1338, 1995; and U.S. patents 5,034,506 and 5,142,047.
PRT
PRT is a protecting group. Optionally, protecting groups are prodrug moieties. Typical PRT groups include R^a, Rβb and Rόc wherein: R6a is an ether- or ester-forming group;
Rόb is a protecting group for amino or the residue of a carboxyl- containing compound; and
Rόc is the residue of an amino-containing compound.
3 ς
Exemplary embodiments of R and R having Rόa, Rθb and Rόc include, by way of example and not limitation, -OR6a -N(R10)(R b) -N(R6b)2, "SR6a, -S(0)OR6a, -S(0)2OR6a, -C(0)R6C, -C(0)OR6a, -N(R6b)(C(O)Rl0), -N(R6b)(C(O)ORl0, -C(O)N(R6b)(Rl0), -C(0)N(R6b)2, -C(N(R6b))(N(RlO)2), -C(N(RlO))(N(RlO)(R6b)), -C(N(R6b))(N(RlO)(R6b)), -C(N(Rl0))(N(R6 )2), -C(N(R6b))(N(R6b)2), -N(Rl0)C(N(Rl0))(N(Rl0)(R6b)), -N(RlO)C(N(R b))(N(RlO)2), -N(R6b)C(N(RlO))(N(RlO)2),
-N(R6b)C(N(R6b))(N(RlO)2), -N(R b)C(N(RlO))(N(RlO)(R6b))/
-N(RlO)C(N(R6b))(N(RlO)(R6b)), -N(RlO)C(N(RlO))(N(R6b)2), -N(R6b)C(N(R6b))(N(Rl )(R6b)), -N(R6b)C(N(Rl0))(N(R6b)2), -N(Rl0)C(N(R6b))(N(R6b)2), -N(R6b)C(N(R b))(N(R6b)2), and =N(R6b). Groups Rήa and R b are not critical functionalities and may vary widely. When not H, their function is to serve as intermediates for the parental drug substance. This does not mean that they are biologically inactive. On the contrary, a principal function of these groups is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs are absorbed more effectively than the parental drug they in fact often possess greater potency in vivo than the parental drug. When not hydrogen, R6a and R6b are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting pro- functionality products, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
R6a is an ether- or ester-forming group. "Ether-forming group" means a group which is capable of forming a stable, covalent bond between the parental molecule and a group having the formula:
S— O-VaO a , J— 0-Va(V1)(V2) , J— 0-Va(V3)
S— 0-Vb(V1)2 , — 0-Vb(V2) , or J— o-Vc Wherein Va is a tetravalent atom typically selected from C and Si; Vb is a trivalent atom typically selected from B, Al, N, and P, more typically N and P; Vc is a divalent atom typically selected from O, S, and Se, more typically O or S; Vi is a group bonded to Va, Vb or Vc by a stable, single covalent bond, typically Vi is H, R2, W5, or -R8W5, still more typically H or R2; V2 is a group bonded to Va or V by a stable, double covalent bond, provided that V2 is not =0, =S or =N-, typically V2 is =C(Vi)2 wherein Vi is as described above; and V3 is a group bonded to Va by a stable, triple covalent bond, typically V3 is ≡C(Vχ) wherein Vi is as described above.
"Ester-forming group" means a group which is capable of forming a stable, covalent bond between the parental molecule and a group having the formula:
S— o-VaO M j_0-vb(v4) , J— o-VdO zM
_— 0-Vd(V4)2 fr-O-VβfV aW , or J—O-Vβ MMa Wherein Va, V , and Vi, are as described above; Vd is a pentavalent atom typically selected from P and N; Ve is a hexavalent atom typically S; and V4 is a group bonded to Va, Vb, Vd or Ve by a stable, double covalent bond, provided that at least one V4 is =0, =S or =N-Vχ, typically V4, when other than =0, =S or =N-, is =C(Vχ)2 wherein Vi is as described above. Protecting groups for -OH functions (whether hydroxy, acid or other functions) are embodiments of "ether- or ester-forming groups".
Particularly of interest are ether- or ester-forming groups that are capable of functioning as protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed under Rόc below. Rόc is capable of protecting hydroxyl or thio groups such that hydrolysis from the parental molecule yields hydroxyl or thio.
In its ester-forming role, R^a typically is bound to any acidic group such as, by way of example and not limitation, a -CO2H or -C(S)OH group, thereby resulting in -Cθ2Rόa- Rόa for example is deduced from the enumerated ester groups of WO 95/07920. Examples of Rfo include
C3-Cχ2 heterocyle (described above) or C6-C12 aryl. These aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5- isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5- pyrimidinyl, C3-Ci2 heterocycle or C6-C12 aryl substituted with halo, Ri, Rl-
O-C1-C12 alkylene, C1-C12 alkoxy, CN, NO2, OH, carboxy, carboxyester, thiol, thioester, C1-C12 haloalkyl (1-6 halogen atoms), C2-C12 alkenyl or C2-C12 alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl (Cι-Cι2 alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy- 4-hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6- hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and 4- dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4- halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4- chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-biscarboxyethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dihalophenyl (including 2,4-difluorophenyl and 3,5-difluorophenyl), 2-, 3- and 4-haloalkylphenyl (1 to 5 halogen atoms, C1-C12 alkyl including 4-trifluoromethylphenyl), 2-, 3- and 4-cyanophenyl, 2-, 3- and 4-nitrophenyl, 2-, 3- and 4-haloalkylbenzyl (1 to 5 halogen atoms, C1-C12 alkyl including 4-trifluoromethylbenzyl and 2-, 3- and 4-trichloromethylphenyl and 2-, 3- and 4-trichloromethylphenyl), 4- N-methylpiperidinyl, 3-N-methylpiperidinyl, 1-ethylpiperazinyl, benzyl, alkylsalicylphenyl (C1-C4 alkyl, including 2-, 3- and 4-ethylsalicylphenyl), 2- ,3- and 4-acetylphenyl, 1,8-dihydroxynaphthyl (-C10H6-OH) and aryloxy ethyl [C6-C9 aryl (including phenoxy ethyl)], 2,2'-dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol, -CόH4CH2- (CH3)2, trimethoxybenzyl,
triethoxybenzyl, 2-alkyl pyridinyl (C1-4 alkyl);
Figure imgf000025_0001
Figure imgf000025_0002
; C4 - C8 esters of 2-carboxyphenyl; and C1-C4 alkylene-C3-C6 aryl (including benzyl, -CH2-pyrrolyl, -CH2- thienyl, -CH2-imidazolyl, -CH2-oxazolyl, -CH2-isoxazolyl, -CH2-thiazolyl,
-CH2-isothiazolyl, -CH2-pyrazolyl, -CH2-pyridinyl and -CH2-pyrimidinyl) substituted in the aryl moiety by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from halogen, C1-C12 alkoxy (including methoxy and ethoxy), cyano, nitro, OH, Cι-Cχ2 haloalkyl (1 to 6 halogen atoms; including -CH2-CC13), C1-C12 alkyl (including methyl and ethyl), C2-C12 alkenyl or C2-
C12 alkynyl; alkoxy ethyl [Cι-C6 alkyl including -CH2-CH2-0-CH3 (methoxy ethyl)]; alkyl substituted by any of the groups set forth above for aryl, in particular OH or by 1 to 3 halo atoms (including -CH3/ -CH(CH3)2, - CH^,
-CH2CH3, -(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -CH2CH2F,
-CH2CH2C1, -CH2CF3, and -CH2CC13);
^^N O
^ — ' ; -N-2-propylmorpholino, 2,3-dihydro-6- hydroxyindene, sesamol, catechol monoester, -CH2-C(0)-N(R1)2, -CH2- S(0)(Rl), -CH2-S(0)2(R1), -CH2-CH(OC(0)CH2R1)-CH2(OC(0)CH2R1), cholesteryl, enolpyruvate (HOOC-C(=CH2)-), glycerol; a 5 or 6 carbon monosaccharide, disaccharide or oligosaccharide (3 to 9 monosaccharide residues); triglycerides such as -D-β-diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C6-26, C6-18 or Cό-io fatty acids such as linoleic, lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic and the like fatty acids) linked to acyl of the parental compounds herein through a glyceryl oxygen of the triglyceride; phospholipids linked to the carboxyl group through the phosphate of the phospholipid; phthalidyl (shown in Fig. 1 of Clayton et al., "Antimicrob. Agents Chemo." 5(6):670-671 [1974]); cyclic carbonates such as (5-Rd-2-oxo-l,3-dioxolen-4-yl) methyl esters (Sakamoto et al, "Chem. Pharm. Bull." 32(6)2241-2248 [1984]) where Rd is Rl, R4 or aryl; and
-CH2C(0)N O
The hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in WO94/21604, or with isopropyl.
As further embodiments, Table A lists examples of Rβa ester moieties that for example can be bonded via oxygen to -C(0)0- and -P(0)(0-)2 groups. Several R6c amidates also are shown, which are bound directly to -C(O)- or -P(0)2- Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N ,N- dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsC03, N,N-dimethylaniline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone). When the group to be protected is a phosphonate, the esters of structures 5-7, 11, 12, 21, and 23- 26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate). TABLE A
1. -CH2-C(0)-N(R1)2 10. -CH2-0-C(0)-C(CH3)3
2. -CH -S(0)(R1) 11. -CH2-CC13
3. -CH2-S(0)2(R1) 12. -C6H5
4. -CH2-0-C(0)-CH2-C6H5 13. -NH-CH2-C(0)0-CH2CH3
5. 3-cholesteryl 14. -N(CH3)-CH2-C(0)0-CH2CH3
6. 3-pyridyl 15. -NHR1
7. N-ethylmorpholino 16. -CH2-0-C(0)-CιoHι5
8. -CH2-0-C(0)-C6H5 17. -CH2-0-C(0)-CH(CH3)2
9. -CH2-0-C(0)-CH CH3 18. -CH2-C#H(OC(0)CH2R1)-CH2-
-(OC(0)CH2R1)
Figure imgf000027_0001
# - chiral center is (R), (S) or racemate.
Other esters that are suitable for use herein are described in EP 632,048.
R6a also includes "double ester" forming profunctionalities such as
-CH2OC(0)OCH3,
Figure imgf000027_0002
, -CH2SCOCH3, -CH2OCON(CH3)2, or alkyl- or aryl-acyloxyalkyl groups of the structure -CH(Rα or W5)0((CO)R37) or -CH(R1 or W5)((CO)OR38) (linked to oxygen of the acidic group) wherein 1^37 and R^g are alkyl, aryl, or alkylaryl groups (see U.S. patent 4,968,788). Frequently R37 and R3 are bulky groups such as branched alkyl, ortho- substituted aryl, meta-substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms. An example is the pivaloyloxymethyl group. These are of particular use with prodrugs for oral administration. Examples of such useful R&a groups are alkylacyloxymethyl esters and their derivatives, including -CH(CH2CH2θCH3)OC(0)C(CH3)3,
Figure imgf000028_0001
; -CH2OC(0)CιoHι5, -CH2OC(0)C(CH3)3, -CH(CH2OCH3)OC(0)C(CH3)3, -CH(CH(CH3)2)OC(0)C(CH3)3, -CH2OC(0)CH2CH(CH3)2, -CH2OC(0)C6Hn, -CH2OC(0)C6H5, -CH2OC(0)CιoHi5, -CH2OC(0)CH2CH3, -CH2OC(0)CH(CH3)2 , -CH2OC(0)C(CH3)3 and -CH2OC(0)CH2C6H5.
For prodrug purposes, the ester typically chosen is one heretofore used for antibiotic drugs, in particular the cyclic carbonates, double esters, or the phthalidyl, aryl or alkyl esters.
As noted, R6&/ Rόc and R6b groups optionally are used to prevent side reactions with the protected group during synthetic procedures, so they function as protecting groups (PRT) during synthesis. For the most part the decision as to which groups to protect, when to do so, and the nature of the PRT will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PRT groups do not need to be, and generally are not, the same if the compound is substituted with multiple PRT. In general, PRT will be used to protect carboxyl, hydroxyl or amino groups. The order of deprotection to yield free groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan. A very large number of Rόa hydroxy protecting groups and Rόc amide-forming groups and corresponding chemical cleavage reactions are described in "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) ("Greene"). See also Kocienski, Philip J.; "Protecting Groups" (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its entirety herein. In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21- 94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 118-154, Chapter 5, Carbonyl Protecting Groups, pages 155-184. For R^a carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other protecting groups for Wi acids see Greene as set forth below. Such groups include by way of example and not limitation, esters, amides, hydrazides, and the like.
In some embodiments the R(_a protected acidic group is an ester of the acidic group and Rfa is the residue of a hydroxyl-containing functionality. In other embodiments, an R6c amino compound is used to protect the acid functionality. The residues of suitable hydroxyl or amino- containing functionalities are set forth above or are found in WO 95/07920. Of particular interest are the residues of amino acids, amino acid esters, polypeptides, or aryl alcohols. Typical amino acid, polypeptide and carboxyl-esterified amino acid residues are described on pages 11-18 and related text of WO 95/07920 as groups LI or L2. WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
Typical Rβa esters for protecting Wi acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication. Typical ester groups are defined at least on WO 95/07920 pages 89-93 (under R31 or R35), the table on page 105, and pages 21-23 (as R). Of particular interest are esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and /or alkylestercarboxy-substituted aryl or alkylaryl, especially phenyl, ortho- ethoxyphenyl, or C1-C4 alkylestercarboxyphenyl (salicylate Cι-Cι2 alkylesters).
The protected acidic groups Wi, particularly when using the esters or amides of WO 95/07920, are useful as prodrugs for oral administration. However, it is not essential that the Wi acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route. When the compounds of the invention having protected groups, in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydrolytic cleavage in vivo to yield the free acid.
One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
Typical R a hydroxy protecting groups described in Greene (pages 14- 118) include Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, γ-
Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, t- Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2- Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2- chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl, 4-Methoxytetrahydrothiopyranyl, 4- Methoxytetrahydropthiopyranyl S,S-Dioxido, l-[(2-Chloro-4- methyl)phenyl]-4-methoxypiperidin-4-yl, 35, l,4-Dioxan-2-yl, Tetrahydrofuranyl, Tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-Octahydro-7,8,8- trimethyl-4,7-methanobenzofuran-2-yl)); Substituted Ethyl Ethers (1-Ethoxyethyl, l-(2-Chloroethoxy)ethyl, 1-Methyl-l-methoxyethyl, 1-Methyl-l-benzyloxyethyl, l-Methyl-l-benzyloxy-2-fluoroethyl, 2,2,2- Trichloroethyl, 2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, f-Butyl, Allyl, p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dinitrophenyl, Benzyl); Substituted Benzyl Ethers (p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p- Nitrobenzyl, p-Halobenzyl, 2,6-Dichlorobenzyl, p-Cyanobenzyl, p- Phenylbenzyl, 2- and 4-Picolyl, 3-Methyl-2-picolyl N-Oxido, Diphenylmethyl, p,p'-Dinitrobenzhydryl, 5-Dibenzosuberyl, Triphenylmethyl, α-Naphthyldiphenylmethyl, p- methoxyphenyldiphenylmethyl, Di(p-methoxyphenyl)phenylmethyl, Tri(p-methoxyphenyl)methyl, 4-(4'
Bromophenacyloxy)phenyldiphenylmethyl, 4,4',4"-Tris(4,5- dichlorophthalimidophenyl)methyl, 4,4', 4"- Tris(levulinoyloxyphenyl)methyl, 4,4',4"-Tris(benzoyloxyphenyl)methyl, 3-(Imidazol-l-ylmethyl)bis(4',4"-dimethoxyphenyl)methyl, l,l-Bis(4- methoxyphenyl)-l'-pyrenylmethyl, 9-Anthryl, 9-(9-Phenyl)xanthenyl, 9-(9- Phenyl-10-oxo)anthryl, l,3-Benzodithiolan-2-yl, Benzisothiazolyl S,S- Dioxido); Silyl Ethers (Trimethylsilyl, Triethylsilyl, Triisopropylsilyl, Dimethylisopropylsilyl, Diethylisopropylsily, Dimethylthexylsilyl, t- Butyldimethylsilyl, -Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl, f-Butylmethoxyphenylsilyl); Esters (Formate, Benzoylformate, Acetate, Choroacetate, Dichloroacetate, Trichloroacetate, Trifluoroacetate, Methoxyacetate, Triphenylmethoxyacetate, Phenoxyacetate, p-Chlorophenoxyacetate, p- poly-Phenylacetate, 3-Phenylpropionate, 4-Oxopentanoate (Levulinate), 4,4- (Ethylenedithio)pentanoate, Pivaloate, Adamantoate, Crotonate, 4-
Methoxycrotonate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate (Mesitoate)); Carbonates (Methyl, 9-Fluorenylmethyl, Ethyl, 2,2,2- Trichloroethyl, 2-(Trimethylsilyl)ethyl, 2-(Phenylsulfonyl)ethyl, 2- (Triphenylphosphonio)ethyl, Isobutyl, Vinyl, Allyl, p-Nitrophenyl, Benzyl, p-Methoxybenzyl, 3,4-Dimethoxybenzyl, o-Nitrobenzyl, p-Nitrobenzyl, S- Benzyl Thiocarbonate, 4-Ethoxy-l-naphthyl, Methyl Dithiocarbonate); Groups With Assisted Cleavage (2-Iodobenzoate, 4-Azidobutyrate, 4- Niotro-4-methylpentanoate, o-(Dibromomethyl)benzoate, 2- Formylbenzenesulfonate, 2-(Methylthiomethoxy)ethyl Carbonate, 4- (Methylthiomethoxy)butyrate, 2-(Methylthiomethoxymethyl)benzoate);
Miscellaneous Esters (2,6-Dichloro-4-methylphenoxyacetate, 2,6-Dichloro-4- (1,1,3,3 tetramethylbutyl)phenoxyacetate, 2,4-Bis(l,l- dimethylpropyl)phenoxyacetate, Chorodiphenylacetate, Isobutyrate, Monosuccinoate, (E)-2-Methyl-2-butenoate (Tigloate), o- (Methoxycarbonyl)benzoate, p-poly-Benzoate, α-Naphthoate, Nitrate, Alkyl N,N,N ',N'-Tetramethylphosphorodiamidate, N-Phenylcarbamate, Borate, Dimethylphosphinothioyl, 2,4-Dinitrophenylsulfenate); and Sulfonates (Sulfate, Methanesulfonate (Mesylate), Benzylsulfonate, Tosylate).
More typically, Rόa hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, trialkylsilyl ethers, tosylates and acetates.
Typical 1,2-diol protecting groups (thus, generally where two OH groups are taken together with the R a protecting functionality) are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-f-Butylethylidene, 1-Phenylethylidene, (4- Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene, 3,4- Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1- Methoxyethylidene, 1-Ethoxyethylidine, 1,2-Dimethoxyethylidene, α- Methoxybenzylidene, l-(N,N-Dimethylamino)ethylidene Derivative, α- (N,N-Dimethylamino)benzylidene Derivative, 2-Oxacyclopentylidene); Silyl Derivatives (Di-f-butylsilylene Group, 1,3-(1, 1,3,3- Tetraisopropyldisiloxanylidene), and Tetra-f-butoxydisiloxane-1,3- diylidene), Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate and Phenyl Boronate.
More typically, 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals.
Table B
Figure imgf000032_0001
wherein R^ is Ci-Cό alkyl. R is H, a protecting group for amino or the residue of a carboxyl- containing compound, in particular H, -C(0)R4, an amino acid, a polypeptide or a protecting group not -C(0)R4, amino acid or polypeptide. When R6b is an amino acid or polypeptide it has the structure Rl5NHCH(Ri6)C(0)-, where R15 is H, an amino acid or polypeptide residue, or R5, and Riό is defined below.
Rl6 is lower alkyl or lower alkyl ( -Cό) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C6-C7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and/or alkylphosphate. Ri6 also is taken together with the amino acid α N to form a proline residue (Riό = -CH2)3-). However, Rχ6 is generally the side group of a naturally-occurring amino acid such as H, -CH3, -CH(CH3)2, -CH -CH(CH3)2, -CHCH3-CH2-CH3, -CH2-CόH5, -CH2CH2-S-CHS, -CH2OH, -CH(OH)-CH3, -CH2-SH, -CH2-C6H4OH, -CH2-CO-NH2, -CH2-CH2-CO-NH2, -CH2-COOH, -CH2-CH2-COOH, -(CH2)4-NH2 and -(CH2)3-NH-C(NH2)-NH2. Riό also includes l-guanidinoprop-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl. Rόb are residues of carboxylic acids for the most part, but any of the typical amino protecting groups described by Greene at pages 315-385 are useful. They include Carbamates (methyl and ethyl, 9-fluorenylmethyl, 9(2-sulfo)fluoroenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-t- buthyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, 4- methoxyphenacyl); Substituted Ethyl (2,2,2-trichoroethyl, 2- trimethylsilylethyl, 2-phenylethyl, l-(l-adamantyl)-l-methylethyl, 1,1- dimethyl-2-haloethyl, l,l-dimethyl-2,2-dibromoethyl, 1,1-dimethy 1-2,2,2- trichloroethyl, l-methyl-l-(4-biphenylyl)ethyl, l-(3,5-di-t-butylphenyl)-l- methylethyl, 2-(2'- and 4'-pyridyl)ethyl, 2-(N,N- dicyclohexylcarboxamido)ethyl, f-butyl, 1-adamantyl, vinyl, allyl, 1- isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N- hydroxypiperidinyl, alkyldithio, benzyl, p-methoxybenzyl, p-nitrobenzyl, p- bromobenzyl, p-chorobenzyl, 2,4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9- anthrylmethyl, diphenylmethyl); Groups With Assisted Cleavage (2- methylthioethyl, 2-methylsulfonylethyl, 2-(/?-toluenesulfonyl)ethyl, [2-(l,3- dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2- phosphonioethyl, 2-triphenylphosphonioisopropyl, l,l-dimethyl-2- cyanoethyl, -choro-p-acyloxybenzyl, p-(dihydroxyboryl)benzyl, 5- benzisoxazolylmethyl, 2-(trifluoromethyl)-6-chromonylmethyl); Groups Capable of Photolytic Cleavage (m-nitrophenyl, 3,5-dimethoxybenzyl, 0- nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, phenyl(o-nitrophenyl)methyl); Urea-Type Derivatives (phenothiazinyl-(lθ)-carbonyl, N'-p- toluenesulfonylaminocarbonyl, N'-phenylaminothiocarbonyl); Miscellaneous Carbamates (f-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2,2-dimethoxycarbonylvinyl, o-(N,N- dimethylcarboxamido)benzyl, l,l-dimethyl-3-(N,N- dimethylcarboxamido)propyl, 1,1-dimethylpropynyl, di(2-pyridyl)methyl, 2- furanylmethyl, 2-Iodoethyl, Isobornyl, Isobutyl, Isonicotinyl, p-(p'- Methoxyphenylazo)benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1- methyl-1 -cyclopropylmethyl, l-methyl-l-(3,5-dimethoxyphenyl)ethyl, 1- methyl-l-(p-phenylazophenyl)ethyl, 1-methyl-l-phenylethyl, 1-methyl-l- (4-pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-t-butylphenyl, 4- (trimethylammonium)benzyl, 2,4,6-trimethylbenzyl); Amides (N-formyl, N-acetyl, N-choroacetyl, N-trichoroacetyl, N-trifluoroacetyl, N- phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, N-p-phenylbenzoyl); Amides With Assisted Cleavage (N-o-nitrophenylacetyl, N-o-nitrophenoxyacetyl, N- acetoacetyl, (N'-dithiobenzyloxycarbonylamino)acetyl, N-3-(p- hydroxyphenyl)propionyl, N-3-(o-nitrophenyl)propionyl, N-2-methyl-2-(o- nitrophenoxy)propionyl, N-2-methyl-2-(o-phenylazophenoxy)propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N- acetylmethionine, N-o-nitrobenzoyl, N-o-(benzoyloxymethyl)benzoyl, 4,5- diphenyl-3-oxazolin-2-one); Cyclic Imide Derivatives (N-phthalimide, N- dithiasuccinoyl, N-2,3-diphenylmaleoyl, N-2,5-dimethylpyrrolyl, N-1,1,4,4- tetramethyldisilylazacyclopentane adduct, 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3-5-triazacyclohexan-2- one, 1-substituted 3,5-dinitro-4-pyridonyl); N-Alkyl and N-Aryl Amines (N-methyl, N-allyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-(l-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), Quaternary Ammonium Salts, N-benzyl, N-di(4-methoxyphenyl)methyl, N-5-dibenzosuberyl, N- triphenylmethyl, N-(4-methoxyphenyl)diphenylmethyl, N-9- phenylfluorenyl, N-2,7-dichloro-9-fluorenylmethylene, N- ferrocenylmethyl, N-2-picolylamine N'-oxide), Imine Derivatives (N-1,1- dimethylthiomethylene, N-benzylidene, N-p-methoxybenylidene, N- diphenylmethylene, N-[(2-pyridyl)mesityl]methylene, N,(N',N'- dimethylaminomethylene, N,N'-isopropylidene, N-p-nitrobenzylidene, N- salicylidene, N-5-chlorosalicylidene, N-(5-chloro-2- hydroxyphenyl)phenylmethylene, N-cyclohexylidene); Enamine Derivatives (N-(5,5-dimethyl-3-oxo-l-cyclohexenyl)); N-Metal Derivatives (N-borane derivatives, N-diphenylborinic acid derivatives, N-
[phenyl(pentacarbonylchromium- or -tungsten)] carbenyl, N-copper or N- zinc chelate); N-N Derivatives (N-nitro, N-nitroso, N-oxide); N-P Derivatives (N-diphenylphosphinyl, N-dimethylthiophosphinyl, N- diphenylthiophosphinyl, N-dialkyl phosphoryl, N-dibenzyl phosphoryl, N-diphenyl phosphoryl); N-Si Derivatives; N-S Derivatives; N-Sulfenyl Derivatives (N-benzenesulfenyl, N-o-nitrobenzenesulfenyl, N-2,4- dinitrobenzenesulfenyl, N-pentachlorobenzenesulfenyl, N-2-nitro-4- methoxybenzenesulfenyl, N-triphenylmethylsulfenyl, N-3- nitropyridinesulfenyl); and N-sulfonyl Derivatives (N-p-toluenesulfonyl, N-benzenesulfonyl, N-2,3,6-trimethyl-4-methoxybenzenesulfonyl, N-2,4,6- trimethoxybenzenesulfonyl, N-2,6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2,3,5,6,-tetramethyl-4- methoxybenzenesulfonyl, N-4-methoxybenzenesulfonyl, N-2,4,6- trimethylbenzenesulfonyl, N-2,6-dimethoxy-4-methylbenzenesulfonyl, N- 2,2,5,7,8-pentamethylchroman-6-sulfonyl, N-methanesulfonyl, N-β- trimethylsilyethanesulfonyl, N-9-anthracenesulfonyl, N-4-(4',8'- dimethoxynaphthylmethyl)benzenesulfonyl, N-benzylsulfonyl, N- trifluoromethylsulfonyl, N-phenacylsulfonyl).
More typically, protected amino groups include carbamates and amides, still more typically, -NHC(0)R! or -N=CR1N(R1)2- Another protecting group, also usefull as a prodrug, particularly for amino or
Figure imgf000035_0001
see for example Alexander, J. et al, "J. Med. Chem." 39:480-486 (1996).
Rόc is the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHS02R , NHC(0)R4, -N(R )2, NH2 or -NH(R )(H), whereby for example the carboxyl or phosphonic acid groups are reacted with the amine to form an amide, as in -C(0)R6c, -P(0)(R6c)2 or -P(0)(OH)(R6C). In general, Rόc has the structure Rl7C(0)CH(Rι6)NH-, where Ri is OH, ORόa, OR5, an amino acid or a polypeptide residue.
Amino acids are low molecular weight compounds, on the order of less than about 1,000 MW, that contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man. Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Of particular interest are hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent.
Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally-occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline.
When Rόb and Rόc are single amino acid residues or polypeptides they usually are substituted at R4 and/or R . Generally, only one of any site in the parental molecule is amidated with an amino acid as described herein, although it is within the scope of this invention to introduce amino acids at more than one permitted site. Usually, a carboxyl group is amidated with an amino acid. In general, the α-amino or α-carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the parental functionalities, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates as described further below). With respect to the carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g. by Rόa, esterified with R5 or amidated with Rόc- Similarly, the amino side chains Riό optionally will be blocked with Rόb or substituted with R5. Such ester or amide bonds with side chain amino or carboxyl groups, like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH <3) or basic (pH >10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments. The esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups. The free acid or base of the parental compound, for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures. When an amino acid residue contains one or more chiral centers, any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used. In general, if the intermediates are to be hydrolyzed non-enzymatically (as would be the case where the amides are used as chemical intermediates for the free acids or free amines), D isomers are useful. On the other hand, L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.
Examples of suitable amino acids whose residues are represented by Rόb and Rόc include the following:
Glycine;
Aminopolycarboxylic acids, e.g., aspartic acid, β-hydroxyaspartic acid, glutamic acid, β-hydroxyglutamic acid, β-methylaspartic acid, β- methylglutamic acid, β,β-dimethylaspartic acid, γ-hydroxyglutamic acid, β,γ- dihydroxyglutamic acid, β-phenylglutamic acid, γ-methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid and 2- aminosebacic acid;
Amino acid amides such as glutamine and asparagine;
Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine, β-aminoalanine, γ-aminobutyrine, ornithine, citruline, homoarginine, homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid;
Other basic amino acid residues such as histidine;
Diaminodicarboxylic acids such as α,α'-diaminosuccinic acid, α,α'- diaminoglutaric acid, α,α'-diaminoadipic acid, α,α'-diaminopimelic acid, α,α'-diamino-β-hydroxypimelic acid, α,α'-diaminosuberic acid, α,α'- diaminoazelaic acid, and α,α'-diaminosebacic acid;
Imino acids such as proline, hydroxyproline, allohydroxyproline, γ- methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2- carboxylic acid; A mono- or di-alkyl (typically Ci - Cs branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, α-methylserine, α-amino-α-methyl-γ- hydroxyvaleric acid, α-amino-α-methyl-δ-hydroxyvaleric acid, α-amino-α- methyl-ε-hydroxycaproic acid, isovaline, α-methylglutamic acid, α- aminoisobutyric acid, α-aminodiethylacetic acid, α-aminodiisopropylacetic acid, α-aminodi-n-propylacetic acid, α-aminodiisobutylacetic acid, α- aminodi-n-butylacetic acid, α-aminoethylisopropylacetic acid, α-amino-n- propylacetic acid, α-aminodiisoamyacetic acid, α-methylaspartic acid, α- methylglutamic acid, 1-aminocyclopropane-l-carboxylic acid, isoleucine, alloisoleucine, tert-leucine, β-methyltryptophan and α-amino-β-ethyl-β- phenylpropionic acid; β-phenylserinyl;
Aliphatic α-amino-β-hydroxy acids such as serine, β-hydroxyleucine, β-hydroxynorleucine, β-hydroxynorvaline, and α-amino-β-hydroxystearic acid; α- Amino, α-, γ-, δ- or ε-hydroxy acids such as homoserine, γ- hydroxynorvaline, δ-hydroxynorvaline and epsilon-hydroxynorleucine residues; canavine and canaline; γ-hydroxyornithine;
2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid; α- Amino- β-thiols such as penicillamine, β-thiolnorvaline or β- thiolbutyrine;
Other sulfur containing amino acid residues including cysteine; homocystine, β-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
Phenylalanine, tryptophan and ring-substituted α amino acids such as the phenyl- or cyclohexylamino acids α-aminophenylacetic acid, α- aminocyclohexylacetic acid and α-amino-β-cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dicloro, o-, m- or p-methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5-nitro- and p- nitro-phenylalanine); furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl- or naphthyl-alanines; and tryptophan analogues and derivatives including kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4- carboxytryptophan; α-Amino substituted amino acids including sarcosine (N- methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N- methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N- benzyl valine; and α-Hydroxy and substituted α-hydroxy amino acids including serine, threonine, allothreonine, phosphoserine and phosphothreonine.
Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond. Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
The polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound. The conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it. Accordingly, the polypeptide or protein may not need to be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final product conjugate should be immunogenic in at least one of such animals. The polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom. Such cleavage sites are flanked by enzymatic recognition structures, e.g. a particular sequence of residues recognized by a peptidolytic enzyme. Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases. Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences. Such enzymes and their substrate requirements in general are well known. For example, a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its α-amino group to the phosphorus or carbon atoms of the compounds herein. In embodiments where wherein the protected group is phosphonate it is expected that this peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond.
Suitable dipeptidyl groups (designated by their single letter code) are AA, AR, AN, AD, AC, AE, AQ, AG, AH, Al, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CH, Cl, CL, CK, CM, CF, CP, CS, CT, CW, CY, CV, EA, ER, EN, ED, EC, EE, EQ, EG, EH, El, EL, EK, EM, EF, EP, ES, ET, EW, EY, EV, QA, QR, QN, QD, QC, QE, QQ, QG, QH, QI, QL, QK, QM, QF, QP, QS, QT, QW, QY, QV, GA, GR, GN, GD, GC, GE, GQ, GG, GH, GI, GL, GK, GM, GF, GP, GS, GT, GW, GY, GV, HA, HR, HN, HD, HC, HE, HQ, HG, HH, HI, HL, HK, HM, HF, HP, HS, HT, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, IH, II, IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LE, LQ, LG, LH, LI, LL, LK, LM, LF, LP, LS, LT, LW, LY, LV, KA, KR, KN, KD, KC, KE, KQ, KG, KH, KI, KL, KK, KM, KF, KP, KS, KT, KW, KY, KV, MA, MR, MN, MD, MC, ME, MQ, MG, MH, MI, ML, MK, MM, MF, MP, MS, MT, MW, MY, MV, FA, FR, FN, FD, FC, FE, FQ, FG, FH, FI, FL, FK, FM, FF, FP, FS, FT, FW, FY, FV, PA, PR, PN, PD, PC, PE, PQ, PG, PH, PI, PL, PK, PM, PF, PP, PS, PT, PW, PY, PV, SA, SR, SN, SD, SC, SE, SQ, SG, SH, SI, SL, SK, SM, SF, SP, SS, ST, SW, SY, SV, TA, TR, TN, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, TP, TS, IT, TW, TY, TV, WA, WR, WN, WD, WC, WE, WQ, WG, WH, WI, WL, WK, WM, WF, WP, WS, WT, WW, WY, WV, YA, YR, YN, YD, YC, YE, YQ, YG, YH, YI, YL, YK, YM, YF, YP, YS, YT, YW, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV. Tripeptide residues are also useful as Rόb or Rόc- When Wi is phosphonate, the sequence -X4-pro-X5- (where X4 is any amino acid residue and X5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond. The carboxy group of X5 optionally is esterified with benzyl.
Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types. Dipeptides and tripeptides lacking an α-amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., "Pharm Res." 9:969-978 (1992). Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds. Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be utilized in the amidate compounds of this invention. Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N (EC 3.4.11.2). In addition, di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine. For example, tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A (EC 3.4.11.7), di- or tripeptides lacking amino acid residues on the N- terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) are poor substrates for endopeptidase 24.11 (EC 3.4.24.11), and peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P (EC 3.4.17). Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases. Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to proteins in order to prepare immunogens.
Recipes and methods for determining stability of compounds in surrogate gastrointestinal secretions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37°C. Such compounds are suitable for use in this embodiment. Note that simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydroyzed in vivo. Prodrugs typically will be stable in the digestive system but are substantially hydroyzed to the parental drug in the digestive lunem, liver or other metabolic organ, or within cells in general.
Additional Embodiments
Another embodiment of the invention is directed to compounds of having formula (VI), (VII), (VIII), (IX) or (X):
Figure imgf000042_0001
Figure imgf000043_0001
wherein R10, R11, R12, R13 and X are defined above. Preferred embodiments of the invention include compounds of the formula (VI). Alternative preferred embodiments of the invention include compounds of the formula (VII). Each of the typical, ordinary or preferred embodiments of formulas
(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and (X), R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and X are freely combinable into typical embodiments of the invention. All combinations of the typical, ordinary or preferred embodiments of the above variables are contemplated to be within the scope of the present invention. All that is required to derive such embodiments is that combination of those typical, ordinary or preferred embodiments of the above identified variables. To avoid redundancy in this disclosure, each of these intended embodiments will not be listed. However, two such embodiments are set forth by way of example and not limitation.
Exemplary combination 1
Another embodiment of the present invention comprises compounds of the formula:
Figure imgf000044_0001
wherein:
R1 is alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms;
2 1 R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2 R groups;
R3 is F, Br, Cl, -CN, or N3;
R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 2 R groups; R5 is F, Br, Cl, I, -CN, N3, -N02, -OR6, -N(R6)2, -SR6, -S(0)R6,
-S(0)2R6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)OR6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6)2, or =0;
R6 is H or PRT; R is alkylene of 1 to 4 carbon atoms, alkenylene of 2 to 4 carbon atoms or alkynylene of 2 to 4 carbon atoms; R 8 is R 7 wherein each said alkylene, alkenylene and alkynylene is independently substituted with 0 to 2 R groups; R9 is R6; each R10 , R11 , R12 is as defined above;
R13 is -OR10 or -OC(0)N(H)( (CR10 2)mlW5); wherein ml is an integer of 1 to 6 and W is as defined above; and
X is -OR6 or 3'-GGTTGG-, wherein R6 is as defined above.
Exemplary combination 2
Another embodiment of the present invention comprises compounds of the formula:
Figure imgf000045_0001
wherein:
R1 is alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms or alkynyl of 2 to 3 carbon atoms;
R 2 is R 1 wherein each said alkyl, alkenyl and alkynyl is
3 independently substituted with 0 to 1 R groups;
R3 is F, Br, Cl or N3;
R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 1 R groups; R5 is F, N3, -OR6, -N(R6)2, -SR6, -C(0)R6, -C(0)OR6, or -OP(0)(OR6)2;
R6 is H;
R is alkylene of 1 to 3 carbon atoms, alkenylene of 2 to 3 carbon atoms or alkynylene of 2 to 3 carbon atoms;
8 7 R is R wherein each said alkylene, alkenylene and alkynylene is independently substituted with 0 to 1 R groups;
9 5a 5a
R is -(CH2)m2W ; wherein m2 is 1, 2 or 3, and W is a monocyclic, saturated, monounsaturated, diunsaturated or aromatic carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I, -CN, N3, -N02, -OR6, -N(R6)2, -SR6, -S(0)R6, -S(0)2R6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2),
-OP(0)(OR6)2, -OP(S)(OR6); each R 10 , R 11 , R 12 is as defined above; R13 is -OH or -OC(0)N(R6)((CH2)m2W5a); wherein m2 is 1, 2 or 3, and W 5a is a monocyclic, saturated, monounsaturated, diunsaturated or aromatic carbocycle having 5 or 6 ring atoms, said carbocycle being substituted with 0 to 3 groups selected from F, Br, Cl, I, -CN, N3, -N02,
-OR6, -N(R )2, -SR6, -S(0)R6, -S(0)2R6, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)N(R6)2, -N(R6)(C(0)R6, -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6)2; and X is -OH or 3'-GGTTGG-.
Another embodiment of the invention is directed to compositions comprising a compound of of the invention and a pharmaceutically- acceptable carrier.
Another embodiment of the invention is directed to methods of detecting the presence or absence of thrombin comprising contacting a sample suspected of containing thrombin with a compound of the invention. Another embodiment of the invention is directed to methods of inhibiting the activity of thrombin comprising contacting a sample suspected of containing thrombin with a compound of the invention.
Another embodiment of the invention is directed to methods of inhibiting the activity of thrombin in a host comprising administering to the host a therapeutically effective amount of a compound of the invention. Two exemplary embodiments of the invention are depicted below:
Figure imgf000047_0001
Figure imgf000048_0001
Stereoisomers
The compounds of the invention are enriched or resolved optical isomers at any or all asymmetric atoms. For example, the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diasteromeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
One or more of the following enumerated methods are used to prepare the enantiomerically enriched or pure isomers herein. The methods are listed in approximately their order of preference, i.e., one ordinarily should employ stereospecific synthesis from chriral precursors before chromatographic resolution before spontaneous crystallization.
Stereospecific synthesis is described in the examples. Methods of this type conveniently are used when the appropriate chiral starting material is available and reaction steps are chosen do not result in undesired racemization at chiral sites. One advantage of stereospecific synthesis is that it does not produce undesired enantiomers that must be removed from the final product, thereby lowering overall synthetic yield. In general, those skilled in the art would understand what starting materials and reaction conditions should be used to obtain the desired enantiomerically enriched or pure isomers by stereospecific synthesis. If an unexpected racemization occurs in a method thought to be stereospecific then one needs only to use one of the following separation methods to obtain the desired product. If a suitable stereospecific synthesis cannot be empirically designed or determined with routine experimentation then those skilled in the art would turn to other methods. One method of general utility is chromotographic resolution of enantiomers on chiral chromatography resins. These resins are packed in columns, commonly called Pirkle columns, and are commercially available. The columns contain a chiral stationary phase. The racemate is placed in solution and loaded onto the column, and thereafter separated by HPLC. See for example, Proceedings Chromatographic Society - International Symposium on Chiral Separations, Sept. 3-4, 1987. Examples of chiral columns that could be used to screen for the optimal separation technique would include Diacel
Chriacel OD, Regis Pirkle Covalent Dphenylglycine, Regis Pirkle Type 1A, Astec Cyclobond II, As tec Cyclobond III, Serva Chiral D-DL=Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck Cellulose Triacetate column, Astec Cyclobond I-Beta, or Regis Pirkle Covalent D- Naphthylalanine. Not all of these columns are likely to be effective with every racemic mixture. However, those skilled in the art understand that a certain amount of routine screening may be required to identify the most effective stationary phase. When using such columns it is desireable to employ embodiments of the compounds of this invention in which the charges are not neutralized, e.g., where acidic functionalities such as carboxyl are not esterified or amidated.
Another method entails converting the enantiomers in the mixture to diasteriomers with chiral auxiliaries and then separting the conjugates by ordinary column chromatography. This is a very suitable method, particularly when the embodiment contains free carboxyl, amino or hydroxyl that will form a salt or covalent bond to a chiral auxiliary.
Chirally pure amino acids, organic acids or organosulfonic acids are all worthwhile exploring as chiral auxiliaries, all of which are well known in the art. Salts with such auxiliaries can be formed, or they can be covalently (but reversibly) bonded to the functional group. For example, pure D or L amino acids can be used to amidate the carboxyl group of embodiments of this invention and then separated by chromatography.
Enzymatic resolution is another method of potential value. In such methods one prepares covalent derivatives of the enantiomers in the racemic mixture, generally lower alkyl esters (for example of carboxyl), and then exposes the derivative to enzymatic cleavage, generally hydrolysis. For this method to be successful an enzyme must be chosen that is capable of stereospecific cleavage, so it is frequently necessary to routinely screen several enzymes. If esters are to be cleaved, then one selects a group of esterases, phosphatases, and Upases and determines their activity on the derivative. Typical esterases are from liver, pancreas or other animal organs, and include porcine liver esterase.
If the enatiomeric mixture separates from solution or a melt as a conglomerate, i.e., a mixture of enantiomerically-pure crystals, then the crystals can be mechanically separated, thereby producing the enantiomerically enriched preparation. This method, however, is not practical for large scale preparations and is of no value for true racemic compounds.
Asymmetric synthesis is another technique for achieving enantiomeric enrichment. For example, a chiral protecting group is reacted with the group to be protected and the reaction mixture allowed to equilibrate. If the reaction is enantiomerically specific then the product will be enriched in that enantiomer.
Further guidance in the separation of enantiomeric mixtures can be found, by way of example and not limitation, in "Enantiomers, Racemates, and resolutions", Jean Jacques, Andre Collet, and Samuel H. Wilen (Krieger Publishing Company, Malabar, FL, 1991, ISBN 0-89464-618-4). In particular, Part 2, Resolution of Enantiomer Mixture, pages 217-435; more particularly, section 4, Resolution by Direct Crystallization, pages 217-251, section 5, Formation and Separation of Diastereomers, pages 251-369, section 6, Crystallization-Induced Asymmetric Transformations, pages 369- 378, and section 7, Experimental Aspects and Art of Resolutions, pages 378- 435; still more particularly, section 5.1.4, Resolution of Alcohols, Transformation of Alcohols into Salt-Forming Derivatives, pages 263-266, section 5.2.3, Covalent Derivatives of Alcohols, Thiols, and Phenols, pages 332-335, section 5.1.1, Resolution of Acids, pages 257-259, section 5.1.2, Resolution of Bases, pages 259-260, section 5.1.3, Resolution of Amino
Acids, page 261-263, section 5.2.1, Covalent Derivatives of Acids, page 329, section 5.2.2, Covalent derivatives of Amines, pages 330-331, section 5.2.4, Covalent Derivatives of Aldehydes, Ketones, and Sulfoxides, pages 335-339, and section 5.2.7, Chromatographic Behavior of Covalent Diastereomers, pages 348-354, are cited as examples of the skill of the art.
The compounds of the invention can also exist as tautomeric isomers in certain cases. For example, ene-amine tautomers can exist for imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
Exemplary Enumerated Compounds.
By way of example and not limitation, embodiment compounds are named below in tabular format (Table 9). Generally, each compound is depicted as a substituted nucleus in which the nucleus is designated by capital letter and each substituent is designated in order by lower case letter or number. Table 1 is a schedule of nuclei. Each nucleus is given a alphabetical designation from Table 1, and this designation appears first in each compound name. Similarly, Tables 2-8 list the selected Qi, Q2, Q3, Q4 Qδ, Qό and Q7 substituents, again by letter or number designation. Accordingly, each named compound will be depicted by a capital letter designating the nucleus from Table 1, followed by a number designating the Qi substituent, a lower case letter designating the Q2 substituent, a number designating the Q3 substituent, a lower case letter designating the Q4 substituent, a number designating the Q5 substituent, a lower case letter designating the Qό substituent, and a number designating the Q7. Thus GS 4097, the compound of Example 14, is represented by A.7.a.8.a.l.a.l. Q1-Q7, it should be understood, do not represent groups or atoms but are simply connectivity designations.
Table 1
Figure imgf000053_0001
Figure imgf000053_0002
B
Table 2a
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000054_0003
10 11
Figure imgf000054_0005
Figure imgf000054_0004
12 13 14
Table 2b
Figure imgf000055_0001
15 16
Figure imgf000055_0002
17 18
Figure imgf000055_0003
19 20
Figure imgf000055_0004
21 22 Table 3
Figure imgf000056_0001
Figure imgf000056_0002
Table 4
Figure imgf000057_0001
Q3-GG-3' Q3-GGT-3' Q3-GGTT-3'
Qa-GGTTG-3' Qa-GGTTGG-3'
Table 5
Q4-H Q4-F Q4-Br Q4-CI
Figure imgf000058_0001
Figure imgf000058_0002
H / CH3
Q4-NH2 Q4-Nχ Q4-N
CH3 XCHa
m
Table 6
CH, ■CH,
Q5-H Q5-CH3 Qc Qc
Figure imgf000059_0001
Table 7
CH, CH,
Q6-H Q6-CH3 QF Qf
Figure imgf000060_0001
Table 8
CH, ■CH,
Q7-H Q7-CH3 Q7- Q7-
Figure imgf000061_0001
Table 9
A.l.a.l.a.l.a.l; A.l.a.l.a.l.a.2; A.l.a.l.a.l.b.l; A.l.a.l.a.l.b.2; A.l.a.l.a.l.c.l;
A.l.a.l.a.l.c.2; A.l.a.l.a.l.d.l; A.l.a.l.a.l.d.2; A.l.a.l.a.l.e.l; A.l.a.l.a.l.e.2;
A.l.a.l.a.l.f.1; A.l.a.l.a.l.f.2; A.l.a.l.a.l.g.l; A.l.a.l.a.l.g.2; A.l.a.l.b.l.a.l; A.l.a.l.b.l.a.2; A.l.a.l.b.l.b.1; A.l.a.l.b.l.b.2; A.l.a.l.b.l.c.l; A.l.a.l.b.l.c.2;
A.l.a.l.b.l.d.1; A.l.a.l.b.l.d.2; A.l.a.l.b.l.e.l; A.l.a.l.b.l.e.2; A.l.a.l.b.l.f.l;
A.l.a.l.b.l.f.2; A.l.a.l.b.l.g.l; A.l.a.l.b.l.g.2; A.l.a.l.f.l.a.l; A.l.a.l.f.l.a.2;
A.l.a.l.f.l.b.l; A.l.a.l.f.l.b.2; A.l.a.l.f.l.c.l; A.l.a.l.f.l.c.2; A.l.a.l.f.l.d.l;
A.l.a.l.f.l.d.2; A.l.a.l.f.l.e.l; A.l.a.l.f.l.e.2; A.l.a.l.f.l.f.l; A.l.a.l.f.l.f.2; A.l.a.l.f.l.g.l; A.l.a.l.f.l.g.2; A.l.a.l.h.l.a.1; A.l.a.l.h.l.a.2; A.l.a.l.h.l.b.1;
A.l.a.l.h.l.b.2; A.l.a.l.h.l.c.l; A.l.a.l.h.l.c.2; A.l.a.l.h.l.d.l; A.l.a.l.h.l.d.2;
A.l.a.l.h.l.e.l; A.l.a.l.h.l.e.2; A.l.a.l.h.l.f.l; A.l.a.l.h.l.f.2; A.l.a.l.h.l.g.1;
A.l.a.l.h.l.g.2; A.l.a.l.l.l.a.l; A.l.a.l.l.l.a.2; A.l.a.l.l.l.b.l; A.l.a.l.l.l.b.2;
A.l.a.l.l.l.c.l; A.l.a.l.l.l.c.2; A.l.a.l.l.l.d.l; A.l.a.l.l.l.d.2; A.l.a.l.l.l.e.l; A.l.a.l.l.l.e.2; A.l.a.l.l.l.f.l; A.l.a.l.l.l.f.2; A.l.a.l.l.l.g.l; A.l.a.l.l.l.g.2;
A.l.a.2.a.l.a.l; A.l.a.2.a.l.a.2; A.l.a.2.a.l.b.l; A.l.a.2.a.l.b.2; A.l.a.2.a.l.c.l;
A.l.a.2.a.l.c.2; A.l.a.2.a.l.d.l; A.l.a.2.a.l.d.2; A.l.a.2.a.l.e.l; A.l.a.2.a.l.e.2;
A.l.a.2.a.l.f.l; A.l.a.2.a.l.f.2; A.l.a.2.a.l.g.l; A.l.a.2.a.l.g.2; A.l.a.2.b.l.a.l;
A.l.a.2.b.l.a.2; A.l.a.2.b.l.b.l; A.l.a.2.b.l.b.2; A.l.a.2.b.l.c.l; A.l.a.2.b.l.c.2; A.l.a.2.b.l.d.l; A.l.a.2.b.l.d.2; A.l.a.2.b.l.e.l; A.l.a.2.b.l.e.2; A.l.a.2.b.l.f.l;
A.l.a.2.b.l.f.2; A.l.a.2.b.l.g.l; A.l.a.2.b.l.g.2; A.l.a.2.f.l.a.l; A.l.a.2.f.l.a.2;
A.l.a.2.f.l.b.l; A.l.a.2.f.l.b.2; A.l.a.2.f.l.c.l; A.l.a.2.f.l.c.2; A.l.a.2.f.l.d.l;
A.l.a.2.f.l.d.2; A.l.a.2.f.l.e.l; A.l.a.2.f.l.e.2; A.l.a.2.f.l.f.l; A.l.a.2.f.l.f.2;
A.l.a.2.f.l.g.l; A.l.a.2.f.l.g.2; A.l.a.2.h.l.a.l; A.l.a.2.h.l.a.2; A.l.a.2.h.l.b.l; A.l.a.2.h.l.b.2; A.l.a.2.h.l.c.l; A.l.a.2.h.l.c.2; A.l.a.2.h.l.d.l; A.l.a.2.h.l.d.2;
A.l.a.2.h.l.e.l; A.l.a.2.h.l.e.2; A.l.a.2.h.l.f.l; A.l.a.2.h.l.f.2; A.l.a.2.h.l.g.l;
A.l.a.2.h.l.g.2; A.l.a.2.1.1.a.l; A.l.a.2.1.1.a.2; A.l.a.2.1.1.b.l; A.l.a.2.1.1.b.2;
A.l.a.2.1.1.c.l; A.l.a.2.1.1.c.2; A.l.a.2.1.1.d.l; A.l.a.2.1.1.d.2; A.l.a.2.1.1.e.l;
A.l.a.2.1.1.e.2; A.l.a.2.1.1.f.l; A.l.a.2.1.1.f.2; A.l.a.2.1.1.g.l; A.l.a.2.1.1.g.2; A.l.a.δ.a.l.a.l; A.l.a.8.a.l.a.2; A.l.a.δ.a.l.b.l; A.l.a.8.a.l.b.2; A.l.a.8.a.l.c.l;
A.l.a.8.a.l.c.2; A.l.a.8.a.l.d.l; A.l.a.8.a.l.d.2; A.l.a.δ.a.l.e.l; A.l.a.8.a.l.e.2;
A.l.a.δ.a.li.l; A.l.a.8.a.l.f.2; A.l.a.8.a.l.g.l; A.l.a.8.a.l.g.2; A.l.a.δ.b.l.a.l;
A.l.a.8.b.l.a.2; A.l.a.δ.b.l.b.l; A.l.a.8.b.l.b.2; A.l.a.8.b.l.c.l; A.l.a.8.b.l.c.2;
A.l.a.8.b.l.d.l; A.l.a.8.b.l.d.2; A.l.a.8.b.l.e.l; A.l.a.8.b.l.e.2; A.l.a.δ.b.l.f.l; A.l.a.8.b.l.f.2; A.l.a.δ.b.l.g.l; A.l.a.δ.b.l.g.2; A.l.a.8.f.l.a.l; A.l.a.8.f.l.a.2;
A.l.a.δ.f.l.b.1; A.l.a.8.f.l.b.2; A.l.a.δ.f.l.c.l; A.l.a.8.f.l.c.2; A.l.a.β.f.l.d.l;
A.l.a.8.f.l.d.2; A.l.a.8.f.l.e.l; A.l.a.δ.f.l.e.2; A.l.a.δ.f.l.f.l; A.l.a.8.f.l.f.2;
A.l.a.δ.f.l.g.l; A.l.a.δ.f.l.g.2; A.l.a.δ.h.l.a.l; A.l.a.δ.h.l.a.2; A.l.a.δ.h.l.b.l;
A.l.a.δ.h.l.b.2; A.l.a.δ.h.l.c.l; A.l.a.δ.h.l.c.2; A.l.a.δ.h.l.d.l; A.l.a.δ.h.l.d.2; A.l.a.8.h.l.e.l; A.l.a.8.h.l.e.2; A.l.a.δ.h.l.f.l; A.l.a.δ.h.l.f.2; A.l.a.δ.h.l.g.l;
A.l.a.δ.h.l.g.2; A.l.a.δ.l.l.a.l; A.l.a.8.1.1.a.2; A.l.a.δ.l.l.b.l; A.l.a.δ.l.l.b.2;
A.l.a.δ.l.l.c.l; A.l.a.δ.l.l.c.2; A.l.a.δ.l.l.d.l; A.l.a.8.1.1.d.2; A.l.a.δ.l.l.e.l;
A.l.a.8.1.1.e.2; A.l.a.δ.l.l.f.l; A.l.a.δ.l.l.f.2; A.l.a.δ.l.l.g.l; A.l.a.8.1.1.g.2;
A.2.a.l.a.l.a.l; A.2.a.l.a.l.a.2; A.2.a.l.a.l.b.l; A.2.a.l.a.l.b.2; A.2.a.l.a.l.c.l; A.2.a.l.a.l.c.2; A.2.a.l.a.l.d.l; A.2.a.l.a.l.d.2; A.2.a.l.a.l.e.l; A.2.a.l.a.l.e.2;
A.2.a.l.a.l.f.l; A.2.a.l.a.l.f.2; A.2.a.l.a.l.g.l; A.2.a.l.a.l.g.2; A.2.a.l.b.l.a.l; A.2.a.l.b.l.a.2; A.2.a.l.b.l.b.l; A.2.a.l.b.l.b.2; A.2.a.l.b.l.c.l; A.2.a.l.b.l.c.2;
A.2.a.l.b.l.d.l; A.2.a.l.b.l.d.2; A.2.a.l.b.l.e.l; A.2.a.l.b.l.e.2; A.2.a.l.b.l.f.l;
A.2.a.l.b.l.f.2; A.2.a.l.b.l.g.l; A.2.a.l.b.l.g.2; A.2.a.l.f.l.a.l; A.2.a.l.f.l.a.2;
A.2.a.l.f.l.b.l; A.2.a.l.f.l.b.2; A.2.a.l.f.l.c.l; A.2.a.l.f.l.c.2; A.2.a.l.f.l.d.l; A.2.a.l.f.l.d.2; A.2.a.l.f.l.e.l; A.2.a.l.f.l.e.2; A.2.a.l.f.l.f.l; A.2.a.l.f.l.f.2;
A.2.a.l.f.l.g.l; A.2.a.l.f.l.g.2; A.2.a.l.h.l.a.l; A.2.a.l.h.l.a.2; A.2.a.l.h.l.b.l;
A.2.a.l.h.l.b.2; A.2.a.l.h.l.c.l; A.2.a.l.h.l.c.2; A.2.a.l.h.l.d.l; A.2.a.l.h.l.d.2;
A.2.a.l.h.l.e.l; A.2.a.l.h.l.e.2; A.2.a.l.h.l.f.l; A.2.a.l.h.l.f.2; A.2.a.l.h.l.g.l;
A.2.a.l.h.l.g.2; A.2.a.l.l.l.a.l; A.2.a.l.l.l.a.2; A.2.a.l.l.l.b.l; A.2.a.l.l.l.b.2; A.2.a.l.l.l.c.l; A.2.a.l.l.l.c.2; A.2.a.l.l.l.d.l; A.2.a.l.l.l.d.2; A.2.a.l.l.l.e.l;
A.2.a.l.l.l.e.2; A.2.a.l.l.l.f.l; A.2.a.l.l.l.f.2; A.2.a.l.l.l.g.l; A.2.a.l.l.l.g.2;
A.2.a.2.a.l.a.l; A.2.a.2.a.l.a.2; A.2.a.2.a.l.b.l; A.2.a.2.a.l.b.2; A.2.a.2.a.l.c.l;
A.2.a.2.a.l.c.2; A.2.a.2.a.l.d.l; A.2.a.2.a.l.d.2; A.2.a.2.a.l.e.l; A.2.a.2.a.l.e.2;
A.2.a.2.a.l.f.l; A.2.a.2.a.l.f.2; A.2.a.2.a.l.g.l; A.2.a.2.a.l.g.2; A.2.a.2.b.l.a.l; A.2.a.2.b.l.a.2; A.2.a.2.b.l.b.l; A.2.a.2.b.l.b.2; A.2.a.2.b.l.c.l; A.2.a.2.b.l.c.2;
A.2.a.2.b.l.d.l; A.2.a.2.b.l.d.2; A.2.a.2.b.l.e.l; A.2.a.2.b.l.e.2; A.2.a.2.b.l.f.l;
A.2.a.2.b.l.f.2; A.2.a.2.b.l.g.l; A.2.a.2.b.l.g.2; A.2.a.2.f.l.a.l; A.2.a.2.f.l.a.2;
A.2.a.2.f.l.b.l; A.2.a.2.f.l.b.2; A.2.a.2.f.l.c.l; A.2.a.2.f.l.c.2; A.2.a.2.f.l.d.l;
A.2.a.2.f.l.d.2; A.2.a.2.f.l.e.l; A.2.a.2.f.l.e.2; A.2.a.2.f.l.f.l; A.2.a.2.f.l.f.2; A.2.a.2.f.l.g.l; A.2.a.2.f.l.g.2; A.2.a.2.h.l.a.l; A.2.a.2.h.l.a.2; A.2.a.2.h.l.b.l;
A.2.a.2.h.l.b.2; A.2.a.2.h.l.c.l; A.2.a.2.h.l.c.2; A.2.a.2.h.l.d.l; A.2.a.2.h.l.d.2;
A.2.a.2.h.l.e.l; A.2.a.2.h.l.e.2; A.2.a.2.h.l.f.l; A.2.a.2.h.l.f.2; A.2.a.2.h.l.g.l;
A.2.a.2.h.l.g.2; A.2.a.2.1.1.a.l; A.2.a.2.1.1.a.2; A.2.a.2.1.1.b.l; A.2.a.2.1.1.b.2;
A.2.a.2.1.1.c.l; A.2.a.2.1.1.c.2; A.2.a.2.1.1.d.l; A.2.a.2.1.1.d.2; A.2.a.2.1.1.e.l; A.2.a.2.1.1.e.2; A.2.a.2.1.1.f.l; A.2.a.2.1.1.f.2; A.2.a.2.1.1.g.l; A.2.a.2.1.1.g.2;
A.2.a.8.a.l.a.l; A.2.a.δ.a.l.a.2; A.2.a.δ.a.l.b.l; A.2.a.8.a.l.b.2; A.2.a.8.a.l.c.l;
A.2.a.δ.a.l.c.2; A.2.a.δ.a.l.d.l; A.2.a.δ.a.l.d.2; A.2.a.δ.a.l.e.l; A.2.a.8.a.l.e.2;
A.2.a.δ.a.l.f.l; A.2.a.8.a.l.f.2; A.2.a.δ.a.l.g.l; A.2.a.δ.a.l.g.2; A.2.a.δ.b.l.a.l;
A.2.a.δ.b.l.a.2; A.2.a.δ.b.l.b.l; A.2.a.δ.b.l.b.2; A.2.a.δ.b.l.c.l; A.2.a.δ.b.l.c.2; A.2.a.δ.b.l.d.l; A.2.a.δ.b.l.d.2; A.2.a.δ.b.l.e.l; A.2.a.δ.b.l.e.2; A.2.a.δ.b.l.f.l;
A.2.a.δ.b.l.f.2; A.2.a.δ.b.l.g.l; A.2.a.δ.b.l.g.2; A.2.a.δ.f.l.a.l; A.2.a.δ.f.l.a.2;
A.2.a.8.f.l.b.l; A.2.a.8.f.l.b.2; A.2.a.δ.f.l.c.l; A.2.a.δ.f.l.c.2; A.2.a.δ.f.l.d.l;
A.2.a.δ.f.l.d.2; A.2.a.δ.f.l.e.l; A.2.a.δ.f.l.e.2; A.2.a.δ.f.l.f.l; A.2.a.8.f.l.f.2;
A.2.a.δ.f.l.g.l; A.2.a.δ.f.l.g.2; A.2.a.δ.h.l.a.l; A.2.a.δ.h.l.a.2; A.2.a.δ.h.l.b.l; A.2.a.δ.h.l.b.2; A.2.a.8.h.l.c.l; A.2.a.δ.h.l.c.2; A.2.a.δ.h.l.d.l; A.2.a.δ.h.l.d.2;
A.2.a.δ.h.l.e.l; A.2.a.δ.h.l.e.2; A.2.a.8.h.l.f.l; A.2.a.δ.h.l.f.2; A.2.a.δ.h.l.g.l;
A.2.a.8.h.l.g.2; A.2.a.δ.l.l.a.l; A.2.a.8.1.1.a.2; A.2.a.δ.l.l.b.l; A.2.a.δ.l.l.b.2;
A.2.a.δ.l.l.c.l; A.2.a.δ.l.l.c.2; A.2.a.8.1.1.d.l; A.2.a.δ.l.l.d.2; A.2.a.δ.l.l.e.l;
A.2.a.δ.l.l.e.2; A.2.a.δ.l.l.f.l; A.2.a.δ.l.l.f.2; A.2.a.δ.l.l.g.l; A.2.a.δ.l.l.g.2; A.δ.a.l.a.l.a.l; A.δ.a.l.a.l.a.2; A.δ.a.l.a.l.b.l; A.8.a.l.a.l.b.2; A.δ.a.l.a.l.c.l;
A.δ.a.l.a.l.c.2; A.δ.a.l.a.l.d.l; A.8.a.l.a.l.d.2; A.δ.a.l.a.l.e.l; A.8.a.l.a.l.e.2;
A.8.a.l.a.l.f.l; A.8.a.l.a.l.f.2; A.8.a.l.a.l.g.l; A.8.a.l.a.l.g.2; A.δ.a.l.b.l.a.l;
A.δ.a.l.b.l.a.2; A.δ.a.l.b.l.b.l; A.δ.a.l.b.l.b.2; A.δ.a.l.b.l.c.l; A.δ.a.l.b.l.c.2;
A.δ.a.l.b.l.d.l; A.δ.a.l.b.l.d.2; A.δ.a.l.b.l.e.l; A.δ.a.l.b.l.e.2; A.δ.a.l.b.l.f.l; A.δ.a.l.b.l.f.2; A.δ.a.l.b.l.g.l; A.δ.a.l.b.l.g.2; A.δ.a.l.f.l.a.l; A.8.a.l.f.l.a.2;
A.8.a.l.f.l.b.l; A.δ.a.l.f.l.b.2; A.δ.a.l.f.l.c.l; A.δ.a.l.f.l.c.2; A.δ.a.l.f.l.d.l; A.δ.a.l.f.l.d.2; A.δ.a.l.f.l.e.l; A.8.a.l.f.l.e.2; A.8.a.l.f.l.f.l; A.8.a.l.f.l.f.2;
A.δ.a.l.f.l.g.l; A.δ.a.l.f.l.g.2; A.8.a.l.h.l.a.l; A.8.a.l.h.l.a.2; A.δ.a.l.h.l.b.l;
A.8.a.l.h.l.b.2; A.δ.a.l.h.l.c.l; A.δ.a.l.h.l.c.2; A.δ.a.l.h.l.d.l; A.8.a.l.h.l.d.2;
A.δ.a.l.h.l.e.l; A.δ.a.l.h.l.e.2; A.δ.a.l.h.l.f.l; A.8.a.l.h.l.f.2; A.8.a.l.h.l.g.l; A.δ.a.l.h.l.g.2; A.δ.a.l.l.l.a.l; A.δ.a.l.l.l.a.2; A.δ.a.l.l.l.b.l; A.δ.a.l.l.l.b.2;
A.δ.a.l.l.l.c.l; A.δ.a.l.l.l.c.2; A.δ.a.l.l.l.d.l; A.δ.a.l.l.l.d.2; A.δ.a.l.l.l.e.l;
A.δ.a.l.l.l.e.2; A.δ.a.l.l.l.f.l; A.δ.a.l.l.l.f.2; A.β.a.l.l.l.g.l; A.δ.a.l.l.l.g.2;
A.8.a.2.a.l.a.l; A.δ.a.2.a.l.a.2; A.δ.a.2.a.l.b.l; A.δ.a.2.a.l.b.2; A.δ.a.2.a.l.c.l;
A.δ.a.2.a.l.c.2; A.δ.a.2.a.l.d.l; A.8.a.2.a.l.d.2; A.8.a.2.a.l.e.l; A.δ.a.2.a.l.e.2; A.δ.a.2.a.l.f.l; A.δ.a.2.a.l.f.2; A.δ.a.2.a.l.g.l; A.δ.a.2.a.l.g.2; A.δ.a.2.b.l.a.l;
A.δ.a.2.b.l.a.2; A.δ.a.2.b.l.b.l; A.8.a.2.b.l.b.2; A.δ.a.2.b.l.c.l; A.δ.a.2.b.l.c.2;
A.δ.a.2.b.l.d.l; A.δ.a.2.b.l.d.2; A.δ.a.2.b.l.e.l; A.δ.a.2.b.l.e.2; A.δ.a.2.b.l.f.l;
A.δ.a.2.b.l.f.2; A.δ.a.2.b.l.g.l; A.δ.a.2.b.l.g.2; A.δ.a.2.f.l.a.l; A.δ.a.2.f.l.a.2;
A.δ.a.2.f.l.b.l; A.δ.a.2.f.l.b.2; A.8.a.2.f.l.c.l; A.δ.a.2.f.l.c.2; A.8.a.2.f.l.d.l; A.δ.a.2.f.l.d.2; A.8.a.2.f.l.e.l; A.8.a.2.f.l.e.2; A.δ.a.2.f.l.f.l; A.δ.a.2.f.l.f.2;
A.δ.a.2.f.l.g.l; A.δ.a.2.f.l.g.2; A.δ.a.2.h.l.a.l; A.δ.a.2.h.l.a.2; A.8.a.2.h.l.b.l;
A.8.a.2.h.l.b.2; A.8.a.2.h.l.c.l; A.δ.a.2.h.l.c.2; A.δ.a.2.h.l.d.l; A.δ.a.2.h.l.d.2;
A.δ.a.2.h.l.e.l; A.δ.a.2.h.l.e.2; A.δ.a.2.h.l.f.l; A.δ.a.2.h.l.f.2; A.δ.a.2.h.l.g.l;
A.δ.a.2.h.l.g.2; A.δ.a.2.1.1.a.l; A.δ.a.2.1.1.a.2; A.8.a.2.1.1.b.l; A.8.a.2.1.1.b.2; A.δ.a.2.1.1.c.l; A.δ.a.2.1.1.c.2; A.δ.a.2.1.1.d.l; A.δ.a.2.1.1.d.2; A.δ.a.2.1.1.e.l;
A.δ.a.2.1.1.e.2; A.δ.a.2.1.1.f.l; A.δ.a.2.1.1.f.2; A.δ.a.2.1.1.g.l; A.δ.a.2.1.1.g.2;
A.δ.a.δ.a.l.a.l; A.δ.a.δ.a.l.a.2; A.δ.a.δ.a.l.b.l; A.8.a.8.a.l.b.2; A.δ.a.δ.a.l.c.l;
A.δ.a.δ.a.l.c.2; A.δ.a.δ.a.l.d.l; A.δ.a.δ.a.l.d.2; A.δ.a.δ.a.l.e.l; A.δ.a.δ.a.l.e.2;
A.δ.a.δ.a.l.f.l; A.δ.a.δ.a.l.f.2; A.δ.a.δ.a.l.g.l; A.δ.a.δ.a.l.g.2; A.δ.a.δ.b.l.a.l; A.δ.a.δ.b.l.a.2; A.δ.a.δ.b.l.b.l; A.δ.a.δ.b.l.b.2; A.δ.a.δ.b.l.c.l; A.8.a.8.b.l.c.2;
A.δ.a.δ.b.l.d.l; A.δ.a.δ.b.l.d.2; A.8.a.8.b.l.e.l; A.δ.a.δ.b.l.e.2; A.δ.a.δ.b.l.f.l;
A.δ.a.δ.b.l.f.2; A.δ.a.δ.b.l.g.l; A.δ.a.δ.b.l.g.2; A.δ.a.δ.f.l.a.l; A.δ.a.δ.f.l.a.2;
A.δ.a.δi.l.b.l; A.8.a.8.f.l.b.2; A.8.a.δ.f.l.c.l; A.δ.a.δ.f.l.c.2; A.δ.a.δ.f.l.d.l;
A.δ.a.8.f.l.d.2; A.8.a.δ.f.l.e.l; A.8.a.δ.f.l.e.2; A.δ.a.δ.f.l.f.l; A.δ.a.δ.f.l.f.2; A.δ.a.δ.f.l.g.l; A.δ.a.δ.f.l.g.2; A.δ.a.δ.h.l.a.l; A.δ.a.δ.h.l.a.2; A.δ.a.δ.h.l.b.l;
A.δ.a.δ.h.l.b.2; A.δ.a.δ.h.l.c.l; A.δ.a.δ.h.l.c.2; A.δ.a.δ.h.l.d.l; A.8.a.8.h.l.d.2;
A.δ.a.δ.h.l.e.l; A.δ.a.δ.h.l.e.2; A.δ.a.8.h.l.f.l; A.δ.a.8.h.l.f.2; A.8.a.8.h.l.g.l;
A.8.a.8.h.l.g.2; A.δ.a.δ.l.l.a.l; A.δ.a.8.1.1.a.2; A.δ.a.δ.l.l.b.l; A.δ.a.δ.l.l.b.2;
A.δ.a.δ.l.l.c.l; A.δ.a.δ.l.l.c.2; A.δ.a.δ.l.l.d.l; A.δ.a.8.1.1.d.2; A.δ.a.δ.l.l.e.l; A.δ.a.δ.l.l.e.2; A.δ.a.δ.l.l.f.l; A.δ.a.δ.l.l.f.2; A.δ.a.δ.l.l.g.l; A.δ.a.δ.l.l.g.2;
A.10.a.l.a.l.a.l; A.10.a.l.a.l.a.2; A.lO.a.l.a.l.b.l; A.10.a.l.a.l.b.2;
A.10.a.l.a.l.c.l; A.lO.a.l.a.l.c.2; A.lO.a.l.a.l.d.l; A.10.a.l.a.l.d.2;
A.10.a.l.a.l.e.l; A.10.a.l.a.l.e.2; A.lO.a.l.a.l.f.l; A.10.a.l.a.l.f.2; A.lO.a.l.a.l.g.l;
A.10.a.l.a.l.g.2; A.lO.a.l.b.l.a.l; A.10.a.l.b.l.a.2; A.lO.a.l.b.l.b.l; A.10.a.l.b.l.b.2; A.lO.a.l.b.l.c.l; A.lO.a.l.b.l.c.2; A.lO.a.l.b.l.d.l;
A.10.a.l.b.l.d.2; A.lO.a.l.b.l.e.l; A.10.a.l.b.l.e.2; A.lO.a.l.b.l.f.l;
A.10.a.l.b.l.f.2; A.lO.a.l.b.l.g.l; A.10.a.l.b.l.g.2; A.lO.a.l.f.l.a.l; A.10.a.l.f.l.a.2;
A.lO.a.li.l.b.l; A.10.a.l.f.l.b.2; A.lO.a.l.f.l.c.l; A.lO.a.l.f.l.c.2; A.lO.a.l.f.l.d.l;
A.10.a.l.f.l.d.2; A.lO.a.l.f.l.e.l; A.10.a.l.f.l.e.2; A.lO.a.l.f.l.f.l; A.10.a.l.f.l.f.2; A.lO.a.l.f.l.g.l; A.10.a.l.f.l.g.2; A.lO.a.l.h.l.a.l; A.10.a.l.h.l.a.2;
A.lO.a.l.h.l.b.1; A.10.a.l.h.l.b.2; A.lO.a.l.h.l.c.l; A.lO.a.l.h.l.c.2; A.10.a.l.h.l.d.l; A.10.a.l.h.l.d.2; A.lO.a.l.h.l.e.l; A.10.a.l.h.l.e.2;
A.10.a.l.h.l.f.l; A.10.a.l.h.l.f.2; A.lO.a.l.h.l.g.l; A.10.a.l.h.l.g.2;
A.10.a.l.l.l.a.l; A.10.a.l.l.l.a.2; A.lO.a.l.l.l.b.l; A.10.a.l.l.l.b.2; A.lO.a.l.l.l.c.l;
A.lO.a.l.l.l.c.2; A.lO.a.l.l.l.d.l; A.10.a.l.l.l.d.2; A.lO.a.l.l.l.e.l; A.10.a.l.l.l.e.2; A.10.a.l.l.l.f.l; A.10.a.l.l.l.f.2; A.lO.a.l.l.l.g.l; A.10.a.l.l.l.g.2; A.10.a.2.a.l.a.l;
A.10.a.2.a.l.a.2; A.10.a.2.a.l.b.l; A.10.a.2.a.l.b.2; A.10.a.2.a.l.c.l;
A.10.a.2.a.l.c.2; A.10.a.2.a.l.d.l; A.10.a.2.a.l.d.2; A.10.a.2.a.l.e.l;
A.10.a.2.a.l.e.2; A.10.a.2.a.l.f.l; A.10.a.2.a.l.f.2; A.10.a.2.a.l.g.l; A.10.a.2.a.l.g.2;
A.10.a.2.b.l.a.l; A.10.a.2.b.l.a.2; A.10.a.2.b.l.b.l; A.10.a.2.b.l.b.2; A.10.a.2.b.l.c.l; A.10.a.2.b.l.c.2; A.10.a.2.b.l.d.l; A.10.a.2.b.l.d.2;
A.10.a.2.b.l.e.l; A.10.a.2.b.l.e.2; A.10.a.2.b.l.f.l; A.10.a.2.b.l.f.2; A.10.a.2.b.l.g.l;
A.10.a.2.b.l.g.2; A.10.a.2.f.l.a.l; A.10.a.2.f.l.a.2; A.10.a.2.f.l.b.l; A.10.a.2.f.l.b.2;
A.10.a.2.f.l.c.l; A.10.a.2.f.l.c.2; A.10.a.2.f.l.d.l; A.10.a.2.f.l.d.2; A.10.a.2.f.l.e.l;
A.10.a.2.f.l.e.2; A.10.a.2.f.l.f.l; A.10.a.2.f.l.f.2; A.10.a.2.f.l.g.l; A.10.a.2.f.l.g.2; A.10.a.2.h.l.a.l; A.10.a.2.h.l.a.2; A.10.a.2.h.l.b.l; A.10.a.2.h.l.b.2;
A.10.a.2.h.l.c.l; A.10.a.2.h.l.c.2; A.10.a.2.h.l.d.l; A.10.a.2.h.l.d.2;
A.10.a.2.h.l.e.l; A.10.a.2.h.l.e.2; A.10.a.2.h.l.f.l; A.10.a.2.h.l.f.2;
A.10.a.2.h.l.g.l; A.10.a.2.h.l.g.2; A.10.a.2.1.1.a.l; A.10.a.2.1.1.a.2;
A.10.a.2.1.1.b.l; A.10.a.2.1.1.b.2; A.10.a.2.1.1.c.l; A.10.a.2.1.1.c.2; A.10.a.2.1.1.d.l; A.10.a.2.1.1.d.2; A.10.a.2.1.1.e.l; A.10.a.2.1.1.e.2; A.10.a.2.1.1.f.l; A.10.a.2.1.1.f.2;
A.10.a.2.1.1.g.l; A.10.a.2.1.1.g.2; A.10.a.8.a.l.a.l; A.10.a.8.a.l.a.2; A.lO.a.δ.a.l.b.l;
A.10.a.δ.a.l.b.2; A.lO.a.δ.a.l.c.l; A.10.a.δ.a.l.c.2; A.lO.a.δ.a.l.d.l;
A.10.a.8.a.l.d.2; A.lO.a.δ.a.l.e.l; A.10.a.8.a.l.e.2; A.lO.a.δ.a.l.f.l;
A.10.a.δ.a.l.f.2; A.lO.a.δ.a.l.g.l; A.10.a.δ.a.l.g.2; A.lO.a.δ.b.l.a.l; A.10.a.8.b.l.a.2; A.10.a.8.b.l.b.l; A.10.a.8.b.l.b.2; A.10.a.8.b.l.c.l;
A.10.a.δ.b.l.c.2; A.lO.a.δ.b.l.d.l; A.10.a.δ.b.l.d.2; A.lO.a.δ.b.l.e.l;
A.10.a.δ.b.l.e.2; A.lO.a.δ.b.l.f.l; A.10.a.8.b.l.f.2; A.lO.a.δ.b.l.g.l; A.10.a.8.b.l.g.2;
A.10.a.8.f.l.a.l; A.10.a.δ.f.l.a.2; A.lO.a.δ.f.l.b.l; A.10.a.δ.f.l.b.2; A.10.a.8.f.l.c.l;
A.10.a.8.f.l.c.2; A.lO.a.δ.f.l.d.l; A.10.a.δ.f.l.d.2; A.10.a.8.f.l.e.l; A.10.a.8.f.l.e.2; A.10.a.δ.f.l.f.l; A.10.a.δ.f.l.f.2; A.lO.a.δ.f.l.g.l; A.10.a.δ.f.l.g.2; A.lO.a.δ.h.l.a.l;
A.10.a.δ.h.l.a.2; A.lO.a.δ.h.l.b.l; A.10.a.δ.h.l.b.2; A.lO.a.δ.h.l.c.l;
A.10.a.δ.h.l.c.2; A.lO.a.δ.h.l.d.l; A.10.a.δ.h.l.d.2; A.lO.a.δ.h.l.e.l;
A.10.a.δ.h.l.e.2; A.lO.a.δ.h.l.f.l; A.10.a.δ.h.l.f.2; A.10.a.δ.h.l.g.l;
A.10.a.δ.h.l.g.2; A.lO.a.δ.l.l.a.l; A.10.a.δ.l.l.a.2; A.lO.a.δ.l.l.b.l; A.10.a.δ.l.l.b.2; A.10.a.8.1.1.c.l; A.10.a.δ.l.l.c.2; A.lO.a.δ.l.l.d.l; A.10.a.δ.l.l.d.2; A.lO.a.δ.l.l.e.l;
A.10.a.δ.l.l.e.2; A.lO.a.δ.l.l.f.l; A.10.a.δ.l.l.f.2; A.lO.a.δ.l.l.g.l; A.10.a.8.1.1.g.2;
A.12.a.l.a.l.a.l; A.12.a.l.a.l.a.2; A.12.a.l.a.l.b.l; A.12.a.l.a.l.b.2;
A.12.a.l.a.l.c.l; A.12.a.l.a.l.c.2; A.12.a.l.a.l.d.l; A.12.a.l.a.l.d.2;
A.12.a.l.a.l.e.l; A.12.a.l.a.l.e.2; A.12.a.l.a.l.f.l; A.12.a.l.a.l.f.2; A.12.a.l.a.l.g.l; A.12.a.l.a.l.g.2; A.12.a.l.b.l.a.l; A.12.a.l.b.l.a.2; A.12.a.l.b.l.b.l;
A.12.a.l.b.l.b.2; A.12.a.l.b.l.c.l; A.12.a.l.b.l.c.2; A.12.a.l.b.l.d.l;
A.12.a.l.b.l.d.2; A.12.a.l.b.l.e.l; A.12.a.l.b.l.e.2; A.12.a.l.b.l.f.l;
A.12.a.l.b.l.f.2; A.12.a.l.b.l.g.l; A.12.a.l.b.l.g.2; A.12.a.l.f.l.a.l; A.12.a.l.f.l.a.2;
A.12.a.l.f.l.b.l; A.12.a.l.f.l.b.2; A.12.a.l.f.l.c.l; A.12.a.l.f.l.c.2; A.12.a.l.f.l.d.l; A.12.a.l.f.l.d.2; A.12.a.l.f.l.e.l; A.12.a.l.f.l.e.2; A.12.a.l.f.l.f.l; A.12.a.l.f.l.f.2;
A.12.a.l.f.l.g.l; A.12.a.l.f.l.g.2; A.12.a.l.h.l.a.l; A.12.a.l.h.l.a.2; A.12.a.l.h.l.b.l; A.12.a.l.h.l.b.2; A.12.a.l.h.l.c.l; A.12.a.l.h.l.c.2;
A.12.a.l.h.l.d.l; A.12.a.l.h.l.d.2; A.12.a.l.h.l.e.l; A.12.a.l.h.l.e.2;
A.12.a.l.h.l.f.l; A.12.a.l.h.l.f.2; A.12.a.l.h.l.g.l; A.12.a.l.h.l.g.2;
A.12.a.l.l.l.a.l; A.12.a.l.l.l.a.2; A.12.a.l.l.l.b.l; A.12.a.l.l.l.b.2; A.12.a.l.l.l.c.l; A.12.a.l.l.l.c.2; A.12.a.l.l.l.d.l; A.12.a.l.l.l.d.2; A.12.a.l.l.l.e.l; A.12.a.l.l.l.e.2;
A.12.a.l.l.l.f.l; A.12.a.l.l.l.f.2; A.12.a.l.l.l.g.l; A.12.a.l.l.l.g.2; A.12.a.2.a.l.a.l;
A.12.a.2.a.l.a.2; A.12.a.2.a.l.b.l; A.12.a.2.a.l.b.2; A.12.a.2.a.l.c.l;
A.12.a.2.a.l.c.2; A.12.a.2.a.l.d.l; A.12.a.2.a.l.d.2; A.12.a.2.a.l.e.l;
A.12.a.2.a.l.e.2; A.12.a.2.a.l.f.l; A.12.a.2.a.l.f.2; A.12.a.2.a.l.g.l; A.12.a.2.a.l.g.2; A.12.a.2.b.l.a.l; A.12.a.2.b.l.a.2; A.12.a.2.b.l.b.l; A.12.a.2.b.l.b.2;
A.12.a.2.b.l.c.l; A.12.a.2.b.l.c.2; A.12.a.2.b.l.d.l; A.12.a.2.b.l.d.2;
A.12.a.2.b.l.e.l; A.12.a.2.b.l.e.2; A.12.a.2.b.l.f.l; A.12.a.2.b.l.f.2; A.12.a.2.b.l.g.l;
A.12.a.2.b.l.g.2; A.12.a.2.f.l.a.l; A.12.a.2.f.l.a.2; A.12.a.2.f.l.b.l; A.12.a.2.f.l.b.2;
A.12.a.2.f.l.c.l; A.12.a.2.f.l.c.2; A.12.a.2.f.l.d.l; A.12.a.2.f.l.d.2; A.12.a.2.f.l.e.l; A.12.a.2.f.l.e.2; A.12.a.2.f.l.f.l; A.12.a.2.f.l.f.2; A.12.a.2.f.l.g.l; A.12.a.2.f.l.g.2;
A.12.a.2.h.l.a.l; A.12.a.2.h.l.a.2; A.12.a.2.h.l.b.l; A.12.a.2.h.l.b.2;
A.12.a.2.h.l.c.l; A.12.a.2.h.l.c.2; A.12.a.2.h.l.d.l; A.12.a.2.h.l.d.2;
A.12.a.2.h.l.e.l; A.12.a.2.h.l.e.2; A.12.a.2.h.l.f.l; A.12.a.2.h.l.f.2;
A.12.a.2.h.l.g.l; A.12.a.2.h.l.g.2; A.12.a.2.1.1.a.l; A.12.a.2.1.1.a.2; A.12.a.2.1.1.b.l; A.12.a.2.1.1.b.2; A.12.a.2.1.1.c.l; A.12.a.2.1.1.c.2; A.12.a.2.1.1.d.l;
A.12.a.2.1.1.d.2; A.12.a.2.1.1.e.l; A.12.a.2.1.1.e.2; A.12.a.2.1.1.f.l; A.12.a.2.1.1.f.2;
A.12.a.2.1.1.g.l; A.12.a.2.1.1.g.2; A.12.a.δ.a.l.a.l; A.12.a.δ.a.l.a.2; A.12.a.δ.a.l.b.l;
A.12.a.δ.a.l.b.2; A.12.a.δ.a.l.c.l; A.12.a.δ.a.l.c.2; A.12.a.δ.a.l.d.l;
A.12.a.δ.a.l.d.2; A.12.a.δ.a.l.e.l; A.12.a.8.a.l.e.2; A.12.a.8.a.l.f.l; A.12.a.δ.a.l.f.2; A.12.a.δ.a.l.g.l; A.12.a.δ.a.l.g.2; A.12.a.δ.b.l.a.l;
A.12.a.δ.b.l.a.2; A.12.a.δ.b.l.b.l; A.12.a.δ.b.l.b.2; A.12.a.δ.b.l.c.l;
A.12.a.δ.b.l.c.2; A.12.a.δ.b.l.d.l; A.12.a.δ.b.l.d.2; A.12.a.δ.b.l.e.l;
A.12.a.δ.b.l.e.2; A.12.a.δ.b.l.f.l; A.12.a.δ.b.l.f.2; A.12.a.δ.b.l.g.l; A.12.a.δ.b.l.g.2;
A.12.a.δ.f.l.a.l; A.12.a.δ.f.l.a.2; A.12.a.δ.f.l.b.l; A.12.a.δ.f.l.b.2; A.12.a.δ.f.l.c.l; A.12.a.δ.f.l.c.2; A.12.a.δ.f.l.d.l; A.12.a.δ.f.l.d.2; A.12.a.δ.f.l.e.l; A.12.a.δ.f.l.e.2;
A.12.a.8.f.l.f.l; A.12.a.δ.f.l.f.2; A.12.a.δ.f.l.g.l; A.12.a.δ.f.l.g.2; A.12.a.δ.h.l.a.l;
A.12.a.δ.h.l.a.2; A.12.a.8.h.l.b.l; A.12.a.δ.h.l.b.2; A.12.a.δ.h.l.c.l;
A.12.a.δ.h.l.c.2; A.12.a.8.h.l.d.l; A.12.a.8.h.l.d.2; A.12.a.8.h.l.e.l;
A.12.a.δ.h.l.e.2; A.12.a.δ.h.l.f.l; A.12.a.δ.h.l.f.2; A.12.a.8.h.l.g.l; A.12.a.8.h.l.g.2; A.12.a.δ.l.l.a.l; A.12.a.8.1.1.a.2; A.12.a.8.1.1.b.l; A.12.a.δ.l.l.b.2;
A.12.a.δ.l.l.c.l; A.12.a.δ.l.l.c.2; A.12.a.8.1.1.d.l; A.12.a.8.1.1.d.2; A.12.a.8.1.1.e.l;
A.12.a.δ.l.l.e.2; A.12.a.8.1.1.f.l; A.12.a.8.1.1.f.2; A.12.a.8.1.1.g.l; A.12.a.δ.l.l.g.2;
A.14.a.l.a.l.a.l; A.14.a.l.a.l.a.2; A.14.a.l.a.l.b.l; A.14.a.l.a.l.b.2;
A.14.a.l.a.l.c.l; A.14.a.l.a.l.c.2; A.14.a.l.a.l.d.l; A.14.a.l.a.l.d.2; A.14.a.l.a.l.e.l; A.14.a.l.a.l.e.2; A.14.a.l.a.l.f.l; A.14.a.l.a.l.f.2; A.14.a.l.a.l.g.l;
A.14.a.l.a.l.g.2; A.14.a.l.b.l.a.l; A.14.a.l.b.l.a.2; A.14.a.l.b.l.b.l;
A.14.a.l.b.l.b.2; A.14.a.l.b.l.c.l; A.14.a.l.b.l.c.2; A.14.a.l.b.l.d.l;
A.14.a.l.b.l.d.2; A.14.a.l.b.l.e.l; A.14.a.l.b.l.e.2; A.14.a.l.b.l.f.l;
A.14.a.l.b.l.f.2; A.14.a.l.b.l.g.l; A.14.a.l.b.l.g.2; A.14.a.l.f.l.a.l; A.14.a.l.f.l.a.2; A.14.a.l.f.l.b.l; A.14.a.l.f.l.b.2; A.14.a.l.f.l.c.l; A.14.a.l.f.l.c.2; A.14.a.l.f.l.d.l;
A.14.a.l.f.l.d.2; A.14.a.l.f.l.e.l; A.14.a.l.f.l.e.2; A.14.a.l.f.l.f.l; A.14.a.l.f.l.f.2; A.14.a.l.f.l.g.l; A.14.a.l.f.l.g.2; A.14.a.l.h.l.a.l; A.14.a.l.h.l.a.2;
A.14.a.l.h.l.b.l; A.14.a.l.h.l.b.2; A.14.a.l.h.l.c.l; A.14.a.l.h.l.c.2;
A.14.a.l.h.l.d.l; A.14.a.l.h.l.d.2; A.14.a.l.h.l.e.l; A.14.a.l.h.l.e.2;
A.14.a.l.h.l.f.l; A.14.a.l.h.l.f.2; A.14.a.l.h.l.g.l; A.14.a.l.h.l.g.2; A.14.a.l.l.l.a.l; A.14.a.l.l.l.a.2; A.14.a.l.l.l.b.l; A.14.a.l.l.l.b.2; A.14.a.l.l.l.c.l;
A.14.a.l.l.l.c.2; A.14.a.l.l.l.d.l; A.14.a.l.l.l.d.2; A.14.a.l.l.l.e.l; A.14.a.l.l.l.e.2;
A.14.a.l.l.l.f.l; A.14.a.l.l.l.f.2; A.14.a.l.l.l.g.l; A.14.a.l.l.l.g.2; A.14.a.2.a.l.a.l;
A.14.a.2.a.l.a.2; A.14.a.2.a.l.b.l; A.14.a.2.a.l.b.2; A.14.a.2.a.l.c.l;
A.14.a.2.a.l.c.2; A.14.a.2.a.l.d.l; A.14.a.2.a.l.d.2; A.14.a.2.a.l.e.l; A.14.a.2.a.l.e.2; A.14.a.2.a.l.f.l; A.14.a.2.a.l.f.2; A.14.a.2.a.l.g.l; A.14.a.2.a.l.g.2;
A.14.a.2.b.l.a.l; A.14.a.2.b.l.a.2; A.14.a.2.b.l.b.l; A.14.a.2.b.l.b.2;
A.14.a.2.b.l.c.l; A.14.a.2.b.l.c.2; A.14.a.2.b.l.d.l; A.14.a.2.b.l.d.2;
A.14.a.2.b.l.e.l; A.14.a.2.b.l.e.2; A.14.a.2.b.l.f.l; A.14.a.2.b.l.f.2; A.14.a.2.b.l.g.l;
A.14.a.2.b.l.g.2; A.14.a.2.f.l.a.l; A.14.a.2.f.l.a.2; A.14.a.2.f.l.b.l; A.14.a.2.f.l.b.2; A.14.a.2.f.l.c.l; A.14.a.2.f.l.c.2; A.14.a.2.f.l.d.l; A.14.a.2.f.l.d.2; A.14.a.2.f.l.e.l;
A.14.a.2.f.l.e.2; A.14.a.2.f.l.f.l; A.14.a.2.f.l.f.2; A.14.a.2.f.l.g.l; A.14.a.2.f.l.g.2;
A.14.a.2.h.l.a.l; A.14.a.2.h.l.a.2; A.14.a.2.h.l.b.l; A.14.a.2.h.l.b.2;
A.14.a.2.h.l.c.l; A.14.a.2.h.l.c.2; A.14.a.2.h.l.d.l; A.14.a.2.h.l.d.2;
A.14.a.2.h.l.e.l; A.14.a.2.h.l.e.2; A.14.a.2.h.l.f.l; A.14.a.2.h.l.f.2; A.14.a.2.h.l.g.l; A.14.a.2.h.l.g.2; A.14.a.2.1.1.a.l; A.14.a.2.1.1.a.2;
A.14.a.2.1.1.b.l; A.14.a.2.1.1.b.2; A.14.a.2.1.1.c.l; A.14.a.2.1.1.c.2; A.14.a.2.1.1.d.l;
A.14.a.2.1.1.d.2; A.14.a.2.1.1.e.l; A.14.a.2.1.1.e.2; A.14.a.2.1.1.f.l; A.14.a.2.1.1.f.2;
A.14.a.2.1.1.g.l; A.14.a.2.1.1.g.2; A.14.a.8.a.l.a.l; A.14.a.8.a.l.a.2; A.14.a.δ.a.l.b.l;
A.14.a.δ.a.l.b.2; A.14.a.δ.a.l.c.l; A.14.a.δ.a.l.c.2; A.14.a.δ.a.l.d.l; A.14.a.δ.a.l.d.2; A.14.a.δ.a.l.e.l; A.14.a.δ.a.l.e.2; A.14.a.δ.a.l.f.l;
A.14.a.δ.a.l.f.2; A.14.a.δ.a.l.g.l; A.14.a.δ.a.l.g.2; A.14.a.δ.b.l.a.l;
A.14.a.δ.b.l.a.2; A.14.a.δ.b.l.b.l; A.14.a.δ.b.l.b.2; A.14.a.δ.b.l.c.l;
A.14.a.δ.b.l.c.2; A.14.a.δ.b.l.d.l; A.14.a.δ.b.l.d.2; A.14.a.δ.b.l.e.l;
A.14.a.δ.b.l.e.2; A.14.a.δ.b.l.f.l; A.14.a.δ.b.l.f.2; A.14.a.δ.b.l.g.l; A.14.a.δ.b.l.g.2; A.14.a.δ.f.l.a.l; A.14.a.8.f.l.a.2; A.14.a.8.f.l.b.l; A.14.a.δ.f.l.b.2; A.14.a.δ.f.l.c.l;
A.14.a.δ.f.l.c.2; A.14.a.8.f.l.d.l; A.14.a.8.f.l.d.2; A.14.a.δ.f.l.e.l; A.14.a.δ.f.l.e.2;
A. .a.δ.f.l.f.l; A.14.a.δ.f.l.f.2; A.14.a.δ.f.l.g.l; A.14.a.δ.f.l.g.2; A.14.a.δ.h.l.a.l;
A.14.a.δ.h.l.a.2; A.14.a.δ.h.l.b.l; A.14.a.8.h.l.b.2; A.14.a.δ.h.l.c.l;
A.14.a.δ.h.l.c.2; A.14.a.δ.h.l.d.l; A.14.a.δ.h.l.d.2; A.14.a.δ.h.l.e.l; A.14.a.8.h.l.e.2; A.14.a.δ.h.l.f.l; A.14.a.δ.h.l.f.2; A.14.a.δ.h.l.g.l;
A.14.a.δ.h.l.g.2; A.14.a.δ.l.l.a.l; A.14.a.δ.l.l.a.2; A.14.a.δ.l.l.b.l; A.14.a.δ.l.l.b.2;
A.14.a.δ.l.l.c.l; A.14.a.δ.l.l.c.2; A.14.a.δ.l.l.d.l; A.14.a.δ.l.l.d.2; A.14.a.8.1.1.e.l;
A.14.a.8.1.1.e.2; A.14.a.8.1.1.f.l; A.14.a.8.1.1.f.2; A.14.a.δ.l.l.g.l; A.14.a.8.1.1.g.2;
A.15.a.l.a.l.a.l; A.15.a.l.a.l.a.2; A.15.a.l.a.l.b.l; A.15.a.l.a.l.b.2; A.15.a.l.a.l.c.l; A.15.a.l.a.l.c.2; A.15.a.l.a.l.d.l; A.15.a.l.a.l.d.2;
A.15.a.l.a.l.e.l; A.15.a.l.a.l.e.2; A.15.a.l.a.l.f.l; A.15.a.l.a.l.f.2; A.15.a.l.a.l.g.l;
A.15.a.l.a.l.g.2; A.15.a.l.b.l.a.l; A.15.a.l.b.l.a.2; A.15.a.l.b.l.b.l;
A.15.a.l.b.l.b.2; A.15.a.l.b.l.c.l; A.15.a.l.b.l.c.2; A.15.a.l.b.l.d.l;
A.15.a.l.b.l.d.2; A.15.a.l.b.l.e.l; A.15.a.l.b.l.e.2; A.15.a.l.b.l.f.l; A.15.a.l.b.l.f.2; A.15.a.l.b.l.g.l; A.15.a.l.b.l.g.2; A.15.a.l.f.l.a.l; A.15.a.l.f.l.a.2;
A.15.a.l.f.l.b.l; A.15.a.l.f.l.b.2; A.15.a.l.f.l.c.l; A.15.a.l.f.l.c.2; A.15.a.l.f.l.d.l; A.15.a.l.f.l.d.2; A.15.a.l.f.l.e.l; A.15.a.l.f.l.e.2; A.15.a.l.f.l.f.l; A.15.a.l.f.l.f.2;
A.15.a.l.f.l.g.l; A.15.a.l.f.l.g.2; A.15.a.l.h.l.a.l; A.15.a.l.h.l.a.2;
A.15.a.l.h.l.b.l; A.15.a.l.h.l.b.2; A.15.a.l.h.l.c.l; A.15.a.l.h.l.c.2;
A.15.a.l.h.l.d.l; A.15.a.l.h.l.d.2; A.15.a.l.h.l.e.l; A.15.a.l.h.l.e.2; A.15.a.l.h.l.f.l; A.15.a.l.h.l.f.2; A.15.a.l.h.l.g.l; A.15.a.l.h.l.g.2;
A.15.a.l.l.l.a.l; A.15.a.l.l.l.a.2; A.15.a.l.l.l.b.l; A.15.a.l.l.l.b.2; A.15.a.l.l.l.c.l;
A.15.a.l.l.l.c.2; A.15.a.l.l.l.d.l; A.15.a.l.l.l.d.2; A.15.a.l.l.l.e.l; A.15.a.l.l.l.e.2;
A.15.a.l.l.l.f.l; A.15.a.l.l.l.f.2; A.15.a.l.l.l.g.l; A.15.a.l.l.l.g.2; A.15.a.2.a.l.a.l;
A.15.a.2.a.l.a.2; A.15.a.2.a.l.b.l; A.15.a.2.a.l.b.2; A.15.a.2.a.l.c.l; A.15.a.2.a.l.c.2; A.15.a.2.a.l.d.l; A.15.a.2.a.l.d.2; A.15.a.2.a.l.e.l;
A.15.a.2.a.l.e.2; A.15.a.2.a.l.f.l; A.15.a.2.a.l.f.2; A.15.a.2.a.l.g.l; A.15.a.2.a.l.g.2;
A.15.a.2.b.l.a.l; A.15.a.2.b.l.a.2; A.15.a.2.b.l.b.l; A.15.a.2.b.l.b.2;
A.15.a.2.b.l.c.l; A.15.a.2.b.l.c.2; A.15.a.2.b.l.d.l; A.15.a.2.b.l.d.2;
A.15.a.2.b.l.e.l; A.15.a.2.b.l.e.2; A.15.a.2.b.l.f.l; A.15.a.2.b.l.f.2; A.15.a.2.b.l.g.l; A.15.a.2.b.l.g.2; A.15.a.2.f.l.a.l; A.15.a.2.f.l.a.2; A.15.a.2.f.l.b.l; A.15.a.2.f.l.b.2;
A.15.a.2.f.l.c.l; A.15.a.2.f.l.c.2; A.15.a.2.f.l.d.l; A.15.a.2.f.l.d.2; A.15.a.2.f.l.e.l;
A.15.a.2.f.l.e.2; A.15.a.2.f.l.f.l; A.15.a.2.f.l.f.2; A.15.a.2.f.l.g.l; A.15.a.2.f.l.g.2;
A.15.a.2.h.l.a.l; A.15.a.2.h.l.a.2; A.15.a.2.h.l.b.l; A.15.a.2.h.l.b.2;
A.15.a.2.h.l.c.l; A.15.a.2.h.l.c.2; A.15.a.2.h.l.d.l; A.15.a.2.h.l.d.2; A.15.a.2.h.l.e.l; A.15.a.2.h.l.e.2; A.15.a.2.h.l.f.l; A.15.a.2.h.l.f.2;
A.15.a.2.h.l.g.l; A.15.a.2.h.l.g.2; A.15.a.2.1.1.a.l; A.15.a.2.1.1.a.2;
A.15.a.2.1.1.b.l; A.15.a.2.1.1.b.2; A.15.a.2.1.1.c.l; A.15.a.2.1.1.c.2; A.15.a.2.1.1.d.l;
A.15.a.2.1.1.d.2; A.15.a.2.1.1.e.l; A.15.a.2.1.1.e.2; A.15.a.2.1.1.f.l; A.15.a.2.1.1.f.2;
A.15.a.2.1.1.g.l; A.15.a.2.1.1.g.2; A.15.a.8.a.l.a.l; A.15.a.δ.a.l.a.2; A.15.a.δ.a.l.b.l; A.15.a.δ.a.l.b.2; A.15.a.δ.a.l.c.l; A.15.a.δ.a.l.c.2; A.15.a.δ.a.l.d.l;
A.15.a.δ.a.l.d.2; A.15.a.δ.a.l.e.l; A.15.a.δ.a.l.e.2; A.15.a.δ.a.l.f.l;
A.15.a.δ.a.l.f.2; A.15.a.δ.a.l.g.l; A.15.a.8.a.l.g.2; A.15.a.8.b.l.a.l;
A.15.a.δ.b.l.a.2; A.15.a.δ.b.l.b.l; A.15.a.δ.b.l.b.2; A.15.a.δ.b.l.c.l;
A.15.a.δ.b.l.c.2; A.15.a.δ.b.l.d.l; A.15.a.δ.b.l.d.2; A.15.a.8.b.l.e.l; A.15.a.8.b.l.e.2; A.15.a.δ.b.l.f.l; A.15.a.δ.b.l.f.2; A.15.a.δ.b.l.g.l; A.15.a.8.b.l.g.2;
A.15.a.8.f.l.a.l; A.15.a.δ.f.l.a.2; A.15.a.δ.f.l.b.l; A.15.a.δ.f.l.b.2; A.15.a.δ.f.l.c.l;
A.15.a.δ.f.l.c.2; A.15.a.δ.f.l.d.l; A.15.a.δ.f.l.d.2; A.15.a.δ.f.l.e.l; A.15.a.δ.f.l.e.2;
A.15.a.δ.f.l.f.l; A.15.a.8.f.l.f.2; A.15.a.δ.f.l.g.l; A.15.a.δ.f.l.g.2; A.15.a.δ.h.l.a.l;
A.15.a.δ.h.l.a.2; A.15.a.δ.h.l.b.l; A.15.a.8.h.l.b.2; A.15.a.8.h.l.c.l; A.15.a.δ.h.l.c.2; A.15.a.δ.h.l.d.l; A.15.a.δ.h.l.d.2; A.15.a.δ.h.l.e.l;
A.15.a.δ.h.l.e.2; A.15.a.δ.h.l.f.l; A.15.a.8.h.l.f.2; A.15.a.δ.h.l.g.l;
A.15.a.δ.h.l.g.2; A.15.a.8.1.1.a.l; A.15.a.8.1.1.a.2; A.15.a.8.1.1.b.l; A.15.a.δ.l.l.b.2;
A.15.a.8.1.1.c.l; A.15.a.δ.l.l.c.2; A.15.a.8.1.1.d.l; A.15.a.8.1.1.d.2; A.15.a.8.1.1.e.l;
A.15.a.8.1.1.e.2; A.15.a.δ.l.l.f.l; A.15.a.δ.l.l.f.2; A.15.a.δ.l.l.g.l; A.15.a.δ.l.l.g.2; A.lό.a.l.a.l.a.l; A.16.a.l.a.l.a.2; A.lό.a.l.a.l.b.l; A.16.a.l.a.l.b.2;
A.lό.a.l.a.l.c.l; A.16.a.l.a.l.c.2; A.lό.a.l.a.l.d.l; A.16.a.l.a.l.d.2;
A.16.a.l.a.l.e.l; A.16.a.l.a.l.e.2; A.lO.a.l.a.l.f.l; A.16.a.l.a.l.f.2; A.lO.a.l.a.l.g.l;
A.16.a.l.a.l.g.2; A.lό.a.l.b.l.a.l; A.16.a.l.b.l.a.2; A.16.a.l.b.l.b.l;
A.16.a.l.b.l.b.2; A.lό.a.l.b.l.c.l; A.16.a.l.b.l.c.2; A.lό.a.l.b.l.d.l; A.16.a.l.b.l.d.2; A.lό.a.l.b.l.e.l; A.16.a.l.b.l.e.2; A.lό.a.l.b.l.f.l;
A.16.a.l.b.l.f.2; A.16.a.l.b.l.g.l; A.16.a.l.b.l.g.2; A.lO.a.l.f.l.a.l; A.16.a.l.f.l.a.2; A.lό.a.l.f.l.b.l; A.16.a.l.f.l.b.2; A.lO.a.l.f.l.c.l; A.16.a.l.f.l.c.2; A.lO.a.l.f.l.d.l;
A.16.a.l.f.l.d.2; A.lO.a.l.f.l.e.l; A.16.a.l.f.l.e.2; A.lO.a.l.f.l.f.l; A.16.a.l.f.l.f.2;
A.16.a.l.f.l.g.l; A.16.a.l.f.l.g.2; A.lό.a.l.h.l.a.l; A.16.a.l.h.l.a.2;
A.16.a.l.h.l.b.l; A.16.a.l.h.l.b.2; A.lό.a.l.h.l.c.l; A.16.a.l.h.l.c.2; A.16.a.l.h.l.d.l; A.16.a.l.h.l.d.2; A.lό.a.l.h.l.e.l; A.16.a.l.h.l.e.2;
A.16.a.l.h.l.f.l; A.16.a.l.h.l.f.2; A.lό.a.l.h.l.g.l; A.16.a.l.h.l.g.2;
A.16.a.l.l.l.a.l; A.16.a.l.l.l.a.2; A.lό.a.l.l.l.b.l; A.16.a.l.l.l.b.2; A.lό.a.l.l.l.c.l;
A.16.a.l.l.l.c.2; A.lό.a.l.l.l.d.l; A.16.a.l.l.l.d.2; A.lό.a.l.l.l.e.l; A.16.a.l.l.l.e.2;
A.16.a.l.l.l.f.l; A.16.a.l.l.l.f.2; A.lό.a.l.l.l.g.l; A.16.a.l.l.l.g.2; A.16.a.2.a.l.a.l; A.16.a.2.a.l.a.2; A.16.a.2.a.l.b.l; A.16.a.2.a.l.b.2; A.16.a.2.a.l.c.l;
A.16.a.2.a.l.c.2; A.16.a.2.a.l.d.l; A.16.a.2.a.l.d.2; A.16.a.2.a.l.e.l;
A.16.a.2.a.l.e.2; A.16.a.2.a.l.f.l; A.16.a.2.a.l.f.2; A.16.a.2.a.l.g.l; A.16.a.2.a.l.g.2;
A.16.a.2.b.l.a.l; A.16.a.2.b.l.a.2; A.16.a.2.b.l.b.l; A.16.a.2.b.l.b.2;
A.16.a.2.b.l.c.l; A.16.a.2.b.l.c.2; A.16.a.2.b.l.d.l; A.16.a.2.b.l.d.2; A.16.a.2.b.l.e.l; A.16.a.2.b.l.e.2; A.16.a.2.b.l.f.l; A.16.a.2.b.l.f.2; A.16.a.2.b.l.g.l;
A.16.a.2.b.l.g.2; A.16.a.2.f.l.a.l; A.16.a.2.f.l.a.2; A.16.a.2.f.l.b.l; A.16.a.2.f.l.b.2;
A.16.a.2.f.l.c.l; A.16.a.2.f.l.c.2; A.16.a.2.f.l.d.l; A.16.a.2.f.l.d.2; A.16.a.2.f.l.e.l;
A.16.a.2.f.l.e.2; A.16.a.2.f.l.f.l; A.16.a.2.f.l.f.2; A.16.a.2.f.l.g.l; A.16.a.2.f.l.g.2;
A.16.a.2.h.l.a.l; A.16.a.2.h.l.a.2; A.16.a.2.h.l.b.l; A.16.a.2.h.l.b.2; A.16.a.2.h.l.c.l; A.16.a.2.h.l.c.2; A.16.a.2.h.l.d.l; A.16.a.2.h.l.d.2;
A.16.a.2.h.l.e.l; A.16.a.2.h.l.e.2; A.16.a.2.h.l.f.l; A.16.a.2.h.l.f.2;
A.16.a.2.h.l.g.l; A.16.a.2.h.l.g.2; A.16.a.2.1.1.a.l; A.16.a.2.1.1.a.2;
A.16.a.2.1.1.b.l; A.16.a.2.1.1.b.2; A.16.a.2.1.1.c.l; A.16.a.2.1.1.c.2; A.16.a.2.1.1.d.l;
A.16.a.2.1.1.d.2; A.16.a.2.1.1.e.l; A.16.a.2.1.1.e.2; A.16.a.2.1.1.f.l; A.16.a.2.1.1.f.2; A.16.a.2.1.1.g.l; A.16.a.2.1.1.g.2; A.16.a.8.a.l.a.l; A.16.a.δ.a.l.a.2; A.lό.a.δ.a.l.b.l;
A.16.a.δ.a.l.b.2; A.lό.a.δ.a.l.c.l; A.16.a.δ.a.l.c.2; A.lό.a.δ.a.l.d.l;
A.16.a.8.a.l.d.2; A.lό.a.δ.a.l.e.l; A.16.a.δ.a.l.e.2; A.lό.a.δ.a.l.f.l;
A.16.a.δ.a.l.f.2; A.lό.a.δ.a.l.g.l; A.16.a.δ.a.l.g.2; A.lό.a.δ.b.l.a.l;
A.16.a.δ.b.l.a.2; A.lό.a.δ.b.l.b.l; A.16.a.δ.b.l.b.2; A.lό.a.δ.b.l.c.l; A.16.a.8.b.l.c.2; A.lό.a.δ.b.l.d.l; A.16.a.δ.b.l.d.2; A.lό.a.δ.b.l.e.l;
A.16.a.δ.b.l.e.2; A.lό.a.δ.b.l.f.l; A.16.a.δ.b.l.f.2; A.lό.a.δ.b.l.g.l; A.16.a.δ.b.l.g.2;
A.16.a.δ.f.l.a.l; A.16.a.δ.f.l.a.2; A.lό.a.δ.f.l.b.l; A.16.a.δ.f.l.b.2; A.lό.a.δ.f.l.c.l;
A.16.a.δ.f.l.c.2; A.lό.a.δ.f.l.d.l; A.16.a.δ.f.l.d.2; A.lό.a.δ.f.l.e.l; A.16.a.δ.f.l.e.2;
A.16.a.δ.f.l.f.l; A.16.a.δ.f.l.f.2; A.lό.a.δ.f.l.g.l; A.16.a.δ.f.l.g.2; A.lό.a.δ.h.l.a.l; A.16.a.8.h.l.a.2; A.16.a.8.h.l.b.l; A.16.a.8.h.l.b.2; A.lό.a.δ.h.l.c.l;
A.16.a.δ.h.l.c.2; A.16.a.δ.h.l.d.l; A.16.a.δ.h.l.d.2; A.lό.a.δ.h.l.e.l;
A.16.a.δ.h.l.e.2; A.16.a.8.h.l.f.l; A.16.a.δ.h.l.f.2; A.lό.a.δ.h.l.g.l;
A.16.a.δ.h.l.g.2; A.lό.a.δ.l.l.a.l; A.16.a.δ.l.l.a.2; A.16.a.8.1.1.b.l; A.16.a.δ.l.l.b.2;
A.lό.a.δ.l.l.c.l; A.16.a.δ.l.l.c.2; A.lό.a.δ.l.l.d.l; A.16.a.8.1.1.d.2; A.16.a.8.1.1.e.l; A.16.a.δ.l.l.e.2; A.lό.a.δ.l.l.f.l; A.16.a.δ.l.l.f.2; A.lό.a.δ.l.l.g.l; A.16.a.8.1.1.g.2;
A.17.a.l.a.l.a.l; A.17.a.l.a.l.a.2; A.17.a.l.a.l.b.l; A.17.a.l.a.l.b.2;
A.17.a.l.a.l.c.l; A.17.a.l.a.l.c.2; A.17.a.l.a.l.d.l; A.17.a.l.a.l.d.2;
A.17.a.l.a.l.e.l; A.17.a.l.a.l.e.2; A.17.a.l.a.l.f.l; A.17.a.l.a.l.f.2; A.17.a.l.a.l.g.l;
A.17.a.l.a.l.g.2; A.17.a.l.b.l.a.l; A.17.a.l.b.l.a.2; A.17.a.l.b.l.b.l; A.17.a.l.b.l.b.2; A.17.a.l.b.l.c.l; A.17.a.l.b.l.c.2; A.17.a.l.b.l.d.l;
A.17.a.l.b.l.d.2; A.17.a.l.b.l.e.l; A.17.a.l.b.l.e.2; A.17.a.l.b.l.f.l; A.17.a.l.b.l.f.2; A.17.a.l.b.l.g.l; A.17.a.l.b.l.g.2; A.17.a.l.f.l.a.l; A.17.a.l.f.l.a.2;
A.17.a.l.f.l.b.l; A.17.a.l.f.l.b.2; A.17.a.l.f.l.c.l; A.17.a.l.f.l.c.2; A.17.a.l.f.l.d.l;
A.17.a.l.f.l.d.2; A.17.a.l.f.l.e.l; A.17.a.l.f.l.e.2; A.17.a.l.f.l.f.l; A.17.a.l.f.l.f.2;
A.17.a.l.f.l.g.l; A.17.a.l.f.l.g.2; A.17.a.l.h.l.a.l; A.17.a.l.h.l.a.2; A.17.a.l.h.l.b.l; A.17.a.l.h.l.b.2; A.17.a.l.h.l.c.l; A.17.a.l.h.l.c.2;
A.17.a.l.h.l.d.l; A.17.a.l.h.l.d.2; A.17.a.l.h.l.e.l; A.17.a.l.h.l.e.2;
A.17.a.l.h.l.f.l; A.17.a.l.h.l.f.2; A.17.a.l.h.l.g.l; A.17.a.l.h.l.g.2;
A.17.a.l.l.l.a.l; A.17.a.l.l.l.a.2; A.17.a.l.l.l.b.l; A.17.a.l.l.l.b.2; A.17.a.l.l.l.c.l;
A.17.a.l.l.l.c.2; A.17.a.l.l.l.d.l; A.17.a.l.l.l.d.2; A.17.a.l.l.l.e.l; A.17.a.l.l.l.e.2; A.17.a.l.l.l.f.l; A.17.a.l.l.l.f.2; A.17.a.l.l.l.g.l; A.17.a.l.l.l.g.2; A.17.a.2.a.l.a.l;
A.17.a.2.a.l.a.2; A.17.a.2.a.l.b.l; A.17.a.2.a.l.b.2; A.17.a.2.a.l.c.l;
A.17.a.2.a.l.c.2; A.17.a.2.a.l.d.l; A.17.a.2.a.l.d.2; A.17.a.2.a.l.e.l;
A.17.a.2.a.l.e.2; A.17.a.2.a.l.f.l; A.17.a.2.a.l.f.2; A.17.a.2.a.l.g.l; A.17.a.2.a.l.g.2;
A.17.a.2.b.l.a.l; A.17.a.2.b.l.a.2; A.17.a.2.b.l.b.l; A.17.a.2.b.l.b.2; A.17.a.2.b.l.c.l; A.17.a.2.b.l.c.2; A.17.a.2.b.l.d.l; A.17.a.2.b.l.d.2;
A.17.a.2.b.l.e.l; A.17.a.2.b.l.e.2; A.17.a.2.b.l.f.l; A.17.a.2.b.l.f.2; A.17.a.2.b.l.g.l;
A.17.a.2.b.l.g.2; A.17.a.2.f.l.a.l; A.17.a.2.f.l.a.2; A.17.a.2.f.l.b.l; A.17.a.2.f.l.b.2;
A.17.a.2.f.l.c.l; A.17.a.2.f.l.c.2; A.17.a.2.f.l.d.l; A.17.a.2.f.l.d.2; A.17.a.2.f.l.e.l;
A.17.a.2.f.l.e.2; A.17.a.2.f.l.f.l; A.17.a.2.f.l.f.2; A.17.a.2.f.l.g.l; A.17.a.2.f.l.g.2; A.17.a.2.h.l.a.l; A.17.a.2.h.l.a.2; A.17.a.2.h.l.b.l; A.17.a.2.h.l.b.2;
A.17.a.2.h.l.c.l; A.17.a.2.h.l.c.2; A.17.a.2.h.l.d.l; A.17.a.2.h.l.d.2;
A.17.a.2.h.l.e.l; A.17.a.2.h.l.e.2; A.17.a.2.h.l.f.l; A.17.a.2.h.l.f.2;
A.17.a.2.h.l.g.l; A.17.a.2.h.l.g.2; A.17.a.2.1.1.a.l; A.17.a.2.1.1.a.2;
A.17.a.2.1.1.b.l; A.17.a.2.1.1.b.2; A.17.a.2.1.1.c.l; A.17.a.2.1.1.c.2; A.17.a.2.1.1.d.l; A.17.a.2.1.1.d.2; A.17.a.2.1.1.e.l; A.17.a.2.1.1.e.2; A.17.a.2.1.1.f.l; A.17.a.2.1.1.f.2;
A.17.a.2.1.1.g.l; A.17.a.2.1.1.g.2; A.17.a.8.a.l.a.l; A.17.a.8.a.l.a.2; A.17.a.δ.a.l.b.l;
A.17.a.δ.a.l.b.2; A.17.a.δ.a.l.c.l; A.17.a.8.a.l.c.2; A.17.a.8.a.l.d.l;
A.17.a.δ.a.l.d.2; A.17.a.δ.a.l.e.l; A.17.a.δ.a.l.e.2; A.17.a.δ.a.l.f.l;
A.17.a.δ.a.l.f.2; A.17.a.δ.a.l.g.l; A.17.a.δ.a.l.g.2; A.17.a.δ.b.l.a.l; A.17.a.δ.b.l.a.2; A.17.a.δ.b.l.b.l; A.17.a.δ.b.l.b.2; A.17.a.δ.b.l.c.l;
A.17.a.8.b.l.c.2; A.17.a.8.b.l.d.l; A.17.a.δ.b.l.d.2; A.17.a.δ.b.l.e.l;
A.17.a.δ.b.l.e.2; A.17.a.δ.b.l.f.l; A.17.a.δ.b.l.f.2; A.17.a.δ.b.l.g.l; A.17.a.δ.b.l.g.2;
A.17.a.δ.f.l.a.l; A.17.a.δ.f.l.a.2; A.17.a.δ.f.l.b.l; A.17.a.δ.f.l.b.2; A.17.a.δ.f.l.c.l;
A.17.a.δ.f.l.c.2; A.17.a.δ.f.l.d.l; A.17.a.δ.f.l.d.2; A.17.a.δ.f.l.e.l; A.17.a.δ.f.l.e.2; A.17.a.8.f.l.f.l; A.17.a.8.f.l.f.2; A.17.a.8.f.l.g.l; A.17.a.8.f.l.g.2; A.17.a.δ.h.l.a.l;
A.17.a.8.h.l.a.2; A.17.a.δ.h.l.b.l; A.17.a.δ.h.l.b.2; A.17.a.δ.h.l.c.l;
A.17.a.8.h.l.c.2; A.17.a.δ.h.l.d.l; A.17.a.δ.h.l.d.2; A.17.a.δ.h.l.e.l;
A.17.a.δ.h.l.e.2; A.17.a.δ.h.l.f.l; A.17.a.δ.h.l.f.2; A.17.a.δ.h.l.g.l;
A.17.a.8.h.l.g.2; A.17.a.8.1.1.a.l; A.17.a.δ.l.l.a.2; A.17.a.δ'.l.l.b.l; A.17.a.δ.l.l.b.2; A.17.a.δ.l.l.c.l; A.17.a.δ.l.l.c.2; A.17.a.δ.l.l.d.l; A.17.a.δ.l.l.d.2; A.17.a.δ.l.l.e.l;
A.17.a.δ.l.l.e.2; A.17.a.δ.l.l.f.l; A.17.a.8.1.1.f.2; A.17.a.δ.l.l.g.l; A.17.a.δ.l.l.g.2;
A.lδ.a.l.a.l.a.l; A.lδ.a.l.a.l.a.2; A.lδ.a.l.a.l.b.l; A.lδ.a.l.a.l.b.2;
A.lδ.a.l.a.l.c.l; A.lδ.a.l.a.l.c.2; A.lδ.a.l.a.l.d.l; A.lδ.a.l.a.l.d.2;
A.lδ.a.l.a.l.e.l; A.lδ.a.l.a.l.e.2; A.lδ.a.l.a.l.f.l; A.lδ.a.l.a.l.f.2; A.lδ.a.l.a.l.g.l; A.lδ.a.l.a.l.g.2; A.18.a.l.b.l.a.l; A.18.a.l.b.l.a.2; A.18.a.l.b.l.b.l;
A.18.a.l.b.l.b.2; A.lδ.a.l.b.l.c.l; A.lδ.a.l.b.l.c.2; A.18.a.l.b.l.d.l;
6δ- A.18.a.l.b.l.d.2; A.lδ.a.l.b.l.e.l; A.lδ.a.l.b.l.e.2; A.lδ.a.l.b.l.f.l;
A.18.a.l.b.l.f.2; A.18.a.l.b.l.g.l; A.lδ.a.l.b.l.g.2; A.lδ.a.l.f.l.a.l; A.lδ.a.l.f.l.a.2;
A.lδ.a.li.l.b.l; A.18.a.l.f.l.b.2; A.lδ.a.l.f.l.c.l; A.lδ.a.l.f.l.c.2; A.lδ.a.l.f.l.d.l;
A.lδ.a.l.f.l.d.2; A.lδ.a.l.f.l.e.l; A.lδ.a.l.f.l.e.2; A.lδ.a.l.f.l.f.l; A.lδ.a.l.f.l.f.2; A.18.a.l.f.l.g.l; A.18.a.l.f.l.g.2; A.lδ.a.l.h.l.a.l; A.lδ.a.l.h.l.a.2;
A.18.a.l.h.l.b.l; A.lδ.a.l.h.l.b.2; A.lδ.a.l.h.l.c.l; A.lδ.a.l.h.l.c.2;
A.18.a.l.h.l.d.l; A.18.a.l.h.l.d.2; A.lδ.a.l.h.l.e.l; A.lδ.a.l.h.l.e.2;
A.lδ.a.l.h.l.f.l; A.lδ.a.l.h.l.f.2; A.lδ.a.l.h.l.g.l; A.lδ.a.l.h.l.g.2;
A.18.a.l.l.l.a.l; A.18.a.l.l.l.a.2; A.lδ.a.l.l.l.b.l; A.lδ.a.l.l.l.b.2; A.lβ.a.l.l.l.c.l; A.lδ.a.l.l.l.c.2; A.lδ.a.l.l.l.d.l; A.lδ.a.l.l.l.d.2; A.lδ.a.l.l.l.e.l; A.lδ.a.l.l.l.e.2;
A.lδ.a.l.l.l.f.1; A.lδ.a.l.l.l.f.2; A.lδ.a.l.l.l.g.l; A.lδ.a.l.l.l.g.2; A.lδ.a.2.a.l.a.l;
A.lδ.a.2.a.l.a.2; A.lδ.a.2.a.l.b.l; A.lδ.a.2.a.l.b.2; A.18.a.2.a.l.c.l;
A.18.a.2.a.l.c.2; A.lδ.a.2.a.l.d.l; A.lδ.a.2.a.l.d.2; A.lδ.a.2.a.l.e.l;
A.lδ.a.2.a.l.e.2; A.lδ.a.2.a.l.f.l; A.lδ.a.2.a.l.f.2; A.lδ.a.2.a.l.g.l; A.lδ.a.2.a.l.g.2; A.lδ.a.2.b.l.a.l; A.lδ.a.2.b.l.a.2; A.lδ.a.2.b.l.b.l; A.lδ.a.2.b.l.b.2;
A.lδ.a.2.b.l.c.l; A.lδ.a.2.b.l.c.2; A.lδ.a.2.b.l.d.l; A.lδ.a.2.b.l.d.2;
A.lδ.a.2.b.l.e.l; A.lδ.a.2.b.l.e.2; A.lδ.a.2.b.l.f.l; A.lδ.a.2.b.l.f.2; A.lδ.a.2.b.l.g.l;
A.lδ.a.2.b.l.g.2; A.lδ.a.2.f.l.a.l; A.lδ.a.2.f.l.a.2; A.18.a.2.f.l.b.l; A.18.a.2.f.l.b.2;
A.lδ.a.2.f.l.c.l; A.lδ.a.2.f.l.c.2; A.lδ.a.2.f.l.d.l; A.lδ.a.2.f.l.d.2; A.lδ.a.2.f.l.e.l; A.lδ.a.2.f.l.e.2; A.lδ.a.2.f.l.f.l; A.lδ.a.2.f.l.f.2; A.18.a.2.f.l.g.l; A.lδ.a.2.f.l.g.2;
A.lδ.a.2.h.l.a.l; A.lδ.a.2.h.l.a.2; A.lδ.a.2.h.l.b.l; A.18.a.2.h.l.b.2;
A.18.a.2.h.l.c.l; A.lδ.a.2.h.l.c.2; A.18.a.2.h.l.d.l; A.18.a.2.h.l.d.2;
A.lδ.a.2.h.l.e.l; A.lδ.a.2.h.l.e.2; A.lδ.a.2.h.l.f.l; A.lδ.a.2.h.l.f.2;
A.18.a.2.h.l.g.l; A.lδ.a.2.h.l.g.2; A.lδ.a.2.1.1.a.l; A.lδ.a.2.1.1.a.2; A.lδ.a.2.1.1.b.l; A.18.a.2.1.1.b.2; A.18.a.2.1.1.c.l; A.lδ.a.2.1.1.c.2; A.18.a.2.1.1.d.l;
A.18.a.2.1.1.d.2; A.lδ.a.2.1.1.e.l; A.lδ.a.2.1.1.e.2; A.18.a.2.1.1.f.l; A.18.a.2.1.1.f.2;
A.lδ.a.2.1.1.g.l; A.lδ.a.2.1.1.g.2; A.lδ.a.δ.a.l.a.l; A.lδ.a.δ.a.l.a.2; A.lδ.a.δ.a.l.b.l;
A.lδ.a.δ.a.l.b.2; A.lδ.a.δ.a.l.c.l; A.lδ.a.δ.a.l.c.2; A.lδ.a.δ.a.l.d.l;
A.lδ.a.δ.a.l.d.2; A.lδ.a.δ.a.l.e.l; A.lδ.a.δ.a.l.e.2; A.18.a.8.a.l.f.l; A.18.a.δ.a.l.f.2; A.lδ.a.δ.a.l.g.l; A.lδ.a.δ.a.l.g.2; A.lδ.a.δ.b.l.a.l;
A.lδ.a.δ.b.l.a.2; A.lδ.a.δ.b.l.b.l; A.lδ.a.δ.b.l.b.2; A.18.a.8.b.l.c.l;
A.lδ.a.δ.b.l.c.2; A.lδ.a.δ.b.l.d.l; A.lδ.a.δ.b.l.d.2; A.18.a.8.b.l.e.l;
A.18.a.8.b.l.e.2; A.lδ.a.δ.b.l.f.l; A.lδ.a.δ.b.l.f.2; A.lδ.a.δ.b.l.g.l; A.lδ.a.δ.b.l.g.2;
A.lδ.a.δ.f.l.a.l; A.lδ.a.δ.f.l.a.2; A.lδ.a.δ.f.l.b.l; A.lδ.a.8.f.l.b.2; A.lδ.a.δ.f.l.c.l; A.lδ.a.δ.f.l.c.2; A.18.a.8.f.l.d.l; A.lδ.a.8.f.l.d.2; A.18.a.8.f.l.e.l; A.18.a.8.f.l.e.2;
A.18.a.δ.f.l.f.l; A.18.a.8.f.l.f.2; A.lδ.a.δ.f.l.g.l; A.18.a.8.f.l.g.2; A.lδ.a.8.h.l.a.l;
A.lδ.a.8.h.l.a.2; A.lδ.a.δ.h.l.b.l; A.lδ.a.δ.h.l.b.2; A.18.a.8.h.l.c.l;
A.lδ.a.8.h.l.c.2; A.lδ.a.δ.h.l.d.l; A.lδ.a.δ.h.l.d.2; A.18.a.8.h.l.e.l;
A.lδ.a.δ.h.l.e.2; A.lδ.a.δ.h.l.f.l; A.lδ.a.δ.h.l.f.2; A.lδ.a.δ.h.l.g.l; A.18.a.δ.h.l.g.2; A.lδ.a.δ.l.l.a.l; A.lδ.a.δ.l.l.a.2; A.18.a.8.1.1.b.l; A.18.a.δ.l.l.b.2;
A.lδ.a.δ.l.l.c.l; A.lδ.a.δ.l.l.c.2; A.lδ.a.δ.l.l.d.l; A.lδ.a.8.1.1.d.2; A.18.a.8.1.1.e.l;
A.lδ.a.δ.l.l.e.2; A.lδ.a.δ.l.l.f.l; A.lδ.a.8.1.1.f.2; A.18.a.8.1.1.g.l; A.lδ.a.δ.l.l.g.2;
A.19.a.l.a.l.a.l; A.19.a.l.a.l.a.2; A.19.a.l.a.l.b.l; A.19.a.l.a.l.b.2;
A.19.a.l.a.l.c.l; A.19.a.l.a.l.c.2; A.19.a.l.a.l.d.l; A.19.a.l.a.l.d.2; A.19.a.l.a.l.e.l; A.19.a.l.a.l.e.2; A.19.a.l.a.l.f.l; A.19.a.l.a.l.f.2; A.19.a.l.a.l.g.l;
A.19.a.l.a.l.g.2; A.19.a.l.b.l.a.l; A.19.a.l.b.l.a.2; A.19.a.l.b.l.b.l; A.19.a.l.b.l.b.2; A.19.a.l.b.l.c.l; A.19.a.l.b.l.c.2; A.19.a.l.b.l.d.l;
A.19.a.l.b.l.d.2; A.19.a.l.b.l.e.l; A.19.a.l.b.l.e.2; A.19.a.l.b.l.f.l;
A.19.a.l.b.l.f.2; A.19.a.l.b.l.g.l; A.19.a.l.b.l.g.2; A.19.a.l.f.l.a.l; A.19.a.l.f.l.a.2;
A.19.a.l.f.l.b.l; A.19.a.l.f.l.b.2; A.19.a.l.f.l.c.l; A.19.a.l.f.l.c.2; A.19.a.l.f.l.d.l; A.19.a.l.f.l.d.2; A.19.a.l.f.l.e.l; A.19.a.l.f.l.e.2; A.19.a.l.f.l.f.l; A.19.a.l.f.l.f.2;
A.19.a.l.f.l.g.l; A.19.a.l.f.l.g.2; A.19.a.l.h.l.a.l; A.19.a.l.h.l.a.2;
A.19.a.l.h.l.b.l; A.19.a.l.h.l.b.2; A.19.a.l.h.l.c.l; A.19.a.l.h.l.c.2;
A.19.a.l.h.l.d.l; A.19.a.l.h.l.d.2; A.19.a.l.h.l.e.l; A.19.a.l.h.l.e.2;
A.19.a.l.h.l.f.l; A.19.a.l.h.l.f.2; A.19.a.l.h.l.g.l; A.19.a.l.h.l.g.2; A.19.a.l.l.l.a.l; A.19.a.l.l.l.a.2; A.19.a.l.l.l.b.l; A.19.a.l.l.l.b.2; A.19.a.l.l.l.c.l;
A.19.a.l.l.l.c.2; A.19.a.l.l.l.d.l; A.19.a.l.l.l.d.2; A.19.a.l.l.l.e.l; A.19.a.l.l.l.e.2;
A.19.a.l.l.l.f.l; A.19.a.l.l.l.f.2; A.19.a.l.l.l.g.l; A.19.a.l.l.l.g.2; A.19.a.2.a.l.a.l;
A.19.a.2.a.l.a.2; A.19.a.2.a.l.b.l; A.19.a.2.a.l.b.2; A.19.a.2.a.l.c.l;
A.19.a.2.a.l.c.2; A.19.a.2.a.l.d.l; A.19.a.2.a.l.d.2; A.19.a.2.a.l.e.l; A.19.a.2.a.l.e.2; A.19.a.2.a.l.f.l; A.19.a.2.a.l.f.2; A.19.a.2.a.l.g.l; A.19.a.2.a.l.g.2;
A.19.a.2.b.l.a.l; A.19.a.2.b.l.a.2; A.19.a.2.b.l.b.l; A.19.a.2.b.l.b.2;
A.19.a.2.b.l.c.l; A.19.a.2.b.l.c.2; A.19.a.2.b.l.d.l; A.19.a.2.b.l.d.2;
A.19.a.2.b.l.e.l; A.19.a.2.b.l.e.2; A.19.a.2.b.l.f.l; A.19.a.2.b.l.f.2; A.19.a.2.b.l.g.l;
A.19.a.2.b.l.g.2; A.19.a.2.f.l.a.l; A.19.a.2.f.l.a.2; A.19.a.2.f.l.b.l; A.19.a.2.f.l.b.2; A.19.a.2.f.l.c.l; A.19.a.2.f.l.c.2; A.19.a.2.f.l.d.l; A.19.a.2.f.l.d.2; A.19.a.2.f.l.e.l;
A.19.a.2.f.l.e.2; A.19.a.2.f.l.f.l; A.19.a.2.f.l.f.2; A.19.a.2.f.l.g.l; A.19.a.2.f.l.g.2;
A.19.a.2.h.l.a.l; A.19.a.2.h.l.a.2; A.19.a.2.h.l.b.l; A.19.a.2.h.l.b.2;
A.19.a.2.h.l.c.l; A.19.a.2.h.l.c.2; A.19.a.2.h.l.d.l; A.19.a.2.h.l.d.2;
A.19.a.2.h.l.e.l; A.19.a.2.h.l.e.2; A.19.a.2.h.l.f.l; A.19.a.2.h.l.f.2; A.19.a.2.h.l.g.l; A.19.a.2.h.l.g.2; A.19.a.2.1.1.a.l; A.19.a.2.1.1.a.2;
A.19.a.2.1.1.b.l; A.19.a.2.1.1.b.2; A.19.a.2.1.1.c.l; A.19.a.2.1.1.c.2; A.19.a.2.1.1.d.l;
A.19.a.2.1.1.d.2; A.19.a.2.1.1.e.l; A.19.a.2.1.1.e.2; A.19.a.2.1.1.f.l; A.19.a.2.1.1.f.2;
A.19.a.2.1.1.g.l; A.19.a.2.1.1.g.2; A.19.a.δ.a.l.a.l; A.19.a.δ.a.l.a.2; A.19.a.δ.a.l.b.l;
A.19.a.δ.a.l.b.2; A.19.a.δ.a.l.c.l; A.19.a.δ.a.l.c.2; A.19.a.8.a.l.d.l; A.19.a.8.a.l.d.2; A.19.a.δ.a.l.e.l; A.19.a.δ.a.l.e.2; A.19.a.δ.a.l.f.l;
A.19.a.δ.a.l.f.2; A.19.a.δ.a.l.g.l; A.19.a.δ.a.l.g.2; A.19.a.δ.b.l.a.l;
A.19.a.δ.b.l.a.2; A.19.a.δ.b.l.b.l; A.19.a.δ.b.l.b.2; A.19.a.δ.b.l.c.l;
A.19.a.δ.b.l.c.2; A.19.a.δ.b.l.d.l; A.19.a.δ.b.l.d.2; A.19.a.δ.b.l.e.l;
A.19.a.δ.b.l.e.2; A.19.a.δ.b.l.f.l; A.19.a.δ.b.l.f.2; A.19.a.δ.b.l.g.l; A.19.a.δ.b.l.g.2; A.19.a.δ.f.l.a.l; A.19.a.δ.f.l.a.2; A.19.a.δ.f.l.b.l; A.19.a.δ.f.l.b.2; A.19.a.δ.f.l.c.l;
A.19.a.δ.f.l.c.2; A.19.a.δ.f.l.d.l; A.19.a.δ.f.l.d.2; A.19.a.δ.f.l.e.l; A.19.a.δ.f.l.e.2;
A.19.a.δ.f.l.f.l; A.19.a.δ.f.l.f.2; A.19.a.δ.f.l.g.l; A.19.a.δ.f.l.g.2; A.19.a.δ.h.l.a.l;
A.19.a.δ.h.l.a.2; A.19.a.δ.h.l.b.l; A.19.a.δ.h.l.b.2; A.19.a.δ.h.l.c.l;
A.19.a.8.h.l.c.2; A.19.a.8.h.l.d.l; A.19.a.δ.h.l.d.2; A.19.a.δ.h.l.e.l; A.19.a.δ.h.l.e.2; A.19.a.δ.h.l.f.l; A.19.a.δ.h.l.f.2; A.19.a.δ.h.l.g.l;
A.19.a.δ.h.l.g.2; A.19.a.δ.l.l.a.l; A.19.a.δ.l.l.a.2; A.19.a.δ.l.l.b.l; A.19.a.δ.l.l.b.2;
A.19.a.8.1.1.c.l; A.19.a.δ.l.l.c.2; A.19.a.δ.l.l.d.l; A.19.a.δ.l.l.d.2; A.19.a.δ.l.l.e.l;
A.19.a.δ.l.l.e.2; A.19.a.δ.l.l.f.l; A.19.a.δ.l.l.f.2; A.19.a.δ.l.l.g.l; A.19.a.δ.l.l.g.2;
A.20.a.l.a.l.a.l; A.20.a.l.a.l.a.2; A.20.a.l.a.l.b.l; A.20.a.l.a.l.b.2; A.20.a.l.a.l.c.l; A.20.a.l.a.l.c.2; A.20.a.l.a.l.d.l; A.20.a.l.a.l.d.2;
A.20.a.l.a.l.e.l; A.20.a.l.a.l.e.2; A.20.a.l.a.l.f.l; A.20.a.l.a.l.f.2; A.20.a.l.a.l.g.l; A.20.a.l.a.l.g.2; A.20.a.l.b.l.a.l; A.20.a.l.b.l.a.2; A.20.a.l.b.l.b.l;
A.20.a.l.b.l.b.2; A.20.a.l.b.l.c.l; A.20.a.l.b.l.c.2; A.20.a.l.b.l.d.l;
A.20.a.l.b.l.d.2; A.20.a.l.b.l.e.l; A.20.a.l.b.l.e.2; A.20.a.l.b.l.f.l;
A.20.a.l.b.l.f.2; A.20.a.l.b.l.g.l; A.20.a.l.b.l.g.2; A.20.a.l.f.l.a.l; A.20.a.l.f.l.a.2; A.20.a.l.f.l.b.l; A.20.a.l.f.l.b.2; A.20.a.l.f.l.c.l; A.20.a.l.f.l.c.2; A.20.a.l.f.l.d.l;
A.20.a.l.f.l.d.2; A.20.a.l.f.l.e.l; A.20.a.l.f.l.e.2; A.20.a.l.f.l.f.l; A.20.a.l.f.l.f.2;
A.20.a.l.f.l.g.l; A.20.a.l.f.l.g.2; A.20.a.l.h.l.a.l; A.20.a.l.h.l.a.2;
A.20.a.l.h.l.b.l; A.20.a.l.h.l.b.2; A.20.a.l.h.l.c.l; A.20.a.l.h.l.c.2;
A.20.a.l.h.l.d.l; A.20.a.l.h.l.d.2; A.20.a.l.h.l.e.l; A.20.a.l.h.l.e.2; A.20.a.l.h.l.f.l; A.20.a.l.h.l.f.2; A.20.a.l.h.l.g.l; A.20.a.l.h.l.g.2;
A.20.a.l.l.l.a.l; A.20.a.l.l.l.a.2; A.20.a.l.l.l.b.l; A.20.a.l.l.l.b.2; A.20.a.l.l.l.c.l;
A.20.a.l.l.l.c.2; A.20.a.l.l.l.d.l; A.20.a.l.l.l.d.2; A.20.a.l.l.l.e.l; A.20.a.l.l.l.e.2;
A.20.a.l.l.l.f.l; A.20.a.l.l.l.f.2; A.20.a.l.l.l.g.l; A.20.a.l.l.l.g.2; A.20.a.2.a.l.a.l;
A.20.a.2.a.l.a.2; A.20.a.2.a.l.b.l; A.20.a.2.a.l.b.2; A.20.a.2.a.l.c.l; A.20.a.2.a.l.c.2; A.20.a.2.a.l.d.l; A.20.a.2.a.l.d.2; A.20.a.2.a.l.e.l;
A.20.a.2.a.l.e.2; A.20.a.2.a.l.f.l; A.20.a.2.a.l.f.2; A.20.a.2.a.l.g.l; A.20.a.2.a.l.g.2;
A.20.a.2.b.l.a.l; A.20.a.2.b.l.a.2; A.20.a.2.b.l.b.l; A.20.a.2.b.l.b.2;
A.20.a.2.b.l.c.l; A.20.a.2.b.l.c.2; A.20.a.2.b.l.d.l; A.20.a.2.b.l.d.2;
A.20.a.2.b.l.e.l; A.20.a.2.b.l.e.2; A.20.a.2.b.l.f.l; A.20.a.2.b.l.f.2; A.20.a.2.b.l.g.l; A.20.a.2.b.l.g.2; A.20.a.2.f.l.a.l; A.20.a.2.f.l.a.2; A.20.a.2.f.l.b.l; A.20.a.2.f.l.b.2;
A.20.a.2.f.l.c.l; A.20.a.2.f.l.c.2; A.20.a.2.f.l.d.l; A.20.a.2.f.l.d.2; A.20.a.2.f.l.e.l;
A.20.a.2.f.l.e.2; A.20.a.2.f.l.f.l; A.20.a.2.f.l.f.2; A.20.a.2.f.l.g.l; A.20.a.2.f.l.g.2;
A.20.a.2.h.l.a.l; A.20.a.2.h.l.a.2; A.20.a.2.h.l.b.l; A.20.a.2.h.l.b.2;
A.20.a.2.h.l.c.l; A.20.a.2.h.l.c.2; A.20.a.2.h.l.d.l; A.20.a.2.h.l.d.2; A.20.a.2.h.l.e.l; A.20.a.2.h.l.e.2; A.20.a.2.h.l.f.l; A.20.a.2.h.l.f.2;
A.20.a.2.h.l.g.l; A.20.a.2.h.l.g.2; A.20.a.2.1.1.a.l; A.20.a.2.1.1.a.2;
A.20.a.2.1.1.b.l; A.20.a.2.1.1.b.2; A.20.a.2.1.1.c.l; A.20.a.2.1.1.c.2; A.20.a.2.1.1.d.l;
A.20.a.2.1.1.d.2; A.20.a.2.1.1.e.l; A.20.a.2.1.1.e.2; A.20.a.2.1.1.f.l; A.20.a.2.1.1.f.2;
A.20.a.2.1.1.g.l; A.20.a.2.1.1.g.2; A.20.a.δ.a.l.a.l; A.20.a.δ.a.l.a.2; A.20.a.δ.a.l.b.l; A.20.a.8.a.l.b.2; A.20.a.8.a.l.c.l; A.20.a.δ.a.l.c.2; A.20.a.δ.a.l.d.l;
A.20.a.δ.a.l.d.2; A.20.a.δ.a.l.e.l; A.20.a.δ.a.l.e.2; A.20.a.δ.a.l.f.l;
A.20.a.δ.a.l.f.2; A.20.a.8.a.l.g.l; A.20.a.8.a.l.g.2; A.20.a.δ.b.l.a.l;
A.20.a.δ.b.l.a.2; A.20.a.8.b.l.b.l; A.20.a.δ.b.l.b.2; A.20.a.δ.b.l.c.l;
A.20.a.δ.b.l.c.2; A.20.a.8.b.l.d.l; A.20.a.δ.b.l.d.2; A.20.a.8.b.l.e.l; A.20.a.δ.b.l.e.2; A.20.a.8.b.l.f.l; A.20.a.δ.b.l.f.2; A.20.a.δ.b.l.g.l; A.20.a.δ.b.l.g.2;
A.20.a.δ.f.l.a.l; A.20.a.δ.f.l.a.2; A.20.a.δ.f.l.b.l; A.20.a.δ.f.l.b.2; A.20.a.8.f.l.c.l;
A.20.a.δ.f.l.c.2; A.20.a.δ.f.l.d.l; A.20.a.δ.f.l.d.2; A.20.a.8.f.l.e.l; A.20.a.8.f.l.e.2;
A.20.a.δ.f.l.f.l; A.20.a.δ.f.l.f.2; A.20.a.δ.f.l.g.l; A.20.a.δ.f.l.g.2; A.20.a.δ.h.l.a.l;
A.20.a.δ.h.l.a.2; A.20.a.δ.h.l.b.l; A.20.a.δ.h.l.b.2; A.20.a.δ.h.l.c.l; A.20.a.δ.h.l.c.2; A.20.a.δ.h.l.d.l; A.20.a.δ.h.l.d.2; A.20.a.δ.h.l.e.l;
A.20.a.δ.h.l.e.2; A.20.a.δ.h.l.f.l; A.20.a.δ.h.l.f.2; A.20.a.δ.h.l.g.l;
A.20.a.δ.h.l.g.2; A.20.a.δ.l.l.a.l; A.20.a.δ.l.l.a.2; A.20.a.δ.l.l.b.l; A.20.a.δ.l.l.b.2;
A.20.a.8.1.1.c.l; A.20.a.8.1.1.c.2; A.20.a.δ.l.l.d.l; A.20.a.δ.l.l.d.2; A.20.a.δ.l.l.e.l;
A.20.a.δ.l.l.e.2; A.20.a.δ.l.l.f.l; A.20.a.δ.l.l.f.2; A.20.a.δ.l.l.g.l; A.20.a.δ.l.l.g.2; A.21.a.l.a.l.a.l; A.21.a.l.a.l.a.2; A.21.a.l.a.l.b.l; A.21.a.l.a.l.b.2;
A.21.a.l.a.l.c.l; A.21.a.l.a.l.c.2; A.21.a.l.a.l.d.l; A.21.a.l.a.l.d.2; A.21.a.l.a.l.e.l; A.21.a.l.a.l.e.2; A.21.a.l.a.l.f.l; A.21.a.l.a.l.f.2; A.21.a.l.a.l.g.l;
A.21.a.l.a.l.g.2; A.21.a.l.b.l.a.l; A.21.a.l.b.l.a.2; A.21.a.l.b.l.b.l;
A.21.a.l.b.l.b.2; A.21.a.l.b.l.c.l; A.21.a.l.b.l.c.2; A.21.a.l.b.l.d.l;
A.21.a.l.b.l.d.2; A.21.a.l.b.l.e.l; A.21.a.l.b.l.e.2; A.21.a.l.b.l.f.l; A.21.a.l.b.l.f.2; A.21.a.l.b.l.g.l; A.21.a.l.b.l.g.2; A.21.a.l.f.l.a.l; A.21.a.l.f.l.a.2;
A.21.a.l.f.l.b.l; A.21.a.l.f.l.b.2; A.21.a.l.f.l.c.l; A.21.a.l.f.l.c.2; A.21.a.l.f.l.d.l;
A.21.a.l.f.l.d.2; A.21.a.l.f.l.e.l; A.21.a.l.f.l.e.2; A.21.a.l.f.l.f.l; A.21.a.l.f.l.f.2;
A.21.a.l.f.l.g.l; A.21.a.l.f.l.g.2; A.21.a.l.h.l.a.l; A.21.a.l.h.l.a.2;
A.21.a.l.h.l.b.l; A.21.a.l.h.l.b.2; A.21.a.l.h.l.c.l; A.21.a.l.h.l.c.2; A.21.a.l.h.l.d.l; A.21.a.l.h.l.d.2; A.21.a.l.h.l.e.l; A.21.a.l.h.l.e.2;
A.21.a.l.h.l.f.l; A.21.a.l.h.l.f.2; A.21.a.l.h.l.g.l; A.21.a.l.h.l.g.2;
A.21.a.l.l.l.a.l; A.21.a.l.l.l.a.2; A.21.a.l.l.l.b.l; A.21.a.l.l.l.b.2; A.21.a.l.l.l.c.l;
A.21.a.l.l.l.c.2; A.21.a.l.l.l.d.l; A.21.a.l.l.l.d.2; A.21.a.l.l.l.e.l; A.21.a.l.l.l.e.2;
A.21.a.l.l.l.f.l; A.21.a.l.l.l.f.2; A.21.a.l.l.l.g.l; A.21.a.l.l.l.g.2; A.21.a.2.a.l.a.l; A.21.a.2.a.l.a.2; A.21.a.2.a.l.b.l; A.21.a.2.a.l.b.2; A.21.a.2.a.l.c.l;
A.21.a.2.a.l.c.2; A.21.a.2.a.l.d.l; A.21.a.2.a.l.d.2; A.21.a.2.a.l.e.l;
A.21.a.2.a.l.e.2; A.21.a.2.a.l.f.l; A.21.a.2.a.l.f.2; A.21.a.2.a.l.g.l; A.21.a.2.a.l.g.2;
A.21.a.2.b.l.a.l; A.21.a.2.b.l.a.2; A.21.a.2.b.l.b.l; A.21.a.2.b.l.b.2;
A.21.a.2.b.l.c.l; A.21.a.2.b.l.c.2; A.21.a.2.b.l.d.l; A.21.a.2.b.l.d.2; A.21.a.2.b.l.e.l; A.21.a.2.b.l.e.2; A.21.a.2.b.l.f.l; A.21.a.2.b.l.f.2; A.21.a.2.b.l.g.l;
A.21.a.2.b.l.g.2; A.21.a.2.f.l.a.l; A.21.a.2.f.l.a.2; A.21.a.2.f.l.b.l; A.21.a.2.f.l.b.2;
A.21.a.2.f.l.c.l; A.21.a.2.f.l.c.2; A.21.a.2.f.l.d.l; A.21.a.2.f.l.d.2; A.21.a.2.f.l.e.l;
A.21.a.2.f.l.e.2; A.21.a.2.f.l.f.l; A.21.a.2.f.l.f.2; A.21.a.2.f.l.g.l; A.21.a.2.f.l.g.2;
A.21.a.2.h.l.a.l; A.21.a.2.h.l.a.2; A.21.a.2.h.l.b.l; A.21.a.2.h.l.b.2; A.21.a.2.h.l.c.l; A.21.a.2.h.l.c.2; A.21.a.2.h.l.d.l; A.21.a.2.h.l.d.2;
A.21.a.2.h.l.e.l; A.21.a.2.h.l.e.2; A.21.a.2.h.l.f.l; A.21.a.2.h.l.f.2;
A.21.a.2.h.l.g.l; A.21.a.2.h.l.g.2; A.21.a.2.1.1.a.l; A.21.a.2.1.1.a.2;
A.21.a.2.1.1.b.l; A.21.a.2.1.1.b.2; A.21.a.2.1.1.c.l; A.21.a.2.1.1.c.2; A.21.a.2.1.1.d.l;
A.21.a.2.1.1.d.2; A.21.a.2.1.1.e.l; A.21.a.2.1.1.e.2; A.21.a.2.1.1.f.l; A.21.a.2.1.1.f.2; A.21.a.2.1.1.g.l; A.21.a.2.1.1.g.2; A.21.a.8.a.l.a.l; A.21.a.8.a.l.a.2; A.21.a.δ.a.l.b.l;
A.21.a.δ.a.l.b.2; A.21.a.δ.a.l.c.l; A.21.a.δ.a.l.c.2; A.21.a.δ.a.l.d.l;
A.21.a.δ.a.l.d.2; A.21.a.δ.a.l.e.l; A.21.a.δ.a.l.e.2; A.21.a.δ.a.l.f.l;
A.21.a.δ.a.l.f.2; A.21.a.δ.a.l.g.l; A.21.a.δ.a.l.g.2; A.21.a.δ.b.l.a.l;
A.21.a.δ.b.l.a.2; A.21.a.δ.b.l.b.l; A.21.a.δ.b.l.b.2; A.21.a.δ.b.l.c.l; A.21.a.8.b.l.c.2; A.21.a.8.b.l.d.l; A.21.a.δ.b.l.d.2; A.21.a.δ.b.l.e.l;
A.21.a.δ.b.l.e.2; A.21.a.δ.b.l.f.l; A.21.a.δ.b.l.f.2; A.21.a.δ.b.l.g.l; A.21.a.δ.b.l.g.2;
A.21.a.δ.f.l.a.l; A.21.a.δ.f.l.a.2; A.21.a.δ.f.l.b.l; A.21.a.δ.f.l.b.2; A.21.a.δ.f.l.c.l;
A.21.a.δ.f.l.c.2; A.21.a.8.f.l.d.l; A.21.a.δ.f.l.d.2; A.21.a.δ.f.l.e.l; A.21.a.δ.f.l.e.2;
A.21.a.δ.f.l.f.l; A.21.a.δ.f.l.f.2; A.21.a.δ.f.l.g.l; A.21.a.δ.f.l.g.2; A.21.a.δ.h.l.a.l; A.21.a.8.h.l.a.2; A.21.a.8.h.l.b.l; A.21.a.8.h.l.b.2; A.21.a.δ.h.l.c.l;
A.21.a.δ.h.l.c.2; A.21.a.δ.h.l.d.l; A.21.a.δ.h.l.d.2; A.21.a.δ.h.l.e.l;
A.21.a.δ.h.l.e.2; A.21.a.δ.h.l.f.l; A.21.a.δ.h.l.f.2; A.21.a.δ.h.l.g.l;
A.21.a.δ.h.l.g.2; A.21.a.δ.l.l.a.l; A.21.a.δ.l.l.a.2; A.21.a.8.1.1.b.l; A.21.a.8.1.1.b.2;
A.21.a.8.1.1.c.l; A.21.a.δ.l.l.c.2; A.21.a.δ.l.l.d.l; A.21.a.δ.l.l.d.2; A.21.a.8.1.1.e.l; A.21.a.δ.l.l.e.2; A.21.a.δ.l.l.f.l; A.21.a.8.1.1.f.2; A.21.a.8.1.1.g.l; A.21.a.δ.l.l.g.2;
A.22.a.l.a.l.a.l; A.22.a.l.a.l.a.2; A.22.a.l.a.l.b.l; A.22.a.l.a.l.b.2; A.22.a.l.a.l.c.l; A.22.a.l.a.l.c.2; A.22.a.l.a.l.d.l; A.22.a.l.a.l.d.2;
A.22.a.l.a.l.e.l; A.22.a.l.a.l.e.2; A.22.a.l.a.l.f.l; A.22.a.l.a.l.f.2; A.22.a.l.a.l.g.l;
A.22.a.l.a.l.g.2; A.22.a.l.b.l.a.l; A.22.a.l.b.l.a.2; A.22.a.l.b.l.b.l;
A.22.a.l.b.l.b.2; A.22.a.l.b.l.c.l; A.22.a.l.b.l.c.2; A.22.a.l.b.l.d.l; A.22.a.l.b.l.d.2; A.22.a.l.b.l.e.l; A.22.a.l.b.l.e.2; A.22.a.l.b.l.f.l;
A.22.a.l.b.l.f.2; A.22.a.l.b.l.g.l; A.22.a.l.b.l.g.2; A.22.a.l.f.l.a.l; A.22.a.l.f.l.a.2;
A.22.a.l.f.l.b.l; A.22.a.l.f.l.b.2; A.22.a.l.f.l.c.l; A.22.a.l.f.l.c.2; A.22.a.l.f.l.d.l;
A.22.a.l.f.l.d.2; A.22.a.l.f.l.e.l; A.22.a.l.f.l.e.2; A.22.a.l.f.l.f.l; A.22.a.l.f.l.f.2;
A.22.a.l.f.l.g.l; A.22.a.l.f.l.g.2; A.22.a.l.h.l.a.l; A.22.a.l.h.l.a.2; A.22.a.l.h.l.b.l; A.22.a.l.h.l.b.2; A.22.a.l.h.l.c.l; A.22.a.l.h.l.c.2;
A.22.a.l.h.l.d.l; A.22.a.l.h.l.d.2; A.22.a.l.h.l.e.l; A.22.a.l.h.l.e.2;
A.22.a.l.h.l.f.l; A.22.a.l.h.l.f.2; A.22.a.l.h.l.g.l; A.22.a.l.h.l.g.2;
A.22.a.l.l.l.a.l; A.22.a.l.l.l.a.2; A.22.a.l.l.l.b.l; A.22.a.l.l.l.b.2; A.22.a.l.l.l.c.l;
A.22.a.l.l.l.c.2; A.22.a.l.l.l.d.l; A.22.a.l.l.l.d.2; A.22.a.l.l.l.e.l; A.22.a.l.l.l.e.2; A.22.a.l.l.l.f.l; A.22.a.l.l.l.f.2; A.22.a.l.l.l.g.l; A.22.a.l.l.l.g.2; A.22.a.2.a.l.a.l;
A.22.a.2.a.l.a.2; A.22.a.2.a.l.b.l; A.22.a.2.a.l.b.2; A.22.a.2.a.l.c.l;
A.22.a.2.a.l.c.2; A.22.a.2.a.l.d.l; A.22.a.2.a.l.d.2; A.22.a.2.a.l.e.l;
A.22.a.2.a.l.e.2; A.22.a.2.a.l.f.l; A.22.a.2.a.l.f.2; A.22.a.2.a.l.g.l; A.22.a.2.a.l.g.2;
A.22.a.2.b.l.a.l; A.22.a.2.b.l.a.2; A.22.a.2.b.l.b.l; A.22.a.2.b.l.b.2; A.22.a.2.b.l.c.l; A.22.a.2.b.l.c.2; A.22.a.2.b.l.d.l; A.22.a.2.b.l.d.2;
A.22.a.2.b.l.e.l; A.22.a.2.b.l.e.2; A.22.a.2.b.l.f.l; A.22.a.2.b.l.f.2; A.22.a.2.b.l.g.l;
A.22.a.2.b.l.g.2; A.22.a.2.f.l.a.l; A.22.a.2.f.l.a.2; A.22.a.2.f.l.b.l; A.22.a.2.f.l.b.2;
A.22.a.2.f.l.c.l; A.22.a.2.f.l.c.2; A.22.a.2.f.l.d.l; A.22.a.2.f.l.d.2; A.22.a.2.f.l.e.l;
A.22.a.2.f.l.e.2; A.22.a.2.f.l.f.l; A.22.a.2.f.l.f.2; A.22.a.2.f.l.g.l; A.22.a.2.f.l.g.2; A.22.a.2.h.l.a.l; A.22.a.2.h.l.a.2; A.22.a.2.h.l.b.l; A.22.a.2.h.l.b.2;
A.22.a.2.h.l.c.l; A.22.a.2.h.l.c.2; A.22.a.2.h.l.d.l; A.22.a.2.h.l.d.2;
A.22.a.2.h.l.e.l; A.22.a.2.h.l.e.2; A.22.a.2.h.l.f.l; A.22.a.2.h.l.f.2;
A.22.a.2.h.l.g.l; A.22.a.2.h.l.g.2; A.22.a.2.1.1.a.l; A.22.a.2.1.1.a.2;
A.22.a.2.1.1.b.l; A.22.a.2.1.1.b.2; A.22.a.2.1.1.c.l; A.22.a.2.1.1.c.2; A.22.a.2.1.1.d.l; A.22.a.2.1.1.d.2; A.22.a.2.1.1.e.l; A.22.a.2.1.1.e.2; A.22.a.2.1.1.f.l; A.22.a.2.1.1.f.2;
A.22.a.2.1.1.g.l; A.22.a.2.1.1.g.2; A.22.a.δ.a.l.a.l; A.22.a.δ.a.l.a.2; A.22.a.δ.a.l.b.l;
A.22.a.δ.a.l.b.2; A.22.a.δ.a.l.c.l; A.22.a.δ.a.l.c.2; A.22.a.δ.a.l.d.l;
A.22.a.δ.a.l.d.2; A.22.a.δ.a.l.e.l; A.22.a.δ.a.l.e.2; A.22.a.8.a.l.f.l;
A.22.a.δ.a.l.f.2; A.22.a.δ.a.l.g.l; A.22.a.δ.a.l.g.2; A.22.a.8.b.l.a.l; A.22.a.8.b.l.a.2; A.22.a.δ.b.l.b.l; A.22.a.δ.b.l.b.2; A.22.a.8.b.l.c.l;
A.22.a.8.b.l.c.2; A.22.a.δ.b.l.d.l; A.22.a.δ.b.l.d.2; A.22.a.δ.b.l.e.l;
A.22.a.δ.b.l.e.2; A.22.a.δ.b.l.f.l; A.22.a.δ.b.l.f.2; A.22.a.8.b.l.g.l; A.22.a.8.b.l.g.2;
A.22.a.δ.f.l.a.l; A.22.a.δ.f.l.a.2; A.22.a.δ.f.l.b.l; A.22.a.δ.f.l.b.2; A.22.a.δ.f.l.c.l;
A.22.a.δ.f.l.c.2; A.22.a.δ.f.l.d.l; A.22.a.δ.f.l.d.2; A.22.a.δ.f.l.e.l; A.22.a.δ.f.l.e.2; A.22.a.δ.f.l.f.l; A.22.a.δ.f.l.f.2; A.22.a.δ.f.l.g.l; A.22.a.δ.f.l.g.2; A.22.a.δ.h.l.a.l;
A.22.a.8.h.l.a.2; A.22.a.δ.h.l.b.l; A.22.a.δ.h.l.b.2; A.22.a.8.h.l.c.l;
A.22.a.8.h.l.c.2; A.22.a.δ.h.l.d.l; A.22.a.δ.h.l.d.2; A.22.a.δ.h.l.e.l;
A.22.a.δ.h.l.e.2; A.22.a.δ.h.l.f.l; A.22.a.δ.h.l.f.2; A.22.a.δ.h.l.g.l;
A.22.a.δ.h.l.g.2; A.22.a.8.1.1.a.l; A.22.a.8.1.1.a.2; A.22.a.δ.l.l.b.l; A.22.a.δ.l.l.b.2; A.22.a.δ.l.l.c.l; A.22.a.δ.l.l.c.2; A.22.a.δ.l.l.d.l; A.22.a.δ.l.l.d.2; A.22.a.δ.l.l.e.l;
A.22.a.8.1.1.e.2; A.22.a.8.1.1.f.l; A.22.a.δ.l.l.f.2; A.22.a.δ.l.l.g.l; A.22.a.δ.l.l.g.2; B.l.a.l.a.l.a.l; B.l.a.l.a.l.a.2; B.l.a.l.a.l.b.l; B.l.a.l.a.l.b.2; B.l.a.l.a.l.c.l;
B.l.a.l.a.l.c.2; B.l.a.l.a.l.d.l; B.l.a.l.a.l.d.2; B.l.a.l.a.l.e.l; B.l.a.l.a.l.e.2;
B.l.a.l.a.li.l; B.l.a.l.a.l.f.2; B.l.a.l.a.l.g.l; B.l.a.l.a.l.g.2; B.l.a.l.b.l.a.l;
B.l.a.l.b.l.a.2; B.l.a.l.b.l.b.l; B.l.a.l.b.l.b.2; B.l.a.l.b.l.c.l; B.l.a.l.b.l.c.2; B.l.a.l.b.l.d.l; B.l.a.l.b.l.d.2; B.l.a.l.b.l.e.l; B.l.a.l.b.l.e.2; B.l.a.l.b.l.f.l;
B.l.a.l.b.l.f.2; B.l.a.l.b.l.g.l; B.l.a.l.b.l.g.2; B.l.a.l.f.l.a.l; B.l.a.l.f.l.a.2;
B.l.a.l.f.l.b.l; B.l.a.l.f.l.b.2; B.l.a.l.f.l.c.l; B.l.a.l.f.l.c.2; B.l.a.l.f.l.d.l;
B.l.a.l.f.l.d.2; B.l.a.l.f.l.e.l; B.l.a.l.f.l.e.2; B.l.a.l.f.l.f.l; B.l.a.l.f.l.f.2;
B.l.a.l.f.l.g.l; B.l.a.l.f.l.g.2; B.l.a.l.h.l.a.l; B.l.a.l.h.l.a.2; B.l.a.l.h.l.b.l; B.l.a.l.h.l.b.2; B.l.a.l.h.l.c.l; B.l.a.l.h.l.c.2; B.l.a.l.h.l.d.l; B.l.a.l.h.l.d.2;
B.l.a.l.h.l.e.1; B.l.a.l.h.l.e.2; B.l.a.l.h.l.f.1; B.l.a.l.h.l.f.2; B.l.a.l.h.l.g.l;
B.l.a.l.h.l.g.2; B.l.a.l.l.l.a.l; B.l.a.l.l.l.a.2; B.l.a.l.l.l.b.l; B.l.a.l.l.l.b.2;
B.l.a.l.l.l.c.l; B.l.a.l.l.l.c.2; B.l.a.l.l.l.d.l; B.l.a.l.l.l.d.2; B.l.a.l.l.l.e.l;
B.l.a.l.l.l.e.2; B.l.a.l.l.l.f.l; B.l.a.l.l.l.f.2; B.l.a.l.l.l.g.l; B.l.a.l.l.l.g.2; B.l.a.2.a.l.a.l; B.l.a.2.a.l.a.2; B.l.a.2.a.l.b.l; B.l.a.2.a.l.b.2; B.l.a.2.a.l.c.l;
B.l.a.2.a.l.c.2; B.l.a.2.a.l.d.l; B.l.a.2.a.l.d.2; B.l.a.2.a.l.e.l; B.l.a.2.a.l.e.2;
B.l.a.2.a.l.f.l; B.l.a.2.a.l.f.2; B.l.a.2.a.l.g.l; B.l.a.2.a.l.g.2; B.l.a.2.b.l.a.l;
B.l.a.2.b.l.a.2; B.l.a.2.b.l.b.l; B.l.a.2.b.l.b.2; B.l.a.2.b.l.c.l; B.l.a.2.b.l.c.2;
B.l.a.2.b.l.d.l; B.l.a.2.b.l.d.2; B.l.a.2.b.l.e.l; B.l.a.2.b.l.e.2; B.l.a.2.b.l.f.l; B.l.a.2.b.l.f.2; B.l.a.2.b.l.g.l; B.l.a.2.b.l.g.2; B.l.a.2.f.l.a.l; B.l.a.2.f.l.a.2;
B.l.a.2.f.l.b.l; B.l.a.2.f.l.b.2; B.l.a.2.f.l.c.l; B.l.a.2.f.l.c.2; B.l.a.2.f.l.d.l;
B.l.a.2.f.l.d.2; B.l.a.2.f.l.e.l; B.l.a.2.f.l.e.2; B.l.a.2.f.l.f.l; B.l.a.2.f.l.f.2;
B.l.a.2.f.l.g.l; B.l.a.2.f.l.g.2; B.l.a.2.h.l.a.l; B.l.a.2.h.l.a.2; B.l.a.2.h.l.b.l;
B.l.a.2.h.l.b.2; B.l.a.2.h.l.c.l; B.l.a.2.h.l.c.2; B.l.a.2.h.l.d.l; B.l.a.2.h.l.d.2; B.l.a.2.h.l.e.l; B.l.a.2.h.l.e.2; B.l.a.2.h.l.f.l; B.l.a.2.h.l.f.2; B.l.a.2.h.l.g.l;
B.l.a.2.h.l.g.2; B.l.a.2.1.1.a.l; B.l.a.2.1.1.a.2; B.l.a.2.1.1.b.l; B.l.a.2.1.1.b.2;
B.l.a.2.1.1.c.l; B.l.a.2.1.1.c.2; B.l.a.2.1.1.d.l; B.l.a.2.1.1.d.2; B.l.a.2.1.1.e.l;
B.l.a.2.1.1.e.2; B.l.a.2.1.1.f.l; B.l.a.2.1.1.f.2; B.l.a.2.1.1.g.l; B.l.a.2.1.1.g.2;
B.l.a.8.a.l.a.l; B.l.a.δ.a.l.a.2; B.l.a.δ.a.l.b.l; B.l.a.δ.a.l.b.2; B.l.a.δ.a.l.c.l; B.l.a.δ.a.l.c.2; B.l.a.δ.a.l.d.l; B.l.a.δ.a.l.d.2; B.l.a.δ.a.l.e.l; B.l.a.δ.a.l.e.2;
B.l.a.δ.a.l.f.l; B.l.a.δ.a.l.f.2; B.l.a.δ.a.l.g.l; B.l.a.δ.a.l.g.2; B.l.a.δ.b.l.a.l;
B.l.a.8.b.l.a.2; B.l.a.δ.b.l.b.l; B.l.a.δ.b.l.b.2; B.l.a.δ.b.l.c.l; B.l.a.8.b.l.c.2;
B.l.a.δ.b.l.d.l; B.l.a.δ.b.l.d.2; B.l.a.δ.b.l.e.l; B.l.a.δ.b.l.e.2; B.l.a.δ.b.l.f.l;
B.l.a.δ.b.l.f.2; B.l.a.δ.b.l.g.l; B.l.a.δ.b.l.g.2; B.l.a.δ.f.l.a.l; B.l.a.8.f.l.a.2; B.l.a.δ.f.l.b.l; B.l.a.δ.f.l.b.2; B.l.a.δ.f.l.c.l; B.l.a.δ.f.l.c.2; B.l.a.δ.f.l.d.l;
B.l.a.δ.f.l.d.2; B.l.a.δ.f.l.e.l; B.l.a.δ.f.l.e.2; B.l.a.δ.f.l.f.l; B.l.a.δ.f.l.f.2;
B.l.a.δ.f.l.g.l; B.l.a.δ.f.l.g.2; B.l.a.δ.h.l.a.1; B.l.a.δ.h.l.a.2; B.l.a.δ.h.l.b.l;
B.l.a.δ.h.l.b.2; B.l.a.δ.h.l.c.l; B.l.a.8.h.l.c.2; B.l.a.δ.h.l.d.l; B.l.a.δ.h.l.d.2;
B.l.a.δ.h.l.e.l; B.l.a.δ.h.l.e.2; B.l.a.δ.h.l.f.l; B.l.a.8.h.l.f.2; B.l.a.8.h.l.g.l; B.l.a.δ.h.l.g.2; B.l.a.δ.l.l.a.l; B.l.a.δ.l.l.a.2; B.l.a.δ.l.l.b.l; B.l.a.8.1.1.b.2;
B.l.a.δ.l.l.c.l; B.l.a.δ.l.l.c.2; B.l.a.δ.l.l.d.l; B.l.a.δ.l.l.d.2; B.l.a.δ.l.l.e.l;
B.l.a.8.1.1.e.2; B.l.a.δ.l.l.f.l; B.l.a.δ.l.l.f.2; B.l.a.δ.l.l.g.l; B.l.a.8.1.1.g.2;
B.2.a.l.a.l.a.l; B.2.a.l.a.l.a.2; B.2.a.l.a.l.b.l; B.2.a.l.a.l.b.2; B.2.a.l.a.l.c.l;
B.2.a.l.a.l.c.2; B.2.a.l.a.l.d.l; B.2.a.l.a.l.d.2; B.2.a.l.a.l.e.l; B.2.a.l.a.l.e.2; B.2.a.l.a.l.f.l; B.2.a.l.a.l.f.2; B.2.a.l.a.l.g.l; B.2.a.l.a.l.g.2; B.2.a.l.b.l.a.l;
B.2.a.l.b.l.a.2; B.2.a.l.b.l.b.l; B.2.a.l.b.l.b.2; B.2.a.l.b.l.c.l; B.2.a.l.b.l.c.2; B.2.a.l.b.l.d.l; B.2.a.l.b.l.d.2; B.2.a.l.b.l.e.l; B.2.a.l.b.l.e.2; B.2.a.l.b.l.f.l;
B.2.a.l.b.l.f.2; B.2.a.l.b.l.g.l; B.2.a.l.b.l.g.2; B.2.a.l.f.l.a.l; B.2.a.l.f.l.a.2;
B.2.a.l.f.l.b.l; B.2.a.l.f.l.b.2; B.2.a.l.f.l.c.l; B.2.a.l.f.l.c.2; B.2.a.l.f.l.d.l;
B.2.a.l.f.l.d.2; B.2.a.l.f.l.e.l; B.2.a.l.f.l.e.2; B.2.a.l.f.l.f.l; B.2.a.l.f.l.f.2; B.2.a.l.f.l.g.l; B.2.a.l.f.l.g.2; B.2.a.l.h.l.a.l; B.2.a.l.h.l.a.2; B.2.a.l.h.l.b.l;
B.2.a.l.h.l.b.2; B.2.a.l.h.l.c.l; B.2.a.l.h.l.c.2; B.2.a.l.h.l.d.l; B.2.a.l.h.l.d.2;
B.2.a.l.h.l.e.l; B.2.a.l.h.l.e.2; B.2.a.l.h.l.f.l; B.2.a.l.h.l.f.2; B.2.a.l.h.l.g.l;
B.2.a.l.h.l.g.2; B.2.a.l.l.l.a.l; B.2.a.l.l.l.a.2; B.2.a.l.l.l.b.l; B.2.a.l.l.l.b.2;
B.2.a.l.l.l.c.l; B.2.a.l.l.l.c.2; B.2.a.l.l.l.d.l; B.2.a.l.l.l.d.2; B.2.a.l.l.l.e.l; B.2.a.l.l.l.e.2; B.2.a.l.l.l.f.l; B.2.a.l.l.l.f.2; B.2.a.l.l.l.g.l; B.2.a.l.l.l.g.2;
B.2.a.2.a.l.a.l; B.2.a.2.a.l.a.2; B.2.a.2.a.l.b.l; B.2.a.2.a.l.b.2; B.2.a.2.a.l.c.l;
B.2.a.2.a.l.c.2; B.2.a.2.a.l.d.l; B.2.a.2.a.l.d.2; B.2.a.2.a.l.e.l; B.2.a.2.a.l.e.2;
B.2.a.2.a.l.f.l; B.2.a.2.a.l.f.2; B.2.a.2.a.l.g.l; B.2.a.2.a.l.g.2; B.2.a.2.b.l.a.l;
B.2.a.2.b.l.a.2; B.2.a.2.b.l.b.l; B.2.a.2.b.l.b.2; B.2.a.2.b.l.c.l; B.2.a.2.b.l.c.2; B.2.a.2.b.l.d.l; B.2.a.2.b.l.d.2; B.2.a.2.b.l.e.l; B.2.a.2.b.l.e.2; B.2.a.2.b.l.f.l;
B.2.a.2.b.l.f.2; B.2.a.2.b.l.g.l; B.2.a.2.b.l.g.2; B.2.a.2.f.l.a.l; B.2.a.2.f.l.a.2;
B.2.a.2.f.l.b.l; B.2.a.2.f.l.b.2; B.2.a.2.f.l.c.l; B.2.a.2.f.l.c.2; B.2.a.2.f.l.d.l;
B.2.a.2.f.l.d.2; B.2.a.2.f.l.e.l; B.2.a.2.f.l.e.2; B.2.a.2.f.l.f.l; B.2.a.2.f.l.f.2;
B.2.a.2.f.l.g.l; B.2.a.2.f.l.g.2; B.2.a.2.h.l.a.l; B.2.a.2.h.l.a.2; B.2.a.2.h.l.b.l; B.2.a.2.h.l.b.2; B.2.a.2.h.l.c.l; B.2.a.2.h.l.c.2; B.2.a.2.h.l.d.l; B.2.a.2.h.l.d.2;
B.2.a.2.h.l.e.l; B.2.a.2.h.l.e.2; B.2.a.2.h.l.f.l; B.2.a.2.h.l.f.2; B.2.a.2.h.l.g.l;
B.2.a.2.h.l.g.2; B.2.a.2.1.1.a.l; B.2.a.2.1.1.a.2; B.2.a.2.1.1.b.l; B.2.a.2.1.1.b.2;
B.2.a.2.1.1.c.l; B.2.a.2.1.1.c.2; B.2.a.2.1.1.d.l; B.2.a.2.1.1.d.2; B.2.a.2.1.1.e.l;
B.2.a.2.1.1.e.2; B.2.a.2.1.1.f.l; B.2.a.2.1.1.f.2; B.2.a.2.1.1.g.l; B.2.a.2.1.1.g.2; B.2.a.δ.a.l.a.l; B.2.a.δ.a.l.a.2; B.2.a.δ.a.l.b.l; B.2.a.δ.a.l.b.2; B.2.a.8.a.l.c.l;
B.2.a.δ.a.l.c.2; B.2.a.δ.a.l.d.l; B.2.a.δ.a.l.d.2; B.2.a.δ.a.l.e.l; B.2.a.δ.a.l.e.2;
B.2.a.δ.a.l.f.l; B.2.a.δ.a.l.f.2; B.2.a.δ.a.l.g.l; B.2.a.δ.a.l.g.2; B.2.a.δ.b.l.a.l;
B.2.a.δ.b.l.a.2; B.2.a.δ.b.l.b.l; B.2.a.δ.b.l.b.2; B.2.a.δ.b.l.c.l; B.2.a.δ.b.l.c.2;
B.2.a.δ.b.l.d.l; B.2.a.δ.b.l.d.2; B.2.a.δ.b.l.e.l; B.2.a.δ.b.l.e.2; B.2.a.δ.b.l.f.l; B.2.a.δ.b.l.f.2; B.2.a.δ.b.l.g.l; B.2.a.8.b.l.g.2; B.2.a.8.f.l.a.l; B.2.a.8.f.l.a.2;
B.2.a.δ.f.l.b.l; B.2.a.δ.f.l.b.2; B.2.a.δ.f.l.c.l; B.2.a.δ.f.l.c.2; B.2.a.δ.f.l.d.l;
B.2.a.δ.f.l.d.2; B.2.a.δ.f.l.e.l; B.2.a.δ.f.l.e.2; B.2.a.δ.f.l.f.l; B.2.a.δ.f.l.f.2;
B.2.a.8.f.l.g.l; B.2.a.8.f.l.g.2; B.2.a.8.h.l.a.l; B.2.a.δ.h.l.a.2; B.2.a.δ.h.l.b.l;
B.2.a.δ.h.l.b.2; B.2.a.δ.h.l.c.l; B.2.a.δ.h.l.c.2; B.2.a.δ.h.l.d.l; B.2.a.δ.h.l.d.2; B.2.a.δ.h.l.e.l; B.2.a.δ.h.l.e.2; B.2.a.δ.h.l.f.l; B.2.a.δ.h.l.f.2; B.2.a.δ.h.l.g.l;
B.2.a.δ.h.l.g.2; B.2.a.δ.l.l.a.l; B.2.a.δ.l.l.a.2; B.2.a.δ.l.l.b.l; B.2.a.δ.l.l.b.2;
B.2.a.δ.l.l.c.l; B.2.a.δ.l.l.c.2; B.2.a.8.1.1.d.l; B.2.a.δ.l.l.d.2; B.2.a.8.1.1.e.l;
B.2.a.δ.l.l.e.2; B.2.a.δ.l.l.f.l; B.2.a.δ.l.l.f.2; B.2.a.δ.l.l.g.l; B.2.a.8.1.1.g.2;
B.δ.a.l.a.l.a.l; B.δ.a.l.a.l.a.2; B.δ.a.l.a.l.b.l; B.δ.a.l.a.l.b.2; B.δ.a.l.a.l.c.l; B.8.a.l.a.l.c.2; B.δ.a.l.a.l.d.l; B.δ.a.l.a.l.d.2; B.δ.a.l.a.l.e.l; B.δ.a.l.a.l.e.2;
B.δ.a.l.a.l.f.1; B.δ.a.l.a.l.f.2; B.δ.a.l.a.l.g.l; B.δ.a.l.a.l.g.2; B.δ.a.l.b.l.a.l;
B.δ.a.l.b.l.a.2; B.δ.a.l.b.l.b.l; B.δ.a.l.b.l.b.2; B.δ.a.l.b.l.c.l; B.δ.a.l.b.l.c.2;
B.δ.a.l.b.l.d.l; B.8.a.l.b.l.d.2; B.β.a.l.b.l.e.l; B.8.a.l.b.l.e.2; B.δ.a.l.b.l.f.l;
B.δ.a.l.b.l.f.2; B.δ.a.l.b.l.g.l; B.δ.a.l.b.l.g.2; B.δ.a.l.f.l.a.l; B.δ.a.l.f.l.a.2; B.δ.a.l.f.l.b.l; B.δ.a.li.l.b.2; B.δ.a.l.f.l.c.l; B.δ.a.l.f.l.c.2; B.δ.a.l.f.l.d.l;
B.δ.a.l.f.l.d.2; B.δ.a.l.f.l.e.l; B.δ.a.l.f.l.e.2; B.δ.a.l.f.l.f.l; B.δ.a.l.f.l.f.2; B.δ.a.l.f.l.g.l; B.δ.a.l.f.l.g.2; B.δ.a.l.h.l.a.l; B.δ.a.l.h.l.a.2; B.δ.a.l.h.l.b.l;
B.δ.a.l.h.l.b.2; B.δ.a.l.h.l.c.l; B.δ.a.l.h.l.c.2; B.δ.a.l.h.l.d.l; B.δ.a.l.h.l.d.2;
B.δ.a.l.h.l.e.l; B.δ.a.l.h.l.e.2; B.δ.a.l.h.l.f.l; B.δ.a.l.h.l.f.2; B.δ.a.l.h.l.g.l;
B.8.a.l.h.l.g.2; B.δ.a.l.l.l.a.l; B.δ.a.l.l.l.a.2; B.δ.a.l.l.l.b.l; B.8.a.l.l.l.b.2; B.8.a.l.l.l.c.l; B.δ.a.l.l.l.c.2; B.δ.a.l.l.l.d.l; B.δ.a.l.l.l.d.2; B.δ.a.l.l.l.e.l;
B.δ.a.l.l.l.e.2; B.δ.a.l.l.l.f.l; B.δ.a.l.l.l.f.2; B.δ.a.l.l.l.g.l; B.δ.a.l.l.l.g.2;
B.δ.a.2.a.l.a.l; B.δ.a.2.a.l.a.2; B.δ.a.2.a.l.b.l; B.δ.a.2.a.l.b.2; B.δ.a.2.a.l.c.l;
B.δ.a.2.a.l.c.2; B.δ.a.2.a.l.d.l; B.8.a.2.a.l.d.2; B.δ.a.2.a.l.e.l; B.δ.a.2.a.l.e.2;
B.δ.a.2.a.l.f.l; B.δ.a.2.a.l.f.2; B.δ.a.2.a.l.g.l; B.δ.a.2.a.l.g.2; B.8.a.2.b.l.a.l; B.8.a.2.b.l.a.2; B.δ.a.2.b.l.b.l; B.δ.a.2.b.l.b.2; B.δ.a.2.b.l.c.l; B.δ.a.2.b.l.c.2;
B.δ.a.2.b.l.d.l; B.δ.a.2.b.l.d.2; B.δ.a.2.b.l.e.l; B.δ.a.2.b.l.e.2; B.8.a.2.b.l.f.l;
B.δ.a.2.b.l.f.2; B.δ.a.2.b.l.g.l; B.δ.a.2.b.l.g.2; B.δ.a.2.f.l.a.l; B.8.a.2.f.l.a.2;
B.δ.a.2.f.l.b.l; B.δ.a.2.f.l.b.2; B.δ.a.2.f.l.c.l; B.8.a.2.f.l.c.2; B.δ.a.2.f.l.d.l;
B.δ.a.2.f.l.d.2; B.8.a.2.f.l.e.l; B.8.a.2.f.l.e.2; B.δ.a.2.f.l.f.l; B.δ.a.2.f.l.f.2; B.δ.a.2.f.l.g.l; B.δ.a.2.f.l.g.2; B.δ.a.2.h.l.a.l; B.δ.a.2.h.l.a.2; B.δ.a.2.h.l.b.l;
B.δ.a.2.h.l.b.2; B.δ.a.2.h.l.c.l; B.δ.a.2.h.l.c.2; B.δ.a.2.h.l.d.l; B.δ.a.2.h.l.d.2;
B.δ.a.2.h.l.e.l; B.δ.a.2.h.l.e.2; B.δ.a.2.h.l.f.l; B.δ.a.2.h.l.f.2; B.δ.a.2.h.l.g.l;
B.δ.a.2.h.l.g.2; B.δ.a.2.1.1.a.l; B.δ.a.2.1.1.a.2; B.δ.a.2.1.1.b.l; B.δ.a.2.1.1.b.2;
B.δ.a.2.1.1.c.l; B.δ.a.2.1.1.c.2; B.δ.a.2.1.1.d.l; B.δ.a.2.1.1.d.2; B.δ.a.2.1.1.e.l; B.δ.a.2.1.1.e.2; B.δ.a.2.1.1.f.l; B.δ.a.2.1.1.f.2; B.δ.a.2.1.1.g.l; B.δ.a.2.1.1.g.2;
B.δ.a.δ.a.l.a.l; B.δ.a.δ.a.l.a.2; B.δ.a.δ.a.l.b.l; B.δ.a.δ.a.l.b.2; B.δ.a.δ.a.l.c.l;
B.δ.a.8.a.l.c.2; B.δ.a.δ.a.l.d.l; B.δ.a.δ.a.l.d.2; B.δ.a.δ.a.l.e.l; B.8.a.δ.a.l.e.2;
B.δ.a.δ.a.l.f.l; B.δ.a.δ.a.l.f.2; B.δ.a.δ.a.l.g.l; B.δ.a.δ.a.l.g.2; B.δ.a.δ.b.l.a.l;
B.8.a.δ.b.l.a.2; B.δ.a.δ.b.l.b.l; B.δ.a.δ.b.l.b.2; B.δ.a.δ.b.l.c.l; B.δ.a.δ.b.l.c.2; B.δ.a.δ.b.l.d.l; B.δ.a.δ.b.l.d.2; B.δ.a.δ.b.l.e.l; B.δ.a.δ.b.l.e.2; B.δ.a.δ.b.l.f.l;
B.δ.a.δ.b.l.f.2; B.δ.a.δ.b.l.g.l; B.δ.a.δ.b.l.g.2; B.δ.a.δ.f.l.a.l; B.δ.a.δ.f.l.a.2;
B.δ.a.δ.f.l.b.l; B.δ.a.δ.f.l.b.2; B.δ.a.δ.f.l.c.l; B.δ.a.δ.f.l.c.2; B.δ.a.δ.f.l.d.l;
B.δ.a.8.f.l.d.2; B.δ.a.δ.f.l.e.l; B.δ.a.δ.f.l.e.2; B.δ.a.δ.f.l.f.l; B.δ.a.δ.f.l.f.2;
B.δ.a.δ.f.l.g.l; B.8.a.8.f.l.g.2; B.δ.a.δ.h.l.a.l; B.δ.a.δ.h.l.a.2; B.δ.a.δ.h.l.b.l; B.δ.a.δ.h.l.b.2; B.δ.a.δ.h.l.c.l; B.δ.a.δ.h.l.c.2; B.δ.a.δ.h.l.d.l; B.δ.a.δ.h.l.d.2;
B.δ.a.δ.h.l.e.1; B.δ.a.δ.h.l.e.2; B.δ.a.δ.h.l.f.l; B.8.a.8.h.l.f.2; B.δ.a.δ.h.l.g.l;
B.δ.a.δ.h.l.g.2; B.δ.a.δ.l.l.a.l; B.δ.a.δ.l.l.a.2; B.δ.a.8.1.1.b.l; B.8.a.δ.l.l.b.2;
B.δ.a.δ.l.l.c.l; B.8.a.δ.l.l.c.2; B.δ.a.δ.l.l.d.l; B.δ.a.δ.l.l.d.2; B.δ.a.δ.l.l.e.l;
B.δ.a.δ.l.l.e.2; B.δ.a.δ.l.l.f.l; B.δ.a.δ.l.l.f.2; B.δ.a.δ.l.l.g.l; B.δ.a.δ.l.l.g.2; B.lO.a.l.a.l.a.l; B.10.a.l.a.l.a.2; B.lO.a.l.a.l.b.l; B.10.a.l.a.l.b.2; B.lO.a.l.a.l.c.l;
B.lO.a.l.a.l.c.2; B.lO.a.l.a.l.d.l; B.10.a.l.a.l.d.2; B.lO.a.l.a.l.e.l; B.10.a.l.a.l.e.2;
B.lO.a.l.a.l.f.l; B.10.a.l.a.l.f.2; B.lO.a.l.a.l.g.l; B.10.a.l.a.l.g.2; B.lO.a.l.b.l.a.l;
B.10.a.l.b.l.a.2; B.lO.a.l.b.l.b.l; B.10.a.l.b.l.b.2; B.lO.a.l.b.l.c.l; B.lO.a.l.b.l.c.2;
B.lO.a.l.b.l.d.l; B.10.a.l.b.l.d.2; B.lO.a.l.b.l.e.l; B.10.a.l.b.l.e.2; B.lO.a.l.b.l.f.l; B.10.a.l.b.l.f.2; B.lO.a.l.b.l.g.l; B.10.a.l.b.l.g.2; B.lO.a.l.f.l.a.l; B.10.a.l.f.l.a.2;
B.lO.a.l.f.l.b.l; B.lO.a.l.f.l.b.2; B.lO.a.l.f.l.c.l; B.lO.a.l.f.l.c.2; B.lO.a.l.f.l.d.l;
B.10.a.l.f.l.d.2; B.lO.a.l.f.l.e.l; B.10.a.l.f.l.e.2; B.lO.a.l.f.l.f.l; B.10.a.l.f.l.f.2;
B.lO.a.l.f.l.g.l; B.10.a.l.f.l.g.2; B.lO.a.l.h.l.a.l; B.10.a.l.h.l.a.2; B.lO.a.l.h.l.b.l;
B.10.a.l.h.l.b.2; B.lO.a.l.h.l.c.l; B.lO.a.l.h.l.c.2; B.lO.a.l.h.l.d.l; B.10.a.l.h.l.d.2; B.lO.a.l.h.l.e.1; B.10.a.l.h.l.e.2; B.lO.a.l.h.l.f.l;
B.10.a.l.h.l.f.2; B.lO.a.l.h.l.g.l; B.10.a.l.h.l.g.2; B.lO.a.l.l.l.a.l; B.10.a.l.l.l.a.2; B.lO.a.l.l.l.b.l; B.10.a.l.l.l.b.2; B.lO.a.l.l.l.c.l; B.lO.a.l.l.l.c.2; B.lO.a.l.l.l.d.l;
B.10.a.l.l.l.d.2; B.lO.a.l.l.l.e.l; B.10.a.l.l.l.e.2; B.lO.a.l.l.l.f.l; B.10.a.l.l.l.f.2;
B.lO.a.l.l.l.g.1; B.10.a.l.l.l.g.2; B.10.a.2.a.l.a.l; B.10.a.2.a.l.a.2; B.10.a.2.a.l.b.l;
B.10.a.2.a.l.b.2; B.10.a.2.a.l.c.l; B.10.a.2.a.l.c.2; B.10.a.2.a.l.d.l; B.10.a.2.a.l.d.2; B.10.a.2.a.l.e.l; B.10.a.2.a.l.e.2; B.10.a.2.a.l.f.l; B.10.a.2.a.l.f.2; B.10.a.2.a.l.g.l;
B.10.a.2.a.l.g.2; B.10.a.2.b.l.a.l; B.10.a.2.b.l.a.2; B.10.a.2.b.l.b.l; B.10.a.2.b.l.b.2;
B.10.a.2.b.l.c.l; B.10.a.2.b.l.c.2; B.10.a.2.b.l.d.l; B.10.a.2.b.l.d.2; B.10.a.2.b.l.e.l;
B.10.a.2.b.l.e.2; B.10.a.2.b.l.f.l; B.10.a.2.b.l.f.2; B.10.a.2.b.l.g.l; B.10.a.2.b.l.g.2;
B.10.a.2.f.l.a.l; B.10.a.2.f.l.a.2; B.10.a.2.f.l.b.l; B.10.a.2.f.l.b.2; B.10.a.2.f.l.c.l; B.10.a.2.f.l.c.2; B.10.a.2.f.l.d.l; B.10.a.2.f.l.d.2; B.10.a.2.f.l.e.l; B.10.a.2.f.l.e.2;
B.10.a.2.f.l.f.l; B.10.a.2.f.l.f.2; B.10.a.2.f.l.g.l; B.10.a.2.f.l.g.2; B.10.a.2.h.l.a.l;
B.10.a.2.h.l.a.2; B.10.a.2.h.l.b.l; B.10.a.2.h.l.b.2; B.10.a.2.h.l.c.l;
B.10.a.2.h.l.c.2; B.10.a.2.h.l.d.l; B.10.a.2.h.l.d.2; B.10.a.2.h.l.e.l;
B.10.a.2.h.l.e.2; B.10.a.2.h.l.f.l; B.10.a.2.h.l.f.2; B.10.a.2.h.l.g.l; B.10.a.2.h.l.g.2; B.10.a.2.1.1.a.l; B.10.a.2.1.1.a.2; B.10.a.2.1.1.b.l; B.10.a.2.1.1.b.2; B.10.a.2.1.1.c.l;
B.10.a.2.1.1.c.2; B.10.a.2.1.1.d.l; B.10.a.2.1.1.d.2; B.10.a.2.1.1.e.l; B.10.a.2.1.1.e.2;
B.10.a.2.1.1.f.l; B.10.a.2.1.1.f.2; B.10.a.2.1.1.g.l; B.10.a.2.1.1.g.2; B.lO.a.δ.a.l.a.l;
B.10.a.δ.a.l.a.2; B.lO.a.δ.a.l.b.l; B.10.a.δ.a.l.b.2; B.lO.a.δ.a.l.c.l; B.10.a.δ.a.l.c.2;
B.lO.a.δ.a.l.d.l; B.10.a.8.a.l.d.2; B.lO.a.δ.a.l.e.l; B.10.a.δ.a.l.e.2; B.lO.a.δ.a.l.f.l; B.10.a.δ.a.l.f.2; B.lO.a.δ.a.l.g.l; B.10.a.8.a.l.g.2; B.lO.a.δ.b.l.a.l; B.10.a.δ.b.l.a.2;
B.lO.a.δ.b.l.b.l; B.10.a.δ.b.l.b.2; B.10.a.8.b.l.c.l; B.10.a.8.b.l.c.2; B.lO.a.δ.b.l.d.l;
B.10.a.δ.b.l.d.2; B.lO.a.δ.b.l.e.l; B.10.a.δ.b.l.e.2; B.lO.a.δ.b.l.f.l; B.10.a.δ.b.l.f.2;
B.lO.a.δ.b.l.g.l; B.10.a.δ.b.l.g.2; B.10.a.8.f.l.a.l; B.10.a.8.f.l.a.2; B.lO.a.δ.f.l.b.l;
B.10.a.δ.f.l.b.2; B.lO.a.δ.f.l.c.l; B.10.a.δ.f.l.c.2; B.lO.a.δ.f.l.d.l; B.10.a.8.f.l.d.2; B.lO.a.δ.f.l.e.l; B.10.a.δ.f.l.e.2; B.lO.a.δ.f.l.f.l; B.10.a.δ.f.l.f.2; B.lO.a.δ.f.l.g.l;
B.10.a.δ.f.l.g.2; B.lO.a.δ.h.l.a.l; B.10.a.δ.h.l.a.2; B.lO.a.δ.h.l.b.l; B.10.a.8.h.l.b.2;
B.10.a.8.h.l.c.l; B.10.a.δ.h.l.c.2; B.lO.a.δ.h.l.d.l; B.10.a.δ.h.l.d.2;
B.10.a.δ.h.l.e.l; B.10.a.δ.h.l.e.2; B.lO.a.δ.h.l.f.l; B.10.a.δ.h.l.f.2; B.lO.a.δ.h.l.g.l;
B.10.a.8.h.l.g.2; B.lO.a.δ.l.l.a.l; B.10.a.δ.l.l.a.2; B.lO.a.δ.l.l.b.l; B.10.a.δ.l.l.b.2; B.lO.a.δ.l.l.c.l; B.10.a.8.1.1.c.2; B.lO.a.δ.l.l.d.l; B.10.a.δ.l.l.d.2; B.lO.a.δ.l.l.e.l;
B.10.a.δ.l.l.e.2; B.lO.a.δ.l.l.f.l; B.10.a.δ.l.l.f.2; B.lO.a.δ.l.l.g.l; B.10.a.8.1.1.g.2;
B.12.a.l.a.l.a.l; B.12.a.l.a.l.a.2; B.12.a.l.a.l.b.l; B.12.a.l.a.l.b.2; B.12.a.l.a.l.c.l;
B.12.a.l.a.l.c.2; B.12.a.l.a.l.d.l; B.12.a.l.a.l.d.2; B.l a.l.a.l.e.l; B.12.a.l.a.l.e.2;
B.12.a.l.a.l.f.l; B.12.a.l.a.l.f.2; B.12.a.l.a.l.g.l; B.12.a.l.a.l.g.2; B.12.a.l.b.l.a.l; B.12.a.l.b.l.a.2; B.12.a.l.b.l.b.l; B.12.a.l.b.l.b.2; B.12.a.l.b.l.c.l; B.12.a.l.b.l.c.2;
B.12.a.l.b.l.d.l; B.12.a.l.b.l.d.2; B.12.a.l.b.l.e.l; B.12.a.l.b.l.e.2; B.12.a.l.b.l.f.l;
B.12.a.l.b.l.f.2; B.12.a.l.b.l.g.l; B.12.a.l.b.l.g.2; B.12.a.l.f.l.a.l; B.12.a.l.f.l.a.2;
B.12.a.l.f.l.b.l; B.12.a.l.f.l.b.2; B.12.a.l.f.l.c.l; B.12.a.l.f.l.c.2; B.12.a.l.f.l.d.l;
B.12.a.l.f.l.d.2; B.12.a.l.f.l.e.l; B.12.a.l.f.l.e.2; B.12.a.l.f.l.f.l; B.12.a.l.f.l.f.2; B.12.a.l.f.l.g.l; B.12.a.l.f.l.g.2; B.12.a.l.h.l.a.l; B.12.a.l.h.l.a.2; B.12.a.l.h.l.b.l;
B.12.a.l.h.l.b.2; B.12.a.l.h.l.c.l; B.12.a.l.h.l.c.2; B.12.a.l.h.l.d.l;
B.12.a.l.h.l.d.2; B.12.a.l.h.l.e.l; B.12.a.l.h.l.e.2; B.12.a.l.h.l.f.l;
B.12.a.l.h.l.f.2; B.12.a.l.h.l.g.l; B.12.a.l.h.l.g.2; B.12.a.l.l.l.a.l; B.12.a.l.l.l.a.2;
B.12.a.l.l.l.b.l; B.12.a.l.l.l.b.2; B.12.a.l.l.l.c.l; B.12.a.l.l.l.c.2; B.12.a.l.l.l.d.l; B.12.a.l.l.l.d.2; B.12.a.l.l.l.e.l; B.12.a.l.l.l.e.2; B.12.a.l.l.l.f.l; B.12.a.l.l.l.f.2;
B.12.a.l.l.l.g.l; B.12.a.l.l.l.g.2; B.12.a.2.a.l.a.l; B.12.a.2.a.l.a.2; B.12.a.2.a.l.b.l; B.12.a.2.a.l.b.2; B.12.a.2.a.l.c.l; B.12.a.2.a.l.c.2; B.12.a.2.a.l.d.l; B.12.a.2.a.l.d.2;
B.12.a.2.a.l.e.l; B.12.a.2.a.l.e.2; B.12.a.2.a.l.f.l; B.12.a.2.a.l.f.2; B.12.a.2.a.l.g.l;
B.12.a.2.a.l.g.2; B.12.a.2.b.l.a.l; B.12.a.2.b.l.a.2; B.12.a.2.b.l.b.l; B.12.a.2.b.l.b.2;
B.12.a.2.b.l.c.l; B.12.a.2.b.l.c.2; B.12.a.2.b.l.d.l; B.12.a.2.b.l.d.2; B.12.a.2.b.l.e.l; B.12.a.2.b.l.e.2; B.12.a.2.b.l.f.l; B.12.a.2.b.l.f.2; B.12.a.2.b.l.g.l; B.12.a.2.b.l.g.2;
B.12.a.2.f.l.a.l; B.12.a.2.f.l.a.2; B.12.a.2.f.l.b.l; B.12.a.2.f.l.b.2; B.12.a.2.f.l.c.l;
B.12.a.2.f.l.c.2; B.12.a.2.f.l.d.l; B.12.a.2.f.l.d.2; B.12.a.2.f.l.e.l; B.12.a.2.f.l.e.2;
B.12.a.2.f.l.f.l; B.12.a.2.f.l.f.2; B.12.a.2.f.l.g.l; B.12.a.2.f.l.g.2; B.12.a.2.h.l.a.l;
B.12.a.2.h.l.a.2; B.12.a.2.h.l.b.l; B.12.a.2.h.l.b.2; B.12.a.2.h.l.c.l; B.12.a.2.h.l.c.2; B.12.a.2.h.l.d.l; B.12.a.2.h.l.d.2; B.12.a.2.h.l.e.l;
B.12.a.2.h.l.e.2; B.12.a.2.h.l.f.l; B.12.a.2.h.l.f.2; B.12.a.2.h.l.g.l; B.12.a.2.h.l.g.2;
B.12.a.2.1.1.a.l; B.12.a.2.1.1.a.2; B.12.a.2.1.1.b.l; B.12.a.2.1.1.b.2; B.12.a.2.1.1.c.l;
B.12.a.2.1.1.c.2; B.12.a.2.1.1.d.l; B.12.a.2.1.1.d.2; B.12.a.2.1.1.e.l; B.12.a.2.1.1.e.2;
B.12.a.2.1.1.f.l; B.12.a.2.1.1.f.2; B.12.a.2.1.1.g.l; B.12.a.2.1.1.g.2; B.12.a.8.a.l.a.l; B.12.a.δ.a.l.a.2; B.12.a.δ.a.l.b.l; B.12.a.δ.a.l.b.2; B.12.a.δ.a.l.c.l; B.12.a.δ.a.l.c.2;
B.12.a.δ.a.l.d.l; B.12.a.δ.a.l.d.2; B.12.a.δ.a.l.e.l; B.12.a.δ.a.l.e.2; B.12.a.δ.a.l.f.l;
B.12.a.δ.a.l.f.2; B.12.a.δ.a.l.g.l; B.12.a.δ.a.l.g.2; B.12.a.δ.b.l.a.l; B.12.a.δ.b.l.a.2;
B.12.a.δ.b.l.b.l; B.12.a.δ.b.l.b.2; B.12.a.δ.b.l.c.l; B.12.a.δ.b.l.c.2; B.12.a.δ.b.l.d.l;
B.12.a.δ.b.l.d.2; B.12.a.δ.b.l.e.l; B.12.a.δ.b.l.e.2; B.12.a.δ.b.l.f.l; B.12.a.δ.b.l.f.2; B.12.a.δ.b.l.g.l; B.12.a.δ.b.l.g.2; B.12.a.δ.f.l.a.l; B.12.a.δ.f.l.a.2; B.12.a.δ.f.l.b.l;
B.12.a.δ.f.l.b.2; B.12.a.δ.f.l.c.l; B.12.a.δ.f.l.c.2; B.12.a.δ.f.l.d.l; B.12.a.δ.f.l.d.2;
B.12.a.δ.f.l.e.l; B.12.a.δ.f.l.e.2; B.12.a.δ.f.l.f.l; B.12.a.8.f.l.f.2; B.12.a.8.f.l.g.l;
B.12.a.8.f.l.g.2; B.12.a.δ.h.l.a.l; B.12.a.δ.h.l.a.2; B.12.a.8.h.l.b.l; B.12.a.8.h.l.b.2;
B.12.a.δ.h.l.c.l; B.12.a.δ.h.l.c.2; B.12.a.δ.h.l.d.l; B.12.a.δ.h.l.d.2; B.12.a.δ.h.l.e.l; B.12.a.δ.h.l.e.2; B.12.a.δ.h.l.f.l; B.12.a.8.h.l.f.2; B.12.a.8.h.l.g.l;
B.12.a.δ.h.l.g.2; B.12.a.δ.l.l.a.l; B.12.a.8.1.1.a.2; B.12.a.8.1.1.b.l; B.12.a.8.1.1.b.2;
B.12.a.8.1.1.c.l; B.12.a.δ.l.l.c.2; B.12.a.8.1.1.d.l; B.12.a.8.1.1.d.2; B.12.a.8.1.1.e.l;
B.12.a.δ.l.l.e.2; B.12.a.δ.l.l.f.l; B.12.a.δ.l.l.f.2; B.12.a.δ.l.l.g.l; B.12.a.δ.l.l.g.2;
B.14.a.l.a.l.a.l; B.14.a.l.a.l.a.2; B.14.a.l.a.l.b.l; B.14.a.l.a.l.b.2; B.14.a.l.a.l.c.l; B.14.a.l.a.l.c.2; B.14.a.l.a.l.d.l; B.14.a.l.a.l.d.2; B.14.a.l.a.l.e.l; B.14.a.l.a.l.e.2;
B.14.a.l.a.l.f.l; B.14.a.l.a.l.f.2; B.14.a.l.a.l.g.l; B.14.a.l.a.l.g.2; B.14.a.l.b.l.a.l;
B.14.a.l.b.l.a.2; B.14.a.l.b.l.b.l; B.14.a.l.b.l.b.2; B.14.a.l.b.l.c.l; B.14.a.l.b.l.c.2;
B.14.a.l.b.l.d.l; B.14.a.l.b.l.d.2; B.14.a.l.b.l.e.l; B.14.a.l.b.l.e.2; B.14.a.l.b.l.f.l;
B.14.a.l.b.l.f.2; B.14.a.l.b.l.g.l; B.14.a.l.b.l.g.2; B.14.a.l.f.l.a.l; B.14.a.l.f.l.a.2; B.14.a.l.f.l.b.l; B.14.a.l.f.l.b.2; B.14.a.l.f.l.c.l; B.14.a.l.f.l.c.2; B.14.a.l.f.l.d.l;
B.14.a.l.f.l.d.2; B.14.a.l.f.l.e.l; B.14.a.l.f.l.e.2; B. .a.l.f.l.f.l; B.14.a.l.f.l.f.2;
B.14.a.l.f.l.g.l; B.14.a.l.f.l.g.2; B.14.a.l.h.l.a.l; B.14.a.l.h.l.a.2; B.14.a.l.h.l.b.l;
B.14.a.l.h.l.b.2; B.14.a.l.h.l.c.l; B.14.a.l.h.l.c.2; B.14.a.l.h.l.d.l;
B.14.a.l.h.l.d.2; B.14.a.l.h.l.e.l; B.14.a.l.h.l.e.2; B.14.a.l.h.l.f.l; B.14.a.l.h.l.f.2; B.14.a.l.h.l.g.l; B.14.a.l.h.l.g.2; B.14.a.l.l.l.a.l; B.14.a.l.l.l.a.2;
B.14.a.l.l.l.b.l; B.14.a.l.l.l.b.2; B.14.a.l.l.l.c.l; B.14.a.l.l.l.c.2; B.14.a.l.l.l.d.l;
B.14.a.l.l.l.d.2; B.14.a.l.l.l.e.l; B.14.a.l.l.l.e.2; B.14.a.l.l.l.f.l; B.14.a.l.l.l.f.2;
B.14.a.l.l.l.g.l; B.14.a.l.l.l.g.2; B.14.a.2.a.l.a.l; B.14.a.2.a.l.a.2; B.14.a.2.a.l.b.l;
B.14.a.2.a.l.b.2; B.14.a.2.a.l.c.l; B.14.a.2.a.l.c.2; B.14.a.2.a.l.d.l; B.14.a.2.a.l.d.2; B.14.a.2.a.l.e.l; B.14.a.2.a.l.e.2; B.14.a.2.a.l.f.l; B.14.a.2.a.l.f.2; B.14.a.2.a.l.g.l;
B.14.a.2.a.l.g.2; B.14.a.2.b.l.a.l; B.14.a.2.b.l.a.2; B.14.a.2.b.l.b.l; B.14.a.2.b.l.b.2; B.14.a.2.b.l.c.l; B.14.a.2.b.l.c.2; B.14.a.2.b.l.d.l; B.14.a.2.b.l.d.2; B.14.a.2.b.l.e.l;
B.14.a.2.b.l.e.2; B.14.a.2.b.l.f.l; B.14.a.2.b.l.f.2; B.14.a.2.b.l.g.l; B.14.a.2.b.l.g.2;
B.14.a.2.f.l.a.l; B.14.a.2.f.l.a.2; B.14.a.2.f.l.b.l; B.14.a.2.f.l.b.2; B.14.a.2.f.l.c.l;
B.14.a.2.f.l.c.2; B.14.a.2.f.l.d.l; B.14.a.2.f.l.d.2; B.14.a.2.f.l.e.l; B.14.a.2.f.l.e.2; B.14.a.2.f.l.f.l; B.14.a.2.f.l.f.2; B.14.a.2.f.l.g.l; B.14.a.2.f.l.g.2; B.14.a.2.h.l.a.l;
B.14.a.2.h.l.a.2; B.14.a.2.h.l.b.l; B.14.a.2.h.l.b.2; B.14.a.2.h.l.c.l;
B.14.a.2.h.l.c.2; B.14.a.2.h.l.d.l; B.14.a.2.h.l.d.2; B.14.a.2.h.l.e.l;
B.14.a.2.h.l.e.2; B.14.a.2.h.l.f.l; B.14.a.2.h.l.f.2; B.14.a.2.h.l.g.l; B.14.a.2.h.l.g.2;
B.14.a.2.1.1.a.l; B.14.a.2.1.1.a.2; B.14.a.2.1.1.b.l; B.14.a.2.1.1.b.2; B.14.a.2.1.1.c.l; B.14.a.2.1.1.c.2; B.14.a.2.1.1.d.l; B.14.a.2.1.1.d.2; B.14.a.2.1.1.e.l; B.14.a.2.1.1.e.2;
B.14.a.2.1.1.f.l; B.14.a.2.1.1.f.2; B.14.a.2.1.1.g.l; B.14.a.2.1.1.g.2; B.14.a.8.a.l.a.l;
B.14.a.8.a.l.a.2; B.14.a.δ.a.l.b.l; B.14.a.δ.a.l.b.2; B.14.a.δ.a.l.c.l; B.14.a.δ.a.l.c.2;
B.14.a.δ.a.l.d.l; B.14.a.δ.a.l.d.2; B.14.a.δ.a.l.e.l; B.14.a.δ.a.l.e.2; B.14.a.δ.a.l.f.l;
B.14.a.δ.a.l.f.2; B.14.a.δ.a.l.g.l; B.14.a.δ.a.l.g.2; B.14.a.δ.b.l.a.l; B.14.a.δ.b.l.a.2; B.14.a.δ.b.l.b.l; B.14.a.δ.b.l.b.2; B.14.a.δ.b.l.c.l; B.14.a.δ.b.l.c.2; B.14.a.δ.b.l.d.l;
B.14.a.δ.b.l.d.2; B.14.a.δ.b.l.e.l; B.14.a.δ.b.l.e.2; B.14.a.δ.b.l.f.l; B.14.a.δ.b.l.f.2;
B.14.a.δ.b.l.g.l; B.14.a.δ.b.l.g.2; B.14.a.δ.f.l.a.l; B.14.a.δ.f.l.a.2; B.14.a.δ.f.l.b.l;
B.14.a.δ.f.l.b.2; B.14.a.δ.f.l.c.l; B.14.a.δ.f.l.c.2; B.14.a.δ.f.l.d.l; B.14.a.δ.f.l.d.2;
B.14.a.δ.f.l.e.l; B.14.a.δ.f.l.e.2; B.14.a.δ.f.l.f.l; B.14.a.δ.f.l.f.2; B.14.a.δ.f.l.g.l; B.14.a.δ.f.l.g.2; B.14.a.δ.h.l.a.l; B.14.a.δ.h.l.a.2; B.14.a.δ.h.l.b.l; B.14.a.8.h.l.b.2;
B.14.a.8.h.l.c.l; B.14.a.δ.h.l.c.2; B.14.a.δ.h.l.d.l; B.14.a.δ.h.l.d.2;
B.14.a.β.h.l.e.l; B.14.a.δ.h.l.e.2; B.14.a.δ.h.l.f.l; B.14.a.δ.h.l.f.2; B.14.a.δ.h.l.g.l;
B.14.a.8.h.l.g.2; B.14.a.8.1.1.a.l; B.14.a.δ.l.l.a.2; B.14.a.δ.l.l.b.l; B.14.a.δ.l.l.b.2;
B.H.a.δ.l.l.c.l; B.14.a.δ.l.l.c.2; B.14.a.8.1.1.d.l; B.14.a.δ.l.l.d.2; B.14.a.δ.l.l.e.l; B.14.a.8.1.1.e.2; B.14.a.8.1.1.f.l; B.14.a.δ.l.l.f.2; B.14.a.δ.l.l.g.l; B.14.a.δ.l.l.g.2;
B.15.a.l.a.l.a.l; B.15.a.l.a.l.a.2; B.lδ.a.l.a.l.b.l; B.15.a.l.a.l.b.2; B.15.a.l.a.l.c.l;
B.15.a.l.a.l.c.2; B.15.a.l.a.l.d.l; B.15.a.l.a.l.d.2; B.15.a.l.a.l.e.l; B.15.a.l.a.l.e.2;
B.15.a.l.a.l.f.l; B.15.a.l.a.l.f.2; B.15.a.l.a.l.g.l; B.15.a.l.a.l.g.2; B.15.a.l.b.l.a.l;
B.15.a.l.b.l.a.2; B.15.a.l.b.l.b.l; B.15.a.l.b.l.b.2; B.15.a.l.b.l.c.l; B.15.a.l.b.l.c.2; B.15.a.l.b.l.d.l; B.15.a.l.b.l.d.2; B.15.a.l.b.l.e.l; B.15.a.l.b.l.e.2; B.15.a.l.b.l.f.l;
B.15.a.l.b.l.f.2; B.15.a.l.b.l.g.l; B.15.a.l.b.l.g.2; B.15.a.l.f.l.a.l; B.15.a.l.f.l.a.2;
B.15.a.l.f.l.b.l; B.15.a.l.f.l.b.2; B.15.a.l.f.l.c.l; B.15.a.l.f.l.c.2; B.15.a.l.f.l.d.l;
B.15.a.l.f.l.d.2; B.15.a.l.f.l.e.l; B.15.a.l.f.l.e.2; B.15.a.l.f.l.f.l; B.15.a.l.f.l.f.2;
B.15.a.l.f.l.g.l; B.15.a.l.f.l.g.2; B.15.a.l.h.l.a.l; B.15.a.l.h.l.a.2; B.15.a.l.h.l.b.l; B.15.a.l.h.l.b.2; B.15.a.l.h.l.c.l; B.15.a.l.h.l.c.2; B.15.a.l.h.l.d.l;
B.15.a.l.h.l.d.2; B.lδ.a.l.h.l.e.l; B.15.a.l.h.l.e.2; B.15.a.l.h.l.f.l;
B.15.a.l.h.l.f.2; B.15.a.l.h.l.g.l; B.15.a.l.h.l.g.2; B.15.a.l.l.l.a.l; B.15.a.l.l.l.a.2;
B.15.a.l.l.l.b.l; B.15.a.l.l.l.b.2; B.15.a.l.l.l.c.l; B.15.a.l.l.l.c.2; B.15.a.l.l.l.d.l;
B.15.a.l.l.l.d.2; B.15.a.l.l.l.e.l; B.15.a.l.l.l.e.2; B.15.a.l.l.l.f.l; B.15.a.l.l.l.f.2; B.15.a.l.l.l.g.l; B.15.a.l.l.l.g.2; B.15.a.2.a.l.a.l; B.15.a.2.a.l.a.2; B.15.a.2.a.l.b.l;
B.15.a.2.a.l.b.2; B.15.a.2.a.l.c.l; B.15.a.2.a.l.c.2; B.15.a.2.a.l.d.l; B.15.a.2.a.l.d.2;
B.15.a.2.a.l.e.l; B.15.a.2.a.l.e.2; B.15.a.2.a.l.f.l; B.15.a.2.a.l.f.2; B.15.a.2.a.l.g.l;
B.15.a.2.a.l.g.2; B.15.a.2.b.l.a.l; B.15.a.2.b.l.a.2; B.15.a.2.b.l.b.l; B.15.a.2.b.l.b.2;
B.15.a.2.b.l.c.l; B.15.a.2.b.l.c.2; B.15.a.2.b.l.d.l; B.15.a.2.b.l.d.2; B.15.a.2.b.l.e.l; B.15.a.2.b.l.e.2; B.15.a.2.b.l.f.l; B.15.a.2.b.l.f.2; B.15.a.2.b.l.g.l; B.15.a.2.b.l.g.2;
B.15.a.2.f.l.a.l; B.15.a.2.f.l.a.2; B.15.a.2.f.l.b.l; B.15.a.2.f.l.b.2; B.15.a.2.f.l.c.l; B.15.a.2.f.l.c.2; B.15.a.2.f.l.d.l; B.15.a.2.f.l.d.2; B.15.a.2.f.l.e.l; B.15.a.2.f.l.e.2;
B.15.a.2.f.l.f.l; B.15.a.2.f.l.f.2; B.15.a.2.f.l.g.l; B.15.a.2.f.l.g.2; B.15.a.2.h.l.a.l;
B.15.a.2.h.l.a.2; B.15.a.2.h.l.b.l; B.15.a.2.h.l.b.2; B.15.a.2.h.l.c.l;
B.15.a.2.h.l.c.2; B.15.a.2.h.l.d.l; B.15.a.2.h.l.d.2; B.15.a.2.h.l.e.l; B.15.a.2.h.l.e.2; B.15.a.2.h.l.f.l; B.15.a.2.h.l.f.2; B.15.a.2.h.l.g.l; B.15.a.2.h.l.g.2;
B.15.a.2.1.1.a.l; B.15.a.2.1.1.a.2; B.15.a.2.1.1.b.l; B.15.a.2.1.1.b.2; B.15.a.2.1.1.c.l;
B.15.a.2.1.1.c.2; B.15.a.2.1.1.d.l; B.15.a.2.1.1.d.2; B.15.a.2.1.1.e.l; B.15.a.2.1.1.e.2;
B.15.a.2.1.1.f.l; B.15.a.2.1.1.f.2; B.15.a.2.1.1.g.l; B.15.a.2.1.1.g.2; B.15.a.8.a.l.a.l;
B.15.a.δ.a.l.a.2; B.15.a.δ.a.l.b.l; B.15.a.δ.a.l.b.2; B.15.a.δ.a.l.c.l; B.15.a.δ.a.l.c.2; B.15.a.δ.a.l.d.l; B.15.a.δ.a.l.d.2; B.15.a.δ.a.l.e.l; B.15.a.8.a.l.e.2; B.15.a.8.a.l.f.l;
B.15.a.8.a.l.f.2; B.15.a.δ.a.l.g.l; B.15.a.8.a.l.g.2; B.15.a.δ.b.l.a.l; B.15.a.δ.b.l.a.2;
B.15.a.δ.b.l.b.l; B.15.a.δ.b.l.b.2; B.15.a.δ.b.l.c.l; B.15.a.δ.b.l.c.2; B.15.a.δ.b.l.d.l;
B.15.a.8.b.l.d.2; B.15.a.8.b.l.e.l; B.15.a.δ.b.l.e.2; B.15.a.8.b.l.f.l; B.15.a.8.b.l.f.2;
B.15.a.δ.b.l.g.l; B.15.a.δ.b.l.g.2; B.15.a.δ.f.l.a.l; B.15.a.8.f.l.a.2; B.15.a.8.f.l.b.l; B.15.a.δ.f.l.b.2; B.15.a.8.f.l.c.l; B.15.a.8.f.l.c.2; B.15.a.8.f.l.d.l; B.15.a.δ.f.l.d.2;
B.15.a.δ.f.l.e.l; B.15.a.δ.f.l.e.2; B.15.a.δ.f.l.f.l; B.15.a.8.f.l.f.2; B.15.a.δ.f.l.g.l;
B.15.a.δ.f.l.g.2; B.15.a.δ.h.l.a.l; B.15.a.δ.h.l.a.2; B.15.a.δ.h.l.b.l; B.15.a.δ.h.l.b.2;
B.15.a.δ.h.l.c.l; B.15.a.δ.h.l.c.2; B.15.a.δ.h.l.d.l; B.15.a.δ.h.l.d.2;
B.15.a.8.h.l.e.l; B.15.a.δ.h.l.e.2; B.15.a.δ.h.l.f.l; B.15.a.δ.h.l.f.2; B.15.a.δ.h.l.g.l; B.15.a.δ.h.l.g.2; B.15.a.δ.l.l.a.l; B.15.a.δ.l.l.a.2; B.15.a.δ.l.l.b.l; B.15.a.δ.l.l.b.2;
B.15.a.δ.l.l.c.l; B.15.a.δ.l.l.c.2; B.15.a.δ.l.l.d.l; B.15.a.δ.l.l.d.2; B.15.a.δ.l.l.e.l;
B.15.a.δ.l.l.e.2; B.15.a.δ.l.l.f.l; B.15.a.δ.l.l.f.2; B.15.a.δ.l.l.g.l; B.15.a.δ.l.l.g.2;
B.lO.a.l.a.l.a.l; B.16.a.l.a.l.a.2; B.lO.a.l.a.l.b.l; B.16.a.l.a.l.b.2; B.lO.a.l.a.l.c.l;
B.16.a.l.a.l.c.2; B.lό.a.l.a.l.d.l; B.16.a.l.a.l.d.2; B.lό.a.l.a.l.e.l; B.16.a.l.a.l.e.2; B.lό.a.l.a.l.f.l; B.16.a.l.a.l.f.2; B.lό.a.l.a.l.g.l; B.16.a.l.a.l.g.2; B.lό.a.l.b.l.a.l;
B.16.a.l.b.l.a.2; B.lό.a.l.b.l.b.l; B.16.a.l.b.l.b.2; B.lό.a.l.b.l.c.l; B.16.a.l.b.l.c.2;
B.lό.a.l.b.l.d.l; B.16.a.l.b.l.d.2; B.lό.a.l.b.l.e.l; B.16.a.l.b.l.e.2; B.lό.a.l.b.l.f.l;
B.16.a.l.b.l.f.2; B.lO.a.l.b.l.g.l; B.16.a.l.b.l.g.2; B.lO.a.l.f.l.a.l; B.16.a.l.f.l.a.2;
B.lό.a.l.f.l.b.l; B.16.a.l.f.l.b.2; B.lό.a.l.f.l.c.l; B.16.a.l.f.l.c.2; B.lό.a.l.f.l.d.l; B.16.a.l.f.l.d.2; B.lό.a.l.f.l.e.l; B.16.a.l.f.l.e.2; B.lό.a.l.f.l.f.l; B.16.a.l.f.l.f.2;
B.lό.a.l.f.l.g.l; B.16.a.l.f.l.g.2; B.lό.a.l.h.l.a.l; B.16.a.l.h.l.a.2; B.16.a.l.h.l.b.l;
B.16.a.l.h.l.b.2; B.lό.a.l.h.l.c.l; B.16.a.l.h.l.c.2; B.lό.a.l.h.l.d.l;
B.16.a.l.h.l.d.2; B.lό.a.l.h.l.e.l; B.16.a.l.h.l.e.2; B.lό.a.l.h.l.f.l;
B.16.a.l.h.l.f.2; B.lό.a.l.h.l.g.l; B.16.a.l.h.l.g.2; B.lό.a.l.l.l.a.l; B.16.a.l.l.l.a.2; B.lό.a.l.l.l.b.l; B.16.a.l.l.l.b.2; B.lό.a.l.l.l.c.l; B.16.a.l.l.l.c.2; B.lό.a.l.l.l.d.l;
B.16.a.l.l.l.d.2; B.lό.a.l.l.l.e.l; B.16.a.l.l.l.e.2; B.lό.a.l.l.l.f.l; B.16.a.l.l.l.f.2;
B.lό.a.l.l.l.g.l; B.16.a.l.l.l.g.2; B.16.a.2.a.l.a.l; B.16.a.2.a.l.a.2; B.16.a.2.a.l.b.l;
B.16.a.2.a.l.b.2; B.16.a.2.a.l.c.l; B.16.a.2.a.l.c.2; B.16.a.2.a.l.d.l; B.16.a.2.a.l.d.2;
B.16.a.2.a.l.e.l; B.16.a.2.a.l.e.2; B.16.a.2.a.l.f.l; B.16.a.2.a.l.f.2; B.16.a.2.a.l.g.l; B.16.a.2.a.l.g.2; B.16.a.2.b.l.a.l; B.16.a.2.b.l.a.2; B.16.a.2.b.l.b.l; B.16.a.2.b.l.b.2;
B.16.a.2.b.l.c.l; B.16.a.2.b.l.c.2; B.16.a.2.b.l.d.l; B.16.a.2.b.l.d.2; B.16.a.2.b.l.e.l;
B.16.a.2.b.l.e.2; B.16.a.2.b.l.f.l; B.16.a.2.b.l.f.2; B.16.a.2.b.l.g.l; B.16.a.2.b.l.g.2;
B.16.a.2.f.l.a.l; B.16.a.2.f.l.a.2; B.16.a.2.f.l.b.l; B.16.a.2.f.l.b.2; B.16.a.2.f.l.c.l;
B.16.a.2.f.l.c.2; B.16.a.2.f.l.d.l; B.16.a.2.f.l.d.2; B.16.a.2.f.l.e.l; B.16.a.2.f.l.e.2; B.16.a.2.f.l.f.l; B.16.a.2.f.l.f.2; B.16.a.2.f.l.g.l; B.16.a.2.f.l.g.2; B.16.a.2.h.l.a.l;
B.16.a.2.h.l.a.2; B.16.a.2.h.l.b.l; B.16.a.2.h.l.b.2; B.16.a.2.h.l.c.l;
60- B.16.a.2.h.l.c.2; B.16.a.2.h.l.d.l; B.16.a.2.h.l.d.2; B.16.a.2.h.l.e.l;
B.16.a.2.h.l.e.2; B.16.a.2.h.l.f.l; B.16.a.2.h.l.f.2; B.16.a.2.h.l.g.l; B.16.a.2.h.l.g.2;
B.16.a.2.1.1.a.l; B.16.a.2.1.1.a.2; B.16.a.2.1.1.b.l; B.16.a.2.1.1.b.2; B.16.a.2.1.1.c.l;
B.16.a.2.1.1.c.2; B.16.a.2.1.1.d.l; B.16.a.2.1.1.d.2; B.16.a.2.1.1.e.l; B.16.a.2.1.1.e.2; B.16.a.2.1.1.f.l; B.16.a.2.1.1.f.2; B.16.a.2.1.1.g.l; B.16.a.2.1.1.g.2; B.lό.a.δ.a.l.a.l;
B.16.a.δ.a.l.a.2; B.lό.a.δ.a.l.b.l; B.16.a.δ.a.l.b.2; B.lό.a.δ.a.l.c.l; B.16.a.δ.a.l.c.2;
B.lό.a.δ.a.l.d.l; B.16.a.δ.a.l.d.2; B.16.a.8.a.l.e.l; B.16.a.δ.a.l.e.2; B.lό.a.δ.a.l.f.l;
B.16.a.δ.a.l.f.2; B.lό.a.δ.a.l.g.l; B.16.a.δ.a.l.g.2; B.lό.a.δ.b.l.a.l; B.16.a.δ.b.l.a.2;
B.lό.a.δ.b.l.b.l; B.16.a.δ.b.l.b.2; B.lό.a.δ.b.l.c.l; B.16.a.δ.b.l.c.2; B.lό.a.δ.b.l.d.l; B.16.a.δ.b.l.d.2; B.lό.a.δ.b.l.e.l; B.16.a.δ.b.l.e.2; B.lό.a.δ.b.l.f.l; B.16.a.δ.b.l.f.2;
B.16.a.δ.b.l.g.l; B.16.a.δ.b.l.g.2; B.lό.a.δ.f.l.a.l; B.16.a.δ.f.l.a.2; B.lό.a.δ.f.l.b.l;
B.16.a.8.f.l.b.2; B.16.a.8.f.l.c.l; B.16.a.δ.f.l.c.2; B.lό.a.δ.f.l.d.l; B.16.a.8.f.l.d.2;
B.lό.a.δi.l.e.l; B.16.a.δ.f.l.e.2; B.lό.a.δ.f.l.f.l; B.16.a.δ.f.l.f.2; B.lό.a.δ.f.l.g.l;
B.16.a.δ.f.l.g.2; B.lό.a.δ.h.l.a.l; B.16.a.δ.h.l.a.2; B.lό.a.δ.h.l.b.l; B.16.a.δ.h.l.b.2; B.16.a.8.h.l.c.l; B.16.a.8.h.l.c.2; B.lό.a.δ.h.l.d.l; B.16.a.δ.h.l.d.2;
B.16.a.δ.h.l.e.l; B.16.a.δ.h.l.e.2; B.lό.a.δ.h.l.f.l; B.16.a.δ.h.l.f.2; B.lό.a.δ.h.l.g.l;
B.16.a.δ.h.l.g.2; B.lό.a.δ.l.l.a.l; B.16.a.δ.l.l.a.2; B.lό.a.δ.l.l.b.l; B.16.a.δ.l.l.b.2;
B.lό.a.δ.l.l.c.l; B.16.a.δ.l.l.c.2; B.lό.a.δ.l.l.d.l; B.16.a.δ.l.l.d.2; B.lό.a.δ.l.l.e.l;
B.16.a.δ.l.l.e.2; B.lό.a.δ.l.l.f.l; B.16.a.8.1.1.f.2; B.lό.a.δ.l.l.g.l; B.16.a.8.1.1.g.2; B.17.a.l.a.l.a.l; B.17.a.l.a.l.a.2; B.17.a.l.a.l.b.l; B.17.a.l.a.l.b.2; B.17.a.l.a.l.c.l;
B.17.a.l.a.l.c.2; B.17.a.l.a.l.d.l; B.17.a.l.a.l.d.2; B.17.a.l.a.l.e.l; B.17.a.l.a.l.e.2;
B.17.a.l.a.l.f.l; B.17.a.l.a.l.f.2; B.17.a.l.a.l.g.l; B.17.a.l.a.l.g.2; B.17.a.l.b.l.a.l;
B.17.a.l.b.l.a.2; B.17.a.l.b.l.b.l; B.17.a.l.b.l.b.2; B.17.a.l.b.l.c.l; B.17.a.l.b.l.c.2;
B.17.a.l.b.l.d.l; B.17.a.l.b.l.d.2; B.17.a.l.b.l.e.l; B.17.a.l.b.l.e.2; B.17.a.l.b.l.f.l; B.17.a.l.b.l.f.2; B.17.a.l.b.l.g.l; B.17.a.l.b.l.g.2; B.17.a.l.f.l.a.l; B.17.a.l.f.l.a.2;
B.17.a.l.f.l.b.l; B.17.a.l.f.l.b.2; B.17.a.l.f.l.c.l; B.17.a.l.f.l.c.2; B.17.a.l.f.l.d.l;
B.17.a.l.f.l.d.2; B.17.a.l.f.l.e.l; B.17.a.l.f.l.e.2; B.17.a.l.f.l.f.l; B.17.a.l.f.l.f.2;
B.17.a.l.f.l.g.l; B.17.a.l.f.l.g.2; B.17.a.l.h.l.a.l; B.17.a.l.h.l.a.2; B.17.a.l.h.l.b.l;
B.17.a.l.h.l.b.2; B.17.a.l.h.l.c.l; B.17.a.l.h.l.c.2; B.17.a.l.h.l.d.l; B.17.a.l.h.l.d.2; B.17.a.l.h.l.e.l; B.17.a.l.h.l.e.2; B.17.a.l.h.l.f.l;
B.17.a.l.h.l.f.2; B.17.a.l.h.l.g.l; B.17.a.l.h.l.g.2; B.17.a.l.l.l.a.l; B.17.a.l.l.l.a.2;
B.17.a.l.l.l.b.l; B.17.a.l.l.l.b.2; B.17.a.l.l.l.c.l; B.17.a.l.l.l.c.2; B.17.a.l.l.l.d.l;
B.17.a.l.l.l.d.2; B.17.a.l.l.l.e.l; B.17.a.l.l.l.e.2; B.17.a.l.l.l.f.l; B.17.a.l.l.l.f.2;
B.17.a.l.l.l.g.l; B.17.a.l.l.l.g.2; B.17.a.2.a.l.a.l; B.17.a.2.a.l.a.2; B.17.a.2.a.l.b.l; B.17.a.2.a.l.b.2; B.17.a.2.a.l.c.l; B.17.a.2.a.l.c.2; B.17.a.2.a.l.d.l; B.17.a.2.a.l.d.2;
B.17.a.2.a.l.e.l; B.17.a.2.a.l.e.2; B.17.a.2.a.l.f.l; B.17.a.2.a.li.2; B.17.a.2.a.l.g.l;
B.17.a.2.a.l.g.2; B.17.a.2.b.l.a.l; B.17.a.2.b.l.a.2; B.17.a.2.b.l.b.l; B.17.a.2.b.l.b.2;
B.17.a.2.b.l.c.l; B.17.a.2.b.l.c.2; B.17.a.2.b.l.d.l; B.17.a.2.b.l.d.2; B.17.a.2.b.l.e.l;
B.17.a.2.b.l.e.2; B.17.a.2.b.l.f.l; B.17.a.2.b.l.f.2; B.17.a.2.b.l.g.l; B.17.a.2.b.l.g.2; B.17.a.2.f.l.a.l; B.17.a.2.f.l.a.2; B.17.a.2.f.l.b.l; B.17.a.2.f.l.b.2; B.17.a.2.f.l.c.l;
B.17.a.2.f.l.c.2; B.17.a.2.f.l.d.l; B.17.a.2.f.l.d.2; B.17.a.2.f.l.e.l; B.17.a.2.f.l.e.2;
B.17.a.2.f.l.f.l; B.17.a.2.f.l.f.2; B.17.a.2.f.l.g.l; B.17.a.2.f.l.g.2; B.17.a.2.h.l.a.l;
B.17.a.2.h.l.a.2; B.17.a.2.h.l.b.l; B.17.a.2.h.l.b.2; B.17.a.2.h.l.c.l;
B.17.a.2.h.l.c.2; B.17.a.2.h.l.d.l; B.17.a.2.h.l.d.2; B.17.a.2.h.l.e.l; B.17.a.2.h.l.e.2; B.17.a.2.h.l.f.l; B.17.a.2.h.l.f.2; B.17.a.2.h.l.g.l; B.17.a.2.h.l.g.2;
B.17.a.2.1.1.a.l; B.17.a.2.1.1.a.2; B.17.a.2.1.1.b.l; B.17.a.2.1.1.b.2; B.17.a.2.1.1.c.l;
δl- B.17.a.2.1.1.c.2; B.17.a.2.1.1.d.l; B.17.a.2.1.1.d.2; B.17.a.2.1.1.e.l; B.17.a.2.1.1.e.2;
B.17.a.2.1.1.f.l; B.17.a.2.1.1.f.2; B.17.a.2.1.1.g.l; B.17.a.2.1.1.g.2; B.17.a.δ.a.l.a.l;
B.17.a.δ.a.l.a.2; B.17.a.δ.a.l.b.l; B.17.a.δ.a.l.b.2; B.17.a.δ.a.l.c.l; B.17.a.δ.a.l.c.2;
B.17.a.8.a.l.d.l; B.17.a.δ.a.l.d.2; B.17.a.δ.a.l.e.l; B.17.a.δ.a.l.e.2; B.17.a.8.a.l.f.l; B.17.a.β.a.l.f.2; B.17.a.δ.a.l.g.l; B.17.a.δ.a.l.g.2; B.17.a.δ.b.l.a.l; B.17.a.δ.b.l.a.2;
B.17.a.8.b.l.b.l; B.17.a.δ.b.l.b.2; B.17.a.δ.b.l.c.l; B.17.a.δ.b.l.c.2; B.17.a.8.b.l.d.l;
B.17.a.δ.b.l.d.2; B.17.a.δ.b.l.e.l; B.17.a.δ.b.l.e.2; B.17.a.δ.b.l.f.l; B.17.a.8.b.l.f.2;
B.17.a.8.b.l.g.l; B.17.a.δ.b.l.g.2; B.17.a.δ.f.l.a.l; B.17.a.δ.f.l.a.2; B.17.a.8.f.l.b.l;
B.17.a.δ.f.l.b.2; B.17.a.δ.f.l.c.l; B.17.a.δ.f.l.c.2; B.17.a.δ.f.l.d.l; B.17.a.δ.f.l.d.2; B.17.a.δ.f.l.e.l; B.17.a.δ.f.l.e.2; B.17.a.8.f.l.f.l; B.17.a.δ.f.l.f.2; B.17.a.8.f.l.g.l;
B.17.a.δ.f.l.g.2; B.17.a.δ.h.l.a.l; B.17.a.8.h.l.a.2; B.17.a.δ.h.l.b.l; B.17.a.δ.h.l.b.2;
B.17.a.δ.h.l.c.l; B.17.a.δ.h.l.c.2; B.17.a.8.h.l.d.l; B.17.a.δ.h.l.d.2;
B.17.a.δ.h.l.e.l; B.17.a.δ.h.l.e.2; B.17.a.δ.h.l.f.l; B.17.a.δ.h.l.f.2; B.17.a.8.h.l.g.l;
B.17.a.δ.h.l.g.2; B.17.a.δ.l.l.a.l; B.17.a.8.1.1.a.2; B.17.a.8.1.1.b.l; B.17.a.8.1.1.b.2; B.17.a.δ.l.l.c.l; B.17.a.8.1.1.c.2; B.17.a.8.1.1.d.l; B.17.a.δ.l.l.d.2; B.17.a.8.1.1.e.l;
B.17.a.δ.l.l.e.2; B.17.a.δ.l.l.f.l; B.17.a.δ.l.l.f.2; B.17.a.δ.l.l.g.l; B.17.a.δ.l.l.g.2;
B.lδ.a.l.a.l.a.l; B.18.a.l.a.l.a.2; B.lδ.a.l.a.l.b.l; B.lδ.a.l.a.l.b.2; B.lδ.a.l.a.l.c.l;
B.lδ.a.l.a.l.c.2; B.lδ.a.l.a.l.d.l; B.lδ.a.l.a.l.d.2; B.lδ.a.l.a.l.e.l; B.lδ.a.l.a.l.e.2;
B.lδ.a.l.a.l.f.l; B.lδ.a.l.a.l.f.2; B.lδ.a.l.a.l.g.l; B.lδ.a.l.a.l.g.2; B.lδ.a.l.b.l.a.l; B.lδ.a.l.b.l.a.2; B.lδ.a.l.b.l.b.l; B.lδ.a.l.b.l.b.2; B.lδ.a.l.b.l.c.l; B.lδ.a.l.b.l.c.2;
B.lδ.a.l.b.l.d.l; B.lδ.a.l.b.l.d.2; B.lδ.a.l.b.l.e.l; B.lδ.a.l.b.l.e.2; B.lδ.a.l.b.l.f.l;
B.18.a.l.b.l.f.2; B.lδ.a.l.b.l.g.l; B.lδ.a.l.b.l.g.2; B.lδ.a.l.f.l.a.l; B.lδ.a.l.f.l.a.2;
B.lδ.a.l.f.l.b.l; B.lδ.a.l.f.l.b.2; B.lδ.a.l.f.l.c.l; B.lδ.a.l.f.l.c.2; B.lδ.a.l.f.l.d.l;
B.18.a.l.f.l.d.2; B.lδ.a.l.f.l.e.l; B.lδ.a.l.f.l.e.2; B.lδ.a.l.f.l.f.l; B.lδ.a.l.f.l.f.2; B.lδ.a.l.f.l.g.l; B.lδ.a.l.f.l.g.2; B.lδ.a.l.h.l.a.l; B.lδ.a.l.h.l.a.2; B.lδ.a.l.h.l.b.l;
B.lδ.a.l.h.l.b.2; B.lδ.a.l.h.l.c.l; B.lδ.a.l.h.l.c.2; B.lδ.a.l.h.l.d.l;
B.lδ.a.l.h.l.d.2; B.lδ.a.l.h.l.e.l; B.lδ.a.l.h.l.e.2; B.lδ.a.l.h.l.f.l;
B.18.a.l.h.l.f.2; B.lδ.a.l.h.l.g.l; B.lδ.a.l.h.l.g.2; B.lδ.a.l.l.l.a.l; B.lδ.a.l.l.l.a.2;
B.lδ.a.l.l.l.b.l; B.lδ.a.l.l.l.b.2; B.lδ.a.l.l.l.c.l; B.lδ.a.l.l.l.c.2; B.lδ.a.l.l.l.d.l; B.18.a.l.l.l.d.2; B.lδ.a.l.l.l.e.l; B.lδ.a.l.l.l.e.2; B.lδ.a.l.l.l.f.l; B.lδ.a.l.l.l.f.2;
B.lδ.a.l.l.l.g.l; B.lδ.a.l.l.l.g.2; B.lδ.a.2.a.l.a.l; B.lδ.a.2.a.l.a.2; B.lδ.a.2.a.l.b.l;
B.18.a.2.a.l.b.2; B.lδ.a.2.a.l.c.l; B.18.a.2.a.l.c.2; B.18.a.2.a.l.d.l; B.lδ.a.2.a.l.d.2;
B.18.a.2.a.l.e.l; B.lδ.a.2.a.l.e.2; B.lδ.a.2.a.l.f.l; B.lδ.a.2.a.l.f.2; B.lδ.a.2.a.l.g.l;
B.lδ.a.2.a.l.g.2; B.lδ.a.2.b.l.a.l; B.lδ.a.2.b.l.a.2; B.lδ.a.2.b.l.b.l; B.lδ.a.2.b.l.b.2; B.lδ.a.2.b.l.c.l; B.lδ.a.2.b.l.c.2; B.lδ.a.2.b.l.d.l; B.lδ.a.2.b.l.d.2; B.lδ.a.2.b.l.e.l;
B.18.a.2.b.l.e.2; B.lδ.a.2.b.l.f.l; B.lδ.a.2.b.l.f.2; B.lδ.a.2.b.l.g.l; B.lδ.a.2.b.l.g.2;
B.18.a.2.f.l.a.l; B.lδ.a.2.f.l.a.2; B.lδ.a.2.f.l.b.l; B.lδ.a.2.f.l.b.2; B.lδ.a.2.f.l.c.l;
B.18.a.2.f.l.c.2; B.lδ.a.2.f.l.d.l; B.lδ.a.2.f.l.d.2; B.18.a.2.f.l.e.l; B.lδ.a.2.f.l.e.2;
B.lδ.a.2.f.l.f.l; B.lδ.a.2.f.l.f.2; B.lδ.a.2.f.l.g.l; B.lδ.a.2.f.l.g.2; B.lδ.a.2.h.l.a.l; B.lδ.a.2.h.l.a.2; B.lδ.a.2.h.l.b.l; B.lδ.a.2.h.l.b.2; B.lδ.a.2.h.l.c.l;
B.18.a.2.h.l.c.2; B.lδ.a.2.h.l.d.l; B.lδ.a.2.h.l.d.2; B.18.a.2.h.l.e.l;
B.18.a.2.h.l.e.2; B.lδ.a.2.h.l.f.l; B.lδ.a.2.h.l.f.2; B.18.a.2.h.l.g.l; B.lδ.a.2.h.l.g.2;
B.18.a.2.1.1.a.l; B.lδ.a.2.1.1.a.2; B.18.a.2.1.1.b.l; B.lδ.a.2.1.1.b.2; B.lδ.a.2.1.1.c.l;
B.18.a.2.1.1.c.2; B.lδ.a.2.1.1.d.l; B.18.a.2.1.1.d.2; B.18.a.2.1.1.e.l; B.lδ.a.2.1.1.e.2; B.18.a.2.1.1.f.l; B.lδ.a.2.1.1.f.2; B.lδ.a.2.1.1.g.l; B.lδ.a.2.1.1.g.2; B.lδ.a.δ.a.l.a.l;
B.lδ.a.8.a.l.a.2; B.18.a.δ.a.l.b.l; B.lδ.a.δ.a.l.b.2; B.18.a.8.a.l.c.l; B.lδ.a.δ.a.l.c.2;
δ2- B.lδ.a.δ.a.l.d.l; B.lδ.a.δ.a.l.d.2; B.lδ.a.δ.a.l.e.l; B.lδ.a.δ.a.l.e.2; B.lδ.a.δ.a.l.f.l;
B.lδ.a.β.a.l.f.2; B.lδ.a.δ.a.l.g.l; B.lδ.a.δ.a.l.g.2; B.lδ.a.δ.b.l.a.l; B.18.a.8.b.l.a.2;
B.lδ.a.δ.b.l.b.l; B.lδ.a.δ.b.l.b.2; B.lδ.a.δ.b.l.c.l; B.lδ.a.δ.b.l.c.2; B.lδ.a.δ.b.l.d.l;
B.lδ.a.δ.b.l.d.2; B.lδ.a.δ.b.l.e.l; B.lδ.a.δ.b.l.e.2; B.lδ.a.δ.b.l.f.l; B.lβ.a.8.b.l.f.2; B.lδ.a.δ.b.l.g.l; B.lδ.a.δ.b.l.g.2; B.lδ.a.δ.f.l.a.l; B.lδ.a.δ.f.l.a.2; B.lδ.a.δ.f.l.b.l;
B.18.a.8.f.l.b.2; B.lδ.a.δ.f.l.c.l; B.lδ.a.δ.f.l.c.2; B.18.a.8.f.l.d.l; B.lδ.a.δ.f.l.d.2;
B.lδ.a.δ.f.l.e.1; B.lδ.a.δ.f.l.e.2; B.lδ.a.δ.f.l.f.l; B.lδ.a.δ.f.l.f.2; B.lδ.a.δ.f.l.g.l;
B.18.a.δ.f.l.g.2; B.lδ.a.δ.h.l.a.1; B.lδ.a.δ.h.l.a.2; B.lδ.a.δ.h.l.b.l; B.lδ.a.8.h.l.b.2;
B.18.a.8.h.l.c.l; B.18.a.δ.h.l.c.2; B.lδ.a.δ.h.l.d.l; B.lδ.a.δ.h.l.d.2; B.18.a.δ.h.l.e.l; B.lδ.a.δ.h.l.e.2; B.lδ.a.δ.h.l.f.l; B.lδ.a.δ.h.l.f.2; B.lδ.a.8.h.l.g.l;
B.18.a.δ.h.l.g.2; B.lδ.a.δ.l.l.a.l; B.lδ.a.δ.l.l.a.2; B.lδ.a.δ.l.l.b.l; B.lδ.a.δ.l.l.b.2;
B.lδ.a.δ.l.l.c.l; B.lδ.a.δ.l.l.c.2; B.lδ.a.δ.l.l.d.l; B.18.a.8.1.1.d.2; B.lδ.a.β.l.l.e.l;
B.lδ.a.δ.l.l.e.2; B.18.a.8.1.1.f.l; B.18.a.δ.l.l.f.2; B.18.a.δ.l.l.g.l; B.lδ.a.δ.l.l.g.2;
B.19.a.l.a.l.a.l; B.19.a.l.a.l.a.2; B.19.a.l.a.l.b.l; B.19.a.l.a.l.b.2; B.19.a.l.a.l.c.l; B.19.a.l.a.l.c.2; B.19.a.l.a.l.d.l; B.19.a.l.a.l.d.2; B.19.a.l.a.l.e.l; B.19.a.l.a.l.e.2;
B.19.a.l.a.l.f.l; B.19.a.l.a.l.f.2; B.19.a.l.a.l.g.l; B.19.a.l.a.l.g.2; B.19.a.l.b.l.a.l;
B.19.a.l.b.l.a.2; B.19.a.l.b.l.b.l; B.19.a.l.b.l.b.2; B.19.a.l.b.l.c.l; B.19.a.l.b.l.c.2;
B.19.a.l.b.l.d.l; B.19.a.l.b.l.d.2; B.19.a.l.b.l.e.l; B.19.a.l.b.l.e.2; B.19.a.l.b.l.f.l;
B.19.a.l.b.l.f.2; B.19.a.l.b.l.g.l; B.19.a.l.b.l.g.2; B.19.a.l.f.l.a.l; B.19.a.l.f.l.a.2; B.19.a.l.f.l.b.l; B.19.a.l.f.l.b.2; B.19.a.l.f.l.c.l; B.19.a.l.f.l.c.2; B.19.a.l.f.l.d.l;
B.19.a.l.f.l.d.2; B.19.a.l.f.l.e.l; B.19.a.l.f.l.e.2; B.19.a.l.f.l.f.l; B.19.a.l.f.l.f.2;
B.19.a.l.f.l.g.l; B.19.a.l.f.l.g.2; B.19.a.l.h.l.a.l; B.19.a.l.h.l.a.2; B.19.a.l.h.l.b.l;
B.19.a.l.h.l.b.2; B.19.a.l.h.l.c.l; B.19.a.l.h.l.c.2; B.19.a.l.h.l.d.l;
B.19.a.l.h.l.d.2; B.19.a.l.h.l.e.l; B.19.a.l.h.l.e.2; B.19.a.l.h.l.f.l; B.19.a.l.h.l.f.2; B.19.a.l.h.l.g.l; B.19.a.l.h.l.g.2; B.19.a.l.l.l.a.l; B.19.a.l.l.l.a.2;
B.19.a.l.l.l.b.l; B.19.a.l.l.l.b.2; B.19.a.l.l.l.c.l; B.19.a.l.l.l.c.2; B.19.a.l.l.l.d.l;
B.19.a.l.l.l.d.2; B.19.a.l.l.l.e.l; B.19.a.l.l.l.e.2; B.19.a.l.l.l.f.l; B.19.a.l.l.l.f.2;
B.19.a.l.l.l.g.l; B.19.a.l.l.l.g.2; B.19.a.2.a.l.a.l; B.19.a.2.a.l.a.2; B.19.a.2.a.l.b.l;
B.19.a.2.a.l.b.2; B.19.a.2.a.l.c.l; B.19.a.2.a.l.c.2; B.19.a.2.a.l.d.l; B.19.a.2.a.l.d.2; B.19.a.2.a.l.e.l; B.19.a.2.a.l.e.2; B.19.a.2.a.l.f.l; B.19.a.2.a.l.f.2; B.19.a.2.a.l.g.l;
B.19.a.2.a.l.g.2; B.19.a.2.b.l.a.l; B.19.a.2.b.l.a.2; B.19.a.2.b.l.b.l; B.19.a.2.b.l.b.2;
B.19.a.2.b.l.c.l; B.19.a.2.b.l.c.2; B.19.a.2.b.l.d.l; B.19.a.2.b.l.d.2; B.19.a.2.b.l.e.l;
B.19.a.2.b.l.e.2; B.19.a.2.b.l.f.l; B.19.a.2.b.l.f.2; B.19.a.2.b.l.g.l; B.19.a.2.b.l.g.2;
B.19.a.2.f.l.a.l; B.19.a.2.f.l.a.2; B.19.a.2.f.l.b.l; B.19.a.2.f.l.b.2; B.19.a.2.f.l.c.l; B.19.a.2.f.l.c.2; B.19.a.2.f.l.d.l; B.19.a.2.f.l.d.2; B.19.a.2.f.l.e.l; B.19.a.2.f.l.e.2;
B.19.a.2.f.l.f.l; B.19.a.2.f.l.f.2; B.19.a.2.f.l.g.l; B.19.a.2.f.l.g.2; B.19.a.2.h.l.a.l;
B.19.a.2.h.l.a.2; B.19.a.2.h.l.b.l; B.19.a.2.h.l.b.2; B.19.a.2.h.l.c.l;
B.19.a.2.h.l.c.2; B.19.a.2.h.l.d.l; B.19.a.2.h.l.d.2; B.19.a.2.h.l.e.l;
B.19.a.2.h.l.e.2; B.19.a.2.h.l.f.l; B.19.a.2.h.l.f.2; B.19.a.2.h.l.g.l; B.19.a.2.h.l.g.2; B.19.a.2.1.1.a.l; B.19.a.2.1.1.a.2; B.19.a.2.1.1.b.l; B.19.a.2.1.1.b.2; B.19.a.2.1.1.c.l;
B.19.a.2.1.1.c.2; B.19.a.2.1.1.d.l; B.19.a.2.1.1.d.2; B.19.a.2.1.1.e.l; B.19.a.2.1.1.e.2;
B.19.a.2.1.1.f.l; B.19.a.2.1.1.f.2; B.19.a.2.1.1.g.l; B.19.a.2.1.1.g.2; B.19.a.δ.a.l.a.l;
B.19.a.δ.a.l.a.2; B.19.a.δ.a.l.b.l; B.19.a.8.a.l.b.2; B.19.a.8.a.l.c.l; B.19.a.8.a.l.c.2;
B.19.a.δ.a.l.d.l; B.19.a.δ.a.l.d.2; B.19.a.δ.a.l.e.l; B.19.a.δ.a.l.e.2; B.19.a.δ.a.l.f.l; B.19.a.8.a.l.f.2; B.19.a.δ.a.l.g.l; B.19.a.δ.a.l.g.2; B.19.a.8.b.l.a.l; B.19.a.8.b.l.a.2;
B.19.a.δ.b.l.b.l; B.19.a.δ.b.l.b.2; B.19.a.δ.b.l.c.l; B.19.a.δ.b.l.c.2; B.19.a.8.b.l.d.l;
63- B.19.a.8.b.l.d.2; B.19.a.δ.b.l.e.l; B.19.a.δ.b.l.e.2; B.19.a.δ.b.l.f.l; B.19.a.δ.b.l.f.2;
B.19.a.δ.b.l.g.l; B.19.a.δ.b.l.g.2; B.19.a.δ.f.l.a.l; B.19.a.δ.f.l.a.2; B.19.a.δ.f.l.b.l;
B.19.a.δ.f.l.b.2; B.19.a.δ.f.l.c.l; B.19.a.δ.f.l.c.2; B.19.a.δ.f.l.d.l; B.19.a.δ.f.l.d.2;
B.19.a.δ.f.l.e.l; B.19.a.δ.f.l.e.2; B.19.a.8.f.l.f.l; B.19.a.δ.f.l.f.2; B.19.a.δ.f.l.g.l; B.19.a.δ.f.l.g.2; B.19.a.δ.h.l.a.l; B.19.a.δ.h.l.a.2; B.19.a.δ.h.l.b.l; B.19.a.δ.h.l.b.2;
B.19.a.δ.h.l.c.l; B.19.a.δ.h.l.c.2; B.19.a.8.h.l.d.l; B.19.a.δ.h.l.d.2;
B.19.a.8.h.l.e.l; B.19.a.δ.h.l.e.2; B.19.a.δ.h.l.f.l; B.19.a.δ.h.l.f.2; B.19.a.δ.h.l.g.l;
B.19.a.δ.h.l.g.2; B.19.a.δ.l.l.a.l; B.19.a.8.1.1.a.2; B.19.a.8.1.1.b.l; B.19.a.δ.l.l.b.2;
B.19.a.δ.l.l.c.l; B.19.a.δ.l.l.c.2; B.19.a.8.1.1.d.l; B.19.a.δ.l.l.d.2; B.19.a.8.1.1.e.l; B.19.a.8.1.1.e.2; B.19.a.8.1.1.f.l; B.19.a.δ.l.l.f.2; B.19.a.8.1.1.g.l; B.19.a.8.1.1.g.2;
B.20.a.l.a.l.a.l; B.20.a.l.a.l.a.2; B.20.a.l.a.l.b.l; B.20.a.l.a.l.b.2; B.20.a.l.a.l.c.l;
B.20.a.l.a.l.c.2; B.20.a.l.a.l.d.l; B.20.a.l.a.l.d.2; B.20.a.l.a.l.e.l; B.20.a.l.a.l.e.2;
B.20.a.l.a.l.f.l; B.20.a.l.a.l.f.2; B.20.a.l.a.l.g.l; B.20.a.l.a.l.g.2; B.20.a.l.b.l.a.l;
B.20.a.l.b.l.a.2; B.20.a.l.b.l.b.l; B.20.a.l.b.l.b.2; B.20.a.l.b.l.c.l; B.20.a.l.b.l.c.2; B.20.a.l.b.l.d.l; B.20.a.l.b.l.d.2; B.20.a.l.b.l.e.l; B.20.a.l.b.l.e.2; B.20.a.l.b.l.f.l;
B.20.a.l.b.l.f.2; B.20.a.l.b.l.g.l; B.20.a.l.b.l.g.2; B.20.a.l.f.l.a.l; B.20.a.l.f.l.a.2;
B.20.a.l.f.l.b.l; B.20.a.l.f.l.b.2; B.20.a.l.f.l.c.l; B.20.a.l.f.l.c.2; B.20.a.l.f.l.d.l;
B.20.a.l.f.l.d.2; B.20.a.l.f.l.e.l; B.20.a.l.f.l.e.2; B.20.a.l.f.l.f.l; B.20.a.l.f.l.f.2;
B.20.a.l.f.l.g.l; B.20.a.l.f.l.g.2; B.20.a.l.h.l.a.l; B.20.a.l.h.l.a.2; B.20.a.l.h.l.b.l; B.20.a.l.h.l.b.2; B.20.a.l.h.l.c.l; B.20.a.l.h.l.c.2; B.20.a.l.h.l.d.l;
B.20.a.l.h.l.d.2; B.20.a.l.h.l.e.l; B.20.a.l.h.l.e.2; B.20.a.l.h.l.f.l;
B.20.a.l.h.l.f.2; B.20.a.l.h.l.g.l; B.20.a.l.h.l.g.2; B.20.a.l.l.l.a.l; B.20.a.l.l.l.a.2;
B.20.a.l.l.l.b.l; B.20.a.l.l.l.b.2; B.20.a.l.l.l.c.l; B.20.a.l.l.l.c.2; B.20.a.l.l.l.d.l;
B.20.a.l.l.l.d.2; B.20.a.l.l.l.e.l; B.20.a.l.l.l.e.2; B.20.a.l.l.l.f.l; B.20.a.l.l.l.f.2; B.20.a.l.l.l.g.l; B.20.a.l.l.l.g.2; B.20.a.2.a.l.a.l; B.20.a.2.a.l.a.2; B.20.a.2.a.l.b.l;
B.20.a.2.a.l.b.2; B.20.a.2.a.l.c.l; B.20.a.2.a.l.c.2; B.20.a.2.a.l.d.l; B.20.a.2.a.l.d.2;
B.20.a.2.a.l.e.l; B.20.a.2.a.l.e.2; B.20.a.2.a.l.f.l; B.20.a.2.a.l.f.2; B.20.a.2.a.l.g.l;
B.20.a.2.a.l.g.2; B.20.a.2.b.l.a.l; B.20.a.2.b.l.a.2; B.20.a.2.b.l.b.l; B.20.a.2.b.l.b.2;
B.20.a.2.b.l.c.l; B.20.a.2.b.l.c.2; B.20.a.2.b.l.d.l; B.20.a.2.b.l.d.2; B.20.a.2.b.l.e.l; B.20.a.2.b.l.e.2; B.20.a.2.b.l.f.l; B.20.a.2.b.l.f.2; B.20.a.2.b.l.g.l; B.20.a.2.b.l.g.2;
B.20.a.2.f.l.a.l; B.20.a.2.f.l.a.2; B.20.a.2.f.l.b.l; B.20.a.2.f.l.b.2; B.20.a.2.f.l.c.l;
B.20.a.2.f.l.c.2; B.20.a.2.f.l.d.l; B.20.a.2.f.l.d.2; B.20.a.2.f.l.e.l; B.20.a.2.f.l.e.2;
B.20.a.2.f.l.f.l; B.20.a.2.f.l.f.2; B.20.a.2.f.l.g.l; B.20.a.2.f.l.g.2; B.20.a.2.h.l.a.l;
B.20.a.2.h.l.a.2; B.20.a.2.h.l.b.l; B.20.a.2.h.l.b.2; B.20.a.2.h.l.c.l; B.20.a.2.h.l.c.2; B.20.a.2.h.l.d.l; B.20.a.2.h.l.d.2; B.20.a.2.h.l.e.l;
B.20.a.2.h.l.e.2; B.20.a.2.h.l.f.l; B.20.a.2.h.l.f.2; B.20.a.2.h.l.g.l; B.20.a.2.h.l.g.2;
B.20.a.2.1.1.a.l; B.20.a.2.1.1.a.2; B.20.a.2.1.1.b.l; B.20.a.2.1.1.b.2; B.20.a.2.1.1.c.l;
B.20.a.2.1.1.c.2; B.20.a.2.1.1.d.l; B.20.a.2.1.1.d.2; B.20.a.2.1.1.e.l; B.20.a.2.1.1.e.2;
B.20.a.2.1.1.f.l; B.20.a.2.1.1.f.2; B.20.a.2.1.1.g.l; B.20.a.2.1.1.g.2; B.20.a.8.a.l.a.l; B.20.a.8.a.l.a.2; B.20.a.δ.a.l.b.l; B.20.a.δ.a.l.b.2; B.20.a.δ.a.l.c.l; B.20.a.δ.a.l.c.2;
B.20.a.δ.a.l.d.l; B.20.a.δ.a.l.d.2; B.20.a.δ.a.l.e.l; B.20.a.δ.a.l.e.2; B.20.a.8.a.l.f.l;
B.20.a.δ.a.l.f.2; B.20.a.δ.a.l.g.l; B.20.a.δ.a.l.g.2; B.20.a.δ.b.l.a.l; B.20.a.8.b.l.a.2;
B.20.a.δ.b.l.b.l; B.20.a.δ.b.l.b.2; B.20.a.δ.b.l.c.l; B.20.a.δ.b.l.c.2; B.20.a.δ.b.l.d.l;
B.20.a.δ.b.l.d.2; B.20.a.δ.b.l.e.l; B.20.a.8.b.l.e.2; B.20.a.8.b.l.f.l; B.20.a.δ.b.l.f.2; B.20.a.δ.b.l.g.l; B.20.a.δ.b.l.g.2; B.20.a.δ.f.l.a.l; B.20.a.8.f.l.a.2; B.20.a.8.f.l.b.l;
B.20.a.8.f.l.b.2; B.20.a.δ.f.l.c.l; B.20.a.δ.f.l.c.2; B.20.a.δ.f.l.d.l; B.20.a.8.f.l.d.2; B.20.a.δ.f.l.e.l; B.20.a.δ.f.l.e.2; B.20.a.δ.f.l.f.l; B.20.a.δ.f.l.f.2; B.20.a.8.f.l.g.l;
B.20.a.δ.f.l.g.2; B.20.a.δ.h.l.a.l; B.20.a.δ.h.l.a.2; B.20.a.δ.h.l.b.l; B.20.a.δ.h.l.b.2;
B.20.a.δ.h.l.c.l; B.20.a.δ.h.l.c.2; B.20.a.δ.h.l.d.l; B.20.a.δ.h.l.d.2;
B.20.a.δ.h.l.e.l; B.20.a.δ.h.l.e.2; B.20.a.δ.h.l.f.l; B.20.a.δ.h.l.f.2; B.20.a.δ.h.l.g.l; B.20.a.δ.h.l.g.2; B.20.a.δ.l.l.a.l; B.20.a.δ.l.l.a.2; B.20.a.δ.l.l.b.l; B.20.a.δ.l.l.b.2;
B.20.a.δ.l.l.c.l; B.20.a.δ.l.l.c.2; B.20.a.δ.l.l.d.l; B.20.a.δ.l.l.d.2; B.20.a.δ.l.l.e.l;
B.20.a.δ.l.l.e.2; B.20.a.8.1.1.f.l; B.20.a.δ.l.l.f.2; B.20.a.δ.l.l.g.l; B.20.a.δ.l.l.g.2;
B.21.a.l.a.l.a.l; B.21.a.l.a.l.a.2; B.21.a.l.a.l.b.l; B.21.a.l.a.l.b.2; B.21.a.l.a.l.c.l;
B.21.a.l.a.l.c.2; B.21.a.l.a.l.d.l; B.21.a.l.a.l.d.2; B.21.a.l.a.l.e.l; B.21.a.l.a.l.e.2; B.21.a.l.a.l.f.l; B.21.a.l.a.l.f.2; B.21.a.l.a.l.g.l; B.21.a.l.a.l.g.2; B.21.a.l.b.l.a.l;
B.21.a.l.b.l.a.2; B.21.a.l.b.l.b.l; B.21.a.l.b.l.b.2; B.21.a.l.b.l.c.l; B.21.a.l.b.l.c.2;
B.21.a.l.b.l.d.l; B.21.a.l.b.l.d.2; B.21.a.l.b.l.e.l; B.21.a.l.b.l.e.2; B.21.a.l.b.l.f.l;
B.21.a.l.b.l.f.2; B.21.a.l.b.l.g.l; B.21.a.l.b.l.g.2; B.21.a.l.f.l.a.l; B.21.a.l.f.l.a.2;
B.21.a.l.f.l.b.l; B.21.a.l.f.l.b.2; B.21.a.l.f.l.c.l; B.21.a.l.f.l.c.2; B.21.a.l.f.l.d.l; B.21.a.l.f.l.d.2; B.21.a.l.f.l.e.l; B.21.a.l.f.l.e.2; B.21.a.l.f.l.f.l; B.21.a.l.f.l.f.2;
B.21.a.l.f.l.g.l; B.21.a.l.f.l.g.2; B.21.a.l.h.l.a.l; B.21.a.l.h.l.a.2; B.21.a.l.h.l.b.l;
B.21.a.l.h.l.b.2; B.21.a.l.h.l.c.l; B.21.a.l.h.l.c.2; B.21.a.l.h.l.d.l;
B.21.a.l.h.l.d.2; B.21.a.l.h.l.e.l; B.21.a.l.h.l.e.2; B.21.a.l.h.l.f.l;
B.21.a.l.h.l.f.2; B.21.a.l.h.l.g.l; B.21.a.l.h.l.g.2; B.21.a.l.l.l.a.l; B.21.a.l.l.l.a.2; B.21.a.l.l.l.b.l; B.21.a.l.l.l.b.2; B.21.a.l.l.l.c.l; B.21.a.l.l.l.c.2; B.21.a.l.l.l.d.l;
B.21.a.l.l.l.d.2; B.21.a.l.l.l.e.l; B.21.a.l.l.l.e.2; B.21.a.l.l.l.f.l; B.21.a.l.l.l.f.2;
B.21.a.l.l.l.g.l; B.21.a.l.l.l.g.2; B.21.a.2.a.l.a.l; B.21.a.2.a.l.a.2; B.21.a.2.a.l.b.l;
B.21.a.2.a.l.b.2; B.21.a.2.a.l.c.l; B.21.a.2.a.l.c.2; B.21.a.2.a.l.d.l; B.21.a.2.a.l.d.2;
B.21.a.2.a.l.e.l; B.21.a.2.a.l.e.2; B.21.a.2.a.l.f.l; B.21.a.2.a.l.f.2; B.21.a.2.a.l.g.l; B.21.a.2.a.l.g.2; B.21.a.2.b.l.a.l; B.21.a.2.b.l.a.2; B.21.a.2.b.l.b.l; B.21.a.2.b.l.b.2;
B.21.a.2.b.l.c.l; B.21.a.2.b.l.c.2; B.21.a.2.b.l.d.l; B.21.a.2.b.l.d.2; B.21.a.2.b.l.e.l;
B.21.a.2.b.l.e.2; B.21.a.2.b.l.f.l; B.21.a.2.b.l.f.2; B.21.a.2.b.l.g.l; B.21.a.2.b.l.g.2;
B.21.a.2.f.l.a.l; B.21.a.2.f.l.a.2; B.21.a.2.f.l.b.l; B.21.a.2.f.l.b.2; B.21.a.2.f.l.c.l;
B.21.a.2.f.l.c.2; B.21.a.2.f.l.d.l; B.21.a.2.f.l.d.2; B.21.a.2.f.l.e.l; B.21.a.2.f.l.e.2; B.21.a.2.f.l.f.l; B.21.a.2.f.l.f.2; B.21.a.2.f.l.g.l; B.21.a.2.f.l.g.2; B.21.a.2.h.l.a.l;
B.21.a.2.h.l.a.2; B.21.a.2.h.l.b.l; B.21.a.2.h.l.b.2; B.21.a.2.h.l.c.l;
B.21.a.2.h.l.c.2; B.21.a.2.h.l.d.l; B.21.a.2.h.l.d.2; B.21.a.2.h.l.e.l;
B.21.a.2.h.l.e.2; B.21.a.2.h.l.f.l; B.21.a.2.h.l.f.2; B.21.a.2.h.l.g.l; B.21.a.2.h.l.g.2;
B.21.a.2.1.1.a.l; B.21.a.2.1.1.a.2; B.21.a.2.1.1.b.l; B.21.a.2.1.1.b.2; B.21.a.2.1.1.c.l; B.21.a.2.1.1.c.2; B.21.a.2.1.1.d.l; B.21.a.2.1.1.d.2; B.21.a.2.1.1.e.l; B.21.a.2.1.1.e.2;
B.21.a.2.1.1.f.l; B.21.a.2.1.1.f.2; B.21.a.2.1.1.g.l; B.21.a.2.1.1.g.2; B.21.a.δ.a.l.a.l;
B.21.a.δ.a.l.a.2; B.21.a.δ.a.l.b.l; B.21.a.δ.a.l.b.2; B.21.a.δ.a.l.c.l; B.21.a.δ.a.l.c.2;
B.21.a.δ.a.l.d.l; B.21.a.δ.a.l.d.2; B.21.a.δ.a.l.e.l; B.21.a.δ.a.l.e.2; B.21.a.8.a.l.f.l;
B.21.a.δ.a.l.f.2; B.21.a.δ.a.l.g.l; B.21.a.δ.a.l.g.2; B.21.a.δ.b.l.a.l; B.21.a.δ.b.l.a.2; B.21.a.8.b.l.b.l; B.21.a.δ.b.l.b.2; B.21.a.8.b.l.c.l; B.21.a.8.b.l.c.2; B.21.a.δ.b.l.d.l;
B.21.a.δ.b.l.d.2; B.21.a.δ.b.l.e.l; B.21.a.δ.b.l.e.2; B.21.a.8.b.l.f.l; B.21.a.δ.b.l.f.2;
B.21.a.β.b.l.g.l; B.21.a.8.b.l.g.2; B.21.a.δ.f.l.a.l; B.21.a.δ.f.l.a.2; B.21.a.δ.f.l.b.l;
B.21.a.δ.f.l.b.2; B.21.a.δ.f.l.c.l; B.21.a.δ.f.l.c.2; B.21.a.8.f.l.d.l; B.21.a.δ.f.l.d.2;
B.21.a.δ.f.l.e.l; B.21.a.δ.f.l.e.2; B.21.a.δ.f.l.f.l; B.21.a.δ.f.l.f.2; B.21.a.8.f.l.g.l; B.21.a.δ.f.l.g.2; B.21.a.δ.h.l.a.l; B.21.a.δ.h.l.a.2; B.21.a.δ.h.l.b.l; B.21.a.δ.h.l.b.2;
B.21.a.δ.h.l.c.l; B.21.a.δ.h.l.c.2; B.21.a.δ.h.l.d.l; B.21.a.δ.h.l.d.2;
65- B.21.a.8.h.l.e.l; B.21.a.δ.h.l.e.2; B.21.a.8.h.l.f.l; B.21.a.δ.h.l.f.2; B.21.a.δ.h.l.g.l;
B.21.a.δ.h.l.g.2; B.21.a.8.1.1.a.l; B.21.a.8.1.1.a.2; B.21.a.δ.l.l.b.l; B.21.a.8.1.1.b.2;
B.21.a.8.1.1.c.l; B.21.a.δ.l.l.c.2; B.21.a.δ.l.l.d.l; B.21.a.δ.l.l.d.2; B.21.a.8.1.1.e.l;
B.21.a.δ.l.l.e.2; B.21.a.δ.l.l.f.l; B.21.a.δ.l.l.f.2; B.21.a.δ.l.l.g.l; B.21.a.8.1.1.g.2; B.22.a.l.a.l.a.l; B.22.a.l.a.l.a.2; B.22.a.l.a.l.b.l; B.22.a.l.a.l.b.2; B.22.a.l.a.l.c.l;
B.22.a.l.a.l.c.2; B.22.a.l.a.l.d.l; B.22.a.l.a.l.d.2; B.22.a.l.a.l.e.l; B.22.a.l.a.l.e.2;
B.22.a.l.a.l.f.l; B.22.a.l.a.l.f.2; B.22.a.l.a.l.g.l; B.22.a.l.a.l.g.2; B.22.a.l.b.l.a.l;
B.22.a.l.b.l.a.2; B.22.a.l.b.l.b.l; B.22.a.l.b.l.b.2; B.22.a.l.b.l.c.l; B.22.a.l.b.l.c.2;
B.22.a.l.b.l.d.l; B.22.a.l.b.l.d.2; B.22.a.l.b.l.e.l; B.22.a.l.b.l.e.2; B.22.a.l.b.l.f.l; B.22.a.l.b.l.f.2; B.22.a.l.b.l.g.l; B.22.a.l.b.l.g.2; B.22.a.l.f.l.a.l; B.22.a.l.f.l.a.2;
B.22.a.l.f.l.b.l; B.22.a.l.f.l.b.2; B.22.a.l.f.l.c.l; B.22.a.l.f.l.c.2; B.22.a.l.f.l.d.l;
B.22.a.l.f.l.d.2; B.22.a.l.f.l.e.l; B.22.a.l.f.l.e.2; B.22.a.l.f.l.f.l; B.22.a.l.f.l.f.2;
B.22.a.l.f.l.g.l; B.22.a.l.f.l.g.2; B.22.a.l.h.l.a.l; B.22.a.l.h.l.a.2; B.22.a.l.h.l.b.l;
B.22.a.l.h.l.b.2; B.22.a.l.h.l.c.l; B.22.a.l.h.l.c.2; B.22.a.l.h.l.d.l; B.22.a.l.h.l.d.2; B.22.a.l.h.l.e.l; B.22.a.l.h.l.e.2; B.22.a.l.h.l.f.l;
B.22.a.l.h.l.f.2; B.22.a.l.h.l.g.l; B.22.a.l.h.l.g.2; B.22.a.l.l.l.a.l; B.22.a.l.l.l.a.2;
B.22.a.l.l.l.b.l; B.22.a.l.l.l.b.2; B.22.a.l.l.l.c.l; B.22.a.l.l.l.c.2; B.22.a.l.l.l.d.l;
B.22.a.l.l.l.d.2; B.22.a.l.l.l.e.l; B.22.a.l.l.l.e.2; B.22.a.l.l.l.f.l; B.22.a.l.l.l.f.2;
B.22.a.l.l.l.g.l; B.22.a.l.l.l.g.2; B.22.a.2.a.l.a.l; B.22.a.2.a.l.a.2; B.22.a.2.a.l.b.l; B.22.a.2.a.l.b.2; B.22.a.2.a.l.c.l; B.22.a.2.a.l.c.2; B.22.a.2.a.l.d.l; B.22.a.2.a.l.d.2;
B.22.a.2.a.l.e.l; B.22.a.2.a.l.e.2; B.22.a.2.a.l.f.l; B.22.a.2.a.l.f.2; B.22.a.2.a.l.g.l;
B.22.a.2.a.l.g.2; B.22.a.2.b.l.a.l; B.22.a.2.b.l.a.2; B.22.a.2.b.l.b.l; B.22.a.2.b.l.b.2;
B.22.a.2.b.l.c.l; B.22.a.2.b.l.c.2; B.22.a.2.b.l.d.l; B.22.a.2.b.l.d.2; B.22.a.2.b.l.e.l;
B.22.a.2.b.l.e.2; B.22.a.2.b.l.f.l; B.22.a.2.b.l.f.2; B.22.a.2.b.l.g.l; B.22.a.2.b.l.g.2; B.22.a.2.f.l.a.l; B.22.a.2.f.l.a.2; B.22.a.2.f.l.b.l; B.22.a.2.f.l.b.2; B.22.a.2.f.l.c.l;
B.22.a.2.f.l.c.2; B.22.a.2.f.l.d.l; B.22.a.2.f.l.d.2; B.22.a.2.f.l.e.l; B.22.a.2.f.l.e.2;
B.22.a.2.f.l.f.l; B.22.a.2.f.l.f.2; B.22.a.2.f.l.g.l; B.22.a.2.f.l.g.2; B.22.a.2.h.l.a.l;
B.22.a.2.h.l.a.2; B.22.a.2.h.l.b.l; B.22.a.2.h.l.b.2; B.22.a.2.h.l.c.l;
B.22.a.2.h.l.c.2; B.22.a.2.h.l.d.l; B.22.a.2.h.l.d.2; B.22.a.2.h.l.e.l; B.22.a.2.h.l.e.2; B.22.a.2.h.l.f.l; B.22.a.2.h.l.f.2; B.22.a.2.h.l.g.l; B.22.a.2.h.l.g.2;
B.22.a.2.1.1.a.l; B.22.a.2.1.1.a.2; B.22.a.2.1.1.b.l; B.22.a.2.1.1.b.2; B.22.a.2.1.1.c.l;
B.22.a.2.1.1.c.2; B.22.a.2.1.1.d.l; B.22.a.2.1.1.d.2; B.22.a.2.1.1.e.l; B.22.a.2.1.1.e.2;
B.22.a.2.1.1.f.l; B.22.a.2.1.1.f.2; B.22.a.2.1.1.g.l; B.22.a.2.1.1.g.2; B.22.a.δ.a.l.a.l;
B.22.a.δ.a.l.a.2; B.22.a.δ.a.l.b.l; B.22.a.δ.a.l.b.2; B.22.a.8.a.l.c.l; B.22.a.8.a.l.c.2; B.22.a.δ.a.l.d.l; B.22.a.δ.a.l.d.2; B.22.a.8.a.l.e.l; B.22.a.δ.a.l.e.2; B.22.a.8.a.l.f.l;
B.22.a.δ.a.l.f.2; B.22.a.δ.a.l.g.l; B.22.a.δ.a.l.g.2; B.22.a.δ.b.l.a.l; B.22.a.δ.b.l.a.2;
B.22.a.δ.b.l.b.l; B.22.a.δ.b.l.b.2; B.22.a.δ.b.l.c.l; B.22.a.8.b.l.c.2; B.22.a.8.b.l.d.l;
B.22.a.δ.b.l.d.2; B.22.a.δ.b.l.e.l; B.22.a.8.b.l.e.2; B.22.a.8.b.l.f.l; B.22.a.8.b.l.f.2;
B.22.a.δ.b.l.g.l; B.22.a.δ.b.l.g.2; B.22.a.δ.f.l.a.l; B.22.a.δ.f.l.a.2; B.22.a.δ.f.l.b.l; B.22.a.δ.f.l.b.2; B.22.a.δ.f.l.c.l; B.22.a.δ.f.l.c.2; B.22.a.δ.f.l.d.l; B.22.a.δ.f.l.d.2;
B.22.a.δ.f.l.e.l; B.22.a.δ.f.l.e.2; B.22.a.δ.f.l.f.l; B.22.a.δ.f.l.f.2; B.22.a.8.f.l.g.l;
B.22.a.δ.f.l.g.2; B.22.a.δ.h.l.a.l; B.22.a.δ.h.l.a.2; B.22.a.δ.h.l.b.l; B.22.a.8.h.l.b.2;
B.22.a.δ.h.l.c.l; B.22.a.δ.h.l.c.2; B.22.a.δ.h.l.d.l; B.22.a.δ.h.l.d.2;
B.22.a.δ.h.l.e.l; B.22.a.δ.h.l.e.2; B.22.a.δ.h.l.f.l; B.22.a.δ.h.l.f.2; B.22.a.δ.h.l.g.l; B.22.a.8.h.l.g.2; B.22.a.δ.l.l.a.l; B.22.a.δ.l.l.a.2; B.22.a.δ.l.l.b.l; B.22.a.8.1.1.b.2;
B.22.a.8.1.1.c.l; B.22.a.δ.l.l.c.2; B.22.a.δ.l.l.d.l; B.22.a.δ.l.l.d.2; B.22.a.δ.l.l.e.l;
- δό- B.22.a.6.1.1.e.2; B.22.a.δ.l.l.f.l; B.22.a.δ.l.l.f.2; B.22.a.δ.l.l.g.l; B.22.a.δ.l.l.g.2;
A.7.a.l.a.l.a.l; A.7.a.l.a.l.a.2; A.7.a.l.a.l.A.l; A.7.a.l.a.l.A.2; A.7.a.l.a.l.c.l;
A.7.a.l.a.l.c.2; A.7.a.l.a.l.d.l; A.7.a.l.a.l.d.2; A.7.a.l.a.l.e.l; A.7.a.l.a.l.e.2;
A.7.a.l.a.l.f.l; A.7.a.l.a.l.f.2; A.7.a.l.a.l.g.l; A.7.a.l.a.l.g.2; A.7.a.l.A.l.a.l; A.7.a.l.A.l.a.2; A.7.a.l.A.l.A.l; A.7.a.l.A.l.A.2; A.7.a.l.A.l.c.l; A.7.a.l.A.l.c.2;
A.7.a.l.A.l.d.l; A.7.a.l.A.l.d.2; A.7.a.l.A.l.e.l; A.7.a.l.A.l.e.2; A.7.a.l.A.l.f.l;
A.7.a.l.A.l.f.2; A.7.a.l.A.l.g.l; A.7.a.l.A.l.g.2; A.7.a.l.f.l.a.l; A.7.a.l.f.l.a.2;
A.7.a.l.f.l.A.l; A.7.a.l.f.l.A.2; A.7.a.l.f.l.c.l; A.7.a.l.f.l.c.2; A.7.a.l.f.l.d.l;
A.7.a.l.f.l.d.2; A.7.a.l.f.l.e.l; A.7.a.l.f.l.e.2; A.7.a.l.f.l.f.l; A.7.a.l.f.li.2; A.7.a.l.f.l.g.l; A.7.a.l.f.l.g.2; A.7.a.l.h.l.a.l; A.7.a.l.h.l.a.2; A.7.a.l.h.l.A.l;
A.7.a.l.h.l.A.2; A.7.a.l.h.l.c.l; A.7.a.l.h.l.c.2; A.7.a.l.h.l.d.l; A.7.a.l.h.l.d.2;
A.7.a.l.h.l.e.l; A.7.a.l.h.l.e.2; A.7.a.l.h.l.f.l; A.7.a.l.h.l.f.2; A.7.a.l.h.l.g.l;
A.7.a.l.h.l.g.2; A.7.a.l.l.l.a.l; A.7.a.l.l.l.a.2; A.7.a.l.l.l.A.l; A.7.a.l.l.l.A.2;
A.7.a.l.l.l.c.l; A.7.a.l.l.l.c.2; A.7.a.l.l.l.d.l; A.7.a.l.l.l.d.2; A.7.a.l.l.l.e.l; A.7.a.l.l.l.e.2; A.7.a.l.l.l.f.l; A.7.a.l.l.l.f.2; A.7.a.l.l.l.g.l; A.7.a.l.l.l.g.2;
A.7.a.2.a.l.a.l; A.7.a.2.a.l.a.2; A.7.a.2.a.l.A.l; A.7.a.2.a.l.A.2; A.7.a.2.a.l.c.l;
A.7.a.2.a.l.c.2; A.7.a.2.a.l.d.l; A.7.a.2.a.l.d.2; A.7.a.2.a.l.e.l; A.7.a.2.a.l.e.2;
A.7.a.2.a.l.f.l; A.7.a.2.a.l.f.2; A.7.a.2.a.l.g.l; A.7.a.2.a.l.g.2; A.7.a.2.A.l.a.l;
A.7.a.2.A.l.a.2; A.7.a.2.A.l.A.l; A.7.a.2.A.l.A.2; A.7.a.2.A.l.c.l; A.7.a.2.A.l.c.2; A.7.a.2.A.l.d.l; A.7.a.2.A.l.d.2; A.7.a.2.A.l.e.l; A.7.a.2.A.l.e.2; A.7.a.2.A.l.f.l;
A.7.a.2.A.l.f.2; A.7.a.2.A.l.g.l; A.7.a.2.A.l.g.2; A.7.a.2.f.l.a.l; A.7.a.2.f.l.a.2;
A.7.a.2.f.l.A.l; A.7.a.2.f.l.A.2; A.7.a.2.f.l.c.l; A.7.a.2.f.l.c.2; A.7.a.2.f.l.d.l;
A.7.a.2.f.l.d.2; A.7.a.2.f.l.e.l; A.7.a.2.f.l.e.2; A.7.a.2.f.l.f.l; A.7.a.2.f.l.f.2;
A.7.a.2.f.l.g.l; A.7.a.2.f.l.g.2; A.7.a.2.h.l.a.l; A.7.a.2.h.l.a.2; A.7.a.2.h.l.A.l; A.7.a.2.h.l.A.2; A.7.a.2.h.l.c.l; A.7.a.2.h.l.c.2; A.7.a.2.h.l.d.l; A.7.a.2.h.l.d.2;
A.7.a.2.h.l.e.l; A.7.a.2.h.l.e.2; A.7.a.2.h.l.f.l; A.7.a.2.h.l.f.2; A.7.a.2.h.l.g.l;
A.7.a.2.h.l.g.2; A.7.a.2.1.1.a.l; A.7.a.2.1.1.a.2; A.7.a.2.1.1.A.l; A.7.a.2.1.1.A.2;
A.7.a.2.1.1.c.l; A.7.a.2.1.1.c.2; A.7.a.2.1.1.d.l; A.7.a.2.1.1.d.2; A.7.a.2.1.1.e.l;
A.7.a.2.1.1.e.2; A.7.a.2.1.1.f.l; A.7.a.2.1.1.f.2; A.7.a.2.1.1.g.l; A.7.a.2.1.1.g.2; A.7.a.δ.a.l.a.l; A.7.a.δ.a.l.a.2; A.7.a.δ.a.l.A.l; A.7.a.δ.a.l.A.2; A.7.a.δ.a.l.c.l;
A.7.a.δ.a.l.c.2; A.7.a.δ.a.l.d.l; A.7.a.δ.a.l.d.2; A.7.a.δ.a.l.e.l; A.7.a.8.a.l.e.2;
A.7.a.δ.a.l.f.l; A.7.a.δ.a.l.f.2; A.7.a.δ.a.l.g.l; A.7.a.δ.a.l.g.2; A.7.a.δ.A.l.a.l;
A.7.a.δ.A.l.a.2; A.7.a.δ.A.l.A.l; A.7.a.δ.A.l.A.2; A.7.a.δ.A.l.c.l; A.7.a.δ.A.l.c.2;
A.7.a.δ.A.l.d.l; A.7.a.δ.A.l.d.2; A.7.a.δ.A.l.e.l; A.7.a.δ.A.l.e.2; A.7.a.δ.A.l.f.l; A.7.a.8.A.l.f.2; A.7.a.8.A.l.g.l; A.7.a.δ.A.l.g.2; A.7.a.δ.f.l.a.l; A.7.a.δ.f.l.a.2;
A.7.a.8.f.l.A.l; A.7.a.δ.f.l.A.2; A.7.a.8.f.l.c.l; A.7.a.8.f.l.c.2; A.7.a.δ.f.l.d.l;
A.7.a.δ.f.l.d.2; A.7.a.δ.f.l.e.l; A.7.a.8.f.l.e.2; A.7.a.8.f.l.f.l; A.7.a.8.f.l.f.2;
A.7.a.δ.f.l.g.l; A.7.a.8.f.l.g.2; A.7.a.8.h.l.a.l; A.7.a.δ.h.l.a.2; A.7.a.8.h.l.A.l;
A.7.a.δ.h.l.A.2; A.7.a.δ.h.l.c.l; A.7.a.δ.h.l.c.2; A.7.a.δ.h.l.d.l; A.7.a.δ.h.l.d.2; A.7.a.δ.h.l.e.l; A.7.a.δ.h.l.e.2; A.7.a.δ.h.l.f.l; A.7.a.δ.h.l.f.2; A.7.a.8.h.l.g.l;
A.7.a.δ.h.l.g.2; A.7.a.δ.l.l.a.l; A.7.a.δ.l.l.a.2; A.7.a.δ.l.l.A.l; A.7.a.δ.l.l.A.2;
A.7.a.8.1.1.c.l; A.7.a.δ.l.l.c.2; A.7.a.8.1.1.d.l; A.7.a.δ.l.l.d.2; A.7.a.δ.l.l.e.l;
A.7.a.δ.l.l.e.2; A.7.a.δ.l.l.f.l; A.7.a.δ.l.l.f.2; A.7.a.δ.l.l.g.l; A.7.a.δ.l.l.g.2;
B.7.a.l.a.l.a.l; B.7.a.l.a.l.a.2; B.7.a.l.a.l.b.l; B.7.a.l.a.l.b.2; B.7.a.l.a.l.c.l; B.7.a.l.a.l.c.2; B.7.a.l.a.l.d.l; B.7.a.l.a.l.d.2; B.7.a.l.a.l.e.l; B.7.a.l.a.l.e.2;
B.7.a.l.a.l.f.l; B.7.a.l.a.l.f.2; B.7.a.l.a.l.g.l; B.7.a.l.a.l.g.2; B.7.a.l.b.l.a.l; B.7.a.l.b.l.a.2; B.7.a.l.b.l.b.l; B.7.a.l.b.l.b.2; B.7.a.l.b.l.c.l; B.7.a.l.b.l.c.2;
B.7.a.l.b.l.d.l; B.7.a.l.b.l.d.2; B.7.a.l.b.l.e.l; B.7.a.l.b.l.e.2; B.7.a.l.b.l.f.l;
B.7.a.l.b.l.f.2; B.7.a.l.b.l.g.l; B.7.a.l.b.l.g.2; B.7.a.l.f.l.a.l; B.7.a.l.f.l.a.2;
B.7.a.l.f.l.b.l; B.7.a.l.f.l.b.2; B.7.a.l.f.l.c.l; B.7.a.l.f.l.c.2; B.7.a.l.f.l.d.l; B.7.a.l.f.l.d.2; B.7.a.l.f.l.e.l; B.7.a.l.f.l.e.2; B.7.a.l.f.l.f.l; B.7.a.l.f.l.f.2;
B.7.a.l.f.l.g.l; B.7.a.l.f.l.g.2; B.7.a.l.h.l.a.l; B.7.a.l.h.l.a.2; B.7.a.l.h.l.b.l;
B.7.a.l.h.l.b.2; B.7.a.l.h.l.c.l; B.7.a.l.h.l.c.2; B.7.a.l.h.l.d.l; B.7.a.l.h.l.d.2;
B.7.a.l.h.l.e.l; B.7.a.l.h.l.e.2; B.7.a.l.h.l.f.l; B.7.a.l.h.l.f.2; B.7.a.l.h.l.g.l;
B.7.a.l.h.l.g.2; B.7.a.l.l.l.a.l; B.7.a.l.l.l.a.2; B.7.a.l.l.l.b.l; B.7.a.l.l.l.b.2; B.7.a.l.l.l.c.l; B.7.a.l.l.l.c.2; B.7.a.l.l.l.d.l; B.7.a.l.l.l.d.2; B.7.a.l.l.l.e.l;
B.7.a.l.l.l.e.2; B.7.a.l.l.l.f.l; B.7.a.l.l.l.f.2; B.7.a.l.l.l.g.l; B.7.a.l.l.l.g.2;
B.7.a.2.a.l.a.l; B.7.a.2.a.l.a.2; B.7.a.2.a.l.b.l; B.7.a.2.a.l.b.2; B.7.a.2.a.l.c.l;
B.7.a.2.a.l.c.2; B.7.a.2.a.l.d.l; B.7.a.2.a.l.d.2; B.7.a.2.a.l.e.l; B.7.a.2.a.l.e.2;
B.7.a.2.a.l.f.l; B.7.a.2.a.l.f.2; B.7.a.2.a.l.g.l; B.7.a.2.a.l.g.2; B.7.a.2.b.l.a.l; B.7.a.2.b.l.a.2; B.7.a.2.b.l.b.l; B.7.a.2.b.l.b.2; B.7.a.2.b.l.c.l; B.7.a.2.b.l.c.2;
B.7.a.2.b.l.d.l; B.7.a.2.b.l.d.2; B.7.a.2.b.l.e.l; B.7.a.2.b.l.e.2; B.7.a.2.b.l.f.l;
B.7.a.2.b.l.f.2; B.7.a.2.b.l.g.l; B.7.a.2.b.l.g.2; B.7.a.2.f.l.a.l; B.7.a.2.f.l.a.2;
B.7.a.2.f.l.b.l; B.7.a.2.f.l.b.2; B.7.a.2.f.l.c.l; B.7.a.2.f.l.c.2; B.7.a.2.f.l.d.l;
B.7.a.2.f.l.d.2; B.7.a.2.f.l.e.l; B.7.a.2.f.l.e.2; B.7.a.2.f.l.f.l; B.7.a.2.f.l.f.2; B.7.a.2.f.l.g.l; B.7.a.2.f.l.g.2; B.7.a.2.h.l.a.l; B.7.a.2.h.l.a.2; B.7.a.2.h.l.b.l;
B.7.a.2.h.l.b.2; B.7.a.2.h.l.c.l; B.7.a.2.h.l.c.2; B.7.a.2.h.l.d.l; B.7.a.2.h.l.d.2;
B.7.a.2.h.l.e.l; B.7.a.2.h.l.e.2; B.7.a.2.h.l.f.l; B.7.a.2.h.l.f.2; B.7.a.2.h.l.g.l;
B.7.a.2.h.l.g.2; B.7.a.2.1.1.a.l; B.7.a.2.1.1.a.2; B.7.a.2.1.1.b.l; B.7.a.2.1.1.b.2;
B.7.a.2.1.1.c.l; B.7.a.2.1.1.c.2; B.7.a.2.1.1.d.l; B.7.a.2.1.1.d.2; B.7.a.2.1.1.e.l; B.7.a.2.1.1.e.2; B.7.a.2.1.1.f.l; B.7.a.2.1.1.f.2; B.7.a.2.1.1.g.l; B.7.a.2.1.1.g.2;
B.7.a.δ.a.l.a.l; B.7.a.8.a.l.a.2; B.7.a.8.a.l.b.l; B.7.a.δ.a.l.b.2; B.7.a.δ.a.l.c.l;
B.7.a.δ.a.l.c.2; B.7.a.8.a.l.d.l; B.7.a.δ.a.l.d.2; B.7.a.δ.a.l.e.l; B.7.a.8.a.l.e.2;
B.7.a.8.a.l.f.l; B.7.a.δ.a.l.f.2; B.7.a.δ.a.l.g.l; B.7.a.δ.a.l.g.2; B.7.a.δ.b.l.a.l;
B.7.a.δ.b.l.a.2; B.7.a.8.b.l.b.l; B.7.a.δ.b.l.b.2; B.7.a.δ.b.l.c.l; B.7.a.8.b.l.c.2; B.7.a.8.b.l.d.l; B.7.a.δ.b.l.d.2; B.7.a.δ.b.l.e.l; B.7.a.δ.b.l.e.2; B.7.a.δ.b.l.f.l;
B.7.a.8.b.l.f.2; B.7.a.δ.b.l.g.l; B.7.a.δ.b.l.g.2; B.7.a.8.f.l.a.l; B.7.a.8.f.l.a.2;
B.7.a.8.f.l.b.l; B.7.a.δ.f.l.b.2; B.7.a.δ.f.l.c.l; B.7.a.8.f.l.c.2; B.7.a.δ.f.l.d.l;
B.7.a.δ.f.l.d.2; B.7.a.δ.f.l.e.l; B.7.a.δ.f.l.e.2; B.7.a.8.f.l.f.l; B.7.a.8.f.l.f.2;
B.7.a.δ.f.l.g.l; B.7.a.δ.f.l.g.2; B.7.a.δ.h.l.a.l; B.7.a.δ.h.l.a.2; B.7.a.δ.h.l.b.l; B.7.a.δ.h.l.b.2; B.7.a.δ.h.l.c.l; B.7.a.8.h.l.c.2; B.7.a.δ.h.l.d.l; B.7.a.δ.h.l.d.2;
B.7.a.δ.h.l.e.l; B.7.a.δ.h.l.e.2; B.7.a.δ.h.l.f.l; B.7.a.δ.h.l.f.2; B.7.a.δ.h.l.g.l;
B.7.a.δ.h.l.g.2; B.7.a.8.1.1.a.l; B.7.a.8.1.1.a.2; B.7.a.δ.l.l.b.l; B.7.a.δ.l.l.b.2;
B.7.a.δ.l.l.c.l; B.7.a.δ.l.l.c.2; B.7.a.8.1.1.d.l; B.7.a.δ.l.l.d.2; B.7.a.8.1.1.e.l;
B.7.a.8.1.1.e.2; B.7.a.δ.l.l.f.l; B.7.a.8.1.1.f.2; B.7.a.8.1.1.g.l; B.7.a.δ.l.l.g.2;
- δδ- Salts and Hydrates The compositions of this invention optionally comprise salts of the compounds herein, especially pharmaceutically acceptable non-toxic salts containing, for example, Na+, Li+, K+' Ca++ and Mg++. Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. Monovalent salts are preferred if a water soluble salt is desired.
Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HC1, HBr, H2Sθ4, H3PO4, or organic sulfonic acids, to basic centers, typically amines of group, or to acidic groups. Finally, it is to be understood that the compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoiochimetric amounts of water as in hydrates.
Also included within the scope of this invention are the salts of the parental compounds with one or more amino acids. Any of the amino acids described above are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
- 69- Methods of Inhibition of Thrombin Another aspect of the invention relates to methods of inhibiting the activity of thrombin comprising the step of treating a sample suspected of containing thrombin with a compound of the invention. Compositions of the invention act as inhibitors of thrombin, as intermediates for such inhibitors or have other utilities as described below. The inhibitors will bind to locations on the surface or in a cavity of thrombin having a geometry unique to thrombin. Compositions binding thrombin may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. In a typical embodiment the compositions bind thrombin with a binding coefficient of less than 10"^M, more typically less than lO'^M, still more typically lO'^M. Once labeled, the substantially irreversibly binding compositions are useful as probes for the detection of thrombin. Accordingly, the invention relates to methods of detecting thrombin in a sample suspected of containing thrombin comprising the steps of: treating a sample suspected of containing thrombin with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label. Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in conventional fashion using functional groups such as hydroxyl or amino. Within the context of the invention samples suspected of containing thrombin include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing an organism which produces thrombin, frequently a pathogenic organism such as a virus. Samples can be contained in any medium including water and organic solvent/water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures. The treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the sample. The addition step comprises any method of administration as described above. If desired, the activity of thrombin after application of the composition can be observed by any method including direct and indirect methods of detecting thrombin activity. Quantitative, qualitative, and semiquantitative methods of determining thrombin activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
Screens for Thrombin Inhibitors Compositions of the invention are screened for inhibitory activity against thrombin by any of the conventional techniques for evaluating enzyme activity. Within the context of the invention, typically compositions are first screened for inhibition of thrombin in vitro and compositions showing inhibitory activity are then screened for activity in vivo. Useful in vitro screens have been described in detail and will not be elaborated here. Colman, R.W., et al; Ed.; "Hemostasis and Thrombosis, Basic Principles and Clinical Practice," 2nd Ed., J.B. Loppincott Company, Philadelphia, 1982, describes methods and materials for such assays. In particular, Simmons, A.; Hemoatology, A Combined Theoretical and Technical Approach, Chapter 20, 2nd Ed., Butterworth-Heinemann, Newton, MA, 1997, pp. 343-360, describes details of a useful assay.
Pharmaceutical Formulations and Routes of Administration The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10. One or more compounds of the invention (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally; it is not necessary to administer them by intrapulmonary or intranasal routes. Surprisingly, (in view of, inter alia, Bamford, M. J., "J. Enzyme Inhibition" 10:1-6 (1995), and especially p. 15, first full paragraph), the anti-influenza compounds of WO 91/16320, WO 92/06691 and U.S. Patent 5,360,817 are successfully administered by the oral or intraperitoneal routes. See Example 161 infra.
While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the invention suitable for oral administration are prepared as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non- aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom. In one embodiment acid hydrolysis of the medicament is obviated by use of an enteric coating. For infections of the eye or other external tissues e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w. Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier. Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of influenza A or B infections as described below. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route. Compounds of the invention are used to provide controlled release pharmaceutical formulations containing as active ingredient one or more compounds of the invention ("controlled release formulations") in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active influenza infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about .01 to about 5 mg/kg body weight per day. More typically, from about .05 to about 0.5 mg/kg body weight per day. For example, for inhalation the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
Active ingredients of the invention are also used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco- properties of the combination. For example, when treating viral infections of the respiratory system, in particular influenza infection, the compositions of the invention are combined with antivirals (such as amantidine, rimantadine and ribavirin), mucolytics, expectorants, bronchialdilators, antibiotics, antipyretics, or analgesics. Ordinarily, antibiotics, antipyretics, and analgesics are administered together with the compounds of this invention.
Metabolites of the Compounds of the Invention Also falling within the scope of this invention are the in vivo metabolic products of the compounds described herein, to the extent such products are novel and unobvious over the prior art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, esterification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. C^ or H^) compound of the invention, administering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no thrombin inhibitory activity of their own.
Additional Uses for the Compounds of This Invention
The compounds of this invention, or the biologically active substances produced from these compounds by hydrolysis or metabolism in vivo, are used as immunogens or for conjugation to proteins, whereby they serve as components of immunogenic compositions to prepare antibodies capable of binding specifically to the protein, to the compounds or to their metabolic products which retain immunologically recognized epitopes (sites of antibody binding). The immunogenic compositions therefore are useful as intermediates in the preparation of antibodies for use in diagnostic, quality control, or the like, methods or in assays for the compounds or their novel metabolic products. The compounds are useful for raising antibodies against otherwise non-immunogenic polypeptides, in that the compounds serve as haptenic sites stimulating an immune response that cross-reacts with the unmodified conjugated protein.
The hydrolysis products of interest include products of the hydrolysis of the protected acidic and basic groups discussed above. As noted above, the acidic or basic amides comprising immunogenic polypeptides such as albumin or keyhole limpet hemocyanin generally are useful as immunogens. The metabolic products described above may retain a substantial degree of immunological cross reactivity with the compounds of the invention. Thus, the antibodies of this invention will be capable of binding to the unprotected compounds of the invention without binding to the protected compounds; alternatively the metabolic products, will be capable of binding to the protected compounds and/or the metabolitic products without binding to the protected compounds of the invention, or will be capable of binding specifically to any one or all three. The antibodies desirably will not substantially cross-react with naturally- occurring materials. Substantial cross-reactivity is reactivity under specific assay conditions for specific analytes sufficient to interfere with the assay results.
The immunogens of this invention contain the compound of this invention presenting the desired epitope in association with an immunogenic substance. Within the context of the invention such association means covalent bonding to form an immunogenic conjugate (when applicable) or a mixture of non-covalently bonded materials, or a combination of the above. Immunogenic substances include adjuvants such as Freund's adjuvant, immunogenic proteins such as viral, bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor, and immunogenic polysaccharides. Typically, the compound having the structure of the desired epitope is covalently conjugated to an immunogenic polypeptide or polysaccharide by the use of a polyfunctional (ordinarily bifunctional) cross-linking agent. Methods for the manufacture of hapten immunogens are conventional per se. and any of the methods used heretofore for conjugating haptens to immunogenic polypeptides or the like are suitably employed here as well, taking into account the functional groups on the precursors or hydrolytic products which are available for cross-linking and the likelihood of producing antibodies specific to the epitope in question as opposed to the immunogenic substance.
Typically the polypeptide is conjugated to a site on the compound of the invention distant from the epitope to be recognized. The conjugates are prepared in conventional fashion. For example, the cross-linking agents N-hydroxysuccinimide, succinic anhydride or alkN=C=Nalk are useful in preparing the conjugates of this invention. The conjugates comprise a compound of the invention attached by a bond or a linking group of 1-100, typically, 1-25, more typically 1-10 carbon atoms to the immunogenic substance. The conjugates are separated from starting materials and by products using chromatography or the like, and then are sterile filtered and vialed for storage.
The compounds of this invention are cross-linked for example through a hydroxyl, carboxyl or amine group. Included within such compounds are amides of polypeptides where the polypeptide serves as an above-described Rόc or Rόb groups.
Animals are typically immunized against the immunogenic conjugates or derivatives and antisera or monoclonal antibodies prepared in conventional fashion. The compounds of the invention are polyfunctional. As such they represent a unique class of monomers for the synthesis of polymers. By way of example and not limitation, the polymers prepared from the compounds of this invention include polyamides and polyesters.
The present compounds are used as monomers to provide access to polymers having unique pendent functionalities. The compounds of this invention are useful in homopolymers, or as comonomers with monomers which do not fall within the scope of the invention. Homopolymers of the compounds of this invention will have utility as cation exchange agents (polyesters or polyamides) in the preparation of molecular sieves (polyamides), textiles, fibers, films, formed articles and the like where an acid functionality is esterified to a hydroxyl group, for example, whereby a pendant basic group is capable of binding acidic functionalities such as are found in polypeptides whose purification is desired. The preparation of these polymers from the compounds of the invention is conventional per se. As polyfunctional compounds with defined geometry and carrying simultaneously polar and non-polar moieties, the compounds of the invention are useful as a unique class of phase transfer agents. By way of example and not limitation, the compounds of the invention are useful in phase transfer catalysis and liquid /liquid ion extraction (LIX). The compounds of the invention optionally contain asymmetric carbon atoms. As such, they are a unique class of chiral auxiliaries for use in the synthesis or resolution of other optically active materials. For example, a racemic mixture of carboxylic acids can be resolved into its component enantiomers by: 1) forming a mixture of diastereomeric esters or amides with a compound of the; 2) separating the diastereomers; and 3) hydrolyzing the ester structure. Racemic alcohols are separated by ester formation with an a compound of the invention. Further, such a method can be used to resolve the compounds of the invention themselves if optically active acids or alcohols are used instead of racemic starting materials.
The compounds of this invention are useful as linkers or spacers in preparing affinity absorption matrices, immobilized enzymes for process control, or immunoassay reagents. The compounds herein contain a multiplicity of functional groups that are suitable as sites for cross-linking desired substances. For example, it is conventional to link affinity reagents such as hormones, peptides, antibodies, drugs, and the like to insoluble substrates. These insolublized reagents are employed in known fashion to absorb binding partners for the affinity reagents from manufactured preparations, diagnostic samples and other impure mixtures. Similarly, immobilized enzymes are used to perform catalytic conversions with facile recovery of enzyme. Bifunctional compounds are commonly used to link analytes to detectable groups in preparing diagnostic reagents.
Many functional groups in the compounds of this invention are suitable for use in cross-linking. For example, a carboxylic or phosphonic acid of group is used to form esters with alcohols or amides with amines of the reagent to be cross-linked. Sites substituted with OH, NHR , SH, azido (which is reduced to amino if desired before cross-linking), CN, N02, amino, guanidino, halo and the like are suitable sites. Suitable protection of reactive groups will be used where necessary while assembling the cross- linked reagent to prevent polymerization of the bifunctional compound of this invention. In general, the compounds here are used by linking them through carboxylic or phosphonic acid to the hydroxyl or amino groups of the first linked partner, then covalently bonded to the other binding. For example a first binding partner such as a steroid hormone is esterified to the carboxylic acid of a compound of this invention and then this conjugate is cross-linked through a hydroxyl to cyanogen bromide activated Sepaharose, whereby immobilized steroid is obtained. Other chemistries for conjugation are well known. See for example Maggio, "Enzyme- Immunoassay" (CRC, 1988, pp 71-135) and references cited therein. As noted above, the therapeutically useful compounds of this invention in which phosphate, carboxyl, hydroxyl, amino, or the like, groups are protected are useful as oral or sustained release forms. In these uses the protecting group is removed in vivo, e.g., hydrolyzed or oxidized, so as to yield the free carboxyl, amino or hydroxyl. Suitable esters or amides for this utility are selected based on the substrate specificity of esterases and/or carboxypeptidases expected to be found within cells where precursor hydrolysis is desired. To the extent that the specificity of these enzymes is unknown, one will screen a plurality of the compounds of this invention until the desired substrate specificity is found. This will be apparent from the appearance of free compound or of antiviral activity. One generally selects amides or esters of the invention compound that are (i) not hydrolyzed or hydrolyzed comparatively slowly in the upper gut, (ii) gut and cell permeable and (iii) hydrolyzed in the cell cytoplasm and/or systemic circulation. Screening assays preferably use cells from particular tissues that are susceptible to influenza infection, e.g. the mucous membranes of the bronchopulmonary tract. Assays known in the art are suitable for determining in vivo bioavailability including intestinal lumen stability, cell permeation, liver homogenate stability and plasma stability assays. However, even if the ester, amide or other protected derivatives are not converted in vivo to the free carboxyl, amino or hydroxyl groups, they remain useful as chemical intermediates.
Exemplary Methods of Making the Compounds of the Invention The invention also relates to methods of making the compositions of the invention. The compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in
"Compendium of Organic Synthetic Methods" (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., "Advanced Organic Chemistry, Third Edition", (John Wiley & Sons, New York, 1985), "Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes", Barry M. Trost, Editor-in- Chief (Pergamon Press, New York, 1993 printing). A number of exemplary methods for the preparation of the compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations are not intended to limit the scope of applicable methods.
Generally, the reaction conditions such as temperature, reaction time, solvents, workup procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, contains detailed descriptions of such conditions. Typically the temperatures will be -100°C to 200°C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. Workup typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20°C), although for metal hydride reductions frequently the temperature is reduced to 0°C to -100°C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.
Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0°C to -100°C) are also common.
Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions).
Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
Exemplary methods of preparing the compounds of the invention are shown in the Schemes below. A detailed description of the methods is found in the Experimental section below.
Oligomer synthesis is conventional and will not be detailed here. References cited herein detail many conventional methods. Details of 6- mer sysnthesis are also provided in Example 1. However, two overall strategies are depicted in Schemes 1 to 13. Schemes 1 to 7 describe a dimer block method of building a 6-mer of the invention. Similarly, Schemes 8 to 13 describe a trimer block method. Thio-linker synthesis is depicted in Schemes 14 to 16 and linking is depicted in Scheme 17 and 18. Details of these methods are provided in Examples 2 to 14.
An alternative route is depicted in Schemes 20 to 22 and is detailed in Examples 15 to 22. Scheme 23-24 shows the biological activity of the products of Schemes 20 to 22. Examples 23 and 24 provide the synthesis and biological activities corresponding to Scheme 24.
"Cι2" as used in the schemes means lauryl ester (-C(0)(CH2)ιoCH3).
Scheme 1
Figure imgf000106_0001
Scheme 2
Figure imgf000106_0002
Scheme 3
Figure imgf000107_0001
Scheme 4
Figure imgf000107_0002
Scheme 5
Figure imgf000108_0001
Scheme 6
Figure imgf000108_0002
Scheme 7
Figure imgf000109_0001
Scheme 8
Figure imgf000110_0001
Scheme 9
Figure imgf000110_0002
Scheme 10
Figure imgf000111_0001
OH
Scheme 11
Figure imgf000112_0001
H
Figure imgf000112_0002
Scheme 12
Figure imgf000113_0001
Scheme 13
Figure imgf000113_0002
Scheme 14
Figure imgf000114_0001
Scheme 15
Figure imgf000114_0002
Scheme 16
Figure imgf000114_0003
Scheme 17
Figure imgf000115_0001
G G
T T G G 31
Scheme 18
Figure imgf000115_0002
Scheme 20
Figure imgf000116_0001
Figure imgf000116_0002
Scheme 21
Figure imgf000117_0001
Scheme 22
Figure imgf000118_0001
Scheme 23
Figure imgf000119_0001
Figure imgf000119_0002
•-305 R = C6H4(CH2)3NHCO-
L3O6 R = α-C10H7(CH2)2NHCC L307 R = β-C10H7(CH2)2NHCO
Figure imgf000119_0003
I
Figure imgf000119_0004
Scheme 24 Linkage No. Oligomer Relative PT
5'-5' 701 3'GGTTGG5'-L301-5'GGTTGG3' 1 .0 702 3'GGTTGG5,-L302-5'GGTTGG3, 0.6 703 3' GGTTGG χ50' -L303- 5°'/ GGTTGG 3' 0.4
704 3,GGTTGG5,-L3O4-5'GGTTGG3' 1.2 705 3' GGTTGG ,50' -L305- 5'/ GGTTGG0 1.0 706 3'GGTTGG5'-L306-5,GGTTGG3, 1.2 707 3'GGTTGG5,-L307-5'GGTTGG3' 1.0
708 3'GGTTGG5'-L 3n0R8-'5'GGTTGG3' 0.9
Modifications of each of the above schemes leads to various analogs of the specific exemplary materials produced above. The above cited citations describing suitable methods of organic synthesis are applicable to such modifications. In each of the above exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example, size exclusion or ion exchange chromatography, high, medium, or low pressure liquid chromatography, small scale and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
Another class of separation methods involves treatment of a mixture with a reagent selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.
Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One skilled in the art will apply techniques most likely to achieve the desired separation.
Examples Example 1 Synthesis of Oligomers: ODN analogs were synthesized by using standard solid-phase DNA chemistry with the H-phosphonate method or the phosphoramidite method on a Biosearch DNA synthesizer. The linker building block suitable for solid-phase synthesis were prepared from a diol by introducing 4,4'-dimethoxytrityl group on one side and H-phosphonate- triethy ammonium salt group or (diisopropylamino)(cyanoethoxy) phosphino group on the other side. ODNs analogs were also synthesized with standard solution-phase method. In the solution-phase method, GGTTGG 6-mer was first prepared through phosphotriester chemistry from suitably protected 3'-deoxyguanosine and thymidine using 2-chlorophenyl- 0,0-bis(l-benzotriazolyl)phosphate as the phosphorylating agent. Then, two GGTTGG 6-mers, which carried isobutyryl group as the protecting group for -NH2 on each G, 2-chlorophenyl group for each phosphate, and phenoxyacetyl group for -OH on terminal G, were linkned together by a linker with phosphoramidite method or phosphotriester method. In the phosphoramidite method, a bisphosphoramidite, prepared from a linker diol and 2-cyanoethyl N,N-diisopropylchlorophosphoramidite, was coupled with two GGTTGG 6-mers in the presence of ethylthiotetrazole (American International Chemical, Inc., MA) followed by oxidation with 12- In the phosphotriester coupling, a linker diol was first phosphorylated with 2 eq of 2-chlorophenyl-0,0-bis(l-benzotriazolyl)phosphate, and the bis-phosphorylated linker diol thus obtained was then directly reacted with two GGTTGG 6-mers in the presence of 1-methylimidazole to give the protected ODN analog. The final deprotecting was carred out by treating the protected ODN analog with syn-2-pyridinealdoxime and 1,1,3,3- tetrametylguanidine at room temperature followed by heating with concentrated aqueous ammonia. ODN analogs thus obtained were purified by reversed-phase HPLC (PRP-1 resin column), and the purity of the ODN analogs (>. 95%) was further confirmed with PAGE and ion-exchange HPLC.
Example 2 5-Hydroxymethyl-2'-deoxyuridine (HMdU): To deoxyuridine (25.5 g,
0.116 mol) was added 37% aq. formaldehyde (80 mL, 1.06 mol) and 1M KOH (80 mL, 0.08 mol). The reaction vessel was capped with rubber septum and venting tube, and heated at 65°C. After 18 h the reaction mixture was cooled, 1M KOH (30 mL, 0.03 mol) was added to raise the pH from 9.5 to 10.5 and heating resumed at 65°C with the reaction vessel capped. After 52 h of heating the reaction mixture was cooled, 1M KOH (30 mL, 0.03 mol) was added to restore the pH to 10.5, the vessel capped and heating resumed at 65°C. The same procedure of cooling, adjusting pH to 10.5 with 30 mL of 1M KOH, and heating to 65°C was repeated at 118 h and 163 h. After 210 h tic (15% CH3OH/CH2Cl2) showed >95% conversion to product (Rf = 0.25). The reaction mixture was cooled, poured into a 2 L Erlenmeyer flask containing H20 (300 mL), and Dowex 50 x 2-100(H+) ion-exchange resin (75 g) was added with vigorous stirring. After stirring 1 h (pH = 2) the resin was filtered, washed with H2O (700 mL) and the supernatant evaporated under vacuum (bath temperature = 24°C). The resulting residue was evaporated from CH3CN (500 mL) and placed under high vacuum. This foam was dissolved into CH3OH (50 mL) with some heating and sonication, and to this solution was added EtOAc (800 mL) with swirling and sonication. The supernatant (containing most of the unreacted deoxyuridine, some product and aqueous formaldehyde) was decanted and the precipitate was placed under high vacuum. The resulting foam was dissolved into CH3OH (50 mL) with heating and sonication and added dropwise over 15 min. to rapidly stirred EtOAc (1.5 L) and allowed to stand at -20°C for 16 h. The flask warmed to r.t, the filtrate decanted, and the solid placed under high vacuum. The solid was evaporated from CH3OH (200 mL), evaporated from CH3CN (300 mL), and placed under high vacuum to yield 25.5 g (0.099 mol, 85%) of white foam (68% pure by HPLC).
Example 3
5-Thioacetylmethyl-2'-deoxyuridine: HMdU (25.5 g, 0.099 mol) was placed in a 1 L flask and DMF (70 mL) was added followed by sonication to bring the solid into solution. To the solution was added dioxane (350 mL), thiolacetic acid (35 mL) and methanesulfonic acid (1.6 mL, 0.025 mol). The flask was capped and sonicated to dissolve the solids. (A few crystals remained out of solution). The flask was equipped with a calcium sulfate dry tube and placed in a 82°C bath with stirring. Stirring was continued at 82°C for 4 h and tic (15% CH3OH/CH2CI2) showed formation of the product (Rf = 0.74) and starting material consumed. (Note: the bath temperature must not be allowed to rise past 90°C.) The flask was cooled to room temperature and Dowex 1 x 8-100 (HCO3") ion-exchange resin (25 g) was added with vigorous stirring for 1 h. CH3OH/CH2CI2 (400 mL, 1/1) was added and stirring continued 30 min. The resin was filtered, washed with CH3OH (100 mL) and the supernatant evaporated. The residue was triturated three times with Et2θ (100 mL) and the supernatant decanted and discarded. The residual solid was dissolved in THF (600 mL) and the insoluable solids removed by filtration (9.0 g) and washed with THF (100 mL). The filtrate was evaporated, dissolved into THF (50 mL) and added drop wise over 20 min. to a rapidly stirred solution of Et20/hexane (900 mL, 2/1), then additional hexane (300 mL) was added and the flask kept at -20°C. The supernatant was decanted and the residue placed under high vacuum to yield 18.1 g (~60 % pure via HPLC) of a slightly yellow foam.
Example 4
5-Thioacetylmethyl-5'-0-dimethoxytrityl-2'-deoxyuridine: 5- Thioacetylmethyl-2'-deoxyuridine (18.1 g, ~ 57.2 mmole) was evaporated from pyridine (250 mL), dissolved into pyridine (600 mL) and dimethoxytrityl chloride (21.3 g, 62.9 mmole) was added in one portion. The flask was purged with Ar, capped, sealed and stirred at r.t. for 24 h. CH3OH was added (6 mL), the mixture stirred for 30 min. and the solvent evaporated. (Note: do not evaporate to complete dryness). EtOAc (1 L) and saturated aq. NaHCθ3 (200 mL) were added, and the mixture transfered to a separatory funnel and the layers separated. The organic layer was washed with sat'd NaHCθ3 (3 x 200 mL) and dried over Na2Sθ4- The solvent was evaporated to a foam and the foam placed under high vacuum. The foam was then dissolved into CH2CI2 (100 mL) and added dropwise over 15 min. to a rapidly stirred solution of hexane/Et2θ (3/1, 3 L) and allowed to stand at r.t. The solid was collected by vacuum filtration and yielded 32.5g of crude product. Silica gel chromatography with 5% iso-propanol / CH2C12 yielded 5.0g (8.1 mmole) of foam that was evaporated from toluene (300 mL). The H-phosphonate of this nucleoside is made by standard procedures.
Example 5
Removal of Pac from DMTO-GG-OPac dimer: To a solution of dimer (12.18 g, 9.49 mmole) in 114 mL THF cooled to 0°C was added 114 mL of 0.2M NaOH and the reaction mixture was stirred at 0°C for 20 mins. An additional 14 mL of 0.2M NaOH was added, and the reaction was stirred at 0°C for 20 mins. Finally two 2 mL portions of 0.2M NaOH were then added in 20 min intervals at 0°C and the reaction was then quenched by addition of 1 equivalent of acetic acid [20 mL of 1.3M acetic acid in THF/H20 (1/1)]. The solution was extracted with CH2CI2 (2x150 mL), the combined organic layers washed with 5% NaHC03 (400 mL), 5% Na2C03 (2x400 mL), dried over anhydrous Na2Sθ4 and evaporated under reduced pressure to give a foam. The crude product was dissolved into 40 mL CH2C12 and precipitated into 400 mL Et20/hexane (1/1) to give 8.7 g (7.57 mmole, 80%) of dimer as a white powder which was dried under vacuum to a constant weight.
Example 6
Removal of Pac from DMTO-TT-OPac dimer: To a solution of dimer (315.5 mg, 0.293 mmole) in THF (2.5 mL) was added 2M NH3 in isopropanol (5 mL) at room temperature and the reaction mixture was stirred for 5.5 hours. The reaction was quenched by the addition of 5% NaHC03 (5 mL), and the product was extracted into CH2C12 (2x7.5 mL). The combined organic layers were washed with 5% NaHCθ3 (15 mL), 5% Na2Cθ3 (15 mL), dried over anhydrous Na2Sθ4 and concentrated to give a foam. The crude product was dissolved into 1 mL CH2CI2 and precipitated into 16 mL E12O/ hexane (1/1) to give the dimer as a white powder which was dried under vacuum to a constant weight.
Example 7
Removal of Pac from DMTO-GGT-OPac trimer: To a solution of trimer (138.5 mg, 0.0823 mmole) in THF (0.8 mL) was added 2 M NH3 in isopropanol (0.8 mL) at room temperature and the reaction mixture was stirred for 16 hours. The reaction was quenched by the addition of 5% NaHCθ3 (1 mL), and the product was extracted into CH2CI2 (2x5 mL). The combined organic layers were washed with 5% NaHC03 (10 mL) , 5% Na2Cθ3 (10 mL), dried over anhydrous Na2Sθ4 and concentrated to give a foam crude product.
Example 8
Preparation of DMTO-G-OLaur: To a solution of DMTO-G-OH (10.0 g, 15.63 mmole) and 1-methylimidizole (3.2 ml, 40.14 mmole) in dichloromethane (200 mL) cooled to 0°C- -10°C was added lauroyl chloride (5.1 ml, 22.05 mmole) and the reaction mixture stirred for 90 minutes at room temperature. The reaction was quenched by the addition of methanol (30 mL) and stirred for another 15 minutes. The resulting solution was slowly added dropwise into saturated NaHCθ3 (200 mL), washed with saturated NaHCθ3 (250 mL), dried over anhydrous Na2Sθ4, and concentrated to give 14.8 g of product.
Example 9
Preparation of HO-G-OLaur: To a solution of DMTO-G-OLaur (7.35g, 8.94 mmole) in dichloromethane (90 mL) and 1-propanol (14 mL) was added 2.0 N NaHSθ4 (103 mL) and the reaction mixture was stirred at room temperature for 46 hours. The reaction was quenched by addition of the organic layer into saturated NaHCθ3 (100 mL) slowly with stirring. The organic layer was washed with saturated NaHCθ3 (100 mL), dried over anhydrous Na2Sθ4, and concentrated. The crude product was dissolved into toluene (20 mL) and precipitated from 200 mL hexane/ether (9/1) to give a white oily solid. The supernatant was decanted and the residue was dried under vacuum to a constant weight (3.23g, two step yield is 80.5%).
Example 10 Preparation of HO-T-OPac: A stirred solution of 43.6 g (80.0 mmol) of 5'DMT-thymidine, 480 mg (3.93 mmol, 0.0491 equiv.) of 4- dimethylaminopyridine, and 16.8 mL (120.5 mmol, 1.51 equiv.) of triethylamine was cooled in an ice /alcohol bath at an external temperature of -10°C - -5°C. The reaction was kept at this temperature until the final bicarbonate workup. To the solution was added 15.46 mL (111.0 mmol, 1.40 equiv.) of phenoxyacetyl chloride dropwise via syringe over two minutes. The reaction mixture was stirred for 30 min., followed by the addition of 40 mL of methanol, and stirring continued for 25 min. 7.80 mL (120.3 mmol, 1.50 equiv.) of methanesulfonic acid (CH3SO3H) was added and after 15 min. TLC showed that the reaction was not complete. An additional 2.00 mL (30.84 mmol, 0.386 equiv.) of CH3SO3H was added, and the mixture stirred for 30 min. This reaction mixture was transferred to a separatory funnel, and added dropwise, with rapid stirring, to 300 mL of sat. NaHCθ3 solution. The addition rate was controlled so that the aqueous layer remained basic at all times. After the additon was complete the layers were separated, the organic layer washed with sat. NaHCθ3 (300 mL), dried (Na2Sθ4), and filtered. The organic layer (ca. 800 mL) was added dropwise to 1 L of hexane, with rapid stirring, and an oil formed initially. Over 24 h a nice precipitate formed that was collected by filtration, rinsed with 300 mL of hexane and dried in vacuo. This afforded 25.65 g (88.9% yield) of product that was used as is.
Example 11
Preparation of 5'-DMTO-T*GGTTGG-OLaur: A mixture of 1.94 g (0.674 mmol, M.W. = 2878 g/mol, 85% purity) of 5'-HO-GGTTGG-OLaur and 690 mg (0.880 mmol, 1.30 equiv., M.W. = 783.9 g/mol) of thioacetylmethyl deoxyuridine (T*) H-phosphonate was concentrated once from dry pyridine (Aldrich Sure Seal). To the residue was added CH3CN/pyridine (8.0 mL, 1/1, both Aldrich Sure Seal) and the solution cooled on an ice/water bath. To this solution was added 1.17 mL of a 0.812M solution of trimethylacetyl chloride (pivaloyl chloride) in CH3CN (0.30 mL of pivaloyl chloride diluted to 3.0 mL with CH3CN). The ice bath was removed and stirring continued for 30 min. at which time tic (10% MeOH in CH2CI2) showed that the reaction was not complete. An additional 0.317 mL of 0.812M pivaloyl chloride in CH3CN was added. After 30 min., 0.317 mL (1.80 mL total, 1.46 mmol, 2.20 equiv.) more of the pivaloyl chloride solution was added. The reaction mixture was stirred for another 30 min. and tic indicated that the reaction was complete. To the reaction mixture was added 9.72 mL (0.972 mmol, 1.44 equiv.) of a 0.10M solution of I2 in 1% H2θ/pyridine. The reaction mixture was stirred for 5 min., diluted with CH2CI2 (200 mL), and washed with an aqueous solution that was 0.10M in triethylammonium bicarbonate (TEAB) and 0.10M in sodium thiosulfate (Na2S203, 2 x 200 mL), followed by 1.0M aq. TEAB, pH = 8.3 (1 x 200 mL). (Note: smaller volumes can probably be used here). The organic layer was dried over Na2Sθ4, filtered, and concentrated to a foam. This was taken up in 8.0 mL CH2Cl2 and precipitated into 60 mL Et20. The precipitate was collected at room temperature using a sintered glass funnel with a medium frit. The precipitate was triturated in Et2θ and after drying in a vacuum dessicator 2.36 g (98.3% yield) of product was obtained.
Example 12
Preparation of 5'-HO-T*GGTTGG-OLaur: 5'-DMTO-T*GGTTGG- OLaur was prepared from 1.41 g (0.490 mmol) of 5'-HO-GGTTGG-OLaur as above, only the product was not precipitated. This afforded 1.98 g of product that contained pyridine. 1.74 g was required for a 100% yield. Thus this material contained an additional 13.7 % of mass. Half of this material (0.245 mmol) was stirred in CH2C12 (4.58 mL) and to this solution was added of n-propanol (0.458 mL) and 2.0M aq. sodium bisulfate (NaHSθ4, 4.58 mL). The biphasic mixture was stirred for 19 h. and then the organic layer was added dropwise, with stirring, to a mixture of CH2Cl2 (50 mL) and l.OM aq. TEAB (50 mL). The layers were separated, and the organic layer washed with l.OM aq. TEAB, dried (Na2S0 ), filtered, and concentrated to a solid. The solid was taken up in 3.0 mL CH2CI2 and precipitated into 50 mL Et2θ. The product was filtered, triturated in Et2θ, and dried in a vacuum dessicator affording 731 mg of product (91.7% yield based on 0.245 mmol of 5'-HO-GGTTGG-OLaur). A preferred synthesis came after the 7-mer (HO- T*GGTTGG-OLaur) was purified by HPLC. This gave the highest product yield and purity upon going from 7-mer to product, but also gave a low yield of 7-mer due to losses from the HPLC purification. This suggests that cleanup of the 7-mer before the final deprotection may be preferred.
Example 13
Preparation of GS 4097 from 5'-HO-T*GGTTGG-OLaur: A solution of 50 mg (0.0154 mmol, based on 100% purity, M.W. = 3255 g/mole, calculated as the mono TEA salt) of 5'-HO-T*GGTTGG-OLaur in 3 mL of 12.5mM KC1 in dioxane/ concentrated NH4OH (1/1) was stirred at room temperature for 4 days. The reaction mixture was concentrated and the crude taken up in H20 (3 mL), extracted with EtOAc (2x2 mL), and concentrated slightly. This afforded 1008 total ODs that was 50% product (via ion-exchange HPLC) corresponding to 504 ODs of product. In a similar experiment the reaction mixture was centrifuged and the supernatant decanted and discarded. The precipitate gave 609 ODs that was 59% product (via ion-exchange HPLC) corresponding to 359 ODs of product. The amount that precipitated seemed to increase over time, six to seven days afforded more precipitate than four days. HPLC product yields for these procedures range from 40-60%. Example 14
Preparation of GS 4097 (1 gram scale): To 1.00 g (M.W. = 3255 g/mol, based on 85% purity 0.261 mmol used) of 5'-HO-T*GGTTGG-OLaur in 15.0 mL of dioxane (not completely soluble) was added 15.0 mL of 25 mM KC1 in cone. NH4OH. The reaction mixture was sealed and stirred at room temperature for 96 h. (a precipitate formed but was not collected). The entire reaction mixture was concentrated on a rotary evaporator (the temperature of the water bath did not exceed 30°C)and to the residue was added H2O (30 mL), and the mixture extracted with of EtOAc (2 x 20 mL) and the aqueous layer concentrated. The residue was taken up in H2O (30.0 mL, not completely homogeneous) and analyzed by ion-exchange HPLC. This afforded 18,480 ODs that was 46.2% product by HPLC corresponding to 8538 ODs of product (17,320 ODs required for 100% yield, 8538 ODs = 49.3% HPLC yield). GS 4097: ∑260 ~ 1.34 x 105 7.46 nmole/OD 34.8 μg/OD MW diester (Na+) = 4660.6 g/mole
Example 15
5'-0-Acetyl-5-iodio-2'-deoxyuridine (21): 5-Iodio-2'-deoxyuridine (5 g, 14 mmol, Peninsula Laboratories, Inc., CA) was co-evaporated with dry DMF (2 x 50 mL) and then suspended in 100 mL of dioxane. Triphenylphosphine (4.7 g, 18 mmol) and glacial acetic acid (2.2 g, 36 mmol) was added. The mixture obtained was heated to 60°C under stirring, and a solution of diethyl azodicarboxylate (3.2 g, 18 mmol) in 50 mL of dioxane was added dropwise to the mixture. Gradually, the suspension became a clear solution. After the addition, the solution was stirred at 60°C for 2 hours. Then, the solution was cooled down to room temperature and concentrated. The residue was dissolved in 50 mL of a solvent mixture of CH2CI2 and MeOH (100:10, v/v) and the solution obtained was set at room temperature overnight. The white crystals generated were removed by filtration and the filtrate was concentrated. The oily residue was further purified with silica gel chromatography using CH2θ2/MeOH = 100/5 (v/v) to give 4.8 g of 5'-0-acetyl-5-iodio-2'-deoxyuridine (21) as a white solid with 87% yield. H NMR (DMSO-d6): d 11.71(s, 1H, NH), 7.98(s, 1H, 6-H), 6.08(t, J = 6.5, 1H, l'-H), 5.39(d, J = 4.5, 1H, 3'-OH), 4.2(m, 3H, 3'-H, 5'-Hab), 3.9(m, 1H, 4'-H), 2.3 and 2.1(2m, 2H, 2'-Hab), 2.1(s, 3H, CH3CO).
Example 16 Compound (22a): 5'-0-Acetyl-5-iodio-2'-deoxyuridine (8 g, 20 mmol) was co-evaporated with dry DMF (2 x 30 mL) and then dissolved in 80 mL of dry DMF. Tri(2-furyl)phosphine (0.14 g, 0.6 mmol, Lancaster Synthesis, Inc., NH) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.137 g, 0.3 mmol) were added to solution. The resulting yellow-green solution was stirred at room temperature for 20 minutes. Then, bis(tributylstannyl)acetylene [(n-Bu)3SnC≡CSn(n-Bu)3, 6.1 g, 10 mmol] was added and the reaction solution obtained was stirred at room temperature for 24 h. The completion of the reaction was confirmed by TLC (Siθ2/CH2Cl2:MeOH = 100:10, v/v), and the solution was concentrated. To the dark residue obtained, 160 mL of CH2CI2 was added, and the resulting mixture was stirred vigorously for 30 min and ultrasonicated for 10 min and then stored at 0°C overnight. The precipitate formed was collected by filtration to give 4 g of compound (22a) as a yellow-green powder with 71% yield. The compound thus obtained had a ^H NMR purity higher than 95% and was used in the subsequent reaction without further purification. iH NMR (DMSO-d6): d 11.68(s, 1H, NH), 7.95(s, 1H, 6-H), 6.11(t, J = 6.5, 1H, l'-H), 5.40(d, J = 4.5, IH, 3'-OH), 4.2(m, 3H, 3'-H, 5'-Hab), 3.9(m, IH, 4'-H), 2.1 - 2.3(m, 2H, 2'-Hab), 2.05(s, 3H, CH3CO).
Example 17
Compound (22b): 5'-0-Acetyl-5-iodio-2'-deoxyuridine (3.2 g, 8 mmol) was co-evaporated with dry DMF (2 x 20 mL) and then dissolved in 50 mL of dry DMF. Tri(2-furyl)phosphine (0.18 g, 0.8 mmol) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.18 g, 0.4 mmol) were added to solution. Nitrogen replacement was carried out, and the resulting yellow-green solution was stirred at room temperature for 10 minutes. Then, frans-bis(tributylstannyl)ethylene, prepared from ethynyltributyltin and tributyltin hydride, [£r ns-(n-Bu)3SnCH=CHSn(n-Bu)3, 2.45 g, 4 mmol] was added and the reaction solution obtained was stirred at 50°C for 10 h. The completion of the reaction was confirmed by TLC
(Siθ2/CH2Cl2:MeOH = 100:10, v/v), and the solution was cooled down to temperature and concentrated. To the dark residue obtained, 20 mL of EtOAc was added, and the resulting mixture was stirred vigorously for 30 min and ultrasonicated for 10 min and then stored at 0°C overnight. The precipitate formed was collected by filtration and the crude product thus obtained was further purified with silica gel chromatography using CH2Cl2/MeOH = 100/15 (v/v) to give 1.1 g of compound (22b) as a pale yellow powder with 49% yield. !H NMR (DMSO-dό): d 11.49(s, IH, NH), 7.66(s, IH, 6-H), 7.21(s, IH, -CH=), 6.17(t, J = 6.5, IH, l'-H), 5.40(d, J = 4.5, IH, 3'-OH), 4.2(m, 3H, 3'-H, 5'-Hab), 3.9(m, IH, 4'-H), 2.1 - 2.3(m, 2H, 2'- Hab), 2.05(s, 3H, CH3CO).
Example 18
Compound (23): Compound (22a) (1.0 g, 1.78 mmol) was dissolved 150 mL of MeOH. After nitrogen replacement, 0.5 g of 10% Pd/C was added to the above solution, and hydrogen replacement was carried out. The hydrogenation was carried out using a balloon at room temperature under normal pressure for 10 hours. The completion of the reaction was confirmed with TLC (Siθ2/CH2θ2:MeOH = 100:10, v/v). The catalyst used was removed by filtration and the flitrate obtained was concentrated to give 1.0 g of compound (23) as a pale yellow solid with 100% yield. The compound thus obtained had a ^H NMR purity higher than 95% and was used in the subsequent reaction without further purification. H NMR (DMSO-d6): d 11.31(s, IH, NH), 7.31(s, IH, 6-H), 6.13(t, J = 6.5, IH, l'-H), 5.39(d, J = 4.5, IH, 3'-OH), 4.2(m, 3H, 3'-H, 5'-Hab), 3.9(m, IH, 4'-H), 2.37(s, 2H, -CH2-), 2.0 - 2.1(m, 2H, 2'-Hab), 2.03(s, 3H, CH3CO).
Example 19
Compound (24): Compound (23) (2.9 g, 5.0 mmol) was dissolved in 20 mL of DMF. To the solution obtained, crushed fine powder potassium carbonate (2.1 g, 15 mmol) and methyl iodide (3.1 g, 4.4 mmol) were added. The resulting solution was stirred at room temperature for 24 hours. The completion of the reaction was further confirmed by TLC (Siθ2/CH2Cl2:MeOH = 100:10, v/v). The solution was concentrated under vacuum. To the oily residue, 200 mL of ethylene chloride was added and the resulting solution was washed with 50 mL of water. The organic phase was dried over Na2Sθ4. After removal of the solvent, the crude product was purified with silica gel chromatography using CH2θ2/MeOH = 100/10 (v/v) to give 2.1 g of compound (24) as a white foam with 69% yield. *H NMR (CDCI3): d 7.28(s, IH, 6-H), 6.27ft J = 6.5, IH, l'-H), 4.2-4.4(m, 3H, 3'- H, 5'-Hab), 4.1(m, IH, 4*-H), 3.31(s, 3H, CH3-N), 2.57(s, 2H, -CH2-), 2.2 - 2.5(m, 2H, 2'-Hab), 2.16(s, 3H, CH3CO).
Example 20
Compound (26): 5'-0-(£-butyldimethylsilyl)-5-iodio-2'-deoxyuridine (0.47 g, 1 mmol), prepared from 5-iodio-2'-deoxyuridine and t- butyldimethylsilyl chloride, was co-evaporated with dry DMF (2 x 5 mL) and then dissolved in 5 mL of dry DMF. Tri(2-furyl)phosphine (0.018 g, 0.08 mmol, Lancaster Synthesis, Inc., NH) and tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3, 0.018 g, 0.08 mmol) were added to solution. The resulting yellow-green solution was stirred at room temperature for 10 minutes. Then, bis(tributylstannyl)acetylene [(n- Bu)3SnC^CSn(n-Bu)3, 0.3 g, 0.5 mmol] was added and the reaction solution obtained was stirred at room temperature for 24 h. The completion of the reaction was confirmed by TLC (Siθ2/CH2θ2:MeOH = 100:10, v/v), and the solution was concentrated. To the dark residue obtained, 5 mL of EtOAc was added, and the resulting mixture was stirred vigorously for 30 min and ultrasonicated for 10 min and then stored at 0°C overnight. The precipitate formed was collected by filtration to give 0.29 g of compound (26) as a white powder with 82% yield. The compound thus obtained had a ^H NMR purity higher than 95% and was used in the subsequent reaction without further purification. lH NMR (DMSO-dό): d 11.65(s, IH, NH), 7.97(s, IH, 6- H), 6.11(t, J = 6.5, IH, l'-H), 5.27(d, J = 4.5, IH, 3'-OH), 4.2(m, IH, 3'-H), 3.9(m, IH, 4'-H), 3.7-3.8(m, 2H, 5'-Hab), 2.1 - 2.3(m, 2H, 2'-Hab), 0.84(s, 9H, CH3C), 0.05(s, 3H, CH3Si).
Example 21
Compound (27): Compound (26) (1.46 g, 2.1 mmol) was co- evaporated with dry DMF (2 x 20 mL) and then dissolved in a solvent mixture containing 130 mL of dry DMF and 70 mL of dry pyridine. To the solution, 4-dimethylaminopyridine (0.25 g, 2.07 mmol) and acetic anhydride (0.85 g, 8.28 mmol) were added. The resulting solution was stirred at room temperature for 10 hours, and TLC (Siθ2/CH2θ2:MeOH = 100:10, v/v) showed the completion of the reaction. After adding 5 mL of MeOH, the reaction solution was concentrated. The residue was dissolved in 150 mL of CH2CI2 and the organic solution was washed with 100 mL of 0.5 M citric acid aqueous solution, 100 mL of 5% NaHCθ3 aqueous solution, and saturated NaCl aqueous solution. After drying over anhydrous Na2Sθ4, the solvent was removed and the brown residue obtained was purified with silica gel chromatography using CH2θ2/MeOH = 100/5 (v/v) to give 1.02 g of the desired product as a white solid with 62% yield. αH NMR (CDCI3): d 9.1(bs, IH, NH), 8.07(s, IH, 6-H), 6.31ft J = 6.5, IH, l'-H), 5.2(m, IH, 3'-H), 4.1(m, IH, 4'-H), 3.9(m, 2H, 5'-Hab), 2.1 and 2.4(2m, 2H, 2'-Hab), 2.09(s, 3H, CH3CO), 0.88(s, 9H, CH3C), 0.11(s, 3H, CH3Si).
Example 22 Compound (28): Compound (27) (0.48 g, 0.62 mmol) was dissolved
50 mL of MeOH. After nitrogen replacement, 0.3 g of 10% Pd/C was added to the above solution, and then, hydrogen replacement was carried out. The hydrogenation was carried out using a balloon at room temperature under normal pressure for 10 hours. The completion of the reaction was confirmed with TLC (Siθ2/CH2Cl2:MeOH = 100:10, v/v). The catalyst used was removed by filtration. To the flitrate obtained, 0.1 g of methanesulfonic acid was added and the solution was stirred at room temperature for 2 hours. TLC analysis (Siθ2/CH2θ2:MeOH = 100:10, v/v) showed the completion of the reaction. Solid NaHCθ3 (0.5 g) was added to the solution and the mixture was stirred vigorously for 30 minutes. Then, the mixture was concentrated. To the residue, 50 mL of water was added and the mixture was extracted with CH2CI2 (2 x 100 mL). The organic phase was dried over Na2Sθ4 and concentrated. The crude product thus obtained was purified with silica gel chromatography using CH2Cl2/MeOH = 100/10 (v/v) to give 0.3 g of compound (28) as a white solid with 70% yield. H NMR (DMSO-d6): d 11.27(s, IH, NH), 7.64(s, IH, 6-H), 6.16ft J = 6.5, IH, l'-H), 5.2(m, IH, 3'-H), 5.10(t, J = 5.0, IH, 5'-OH), 3.9(m, IH, 4'-H), 3.6(m, 2H, , 5'-Hab), 2.36(s, 2H, -CH2-), 2.2(m, 2H, 2'-Hab), 2.05(s, 3H, CH3CO). Example 23
Synthesis of Oligomers: ODNs analogs were synthesized by using standard solid-phase DNA chemistry on controlled pore glass (CPG) support with the H-phosphonate method or the phosphoramidite method on a Biosearch DNA synthesizer. For ODNs analogs 301 - 308, the first part of the molecules, up to 7-mer, was assembled with a standard 3' to 5' manner using the standard building blocks. After connecting the linker part, the rest of the molecules was built up with a 5' to 3' manner using inverted polarity building blocks. The linker building blocks suitable for solid-phase synthesis were prepared by the methods mentioned above, by introducing 4,4'-dimethoxytrityl group on one side and H-phosphonate- triethyammonium salt group or (diisopropylamino)- (cyanoethoxy)phosphino group on the other side. The inverted polarity building blocks, including the corresponding CPG support, were prepared from N2-isobutyryl-2'-deoxyguanosine and thymidine (Chem-Impex, IL) by introducing 4,4'-dimethoxytrityl group on 3'-OH and H-phosphonate- triethyammonium salt group or (diisopropylamino)- (cyanoethoxy)phosphino group on 5'-OH with standard methods.
Example 24
Assay: Simmons, A.; Hemoatology, A Combined Theoretical and Technical Approach, Chapter 20, 2nd Ed., Butterworth-Heinemann, Newton, MA, 1997, pp. 343-360, describes details of the assay.
Relative prothrombin time (PT) data (average values from 2 - 4 measurements at different concentrations of the testing compound) were included in the experiment section.
Relative PT = (PTι-100)/(PT2 -100)
PTi: Increasing in PT time (percentage) of testing compound as compared to control. PT2: Increasing in PT time (percentage) of GS 522 as compared to control (blank) measured at the same day.
Standard PT data for GS 522: 150 at 2 m and 250 at 4 m.
All literature and patent citations above are hereby expressly incorporated by reference in their entirety at the locations of their citation. Specifically cited sections or pages of the above cited works are incorporated by reference with specificity. The invention has been described in detail sufficient to allow one of ordinary skill in the art to make and use the subject matter of the following claims. It is apparent that certain modifications of the methods and compositions of the following claims can be made within the scope and spirit of the invention.

Claims

What is claimed is:
A compound of the formula (I), (II), (III), (IV) or (V):
Figure imgf000136_0001
Figure imgf000137_0001
wherein: R is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms;
R 2 is R 1 wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R groups;
R3 is F, Br, Cl, I, -CN, or N3; R is R wherein each said alkyl, alkenyl and alkynyl is independently substituted with 0 to 3 R groups;
R5 is R3, -N02, -OR6, -N(R6)2, -SR6, -S(0)R6, -S(0)2R6, -SOR6, -S(0)OR6, -S(0)2OR6, -SN(R6)2, -S(0)N(R6)2, -S(0)2N(R6)2, -C(0)R6, -C(0)OR6, -OC(0)R6, -OC(0)OR6, -OC(0)N(R6)2, -N(R6)(C(0)R6), -N(R6)(C(0)OR6), -C(0)N(R6)2, -C(NR6)(N(R6)2), -N(R6)C(N(R6))(N(R6)2), -OP(0)(OR6)2, -OP(S)(OR6)2, =0, =S, or =N(R6);
R6 is H, PRT or R2;
R ,7 i ΓÇós alkylene of 1 to 6 carbon atoms, alkenylene of 2 to 6 carbon atoms or alkynylene of 2 to 6 carbon atoms;
R 8 is R 7 wherein each said alkylene, alkenylene and alkynylene is independently substituted with 0 to 3 R groups; R9 is R6 or -R8W5; each R 10 is independently selected from H or R 2 ; each R 11 is independently selected from H, R 2 or R 3 ; each R is independently selected from H, R or R , wherein when R12 is R5 then R5 is not =0, =S, or =N(R6); each R13 is independently selected from H, R4, R5, R9, -OR9, -N(R9)2,
-SR9, -S(0)R9, -S(0)2R9, -SOR9, -S(0)OR9, -S(0)2OR9, -SN(R9)2, -S(0)N(R9)2,
-S(0)2N(R9)2, -C(0)R9, -C(0)OR9, -OC(0)R9, -OC(0)OR9, -OC(0)N(R9)2,
-N(R9)(C(0)R9), -N(R9)(C(0)OR9), -C(0)N(R9)2, -C(NR9)(N(R9)2), or -N(R9)C(N(R9))(N(R9)2, wherein when R13 is R5 then R5 is not =0, =S, or
=N(R6);
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R5 groups; each X is independently selected from R12, 3'-G-, 3'-GG-, 3'-TGG-, 3'-TTGG-, 3'-GTTGG-, or 3'-GGTTGG-; and the salts, solvates, resolved enantiomers or purified diastereomers thereof; provided that the compound of formula (VI) is excluded
Figure imgf000138_0001
wherein: each X and R13 are -OH; and each R10, R11 and R12 are H.
2. A compound of claim 1 in isolated and purified form.
3. A compound of claim 1 having formula (VI), (VII), (Vπi), (IX) or (X):
Figure imgf000139_0001
Figure imgf000140_0001
4. The compound of claim 1 wherein each R is H.
5. The compound of claim 1 wherein each R 11 is H.
6. The compound of claim 1 wherein each R 12 is H.
7. The compound of claim 1 wherein each R 13 is -OR ft .
8. The compound of claim 1 wherein each R 13 is -OH.
9. The compound of claim 1 wherein each R13 is -OC(0)N(R6)(R9).
10. The compound of claim 1 wherein each R13 is -OC(0)N(H)(R8W5).
11. The compound of claim 1 wherein each R 13 is
-OC(0)N(H)(CH2CH2Ph).
12. The compound of claim 1 wherein each X is -OR .
13. The compound of claim 1 wherein each X is -OH.
14. The compound of claim 1 wherein each X is -OP(0)(OR ).
15. The compound of claim 1 wherein each X is 3'-GGTTGG-.
16. A compound of claim 1 selected from Table 6.
17. A composition comprising a compound of claim 1 and a pharmaceutically-acceptable carrier.
18. A method of detecting the presence or absence of thrombin comprising contacting a sample suspected of containing thrombin with a compound of claim 1.
19. A method of inhibiting the activity of thrombin comprising contacting a sample suspected of containing thrombin with a compound of claim 1.
20. A method of inhibiting the activity of thrombin in a host comprising administering to the host a therapeutically effective amount of a compound of claim 1.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992014843A1 (en) * 1991-02-21 1992-09-03 Gilead Sciences, Inc. Aptamer specific for biomolecules and method of making

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992014843A1 (en) * 1991-02-21 1992-09-03 Gilead Sciences, Inc. Aptamer specific for biomolecules and method of making

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CUSHLEY, ROBERT J. ET AL: "Nucleosides. LIII. Transformation of pyrimidine nucleosides in alkaline media. 2. Reactions of 5-fluorouracil derivatives with sodium deuteroxide" TETRAHEDRON LETT. (1968), (52), 5393-6 , XP002095456 *
GROMOVA, M. ET AL: "The direct effect of heavy ions and electrons on thymidine in the solid state" INT. J. RADIAT. BIOL. (1998), 74(1), 81-97, XP002095454 *
GUPTA, V. S. ET AL: "Synthesis and cell culture studies on the antiviral activity of 5-mercaptomethyl-2'-deoxyuridine" J. MED. CHEM. (1975), 18(10), 973-6, XP002095455 cited in the application *
SHAW, ANTHONY A. ET AL: "Radical combination processes under the direct effects of gamma radiation on thymidine" J. CHEM. SOC., PERKIN TRANS. 2 (1990), (12), 2063-70, XP002095453 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8871737B2 (en) 2010-09-22 2014-10-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US9278990B2 (en) 2010-09-22 2016-03-08 Alios Biopharma, Inc. Substituted nucleotide analogs
US8980865B2 (en) 2011-12-22 2015-03-17 Alios Biopharma, Inc. Substituted nucleotide analogs
US9605018B2 (en) 2011-12-22 2017-03-28 Alios Biopharma, Inc. Substituted nucleotide analogs
US8916538B2 (en) 2012-03-21 2014-12-23 Vertex Pharmaceuticals Incorporated Solid forms of a thiophosphoramidate nucleotide prodrug
US9856284B2 (en) 2012-03-21 2018-01-02 Alios Biopharma, Inc. Solid forms of a thiophosphoramidate nucleotide prodrug
US9012427B2 (en) 2012-03-22 2015-04-21 Alios Biopharma, Inc. Pharmaceutical combinations comprising a thionucleotide analog

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