WO1999014185A1 - Compounds containing six-membered rings, processes for their preparation, and their use as medicaments - Google Patents

Compounds containing six-membered rings, processes for their preparation, and their use as medicaments Download PDF

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Publication number
WO1999014185A1
WO1999014185A1 PCT/US1998/019355 US9819355W WO9914185A1 WO 1999014185 A1 WO1999014185 A1 WO 1999014185A1 US 9819355 W US9819355 W US 9819355W WO 9914185 A1 WO9914185 A1 WO 9914185A1
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WIPO (PCT)
Prior art keywords
lli
group
independently
substituted
groups
Prior art date
Application number
PCT/US1998/019355
Other languages
French (fr)
Inventor
Norbert W. Bischofberger
Terrence C. Dahl
Michael J. M. Hitchcock
Choung U. Kim
Willard Lew
Hongtao Liu
Roger G. Mills
Matthew A. Williams
Original Assignee
Gilead Sciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Priority to EP98949356A priority Critical patent/EP1015417A1/en
Priority to IL13469198A priority patent/IL134691A0/en
Priority to NZ502988A priority patent/NZ502988A/en
Priority to BR9812649-0A priority patent/BR9812649A/en
Priority to KR1020007002880A priority patent/KR20010024123A/en
Priority to CA002303323A priority patent/CA2303323A1/en
Priority to EA200000332A priority patent/EA003989B1/en
Priority to AU95694/98A priority patent/AU747702B2/en
Priority to JP2000511738A priority patent/JP2001516739A/en
Publication of WO1999014185A1 publication Critical patent/WO1999014185A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/62—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • Neuraminidase also known as sialidase, acylneuraminyl hydrolase, and EC 3.2.1.18 is an enzyme common among animals and a number of microorganisms. It is a glycohydrolase that cleaves terminal alpha- ketosidically linked sialic acids from glycoproteins, glycolipids and
  • oiigiosaccharides 35 oiigiosaccharides.
  • Many of the microorganisms containing neuraminidase are pathogenic to man and other animals including fowl, horses, swine and seals. These pathogenic organisms include influenza virus.
  • Neuraminidase has been implicated in the pathogenicity of influenza viruses. It is thought to help the elution of newly synthesized virons from infected cells and assist in the movement of the virus (through its hydrolase activity) through the mucus of the respiratory tract.
  • a principal object of the invention is inhibition of viruses, in particular influenza viruses.
  • an object is inhibition of glycolytic enzymes such as neuraminidase, in particular the selective inhibition of viral or bacterial neuraminidases.
  • An additional object of the invention is to provide neuraminidase inhibitors that have a retarded rate of urinary excretion, that enter into nasal or pulmonary secretions from the systemic circulation, that have sufficient oral bioavailability to be therapeutically effective, 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 neuraminidase inhibitors.
  • a still further object is to provide improved methods for administration of known and novel neuraminidase inhibitors.
  • An additional object is to provide compositions useful in preparing polymers, surfactants or immunogens and for use in other industrial processes and articles
  • a 2 is -C(Jl)2-, -NQi)-, -N(O)Qi)-, -S-, -S(O)-, -S(0) 2 - or -O-;
  • El is -(CRiR ⁇ )miWi;
  • Gi is N3, -CN, -OH, -OR6a, -N ⁇ 2, or -(CRlRl) m lW2;
  • Ti is -NR1W3, H, -R3, -R5, a heterocycle, or is taken together with Ui or Gi to form a group having the structure
  • Ui is H, -R3 or -X1W6;
  • Jl and Jia are independently Ri, Br, Cl, F, I, CN, NO2 or N3;
  • J2 and J2a are independently H or Ri;
  • Rl is independently H or alkyl of 1 to 12 carbon atoms;
  • R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR6a, -ORi, -N(R ⁇ )2, -N(R ⁇ )(R 6b ), -N(R6b) 2 , -SRi, -SR6 a , -S(0)R ⁇ , -S(0) 2 R ⁇ , -S(0)OR ⁇ , -S(0)OR6a, -S(0) 2 OR ⁇ , -S(0) 2 OR6a, -C(0)OR ⁇ , -C(0)R6o - (0)OR6 a , -OC(0)R ⁇ , -N(R ⁇ )(C(O)R , -N(R6b)(C(0)R ⁇ ), -N(R ⁇ )(C(0)OR ⁇ ), -N(R b )(C(0)OR ⁇ ), -C(0)N(R ⁇ ) 2/ -C(0)N(R6b)(Ri), -C(0)N(R6b)2,
  • R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
  • R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
  • R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
  • R6a is independently H or an ether- or ester-forming group;
  • R6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
  • R6 C is independently H or the residue of an amino-containing compound
  • Wi is a group comprising an acidic hydrogen, a protected acidic group, or an R£ c amide of the group comprising an acidic hydrogen
  • W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom or a group derivatizable to a basic heteroatom
  • W3 is W4 or W5;
  • W4 is R5 or -C(0)R5, -C(0)Ws, -SO2R5, or -SO2W5;
  • W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
  • W 6 is -R5, -W5, -R5aW 5 , -C(0)OR6a, -C(0)R6o -C(C»)N(R6b)2, -C(NR6b)(N(R 6 b)2), -C(NR 6 b)(N(H)(R6b)), -C(N(H)(N(R 6 b)2), -C(S)N(R 6 b)2, or -C(0)R2;
  • Xi is a bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH2)-,
  • Ei is COOH, P(0)(OH)2, SOOH, SO3H, or tetrazol;
  • Gi is CN, N(H)R20, N3, SR20/ OR2O/ guanidino, -N(H)CN 20 -
  • R20 is H; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an NO2 group, an NH2 group or a COOH group;
  • J2 is H and J2a is H, CN or N3;
  • Ui is CH 2 YR20a, CHYR 2 0aCH 2 YR20a or CHYR20aCHYR 2 0aCH2YR20a,
  • R20a is H or acyl having 1 to 4 carbon atoms; (k) 0 to 2 YR20a are H, and
  • Gi is hydrogen, N(R20a) 2/ SR20 or OR20a ;
  • Ti is -NHC(O)R 20b , where R 20b is an unsubstituted or halogen-substituted linear or cyclic alkyl group of 1 to 6 carbon atoms, or SR 20a , OR 20a , COOH or alkyl /aryl ester thereof, N0 2 , C(R 20a ) 3 , CH 2 COOH or alkyl/aryl ester thereof, CH 2 N0 2 or CH 2 NHR 2 0b ;
  • R 20a is hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; or an unsubstituted aryl group or an aryl substituted by a halogen, an allyl group, an OH group, an NO2 group, an NH 2 group or a COOH group;
  • J 2 is H or J 2a is hydrogen, N(R 2 0a) 2/ SR 0a or OR 20a ;
  • Ui is CH YR 20a , CHYR 2 0CH 2 YR 20a or
  • El is -(CRiRi)mlWi;
  • Gi is N3, -CN, -OH, -OR6a, -NO2, or -(CR ⁇ R ⁇ ) m iW2;
  • Ti is -NR1W3, a heterocycle, or is taken together with Ui or Gi to form a group having the structure
  • Ui is H or -X W6 and, if -XlW6, then Ui is a branched chain;
  • Jl and Jia are independently R , Br, Cl, F, I, CN, NO2 or N3;
  • J2 and J2a are independently H or R ;
  • Ri is independently H or alkyl of 1 to 12 carbon atoms;
  • R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3 , -N0 2/ -OR ⁇ a , -ORi, -N(R ⁇ ) 2/ -N(R ⁇ )(R6b), -N(R6b) 2 , -SRi, -SR6 a , -S(0)R ⁇ , -S(0) 2 R ⁇ , -S(0)OR!, -S(0)OR6 a , -S(0) 2 OR ⁇ , -S(0) 2 OR a/ -C(0)OR ⁇ , -C(0)R6c, - (0)OR a , -OC(0)R ⁇ ,
  • R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
  • R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
  • R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
  • R6a is independently H or an ether- or ester-forming group
  • R is independently H, a protecting group for amino or the residue of a carboxyl-containing compound
  • R6 C is independently H or the residue of an amino-containing compound
  • Wi is a group comprising an acidic hydrogen, a protected acidic group, or an R ⁇ c amide of the group comprising an acidic hydrogen;
  • W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R(fo amide of the basic heteroatom;
  • W3 is W4 or W5;
  • W4 is R5 or -C(0)R5, -C(0)Ws, -SO2R5, or -SO2W5;
  • W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
  • W 6 is -R 5 , -W 5 , -R5aW 5 , -C(0)OR6 a , -C(0)R 6c , -C(0)N(R6b)2, -C(NR 6 b)(N(R 6 b)2) / -C(S)N(R 6 b)2, or -C(0)R 2;
  • Xi is a bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH2)-,
  • Another embodiment of the invention is directed to compounds of the formula:
  • Ei is -(CRiRi)miW ⁇
  • Gi is N3, -CN, -OH, -OR 6a , -NO2, or -(CR ⁇ R ⁇ )miW ;
  • Ti is -NR1W3, a heterocycle, or is taken together with Ui or Gi to form a group having the structure
  • Ui is H or -X1W6;
  • Ji and J ⁇ a are independently Ri, Br, Cl, F, I, CN, NO2 or N3;
  • J2 and J2a are independently H or Ri;
  • Rl is independently H or alkyl of 1 to 12 carbon atoms;
  • R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR a , -ORi, -N(R ⁇ )2, -N(R ⁇ )(R b), -N(R 6b )2, -SRi, -SR a , -S(0)R 1/ -S(0) 2 R ⁇ , -S(0)OR ⁇ , -S(0)0R6 a , -S(0) 2 OR ⁇ , -S(0) 2 OR6 a , -C(0)OR ⁇ , -C(0)R 6c , -C(0)OR6 a , -OC(0)R ⁇ ,
  • R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
  • R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
  • R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
  • R6a i independently H or an ether- or ester-forming group;
  • R,5 b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
  • R6 C is independently H or the residue of an amino-containing compound
  • Wi is a group comprising an acidic hydrogen, a protected acidic group, or an R ⁇ c amide of the group comprising an acidic hydrogen
  • W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom
  • W3 is W or W5;
  • W4 is R5 or -C(0)R5, -C(0)Ws, -SO2R5, or -SO2W5;
  • W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
  • W 6 is -R 5 , -W 5 , -R5aW 5 , -C(0)OR 6a , -C(0)R 6c , -C(0)N(R ⁇ b)2, -C(NR6b)(N(R 6 b)2), -C(S)N(R 6 b)2, or -C(0)R 2;
  • Xl is -O-, -N(H)-, -N(W 6 )-, -N(OH)-, -N(OW 6 )-, -N(NH )-, -N(N(H)(W 6 ))-, -N(N(W 6 )2)-, -N(H)N(W 6 )-, -S-, -SO-, or -S0 2 -; and each mi is independently an integer from 0 to 2; and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
  • Ei is -C0 2 R ⁇
  • Gi is -NH 2 , -N(H)(R5) or -N(H)(C(N(H))(NH 2 ));
  • Ti is -N(H)(C(0)CH 3 );
  • Ui is -OR o;
  • R l is H or an alkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms
  • R 0 is a branched alkyl of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms; and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
  • Another embodiment of the invention is directed to compounds of formulas (VII) or (VIII):
  • Ei is -(CRiRi)miWi;
  • Gi is N 3 , -CN, -OH, -OR 6a , -N0 2 , or -(CRiRi) m iW 2 ;
  • Ti is -NR1W3, a heterocycle, or is taken together with Gi to form a group having the structure
  • Ui is -XiW ⁇
  • Jl and Jia are independently Ri, Br, Cl, F, I, CN, NO2 or N3; J2 and J2a are independently H or Ri;
  • Rl is independently H or alkyl of 1 to 12 carbon atoms
  • R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR ⁇ a, -ORi, -N(R ⁇ )2, -N(R ⁇ )(R6b), -N(R6b)2, -SRi, -SR a , -S(0)R ⁇ , -S(0) 2 R ⁇ , -S(0)OR ⁇ , -S(0)OR6 a , -S(0) 2 OR ⁇ , -S(0)2 ⁇ R6a, -C(0)OR ⁇ , -0(0) ⁇ , -C(0)OR6 a , -OC(0)R ⁇ , -N(R ⁇ )(C(0)R ⁇ ), -N(R 6b )(C(0)R 1 ), -N(R ⁇ )(C(0)OR ⁇ ), -N(R6 b )(C(0)OR ⁇ ), -C(0)N(R ⁇ ) 2 , -C(0)N(R ⁇ b )(R ⁇ ), -C(0)N(R6
  • R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
  • R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups
  • R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
  • R6a is independently H or an ether- or ester-forming group;
  • R6 b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
  • R ⁇ c is independently H or the residue of an amino-containing compound
  • Wi is a group comprising an acidic hydrogen, a protected acidic group, or an R c amide of the group comprising an acidic hydrogen
  • W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom;
  • W3 is W4 or W5;
  • W4 is R5 or -C(0)R 5 , -C(0)W 5 , -SO2R5, or -SO2W5;
  • W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
  • W 6 is -R 5 , -W 5 , -R5aW 5 , -C(0)OR6a, -C(0)R 6c , -C(0)N(R6b)2, -C(NR6b)(N(R 6 b)2), -C(NR6 b )(N(H)(R6b)), -C(N(H)(N(R6b)2), -C(S)N(R6b)2, or -C(0)R2;
  • Xl is a bond, -O-, -N(H)-, -N(W6)-, -S-, -SO-, or -SO2-; and each mi is independently an integer from 0 to 2; provided, however, that compounds are excluded wherein Ui is H or -CH2CH(OH)CH2(OH); and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
  • a compound or composition of the invention that further comprises a pharmaceutically-acceptable carrier.
  • the activity of neuraminidase is inhibited by a method comprising the step of treating a sample suspected of containing neuraminidase with a compound or composition of the invention.
  • Another embodiment of the invention provides a method for inhibiting the activity of neuraminidase comprising the step of contacting a sample suspected of containing neuraminidase with the composition embodiments of the invention.
  • Another embodiment of this invention is a method for the treatment or prophylaxis of viruses, particularly influenza virus infection in a host comprising administration to the host, by a route other than topically to the respiratory tract, of a therapeutically effective dose of an antivirally active compound described in WO 91/16320, WO 92/06691 or US patent 5,360,817.
  • novel methods for synthesis of the compounds of this invention are provided.
  • a method for using a compound of the formula 281 wherein the method comprises treating compound 281 with a compound of the formula R5-XI-H to form a compound of the formula 281.1
  • R51 is an acid stable protecting group for a carboxylic acid; and R54 aziridine activating group.
  • R50 is a 1,2 diol protecting group
  • R51 is an acid stable carboxylic acid protecting group
  • R52 is a hydroxy activating group.
  • Figs. 1 and 2 depict the arterial oxygen saturation (Sa ⁇ 2) levels of influenza-A infected mice treated with varying i.p. doses of GG167 (4- guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid), a known anti- influenza compound (Fig. 1) and compound 203 of this invention (Fig. 2): 50, 10, 2 and 0.5 mpk (mg/kg/day) of test compounds and saline control are designated, respectively, by squares, solid circles, triangles, diamonds and open circles. In all Figures, *P ⁇ 0.05, **P ⁇ 0.01 compared to the saline controls.
  • Figs. 3-5 compare the Sa ⁇ 2 levels achieved in influenza A infected mice treated with p.o. doses of ribavirin (triangles), compound 203 (squares) and GG167 (solid circles); saline controls are open circles: Fig. 3: 150 mpk of each of compound 203 and GG167, 100 mpk ribavirin; Fig. 4: 50 mpk of each of compound 203 and GG167, 32 mpk of ribavirin; Fig. 5: 10 mpk of each of compound 203 and GG167, 10 mpk of ribavirin.
  • Figs. 6-8 depict the Sa ⁇ 2 levels in influenza A infected mice treated with low p.o. doses of compounds 262 (circles) and 260 (solid squares) and GG167 (triangles); saline controls are open circles and uninfected controls are open squares: Fig. 6: mpk of each of the test compounds; Fig. 7: 1 mpk of each test compound; Fig. 8: 0.1 mpk of each test compound.
  • compositions of the Invention exclude compounds heretofore known. However, as will be further apparent below in other embodiments it is within the invention to use for antiviral purposes known compounds heretofore only produced and used as intermediates in the preparation of antiviral compounds. 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 WO 91/16320, WO 92/06691, US Patent 5,360,817 or Chandler, M. et al., "J. Chem. Soc. Perkin Trans. 1", 1189-1197 (1995).
  • 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. It should be understood, however, that other embodiments of this invention more fully described below contemplate the use of compounds that are in fact specifically disclosed in WO 91/16320, WO 92/06691, or US Patent 5,360,817, including those in which YR ⁇ is free hydroxyl, or hydroxyl protected by a readily hydrolyzable group such as acetyl. In this instance, however, the compounds are delivered by novel routes of administration. In another embodiment, the compounds herein exclude those in which
  • Ei is -C ⁇ 2H, -P(0)(OH)2, -NO2, -SO2H, -SO3H, tetrazolyl, -CH2CHO, -CHO, or -CH(CHO)2;
  • Gi is -CN, N3,-NHR20, NR20, -OR20, guanidino, SR20/ -N(R20) ⁇ O, -N(R20)(OR20), -N(H)(R2 ⁇ )N(R2 ⁇ )2, unsubstituted pyrimidinyl, or unsubstituted (pyrimidinyl)methyl;
  • Ti is -NHR20/ -NO2; and R20 is H; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an NO2 group, an NH2 group or a COOH group;
  • Xi is a bond, -CH2- or -CH2CH2-; in which case W6 is not H, W7 or -CH2W7 wherein W7 is H, -OR ⁇ a, -ORi, -N(Ri) 2 , -N(Ri)(R 6 b), -N(R 6 b)2, -SRi, or -SR 6a .
  • A2 is O;
  • Ei is COOH, P(0)(OH) 2 , N0 2 , SOOH, S0 3 H, tetrazole,
  • Gi is hydrogen, N(R 0 a ) 2 , SR 20a or OR 20a ;
  • Ti is -NHC(O)R 20b , where R 20b is an unsubstituted or halogen-substituted linear or cyclic alkyl group of 1 to 6 carbon atoms, or SR 20a , OR 20a , COOH or alkyl /aryl ester thereof, N0 2 , C(R 20a ) 3 , CH 2 COOH or alkyl/aryl ester thereof, CH N0 2 or CH 2 NHR 2 0b ;
  • R 20a is hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; or an unsubstituted aryl group or an aryl substituted by a halogen, an allyl group, an OH group, an N0 2 group, an NH 2 group or a COOH group;
  • Ji is H and J ⁇ a is H, OR 0a , F, Cl, Br, CN, NHR 20a , SR 0 a or CH 2 X wherein X is NHR " a , halogen or OR 0 a ;
  • J 2 is H or J 2a is hydrogen, N(R 20a ) , SR 20a or OR 20a ;
  • R 20a represents a covalent bond when Y is hydrogen and and pharmacologically acceptable salts or derivatives thereof.
  • the compounds of this invention are those in which Ui is not -CH2OH, -CH2OAC, or -CH2 ⁇ CH2Ph.
  • the compounds of this invention are those in which Ei is not -CH2OH, -CH2OTMS, or -CHO.
  • the compounds of this invention are those in which Ui is not bonded directly to the nuclear ring by a carbon atom or Ui is not substituted with hydroxyl or hydroxyester, in particular Ui is not polyhydroxyalkane, especially -CH(OH)CH(OH)CH2 ⁇ H.
  • Ui is a branched chain group R5 as described below or a carbocycle which is substituted with at least one group R5.
  • A2 is -O- or -CH2-; Ei is -CO2H;
  • Gi is -N(H)(C(NH)(NH2)); Ti is -N(H)(Ac); and
  • A2 is -O- or -CH2-
  • Gi is -NH2
  • Ti is -N(H)(Ac); and Ul is -CH2 ⁇ H;
  • El is -CH2OH or -CH2OTMS; Gi is -N3; Ti is -N(H)(Ac); and
  • Ui is -CH2 ⁇ CH2Ph
  • El is -CO2H or -CO2CH3; Gi is -N3;
  • Ti is -N(H)(Ac); and Ui is -CH2OH;
  • Ti is -N(H)(Ac); and Ui is -CH2 ⁇ CH2Ph; 6.
  • 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, benzofuranyi, 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, 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 ⁇ - carboline.
  • nitrogen bonded heterocycles include 1- aziridyl, 1-azetedyl, 1-pyrrolyl, 1 -imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Alkyl as used herein, unless stated to the contrary, is C1-C12 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 fe-Bu, ⁇ -butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (i-Bu, i-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH3, 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-
  • compositions of the invention comprise compounds of either formula:
  • the compounds of Formula I are chosen.
  • Ji and J ⁇ a are independently Ri, Br, Cl, F, I, CN, NO2 or N3, typically
  • Rl or F more typically H or F, more typically yet H.
  • J2 and J2a are independently H or Ri, typically H.
  • Ei is -(CRiRi)mlW ⁇ .
  • Rl is H or alkyl of 1 to 12 carbon atoms, usually H or an alkyl of 1 to 4 or 5 to 10 carbon atoms, still more typically, H or an alkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, more typically yet, H or an alkyl of 1 to 3 carbon atoms selected from methyl, ethyl, n-propyl, and i-propyl.
  • Ri is H.
  • ml is an integer of 0 to 2, typically 0 or 1, most typically 0.
  • m2 is an integer of 0 to 1.
  • m3 is an integer of 1 to 3.
  • Wi is a group comprising an acidic hydrogen, a protected acidic group or an R6c amide of the group comprising an acidic hydrogen which, within the context of the invention, means a group having a hydrogen atom that can be removed by a base yielding an anion or its corresponding salt or solvate.
  • the general principles of acidity and basicity of organic materials are well understood and are to be understood as defining Wi . They will not be detailed here. However, a description appears in Streitwieser, A.; and Heathcock, C. H.; "Introduction to Organic Chemistry, Second Edition” (Macmillan, New York, 1981), pages 60-64.
  • -OSO3H, -SO3H, -SO2H, -OPO3H2, -P0 3 (R6a)2, -PO3H2, -P0 3 (H)(R6a), and -OP ⁇ 3(R6a)2- Ei typically is Wi, and Wi typically is -CO2H, -C ⁇ 2R6a,
  • CO2R4 or CO2R1
  • Wi may also be a protected acidic group, which, within the context of the invention means an acidic group as described above that has been protected by one of the groups commonly used in the art for such groups and are described below under R6 a - More typically, protected Wi is -CO2R1,- SO3R1, -S(0)OR ⁇ , -P(0)(OR ⁇ )2, -C(0)NHS ⁇ 2R4, or -S ⁇ 2NHC(0)-R4, wherein Rl and R4 are defined above.
  • Ei groups are listed in Tables 3a through 3b.
  • Gi is N3, -CN, -OH, OR a/ -NO2 or -(CRiRi) m iW2, wherein Ri and ml are defined above.
  • Gi is -(CR ⁇ R ⁇ )ml 2-
  • W2 is a group comprising a basic heteroatom, a protected basic heteroatom or an R6b amide of the basic heteroatom.
  • W2 generally comprises a basic heteroatom, which, within the context of the invention means an atom other than carbon which is capable of protonation, typically by an acidic hydrogen having an acidity in the range described above for Wi.
  • the basic principles of basicity are described in Streitwieser and Heathcock (op.
  • Basic heteroatoms include the heteroatoms common in organic compounds which have an un-shared, non-bonding, n- type, or the like, electron pair.
  • typical basic heteroatoms include the oxygen, nitrogen, and sulfur atoms of groups such as alcohols, amines, amidines, guanidines, sulfides, and the like, frequently, amines, amidines and guanidines.
  • W2 is amino or an amino alkyl (generally lower alkyl Cl to C ⁇ ) group such as aminomethyl, aminoethyl or aminopropyl; an amidinyl, or an amidinoalkyl group such as amidinomethyl, amidinoethyl, or amidinopropyl; or guanidinyl, or a guanidinoalkyl group such as guanidinomethyl, guanidinoethyl, or guanidinopropyl (in each instance wherein the alkyl group serves to bridge the basic substituent to the carbocyclic ring).
  • an amino alkyl generally lower alkyl Cl to C ⁇
  • an amidinyl, or an amidinoalkyl group such as amidinomethyl, amidinoethyl, or amidinopropyl
  • guanidinyl, or a guanidinoalkyl group such as guanidinomethyl, guanidinoethyl, or guanidinoprop
  • W2 is amino, amidino, guanidino, heterocycle, heterocycle substituted with 1 or 2 amino or guanidino groups (usually 1), or an alkyl of 2 to 3 carbon atoms substituted with amino or guanidino, or such alkyl substituted with an amino and a second group selected from the group consisting of hydroxy and amino.
  • W2 optionally is a protected basic heteroatom which within the context of the invention means a basic heteroatom as described above that has been protected by R6b such as one of the groups common in the art.
  • groups are described in detail in Greene ⁇ op. cit.) as set forth below.
  • groups include by way of example and not limitation, amides, carbamates, amino acetals, imines, enamines, N-alkyl or N-aryl phosphinyls, N-alkyl or N-aryl sulfenyls or sulfonyls, N-alkyl or N-aryl silyls, thioethers, thioesters, disulfides, sulfenyls, and the like.
  • the protecting group R6b will be cleavable under physiological conditions, typically it will be cleavable in vivo where, for example, the basic heteroatom forms an amide with an organic acid or an amino acid such as a naturally occurring amino acid or a polypeptide as described below for the R6 a group.
  • Gi is selected from the group consisting of:
  • Ti is -NR1W3, -R3, -R5 or heterocycle, or is taken together with Ui or Gi to form a group having the structure
  • Ti is -NRi, W3 or heterocycle.
  • Ti is selected from the group consisting of:
  • W3 is W4 or W5, wherein W4 is R5 or -C(0)R5, -C(0)W5, -SO2R5, or
  • W3 is -C(0)R5 or W5.
  • R2 is independently R3 or R4 as defined below, with the proviso that each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR ⁇ a, -ORi, -N(R ⁇ ) 2/
  • R3 is F, Cl, -CN, N3, N0 2 , -OR6a, -ORi, -N(R ⁇ )2, -N(R ⁇ )(R 6 b), -N(R6b)2, "SR
  • R4 is alkyl of 1 to 12 carbon atoms, and alkynyl or alkenyl of 2 to 12 carbon atoms.
  • the alkyl Rj's are typically of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms and the alkenyl and alkynyl Rj's are typically of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms.
  • R4 ordinarily is alkyl (as defined above).
  • R4 alkenyl groups are of 2, 3 or 4 carbon atoms.
  • R4 alkynyl it 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). More typically, R4
  • R5 is an alkyl of 1 to 4 carbon atoms substituted with 0 to 3 fluorine atoms.
  • R5 a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups.
  • R5 a 's are of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms when alkylene and of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms when alkenylene or alkynylene.
  • Each of the typical R4 groups is a typical R5a group with the proviso that one of the hydrogen atoms of the described R4 group is removed to form the open valence to a carbon atom through which the second bond to the R5a i attached.
  • Rl4 is normal or terminally secondary Ci-C ⁇ alkyl.
  • W5 is a carbocycle or heterocycle, with the proviso that each W5 is independently substituted with 0 to 3 R2 groups.
  • W5 carbocycles and Ti and W5 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.
  • Each W5 is independently substituted with 0 to 3 R2 groups.
  • Ti and W5 are a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle.
  • Ti or W5 has 3 to 10 ring atoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6 ring atoms.
  • the Ti and 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.
  • W5 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-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
  • a Ti or 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, Ti and 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).
  • Ti and 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.
  • Ti and W5 heterocycles are selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, or pyrrolyl.
  • the heterocycle of Ti and W5 is bonded through a carbon atom or nitrogen atom thereof. Still more typically Ti heterocycles are bonded by a stable covalent bond through a nitrogen atom thereof to the cyclohexene ring of the compositions of the invention and W5 heterocycles are bonded by a stable covalent bond through a carbon or nitrogen atom thereof to the cyclohexene ring of the compositions of the invention. Stable covalent bonds are chemically stable structures as described above. W5 optionally is selected from the group consisting of:
  • Xl is a bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW ⁇ )-, -N(NH2)-, -N(N(H)(W6))-, -N(N(W 6 )2)-, -N(H)N(W6)-, -S-, -SO-, or -SO2-;
  • Xl is a bond, -O-, -N(H)-, -N(Rs)-, -N(OH)-, -N(OR5)-, -N(NH2)-, -N(N(H)(R5))-, -N(N(R5)2)-, -N(H)N(Rs)-, -S-, -SO-, or -SO2-, more typically Xl is a bond, -O-, -NRi-, -N(OR ⁇ )-, -N(NR
  • W 6 is -R5, -W 5 , -R5aW 5 , -C(0)OR6a, -C(0)R 6 -C(0)N(R6b)2, -C(NR6b)(N(R6b)2), -C(NR ⁇ b)(N(H)(R6b)), -C(N(H)(N(R 6 b)2), -C(S)N(R6b)2, or -C(0)R2, typically W is -R5, -W5, or -R5aWs; in some embodiments, W6 is Ri, -C(0)-Ri, -CHR1W7, -CH(R ⁇ ) a W7, -CH(W7)2, (where, W7 is monovalent a is 0 or 1, but is 0 when W7 is divalent) or -C(0)W7.
  • W6 is -CHR1W7 or -C(0)W7, or W6 is -(CH 2 ) m lCH((CH2)m3R3)2, -(CH2)mlC((CH 2 )m3R3)3; -(CH 2 ) m lCH((CH 2 ) m 3R5aW 5 )2; -(CH 2 )mlCH((CH2)m3R3)((CH 2 )m3R5aW5);
  • W7 is R3 or R5, but typically is alkyl of 1 to 12 carbons substituted with 0 to 3 R3 groups, the latter typically selected from the group consisting of
  • W7 is -ORi or an alkyl of 3 to 12 carbon atoms substituted with ORi.
  • Ui is RiO-, -OCFTR1W7,
  • E2 is Ei, but is typically selected from the group consisting of:
  • G2 is Gi, but is typically selected from the group consisting of:
  • T2 is R4 or R5.
  • T2 is alkyl of 1 to 2 carbon atoms substituted with 0 to 3 fluorine atoms.
  • U2 is one of:
  • R7 is H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OAc (-0-C(0)CH3), -OH, -NH2, or -SH, typically H, -CH3 or -CH2CH3.
  • Groups R 6a 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.
  • active prodrugs are absorbed more effectively than the parental drug they in fact often possess greater potency in vivo than the parental drug.
  • R6a and R6b are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs.
  • 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.
  • R ⁇ a is H or 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;
  • V is a divalent atom typically selected from O, S, and Se, more typically S;
  • Vi is a group bonded to V a , Vb or Vc by a stable, single covalent bond, typically Vi is W6 groups, more typically Vi is H, R2, W5, or -R5aW5, still more typically H or R2;
  • V3 is a group bonded to Va by a stable, triple covalent bond, typically V3 is ⁇ C
  • Va, Vb, 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". 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 R ⁇ below. R6 is capable of protecting hydroxyl or thio groups such that hydrolysis from the parental molecule yields hydroxyl or thio.
  • R6a In its ester-forming role, R6a 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 6a - R ⁇ a for example is deduced from the enumerated ester groups of WO 95/07920.
  • R f , a include
  • C 3 -Ci2 heterocyle (described above) or C 6 -C 12 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,
  • Such groups include 2-, 3- and 4-alkoxyphenyl ( -C 1 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-, 2,6
  • triglycerides such as ⁇ -D- ⁇ -diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C6-26/ ⁇ -is or C6- 1 0 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
  • 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.
  • R 6a 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).
  • 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).
  • chiral center is (R), (S) or racemate.
  • R6a also includes "double ester" forming profunctionalities such as
  • R37 and R38 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 6a groups are alkylacyloxymethyl esters and their derivatives, including -CH(CH 2 CH 2 OCH 3 )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.
  • R6a, 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.
  • 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.
  • 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 R6a 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 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 C 1 -C 4 alkylestercarboxyphenyl (salicylate C 1 -C 12 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, f-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-
  • 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-i-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.
  • R9 is C1-C6 alkyl
  • R6b i 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.
  • Amide-forming R6b are found for instance in group Gi.
  • R£b is an amino acid or polypeptide it has the structure Ri5NHCH(Ri6)C(0)-, where R l 5 is H, an amino acid or polypeptide residue, or R5, and Ri6 is defined below.
  • Rl6 is lower alkyl or lower alkyl (Ci-C ⁇ ) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C 6 -C 7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulf oxide, and /or alkylphosphate.
  • Ri 6 is generally the side group of a naturally-occurring amino acid such as H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CHCH 3 -CH 2 -CH 3/ -CH 2 -C 6 H 5 , -CH 2 CH 2 -S-CH 3 , -CH 2 OH, -CH(OH)-CH 3 , -CH 2 -SH, -CH 2 -C 6 H 4 OH, -CH 2 -CO- NH 2 , -CH 2 -CH2-CO-NH2, -CH 2 -COOH, -CH2-CH 2 -COOH, -(CH 2 ) 4 -NH 2 and -(CH 2 ) 3 -NH-C(NH 2 )-NH 2 .
  • R ⁇ 6 also includes l-guanidinoprop-3-yl, benzyl, 4- hydroxybenzyl, imidazol-4-yl,
  • R6b 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-f-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, l,l-dimethyl-2-haloethyl, l,l-dimethyl-2,2- dibromoethyl, l,l
  • Methoxyphenylazo)benzyl 1-methylcyclobutyl, 1-methylcyclohexyl, 1- methyl-1-cyclopropylmethyl, l-methyl-l-(3,5-dimethoxyphenyl)ethyl, 1- methy 1-1 -(p-phenylazopheny l)ethy 1, 1 -methy 1-1 -pheny lethy 1, 1 -methy 1-1 -(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,
  • Another protecting group, also usefull as a prodrug at the Gi site, particularly for amino or -NH(Rs), is:
  • R6c is H or the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHSO2R4, NHC(0)R4, -N(R4)2, NH2 or -NH(R4)(H), whereby for example the carboxyl or phosphonic acid groups of W are reacted with the amine to form an amide, as in -C(0)R6c, -P(0)(R6 C ) 2 or -P(0)(OH)(R6 )-
  • R6c has the structure R ⁇ C(0)CH(Ri6)NH-, where R17 is OH, OR6a, 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.
  • R6b and R6c are single amino acid residues or polypeptides they usually are substituted at R3, W6, W and /or W2, but typically only Wi or W2-
  • These conjugates are produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example) and W2-
  • conjugates are formed between Wi and an amino group of an amino acid or polypeptide.
  • 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 of Wi 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 R6a esterified with R5 or amidated with R ⁇ c- Similarly, the amino side chains Ri6 optionally will be blocked with R6b or substituted with R5.
  • 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.
  • Suitable amino acids whose residues are represented by R 6 t > and R-sc include the following: Glycine;
  • 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-propy
  • 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
  • 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.
  • 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.
  • Wi 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, AI, 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, MM, 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 ° r 6c-
  • 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 ester if ied 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).
  • T is -NR1W3, a heterocycle, or is taken together with Gi to form a group having the structure
  • Xl is a bond, -O-, -N(H)-, -N(Rs)-, -S-, -SO-, or -SO2-; and provided, however, that compounds are excluded wherein Ui is H or -CH2CH(OH)CH2(OH); and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
  • Stereoisomers 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 chiral 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.
  • 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 lipases 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.
  • Tables la and lb are a schedule of nuclei which differ principally by the position of ring unsaturation and the nature of ring substituents. Each nucleus is given a alphabetical designation from Tables la and lb, and this designation appears first in each compound name.
  • Tables 2a- av, 3a-b, 4a-c, and 5a-d list the selected Qi, Q 2 , 3 and Q 4 substituents, again by letter or number designation.
  • each named compound will be depicted by a capital letter designating the nucleus from Table la-lb, followed by a number designating the Qi substituent, a lower case letter designating the Q 2 substituent, a number designating the Q 3 substituent, and a lower case letter or letters designating the Q 4 substituent.
  • structure 8, scheme 1 is represented by A.49.a.4.i. Q1-Q4, it should be understood, do not represent groups or atoms but are simply connectivity designations.
  • E.33.g.6.v E.33.g.ll.i; E.33.g.ll.v; E.33.g.l4.i; E.33.g.l4.v; E.33.g.l5.i; E.33.g.l5.v;
  • H.17.a.l8.v H.17.a.25.i; H.17.a.25.v; H.17.e.4.i; H.17.e.4.v; H.17.e.6.i; H.17.e.6.v;
  • H.17.1.4.V H.17.1.6.i; H.17.1.6.v; H.17.1.11.i; H.17.1.11.v; H.17.1.14.i; H.17.1.14.V;
  • L.33.g.6.v L.33.g.ll.i; L.33.g.ll.v; L.33.g.l4.i; L.33.g.l4.v; L.33.g.l5.i; L.33.g.l5.v;
  • L.33.o.4.v L.33.o.6.i; L.33.o.6.v; L.33.o.ll.i; L.33.o.ll.v; L.33.o.l4.i; L.33.o.l4.v;
  • L.49.g.4.v L.49.g.6.i; L.49.g.6.v; L.49.g.ll.i; L.49.g.ll.v; L.49.g.l4.i; L.49.g.l4.v;

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Abstract

Novel compounds are described. The compounds generally comprise an acidic group, a basic group, a substituted amino or N-acyl and a group having an optionally hydroxylated alkane moiety. Pharmaceutical compositions comprising the inhibitors of the invention are also described. Methods of inhibiting neuraminidase in samples suspected of containing neuraminidase are also described. Antigenic materials, polymers, antibodies, conjugates of the compounds of the invention with labels, and assay methods for detecting neuraminidase activity are also described.

Description

COMPOUNDS CONTAINING SIX-MEMBERED RINGS, PROCESSES FOR THEIR PREPARATION, AND THEIR USE AS MEDICAMENTS
Cross Referenced to Related Applications This application is based upon United States Provisional Application
10 Serial Number 60/060,195, filed September 26, 1997, United States Patent
Application Serial Number 08/938,644, filed September 26, 1997, and United States Provisional Application Serial Number 60/059,308, filed September 17, 1997.
This application is also related to United States Patent Application
15 Serial Number 08/653,034, filed March 24, 1996, which was a continuation- in-part application of United States Patent Application Serial Number 08/606,624, filed February 26, 1996, which was a continuation-in-part application of United States Patent Application Serial Number 08/580,567, filed December 29, 1995, which was a continuation-in-part application of
20 United States Patent Application Serial Number 08/476,946, filed June 6, 1995, which was a continuation-in-part application of United States Patent Application Serial Number 08/395,245, filed February 27, 1995, all of which are incorporated herein by reference in their entirety. This application is related to United States Patent Application Serial Number 08/917,640, filed
25 August 22, 1997, which describes methods of making carbocyclic compounds in particular methods of making GS 4104, phosphate salt, and is incorporated by reference in its entirety.
30 Field of the Invention
Neuraminidase (also known as sialidase, acylneuraminyl hydrolase, and EC 3.2.1.18) is an enzyme common among animals and a number of microorganisms. It is a glycohydrolase that cleaves terminal alpha- ketosidically linked sialic acids from glycoproteins, glycolipids and
35 oiigiosaccharides. Many of the microorganisms containing neuraminidase are pathogenic to man and other animals including fowl, horses, swine and seals. These pathogenic organisms include influenza virus.
Neuraminidase has been implicated in the pathogenicity of influenza viruses. It is thought to help the elution of newly synthesized virons from infected cells and assist in the movement of the virus (through its hydrolase activity) through the mucus of the respiratory tract.
Brief Description of Related Art von Itzstein, M. et al; "Nature", 363(6428):418-423 (1993), discloses the rational design of sialidase-based inhibitors of influenza virus replication. Colman, P. M. et al; International Patent Publication No. WO
92/06691 (Int. App. No. PCT/AU90/00501, publication date April 30, 1992), von Itzstein, L. M. et al.; European Patent Publication No. 0 539 204 Al (EP
App. No. 92309684.6, publication date April 28, 1993), and von Itzstein, L. M. et al.; International Publication No. WO 91/16320 (Int. App. No. PCT/AU91/00161, publication date October 31, 1991) disclose compounds that bind neuraminidase and are asserted to exhibited antiviral activity in vivo.
Objects of the Invention A principal object of the invention is inhibition of viruses, in particular influenza viruses. In particular, an object is inhibition of glycolytic enzymes such as neuraminidase, in particular the selective inhibition of viral or bacterial neuraminidases.
An additional object of the invention is to provide neuraminidase inhibitors that have a retarded rate of urinary excretion, that enter into nasal or pulmonary secretions from the systemic circulation, that have sufficient oral bioavailability to be therapeutically effective, 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 neuraminidase inhibitors.
A still further object is to provide improved methods for administration of known and novel neuraminidase 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 a whole.
Summary of the Invention Compounds, or compositions having formula (I) or (II) are provided herein:
Figure imgf000005_0001
wherein
Al is -C(Jι)=, -N= or -N(0)=; A2 is -C(Jl)2-, -NQi)-, -N(O)Qi)-, -S-, -S(O)-, -S(0)2- or -O-;
El is -(CRiRι)miWi;
Gi is N3, -CN, -OH, -OR6a, -Nθ2, or -(CRlRl)mlW2; Ti is -NR1W3, H, -R3, -R5, a heterocycle, or is taken together with Ui or Gi to form a group having the structure
Figure imgf000005_0002
Ui is H, -R3 or -X1W6;
Jl and Jia are independently Ri, Br, Cl, F, I, CN, NO2 or N3;
J2 and J2a are independently H or Ri;
Rl is independently H or alkyl of 1 to 12 carbon atoms; R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -N02, -OR6a, -ORi, -N(Rι)2, -N(Rι)(R6b), -N(R6b)2, -SRi, -SR6a, -S(0)Rι, -S(0)2Rι, -S(0)ORι, -S(0)OR6a, -S(0)2ORι, -S(0)2OR6a, -C(0)ORι, -C(0)R6o - (0)OR6a, -OC(0)Rι, -N(Rι)(C(O)R , -N(R6b)(C(0)Rι), -N(Rι)(C(0)ORι), -N(R b)(C(0)ORι), -C(0)N(Rι)2/ -C(0)N(R6b)(Ri), -C(0)N(R6b)2, -C(NRι)(N(Rι)2), -C(N(R6b))(N(Rι)2), -C(N(R1))(N(R1)(R6b)), -C(N(R6b))(N(Rι)(R6b)), -C(N(Rι))(N(R6b)2), -C(N(R6b))(N(R6b)2), -N(R1)C(N(Rι))(N(Rι)2), -N(Rι)C(N(Rι))(N(Rι)(R6b)), -N(Rι)C(N(R6b))(N(Rι)2), -N(R6b)C(N(Rι))(N(Rι)2), -N(R6b)C(N(R6b))(N(Rι)2), -N(R6b)C(N(Rι))(N(Rι)(R6b)), -N(R1)C(N(R6b))(N(R1)(R6b)), -N(Rι)C(N(Rι))(N(R6b)2), -N(R6b)C(N(R6b))(N(Rι)(R6b)), -N(R6b)C(N(R1))(N(R6b)2), -N(R1)C(N(R6b))(N(R6b)2), -N(R6b)C(N(R6b))(N(R6b)2), =0, =S, =N(Rι), =N(R6b) or W5;
R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups; R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups; R6a is independently H or an ether- or ester-forming group; R6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R6C is independently H or the residue of an amino-containing compound;
Wi is a group comprising an acidic hydrogen, a protected acidic group, or an R£c amide of the group comprising an acidic hydrogen; W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom or a group derivatizable to a basic heteroatom; W3 is W4 or W5;
W4 is R5 or -C(0)R5, -C(0)Ws, -SO2R5, or -SO2W5; W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is -R5, -W5, -R5aW5, -C(0)OR6a, -C(0)R6o -C(C»)N(R6b)2, -C(NR6b)(N(R6b)2), -C(NR6b)(N(H)(R6b)), -C(N(H)(N(R6b)2), -C(S)N(R6b)2, or -C(0)R2; Xi is a bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH2)-,
-N(N(H)(W6))~, -N(N(W6)2)-, -N(H)N(W6)-, -S-, -SO-, or -SO2-; and each mi is independently an integer from 0 to 2; provided, however, that compounds are excluded that are described in WO 91/16320 at page 3, line 23 to page 5, line 6, which appear to include compounds wherein:
(a) Ai is -CH= or -N= and A2 is -CH2-; (b) Ei is COOH, P(0)(OH)2, SOOH, SO3H, or tetrazol;
(c) Gi is CN, N(H)R20, N3, SR20/ OR2O/ guanidino, -N(H)CN 20 -
Figure imgf000007_0001
(e) R20 is H; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an NO2 group, an NH2 group or a COOH group;
(f) Jl is H and Jia is H, F Cl, Br or CN,
(g) J2 is H and J2a is H, CN or N3;
(h) Ui is CH2YR20a, CHYR20aCH2YR20a or CHYR20aCHYR20aCH2YR20a,
(1) R20a is H or acyl having 1 to 4 carbon atoms;
Figure imgf000007_0002
(k) 0 to 2 YR20a are H, and
(1) successive Y moieties in a Ui group are the same or different, and when Y is H then R20a is a covalent bond, and provided that if Gi is N3 then Ui is not -CH2OCH2PI1. and the pharmaceutically acceptable salts and solvates thereof; and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Also excluded herein are compounds described in WO 92/06691 at Page 9, Line 26, to Page 11, Line 5, which appear to include compounds of the formula II wherein:
Figure imgf000007_0003
(b) Ei is COOH, P(0)(OH)2, N02, SOOH, SO3H, tetrazole,
CH2CHO, CHO, CH(CHO)2 or where Ei is COOH, P(0)(OH)2, SOOH or SO3H, an ethyl, methyl or pivaloyl ester thereof;
(c) Gi is hydrogen, N(R20a)2/ SR20 or OR20a;
(d) Ti is -NHC(O)R20b, where R20b is an unsubstituted or halogen-substituted linear or cyclic alkyl group of 1 to 6 carbon atoms, or SR20a, OR20a, COOH or alkyl /aryl ester thereof, N02, C(R20a)3, CH2COOH or alkyl/aryl ester thereof, CH2N02 or CH2NHR20b;
(e) R20a is hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; or an unsubstituted aryl group or an aryl substituted by a halogen, an allyl group, an OH group, an NO2 group, an NH2 group or a COOH group;
(f) Ji is H and Jιa is H, OR2°a, F, Cl, Br, CN, NHR2° , SR2°a or CH2X wherein X is NHR2^, halogen or OR20a;
(g) J2 is H or J2a is hydrogen, N(R20a)2/ SR 0a or OR20a; (h) Ui is CH YR20a, CHYR20CH2YR20a or
CHYR2" CHYR20aCH2YR20a where Y is O, S or H, and successive Y moieties in Ui are the same or different and R2 a represents a covalent bond when Y is hydrogen and and pharmacologically acceptable salts or derivatives thereof. Another embodiment of the invention is directed to compounds of the formula:
Figure imgf000008_0001
(III) (IV) wherein
El is -(CRiRi)mlWi;
Gi is N3, -CN, -OH, -OR6a, -NO2, or -(CRιRι)miW2;
Ti is -NR1W3, a heterocycle, or is taken together with Ui or Gi to form a group having the structure
Figure imgf000009_0001
Ui is H or -X W6 and, if -XlW6, then Ui is a branched chain;
Jl and Jia are independently R , Br, Cl, F, I, CN, NO2 or N3;
J2 and J2a are independently H or R ; Ri is independently H or alkyl of 1 to 12 carbon atoms;
R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -N02/ -ORόa, -ORi, -N(Rι)2/ -N(Rι)(R6b), -N(R6b)2, -SRi, -SR6a, -S(0)Rι, -S(0)2Rι, -S(0)OR!, -S(0)OR6a, -S(0)2ORι, -S(0)2OR a/ -C(0)ORι, -C(0)R6c, - (0)OR a, -OC(0)Rι,
-N(R1)(C(0)R1), -N(R6b)(C(0)R1), -N(Rι)(C(0)ORι), -N(R6b)(C(0)ORι), -C(0)N(Rι)2 -C(0)N(R6b)(Rι) -C(0)N(R6b)2, -C(NRι)(N(Rι)2), -C(N(R6b))(N(R1)2), -C(N(R1))(N(Rι)(R6b)), -C(N(R6b))(N(Rι)(R6b))/ -C(N(Rι))(N(R6b)2), -C(N(R6b))(N(R6b)2), -N(R1)C(N(R1))(N(R1)2), -N(R1)C(N(Rι))(N(Rι)(R6b)), -N(Rι)C(N(R6b))(N(Rι)2), -N(R6b)C(N(R1))(N(Rι)2), -N(R6b)C(N(R6b))(N(R1)2), -N(R6b)C(N(Rι))(N(R1)(R6b))/ -N(Rι)C(N(R6b))(N(R1)(R6b)), -N(R1)C(N(Rι))(N(R6b)2), -N(R6b)C(N(R6b))(N(R1)(R6b))/ -N(R6b)C(N(Rι))(N(R6b)2), -N(R1)C(N(R6b))(N(R6b)2), -N(R6b)C(N(R6b))(N(R6b)2)/ =0, =S, =N(Rι) or =N(R6b);
R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups; R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
R6a is independently H or an ether- or ester-forming group;
R , is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R6C is independently H or the residue of an amino-containing compound;
Wi is a group comprising an acidic hydrogen, a protected acidic group, or an R^c amide of the group comprising an acidic hydrogen;
W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R(fo amide of the basic heteroatom; W3 is W4 or W5; W4 is R5 or -C(0)R5, -C(0)Ws, -SO2R5, or -SO2W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is -R5, -W5, -R5aW5, -C(0)OR6a, -C(0)R6c, -C(0)N(R6b)2, -C(NR6b)(N(R6b)2)/ -C(S)N(R6b)2, or -C(0)R2; Xi is a bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH2)-,
-N(N(H)(W6))-, -N(N(W6)2)-, -N(H)N(W6)-, -S-, -SO-, or -SO2-; and each mi is independently an integer from 0 to 2; and the salts, solvates, resolved enantiomers and purified diastereomers thereof. Another embodiment of the invention is directed to compounds of the formula:
Figure imgf000010_0001
(M l) wherein
Ei is -(CRiRi)miWι; Gi is N3, -CN, -OH, -OR6a, -NO2, or -(CRιRι)miW ;
Ti is -NR1W3, a heterocycle, or is taken together with Ui or Gi to form a group having the structure
Figure imgf000010_0002
Ui is H or -X1W6; Ji and Jιa are independently Ri, Br, Cl, F, I, CN, NO2 or N3;
J2 and J2a are independently H or Ri; Rl is independently H or alkyl of 1 to 12 carbon atoms; R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -N02, -OR a, -ORi, -N(Rι)2, -N(Rι)(R b), -N(R6b)2, -SRi, -SR a, -S(0)R1/ -S(0)2Rι, -S(0)ORι, -S(0)0R6a, -S(0)2ORι, -S(0)2OR6a, -C(0)ORι, -C(0)R6c, -C(0)OR6a, -OC(0)Rι,
-N(R!)(C(0)Rι), -N(R6b)(C(0)Rι), -N(R1)(C(0)OR1), -N(R6b)(C(0)ORι), -C(0)N(Rι)2, -C(0)N(R6b)(Rι), -C(0)N(R6b)2, -C(NR1)(N(R1)2), -C(N(R6b))(N(Rι)2), -C(N(R1))(N(R1)(R6b)), -C(N(R6b))(N(R1)(R6b)), -C(N(Rι))(N(R6b)2), -C(N(R6b))(N(R6b)2), -N(R1)C(N(R1))(N(R1)2), -N(R1)C(N(R1))(N(R1)(R6b)), -N(Rι)C(N(R6b))(N(Rι)2), -N(R6b)C(N(Rι))(N(Rι)2), -N(R6b)C(N(R6b))(N(R1)2), -N(R6b)C(N(Rι))(N(R1)(R6b)), -N(R1)C(N(R6b))(N(R1)(R6b)), -N(Rι)C(N(R1))(N(R6b)2), -N(R6b)C(N(R6b))(N(R1)(R6b)), -N(R6b)C(N(R1))(N(R6b)2), -N(R1)C(N(R6b))(N(R6b)2), -N(R6b)C(N(R6b))(N(R6b)2)/ =0, =S, =N(Rι) or =N(R6b);
R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups; R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups; R6a i independently H or an ether- or ester-forming group; R,5b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R6C is independently H or the residue of an amino-containing compound;
Wi is a group comprising an acidic hydrogen, a protected acidic group, or an Rόc amide of the group comprising an acidic hydrogen; W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom; W3 is W or W5;
W4 is R5 or -C(0)R5, -C(0)Ws, -SO2R5, or -SO2W5; W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is -R5, -W5, -R5aW5, -C(0)OR6a, -C(0)R6c, -C(0)N(Rόb)2, -C(NR6b)(N(R6b)2), -C(S)N(R6b)2, or -C(0)R2;
Xl is -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH )-, -N(N(H)(W6))-, -N(N(W6)2)-, -N(H)N(W6)-, -S-, -SO-, or -S02-; and each mi is independently an integer from 0 to 2; and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention is directed to compounds of the formula:
Figure imgf000012_0001
wherein:
Ei is -C02Rχ;
Gi is -NH2, -N(H)(R5) or -N(H)(C(N(H))(NH2)); Ti is -N(H)(C(0)CH3); Ui is -OR o;
Rl is H or an alkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms; and
R 0 is a branched alkyl of 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms; and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention is directed to compounds of formulas (VII) or (VIII):
Figure imgf000012_0002
wherein
Ei is -(CRiRi)miWi;
Gi is N3, -CN, -OH, -OR6a, -N02, or -(CRiRi)miW2;
Ti is -NR1W3, a heterocycle, or is taken together with Gi to form a group having the structure
Figure imgf000013_0001
Ui is -XiWβ;
Jl and Jia are independently Ri, Br, Cl, F, I, CN, NO2 or N3; J2 and J2a are independently H or Ri;
Rl is independently H or alkyl of 1 to 12 carbon atoms;
R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -N02, -ORβa, -ORi, -N(Rι)2, -N(Rι)(R6b), -N(R6b)2, -SRi, -SR a, -S(0)Rι, -S(0)2Rι, -S(0)ORι, -S(0)OR6a, -S(0)2ORι, -S(0)2θR6a, -C(0)ORι, -0(0)^, -C(0)OR6a, -OC(0)Rι, -N(Rι)(C(0)Rι), -N(R6b)(C(0)R1), -N(Rι)(C(0)ORι), -N(R6b)(C(0)ORι), -C(0)N(Rι)2, -C(0)N(Rδb)(Rι), -C(0)N(R6b)2, -C(NRι)(N(Rι)2), -C(N(R6b))(N(Rι)2), -C(N(R1))(N(R1)(R6b)), -C(N(R6b))(N(R1)(R6b)), -C(N(Rι))(N(R6b)2), -C(N(R6b))(N(R6b)2), -N(R1)C(N(R1))(N(Rι)2), -N(Rι)C(N(Rι))(N(Rι)(R6b)), -N(Rι)C(N(R6b))(N(Rι)2), -N(R6b)C(N(Rι))(N(Rι)2), -N(R6b)C(N(R6b))(N(R1)2), -N(R6b)C(N(Rι))(N(Rι)(R6b)), -N(Rι)C(N(R6b))(N(R1)(R6b)), -N(Rι)C(N(Rι))(N(R6b)2), -N(R6b)C(N(R6b))(N(Rι)(R6b)), -N(R6b)C(N(Rι))(N(R6b)2), -N(R1)C(N(R6b))(N(R6b)2), -N(R6b)C(N(R b))(N(R b)2), =0, =S, =N(Rι) or =N(R6b);
R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups; R6a is independently H or an ether- or ester-forming group; R6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound;
R^c is independently H or the residue of an amino-containing compound; Wi is a group comprising an acidic hydrogen, a protected acidic group, or an R c amide of the group comprising an acidic hydrogen;
W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom; W3 is W4 or W5;
W4 is R5 or -C(0)R5, -C(0)W5, -SO2R5, or -SO2W5;
W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is -R5, -W5, -R5aW5, -C(0)OR6a, -C(0)R6c, -C(0)N(R6b)2, -C(NR6b)(N(R6b)2), -C(NR6b)(N(H)(R6b)), -C(N(H)(N(R6b)2), -C(S)N(R6b)2, or -C(0)R2;
Xl is a bond, -O-, -N(H)-, -N(W6)-, -S-, -SO-, or -SO2-; and each mi is independently an integer from 0 to 2; provided, however, that compounds are excluded wherein Ui is H or -CH2CH(OH)CH2(OH); and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
In another embodiment of the invention a compound or composition of the invention is provided that further comprises a pharmaceutically-acceptable carrier.
In another embodiment of the invention the activity of neuraminidase is inhibited by a method comprising the step of treating a sample suspected of containing neuraminidase with a compound or composition of the invention. Another embodiment of the invention provides a method for inhibiting the activity of neuraminidase comprising the step of contacting a sample suspected of containing neuraminidase with the composition embodiments of the invention.
Another embodiment of this invention is a method for the treatment or prophylaxis of viruses, particularly influenza virus infection in a host comprising administration to the host, by a route other than topically to the respiratory tract, of a therapeutically effective dose of an antivirally active compound described in WO 91/16320, WO 92/06691 or US patent 5,360,817.
In other embodiments, novel methods for synthesis of the compounds of this invention are provided. In one such embodiment, a method is provided for using a compound of the formula 281 wherein the method comprises treating compound 281 with a compound of the formula R5-XI-H to form a compound of the formula 281.1
Figure imgf000015_0001
281 281.1 wherein: Xi and R5 are as described above;
R51 is an acid stable protecting group for a carboxylic acid; and R54 aziridine activating group.
In another embodiment, a method is provided for using a compound of the formula:
Figure imgf000015_0002
Quinic Acid
wherein the method comprises treating Quinic acid with a geminal dialkoxyalkane or geminal dialkoxy cycloalkane and acid to form a compound of the formula:
Figure imgf000015_0003
274 treating compound 274 with a metal alkoxide and an alkanol to form a compound of the formula:
Figure imgf000016_0001
275 treating compound 275 with a sulfonic acid halide and an amine to form a compound of the formula:
Figure imgf000016_0002
276 ; and treating compound 276 with a dehydrating agent followed by an acid and an alkanol to form a compound of the formula:
Figure imgf000016_0003
272 wherein:
R50 is a 1,2 diol protecting group; R51 is an acid stable carboxylic acid protecting group; and
R52 is a hydroxy activating group.
Brief Description of the Drawings
Figs. 1 and 2 depict the arterial oxygen saturation (Saθ2) levels of influenza-A infected mice treated with varying i.p. doses of GG167 (4- guanidino-2,4-dideoxy-2,3-dehydro-N-acetylneuraminic acid), a known anti- influenza compound (Fig. 1) and compound 203 of this invention (Fig. 2): 50, 10, 2 and 0.5 mpk (mg/kg/day) of test compounds and saline control are designated, respectively, by squares, solid circles, triangles, diamonds and open circles. In all Figures, *P<0.05, **P<0.01 compared to the saline controls.
Figs. 3-5 compare the Saθ2 levels achieved in influenza A infected mice treated with p.o. doses of ribavirin (triangles), compound 203 (squares) and GG167 (solid circles); saline controls are open circles: Fig. 3: 150 mpk of each of compound 203 and GG167, 100 mpk ribavirin; Fig. 4: 50 mpk of each of compound 203 and GG167, 32 mpk of ribavirin; Fig. 5: 10 mpk of each of compound 203 and GG167, 10 mpk of ribavirin.
Figs. 6-8 depict the Saθ2 levels in influenza A infected mice treated with low p.o. doses of compounds 262 (circles) and 260 (solid squares) and GG167 (triangles); saline controls are open circles and uninfected controls are open squares: Fig. 6: mpk of each of the test compounds; Fig. 7: 1 mpk of each test compound; Fig. 8: 0.1 mpk of each test compound.
Detailed Description
Compositions of the Invention. The compounds of this invention exclude compounds heretofore known. However, as will be further apparent below in other embodiments it is within the invention to use for antiviral purposes known compounds heretofore only produced and used as intermediates in the preparation of antiviral compounds. 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 WO 91/16320, WO 92/06691, US Patent 5,360,817 or Chandler, M. et al., "J. Chem. Soc. Perkin Trans. 1", 1189-1197 (1995).
The foregoing notwithstanding, in an embodiment of the invention one identifies compounds that may fall within the generic scope of WO
91/16320, WO 92/06691, or US Patent 5,360,817 but which have (a) formula la of the '320 application, (b) carbon for group "A" in the '320 application, and (c) R5 of the '320 and '691 applications being "-CH2YR6, -CHYR6CH2YR6 or -CHYR6CHYR6CH2YR6" where YR6 cannot be either OH or protected OH in which the protecting group is capable of hydrolysis to yield the free OH under conditions of the human gastrointestinal tract, i.e. the compounds are stable to hydrolysis in the gastrointestinal tract. Thus, typically excluded from this embodiment are compounds of the '320 or '691 applications where R5 therein is acetyl or other carbacyl having 1-4 carbon atoms. 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. It should be understood, however, that other embodiments of this invention more fully described below contemplate the use of compounds that are in fact specifically disclosed in WO 91/16320, WO 92/06691, or US Patent 5,360,817, including those in which YR^ is free hydroxyl, or hydroxyl protected by a readily hydrolyzable group such as acetyl. In this instance, however, the compounds are delivered by novel routes of administration. In another embodiment, the compounds herein exclude those in which
(a) Ei is -Cθ2H, -P(0)(OH)2, -NO2, -SO2H, -SO3H, tetrazolyl, -CH2CHO, -CHO, or -CH(CHO)2;
(b) Gi is -CN, N3,-NHR20, NR20, -OR20, guanidino, SR20/ -N(R20)→O, -N(R20)(OR20), -N(H)(R2θ)N(R2θ)2, unsubstituted pyrimidinyl, or unsubstituted (pyrimidinyl)methyl;
(c) Ti is -NHR20/ -NO2; and R20 is H; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; an allyl group or an unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an NO2 group, an NH2 group or a COOH group;
(d) each Ji is H; and
(e) Xi is a bond, -CH2- or -CH2CH2-; in which case W6 is not H, W7 or -CH2W7 wherein W7 is H, -ORβa, -ORi, -N(Ri)2, -N(Ri)(R6b), -N(R6b)2, -SRi, or -SR6a.
Also excluded herein are compounds described in WO 92/06691 at Page 9, Line 26, to Page 11, Line 5, which appear to include compounds of the formula II wherein:
(a) A2 is O; (b) Ei is COOH, P(0)(OH)2, N02, SOOH, S03H, tetrazole,
CH2CHO, CHO, CH(CHO)2 or where Ei is COOH, P(0)(OH)2, SOOH or S03H, an ethyl, methyl or pivaloyl ester thereof;
(c) Gi is hydrogen, N(R 0a)2, SR20a or OR20a;
(d) Ti is -NHC(O)R20b, where R20b is an unsubstituted or halogen-substituted linear or cyclic alkyl group of 1 to 6 carbon atoms, or SR20a, OR20a, COOH or alkyl /aryl ester thereof, N02, C(R20a)3, CH2COOH or alkyl/aryl ester thereof, CH N02 or CH2NHR20b;
(e) R20a is hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic alkyl group having 1 to 6 carbon atoms, or a halogen-substituted analogue thereof; or an unsubstituted aryl group or an aryl substituted by a halogen, an allyl group, an OH group, an N02 group, an NH2 group or a COOH group; (f) Ji is H and Jιa is H, OR 0a, F, Cl, Br, CN, NHR20a, SR 0a or CH2X wherein X is NHR "a, halogen or OR 0a; (g) J2 is H or J2a is hydrogen, N(R20a) , SR20a or OR20a;
(h) Ui is CH2YR2« , CHYR2»CH2YR2»a or
CHYR20aCHYR2« CH2YR 0a where Y is O, S or H, and successive Y moieties in Ui are the same or different and
R20a represents a covalent bond when Y is hydrogen and and pharmacologically acceptable salts or derivatives thereof. In a further embodiment, the compounds of this invention are those in which Ui is not -CH2OH, -CH2OAC, or -CH2θCH2Ph. In a further embodiment, the compounds of this invention are those in which Ei is not -CH2OH, -CH2OTMS, or -CHO.
In a further embodiment, the compounds of this invention are those in which Ui is not bonded directly to the nuclear ring by a carbon atom or Ui is not substituted with hydroxyl or hydroxyester, in particular Ui is not polyhydroxyalkane, especially -CH(OH)CH(OH)CH2θH. In a further embodiment, Ui is a branched chain group R5 as described below or a carbocycle which is substituted with at least one group R5.
In a further embodiments, excluded from the invention are compounds of the formula:
Figure imgf000020_0001
wherein:
1. In formula (V): A2 is -O- or -CH2-; Ei is -CO2H;
Gi is -N(H)(C(NH)(NH2)); Ti is -N(H)(Ac); and
Ul is of the formula: OH or
HO
OH OH 2. In formula (V):
A2 is -O- or -CH2-;
Ei is -CO2H;
Gi is -NH2;
Ti is -N(H)(Ac); and Ul is -CH2θH;
3. In formula (V): A2 -CH2-;
El is -CH2OH or -CH2OTMS; Gi is -N3; Ti is -N(H)(Ac); and
Ui is -CH2θCH2Ph;
4. In formula (V): A2 -CH2-;
El is -CO2H or -CO2CH3; Gi is -N3;
Ti is -N(H)(Ac); and Ui is -CH2OH;
5. In formula (V): A2 -CH2-; Ei is -CO2H, -CHO, or -CH2OH; Gi is -N3;
Ti is -N(H)(Ac); and Ui is -CH2θCH2Ph; 6. In formula (VI): A2 -CH2-;
Ei is -CO2H; Gi is -OCH3; Ti is -NH2; and Ui is -CH2OH; and 7. In formula (VI):
A2 -CH2-; Ei is -CO2H; Gi is -OCH3; Ti is -N(H)(Ac); and Ui is -CH2OAC
Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "Ri" or "Rόa"/ then it will be understood that the groups may be the same or different, i.e., each group is independently selected. "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, benzofuranyi, 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, lH-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. "Alkyl" as used herein, unless stated to the contrary, is C1-C12 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 fe-Bu, ≤-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (i-Bu, i-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). Examples of alkyl groups appear in Table 2 as groups 2-5, 7, 9, and 100-399.
The compositions of the invention comprise compounds of either formula:
Figure imgf000023_0001
( (ID
In the typical embodiment, the compounds of Formula I are chosen. Ji and Jιa are independently Ri, Br, Cl, F, I, CN, NO2 or N3, typically
Rl or F, more typically H or F, more typically yet H.
J2 and J2a are independently H or Ri, typically H. Al is -C(Jι)=, or -N=, typically -C(Jι)=, more typically -CH=. A2 is -CQι)2-, -N(Jι)-, -N(0)(Jl)-, -N(0)=, -S-, -S(O)-, -S(0)2- or -O-, typically -C(Jι)2-, -N(Jι)-, -S-, or -O-, more typically -C(Jι)2-, or -O-, more typically yet -CH2- or -O-, still more typically -CH2-.
Ei is -(CRiRi)mlWι.
Typically, Rl is H or alkyl of 1 to 12 carbon atoms, usually H or an alkyl of 1 to 4 or 5 to 10 carbon atoms, still more typically, H or an alkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, more typically yet, H or an alkyl of 1 to 3 carbon atoms selected from methyl, ethyl, n-propyl, and i-propyl. Most typically Ri is H. ml is an integer of 0 to 2, typically 0 or 1, most typically 0. m2 is an integer of 0 to 1. m3 is an integer of 1 to 3.
Wi is a group comprising an acidic hydrogen, a protected acidic group or an R6c amide of the group comprising an acidic hydrogen which, within the context of the invention, means a group having a hydrogen atom that can be removed by a base yielding an anion or its corresponding salt or solvate. The general principles of acidity and basicity of organic materials are well understood and are to be understood as defining Wi . They will not be detailed here. However, a description appears in Streitwieser, A.; and Heathcock, C. H.; "Introduction to Organic Chemistry, Second Edition" (Macmillan, New York, 1981), pages 60-64. Generally, acidic groups of the invention have pK values less than that of water, usually less than pK = 10, typically less than pK = 8, and frequently less than pK = 6. They include tetrazoles and the acids of carbon, sulfur, phosphorous and nitrogen, typically the carboxylic, sulfuric, sulfonic, sulfinic, phosphoric and phosphonic acids, together with the R6C amides and R6b esters of those acids (R6c and R6b are defined below). Exemplary Wi are -CO2H, -Cθ2R6a. -OSO3H, -SO3H, -SO2H, -OPO3H2, -P03(R6a)2, -PO3H2, -P03(H)(R6a), and -OPθ3(R6a)2- Ei typically is Wi, and Wi typically is -CO2H, -Cθ2R6a,
-CO2R4 or CO2R1, and most typically is CO2R14 wherein R14 is normal or terminally secondary C1-C6 alkyl.
Wi may also be a protected acidic group, which, within the context of the invention means an acidic group as described above that has been protected by one of the groups commonly used in the art for such groups and are described below under R6a- More typically, protected Wi is -CO2R1,- SO3R1, -S(0)ORι, -P(0)(ORι)2, -C(0)NHSθ2R4, or -Sθ2NHC(0)-R4, wherein Rl and R4 are defined above.
Most typically, Ei is selected from -C(0)0(CH2)bCH((CH2) CH3)2 where b = 0 to 4, c = 0 to 4, and b + c = 1 to 4, or from the group of
Figure imgf000025_0001
■ Z VP °" C CHH 3 3 ■ a"tl J A>-N* •
Exemplary Ei groups are listed in Tables 3a through 3b. Gi is N3, -CN, -OH, OR a/ -NO2 or -(CRiRi)miW2, wherein Ri and ml are defined above. Ordinarily, Gi is -(CRιRι)ml 2- W2 is a group comprising a basic heteroatom, a protected basic heteroatom or an R6b amide of the basic heteroatom. W2 generally comprises a basic heteroatom, which, within the context of the invention means an atom other than carbon which is capable of protonation, typically by an acidic hydrogen having an acidity in the range described above for Wi. The basic principles of basicity are described in Streitwieser and Heathcock (op. cit.) and provide meaning for the term basic heteroatom as will be understood by those ordinarily skilled in the art. Generally, the basic heteroatoms employed in the compounds of the invention have pK values for the corresponding protonated form that are in the range of values described above for Wi. Basic heteroatoms include the heteroatoms common in organic compounds which have an un-shared, non-bonding, n- type, or the like, electron pair. By way of example and not limitation, typical basic heteroatoms include the oxygen, nitrogen, and sulfur atoms of groups such as alcohols, amines, amidines, guanidines, sulfides, and the like, frequently, amines, amidines and guanidines. Ordinarily, W2 is amino or an amino alkyl (generally lower alkyl Cl to Cβ) group such as aminomethyl, aminoethyl or aminopropyl; an amidinyl, or an amidinoalkyl group such as amidinomethyl, amidinoethyl, or amidinopropyl; or guanidinyl, or a guanidinoalkyl group such as guanidinomethyl, guanidinoethyl, or guanidinopropyl (in each instance wherein the alkyl group serves to bridge the basic substituent to the carbocyclic ring). More typically, W2 is amino, amidino, guanidino, heterocycle, heterocycle substituted with 1 or 2 amino or guanidino groups (usually 1), or an alkyl of 2 to 3 carbon atoms substituted with amino or guanidino, or such alkyl substituted with an amino and a second group selected from the group consisting of hydroxy and amino. The heterocycles useful as W2 include typically N or S- containing 5 or 6 membered rings, wherein the ring contains 1 or 2 heteroatoms. Such heterocycles generally are substituted at ring carbon atoms. They may be saturated or unsaturated and may be linked to the core cyclohexene by lower alkyl (ml=l or 2) or by -NRi-. Still more typically, W2 is -NHRi, -C(NH)(NH2), -NRι-C(NRι)(NRiR3), -NH-C(NH)(NHR3), -NH-C(NH)(NHRi), -NH-C(NH)NH2, -CH(CH2NHRi)(CH2θH), -CH(CH2NHRι)(CH2NHRi), -CH(NHRι), -(CRiRι)m2-CH(NHRi)Ri, -CH(OH)-(CRlRl)m2-CH(NHRi)Ri, or -CH(NHRι)-(CRiRi)m2-CH(OH)Rι, -(CRiRi)m2-S-C(NH)NH2, -N=C(NHRι)(R3), -N=C(SRi)N(Rι)2, -N(Rι)C(NH)N(Rι)C=N, or -N=C(NHRι)(Rι); wherein each m2 is ordinarly 0, and ordinarily Ri is H and R3 is C(0)N(Rι)2-
W2 optionally is a protected basic heteroatom which within the context of the invention means a basic heteroatom as described above that has been protected by R6b such as one of the groups common in the art. Such groups are described in detail in Greene {op. cit.) as set forth below. Such groups include by way of example and not limitation, amides, carbamates, amino acetals, imines, enamines, N-alkyl or N-aryl phosphinyls, N-alkyl or N-aryl sulfenyls or sulfonyls, N-alkyl or N-aryl silyls, thioethers, thioesters, disulfides, sulfenyls, and the like. In some embodiments, the protecting group R6b will be cleavable under physiological conditions, typically it will be cleavable in vivo where, for example, the basic heteroatom forms an amide with an organic acid or an amino acid such as a naturally occurring amino acid or a polypeptide as described below for the R6a group. Typically Gi is selected from the group consisting of:
Figure imgf000027_0001
Figure imgf000027_0002
H H H
Λ H3 S/^CH3 S/N^^CH^
Figure imgf000027_0003
CH3 r^"3 /N-CH3 and s^— CH3 .
Further exemplary Gi groups are listed in Table 4.
Ti is -NR1W3, -R3, -R5 or heterocycle, or is taken together with Ui or Gi to form a group having the structure
Figure imgf000028_0001
where R6b i defined below, and Ri and W3 are defined above. Typically Ti is -NRi, W3 or heterocycle. Generally Ti is selected from the group consisting of:
0 0 0
H3C^N^ FH2C^N^ HF2C"^N^
H ' H ' H '
Figure imgf000028_0002
Exemplary Ti groups are listed in Table 5.
W3 is W4 or W5, wherein W4 is R5 or -C(0)R5, -C(0)W5, -SO2R5, or
-SO2W5. Typically, W3 is -C(0)R5 or W5. R2 is independently R3 or R4 as defined below, with the proviso that each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -N02, -ORβa, -ORi, -N(Rι)2/
-N(Rι)(R6b), -N(R6b)2, -SRi, -SR6a, -S(0)Rι, -S(0)2Rι, -S(0)ORι, -S(0)OR6a,
-S(0)2ORι, -S(0)2OR6a, -C(0)ORι, -C(0)R6 -C(0)OR6a, -OC(0)Rι, -N(Rι)(C(0)Rι), -N(R6b)(C(0)Rι), -N(Rι)(C(0)ORι), -N(R6b)(C(0)ORι),
-C(0)N(Rι)2/ -C(0)N(R6b)(Rl), -C(0)N(R6b)2/ -C(NRι)(N(Rι)2),
-C(N(R6b))(N(Rι)2), -C(N(Rι))(N(Rι)(R6b)), -C(N(R6b))(N(Rι)(R6b)),
-C(N(Rι))(N(R6b)2)/ -C(N(R6b))(N(R6b)2), -N(Rι)C(N(Rι))(N(Rι)2),
-N(Rι)C(N(Rι))(N(Rι)(R6b)), -N(Rι)C(N(R6b))(N(Rι)2), -N(R6b)C(N(Rι))(N(Rι)2), -N(R6b)C(N(R6b))(N(Rι)2),
-N(R6b)C(N(R1))(N(Rι)(R6b)), -N(Rι)C(N(R6b))(N(Rι)(R6b)),
-N(Rι)C(N(Rι))(N(R6b)2), -N(R6b)C(N(R6b))(N(R1)(R6b)),
-N(R6b)C(N(Rι))(N(R6b)2), -N(Rι)C(N(R6b))(N(R6b)2),
-N(R6b)C(N(R6b))(N(R6b)2), =0, =S, =N(Rι), =N(R6b) or W5- Typically R3 is F, Cl, -CN, N3, N02, -OR6a, -ORi, -N(Rι)2, -N(Rι)(R6b), -N(R6b)2, "SR
-SRβa, -C(0)ORι, -C(0)Rβo -C(0)OR6a, -OC(0)Rι, -NRιC(0)Rι, -N(R6b)C(0)Rι, -C(0)N(Rι)2, -C(0)N(R6b)(Rl), -C(0)N(R6b)2, or =0. More typical R3 groups comprising Rβ include -C(0)N(Rόb)2 or -C(0)N(R6 )(Rι). More typically yet R3 is F, Cl, -CN, N3, -ORi, -N(Rι)2, -SRi, -C(0)ORi, -OC(0)Ri, or =0. More typically still, R3 is F, -ORi, -N(Rχ)2, or =0. In the context of the present application, "=0" denotes a double bonded oxygen atom (oxo), and "=S" =N(R6b) and "=N(R )" denote the sulfur and nitrogen analogs.
R4 is alkyl of 1 to 12 carbon atoms, and alkynyl or alkenyl of 2 to 12 carbon atoms. The alkyl Rj's are typically of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms and the alkenyl and alkynyl Rj's are typically of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. R4 ordinarily is alkyl (as defined above). When R4 is alkenyl it 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.- HCH3), 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). More typically, R4 alkenyl groups are of 2, 3 or 4 carbon atoms. When R4 is alkynyl it 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). More typically, R4 alkynyl groups are of 2, 3 or 4 carbon atoms. R5 is R4, as defined above, or R4 substituted with 0 to 3 R3 groups.
Typically R5 is an alkyl of 1 to 4 carbon atoms substituted with 0 to 3 fluorine atoms.
R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups. As defined above for R4, R5a's are of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms when alkylene and of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms when alkenylene or alkynylene. Each of the typical R4 groups is a typical R5a group with the proviso that one of the hydrogen atoms of the described R4 group is removed to form the open valence to a carbon atom through which the second bond to the R5a i attached.
Rl4 is normal or terminally secondary Ci-Cό alkyl. W5 is a carbocycle or heterocycle, with the proviso that each W5 is independently substituted with 0 to 3 R2 groups. W5 carbocycles and Ti and W5 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. Each W5 is independently substituted with 0 to 3 R2 groups. Typically, Ti and W5 are a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. More typically, Ti or W5 has 3 to 10 ring atoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6 ring atoms. The Ti and 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-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-1-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
A Ti or 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, Ti and 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). Ti and 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 Ti and 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 Ti and W5 is bonded through a carbon atom or nitrogen atom thereof. Still more typically Ti heterocycles are bonded by a stable covalent bond through a nitrogen atom thereof to the cyclohexene ring of the compositions of the invention and W5 heterocycles are bonded by a stable covalent bond through a carbon or nitrogen atom thereof to the cyclohexene ring of the compositions of the invention. Stable covalent bonds are chemically stable structures as described above. W5 optionally is selected from the group consisting of:
Figure imgf000031_0001
Ul is H or -XiW6, but typically the latter.
Xl is a bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OWό)-, -N(NH2)-, -N(N(H)(W6))-, -N(N(W6)2)-, -N(H)N(W6)-, -S-, -SO-, or -SO2-; typically, Xl is a bond, -O-, -N(H)-, -N(Rs)-, -N(OH)-, -N(OR5)-, -N(NH2)-, -N(N(H)(R5))-, -N(N(R5)2)-, -N(H)N(Rs)-, -S-, -SO-, or -SO2-, more typically Xl is a bond, -O-, -NRi-, -N(ORι)-, -N(NRιRι)-, -S-, -SO-, or -SO2-. Ordinarily Xl is -O-, -NH-, -S-, -SO-, or -SO2-.;
W6 is -R5, -W5, -R5aW5, -C(0)OR6a, -C(0)R6 -C(0)N(R6b)2, -C(NR6b)(N(R6b)2), -C(NRόb)(N(H)(R6b)), -C(N(H)(N(R6b)2), -C(S)N(R6b)2, or -C(0)R2, typically W is -R5, -W5, or -R5aWs; in some embodiments, W6 is Ri, -C(0)-Ri, -CHR1W7, -CH(Rι)aW7, -CH(W7)2, (where, W7 is monovalent a is 0 or 1, but is 0 when W7 is divalent) or -C(0)W7. In some embodiments, W6 is -CHR1W7 or -C(0)W7, or W6 is -(CH2)mlCH((CH2)m3R3)2, -(CH2)mlC((CH2)m3R3)3; -(CH2)mlCH((CH2)m3R5aW5)2; -(CH2)mlCH((CH2)m3R3)((CH2)m3R5aW5);
-(CH2)mlC((CH2)m3R3)2(CH2)m3R5aW5), (CH2)mlC((CH2)m3R5aW5)3 or -( H2)ml ((CH2)m3R3)((CH2)m3R5aW5)2; and wherein m3 is an integer from 1 to 3.
W7 is R3 or R5, but typically is alkyl of 1 to 12 carbons substituted with 0 to 3 R3 groups, the latter typically selected from the group consisting of
-NRι(R6b), -N(R6b)2/ -OR6a, or SR6a- More typically, W7 is -ORi or an alkyl of 3 to 12 carbon atoms substituted with ORi.
In general, Ui is RiO-, -OCFTR1W7,
Figure imgf000032_0001
Exemplary Ui groups are listed in Table 2.
An embodiment of the invention comprises a compound of the formula:
Figure imgf000032_0002
wherein E2 is Ei, but is typically selected from the group consisting of:
O O
A Q> P
OH O-R 6a V ^OH
Figure imgf000033_0001
and wherein G2 is Gi, but is typically selected from the group consisting of:
Figure imgf000033_0002
and wherein T2 is R4 or R5. Generally, T2 is alkyl of 1 to 2 carbon atoms substituted with 0 to 3 fluorine atoms. U2 is one of:
Figure imgf000034_0001
wherein R7 is H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OAc (-0-C(0)CH3), -OH, -NH2, or -SH, typically H, -CH3 or -CH2CH3. Groups R6a and Rβb 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.
R^a is H or 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— 0-Va(V1)3 t J— 0-Va(V1)(V2) , J— 0-Va(V3)
J— 0-Vb(V1)2 - S— 0-Vb(V2) , or J— O-Ve 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; V is a divalent atom typically selected from O, S, and Se, more typically S; Vi is a group bonded to Va, Vb or Vc by a stable, single covalent bond, typically Vi is W6 groups, more typically Vi is H, R2, W5, or -R5aW5, still more typically H or R2; V2 is a group bonded to Va or Vb 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(Vι) 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-Va M S— o-vb(v4) , ϊ— o-v^v zW
J— 0-Vd(V4)2 t-O-V.MtøV.j) , or ϊ— O-V^XV^a
Wherein Va, Vb, 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, V or Ve by a stable, double covalent bond, provided that at least one V4 is =0, =S or =N-Vι, typically V4, when other than =0, =S or =N~, is =C(Vι)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 Rβ below. R6 is capable of protecting hydroxyl or thio groups such that hydrolysis from the parental molecule yields hydroxyl or thio.
In its ester-forming role, R6a 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 -Cθ2R6a- Rόa for example is deduced from the enumerated ester groups of WO 95/07920. Examples of Rf,a include
C3-Ci2 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, Ri- O-C1-C12 alkylene, C1-C12 alkoxy, CN, NO2, OH, carboxy, carboxyester, thiol, thioester, C1-C12 haloalkyl (1-6 halogen atoms), C2- 2 alkenyl or C2-C12 alkynyl. Such groups include 2-, 3- and 4-alkoxyphenyl ( -C12 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 (-C10JH6-OH) and aryloxy ethyl [C6-C9 aryl (including phenoxy ethyl)], 2,2'-dihydroxybiphenyl, 2-, 3- and 4-N,N-dialkylaminophenol, -C6H4CH2- N(CH3)2, trimethoxybenzyl, triethoxybenzyl, 2-alkyl pyridinyl (C1-4 alkyl);
Figure imgf000036_0001
; ; ; C4 - Cs 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, -C12 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 [Ci-Cβ alkyl including -CH -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, -C(CH3)3, -CH2CH3,, -(CH2)2CH3, -(CH2)3CH3, -(CH2)4CH3, -(CH2)5CH3, -CH2CH2F, -CH2CH2C1, -CH2CF3, and -CH2CCI3);
Figure imgf000037_0001
; -N-2-propylmorpholino, 2,3-dihydro-6- hydroxyindene, sesamol, catechol monoester, -CH2-C(0)-N(R1)2, -CH2-S(0)(R!), -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 α-D-β-diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C6-26/ β-is or C6-10 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 R6a 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 Wi is 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(Rι)2 10. -CH2-0-C(0)-C(CH3)3
2. -CH2-S(0)(Rι) 11. -CH2-CC13
3. -CH2-S(0)2(Rι) 12. -CβHs 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. -NHRi
7. N-ethylmorpholino 16. -CH2-0-C(0)-CιoHi5
8. -CH2-0-C(0)-C6H5 17. -CH2-0-C(0)-CH(CH3)2 9. -CH2-0-C(0)-CH2CH3 18. -CH2-C#H(OC(0)CH2Rι)-CH2- -(OC(0)CH2Rι)
Figure imgf000038_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
Figure imgf000038_0002
-CH2θC(0)OCH3, o , -CH2SCOCH3, -CH2θCON(CH3)2, or alkyl- or aryl-acyloxyalkyl groups of the structure -CH(Rι or W5)0((CO)R37) or -CH(Rι or W5)((CO)OR3β) (linked to oxygen of the acidic group) wherein R37 and R38 are alkyl, aryl, or alkylaryl groups (see U.S. patent 4,968,788). Frequently R37 and R38 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 R6a groups are alkylacyloxymethyl esters and their derivatives, including -CH(CH2CH2OCH3)OC(0)C(CH3)3,
Figure imgf000039_0001
; -CH2OC(0)CιoHi5, -CH2OC(0)C(CH3)3,
-CH(CH20CH3)0C(0)C(CH3)3, -CH(CH(CH3)2)OC(0)C(CH3)3, -CH2θC(0)CH2CH(CH3)2, -CH2OC(0)C6Hιι, -CH2OC(0)C6H5, -CH2OC(0)CιoHi5, -CH2θC(0)CH2CH3, -CH2OC(0)CH(CH3)2 ,
-CH2OC(0)C(CH3)3 and -CH2θC(0)CH2C H5- 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, R6a, 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 R6a hydroxy protecting groups and R6c 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 Rβa 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 R6a 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 R6a 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 C1-C12 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, f-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-
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 -Methoxy cyciohexyl, 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- 1-benzyloxyethyl, l-Methyl-l-benzyloxy-2-fluoroethyl, 2,2,2-Trichloroethyl, 2-Trimethylsilylethyl, 2-(Phenylselenyl)ethyl, ,-Butyl, Allyl, p-Chlorophenyl, p-Methoxyphenyl, 2,4-Dirύtrophenyl, 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, f-Butyldiphenylsilyl, Tribenzylsilyl, Tri-p-xylylsilyl, Triphenylsilyl, Diphenylmethylsilyl, i-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 Rβa protecting functionality) are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1-i-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-i-butylsilylene Group, 1,3-(1,1,3,3
Tetraisopropyldisiloxanylidene), and Tetra-f-butoxydisiloxane-l,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 imgf000043_0001
wherein R9 is C1-C6 alkyl.
R6b i 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. Amide-forming R6b are found for instance in group Gi. When R£b is an amino acid or polypeptide it has the structure Ri5NHCH(Ri6)C(0)-, where Rl5 is H, an amino acid or polypeptide residue, or R5, and Ri6 is defined below.
Rl6 is lower alkyl or lower alkyl (Ci-Cβ) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C6-C7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulf oxide, and /or alkylphosphate. Ri6 also is taken together with the amino acid α N to form a proline residue (Ri6 = -CH2)3-). However, Ri6 is generally the side group of a naturally-occurring amino acid such as H, -CH3, -CH(CH3)2, -CH2-CH(CH3)2, -CHCH3-CH2-CH3/ -CH2-C6H5, -CH2CH2-S-CH3, -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. Rχ6 also includes l-guanidinoprop-3-yl, benzyl, 4- hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl and ethoxyphenyl.
R6b 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-f-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, l,l-dimethyl-2-haloethyl, l,l-dimethyl-2,2- dibromoethyl, l,l-dimethyl-2,2,2-trichloroethyl, l-methyl-l-(4- biphenylyl)ethyl, l-(3,5-di-.-butylphenyl)-l-methylethyl, 2-(2'- and 4'- pyridyl)ethyl, 2-(N,N-dicyclohexylcarboxamido)ethyl, t-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-(p-toluenesulfonyl)ethyl, [2-(l,3- dithianyl)]methyl, 4-methylthiophenyl, 2,4-dimethylthiophenyl, 2- phosphonioethyl, 2-triphenylphosphonioisopropyl, l,l-dimethyl-2- cyanoethyl, m-choro-p-acyloxybenzyl, j?-(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, cyciohexyl, 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- methy 1-1 -(p-phenylazopheny l)ethy 1, 1 -methy 1-1 -pheny lethy 1, 1 -methy 1-1 -(4- pyridyl)ethyl, phenyl, p-(phenylazo)benzyl, 2,4,6-tri-ιt-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- diphenylthiophosphinyi, 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)Rι or -N=CRιN(Rι)2. Another protecting group, also usefull as a prodrug at the Gi site, particularly for amino or -NH(Rs), is:
Figure imgf000046_0001
see for example Alexander, J. et al, "J. Med. Chem." 39:480-486 (1996). R6c is H or the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHSO2R4, NHC(0)R4, -N(R4)2, NH2 or -NH(R4)(H), whereby for example the carboxyl or phosphonic acid groups of W are reacted with the amine to form an amide, as in -C(0)R6c, -P(0)(R6C)2 or -P(0)(OH)(R6 )- In general, R6c has the structure Rι C(0)CH(Ri6)NH-, where R17 is OH, OR6a, 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 R6b and R6c are single amino acid residues or polypeptides they usually are substituted at R3, W6, W and /or W2, but typically only Wi or W2- These conjugates are produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example) and W2- Similarly, conjugates are formed between Wi and an amino group of an amino acid or polypeptide. 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 of Wi 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 R6a esterified with R5 or amidated with Rόc- Similarly, the amino side chains Ri6 optionally will be blocked with R6b 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 R6t> and R-sc 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-1-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- benzylvaline; 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 Wi 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, AI, 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, MM, 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, EI, 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, LA, LR, 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, TT, 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 R»$b °r 6c- 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 ester if ied 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.
Another embodiment of the invention relates to compositions of the formula (VII) or (VIII):
Figure imgf000053_0001
(VII) (VIM) wherein Ei, Gi, Ti, Ui, Ji, Jιa, J2 and J2a are as defined above except:
T is -NR1W3, a heterocycle, or is taken together with Gi to form a group having the structure
Figure imgf000053_0002
Xl is a bond, -O-, -N(H)-, -N(Rs)-, -S-, -SO-, or -SO2-; and provided, however, that compounds are excluded wherein Ui is H or -CH2CH(OH)CH2(OH); and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
Each of the typical or ordinary embodiments of formula (I)-(VI) detailed above are also typical embodiments of formula (VII) and (VIII).
The synthesis of a number of compounds of the formula (VII) and (VIII) wherein Ui is H or -CH2CH(OH)CH2(OH) are provided in Nishimura, Y. et al., "J. Antibiotics" 46(2):300; 46(12):1883 (1993); and "Nat. Prod. Lett.", 1(1):39 (1992). Attachment of Ul groups of the present invention proceed as described therein.
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 chiral 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 π, Astec 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 lipases 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.
Exemplary stereochemistry of the compounds of this invention is set forth below in Table C.
Table C
Figure imgf000056_0001
Formula (I)
Figure imgf000057_0001
Formula (I)
Figure imgf000057_0002
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 6). 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. Tables la and lb are a schedule of nuclei which differ principally by the position of ring unsaturation and the nature of ring substituents. Each nucleus is given a alphabetical designation from Tables la and lb, and this designation appears first in each compound name. Similarly, Tables 2a- av, 3a-b, 4a-c, and 5a-d list the selected Qi, Q2, 3 and Q4 substituents, again by letter or number designation. Accordingly, each named compound will be depicted by a capital letter designating the nucleus from Table la-lb, followed by a number designating the Qi substituent, a lower case letter designating the Q2 substituent, a number designating the Q3 substituent, and a lower case letter or letters designating the Q4 substituent. Thus, structure 8, scheme 1, is represented by A.49.a.4.i. Q1-Q4, it should be understood, do not represent groups or atoms but are simply connectivity designations.
Table la
Figure imgf000059_0001
A B C
Figure imgf000059_0002
j K L
Figure imgf000059_0003
M N 0
Figure imgf000059_0004
P Q R Table lb
C
Figure imgf000060_0001
T U
Figure imgf000060_0002
V
Table 2a
Figure imgf000061_0001
Figure imgf000061_0002
8
Figure imgf000061_0003
10 1 1 12
Figure imgf000061_0004
13 14 15 16
Figure imgf000061_0005
17 18 19 20
Figure imgf000061_0006
21 22 23 24 Table 2b
Figure imgf000062_0001
25 26 27 28
Figure imgf000062_0002
29 30 31 32
Figure imgf000062_0003
33 34 35 36
Figure imgf000062_0004
37 38 39 40
Figure imgf000062_0005
41 42 43 44
Figure imgf000062_0006
45 46 47 48 Table 2c
Figure imgf000063_0001
49 50 51
Figure imgf000063_0002
52 53 54
Figure imgf000063_0003
55 56 57
Figure imgf000063_0004
61 62 63
Figure imgf000063_0005
64 65 66 Table 2d
Figure imgf000064_0001
67 68 69
Figure imgf000064_0002
70 71 72
Figure imgf000064_0003
73 74 75
Figure imgf000064_0004
76 77 78
Figure imgf000064_0005
79 80 81
Figure imgf000064_0006
82 83 84 Table 2e
Figure imgf000065_0001
85 86 87
Figure imgf000065_0002
88 89 90
Figure imgf000065_0003
91 92 93
NH NH O NH
HoN Qi H N QI H2N Λ Qi
94 95 96
H3C>
O Q- H3C'°N'^C.1
97 98
Figure imgf000065_0004
100 101 102 Table 2f
Figure imgf000066_0001
103 104 105
Figure imgf000066_0002
106 107 108
Figure imgf000066_0003
109 110 111
Figure imgf000066_0004
112 113 114
Figure imgf000066_0005
115 116 117
Figure imgf000066_0006
118 119 120 Table 2g
Figure imgf000067_0001
121 122 123
Figure imgf000067_0002
124 125 126
Figure imgf000067_0003
127 128 129
3
Figure imgf000067_0004
130 131 132
Figure imgf000067_0005
133 134 135
Figure imgf000067_0006
136 137 138 Table 2h
Figure imgf000068_0001
139 140 141
Figure imgf000068_0002
Figure imgf000068_0003
144 145
Figure imgf000068_0004
146 147
Figure imgf000068_0005
148 149
Figure imgf000068_0006
150 151 Table 2i
Figure imgf000069_0001
152 153 154
Figure imgf000069_0002
164 165 166
Figure imgf000069_0003
Table 2j
Figure imgf000070_0001
170 171 172
Figure imgf000070_0002
173
174 175
Figure imgf000070_0003
176 177 178
Figure imgf000070_0004
182 183 184
Figure imgf000070_0005
185 186 187 Table 2k
Figure imgf000071_0001
Figure imgf000071_0002
191 192 193
Figure imgf000071_0003
Figure imgf000071_0004
197 198 199
Figure imgf000071_0005
200 201
Figure imgf000071_0006
Table 21
Figure imgf000072_0001
205 206 207
Figure imgf000072_0002
208 209 210
Figure imgf000072_0003
21 1 212 213
Figure imgf000072_0004
214 215 216
Figure imgf000072_0005
Table 2m
Figure imgf000073_0001
223 224 225
Figure imgf000073_0002
226 227 228
Figure imgf000073_0003
229 230 231
Figure imgf000073_0004
232 233 234
Figure imgf000073_0005
235 236 237
Figure imgf000073_0006
238 239 240 Table 2n
Figure imgf000074_0001
244 245 246
Figure imgf000074_0002
247 248 249
Figure imgf000074_0003
250 251 252
Figure imgf000074_0004
253 254 255
Figure imgf000074_0005
256 257 258 Table 2o
Figure imgf000075_0001
259 260 261
Figure imgf000075_0002
262 263 264
,
Figure imgf000075_0003
265 266 267
Figure imgf000075_0004
268 269 270
Figure imgf000075_0005
271 272 273
Figure imgf000075_0006
274 275 276 Table 2p
Figure imgf000076_0001
277 278 279
Figure imgf000076_0002
280 281 282
Figure imgf000076_0003
292 293 294 Table 2q
Figure imgf000077_0001
295 296 297
Figure imgf000077_0002
Figure imgf000077_0003
301 302 303
Figure imgf000077_0004
304 305 306
Figure imgf000077_0005
307 308 309
Figure imgf000077_0006
310 31 1 312 Table 2r
Figure imgf000078_0001
316 317 318
Figure imgf000078_0002
322 323 324
Figure imgf000078_0003
325 326 327
Figure imgf000078_0004
328 329 330 Table 2s
Figure imgf000079_0001
331 332 333
Figure imgf000079_0002
334 335 336
Figure imgf000079_0003
337 338 339
Figure imgf000079_0004
340 341 342
Figure imgf000079_0005
343 344 345
Figure imgf000079_0006
346 347 348 Table 2t
Figure imgf000080_0001
352 353 354
Figure imgf000080_0002
355 356 357
Figure imgf000080_0003
358 359 360
Figure imgf000080_0004
361 362 363
Figure imgf000080_0005
364 365 366 Table 2u
Figure imgf000081_0001
367 368 369
Figure imgf000081_0002
370 371 372
Figure imgf000081_0003
Table 2v
Figure imgf000082_0001
397 398 399 Table 2w
Figure imgf000083_0001
400 401 402
Figure imgf000083_0002
403 404 405 406
Figure imgf000083_0003
407 408 409 410
Figure imgf000083_0004
411 412 413
Figure imgf000083_0005
414 415 416
CH,
Qr XH, Qr Qv
417 418 419
Figure imgf000084_0001
420 421 422
Figure imgf000084_0002
423 424 425
Figure imgf000084_0003
426 427 428
Figure imgf000084_0004
429 430 431
Figure imgf000084_0005
432 433 434 435
Figure imgf000084_0006
436 437 438 439 Table 2y
Figure imgf000085_0001
440 441 442 443
Figure imgf000085_0002
444 445 446 447
Figure imgf000085_0003
448 449 450 451
Figure imgf000085_0004
452 453 454 455
Figure imgf000085_0005
458 459
456 457
Figure imgf000085_0006
460 461 462 666 Table 2z
Figure imgf000086_0001
463 464 465 466
Figure imgf000086_0002
467 468 469
Figure imgf000086_0003
470 471 472
Figure imgf000086_0004
473 474 475 476
Figure imgf000086_0005
477 478 479 480
QI
Figure imgf000086_0006
481 482 483 Table 2aa
Figure imgf000087_0001
484 485 486
Figure imgf000087_0002
487 488 489 490
Figure imgf000087_0003
491 492 493 494
Figure imgf000087_0004
495 496 497
Figure imgf000087_0005
498 499 500
Figure imgf000087_0006
501 502 503 504 Table 2ab
Figure imgf000088_0001
505 506 507 508
Figure imgf000088_0002
509 510 511 512
Figure imgf000088_0003
513 514 515 516
Figure imgf000088_0004
517 518 519 520
Q<v CH°3 °'v CH3° o, C C H H3
Figure imgf000088_0005
521 522 523 524
Figure imgf000088_0006
525 526 527 Table 2ac
Figure imgf000089_0001
528 529 530 531
Figure imgf000089_0002
532 533 534 535
Figure imgf000089_0003
536 537 538
Figure imgf000089_0004
539 540 541
Figure imgf000089_0005
545 546 547 548 Table 2ad
Figure imgf000090_0001
549 550 551
Q >
Figure imgf000090_0002
552 553 554
Figure imgf000090_0003
555 556 557 558
Figure imgf000090_0004
559 560 561 562
Figure imgf000090_0005
563 564 565 566
Figure imgf000090_0006
,
567 568 569
Table 2ae
Figure imgf000091_0001
570 571 572
Figure imgf000091_0002
573 574 575
Figure imgf000091_0003
576 577 578 579
Figure imgf000091_0004
580 581 582 583
Figure imgf000091_0005
588 589 590 Table 2af
Figure imgf000092_0001
591 592
Figure imgf000092_0002
593 594 595
Figure imgf000092_0003
596 597 598
Figure imgf000092_0004
599 600 601
Figure imgf000092_0005
602 603 604
Figure imgf000092_0006
605 606 607 Table 2ag
Figure imgf000093_0001
608 609 610
Figure imgf000093_0002
61 1 612 613
Figure imgf000093_0003
614 615 616
Figure imgf000093_0004
617 618 619 620
Figure imgf000093_0005
621 622 623
Figure imgf000093_0006
624 625 626 627 Table 2ah
Figure imgf000094_0001
628 629 630
Figure imgf000094_0002
631 632 633
Figure imgf000094_0003
634 635 636
Figure imgf000094_0004
640 641 642 643
Figure imgf000094_0005
644 645 646 647 Table2ai
Figure imgf000095_0001
648 649 650
Figure imgf000095_0002
651 652 653
Figure imgf000095_0003
654 655 656
Figure imgf000095_0004
657 658 659
Figure imgf000095_0005
660 661 662
Figure imgf000095_0006
663 664 665 Table 3a
Figure imgf000096_0001
Figure imgf000096_0002
Figure imgf000096_0003
I
Figure imgf000096_0004
m
Figure imgf000096_0005
Table 3b
Figure imgf000097_0001
Figure imgf000097_0002
w X y
Figure imgf000097_0003
B C D
Figure imgf000097_0004
E F Table 4a
Q3-OH Q3-N3 Q3-N02 Q3-NH2
1 2 3
Figure imgf000098_0001
6 8
Figure imgf000098_0002
10 1 1 12
Figure imgf000098_0003
13 14 15 16
Figure imgf000098_0004
17 18 19 20
Figure imgf000098_0005
21 22 23 24 Table 4b
Figure imgf000099_0001
25 26 27 28
Figure imgf000099_0002
29 30 31 32
Figure imgf000099_0003
33 34 35 36
Figure imgf000099_0004
37 38 39 40
Figure imgf000099_0005
41 42 43
Figure imgf000099_0006
44 45 Table 4c
Figure imgf000100_0001
46 47 48
Figure imgf000100_0002
49 50 51
CH3 /CH3
Q3-"N ΌH3 Q^N\^CH,
52 53
Table 5a
Figure imgf000101_0001
Figure imgf000101_0002
Figure imgf000101_0003
m
Figure imgf000101_0004
C VH",3 F2HC γ N Q4
Figure imgf000101_0005
Table 5b
Figure imgf000102_0001
w
Figure imgf000102_0002
aa ab ac
Figure imgf000102_0003
ad ae af ag
Figure imgf000102_0004
Figure imgf000102_0005
al am an ao Table 5c
Figure imgf000103_0001
ap aq ar as
H H3CN H
H2N-Q4 N-Q4 N-Q4 N-Q4 H3C H3C H3C—
at au av aw
H3C'°-Q4 H3C^O-Q4 H3C.S.Q4 H3C^S.Q4
ax ay az ba
Figure imgf000103_0002
bb be bd be
Figure imgf000103_0003
bf bg bh
Figure imgf000103_0004
bi I bj bk Table 6 - Exemplary Enumerated Compounds
A.17.a.4.i; A.17.a.4.v; A.17.a.6.i; A.17.a.6.v; A.17.a.ll.i; A.17.a.ll.v; A.17.a.l4.i;
A.17.a.l4.v; A.17.a.l5.i; A.17.a.l5.v; A.17.a.l8.i; A.17.a.l8.v; A.17.a.25.i; A.17.a.25.v; A.17.e.4.i; A.17.e.4.v; A.17.e.6.i; A.17.e.6.v; A.17.e.ll.i; A.17.e.ll.v;
A.17.e.l4.i; A.17.e.l4.v; A.17.e.l5.i; A.17.e.l5.v; A.17.e.l8.i; A.17.e.l8.v;
A.17.e.25.i; A.17.e.25.v; A.17.g.4.i; A.17.g.4.v; A.17.g.6.i; A.17.g.6.v; A.17.g.ll.i;
A.17.g.ll.v; A.17.g.l4.i; A.17.g.l4.v; A.17.g.l5.i; A.17.g.l5.v; A.17.g.l8.i;
A.17.g.l8.v; A.17.g.25.i; A.17.g.25.v; A.17.1.4.i; A.17.1.4.v; A.17.1.6.i; A.17.1.6.v; A.17.1.11.i; A.17.1.11.v; A.17.1.14.i; A.17.1.14.v; A.17.1.15.i; A.17.1.15.v;
A.17.1.18.i; A.17.1.18.v; A.17.1.25.i; A.17.1.25.v; A.17.m.4.i; A.17.m.4.v;
A.17.m.6.i; A.17.m.6.v; A.17.m.ll.i; A.17.m.ll.v; A.17.m.l4.i; A.17.m.l4.v;
A.17.m.l5.i; A.17.m.l5.v; A.17.m.l8.i; A.17.m.l8.v; A.17.m.25.i; A.17.m.25.v;
A.17.o.4.i; A.17.o.4.v; A.17.o.6.i; A.17.o.6.v; A.17.o.ll.i; A.17.o.ll.v; A.17.o.l4.i; A.17.o.l4.v; A.17.o.l5.i; A.17.o.l5.v; A.17.o.l8.i; A.17.o.l8.v;
A.17.o.25.i; A.17.o.25.v; A.33.a.4.i; A.33.a.4.v; A.33.a.6.i; A.33.a.6.v; A.33.a.ll.i;
A.33.a.ll.v; A.33.a.l4.i; A.33.a.l4.v; A.33.a.l5.i; A.33.a.l5.v; A.33.a.l8.i;
A.33.a.l8.v; A.33.a.25.i; A.33.a.25.v; A.33.e.4.i; A.33.e.4.v; A.33.e.6.i; A.33.e.6.v;
A.33.e.ll.i; A.33.e.ll.v; A.33.e.l4.i; A.33.e.l4.v; A.33.e.l5.i; A.33.e.l5.v; A.33.e.l8.i; A.33.e.l8.v; A.33.e.25.i; A.33.e.25.v; A.33.g.4.i; A.33.g.4.v; A.33.g.6.i;
A.33.g.6.v; A.33.g.ll.i; A.33.g.ll.v; A.33.g.l4.i; A.33.g.l4.v; A.33.g.l5.i;
A.33.g.l5.v; A.33.g.l8.i; A.33.g.l8.v; A.33.g.25.i; A.33.g.25.v; A.33.1.4.i;
A.33.1.4.v; A.33.1.6.i; A.33.1.6.v; A.33.1.11.i; A.33.1.11.v; A.33.1.14.i; A.33.1.14.v;
A.33.1.15.i; A.33.1.15.v; A.33.1.18.i; A.33.1.18.v; A.33.1.25.i; A.33.1.25.v; A.33.m.4.i; A.33.m.4.v; A.33.m.6.i; A.33.m.6.v; A.33.m.ll.i; A.33.m.ll.v;
A.33.m.l4.i; A.33.m.l4.v; A.33.m.l5.i; A.33.m.l5.v; A.33.m.l8.i; A.33.m.l8.v;
A.33.m.25.i; A.33.m.25.v; A.33.o.4.i; A.33.o.4.v; A.33.o.6.i; A.33.o.6.v;
A.33.o.ll.i; A.33.o.ll.v; A.33.o.l4.i; A.33.o.l4.v; A.33.o.l5.i; A.33.o.l5.v;
A.33.o.l8.i; A.33.o.l8.v; A.33.o.25.i; A.33.o.25.v; A.49.a.4.i; A.49.a.4.v; A.49.a.6.i; A.49.a.6.v; A.49.a.ll.i; A.49.a.ll.v; A.49.a.l4.i; A.49.a.l4.v;
A.49.a.l5.i; A.49.a.l5.v; A.49.a.l8.i; A.49.a.l8.v; A.49.a.25.i; A.49.a.25.v;
A.49.e.4.i; A.49.e.4.v; A.49.e.6.i; A.49.e.6.v; A.49.e.ll.i; A.49.e.ll.v; A.49.e.l4.i;
A.49.e.l4.v; A.49.e.l5.i; A.49.e.l5.v; A.49.e.l8.i; A.49.e.l8.v; A.49.e.25.i;
A.49.e.25.v; A.49.g.4.i; A.49.g.4.v; A.49.g.6.i; A.49.g.6.v; A.49.g.ll.i; A.49.g.ll.v; A.49.g.l4.i; A.49.g.l4.v; A.49.g.l5.i; A.49.g.l5.v; A.49.g.l8.i; A.49.g.l8.v;
A.49.g.25.i; A.49.g.25.v; A.49.1.4.i; A.49.1.4.v; A.49.1.6.i; A.49.1.6.v; A.49.1.11.i;
A.49.1.11.V; A.49.1.14.i; A.49.1.14.v; A.49.1.15.i; A.49.1.15.V; A.49.1.18.i;
A.49.1.18.V; A.49.1.25.i; A.49.1.25.V; A.49.m.4.i; A.49.m.4.v; A.49.m.6.i;
A.49.m.6.v; A.49.m.ll.i; A.49.m.ll.v; A.49.m.l4.i; A.49.m.l4.v; A.49.m.l5.i; A.49.m.l5.v; A.49.m.l8.i; A.49.m.l8.v; A.49.m.25.i; A.49.m.25.v; A.49.o.4.i;
A.49.o.4.v; A.49.o.6.i; A.49.o.6.v; A.49.o.ll.i; A.49.o.ll.v; A.49.o.l4.i;
A.49.o.l4.v; A.49.o.l5.i; A.49.o.l5.v; A.49.o.l8.i; A.49.o.l8.v; A.49.o.25.i;
A.49.o.25.v; B.17.a.4.i; B.17.a.4.v; B.17.a.6.i; B.17.a.6.v; B.17.a.ll.i; B.17.a.ll.v;
B.17.a.l4.i; B.17.a.l4.v; B.17.a.l5.i; B.17.a.l5.v; B.17.a.l8.i; B.17.a.l8.v; B.17.a.25.i; B.17.a.25.v; B.17.e.4.i; B.17.e.4.v; B.17.e.6.i; B.17.e.6.v; B.17.e.ll.i;
B.17.e.ll.v; B.17.e.l4.i; B.17.e.l4.v; B.17.e.l5.i; B.17.e.l5.v; B.17.e.l8.i; B.17.e.l8.v; B.17.e.25.i; B.17.e.25.v; B.17.g.4.i; B.17.g.4.v; B.17.g.6.i; B.17.g.6.v;
B.17.g.ll.i; B.17.g.ll.v; B.17.g.l4.i; B.17.g.l4.v; B.17.g.l5.i; B.17.g.l5.v;
B.17.g.l8.i; B.17.g.l8.v; B.17.g.25.i; B.17.g.25.v; B.17.1.4.i; B.17.1.4.v; B.17.1.6.i;
B.17.1.6.v; B.17.1.11.i; B.17.1.11.v; B.17.1.14.i; B.17.1.14.v; B.17.1.15.i; B.17.1.15.v; B.17.1.18.i; B.17.1.18.v; B.17.1.25.i; B.17.1.25.v; B.17.m.4.i; B.17.m.4.v; B.17.m.6.i;
B.17.m.6.v; B.17.m.ll.i; B.17.m.ll.v; B.17.m.l4.i; B.17.m.l4.v; B.17.m.l5.i;
B.17.m.l5.v; B.17.m.l8.i; B.17.m.l8.v; B.17.m.25.i; B.17.m.25.v; B.17.o.4.i;
B.17.o.4.v; B.17.o.6.i; B.17.o.6.v; B.17.o.ll.i; B.17.o.ll.v; B.17.o.l4.i; B.17.o.l4.v;
B.17.o.l5.i; B.17.o.l5.v; B.17.o.l8.i; B.17.o.l8.v; B.17.o.25.i; B.17.o.25.v; B.33.a.4.i; B.33.a.4.v; B.33.a.6.i; B.33.a.6.v; B.33.a.ll.i; B.33.a.ll.v; B.33.a.l4.i;
B.33.a.l4.v; B.33.a.l5.i; B.33.a.l5.v; B.33.a.l8.i; B.33.a.l8.v; B.33.a.25.i;
B.33.a.25.v; B.33.e.4.i; B.33.e.4.v; B.33.e.6.i; B.33.e.6.v; B.33.e.ll.i; B.33.e.ll.v;
B.33.e.l4.i; B.33.e.l4.v; B.33.e.l5.i; B.33.e.l5.v; B.33.e.l8.i; B.33.e.l8.v;
B.33.e.25.i; B.33.e.25.v; B.33.g.4.i; B.33.g.4.v; B.33.g.6.i; B.33.g.6.v; B.33.g.ll.i; B.33.g.ll.v; B.33.g.l4.i; B.33.g.l4.v; B.33.g.l5.i; B.33.g.l5.v; B.33.g.l8.i;
B.33.g.l8.v; B.33.g.25.i; B.33.g.25.v; B.33.1.4.i; B.33.1.4.v; B.33.1.6.i; B.33.1.6.v;
B.33.1.11.i; B.33.1.11.V; B.33.1.14.i; B.33.1.14.v; B.33.1.15.i; B.33.1.15.v; B.33.1.18.i;
B.33.1.18.v; B.33.1.25.i; B.33.1.25.V; B.33.m.4.i; B.33.m.4.v; B.33.m.6.i;
B.33.m.6.v; B.33.m.ll.i; B.33.m.ll.v; B.33.m.l4.i; B.33.m.l4.v; B.33.m.l5.i; B.33.m.l5.v; B.33.m.l8.i; B.33.m.l8.v; B.33.m.25.i; B.33.m.25.v; B.33.o.4.i;
B.33.o.4.v; B.33.o.6.i; B.33.o.6.v; B.33.o.ll.i; B.33.o.ll.v; B.33.o.l4.i; B.33.o.l4.v;
B.33.o.l5.i; B.33.o.l5.v; B.33.o.l8.i; B.33.o.l8.v; B.33.o.25.i; B.33.o.25.v;
B.49.a.4.i; B.49.a.4.v; B.49.a.6.i; B.49.a.6.v; B.49.a.ll.i; B.49.a.ll.v; B.49.a.l4.i;
B.49.a.l4.v; B.49.a.l5.i; B.49.a.l5.v; B.49.a.l8.i; B.49.a.l8.v; B.49.a.25.i; B.49.a.25.v; B.49.e.4.i; B.49.e.4.v; B.49.e.6.i; B.49.e.6.v; B.49.e.ll.i; B.49.e.ll.v;
B.49.e.l4.i; B.49.e.l4.v; B.49.e.l5.i; B.49.e.l5.v; B.49.e.l8.i; B.49.e.l8.v;
B.49.e.25.i; B.49.e.25.v; B.49.g.4.i; B.49.g.4.v; B.49.g.6.i; B.49.g.6.v; B.49.g.ll.i;
B.49.g.ll.v; B.49.g.l4.i; B.49.g.l4.v; B.49.g.l5.i; B.49.g.l5.v; B.49.g.l8.i;
B.49.g.l8.v; B.49.g.25.i; B.49.g.25.v; B.49.1.4.i; B.49.1.4.v; B.49.1.6.i; B.49.1.6.V; B.49.1.11.i; B.49.1.11.V; B.49.1.14.i; B.49.1.14.V; B.49.1.15.i; B.49.1.15.v; B.49.1.18.i;
B.49.1.18.V; B.49.1.25.i; B.49.1.25.V; B.49.m.4.i; B.49.m.4.v; B.49.m.6.i;
B.49.m.6.v; B.49.m.ll.i; B.49.m.ll.v; B.49.m.l4.i; B.49.m.l4.v; B.49.m.l5.i;
B.49.m.l5.v; B.49.m.l8.i; B.49.m.l8.v; B.49.m.25.i; B.49.m.25.v; B.49.o.4.i;
B.49.o.4.v; B.49.o.6.i; B.49.o.6.v; B.49.o.ll.i; B.49.o.ll.v; B.49.o.l4.i; B.49.o.l4.v; B.49.o.l5.i; B.49.o.l5.v; B.49.o.l8.i; B.49.o.l8.v; B.49.o.25.i; B.49.o.25.v;
E.17.a.4.i; E.17.a.4.v; E.17.a.6.i; E.17.a.6.v; E.17.a.ll.i; E.17.a.ll.v; E.17.a.l4.i;
E.17.a.l4.v; E.17.a.l5.i; E.17.a.l5.v; E.17.a.l8.i; E.17.a.l8.v; E.17.a.25.i;
E.17.a.25.v; E.17.e.4.i; E.17.e.4.v; E.17.e.6.i; E.17.e.6.v; E.17.e.ll.i; E.17.e.ll.v;
E.17.e.l4.i; E.17.e.l4.v; E.17.e.l5.i; E.17.e.l5.v; E.17.e.l8.i; E.17.e.l8.v; E.17.e.25.i; E.17.e.25.v; E.17.g.4.i; E.17.g.4.v; E.17.g.6.i; E.17.g.6.v; E.17.g.ll.i; E.17.g.ll.v;
E.17.g.l4.i; E.17.g.l4.v; E.17.g.l5.i; E.17.g.l5.v; E.17.g.l8.i; E.17.g.l8.v; E.17.g.25.i;
E.17.g.25.v; E.17.1.4.i; E.17.1.4.V; E.17.1.6.i; E.17.1.6.v; E.17.1.11.i; E.17.1.11.V;
E.17.1.14.i; E.17.1.14.v; E.17.1.15.i; E.17.1.15.v; E.17.1.18.i; E.17.1.18.v; E.17.1.25.i;
E.17.1.25.v; E.17.m.4.i; E.17.m.4.v; E.17.m.6.i; E.17.m.6.v; E.17.m.ll.i; E.17.m.ll.v; E.17.m.l4.i; E.17.m.l4.v; E.17.m.l5.i; E.17.m.l5.v; E.17.m.l8.i;
E.17.m.l8.v; E.17.m.25.i; E.17.m.25.v; E.17.o.4.i; E.17.o.4.v; E.17.o.6.i; E.17.o.6.v;
E.17.o.ll.i; E.17.o.ll.v; E.17.o.l4.i; E.17.o.l4.v; E.17.o.l5.i; E.17.o.l5.v; E.17.o.l8.i; E.17.o.l8.v; E.17.o.25.i; E.17.o.25.v; E.33.a.4.i; E.33.a.4.v; E.33.a.6.i;
E.33.a.6.v; E.33.a.ll.i; E.33.a.ll.v; E.33.a.l4.i; E.33.a.l4.v; E.33.a.l5.i; E.33.a.l5.v;
E.33.a.l8.i; E.33.a.l8.v; E.33.a.25.i; E.33.a.25.v; E.33.e.4.i; E.33.e.4.v; E.33.e.6.i;
E.33.e.6.v; E.33.e.ll.i; E.33.e.ll.v; E.33.e.l4.i; E.33.e.l4.v; E.33.e.l5.i; E.33.e.l5.v; E.33.e.l8.i; E.33.e.l8.v; E.33.e.25.i; E.33.e.25.v; E.33.g.4.i; E.33.g.4.v; E.33.g.6.i;
E.33.g.6.v; E.33.g.ll.i; E.33.g.ll.v; E.33.g.l4.i; E.33.g.l4.v; E.33.g.l5.i; E.33.g.l5.v;
E.33.g.l8.i; E.33.g.l8.v; E.33.g.25.i; E.33.g.25.v; E.33.1.4.i; E.33.1.4.v; E.33.1.6.i;
E.33.1.6.v; E.33.1.11.i; E.33.1.11.v; E.33.1.14.i; E.33.1.14.v; E.33.1.15.i; E.33.1.15.v;
E.33.1.18.i; E.33.1.18.v; E.33.1.25.i; E.33.1.25.v; E.33.m.4.i; E.33.m.4.v; E.33.m.6.i; E.33.m.6.v; E.33.m.ll.i; E.33.m.ll.v; E.33.m.l4.i; E.33.m.l4.v; E.33.m.l5.i;
E.33.m.l5.v; E.33.m.l8.i; E.33.m.l8.v; E.33.m.25.i; E.33.m.25.v; E.33.o.4.i;
E.33.o.4.v; E.33.o.6.i; E.33.o.6.v; E.33.o.ll.i; E.33.o.ll.v; E.33.o.l4.i; E.33.o.l4.v;
E.33.o.l5.i; E.33.o.l5.v; E.33.o.l8.i; E.33.o.l8.v; E.33.o.25.i; E.33.o.25.v; E.49.a.4.i;
E.49.a.4.v; E.49.a.6.i; E.49.a.6.v; E.49.a.ll.i; E.49.a.ll.v; E.49.a.l4.i; E.49.a.l4.v; E.49.a.l5.i; E.49.a.l5.v; E.49.a.l8.i; E.49.a.l8.v; E.49.a.25.i; E.49.a.25.v; E.49.e.4.i;
E.49.e.4.v; E.49.e.6.i; E.49.e.6.v; E.49.e.ll.i; E.49.e.ll.v; E.49.e.l4.i; E.49.e.l4.v;
E.49.e.l5.i; E.49.e.l5.v; E.49.e.l8.i; E.49.e.l8.v; E.49.e.25.i; E.49.e.25.v; E.49.g.4.i;
E.49.g.4.v; E.49.g.6.i; E.49.g.6.v; E.49.g.ll.i; E.49.g.ll.v; E.49.g.l4.i; E.49.g.l4.v;
E.49.g.l5.i; E.49.g.l5.v; E.49.g.l8.i; E.49.g.l8.v; E.49.g.25.i; E.49.g.25.v; E.49.1.4.i; E.49.1.4.V; E.49.1.6.i; E.49.1.6.V; E.49.1.11.i; E.49.1.11.v; E.49.1.14.i; E.49.1.14.v;
E.49.1.15.i; E.49.1.15.V; E.49.1.18.i; E.49.1.18.v; E.49.1.25.i; E.49.1.25.V; E.49.m.4.i;
E.49.m.4.v; E.49.m.6.i; E.49.m.6.v; E.49.m.ll.i; E.49.m.ll.v; E.49.m.l4.i;
E.49.m.l4.v; E.49.m.l5.i; E.49.m.l5.v; E.49.m.l8.i; E.49.m.l8.v; E.49.m.25.i;
E.49.m.25.v; E.49.o.4.i; E.49.o.4.v; E.49.o.6.i; E.49.o.6.v; E.49.o.ll.i; E.49.o.ll.v; E.49.o.l4.i; E.49.o.l4.v; E.49.o.l5.i; E.49.o.l5.v; E.49.o.l8.i; E.49.o.l8.v;
E.49.o.25.i; E.49.o.25.v; H.17.a.4.i; H.17.a.4.v; H.17.a.6.i; H.17.a.6.v; H.17.a.ll.i;
H.17.a.ll.v; H.17.a.l4.i; H.17.a.l4.v; H.17.a.l5.i; H.17.a.l5.v; H.17.a.l8.i;
H.17.a.l8.v; H.17.a.25.i; H.17.a.25.v; H.17.e.4.i; H.17.e.4.v; H.17.e.6.i; H.17.e.6.v;
H.17.e.ll.i; H.17.e.ll.v; H.17.e.l4.i; H.17.e.l4.v; H.17.e.l5.i; H.17.e.l5.v; H.17.e.l8.i; H.17.e.l8.v; H.17.e.25.i; H.17.e.25.v; H.17.g.4.i; H.17.g.4.v; H.17.g.6.i;
H.17.g.6.v; H.17.g.ll.i; H.17.g.ll.v; H.17.g.l4.i; H.17.g.l4.v; H.17.g.l5.i;
H.17.g.l5.v; H.17.g.l8.i; H.17.g.l8.v; H.17.g.25.i; H.17.g.25.v; H.17.1.4.i;
H.17.1.4.V; H.17.1.6.i; H.17.1.6.v; H.17.1.11.i; H.17.1.11.v; H.17.1.14.i; H.17.1.14.V;
H.17.1.15.i; H.17.1.15.v; H.17.1.18.i; H.17.1.18.V; H.17.1.25.i; H.17.1.25.V; H.17.m.4.i; H.17.m.4.v; H.17.m.6.i; H.17.m.6.v; H.17.m.ll.i; H.17.m.ll.v;
H.17.m.l4.i; H.17.m.l4.v; H.17.m.l5.i; H.17.m.l5.v; H.17.m.l8.i; H.17.m.l8.v;
H.17.m.25.i; H.17.m.25.v; H.17.o.4.i; H.17.o.4.v; H.17.o.6.i; H.17.o.6.v;
H.17.o.ll.i; H.17.o.ll.v; H.17.o.l4.i; H.17.o.l4.v; H.17.o.l5.i; H.17.o.l5.v;
H.17.o.l8.i; H.17.o.l8.v; H.17.o.25.i; H.17.o.25.v; H.33.a.4.i; H.33.a.4.v; H.33.a.6.i; H.33.a.6.v; H.33.a.ll.i; H.33.a.ll.v; H.33.a.l4.i; H.33.a.l4.v;
H.33.a.l5.i; H.33.a.l5.v; H.33.a.l8.i; H.33.a.l8.v; H.33.a.25.i; H.33.a.25.v;
H.33.e.4.i; H.33.e.4.v; H.33.e.6.i; H.33.e.6.v; H.33.e.ll.i; H.33.e.ll.v; H.33.e.l4.i;
H.33.e.l4.v; H.33.e.l5.i; H.33.e.l5.v; H.33.e.l8.i; H.33.e.l8.v; H.33.e.25.i;
H.33.e.25.v; H.33.g.4.i; H.33.g.4.v; H.33.g.6.i; H.33.g.6.v; H.33.g.ll.i; H.33.g.ll.v; H.33.g.l4.i; H.33.g.l4.v; H.33.g.l5.i; H.33.g.l5.v; H.33.g.l8.i; H.33.g.l8.v;
H.33.g.25.i; H.33.g.25.v; H.33.1.4.i; H.33.1.4.V; H.33.1.6.i; H.33.1.6.v; H.33.1.11.i;
H.33.1.11.v; H.33.1.14.i; H.33.1.14.v; H.33.1.l5.i; H.33.1.15.v; H.33.1.18.i; H.33.1.18.V; H.33.1.25.i; H.33.1.25.v; H.33.m.4.i; H.33.m.4.v; H.33.m.6.i;
H.33.m.6.v; H.33.m.ll.i; H.33.m.ll.v; H.33.m.l4.i; H.33.m.l4.v; H.33.m.l5.i;
H.33.m.l5.v; H.33.m.l8.i; H.33.m.l8.v; H.33.m.25.i; H.33.m.25.v; H.33.o.4.i;
H.33.o.4.v; H.33.o.6.i; H.33.o.6.v; H.33.o.ll.i; H.33.o.ll.v; H.33.o.l4.i; H.33.o.l4.v; H.33.o.l5.i; H.33.o.l5.v; H.33.o.l8.i; H.33.o.l8.v; H.33.o.25.i;
H.33.o.25.v; H.49.a.4.i; H.49.a.4.v; H.49.a.6.i; H.49.a.6.v; H.49.a.ll.i; H.49.a.ll.v;
H.49.a.l4.i; H.49.a.l4.v; H.49.a.l5.i; H.49.a.l5.v; H.49.a.l8.i; H.49.a.l8.v;
H.49.a.25.i; H.49.a.25.v; H.49.e.4.i; H.49.e.4.v; H.49.e.6.i; H.49.e.6.v; H.49.e.ll.i;
H.49.e.ll.v; H.49.e.l4.i; H.49.e.l4.v; H.49.e.l5.i; H.49.e.l5.v; H.49.e.l8.i; H.49.e.l8.v; H.49.e.25.i; H.49.e.25.v; H.49.g.4.i; H.49.g.4.v; H.49.g.6.i; H.49.g.6.v;
H.49.g.ll.i; H.49.g.ll.v; H.49.g.l4.i; H.49.g.l4.v; H.49.g.l5.i; H.49.g.l5.v;
H.49.g.l8.i; H.49.g.l8.v; H.49.g.25.i; H.49.g.25.v; H.49.1.4.i; H.49.1.4.v; H.49.1.6.i;
H.49.1.6.V; H.49.1.11.i; H.49.1.11.v; H.49.1.14.i; H.49.1.14.V; H.49.1.15.i;
H.49.1.15.v; H.49.1.18.i; H.49.1.18.v; H.49.1.25.i; H.49.1.25.v; H.49.m.4.i; H.49.m.4.v; H.49.m.6.i; H.49.m.6.v; H.49.m.ll.i; H.49.m.ll.v; H.49.m.l4.i;
H.49.m.l4.v; H.49.m.l5.i; H.49.m.l5.v; H.49.m.l8.i; H.49.m.l8.v; H.49.m.25.i;
H.49.m.25.v; H.49.o.4.i; H.49.o.4.v; H.49.o.6.i; H.49.o.6.v; H.49.o.ll.i;
H.49.o.ll.v; H.49.o.l4.i; H.49.o.l4.v; H.49.o.l5.i; H.49.o.l5.v; H.49.o.l8.i;
H.49.o.l8.v; H.49.o.25.i; H.49.o.25.v; I.17.a.4.i; I.17.a.4.v; I.17.a.6.i; I.17.a.6.v; I.17.a.ll.i; I.17.a.ll.v; I.17.a.l4.i; I.17.a.l4.v; I.17.a.l5.i; I.17.a.l5.v; I.17.a.l8.i;
I.17.a.l8.v; I.17.a.25.i; I.17.a.25.v; I.17.e.4.i; I.17.e.4.v; I.17.e.6.i; I.17.e.6.v;
I.17.e.ll.i; I.17.e.ll.v; I.17.e.l4.i; I.17.e.l4.v; I.17.e.l5.i; I.17.e.l5.v; I.17.e.l8.i;
I.17.e.l8.v; I.17.e.25.i; I.17.e.25.v; I.17.g.4.i; I.17.g.4.v; I.17.g.6.i; I.17.g.6.v;
I.17.g.ll.i; I.17.g.ll.v; I.17.g.l4.i; I.17.g.l4.v; I.17.g.l5.i; I.17.g.l5.v; I.17.g.l8.i; I.17.g.l8.v; I.17.g.25.i; I.17.g.25.v; I.17.1.4.i; 1.17.1.4. v; I.17.1.6.i; I.17.1.6.V;
I.17.1.11.i; I.17.1.11.v; I.17.1.14.i; I.17.1.14.v; I.17.1.15.i; I.17.1.15.V; I.17.1.18.i;
I.17.1.18.V; I.17.1.25.i; I.17.1.25.V; I.17.m.4.i; I.17.m.4.v; I.17.m.6.i; I.17.m.6.v;
I.17.m.ll.i; I.17.m.ll.v; I.17.m.l4.i; I.17.m.l4.v; I.17.m.l5.i; I.17.m.l5.v;
I.17.m.l8.i; I.17.m.l8.v; I.17.m.25.i; I.17.m.25.v; I.17.o.4.i; I.17.o.4.v; I.17.o.6.i; I.17.0.6.V; I.17.o.ll.i; I.17.o.ll.v; I.17.o.l4.i; I.17.o.l4.v; I.17.o.l5.i; I.17.o.l5.v;
I.17.o.l8.i; I.17.o.l8.v; I.17.o.25.i; I.17.o.25.v; I.33.a.4.i; I.33.a.4.v; I.33.a.6.i;
I.33.a.6.v; I.33.a.ll.i; I.33.a.ll.v; I.33.a.l4.i; I.33.a.l4.v; I.33.a.l5.i; I.33.a.l5.v;
I.33.a.l8.i; I.33.a.l8.v; I.33.a.25.i; I.33.a.25.v; I.33.e.4.i; I.33.e.4.v; I.33.e.6.i;
I.33.e.6.v; I.33.e.ll.i; I.33.e.ll.v; I.33.e.l4.i; I.33.e.l4.v; I.33.e.l5.i; I.33.e.l5.v; I.33.e.l8.i; I.33.e.l8.v; I.33.e.25.i; I.33.e.25.v; I.33.g.4.i; I.33.g.4.v; I.33.g.6.i;
I.33.g.6.v; I.33.g.ll.i; I.33.g.ll.v; I.33.g.l4.i; I.33.g.l4.v; I.33.g.l5.i; I.33.g.l5.v;
I.33.g.l8.i; I.33.g.l8.v; I.33.g.25.i; I.33.g.25.v; I.33.1.4.i; I.33.1.4.v; I.33.1.6.i;
I.33.1.6.V; I.33.1.11.i; I.33.1.11.V; I.33.1.14.i; I.33.1.14.v; I.33.1.15.i; I.33.1.15.V;
I.33.1.18.i; I.33.1.18.v; I.33.1.25.i; I.33.1.25.V; I.33.m.4.i; I.33.m.4.v; I.33.m.6.i; I.33.m.6.v; I.33.m.ll.i; I.33.m.ll.v; I.33.m.l4.i; I.33.m.l4.v; I.33.m.l5.i;
I.33.m.l5.v; I.33.m.l8.i; I.33.m.l8.v; I.33.m.25.i; I.33.m.25.v; I.33.o.4.i; I.33.o.4.v;
I.33.o.6.i; I.33.o.6.v; I.33.o.ll.i; I.33.o.ll.v; I.33.o.l4.i; I.33.o.l4.v; I.33.o.l5.i;
I.33.o.l5.v; I.33.o.l8.i; I.33.o.l8.v; I.33.o.25.i; I.33.o.25.v; I.49.a.4.i; I.49.a.4.v;
I.49.a.6.i; I.49.a.6.v; I.49.a.ll.i; I.49.a.ll.v; I.49.a.l4.i; I.49.a.l4.v; I.49.a.l5.i; I.49.a.l5.v; I.49.a.l8.i; I.49.a.l8.v; I.49.a.25.i; I.49.a.25.v; I.49.e.4.i; I.49.e.4.v;
I.49.e.6.i; I.49.e.6.v; I.49.e.ll.i; I.49.e.ll.v; I.49.e.l4.i; I.49.e.l4.v; I.49.e.l5.i;
I.49.e.l5.v; I.49.e.l8.i; I.49.e.l8.v; I.49.e.25.i; I.49.e.25.v; I.49.g.4.i; I.49.g.4.v; I.49.g.6.i; I.49.g.6.v; I.49.g.ll.i; I.49.g.ll.v; I.49.g.l4.i; I.49.g.l4.v; I.49.g.l5.i;
I.49.g.l5.v; I.49.g.l8.i; I.49.g.l8.v; I.49.g.25.i; I.49.g.25.v; I.49.1.4.i; I.49.1.4.V;
I.49.1.6.i; I.49.1.6.v; I.49.1.11.i; I.49.1.11.v; I.49.1.14.i; I.49.1.14.v; I.49.1.15.i;
I.49.1.15.V; I.49.1.18.i; I.49.1.18.V; I.49.1.25.i; I.49.1.25.V; I.49.m.4.i; I.49.m.4.v; I.49.m.6.i; I.49.m.6.v; I.49.m.ll.i; I.49.m.ll.v; I.49.m.l4.i; I.49.m.l4.v;
I.49.m.l5.i; I.49.m.l5.v; I.49.m.l8.i; I.49.m.l8.v; I.49.m.25.i; I.49.m.25.v;
I.49.o.4.i; I.49.o.4.v; I.49.o.6.i; I.49.o.6.v; I.49.o.ll.i; I.49.o.ll.v; I.49.o.l4.i;
I.49.o.l4.v; I.49.o.l5.i; I.49.o.l5.v; I.49.o.l8.i; I.49.o.l8.v; I.49.o.25.i; I.49.o.25.v;
L.17.a.4.i; L.17.a.4.v; L.17.a.6.i; L.17.a.6.v; L.17.a.ll.i; L.17.a.ll.v; L.17.a.l4.i; L.17.a.l4.v; L.17.a.l5.i; L.17.a.l5.v; L.17.a.l8.i; L.17.a.l8.v; L.17.a.25.i;
L.17.a.25.v; L.17.e.4.i; L.17.e.4.v; L.17.e.6.i; .17.e.6.v; L.17.e.ll.i; L.17.e.ll.v;
L.17.e.l4.i; L.17.e.l4.v; L.17.e.l5.i; L.17.e.l5.v; L.17.e.l8.i; L.17.e.l8.v; L.17.e.25.i;
L.17.e.25.v; L.17.g.4.i; L.17.g.4.v; L.17.g.6.i; L.17.g.6.v; L.17.g.ll.i; L.17.g.ll.v;
L.17.g.l4.i; L.17.g.l4.v; L.17.g.l5.i; L.17.g.l5.v; L.17.g.l8.i; L.17.g.l8.v; L.17.g.25.i; L.17.g.25.v; L.17.1.4.i; L.17.1.4.v; L.17.1.6.i; L.17.1.6.v; L.17.1.11.i; L.17.1.11.v;
L.17.1.14.i; L.17.1.14.V; L.17.1.15.i; L.17.1.15.V; L.17.1.18.i; L.17.1.18.V; L.17.1.25.i;
L.17.1.25.V; L.17.m.4.i; L.17.m.4.v; L.17.m.6.i; L.17.m.6.v; L.17.m.ll.i;
L.17.m.ll.v; L.17.m.l4.i; L.17.m.l4.v; L.17.m.l5.i; L.17.m.l5.v; L.17.m.l8.i;
L.17.m.l8.v; L.17.m.25.i; L.17.m.25.v; L.17.o.4.i; L.17.o.4.v; L.17.o.6.i; L.17.o.6.v; L.17.o.ll.i; L.17.o.ll.v; L.17.o.l4.i; L.17.o.l4.v; L.17.o.l5.i; L.17.o.l5.v;
L.17.o.l8.i; L.17.o.l8.v; L.17.o.25.i; L.17.o.25.v; L.33.a.4.i; L.33.a.4.v; L.33.a.6.i;
L.33.a.6.v; L.33.a.ll.i; L.33.a.ll.v; L.33.a.l4.i; L.33.a.l4.v; L.33.a.l5.i; L.33.a.l5.v;
L.33.a.l8.i; L.33.a.l8.v; L.33.a.25.i; L.33.a.25.v; L.33.e.4.i; L.33.e.4.v; L.33.e.6.i;
L.33.e.6.v; L.33.e.ll.i; L.33.e.ll.v; L.33.e.l4.i; L.33.e.l4.v; L.33.e.l5.i; L.33.e.l5.v; L.33.e.l8.i; L.33.e.l8.v; L.33.e.25.i; L.33.e.25.v; L.33.g.4.i; L.33.g.4.v; L.33.g.6.i;
L.33.g.6.v; L.33.g.ll.i; L.33.g.ll.v; L.33.g.l4.i; L.33.g.l4.v; L.33.g.l5.i; L.33.g.l5.v;
L.33.g.l8.i; L.33.g.l8.v; L.33.g.25.i; L.33.g.25.v; L.33.1.4.i; L.33.1.4.v; L.33.1.6.i;
L.33.1.6.V; L.33.1.11.i; L.33.1.11.v; L.33.1.14.i; L.33.1.14.v; L.33.1.15.i; L.33.1.15.v;
L.33.1.18.i; L.33.1.18.V; L.33.1.25.i; L.33.1.25.V; L.33.m.4.i; L.33.m.4.v; L.33.m.6.i; L.33.m.6.v; L.33.m.ll.i; L.33.m.ll.v; L.33.m.l4.i; L.33.m.l4.v; L.33.m.l5.i;
L.33.m.l5.v; L.33.m.l8.i; L.33.m.l8.v; L.33.m.25.i; L.33.m.25.v; L.33.o.4.i;
L.33.o.4.v; L.33.o.6.i; L.33.o.6.v; L.33.o.ll.i; L.33.o.ll.v; L.33.o.l4.i; L.33.o.l4.v;
L.33.o.l5.i; L.33.o.l5.v; L.33.o.l8.i; L.33.o.l8.v; L.33.o.25.i; L.33.o.25.v; L.49.a.4.i;
L.49.a.4.v; L.49.a.6.i; L.49.a.6.v; L.49.a.ll.i; L.49.a.ll.v; L.49.a.l4.i; L.49.a.l4.v; L.49.a.l5.i; L.49.a.l5.v; L.49.a.l8.i; L.49.a.l8.v; L.49.a.25.i; L.49.a.25.v; L.49.e.4.i;
L.49.e.4.v; L.49.e.6.i; L.49.e.6.v; L.49.e.ll.i; L.49.e.ll.v; L.49.e.l4.i; L.49.e.l4.v;
L.49.e.l5.i; L.49.e.l5.v; L.49.e.l8.i; L.49.e.l8.v; L.49.e.25.i; L.49.e.25.v; L.49.g.4.i;
L.49.g.4.v; L.49.g.6.i; L.49.g.6.v; L.49.g.ll.i; L.49.g.ll.v; L.49.g.l4.i; L.49.g.l4.v;
L.49.g.l5.i; L.49.g.l5.v; L.49.g.l8.i; L.49.g.l8.v; L.49.g.25.i; L.49.g.25.v; L.49.1.4.i; L.49.1.4.V; L.49.1.6.i; L.49.1.6.V; L.49.1.11.i; L.49.1.11.v; L.49.1.14.i; L.49.1.14.V;
L.49.1.15.i; L.49.1.15.V; L.49.1.18.i; L.49.1.18.V; L.49.1.25.i; L.49.1.25.v; L.49.m.4.i;
L.49.m.4.v; L.49.m.6.i; L.49.m.6.v; L.49.m.ll.i; L.49.m.ll.v; L.49.m.l4.i;
L.49.m.l4.v; L.49.m.l5.i; L.49.m.l5.v; L.49.m.l8.i; L.49.m.l8.v; L.49.m.25.i;
L.49.m.25.v; L.49.o.4.i; L.49.o.4.v; L.49.o.6.i; L.49.o.6.v; L.49.o.ll.i; L.49.o.ll.v; L.49.o.l4.i; L.49.o.l4.v; L.49.o.l5.i; L.49.o.l5.v; L.49.o.l8.i; L.49.o.l8.v;
L.49.o.25.i; L.49.o.25.v; B.93.a.4.i; B.93.a.4.v; B.93.a.6.i; B.93.a.6.v; B.93.a.ll.i;
B.93.a.ll.v; B.93.a.l4.i; B.93.a.l4.v; B.93.a.l5.i; B.93.a.l5.v; B.93.a.l8.i; B.93.a.l8.v; B.93.a.25.i; B.93.a.25.v; B.93.e.4.i; B.93.e.4.v; B.93.e.6.i; B.93.e.6.v;
B.93.e.ll.i; B.93.e.ll.v; B.93.e.l4.i; B.93.e.l4.v; B.93.e.l5.i; B.93.e.l5.v;
B.93.e.l8.i; B.93.e.l8.v; B.93.e.25.i; B.93.e.25.v; B.93.g.4.i; B.93.g.4.v; B.93.g.6.i;
B.93.g.6.v; B.93.g.ll.i; B.93.g.ll.v; B.93.g.l4.i; B.93.g.l4.v; B.93.g.l5.i; B.93.g.l5.v; B.93.g.l8.i; B.93.g.l8.v; B.93.g.25.i; B.93.g.25.v; B.93.1.4.i; B.93.1.4.v;
B.93.1.6.i; B.93.1.6.v; B.93.1.11.i; B.93.1.11.v; B.93.1.14.i; B.93.1.14.v; B.93.1.15.i;
B.93.1.15.v; B.93.1.18.i; B.93.1.18.v; B.93.1.25.i; B.93.1.25.v; B.93.m.4.i; B.93.m.4.v;
B.93.m.6.i; B.93.m.6.v; B.93.m.ll.i; B.93.m.ll.v; B.93.m.l4.i; B.93.m.l4.v;
B.93.m.l5.i; B.93.m.l5.v; B.93.m.l8.i; B.93.m.l8.v; B.93.m.25.i; B.93.m.25.v; B.93.o.4.i; B.93.o.4.v; B.93.o.6.i; B.93.o.6.v; B.93.o.ll.i; B.93.o.ll.v; B.93.o.l4.i;
B.93.o.l4.v; B.93.o.l5.i; B.93.o.l5.v; B.93.o.l8.i; B.93.o.l8.v; B.93.o.25.i;
B.93.o.25.v; B.94.a.4.i; B.94.a.4.v; B.94.a.6.i; B.94.a.6.v; B.94.a.ll.i; B.94.a.ll.v;
B.94.a.l4.i; B.94.a.l4.v; B.94.a.l5.i; B.94.a.l5.v; B.94.a.l8.i; B.94.a.l8.v;
B.94.a.25.i; B.94.a.25.v; B.94.e.4.i; B.94.e.4.v; B.94.e.6.i; B.94.e.6.v; B.94.e.ll.i; B.94.e.ll.v; B.94.e.l4.i; B.94.e.l4.v; B.94.e.l5.i; B.94.e.l5.v; B.94.e.l8.i;
B.94.e.l8.v; B.94.e.25.i; B.94.e.25.v; B.94.g.4.i; B.94.g.4.v; B.94.g.6.i; B.94.g.6.v;
B.94.g.ll.i; B.94.g.ll.v; B.94.g.l4.i; B.94.g.l4.v; B.94.g.l5.i; B.94.g.l5.v;
B.94.g.l8.i; B.94.g.l8.v; B.94.g.25.i; B.94.g.25.v; B.94.1.4.i; B.94.1.4.v; B.94.1.6.i;
B.94.1.6.v; B.94.1.11.i; B.94.1.11.v; B.94.1.14.i; B.94.1.14.v; B.94.1.15.i; B.94.1.15.v; B.94.1.18.i; B.94.1.18.V; B.94.1.25.i; B.94.1.25.V; B.94.m.4.i; B.94.m.4.v; B.94.m.6.i;
B.94.m.6.v; B.94.m.ll.i; B.94.m.ll.v; B.94.m.l4.i; B.94.m.l4.v; B.94.m.l5.i;
B.94.m.l5.v; B.94.m.l8.i; B.94.m.l8.v; B.94.m.25.i; B.94.m.25.v; B.94.o.4.i;
B.94.o.4.v; B.94.o.6.i; B.94.o.6.v; B.94.o.ll.i; B.94.o.ll.v; B.94.o.l4.i; B.94.o.l4.v;
B.94.o.l5.i; B.94.o.l5.v; B.94.o.l8.i; B.94.o.l8.v; B.94.o.25.i; B.94.o.25.v; E.93.a.4.i; E.93.a.4.v; E.93.a.6.i; E.93.a.6.v; E.93.a.ll.i; E.93.a.ll.v; E.93.a.l4.i;
E.93.a.l4.v; E.93.a.l5.i; E.93.a.l5.v; E.93.a.l8.i; E.93.a.l8.v; E.93.a.25.i;
E.93.a.25.v; E.93.e.4.i; E.93.e.4.v; E.93.e.6.i; E.93.e.6.v; E.93.e.ll.i; E.93.e.ll.v;
E.93.e.l4.i; E.93.e.l4.v; E.93.e.l5.i; E.93.e.l5.v; E.93.e.l8.i; E.93.e.l8.v; E.93.e.25.i;
E.93.e.25.v; E.93.g.4.i; E.93.g.4.v; E.93.g.6.i; E.93.g.6.v; E.93.g.ll.i; E.93.g.ll.v; E.93.g.l4.i; E.93.g.l4.v; E.93.g.l5.i; E.93.g.l5.v; E.93.g.l8.i; E.93.g.l8.v; E.93.g.25.i;
E.93.g.25.v; E.93.1.4.i; E.93.1.4.v; E.93.1.6.i; E.93.1.6.v; E.93.1.11.i; E.93.1.11.v;
E.93.1.14.i; E.93.1.14.v; E.93.1.15.i; E.93.1.15.v; E.93.1.18.i; E.93.1.18.v; E.93.1.25.i;
E.93.1.25.v; E.93.m.4.i; E.93.m.4.v; E.93.m.6.i; E.93.m.6.v; E.93.m.ll.i;
E.93.m.ll.v; E.93.m.l4.i; E.93.m.l4.v; E.93.m.l5.i; E.93.m.l5.v; E.93.m.l8.i; E.93.m.l8.v; E.93.m.25.i; E.93.m.25.v; E.93.o.4.i; E.93.o.4.v; E.93.o.6.i; E.93.o.6.v;
E.93.o.ll.i; E.93.o.ll.v; E.93.o.l4.i; E.93.o.l4.v; E.93.o.l5.i; E.93.o.l5.v;
E.93.o.l8.i; E.93.o.l8.v; E.93.o.25.i; E.93.o.25.v; E.94.a.4.i; E.94.a.4.v; E.94.a.6.i;
E.94.a.6.v; E.94.a.ll.i; E.94.a.ll.v; E.94.a.l4.i; E.94.a.l4.v; E.94.a.l5.i; E.94.a.l5.v;
E.94.a.l8.i; E.94.a.l8.v; E.94.a.25.i; E.94.a.25.v; E.94.e.4.i; E.94.e.4.v; E.94.e.6.i; E.94.e.6.v; E.94.e.ll.i; E.94.e.ll.v; E.94.e.l4.i; E.94.e.l4.v; E.94.e.l5.i; E.94.e.l5.v;
E.94.e.l8.i; E.94.e.l8.v; E.94.e.25.i; E.94.e.25.v; E.94.g.4.i; E.94.g.4.v; E.94.g.6.i;
E.94.g.6.v; E.94.g.ll.i; E.94.g.ll.v; E.94.g.l4.i; E.94.g.l4.v; E.94.g.l5.i; E.94.g.l5.v;
E.94.g.l8.i; E.94.g.l8.v; E.94.g.25.i; E.94.g.25.v; E.94.1.4.i; E.94.1.4.V; E.94.1.6.i;
E.94.1.6.v; E.94.1.11.i; E.94.1.11.v; E.94.1.14.i; E.94.1.14.v; E.94.1.15.i; E.94.1.15.v; E.94.1.18.i; E.94.1.18.V; E.94.1.25.i; E.94.1.25.v; E.94.m.4.i; E.94.m.4.v; E.94.m.6.i;
E.94.m.6.v; E.94.m.ll.i; E.94.m.ll.v; E.94.m.l4.i; E.94.m.l4.v; E.94.m.l5.i;
E.94.m.l5.v; E.94.m.l8.i; E.94.m.l8.v; E.94.m.25.i; E.94.m.25.v; E.94.o.4.i; E.94.o.4.v; E.94.o.6.i; E.94.o.6.v; E.94.o.ll.i; E.94.o.ll.v; E.94.o.l4.i; E.94.o.l4.v; E.94.o.l5.i; E.94.o.l5.v; E.94.o.l8.i; E.94.o.l8.v; E.94.o.25.i; E.94.o.25.v; I.93.a.4.i;
.93.a.4.v; I.93.a.6.i; I.93.a.6.v; I.93.a.ll.i; I.93.a.ll.v; I.93.a.l4.i; I.93.a.l4.v;
.93.a.l5.i; I.93.a.l5.v; I.93.a.l8.i; I.93.a.l8.v; I.93.a.25.i; I.93.a.25.v; I.93.e.4.i;
.93.e.4.v; I.93.e.6.i; I.93.e.6.v; I.93.e.ll.i; I.93.e.ll.v; I.93.e.l4.i; I.93.e.l4.v;
.93.e.l5.i; I.93.e.l5.v; I.93.e.l8.i; I.93.e.l8.v; I.93.e.25.i; I.93.e.25.v; I.93.g.4.i;
.93.g.4.v; I.93.g.6.i; I.93.g.6.v; I.93.g.ll.i; I.93.g.ll.v; I.93.g.l4.i; I.93.g.l4.v;
.93.g.l5.i; I.93.g.l5.v; I.93.g.l8.i; I.93.g.l8.v; I.93.g.25.i; I.93.g.25.v; I.93.1.4.i;
93.1.4.V; I.93.1.6.i; I.93.1.6.v; I.93.1.11.i; I.93.1.11.v; I.93.1.14.i; I.93.1.14.v; I.93.1.15.i; I.93.1.15.V; I.93.1.18.i; I.93.1.18.V; I.93.1.25.i; I.93.1.25.V; I.93.m.4.i;
.93.m.4.v; I.93.m.6.i; I.93.m.6.v; I.93.m.ll.i; I.93.m.ll.v; I.93.m.l4.i;
.93.m.l4.v; I.93.m.l5.i; I.93.m.l5.v; I.93.m.l8.i; I.93.m.l8.v; I.93.m.25.i;
.93.m.25.v; I.93.o.4.i; I.93.o.4.v; I.93.o.6.i; I.93.o.6.v; I.93.o.ll.i; I.93.o.ll.v;
.93.o.l4.i; I.93.o.l4.v; I.93.o.l5.i; I.93.o.l5.v; I.93.o.l8.i; I.93.o.l8.v; I.93.o.25.i; I.93.o.25.v; I.94.a.4.i; I.94.a.4.v; I.94.a.6.i; I.94.a.6.v; I.94.a.ll.i; I.94.a.ll.v;
.94.a.l4.i; I.94.a.l4.v; I.94.a.l5.i; I.94.a.l5.v; I.94.a.l8.i; I.94.a.l8.v; I.94.a.25.i;
.94.a.25.v; I.94.e.4.i; I.94.e.4.v; I.94.e.6.i; I.94.e.6.v; I.94.e.ll.i; I.94.e.ll.v;
.94.e.l4.i; I.94.e.l4.v; I.94.e.l5.i; I.94.e.l5.v; I.94.e.l8.i; I.94.e.l8.v; I.94.e.25.i;
.94.e.25.v; I.94.g.4.i; I.94.g.4.v; I.94.g.6.i; I.94.g.6.v; I.94.g.ll.i; I.94.g.ll.v; I.94.g.l4.i; I.94.g.l4.v; I.94.g.l5.i; I.94.g.l5.v; I.94.g.l8.i; I.94.g.l8.v; I.94.g.25.i;
.94.g.25.v; I.94.1.4.i; I.94.1.4.v; I.94.1.6.i; I.94.1.6.V; I.94.1.11.i; I.94.1.11.v; I.94.1.14.i;
.94.1.14.V; I.94.1.15.i; I.94.1.15.V; I.94.1.18.i; I.94.1.18.V; I.94.1.25.Ϊ; I.94.1.25.v;
.94.m.4.i; I.94.m.4.v; I.94.m.6.i; I.94.m.6.v; I.94.m.ll.i; I.94.m.ll.v; I.94.m.l4.i;
.94.m.l4.v; I.94.m.l5.i; I.94.m.l5.v; I.94.m.l8.i; I.94.m.l8.v; I.94.m.25.i; I.94.m.25.v; I.94.o.4.i; I.94.o.4.v; I.94.o.6.i; I.94.o.6.v; I.94.o.ll.i; I.94.o.ll.v;
94.o.l4.i; I.94.o.l4.v; I.94.o.l5.i; I.94.o.l5.v; I.94.o.l8.i; I.94.o.l8.v; I.94.o.25.i;
94.o.25.v; L.93.a.4.i; L.93.a.4.v; L.93.a.6.i; L.93.a.6.v; L.93.a.ll.i; L.93.a.ll.v; L.93.a.l4.i; L.93.a.l4.v; L.93.a.l5.i; L.93.a.l5.v; L.93.a.l8.i; L.93.a.l8.v; L.93.a.25.i; L.93.a.25.v; L.93.e.4.i; L.93.e.4.v; L.93.e.6.i; L.93.e.6.v; L.93.e.ll.i; L.93.e.ll.v; L.93.e.l4.i; L.93.e.l4.v; L.93.e.l5.i; L.93.e.l5.v; L.93.e.l8.i; L.93.e.l8.v; L.93.e.25.i; L.93.e.25.v; L.93.g.4.i; L.93.g.4.v; L.93.g.6.i; L.93.g.6.v; L.93.g.ll.i; L.93.g.ll.v; L.93.g.l4.i; L.93.g.l4.v; L.93.g.l5.i; L.93.g.l5.v; L.93.g.l8.i; L.93.g.l8.v; L.93.g.25.i; L.93.g.25.v; L.93.1.4.i; L.93.1.4.v; L.93.1.6.i; L.93.1.6.V; L.93.1.11.i; L.93.1.11.V; L.93.1.14.i; L.93.1.14.v; L.93.1.15.i; L.93.1.15.v; L.93.1.18.i; L.93.1.18.v; L.93.1.25.i; L.93.1.25.v; L.93.m.4.i; L.93.m.4.v; L.93.m.6.i; L.93.m.6.v; L.93.m.ll.i;
L.93.m.ll.v; L.93.m.l4.i; L.93.m.l4.v; L.93.m.l5.i; L.93.m.l5.v; L.93.m.l8.i; L.93.m.l8.v; L.93.m.25.i; L.93.m.25.v; L.93.o.4.i; L.93.o.4.v; L.93.o.6.i; L.93.o.6.v; L.93.o.ll.i; L.93.o.ll.v; L.93.o.l4.i; L.93.o.l4.v; L.93.o.l5.i; L.93.o.l5.v; L.93.o.l8.i; L.93.o.l8.v; L.93.o.25.i; L.93.o.25.v; L.94.a.4.i; L.94.a.4.v; L.94.a.6.i; L.94.a.6.v; L.94.a.ll.i; L.94.a.ll.v; L.94.a.l4.i; L.94.a.l4.v; L.94.a.l5.i; L.94.a.l5.v; L.94.a.l8.i; L.94.a.l8.v; L.94.a.25.i; L.94.a.25.v; L.94.e.4.i; L.94.e.4.v; L.94.e.6.i; L.94.e.6.v; L.94.e.ll.i; L.94.e.ll.v; L.94.e.l4.i; L.94.e.l4.v; L.94.e.l5.i; L.94.e.l5.v; L.94.e.l8.i; L.94.e.l8.v; L.94.e.25.i; L.94.e.25.v; L.94.g.4.i; L.94.g.4.v; L.94.g.6.i; L.94.g.6.v; L.94.g.ll.i; L.94.g.ll.v; L.94.g.l4.i; L.94.g.l4.v; L.94.g.l5.i; L.94.g.l5.v; L.94.g.l8.i; L.94.g.l8.v; L.94.g.25.i; L.94.g.25.v; L.94.1.4.i; L.94.1.4.v; L.94.1.6.i; L.94.1.6.V; L.94.1.11.i; L.94.1.11.v; L.94.1.14.i; L.94.1.14.V; L.94.1.15.i; L.94.1.15.v; L.94.1.18.i; L.94.1.18.v; L.94.1.25.i; L.94.1.25.v; L.94.m.4.i; L.94.m.4.v; L.94.m.6.i; L.94.m.6.v; L.94.m.ll.i; L.94.m.ll.v; L.94.m.l4.i; L.94.m.l4.v; L.94.m.l5.i;
L.94.m.l5.v; L.94.m.l8.i; L.94.m.l8.v; L.94.m.25.i; L.94.m.25.v; .94.o.4.i;
L.94.0.4.V; L.94.o.6.i; L.94.o.6.v; L.94.o.ll.i; L.94.o.ll.v; L.94.o.l4.i; L.94.o.l4.v;
L.94.o.l5.i; L.94.o.l5.v; L.94.o.l8.i; L.94.o.l8.v; L.94.o.25.i; L.94.o.25.v; 0.93.a.4.i; 0.93.a.4.v; 0.93.a.6.i; 0.93.a.6.v; 0.93.a.ll.i; 0.93.a.ll.v; 0.93.a.l4.i; 0.93.a.l4.v;
0.93.a.l5.i; 0.93.a.l5.v; 0.93.a.l8.i; 0.93.a.l8.v; 0.93.a.25.i; 0.93.a.25.v;
0.93.e.4.i; 0.93.e.4.v; 0.93.e.6.i; 0.93.e.6.v; 0.93.e.ll.i; 0.93.e.ll.v; 0.93.e.l4.i;
0.93.e.l4.v; 0.93.e.l5.i; 0.93.e.l5.v; 0.93.e.l8.i; 0.93.e.l8.v; 0.93.e.25.i;
0.93.e.25.v; 0.93.g.4.i; 0.93.g.4.v; 0.93.g.6.i; 0.93.g.6.v; 0.93.g.ll.i; 0.93.g.ll.v; 0.93.g.l4.i; 0.93.g.l4.v; 0.93.g.l5.i; 0.93.g.l5.v; 0.93.g.l8.i; 0.93.g.l8.v;
0.93.g.25.i; 0.93.g.25.v; 0.93.1.4.i; 0.93.1.4.v; 0.93.1.6.i; 0.93.1.6.v; 0.93.1.11.i;
0.93.1.11.V; 0.93.1.14.i; 0.93.1.14.v; 0.93.1.15.i; 0.93.1.15.v; 0.93.1.18.i;
0.93.1.18.V; 0.93.1.25.i; 0.93.1.25.V; 0.93.m.4.i; 0.93.m.4.v; 0.93.m.6.i;
0.93.m.6.v; 0.93.m.ll.i; 0.93.m.ll.v; 0.93.m.l4.i; 0.93.m.l4.v; 0.93.m.l5.i; 0.93.m.l5.v; 0.93.m.l8.i; 0.93.m.l8.v; 0.93.m.25.i; 0.93.m.25.v; 0.93.o.4.i;
0.93.o.4.v; 0.93.o.6.i; 0.93.o.6.v; 0.93.o.ll.i; 0.93.o.ll.v; 0.93.o.l4.i;
0.93.o.l4.v; 0.93.o.l5.i; 0.93.o.l5.v; 0.93.o.l8.i; 0.93.o.l8.v; 0.93.o.25.i;
0.93.o.25.v; 0.94.a.4.i; 0.94.a.4.v; 0.94.a.6.i; 0.94.a.6.v; 0.94.a.ll.i; 0.94.a.ll.v;
0.94.a.l4.i; 0.94.a.l4.v; 0.94.a.l5.i; 0.94.a.l5.v; 0.94.a.l8.i; 0.94.a.l8.v; 0.94.a.25.i; 0.94.a.25.v; 0.94.e.4.i; 0.94.e.4.v; 0.94.e.6.i; 0.94.e.6.v; 0.94.e.ll.i;
0.94.e.ll.v; 0.94.e.l4.i; 0.94.e.l4.v; 0.94.e.l5.i; 0.94.e.l5.v; 0.94.e.l8.i;
0.94.e.l8.v; 0.94.e.25.i; 0.94.e.25.v; 0.94.g.4.i; 0.94.g.4.v; 0.94.g.6.i; 0.94.g.6.v;
0.94.g.ll.i; 0.94.g.ll.v; 0.94.g.l4.i; 0.94.g.l4.v; 0.94.g.l5.i; 0.94.g.l5.v;
0.94.g.l8.i; 0.94.g.l8.v; 0.94.g.25.i; 0.94.g.25.v; 0.94.1.4.i; 0.94.1.4.v; 0.94.1.6.i; 0.94.1.6.V; 0.94.1.11.i; 0.94.1.11.v; 0.94.1.14.i; 0.94.1.14.v; 0.94.1.15.i; 0.94.1.15.v;
0.94.1.18.i; 0.94.1.18.V; 0.94.1.25.i; 0.94.1.25.V; 0.94.m.4.i; 0.94.m.4.v;
0.94.m.6.i; 0.94.m.6.v; 0.94.m.ll.i; 0.94.m.ll.v; 0.94.m.l4.i; 0.94.m.l4.v;
0.94.m.l5.i; 0.94.m.l5.v; 0.94.m.l8.i; 0.94.m.l8.v; 0.94.m.25.i; 0.94.m.25.v;
0.94.o.4.i; 0.94.o.4.v; 0.94.o.6.i; 0.94.o.6.v; 0.94.o.ll.i; 0.94.o.ll.v; 0.94.o.l4.i; 0.94.o.l4.v; 0.94.o.l5.i; 0.94.o.l5.v; 0.94.o.l8.i; 0.94.o.l8.v; 0.94.o.25.i;
0.94.o.25.v; P.93.a.4.i; P.93.a.4.v; P.93.a.6.i; P.93.a.6.v; P.93.a.ll.i; P.93.a.ll.v;
P.93.a.l4.i; P.93.a.l4.v; P.93.a.l5.i; P.93.a.l5.v; P.93.a.l8.i; P.93.a.l8.v; P.93.a.25.i;
P.93.a.25.v; P.93.e.4.i; P.93.e.4.v; P.93.e.6.i; P.93.e.6.v; P.93.e.ll.i; P.93.e.ll.v;
P.93.e.l4.i; P.93.e.l4.v; P.93.e.l5.i; P.93.e.l5.v; P.93.e.l8.i; P.93.e.l8.v; P.93.e.25.i; P.93.e.25.v; P.93.g.4.i; P.93.g.4.v; P.93.g.6.i; P.93.g.6.v; P.93.g.ll.i; P.93.g.ll.v;
P.93.g.l4.i; P.93.g.l4.v; P.93.g.l5.i; P.93.g.l5.v; P.93.g.l8.i; P.93.g.l8.v; P.93.g.25.i;
P.93.g.25.v; P.93.1.4.i; P.93.1.4.V; P.93.1.6.i; P.93.1.6.v; P.93.1.11.i; P.93.1.11.V;
P.93.1.14.i; P.93.1.14.v; P.93.1.15.i; P.93.1.15.V; P.93.1.18.i; P.93.1.18.V; P.93.1.25.i;
P.93.1.25.v; P.93.m.4.i; P.93.m.4.v; P.93.m.6.i; P.93.m.6.v; P.93.m.ll.i; P.93.m.ll.v; P.93.m.l4.i; P.93.m.l4.v; P.93.m.l5.i; P.93.m.l5.v; P.93.m.l8.i;
P.93.m.l8.v; P.93.m.25.i; P.93.m.25.v; P.93.o.4.i; P.93.o.4.v; P.93.o.6.i; P.93.o.6.v;
P.93.o.ll.i; P.93.o.ll.v; P.93.o.l4.i; P.93.o.l4.v; P.93.o.l5.i; P.93.o.l5.v;
P.93.o.l8.i; P.93.o.l8.v; P.93.o.25.i; P.93.o.25.v; P.94.a.4.i; P.94.a.4.v; P.94.a.6.i;
P.94.a.6.v; P.94.a.ll.i; P.94.a.ll.v; P.94.a.l4.i; P.94.a.l4.v; P.94.a.l5.i; P.94.a.l5.v; P.94.a.l8.i; P.94.a.l8.v; P.94.a.25.i; P.94.a.25.v; P.94.e.4.i; P.94.e.4.v; P.94.e.6.i;
P.94.e.6.v; P.94.e.ll.i; P.94.e.ll.v; P.94.e.l4.i; P.94.e.l4.v; P.94.e.l5.i; P.94.e.l5.v;
P.94.e.l8.i; P.94.e.l8.v; P.94.e.25.i; P.94.e.25.v; P.94.g.4.i; P.94.g.4.v; P.94.g.6.i; P.94.g.6.v; P.94.g.ll.i; P.94.g.ll.v; P.94.g.l4.i; P.94.g.l4.v; P.94.g.l5.i; P.94.g.l5.v;
P.94.g.l8.i; P.94.g.l8.v; P.94.g.25.i; P.94.g.25.v; P.94.1.4.i; P.94.1.4.V; P.94.1.6.i;
P.94.1.6.V; P.94.1.11.i; P.94.1.11.V; P.94.1.14.i; P.94.1.14.V; P.94.1.15.i; P.94.1.15.V;
P.94.1.18.i; P.94.1.18.v; P.94.1.25.i; P.94.1.25.v; P.94.m.4.i; P.94.m.4.v; P.94.m.6.i; P.94.m.6.v; P.94.m.ll.i; P.94.m.ll.v; P.94.m.l4.i; P.94.m.l4.v; P.94.m.l5.i;
P.94.m.l5.v; P.94.m.l8.i; P.94.m.l8.v; P.94.m.25.i; P.94.m.25.v; P.94.o.4.i;
P.94.o.4.v; P.94.o.6.i; P.94.o.6.v; P.94.o.ll.i; P.94.o.ll.v; P.94.o.l4.i; P.94.o.l4.v;
P.94.o.l5.i; P.94.o.l5.v; P.94.o.l8.i; P.94.o.l8.v; P.94.o.25.i; P.94.o.25.v; A.2.a.4.o;
A.2.a.4.bh; A.2.a.4.bi; A.2.a.4.bj; A.2.a.4.bk; A.2.a.ll.o; A.2.a.ll.bh; A.2.a.ll.bi; A.2.a.ll.bj; A.2.a.ll.bk; A.2.a.l5.i; A.2.a.l5.o; A.2.a.l5.bh; A.2.a.l5.bi;
A.2.a.l5.bj; A.2.a.l5.bk; A.2.a.37.i; A.2.a.37.o; A.2.a.37.bh; A.2.a.37.bi;
A.2.a.37.bj; A.2.a.37.bk; A.2.a.38.i; A.2.a.38.o; A.2.a.38.bh; A.2.a.38.bi;
A.2.a.38.bj; A.2.a.38.bk; A.2.a.39.i; A.2.a.39.o; A.2.a.39.bh; A.2.a.39.bi;
A.2.a.39.bj; A.2.a.39.bk; A.2.a.40.i; A.2.a.40.o; A.2.a.40.bh; A.2.a.40.bi; A.2.a.40.bj; A.2.a.40.bk; A.2.a.41.i; A.2.a.41.o; A.2.a.41.bh; A.2.a.41.bi;
A.2.a.41.bj; A.2.a.41.bk; A.2.a.42.i; A.2.a.42.o; A.2.a.42.bh; A.2.a.42.bi;
A.2.a.42.bj; A.2.a.42.bk; A.2.a.43.i; A.2.a.43.o; A.2.a.43.bh; A.2.a.43.bi;
A.2.a.43.bj; A.2.a.43.bk;
A.3.a.4.o; A.3.a.4.bh; A.3.a.4.bi; A.3.a.4.bj; A.3.a.4.bk; A.3.a.ll.o; A.3.a.ll.bh; A.3.a.ll.bi; A.3.a.ll.bj; A.3.a.ll.bk; A.3.a.l5.i; A.3.a.l5.o; A.3.a.l5.bh;
A.3.a.l5.bi; A.3.a.l5.bj; A.3.a.l5.bk; A.3.a.37.i; A.3.a.37.o; A.3.a.37.bh;
A.3.a.37.bi; A.3.a.37.bj; A.3.a.37.bk; A.3.a.38.i; A.3.a.38.o; A.3.a.38.bh;
A.3.a.38.bi; A.3.a.38.bj; A.3.a.38.bk; A.3.a.39.i; A.3.a.39.o; A.3.a.39.bh;
A.3.a.39.bi; A.3.a.39.bj; A.3.a.39.bk; A.3.a.40.i; A.3.a.40.o; A.3.a.40.bh; A.3.a.40.bi; A.3.a.40.bj; A.3.a.40.bk; A.3.a.41.i; A.3.a.41.o; A.3.a.41.bh;
A.3.a.41.bi; A.3.a.41.bj; A.3.a.41.bk; A.3.a.42.i; A.3.a.42.o; A.3.a.42.bh;
A.3.a.42.bi; A.3.a.42.bj; A.3.a.42.bk; A.3.a.43.i; A.3.a.43.o; A.3.a.43.bh;
A.3.a.43.bi; A.3.a.43.bj; A.3.a.43.bk; A.4.a.4.o; A.4.a.4.bh; A.4.a.4.bi; A.4.a.4.bj;
A.4.a.4.bk; A.4.a.ll.o; A.4.a.ll.bh; A.4.a.ll.bi; AAa.ll.bj; A.4.a.ll.bk; A.4.a.l5.i; A.4.a.l5.o; A.4.a.l5.bh; A.4.a.l5.bi; A.4.a.l5.bj; A.4.a.l5.bk; A.4.a.37.i;
A.4.a.37.o; A.4.a.37.bh; A.4.a.37.bi; A.4.a.37.bj; A.4.a.37.bk; A.4.a.38.i;
A.4.a.38.o; A.4.a.38.bh; A.4.a.38.bi; A.4.a.38.bj; A.4.a.38.bk; A.4.a.39.i;
A.4.a.39.o; A.4.a.39.bh; A.4.a.39.bi; A.4.a.39.bj; A.4.a.39.bk; A.4.a.40.i;
A.4.a.40.o; A.4.a.40.bh; A.4.a.40.bi; A.4.a.40.bj; A.4.a.40.bk; A.4.a.41.i; A.4.a.41.o; A.4.a.41.bh; A.4.a.41.bi; A.4.a.41.bj; A.4.a.41.bk; A.4.a.42.i;
A.4.a.42.o; A.4.a.42.bh; A.4.a.42.bi; A.4.a.42.bj; A.4.a.42.bk; A.4.a.43.i;
A.4.a.43.o; A.4.a.43.bh; A.4.a.43.bi; A.4.a.43.bj; A.4.a.43.bk; A.7.a.4.o; A.7.a.4.bh;
A.7.a.4.bi; A.7.a.4.bj; A.7.a.4.bk; A.7.a.ll.o; A.7.a.ll.bh; A.7.a.ll.bi; A.7.a.ll.bj;
A.7.a.ll.bk; A.7.a.l5.i; A.7.a.l5.o; A.7.a.l5.bh; A.7.a.l5.bi; A.7.a.l5.bj; A.7.a.l5.bk; A.7.a.37.i; A.7.a.37.o; A.7.a.37.bh; A.7.a.37.bi; A.7.a.37.bj;
A.7.a.37.bk; A.7.a.38.i; A.7.a.38.o; A.7.a.38.bh; A.7.a.38.bi; A.7.a.38.bj;
A.7.a.38.bk; A.7.a.39.i; A.7.a.39.o; A.7.a.39.bh; A.7.a.39.bi; A.7.a.39.bj;
A.7.a.39.bk; A.7.a.40.i; A.7.a.40.o; A.7.a.40.bh; A.7.a.40.bi; A.7.a.40.bj;
A.7.a.40.bk; A.7.a.41.i; A.7.a.41.o; A.7.a.41.bh; A.7.a.41.bi; A.7.a.41.bj; A.7.a.41.bk; A.7.a.42.i; A.7.a.42.o; A.7.a.42.bh; A.7.a.42.bi; A.7.a.42.bj;
A.7.a.42.bk; A.7.a.43.i; A.7.a.43.o; A.7.a.43.bh; A.7.a.43.bi; A.7.a.43.bj;
A.7.a.43.bk; A.17.a.4.i; A.17.a.4.o; A.17.a.4.bh; A.17.a.4.bi; A.17.a.4.bj; A.17.a.4.bk; A.17.a.ll.i; A.17.a.ll.o; A.17.a.ll.bh; A.17.a.ll.bi; A.17.a.ll.bj; A.17.a.ll.bk; A.17.a.l5.i; A.17.a.l5.o; A.17.a.l5.bh; A.17.a.l5.bi; A.17.a.l5.bj A.17.a.l5.bk; A.17.a.37.i; A.17.a.37.o; A.17.a.37.bh; A.17.a.37.bi; A.17.a.37.bj A.17.a.37.bk; A.17.a.38.i; A.17.a.38.o; A.17.a.38.bh; A.17.a.38.bi; A.17.a.38.bj A.17.a.38.bk; A.17.a.39.i; A.17.a.39.o; A.17.a.39.bh; A.17.a.39.bi; A.17.a.39.bj A.17.a.39.bk; A.17.a.40.i; A.17.a.40.o; A.17.a.40.bh; A.17.a.40.bi; A.17.a.40.bj A.17.a.40.bk; A.17.a.41.i; A.17.a.41.o; A.17.a.41.bh; A.17.a.41.bi; A.17.a.41.bj A.17.a.41.bk; A.17.a.42.i; A.17.a.42.o; A.17.a.42.bh; A.17.a.42.bi; A.17.a.42.bj A.17.a.42.bk; A.17.a.43.i; A.17.a.43.o; A.17.a.43.bh; A.17.a.43.bi; A.17.a.43.bj A.17.a.43.bk; A.18.a.4.i; A.18.a.4.o; A.18.a.4.bh; A.18.a.4.bi; A.18.a.4.bj;
A.18.a.4.bk; A.18.a.ll.i; A.l&a.ll.o; A.lδ.a.ll.bh; A.18.a.ll.bi; A.lδ.a.ll.bj; A.18.a.ll.bk; A.18.a.l5.i; A.18.a.l5.o; A.18.a.l5.bh; A.18.a.l5.bi; A.18.a.l5.bj A.18.a.l5.bk; A.18.a.37.i; A.18.a.37.o; A.18.a.37.bh; A.18.a.37.bi; A.18.a.37.bj A.18.a.37.bk; A.18.a.38.i; A.18.a.38.o; A.18.a.38.bh; A.18.a.38.bi; A.18.a.38.bj A.18.a.38.bk; A.18.a.39.i; A.18.a.39.o; A.18.a.39.bh; A.18.a.39.bi; A.18.a.39.bj A.18.a.39.bk; A.18.a.40.i; A.18.a.40.o; A.18.a.40.bh; A.18.a.40.bi; A.18.a.40.bj A.18.a.40.bk; A.18.a.41.i; A.18.a.41.o; A.18.a.41.bh; A.18.a.41.bi; A.18.a.41.bj A.18.a.41.bk; A.18.a.42.i; A.18.a.42.o; A.18.a.42.bh; A.18.a.42.bi; A.18.a.42.bj A.18.a.42.bk; A.18.a.43.i; A.18.a.43.o; A.18.a.43.bh; A.18.a.43.bi; A.18.a.43.bj A.18.a.43.bk; A.19.a.4.i; A.19.a.4.o; A.19.a.4.bh; A.19.a.4.bi; A.19.a.4.bj;
A.19.a.4.bk; A.19.a.ll.i; A.19.a.ll.o; A.19.a.ll.bh; A.19.a.ll.bi; A.19.a.ll.bj; A.19.a.ll.bk; A.19.a.l5.i; A.19.a.l5.o; A.19.a.l5.bh; A.19.a.l5.bi; A.19.a.l5.bj A.19.a.l5.bk; A.19.a.37.i; A.19.a.37.o; A.19.a.37.bh; A.19.a.37.bi; A.19.a.37.bj A.19.a.37.bk; A.19.a.38.i; A.19.a.38.o; A.19.a.38.bh; A.19.a.38.bi; A.19.a.38.bj A.19.a.38.bk; A.19.a.39.i; A.19.a.39.o; A.19.a.39.bh; A.19.a.39.bi; A.19.a.39.bj A.19.a.39.bk; A.19.a.40.i; A.19.a.40.o; A.19.a.40.bh; A.19.a.40.bi; A.19.a.40.bj A.19.a.40.bk; A.19.a.41.i; A.19.a.41.o; A.19.a.41.bh; A.19.a.41.bi; A.19.a.41.bj A.19.a.41.bk; A.19.a.42.i; A.19.a.42.o; A.19.a.42.bh; A.19.a.42.bi; A.19.a.42.bj A.19.a.42.bk; A.19.a.43.i; A.19.a.43.o; A.19.a.43.bh; A.19.a.43.bi; A.19.a.43.bj A.19.a.43.bk; A.97.a.4.i; A.97.a.4.o; A.97.a.4.bh; A.97.a.4.bi; A.97.a.4.bj;
A.97.a.4.bk; A.97.a.ll.i; A.97.a.ll.o; A.97.a.U.bh; A.97.a.ll.bi; A.97.a.ll.bj; A.97.a.ll.bk; A.97.a.l5.i; A.97.a.l5.o; A.97.a.l5.bh; A.97.a.l5.bi; A.97.a.l5.bj A.97.a.l5.bk; A.97.a.37.i; A.97.a.37.o; A.97.a.37.bh; A.97.a.37.bi; A.97.a.37.bj A.97.a.37.bk; A.97.a.38.i; A.97.a.38.o; A.97.a.38.bh; A.97.a.38.bi; A.97.a.38.bj A.97.a.38.bk; A.97.a.39.i; A.97.a.39.o; A.97.a.39.bh; A.97.a.39.bi; A.97.a.39.bj A.97.a.39.bk; A.97.a.40.i; A.97.a.40.o; A.97.a.40.bh; A.97.a.40.bi; A.97.a.40.bj A.97.a.40.bk; A.97.a.41.i; A.97.a.41.o; A.97.a.41.bh; A.97.a.41.bi; A.97.a.41.bj A.97.a.41.bk; A.97.a.42.i; A.97.a.42.o; A.97.a.42.bh; A.97.a.42.bi; A.97.a.42.bj A.97.a.42.bk; A.97.a.43.i; A.97.a.43.o; A.97.a.43.bh; A.97.a.43.bi; A.97.a.43.bj A.97.a.43.bk; A.98.a.4.i; A.98.a.4.o; A.98.a.4.bh; A.98.a.4.bi; A.98.a.4.bj;
A.98.a.4.bk; A.98.a.ll.i; A.98.a.ll.o; A.98.a.ll.bh; A.98.a.ll.bi; A.98.a.ll.bj; A.98.a.ll.bk; A.98.a.l5.i; A.98.a.l5.o; A.98.a.l5.bh; A.98.a.l5.bi; A.98.a.l5.bj A.98.a.l5.bk; A.98.a.37.i; A.98.a.37.o; A.98.a.37.bh; A.98.a.37.bi; A.98.a.37.bj A.98.a.37.bk; A.98.a.38.i; A.98.a.38.o; A.98.a.38.bh; A.98.a.38.bi; A.98.a.38.bj A.98.a.38.bk; A.98.a.39.i; A.98.a.39.o; A.98.a.39.bh; A.98.a.39.bi; A.98.a.39.bj A.98.a.39.bk; A.98.a.40.i; A.98.a.40.o; A.98.a.40.bh; A.98.a.40.bi; A.98.a.40.bj A.98.a.40.bk; A.98.a.41.i; A.98.a.41.o; A.98.a.41.bh; A.98.a.41.bi; A.98.a.41.bj A.98.a.41.bk; A.98.a.42.i; A.98.a.42.o; A.98.a.42.bh; A.98.a.42.bi; A.98.a.42.bj;
A.98.a.42.bk; A.98.a.43.i; A.98.a.43.o; A.98.a.43.bh; A.98.a.43.bi; A.98.a.43.bj;
A.98.a.43.bk; A.2.a.4.i; A.3.a.4.i; A.4.a.4.i; A.5.a.4.i; A.6.a.4.i; A.7.a.4.i; A.9.a.4.i;
A.10.a.4.i; A.15.a.4.i; A.100.a.4.i; A.101.a.4.i; A.102.a.4.i; A.103.a.4.i; A.104.a.4.i; A.105.a.4.i; A.106.a.4.i; A.107.a.4.i; A.108.a.4.i; A.109.a.4.i; A.110.a.4.i;
A.lll.a.4.i; A.112.a.4.i; A.113.a.4.i; A.114.a.4.i; A.115.a.4.i; A.116.a.4.i;
A.117.a.4.i; A.118.a.4.i; A.119.a.4.i; A.120.a.4.i; A.121.a.4.i; A.122.a.4.i;
A.123.a.4.i; A.124.a.4.i; A.125.a.4.i; A.126.a.4.i; A.127.a.4.i; A.128.a.4.i;
A.129.a.4.i; A.130.a.4.i; A.131.a.4.i; A.132.a.4.i; A.133.a.4.i; A.134.a.4.i; A.135.a.4.i; A.136.a.4.i; A.137.a.4.i; A.138.a.4.i; A.139.a.4.i; A.140.a.4.i;
A.141.a.4.i; A.142.a.4.i; A.143.a.4.i; A.144.a.4.i; A.145.a.4.i; A.146.a.4.i;
A.147.a.4.i; A.148.a.4.i; A.149.a.4.i; A.150.a.4.i; A.151.a.4.i; A.152.a.4.i;
A.153.a.4.i; A.154.a.4.i; A.155.a.4.i; A.156.a.4.i; A.157.a.4.i; A.158.a.4.i;
A.159.a.4.i; A.160.a.4.i; A.161.a.4.i; A.162.a.4.i; A.163.a.4.i; A.164.a.4.i; A.165.a.4.i; A.166.a.4.i; A.167.a.4.i; A.168.a.4.i; A.169.a.4.i; A.170.a.4.i;
A.171.a.4.i; A.172.a.4.i; A.173.a.4.i; A.174.a.4.i; A.175.a.4.i; A.176.a.4.i;
A.177.a.4.i; A.178.a.4.i; A.179.a.4.i; A.180.a.4.i; A.181.a.4.i; A.182.a.4.i;
A.183.a.4.i; A.184.a.4.i; A.185.a.4.i; A.186.a.4.i; A.187.a.4.i; A.188.a.4.i;
A.189.a.4.i; A.190.a.4.i; A.191.a.4.i; A.192.a.4.i; A.193.a.4.i; A.194.a.4.i; A.195.a.4.i; A.196.a.4.i; A.197.a.4.i; A.198.a.4.i; A.199.a.4.i; A.200.a.4.i;
A.201.a.4.i; A.202.a.4.i; A.203.a.4.i; A.204.a.4.i; A.205.a.4.i; A.206.a.4.i;
A.207.a.4.i; A.208.a.4.i; A.209.a.4.i; A.210.a.4.i; A.211.a.4.i; A.212.a.4.i;
A.213.a.4.i; A.214.a.4.i; A.215.a.4.i; A.216.a.4.i; A.217.a.4.i; A.218.a.4.i;
A.219.a.4.i; A.220.a.4.i; A.221.a.4.i; A.222.a.4.i; A.223.a.4.i; A.224.a.4.i; A.225.a.4.i; A.226.a.4.i; A.227.a.4.i; A.228.a.4.i; A.229.a.4.i; A.230.a.4.i;
A.231.a.4.i; A.232.a.4.i; A.233.a.4.i; A.234.a.4.i; A.235.a.4.i; A.236.a.4.i;
A.237.a.4.i; A.238.a.4.i; A.239.a.4.i; A.240.a.4.i; A.241.a.4.i; A.242.a.4.i;
A.243.a.4.i; A.244.a.4.i; A.245.a.4.i; A.246.a.4.i; A.247.a.4.i; A.248.a.4.i;
A.249.a.4.i; A.250.a.4.i; A.251.a.4.i; A.252.a.4.i; A.253.a.4.i; A.254.a.4.i; A.255.a.4.i; A.256.a.4.i; A.257.a.4.i; A.258.a.4.i; A.259.a.4.i; A.260.a.4.i;
A.261.a.4.i; A.262.a.4.i; A.263.a.4.i; A.264.a.4.i; A.265.a.4.i; A.266.a.4.i;
A.267.a.4.i; A.268.a.4.i; A.269.a.4.i; A.270.a.4.i; A.271.a.4.i; A.272.a.4.i;
A.273.a.4.i; A.274.a.4.i; A.275.a.4.i; A.276.a.4.i; A.277.a.4.i; A.278.a.4.i;
A.279.a.4.i; A.280.a.4.i; A.281.a.4.i; A.282.a.4.i; A.283.a.4.i; A.284.a.4.i; A.285.a.4.i; A.286.a.4.i; A.287.a.4.i; A.288.a.4.i; A.289.a.4.i; A.290.a.4.i;
A.291.a.4.i; A.292.a.4.i; A.293.a.4.i; A.294.a.4.i; A.295.a.4.i; A.296.a.4.i;
A.297.a.4.i; A.298.a.4.i; A.299.a.4.i; A.300.a.4.i; A.301.a.4.i; A.302.a.4.i;
A.303.a.4.i; A.304.a.4.i; A.305.a.4.i; A.306.a.4.i; A.307.a.4.i; A.308.a.4.i;
A.309.a.4.i; A.310.a.4.i; A.311.a.4.i; A.312.a.4.i; A.313.a.4.i; A.314.a.4.i; A.315.a.4.i; A.316.a.4.i; A.317.a.4.i; A.318.a.4.i; A.319.a.4.i; A.320.a.4.i;
A.321.a.4.i; A.323.a.4.i; A.324.a.4.i; A.325.a.4.i; A.326.a.4.i; A.327.a.4.i;
A.328.a.4.i; A.329.a.4.i; A.330.a.4.i; A.331.a.4.i; A.332.a.4.i; A.333.a.4.i;
A.334.a.4.i; A.335.a.4.i; A.336.a.4.i; A.337.a.4.i; A.338.a.4.i; A.339.a.4.i;
A.340.a.4.i; A.341.a.4.i; A.342.a.4.i; A.343.a.4.i; A.344.a.4.i; A.345.a.4.i; A.346.a.4.i; A.347.a.4.i; A.348.a.4.i; A.349.a.4.i; A.350.a.4.i; A.351.a.4.i;
A.352.a.4.i; A.353.a.4.i; A.354.a.4.i; A.355.a.4.i; A.356.a.4.i; A.357.a.4.i;
A.358.a.4.i; A.359.a.4.i; A.360.a.4.i; A.361.a.4.i; A.362.a.4.i; A.363.a.4.i; A.364.a.4.i; A.365.a.4.i; A.366.a.4. i; A.367.a.4. ,i; A.368.3.4.i; A.369.a.4.i;
A.370.a.4.i; A.371.a.4.i; A.372.a.4. i; A.373.a.4. i; A.374.3.4.i; A.375.3.4.i;
A.376.a.4.i; A.377.a.4.i; A.378.a.4. i; A.379.3.4. i; A.380.3.4.i; A.381.a.4.i;
A.382.a.4.i; A.383.a.4.i; A.384.a.4. i; A.385.a.4. i; A.386.a.4.i; A.387.a.4.i; A.388.a.4.i; A.389.a.4.i; A.390.3.4. i; A.391.a.4. i; A.392.a.4.i; A.393.a.4.i;
A.394.a.4.i; A.395.a.4.i; A.396.a.4. i; A.397.3.4. i; A.398.a.4.i; A.399.3.4.i;
A.400.a.4.i; A.401.a.4.i; A.402.a.4. i; A.403.a.4. i; A.404.3.4.i; A.405.3.4.i;
A.406.a.4.i; A.407.a.4.i; A.408.a.4. i; A.409.a.4. i; A.410.3.4.i; A.411.3.4.i;
A.412.a.4.i; A.413.a.4.i; A.414.a.4. i; A.415.a.4. i; A.416.3.4.i; A.417.3.4.Ϊ; A.418.a.4.i; A.419.a.4.i; A.420.a.4. i; A.421.a.4. ,i; A.422.3.4.i; A.423.3.4.i;
A.424.a.4.i; A.425.a.4.i; A.426.a.4, i; A.427.3.4. i; A.428.3.4.i; A.429.3.4.i;
A.430.a.4.i; A.431.a.4.i; A.432.a.4. i; A.433.3.4..i; A.434.3.4.i; A.435.3.4.i;
A.436.a.4.i; A.437.a.4.i; A.438.a.4, i; A.439.3.4. i; A.440.3.4.i; A.441.3.4.i;
A.442.a.4.i; A.443.a.4.i; A.444.a.4. i; A.445.3.4. i; A.446.a.4.i; A.447.3.4.i; A.448.a.4.i; A.449.a.4.i; A.450.a.4. i; A.451.3.4. i; A.452.a.4.i; A.453.3.4.i;
A.454.a.4.i; A.455.a.4.i; A.456.a.4 i; A.457.a.4. ,i; A.458.3.4.i; A.459.3.4.i;
A.460.a.4.i; A.461.a.4.i; A.462.3.4 i; A.463.3.4..i; A.464.3.4.i; A.465.a.4.i;
A.466.a.4.i; A.467.a.4.i; A.468.a.4, i; A.469.3.4..i; A.470.a.4.i; A.471.a.4.i;
A.472.a.4.i; A.473.a.4.i; A.474.a.4, i; A.475.3.4. i; A.476.3.4.i; A.477.3.4.i; A.478.a.4.i; A.479.a.4.i; A.480.3.4, i; A.481.3.4. i; A.482.a.4.i; A.483.3.4.i;
A.484.a.4.i; A.485.a.4.i; A.486.3.4 i; A.487.3.4, .i; A.488.3.4.i; A.489.3.4.i;
A.490.a.4.i; A.491.a.4.i; A.492.3.4 i; A.493.3.4..i; A.494.3.4.i; A.495.3.4.i;
A.496.a.4.i; A.497.a.4.i; A.498.3.4 i; A.499.a.4. i; A.500.3.4.i; A.501.3.4.i;
A.502.a.4.i; A.503.a.4.i; A.504.3.4 i; A.505.a.4. ,i; A.506.3.4.i; A.507.a.4.i; A.508.a.4.i; A.509.a.4.i; A.510.3.4 i; A.511.3.4. ,i; A.512.3.4.i; A.512.a.4.i;
A.513.a.4.i; A.514.a.4.i; A.515.a.4 i; A.516.a.4 ,i; A.517.3.4.i; A.518.a.4.i;
A.519.a.4.i; A.520.a.4.i; A.521.3.4 i; A.522.a.4.i; A.523.a.4.i; A.524.3.4.i;
A.525.a.4.i; A.526.a.4.i; A.527.a.4 i; A.528.3.4 i; A.529.a.4.i; A.530.3.4.i;
A.531.a.4.i; A.532.a.4.i; A.533.a.4 i; A.534.3.4, .i; A.535.a.4.i; A.536.a.4.i; A.537.a.4.i; A.538.a.4.i; A.539.a.4 i; A.540.a.4, .i; A.541.a.4.i; A.542.a.4.i;
A.543.a.4.i; A.544.a.4.i; A.545.3.4 i; A.546.a.4.i; A.547.a.4.i; A.548.a.4.i;
A.549.a.4.i; A.550.a.4.i; A.551.a.4.i; A.552.3.4.i; A.553.3.4.i; A.554.a.4.i;
A.555.a.4.i; A.556.a.4.i; A.557.3.4 i; A.558.a.4.i; A.559.3.4.i; A.560.3.4.i;
A.561.a.4.i; A.562.a.4.i; A.563.a.4 i; A.564.a.4.i; A.565.3.4.i; A.566.3.4.i; A.567.a.4.i; A.568.a.4.i; A.569.a.4 i; A.570.3.4 i; A.571.3.4 ; A.572.a.4.i;
A.573.a.4.i; A.574.a.4.i; A.575.a.4.i; A.576.3.4 i; A.577.3.4.i; A.578.a.4.i;
A.579.a.4.i; A.580.a.4.i; A.581.a.4 i; A.582.3.4 i; A.583.3.4.i; A.584.a.4.i;
A.585.a.4.i; A.586.a.4.i; A.587.3.4.i; A.588.3.4 i; A.589.3.4.i; A.590.a.4.i;
A.591.a.4.i; A.592.a.4.i; A.593.a.4.i; A.594.3.4 i; A.595.3.4.i; A.596.a.4.i; A.597.a.4.i; A.598.a.4.i; A.599.a.4.i; A.600.3.4 Λ; A.601.3.4 ; A.602.a.4.i;
A.603.a.4.i; A.604.a.4.i; A.605.a.4.i; A.606.3.4.i; A.607.3.4.i; A.608.a.4.i;
A.609.a.4.i; A.610.a.4.i; A.όll.a.4.i; A.612.3.4.i; A.613.a.4.i; A.614.a.4.i;
A.615.a.4.i; A.616.a.4.i; A.617.a.4 i; A.618.3.4.i; A.619.3.4.i; A.620.3.4.i;
A.621.a.4.i; A.622.a.4.i; A.623.a.4.i; A.624.3.4.i; A.625.3.4.i; A.626.3.4.i; A.627.a.4.i; A.628.a.4.i; A.629.3.4.i; A.630.3.4.i; A.631.3.4.i; A.632.a.4.i;
A.633.a.4.i; A.634.a.4.i; A.635.a.4.i; A.636.a.4.i; A.637.3.4.i; A.638.3.4.i;
A.639.a.4.i; A.640.a.4.i; A.641.a.4 i; A.642.a.4.i; A.643.3.4.i; A.644.3.4.i; A.645.3.4.i; A.646.3.4 i; A.647.3.4.i; A.648.3.4.i; A 649.3.4.i; A.650.3.4.i; A.651.3.4.i; A.652.3.4 i; A.653.3.4.i; A.654.3.4.Ϊ; A ,655.3.4.i; A.656.3.4.i; A.657.3.4.i; A.658.3.4.i; A.659.3.4.i; A.660.3.4.i; A ,2.3.11.i; A.3.3.11.i; A.4 3.11
A ,5.a.ll.i; A.ό.a.ll.i; A.7.3.11.i; A.9.3.11.i; A.10.3.ll.i; A.15.3.11.i; A.100, 3.11 A. lOl.a.ll. A.102.3. ll.i; A.103.3.11.i; A.104.a.ll .i; A.105.3.11.i A.106.a ll.i A.107.a.ll. A.108.3. ll.i; A.109.a.ll.i; A.110.3.11 i; A.111.3.11.i A.112.3 .11. A 113.a.ll. A.114.3. ll.i; A.115.3.11.i; A.116.3.11.i; A.117.3.11.i A.118.3 ,11. A 119.a.ll. A.120.3. ll.i; A.121.a.ll.i; A.122.a.ll i; A.123.3.11.i A.124.3 .11. A.125.a.ll. A.126.3 ll.i; A.127.3.11.i; A.128.3.11.i; A.129.3.11.i A.130.a .11. A..131.3.11. A.132.3 ll.i; A.133.3.11.i; A.134.3.11 i; A.135.a.ll.i A.136.3 ,11. A..137.3.11. A.138.3. ll.i; A.139.3.11.i; A.140.a.ll .i; A.141.a.ll.i A.142.3 11. A. ,143.3.11. A.144.3. ll.i; A.145.a.ll.i; A.146.3.11.i; A.147.a.ll.i A.148.3 ,11. A. ,149.a.ll. A.150.3. ll.i; A.151.3.11.i; A.152.3.11 i; A.153.3.11.i A.154.3 11. A. ,155.a.ll. A.156.3. ll.i; A.157.3.11.i; A.158.a.ll i; A.159.3.11.i A.160.3 11. A..161.3.11. A.162.3. ll.i; A.163.a.ll.i; A.164.3.11 i; A.165.3.11.i A.166.3 11. A..167.3.11. A.168.3 ll.i; A.169.3.1U; A.170.3.11 i; A.m.a.ll.i A.172.3 11. A..173.3.11. A.174.3 ll.i; A.175.3.11.i; A.176.3.11.i; A.177.3.11.i A.178.3 ,11. A..179.3.11. A.180.3. ll.i; A.181.3.11.i; A.182.a.ll .i; A.183.3.11.i A.184.a 11. A..185.3.11. A.186.3. ll.i; A.187.3.1U; A.188.a.ll .i; A.189.a.ll.i A.190.3 11. A..191.3.11. A.192.3. ll.i; A.193.a.ll.i; A.194.3.11 i; A.195.3.11.i A.196.3 ,11. A..197.3.11. A.198.3 ll.i; A.199.3.1U; A.200.3.11.i; A.201.3.11.i A.202.3 ,11. A..203.3.11. A.204.3 ll.i; A.205.3.11.i; A.206.3.11 i; A.207.3.11.i A.208.3 ,11. A..209.3.11. A.210.3 ll.i; A.211.3.11.i; A.212.3.11 i; A.213.3.11.i A.214.3 .11. A..215.3.11. A.216.3 ll.i; A.217.3.1U; A.218.3.11 ,i; A.219.3.11.i A.220.3 .11. A..221.3.11. A.222.3 ll.i; A.223.3.11.i; A.224.3.11.i; A.225.3.11.i A.226.3 ,11. A..227.3.11. A.228.3 ll.i; A.229.3.1U; A.230.3.11 i; A.231.3.11.i A.232.3 11. A..233.3.11. A.234.3 ll.i; A.235.3.11.i; A.236.3.11.i; A.237.a.ll.i A.238.3 11. A..239.3.11. A.240.3 ll.i; A.241.3.11.i; A.242.3.11 i; A.243.3.11.i A.244.3 .11. A..245.3.11. A.246.3 ll.i; A.247.a.ll.i; A.248.3.11.i; A.249.a.ll.i A.250.3 ,11. A..251.3.11. A.252.3 ll.i; A.253.3.11.i; A.254.3.11 ,i; A.255.a.ll.i A.256.3 11. A..257.3.11. A.258.3 ll.i; A.259.3.11.i; A.260.3.11 i; A.261.3.11.i A.262.a ,11. A..263.3.11. A.264.3 ll.i; A.265.a.ll.i; A.266.3.11 I; A.267.3.11.i A.268.3 ,11. A..269.3.11. A.270.3 ll.i; A.271.a.ll.i; A.272.3.11 i; A.273.a.ll.i A.274.3 11. A..275.3.11. A.276.3 ll.i; A.277.3.11.i; A.278.3.11 i; A.279.a.ll.i A.280.3 ,11. A..281.a.ll. A.282.3 ll.i; A.283.3.11.i; A.284.3.11 i; A.285.a.ll.i A.286.3 11. A .287.a.ll. A.288.3 ll.i; A.289.3.11.i; A.290.3.11 i; A.291.3.11.i A.292.3 ,11. A .293.3.11. A.294.3. ll.i; A.295.a.ll.i; A.296.a.ll i; A.297.3.11.i A.298.3 ,11. A .299.3.11. A.300.3. ll.i; A.301.3.11.i; A.302.3.11.i; A.303.3.11.i A.304.a .11. A .305.3.11. A.306.3. ll.i; A.307.3.11.i; A.308.3.11 i; A.309.a.ll.i A.310.a .11. A .311.a.ll. A.312.3. ll.i; A.313.3.11.i; A.314.3.11 i; A.315.a.ll.i A.316.a .11. A .317.a.ll. A.318.3. ll.i; A.319.a.ll.i; A.320.a.ll .i; A.321.a.ll.i A.323.a .11. A .324.3.11. A.325.3 ll.i; A.326.3.11.i; A.327.3.11 i; A.328.3.11.i A.329.3 ,11. A .330.3.11. A.331.3. ll.i; A.332.3.11.i; A.333.3.11 i; A.334.3.11.i A.335.3 ,11. A .336.3.11. A.337.3. ll.i; A.338.3.11.i; A.339.3.11 i; A.340.3.11.i A.341.3 .11. A .342.a.ll. A.343.3. ll.i; A.344.3.11.i; A.345.3.11.i; A.346.3.11.i A.347.3 ,11. A .348.a.ll. A.349.3. ll.i; A.350.a.ll.i; A.351.a.ll i; A.352.3.1U A.353.3 ,11. A .354.3.11. A.355.3. ll.i; A.356.3.11.i; A.357.3.11 i; A.358.a.ll.i A.359.3 ,11. A.360.3. ll.i; A.361.3. ll.i; A.362.a ll.i; A.363.a. ll.i; A .364.a.lli; A.365.3.11i;
A.366.3. ll.i; A.367.3. ll.i; A.368.3 ll.i; A.369.3. ll.i; A..370.a.lli; A.371.3.11i;
A.372.3. ll.i; A.373.3. ll.i; A.374.3. ll.i; A.375.3. ll.i; A. ,376.3.11i; A.377.3.11i;
A.378.3. ll.i; A.379.a Hi; A.380.3. Hi; A.381.a. ll.i; A..382.3.11i; A.383.a.lli;
A.384.3. ll.i; A.385.a. ll.i; A.386.3. ll.i; A.387.a. ll.i; A, .388.3.11i; A.389.a.lli;
A.390.3. ll.i; A.391.3 ll.i; A.392.3. ll.i; A.393.3. ll.i; A..394.a.lli; A.395.3.11i;
A.396.3. ll.i; A.397.a. Hi; A.398.3. Hi; A.399.3. ll.i; A..400.a.lli; A.401.3.11i;
A.402.3. ll.i; A.403.a. ll.i; A.404.3. Hi; A.405.3. ll.i; A, .406.3.11i; A.407.3.11i;
A.408.3. ll.i; A.409.3. ll.i; A.410.3. Hi; A.411.3. ll.i; A, .412.3.11i; A.413.3.11i;
A.414.3. ll.i; A.415.3. ll.i; A.416.3. Hi; A.417.3. ll.i; A .418.3.11i; A.419.3.11i;
A.420.3. Hi; A.421.3. Hi; A.422.3. Hi; A.423.3. ll.i; A..424.3.11..; A.425.3.11i;
A.426.3 Hi; A.427.3. ll.i; A.428.3. Hi; A.429.3. ll.i; A..430.3.11i; A.431.a.lli;
A.432.3. Hi; A.433.3. ll.i; A.434.3. Hi; A.435.3. ll.i; A, .436.3.11i; A.437.a.lli;
A.438.3. Hi; A.439.3. ll.i; A.440.3. Hi; A.441.3. ll.i; A, .442.3.11i; A.443.3.11i;
A.444.3. Hi; A.445.3. Hi; A.446.3. Hi; A.447.3. ll.i; A..448.3.11i; A.449.3.11i;
A.450.3. Hi; A.451.a. Hi; A.452.3, Hi; A.453.3. ll.i; A..454.3.11i; A.455.3.11i;
A.456.3. Hi; A.457.a. Hi; A.458.3. Hi; A.459.3. ll.i; A..460.3.11i; A.461.3.11i;
A.462.3. Hi; A.463.3. Hi; A.464.3. Hi; A.465.3. ll.i; A..466.3.11i; A.467.3.11i;
A.468.3. Hi; A.469.3. Hi; A.470.3 Hi; A.471.3. ll.i; A, .472.3.11i; A.473.3.11i;
A.474.3. Hi; A.475.3. Hi; A.476.3 Hi; A.477.3. ll.i; A..478.3.11i; A.479.3.11i;
A.480.3. Hi; A.481.3. Hi; A.482.3 Hi; A.483.3. ll.i; A..484.3.11i; A.485.3.11i;
A.486.3. Hi; A.487.3, Hi; A.488.3 Hi; A.489.3. ll.i; A..490.3.11i; A.491.3.11i;
A.492.3. Hi; A.493.3. Hi; A.494.3, Hi; A.495.3. ll.i; A..496.3.11i; A.497.a.lli;
A.498.3. Hi; A.499.3, Hi; A.500.3, Hi; A.501.3. ll.i; A..502.a.lli; A.503.a.lli;
A.504.3. Hi; A.505.3. Hi; A.506.3 Hi; A.507.3. ll.i; A..508.a.lli; A.509.3.11i;
A.510.3. Hi; A.511.3, Hi; A.512.a Hi; A.512.3. ll.i; A..513.3.11i; A.514.3.11i;
A.515.3. Hi; A.516.3 Hi; A.517.a Hi; A.518.a. Hi; A..519.3.11i; A.520.3.11i;
A.521.3. Hi; A.522.3 Hi; A.523.3 Hi; A.524.a. ll.i; A, .525.3.11i; A.526.3.11i;
A.527.3. Hi; A.528.3 Hi; A.529.3 Hi; A.530.a. ll.i; A..531.a.lli; A.532.a.lli;
A.533.3. Hi; A.534.a Hi; A.535.a Hi; A.536.3. Hi; A, .537.3.11i; A.538.a.lli;
A.539.3. Hi; A.540.a Hi; A.541.a Hi; A.542.3. Hi; A..543.3.11i; A.544.3.11i;
A.545.3. Hi; A.546.3 Hi; A.547.3 Hi; A.548.a. Hi; A..549.3.11i; A.550.3.11i;
A.551.3. Hi; A.552.3 Hi; A.553.a Hi; A.554.3. Hi; A, .555.3.11i; A.556.3.11i;
A.557.3. Hi; A.558.3 Hi; A.559.a Hi; A.560.3. Hi; A..561.a.lli; A.562.a.lli;
A.563.3. Hi; A.564.3 Hi; A.565.3 Hi; A.566.3. Hi; A..567.3.11i; A.568.a.lli;
A.569.a. Hi; A.570.3 Hi; A.571.3 Hi; A.572.a. Hi; A, .573.3.11i; A.574.a.lli;
A.575.a. Hi; A.576.a Hi; A.577.a ll.i; A.578.a. Hi; A .579.3.11i; A.580.3.11i;
A.581.3. Hi; A.582.a Hi; A.583.a Hi; A.584.3. Hi; A .585.3.11i; A.586.3.11i;
A.587.3. Hi; A.588.3 Hi; A.589.a .Hi; A.590.3. Hi; A 591.3.11i; A.592.a.lli;
A.593.3. Hi; A.594.3 Hi; A.595.3 ll.i; A.596.3. Hi; A 597.a.lli; A.598.a.lli;
A.599.3. Hi; A.600.3 Hi; A.601.a ll.i; A.602.3. Hi; A .603.3.11i; A.604.3.11i;
A.605.3. Hi; A.606.3 Hi; A.607.a Hi; A.608.3. Hi; A 609.3.11i; A.610.3.11i;
A.611.a. Hi; A.612.a Hi; A.613.a Hi; A.614.3. Hi; A .615.a.lli; A.616.3.11i;
A.617.a. Hi; A.618.3 Hi; A.619.3 Hi; A.620.3, Hi; A ,621.a.lli; A.622.3.11i;
A.623.3..Hi; A.624.3 Hi; A.625.3 ll.i; A.626.3. Hi; A 627.3.11i; A.628.3.11i;
A.629.3. Hi; A.630.3 Hi; A.631.3.Hi; A.632.3. Hi; A .633.3.11 i; A.634.3.11i;
A.635.3. Hi; A.636.a Hi; A.637.a Hi; A.638.3. Hi; A 639.3.11i; A.640.a.lli; A.641.3.11i; A.642.a.lli; A.643.a.lli; A.644.a.lli; A.645.a.lli; A.646.3.11i;
A.647.a.lli; A.648.a.lli; A.649.a.lli; A.650.a.lli; A.651.a.lli; A.652.a.lli;
A.653.a.lli; A.654.a.lli; A.655.a.lli; A.656.a.lli; A.657.a.lli; A.658.a.lli;
A.659.a.lli; A.660.a.lli; A.2.b.4.i; A.3.b.4.i; A.4.b.4.i; A.5.b.4.i; A.6.b.4.i; A.7.b.4.i; A.9.b.4.i; A.10.b.4.i; A.15.b.4.i; A.100.b.4.i; A.101.b.4.i; A.102.b.4.i;
A.103.b.4.i; A.104.b.4i; A.105.b.4.i; A.106.b.4.i; A.107.b.4.i; A.108.b.4.i;
A.109.b.4.i; A.110.b.4.i; A.lll.b.4.i; A.112.b.4.i; A.113.b.4.i; A.114.b.4.i;
A.115.b.4.i; A.116.b.4.i; A.117.b.4.i; A.118.b.4.i; A.119.b.4.i; A.120.b.4.i;
A.121.b.4.i; A.122.b.4.i; A.123.b.4.i; A.124.b.4.i; A.125.b.4.i; A.126.b.4.i; A.127.b.4.i; A.128.b.4.i; A.129.b.4.i; A.130.b.4.i; A.131.b.4.i; A.132.b.4.i;
A.133.b.4.i; A.134.b.4.i; A.135.b.4i; A.136.b.4.i; A.137.b.4.i; A.138.b.4.i;
A.139.b.4i; A.140.b.4.i; A.141.b.4.i; A.142.b.4.i; A.143.b.4.i; A.144.b.4.i;
A.145.b.4.i; A.146.b.4.i; A.147.b.4.i; A.148.b.4.i; A.149.b.4.i; A.150.b.4.i;
A.151.b.4.i; A.152.b.4.i; A.153.b.4.i; A.154.b.4.i; A.155.b.4.i; A.156.b.4.i; A.157.b.4.i; A.158.b.4.i; A.159.b.4.i; A.160.b.4.i; A.161.b.4.i; A.162.b.4.i;
A.163.b.4.i; A.164.b.4.i; A.165.b.4.i; A.166.b.4.i; A.167.b.4.i; A.168.b.4.i;
A.169.b.4.i; A.170.b.4.i; A.171.b.4.i; A.172.b.4.i; A.173.b.4.i; A.174.b.4.i;
A.175.b.4.i; A.176.b.4.i; A.177.b.4.i; A.178.b.4.i; A.179.b.4.i; A.180.b.4.i;
A.181.b.4.i; A.182.b.4.i; A.183.b.4.i; A.184.b.4.i; A.185.b.4.i; A.186.b.4.i; A.187.b.4.i; A.188.b.4.i; A.189.b.4.i; A.190.b.4.i; A.191.b.4.i; A.192.b.4.i;
A.193.b.4.i; A.194.b.4.i; A.195.b.4.i; A.196.b.4.i; A.197.b.4.i; A.198.b.4.i;
A.199.b.4.i; A.200.b.4.i; A.201.b.4.i; A.202.b.4.i; A.203.b.4.i; A.204.b.4i;
A.205.b.4.i; A.206.b.4.i; A.207.b.4.i; A.208.b.4.i; A.209.b.4.i; A.210.b.4.i;
A.211.b.4.i; A.212.b.4.i; A.213.b.4.i; A.214.b.4.i; A.215.b.4.i; A.216.b.4i; A.217.b.4.i; A.218.b.4.i; A.219.b.4.i; A.220.b.4.i; A.221.b.4.i; A.222.b.4.i;
A.223.b.4.i; A.224.b.4.i; A.225.b.4.i; A.226.b.4.i; A.227.b.4.i; A.228.b.4.i;
A.229.b.4.i; A.230.b.4.i; A.231.b.4.i; A.232.b.4.i; A.233.b.4.i; A.234.b.4.i;
A.235.b.4.i; A.236.b.4.i; A.237.b.4.i; A.238.b.4.i; A.239.b.4.i; A.240.b.4.i;
A.241.b.4.i; A.242.b.4.i; A.243.b.4.i; A.244.b.4.i; A.245.b.4.i; A.246.b.4.i; A.247.b.4.i; A.248.b.4.i; A.249.b.4.i; A.250.b.4.i; A.251.b.4.i; A.252.b.4.i;
A.253.b.4i; A.254.b.4.i; A.255.b.4.i; A.256.b.4.i; A.257.b.4.i; A.258.b.4.i;
A.259.b.4.i; A.260.b.4.i; A.261.b.4.i; A.262.b.4.i; A.263.b.4.i; A.264.b.4.i;
A.265.b.4.i; A.266.b.4.i; A.267.b.4.i; A.268.b.4.i; A.269.b.4.i; A.270.b.4.i;
A.271.b.4.i; A.272.b.4.i; A.273.b.4.i; A.274.b.4.i; A.275.b.4.i; A.276.b.4.i; A.277.b.4.i; A.278.b.4.i; A.279.b.4.i; A.280.b.4.i; A.281.b.4.i; A.282.b.4.i;
A.283.b.4.i; A.284.b.4.i; A.285.b.4.i; A.286.b.4.i; A.287.b.4.i; A.288.b.4.i;
A.289.b.4.i; A.290.b.4.i; A.291.b.4.i; A.292.b.4.i; A.293.b.4.i; A.294.b.4.i;
A.295.b.4.i; A.296.b.4.i; A.297.b.4.i; A.298.b.4.i; A.299.b.4.i; A.300.b.4.i;
A.301.b.4.i; A.302.b.4.i; A.303.b.4.i; A.304.b.4.i; A.305.b.4.i; A.306.b.4.i; A.307.b.4.i; A.308.b.4.i; A.309.b.4.i; A.310.b.4.i; A.311.b.4.i; A.312.b.4.i;
A.313.b.4.i; A.314.b.4.i; A.315.b.4.i; A.316.b.4.i; A.317.b.4.i; A.318.b.4.i;
A.319.b.4.i; A.320.b.4.i; A.321.b.4.i; A.323.b.4.i; A.324.b.4.i; A.325.b.4i;
A.326.b.4.i; A.327.b.4.i; A.328.b.4.i; A.329.b.4.i; A.330.b.4.i; A.331.b.4.i;
A.332.b.4.i; A.333.b.4.i; A.334.b.4.i; A.335.b.4.i; A.336.b.4.i; A.337.b.4.i; A.338.b.4.i; A.339.b.4.i; A.340.b.4.i; A.341.b.4.i; A.342.b.4.i; A.343.b.4.i;
A.344.b.4.i; A.345.b.4.i; A.346.b.4.i; A.347.b.4.i; A.348.b.4.i; A.349.b.4.i;
A.350.b.4.i; A.351.b.4.i; A.352.b.4.i; A.353.b.4.i; A.354.b.4.i; A.355.b.4.i; A.356.b.4.i; A.357.b.4. i; A.358.b.4.i; A.359.b 4i; A.360.b.4 i; A.361.b.4.i;
A.362.b.4.i; A.363.b.4 ,i; A.364.b.4.i; A.365.b 4i; A.366.b.4. i; A.367.b.4.i;
A.368.b.4.i; A.369.b.4. i; A.370.b.4.i; A.371.b.4i; A.372.b.4 i; A.373.b.4.i;
A.374.b.4i; A.375.b.4. i; A.376.b.4.i; A.377.b.4i; A.378.b.4. i; A.379.b.4.i; A.380.b.4.i; A.381.b.4. ,i; A.382.b.4.i; A.383.b.4i; A.384.b.4 i; A.385.b.4.i;
A.386.b.4.i; A.387.b.4, ,i; A.388.b.4.i; A.389.b 4i; A.390.b.4 i; A.391.b.4.i;
A.392.b.4.i; A.393.b.4. i; A.394.b.4.i; A.395.b.4i; A.396.b.4 i; A.397.b.4.i;
A.398.b.4.i; A.399.b.4. i; A.400.b.4.i; A.401.b 4i; A.402.b.4 i; A.403.b.4.i;
A.404.b.4.i; A.405.b.4, i; A.406.b.4i; A.407.b 4i; A.408.b.4 i; A.409.b.4.i; A.410.b.4.i; A.411.b.4, i; A.412.b.4.i; A.413.b.4i; A.414.b.4 i; A.415.b.4.i;
A.416.b.4.i; A.417.b.4. i; A.418.b.4.i; A.419.b 4i; A.420.b.4. i; A.421.b.4.i;
A.422.b.4i; A.423.b.4. i; A.424.b.4.i; A.425.b.4i; A.426.b.4. i; A.427.b.4.i;
A.428.b.4.i; A.429.b.4, i; A.430.b.4.i; A.431.b 4i; A.432.b.4. i; A.433.b.4.i;
A.434.b.4.i; A.435.b.4, i; A.436.b.4.i; A.437.b 4i; A.438.b.4. i; A.439.b.4.i; A.440.b.4.i; A.441.b.4 i; A.442.b.4.i; A.443.b.4i; A.444.b.4. i; A.445.b.4.i;
A.446.b.4.i; A.447.b.4 i; A.448.b.4.i; A.449.b.4i; A.450.b.4. i; A.451.b.4.i;
A.452.b.4.i; A.453.b.4 i; A.454.b.4.i; A.455.b, ,4.i; A.456.b.4. i; A.457.b.4.i;
A.458.b.4.i; A.459.b.4 i; A.460.b.4.i; A.461.b .4i; A.462.b.4. i; A.463.b.4.i;
A.464.b.4.i; A.465.b.4 i; A.466.b.4.i; A.467.b .4i; A.468.b.4. i; A.469.b.4.i; A.470.b.4.i; A.471.b.4 i; A.472.b.4.i; A.473.b .4i; A.474.b.4. i; A.475.b.4.i;
A.476.b.4.i; A.477.b.4 i; A.478.b.4.i; A.479.b .4i; A.480.b.4, i; A.481.b.4.i;
A.482.b.4.i; A.483.b.4 i; A.484.b.4.i; A.485.b .4i; A.486.b.4. i; A.487.b.4.i;
A.488.b.4.i; A.489.b.4 i; A.490.b.4.i; A.491.b .4i; A.492.b.4, i; A.493.b.4.i;
A.494.b.4.i; A.495.b.4 i; A.496.b.4.i; A.497.b .4i; A.498.b.4, i; A.499.b.4.i; A.500.b.4.i; A.501.b.4 i; A.502.b.4.i; A.503.b .4i; A.504.b.4, i; A.505.b.4.i;
A.506.b.4.i; A.507.b.4 i; A.508.b.4.i; A.509.b .4i; A.510.b.4. i; A.511.b.4.i;
A.512.b.4.i; A.512.b.4 i; A.513.b.4.i; A.514.b .4i; A.515.b.4. i; A.516.b.4.i;
A.517.b.4.i; A.518.b.4 i; A.519.b.4.i; A.520.b .4i; A.521.b.4 i; A.522.b.4.i;
A.523.b.4.i; A.524.b.4 i; A.525.b.4.i; A.526.b .4i; A.527.b.4 i; A.528.b.4.i; A.529.b.4.i; A.530.b.4 i; A.531.b.4.i; A.532.b .4i; A.533.b.4 i; A.534.b.4.i;
A.535.b.4.i; A.536.b.4 i; A.537.b.4.i; A.538.b .4i; A.539.b.4 i; A.540.b.4.i;
A.541.b.4.i; A.542.b.4 ,i; A.543.b.4.i; A.544.b .4i; A.545.b.4 i; A.546.b.4.i;
A.547.b.4.i; A.548.b.4 i; A.549.b.4.i; A.550.b .4i; A.551.b.4 i; A.552.b.4.i;
A.553.b.4.i; A.554.b.4 i; A.555.b.4.i; A.556.b .4i; A.557.b.4 ,i; A.558.b.4.i; A.559.b.4.i; A.560.b.4 i; A.561.b.4.i; A.562.b .4i; A.563.b.4 ,i; A.564.b.4.i;
A.565.b.4.i; A.566.b.4 i; A.567.b.4.i; A.568.b .4i; A.569.b.4 i; A.570.b.4.i;
A.571.b.4.i; A.572.b.4 i; A.573.b.4.i; A.574.b .4i; A.575.b.4 i; A.576.b.4.i;
A.577.b.4.i; A.578.b.4 i; A.579.b.4i; A.580.b .4i; A.581.b.4 i; A.582.b.4.i;
A.583.b.4.i; A.584.b.4 i; A.585.b.4.i; A.586.b .4i; A.587.b.4 i; A.588.b.4.i; A.589.b.4.i; A.590.b.4 i; A.591.b.4.i; A.592.b .4i; A.593.b.4 i; A.594.b.4.i;
A.595.b.4.i; A.596.b.4 i; A.597.b.4.i; A.598.b .4i; A.599.b.4 i; A.600.b.4.i;
A.601.b.4.i; A.602.b.4 i; A.603.b.4.i; A.604.b 4i; A.605.b.4 i; A.606.b.4.i;
A.607.b.4.i; A.608.b.4 i; A.609.b.4.i; A.όlO.b .4i; A.611.b.4 i; A.612.b.4.i;
A.613.b.4.i; A.614.b.4 i; A.615.b.4.i; A.616.b 4i; A.617.b.4 i; A.618.b.4.i; A.619.b.4.i; A.620.b.4 ,i; A.621.b.4.i; A.622.b 4i; A.623.b.4 i; A.624.b.4.i;
A.625.b.4.i; A.626.b.4 i; A.627.b.4.i; A.628.b .4i; A.629.b.4 i; A.630.b.4.i;
A.631.b.4.i; A.632.b.4 i; A.633.b.4.i; A.634.b .4i; A.635.b.4 i; A.636.b.4.i; A.637.b.4.i; A.638.b.4.i; A.639.b.4.i; A.640.b.4.i; A.641.b.4.i; A.642.b.4i;
A.643.b.4.i; A.644.b.4.i; A.645.b.4.i; A.646.b.4.i; A.647.b.4.i; A.648.b.4.i;
A.649.b.4.i; A.650.b.4.i; A.651.b.4.i; A.652.b.4.i; A.653.b.4.i; A.654.b.4.i;
A.655.b.4.i; A.656.b.4.i; A.657.b.4.i; A.658.b.4.i; A.659.b.4.i; A.660.b.4.i; A.2.b.lli; A.3.b.lli; A.4.b.lli; A.5.b.lli; A.ό.b.lli; A.7.b.lli; A.9.b.H.i; A.lO.b.lli;
A.15.b.lli; A.lOO.b.lli; A.lOl.b.lli; A.102.b.lli; A.103.b.lli; A.104.b.lli;
A.105.b.lli; A.lOO.b.lli; A.107.b.lli; A.108.b.lli; A.109.b.lli; A.llO.b.ll.i;
Aπi.b.lli; A.112.b.ll.i; A. .b.lli; A.114.b.ll.i; A.115.b.ll.i; A.llO.b.ll.i;
A.117.b.ll.i; A.118.b.π.i; A.119.b.π.i; A.120.b.lli; A.121.b.lli; A.122.b.lli; A.123.b.lli; A.124.b.lli; A.125.b.lli; A.126.b.lli; A.127.b.lli; A.128.b.lli;
A.129.b.lli; A.130.b.lli; A.131.b.lli; A.132.b.lli; A.133.b.lli; A.134.b.lli;
A.135.b.lli; A.136.b.lli; A.137.b.lli; A.138.b.lli; A.139.b.lli; A.140.b.lli;
A.141.b.lli; A.142.b.lli; A.143.b.lli; A.144.b.lli; A.145.b.lli; A.146.b.lli;
A.147.b.lli; A.148.b.lli; A.149.b.lli; A.150.b.lli; A.151.b.lli; A.152.b.lli; A.153.b.lli; A.154.b.lli; A.155.b.lli; A.156.b.lli; A.157.b.lli; A.158.b.lli;
A.159.b.lli; A.lOO.b.lli; A.161.b.lli; A.162.b.lli; A.163.b.lli; A.164.b.lli;
A.165.b.lli; A.166.b.lli; A.167.b.lli; A.168.b.lli; A.169.b.lli; A.170.b.lli;
A.171.b.lli; A.172.b.lli; A.173.b.lli; A.174.b.lli; A.175.b.lli; A.176.b.lli;
A.177.b.lli; A.178.b.lli; A.179.b.lli; A.180.b.lli; A.181.b.lli; A.182.b.lli; A.183.b.lli; A.184.b.lli; A.185.b.lli; A.186.b.lli; A.187.b.lli; A.188.b.lli;
A.189.b.lli; A.190.b.lli; A.191.b.lli; A.192.b.lli; A.193.b.lli; A.194.b.lli;
A.195.b.lli; A.196.b.lli; A.197.b.lli; A.198.b.lli; A.199.b.lli; A.200.b.lli;
A.201.b.lli; A.202.b.lli; A.203.b.lli; A.204.b.lli; A.205.b.lli; A.206.b.lli;
A.207.b.lli; A.208.b.lli; A.209.b.lli; A.210.b.lli; A.211.b.lli; A.212.b.lli; A.213.b.lli; A.214.b.lli; A.215.b.lli; A.216.b.lli; A.217.b.lli; A.218.b.lli;
A.219.b.lli; A.220.b.lli; A.221.b.lli; A.222.b.lli; A.223.b.lli; A.224.b.lli;
A.225.b.lli; A.226.b.lli; A.227.b.lli; A.228.b.lli; A.229.b.lli; A.230.b.lli;
A.231.b.lli; A.232.b.lli; A.233.b.lli; A.234.b.lli; A.235.b.H.i; A.236.b.lli;
A.237.b.lli; A.238.b.lli; A.239.b.lli; A.240.b.lli; A.241.b.lli; A.242.b.lli; A.243.b.lli; A.244.b.lli; A.245.b.lli; A.246.b.H.i; A.247.b.lli; A.248.b.lli;
A.249.b.lli; A.250.b.lli; A.251.b.lli; A.252.b.lli; A.253.b.lli; A.254.b.lli;
A.255.b.lli; A.256.b.lli; A.257.b.lli; A.258.b.lli; A.259.b.lli; A.260.b.lli;
A.261.b.ll.i; A.262.b.lli; A.263.b.lli; A.264.b.lli; A.265.b.lli; A.266.b.lli;
A.267.b.lli; A.268.b.lli; A.269.b.lli; A.270.b.lli; A.271.b.lli; A.272.b.lli; A.273.b.lli; A.274.b.lli; A.275.b.lli; A.276.b.lli; A.277.b.lli; A.278.b.lli;
A.279.b.lli; A.280.b.lli; A.281.b.lli; A.282.b.lli; A.283.b.lli; A.284.b.lli;
A.285.b.lli; A.286.b.lli; A.287.b.lli; A.288.b.lli; A.289.b.lli; A.290.b.lli;
A.291.b.lli; A.292.b.lli; A.293.b.lli; A.294.b.lli; A.295.b.lli; A.296.b.lli;
A.297.b.lli; A.298.b.lli; A.299.b.lli; A.300.b.lli; A.301.b.lli; A.302.b.lli; A.303.b.lli; A.304.b.lli; A.305.b.lli; A.306.b.lli; A.307.b.lli; A.308.b.lli;
A.309.b.lli; A.310.b.lli; A.311.b.lli; A.312.b.lli; A.313.b.lli; A.314.b.lli;
A.315.b.lli; A.316.b.lli; A.317.b.lli; A.318.b.lli; A.319.b.lli; A.320.b.lli;
A.321.b.lli; A.323.b.lli; A.324.b.lli; A.325.b.lli; A.326.b.lli; A.327.b.lli;
A.328.b.lli; A.329.b.lli; A.330.b.lli; A.331.b.lli; A.332.b.H.i; A.333.b.lli; A.334.b.lli; A.335.b.lli; A.336.b.lli; A.337.b.lli; A.338.b.lli; A.339.b.lli;
A.340.b.lli; A.341.b.lli; A.342.b.lli; A.343.b.lli; A.344.b.lli; A.345.b.lli;
A.346.b.lli; A.347.b.lli; A.348.b.lli; A.349.b.lli; A.350.b.lli; A.351.b.lli; A 352.b.ll. i; A.353.b. Hi; A.354.b. ll.i; A.355.b. lli; A.356.b ll.i; A.357.b. Hi;
A. 358.b.ll i; A.359.b. ll.i; A.360.b ll.i; A.361.b. ll.i; A.362.b ll.i; A.363.b. Hi;
A 364.b.ll i; A.365.b Hi; A.366.b ll.i; A.367.b. Hi; A.368.b. ll.i; A.369.b. Hi;
A. 370.b.ll. i; A.371.b Hi; A.372.b. ll.i; A.373.b. ll.i; A.374.b ll.i; A.375.b. Hi;
A. 376.b.ll. i; A.377.b. ll.i; A.378.b. ll.i; A.379.b. ll.i; A.380.b ll.i; A.381.b. Hi;
A 382.b.ll. i; A.383.b. lli; A.384.b. ll.i; A.385.b. ll.i; A.386.b ll.i; A.387.b. Hi;
A. 388.b.ll. i; A.389.b. Hi; A.390.b. ll.i; A.391.b. Hi; A.392.b ll.i; A.393.b. ll.i;
A. 394.b.ll. i; A.395.b. Hi; A.396.b. ll.i; A.397.b. Hi; A.398.b. ll.i; A.399.b. Hi;
A. 400.b.ll. i; A.401.b. Hi; A.402.b. ll.i; A.403.b. ll.i; A.404.b ll.i; A.405.b, Hi;
A. 406.b.ll. i; A.407.b. Hi; A.408.b. ll.i; A.409.b. Hi; A.410.b ll.i; A.411.b. Hi;
A. 412.b.ll, ,i; A.413.b. ll.i; A.414.b. ll.i; A.415.b. ll.i; A.416.b. ll.i; A.417.b. Hi;
A. 418.b.ll. i; A.419.b. lli; A.420.b. ll.i; A.421.b. ll.i; A.422.b. ll.i; A.423.b, Hi;
A. 424.b.ll, i; A.425.b. ll.i; A.426.b. ll.i; A.427.b. ll.i; A.428.b. ll.i; A.429.b. ll.i;
A. 430.b.ll, i; A.431.b. ll.i; A.432.b. ll.i; A.433.b. Hi; A.434.b. ll.i; A.435.b. Hi;
A. 436.b.ll. i; A.437.b. ll.i; A.438.b. Hi; A.439.b. ll.i; A.440.b. ll.i; A.441.b, Hi;
A. ,442.b.ll, i; A.443.b. ll.i; A.444.b. ll.i; A.445.b. Hi; A.446.b. ll.i; A.447.b, ll.i;
A. 448.b.ll, i; A.449.b. ll.i; A.450.b. Hi; A.451.b. ll.i; A.452.b. Hi; A.453.b, ll.i;
A. ,454.b.ll, i; A.455.b. ll.i; A.456.b. ll.i; A.457.b. Hi; A.458.b. ll.i; A.459.b, ll.i;
A. ,460.b.ll i; A.461.b. ll.i; A.462.b. ll.i; A.463.b. ll.i; A.464.b. ll.i; A.465.b, Hi;
A. ,466.b.ll i; A.467.b. lli; A.468.b. ll.i; A.469.b. ll.i; A.470.b. ll.i; A.471.b, ll.i;
A. ,472.b.ll i; A.473.b. ll.i; A.474.b. ll.i; A.475.b. ll.i; A.476.b. ll.i; A.477.b, ll.i;
A. ,478.b.ll i; A.479.b. ll.i; A.480.b. Hi; A.481.b. ll.i; A.482.b. ll.i; A.483.b, Hi;
A. ,484.b.ll i; A.485.b. Hi; A.486.b. ll.i; A.487.b. Hi; A.488.b. Hi; A.489.b, Hi;
A, ,490.b.ll i; A.491.b, Hi; A.492.b. Hi; A.493.b. Hi; A.494.b. ll.i; A.495.b Hi;
A, ,496.b.ll i; A.497.b. Hi; A.498.b. ll.i; A.499.b. Hi; A.500.b. ll.i; A.501.b, ll.i;
A. ,502.b.ll i; A.503.b, ll.i; A.504.b. ll.i; A.505.b. ll.i; A.506.b. ll.i; A.507.b Hi;
A, ,508.b.ll i; A.509.b ll.i; A.510.b. Hi; A.511.b. ll.i; A.512.b. ll.i; A.512.b ll.i;
A, ,513.b.ll i; A.514.b, Hi; A.515.b. ll.i; A.516.b. ll.i; A.517.b. ll.i; A.518.b ll.i;
A ,519.b.ll i; A.520.b ll.i; A.521.b. ll.i; A.522.b. ll.i; A.523.b. Hi; A.524.b Hi;
A, ,525.b.ll i; A.526.b Hi; A.527.b. ll.i; A.528.b. ll.i; A.529.b. ll.i; A.530.b ll.i;
A .531.b.ll i; A.532.b Hi; A.533.b. ll.i; A.534.b. ll.i; A.535.b. ll.i; A.536.b Hi;
A. .537.b.ll i; A.538.b lli; A.539.b. Hi; A.540.b. ll.i; A.541.b. ll.i; A.542.b Hi;
A .543.b.ll i; A.544.b Hi; A.545.b. ll.i; A.546.b. ll.i; A.547.b. ll.i; A.548.b ll.i;
A .549.b.ll i; A.550.b Hi; A.551.b. Hi; A.552.b. Hi; A.553.b. Hi; A.554.b Hi;
A .555.b.ll i; A.556.b Hi; A.557.b. Hi; A.558.b. ll.i; A.559.b. ll.i; A.560.b Hi;
A. 561.b.ll i; A.562.b Hi; A.563.b. Hi; A.564.b. Hi; A.565.b. ll.i; A.566.b Hi;
A. 567.b.ll i; A.568.b Hi; A.569.b Hi; A.570.b. ll.i; A.571.b. ll.i; A.572.b Hi;
A, 573.b.ll i; A.574.b Hi; A.575.b ll.i; A.576.b. Hi; A.577.b. ll.i; A.578.b Hi;
A 579.b.ll i; A.580.b Hi; A.581.b Hi; A.582.b. Hi; A.583.b. ll.i; A.584.b Hi;
A 585.b.ll i; A.586.b Hi; A.587.b Hi; A.588.b. Hi; A.589.b. Hi; A.590.b Hi;
A 591.b.ll i; A.592.b Hi; A.593.b ll.i; A.594.b. Hi; A.595.b. ll.i; A.596.b Hi;
A 597.b.ll i; A.598.b ll.i; A.599.b ll.i; A.600.b. Hi; A.όOl.b. ll.i; A.602.b ll.i;
A .603.b.ll i; A.604.b Hi; A.605.b ll.i; A.606.b. Hi; A.607.b. ll.i; A.608.b ll.i;
A .609.b.ll i; A.όlO.b Hi; A.όll.b Hi; A.612.b. Hi; A.613.b. ll.i; A.614.b Hi;
A .615.b.ll i; A.616.b ll.i; A.617.b ll.i; A.618.b. Hi; A.619.b. ll.i; A.620.b Hi;
A 621.b.ll i; A.622.b ll.i; A.623.b Hi; A.624.b. Hi; A.625.b. Hi; A.626.b Hi;
A .627.b.ll i; A.628.b Hi; A.629.b ll.i; A.630.b. Hi; A.631.b Hi; A.632.b Hi; A 633.b.lli; A.634.b.lli; A.635.b.ll.i; A.636 ll.i; A.637.b.lli; A.638.b.lli; A 639.b.lli; A.640.b.lli; A.641.b.ll.i; A.642 Hi; A.643.b.H.i; A.644.b.lli; A.645.b.lli; A.646.b.lli; A.647.b.ll.i; A.648 Hi; A.649.b.lli; A.650.b.lli; A 651.b.lli; A.652.b.lli; A.653.b.ll.i; A.654 ll.i; A.655.b.lli; A.656.b.lli;
A,657.b.lli; A.658.b.lli; A.659.b.ll.i; A.660 Hi; A.2.x.4.i; A.3.X.4. A.4.x.4.i;
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A.421.X.11. A.422.X.11 A.423.X.11 ; A.424.X.11. A.425.X.11, .; A.426.X.11.
A.427.X.11. A.428.X.11 A.429.X.11 ; A.430.X.11. A.431.X.11, A.432.X.11
A.433.X.11. A.434.X.11 A.435.X.11 ; A.436.X.11. A.437.X.11, A.438.X.11,
A.439.X.11. A.440.X.11 A.441.X.11 ; A.442.X.11. A.443.X.11. A.444.X.11.
A.445.X.11. A.446.X.11 A.447.X.11 ; A.448.X.11. A.449.X.11. A.450.X.11,
A.451.X.11. A.452.X.11 A.453.X.11 ; A.454.X.11. A.455.X.11. ; A.456.X.11.
A.457.X.11. A.458.X.11 A.459.X.11 ; A.460.X.11. A.461.X.11 .; A.462.X.11
A.463.X.11. A.464.X.11 A.465.X.11 ; A.466.X.11. A.467.X.11, .; A.468.X.11
A.469.X.11. A.470.X.11 A.471.X.11 ; A.472.X.11. A.473.X.11. .; A.474.X.11,
A.475.X.11. A.476.X.11 A.477.X.11 ; A.478.X.11. A.479.X.11. .; A.480.X.11.
A.481.X.11. A.482.X.11 A.483.X.11 ; A.484.X.11. A.485.X.11, i; A.486.X.11.
A.487.X.11. A.488.X.11 A.489.X.11 ; A.490.X.11. A.491.X.11, A.492.X.11,
A.493.X.11. A.494.X.11 A.495.X.11 ; A.496.X.11. A.497.X.11, .; A.498.X.11,
A.499.X.11. A.500.X.11 A.501.X.11 ; A.502.X.11. A.503.X.11, ; A.504.X.11,
A.505.X.11. A.506.X.11 A.507.X.11 ; A.508.X.11. A.509.X.11, ; A.510.X.11
A.511.X.11. A.512.X.11 A.512.X.11 ; A.513.X.11. A.514.X.11, .; A.515.X.11,
A.516.X.11. A.517.X.11 A.518.X.11 ; A.519.X.11. A.520.X.11, .; A.521.X.11,
A.522.X.11. A.523.X.11 A.524.X.11 ; A.525.X.11. A.526.X.11. .; A.527.X.11,
A.528.X.11. A.529.X.11 A.530.X.11 ; A.531.X.11. A.532.X.11. .; A.533.X.11,
A.534.X.11. A.535.X.11 A.536.X.11 ; A.537.X.11. A.538.X.11, .; A.539.X.11
A.540.X.11. A.541.X.11 A.542.X.11 ; A.543.X.11. A.544.X.11, .; A.545.X.11
A.546.X.11. A.547.X.11 A.548.X.11 ; A.549.X.11. A.550.X.11, .; A.551.X.11
A.552.X.11. A.553.X.11 A.554.X.11 ; A.555.X.11. A.556.X.11, ; A.557.X.11
A.558.X.11. A.559.X.11 A.560.X.11 ; A.561.X.11. A.562.X.11 .; A.563.X.11
A.564.X.11. A.565.X.11 A.566.X.11 ; A.567.X.11. A.568.X.11 ; A.569.X.11
A.570.X.11. A.571.X.11 A.572.X.11 ; A.573.X.11. A.574.X.11 ; A.575.X.11
A.576.X.11. A.577.X.11 A.578.X.11 ; A.579.X.11. A.580.X.11 A.581.X.11
A.582.X.11. A.583.X.11 A.584.X.11 ; A.585.X.11. A.586.X.11 ; A.587.X.11
A.588.X.11. A.589.X.11 A.590.X.11 ; A.591.X.11. A.592.X.11 A.593.X.11
A.594.X.11. A.595.X.11 A.596.X.11 ; A.597.X.11. A.598.X.11 A.599.X.11
A.600.X.11. A.601.X.11 A.602.X.11 ; A.603.X.11. A.604.X.11 ; A.605.X.11
A.606.X.11. A.607.X.11 A.608.X.11 ; A.609.X.11. A.610.X.11 A.611.X.11
A.612.X.11. A.613.X.11 A.614.X.11 ; A.615.X.11. A.616.X.11 ; A.617.X.11
A.618.X..11. A.619.X.11 A.620.X.11 ; A.621.X.11. A.622.X.11 i; A.623.X.11 A.624.x.lli; A.625.x.lli; A.626.x.lli; A.627.X ll.i; A.628.x.lli; A.629.x.lli;
A.630.x.lli; A.631.x.lli; A.632.x.lli; A.633.X. ll.i; A.634.x.lli; A.635.x.lli;
A.636.x.lli; A.637.x.lli; A.638.x.lli; A.639.X ll.i; A.640.x.lli; A.641.x.lli;
A.642.x.lli; A.643.x.lli; A.644.x.lli; A.645.X ll.i; A.646.x.lli; A.647.x.lli; A.648.x.lli; A.649.x.lli; A.650.x.lli; A.651.X. Hi; A.652.x.lli; A.653.x.lli;
A.654.x.lli; A.655.x.lli; A.656.x.lli; A.657.X. Hi; A.658.x.lli; A.659.x.lli;
A.660.x.lli; A.2.y.4.i; A.3.y.4.i; A.4.y.4.i; A.5.y .4i; A.6.y.4.i; A.7.y.4.i; A.9.y.4.i;
A.10.y.4.i; A.15.y.4.i; A.100.y.4.i; A.101.y.4.i; A.102.y.4.i; A.103.y.4.i; A.104.y.4.i;
A.105.y.4.i; A.106.y.4.i; A.107.y.4.i; A.108.y.4.i; A.109.y.4 i; AHO.y.4 A.lll.y.4.i; A.112.y.4.i; A.113.y.4.i; A.114.y.4.i; A.115.y.4 i; A.116.y.4
A.117.y.4.i; A.118.y.4.i; A.119.y.4.i; A.120.y.4.i; A.121.y.4 i; A.122.y.4.
A.123.y.4.i; A.124.y.4.i; A.125.y.4.i; A.126.y.4.i; A.127.y.4 i; A.128.y.4.
A.129.y.4.i; A.130.y.4.i; A.131.y.4.i; A.132.y.4.i; A.133.y.4. i; A.134.y.4.
A.135.y.4.i; A.136.y.4.i; A.137.y.4.i; A.138.y.4.i; A.139.y.4 i; A.140.y.4. A.141.y.4.i; A.142.y.4.i; A.143.y.4.i; A.144.y.4.i; A.145.y.4. i; A.146.y.4.
A.147.y.4.i; A.148.y.4.i; A.149.y.4.i; A.150.y.4.i; A.151.y.4. i; A.152.y.4.
A.153.y.4.i; A.154.y.4.i; A.155.y.4.i; A.156.y.4.i; A.157.y.4. i; A.158.y.4.
A.159.y.4.i; A.160.y.4.i; A.161.y.4.i; A.162.y.4.i; A.163.y.4. i; A.164.y.4.
A.165.y.4.i; A.166.y.4.i; A.167.y.4.i; A.168.y.4.i; A.169.y.4. i; A.170.y.4. A.171.y.4.i; A.172.y.4.i; A.173.y.4.i; A.174.y.4.i; A.175.y.4. i; A.176.y.4.
A.177.y.4.i; A.178.y.4.i; A.179.y.4.i; A.180.y.4.i; A.181.y.4. i; A.182.y.4.
A.183.y.4.i; A.184.y.4.i; A.185.y.4.i; A.186.y.4.i; A.187.y.4. i; A.188.y.4.
A.189.y.4.i; A.190.y.4.i; A.191.y.4.i; A.192.y.4.i; A.193.y.4. i; A.194.y.4.
A.195.y.4.i; A.196.y.4.i; A.197.y.4.i; A.198.y.4.i; A.199.y.4. i; A.200.y.4. A.201.y.4.i; A.202.y.4.i; A.203.y.4.i; A.204.y.4.i; A.205.y.4. i; A.206.y.4.
A.207.y.4.i; A.208.y.4.i; A.209.y.4.i; A.210.y.4.i; A.211.y.4. i; A.212.y.4.
A.213.y.4.i; A.214.y.4.i; A.215.y.4.i; A.216.y.4.i; A.217.y.4. i; A.218.y.4.
A.219.y.4.i; A.220.y.4.i; A.221.y.4.i; A.222.y.4.i; A.223.y.4. i; A.224.y.4.
A.225.y.4.i; A.226.y.4.i; A.227.y.4.i; A.228.y.4.i; A.229.y.4. i; A.230.y.4. A.231.y.4.i; A.232.y.4.i; A.233.y.4.i; A.234.y.4.i; A.235.V.4. i; A.236.y.4.
A.237.y.4.i; A.238.y.4.i; A.239.y.4.i; A.240.y.4.i; A.241.y.4 i; A.242.y.4.
A.243.y.4.i; A.244.y.4.i; A.245.y.4.i; A.246.y.4.i; A.247.y.4. i; A.248.y.4.
A.249.y.4.i; A.250.y.4.i; A.251.y.4.i; A.252.y.4.i; A.253.y.4. i; A.254.y.4.
A.255.y.4.i; A.256.y.4.i; A.257.y.4.i; A.258.y.4.i; A.259.y.4. i; A.260.y.4. A.261.y.4.i; A.262.y.4.i; A.263.y.4.i; A.264.y.4.i; A.265.y.4. i; A.266.y.4.
A.267.y.4.i; A.268.y.4.i; A.269.y.4.i; A.270.y.4.i; A.271.y.4. i; A.272.y.4.
A.273.y.4.i; A.274.y.4.i; A.275.y.4.i; A.276.y.4.i; A.277.y.4. i; A.278.y.4.
A.279.y.4.i; A.280.y.4.i; A.281.y.4.i; A.282.y.4.i; A.283.y.4. i; A.284.y.4.
A.285.y.4.i; A.286.y.4.i; A.287.y.4.i; A.288.y.4.i; A.289.y.4. i; A.290.y.4. A.291.y.4.i; A.292.y.4.i; A.293.y.4.i; A.294.y.4.i; A.295.y.4 i; A.296.y.4.
A.297.y.4.i; A.298.y.4.i; A.299.y.4.i; A.300.y.4.i; A.301.y.4. i; A.302.y.4.
A.303.y.4.i; A.304.y.4.i; A.305.y.4.i; A.306.y.4.i; A.307.y.4. i; A.308.y.4.
A.309.y.4.i; A.310.y.4.i; A.311.y.4.i; A.312.y.4.i; A.313.y.4 i; A.314.y.4.
A.315.y.4.i; A.316.y.4.i; A.317.y.4.i; A.318.y.4.i; A.319.y.4 i; A.320.y.4. A.321.y.4.i; A.323.y.4.i; A.324.y.4.i; A.325.y.4.i; A.326.y.4 i; A.327.y.4.
A.328.y.4.i; A.329.y.4.i; A.330.y.4.i; A.331.y.4.i; A.332.y.4 i; A.333.y.4.
A.334.y.4.i; A.335.y.4.i; A.336.y.4.i; A.337.y.4.i; A.338.y.4 i; A.339.y.4. A .340.y.4, A.341. y.4i; A.342.y.4. A.343.y.4.i A.344.y.4. A.345.y.4.i;
A .346.y.4.: A.347. y.4.i; A.348.y.4. A.349.y.4. A.350.y.4. A.351.y.4.i;
A .352.y.4.: A.353 y.4.i; A.354.y.4. A.355.y.4. A.356.y.4. A.357.y.4.i;
A. .358.y.4. A.359. y.4.i; A.360.y.4. A.361.y.4. A.362.y.4. A.363.y.4.i;
A .364.y.4.; A.365. y.4i; A.366.y.4. A.367.y.4. A.368.y.4. A.369.y.4.i;
A .370.y.4.i, A.371. y.4.i; A.372.y.4. A.373.y.4. A.374.y.4. A.375.y.4.i;
A .376.y.4.ι A.377, y.4.i; A.378.y.4, A.379.y.4. A.380.y.4. A.381.y.4.i;
A .382.y.4 A.383 y.4.i; A.384.y.4, A.385.y.4. A.386.y.4. A.387.y.4.i;
A .388.y.4.ι A.389 y.4i; A.390.y.4, A.391.y.4. A.392.y.4. A.393.y.4.i;
A .394.y.4. A.395 y.4.i; A.396.y.4, A.397.y.4. A.398.y.4. A.399.y.4.i;
A .400.y.4.ι A.401 y.4.i; A.402.y.4, A.403.y.4. A.404.y.4. A.405.y.4.i;
A .406.y.4. A.407. y.4i; A.408.y.4, A.409.y.4. A.410.y.4. A.411.y.4.i;
A .412.y.4. A.413. y.4.i; A.414.y.4, A.415.y.4. A.416.y.4. A.417.y.4.i;
A .418.y.4.i A.419. y.4.i; A.420.y.4. A.421.y.4. A.422.y.4. A.423.y.4.i;
A. .424.y.4. A.425. y.4.i; A.426.y.4 A.427.y.4. A.428.y.4. A.429.y.4.i;
A .430.y.4.: A.431. y.4.i; A.432.y.4 A.433.y.4. A.434.y.4. A.435.y.4i;
A .436.y.4 A.437. y.4.i; A.438.y.4 A.439.y.4. A.440.y.4. A.441.y.4.i;
A .442.y.4.: A.443. y.4.i; A.444.y.4, A.445.y.4. A.446.y.4. A.447.y.4.i;
A .448.y.4. A.449. y.4.i; A.450.y.4 A.451.y.4. A.452.y.4. A.453.y.4.i;
A .454.y.4. A.455. y.4.i; A.456.y.4 A.457.y.4. A.458.y.4. A.459.y.4.i;
A .460.y.4. A.461. y.4.i; A.462.y.4 A.463.y.4. A.464.y.4. A.465.y.4.i;
A .466.y.4.: A.467. y.4.i; A.468.y.4 A.469.y.4. A.470.y.4. A.471.y.4.i;
A .472.y.4.. A.473. y.4.i; A.474.y.4 A.475.y.4. A.476.y.4. A.477.y.4.i;
A .478.y.4.i A.479. y.4.i; A.480.y.4 A.481.y.4. A.482.y.4. A.483.y.4i;
A .484.y.4 A.485. y-4i; A.486.y.4 A.487.y.4. A.488.y.4. A.489.y.4.i;
A .490.y.4 A.491. y.4.i; A.492.y.4 A.493.y.4. A.494.y.4. A.495.y.4.i;
A .496.y.4 A.497. y.4.i; A.498.y.4 A.499.y.4. A.500.y.4. A.501.y.4.i;
A .502.y. A.503. y.4i; A.504.y.4 A.505.y.4. A.506.y.4. A.507.y.4.i;
A .508.y. .4i; A.509. y.4.i; A.510.y.4 A.511.y.4. A.512.y.4. A.512.y.4.i;
A .513.y..4i; A.514. y.4i; A.515.y.4 A.516.y.4. A.517.y.4. A.518.y.4.i;
A .519.' .4i; A.520. y.4.i; A.521.y.4 A.522.y.4. A.523.y.4. A.524.y.4.i;
A .525.: .4i; A.526. y.4i; A.527.y.4 A.528.y.4. A.529.y.4. A.530.y.4.i;
A .531.: •4.i A.532. y.4.i; A.533.y.4 A.534.y.4. A.535.y.4, A.536.y.4.i;
A .537. •y.4.i A.538, y.4.i; A.539.y.4 A.540.y.4. A.541.y.4. A.542.y.4.i;
A .543. •y.4i A.544, y.4i; A.545.y.4 A.546.y.4. A.547.y.4. A.548.y.4.i;
A .549 '..'y.4.i; A.550. y.4i; A.551.y.4 A.552.y.4. A.553.y.4. A.554.y.4.i;
A .555.y.4.i, A.556, y.4i; A.557.y.4 A.558.y.4. A.559.y.4, A.560.y.4.i;
A .561.y.4.i, A.562, y.4.i; A.563.y.4 A.564.y.4. A.565.y.4, A.566.y.4.i;
A .567.y.4.i, A.568, y.4.i; A.569.y.4 A.570.y.4. A.571.y.4. A.572.y.4.i;
A .573.y.4.i, A.574, ,y.4.i; A.575.y.4 A.576.y.4. A.577.y.4, A.578.y.4.i;
A .579.y.4.i, A.580 ,y.4.i; A.581.y.4 A.582.y.4. A.583.y.4, A.584.y.4.i;
A, .585.y.4.i, A.586 ,y.4.i; A.587.y.4 A.588.y.4. A.589.y.4 A.590.y.4.i;
A .591.y.4.i, A.592 ,y.4.i; A.593.y.4 A.594.y.4. A.595.y.4 A.596.y.4.i;
A ,.597.y.4.i, A.598 ,y.4.i; A.599.y.4 A.600.y.4. A.601.y.4, A.602.y.4.i;
A .603.y.4.i; A.604 ,y.4.i; A.605.y.4 A.606.y.4. A.607.y.4. A.608.y.4.i;
A .609.y.4. A.610 ■y.4i; A.611.y.4 A.612.y.4. A.613.y.4 A.614.y.4.i;
A .615.y.4.i; A.616 ,y.4.i; A.617.y.4 A.618.y.4. A.619.y.4 A.620.y.4.i; A .621.y.4.i; A.622.y.4. i; A.623.y.4.i; A.624.y.4 i; A.625.y.4.i; A.626.y.4.i;
A. .627.y.4.i; A.628.y.4. i; A.629.y.4.i; A.630.y.4 i; A.631.y.4.i; A.632.y.4.i;
A .633.y.4.i; A.634.y.4. i; A.635.y.4.i; A.636.y.4 i; A.637.y.4.i; A.638.y.4.i;
A. .639.y.4.i; A.640.y.4. i; A.641.y.4.i; A.642.y.4 i; A.643.y.4.i; A.644.y.4.i;
A .645.y.4.i; A.646.y.4, i; A.647.y.4.i; A.648.y.4 i; A.649.y.4.i; A.650.y.4.i;
A. . .665511..yy..44..ii;; AA..665522..yy..44,, i; A.653.y.4.i; A.654.y.4 i; A.655.y.4.i; A.656.y.4.i;
A.. .665577..yy..44..ii;; AA..665588..yy..44.. i; A.659.y.4.i; A.660.y.4 i; A.2.y.lli; A.3.y.lli; A.4.y.lli;
A . .55..yy..llllii;; AA..όό..yy..llllii;; A.7.y.lli; A.9.y.lli; A. lO.y.lli; A.15.y.lli; A.lOO.y.lli;
A . ..llOOll..yy..llllii;; AA..110022..yy.. Hi; A.103.y.lli; A.104.y.lli; A.105.y.lli; A.lOO.y.lli;
A ..110077..yy..llllii;; AA..110088..yy.. Hi; A.109.y.lli; A.110.y.lli; A.πi.y.ll.i; A.112.y.ll.i;
A . m113. -yr.1l1li ;;• A Δ . ι1i14/i. -yf. ll.i; A.115.y.ll.i; A.116.y.lli; A.117.y.ll.i; A.118.y.ll.i;
A .119.y.ll.i; A.120.y.: Hi; A.121.y.lli; A.122.y.lli; A.123.y.lli; A.124.y.lli;
A .1 12255.yy..llllii;; A A..112266.yy. ll.i; A.127. y.lli; A.128.y.lli; A.129.y.lli; A.130.y.lli;
A 1 13^11 .y.1l1li i;- A Δ. Λ13V2> - y Hi; A.133.y.lli; A.134.y.lli; A.135.y.lli; A.136.y.lli;
A 137y.Hi; A.138 y ll.i; A.139.y.lli; A.140 •y.lli; A.141.y.lli; A.142.y.lli;
A 143 y.lli; A.144 y ll.i; A.145.y.lli; A.146 •y.lli; A.147.y.lli; A.148.y.lli;
A 149y.lli; A.150 y ll.i; A.151.y.lli; A.152.y.lli; A.153.y.lli; A.154.y.lli;
A . 115555 ..yy..lllli. i;; AA..115566.yy. ll.i; A.157.y.lli; A.158.y.lli; A.159.y.lli; A.lOO.y.lli;
A . 1lAό1l.vy.1l1l. i•;• A A.116629.y. ll.i; A.163.y.lli; A.164.y.lli; A.165.y.lli; A.166.y.lli;
A, .167.y.ll. i; A.168.y. ll.i; A.169.y.lli; A.170.y.lli; A.171.y.lli; A.172.y.lli;
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A .179.y.ll. i; A.180.y. ll.i; A.181.y.lli; A.182 y.lli; A.183.y.lli; A.184.y.lli;
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A .191.y.ll. i; A.192.y Hi; A.193.y.lli; A.194 y.lli; A.195.y.lli; A.196.y.lli;
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A. 627.Z.11 A.628.Z.11. A.629.z.lli; A.630.z.lli A.631.Z. ll.i; A.632.z.lli; A 633.Z.11 A.634.Z.11. A.635.z.lli; A.636.z.lli A.637.Z, ll.i; A.638.z.lli; A 639.Z.11 A.640.Z.11. A.641.z.lli; A.642.z.lli A.643.Z, Hi; A.644.z.lli; A 645.Z.11 A.646.Z.11. A.647.z.lli; A.648.z.lli A.649.Z, Hi; A.650.z.lli; A. 651. z.ll A.652.Z.11. A.653.z.lli; A.654.z.lli A.655.Z, ll.i; A.656.z.lli; A. 657.Z.11 A.658.Z.11. A.659.z.lli; A.660.z.lli; A.2.A.4.i; A.3.A.4.i; A. 4.A.4.i; A 5.A.4.i; A.6.A.4.i; A.7.A.4.i; A.9.A.4.i; A.10.A.4.i; A.15.A.4.i; A. 100.A.4 A.101.A.4.i; A.102.A.4.i; A.103.A.4 i; A.104.A.4.i; A.105.A.4.i A. 106.A.4 A.107.A.4.i; A.108.A.4.i; A.109.A.4 i; A.110.A.4.i; A.lll.A.4.i A. 112.A.4 A.113.A.4i; A.114.A.4.i; A.115.A.4. i; A.116.A.4.i; A.117.A.4.i A. 118.A.4. A.119.A.4.i; A.120.A.4.i; A.121.A.4. i; A.122.A.4.i; A.123.A.4.i A. 124.A.4. A.125.A.4.i; A.126.A.4.i; A.127.A.4. i; A.128.A.4.i; A.129.A.4.i A. 130.A.4. A.131.A.4.i; A.132.A.4.i; A.133.A.4. i; A.134.A.4.i; A.135.A.4.i A. 136.A.4. A.137.A.4.i; A.138.A.4.i; A.139.A.4. i; A.140.A.4.i; A.141.A.4.i A. 142.A.4. A.143.A.4.i; A.144.A.4.i; A.145.A.4. i; A.146.A.4.i; A.147.A.4.i A. 148.A.4. A.149.A.4.i; A.150.A.4.i; A.151.A.4 i; A.152.A.4.i; A.153.A.4.i A. 154.A.4. A.155.A.4.i; A.156.A.4.i; A.157.A.4. i; A.158.A.4.i; A.159.A.4.i A. 160.A.4. A.161.A.4.i; A.162.A.4.i; A.163.A.4. i; A.164.A.4.i; A.165.A.4.i A. 166.A.4. A.167.A.4.i; A.168.A.4.i; A.169.A.4. i; A.170.A.4.i; A.171.A.4.i A. 172.A.4. A.173.A.4.i; A.174.A.4.i; A.175.A.4 i; A.176.A.4.i; A.177.A.4.i A. 178.A.4. A.179.A.4.i; A.180.A.4.i; A.181.A.4. i; A.182.A.4.i; A.183.A.4.Ϊ A. 184.A.4. A.185.A.4.i; A.186.A.4.i; A.187.A.4. i; A.188.A.4.i; A.189.A.4.i A. 190.A.4. A.191.A.4.i; A.192.A.4i; A.193.A.4 i; A.194.A.4.i; A.195.A.4.i A. 196.A.4. A.197.A.4.i; A.198.A.4.i; A.199.A.4 i; A.200.A.4.i; A.201.A.4.i A. 202.A.4. A.203.A.4.i; A.204.A.4.i; A.205.A.4. i; A.206.A.4.i; A.207.A.4.i A. 208.A.4. A.209.A.4.i; A.210.A.4i; A.211.A.4. i; A.212.A.4.i; A.213.A.4.i A. 214.A.4. A.215.A.4.i; A.216.A.4.i; A.217.A.4. i; A.218.A.4.i; A.219.A.4.i A. 220.A.4. A.221.A.4.i; A.222.A.4.i; A.223.A.4. i; A.224.A.4.i; A.225.A.4.i A. 226.A.4. A.227.A.4.i; A.228.A.4.i; A.229.A.4 i; A.230.A.4.i; A.231.A.4.Ϊ A. 232.A.4. A.233.A.4.i; A.234.A.4.i; A.235.A.4 i; A.236.A.4.i; A.237.A.4.Ϊ A, 238.A.4. A.239.A.4.i; A.240.A.4.i; A.241.A.4 i; A.242.A.4.i; A.243.A.4.i A, 244.A.4. A.245.A.4.i; A.246.A.4.i; A.247.A.4 i; A.248.A.4.i; A.249.A.4.Ϊ A. 250.A.4. A.251.A.4.i; A.252.A.4.i; A.253.A.4. i; A.254.A.4.i; A.255.A.4.Ϊ A, 256.A.4. A.257.A.4.i; A.258.A.4.i; A.259.A.4 i; A.260.A.4.i; A.261.A.4.1 A, 262.A.4. A.263.A.4.i; A.264.A.4.i; A.265.A.4 i; A.266.A.4.i; A.267.A.4.Ϊ A 268.A.4. A.269.A.4.i; A.270.A.4.i; A.271.A.4 i; A.272.A.4.i; A.273.A.4.i A 274.A.4. A.275.A.4.i; A.276.A.4.i; A.277.A.4 i; A.278.A.4.i; A.279.A.4.i A 280.A.4. A.281.A.4.i; A.282.A.4.i; A.283.A.4 i; A.284.A.4.i; A.285.A.4.i A .286.A.4. A.287.A.4.i; A.288.A.4.i; A.289.A.4. i; A.290.A.4.i; A.291.A.4.i A .292.A.4. A.293.A.4.i; A.294.A.4.i; A.295.A.4 i; A.296.A.4.i; A.297.A.4.i A .298.A.4. A.299.A.4.i; A.300.A.4.i; A.301.A.4 i; A.302.A.4.i; A.303.A.4.Ϊ A .304.A.4. A.305.A.4.i; A.306.A.4.i; A.307.A.4. i; A.308.A.4.i; A.309.A.4.i A 310.A.4. A.311.A.4.i; A.312.A.4.i; A.313.A.4 i; A.314.A.4.i; A.315.A.4.i A 316.A.4. A.317.A.4.i; A.318.A.4.i; A.319.A.4 i; A.320.A.4.i; A.321.A.4.i A.323.A.4.i; A.324.A.4.i; A.325.A.4.i; A.326.A.4.i; A.327.A.4.i; A.328.A.4.i;
A.329.A.4.i; A.330.A.4.i; A.331.A.4.i; A.332.A.4.i; A.333.A.4.i; A.334.A.4.i;
A.335.A.4.i; A.336.A.4.i; A.337.A.4.i; A.338.A.4.i; A.339.A.4.i; A.340.A.4.i;
A.341.A.4.i; A.342.A.4.i; A.343.A.4.i; A.344.A.4.i; A.345.A.4.i; A.346.A.4.i; A.347.A.4.i; A.348.A.4.i; A.349.A.4.i; A.350.A.4.i; A.351.A.4.i; A.352.A.4.i;
A.353.A.4.i; A.354.A.4.i; A.355.A.4.i; A.356.A.4.1; A.357.A.4.i; A.358.A.4.i;
A.359.A.4.i; A.360.A.4.i; A.361.A.4.i; A.362.A.4.i; A.363.A.4.i; A.364.A.4.i;
A.365.A.4.i; A.366.A.4.i; A.367.A.4.i; A.368.A.4.i; A.369.A.4.i; A.370.A.4.i;
A.371.A.4.i; A.372.A.4.i; A.373.A.4.i; A.374.A.4.i; A.375.A.4.i; A.376.A.4.i; A.377.A.4.i; A.378.A.4.i; A.379.A.4.i; A.380.A.4.i; A.381.A.4.i; A.382.A.4i;
A.383.A.4.i; A.384.A.4.i; A.385.A.4.i; A.386.A.4.i; A.387.A.4.i; A.388.A.4.i;
A.389.A.4.i; A.390.A.4.i; A.391.A.4.i; A.392.A.4.i; A.393.A.4.i; A.394.A.4.i;
A.395.A.4.i; A.396.A.4.i; A.397.A.4.i; A.398.A.4.i; A.399.A.4.i; A.400.A.4.i;
A.401.A.4.i; A.402.A.4.i; A.403.A.4.i; A.404.A.4.i; A.405.A.4i; A.406.A.4.i; A.407.A.4.i; A.408.A.4.i; A.409.A.4.i; A.410.A.4.i; A.411.A.4.i; A.412.A.4.i;
A.413.A.4.i; A.414.A.4.i; A.415.A.4.i; A.416.A.4.i; A.417.A.4.i; A.418.A.4.i;
A.419.A.4.i; A.420.A.4i; A.421.A.4.i; A.422.A.4.i; A.423.A.4i; A.424.A.4.i;
A.425.A.4.i; A.426.A.4.i; A.427.A.4.i; A.428.A.4.i; A.429.A.4.i; A.430.A.4.i;
A.431.A.4.i; A.432.A.4.i; A.433.A.4.i; A.434.A.4.i; A.435.A.4.i; A.436.A.4.i; A.437.A.4.i; A.438.A.4.i; A.439.A.4.i; A.440.A.4.i; A.441.A.4.i; A.442.A.4.i;
A.443.A.4.i; A.444.A.4.i; A.445.A.4.i; A.446.A.4.i; A.447.A.4.i; A.448.A.4.i;
A.449.A.4.i; A.450.A.4.i; A.451.A.4.i; A.452.A.4.i; A.453.A.4.i; A.454.A.4.i;
A.455.A.4.i; A.456.A.4.i; A.457.A.4.i; A.458.A.4.i; A.459.A.4.i; A.460.A.4.i;
A.461.A.4.i; A.462.A.4.i; A.463.A.4.i; A.464.A.4.i; A.465.A.4.i; A.466.A.4.i; A.467.A.4.i; A.468.A.4.i; A.469.A.4.i; A.470.A.4.i; A.471.A.4.i; A.472.A.4.i;
A.473.A.4.i; A.474.A.4.i; A.475.A.4.i; A.476.A.4.i; A.477.A.4.i; A.478.A.4.i;
A.479.A.4.i; A.480.A.4.i; A.481.A.4.i; A.482.A.4.i; A.483.A.4.i; A.484.A.4.i;
A.485.A.4.i; A.486.A.4.i; A.487.A.4.i; A.488.A.4.i; A.489.A.4.i; A.490.A.4.i;
A.491.A.4.i; A.492.A.4.i; A.493.A.4.i; A.494.A.4.i; A.495.A.4.i; A.496.A.4.i; A.497.A.4.i; A.498.A.4i; A.499.A.4.i; A.500.A.4.i; A.501.A.4.i; A.502.A.4.i;
A.503.A.4.i; A.504.A.4.i; A.505.A.4.i; A.506.A.4.i; A.507.A.4.i; A.508.A.4.i;
A.509.A.4.i; A.510.A.4.i; A.511.A.4.i; A.512.A.4.i; A.512.A.4.i; A.513.A.4.i;
A.514.A.4i; A.515.A.4.i; A.516.A.4.i; A.517.A.4.i; A.518.A.4.i; A.519.A.4.i;
A.520.A.4.i; A.521.A.4.i; A.522.A.4.i; A.523.A.4.i; A.524.A.4.i; A.525.A.4.i; A.526.A.4.i; A.527.A.4.i; A.528.A.4.i; A.529.A.4.i; A.530.A.4.i; A.531.A.4.i;
A.532.A.4.i; A.533.A.4.i; A.534.A.4.i; A.535.A.4.i; A.536.A.4.i; A.537.A.4.i;
A.538.A.4.i; A.539.A.4.i; A.540.A.4.i; A.541.A.4.i; A.542.A.4.i; A.543.A.4.i;
A.544.A.4.i; A.545.A.4.i; A.546.A.4.i; A.547.A.4.i; A.548.A.4.i; A.549.A.4.i;
A.550.A.4.i; A.551.A.4.i; A.552.A.4.i; A.553.A.4.i; A.554.A.4.i; A.555.A.4.i; A.556.A.4.i; A.557.A.4.i; A.558.A.4.i; A.559.A.4.i; A.560.A.4.i; A.561.A.4.i;
A.562.A.4.i; A.563.A.4.i; A.564.A.4.i; A.565.A.4.i; A.566.A.4.i; A.567.A.4.i;
A.568.A.4.i; A.569.A.4.i; A.570.A.4.i; A.571.A.4.i; A.572.A.4.i; A.573.A.4.i;
A.574.A.4.i; A.575.A.4.i; A.576.A.4.i; A.577.A.4.i; A.578.A.4.i; A.579.A.4.i;
A.580.A.4.i; A.581.A.4.i; A.582.A.4.i; A.583.A.4.i; A.584.A.4.i; A.585.A.4.i; A.586.A.4.i; A.587.A.4.i; A.588.A.4.i; A.589.A.4.i; A.590.A.4.i; A.591.A.4.i;
A.592.A.4.i; A.593.A.4.i; A.594.A.4.i; A.595.A.4.i; A.596.A.4.i; A.597.A.4.i;
A.598.A.4.i; A.599.A.4.i; A.600.A.4.i; A.601.A.4i; A.602.A.4.i; A.603.A.4.i; A.604.A.4.i; A.605.A.4.i; A.606.A. ,4.i; A.607.A.4.i A.608.A.4.i; A.609.A.4.i
A.610.A.4.i; A.611.A.4.i; A.612.A, .4i; A.613.A.4.i A.614.A.4.i; A.615.A.4.i
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A.646.A.4.i; A.647.A.4.i; A.648.A •4i; A.649.A.4.i A.650.A.4.i; A.651.A.4.i
A.652.A.4.i; A.653.A.4.i; A.654.A •4i; A.655.A.4i A.656.A.4.i; A.657.A.4.i A.658.A.4.i; A.659.A.4.i; A.660.A, ,4.i; A.2.A.lli; A.3.A.lli; A.4.A.lli;
A.5.A.1U; A.6.A.lli; A.7.A.lli; A.9.A.lli; A.lO.A.lli; A.15.A.lli;
A.100.A.lli; A.lOl.A.lli; A.102. A.lli; A.103.A.lli; A.104.A.lli
A.105.A.lli; A.lOό.A.lli; A.107. A.lli; A.108.A.lli; A.109.A.lli
A.110.A.ll.i; A.lll.A.ll.i; A.112. A.lli; A.113.A.lli; A.li4.A.lli A.115.A.ll.i; A.116.A.ll.i; A.117. A.lli; A.llδ.A.lli; A.π9.A.lli
A.120.A.lli; A.121.A.lli; A.122. A.ll.i; A.123.A.lli; A.124.A.lli
A.125.A.lli; A.126.A.lli; A.127. A.ll.i; A.128.A.lli; A.129.A.lli
A.130.A.lli; A.131.A.lli; A.132. A.ll.i; A.133.A.lli; A.134.A.lli
A.135.A.lli; A.136.A.lli; A.137. A.ll.i; A.138.A.lli; A.139.A.lli A.140.A.lli; A.141.A.lli; A.142. A.ll.i; A.143.A.lli; A.144.A.lli
A.145.A.lli; A.146.A.lli; A.147. A.ll.i; A.148.A.lli; A.149.A.lli
A.150.A.1U; A.151.A.lli; A.152. A.ll.i; A.153.A.lli; A.154.A.lli
A.155.A.lli; A.156.A.lli; A.157. A.ll.i; A.158.A.lli; A.159.A.ll.i
A.160.A.lli; A.lOl.A.lli; A.162. A.ll.i; A.163.A.lli; A.164.A.lli A.165.A.lli; A.166.A.lli; A.167. A.ll.i; A.168.A.lli; A.169.A.lli
A.170.A.lli; A.171.A.lli; A.172. A.ll.i; A.173.A.lli; A.174.A.lli
A.175.A.lli; A.176.A.lli; A.177. A.ll.i; A.178.A.lli; A.179.A.lli
A.180.A.lli; A.lδl.A.lli; A.182. A.ll.i; A.183.A.lli; A.184.A.lli
A.185.A.lli; A.186.A.lli; A.187. A.ll.i; A.188.A.lli; A.189.A.lli A.190.A.lli; A.191.A.lli; A.192. A.ll.i; A.193.A.lli; A.194.A.lli
A.195.A.lli; A.196.A.lli; A.197. A.ll.i; A.198.A.lli; A.199.A.lli
A.200.A.lli; A.201.A.lli; A.202. A.ll.i; A.203.A.lli; A.204.A.lli
A.205.A.lli; A.206.A.lli; A.207. A.ll.i; A.208.A.lli; A.209.A.lli
A.210.A.lli; A.211.A.lli; A.212. .lli; A.213.A.lli; A.214.A.lli A.215.A.lli; A.216.A.lli; A.217. A.ll.i; A.218.A.lli; A.219.A.lli
A.220.A.lli; A.221.A.lli; A.222. ,A.lli; A.223.A.lli; A.224.A.lli
A.225.A.lli; A.226.A.lli; A.227..AH.i; A.228.A.lli; A.229.A.lli
A.230.A.lli; A.231.A.lli; A.232, •A.lli; A.233.A.lli; A.234.A.lli
A.235.A.lli; A.236.A.lli; A.237, •A.ll.i; A.238.A.lli; A.239.A.lli A.240.A.lli; A.241.A.lli; A.242. •A.ll.i; A.243.A.lli; A.244.A.lli
A.245.A.lli; A.246.A.lli; A.247, •A.ll.i; A.248.A.lli; A.249.A.lli
A.250.A.lli; A.251.A.lli; A.252, •A.ll.i; A.253.A.lli; A.254.A.lli
A.255.A.lli; A.256.A.lli; A.257, .A.ll.i; A.258.A.lli; A.259.A.ll.i
A.260.A.lli; A.261.A.lli; A.262, •A.ll.i; A.263.A.lli; A.264.A.lli A.265.A.lli; A.266.A.lli; A.267, •A.ll.i; A.268.A.lli; A.269.A.lli
A.270.A.lli; A.271.A.lli; A.272, •A.ll.i; A.273.A.lli; A.274.A.lli
A.275.A.lli; A.276.A.lli; A.277, •A.lli; A.278.A.lli; A.279.A.lli A.280. AH. A.281. All. A.282.A. ll.i; A.283. A.ll A.284. A.ll.i A 285. AH. A.286. A l. A.287.A. ll.i; A.288. A.ll A.289. All. A.290.A.11. A.291 All. A.292.A. Hi; A.293. A l A.294. All. A.295. AH. A.296 All. A.297.A. ll.i; A.298 All A.299. All. A.300. AH. A.301. AH. A.302.A ll.i; A.303 All A.304. All. A.305.A.11. A.306 AH. A.307.A. ll.i; A.308 A l A.309. All. A.310.A.11. A.311 All. A.312.A ll.i; A.313 A l A.314. All. A.315.A.11. A.316. AH. A.317.A ll.i; A.318 All A.319. All. A.320.A.11. A.321. AH. A.323.A Hi; A.324 All A.325. All. A.326. AH. A.327. AH. A.328.A. ll.i; A.329 All A.330. All. A.331.A.11. A.332. A.11. A.333.A. Hi; A.334 All A.335. All. A. ,336.A.ll. A.337. AH. A.338.A. Hi; A.339 A l A.340. All. A..341.A.11. A.342. AH. A.343.A. Hi; A.344 A l A.345. All. A.346.A.11. A.347. A.11. A.348.A. Hi; A.349 A l A.350. A l. A.351.A.11. A.352. A.11. A.353.A. ll.i; A.354 All A.355. A l. A. ,356. AH. A.357. AH. A.358.A. Hi; A.359 A l A.360. All. A.361.A.11. A.362. A.ll. A.363.A. Hi; A.364 A l A.365. All. A.366.A.11. A.367. All. A.368.A. ll.i; A.369 A l A.370. A l. A.371.A.11. A.372. A.ll. A.373.A. ll.i; A.374 A l A.375. All. A.376.A.11. A.377. A.ll. A.378.A ll.i; A.379 All A.380. All. A..381.A.11. A.382. A.ll. A.383.A ll.i; A.384 All A.385. All. A..386.A.11. A.387. AH. A.388.A. ll.i; A.389 All A.390. All. A..391.A.11. A.392. A.ll. A.393.A. Hi; A.394 All A.395. All. A..396.A.11. A.397. A.ll. A.398.A. Hi; A.399 All A.400. All. A. •401.A.11. A.402. All. A.403.A. Hi; A.404 All A.405. All. A. •406.A.11, A.407. All. A.408.A ll.i; A.409 All A.410, All. A..411.A.11. A.412. All. A.413.A. ll.i; A.414 A l A.415. All. A, •416.A.11, A.417. All. A.418.A ll.i; A.419 A l A.420, All. A, •421.A.11, A.422. A l. A.423.A. ll.i; A.424 A l A.425, All. A, •426.A.11, A.427, All. A.428.A. ll.i; A.429 A l A.430. A l. A, .431.A.11, A.432. A l. A.433.A. ll.i; A.434 A l A.435. All. A, .436. A.11 A.437, A l. A.438.A. Hi; A.439 A l A.440, All. A, .441.A.11, A.442. All. A.443.A. ll.i; A.444 All A.445. All. A, .446. A.11 A.447, All. A.448.A. ll.i; A.449 A l A.450. All. A .451.A.11 A.452. A.ll. A.453.A. Hi; A.454 AH A.455. All. A, .456.A.11 A.457, All. A.458.A. ll.i; A.459 A l A.460. All. A .461.A.11 A.462, All. A.463.A. Hi; A.464 AH A.465, All. A .466.A.11 A.467. All. A.468.A. Hi; A.469 All A.470, All. A .471. A.11 A.472, AH. A.473.A. ll.i; A.474 A l A.475, All. A .476.A.11 A.477 A l. A.478.A. Hi; A.479 A l A.480, All. A 481.A.11 A.482. A.ll. A.483.A. Hi; A.484 A l A.485, All. A 486.A.11 A.487. All. A.488.A. ll.i; A.489 A l A.490. All. A 491.A.11 A.492. All. A.493.A. ll.i; A.494 A l A.495, All. A, 496.A.11 A.497. All. A.498.A. ll.i; A.499 A l A.500 All. A •501.A.11. A.502. All. A.503.A. ll.i; A.504 A l A.505. All. A 506.A.11 A.507, All. A.508.A. ll.i; A.509 A l A.510 AH. A .511.A.11 A.512 All. A.512.A. ll.i; A.513 A l A.514 A l. A.515.A.111; A.516.A.1U; A 517.A.lli; A.518.A.lli; A.519.A.lli; A520AH1; A.521.A.lli; A 522.A.lli; A.523.A.lli; A.524.A.lli; A.525.A.lli; A.526.A.lli; A 527A.lli; A.528.A.lli; A.529.A.lli; A.530.A.lli; A.531.A.lli; A 532A.lli; A.533.A.lli; A.534.A.lli; A535AH1; A.536.A.lli; A 537.A.lli; A.538.A.lli; A.539.A.lli; A.540.A.lli; A.541.A.lli; A.542.A.lli; A.543.A.lli; A.544.A.lli; A.545.A.lli; A.546.A.1U; A 547AH.i; A.548.A.lli; A.549.A.lli; A.550.A.lli; A.551.A.lli; A 552.A.1U; A.553.A.lli; A.554.A.lli; A.555.A.lli; A.556.A.lli; A.557.A.lli; A.558.A.lli; A.559.A.lli; A.560.A.lli; A.561.A.lli; A.562AH.i; A.563.A.lli; A.564.A.lli; A565A.lli; A566.AH.i; A.567.AH1; A568A.lli; A.569.A.1U; A.570. A.ll.i; A.571.A.1U; A.572A.lli; A.573.A.lli; A.574.A.lli; A.575.A.lli; A.576.A.lli; A. •577.A.lli; A.578A.lli; A.579.A.lli; A580AH.i; A.581.A.lli; A. •582.A.lli; A.583.A.lli; A.584.A.lli; A585AH1; A.586.A.lli; A. •587.A.lli; A.588.A.lli; A.589.A.lli; A.590.A.lli; A.591.A.lli; A. •592.A.lli; A.593.A.lli; A.594.A.lli; A595A111; A.596.A.lli; A..597 Alii; A.598.A.lli; A.599 A.ll.i; A.όOOA.lli; A.601.A.H.i; A. ,602.A.lli; A.603.A.lli; A.604.A.lli; A.605.A.lli; A.606.A.lli; A. ,607AH.i; A.608.A.lli; A.609 A.lli; A.610.A.lli; A.611.A.lli; A..612.A.1U; A.613.A.lli; A.614.A.lli; A615A.111; A.616.A.lli; A. ,617.A.lli; A.618.A.lli; A.619.A.lli; A.620.A.lli; A.621.A.1U; A. ,622.A.lli; A.623.A.lli; A.624.A.lli; A.625.A.lli; A.626.A.lli; A..627.A.1U; A.628.A.lli; A.629 A.ll.i; A630AH1; A631.A111; A. ,632AH.i; A633AH.i; A.634.A.lli; A.635.A.lli; A.636.A.lli; A, ,637.A.lli; A638A.lli; A.639.A.lli; A640A.lli; A.641.A.lli; A. •642A.lli; A.643.A.lli; A.644.A.lli; A.645.A.lli; A.646.A.1U; A, .647AH.i; A.648.A.lli; A.649.A.H.i; A.650.A.lli; A.651.A.lli; A..652AH.i; A.653.A.lli; A.654.A.lli; A.655.A.lli; A.656.A.lli; A .657AH.i; A.658.A.lli; A.659.A.lli; A.660.A.lli; A.2.B.41; A.3.B. ,4.i; A.4.B.4.i; A.5.B.4.i; A.6.B.41; A.7.B.4 i; A.9.B.4.i; A.10.B.4.i; A.15.B.41; A.lOO.B i; A.101.B.4.i; A.102.B.4.i; A. 103.B.4.i;
A.104.B.4.i, A.105.B.4.i A.106.B.4. A.107.B.4.Ϊ A.108.B.4.i A.109.B.4. i;
A.110.B.4.i, A.lll.B.4.i AH2.B.4. A.113.B.4.i A.114.B.4.i A.115.B.4. i
A116.B.41, A.117.B.4.i A.118.B.4. A.119.B.4.i A.120.B.4.i A.121.B.4. i
A122.B.4.i. A.123.B.41 A.124.B.4. A.125.B.4.i A.126.B.4.i A127.B.4 i
A128.B.4.i/ A.129.B.4.i A.130.B.4. A.131.B.4.i A132.B.4.i A.133.B.4. i
A134.B.4.i/ A.135.B.4.i A.136.B.4. A.137.B.4.i. A.138.B.4.i A.139.B.4. i
A140.B.41 A.141.B.4.i A.142.B.4. A.143.B.4.i A144.B.4.i A.145.B.4 i
A.146.B.4.i A.147.B.4.i A.148.B.4. A.149.B.4.i A.150.B.4.i A.151.B.4 i
A.152.B.4.i A.153.B.41 A154.B.4. A.155.B.4.Ϊ A.156.B.4.Ϊ A157.B.4 i
A.158.B.4.i A159.B.41 A160.B.4. A.161.B.4.i A.162.B.4.Ϊ A.163.B.4 i
A.164.B.4.i A.165.B.4.i A.166.B.4. A.167.B.4.i A.168.B.4.Ϊ A.169.B.4 i
A.170.B.4.i A.171.B.41 A172.B.4. A.173.B.4.i A.174.B.4.Ϊ A.175.B.4 i
A176.B.4.i A.177.B.4.i A178.B.4. A.179.B.4.i A.180.B.4.Ϊ A181.B.4 i
A.182.B.4.i A.183.B.4.i A184.B.4. A.185.B.4.i A.186.B.4.i. A187.B.4 i
A.188.B.4.i , A.189.B.4.i A.190.B.4. A.191.B.4.i A.192.B.4.i A.193.B.4 i
A194.B.41 ; A.195.B.4.i A196.B.4. A.197.B.4.i A.198.B.4.i A.199.B.4 i A.200.B.4.i; A.201.B.4.i; A.202.B.4.i; A.203.B.4.i; A.204.B.4.i; A.205.B.41;
A206.B.41; A.207.B.4.i; A.208.B.4.i; A.209.B.4.i; A.210.B.4.i; A.211.B.4.i;
A212.B.4.i; A.213.B.4.i; A214.B.4.i; A.215.B.4.i; A.216.B.4.i; A217.B.4.i;
A218.B.4.i; A.219.B.4.i; A220.B.4.i; A.221.B.4.i; A222.B.4.i; A.223.B.41; A.224.B.41; A.225.B.4.i; A.226.B.4.i; A.227.B.4.i; A228.B.4.i; A229.B.4.i;
A230.B.4.i; A.231.B.41; A232.B.41; A.233.B.4.i; A234.B.41; A235.B.41;
A236.B.4.i; A.237.B.4.i; A238.B.4.i; A.239.B.4.i; A.240.B.4.i; A.241.B.4.i;
A.242.B.41; A.243.B.4.i; A244.B.4.i; A.245.B.4.i; A.246.B.41; A.247.B.4.i;
A248.B.4.i; A.249.B.4.i; A.250.B.41; A.251.B.4.i; A252.B.4.i; A253.B.4.i; A254.B.4.i; A.255.B.4.i; A256.B.4.i; A.257.B.4.i; A258.B.4.i; A259.B.4.i;
A260.B.4.i; A.261.B.4.i; A.262.B.41; A.263.B.4.i; A264.B.4.i; A.265.B.4i;
A266.B.4.i; A267.B.4.i; A268.B.4.i; A.269.B.4.i; A270.B.4.i; A271.B.4.i;
A.272.B.41; A.273.B.4.i; A274.B.4.i; A.275.B.4.i; A.276.B.4.i; A277.B.4.i;
A.278.B.41; A.279.B.4.i; A280.B.4.i; A.281.B.4.i; A.282.B.4.i; A283.B.4.i; A284.B.4.i; A.285.B.4.i; A286.B.4.i; A.287.B.4.i; A288.B.4.i; A.289.B.41;
A290.B.4.i; A.291.B.4.i; A.292.B.41; A.293.B.4.i; A294.B.4.i; A295.B.4.i;
A296.B.4.i; A.297.B.41; A298.B.4.i; A.299.B.4.i; A.300.B.4.i; A.301.B.4.i;
A302.B.4.i; A.303.B.4.i; A.304.B.4.i; A.305.B.4.i; A.306.B.4.i; A307.B.4.i;
A308.B.41; A.309.B.4.i; A.310.B.4.i; A.311.B.4.i; A.312.B.4.i; A313.B.4.i; A314.B.4.i; A.315.B.4.i; A316.B.41; A.317.B.4.i; A.318.B.4.i; A.319.B.4.i;
A320.B.4.i; A.321.B.4.i; A.323.B.4.i; A.324.B.4.i; A.325.B.4.i; A.326.B.41;
A.327.B.4.i; A.328.B.4.i; A.329.B.4.i; A.330.B.4.i; A.331.B.4.i; A332.B.4.i;
A.333.B.4.i; A.334.B.4.i; A335.B.4.i; A.336.B.4.i; A.337.B.4.i; A.338.B.4.i;
A.339.B.41; A.340.B.4.i; A341.B.4.i; A.342.B.4.i; A343.B.4.i; A.344.B.41; A345.B.4.i; A.346.B.4.i; A347.B.41; A.348.B.4i; A.349.B.4.i; A.350.B.4.i;
A351.B.4.i; A.352.B.4.i; A.353.B.4.i; A.354.B.4.i; A.355.B.4.i; A356.B.4.i;
A.357.B.4.i; A.358.B.4.i; A359.B.4.i; A.360.B.4.i; A.361.B.4.i; A362.B.4.i;
A363.B.4.i; A.364.B.4.i; A.365.B.4.i; A.366.B.4.i; A.367.B.4.i; A.368.B.4.i;
A369.B.41; A.370.B.4.i; A.371.B.4.i; A.372.B.4.i; A.373.B.4.i; A.374.B.4.i; A.375.B.4.i; A.376.B.4.i; A377.B.4.i; A.378.B.4.i; A.379.B.4.i; A.380.B.4.i;
A381.B.4.i; A.382.B.4.i; A383.B.4.i; A.384.B.4.i; A.385.B.4.i; A.386.B.41;
A.387.B.4.i; A.388.B.4.i; A.389.B.4.i; A.390.B.4.i; A.391.B.4.i; A.392.B.41;
A.393.B.4.i; A.394.B.4.i; A.395.B.4.i; A.396.B.4.i; A397.B.4.i; A.398.B.4.i;
A.399.B.4.i; A.400.B.4.i; A.401.B.4.i; A.402.B.4.i; A.403.B.4.i; A.404.B.41; A.405.B.41; A.406.B.4.i; A.407.B.4.i; A.408.B.4.i; A409.B.4.i; A410.B.4i;
A411.B.4.i; A.412.B.4.i; A413.B.4.i; A.414.B.4.i; A415.B.4.i; A416.B.4.i;
A417.B.4.i; A.418.B.4.i; A419.B.4.i; A.420.B.4.i; A.421.B.4i; A.422.B.41;
A.423.B.4.i; A.424.B.4.i; A.425.B.4.i; A.426.B.4.i; A.427.B.4.i; A.428.B.4.i;
A.429.B.4.i; A.430.B.41; A431.B.4.i; A.432.B.4.i; A.433.B.4.i; A.434.B.41; A.435.B.4.i; A.436.B.4.i; A437.B.4.i; A.438.B.4.i; A.439.B.4.i; A.440.B.4.i;
A.441.B.4.i; A.442.B.4.i; A.443.B.4.i; A.444.B.4.i; A.445.B.4.i; A.446.B.4.i;
A447.B.4.i; A.448.B.4.i; A449.B.4.i; A.450.B.4.i; A.451.B.4.i; A.452.B.41;
A.453.B.4.i; A.454.B.4.i; A.455.B.4.i; A.456.B.4.i; A.457.B.4.i; A.458.B.4.i;
A459.B.4.i; A.460.B.4.i; A.461.B.4.i; A.462.B.4.i; A.463.B.4.i; A.464.B.4.i; A465.B.41; A.466.B.4.i; A.467.B.4.i; A.468.B.4.i; A.469.B.4.i; A.470.B.4.i;
A471.B.4.i; A.472.B.4.i; A473.B.4.i; A.474.B.4.i; A.475.B.4.i; A.476.B.4.i;
A.477.B.41; A.478.B.4.i; A.479.B.4.i; A.480.B.4.i; A481.B.4.i; A.482.B.4.i; A 483.B.41; A.484 B.4.i; A.485.B.4. A.486. B.4 A.487.B.4. A.488.B.4.i
A 489.B.41; A.490 B.4.i; A.491.B.4. A.492. B.4 A.493.B.4. A494.B.4.
A, 495.B.4.i; A.496. B.4.i; A.497.B.4. A.498. B.4 A499.B.4. A.500.B.4.
A.501.B.4.i; A.502. B.4.i; A503.B.4. A.504. B.4. A505.B.4. A.506.B.4.
A.507.B.4.i; A.508. B.4.i; A509.B.4. A.510. B.4. A.511.B.4. A.512.B.4.
A.512.B.4.i; A.513. B.4.i; A514.B.4. A.515. B.4. A.516.B.4. A.517.B.4.
A.518.B.4.i; A.519. B.4.i; A520.B.4. A.521. B.4. A.522.B.4. A.523.B.4.
A.524.B.4.i; A.525. B.4.i; A.526.B.4. A.527. B.4. A.528.B.4. A.529.B.4.
A.530.B.4.i; A.531. B.4.i; A.532.B.4. A.533. B.4. A.534.B.4. A535.B.4.
A.536.B.4.i; A.537, B.4.i; A538.B.4. A.539. B.4. A.540.B.4. A.541.B.4.
A.542.B.4.i; A.543. B.4.i; A544.B.4. A.545. B.4. A.546.B.4. A547.B.4.
A.548.B.4.i; A.549. B.4.i; A550.B.4. A.551. B.4. A552.B.4. A553.B.4.
A.554.B.4.i; A.555. B.4.i; A.556.B.4. A.557. B.4. A.558.B.4. A.559.B.4.
A.560.B.4.i; A.561. B.4.i; A.562.B.4. A.563. B.4. A564.B.4. A565.B.4.
A.566.B.4.i; A.567. B.4.i; A.568.B.4. A.569. B.4. A.570.B.4. A.571.B.4.
A.572.B.4.i; A.573. B.4.i; A.574.B.4. A.575. B.4. A.576.B.4. A.577.B.4.
A.578.B.4.i; A.579. B.4.i; A580.B.4. A.581. B.4. A.582.B.4. A.583.B.4.
A.584.B.41; A.585. B.4.i; A.586.B.4, A.587. B.4. A.588.B.4. A.589.B.4.
A.590.B.4.i; A.591. B.4.i; A.592.B.4. A.593. B.4. A.594.B.4. A.595.B.4.
A.596.B.4.i; A.597 B.4.i; A.598.B.4. A.599. B.4. A.600.B.4. A.601.B.4.
A.602.B.4.i; A.603, B.4.i; A.604.B.4. A.605. B.4. A.606.B.4. A.607.B.4.
A.608.B.41; A.609 B.4.i; A610.B.4, A.611. B.4. A.612.B.4. A.613.B.4.
A.614.B.4.i; A.615 B.4.i; A616.B.4, A.617. B.4. A618.B.4. A.619.B.4.
A.620.B.4.i; A.621 B.4.i; A.622.B.4 A.623. B.4. A.624.B.4. A.625.B.4.
A.626.B.41; A.627 B.4.i; A628.B.4. A.629. B.4. A.630.B.4. A.631.B.4.
A.632.B.4.i; A.633 B.4.i; A.634.B.4 A.635. B.4. A.636.B.4. A.637.B.4.
A.638.B.4.i; A.639 B.4.i; A.640.B.4 A.641. B.4. A.642.B.4. A.643.B.4.
A, 644.B.4.i; A.645 B.4.i; A.646.B.4 A.647. B.4. A.648.B.4. A.649.B.4.
A ,650.B.4i; A.651 ,B.4.i; A.652.B.4 A.653. B.4. A.654.B.4. A655.B.4.
A, 656.B.41; A.657.B.4.i; A658.B.4.i; A.659.B.4.i; A.660.B.4. A.2.BH.i;
A. 3.B.111; A.4.B.lli; A.5.B.lli; A.ό.B.lli; A.7.Blli; A.9.B.lli; AlO.BH.i;
A 15.B.lli; A.lOO.B.lli; A.lOl.BH.i; A102.B.lli; A.103.B.lli; A104.BH.i;
A 105.B11. A.lOO.B.lli A107.BH.i; A108.B.lli A.109.B.lli; AHO.BH.i
A lll.B.ll. A.m.B.lli A.113.B.lli; A.114.B.ll.i AH5.B.111; A.llό.B.ll.i
A 117.B11. A.118.B.lli. A.119.B.lli; A120.B.lli A.121.B.lli; A122.BH.i
A 123.B11. A124.BH.i A125.BH.i; A126.BH.i A.127.B.lli; A.128.B.lli.
A 129.B11. A130.BH.i A.131.B.lli; A.132.B.lli. A.133.B.lli; A.134.B.lli
A 135.B.11. A.136.B.lli A.137.B.lli; A.138.B.lli. A.139.B.1U; A.140.BH.i
A 141.B.11. A142.B.lli A.143.B.lli; A.144.B.lli. A.145.B.lli; A.146.B.lli.
A 147.B11. A148.BH.i A.149.B.lli; A.150.B.lli. A.151.B.lli; A.152.B.lli.
A 153.B11. A.154.BH.i A.155.B.lli; A156.B.lli A157.B.lli; A.158.B.lli.
A, 159.B11. A.lOO.B.lli Alόl.BH.i; A.162.B.lli A.163.B.lli; A.164.B.lli.
A, .165.B.11. A166.BH.i A.167.B.lli; A.168.B.lli A.169.B.lli; A170.BH1
A. 171.B11. A172.BH.i A.173.B.lli; A.174.B.lli A.175.B.lli; A.176.B.lli
A 177.B11. A.178.B.lli A.179.B.lli; A.180.B.lli A.181.B.lli; A.182.B111
A 183.B.11. A184.B.lli A.185.B.lli; A.186.B.lli. A187.B.lli; A.188.B.lli
A 189.B11. A190.BH.i A.191.B.lli; A.192.B.lli A.193.B.lli; A194.B.lli A 195.B.11. A.196.B.11. i; A.197 B.ll.i; A.198.B.1U; A.199. B.ll i; A.200.B11, i; A 201.B.11. A.202.B.11. i; A.203. B.ll.i; A.204.B.lli; A.205. B.ll i; A.206.B.11. i; A.207.B11 A.208.B.11. i; A.209. B.ll.i; A.210.B.lli; A.211. B.ll. i; A.212.B.11. i;
A, .213.B.11. A.214.B.11. i; A.215. B.ll.i; A.216.B.1U; A.217 B.ll i; A218.B.H i; A, 219.B11. A.220.B.11. i; A.221 B.ll.i; A.222.B.1U; A.223 B.ll. i; A224.B.H i; A .225.B11. A.226.B.11. i; A.227 B.ll.i; A.228.B.lli; A.229. B.ll i; A230.B.H i; A..231.B.11. A.232.B.11. i; A.233. B.ll.i; A.234.B.lli; A.235. B.ll. i; A.236.B.11. i; A. •237.B.11. A.238.B.11. i; A.239 B.ll.i; A.240.B.lli; A.241. B.ll. i; A242.B.H i; A.243.B.11. A.244.B11. i; A.245. B.ll.i; A246.BH.i; A.247. B.ll i; A.248.B.11. i; A, 249.B.H A.250.B.11. i; A.251. B.ll.i; A.252.B.lli; A.253. B.ll i; A.254.B.11. i; A.255.B11, A.256.B.11. i; A.257, B.ll.i; A258.B.lli; A.259. B.ll i; A.260.BH, i; A.261.B11. A.262.B.11. i; A.263. B.ll.i; A.264.Blli; A.265. B.ll i; A.266.B.11. i; A, 267.B11 A.268.B.11. i; A.269. B.ll.i; A.270.B.lli; A.271. B.ll i; A.272.B.H i; A, .273.B11, A.274.B11. i; A.275. B.ll.i; A.276.B.lli; A.277. B.ll i; A278.BH, i; A .279.B.11. A.280.B.11. i; A.281. B.ll.i; A.282.B.lli; A.283. B.ll i; A.284.B.11, i; A •285.B.11 A.286.B.11. i; A.287. B.ll.i; A.288.B.lli; A.289. B.ll i; A.290.B.11. i; A •291.B.11 A.292.B.11. i; A.293. B.ll.i; A.294.B.lli; A.295. B.ll i; A.296.B.11. i; A •297.B11 A.298.B.11. i; A.299. B.ll.i; A.300.B.lli; A.301. B.ll i; A.302.B.11. i; A •303.B11 A.304.B.11. i; A.305. Bill; A.306.B.lli; A.307, B.ll i; A.308.B.11, i; A •309.B11 A.310.B.11. i; A.311. B.ll.i; A.312.B.lli; A.313. B.ll i; A.314.B.11. i; A •315.B.11 A.316.B.11. i; A.317. B.ll.i; A.318.B.lli; A.319, B.ll i; A.320.B.11. i; A..321.B.11 A.323.B.11. i; A.324. B.ll.i; A.325.B.lli; A.326. B.ll i; A.327.BH i; A..328.B.11 A.329.B.11. i; A.330. B.ll.i; A.331.B.lli; A.332. B.ll i; A.333.B.11. i; A..334.B11 A.335.B.11. i; A.336. B.ll.i; A.337.B.lli; A.338, B.ll i; A.339.BH i; A..340.B11 A.341.B.11. i; A.342. B.ll.i; A.343.B.lli; A.344, B.ll i; A.345.B.11. i; A..346.B11 A.347.B.11. i; A.348. B.ll.i; A.349.B.lli; A.350, B.ll i; A.351.B.11. i; A..352.B.11 A.353.B.11. i; A.354. B.ll.i; A.355.B.lli; A.356, B.ll i; A.357.B.11. i; A..358.B11 A.359.B.11. i; A.360. B.ll.i; A.361.B.1U; A.362, B.ll i; A.363.B.11. i; A..364.B.11 A.365.B.11. i; A.366. B.ll.i; A.367.B.lli; A.368 B.ll i; A.369.B.11. i; A, .370.B11 A.371.B.11. i; A.372. B.ll.i; A.373.B.lli; A.374 B.ll i; A.375.B.11. i; A, .376.B11 A.377.B.11.1; A.378. B.ll.i; A.379.B.lli; A.380 B.ll i; A.381.B.11 i; A, .382.B.11 A.383.B11. i; A.384, B.ll.i; A.385.B.lli; A.386 B.ll i; A.387.B.11 i; A 388.B.11 A.389.B.11. i; A.390, B.ll.i; A.391.B.lli; A.392 B.ll i; A.393.B.11 i; A .394.B.11 A.395.B.11. i; A.396 B.ll.i; A.397.B.lli; A.398 B.ll i; A.399.B.11 i; A •400.B11 A.401.B.11. i; A.402, B.ll.i; A.403.B.lli; A.404 B.ll i; A.405.B.11 i; A ..406.B.11 A.407.B.11. i; A.408.B.ll.i; A.409.B.lli; A.410 B.ll i; A.411.B.11 i; A 412.B.11 A.413.B.11 i; A.414.B.ll.i; A.415.B.lli; A.416 B.ll A.417.B.11 i; A .418.B.11 A.419.B.11 i; A.420.B.ll.i; A.421.B.1U; A.422 B.ll A.423.B.11 i; A ..424.B.11 A.425.B.11 i; A.426.B.ll.i; A427.B.lli; A.428 B.ll A.429.B.11 i; A ..430.B.11 A.431.B.11 i; A.432 •B.ll.i; A.433.B.lli; A.434 B.ll A.435.B.11 i; A 436.B11 A.437.B.11 i; A.438.B.ll.i; A.439.B.lli; A.440 B.ll A.441.B.11 •i; A ..442.B.11 A.443.B.11 i; A.444.B.ll.i; A.445.B.lli; A.446 B.ll A.447.B.11 i; A ..448.B.11 A.449.B.11 i; A.450.B.ll.i; A.451.B.lli; A.452 B.ll i; A.453.B.11 i; A .454.B.11 A.455.B.11 i; A.456 B.ll.i; A457.B.lli; A.458 B.ll i; A459.B.11 i; A 460.B11 A.461.B.11 i; A.462 B.ll.i; A.463.B.lli; A.464 B.ll i; A.465.B.11 i; A .466.B11 A.467.B11 i; A.468 B.ll.i; A.469.B.lli; A.470 B.ll i; A.471.B.11 i; A 472.B.11 A.473.B.11 i; A.474 B.ll.i; A.475.B.lli; A.476 B.ll i; A.477.B.11 i; A.478. B.ll.i; A.479.B.lli; A.480.BH A481.B.11 A.482.B.11. A.483. B.ll
A.484 B.ll.i; A.485.B.lli; A.486.BH A.487.B.11 A.488.B.11. A.489. B.ll
A.490. B.ll.i; A.491.BH.i; A.492.BH A493.BH. A.494.B.11. A.495. B.ll
A.496. B.ll.i; A.497.BH.i; A.498.BH A499.BH. A.500.B.11. A.501. B.ll
A.502 B.ll.i; A.503.Blli; A.504.B11 A.505.B11. A.506.B.11. A.507. B.ll
A.508. B.lli; A.509.B1U; A.510.B11 A511.B11. A.512.B.11. A.512. B.ll
A.513. B.ll.i; A.514.BH.i; A.515.BH A.516.B.11. A.517.B.11. A.518. B.ll
A.519. B.ll.i; A.520.BH.i; A.521.B.11 A.522.B.11. A.523.B.11. A524. B.ll
A.525. B.ll.i; A.526.Blli; A.527.B.11 A528.B11. A.529.B.11. A.530. B.ll,
A.531. B.ll.i; A.532.BH.i; A.533.B.11 A534.B11. A.535.B.11. A.536. B.ll
A.537, B.ll.i; A.538.BH.i; A.539.B.11 A.540.B.11 A541.BH. A.542. B.ll.
A.543. B.ll.i; A.544.Blli; A.545.B.11 A546.BH. A547.B11. A.548. B.ll.
A.549 B.ll.i; A.550.BH.i; A.551.B.11 A.552.B.11 A.553.B11. A.554. B.ll.
A.555 B.ll.i; A.556.BH.i; A.557.B.11 A.558.B11. A559.B11. A.560. B.ll.
A.561. B.ll.i; A.562.BH.i; A.563.B.11 A.564.B11. A.565.B.11. A.566. B.ll.
A.567. B.ll.i; A.568.BH.i; A.569.B.11 A.570.B11. A571.B11. A.572. B.ll.
A.573.B.ll.i; A.574.BH.i; A.575.B.11 A.576.B11. A.577.B.11. A.578. B.ll,
A.579 Bill; A.580.B.lli; A.581.B.11 A582.B11. A.583.B.11. A.584. B.ll.
A.585..B.ll.i; A.586.Blli; A.587.B.11 A588.B11. A.589.B.11. A.590. B.ll.
A.591..B.ll.i; A.592.BH.i; A.593.B.11 A.594.B11. A.595.B.11. A.596. B.ll,
A.597..B.ll.i; A.598.BH.i; A.599.B.11 A.600.B.11. A.601.B.11. A.602. B.ll,
A.603..B.ll.i; A.604.B.lli; A.605.B.11 A.606.BH. A.607.B.11. A.608. B.ll
A.609..B.ll.i; A.όlO.B.lli; A.611.B.11 A.612.B.11. A.613.B.11. A.614. B.ll
A.615..B.ll.i; A.616.BH.i; A.617.B.11 A.618.B.11. A.619.B.11. A.620. B.ll
A.621..B.ll.i; A.622.BH.i; A.623.B.11 A.624.B.11. A.625.B.11. A.626. B.ll,
A.627..B.ll.i; A.628.B1U; A.629.B.11 A.630.B11. A.631.B.11. A.632. B.ll
A.633..B.ll.i; A.634.Blli; A.635.B.11 A.636.B11. A.637.B11. A.638. B.ll
A.639..Bill; A.640.B.lli; A.641.B.11 A.642.B11. A.643.B.11. A.644. B.ll
A.645..B.ll.i; A.646.BH.i; A.647.B11 A.648.B11. A.649.B.11. A.650. B.ll
A.651, .B.ll.i; A.652.BH.i; A.653.B.11 A654.B11. A.655.B.11. A.656. B.ll
A.657, .Bill; A658.Blli; A.659.B.11 A.660.B.11 A.2.C.41; A.3.C.41;
A.4.C.4i; A5.C.4.i; A.6.C 4i; A.7.C.4 A.9.C.4.i; A.10.C.41; A.15 •C.4.i;
A.100. C.4.i; A.101.C.4.Ϊ A.102.C.4.i; A103.C.4.i; A.104.C.4.i A.105.C.4i
A.106. •C.4.i; A107.C.4.i A.108.C.4.i; A.109.C.4.i; A.110.C.41 A.lll.C4i
A.112. •C.4.i; A.113.C.4.1 A.114.C.4.i; A.115.C.4i; A.116.C.41. A117.C.4.i,
A.118, •C.4.i; A.119.C.4.i A.120.C.4.i; A.121.C.4.i; A.122.C.4.i A123.C.4.i
A.124..C.4.i; A.125.C.4.i A.126.C.4.i; A.127.C.41; A.128.C.4.Ϊ A.129.C.4.i
A.130, .C.4.i; A.131.C.4.i A.132.C.4.i; A133.C.4.i; A.134.C.41 A.135.C.4i
A.136, ,C.4.i; A.137.C.4.i A.138.C.4.i; A.139.C.41; A.140.C.4.i A.141.C.4.i.
A.142, .C.4.i; A.143.C.4.i A.144.C.4.i; A.145.C4.i; A.146.C.4.i A147.C.4.i
A.148.C.4.i; A149.C.41 A.150.C.4.i; A.151.C.4.i; A.152.C.4.i A153.C.41
A.154.C.4.i; A.155.C.4.i. A.156.C.4i; A157.C.4.i; A.158.C.4.i. A.159.C.4.i.
A.160.C.4.i; A.161.C.4.i A.162.C.41; A.163.C.4.i; A.164.C.4.i A.165.C.4.i.
A.166.C.4.i; A167.C.4.i A.168.C.4.i; A.169.C.4.i; A170.C.4.i A171.C.4.i
A.172 C.4.i; A173.C.4.i A.174.C.41; A175.C.4.i; A176.C.4.i A.177.C.4.i
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C.ll.i; A.540.C111; A.541.C.lli; A.542CH 1; A.543CH i; A.544CH A.545. C.ll.i; A.546.C111; A.547.C.111; A.548.C111; A.549CH. i; A.550CH. A.551. C.ll.i; A.552.C.111; A.553.C.lli; A.554.C.111; A.555CH. i; A.556.C11. A.557. C.ll.i; A.558.C111; A.559.C.H1; A.560.C.111; A.561CH. i; A.562CH A.563. C.ll.i; A.564.C111; A.565.C111; A.566.C.111; A.567.C11. i; A.568CH A.569. C.ll.i; A.570.C111; A.571.C.lli; A.572.C.111; A.573.C11 i; A.574CH A.575. C.ll.i; A.576.C111; A.577. C.ll.i; A.578.C.111; A579C11. i; A.580CH. A.581. C.ll.i; A.582.C.111; A.583.C111; A.584.C.11 i; A.585.CH i; A.586CH. A.587. C.ll.i; A588.C111; A.589.CH1; A.590.C.111; A.591CH. i; A592.CH. A.593. C.ll.i; A594.CH1; A.595.C111; A.596.C.111; A.597C11. i; A.598CH A.599. C.ll.i; A.600.CH1; A.601.CH1; A.602.C.111; A.603CH i; A.604CH. A.605. C.ll.i; A.606.CH1; A.607.CH1; A.608.C.111; A.609CH i; A.610CH. A.611. C.ll.i; A.612.CH1; A.613.C.lli; A.614.C.111; A615.CH i; A.616CH. A.617..Clli; A.618.C111; A.619.C.lli; A.620.C.11 i; A.621C11 i; A.622CH. A.623. C.ll.i; A.624.C111; A.625.C111; A.626.C.11 i; A627C11. i; A.628CH. A.629. C.ll.i; A.630.C111; A.631C111; A.632.C.111; A633C11 i; A.634CH. A.635. C.ll.i; A.636.C111; A.637.C111; A.638.C111; A.639C11 i; A640.CH. A.641. C.ll.i; A.642.C111; A.643.C.111; A.644.C.111; A.645.C11 i; A646.CH. A.647. C.ll.i; A.648.C111; A.649C111; A650C111; A.651.C11 i; A652.C11. A.653. lli; A.654.C111; A.655.C111; A656C111; A.657C11 i; A.658.CH. A.659..Clli; A.660.CH1; A2.D.41; A.3.D.41; A.4. D.41; A.5.D.4. i; A6.D.41; A.7.D .41; A.9.D.41; A10.D.41; A15.D.41; A.IOO.D .41; A101.D.41; A102.D.41; A.103, D.41; A.104. D.41 A105.D.41; A106.D.41; A.107.D.41; A108.D.41 A.109, D.41; A.110. D.41 A111.D.41; AH2.D.41; AH3.D.41; A.114.D.4.i A.115. D.41; A.116. D.41 A.117.D.41; A118.D.41; AH9.D.41; A120.D.41 A.121, D.41; A.122. D.41 A.123.D.41; A124.D.41; A125.D.41; A126.D.41 A.127 D.41; A.128. 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A216.D.4 A.217. D.4 A.218. D.4. A.219 D.4. A.220. D.4. A.221. D.4. A.222.D.4 A.223. D.4 A.224. D.4. A.225 D.4. A.226. D.4. A.227. D.4. A228.D.4 A.229. D.4 A.230. D.4. A.231 D.4. A.232. D.4. A.233. D.4. A.234.D.4 A.235. D.4. A.236. D.4. A.237 D.4. A.238. D.4. A.239. D.4. A.240.D.4 A.241. D.4 A.242. D.4. A.243 D.4. A.244. D.4. A.245. D.4. A246.D.4 A.247. D.4. A.248. D.4. A.249 D.4. A.250. D.4. A.251. D.4. A.252.D.4 A.253. D.4. A.254. D.4. A.255 D.4. A.256. D.4. A.257. D.4. A258.D.4 A.259. D.4. A.260. D.4. A.261 D.4. A.262. D.4. A.263. D.4. A.264.D.4 A.265. D.4. A.266. D.4. A.267 D.4. A.268. D.4. A.269. D.4. A270.D.4 A.271. D.4. A.272. D.4. A.273 D.4. A.274. D.4. A.275. D.4. A276.D.4 A.277. D.4. A.278. D.4. A.279 D.4. A.280. D.4. A.281. D.4. A282.D.4 A.283. D.4. A.284. D.4. A.285 D.4. A.286. D.4. A.287. D.4. A.288.D.4 A.289. D.4. A.290. D.4. A.291 D.4. A.292. D.4. A.293. D.4. A.294.D.4 A.295. D.4. A.296. D.4. A.297 D.4. A.298. D.4. A.299. D.4. A.300.D.4 A.301. D.4. A.302. D.4. A.303 D.4. 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D.4. A.480.D.4. A.481.D.4. A 482.D.41 ; A483.D.4 A.484.D A.485. D.4. A.486.D.4. A.487.D.4. A. 488.D.41 ; A489.D.4 A.490.D A.491. D.4. A.492.D.4. A.493.D.4. A. 494.D.41 ; A495.D.4 A.496.D. A.497. D.4. A.498.D.4. A499.D.4. A. 500.D.41 ; A.501.D.4 A.502.D. A.503. D.4. A.504.D.4. A505.D.4. A 506.D.41 ; A507.D.4 A.508.D. A.509. D.4. A510.D.4. A.5H.D.4. A. 512.D.41 ; A.512.D.4 A.513.D A.514. D.4. A515.D.4 A.516.D.4. A. 517.D.41 ; A518.D.4 A.519.D A.520. D.4. A521.D.4 A.522.D.4. A. 523.D.41 ; A524.D.4 A.525.D A.526. D.4. A527.D.4. A528.D.4. A, 529.D.41 ; A530.D.4 A.531.D. A.532. D.4. A.533.D.4. A.534.D.4 A. 535.D.41 ; A536.D.4 A.537.D A.538. D.4. A.539.D.4. A.540.D.4.: A. 541.D.41 ; A542.D.4 A.543.D. A.544. D.4. A.545.D.4. A.546.D.4. A. 547.D.41 ; A548.D.4 A.549.D. A.550. D.4. A.551.D.4. A.552.D.4. A. 553.D.41 ; A554.D.4 A.555.D A.556. D.4. A.557.D.4. A.558.D.4. A. 559.D.41 ; A.560.D.4 A.561.D. A.562. D.4. A.563.D.4. A.564.D.4. A. 565.D.41 ; A.566.D.4 A.567.D A.568. D.4. A.569.D.4. A.570.D.4. A. 571.D.41 ; A.572.D.4 A.573.D A.574. D.4. A.575.D.4. A.576.D.4. A. 577.D.41 ; A578.D.4 A.579.D. A.580. D.4. A.581.D.4. A.582.D.4. A. 583.D.41 ; A.584.D.4 A.585.D. A.586. D.4. A.587.D.4. A.588.D.4. A. 589.D.41 ; A590.D.4 A.591.D. A.592. D.4. A.593.D.4. A.594.D.4. A. 595.D.41 ; A596.D.4 A.597.D. A.598. D.4. A.599.D.4. A.600.D.4. A. 601.D.41 ; A.602.D.4 A.603.D. A.604. D.4. A605.D.4. A.606.D.4. A. 607.D.41 ; A608.D.4 A.609.D. ; A.610, D.4. A611.D.4. A.612.D.4. A. 613.D.41 ; A.614.D.4 A.615.D. A.616, D.4. A.617.D.4. A.618.D.4. A. 619.D.41 ; A.620.D.4 A.621.D. A.622, D.4. A623.D.4. A.624.D.4. A. 625.D.41 ; A626.D.4 A.627.D. A.628, D.4. A629.D.4. A.630.D.4. A. 631.D.41 ; A.632.D.4 A.633.D. A.634. D.4. A.635.D.4. A.636.D.4. A. 637.D.41 ; A638.D.4 A.639.D. A.640, D.4. A.641.D.4. A642.D.4 A. 643.D.41 ; A.644.D.4 ; A.645.D. A.646, D.4. A.647.D.4. A.648.D.4 A. 649.D.41 ; A.650.D.4 A.651.D. A.652. D.4. A.653.D.4. A654.D.4. A. 655.D.41 ; A.656.D.4 A.657.D. A.658, D.4. A.659.D.41 A.660.D.4. A. 2.D.111; A.3.D.111; A4.D.H1; A.5.DH1; A.6.D111; A.7.DH1; A.9.D. Hi; A. lO.D.lli; A.15.DH i; A.100.D.111; AlOl.D.ll.i; A102.D.111; A.103.D 111; A. 104.D.111 A.105.D 111; A.106. A107.DH.i; A108.D111 A.109 Dili; A. llO.D.ll.i A.lll.D 111; A.112. A.113.D.lli; A114.D111 A.115, Dili; A.116.D111 A.117.D ll.i; A.118. A.119.D.lli; A120.D111 A.121, Dili; A.122.D.111 A.123.D 111; A.124. A125.DH.i; A126.D111 A.127 Dili; A.128.D.11.Ϊ A.129.D. ll.i; A.130. A.131.D.111; A132.D111 A.133 Dili; A, 134.D.111 A.135.D. ll.i; A.136. A137.D111; A.138.D.111 A.139 Dili; A 140.D111 A.141.D. ll.i; A.142. A143.D111; A.144.D111 A.145, Dill; A 146.D111 A.147.D. ll.i; A.148. A149.D111; A.150.D.111 A.151 Dili; A 152.D111 A.153.D ll.i; A.154. A.155.D.111; A156.DH1 A.157 Dili; A 158.D111 A.159.D ll.i; A.160. A.161.D111; A162.D111 A.163 Dili; A 164.DH1 A.165.D 111; A.166. A.167.D.111; A168.D111 A.169 Dili; A 170.D.111; A.171.D. ll.i; A.172. Dili; A.173.D.111; A174.D.lli A.175 Dili; A.176.D11 A.177.D.ll.i;A 178.DH. A.179 D.ll. A.180.D.11. A.181. D.ll. A. 182.D11 A.183.D.111;A 184.D.11. A.185 D.ll. A.186.D.11. A.187, D.ll A. 188.D.H. A.189.D.ll.i ;A 190.D.11. A.191 D.ll. A.192.D.11. A.193. D.ll A. 194.D.H. A.195.D. 111 ;A 196.D.11. A.197 D.ll. A.198.D.11. A.199. D.ll A. 200.D.11,: A.201.D. 111 ;A 202.D.11. A.203 D.ll. A.204.D.11. A.205, D.ll A. 206.D11. A.207.D.ll.i ;A 208.D.11. A.209 D.ll. A.210.D.11. A.211, D.ll. A. 212.D.11. A.213.D. 111 ;A 214.D.11. A.215. D.ll. A.216.D.11. A.217, D.ll A. 218.D11. A.219.D. 111 ;A 220.D.11. A.221 D.ll. A.222.D.11. A.223, D.ll A. 224.D11. A.225.D.ll.i ;A 226.D.11. A.227 D.ll. A.228.D.11. A.229, D.ll. A. 230.D.11. A.231.D.ll.i ;A 232.D.11. A.233 D.ll. A.234.D.11. A.235. D.ll. A. 236.D.H. A.237.D. 111 ;A 238.D.H. A.239 D.ll. A.240.D.11. A.241. D.ll A. 242.D.H. A.243.D.ll.i ;A 244.D.H, A.245 D.ll. A.246.D.11. A.247. D.ll. A. 248.D.11. A.249.D.ll.i ;A 250.D.11. A.251 D.ll. A.252.D.11. A.253. 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A608.F.4 i; A.609.F.41; A.610.F.41; A611.F.41; A.612.F.41; A, .613.F.4. A614.F.4 i; A.615.F.41; A.616.F.41; A.617.F.41; A618.F.41; A, .619.F.4. A.620.F.41; A621.F.41; A.622.F.41; A.623.F.41; A624.F.41; A .625.F.4. A.626.F.41; A.627.F.41; A.628.F.41; A.629.F.41; A.630.F.41; A .631.F.4. A.632.F.4 i; A.633.F.41; A.634.F.41; A.635.F.41; A.636.F.41; A, .637.F.4. A.638.F.41; A.639.F.41; A.640.F.41; A.641.F.41; A.642.F.41; A .643.F.4. A.644.F.41; A.645.F.41; A.646.F.41; A647.F.41; A.648.F.41; A ..649.F.4. A650.F.4 ,i; A.651.F.41; A.652.F.41; A653.F.41; A.654.F.41; A 655.F.4. A656.F.41; A.657.F.41; A.658.F.41; A659.F.41; A.660.F.41; A ,2.F.lli; A3.F.H1; A.4.F.H1; A.5.FH1; A6.F111; A.7.FH1; A.9.FH1; A lO.F.lll; A15.F.11 ,i; A.lOO.F.lli; A.101.F.111; A.102.FH1; A.103.FH1; A 104.F.H1; A.105.F. 111; A.106.F.111; A107.F.111 A108.FH.i; A.109.F.lli. A llO.F.lli; A.lll.F.111; A.112.F.111; AH3.F111 A.114.F.111; A.115.FH.i A ..116.F.111; A.117.F. ll.i; A118.F.111; AH9.F.111 A120.F.111; A.121.FH1 A 122.F.111 A.123.F ll.i; A.124.F.111; A.125.F.111. A126.F111; A127.FH.i A ..128.F.111. A.129.F. ll.i; A130.F.111; A.131.F.111 A.132.F111; A.133.F.111 A 134.F111 A.135.F. ll.i; A136.F.111; A137.F.111 A.138.F.111; A.139.F.111 A 140.F.111 A.141.F. ll.i; A142.F111; A143.F111 A.144.F111; A.145.F111 A 146.F111; A.147.F. ll.i; A.148.FH1; A.149.F.111 A.150.FH1; A.151.F.111. A 152.F111; A.153.F. ll.i; A154.FH.i; A155.F.111 A.156.F.111; A.157.FH1 A.158.F.11. A.159.F. ll.i; A.160.F11 A.161.F.11. A.162.F.11. A.163 F.ll. A.164.F11. A.165.F. ll.i; A.166.F11 A.167.F.11. A.168.F.11. A.169 F.ll. A.170.F11. A.171.F.111; A.172.F.11 A.173.F.11. A174.F.11. A.175. F.ll. A.176.F11. A.177.F. ll.i; A.178.F11 A.179.F.11. A.180.F.11. A.181 F.ll. A.182.F11. A.183.F. ll.i; A.184.F11 A.185.F.11. A.186.F.11. A.187. F.ll. A.188.F11. A.189.F.111; A.190.F11 A.191.F.11. A.192.F.11. A.193 F.ll. A.194.F11. A.195.F. ll.i; A.196.F11 A.197.F.11. A.198.F.11. A.199, F.ll. A.200.F11. A.201.F.111; A.202.F11 A203.F.11. A.204.F.11. A.205, F.ll. A. •206.F11. A.207.F. ll.i; A.208.F.H A209.F.11. A.210.F.11. A.211, F.ll. A. •212.F11. A.213.F. ll.i; A.214.F11 A.215.F.11. A.216.F.11. A.217, F.ll. A. •218.F11. A.219.F. ll.i; A.220.F11 A.221.F.11. A.222.F.11. A.223, F.ll. A. •224.F11. A.225.F. ll.i; A.226.F11 A227.F11. A.228.F.11. A.229 F.ll. A •230.F11. A.231.F. ll.i; A.232.F11 A.233.F.11, A.234.F.11. A.235, F.ll. A, •236.F11. A.237.F. ll.i; A 238.F.11 A.239.F.11. A.240.F.11. A.241 F.ll. A •242.F11. A.243.F.111; A.244.F11 A.245.F.11, A.246.F.11. A.247 F.ll. A. •248.F11. A.249.F. ll.i; A.250.F.11 A.251.F.11. A252.F.11. A.253. F.ll. A, •254.F11. A.255.F. ll.i; A.256.F.11 A.257.F.11. A.258.F.11. A.259, F.ll. A, •260.F11. A.261.F. ll.i; A.262.F.11 A.263.F.11. A.264.F.11. A.265, F.ll. A, •266.F11. A.267.F.111; A.268.F11 A.269.F.11. A.270.F.11. A.271, F.ll. A .272.F.11. A.273.F. ll.i; A.274.F11 A275.F.11. A.276.F.11. A.277, F.ll. A .278.F11. A.279.F. ll.i; A.280.F.11 A.281.F.11. A.282.F.11. A.283 F.ll. A .284.F11. A.285.F. ll.i; A.286.F.11 A.287.F.11. A.288.F.11. A.289 F.ll. A .290.F11. A.291.F.111; A.292.F11 A.293.F.11. A294.F.11. A.295, F.ll. A •296.F11. A.297.F. ll.i; A.298.F11 A.299.F.11. A.300.F.11. A.301, F.ll. A .302.F11. A.303.F.111; A.304.F11 A.305.FH. A.306.F.11. A.307, F.ll. A, .308.F.11. A.309.F. ll.i; A.310.F11 A311.F.11. A.312.F.11. A.313, F.ll. A .314.F.11. A.315.F. ll.i; A.316.F.11 A.317.F.11. A.318.F.11. A.319, F.ll. A .320.F11. A.321.F. ll.i; A.323.F.11 A.324.F.11. A.325.F.11. A.326, F.ll. A..327.F11. A.328.F.111; A.329.F.11 A.330.F.11. A.331.F.11. A.332. F.ll. A .333.F11. A.334.F. ll.i; A, 335.F.11 A.336.F.11, A.337.F.11. A.338 F.ll. A .339.F11. A.340.F. ll.i; A, .341.F.11 A.342.F.11. A.343.F.11. A.344 F.ll. A .345.F11. A.346.F. ll.i; A, .347.F11 A.348.F.11, A.349.F.H. A.350 F.ll. A .351.F.11. A.352.F.111; A, 353.F11 A.354.F.11. A.355.F.11. A.356, F.ll. A .357.F11. A.358.F. ll.i; A, 359.F11 A.360.F.11. A.361.F.11. A.362 F.ll. A .363.F11. A.364.F. ll.i; A, 365.F.11 A.366.F.11. A.367.F.11. A.368 F.ll. A .369.F11. A.370.F. ll.i; A 371.F11 A.372.F.11. A.373.F.11. A.374 F.ll. A .375.F11. A.376.F.111; A 377.F11 A.378.F.11. A.379.F11. A.380 F.ll. A .381.F.11. A.382.F. Hi; A 383.F.11 A.384.F.11. A.385.F.11. A.386 F.ll. A .387.F11. A.388.F. ll.i; A 389.F11 A.390.F.11. A.391.F.11. A.392 F.ll. A .393.F11. A.394.F. ll.i; A .395.F11 A396.F.11 A.397.F.11. A.398 F.ll. A 399.F11. A.400.F.111; A .401.F.11 A.402.F.11 A.403.F.11. A.404 F.ll. A 405.F11. A.406.F. ll.i; A .407.F.11 A.408.F.11. A.409.F.11. A.410 F.ll. A .411.F.11. A.412.F. ll.i; A .413.F11 A.414.F.11. A.415.F.11. A.416 F.ll. A ..417.F.11. A.418.F.111; A .419.F.H A.420.F.11. A.421.F.11. A.422 F.ll. A 423.F11. A.424.F. ll.i; A .425.F11 A.426.F.11. A.427.F.11. A.428 F.ll. A 429.F11. A.430.F. ll.i; A 431.F.11 A.432.F.11. A.433.F.11. A.434 F.ll. A 435.F11. A.436.F. ll.i; A .437.F.11 A.438.F.11. A.439.F.11. A.440 F.ll. A.441.F.H1; A.442.FH1; A.443.FH1; A.444.FH1; A.445.F111; A.446.F.H.
A.447.F.H1; A.448.F.111; A.449.F111; A.450.F.111; A451.F.111; A.452.F11.
A453.F111; A.454.F.111; A.455.F.111; A.456.FH1; A457.FH.i; A.458.F.H.
A.459.FH1; A.460.F111; A461.FH1; A462.FH1; A.463.F111; A.464.FH. A465.F111; A466.FH.i; A.467.F.111; A.468.FH1; A469.F.111; A.470.F.H.
A471.F111; A472.FH.i; A.473.F.H1; A474.FH1; A.475.FH1; A.476.F.H.
A477.F111; A478.FH.i; A.479.FH1; A480.F.111; A.481.FH1; A.482.F11.
A483.FH.i; A484.FH.i; A.485.FH1; A.486.FH1; A.487.F111; A.488.F.H.
A489.F.H1; A490.FH.i; A491.F.111; A492.FH1; A.493.F111; A.494.F.H. A.495.F.H1; A496.F.111; A.497.FH1; A.498.F.111; A499.FH.i; A.500.F11.
A.501.F.1U; A.502.FH1; A503.FH.i; A.504.F111; A505.FH.i; A.506.F.H.
A507.FH.i; A.508.F111; A509.FH.i; A510.F.111; A.511.FH1; A.512.FH.
A512.FH1; A513.F111; A514.F.111; A.515.F111; A.516.F.111; A.517.F.H.
A518.FH1; A519.F.111; A.520.F.111; A.521.F111; A522.F.111; A.523.FH. A524.F111; A.525.F.111; A.526.FH1; A.527.F111; A.528.F.111; A.529.F11.
A.530.F.H1; A.531.F.111; A.532.FH1; A.533.F111; A.534.F111; A.535.FH.
A.536.F111; A537.F.111; A.538.FH1; A.539.F.111; A.540.F111; A.541.FH.
A.542.F111; A.543.F111; A.544.FH1; A.545.F.111; A.546.F111; A.547.F.11.
A548.FH1; A.549.F.111; A.550.F111; A.551.F111; A.552.F111; A.553.FH. A.554.F.111; A.555.F.111; A.556.F.111; A.557.F111; A.558.F.111; A.559.FH.
A.560.F111; A.561.F111; A.562.FH1; A.563.F.111; A.564.F111; A.565.FH.
A.566.F.111; A.567.F.111; A.568.FH1; A.569.F.111; A.570.F.H1; A.571.FH.
A572.FH1; A573.F111; A.574.FH1; A.575.FH1; A.576.F.111; A.577.FH.
A.578.F111; A.579.F.111; A.580.F111; A.581.F.111; A.582.F.111; A.583.F11. A584.F.111; A.585.FH1; A.586.FH1; A.587.FH1; A.588.F.111; A.589.FH.
A.590.F111; A.591.F111; A.592.FH1; A.593.F111; A.594.F.111; A.595.FH.
A596.F111; A.597.F111; A.598.FH1; A.599.F.111; A.600.F.111; A.601.FH.
A602.F.111; A603.F.111; A.604.FH1; A.605.F111; A.606.F.111; A.607.F.11.
A608.F111; A.609.F.H1; A.610.FH1; A.611.F.111; A.612.F.111; A.613.FH. A.614.F111; A.615.F.H1; A.616.F111; A617.F111; A.618.F.111; A.619.FH.
A620.F.111; A621.F.111; A.622.F111; A.623.F111; A.624.F.111; A.625.FH.
A.626.F111; A.627.F111; A628.FH.i; A.629.F111; A630.F111; A.631.F11.
A.632.FH1; A.633.F.111; A634.FH.i; A.635.F.111; A.636.F111; A.637.F11.
A.638.F.111; A639.F111; A.640.F.111; A.641.F.111; A.642.F.111; A.643.F.H. A644.F111; A.645.FH.i; A.646.F.111; A.647.FH1; A.648.FH1; A.649.F11.
A650.F.H1; A.651.F111; A.652.F111; A.653.F.111; A654.F111; A.655.F11.
A656.FH.i; A657.FH1; A.658.FH1; A.659.F.111; A660.F.111; A.2.3.441;
A.3.3.441; A.4.3.441; A.5.3.441; A.9.3.441; A100.a.44.i; A.101.3.441; A.102.3.441;
A.103.3.441; A104.a.44.i; A.105.3.441; A.106.3.441; A.107.3.441; A.108.3.441; A.109.3.441; A.110.3.441; Alll.a.44i; A112.a.44i; A.113.3.441; A.114.3.441;
A115.a.44i; A.116.3.441; A.117.3.441; A.118.3.441; A.119.3.441; A.120.3.441;
A.121.3.441; A.122.3.441; A.123.3.441; A124.a.44.i; A.125.3.441; A.126.3.441;
A.127.3.441; A.128.3.441; A.129.3.441; A.130.3.441; A.131.3.441; A.132.3.441;
A.133.3.441; A.134.3.441; A.135.3.441; A.136.3.441; A.137.a.44i; A.138.3.441; A.139.3.441; A.140.3.441; A.141.3.441; A142.a.44i; A.143.3.441; A144.a.44.i;
A145.a.44.i; A.146.3.441; A.147.3.441; A.148.3.441; A.149.3.441; A.150.3.441;
A.151.3.441; A.152.3.441; A.153.3.441; A154.3.441; A.155.3.441; A.156.3.441; A, 157.3.44 i; A.158.3.44. A159.3.441; A.160.3.441 A.161.3.441; A.162.3.441;
A.163.3.44. i; A.164.3.44. A.165.3.441; A.166. 3.44. A.167.3.441; A.168.3.44.
A 169.3.44. i; A.170.3.44. A.171.3.441; A.172. 3.44. A.173.3.441; A.174.3.441
A 175.3.44 i; A.176.3.44. A.177.3.441; A.178. a.44. A.179.3.441; A.180.3.441
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A 283.3.44 i; A.284.3.44. A.285.3.441; A.286. 3.44. A.287.3.441; A.288.3.44.
A 289.3.44 i; A.290.3.44. A.291.3.441; A.292. 3.44. A.293.3.441; A.294.3.44.
A, 295.3.44 i; A296.a.44. A.297.a.44i; A.298. a.44. A.299.3.441; A.300.3.44.
A 301.3.44. i; A.302.3.44. A.303.a.44i; A.304. 3.44. A.305.a.44.i; A.306.3.44.
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A .313.3.44 i; A314.a.44. A.315.a.44.i; A.316. 3.44. A.317.3.441; A.318.3.44.
A .319.3.44 i; A.320.3.44. A.321.3.441; A.322. a.44. A.323.3.441; A.324.3.44.
A .325.3.44 i; A.326.3.44. A.327.3.441; A.328. a.44. A.329.a.44.i; A.330.3.44.
A 331.3.44 i; A.332.3.44. A.333.3.441; A.334. 3.44. A.335.3.441; A.336.3.441
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A 355.3.44 i; A.356.3.44. A.357.3.441; A.358. a.44. B.2.3.441; B.3.3.441;
B.4.3.441; B >.5.a.44i; B.9 3.441; B.100.3.441; B. lOl.a 441; B.102.3.441; B.103.3.441;
B.104.3.44 i; B.105.3.44. B106.a.44.i; B.107.3, 441; B.108.3.441 B.109.3.441
B.110.3.44. i; Blll.a.44. B.112.3.441; B.113.3.441; B.114.3.44. B.115.3.441
B 116.3.44 i; B117.a.44. B.118.3.441; B.119.3 441; B.120.3.44. B.121.3.441
B 122.3.44. i; B.123.3.44. B.124.3.441; B.125.3.441; B.126.3.44. B.127.3.441
B 128.3.44. i; B.129.3.44. B.130.3.441; B.131.a .441; B.132.3.44. B.133.3.441
B 134.3.44 i; B.135.3.44. B.136.3.441; B.137.3.441; B138.a.44. B139.a.44i
B.140.3.44 i; B.141.3.44. B142.a.44.i; B.143.3.441; B.144.3.44. B145.a.44i
B 146.3.44. i; B.147.3.44. B.148.3.441; B.149.3.441; B.150.3.44. B151.a.44i
B 152.3.44 i; B.153.3.44. B.154.3.441; B.155.3.441; B.156.3.44. B.157.3.441
B 158.a.44. i; B.159.3.44. B.160.3.441; B.161.3.441; B.162.3.44. B.163.3.441
B 164.3.44 i; B.165.3.44. B.166.3.441; B.167.3.441; B.168.3.44. B.169.3.441
B 170.3.44. i; B.171.a.44. .; B.172.3.441; B.173.3.441; B.174.3.44. B.175.3.441 B.176.3.441; B.177.a.44.i; B.178.3.441; B.179.3.441; B.180.3.44. B.181.3.441
B.182.3.441; B.183.3.441; B.184.3.441; B.185.3.441; B.186.3.44. B.187.3.441
B.188.3.441; B.189.3.441; B.190.3.441; B.191.3.441; B.192.3.44. B.193.3.441
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B.206.3.441; B.207.a.44i; B.208.a.44.i; B.209.a.44.i; B.210.3.44. B.211.a.44i
B.212.3.441; B.213.3.441; B.214.3.441; B.215.3.441; B.216.3.44. B.217.3.441
B.218.3.441; B.219.3.441; B.220.3.441; B.221.3.441; B.222.3.44. B.223.3.441
B.224.3.441; B.225.3.441; B.226.3.441; B.227.3.441; B.228.3.44. B.229.3.441 B.230.3.441; B.231.3.441; B.232.3.441; B.233.3.441; B.234.3.44. B.235.3.441
B.236.3.441; B.237.3.441; B.238.a.44i; B.239.a.44i; B.240.a.44. B.241.3.441
B.242.a.44.i; B.243.3.441; B.244.3.441; B.245.3.441; B.246.3.44. B.247.3.441
B.248.3.441; B.249.a.44i; B.250.a.44.i; B.251.3.441; B.252.3.44. B.253.3.441
B.254.3.441; B.255.3.441; B.256.3.441; B.257.3.441; B.258.3.44. B.259.3.441 B.260.3.441; B.261.a.44i; B.262.3.441; B.263.3.441; B.264.a.44. B.265.3.441
B.266.a.44.i; B.267.3.441; B.268.3.441; B.269.3.441; B.270.3.44. B.271.3.441
B.272.3.441; B.273.3.441; B.274.a.44.i; B.275.a.44.i; B.276.3.44. B.277.3.441
B.278.a.44i; B.279.3.441; B.280.3.441; B.281.3.441; B.282.3.44. B.283.a.44i
B.284.3.441; B.285.3.441; B.286.3.441; B.287.3.441; B.288.3.44. B.289.3.441 B.290.3.441; B.291.3.441; B.292.3.441; B.293.a.44i; B.294.3.44. B.295.3.441
B.296.3.441; B.297.3.441; B.298.a.44.i; B.299.a.44i; B.300.3.44. B.301.3.441
B.302.a.44i; B.303.3.441; B.304.3.441; B.305.3.441; B.306.3.44. B.307.3.441
B.308.3.441; B.309.a.44i; B.310.3.441; B.311.3.441; B.312.3.44. B.313.3.441
B.314.3.441; B.315.3.441; B.316.a.44.i; B.317.a.44.i; B.318.3.44. B.319.3.441 B.320.3.441; B.321.3.441; B.322.3.441; B.323.3.441; B.324.3.44. B.325.a.44i
B.326.3.441; B.327.3.441; B.328.a.44.i; B.329.3.441; B.330.3.44. B.331.a.44i
B.332.3.441; B.333.3.441; B.334.3.441; B.335.3.441; B.336.a.44. B.337.3.441
B.338.3.441; B.339.3.441; B.340.3.441; B.341.3.441; B.342.3.44. B.343.3.441
B.344.3.441; B.345.3.441; B.346.3.441; B.347.a.44i; B.348.3.44. B.349.3.441 B.350.a.44.i; B.351.3.441; B.352.a.44i; B.353.3.441; B.354.3.44. B.355.3.441
B.356.a.44.i; B.357.a.44i; B.358.3.441; E.2.3.441; E.3.a.44i; E.4, 3.441; E.5.a.44.i;
E.9.3.441; E.100.3.441; E.101.a.44i; E.102.a.44i; E.103.3.441; E 104.3.441;
E.105.3.441; E.106.3.441; E.107.3.441; E.108.3.441; E.109.3.44. E.110.3.44.i;
Elll.3.441; E.112.a.44i; E.113.a.44.i; E.114.3.441; E.115.a.44. E.116.3.441; E.117.a.44.i; E.118.3.441; E.119.3.441; E.120.3.441; E.121.3.44. E.122.3.441;
E.123.3.441; E.124.3.441; E.125.3.441; E.126.3.441; E.127.3.44. E.128.3.441;
E129.a.44.i; E130.a.44.i; E.131.3.441; E.132.3.441; E.133.3.44. E.134.3.441;
E.135.3.441; E.136.3.441; E.137.3.441; E.138.3.441; E.139.3.44. E.140.3.441;
E.141.a.44.i; E.142.a.44.i; E143.a.44.i; E.144.a.44i; E.145.a.44. E146.a.44.i; E147.a.44i; E.148.3.441; E.149.3.441; E.150.3.441; E151.a.44. E.152.3.441;
E.153.3.441; E.154.3.441; E.155.3.441; E.156.3.441; E.157.a.44. E158.a.44.i;
E159.a.44.i; E.160.3.441; E.161.3.441; E.162.3.441; E163.a.44. E.164.3.441;
E.165.a.44i; E166.a.44i; E167.a.44i; E.168.3.441; E.169.3.44. E.170.3.441;
E171.a.44.i; E.172.3.441; E.173.3.441; E.174.a.44i; E175.a.44. E176.a.44i; E177.a.44.i; E.178.3.441; E.179.3.441; E.180.a.44i; E.181.3.44. E.182.3.441;
E183.a.44.i; E184.a.44i; E185.a.44i; E186.a.44.i; E.187.3.44. E.188.3.441;
E189.a.44i; E.190.3.441; E.191.3.441; E.192.3.441; E.193.a.44. E.194.3.441; E 195.3.44 i; E.196.3.441; E.197, 3.441; E.198.3.441 E.199.3.44. E.200.3.44.
E 201.a.44 i; E.202.3.441; E.203.3.441; E.204.3.44. E.205.3.44. E.206.3.44.
E 207.a.44. i; E.208.3.44 i; E.209.3.441; E.210.3.44. E.211.3.44. E.212.3.44.
E.213.3.44. i; E.214.3.44 i; E.215.3.441; E.216.3.44. E.217.3.44. E.218.3.44
E.219.3.44. i; E.220.3.44. i; E.221.3.441; E.222.3.44. E.223.3.44. E.224.3.44
E.225.3.44 i; E.226.3.44 i; E.227.3.441; E.228.3.44. E.229.3.44. E.230.3.44
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E.237.3.44 i; E.238.3.441; E.239. a.44i; E.240.3.44. E.241.a.44. E.242.3.44
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E.255.3.44. i; E.256.3.44. i; E.257, 3.441; E.258.3.44. E.259.a.44. E.260.3.44
E.261.3.44. i; E.262.3.44. i; E.263, 3.441; E.264.3.44. E.265.a.44. E.266.3.44
E.267.3.44 i; E.268.3.44 i; E.269 3.441; E.270.3.44. E.271.a.44. E.272.3.44
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E.279.3.44 i; E.280.3.44. i; E.281, 3.441; E.282.3.44. E.283.3.44. E.284.3.44.
E.285.3.44 i; E.286.3.44 i; E.287.3.441; E.288.a.44. E.289.3.44. E.290.3.44.
E. ,291.3.44. i; E.292.3.44. i; E.293, 3.441; E.294.a.44. E.295.3.44. E.296.3.44.
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B 219.3.41; B.220.3.41 B.221.3 41; B.222.3.41; B.223.3.41 B.224.3.41; B.225.3.41,
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B.240.3.41; B.241.3.41; B.242.3.41; B.243.3.41 B.244.3.41; B.245.3.41; B.246.3.41;
B.247.3.41; B.248.3.41; B.249.3.41; B.250.3.41 B.251.3.41; B.252.3.41; B.253.3.41;
B.254.3.41; B.255.3.41; B.256.3.41; B.257.3.41 B.258.3.41; B.259.3.41; B.260.3.41; B.261.3.41; B.262.3.41; B.263.3.41; B.264.3.41 B.265.3.41; B.266.3.41; B.267.3.41;
B.268.3.41; B.269.3.41; B.270.3.41; B.271.3.41 B.272.3.41; B.273.3.41; B.274.3.41;
B.275.3.41; B.276.3.41; B.277.a.4.i; B.278.a.4.i B.279.3.41; B.280.3.41; B.281.3.41;
B.282.3.41; B.283.3.41; B.284.3.41; B.285.3.41, B.286.3.41; B.287.a.4.i; B.288.3.41;
B.289.3.41; B.290.3.41; B.291.3.41; B.292.a.4.i B.293.3.41; B.294.3.41; B.295.3.41; B.296.a.4.i; B.297.3.41; B.298.3.41; B.299.a.4.i B.300.a.4.i; B.301.3.41; B.302.3.41;
B.303.a.4.i; B.304.3.41; B.305.3.41; B.306.3.41, B.307.3.41; B.308.3.41; B.309.3.41;
B.310.3.41; B.311.3.41; B.312.3.41; B.313.3.41 B.314.3.41; B.315.3.41; B.316.3.41;
B.317.3.41; B.318.3.41; B.319.a.4.i; B.320.a.4.i B.321.3.41; B.322.3.41; B.323.3.41;
B.324.a.4i; B.325.3.41; B.326.3.41; B.327.3.41 B.328.3.41; B.329.a.4.i; B.330.a.4.i; B.331.a.4.i; B.332.a.4.i; B.333.a.4.i; B.334.a.4.i B.335.3.41; B.336.3.41; B.337.3.41;
B.338.3.41; B.339.a.4.i; B.340.a.4.i; B.341.a.4.i B.342.a.4.i; B.343.3.41; B.344.3.41;
B.345.3.41; B.346.a.4.i; B.347.3.41; B.348.3.41 B.349.3.41; B.350.3.41; B.351.3.41;
B.352.3.41; B.353.3.41; B.354.3.41; B.355.3.41 B.356.3.41; B.357.3.41; B.358.3.41;
E.2.a.4.i; E.3.a.4.i; E.4.3.41; E.5.3.41; E.9.3.41; E.100.3.41; E101.a.4.i; E.102.a.4.i; E.103.3.41; E.104.3.41; E.105.a.4.i; E.106.a.4.i; E.107.3.41; E.108.3.41; E.109.3.41;
E.110.a.4.i; E.lll.a.4.i; E.112.3.41; E.113.3.41; E.114.3.41; E.115.3.41; E.116.3.41;
E.117.3.41; E.118.a.4i; E.119.a.4.i; E.120.a.4.i; E.121.a.4.i; E.122.3.41; E.123.3.41;
E.124.3.41; E.125.a.4.i; E.126.3.41; E127.a.4.i; E.128.3.41; E.129.3.41; E.130.3.41;
E.131.a.4.i; E.132.a.4.i; E.133.3.41; E.134.3.41; E.135.3.41; E.136.3.41; E.137.3.41; E.138.3.41; E.139.3.41; E.140.3.41; E.141.3.41; E.142.3.41; E.143.3.41; E144.a.4.i;
E145.a.4.i; E146.a.4.i; E147.a.4.i; E.148.a.4.i; E.149.3.41; E.150.3.41; E.151.a.4.i;
E.152.a.4.i; E.153.3.41; E.154.3.41; E.155.a.4.i; E.156.3.41; E.157.3.41; E158.a.4.i;
E.159.3.41; E.160.a.4.i; E.161.3.41; E.162.3.41; E.163.3.41; E.164.3.41; E.165.3.41;
E.166.3.41; E.167.3.41; E.168.3.41; E.169.3.41; E.170.3.41; E.171.3.41; E.172.3.41; E.173.3.41; E.174.a.4.i; E.175.a.4.i; E176.a.4.i; E.177.3.41; E.178.3.41; E.179.3.41;
E.180.3.41; E.181.3.41; E.182.3.41; E.183.3.41; E.184.3.41; E.185.3.41; E.186.3.41;
E.187.a.4.i; E.188.3.41; E.189.a.4.i; E.190.a.4i; E.191.3.41; E.192.3.41; E.193.3.41;
E194.a.4.i; E.195.3.41; E.196.3.41; E.197.3.41; E.198.3.41; E.199.a.4.i; E.200.a.4.i;
E.201.3.41; E.202.a.4.i; E.203.3.41; E.204.3.41; E.205.3.41; E.206.3.41; E.207.3.41; E.208.3.41; E.209.3.41; E.210.3.41; E.211.3.41; E.212.3.41; E.213.a.4.i; E.214.3.41;
E.215.3.41; E.216.3.41; E.217.3.41; E.218.3.41; E.219.3.41; E.220.3.41; E.221.3.41;
E.222.3.41; E.223.3.41; E.224.3.41; E.225.a.4.i; E.226.a.4.i; E.227.3.41; E.228.3.41;
E.229.3.41; E.230.3.41; E.231.3.41; E.232.a.4.i; E.233.a.4.i; E.234.3.41; E.235.3.41;
E.236.3.41; E.237.3.41; E.238.3.41; E.239.3.41; E.240.a.4.i; E.241.3.41; E.242.a.4.i; E.243.3.41; E.244.3.41; E.245.3.41; E.246.3.41; E.247.3.41; E.248.3.41; E.249.3.41;
E.250.3.41; E.251.3.41; E.252.3.41; E.253.3.41; E.254.a.4.i; E.255.3.41; E.256.3.41;
E.257.3.41; E.258.3.41; E.259.3.41; E.260.3.41; E.261.3.41; E.262.3.41; E.263.3.41;
E.264.3.41; E.265.a.4.i; E.266.3.41; E.267.3.41; E.268.3.41; E.269.3.41; E.270.3.41;
E.271.3.41; E.272.3.41; E.273.3.41; E.274.3.41; E.275.a.4.i; E.276.3.41; E.277.3.41; E.278.3.41; E.279.3.41; E.280.3.41; E.281.3.41; E.282.a.4.i; E.283.3.41; E.284.3.41;
E.285.3.41; E.286.3.41; E.287.3.41; E.288.3.41; E.289.3.41; E.290.3.41; E.291.3.41;
E.292.3.41; E.293.3.41; E.294.3.41; E.295.3.41; E.296.3.41; E.297.3.41; E.298.3.41; E.299.3.41; E.300.3 1; E.301.3.41; E.302.a.4.i; E.303.3.41; E.304.3.41; E .305.3.41; E.306.3.41; E.307.3 i; E.308.3.41; E.309.3.41; E.310.3.41; E.311.3.41; E 312.3.41; E.313.3.41; E.314.3 i; E.315.3.41; E.316.a.4.i; E.317.3.41; E.318.3.41; E 319.3.41; E.320.3.41; E.321.3 1; E.322.3.41; E.323.a.4.i; E.324.a.4.i; E.325.3.41; E .326.3.41; E.327.3.41; E.328.3 i; E.329.3.41; E.330.a.4.i; E.331.3.41; E.332.3.41; E .333.3.41; E.334.3.41; E.335.a i; E.336.a.4.i; E.337.3.41; E.338.3.41; E.339.a.4.i; E .340.3.41; E.341.a.4.i; E.342.3 i; E.343.3.41; E.344.a.4.i; E.345.3.41; E.346.3.41; E .347.3.41; E.348.3.41; E.349.3 i; E.350.3.41; E.351.a.4.i; E.352.a.4.i; E.353.3.41; E .354.3.41; E.355.3.41; E.356.a i; E.357.3.41; E.358.3.41; B.2.3.111; B.3.alli; B.4.3.111; B.5.a.lli; B.9.a.ll BlOO.a.lli; B.lOl.a.lli; B.102.3.111; B.103.a.ll. i; B104.3.H1; B105 Ill; B 106.3.11. B.107.3.111 B.108.3.11. B.109 3.111, B.110.3.111; Bill ll.i; B 112.3.11. B.113.3.11. B.114.3.11. B.115 s.ll.i B.116.3.11.i; B.117 111; B.118.3.11. B.119.3.11. B.120.3.11. B.121 3.111 B122.3.11i; B.123 ll.i; B.124.3.11. B.125.3.11. B.126.3.11. B.127 3.111 B.128.3.111; B.129 ll.i; B.130.3.11. B.131.3.11. B.132.3.11. B.133 3.111 B134.3.111; B.135. ll.i; B.136.3.11. B.137.3.11. B.138.3.11. B.139 3.111 B140.alli; B.141. ll.i; B.142.aH. B.143.a.ll. B.144.a.ll. B.145 3.111 B.146.3.111; B.147 111; B.148.3.11. B149.aH. B.150.3.11. B.151 3.111 B.152.a.lli; B.153 ll.i; B.154.3.11. B.155.all. B.156.3.11. B.157 3.111, B.158.3.111; B.159 ll.i; B.160.3.11. B.161.3.11. B162.aH. B.163.3.111 B164.3.H1; B.165. 111; B.166.a.H. B.167.all. B.168.3.11. B.169.3.111 B.170.3.111; B.171 ll.i; B.172.3.11. B.173.3.11. B.174.3.11. B.175 3.111 B.176.a.lli; B.177 ll.i; B.178.3.11. B.179.a.ll. B.180.3.11. B.181.3.111, B182.3.111; B.183. 111; B.184.3.11. B.185.3.11. B.186.3.11. B.187 3.111, B188.3.111; B.189 Ill; B.190.3.11. B.191.3.11. B.192.3.11. B193.3.111. B194.3.111; B.195. ll.i; B.196.3.11. B.197.all B.198.3.11. B.199.3.111 B.200.3.111; B.201 111; B.202.aH. B.203.3.11. B.204.3.11. B.205 3.111 B.206.3.111; B.207 111; B.208.3.11. B.209.3.11. B.210.3.11. B.211.3.111 B.212.3.111; B.213 ll.i; B 214.3.11. B.215.3.11. B.216.a.ll. B.217.3.111 B.218.3.111; B.219 ll.i; B 220.3.11. B.221.3.11. B.222.3.11. B.223.3.111 B.224.3.111; B.225. ll.i; B, 226.3.11. B.227.3.11. B.228.3.11. B.229 3.111 B.230.3.111; B.231 111; B, 232.3.11. B.233.3.11. B.234.3.11. B.235.3.111 B.236.3.111; B.237 ll.i; B 238.3.11. B.239.all. B.240.a.ll. B.241.3.111 B.242.3.111; B.243 ll.i; B 244.3.11. B.245.3.11. B.246.3.11. B.247.3.111 B.248.3.111; B.249 111; B 250.3.11. B.251.3.11. B.252.3.11. B.253.3.111 B.254.3.111; B.255 111; B 256.3.11. B.257.3.11. B.258.a.ll. B.259.3.111 B.260.3.111; B.261 ll.i; B 262.3.11. B.263.3.11. B.264.3.11. B.265.3.111 B.266.3.111; B.267 ll.i; B 268.3.11. B.269.3.11. B.270.3.11. B.271.3.111 B.272.3.111; B.273 111; B ,274.3.11. B.275.3.11. B.276.3.11. B.277.3.111 B.278.3.111; B.279 ll.i; B 280.all. B.281.3.11. B.282.3.11. B.283. a.lli B.284.3.111; B.285 111; B 286.3.11. B.287.3.11. B.288.3.11. B.289.3.111 B.290.3.111; B.291 111; B ,292.3.11. B.293.3.11. B.294.3.11. B.295.3.111 B.296.3.111; B.297 ll.i; B ,298.all. B.299.3.11. B.300.3.11. B.301. a.lli B.302.3.111; B.303 ll.i; B ,304.all. B.305.3.11. B.306.3.11. B.307.3.111 B.308.3.111; B.309 ll.i; B .310.3.11. B.311.3.11. B.312.3.11. B.313.3.111 B.314.3.111; B.315 ll.i; B 316.a.ll. B.317.all. B.318.3.11. B.319.3.111 B.320.3.111; B.321 ll.i; B .322.3.11. B.323.all. B.324.a.ll. B.325. a.ll.i B.326.3.11. B.327.3.11. B.328.3 Hi; B.329.3.111; B.330.alli; B.331.3.11i; B.332.3. 11. B.333.a ,11. ; B.334.3111; B.335.3.111; B.336.alli; B.337.3.111; B.338.3. 11. B.339.3 11. B.340.3 Hi; B.341.3.111; B.342.3.111; B.343.alli; B.344.3. 11. B.345.3 .11. B.346.3 ll.i; B.347.a.lli; B.348.a.lli; B.349.alli; B.350.3. 11. B.351.3 .11. B.352.3111; B.353.3.111; B.354.3.111; B.355.3.111; B.356.3. 11. B.357.3. 11 ; B.358.3. ll.i; E.2.3.111; E.3.alli; E.4.alli; E.5.alli; E.9.3.11 i; E. 100.3.11 i; E 101.3.111; E.102.3.111; E.103.3.111; E.104.3.111; E.105.3. 11 ElOό.a. 11. E.107.3. 111; E. 108.all E.109.3.11. .; EHO.slli E.111.3. 11 E112.a .11. E.113.3. ll.i; E. H4.a.ll. E.115.3.11. .; E.116.a.lli E.117.3. 11. E.118.a 11. E.119.3 ll.i; E. 120.3.11. E.121.3.11. .; E.122.a.lli E.123.3. 11. E124.a 11. E.125.3. Ill; E. 126.3.11. E.127.all. .; E.128.3.11.i E.129.3. 11. E130.a ,11. E.131.3 111; E. 132.3.11. E.133.3.11. E.134.3.111 E.135.3. 11. E136.a ,11. E.137.3 111; E. 138.a.ll. E.139.3.11. E.140.3.111 E.141.3. 11. E.142.3. 11. E.143.3. ll.i; E. 144.3.11. E.145.3.11. E.146.3.11.i E.147.3. 11. E.148.3 11. E.149.3 111; E. 150.3.11. E.151.3.11. E.152.3.111 E.153.3. 11. E154.a. 11. E.155.3.111; E. 156.3.11. E.157.all. E.158.3.111 E.159.3. 11. E.lόO.a. 11. E.161.3. Hi; E. 162.3.11. E.163.3.11. E.164.a.lli E165.a. 11. E166.a. 11. E.167.3. ll.i; E. 168.a.ll. E.169.all. .; E170.alli E.171.3. 11. E.172.3. 11. E.173.3. ll.i; E. 174.aH. E.175.3.11. .; E.176.3.111 E.177.3. 11. E178.a. 11. .; E179.a. ll.i; E. 180.3.11. E.181.3.11. ; E.182.3.111 E.183.3. 11. E.184.3. 11. E.185.3 Hi; E. 186.3.11. E.187.all. ; E188.3.11i E.189.3. 11. E190.a. 11. E.191.3 ll.i; E. 192.3.11. E193.aH. .; E.194.3.111 E.195.3. 11. E.196.3. 11. E.197.3 111; E. 198.a.ll. E.199.3.11. .; E.200.3.111 E.201.3. 11. E.202.a. 11. E.203.3 Ill; E. 204.3.11. E.205.3.11. .; E.206.3111 E.207.3. 11. E.208.a. .11. E.209.3. Ill; E. 210.3.11. E.211.a.ll. .; E.212.3.111 E.213.3. 11. E.214.3 11. E.215.3. HI; E. 216.3.11. E.217.3.11. E.218.3.111 E.219.3. 11. E.220.3 11. . E.221.3. ll.i; E. 222.3.11. E.223.3.11. E.224.3111 E.225.3. 11. E.226.3 11. .; E.227.3. ll.i; E. 228.aH. E.229.3.11. E.230.3.111 E.231.3. 11. E.232.a. 11. E.233.3. Hi; E. 234.3.11. E.235.3.11. E.236.3.111 E.237.a. 11. E.238.3 .11. E.239.3. ll.i; E. 240.3.11. E.241.3.11. E.242.alll E.243.a. 11. E.244.a 11. E.245.a. ll.i; E. 246.3.11. E.247.3.11. E.248.a.lli E.249.3. 11. E.250.3 .11. .; E.251.3 ll.i; E. 252.aH. E.253.3.11. E.254.3.111 E.255.3. 11. E.256.3 11. E.257.a. ll.i; E. 258.3.11. E.259.3.11. ; E.260.alli E.261.3. 11. E.262.3 11. ; E.263.3. ll.i; E. 264.3.11. E.265.3.11. E.266.3.111 E.267.3. 11. E.268.a. 11. i; E.269.3 Ill; E. 270.3.11. E.271.3.11. E.272.3.111 E.273.3. 11. E.274.a 11. .; E.275.3 ll.i; E. 276.3.11. E.277.3.11. E.278.3.111 E.279.3. 11. E.280.3 11. E.281.3 Ill; E. 282.a.ll. E.283.3.11. E.284.3.111 E.285.3. 11. E.286.3 11. .; E.287.3 Ill; E. 288.3.11. E.289.3.11. E.290.3.111 E.291.3. 11. E.292.3 11. .; E.293.3 Ill; E. 294.all. E.295.3.11. ; E.296.3.111 E.297.3. 11. E.298.3 .11. E.299.3. ll.i; E. 300.3.11. E.301.3.11. ; E.302.3.111 E.303.3. 11. E.304.3 11. E.305.3. Ill; E. 306.3.11. E.307.3.11. ; E.308.3111 E.309.3. 11. E.310.3 .11. ; E.311.a Ill; E. •312.a.ll. E.313.3.11. i; E.314.3.111 E.315.3. 11. E.316.3 11. E.317.3 ll.i; E. 318.aH. E.319.3.11. E.320.3.111 E.321.3. 11. E.322.3 .11. E.323.3. ll.i; E. 324.3.11. E.325.3.11. E.326.3.111 E.327.3. 11. E.328.3 11. .; E.329.3. ll.i; E. 330.3.11. E.331.3.11. E.332.3.111 E.333.3. 11. E.334.3 11. E.335.a. ll.i; E. 336.3.11. E.337.a.ll. E.338.3.11.i E.339.3. 11. E.340.3 .11. E.341.3. ll.i; E. ,342.all. E.343.3.11. E.344.3.111 E.345.3.111; E.346.3.111; E.347.3.111; E.348.3.111; E.349.3.111; E.350.3.111;
E.351.3.111; E.352.3.111; E.353.3.111; E.354.a.lli; E.355.a.lli; E.356.3.111;
E.357.3.111; E.358.3.111; A.661.3.41; A.662.a.4.i; A.663.a.4.i; A.664.3.41;
A.665.3.41; B.661.3.41; B.662.3.41; B.663.3.41; B.664.3.41; B.665.3.41; C.661.3.41; C.662.3.41; C.663.3.41; C.664.3.41; C.665.3.41; A.661.3.111; A.662.a.lll;
A663.alli; A.664.3.111; A665.3.111; B.661.3.111; B.662.3.111; B.663.3.111;
B.664.3.111; B.665.3.111; C.661.3.111; C662.alli; C663.alli; C664.3.11i;
C.665.3111; A.661.a.44i; A.662.a.44.i; A663.a.44i; A.664.3.441; A.665.3.441;
B.661.3.441; B.662.3.441; B.663.3.441; B.664.3.441; B.665.3.441; C.661.3.441; C.662.3.441; C.663.3.441; C.664.3.441; C.665.3.441; A.666.3.41; A.666.alli;
A.666.a.44.i; A666.b.4.i; A.666.b.ll.i; A666.b.44i; A.666.X.41; A.666.X.111;
A666.X.441; A666.y.4.i; A.666.ylli; A666.y.44i; A.666.Z.41; A666.zlli;
A.666.Z.441; A.666A.41; A.666A111; A.666A.441; A.666.B.41; A.666.BH1;
A.666.B.441; A.666.C41; A.666.C.111; A.666.C441; A.666.D.41; A666.DH.i; A666.D.441; A.666.E.41; A.666.EH1; A666.E.441; A.666.F.41; A666.F.ll.i;
A666.F.441; B.666.3.41; B.666.3.111; B.666.a.44i; B.666.b.4.i; B.666.bll.i;
B.666.b.44i; B.666.X.41; B.666.X.111; B.666.X.441; B.666.y.4.i; B.666.y.lli;
B.666.y.44i; B.666.Z.41; B.666.Z.111; B.666.Z.441; B.666.B.41; B.666.BH1;
B.666.B.441; B.666.B.41; B.666.B.111; B.666.B.441; B.666.C41; B.666.CH1; B.666.C441; B.666.D.41; B.666.D.H1; B.666.D.441; B.666.E.41; B.666.EH1;
B.666.E.441; B.666.F.41; B.666.F111; B.666.F.441; E.666.3.41; E.666.3.111;
E.666.3.441; E.666.b.4.i; E.666.blli; E.666.b.44i; E.666.X.41; E.666.X.H1;
E.666.X.441; E.666.y.4.i; E.666.y.lll; E.666.y.44.i; E.666.Z.41; E.666.Z.H1;
E.666.Z.441; E.666.E.41; E.666.E.111; E.666.E.441; E.666.B.41; E.666.BH1; E.666.B.441; E.666.C.41; E.666.C.111; E.666.C441; E.666.D.41; E.666.DH1;
E.666.D.441; E.666.E.41; E.666.E111; E.666.E.441; E.666.F.41; E.666.F111;
E.666.F.441; A.2.3.461; A.3.3.461; A.4.3.461; A.5.a.46.i; A.7.a.46i; A.9.3.461;
A.100.3.46.i; A.101.a.46i; A102.a.46i; A.103.a.46i; A.104.3.461; A.105.a.46i;
A.106.3.461; A.107.3.461; A.108.a.46i; A.109.a.46i; A.110.a.46i; Alll.3.461; A.112.3.461; A.113.3.461; A.114.3.461; A.115.a.46i; A.116.a.46.i; A.117.a.46.i;
A118.a.46i; A.119.3.461; A120.a.46i; A121.a.46i; A.122.a.46i; A.123.a.46.i;
A.124.3.461; A.125.3.461; A.126.3.461; A.127.a.46i; A.128.3.461; A129.a.46.i;
A130.a.46.i; A131.a.46i; A132.a.46.i; A133.a.46.i; A134.a.46i; A135.a.46i;
A136.a.46i; A137.a.46i; A.138.3.461; A139.a.46i; A.140.3.461; A.141.3.461; A.2.3.471; A.3.3.471; A.4.3.471; A.5.3.471; A.7.a.47i; A.9.a.47i; A.100.3.471;
A.101.3.47.i; A.102.3.471; A.103.3.471; A.104.3.471; A.105.3.471; A.106.3.471;
A.107.3.471; A.108.3.471; A.109.3.471; A110.a.47.i; A.lll.a.47i; A112.a.47i;
A.113.3.471; A.114.3.471; A.115.3.471; A116.a.47i; A.117.3.471; A.118.3.471;
A.119.3.471; A120.a.47i; A.121.a.47.i; A.122.3.471; A.123.3.471; A.124.3.471; A125.a.47i; A126.a.47i; A127.a.47.i; A.128.a.47.i; A129.a.47.i; A130.a.47i;
A.131.a.47.i; A.132.3.471; A.133.3.471; A134.a.47i; A.135.a.47.i; A136.a.47.i;
A.137.3.471; A.138.3.471; A.139.3.471; A140.a.47i; A141.a.47i; A.2.a.48i;
A.3.3.481; A.4.3.481; A.5.3.481; A.7.3.481; A.9.a.48i; A100.a.48i; A.101.3.481;
A.102.3.481; A.103.3.481; A104.a.48.i; A.105.a.48i; A.106.a.48i; A107.a.48i; A.108.3.481; A.109.3.481; A.110.a.48.i; Alll.a.48i; A.112.a.48.i; A.113.a.48i;
A.114.3.481; A.115.3.481; A.116.3.481; A.117.3.481; A.118.3.481; A.119.3.481;
A.120.3.481; A121.a.48i; A122.a.48i; A123.a.48i; A.124.a.48i; A.125.3.481; A.126.3.481; A127.a.48.i; A128.a.48.i; A129.a.48i; A130.a.48i; A131.a.48.i;
A132.a.48i; A.133.3.481; A.134.3.481; A.135.3.481; A.136.a.48.i; A137.a.48.i;
A.138.3.481; A139.a.48i; A140.a.48i; A.141.3.481; A.2.3.491; A.3.3.491;
A.4.3.491; A.5.3.491; A.7.3.491; A.9.3.491; A100.a.49i; A.101.3.491; A.102.3.491; A.103.3.491; A.104.3.491; A.105.3.491; A.106.3.491; A.107.3.491; A.108.3.491;
A.109.3.491; AHO.3.491; Alll.3.491; A.112.3.491; A.113.3.491; A114.3.49.i;
A.115.3.491; A.116.3.491; A.117.3.491; A.118.3.491; A.119.3.491; A.120.3.491;
A.121.3.491; A.122.3.491; A.123.3.491; A124.a.49.i; A125.a.49.i; A126.a.49.i;
A.127.3.491; A.128.3.491; A.129.3.491; A.130.3.491; A.131.3.491; A.132.3.491; A.133.3.491; A.134.3.491; A.135.3.491; A.136.3.491; A.137.3.491; A.138.3.491;
A.139.3.491; A.140.3.491; A.141.3.491; A.2.3.501; A.3.3.501; A4.a.50.i; A5.a.50.i;
A.7.3.501; A.9.3.501; A.100.3.501; A.101.3.501; A.102.3.501; A.103.3.501;
A.104.3.501; A.105.3.501; A.106.3.501; A.107.3.501; A.108.3.501; A.109.3.501;
A110.3.50i; A111.3.50.i; A.112.3.501; A113.a.50i; A.114.a.50i; A.115.3.501; A.116.3.501; A.117.3.501; A.118.3.501; A.119.3.501; A.120.3.501; A.121.3.501;
A.122.3.501; A.123.a.50i; A124.a.50i; A.125.3.501; A.126.3.501; A.127.3.501;
A.128.3.501; A.129.3.501; A.130.3.501; A.131.3.501; A.132.3.501; A.133.3.501;
A134.a.50.i; A135.a.50.i; A.136.3.501; A137.a.50i; A.138.a.50.i; A139.a.50.i;
A.140.3.501; A.141.3.501; A.2.a.51i; A3.a.51i; A.4.3.511; A.5.3.511; A.7.3.511; A.9.3.511; A.100.3.511; A.101.3.511; A.102.3.511; A.103.a.51i; A.104.a.51.i;
A.105.3.511; A.106.3.511; A.107.3.511; A.108.3.511; A.109.a.51.i; A110.a.51i;
Alll.3.511; A.112.3.511; A.113.3.511; A.114.3.511; A.115.3.511; A.116.3.511;
A.117.3.511; A.118.3.511; A.119.3.511; A.120.3.511; A.121.3.511; A.122.3.511;
A.123.3.511; A.124.3.511; A.125.3.511; A.126.3.511; A.127.3.511; A.128.3.511; A.129.3.511; A.130.3.511; A.131.3.511; A.132.3.511; A.133.3.511; A.134.3.511;
A135.a.51i; A136.a.51i; A.137.3.511; A.138.3.511; A.139.3.511; A.140.3.511;
A.141.3.511; A2.b.46i; A.3.b.46i; A4.b.46i; A.5.b.46i; A.7.b.46i; A.9.b.46i;
A100.b.46i; A.101.b.46i; A.102.b.46.i; A103.b.46i; A.104.b.46.i; A105.b.46.i;
A106.b.46.i; A107.b.46i; A.108.b.46.i; A109.b.46.i; A110.b.46i; Alll.b.46i; A112.b.46i; A113.b.46i; A.114.b.46i; A.115.b.46.i; A.116.b.46.i; A117.b.46i;
A.118.b.46i; A.119.b.46i; A.120.b.46i; A.121.b.46i; A.122.b.46i; A.123.b.46i;
A.124.b.46i; A.125.b.46i; A.126.b.46i; A.127.b.46i; A.128.b.46i; A.129.b.46i;
A.130.b.46i; A.131.b.46i; A.132.b.46i; A.133.b.46i; A.134.b.46i; A.135.b.46i;
A136.b.46i; A.137.b.46i; A.138.b.46i; A.139.b.46i; A.140.b.46i; A141.b.46.i; A2.b.47i; A.3.b.47i; A.4.b.47.i; A.5.b.47i; A.7.b.47i; A.9.b.47.i; A.100.b.47i;
A.101.b.47.i; A.102.b.47i; A.103.b.47i; A.104.b.47i; A.105.b.47i; A.106.b.47i;
A107.b.47.i; A.108.b.47i; A.109.b.47i; A.110.b.47i; Alll.b.47.i; A.112.b.47i;
A.113.b.47i; A.114.b.47i; A.115.b.47i; A.116.b.47i; A.117.b.47i; A.118.b.47i;
A119.b.47.i; A.120.b.47i; A.121.b.47i; A122.b.47i; A.123.b.47i; A.124.b.47i; A.125.b.47.i; A.126.b.47i; A127.b.47i; A.128.b.47i; A.129.b.47i; A130.b.47.i;
A131.b.47.i; A.132.b.47i; A.133.b.47.i; A.134.b.47i; A.135.b.47i; A.136.b.47i;
A137.b.47.i; A.138.b.47i; A139.b.47.i; A.140.b.47i; A.141.b.47i; A.2.b.48.i;
A3.b.48.i; A.4.b.48i; A.5.b.48i; A.7.b.48i; A.9.b.48i; A.100.b.48i; A.101.b.48i;
A102.b.48.i; A.103.b.48i; A.104.b.48i; A.105.b.48i; A.106.b.48i; A107.b.48.i; A.108.b.48i; A.109.b.48i; A.110.b.48i; A.lll.b.48i; A112.b.48.i; A.113.b.48i;
A114.b.48.i; A.115.b.48i; A116.b.48i; A.117.b.48i; A118.b.48.i; A119.b.48.i;
A120.b.48.i; A.121.b.48i; A.122.b.48i; A.123.b.48i; A.124.b.48i; A125.b.48i; A126.b.48i; A.127.b.48i; A.128.b.48.i; A.129.b.48i; A.130.b.48i; A.131.b.48i;
A132.b.48.i; A.133.b.48i; A.134.b.48i; A.135.b.48i; A.136.b.48i; A.137.b.48i;
A138.b.48.i; A.139.b.48i; A.140.b.48i; A.141.b.48i; A.2.b.49i; A.3.b.49.i;
A.4.b.49.i; A.5.b.49i; A.7.b.49.i; A.9.b.49i; A.100.b.49i; A.101.b.49i; A.102.b.49.i; A103.b.49.i; A.104.b.49i; A.105.b.49i; A.106.b.49i; A.107.b.49i; A.108.b.49i;
A109.b.49.i; A.110.b.49i; A.lll.b.49i; A.112.b.49i; A.113.b.49i; A114.b.49.i;
A115.b.49.i; A.116.b.49i; A.117.b.49i; A.118.b.49i; A.119.b.49i; A.120.b.49i;
A121.b.49i; A.122.b.49i; A.123.b.49i; A.124.b.49i; A.125.b.49i; A.126.b.49i;
A.127.b.49i; A.128.b.49i; A.129.b.49i; A.130.b.49i; A.131.b.49i; A.132.b.49i; A.133.b.49i; A.134.b.49i; A.135.b.49.i; A.136.b.49i; A.137.b.49i; A.138.b.49.i;
A.139.b.49.i; A.140.b.49i; A.141.b.49i; A2.b.50i; A.3.b.50i; A.4.b.50.i; A5.b.50.i;
A7.b.50.i; A.9.b.50i; A.100.b.50i; A.101.b.50i; A.102.b.50i; A.103.b.50i;
A104.b.50.i; A.105.b.50i; A.106.b.50i; A.107.b.50i; A.108.b.50.i; A.109.b.50i;
A.110.b.50i; A.lll.b.50i; A.112.b.50i; A.113.b.50i; A.114.b.50.i; A.115.b.50.i; A.116.b.50i; A.117.b.50i; A.118.b.50i; A.119.b.50i; A.120.b.50.i; A.121.b.50.i;
A122.b.50.i; A.123.b.50i; A124.b.50i; A.125.b.50i; A.126.b.50i; A127.b.50.i;
A128.b.50i; A.129.b.50i; A.130.b.50i; A.131.b.50i; A.132.b.50i; A.133.b.50i;
A.134.b.50i; A.135.b.50i; A.136.b.50i; A.137.b.50i; A.138.b.50i; A.139.b.50i;
A.140.b.50i; A.141.b.50i; A.2.b.51i; A.3.b.51i; A.4.b.51i; A.5.b.51i; A.7.b.51i; A9.b.51i; A.100.b.51i; A.101.b.51i; A.102.b.51i; A.103.b.51i; A104.b.51i;
A.105.b.51i; A.106.b.51i; A.107.b.51i; A.108.b.51i; A.109.b.51i; A.110.b.51i;
Alll.b.51.i; A.112.b.51i; A.113.b.51i; A.114.b.51i; A.115.b.51i; A.116.b.51i;
A.117.b.51i; A.118.b.51i; A.119.b.51.i; A.120.b.51i; A.121.b.51i; A.122.b.51i;
A.123.b.51i; A.124.b.51i; A.125.b.51i; A.126.b.51i; A.127.b.51i; A.128.b.51i; A129.b.51.i; A.130.b.51i; A131.b.51.i; A.132.b.51i; A133.b.51i; A.134.b.51i;
A.135.b.51i; A.136.b.51i; A.137.b.51i; A.138.b.51i; A.139.b.51i; A.140.b.51i;
A141.b.51.i; A.2.X.461; A.3.X.461; A.4.X.461; A.5.X.461; A.7.X.461; A.9.X.461;
A100.X.461; A.lθl.x.461; A102.X.461; A103.X.461; A.104.X.461; A105.X.461;
A106.X.461; A.107.X.461; A108.X.461; A109.X.461; AHO.x.461; A.lll.x.461; AH2.X.461; A.H3.X.461; A114.X.461; A115.X.461; A116.X.461; A117.X.461;
AH8.X.461; A119.X.461; A120.X.461; A.121.X.461; A.122.X.461; A123.X.461;
A124.X.461; A.125.X.461; A126.X.461; A127.X.461; A128.X.461; A129.X.461;
A130.X.461; A131.X.461; A132.X.461; A133.X.461; A.134.X.461; A135.X.461;
A136.X.461; A137.X.461; A138.X.461; A.139.X.461; A140.X.461; A141.X.461; A2.X.471; A.3.X.471; A.4.X.471; A.5.X.471; A7.X.471; A.9.X.471; AlOO.x.471;
A101.X.471; A102.X.471; A103.X.471; A.104.X.471; A.105.X.471; A106.X.471;
A107.X.471; A.108.X.471; A109.X.471; A.llO.x.471; Alll.x.471; AH2.X.471;
AH3.X.471; A.114.X.471; A115.X.471; AH6.X.471; A.117.X.471; AH8.X.471;
A.H9.X.471; A120.X.471; A121.X.471; A122.X.471; A.123.X.471; A124.X.471; A.125.X.471; A.126.X.471; A127.X.471; A.128.X.471; A.129.X.471; A.130.X.471;
A131.X.471; A.132.X.471; A.133.X.471; A134.X.471; A135.X.471; A136.X.471;
A137.X.471; A138.X.471; A139.X.471; A.140.X.471; A141.X.471; A.2.X.481;
A.3.X.481; A.4.X.481; A.5.X.481; A7.X.481; A.9.X.481; AlOO.x.481; Alθl.x.481;
A102.X.481; A.103.X.481; A104.X.481; A.105.X.481; A106.X.481; A107.X.481; A108.X.481; A109.X.481; AHO.x.481; A.lll.x.481; A.112.X.481; AH3.X.481;
AH4.X.481; A.115.X.481; AH6.X.481; A.117.x.48.i; A118.X.481; AH9.X.481;
A120.X.481; A121.X.481; A.122.X.481; A123.X.481; A124.X.481; A125.X.481; A.126.X.481; A.127.X.481; A.128.X.481; A.129.X.481; A.130.X.481; A131.X.481; A.132.X.481; A133.X.481; A134.X.481; A135.X.481; A.136.X.481; A137.X.481; A.138.X.481; A139.X.481; A140.X.481; A141.X.481; A.2.X.491; A3.X.491;
A.4.X.491; A5.X.491; A.7.X.491; A.9.X.491; AlOO.x.491; Alθl.x.491; A102.X.491; A.103.X.491; A104.X.491; A105.X.491; A106.X.491; A107.X.491; A108.X.491; A.109.X.491; AHO.x.491; Alll.x.491; AH2.X.491; A.113.X.491; AH4.X.491;
A. H5.X.491; A116.X.491; A117.X.491; AH8.X.491; A.119.X.491; A120.X.491; A.121.X.491; A122.X.491; A123.X.491; A124.X.491; A.125.X.491; A126.X.491; A.127.X.491; A128.X.491; A129.X.491; A130.X.491; A131.X.491; A132.X.491;
A.133.X.491; A134.X.491; A135.X.491; A136.X.491; A137.X.491; A138.X.491; A.139.X.491; A140.X.491; A141.X.491; A2.X.501; A3.X.501; A.4.X.501; A.5.X.501;
A.7.X.501; A.9.X.501; A100.x.50i; Alθl.x.501; A102.X.501; A103.X.501; A.104.X.501; A105.X.501; A106.X.501; A107.X.501; A108.X.501; A109.X.501; A. H0.X.501; A.111.X.501; A112.X.501; AH3.X.501; A.H4.X.501; AH5.X.501; A. H6.X.501; AH7.X.501; AH8.X.501; AH9.X.501; A.120.X.501; A121.X.501; A.122.X.501; A123.X.501; A124.X.501; A.125.X.501; A.126.X.501; A127.X.501; A.128.X.501; A129.X.501; A130.X.501; A131.X.501; A.132.X.501; A133.X.501; A.134.X.501; A.135.X.501; A136.X.501; A137.X.501; A.138.X.501; A139.X.501; A.140.X.501; A141.X.501; A.2.X.511; A.3.X.511; A.4.X.511; A.5.X.511; A.7.X.511; A.9.X.511; A.lOO.x.511; Alθl.x.511; A.102.X.511; A103.X.511; A104.X.511; A.105.X.511; A.106.X.511; A107.X.511; A108.X.511; A.109.X.511; AHO.x.511; A.1H.X.511; AH2.X.511; AH3.X.511; AH4.X.511; A.115.X.511; AH6.X.511; A. H7.X.511; AH8.X.511; A119.X.511; A120.X.511; A.121.X.511; A122.X.511; A.123.X.511; A124.X.511; A125.X.511; A126.X.511; A.127.X.511; A128.X.511; A.129.X.511; A130.X.511; A131.X.511; A132.X.511; A.133.X.511; A134.X.511; A.135.X.511; A136.X.511; A.137.x.51.i; A138.X.511; A.139.X.511; A140.X.511; A.141.X.511; A.2.y.46i; A.3.y.46i; A.4.y.46.i; A.5.y.46.i; A.7.y.46i; A.9.y.46.i; A.100.y.461; A101.y.46i; A.102.y.46i A103.y.46.i; A.104.y.46.i; A105.y.46.i; A.106.y.46.i; A107.y.46i; A108.y.46i; A109.y.46i; A.110.y.46i; A.lll.y.46i; A. H2.y.46.i; A113.y.46i; A.114.y.46.i; A.115.y.46.i; A116.y.46i; A117.y.46.i; A.118.y.461; A119.y.46i; A120.y.46i; A.121.y.46.i; A.122.y.46.i; A123.y.46.i; A, ,124.y.46.i; A125.y.46i; A126.y.46.i; A.127.y.46i; A.128.y.46i; A129.y.46i; A, 130.y.46.i; A131.y.46i; A.132.y.46i; A133.y.46i; A.134.y.46i; A135.y.46.i; A 136.y.46.i; A137.y.46i; A138.y.46i; A139.y.46i; A140.y.46i; A141.y.46i; A, ,2.y.47.i; A.3.y.47i; A.4.y.47i; A.5.y.47i; A.7.y.47.i; A.9.y.47.i; A100.y.47.i; A, ,101.y.47i; A102.y.47i; A103.y.47i; A104.y.47i; A.105.y.47.i; A106.y.47.i; A ,107.y.47.i; A108.y.47i; A109.y.47i; A.110.y.47i; A.lll.y.47i; A112.y.47.i; A, H3.y.47i; A114.y.47i; A115.y.47i; A116.y.47i; A.117.y.47i; A118.y.47i; A, ,119.y.47i; A.120.y.47i; A.121.y.47.i; A122.y.47.i; A.123.y.47.i; A124.y.47.i; A, ,125.y.47i; A126.y.47i; A.127.y.47i; A128.y.47.i; A129.y.47i; A130.y.47i; A ,131.y.47.i; A132.y.47i; A133.y.47i; A134.y.47.i; A135.y.47i; A136.y.47.i; A ,137.y.47.i; A138.y.47.i; A139.y.47i; A140.y.47i; A.141.y.47.i; A2.y.48i; A .3.y.48.i; A4.y.48i; A.5.y.48.i; A.7.y.48i; A.9.y.48i; A100.y.48i; A.101.y.48.i; A ,102.y.48.i; A.103.y.48i; A104.y.48.i; A105.y.48i; A.106.y.48i; A107.y.48.i; A ,108.y.48.i; A109.y.48.i; A.110.y.48i; A.lll.y.48.i; A.112.y.48i; A113.y.48i; A H4.y.48.i; A.115.y.48.i; A116.y.48i; A117.y.48i; A118.y.48i; A119.y.48i; A 120.y.48.i; A.121.y.48.i; A.122.y.48i; A.123.y.48i; A124.y.48i; A125.y.48i; A 126.y.48. A.127.y.48i; A128.y.48.i; A129.y.48i; A130.y.48.i; A131.y.48.i;
A. 132.y.48.: A133.y.48i; A.134.y.48.i; A135.y.48i; A.136.y.48i; A137.y.48.i;
A, 138.y.48 , A139.y.48i; A140.y.48.i; A141.y.48i; A2.y.49i; A.3.y.49.i;
A, .4.y.49.i; A.J 5.y.491; A.7.y.49i; A.9.y.49i; A100.y.49i; A.101.y.49.i; A102.y.49i;
A. 103.y.49 A104.y.49i; A.105.y.49.i; A106.y.49.i; A.107.y.49.i; A108.y.49.i;
A. 109.y.49. A110.y.49i; Alll.y.49i; A.112.y.49.i; A113.y.49.i; A.114.y.49.i;
A 115.y.49. A116.y.49i; A.117.y.49.i; A.118.y.49.i; A.119.y.49.i; A.120.y.49.i;
A. 121.y.49. A.122.y.49i; A.123.y.49.i; A.124.y.49.i; A.125.y.49.i; A126.y.49i;
A. 127.y.49. A.128.y.49.i; A129.y.49.i; A.130.y.49.i; A.131.y.49.i; A.132.y.49.i;
A 133.y.49. A.134.y.49.i; A.135.y.49.i; A.136.y.49.i; A.137.y.49.i; A.138.y.49.i;
A. 139.y.49.^ A.140.y.49.i; A.141.y.49.i; A.2.y.50.i; A.3.y.50.i; A.4.y.50.i; A.5.y.50.i;
A .7.y.50i; A 9.y.50i; A.100.y.50.i; A.101.y.50.i; A.102.y.50.i; A.103.y.50.i;
A. 104.y.50. A.105.y.50.i; A.106.y.50.i; A.107.y.50.i; A.108.y.50.i; A.109.y.50.i;
A. 110.y.50. A.lll.y.50.i; A.112.y.50.i; A.113.y.50.i; A.114.y.50.i; A.115.y.50.i;
A, 116.y.50. A.117.y.50.i; A.118.y.50.i; A.119.y.50.i; A.120.y.50.i; A.121.y.50.i;
A, 122.y.50. A.123.y.50.i; A.124.y.50i; A.125.y.50.i; A.126.y.50i; A.127.y.50.i;
A, 128.y.50. A.129.y.50i; A.130.y.50i; A.131.y.50.i; A.132.y.50.i; A.133.y.50.i;
A. 134.y.50. A.135.y.50.i; A.136.y.50i; A.137.y.50.i; A.138.y.50i; A.139.y.50.i;
A, 140.y.50. . A.141.y.50.i; A.2.y.51.i; A.3.y.51.i; A.4.y.51.i; A.5.y.51.i; A.7.y.51.i;
A. .9.y.51i; A 100.y.51.i; A.101.y.51.i; A.102.y.51.i; A.103.y.51.i; A.104.y.51.i;
A, 105.y.51 A.106.y.51.i; A.107.y.51.i; A.108.y.51.i; A.109.y.51.i; A.110.y.51.i;
A ll.y.51.. A.112.y.51.i; A.113.y.51.i; A.114.y.51.i; A.115.y.51.i; A.116.y.51.i;
A 117.y.51.: A.118.y.51.i; A.119.y.51.i; A.120.y.51.i; A.121.y.51.i; A.122.y.51.i;
A. 123.y.51. A.124.y.51.i; A.125.y.51.i; A.126.y.51.i; A.127.y.51.i; A.128.y.51.i;
A. 129.y.51. A.130.y.51.i; A.131.y.51.i; A.132.y.51.i; A.133.y.51.i; A.134.y.51.i;
A. 135.y.51. A.136.y.51.i; A.137.y.51.i; A.138.y.51.i; A.139.y.51.i; A.140.y.51.i;
A. 141.y.51 A.2.Z.461; A.3.Z.461; A.4.Z.461; A.5.Z.461; A.7.Z.461; A.9.Z.461;
A, lOO.z.46 A.lθl.z.461; A.102.Z.46. ; A.103.Z.461; A.104.Z.461; A105.Z.461;
A, 106.Z ...46, A107.Z.461; A.108.Z.46. ; A.109.Z.461; A.110.z.46.i; Alll.z.461;
A, 112.Z :..46. A.113.Z.461; A114.Z.46. ; A.115.Z.461; A.116.Z.461; A.117.Z.461;
A, 118.Z -,.46. A.119.Z.461; A.120.Z.46. ; A.121.Z.461; A122.Z.461; A.123.Z.461;
A, 124.Z :.46. A125.Z.461; A.126.Z.46. ; A.127.Z.461; A.128.Z.461; A.129.Z.461;
A. 130.Z. .461; A131.Z.461; A.132.Z.46. ; A.133.Z.461; A134.Z.461; A135.Z.461;
A, 136.Z. .461; A.137.Z.461; A.138.Z.46. ; A.139.Z.461; A140.Z.461; A141.Z.461;
A .2.Z :,.47 1.i; A, 3.Z.471; A.4.Z.471; A.5.Z.471; A.7.Z.471; A.9.Z.471; AlOO.z.471;
A 101.: ;.47.i; A102.Z.471; A103.Z.471; A104.Z.471; A105.Z.471; A106.Z.471;
A 107.: ;.47i; A108.Z.471; A109.Z.471; AHO.z.471; Alll.z.471; A.H2.Z.471;
A 113.: ;.47i; A.114.Z.471; AH5.Z.471; A116.Z.471; A.117.Z.471; AH8.Z.471;
A, 119 .Z.471; A120.Z.471; A121.Z.471; A122.Z.471; A123.Z.471; A124.Z.471;
A 125. .Z.471; A126.Z.471; A.127.Z.471; A128.Z.471; A129.Z.471; A130.Z.471;
A .131 .z.47.i; A132.Z.471; A133.Z.471; A134.Z.471; A.135.Z.471; A136.Z.471;
A 137 ..z: .47._, A138.Z.471; A.139.Z.471; A140.Z.471; A.141.Z.471; A2.Z.481;
A .3.z ;.48i; A..4.Z.481; A.5.Z.481; A.7.Z.481; A.9.Z.481; A.lOO.z.481; A.lθl.z.481;
A .1 _0.22..z: .48i; A.103.Z.481; A.104.Z.481; A.105.Z.481; A.106.Z.481; A107.Z.481;
A 108.Z.481; A.109.Z.481; A.110.z.48.i; A.lll.z.481; A.112.Z.481; AH3.Z.481;
A H4.Z.481; AH5.Z.481; AH6.Z.481; A117.Z.481; A.118.Z.481; AH9.Z.481;
A. 120.Z.48.:' A121.Z.481; A.122.Z.481; A.123.Z.481; A.124.z.48.i; A.125.Z.481; A126.Z.481; A127.Z.481; A128.Z.481; A129.Z.481; A130.Z.481; A131.Z.481;
A132.Z.481; A.133.Z.481; A134.Z.481; A135.Z.481; A.136.Z.481; A137.Z.481;
A138.Z.481; A139.Z.481; A140.Z.481; A141.Z.481; A.2.Z.491; A.3.Z.491;
A4.Z.491; A5.Z.491; A7.Z.491; A9.Z.491; AlOO.z.491; Alθl.z.491; A.102.Z.491; A103.Z.491; A104.Z.491; A105.Z.491; A106.Z.491; A107.Z.491; A108.Z.491;
A109.Z.491; A110.z.49i; Alll.z.491; A112.Z.491; AH3.Z.491; A114.z.49.i;
AH5.Z.491; AH6.Z.491; AH7.Z.491; AH8.Z.491; AH9.Z.491; A120.Z.491;
A.121.Z.491; A122.Z.491; A123.Z.491; A124.Z.491; A125.Z.491; A126.Z.491;
A127.Z.491; A128.Z.491; A129.Z.491; A130.Z.491; A.131.Z.491; A132.Z.491; A133.Z.491; A134.Z.491; A135.Z.491; A136.Z.491; A137.Z.491; A138.Z.491;
A139.Z.491; A140.Z.491; A141.Z.491; A2.Z.501; A3.Z.501; A.4.Z.501; A.5.z.50.i;
A7.Z.501; A.9.Z.501; A100.z.50i; A.lθl.z.501; A102.Z.501; A.103.Z.501;
A104.Z.501; A105.Z.501; A106.Z.501; A107.Z.501; A108.Z.501; A109.Z.501;
A.H0.Z.501; Alll.z.501; A.112.Z.501; A113.Z.501; AH4.Z.501; AH5.Z.501; A116.Z.501; A.117.Z.501; AH8.Z.501; AH9.Z.501; A120.Z.501; A121.Z.501;
A.122.Z.501; A123.Z.501; A124.Z.501; A.125.Z.501; A126.Z.501; A127.Z.501;
A128.Z.501; A129.Z.501; A130.Z.501; A131.Z.501; A.132.Z.501; A133.Z.501;
A134.Z.501; A135.Z.501; A136.Z.501; A137.Z.501; A.138.Z.501; A.139.Z.501;
A140.Z.501; A141.Z.501; A2.Z.511; A3.Z.511; A4.Z.511; A.5.Z.511; A.7.Z.511; A.9.Z.511; A.lOO.z.511; Alθl.z.511; A102.Z.511; A103.Z.511; A.104.z.51.i;
A105.Z.511; A106.Z.511; A107.Z.511; A108.Z.511; A.109.z.51.i; AHO.z.511;
A.111.Z.511; AH2.Z.511; A.113.Z.511; A.114.Z.511; A115.Z.511; AH6.Z.511;
AH7.Z.511; A118.Z.511; A119.Z.511; A120.Z.511; A121.Z.511; A122.Z.511;
A123.Z.511; A124.Z.511; A125.Z.511; A126.Z.511; A127.Z.511; A.128.Z.511; A129.Z.511; A130.Z.511; A.131.Z.511; A132.Z.511; A133.Z.511; A134.Z.511;
A.135.Z.511; A.136.Z.511; A137.Z.511; A138.Z.511; A139.Z.511; A140.Z.511;
A141.Z.511; A.2A.461; A.3A.461; A4A.461; A.5A.461; A.7.A461; A.9.A461;
A100A.461; A.101.A.461; A102A.461; A103A.461; A104A.461;
A105.A461; A106A.461; A107A.461; A.108A.461; A109A.461; A.110.A461; A111A.461; AH2A46i; AH3A.461; A.114A.461;
AH5A.46.i; A.116.A461; A117.A46i; A.118A.461; A.119A.461;
A120A.461; A121A.461; A.122A.461; A.123A.461; A124A.461;
A125.A46i; A126A.461; A127A.461; A128.A461; A129A.461;
A130.A461; A131A.461; A.132A.461; A133.A46i; A134A.461; A.135.A461; A136.A46i; A137.A46i; A.138A.461; A139A.461;
A140A.461; A141A.461; A.2A.471; A3A.471; A.4A.471; A.5A.471;
A7A.471; A.9.A471; A.100A.471; A.101A.471; A.102A.471; A103A.471;
A.104.A471; A.105A.471; A106A.471; A107A.471; A.108A.471;
A109.A47i; AH0A.47i; A.111A.471; AH2A.47i; A.113A.471; AH4A.47i; A.115A.471; A116.A471; AH7.A47i; A.118A.471;
A119A47.i; A120A.471; A.121.A471; A.122A.471; A.123A.471;
A124A.471; A125A.471; A126A.471; A127A.471; A.128A.471;
A.129.A471; A.130A.471; A131.A471; A.132A.471; A.133A.471;
A134.A471; A135A.471; A.136A.471; A.137A.471; A138A.471; A139.A471; A.140A.471; A141A.471; A.2A.481; A.3.A481; A.4.A481;
A.5.A.481; A.7A.481; A.9A.481; A.100A.481; A101A.481; A.102.A481;
A.103.A481; A.104A.481; A105A.481; A106A.481; A.107A.481; A.108.A.481; A.109.A.481; A.110A.481; A.111.A.481; A.112A.481;
A.113.A.481; A.114.A.481; A115A.481; AH6A.481; A.117A.481;
A.H8.A48.i; A.119.A481; A.120.A.481; A.121 A.481; A122A.481;
A.123.A481; A.124.A.481; A.125A.481; A126A.481; A127A.481; A.128.A481; A129A.481; A.130.A.481; A.131.A.481; A132A.481;
A.133.A.481; A.134.A481; A.135A.481; A.136.A.481; A137A.481;
A.138.A481; A139A.481; A140A.481; A.141.A.481; A.2A.491; A.3A.491;
A4A.491; A5.A491; A.7A.491; A.9A.491; A100A.491; A101A.491;
A102A.491; A.103A.491; A.104A.491; A.105.A.491; A.106A.491; A.107A.491; A108A.491; A109A.491; AH0A.49i; AH1A.491;
AH2.A491; AH3A.491; A.114A49i; AH5A.49i; AH6A.491;
AH7.A49.i; AH8A.491; AH9.A491; A120A.491; A121A.491;
A.122.A491; A123A.491; A124A.491; A125A.491; A126A.491;
A127.A49.i; A128A.491; A.129.A491; A130A.491; A131A.491; A132.A491; A133.A49.i; A134.A491; A135A.491; A136A.491;
A.137.A491; A138A.491; A.139A.491; A.140.A.491; A141A.491; A.2.A501;
A3A.501; A.4.A501; A.5A.501; A.7A.501; A.9A.501; A100A.501;
A101A50i; A.102.A501; A.103A.501; A104A.501; A.105.A.501;
A106A50i; A.107A.501; A108A.501; A.109A.501; A.110A.501; A.111.A.501; A112A.50.i; A.113A.501; A.114A.501; A.115A.501;
AH6.A50.i; A117A50.i; A.118A.501; A.119.A501; A120A.501;
A.121.A.501; A.122.A.501; A123.A501; A.124.A501; A.125A.501;
A.126A.501; A.127.A501; A128.A50i; A.129.A501; A130A.501;
A131.A501; A.132A.501; A133A.501; A.134A.501; A.135A.501; A136.A50.i; A.137A.501; A.138.A501; A139A.501; A140A.501;
A141A50.i; A.2A.511; A.3A.511; A.4.A511; A.5A.511; A.7A.511;
A.9A.511; A100A.511; A101A.511; A102A.511; A.103.A.511; A.104A.511;
A.105A511; A.106.A.511; A.107A.511; A.108.A.511; A109A.511;
A110A51i; A.111.A.511; A.112A.511; A113.A.511; A.114A.511; A.115A.511; A.116A.511; A117.A51i; A.118A.511; A.119A.51i;
A.120A.511; A121A.511; A.122A.511; A.123A.511; A.124A.511;
A.125A.511; A126A.511; A.127A511; A.128.A511; A129A.511;
A.130A511; A.131.A.511; A132A511; A133.A51i; A.134A.511;
A.135.A511; A.136.A511; A137.A51i; A.138.A511; A.139.A.511; A.140.A.511; A141A.511; A2.B.461; A.3.B.461; A.4.B.461; A5.B.461;
A7.B.461; A.9.B.461; A.100.B.461; A101.B.461; A102.B.461; A103.B.461;
A104.B.461; A105.B.461; A106.B.461; A107.B.461; A108.B.461; A109.B.461;
AH0.B.461; A.111.B.461; A112.B.461; A113.B.461; A.114.B.461; AH5.B.461;
AH6.B.46.i; A.117.B.461; AH8.B.461; A119.B.461; A120.B.461; A121.B.461; A122.B.461; A123.B.461; A124.B.461; A125.B.461; A126.B.461; A127.B.461;
A128.B.461; A129.B.461; A130.B.461; A131.B.461; A.132.B.461; A133.B.461;
A134.B.461; A135.B.461; A136.B.461; A137.B.461; A.138.B.461; A139.B.461;
A140.B.461; A141.B.461; A.2.B.471; A.3.B.471; A.4.B.471; A.5.B.471;
A7.B.471; A.9.B.471; A100.B.471; A101.B.471; A.102.B.471; A103.B.471; A104.B.471; A.105.B.471; A106.B.471; A107.B.471; A.108.B.471; A109.B.471;
A110.B.471; A.1H.B.471; AH2.B.471; A113.B.471; A114.B.471; AH5.B.471;
AH6.B.471; A117.B.471; A.118.B.471; A119.B.471; A120.B.471; A121.B.471; A122.B.471; A123.B.471; A124.B.471; A.125.B..471; A126.B.471; A127.B.471;
A128.B.471; A.129.B.471; A130.B.471; A.131.B.471; A.132.B.471; A133.B.471;
A134.B.471; A.135.B.471; A136.B.471; A.137.B.471; A138.B.471; A139.B.471;
A140.B.471; A141.B.471; A.2.B.481; A.3.B.481; A.4.B.481; A.5.B.481; A.7.B.481; A9.B.481; A100.B.481; A101.B.481; A102.B.481; A.103.B.481;
A104.B.481; A105.B.481; A106.B.481; A.107.B..481; A108.B.481; A109.B.481;
AH0.B.481; A1H.B.481; AH2.B.481; A.113.B..481; A114.B.481; AH5.B.481;
AH6.B.481; A117.B.481; AH8.B.48.i; A.119.B..481; A120.B.481; A121.B.481;
A.122.B.481; A.123.B.481; A124.B.481; A.125.B..481; A126.B.481; A127.B.481; A128.B.481; A129.B.481; A130.B.481; A.131.B..481; A.132.B.481; A133.B.481;
A134.B.481; A135.B.481; A136.B.481; A.137.B .481; A138.B.481; A139.B.481;
A140.B.481; A141.B.481; A2.B.491; A3.B.491; A.4.B.491; A.5.B.491;
A.7.B.491; A.9.B.491; A100.B.491; A.101.B.491; A102.B.491; A103.B.491;
A104.B.491; A.105.B.491; A106.B.491; A.107.B..491; A108.B.491; A.109.B.491; A110.B.491; A.111.B.491; A.112.B.491; A.113.B. ,491; A114.B.491; AH5.B.491;
AH6.B.491; A117.B.491; A118.B.491; A.119.B..491; A.120.B.491; A121.B.491;
A122.B.491; A123.B.491; A124.B.491; A.125.B..491; A.126.B.491; A.127.B.491;
A128.B.491; A129.B.491; A.130.B.491; A.131.B..491; A.132.B.491; A.133.B.491;
A134.B.491; A135.B.491; A136.B.491; A.137.B, .491; A.138.B.491; A139.B.491; A.140.B.491; A141.B.491; A.2.B.501; A.3.B.501; A.4.B.501; A.5.B.501;
A.7.B.501; A.9.B.501; A100.B.501; A101.B.501; A102.B.501; A.103.B.501;
A104.B.501; A105.B.501; A106.B.501; A.107.B..501; A108.B.501; A109.B.501;
A110.B.501; A.111.B.501; AH2.B.501; A.113.B, .501; A.H4.B.501; A115.B.501;
AH6.B.501; A117.B.501; A118.B.501; A.119.B..501; A120.B.501; A.121.B.501; A122.B.501; A.123.B.501; A124.B.501; A.125.B, .501; A126.B.501; A127.B.501;
A128.B.501; A.129.B.501; A130.B.501; A.131.B..501; A132.B.501; A.133.B.501;
A134.B.501; A135.B.501; A.136.B.501; A.137.B..501; A.138.B.501; A139.B.501;
A140.B.501; A141.B.501; A2.B.511; A.3.B.511; A.4.B.511; A.5.B.511;
A7.B.511; A.9.B.511; A.100.B.511; A.101.B.511; A.102.B.511; A.103.B.511; A104.B.511; A105.B.511; A106.B.511; A.107.B..511; A.108.B.511; A109.B.511;
A.110.B.511; A.111.B.511; AH2.B.511; A.113.B..511; A114.B.511; A115.B.511;
A.116.B.511; A117.B.511; A.118.B.511; A.119.B .511; A.120.B.511; A.121.B.511;
A122.B.511; A.123.B.511; A.124.B.511; A.125.B. ,511; A.126.B.511; A127.B.511;
A128.B.511; A129.B.511; A130.B.511; A.131.B..511; A132.B.511; A.133.B.511; A134.B.511; A135.B.511; A136.B.511; A.137.B..511; A.138.B.511; A139.B.511;
A140.B.511; A141.B.511; A.2.C461; A.3.C461; A.4.C461; A.5.C461;
A7.C461; A.9.C461; A100.C461; A101.C461; A.102.C461; A103.C461;
A104.C461; A105.C46i; A.106.C461; A.107.C 461; A108.C461; A.109.C461
A.110.C461; A.111.C461; AH2.C.461; A.113.C ,461; A114.C46i; AH5.C461 A.116.C461; A.117.C461; A118.C461; A.119.C ,461; A.120.C461; A.121.C.46.i.
A122.C461; A123.C461; A124.C461; A.125.C .461; A.126.C461; A127.C46i
A128.C461; A129.C461; A.130.C461; A.131.C .461; A132.C461; A133.C46i
A134.C461; A.135.C461; A136C.461; A.137.C 461; A.138.C461; A139.C461
A140.C461; A.141.C.461; A.2.C471; A.3.C471; A.4.C471; A.5.C471; A.7.C471; A.9.C471; A100.C471; A.101.C471; A.102.C471; A.103.C471;
A.104.C471; A105.C471; A106.C471; A.107.C .471; A.108.C471; A109.C47i;
AH0.C471; A.111.C471; A.H2.C471; A.113.C .471; AH4.C471; A.115.C47i; A116.C471; A.117.C471; A.118.C471; A119.C471; A120.C471; A.121.C471;
A122.C471; A.123.C471; A124.C471; A125.C471; A.126.C.471; A127.C471;
A128.C471; A.129.C471; A130.C471; A.131.C.471; A132C.471; A.133.C471;
A134.C471; A135.C471; A136.C471; A137.C47i; A138C.471; A.139.C.471; A.140.C471; A141.C471; A.2.C481; A3.C481; A.4.C481; A5.C481;
A7.C481; A.9.C481; A100.C481; A.101.C481; A.102.C481; A103.C48i;
A.104.C481; A.105.C.481; A106.C481; A.107.C481; A.108.C481; A109.C48.i;
A110.C48i; AH1.C481; A.H2.C481; AH3.C481; AH4.C.481; A115.C48.i;
A116.C48.i; A117.C48i; A118.C48i; A119.C481; A.120.C481; A121.C48i; A.122.C481; A.123.C481; A124.C48i; A125.C481; A.126.C481; A.127.C481;
A128.C481; A129.C481; A.130.C.481; A131.C481; A132.C481; A133.C48.i;
A.134.C481; A135.C481; A.136.C481; A137.C481; A138.C481; A139.C48i;
A140.C481; A.141.C481; A.2.C491; A.3.C491; A.4.C491; A.5.C491;
A7.C491; A.9.C491; A.100.C.491; A.101.C491; A.102.C491; A.103.C491; A104.C491; A105.C491; A106.C491; A107.C491; A108.C491; A.109.C491;
AH0.C491; A.111.C.491; A112.C491; A.113.C491; A.114.C.491; A115.C.491;
A.116.C49i; A.117.C491; A.118.C491; A.119.C491; A.120.C491; A.121.C491;
A.122.C.491; A.123.C491; A.124.C491; A125.C491; A.126.C491; A127.C49i;
A128.C491; A.129.C491; A.130.C.491; A131.C491; A132.C491; A133.C.491; A.134.C491; A.135.C491; A136.C491; A.137.C491; A.138.C491; A139.C491;
A.140.C.491; A.141.C491; A.2.C501; A3.C501; A.4.C501; A.5.C501;
A.7.C501; A.9.C501; A100.C501; A.101.C.501; A.102.C501; A103.C501;
A.104.C501; A.105.C.501; A.106.C.501; A107.C501; A.108.C501; A109.C50i;
A110.C501; A.lll.C.50.i; A112.C501; A113.C50i; A.114.C501; A115.C50.i; A116.C50.i; A117.C50i; A.118.C501; A119.C501; A120.C501; A.121.C.50.i;
A122.C501; A.123.C501; A.124.C.501; A.125.C501; A126.C501; A.127.C501;
A.128.C.501; A.129.C501; A130.C501; A.131.C501; A.132.C501; A133.C501;
A134.C501; A135.C501; A.136.C501; A.137.C501; A.138.C501; A139.C501;
A.140.C.501; A.141.C501; A.2.C511; A.3.C511; A.4.C.511; A.5.C511; A.7.C511; A.9.C511; A.100.C.511; A.101.C511; A102.C511; A103.C511;
A.104.C.511; A105.C51i; A.106.C511; A.107.C511; A108.C511; A109.C51i;
A.110.C511; A111.C511; A.112.C511; A.113.C511; A.114.C511; A.115.C511;
A.116.C.511; A117.C51i; A118.C51i; A.119.C.511; A120.C51i; A.121.C.511;
A.122.C511; A.123.C511; A.124.C511; A125.C511; A126.C511; A.127.C511; A128.C511; A129.C51i; A130.C511; A131.C511; A132.C511; A.133.C511;
A134.C511; A.135.C511; A136.C511; A.137.C511; A138.C511; A139.C511;
A.140.C.511; A.141.C.511; A2.D.461; A.3.D.461; A.4.D.461; A.5.D.461;
A.7.D.461; A.9.D.461; A100.D.461; A101.D.461; A.102.D.461; A103.D.461;
A104.D.461; A105.D.461; A106.D.461; A107.D.461; A108.D.461; A109.D.461; A.110.D.461; A.111.D.461; A.112.D.461; A.113.D.461; A.114.D.461; AH5.D.461;
A.116.D.461; A117.D.461; A.118.D.461; A.119.D.461; A120.D.461; A121.D.461;
A122.D.461; A123.D.461; A124.D.461; A125.D.461; A126.D.461; A127.D.461;
A128.D.461; A.129.D.461; A130.D.461; A.131.D.461; A.132.D.461; A133.D.461;
A134.D.461; A.135.D.461; A136.D.461; A137.D.461; A138.D.461; A139.D.461; A140.D.461; A141.D.461; A.2.D.471; A3.D.471; A.4.D.471; A.5.D.471;
A7.D.471; A.9.D.471; A100.D.471; A101.D.471; A102.D.471; A103.D.471;
A104.D.471; A105.D.471; A106.D.471; A107.D.471; A108.D.471; A109.D.471; A110.D.471; AH1.D.471; A112.D.471; AH3.D.471; A114.D.471; AH5.D.47.
AH6.D.471; A.117.D.471; A.118.D.471; A.119.D.471; A120.D.471; A121.D.47.
A122.D.471; A123.D.471; A124.D.471; A125.D.471; A.126.D.471; A127.D.47.
A128.D.471; A129.D.471; A.130.D.471; A131.D.471; A132.D.471; A133.D.47. A134.D.471; A135.D.471; A136.D.471; A137.D.471; A138.D.471; A139.D.47.
A140.D.471; A141.D.471; A2.D.481; A3.D.481; A.4.D.481; A5.D.481;
A7.D.481; A9.D.481; A100.D.481; A.101.D.481; A102.D.481; A103.D.481;
A104.D.481; A105.D.481; A106.D.481; A107.D.481; A108.D.481; A109.D.48.
AH0.D.481; AH1.D.481; A112.D.481; AH3.D.481; A114.D.481; AH5.D.48. AH6.D.481; A117.D.481; A.118.D.481; AH9.D.481; A120.D.481; A121.D.48.
A122.D.481; A123.D.481; A124.D.481; A125.D.481; A126.D.481; A127.D.48.
A128.D.481; A129.D.481; A130.D.481; A131.D.481; A132.D.481; A133.D.48.
A134.D.481; A135.D.481; A136.D.481; A137.D.481; A138.D.481; A139.D.48.
A140.D.481; A141.D.481; A.2.D.491; A3.D.491; A.4.D.491; A5.D.491; A.7.D.491; A9.D.491; A100.D.491; A101.D.491; A102.D.491; A103.D.491;
A104.D.491; A.105.D.491; A106.D.491; A107.D.491; A108.D.491; A109.D.49.
AH0.D.491; A.H1.D.491; A112.D.491; A113.D.491; A.114.D.491; AH5.D.49.
A116.D.491; A117.D.491; A.118.D.491; A119.D.491; A.120.D.491; A121.D.49.
A122.D.491; A123.D.491; A124.D.491; A125.D.491; A126.D.491; A127.D.49. A128.D.491; A129.D.491; A130.D.491; A131.D.491; A.132.D.491; A133.D.49.
A134.D.491; A135.D.491; A136.D.491; A137.D.491; A138.D.491; A139.D.49.
A140.D.491; A141.D.491; A.2.D.501; A3.D.501; A.4.D.501; A.5.D.501;
A.7.D.501; A9.D.501; A100.D.501; A101.D.501; A102.D.501; A103.D.501;
A104.D.501; A105.D.501; A106.D.501; A107.D.501; A108.D.501; A109.D.50. A.H0.D.501; AH1.D.501; AH2.D.501; AH3.D.501; A114.D.501; A.H5.D.50.
AH6.D.501; A117.D.501; A.118.D.501; AH9.D.501; A120.D.501; A121.D.50.
A122.D.501; A.123.D.501; A.124.D.501; A125.D.501; A.126.D.501; A127.D.50.
A128.D.501; A.129.D.501; A130.D.501; A131.D.501; A132.D.501; A133.D.50.
A134.D.501; A135.D.501; A136.D.501; A137.D.501; A138.D.501; A139.D.50. A140.D.501; A141.D.501; A.2.D.511; A.3.D.511; A.4.D.511; A5.D.511;
A7.D.511; A.9.D.511; A100.D.511; A.101.D.511; A102.D.511; A103.D.511;
A104.D.511; A.105.D.511; A.106.D.511; A107.D.511; A108.D.511; A109.D.51.
A.H0.D.511; A.111.D.511; AH2.D.511; A.113.D.511; AH4.D.511; A.H5.D.51.
A.H6.D.511; A.117.D.511; AH8.D.511; AH9.D.511; A120.D.511; A121.D.51. A122.D.511; A123.D.511; A124.D.511; A125.D.511; A126.D.511; A127.D.51.
A128.D.511; A129.D.511; A130.D.511; A131.D.511; A132.D.511; A133.D.51.
A134.D.511; A135.D.511; A136.D.511; A137.D.511; A.138.D.511; A139.D.51.
A140.D.511; A.141.D.511; A2.E.461; A.3.E.461; A4.E.461; A.5.E.461; A7.E.46
A9.E.461; A100.E.461; A101.E.461; A102.E.461; A103.E.461; A104.E.461; A105.E.461; A106.E.461; A107.E.461; A108.E.461; A109.E.461; AH0.E.461;
AH1.E.461; AH2.E.461; AH3.E.461; AH4.E.461; AH5.E.461; A116.E.461;
A.H7.E.461; A.118.E.461; AH9.E.461; A120.E.461; A121.E.461; A122.E.461;
A123.E.461; A124.E.461; A125.E.461; A126.E.461; A127.E.461; A128.E.461;
A129.E.461; A130.E.461; A.131.E.461; A132.E.461; A133.E.461; A134.E.461; A135.E.461; A136.E.461; A137.E.461; A138.E.461; A139.E.461; A.140.E.461;
A141.E.461; A.2.E.471; A.3.E.471; A.4.E.471; A.5.E.471; A.7.E.471; A.9.E.471;
A100.E.471; A.101.E.471; A102.E.471; A103.E.471; A.104.E.471; A105.E.471; A.106.E.471; A.107.E.471; A.108. E.471; A.109. E.471; A.110.E.471; AHl.E.47.i A. 112.E.471; A.113.E 471; A.114. E.471; A.115, E.471; A.116.E.471; AH7.E.47i
A. 118.E.471; A.119.E 471; A.120. E.471; A.121, E.471; A122.E.471; A123.E.471 A. 124.E.471; A.125.E.471; A.126. E.471; A.127, E.471; A128.E.471; A129.E.471 A. 130.E.471; A.131.E, 471; A.132. E.471; A.133. E.471; A134.E.471; A135.E.471 A. 136.E.471; A.137.E, 471; A.138. E.471; A.139, E.471; A.140.E.471; A141.E.471
A. 2.E.481; A.3.E.481; A.4.E.481; A5.E.481; A.7.E.481; A.9.E.481; A100.E.481; A. 101.E.481; A.102.E.481; A.103. E.481; A.104, E.481; A105.E.481 A106.E.481; A. 107.E.481; A.108.E.481; A.109. E.481; A.HO, E.481; A.1H.E.481 AH2.E.481; A. H3.E.481; A.114.E.481; A.115. E.481; A.116, E.481; A.117.E.481 A118.E.481; A. H9.E.481; A.120.E.481; A.121. E.481; A.122, E.481; A123.E.481 A124.E.481; A. 125.E.481; A.126.E.481; A.127. E.481; A.128, E.481; A129.E.481 A130.E.481; A. 131.E.481; A.132.E.481; A.133. E.481; A.134, E.481; A135.E.481 A136.E.481; A. 137.E.481; A.138.E.481; A.139. E.481; A.140. E.481; A141.E.481 A.2.E.491; A. 3.E.491; A.4.E.491; A.5.E.491; A7.E.491; A.9.E.491; A100.E.491; A101.E.491; A. 102.E.491; A.103.E.491; A.104. E.491; A.105. E.491; A106.E.491 A.107.E.491; A. 108.E.491; A.109.E.491; A.110. E.491; A.lli, E.491; A112.E.491 AH3.E.491; A. 114.E.491; A.115.E.491; A.116. E.491; A.117, E.491; AH8.E.491 A119.E.491; A. 120.E.491; A.121.E.491; A.122. E.491; A.123, E.491; A124.E.491 A.125.E.491; A. 126.E.491; A.127.E.491; A.128. E.491; A.129, E.491; A130.E.491 A.131.E.491; A. 132.E.491; A.133.E.491; A.134. E.491; A.135 E.491; A136.E.491 A.137.E.491; A. 138.E.491; A139.E. ,491; A.140. E.491; A.141, E.491; A.2.E.501; A.3.E.501; A. 4.E.501; A.5.E.501; A7.E.501; A9.E.501; A.100.E.501; A101.E.501; A. 102.E.501; A.103.E. ,501; A.104. E.501; A.105 E.501; A.106.E.501; A.107.E. 501 A. 108.E.501; A.109.E.501; A.110. E.501; A.lli, E.501; A.112.E.501; A.113.E.501 A. 114.E.501; A.115.E.501; A.116. E.501; A.117 E.501; AH8.E.501; A.119.E.501 A. 120.E.501; A.121.E. ,501; A.122. E.501; A.123, E.501; A.124.E.501; A.125.E.501 A. 126.E.501; A.127.E. ,501; A.128. E.501; A.129 E.501; A130.E.501; A.131.E.501 A. 132.E.501; A.133.E. ,501; A.134. E.501; A.135 E.501; A.136.E.501; A.137.E.501 A. 138.E.501; A.139.E..501; A.140. E.501; A.141 E.501; A2.E.511; A3.E.511; A. 4.E.511; A .5.E.511; A7.E.511; A.9.E.511; A, 100.E.511; A.101.E.511; A. 102.E.511; A.103.E..511; A.104. ,E.51.i; A.105 E.511; A106.E.511; A.107.E. 511 A, 108.E.511; A.109.E..511; A.110..E.511; A.lli E.511; A.112.E.511; A.113.E.511 A, 114.E.511; A.115.E..511; A.116. ,E.51.i; A.117 E.511; AH8.E.511; A.119.E.511 A, 120.E.511; A.121.E..511; A.122. •E.511; A.123 E.511; A124.E.511; A.125.E.511 A 126.E.511; A.127.E. ,511; A.128. •E.511; A.129 E.511; A130.E.511; A.131.E.511 A 132.E.511; A.133.E. ,511; A.134, .E.511; A.135 E.511; A136.E.511; A.137.E.511 A 138.E.511; A.139.E .511; A.140.E.511; A.141.E.511; A.2.F.461; A3.F.461; A, 4.F.461; A •5.F.461; A7.F.461; A.9.F.461; A, 100.F.461; A.101.F.461; A 102.F.461; A.103.F. ,461; A104.F.461; A.105 F.461; A.106.F.461; A.107.F. 461 A 108.F.461; A.109.F..461; A.110. F.461; A.lli F.461; A112.F.461; A.113.F.461 A H4.F.461; A.115.F. ,461; A.116 F.461; A.117 F.461; A.118.F.461; A.119.F.461, A 120.F.461; A.121.F..461; A.122.F.461; A.123 F.461; A124.F.461; A.125.F.461, A 126.F.461; A.127.F..461; A.128 F.461; A.129 F.461; A130.F.461; A.131.F.461 A 132.F.461; A.133.F. ,461; A.134.F.461; A.135 F.461; A136.F.461; A.137.F.461 A 138.F.461; A.139.F, .461; A.140 F.461; A.141 F.461; A.2.F.471; A.3.F.471; A .4.F.471; A .5.F.471; A.7.F.471; A.9.F.471; A 100.F.471; A.101.F.471; A102.F.471; A103.F.471; A.104.F.471; A.105.F.471; A.106.F.471; A107.F.471;
A108.F.471; A.109.F.471; A110.F.471; A111.F.471; A112.F.471; A113.F.471;
AH4.F.471; A.115.F.471; A.116.F.471; AH7.F.471; A.118.F.471; AH9.F.471;
A120.F.471; A121.F.471; A122.F.471; A123.F.471; A124.F.471; A125.F.471; A126.F.471; A127.F.471; A128.F.471; A129.F.471; A130.F.471; A131.F.471;
A132.F.471; A133.F.471; A134.F.471; A135.F.471; A136.F.471; A137.F.471;
A138.F.471; A139.F.471; A140.F.471; A141.F.471; A.2.F.481; A3.F.481;
A4.F.481; A5.F.481; A7.F.481; A.9.F.481; A100.F.481; A101.F.481;
A102.F.481; A103.F.481; A104.F.481; A105.F.481; A106.F.481; A107.F.481; A108.F.481; A.109.F.481; A.110.F.481; A.H1.F.481; A.112.F.481; AH3.F.481;
AH4.F.481; A.115.F.481; A.116.F.481; AH7.F.481; A118.F.481; A119.F.481;
A120.F.481; A121.F.481; A122.F.481; A123.F.481; A124.F.481; A125.F.481;
A126.F.481; A.127.F.481; A128.F.481; A.129.F.481; A130.F.481; A131.F.481;
A132.F.481; A133.F.481; A134.F.481; A135.F.481; A136.F.481; A137.F.481; A138.F.481; A139.F.481; A140.F.481; A141.F.481; A.2.F.491; A3.F.491;
A4.F.491; A5.F.491; A.7.F.491; A9.F.491; A100.F.491; A101.F.491;
A102.F.491; A103.F.491; A.104.F.491; A105.F.491; A.106.F.491; A107.F.491;
A108.F.491; A.109.F.491; A.110.F.491; A.111.F.491; A112.F.491; A113.F.491;
A.H4.F.491; A.115.F.491; A116.F.491; A117.F.491; A.118.F.491; A119.F.491; A120.F.491; A.121.F.491; A.122.F.491; A123.F.491; A124.F.491; A.125.F.491;
A.126.F.491; A127.F.491; A.128.F.491; A.129.F.491; A.130.F.491; A131.F.491;
A132.F.491; A.133.F.491; A134.F.491; A135.F.491; A136.F.491; A137.F.491;
A138.F.491; A139.F.491; A.140.F.491; A141.F.491; A.2.F.501; A.3.F.501;
A4.F.501; A.5.F.501; A.7.F.501; A.9.F.501; A100.F.501; A.101.F.501; A102.F.501; A103.F.501; A104.F.501; A105.F.501; A106.F.501; A107.F.501;
A108.F.501; A109.F.501; A.110.F.501; A111.F.501; A112.F.501; AH3.F.501;
AH4.F.501; A115.F.501; A.116.F.501; A.117.F.501; A.118.F.501; A.H9.F.501;
A120.F.501; A121.F.501; A122.F.501; A123.F.501; A.124.F.501; A125.F.501;
A126.F.501; A127.F.501; A128.F.501; A129.F.501; A.130.F.501; A131.F.501; A132.F.501; A.133.F.501; A134.F.501; A.135.F.501; A.136.F.501; A137.F.501;
A138.F.501; A139.F.501; A.140.F.501; A.141.F.501; A.2.F.511; A.3.F.511;
A4.F.511; A.5.F.511; A.7.F.511; A.9.F.511; A100.F.511; A101.F.511;
A102.F.511; A.103.F.511; A104.F.511; A105.F.511; A106.F.511; A107.F.511;
A108.F.511; A109.F.511; AH0.F.511; A111.F.511; A.112.F.511; A113.F.511; AH4.F.511; A.115.F.511; A116.F.511; A117.F.511; A118.F.511; AH9.F.511;
A120.F.511; A.121.F.511; A122.F.511; A.123.F.511; A.124.F.511; A.125.F.511;
A126.F.511; A.127.F.511; A.128.F.511; A129.F.511; A130.F.511; A.131.F.511;
A132.F.511; A133.F.511; A134.F.511; A135.F.511; A.136.F.511; A137.F.511;
A.138.F.511; A.139.F.511; A.140.F.511; A141.F.511;
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 alksline esrth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically the Wi group carboxylic acid. Monovalent sslts sre preferred if a wster 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 3re sslts contsining Li+, N3+, 3nd K+. A less soluble metsl salt can be precipitsted from the solution of a more soluble sslt by addition of the suitable metsl compound.
In sddition, salts may be formed from acid addition of certain organic 3nd inorgsnic scids, e.g., HCl, HBr, H2Sθ4, H3Pθ4, or orgsnic sulfonic acids, to basic centers, typically amines of group Gi, or to acidic groups such as Ei. 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.
Methods of Inhibition of Neuraminidase. Another aspect of the invention relates to methods of inhibiting the activity of neuraminidase comprising the step of treating a sample suspected of containing neuraminidase with a compound of the invention.
Compositions of the invention act as inhibitors of neuraminidase, 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 neuraminidsse having a geometry unique to neuraminidase. Compositions binding neuraminidase 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 neuraminidase with a binding coefficient of less than 10" ^M, more typically less than lO'^M, still more typically 10"^M. Once labeled, the substantially irreversibly binding compositions sre useful 3S probes for the detection of neursminidsse. Accordingly, the invention relates to methods of detecting neursminidsse in 3 sample suspected of containing neursminidsse comprising the steps of: tresting a sample suspected of containing neursminidsse with 3 composition comprising 3 compound of the invention bound to a lsbel; 3nd observing the effect of the ssmple on the sctivity of the label. Suitable labels axe well known in the disgnostics field snd include stsble free rsdicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups snd chromogens. The compounds herein 3re lsbeled in conventionsl fashion using functional groups such ss hydroxyl or
Within the context of the invention ssmples suspected of contsining neursminidsse include nstural or msn-msde msterisls such ss living orgsnisms; tissue or cell cultures; biologicsl samples such as biological material ssmples (blood, serum, urine, cerebrospinsl fluid, tesrs, sputum, S3UV3, tissue ssmples, snd the like); lsborstory ssmples; food, wster, or sir ssmples; bioproduct ssmples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; end the like. Typicslly the sample will be suspected of containing an organism which produces neursminidsse, frequently a psthogenic organism such as a virus. Ssmples csn be contsined in sny medium including wster 3nd orgsnic solvent/wster mixtures. Ssmples include living orgsnisms such ss humsns, 3nd man made msterisls such ss cell cultures.
The tresting 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 sddition step comprises sny method of sdministrstion ss described sbove.
If desired, the activity of neuraminidase after spplicstion of the composition csn be observed by sny method including direct snd indirect methods of detecting neursminidsse sctivity. Qusntitstive, quslitstive, and semiquantitstive methods of determining neursminidsse sctivity sre all contemplated. Typicslly one of the screening methods described sbove sre spplied, however, any other method such as observation of the physiological properties of a living organism are also applicsble. Orgsnisms thst contsin neursminidsse include bscteris (Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, and Arthrobscter sialophilus) and viruses (especially orthomyxoviruses or parsmyxoviruses such ss influenzs virus A snd B, parsinfluenzs virus, mumps virus, Newcsstle disesse virus, fowl plsgue virus, snd sendsi virus). Inhibition of neursminidsse sctivity obtsined from or found within sny of these orgsnisms is within the objects of this invention. The virology of influenzs viruses is described in "Fundsmentsl Virology" (Rsven Press, New York, 1986), Chspter 24. The compounds of this invention sre useful in the trestment or prophylsxis of such infections in animals, e.g. duck, rodents, or swine, or in man. However, in screening compounds capsble of inhibiting influenzs viruses it should be kept in mind that the results of enzyme assays may not correlate with cell culture ssssys, as shown Table 1 of Chandler et al., supra. Thus, a plaque reduction assay should be the primary screening tool.
Screens for Neuraminidase Inhibitors.
Compositions of the invention are screened for inhibitory activity against neursminidsse by sny of the conventionsl techniques for evslusting enzyme sctivity. Within the context of the invention, typicslly compositions are first screened for inhibition of neuraminidase in vitro and compositions showing inhibitory activity are then screened for sctivity in vivo. Compositions hsving in vitro Ki (inhibitory constants) of less then about 5 X 10"6 M, typically less than 3bout 1 X 10'7 M snd prefersbly less then sbout 5 X 10"^ M are preferred for in vivo use.
Useful in vitro screens have been described in detail and will not be elaborsted here. However, von Itzstein, M. et al; "Nsture", 363(6428):418- 423 (1993), in psrticulsr page 420, column 2, full paragraph 3, to page 421, column 2, first psrtisl psrsgrsph, describes a suitsble in vitro ssssy of Potier, M.; et al.; Analyt. Biochem.", 94:287-296 (1979), as modified by Chong, A.K.J.; et al.; "Biochem. Biophys. Acts", 1077:65-71 (1991); snd Colmsn, P. M.; et si.; Internstionsl Pubiicstion No. WO 92/06691 (Int. App. No. PCT/AU90/00501, pubiicstion dste April 30, 1992) page 34, line 13, to page 35, line 16, describes another useful in vitro screen.
In vivo screens have also been described in detail, see von Itzstein, M. et al.; op. cit., in particular page 421, column 2, first full paragraph, to page 423, column 2, first psrtisl psrsgraph, and Colman, P. M.; et al.; op. cit. page 36, lines 1-38, describe suitable in vivo screens. Phsrmaceutical Formulations and Routes of Administration. The compounds of this invention are formulsted with conventionsl csrriers 3nd excipients, which will be selected in sccord with ordinsry prsctice. Tsblets will contsin excipients, glidsnts, fillers, binders snd the like. Aqueous formulstions 3re prepsred in sterile form, snd when intended for delivery by other thsn orsl sdministration generally will be isotonic. All formulstions will optionslly contsin excipients such ss those set forth in the "Hsndbook of Pharmaceuticsl Excipients" (1986). Excipients include sscorbic scid snd other sntioxidsnts, chelsting sgents such 3S EDTA, csrbohydrstes such ss dextrin, hydroxyslkylcellulose, hydroxyslkylmethylcellulose, stesric scid and the like. The pH of the formulations rsnges from sbout 3 to sbout 11, but is ordinsrily sbout 7 to 10.
One or more compounds of the invention (herein referred to ss the sctive ingredients) sre sdministered by sny route sppropriste to the condition to be trested. Suitsble routes include orsl, rectsl, nsssl, topicβl (including buccsl snd sublingusl), vsginsl snd psrentersl (including subcutsneous, intrsmusculsr, intrsvenous, intrsdermsl, intrsthecsl snd epidursl), 3nd the like. It will be spprecisted thst the preferred route msy vsry with for exsmple the condition of the recipient. An sdvsntsge of the compounds of this invention is thst they 3re orslly biosvsilsble snd csn be dosed orslly; it is not necesssry to sdminister them by intrspulmonsry or intrsnasal routes. Surprisingly, (in view of, inter alia. Bamford, M. J., "J. Enzyme Inhibition" 10:1-6 (1995), and especially p. 15, first full psrsgrsph), the snti-influenza compounds of WO 91/16320, WO 92/06691 and U.S.
Patent 5,360,817 sre successfully sdministered by the orsl or intrsperitonesl routes. See Exsmple 161 infrs.
While it is possible for the sctive ingredients to be sdministered βlone it may be preferable to present them ss priarmsceuticsl formulstions. The formulstions, both for veterinsry snd for human use, of the invention comprise at lesst one sctive ingredient, ss sbove defined, together with one or more scceptsble csrriers therefor snd optionslly other therspeutic ingredients. The carrier(s) must be "acceptsble" in the sense of being compstible with the other ingredients of the formulstion snd physiologicslly innocuous to the recipient thereof.
The formulstions include those suitsble for the foregoing sdministrstion routes. The formulstions msy conveniently be presented in unit dossge form snd msy be prepsred by sny of the methods well known in the srt of phsrmscy. Techniques snd formulstions generslly sre found in Remington's Phsrmsceuticsl Sciences (Msck Publishing Co., Esston, PA). Such methods include the step of bringing into sssocistion the sctive ingredient with the carrier which constitutes one or more accessory ingredients. In genersl the formulstions sre prepsred by uniformly snd intimstely bringing into sssocistion the sctive ingredient with liquid csrriers or finely divided solid csrriers or both, snd then, if necesssry, shsping the product.
Formulstions of the invention suitsble for orsl sdministrstion 3re prepsred 3S discrete units such ss cspsules, cschets or tsblets esch contsining s predetermined smount of the sctive ingredient; ss a powder or grsnules; ss solution or a suspension in sn squeous liquid or s non-squeous liquid; or ss sn oil-in-w3ter liquid emulsion or a wster-in-oil liquid emulsion. The sctive ingredient msy slso be presented ss a bolus, electusry or psste.
A tsblet is msde by compression or molding, optionslly with one or more sccessory ingredients. Compressed tsblets msy be prepsred by compressing in a suitsble mschine the sctive ingredient in a free-flowing form such ss a powder or grsnules, optionslly mixed with a binder, lubricsnt, inert diluent, preservstive, surfsce sctive or dispersing sgent. Molded tsblets msy be msde by molding in s suitsble mschine a mixture of the powdered sctive ingredient moistened with sn inert liquid diluent. The tsblets msy optionslly be costed or scored and optionally are formulated so as to provide slow or controlled release of the sctive ingredient therefrom. In one embodiment scid hydrolysis of the medicsment is obvisted by use of sn enteric costing.
For infections of the eye or other externsl tissues e.g. mouth snd skin, the formulstions 3re prefersbly spplied ss a topicsl ointment or cresm contsining the sctive ingredient(s) in sn smount of, for exsmple, 0.075 to
20% w/w (including sctive 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 snd most prefersbly 0.5 to 10% w/w. When formulsted in sn ointment, the sctive ingredients msy be employed with either s psrsffinic or s wster-miscible ointment bsse. Alternstively, the sctive ingredients msy be formulsted in a cresm with 3n oil-in-wster cresm bsse. If desired, the squeous phsse of the cresm bsse msy include, for exsmple, st lesst 30% w/w of a polyhydric slcohol, i.e. sn slcohol hsving two or more hydroxyl groups such 3s propylene glycol, butsne 1,3-diol, msnnitol, sorbitol, glycerol snd polyethylene glycol (including PEG 400) snd mixtures thereof. The topicsl formulstions msy desirsbly include s compound which enhsnces sbsorption or penetration of the sctive ingredient through the skin or other sffected sress. Exsmples of such dermsl penetrstion enhsncers include dimethyl sulphoxide 3nd relsted snslogs.
The oily phsse of the emulsions of this invention msy be constituted from known ingredients in a known msnner. While the phsse msy comprise merely sn emulsifier (otherwise known ss sn emulgent), it desirsbly comprises s mixture of st lesst one emulsifier with a fst or sn oil or with both s fst snd sn oil. Prefersbly, s hydrophilic emulsifier is included together with a lipophilic emulsifier which sets as a stsbilizer. It is slso preferred to include both 3n oil snd a f3t. Together, the emulsifier(s) with or without stsbilizer(s) mske up the so-c3lled emulsifying wax, and the wax together with the oil and fst mske up the so-cslled emulsifying ointment bβse which forms the oily dispersed phsse of the cresm formulstions. Emulgents 3nd emulsion stsbilizers suitsble for use in the formul3tion of the invention include Tween® 60, Sp3n® 80, cetostesryl slcohol, benzyl slcohol, myristyl slcohol, glyceryl mono-stesrste snd sodium lsuryl sulfste.
The choice of suitsble oils or fsts for the formulstion is bssed on schieving the desired cosmetic properties. The cresm should prefersbly be s non-gressy, non-stsining snd wsshsble product with suitsble consistency to svoid lesksge from tubes or other contsiners. Strsight or branched chsin, mono- or dibssic slkyl esters such ss di-isosdipste, isocetyl stesrate, propylene glycol diester of coconut fstty scids, isopropyl myristste, decyl oleste, isopropyl pslmitste, butyl stearate, 2-ethylhexyl pslmitste or s blend of brsnehed chsin esters known ss Crodsmol CAP msy be used, the lsst three being preferred esters. These msy be used slone or in combinstion depending on the properties required. Alternstively, high melting point lipids such ss white soft psraffin snd/or liquid paraffin or other mineral oils sre used. Formulstions suitsble for topicsl sdministrstion to the eye slso include eye drops wherein the sctive ingredient is dissolved or suspended in s suitsble csrrier, especially sn squeous solvent for the sctive ingredient. The sctive ingredient is prefersbly present in such formulstions in a concentration of 0.5 to 20%, sdvsntsgeously 0.5 to 10% psrticulsrly sbout
Figure imgf000183_0001
Formulstions suitsble for topicsl sdministrstion in the mouth include lozenges comprising the sctive ingredient in a flsvored bssis, ususlly sucrose snd scscis or tragacsnth; pastilles comprising the sctive ingredient in sn inert bssis such ss gelstin snd glycerin, or sucrose snd 3cscis; 3nd mouthwsshes comprising the sctive ingredient in a suitsble liquid csrrier.
Formulstions for rectsl sdministrstion msy be presented ss s suppository with a suitsble bsse comprising for exsmple cocos butter or a sslicylste.
Formulstions suitsble for intrspulmonary or nsssl sdministrstion hsve s psrticle size for example in the range of 0.1 to 500 microns (including psrticle sizes in a range between 0.1 snd 500 microns in increments microns such ss 0.5, 1, 30 microns, 35 microns, etc.), which is sdministered by rapid inhslstion through the nsssl pssssge or by inhslstion through the mouth so ss to resch the slveolsr sscs. Suitsble formulstions include squeous or oily solutions of the sctive ingredient. Formulstions suitsble for serosol or dry powder sdministrstion msy be prepsred sccording to conventionsl methods snd msy be delivered with other therapeutic sgents such ss compounds heretofore used in the trestment or prophylsxis of influenzs A or B infections ss described below. Formulstions suitsble for vaginal administration may be presented as pessaries, tsmpons, cresms, gels, psstes, fosms or spray formulstions contsining in sddition to the sctive ingredient such csrriers ss sre known in the srt to be sppropriste.
Formulstions suitsble for psrenteral sdministrstion include squeous snd non-squeous sterile injection solutions which msy contsin snti- oxidsnts, buffers, bscterioststs snd solutes which render the formulstion 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 exsmple sesled ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the sddition of the sterile liquid csrrier, for exsmple wster for injection, immedistely prior to use. Extemporaneous injection solutions snd suspensions sre prepsred from sterile powders, granules snd tsblets of the kind previously described. Preferred unit dossge formulstions sre those contsining s dsily dose or unit dsily sub-dose, ss herein sbove recited, or sn sppropriste fraction thereof, of the sctive ingredient.
It should be understood thst in sddition to the ingredients psrticulsrly mentioned sbove the formulstions of this invention msy include other sgents conventionsl in the srt hsving regsrd to the type of formulstion in question, for exsmple those suitsble for oral sdministrstion msy include flsvoring sgents.
The invention further provides veterinsry compositions comprising 3t lesst one sctive ingredient ss sbove defined together with a veterinsry csrrier therefor.
Veterinsry csrriers sre msterisls useful for the purpose of sdministering the composition snd msy be solid, liquid or gsseous msterisls which sre otherwise inert or scceptsble in the veterinsry srt snd sre compstible with the sctive ingredient. These veterinsry compositions
Figure imgf000184_0001
be sdministered orally, psrenterally or by sny other desired route.
Compounds of the invention sre used to provide controlled relesse phsrmsceuticsl formulstions contsining ss sctive ingredient one or more compounds of the invention ("controlled relesse formulstions") in which the relesse of the sctive ingredient sre controlled snd regulsted to sllow less frequency dosing or to improve the phsrmscokinetic or toxicity profile of s given sctive ingredient.
Effective dose of sctive ingredient depends st lesst on the nsture of the condition being trested, toxicity, whether the compound is being used prophylscticslly (lower doses) or sgsinst sn sctive influenzs infection, the method of delivery, snd the phsrmsceuticsl formulstion, snd will be determined by the clinicisn using conventionsl dose escslstion studies. It csn 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 sbout .05 to sbout 0.5 mg/kg body weight per dsy. For exsmple, for inhslstion the dsily csndidste dose for sn sdult humsn of spproximstely 70 kg body weight will range from 1 mg to 1000 mg, prefersbly between 5 mg snd 500 mg, snd msy tske the form of single or multiple doses.
Typicsl doses include 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 157, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, snd 1000 mg of GS 4104, phosphste salt, once or twice a dsy; more typicslly, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 125, 130, 135, 140, 145, 150, 157, 200 mg of GS 4104, phosphste sslt, once or twice s dsy; more typicslly still 20, 50, 75, 100, 150 snd 200 mg of GS 4104, phosphste sslt, once or twice a dsy; more typicslly yet 75 or 150 mg of GS 4104, phosphste sslt, once or twice 3 dsy.
Active ingredients of the invention sre slso used in combinstion with other sctive ingredients. Such combinstions sre selected bssed on the condition to be trested, cross-resctivities of ingredients 3nd phsrmsco- properties of the combinstion. For exsmple, when tresting viral infections of the respiratory system, in psrticulsr influenzs infection, the compositions of the invention sre combined with sntivirals (such ss smsntidine, rimsntsdine snd ribsvirin), mucolytics, expectorants, bronchisldilstors, sntibiotics, sntipyretics, or snslgesics. Ordinsrily, sntibiotics, sntipyretics, snd snslgesics sre sdministered together with the compounds of this invention.
Metsbolites of the Compounds of the Invention Also fslling within the scope of this invention 3re the in vivo metsbolic products of the compounds described herein, to the extent such products sre novel snd unobvious over the prior srt. Such products msy result for exsmple from the oxidstion, reduction, hydrolysis, smidstion, esterificstion snd the like of the sdministered compound, primsrily due to enzym3tic processes. Accordingly, the invention includes novel 3nd unobvious compounds produced by a process comprising contscting a compound of this invention with 3 mammal for a period of time sufficient to yield a metsbolic product thereof. Such products typicslly sre identified by prepsring a rsdiolsbelled (e.g. C^4 or H3) compound of the invention, sdministering it psrenterslly in s detectsble dose (e.g. grester thsn sbout 0.5 mg/kg) to 3n snimsl such ss rat, mouse, guinea pig, monkey, or to man, sllowing sufficient time for metsbolism to occur (typicslly sbout 30 seconds to 30 hours) snd isolsting its conversion products from the urine, blood or other biologicsl ssmples. These products sre essily isolsted since they sre lsbeled (others sre isolsted by the use of sntibodies cspsble of binding epitopes surviving in the metsbolite). The metsbolite structures sre determined in conventionsl fsshion, e.g. by MS or NMR snslysis. In general, snslysis of metsbolites is done in the ssme wsy 3S conventionsl drug metsbolism studies well-known to those skilled in the srt. The conversion products, so long ss they sre not otherwise found in vivo, sre useful in disgnostic ssssys for therapeutic dosing of the compounds of the invention even if they possess no neursminidsse inhibitory sctivity of their own.
Additionsl Uses for the Compounds of This Invention. The compounds of this invention, or the biologicslly sctive substsnces produced from these compounds by hydrolysis or metsbolism in vivo, sre used ss immunogens or for conjugstion to proteins, whereby they serve ss components of immunogenic compositions to prepsre sntibodies cspsble of binding specificslly to the protein, to the compounds or to their metsbolic products which retsin immunologicsUy recognized epitopes (sites of sntibody binding). The immunogenic compositions therefore 3re useful ss intermedistes in the prepsrstion of sntibodies for use in disgnostic, quslity control, or the like, methods or in ssssys for the compounds or their novel metsbolic products. The compounds are useful for raising antibodies 3g3inst otherwise non-immunogenic polypeptides, in thst the compounds serve ss hsptenic sites stimul3ting sn immune response thst cross-resets with the unmodified conjugsted protein.
The hydrolysis products of interest include products of the hydrolysis of the protected scidic snd bssic groups discussed sbove. As noted sbove, the scidic or bssic smides comprising immunogenic polypeptides such ss slbumin or keyhole limpet hemocysnin generally are useful as immunogens. The metsbolic products described sbove msy retsin 3 substsntisl degree of immunologicsl cross resctivity with the compounds of the invention. Thus, the sntibodies of this invention will be cspsble of binding to the unprotected compounds of the invention without binding to the protected compounds; slternstively the metsbolic products, will be cspsble of binding to the protected compounds snd /or the metsbolitic products without binding to the protected compounds of the invention, or will be cspβble of binding specificslly to sny one or all three. The antibodies desirsbly will not substsntislly cross-reset with nsturally-occurring msterisls. Substsntisl cross-resctivity is resctivity under specific ssssy conditions for specific snslytes sufficient to interfere with the ssssy results.
The immunogens of this invention contsin the compound of this invention presenting the desired epitope in sssocistion with sn immunogenic substsnee. Within the context of the invention such sssocistion mesns covslent bonding to form sn immunogenic conjugste (when spplicsble) or a mixture of non-covslently bonded msterisls, or a combinstion of the sbove. Immunogenic substsnees include sdjuvsnts such ss Freund's sdjuvsnt, immunogenic proteins such as viral, bacterisl, yesst, plsnt snd snimsl polypeptides, in psrticulsr keyhole limpet hemocysnin, serum slbumin, bovine thyroglobulin or soybesn trypsin inhibitor, snd immunogenic polysscchsrides. Typicslly, the compound hsving the structure of the desired epitope is covslently conjugsted to sn immunogenic polypeptide or polysscchsride by the use of a polyfunctionsl (ordinsrily bifunctionsl) cross-linking agent. Methods for the msnufscture of hspten immunogens sre conventionsl per se. snd sny of the methods used heretofore for conjugsting hsptens to immunogenic polypeptides or the like sre suitsbly employed here ss well, tsking into sccount the functionsl groups on the precursors or hydrolytic products which sre svsilsble for cross-linking snd the likelihood of producing sntibodies specific to the epitope in question ss opposed to the immunogenic substsnee.
Typicslly the polypeptide is conjugsted to a site on the compound of the invention distsnt from the epitope to be recognized.
The conjugstes 3re prepsred in conventionsl fsshion. For exsmple, the cross-linking sgents N-hydroxysuccinimide, succinic snhydride or slkN=C=N3lk are useful in preparing the conjugates of this invention. The conjugstes comprise a compound of the invention sttsched by s bond or a linking group of 1-100, typicslly, 1-25, more typicslly 1-10 csrbon stoms to the immunogenic substsnee. The conjugstes sre sepsrsted from stsrting msterisls snd by products using chromstography or the like, snd then sre sterile filtered snd visled for store ge.
The compounds of this invention sre cross-linked for exsmple through sny one or more of the following groups: a hydroxyl group of Ui; s csrboxyl group of Ei; a csrbon stom of Ui, Ei, Gi, or Ti, in substitution of H; 3nd sn smine group of Gi. Included within such compounds sre srnides of polypeptides where the polypeptide serves ss an above-described R6C or ^6b groups.
Animals 3re typicslly immunized sgsinst the immunogenic conjugstes or derivstives snd sntisers or monoclonsl sntibodies prepsred in conventionsl fsshion.
The compounds of the invention sre useful for msintsining the structursl integrity of glycoproteins in recombinsnt cell culture, i.e., they sre sdded to fermentstions in which glycoproteins sre being produced for recovery so ss to inhibit neursminidsse-cstslyzed clesvsge of the desired glycoproteins. This is of psrticulsr vslue in the recombinsnt synthesis of proteins in heterologous host cells thst msy dissdvsntsgeously degrade the csrbohydrste portion of the protein being synthesized.
The compounds of the invention sre polyfunctionsl. As such they represent s unique clsss of monomers for the synthesis of polymers. By wsy of exsmple snd not limitstion, the polymers prepsred from the compounds of this invention include polysmides snd polyesters. The present compounds sre used ss monomers to provide sccess to polymers hsving unique pendent functionslities. The compounds of this invention sre useful in homopolymers, or ss 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 prepsrstion of moleculsr sieves
(polysmides), textiles, fibers, films, formed srticles snd the like where the scid functionslity Ei is esterified to s hydroxyl group in Ui, for exsmple, whereby the pendsnt bssic group Gi is cspsble of binding scidic functionslities such ss sre found in polypeptides whose purificstion is desired. Polysmides sre prepsred by cross-linking Ei snd Gi, with Ui snd the sdjscent portion of the ring remsining free to function ss a hydrophilic or hydrophobic sffinity group, depending up the selection of the Ui group. The prepsrstion of these polymers from the compounds of the invention is conventionsl per se. The compounds of the invention sre slso useful ss s unique clsss of polyfunctionsl surfsctsnts. Psrticulsrly when Ui does not contsin s hydrophilic substituent and is, for example, alkyl or alkoxy, the compounds have the properties of bi-functional surfactants. As such they have useful surfsctsnt, surfsce costing, emulsion modifying, rheology modifying snd surf see wetting properties. As polyfunctionsl compounds with defined geometry snd csrrying simultsneously polsr snd non-polsr moieties, the compounds of the invention sre useful ss a unique clsss of phsse transfer 3gents. By wsy of exsmple snd not limitstion, the compounds of the invention sre useful in phsse transfer cstslysis snd liquid /liquid ion extraction (LIX). The compounds of the invention optionslly contsin ssymmetric csrbon stoms in groups Ui, El, Gi, snd Ti. As such, they sre a unique clsss of chiral suxilisries for use in the synthesis or resolution of other opticslly sctive msterisls. For exsmple, a racemic mixture of carboxylic acids csn be resolved into its component ensntiomers by: 1) forming a mixture of disstereomeric esters or smides with a compound of the invention wherein Ui is sn ssymmetric hydroxyslksne or smino slksne group; 2) sepsrating the disstereomers; snd 3) hydrolyzing the ester structure. Rscemic slcohols 3re sepsrated by ester forms tion with sn scid group of Ei. Further, such a method csn be used to resolve the compounds of the invention themselves if opticslly sctive scids or slcohols sre used instesd of rscemic stsrting msterisls.
The compounds of this invention are useful as linkers or spacers in preparing sffinity sbsorption mstrices, immobilized enzymes for process control, or immunossssy resgents. The compounds herein contsin s multiplicity of functionsl groups thst sre suitsble ss sites for cross-linking desired substsnees. For exsmple, it is conventionsl to link sffinity resgents such 3s hormones, peptides, sntibodies, drugs, snd the like to insoluble substrates. These insolublized resgents sre employed in known fsshion to sbsorb binding psrtners for the sffinity resgents from msnufsctured prepsrations, disgnostic ssmples snd other impure mixtures. Similsrly, immobilized enzymes sre used to perform cstslytic conversions with fscile recovery of enzyme. Bifunctionsl compounds sre commonly used to link snslytes to detectsble groups in prepsring disgnostic resgents.
Msny functionsl groups in the compounds of this invention sre suitsble for use in cross-linking. For exsmple, the csrboxylic or phosphonic scid of group Ei is used to form esters with slcohols or smides with smines of the resgent to be cross-linked. The Gi sites substituted with OH, NHRi, SH, szido (which is reduced to smino if desired before cross-linking), CN, Nθ2, smino, gusnidino, hslo snd the like sre suitsble sites. Suitsble protection of resctive groups will be used where necesssry while sssembling the cross-linked resgent to prevent polymerizstion of the bifunctionsl compound of this invention. In general, the compounds here sre used by linking them through csrboxylic or phosphonic scid to the hydroxyl or smino groups of the first linked psrtner, then covslently bonded to the other binding psrtner through a T\ or Gi group. For exsmple a first binding psrtner such ss a steroid hormone is esterified to the csrboxylic scid of 3 compound of this invention 3nd then this conjugste is cross-linked through s Gi hydroxyl to cysnogen bromide sctivsted Sepshsrose, whereby immobilized steroid is obtsined. Other chemistries for conjugstion sre well known. See for exsmple Msggio, "Enzyme-Immunossssy" (CRC, 1988, pp 71-135) 3nd references cited therein.
As noted sbove, the therspeuticslly useful compounds of this invention in which the Wi, or Gi csrboxyl, hydroxyl or amino groups are protected sre useful ss oral or sustsined relesse forms. In these uses the protecting group is removed in vivo, e.g., hydrolyzed or oxidized, so 3S to yield the free csrboxyl, smino or hydroxyl. Suitsble esters or smides for this utility sre selected bssed on the substrate specificity of esterases snd/ or csrboxypeptidsses expected to be found within cells where precursor hydrolysis is desired. To the extent thst 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 sppesrance of free compound or of sntivirsl sctivity. One generally selects smides or esters of the invention compound thst sre (i) not hydrolyzed or hydrolyzed compsratively slowly in the upper gut, (ii) gut snd cell permesble snd (iii) hydrolyzed in the cell cytoplssm snd /or systemic circulstion. Screening ssssys prefersbly use cells from psrticulsr tissues thst sre susceptible to influenzs infection, e.g. the mucous membranes of the bronchopulmonsry tract. Asssys known in the srt are suitable for determining in vivo biosvsilsbility including intestinsl 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 csrboxyl, smino or hydroxyl groups, they remsin useful ss chemicsl intermedistes.
Exemplsry Methods of Msking the Compounds of the Invention. The invention slso relstes to methods of msking the compositions of the invention. The compositions sre prepsred by sny of the spplicsble techniques of orgsnic synthesis. Msny such techniques are well known in the srt. However, msny of the known techniques sre elsborated in "Compendium of Orgsnic Synthetic Methods" (John Wiley & Sons, New York), Vol. 1, Isn T. Hsrrison snd Shuyen Hsrrison, 1971; Vol. 2, Isn T. Hsrrison snd Shuyen Hsrrison, 1974; Vol. 3, Louis S. Hegedus snd Leroy Wsde, 1977; Vol. 4, Leroy G. Wsde, jr., 1980; Vol. 5, Leroy G. Wsde, Jr., 1984; snd Vol. 6, Michsel B. Smith; ss well ss Msrch, J., "Advsnced Orgsnic Chemistry, Third Edition", (John Wiley & Sons, New York, 1985), "Comprehensive Orgsnic Synthesis. Selectivity, Strategy & Efficiency in Modern Orgsnic Chemistry. In 9 Volumes", Bsrry M. Trost, Editor-in-Chief (Pergsmon Press, New York, 1993 printing).
A number of exemplsry methods for the prepsrstion of the compositions of the invention sre provided below. These methods sre intended to illustrate the nsture of such prepsrstions sre not intended to limit the scope of spplicsble methods.
Generally, the resction conditions such as temperature, reaction time, solvents, workup procedures, and the like, will be those common in the art for the psrticulsr resction to be performed. The cited reference msterisl, together with msterisl cited therein, contsins detailed descriptions of such conditions. Typically the temperatures will be -100°C to 200°C, solvents will be aprotic or protic, snd resction times will be 10 seconds to 10 dsys. Workup typicslly consists of quenching sny unrescted resgents followed by psrtition between a wster/ orgsnic lsyer system (extraction) snd sepsrating the lsyer contsining the product. Oxidstion snd reduction resctions sre typicslly csrried out st temperstures nesr room temperature (sbout 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 3re typicslly carried out at temperstures nesr room temperature, slthough for non-equilibrating, kineticslly controlled condens3tions reduced temperstures (0°C to -100°C) sre slso common. Solvents csn be either protic (common in equilibrsting resctions) or sprotic (common in kineticslly controlled resctions). Stsndsrd synthetic techniques such ss szeotropic removsl of resction by-products snd use of snhydrous resction conditions (e.g. inert gss environments) sre common in the srt snd will be spplied when spplicsble.
One exemplsry method of prepsring the compounds of the invention is shown in Scheme 1 below. A detsiled description of the methods is found in the Experiments! section below.
Scheme 1
Figure imgf000193_0001
Shikimic Acid
Figure imgf000193_0002
Figure imgf000193_0003
Figure imgf000193_0004
Figure imgf000193_0005
8 Modificstions of Scheme 1 to form sdditionsl embodiments is shown in Schemes 2-4.
Scheme 2
Figure imgf000194_0001
10 11
Figure imgf000194_0002
12
Scheme 2
Aziridine 5 is converted to the amino nitrile 9 by Yb(CN)3 catalyzed addition of TMSCN according to the procedure of Utimoto and co-workers, "Tetrahedron Lett.", 31:6379 (1990). Conversion of nitrile 9 to the corresponding amidine 10 is accomplished using a standsrd three step sequence: i) H2S; ii) CH3I; iii) NH4OAC. A typicsl conversion is found in "J. Med. Chem.", 36:1811 (1993).
Nitrile 9 is converted to the smino methyl compound 11 by reduction using sny of the svsilsble methods found in "Modern Synthetic Resctions" 2nd ed. H.O. House, Benjsmin/Cummings Publishing Co., 1972.
Amino methyl compound 11 is converted to the bis-Boc protected gusnidino compound 12 by tresting 11 with N,N'-bis-Boc-lH-pyrazole-l- carboxamidine according to the method found in "Tetrahedron Lett.", 36:299 (1995). Scheme 3
Figure imgf000195_0001
Scheme 3
The sziridine 5 is opened with α-cysno scetic scid t-butyl ester to give 13. Aziridine openings of this type sre found in "Tetrshedron Lett.", 23:5021 (1982). Selective hydrolysis of the t-butyl ester moiety under scidic condtions followed by decsrboxylstion gives nitrile 14.
Reduction of 14 to the smino ethyl derivstive 15 is sccomplished in the ssme fsshion ss the conversion of 9 to 11. The smine 15 is then converted into the gusnidino derivstive 16 with N,N'-bis-Boc-lH-pyrazole- l-c3rbox3midine sccording to the method found in "Tetrshedron Lett.", 36:299 (1995).
The nitrile 14 is converted to the corresponding smidine 17 using the ssme sequence described sbove for the conversion of 9 to 10. Scheme 4
θ
Figure imgf000196_0001
Scheme 4
The epoxy slcohol 1 is protected (PG=protecting group), for exsmple with MOMC1. Typicsl conditions sre found in "Protective Groups in Orgsnic Synthesis" 2nd ed.,T.W. Greene snd P.G.M. Wuts, John Wiley & Sons, New York, NY, 1991.
The epoxide 19 is opened with NsN3/NH4Cl to the smino slcohol 20 sccording to the procedure of Shsrpless snd co-workers, "J. Org. Chem.", 50:1557 (1985).
Reduction of 20 to the N-scetyl sziridine 21 is sccomplished in a three step sequence: 1) MsCl/triethyl smine; 2) H2/Pd; 3) AcCl/pyridine. Such trsnsformstions csn be found in "Angew. Chem. Int. Ed. Engl.", 33:599 (1994).
Aziridine 21 is converted to the szido smide 22 by opening with NsN3/NH4Cl in DMF st 65°C ss described in "J. Chem. Soc. Perkin Trans I", 801 (1976).
Removsl of the MOM protecting group of 22 is 3ccomplished using the methods described in "Protective Groups in Orgsnic Synthesis" 2nd ed.,T.W. Greene snd P.G.M. Wuts, John Wiley & Sons, New York, NY, 1991. The resulting slcohol is converted directly to sziridine 24 with TsCl in pyridine. Such trsnsformstions sre found in "Angew. Chem. Int. Ed. Engl.", 33:599 (1994).
Aziridine 24 is then rescted with ROH, RNH2, RSH or sn orgsnometsllic (metsl-R) to give the corresponding ring opened derivstives 25, 26, 27 snd 27.1 respectively. Aziridine openings of this type sre found in "Tetrahedron Lett.", 23:5021 (1982) snd "Angew. Chem. Int. Ed. Engl.", 33:599 (1994).
Scheme 5
Another clsss of compounds of the invention sre prepsred by the method of Schemes 5a and 5b. Quinic acid is converted to 28 by the method of Shing, T.K.M.; et al.; "Tetrahedron", 47(26):4571 (1991). Mesylation with MsCl in TEA/CH2CI2 will give 29 which is reacted with NaN3 in DMF to give 30. Resction of 30 with TFA in CH2CI2 will give 31 which is mesylsted with MsCl in TEA/CH2CI2 to give 32. Resction with triphenylphosphine in wster will give 33 which is converted to 35 by sequential spplicstion of: 1) CH3C(0)C1 in pyridine, 2) NsN3 in DMF, snd 3) NsH in THF. Alkylstion of 35 with a wide vsriety of nucleophiles common in the srt will provide s number of compounds such ss 36. Methods for elsborstion of the compounds such ss 36 to other embodiments of the invention will be similsr to those described sbove. Scheme 5a
Figure imgf000198_0001
Quinic Acid 28
Op 0",'-
Figure imgf000198_0002
29 30
Figure imgf000198_0003
31
Figure imgf000198_0004
Scheme 5b
Figure imgf000199_0001
34 35
Figure imgf000199_0002
36
Figure imgf000199_0003
37 38
Scheme 6
Figure imgf000200_0001
51 22
Figure imgf000200_0002
54 55 56
Scheme 6 Another clsss of compounds of the invention sre prepsred by the method of Scheme 6. Protected slcohol 22 (PG=methoxymethyl ether) is deprotected under stsndsrd conditions described in "Protective Groups in Orgsnic Synthesis" 2nd ed., T.W. Greene snd P.G.M. Wuts, John Wiley & Sons, New York, NY, 1991. Alcohol 51 is converted to scetste 52 with scetic snhydride snd pyridine under stsndsrd conditions. Acetste 52 is trested with TMSOTf or BF3«OEt to sfford oxszoline 53. Such trsnsformstions 3re described in "Liebigs Ann. Chem.", 129 (1991) 3nd "Csrbohydrste Resesrch", 181 (1993), respectively. Alternstively, slcohol 51 is transformed to oxszoline 53 by conversion to the corresponding mesylste or tosylste 23 snd subsequently cyclized to the oxszoline under stsndsrd conditions, ss described in "J. Org. Chem.", 50:1126 (1985) snd "J. Chem. Soc", 1385 (1970). Oxszoline 53 is rescted with ROH, RR'NH, or RSH (wherein R snd R' sre selected to be consistent with the definition of W6 sbove) provide the corresponding ring opened derivstives 54, 55, snd 56 respectively. Such trsnsformstions sre described in "J. Org. Chem.", 49:4889 (1984) snd "Chem. Rev.", 71:483 (1971).
Schemes 7-63
Other exemplsry methods of prepsring the compounds of the invention ate shown in Schemes 7-63 below. A detsiled description of the methods is found in the Experiments! section below.
Scheme 7a
Figure imgf000201_0001
62
Quinic Acid
Figure imgf000201_0002
64 R- = R2 = O 28 R, = OH, R2 = H 63
Figure imgf000201_0003
66 R = H 68 R-) = R = H 67 R = Piv 69 R + R2 = -S(O)- Scheme 7b
Figure imgf000202_0001
Figure imgf000202_0002
Figure imgf000202_0003
74 R = N3
75 R = NH2
Scheme 7c
Figure imgf000203_0001
74 78 R = N3
79 R = NH2
Figure imgf000203_0002
76
77
Figure imgf000203_0003
N-
80 81 R = N3
82 R = NH2
Scheme 8
Figure imgf000204_0001
91 92
Figure imgf000204_0002
93 94
Scheme 9
Figure imgf000204_0003
Figure imgf000204_0004
103 Scheme 10
Figure imgf000205_0001
114 115
Scheme 11
Figure imgf000205_0002
63 123
Figure imgf000205_0003
124 Scheme 12
Figure imgf000206_0001
130 131
Figure imgf000206_0002
Scheme 13
Figure imgf000206_0003
22 51
Figure imgf000206_0004
150 151 Scheme 14
Figure imgf000207_0001
152
Figure imgf000207_0002
153
Scheme 15a
Figure imgf000208_0001
160 161
Figure imgf000208_0002
162 163
Figure imgf000208_0003
165 166
Scheme 15b
Figure imgf000208_0004
167
Figure imgf000208_0005
168 Scheme 16
1 19
Figure imgf000209_0002
170
Figure imgf000209_0003
22
Figure imgf000209_0004
114 171
Scheme 17
Figure imgf000210_0001
Shikimic Acid 180
Figure imgf000210_0002
130 131
Figure imgf000210_0003
181 184
Figure imgf000210_0004
170 182
Figure imgf000210_0005
N3
183 Scheme 18
Figure imgf000211_0001
183 190
Figure imgf000211_0002
191
Scheme 19
Figure imgf000211_0003
200 201
Figure imgf000211_0004
202 203 Scheme 20
Figure imgf000212_0001
NH
102 204
Scheme 21
Figure imgf000212_0002
205 206
Figure imgf000212_0003
207 208 Scheme 22
Figure imgf000213_0001
205 209
Figure imgf000213_0002
210 211
Scheme 23
Figure imgf000213_0003
210 212
Figure imgf000213_0004
NHBoc NH2
213 214 Scheme 24
Figure imgf000214_0001
205 215
Figure imgf000214_0002
216 217
Scheme 25
Figure imgf000214_0003
Figure imgf000214_0004
219 220 Scheme 26
Figure imgf000215_0001
183 221
Figure imgf000215_0002
222 223
Scheme 27
Figure imgf000215_0003
222 224
Figure imgf000215_0004
225 226 Scheme 28
Figure imgf000216_0001
183 227
Figure imgf000216_0002
228 229
Scheme 29
Figure imgf000216_0003
183 230
Figure imgf000216_0004
231 232 Scheme 30
Figure imgf000217_0001
183 233
Figure imgf000217_0002
234 235
Scheme 31
Figure imgf000217_0003
241
Figure imgf000217_0004
243 Scheme 32
Figure imgf000218_0001
244
Figure imgf000218_0002
205 245
Figure imgf000218_0003
200 102
Scheme 33
Figure imgf000219_0001
228 250
Figure imgf000219_0002
228 251
Figure imgf000219_0003
252 Scheme 34
Figure imgf000220_0001
227 260
Figure imgf000220_0002
261 262
Scheme 35
Figure imgf000220_0003
NH, HN NHBoc
T
NBoc
262 263
Figure imgf000220_0004
NH
264 Scheme 36
Figure imgf000221_0001
Shikimic Acid 270
Figure imgf000221_0002
271
Figure imgf000221_0003
272
Figure imgf000221_0004
273
Scheme 37
Figure imgf000222_0001
275
Figure imgf000222_0002
276
Figure imgf000222_0003
272
Scheme 38
Figure imgf000223_0001
273 277
Figure imgf000223_0002
278
Figure imgf000223_0003
Figure imgf000223_0004
280
Figure imgf000223_0005
281 Scheme 39
Figure imgf000224_0001
281 282
Figure imgf000224_0002
283
Figure imgf000224_0003
284
Scheme 40
Figure imgf000224_0004
285
Figure imgf000224_0005
286 Scheme 40.1
Figure imgf000225_0001
Additional embodiments of methods of msking snd using compositions of the invention sre depicted in Schemes 36-40.1. One sspect of the invention is directed to methods of msking compounds of the invention comprising processes A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V or W of Schemes 36-40.1, slone or in combinstion with esch other. Table 27 describes exemplary method embodiments of processes A- W. Esch embodiment is 3n individusl method using the unit processes A- W slone or in combinstion. Esch method embodiment of Table 27 is separated by a ";". If the embodiment is a single letter thsn it corresponds to one of the processes A-W. If it is more thsn one letter thsn it corresponds to esch of the processes performed sequentislly in the order indicsted.
Other sspects of the invention sre directed to methods of using shikimic scid to prepsre compound 270 shown ss A in Scheme 36, methods of using compound 270 to prepsre compound 271 shown ss B in Scheme 36, methods of using compound 271 to prepsre compound 272 shown ss C in Scheme 36, methods of using compound 272 to prepsre compound 273 shown ss D in Scheme 36, methods of using quinic scid to prepsre compound 274 shown ss E in Scheme 37, methods of using compound 274 to prepsre compound 275 shown ss F in Scheme 37, methods of using compound 275 to prepsre compound 276 shown ss G in Scheme 37, methods of using compound 276 to prepsre compound 272 shown ss H in Scheme 37, methods of using compound 273 to prepsre compound 277 shown ss I in Scheme 38, methods of using compound 277 to prepsre compound 278 shown ss J in Scheme 38, methods of using compound 278 to prepsre compound 279 shown ss K in Scheme 38, methods of using compound 279 to prepsre compound 280 shown ss L in Scheme 38, methods of using compound 280 to prepsre compound 281 shown ss M in Scheme 38, methods of using compound 281 to prepsre compound 282 shown ss N in Scheme 39, methods of using compound 282 to prepsre compound 283 shown ss O in Scheme 39, methods of using compound 283 to prepsre compound 284 shown 3S P in Scheme 39, methods of using compound 283 to prepsre compound 285 shown ss Q in Scheme 40, methods of using compound 285 to prepsre compound 286 shown ss R in Scheme 40, methods of using compound 287 to prepsre compound 288 shown ss S in Scheme 40.1, methods of using compound 288 to prepare compound 289 shown as T in Scheme 40.1, methods of using compound 289 to prepare compound 290 shown as U in Scheme 40.1, methods of using compound 290 to prepare compound 291 shown as V in Scheme 40.1, and methods of using compound 291 to prepare compound 292 shown as W in Scheme 40.1.
General sspects of these exemplsry methods 3re described below snd in the Exsmples. Esch of the products of the following processes is optionslly sepsrsted, isolsted, snd/or purified prior to its use in subsecquent processes.
The terms "trested", "tresting", "trestment", snd the like, mesn contscting, mixing, rescting, sllowing to reset, bringing into contsct, 3nd other terms common in the srt for indicsting thst one or more chemicsl entities is trested in such a msnner 3S to convert it to one or more other chemicsl entities. This mesns thst "tresting compound one with compound two" is synonymous with "sllowing compound one to reset with compound two", "contscting compound one with compound two", "rescting compound one with compound two", snd other expressions common in the srt of orgsnic synthesis for ressonsbly indicsting thst compound one wss "trested", "rescted", "sllowed to reset", etc., with compound two.
"Tresting" indicstes the ressonsble snd ususl msnner in which orgsnic chemicsls sre sllowed to reset. Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (-100°C to 250°C, typicslly -78°C to 150°C, more typicslly -78°C to 100°C, still more typically 0°C to 100°C), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis are used in selecting the conditions snd sppsrstus for "tresting" in a given process. In psrticulsr, one of ordinsry skill in the srt of orgsnic sysnthesis selects conditions snd sppsrstus ressonsbly expected to successfully csrry out the chemicsl resctions of the described processes bssed on the knowledge in the srt.
Process A. Scheme 36
Shikimic scid is used to prepsre compound 270 by the following process.
The cis-4,5-diol function of shikimic scid is differentisted from the csrboxylic scid st csrbon 1 by selective protection of these two functionslities. Typicslly the cis-4,5-diol function is protected ss s cyclic ketsl snd the csrboxylic scid function is protected ss 3n ester.
R50 is sn scid lsbile 1,2-diol protecting group such ss those described in the sbove cited work of Greene, typicslly s cyclic ketsl or scetsl, more typicslly, 3 ketsl of cyclohexsnone or scetone. R51 is sn scid stsble csrboxylic scid protecting group such ss those described in the sbove cited work of Greene, typicslly s linesr, brsnched or cyclic slkyl, slkenyl, or slkynyl of 1 to 12 csrbon stoms such ss those shown ss groups 2-7, 9-10, 15, or 100-660 of Table 2, more typically 3 linesr or brsnched slkyl of 1 to 8 csrbon stoms such ss those shown ss groups 2-5, 9, or 100-358 of Table 2, still more typically 3 linesr or brsnched slkyl of 1 to 6 csrbon stoms such ss those shown ss groups 2-5, 9, or 100-141 of Table 2, more typically yet, R51 is methyl, ethyl, n- propyl, i-propyl, n-butyl, sec-butyl, i-butyl, or t-butyl. SWkirnic acid is rescted to protect the csrboxylic scid with group R51 snd the cis-4,5-diol with group R50- Typicslly shikimic scid is trested with sn slcohol, such ss methsnol, ethsnol, n-propsnol, or i-propsnol, 3nd sn scid cstslyst, such ss a minersl scid or 3 sulfonic scid such ss methsne, benzene or toluene sulfonic scid, followed by a dislkyl ketsl or scetsl of a ketone or sldehyde, such ss 2,2-dimethoxy-propsne, or 1,1-dimethoxy- cyclohexsne, in the presence of the corresponding ketone or aldehyde, such as acetone or cyclohexsnone. Optionslly, the product of the slcohol snd scid cstslyst trestment is sepsrsted, isolsted snd /or purified prior to trestment with dislkyl ketsl or scetsl. Alternstively shikimic scid is trested with CH2N2.
Typicslly, the process comprises tresting shikimic acid with an slksnol 3nd a sulfonic scid followed by tresting with a geminsl- dislkoxyslksne or geminsl dislkoxycycloslksne snd sn slksnone or cycloslksnone to form compound 270. More typicslly, the process comprises tresting shikimic scid with sn slksnol snd 3 sulfonic scid; evsporsting excess slksnol to form a residue; tresting the residue with 3 geminsl- dislkoxyslksne or geminsl-dislkoxycycloslksne snd sn slksnone or cycloslksnone to form compound 270. Still more typicslly, the process comprises tresting shikimic 3cid with methsnol snd psrs-toluenesulfonic scid; evsporsting excess methsnol to form s residue; tresting the residue with 2,2-dimethoxypropsne snd scetone to form compound 270. An exemplsry embodiment of this process is given ss Exsmple 55 below.
Process B. Scheme 36 Compound 270 is used to prepsre compound 271 by the following process.
The hydroxy group st position 3 is sctivsted, typicslly, sctivsted towsrd displscement resctions, more typicslly, sctivsted towsrd epoxide ring forming displscement with sn slcohol 3t position 4. R52 is sn slcohol sctivsting group, typicslly, sn sctivsting group towsrd displscement resctions, more typicslly, sn sctivsting group towsrd epoxide ring forming displscement with sn slcohol st position 4. Such groups include those typicsl in the srt such ss sulfonic scid esters, more typicslly, methsne, benzene or toluene sulfonic scid esters. In one embodiment, R52, tsken together with O (i.e. -OR52), is a lesving group such ss those common in the srt.
Typicslly the process comprises tresting compound 270 with sn scid hslide to form compound 271. More typicslly, the process comprises tresting compound 270 with s sulfonic scid hslide in a suitsble solvent to form compound 271. Still more typicslly, the process comprises tresting compound 270 with s sulfonic scid hslide in a suitsble solvent such ss sn smine, optionslly, in the presence of a cosolvent, such ss s hsloslksne, to form compound 271. More typicslly yet, the process comprises tresting compound 270 with methsne sulfonyl chloride in triethylsmine/dichloromethsne to form compound 271.
An exemplsry embodiment of this process is given ss Exsmple 56 below.
Process C. Scheme 36 Compound 271 is used to prepsre compound 272 by the following process.
The scid lsbile protecting group (R50) for the hydroxy groups st positions 4 snd 5 is removed. Typicslly, R50 is removed without substsintislly removing bsse bile csrboxylic scid protecting groups (e.g. R51) or hydroxy sctivsting groups (e.g. R52)- Still more typicslly, R50 is clesved under scidic conditions. Typicslly the process comprises tresting compound 271 with s protic solvent, more typicslly, in the presence of sn scid cstslyst ss described sbove. Still more typicslly, the process comprises tresting compound 271 with sn slksnol ss described sbove snd sn scid cstslyst ss described sbove. More typicslly yet, the process comprises tresting compound 271 with methsnol snd psrs-toluene sulfonic scid to produce compound 272.
An exemplsry embodiment of this process is given ss Exsmple 57 below.
Process P. Scheme 36
Compound 272 is used to prepsre compound 273 by the following process.
The sctivsted hydroxy group st position 3 of compound 272 is displsced by the hydroxy 3t position 4 of compound 272 to produce epoxide compound 273. Typicslly the displscement is cstslyzed by a suitsble bsse, more typicslly, 3n smine bsse such ss DBU or DBN.
Typicslly the process comprises tresting compound 272 with a bssic cstslyst, optionslly in the presecnce of s suitsble solvent. Still more typicslly, the process comprises tresting compound 272 with sn smine bsse in 3 polsr, non-protic solvent such ss diethyl ether or THF. More typicslly yet, the process comprises tresting compound 272 with DBU in THF to produce compound 273.
An exemplsry embodiment of this process is given as Example 58 below.
Process E. Scheme 37
Quinic acid is used to prepare compound 274 by the following process.
The cis-4,5-diol function of quinic scid is differentiated from the csrboxylic scid st csrbon 1 by selective protection of these two functionslities. Typicslly the cis-4,5-diol function is protected ss s cyclic ketsl snd the csrboxylic 3cid function is protected ss s lsctone with the hydroxy group st position 3.
R50 is ss described sbove.
Typicslly, the process comprises tresting quinic scid with s geminsl- dislkoxyslksne or geminsl dislkoxycycloslksne, ss described sbove, snd sn slksnone or cycloslksnone, ss described sbove, optionslly, in the presence of an scid cstslyst, ss described sbove, to form compound 274. More typicslly, the process comprises tresting quinic scid with s geminsl-dislkoxyslksne or geminsl-dislkoxycycloslksne, sn slksnone or cycloslksnone, snd sn scid cstslyst to form compound 270. Still more typicslly, the process comprises tresting quinic scid with 2,2-dimethoxypropsne, scetone, snd psrs- toluenesulfonic scid to form compound 274.
An exemplsry embodiment of this process is given ss Exsmple 101 below.
Process F. Scheme 37
Compound 274 is used to prepsre compound 275 by the following process.
The Isctone is opened to form compound 275. Typicslly, the Isctone is opened to produce 3 protected csrboxylic acid at position 1 and a free hydroxy at position 3. More typicslly, the Isctone is opened under bssic conditions to produce sn R51 protected csrboxylic scid st position 1 snd s free hydroxy group 3t position 3.
R5I is ss described sbove.
Typicslly compound 274 is trested with a suitable base in a suitable protic solvent. More typicslly compound 275 is trested with a metsl slkoxide bsse, such as sodium, potassium or lithium alkoxide, in an alkanol, as described above. Still more typically, compound 274 is treated with NaOMe in MeOH to produce compound 275.
An exemplsry embodiment of this process is given as Example 102 below.
Process G, Scheme 7
Compound 275 is used to prepare compound 276 by the following process. The hydroxy group at position 3 is activated, typically, activsted toward displscement resctions, more typicslly, sctivsted towsrd epoxide ring forming displscement with sn slcohol st position 4.
R52 is sn slcohol sctivsting group, typicslly, an activating group toward displacement reactions, more typically, sn sctivating group toward epoxide ring forming displacement with an alcohol at position 4. Such groups include those typical in the art such as sulfonic acid esters, more typically, methsne, benzene or toluene sulfonic scid esters. In one embodiment, R52, tsken together with O (i.e. -OR52), is s lesving group such ss those common in the srt.
Typicslly the process comprises tresting compound 275 with sn 3cid hslide to form compound 276. More typicslly, the process comprises tresting compound 275 with a sulfonic scid hslide in a suitsble solvent to form compound 276. Still more typicslly, the process comprises tresting compound 275 with 3 sulfonic scid hslide in s suitsble solvent such ss sn smine, optionslly, in the presence of s cosolvent, such ss a hsloslksne, to form compound 276. More typicslly yet, the process comprises tresting compound 275 with p-toluene sulfonyl chloride in pyridine dichloromethθne to form compound 276.
An exemplsry embodiment of this process is given ss Exsmple 103 below.
Process H. Scheme 37
Compound 276 is used to prepsre compound 272 by the following process.
The hydroxy group 3t position 1 is eliminsted snd the cis-4,5-diol protecting group is removed. The hydroxy group st position 1 is eliminsted to form sn olefinic bond between positions 1 snd 6 snd the cis-4,5-diol protecting group is removed to regenerate the cis-4,5-diol.
Typicslly the process comprises tresting compound 276 with s suitsble dehydrating sgent, such ss s mineral scid (HCl, H2SO4) or Sθ2Cl2- More typicslly, compound 276 is trested with SO2CI2, followed by sn slksnol, optionslly in the presence of sn scid cstslyst. Still more typicslly, compound 276 is trested with SO2CI2 in s suitsble polsr, sprotic solvent, such ss sn smine to form sn olefin; the olefin is trested with sn slksnol, ss described sbove, 3nd sn scid cstslyst, ss described sbove, to form compound 272. More typicslly yet, compound 276 is trested with SO2CI2 in pyridine/CH"2Cl2 at a temperature between -100°C and 0°C, typically -100°C and -10°C, more typically -78°C, to form an olefin; the olefin is treated with methanol 3nd psra-toluene sulfonic scid to form compound 272.
An exemplsry embodiment of this process is given ss Exsmple 104 below. Process I. Scheme 38
Compound 273 is used to prepsre compound 277 by the following process.
The hydroxy group st position 5 is protected. Typicslly the protecting group is sn scid lsbile hydroxy protecting. More typicslly, the protecting group resists transfer to sdjscent hydroxy groups.
R53 is sn scid lsbile hydroxy protecting group such ss those described in the sbove cited work of Greene. More typicslly, R53 is sn scid clesvsble ether, still more typicslly, R53 is methoxymethyl (MOM, CH3X-CH2-). Typicslly the process comprises tresting compound 273 with s hydroxy protecting group resgent ss described in Greene. More typicslly the process comprises tresting compound 273 with 3 substituted or unsubstituted hsloslksne or slkene, such ss methoxymethyl chloride (MOM chloride, CPI3-O-CH2-CI), in s suitsble solvent, such ss a polsr, sprotic solvent. Still more typicslly, the process comprises tresting compound 273 with MOM chloride in sn smine solvent. More typically yet, the process comprises treating compound 273 with MOM chloride in diisoproply ethyl smine.
An exemplsry embodiment of this process is given ss Exsmple 59 below.
Process T. Scheme 38
Compound 277 is used to prepsre compound 278 by the following process. The epoxide st positions 3 3nd 4 is opened to form sn szide. More typicslly, the epoxide st positions 3 snd 4 is opened to form a 3-szido-4- hydroxy compound 278.
Typicslly the process comprises tresting compound 277 with sn szide sslt in 3 suitsble solvent. More typicslly, the process comprises tresting compound 277 with sodium szide snd a mild bsse, such ss sn smmonium hslide, in a polsr, protic solvent, such ss sn slksnol or wster. Still more typicslly, the process comprises tresting compound 277 with sodium szide snd ammonium chloride in water /methsnol solution to produce compound 278. An exemplsry embodiment of this process is given ss Exsmple 60 below. Process K. Scheme 38
Compound 278 is used to prepsre compound 279 by the following process.
The hydroxy group st position 4 of compound 278 is displsced by the 3-3zido group to form the sziridine compound 279.
Typicslly the process comprises tresting compound 278 with a hydroxy sctivsting group ss described sbove, sn orgsnophosphine snd a bsse. More typicslly the process comprises tresting compound 278 with a sulfonic scid hslide, such ss those described sbove, to form sn sctivsted hydroxy compound, tresting the sctivsted hydroxy compound with trislkyl or tri srylphosphine, such ss triphenylphosphine, to form s phosphonium sslt, snd tresting the phosphonium sslt with a bsse, such ss sn smine, to form compound 279. Still more typicslly, the process comprises tresting compound 278 with mesyl chloride, to form sn sctivsted hydroxy compound, tresting the activated hydroxy compound with triphenylphosphine, to form a phosphonium salt, and treating the phosphonium salt with triethylamine and H2O, to form compound 279.
An exemplary embodiment of this process is given as Examples 61 and 62 below.
Process L. Scheme 38
Compound 279 is used to prepare compound 280 by the following process.
The sziridine compound 279 is opened with szide to form szido smine 280.
Typicslly the process comprises tresting compound 279 with with sn szide sslt in 3 suitsble solvent. More typicslly, the process comprises tresting compound 279 with sodium szide snd a mild base, such ss sn ammonium halide, in a polar, aprotic solvent, such as an ether, amine, or amide. Still more typically, the process comprises treating compound 279 with sodium azide and ammonium chloride in DMF solution to produce compound 280.
An exemplary embodiment of this process is given ss Exsmple 63 below.
Process M. Scheme 38 Compound 280 is used to prepsre compound 281 by the following process.
The protected hydroxy group 3t position 5 is displsced by the smine st position 4 to form sziridine 281. Typicslly the sziridine 281 is substituted with sn scid lsbile group, more typicslly 3n sziridine sctivsting group.
R54 is sn scid lsbile group, typicslly sn scid lsbile smine protecting group such ss those described in the sbove cited work of Greene. More typicslly, R54 is sn sziridine sctivsting group, still more typicslly, a group cspable of activsting an sziridine towsrd 3cid cstslyzed ring opening. Typicsl R54 groups include by wsy of exsmple snd not limitstion, 3 linesr or brsnched 1-oxo-slk-l-yl group of 1 to 12 csrbons wherein the slkyl portion is 3 1 to 11 csrbon linesr or brsnched chsin slkyl group (such ss CH3(CH2)ZC(0)-, z is 3n integer from 0 to 10, i.e. scetyl CH3C(0)-, etc.), substituted methyl (e.g. triphenylmethyl, PI13C-, trityl, Tr), or a csrbsmste such ss BOC or Cbz or s sulfonste (e.g. slkyl sulphonstes such ss methyl sulphonste). More typicsl R54 groups include triphenylmethyl snd 1-oxo- slk-l-yl groups hsving 1 to 8, still more typicslly, 1, 2, 3, 4, 5, or 6, more typicslly yet, 2 or 3 csrbon stoms.
Typicslly the process comprises tresting compound 280 with a deprotecting sgent to remove group R53, sn R54 producing resgent such ss those described in Greene (R54-h3lide, such ss acetylchloride, or TrXl, or R54-O-R54, such as acetic snhydride), snd a hydroxy activating group such as those described in process B, Scheme 36. More typically the process comprises treating compound 280 with a polar, protic solvent, optionally in the presence of an acid catslyst ss described sbove, to form s first intermediste; tresting the first intermediste with Tr-Cl in a polsr, sprotic solvent, such ss sn smine, to form s second intermediste; snd tresting the second intermediste with s sulfonic scid hslide, such 3S mesyl chloride or psra toluene sulfonyl chloride, in a polsr sprotic solvent, such ss sn smine, to produce compound 281. Still more typicslly, the process comprises tresting compound 280 with methsnol snd HCl, to form s first intermediste; tresting the first intermediste with Tr-Cl snd triethylsmine, to form a second intermediste; snd tresting the second intermediste with mesyl chloride snd triethylsmine, to produce compound 281. An exemplsry embodiment of this process is given ss Exsmple 64 below. Process N. Scheme 39
Compound 281 is used to prepsre compound 282 by the following process. Aziridine 281 is opened snd the resulting smine is substituted with sn R55 group to form compound 282. Typicslly, sziridine 281 is opened by scid cstslyzed ring opening snd the resulting smine is scylsted.
R55 is W3 ss defined sbove. Typicslly R55 is -C(0)R5. More typicslly, R55 is -C(0)Rι. Still more typicslly, R55 is -C(0)CH3. R56 is Ui ss described sbove. Typicslly R56 is W6-O-, W6-S-, or W6-
N(H)-. More typicslly, 56 is R5-O-/ R5-S-, or R5-N(H)-, still more tyicslly, R56 is R5-O-, still more typicslly yet, R56 is Ri-O-.
Typicslly the process comprises tresting compound 281 with sn scid cstslyst snd s compound of the formuls W6-X1-H, wherein Xl is 3S defined sbove to form sn smine intermediste; snd tresting the smine intermediste with s compound of the formuls W3-X1-W3, W3-X10, wherein Xχo is a lesving group, to form compound 282. The scid cstslyst is typicslly a Lewis 3cid cstslyst common in the srt, such ss BF3»Et2θ, T-CI3, TMSOTf, Sml2(THF)2, LiClθ4, Mg(Clθ4)2, Ln(OTf)3 (where Ln=Yb, Gd, Nd), Ti(Oi- Pr)4, AICI3, AlBr3, BeCl2, CdC-2, ZnCl2, BF3, BCI3, BBr3, GsCtø, GsB , ΗCI4, TiBr4, ZrCU, SnCl4, SnBr4, SbC-5, SbCl3, BiCl3, FeC-3, UCI4, ScCtø, YCI3, LsCl3, CeCl3, PrCl3, NdCtø, SmCtø, EuCl3, GdCl3, TbCtø, LuCl3, DyCtø, H0CI3, ErCl3, TmCl3, YbCl3, Znl2, Al(OPri)3, Al(scsc)3, ZnBr2, for SnCU. Xl is typicslly -O-, -S-, or -N(H)-. X10 is typicslly s hslide such as Cl, Br, or I. More typically, the process comprises tresting compound 281 with 3 compound of the formu R5-OH, R5-SH, or R5-NH2, snd BF3»Et2θ to form sn intermediste; snd tresting the intermediste with sn slksnoic scid snhydride to form compound 282. Still more typicslly, the process comprises tresting compound 281 with s compound of the formuls R5-OH snd BF3»Et2θ to form an intermediate; snd tresting the intermediste with s substituted or unsubstituted scetic snhydride to form compound 282. Exemplsry compounds of the formuls R5-OH include those described by Table 2, groups 2-7, 9-10, 15, and 100-660 wherein Qi is -OH. Further exemplary compounds of the formuls R5-OH include those shown in Table 25 below (together with their Chemical Abstracts Service Registry Numbers) and those shown in Table 26 below (together with their Chemical Abstracts Service Registry Numbers, snd Aldrich Chemicsl Compsny Product Numbers). More typicsl exemplsry compounds of the formuls R5-OH sre those described by Table 2, groups 2-5, 9, and 100-141 wherein Qi is XH. In snother embodiment of Process N, Scheme 39, R55 is H. Typicslly this process embodiment comprises tresting compound 281 with sn scid cstslyst snd a compound of the formuls R56-X1-H, wherein Xl is ss defined sbove to form sn smine intermediste to form compound 282. The scid cstslyst snd Xisre ss described sbove. More typicslly, the process comprises tresting compound 281 with a compound of the formuls R5-OH, R5-SH, or R5-NH2, snd BF3»Et2θ to form compound 282. Still more typicslly, the process comprises tresting compound 281 with a compound of the formuls R5-OH snd BF3»Et2θ to form compound 282. Exemplsry compounds of the formuls R5XH sre described sbove.
Exemplsry embodiments of this process sre given ss Exsmples 65, 86, 92, snd 95 below.
Process O. Scheme 39
Compound 282 is used to prepsre compound 283 by the following process. The szide of compound 282 is reduced to form smino compound 283.
Typicslly the process comprises tresting compound 282 with a reducing sgent to form compound 283. More typicslly the process comprises tresting compound 282 with hydrogen gss snd s cstslyst (such ss plstinum on csrbon or Lindlsr's cstslyst), or reducing resgents (such ss a trialkyl or trisryl phosphine ss described sbove). More typicslly still, the process comprises tresting compound 282 with triphenylphosphine in W3ter/THF to form compound 283.
Exemplsry embodiments of this process sre given ss Exsmples 87, 93, snd 96 below.
Process P. Scheme 39
Compound 283 is used to prepsre compound 284 by the following process.
The csrboxylic scid protecting group is removed. Typicslly the process comprises tresting compound 283 with s bsse.
More typicslly, the process comprises tresting compound 283 with s metsl hydroxide in s suitsble solvent such ss sn sprotic, polsr solvent. More typicslly still, the process comprises tresting compound 283 with squeous potsssium hydroxide in THF to produce compound 284.
Exemplsry embodiments of this process 3re given ss Exsmples 88, 94, snd 97 below.
Process O. Scheme 40
Compound 283 is used to prepsre compound 285 by the following process. The smine is converted to s protected gusnidine.
R57 is s gusnidine protecting group common in the srt, such 3S BOC or Me.
Typicslly the process comprises tresting compound 283 with a gusnidylsting resgent such ss those common in the srt. Exemplsry resgents include Bis-BOC Thio-Ures sminoiminomethsnesulfonic scid (Kim; et al.; "Tet. Lett." 29(26):3183-3186 (1988) snd 1-guanylpyrazoles (Bernstowicz; et al.; "Tet. Lett." 34(21):3389-3392 (1993). More typically, the process comprises treating compound 283 with Bis-BOC Thio-Ures scid. Still more typicslly, the process comprises tresting compound 283 with Bis-BOC Thio-Ures scid snd HgCl2 to form compound 285.
An exemplsry embodiment of this process is given ss Exsmple 67 below.
Process R. Scheme 40 Compound 285 is used to prepsre compound 286 by the following process.
The csrboxylic scid snd gusnidine protecting groups sre removed. Typicslly the process comprises tresting compound 285 with 3 bsse; followed by tresting with sn scid, ss described sbove. More typicslly the process comprises tresting compound 285 with s metsl hydroxide bsse, described sbove, to form sn intermediste; snd tresting the intermediste with scid to form compound 286. Still more typicslly the process comprises tresting compound 285 with squeous potsssium hydroxide 3nd THF, to form sn intermediste; snd tresting the intermediste with TFA to form compound 286. Process S. Scheme 40.1
Compound 287 is used to prepare compound 288 by the following process.
El, Jl snd J2 of compounds 287 snd 288 sre as described above. Typically, El is -CO2R51 as described above. Typicslly, Ji is H, F, or methyl, more typicslly, H. Typicslly, J2 is H or s linesr or brsnched slkyl of 1 to 6 csrbon stoms, more typicslly, H, methyl, ethyl, n-propyl, or i-propyl, still more typicslly, H.
R60 and R61 are groups capsble of rescting to form the R&j (defined below) substituted sziridine ring of compound 288. Typicslly, one of R 0 or R61 is 3 primsry or secondsry smine, or s group cspsble of being converted to 3 primsry or secondsry smine. Such groups for R60 and Rόl include by way of example and not limitation, -NH2, -N(H)(R6b), -N(R6b)2, -N(H)(Ri), -N(Rι)(R6b)/ and -N3. The other of R60 and R61 is typicslly s group cspsble of being displsced by a primsry or secondsry amine to form an sziridine. Such groups include by wsy of exsmple snd not limitstion, -OH, -OR63, Br, Cl, snd I. Typicslly, R60 and R61 are in a trans configuration. More typically, R60 is a primary or secondsry smine, or a group cspable of being converted to a primary or secondary amine and R61 is a group capsble of being displsced by a primsry or secondsry smine to form an aziridine. Still more typically, R60 is β-azido or β-NH2, snd R61 is α-OH, α-OMesyl, or α-OTosyl. R62 is described below in Process U, Scheme 40.1. The process comprises tresting compound 287 to form compound 288. This is typicslly sccomplished by tresting compound 287 to displace R61 by R60- More typicslly, compound 287 is trested to sctivste R61 towsrd displscement by R60- Still more typicslly, compound 287 is trested to sctivste Rόi towsrd displscement by R60 and R^o is activated toward displscement of R61- If both R60 and R61 sre sctivsted, the sctivstions csn be performed simultsneously or sequentially. If the activations are performed sequentially, they csn be performed in sny order, typicslly the sctivstion of R£i precedes the sctivstion of R60-
Activstion of R61 towsrd displscement by R60 is typicslly sccomplished by tresting compound 287 with 3 hydroxy sctivsting resgent such ss mesyl or tosyl chloride. Activstion of R60 towsrd displscement of R61 is typicslly sccomplished by tresting compound 287 to form a primsry or secondsry smine snd tresting the smine with s bsse. By wsy of exsmple snd not limitstion, compound 287 is trested with a reducing sgent cspsble of reducing sn szide to sn smine snd a bsse.
In one embodiment of this process, compound 287 is trested with sn R61 sctivsting resgent, snd sn Rβo sctivsting resgent to produce compound 288. In snother embodiment, compound 287 is trested in a suitsble solvent with sn R6i sctivsting resgent, snd sn R60 sctivsting resgent to produce compound 288. In snother embodiment, compound 287 is trested with sn R61 sctivsting resgent, sn R60 sctivsting resgent, snd a bsse to produce compound 288. In snother embodiment, compound 287 is trested in a suitable solvent with an R61 sctivsting resgent, 3n R60 sctivsting resgent, snd a bsse to produce compound 288. In snother embodiment, compound 287 wherein R60 is sn szide is trested with 3n R61 sctivsting resgent, 3nd sn szide reducing resgent to produce compound 288. In snother embodiment, compound 287 wherein R60 is 3n szide is trested in a suitsble solvent with sn R$ sctivsting resgent, snd 3n szide reducing resgent to produce compound 288. In snother embodiment, compound 287 wherein R60 is an azide is trested with sn R61 sctivsting resgent, sn szide reducing resgent, snd s bsse to produce compound 288. In snother embodiment, compound 287 wherein R60 is sn szide is trested in a suitsble solvent with sn R61 sctivsting resgent, sn szide reducing resgent, snd s bsse to produce compound 288. In snother embodiment, compound 287 wherein R^o is an azide and R61 is a hydroxy, is trested with a hydroxy sctivsting resgent, snd sn szide reducing resgent to produce compound 288. In snother embodiment, compound 287 wherein R60 is sn szide snd R61 is s hydroxy, is trested in s suitsble solvent with 3n hydroxy sctivsting resgent, snd sn szide reducing resgent to produce compound 288. In snother embodiment, compound 287 wherein R60 is sn szide snd R61 is a hydroxy, is trested with a hydroxy sctivsting resgent, sn szide reducing resgent, snd s bsse to produce compound 288. In snother embodiment, compound 287 wherein R60 is sn szide snd R61 is a hydroxy, is trested in a suitsble solvent with a hydroxy sctivsting resgent, an azide reducing resgent, snd s bsse to produce compound 288.
An exemplsry embodiments of this process sre given ss Process K, Scheme 38, sbove.
Process T. Scheme 40.1
Compound 288 is used to prepsre compound 289 by the following process.
R64 is typicslly H, R6b or a group cspsble of being converted to H or R6b-. More typicslly, R64 is H. R£5 is typicslly Gi or a group cspsble of being converted to Gi. More typicslly, R65 is -N3, -CN, or -(CRiRi)mlW2- More typicslly R65 is -N3, -NH2, -N(H)(Rβb), -N(R6b)2, -CH2N3, or -CH2CN.
Typicslly, compound 288 is trested to form smine 289. More typicslly, compound 288 is trested with a nucleophile, typicslly s nitrogen nucleophile such ss R65, s C3tionic sslt of R65, or a protonsted snslog of R65, such 3S by wsy of exsmple snd not limitstion, NH3, sn szide sslt (such ss NsN3, KN3, or the like), HCN, a cysnide sslt (such 3S NsCN, KCN, or the like), or s sslt of 3 cysnoslkyl (e.g. (CH2CN)-) (such ss NsCH2CN, KCH2CN, or the like). Still more typicslly, compound 288 is trested with sn szide sslt. Optionslly s bsse, typicslly a mild bsse such ss sn ammonium halide 3nd a solvent, typicslly a pol3r, sprotic solvent, such ss an ether, amine, or amide are used. In one embodiment, compound 288 is trested with a nucleophile. In snother embodiment, compound 288 is trested with a nucleophile in s suitsble solvent to produce compound 289. In snother embodiment, compound 288 is trested with 3 nucleophile snd s bsse to produce compound 289. In snother embodiment, compound 288 is trested with 3 nucleophile snd a bsse in a suitsble solvent to produce compound 289. In snother embodiment, compound 288 is trested with a nitrogen nucleophile to produce compound 289. In snother embodiment, compound 288 is trested with a nitrogen nucleophile in s suitsble solvent to produce compound 289. In snother embodiment, compound 288 is trested with a nitrogen nucleophile snd a bsse to produce compound 289. In snother embodiment, compound 288 is trested with s nitrogen nucleophile snd s bsse in a suitsble solvent to produce compound 289. In snother embodiment, compound 288 is trested with 3n szide sslt to produce compound 289. In snother embodiment, compound 288 is trested with 3n szide sslt in 3 suitsble solvent to produce compound 289. In snother embodiment, compound 288 is trested with sn szide sslt snd a bsse to produce compound 289. In snother embodiment, compound 288 is trested with 3n szide sslt snd s bsse in a suitsble solvent to produce compound 289. An exemplsry embodiment of this process is given 3S Process L, Scheme 38, sbove. Process U. Scheme 40.1
Compound 289 is used to prepsre compound 290 by the following process.
R62 is s group cspsble of rescting with sn smine to form the R66 (defined below) substituted sziridine ring of compound 290. Typicslly, R 2 is s group cspsble of being displsced by s primsry or secondsry smine to form sn sziridine. Such groups include by wsy of exsmple snd not limitstion, -OR53, -OH, -OR63, Br, Cl, snd I. Typicslly, R62 is in s trans configuration relstive to the nitrogen in position 4. More typicslly, R62 i -OR53-
R64 is H or R6b typicslly sn scid lsbile protecting group such ss R54. R66 is H, R6b or R54.
The process comprises tresting compound 289 to form compound 290. This is typicslly sccomplished by tresting compound 289 to displsce R62 by the smine st position 4. More typicslly, compound 289 is trested to sctivste the smine st position 4 towsrd displscement of R62- Still more typicslly, compound 289 is trested to sctivste the smine at position 4 toward displscement of R62, and R62 is sctivsted towsrd displscement by the smine st position 4. If both R62 and the smine st position 4 sre sctivsted, the sctivstions csn be performed simultsneously or sequentislly. If the
3Ctivstions sre performed sequentislly, they csn be performed in sny order, typicslly the sctivstion of R62 precedes the activation of the amine at position 4.
Activstion of R62 towsrd displscement by the amine at position 4 is typically accomplished by treating compound 289 with a hydroxy activating agent such as those described in process B, Scheme 36. Optionslly, R62 is deprotected prior to sctivstion. Activstion of the smine 3t position 4 towsrd R62 displscement is typicslly sccomplished by tresting compound 289 to form 3 primsry or secondsry smine snd tresting the smine with sn 3cid cstslyst such ss those described in Process N, Scheme 39, sbove.
Typicslly when R62 is -OR53 snd R66 is R56 the process comprises tresting compound 289 with s deprotecting sgent to remove group R53, sn R54 producing resgent such ss those described in Greene (R54-hslide, such ss scetylchloride, or Tr-Cl, or R54-O-R54, such ss scetic snhydride), snd a hydroxy sctivsting group such ss those described in Process B, Scheme 36. More typicslly the process comprises tresting compound 289 with a polsr, protic solvent, optionslly in the presence of sn scid cstslyst ss described sbove, to form a first intermediste; tresting the first intermediste with Tr-Cl in s polsr, sprotic solvent, such ss sn smine, to form a second intermediste; snd tresting the second intermediste with s sulfonic scid hslide, such ss mesyl chloride or para toluene sulfonyl chloride, in a polsr sprotic solvent, such ss 3n smine, to produce compound 290. Still more typicslly, the process comprises tresting compound 289 with methsnol snd HCl, to form a first intermediste; tresting the first intermediste with Tr-Cl snd triethylsmine, to form a second intermediste; snd tresting the second intermediste with mesyl chloride snd triethylsmine, to produce compound 290.
In one embodiment compound 289 is trested with sn scid cstslyst to produce compound 290. In snother embodiment compound 289 is trested with sn scid cstslyst in s suitsble solvent to produce compound 290. In snother embodiment compound 289 is trested with a hydroxy activ3ting resgent snd sn scid cstslyst to produce compound 290. In snother embodiment compound 289 is trested with a hydroxy activating reagent snd an acid cstslyst in s suitsble solvent to produce compound 290. In snother embodiment compound 289 is trested with s hydroxy deprotecting resgent, a hydroxy sctivsting resgent snd sn scid cstslyst to produce compound 290. In snother embodiment compound 289 is treated with a hydroxy activating reagent snd sn scid cstalyst in a suitable solvent to produce compound 290.
An exemplary embodiment of this process is given as Process M,
Scheme 38, above.
Process V. Scheme 40.1
Compound 290 is used to prepare compound 291 by the following process.
Aziridine 290 is treated to form compound 291. Typically, aziridine 290 is opened by acid catalyzed ring opening and the resulting amine is acylsted.
R68 is independently H, Rόb, Rl or R55 as defined above. Typically R55 is -C(0)R5. Typicslly one R68 is H or R6b and the other is W3.
R67 is Ui as described above. Typically R67 is W6-O-, W6-S-, or W6- N(H)-. More typically, R67 is R5-O-, R5-S-, or Rs-N(H)-.
Typically the process comprises treating compound 290 with an acid catalyst and a compound of the formula W6-X1-H, wherein Xl is as defined sbove to form sn smine intermediste; snd tresting the smine intermediste with a compound of the formuls W3-X1-W3, or W3-X10, wherein X10 is s lesving group, to form compound 291. The trestment with s compound of the formuls W6-X1-H snd sn scid cstslyst msy be prior to or simultsneous with the trestment with s compound of the formuls W3-X1-W3, or W3-X10- The scid cstslyst is typicslly one of those described in Process N, Scheme 39, sbove. More typicslly, the process comprises tresting compound 290 with a compound of the formuls R5-OH, R5-SH, or R5-NH2 snd sn 3cid cstslyst; snd tresting the intermediste with sn slksnoic scid snhydride to form compound 291.
One embodiment comprises tresting compound 290 with a compound of the formuls Wό-Xl-H snd sn scid cstslyst to produce compound 291. Another embodiment comprises tresting compound 290 with s compound of the formuls W6-X1-H snd an acid cstslyst in a suitsble solvent to produce compound 291. Another embodiment comprises tresting compound 290 with a compound of the formula Wό-Xl-H, an scid cstslyst snd s compound of the formuls W3-X1-W3 or W3-X10 to produce compound 291. Another embodiment comprises tresting compound 290 with 3 compound of the formuls W6-X1-H, sn scid cstslyst snd a compound of the formuls W3-X1-W3 or W3-X10 in 3 suitsble solvent to produce compound 291.
Exemplsry embodiments of this process are given as Process N, Scheme 39, above. Process W. Scheme 40.1
Compound 291 is used to prepsre compound 292 by the following process.
Compound 291 is trested to form compound 292. Typicslly R65 is converted to form Gi. Ui is sn embodiment of R67 snd Ti is sn embodiment of -N(R68)2 prepsred in Process V, Scheme 40.1, sbove.
In one embodiment, R65 is deprotected, slkylsted, gusnidiny ted, oxidized or reduced to form Gi. Any number of such trestments csn be performed in sny order or simultsneously. By wsy of exsmple snd not limitstion, when R65 is szido, embodiments of this process include Processes O, OQ, OQR, 3nd OP. Typicsl slkylsting agents are those common in the art including, by wsy of exsmple snd not limitstion, sn slkyl hslide such ss methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, n- propyl iodide, n-propyl bromide, i-propyl iodide, i-propyl bromide; snd 3n olefin oxide such ss ethylene oxide or propylene oxide. A bsse cstslyst ss described herein msybe optionslly employed in the slkyl3tion step.
One embodiment comprises tresting compound 291 wherein R65 is szido with a reducing sgent to produce compound 292. Another embodiment comprises tresting compound 291 wherein R65 is szido with a reducing sgent to produce compound 292 in a suitsble solvent. Another embodiment comprises tresting compound 291 wherein R65 is smino with sn slkylsting sgent to produce compound 292. Another embodiment comprises tresting compound 291 wherein R65 is smino with sn slkylsting sgent to produce compound 292 in a suitsble solvent. Another embodiment comprises tresting compound 291 wherein R65 is szido with a reducing sgent snd sn slkylsting sgent to produce compound 292. Another embodiment comprises tresting compound 291 wherein R65 is szido with a reducing sgent snd sn slkylsting sgent to produce compound 292 in 3 suitsble solvent. .Another embodiment comprises tresting compound 291 wherein R65 is smino with sn slkylsting sgent 3nd a bsse cstslyst to produce compound 292. Another embodiment comprises tresting compound 291 wherein R65 is smino with sn slkylsting sgent snd s bsse cstslyst to produce compound 292 in a suitsble solvent. Another embodiment comprises tresting compound 291 wherein R65 is szido with a reducing agent, an slkylsting sgent snd a bsse cstslyst to produce compound 292. Another embodiment comprises tresting compound 291 wherein R65 is szido with a reducing sgent, sn slkylsting sgent snd a bsse cstslyst to produce compound 292 in a suitsble solvent.
Exemplsry embodiments of this process sre given as Process O, Scheme 39, above.
Exemplsry embodiments of this process sre given ss Exsmples 68 snd 69 below. Table 25 - Exemplsry Compounds of Formuls R5-OH (CAS No.)
C4 Fluoro Alcohols
(R*,R*)-(±)-3-fluoro-2-Butsnol (139755-61-6) l-fluoro-2-Butsnol (124536-12-5)
(R)-3-fluoro-l-Butsnol (120406-57-7)
3-fluoro-l-But3nol (19808-95-8)
4-fluoro-2-But3nol (18804-31-4)
(R*,S*)-3-fluoro-2-Butsnol (6228-94-0) (R*,R*)-3-fluoro-2-But3nol (6133-82-0)
2-fluoro-l-Butsnol (4459-24-9)
2-fluoro-2-methyl-l-Propsnol (3109-99-7)
3-fluoro-2-Butsnol (1813-13-4)
4-fluoro-l-But3nol (372-93-0) l-fluoro-2-methyl-2-Propsnol (353-80-0)
C5 Fluoro Alcohols
2-fluoro-l-Pent3nol (123650-81-7)
(R)-2-fluoro-3-methyl-l-Butsnol (113943-11-6) (S)-2-fluoro-3-methyl-l-Butsnol (113942-98-6)
4-fluoro-3-methyl-l-But3nol (104715-25-5) l-fluoro-3-Pentsnol (30390-84-2)
4-fluoro-2-Pentsnol (19808-94-7)
5-fluoro-2-Pentsnol (18804-35-8) 3-fluoro-2-methyl-2-Butsnol (7284-96-0)
2-fluoro-2-methyl-l-Butsnol (4456-02-4)
3-fluoro-3-methyl-2-But3nol (1998-77-2)
5-fluoro-l-Pentsnol (592-80-3) C6 Fluoro Alcohols
(R-(R*,S*))-2-fluoro-3-methyl-l-Pentsnol (168749-88-0) l-fluoro-2,3-dimethyl-2-But3nol (161082-90-2)
2-fluoro-2,3-dimethyl-l-But3nol (161082-89-9)
(R)-2-fluoro-4-methyl-l-Pentsnol (157988-30-2) (S-(R*,R*))-2-fluoro-3-methyl-l-Pent3nol (151717-18-9)
(R'^^-fluoro-S-methyl-l-Pentsnol (151657-14-6)
(S)-2-fluoro-3,3-dimethyl-l-But3nol (141022-94-8)
(M)-2-fluoro-2-methyl-l-Pentsnol (137505-57-8)
(S)-2-fluoro-l-Hex3nol (127608-47-3) 3-fluoro-3-methyl-l-Pentsnol (112754-22-0)
3-fluoro-2-methyl-2-Pent3nol (69429-54-5)
2-fluoro-2-methyl-3-Pentsnol (69429-53-4) l-fluoro-3-Hexsnol (30390-85-3)
5-fluoro-2-methyl-2-Pent3nol (21871-78-3) 5-fluoro-3-Hexsnol (19808-92-5)
4-fluoro-3-methyl-2-Pentsnol (19808-90-3) 4-fluoro-4-methyl-2-Pentsnol (19031-69-7) l-fluoro-3,3-dimethyl-2-Butsnol (4604-66-4) 2-fluoro-2-methyl-l-Pentsnol (4456-03-5) 2-fluoro-4-methyl-l-Pent3nol (4455-95-2) 2-fluoro-l-Hexsnol (1786-48-7)
3-fluoro-2,3-dimethyl-2-But3nol (661-63-2) 6-fluoro-l-Hexsnol (373-32-0)
C7 Fluoro Alcohols 5-fluoro-5-methyl-l-Hexsnol (168268-63-1)
(R)-l-fluoro-2-methyl-2-Hexsnol ( 153683-63-7) (S)-3-fluoro-l-Heptsnol (141716-56-5) (S)-2-fluoro-2-methyl-l-Hex3nol (132354-09-7) (R)-3-fluoro-l-Heptsnol (120406-54-4) (S)-2-fluoro-l-Hept3nol (110500-31-7) l-fluoro-3-Heptsnol (30390-86-4) 7-fluoro-2-Heptsnol (18804-38-1) 2-ethyl-2-(fluoromethyl)-l-Butsnol (14800-35-2) 2-(fluoromethyl)-2-methyl-l-Pentsnol (13674-80-1) 2-fluoro-5-methyl-l-Hexsnol (4455-97-4) 2-fluoro-l-Heptsnol (1786-49-8) 7-fluoro-l-Hept3nol (408-16-2)
C8 Fluoro Alcohols (M)-2-fluoro-2-methyl-l-Heptsnol (137505-55-6)
6-fluoro-6-methyl-l-Heptsnol (135124-57-1) l-fluoro-2-Octsnol (127296-11-1)
(R)-2-fluoro-l-Octsnol (118205-91-7)
(±)-2-fluoro-2-methyl-l-Heptsnol (117169-40-1) (S)-2-fluoro-l-Oct3nol (110500-32-8)
(S)-l-fluoro-2-Oct3nol (110270-44-5)
(R)-l-fluoro-2-Octsnol (110270-42-3)
(±)-l-fluoro-2-Octsnol (110229-70-4)
2-fluoro-4-methyl-3-Hept3nol (87777-41-1) 2-fluoro-6-methyl-l-Heptsnol (4455-99-6)
2-fluoro-l-Octsnol (4455-93-0)
8-fluoro-l-Oct3nol (408-27-5)
C9 Fluoro Alcohols 6-fluoro-2,6-dimethyl-2-Heptsnol (160981-64-6) (S)-3-fluoro-l-Non3nol (160706-24-1) (R-(R*,R*))-3-fluoro-2-Nonsnol (137909-46-7) (R-(R*,S*))-3-fluoro-2-Non3nol (137909-45-6) 3-fluoro-2-Nonsnol (137639-20-4) (S-(R*,R*))-3-fluoro-2-Nonsnol (137639-19-1) (S-(R*,S*))-3-fluoro-2-Nonsnol (137639-18-0) (±)-3-fluoro-l-Nonsnol (134056-76-1) 2-fluoro-l-Nonsnol (123650-79-3) 2-fluoro-2-methyl-l-Octsnol (120400-89-7) (R)-2-fluoro-l-Non3nol (118243-18-8) (S)-l fluoro-2-Nonsnol (111423-41-7) (S)-2-fluoro-l-Nonsnol (110500-33-9) l-fluoro-3-Nonsnol (30390-87-5) 2-fluoro-2,6-dimethyl-3-Hept3nol (684-74-2) 9-fluoro-l-Nonsnol (463-24-1) C O Fluoro Alcohols
4-fluoro-l-Dec3nol (167686-45-5)
(P)-10-fluoro-3-Decsnol (145438-91-1)
(R-(R*,R*))-3-fluoro-5-methyl-l-Nonsnol (144088-79-9)
(P)-10-fluoro-2-Decsnol (139750-57-5) l-fluoro-2-Dec3nol (130876-22-1)
(S)-2-fluoro-l-Decsnol (127608-48-4)
(R)-l-fluoro-2-Dec3nol (119105-16-7)
(S)-l-fluoro-2-Decsnol (119105-15-6)
2-fluoro-l-Decsnol (110500-35-1) l-fluoro-5-Decsnol (106533-31-7)
4-fluoro-2,2,5,5-tetrsmethyl-3-Hexsnol (24212-87-1) lO-fluoro-l-Decsnol (334-64-5)
I Fluoro Alcohols lO-fluoro-2-methyl-l-Decsnol (139750-53-1)
2-fluoro-l-Undec3nol (110500-34-0)
8-fluoro-5,8-dimethyl-5-Nonsnol (110318-90-6) ll-fluoro-2-Undecanol (101803-63-8)
11-fluoro-l-Undecanol (463-36-5)
C12 Fluoro Alcohols
1 l-fluoro-2-methyl-l-Undecsnol (139750-52-0) l-fluoro-2-Dodecsnol (132547-33-2)
(R*,S*)-7-fluoro-6-Dodecsnol (130888-52-7) (R*,R*)-7-fluoro-6-Dodecsnol (130876-18-5)
(S)-2-fluoro-l-Dodecsnol (127608-49-5)
12-fluoro-2-penty 1-Heptsnol (120400-91 -1 )
(R*,S*)-(±)-7-fluoro-6-Dodecsnol (119174-39-9)
(R*,R*)-(±)-7-fluoro-6-Dodec3nol (119174-38-8) 2-fluoro-l-Dodecsnol (110500-36-2) ll-fluoro-2-methyl-2-Undec3nol (101803-67-2)
1-fluoro-l-Dodecsnol (100278-87-3)
12-fluoro-l-Dodecsnol (353-31-1) C4 Nitro Alcohols (R)-4-nitro-2-Butsnol (129520-34-9) (S)-4-nitro-2-But3nol (120293-74-5) 4-nitro-l-But3nol radicsl ion(l-) (83051-13-2) (R*,S*)-3-nitro-2-Butsnol (82978-02-7) (R*,R*)-3-nitro-2-Butsnol (82978-01-6) 4-nitro-l-Butsnol (75694-90-5) (±)-4-nitro-2-But3nol (72959-86-5) 4-nitro-2-But3nol (55265-82-2), l-3ci-nitro-2-Butsnol (22916-75-2) 3-3ci-nitro2-Butsnol (22916-74-1) 2-methyl-3-nitro-l-Prop3nol (21527-52-6) 3-nitro-2-Butsnol (6270-16-2) 2-methyl-l-nitro-2-Prop3nol (5447-98-3) 2-sci-nitro-l-But3nol (4167-97-9) l-nitro-2-But3nol (3156-74-9) 2-nitro-l-Butsnol (609-31-4) 2-methyl-2-nitro-l-Prop3nol (76-39-1) C5 Nitro Alcohols
(R)-3-methyl-3-nitro-2-But3nol (154278-27-0) 3-methyl-l-nitro-l-Butsnol (153977-20-9) (±)-l-nitro-3-Pentsnol (144179-64-6) (S)-l-nitro-3-Pentsnol (144139-35-5) (R)-l-nitro-3-Pent3nol (144139-34-4)
(R)-3-methyl-l-nitro-2-Butsnol (141434-98-2) (±)-3-methyl-l-nitro-2-Butsnol (141377-55-1) (R*,R*)-3-nitro-2-Pentsnol (138751-72-1) (R*,S*)-3-nitro-2-Pent3nol (138751-71-0) (R*,R*)-2-nitro-3-Pent3nol (138668-26-5) (R*,S*)-2-nitro-3-Pentsnol (138668-19-6) 3-nitro-l-Pentsnol (135462-98-5) (R)-5-nitro-2-Pent3nol (129520-35-0) (S)-5-nitro-2-Pentsnol (120293-75-6) 4-nitro-l-Pent3nol (116435-64-4)
(±)-3-methyl-3-nitro-2-Butsnol (114613-30-8) (S)-3-methyl-3-nitro-2-Butsnol (109849-50-5) 3-methyl-4-nitro-2-Butsnol (96597-30-7) (±)-5-nitro-2-Pent3nol (78174-81-9) 2-methyl-2-nitro-l-Butsnol (77392-55-3) 3-methyl-2-nitro-l-But3nol (77392-54-2) 3-methyl-4-nitro-l-Butsnol (75694-89-2) 2-methyl-4-nitro-2-But3nol (72183-50-7) 3-methyl-3-nitro-l-Butsnol (65102-50-3) 5-nitro-2-Pent3nol (54045-33-9)
2-methyl-3-sci-nitro-2-But3nol (22916-79-6) 2-methyl-l-sci-nitro-2-But3nol (22916-78-5) 2-methyl-3-nitro-2-Butsnol (22916-77-4) 2-methyl-l-nitro-2-But3nol (22916-76-3) 5-nitro-l-Pentsnol (21823-27-8) 2-methyl-3-nitro-l-But3nol (21527-53-7) 2-nitro-3-Pentsnol (20575-40-0)
3-methyl-3-nitro-2-Butsnol (20575-38-6) 3-nitro-2-Pentsnol (5447-99-4) 2-nitro-l-Pent3nol (2899-90-3) 3-methyl-l -nitro-2-But3nol (2224-38-6) l-nitro-2-Pentsnol (2224-37-5)
C6 Nitro Alcohols
(-)-4-methyl-l-nitro-2-Pent3nol (158072-33-4) 3-(nitromethyl)-3-Pentsnol (156544-56-8) (R*,R*)-3-methyl-2-nitro-3-Pent3nol (148319-17-9) (R*,S*)-3-methyl-2-nitro-3-Pentsnol (148319-16-8) 6-nitro-2-Hexsnol (146353-95-9) (±)-6-nitro-3-Hex3nol (144179-63-5) (S)-6-nitro-3-Hexsnol (144139-33-3) (R)-6-nitro-3-Hexsnol (144139-32-2) 3-nitro-2-Hexsnol (127143-52-6) 5-nitro-2-Hex3nol (110364-37-9) 4-methyl-l-nitro-2-Pentsnol (102014-44-8) (R*,S!+)-2-methyl-4-nitro-3-Pent3nol (82945-29-7) (R* ,R*)-2-methyl-4-nitro-3-Pentsnol (82945-20-8) 2-methyl-5-nitro-2-Pent3nol (79928-61-3) 2,3-dimethyl-l-nitro-2-Butsnol (68454-59-1) 2-methyl-3-nitro-2-Pent3nol (59906-62-6) 3,3-dimethyl-l-nitro-2-But3nol (58054-88-9) 2,3-dimethyl-3-nitro-2-But3nol (51483-61-5) 2-methyl-l-nitro-2-Pentsnol (49746-26-1 ) 3,3-dimethyl-2-nitro-l-Butsnol (37477-66-0) 6-nitro-l-Hexsnol (31968-54-4) 2-methyl-3-nitro-l-Pent3nol (21527-55-9) 2,3-dimethyl-3-nitro-l-Butsnol (21527-54-8) 2-methyl-4-nitro-3-Pent3nol (20570-70-1 ) 2-methyl-2-nitro-3-Pentsnol (20570-67-6) 2-nitro-3-Hexsnol (5448-00-0) 4-nitro-3-Hex3nol (5342-71-2) 4-methyl-4-nitro-l-Pent3nol (5215-92-9) l-nitro-2-Hexsnol (2224-40-0)
C7 Nitro Alcohols l-nitro-4-Hept3nol (167696-66-4) (R)-l-nitro-2-Hept3nol (146608-19-7) 7-nitro-l-Heptsnol (133088-94-5) (R*,S*)-3-nitro-2-Heptsnol (127143-73-1) (R*,R*)-3-nitro-2-Heptsnol (127143-72-0) (R*,S*)-2-nitro-3-Heptsnol (127143-71-9) (R*,R*)-2-nitro-3-Heptsnol (127143-70-8) (R*,S*)-2-methyl-5-nitro-3-Hexanol (103077-95-8) (R*,R*)2-methyl-5-nitro-3-Hexanol (103077-87-8) 3-ethyl-4-nitro-l-Pentanol (92454-38-1 ) 3-ethyl-2-nitro-3-Pent3nol (77922-54-4) 2-nitro-3-Heptsnol (61097-77-6) 2-methyl-l-nitro-3-Hex3nol (35469-17-1) 2-methyl-4-nitro-3-Hexsnol (20570-71-2) 2-methyl-2-nitro-3-Hex3nol (20570-69-8) 5-methyl-5-nitro-2-Hexsnol (7251-87-8) l-nitro-2-Hept3nol (6302-74-5) 3-nitro-4-Heptsnol (5462-04-4) 4-nitro-3-Hept3nol (5342-70-1)
C8 Nitro Alcohols (±)-l-nitro-3-Oct3nol (141956-93-6) l-nitro-4Xctanol (167642-45-7) (S)-l-nitro-4-Octsnol (167642-18-4)
6-methyl-6-nitro-2-Heptsnol (142991-77-3) (R*,S*)-2-nitro-3-Octsnol (135764-74-8) (R*,R*)-2-nitro-3-Octsnol (135764-73-7) 5-nitro-4-Octsnol (132272-46-9) (R*,R*)-3-nitro-4-Oct3nol (130711-79-4) (R* ,S*)-3-nitro-4-Octsnol (130711-78-3) 4-ethyl-2-nitro-3-Hex3nol (126939-74-0) 2-nitro-3-Octsnol (126939-73-9) l-nitro-3-Oct3nol (126495-48-5) (R*,R*)-(±)-3-nitro-4-Oct3nol (118869-22-0) (R*,S*)-(±)-3-nitro-4-Octsnol (118869-21-9) 3-nitro-2-Octsnol (127143-53-7) (R*,S*)-2-methyl-5-nitro-3-Heptsnol (103078-03-1) (R*,R*)-2-methyl-5-nitro-3-Heptsnol (103077-90-3) 8-nitro-lXctsnol (101972-90-1) (±)-2-nitro-l-Octsnol (96039-95-1 ) 3,4-dimethyl-l-nitro-2-Hexsnol (64592-02-5) 3-(nitromethyl)-4-Hept3nol (35469-20-6) 2,5-dimethyl-l-nitro-3-Hexsnol (35469-19-3) 2-methyl-l-nitro-3-Hept3nol (35469-18-2)
2,4,4- trimethy 1-1 -nitro-2-Pentsnol (35223-67-7) 2,5-dimethyl-4-nitro-3-Hex3nol (22482-65-1 ) 2-nitro-l-Octsnol (2882-67-9) l-nitro-2-Octsnol (2224-39-7)
C9 Nitro Alcohols 4-nitro-3-Non3nol (160487-89-8) (R*,R*)-3-ethyl-2-nitro-3-Hept3nol (148319-18-0) 2,6-dimethyl-6-nitro-2-Heptsnol (117030-50-9) (R*,S*)-2-nitro-4-Nonsnol (103077-93-6) (R*,R*)-2-nitro-4-Nonsnol (103077-85-6) 2-nitro-3-Non3nol (99706-65-7) 9-nitro-l-Nonsnol (81541-84-6) 2-methyl-l-nitro-3X>ctsnol (53711-06-1) 4-nitro-5-Nonsnol (34566-13-7) 2-methyl-3-(nitromethyl)-3-Heptenol (5582-88-7) l-nitro-2-Non3nol (4013-87-0)
CIO Nitro Alcohols
2-nitro-4-Decsnol (141956-94-7)
(R*,S*)-3-nitro-4-Dec3nol (135764-76-0) (R*,R*)-3-nitro-4-Decsnol (135764-75-9)
5,5-dimethyl-4-(2-nitroethyl)-l-Hex3nol (133088-96-7)
(R*,R*)-(±)-3-nitro-4-Decsnol (118869-20-8)
(R*,S*)-(±)-3-nitro-4-Decsnol (118869-19-5)
5-nitro-2-Decsnol (112882-29-8) 3-nitro-4-Decsnol (93297-82-6)
4,6,6-trimethy 1-1 -nitro-2-Heptsnol (85996-72-1 )
2-methyl-2-nitro-3-Nonsnol (80379-17-5) l-nitro-2-Dec3nol (65299-35-6)
2,2,4,4-tetrsmethyl-3-(nitromethyl)-3-Pent3nol (58293-26-8)
Cll Nitro Alcohols ll-nitro-5-Undecsnol (167696-69-7)
(R*,R*)-2-nitro-3-Undec3nol (144434-56-0)
(R*,S*)-2-nitro-3-Undecsnol (144434-55-9) 2-nitro-3-Undec3nol (143464-92-0)
2,2-dimethy l-4-nitro-3-Nonsnol (126939-76-2)
4,8-dimethyl-2-nitro-l-Nonsnol (118304-30-6)
11-nitro-l-Undecsnol (81541-83-5) C12 Nitro Alcohols
2-methyl-2-nitro-3-Undec3nol (126939-75-1)
2-nitro-l-Dodecsnol (62322-32-1) l-nitro-2-Dodec3nol (62322-31-0)
2-nitro-3-Dodecsnol (82981-40-6) 12-nitro-l-Dodec3nol (81541-78-8) Table 26 - Exemplsry Compounds of Formuls R5-OH (CAS No./Aldrich No.)
3-BROMO-l-PROPANOL 627189 167169 l,3-DICHLORO-2-PROPANOL 96231 184489
3-CHLORO-2,2-DIMETHYL-l-PROPANOL 13401564 189316
2,2-BIS(CHLOROMETHYL)-l-PROPANOL 5355544 207691 l,3-DIFLUORO-2-PROPANOL 453134 176923
2-(METHYLTHIO)ETHANOL 5271385 226424
2-(DIBUTYLAMINO)ETHANOL 102818 168491
2-(DπSOPROPYLAMINO)ETHANOL 96800 168726
3-METHYL-3-BUTEN-1-OL 763326 129402
2-METHYL-3-BUTEN-2-OL 115184 136816
3-METHYL-2-BUTEN-1-OL 556821 162353
4-HEXEN-l-OL 928927 237604
5-HEXEN-l-OL 821410 230324
CIS-2-HEXEN-1-OL 928949 224707
TRANS-3-HEXEN-l-OL 928972 224715
TRANS-2-HEXEN-l-OL 928950 132667
(+/-)-6-METHYL-5-HEPTEN-2XL 4630062 195871
DIHYDROMYRCENOL 18479588 196428
TRANS,TRANS-2,4-HEX ADIEN-1 -OL 17102646 183059
2,4-DIMETHYL-2,6-HEPTADIEN-l-OL 80192569 238767
GERANIOL 106241 163333
3-BUTYN-l-OL 927742 130850
3-PENTYN-l-OL 10229104 208698
ISETHIONIC ACID, SODIUM SALT 1562001 220078
(4-(2-HYDROXYETHYL)-l-PIPERAZINE-
PROPANESULFONIC ACID) 16052065 163740 FIEPES, SODIUM SALT 75277393 233889 1-METHYLCYCLOPROPANEMETHANOL 2746147 236594 2-METHYLCYCLOPROPANEMETHANOL 6077721 233811 (+/-)-CHRYSANTHEMYL ALCOHOL 18383590 194654 CYCLOBUTANEMETHANOL 4415821 187917 3-CYCLOPENTYL-l-PROPANOL 767055 187275 1-ETHYNYLCYCLOPENTANOL 17356193 130869 3-METHYLCYCLOHEXANOL 591231 139734 3,3,5,5-TETRAMETHYLCYCLOHEXANOL 2650400 190624 4-CYCLOHEXYL-l-BUTANOL 4441570 197408 DIHYDROCARVEOL 619012 218421 (lS,2R,5S)-(+)-MENTHOL 15356704 224464 (lS,2S,5R)-(+)-NEOMENTHOL 2216526 235180 (lS,2R,5R)-(+)-ISOMENTHOL 23283978 242195 (+/-)-3-CYCLOHEXENE-l-METHANOL 72581329 162167 (+)-P-MENTH-l-EN-9-OL 13835308 183741 (S)-(-)-PERILLYL ALCOHOL 536594 218391 TERPINEN-4XL 562743 218383
ALPHA-TERPINEOL 98555 218375
(+/-)-TRANS-P-MENTH-6-ENE-2,8-DIOL 32226543 247774
CYCLOHEPTANEMETHANOL 4448753 138657
TETRAHYDROFURFURYL ALCOHOL 97994 185396
(S)-(+)-2-PYRROLIDINEMETHANOL 23356969 186511 l-METHYL-2-PYRROLIDINEETHANOL 67004642 139513 l-ETHYL-4-FIYDROXYPIPERIDINE 3518830 224634
3-HYDROXYPIPERIDINE HYDROCHLORIDE 64051792 174416
(+/-)-2-PIPERIDINEMETHANOL 3433372 155225
3-PIPERIDINEMETHANOL 4606659 155233 l-METHYL-2-PIPERIDINEMETHANOL 20845345 155241 l-METΪTYL-3-PIPERIDINEMETHANOL 7583531 146145
2-PIPERIDINEETHANOL 1484840 131520
4-HYDROXYPIPERIDINE 5382161 128775
4-METHYL-l-PIPERAZINEPROPANOL 5317339 238716
EXO-NORBORNEOL 497370 179590
ENDO-NORBORNEOL 497369 186457
5-NORBORNENE-2-METHANOL 95125 248533
(+/-)-3-METHYL-2-NORBORNANEMETHANOL 6968758 130575
((lS)-ENDO)-(-)-BORNEOL 464459 139114
(lR)-ENDO-(+)-FENCHYL ALCOHOL 2217029 196444
9-ETHYLBICYCLO(3.3.1)NONAN-9-OL 21951333 193895
(+/-)-ISOPINOCAMPPiEOL 51152115 183229
(S)-CIS-VERBENOL 18881044 247065
(lR,2R,3R,5S)-(-)-ISOPINOCAMPHEOL 25465650 221902
(lR)-(-)-MYRTENOL 515004 188417
1-ADAMANTANOL 768956 130346
3,5-DIMETHYL-l-ADAMANTANOL 707379 231290
2-ADAMANTANOL 700572 153826
1 - AD AM ANT ANEMETHANOL 770718 184209
1 - AD AM ANTANEETH ANOL 6240115 188115
3-FURANMETHANOL 4412913 196398
FURFURYL ALCOHOL 98000 185930
2-(3-THIENYL)ETHANOL 13781674 228796
4-METHYL-5-IMIDAZOLEMETHANOL
HYDROCHLORIDE 38585625 227420 METRONIDAZOLE 443481 226742 4-(HYDROXYMETHYL)IMIDAZOLE
HYDROCHLORIDE 32673419 219908 4-METHYL-5-TH1AZOLEETHANOL 137008 190675 2-(2-HYDROXYETHYL)PYRIDINE 103742 128643 2-HYDROXY-6-METHYLPYRIDINE 3279763 128740 4-PYRIDYLCARBINOL 586958 151629 3-PYRIDYLCARBINOL N-OXIDE 6968725 184446 l-BENZYL-4-HYDROXYPIPERIDINE 4727724 152986 l-(4XHLOROPHENYL)-l-
CYCLOPENTANEMETHANOL 80866791 188697
(4S,5SM-)-2-METHYL-5-PHENYL-2-OXAZOLINE- 4-METHANOL 53732415 187666
6-(4XHLOROPHENYL)-4,5-DIHYDRO-2-(2- HYDROXYBUTYL)-3(2H)-PYRIDAZINONE 38958826 243728
N-(2-HYDROXYETHYL)PHTHALIMIDE 3891074 138339
2-NAPHTFLALENEETHANOL 1485070 188107
1-NAPHTHALENEETHANOL 773999 183458
2-ISOPROPYLPHENOL 88697 129526
4XHLORO-ALPHA.ALPHA-
DIMETHYLPHENETHYL ALCOHOL 5468973 130559
4-FLUORO-ALPHA-METHYLBENZYL ALCOHOL 403418 132705
3-PHENYL-l-PROPANOL 122974 140856
3-(4-METHOXYPHENYL)-l-PROPANOL 5406188 142328
4-FLUOROPHENETHYL ALCOHOL 7589277 154172
4-METHOXYPHENETHYL ALCOHOL 702238 154180
TRANS-2-METHYL-3-PHENYL-2-PROPEN-1-OL 1504558 155888
2-ANILINOETHANOL 122985 156876
3-FLUOROBENZYL ALCOHOL 456473 162507
2-FLUOROBENZYL ALCOHOL 446515 162515
2-METHYL-1-PFΪENYL-2-PROPANOL 100867 170275
ALPHA-(CHLOROMETHYL)-2,4- DICHLOROBENZYL ALCOHOL 13692143 178403
2-PHENYL-l-PROPANOL 1123859 179817
4XHLOROPHENETHYL ALCOHOL 1875883 183423 4-BROMOPHENETHYL ALCOHOL 4654391 183431 4-NLTROPHENETHYL ALCOHOL 100276 183466 2-NΓΓROPHENETHΎL ALCOHOL 15121843 183474 BETA-ETHYLPHENETΉΎL ALCOHOL 2035941 183482
4-PHENYL-l-BUTANOL 3360416 184756 2-METHOXYPHENETHYL ALCOHOL 7417187 187925 3-METHOXYPHENETHYL ALCOHOL 5020417 187933 3-PHENYL-l-BUTANOL 2722363 187976 2-METHYLPHENETHYL ALCOHOL 19819988 188123 3-METHYLPHENETHYL ALCOHOL 1875894 188131 4-METΗYLPHENETHYL ALCOHOL 699025 188158 5-PHENYL-l-PENTANOL 10521912 188220 4-(4-METHOXYPHENYL)-l-BUTANOL 22135508 188239 4-(4-NITROPHENYL)-l-BUTANOL 79524202 188751 3,3-DIPHENYL-l-PROPANOL 20017678 188972 l-PHENYL-2-PROPANOL 14898874 189235 (+/-)-AI-PHA-ETHYLPHENETHYL ALCOHOL 701702 190136 l,l-DIPHENYL-2-PROPANOL 29338496 190756 3XHLOROPHENETHYL ALCOHOL 5182445 193518 2XHLOROPHENETHYL ALCOHOL 19819955 193844 (+ /-)-l-PHENYL-2-PENTANOL 705737 195286 2,2-DIPHENYLETHANOL 1883325 196568
4-ETHOXY-3-METHOXYPHENETHYL ALCOHOL 77891293 197599 3,4-DIMETHOXYPHENETHYL ALCOHOL 7417212 197653 3-(3,4-DIMETHOXYPHENYL)-1-PROPJANOL 3929473 197688 2-(4-BROMOPHENOXY)ETHANOL 34743889 198765 2-FLUOROPHENETHYL ALCOHOL 50919067 228788 3-(TRIFLUOROMETHYL)PHENETHYL ALCOHOL 455016 230359 2-(PHENYLTHIO)ETHANOL 699127 232777 l-(2-METHOXYPHENYL)-2-PROPANOL 15541261 233773
Table 27 - Exemplary Method Embodiments of Processes A-R
A; B; C; D; I; J; K; L; M; N; O; P; Q; R; E; F; G; H; AB; BC; CD; DI; IJ; JK; KL; LM; MN; NO; OP; OQ; QR; EF; FG; GH; HI; ABC; BCD; CDI; DIJ; IJK; JKL; KLM; LMN; MNO; NOP; NOQ; OQR; EFG; FGH; GHI; HIJ; ABDC; BCDI; CDIJ; DIJK; ITKL; JKLM; KLMN; LMNO; MNOP; MNOQ; NOQR; EFHG; FGHT; GHIJ; HTJK; ABCDI; BCDIJ; CDIJK; DIJKL; IJKLM; JKLMN; KLMNO; LMNOP; LMNOQ; MNOQR; EFGFfl; FGHIJ; GHIJK; HTJKL; ABCDIJ; BCDIJK; CDIJKL; DIJKLM; IJKLMN; JKLMNO; KLMNOP; KLMNOQ; LMNOQR; EFGHIJ; FGHTJK; GHIJKL; HIJKLM; ABCDITK; BCDIJKL; CDIJKLM; DIJKLMN; ITKLMNO; JKLMNOP; JKLMNOQ; KLMNOQR; EFGHIJK; FGHTJKL; GHIJKLM; HITKLMN; ABCDITKL; BCDIJKLM; CDIJKLMN; DIJKLMNO; IJKLMNOP; IJKLMNOQ; JKLMNOQR; EFGMTKL; FGHIJKLM; GHTJKLMN; HTJKLMNO; ABCDIJKLM; BCDIJKLMN; CDITKLMNO; DIJKLMNOP; DIJKLMNOQ; IJKLMNOQR; EFGHTJKLM; FGHIJKLMN; GHTJKLMNO; HTJKLMNOP; HTJKLMNOQ; ABCDIJKLMN; BCDIJKLMNO; CDIJKLMNOP; CDITKLMNOQ; DIJKLMNOQR; EFGHIJKLMN; FGHIJKLMNO; GHITKLMNOP; GHTJKLMNOQ; HTJKLMNOQR; ABCDIJKLMNO; BCDIJKLMNOP; BCDIJKLMNOQ; CDITKLMNOQR; EFGHIJKLMNO; FGHTJKLMNOP; FGHIJKLMNOQ; GHITKLMNOQR; ABCDIJKLMNOP; ABCDIJKLMNOQ; BCDIJKLMNOQR; EFGHIJKLMNOP; EFGHTJKLMNOQ; FGHIJKLMNOQR; ABC DIJKLMNOQR; EFGHIJKLMNOQR; S; T; U; V; W; ST; TU; UV; VW; STU; TUV; UVW; STUV; TUVW; STUVW.
Scheme 41
Figure imgf000257_0001
300 301
Figure imgf000257_0002
302 303
Figure imgf000257_0003
Figure imgf000257_0004
307 308 309
Scheme 41
The smine 300 (sn intermediste in Exsmple 52, optionslly purified prior to use) is trested with Boc snhydride to give the mono Boc protected smine 301. Such a transformstion is found in Greene, T.W. "Protective Groups in Orgsnic Synthesis" 2nd Ed. (John Wiley & Sons, New York, 1991) psges 327-328.
Methyl ester 301 is reduced to the corresponding primsry sllylic slcohol 302 with DIBAL st low tempersture. Such s conversion is described by Gsrner, P. snd Psrk, J. M., "J. Org. Chem.", 52:2361 (1987). The primsry slcohol 302 is protected ss its p-methoxy benzyl ether derivstive 303 by trestment with 4-methoxybenzyl chloride under bssic conditions. Such a conversion is described in Horits, K. et. si., "Tetrahedron", 42:3021 (1986).
The MOM snd Boc protecting groups of 303 are removed by treatment with TFA/CH2CI2 to give the amino alcohol 304. Such transformstions sre found in Greene, T.W. "Protective Groups in Orgsnic Synthesis", 2nd. Ed. (John Wiley & Sons, New York, 1991).
Conversion of 304 into the corresponding trityl protected sziridine 305 is sccomplished in a one pot resction two step sequence: 1) TrCl/TEA, 2) MsCl /TEA. Such a transformstion hss been previously described.
Aziridine 305 is then converted the corresponding Boc protected derivstive 307 by first removal of the trityl group with HCl/ acetone to give 306. Such a transformation is described in Hanson, R. W. and Law, H. D. "J. Chem. Soc", 7285 (1965). Aziridine 306 is then converted into the corresponding Boc derivstive 307 by trestment with Boc snhydride. Such a conversion is described in Fitremsnn, J., et. al. "Tetrshedron Lett.", 35:1201 (1994).
The sllylic sziridine 307 is opened selectively st the sllylic position with a higher order orgsnocuprste in the presence of BF3-Et2θ st low tempersture to give the opened sdduct 308. Such an opening is described in Hudlicky, T., et. al. "Synlett." 1125 (1995).
The Boc protected amine 308 is converted into the N-acetyl derivstive 309 in a two step sequence: 1) TFA/CH2CI2; 2) Ac2θ/pyridine. Such trsnsformstions csn be found in Greene, T.W., "Protective Groups in Orgsnic Synthesis", 2nd. Ed. (John Wiley & Sons, New York, 1991) psges 327- 328 snd psges 351-352. Benzyl ether 309 is deprotected with DDQ st room tempersture to give the primsry sllylic slcohol 310. Such a trsnsformstion is found in Horits, K., et. al. "Tetrahedron" 42:3021 (1986).
Alcohol 310 is oxidized 3nd converted in a one pot resction into the methyl ester 311 vis s Corey oxidstion using Mn02/AcOH/MeOH/NsCN. Such s trsnsformstion csn be found in Corey, E. J., et. al. "J. Am. Chem. Soc", 90:5616 (1968).
Azido ester 311 is converted into amino scid 312 in a two step sequence 1) PΪ13P/H2O/THF; 2) KOH/THF. Such s conversion hss been described previously.
Scheme 42
Figure imgf000260_0001
320 321
Figure imgf000260_0002
322 323
τrN
Figure imgf000260_0003
324 325
Figure imgf000260_0004
326 Scheme 42
The known fluoro scetste 320 (Sutherlsnd, J. K., et.sl. "J. Chem. Soc. Chem. Commun." 464 (1993) is deprotected to the free slcohol snd then converted into the corresponding mesylste 321 in two steps: 1) NsOMe; 2) MsCl/TEA. Such trsnsformstions sre described in Greene, T.W.,
"Protective Groups in Orgsnic Synthesis", 2nd. Ed. (John Wiley & Sons, New York, 1991).
Deprotection of 321 under scidic conditions gives diol 322 which is cydized to the epoxy slcohol 323 under bssic conditions. Such a conversion hss been previously described.
Conversion of 323 to the N-trityl protected sziridine 324 is sccomplished with the following sequence: 1) MOMC1/TEA; 2) NsN3/NH4Cl; 3) MsCl/TEA; 4) PPI 3/TEA/H2O; 5) NsN3/NH4Cl; 6) HCl/MeOH; 7) i)TrCl, ii) MsCl/TEA. Such s sequence hss been previously described.
The sziridine 324 is then opened with the sppropriste slcohol under Lewis scid conditions snd then trested with AC2O/ pyridine to give the scetylsted product 325. Such a transformstion has been previously described. The ester 325 is converted to the corresponding amino sdd 326 in a two step sequence: 1) PPh3/H2θ/THF; 2) KOH/THF. Such 3 transformstion hss been previously described.
United Ststes Pstent No. 5,214,165, snd in psrticulsr, the "Descriptions snd Exsmples" at column 9, line 61 to column 18, line 26, describes the preparation of 6α snd 6β fluoro Shikimic scid (numbering is ss described therein). These fluoro compounds sre suitsble stsrting msterisls for methods of msking compounds of the invention thst use Shikimic scid.
Scheme 43
Figure imgf000262_0001
330 331
Figure imgf000262_0002
332 333
Figure imgf000262_0003
334 335
Figure imgf000262_0004
336 337 Scheme 43
Unssturated ester 330 (obtainsble by stsndsrd sctetylstion methods from the scetonide slcohol described in Csmpbell, M. M., et. al., "Synthesis",
179 (1993)) is reacted with the appropriste orgsnocuprste where R is the ligsnd to be trsnsferred from the orgsnocuprste (R is Jιa). The resultsnt intermediste is then trapped with PhSeCl to give 331 which is then trested with 30% H2O2 to give the α,β-uns3turated ester 332. Such a trsnsformstion csn be found in Hsysshi, Y., et. al, "J. Org. Chem." 47:3428 (1982).
Acetate 332 is then converted into the corresponding mesylste 333 in s two step sequence: 1) NsOMe/MeOH; 2) MsCl/TEA. Such a trsnsformstion hss been previously described snd csn slso be found in Greene, T.W.,
"Protective Groups in Orgsnic Synthesis", 2nd. Ed. (John Wiley & Sons,
New York, 1991).
The scetonide 333 is then converted into the epoxy slcohol 334 in s two step sequence: 1) p-TsOH/MeOH/Δ; 2) DBU/THF. Such a transformstion hss been previously described.
Conversion of epoxide 334 into N-trityl aziridine 335 is accomplished by the following sequence: 1) MOMC1/TEA; 2) NaN3/NH4Cl; 3) MsCl/TEA;
4) PPh3/TEA/H2θ; 5) N3N3/NH4CI; 6) HCl/MeOH; 7) i)TrCl, ii) MsCl/TEA. Such s sequence hss been previously described.
The sziridine 335 is then opened with the appropriste slcohol under
Lewis scid conditions snd then trested with AC2O/ pyridine to give the scetylsted product 336. Such a trsnsformstion has been previously described. The szido ester 336 is converted to the corresponding smino scid 337 in s two step sequence: 1) PPh3/H2θ/THF; 2) KOH/THF. Such a trsnsformstion hss been previously described.
Schemes 44 snd 45 sre referred to in the examples.
Scheme 44
Figure imgf000264_0001
228 340
Figure imgf000264_0002
341 342
Scheme 45
Figure imgf000264_0003
345 346
Figure imgf000264_0004
347 Scheme 46
Figure imgf000265_0001
600 601
Figure imgf000265_0002
602 603
Figure imgf000265_0003
604 605
Figure imgf000265_0004
606 607 Scheme 47
Figure imgf000266_0001
607 608 609
Figure imgf000266_0002
610 611
Figure imgf000266_0003
610 612 613
Figure imgf000266_0004
614 615
Scheme 48
Figure imgf000267_0001
614 615 616
Figure imgf000267_0002
617 618
Figure imgf000267_0003
619 620
Scheme 49
Figure imgf000268_0001
260 265
Figure imgf000268_0002
266
Scheme 50
Figure imgf000269_0001
Ar = p-CH3OX6H4 Ar = p-CH30-C6H4
Figure imgf000269_0002
703 702
Figure imgf000269_0003
704 705 Scheme 51
Figure imgf000270_0001
705
706
Figure imgf000270_0002
708
Figure imgf000270_0003
710 711 Scheme 52
Figure imgf000271_0001
260 800
Figure imgf000271_0002
801
Scheme 53
Figure imgf000272_0001
260 802
Figure imgf000272_0002
803
Scheme 54
P
Figure imgf000273_0001
804 805 806
Scheme 55
Figure imgf000273_0002
807a, 807b 808a, 808b
Figure imgf000273_0003
809a, 809b Scheme 56
Figure imgf000274_0001
810 811
Figure imgf000274_0002
812
Scheme 57
Figure imgf000274_0003
813 814
Figure imgf000274_0004
815 Scheme 58
Figure imgf000275_0001
816 817
Figure imgf000275_0002
818 819
Figure imgf000275_0003
820 821
Figure imgf000275_0004
822
Scheme 59
Figure imgf000276_0001
816 823
Figure imgf000276_0002
824
Scheme 60
Figure imgf000276_0003
820 825
Figure imgf000276_0004
826 Scheme 61
Figure imgf000277_0001
816 827
Figure imgf000277_0002
828 829
Figure imgf000277_0003
830
Scheme 62
Figure imgf000278_0001
Quinic Acid 900 901
Figure imgf000278_0002
902 903
Figure imgf000278_0003
904 905 906
Figure imgf000278_0004
09
907 908 9
Figure imgf000278_0005
Scheme 63
Figure imgf000279_0001
913 914
Figure imgf000279_0002
915 916
Scheme 64
Figure imgf000279_0003
713 Modificstion of the exemplsry stsrting msterisls to form different Ei groups hss been described in detail snd will not be elsborsted here. See Fleet, G.W.J. et al.; "J. Chem. Soc. Perkin Trans. I", 905-908 (1984), Fleet, G.W.J. et al.; "J. Chem. Soc, Chem. Commun.", 849-850 (1983), Yee, Ying K. et al.; "J. Med. Chem.", 33:2437-2451 (1990); Olson, RE. et al; "Bioorganic & Medicinal Chemistry Letters", 4(18):2229-2234 (1994); Ssntells, J.B. m et al.; "Bioorganic & Medicinsl Chemistry Letters", 4(18):2235-2240 (1994); Judd, D.B. et al.; "J. Med. Chem.", 37:3108-3120 (1994) snd Lombsert, S. De et al.; "Bioorganic & Medicinal Chemistry Letters", 5(2):151-154 (1994). The Ei sulfur analogs of the carboxylic scid compounds of the invention sre prepsred by sny of the stsndsrd techniques. By wsy of exsmple snd not limitstion, the csrboxylic scids sre reduced to the slcohols by stsndsrd methods. The alcohols sre converted to hslides or sulfonic scid esters by stsndsrd methods snd the resulting compounds are reacted with NaSH to produce the sulfide product. Such reactions are described in Patsi, "The Chemistry of the Thiol Group" (John Wiley, New York, 1974), pt. 2, snd in psrticulsr psges 721-735.
Modificstions of esch of the sbove schemes lesds to vsrious snslogs of the specific exemplsry msterisls produced sbove. The sbove cited citstions describing suitsble methods of orgsnic synthesis sre spplicsble to such modificstions.
In esch of the sbove exemplsry schemes it may be advantageous to separate resction products from one another and/or from starting msterisls. The desired products of esch step or series of steps is sepsrsted snd/or purified (hereinsfter sepsrsted) to the desired degree of homogeneity by the techniques common in the srt. Typicslly such sepsrations involve multiphsse extraction, crystsllizstion from 3 solvent or solvent mixture, distillstion, sublimstion, or chromstography. Chromstography csn involve sny number of methods including, for exsmple, size exclusion or ion exchsnge chromstogrsphy, high, medium, or low pressure liquid chromstography, smsll scale and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
Another clsss of sepsrstion methods involves trestment of a mixture with s resgent selected to bind to or render otherwise sepsrable a desired product, unrescted stsrting material, reaction by product, or the like. Such resgents include sdsorbents or sbsorbents such ss activated carbon, molecular sieves, ion exchange media, or the like. Alternstively, the resgents csn be scids in the csse of a bssic msterisl, bsses in the csse of sn scidic msterisl, binding resgents such ss sntibodies, binding proteins, selective chelstors such ss crown ethers, liquid /liquid ion extraction resgents (LIX), or the like.
Selection of sppropriste methods of separation depends on the nature of the msterisls involved. For exsmple, boiling point, snd moleculsr weight in distillstion snd sublimstion, presence or sbsence of polsr functionsl groups in chromstography, stsbility of materials in acidic 3nd bssic medis in multiphsse extraction, snd the like. One skilled in the srt will spply techniques most likely to schieve the desired sepsrstion. All literature and pstent citstions above are hereby expressly incorporated by reference at the locations of their citation. Specifically cited sections or psges of the above cited works are incorporated by reference with specificity. The invention has been described in detsil sufficient to sllow one of ordinsry skill in the srt to mske snd use the subject mstter of the following clsims. It is sppsrent thst certsin modifications of the methods and compositions of the following claims can be made within the scope snd spirit of the invention.
Enteric Protection
Another embodiment of the present invention is directed towsrd enteric protected forms of the compounds of the invention. As used herein the term "enteric protection" mesns protecting a compound of the invention in order to svoid exposing s portion of the gsstrointestinsl tract, typicslly the upper gsstrointestinsl tract, in psrticu r the stomsch snd esophsgus, to the compound of this invention. In this wsy gsstric mucossl tissue is protected sgsinst rates of exposure to a compound of the invention which produce adverse effects such as nausea; and, alternatively, a compound of the invention is protected from conditions present in one or more portions of the gastrointestinal tract, typically the upper gastrointestinal tract.
By way of example and not limitstion, such entericslly protected forms include enteric coated vehicles, such as enteric coated tablets, enteric coated granules, enteric coated beads, enteric coated particles, enteric coated micropsrticles, snd enteric costed cspsules. In preferred embodiments, a compound of the invention is placed in s suitsble vehicle such ss a tablet, granule or cspsule, snd the vehicle is costed with s pharmsceuticslly scceptsble enteric costing. In slternstive preferred embodiments, a compound of the invention is prepsred ss entericslly protected grsnules, psrticles, micropsrticles, spheres, microspheres, or colloids, snd the enteric protected grsnules, psrticles, micropsrticles, spheres, microspheres, or colloids, sre prepsred ss phsrmsceuticslly scceptsble dossge forms such ss tsblets, grsnules, cspsules, or suspensions. One sspect of the invention is directed to enteric-costed dossge forms of the compounds of the invention to effect delivery to the intestine of a humsn or other mammal, preferably to the small intestine, of a pharmsceuticsl composition comprised of a therapeuticslly effective smount of sbout 0.1-1000 mg of an active ingredient and optional pharm3ceutic3lly acceptable excipients.
The term "vehicle" as used herein includes pharmsceuticslly scceptsble dose vehicles. Msny vehicles sre well known in the srt cited herein such ss tsblet, costed tsblet, cspsule, hsrd cspsule, soft gelstin cspsule, psrticle, micropsrticle, sphere, microsphere, colloid, microencspsulstioned, sustsined relesse, semisolid, suppository or granule vehicles.
The term "phsrmaceutically-acceptable excipients" as used herein includes any physiologically inert, pharmscologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular compound of the invention selected for use. These excipients are described elsewhere herein. The excipients may, but need not, provide enteric protection.
The term "unit dose" is used herein in the conventional sense to mean a single application or sdministrstion of the compound of this invention to the subject being trested in sn amount as stated below. It should be understood that a therapeutic or prophylactic dosage can be given in one unit dose, or alternatively, in multiples of two or more of such dose units with the total adding up to the desired amount of compound for a given time period.
In general, the oral unit dosage form compositions of this invention, preferably employ from about 1 to about 1000 milligrams (mg), typically, about 10 to 500 mg, more typically from about 50 to about 300 mg, more typicslly yet, 75 mg of the compound for esch unit dose. The sctusl smount will vsry depending upon the sctive compound selected.
In typicsl embodiments, sn enteric protectsnt is spplied to the vehicle contsining the compound, or to the compound without vehicle, the protectsnt prevents nsuses inducing exposure, contsct or rates of exposure of the mouth, esophsgus or stomsch with the compound, but which relesses the compound for sbsorption when the dossge form pssses into the proximsl portion of the lower gsstrointestinsl tract, or in some embodiments, substsntislly only in the colon. The relstive proportions of the protectsnt snd compound of the invention sre vsried to schieve optimum sbsorption depending on the compound selected. The minimum or maximum amount of enteric protectant by weight percent is not critical. Typically, enteric protected embodiments contain less than about 50% enteric coating by weight. More typically about 1% to sbout 25%, still more typicslly, sbout 1% to sbout 15%, more typicslly yet, about 1% to about 10% (all by weight).
A number of monographs describe enteric protection and related technology which are useful in preparing the entericslly protected compositions of the invention. Such monographs include: "Theory snd Practice of Industrisl Phsrmβcy," 3rd ed. Les & Febiger, Philsdelphis, 1986 (ISBN 0-8121-0977-5); Lehmsnn, K.; "Practical Course in Laquer Coating,", Eudragit, 1989; Lieberman; Lachman, L.; Schwartz, "Pharmaceutical Dosage Forms: Tsblets", 1990, Dekker (ISBN: 0-8247-8289-5); Lee, Ping I. Editor Good, Willism R. Editor, "Controlled-Relesse Technology: Pharmaceutical Applications", ACS Symposium Ser.Vol. 348 (ISBN: 0-608-03871-7); Wilson, Billie E.; Shannon, Margret T., "Dosage Calculstion: A Simplified Approsch", 1996, Appleton & Lsnge (ISBN: 0-8385-9297-X); Liebermsn, Herbert A. Editor Rieger, Msrtin M., "Phsrmaceutical Dosage Forms - Disperse Systems", 1996, Dekker (ISBN: 0-8247-9387-0); "Basic Tests for Pharmaceutical Dosage Forms", 1995, World Health (ISBN: 92-4-154418-X); Karss, D. R., Editor; Stephenson, R. A., Editor, "Excipients & Delivery Systems for Phsrmsceutical Formulations: Proceedings of the "Formulate '94" British Association for Chemical Specialties Symposium", 1995, CRC Pr (ISBN: 0-85404-715-8); Ansel, Howard C; Popovich, Nicholas G.; Allen, Lloyd V., "Pharmsceuticsl Dossge Forms & Drug Delivery Systems, 6th ed.", 1994, Willisms & Wilkins (ISBN: 0-683-01930-9); "The Sourcebook for Innovstive Drug Delivery: Msnufscturers of Devices & Phsrmsceuticsls, Suppliers of Products & Services, Sources of Informstion", 1987, Csnon Comns (ISBN: 0- 9618649-0-7); Chiellini, E., Editor; Giusti, G., Editor; Miglisresi, C, Editor; Nicolsis, L., Editor, "Polymers in Medicine II: Biomedicsl & Phsrmsceuticsl Applicstions", 1986, Plenum (ISBN: 0-306-42390-1); "Phsrmsceuticsl Aerosol: A Drug Delivery System in Transition", 1994, Technomic (ISBN: 0-87762- 971-4); Avis; Liebermsn, L.; Lschmsn, "Phsrmsceuticsl Dossge Forms: Psrenteral Medicstion, 2nd Expended; Revised ed.", 1992, Dekker (ISBN: 0- 8247-9020-0); Lsffer, U., Editor; Bschmsnn, I., Editor; Metzger, U., Editor, "Implsntsble Drug Delivery Systems", 1991, S Ksrger (ISBN: 3-8055-5434-6); Borchsrdt, Ronsld T., Editor; Repts, Arnold J., Editor; Stells, Vslentino J., Editor, "Directed Drug Delivery: A Multidisciplinsry Approsch", 1985, Humana (ISBN: 0-89603-089-X); Anderson, James M., Editor, "Advances in Drug Delivery Systems 5: Proceedings of the Fifth International Symposium on Recent Advances in Drug Delivery Systems, Sslt Lske City, UT, U. S. A., Februsry 25-28, 1991", Elsevier (ISBN: 0-444-88664-8); Turco, Sslvstore J.; King, Robert E., "Sterile Dossge Forms: Their Prepsrstion & Clinicsl Applicstion", 1987, Williams & Wilkins (ISBN: 0-8121-1067-6); Tomlinson, E., Editor; Davis, S. S., Editor, "Site-Specific Drug Delivery: Cell Biology, Medical & Phsrmsceuticsl Aspects", 1986, Wiley (ISBN: 0-471-91236-0); Hess, H., Editor, "Pharmaceutical Dosage Forms & Their Use", 1986, Hogrefe & Huber Pubs (ISBN: 3-456-81422-4); Avis; Lieberman; Lachmsn, "Pharmaceutical Dosage Forms, Vol. 2", 1986, Dekker (ISBN: 0-8247-7085-4); Carstensen, Jens T., "Phsrmaceutics of Solids & Solid Dosage Forms", 1977, Wiley (ISBN: 0-471-13726-X); Robinson, Joseph R, Editor, "Ophthalmic Drug Delivery Systems", 1980, Am Pr rm Assn (ISBN: 0-917330-32-3); Ansel, Howsrd C, "Introduction to Phsrmsceuticsl Dossge Forms, 4th ed.", 1985, Willisms & Wilkins (ISBN: 0-8121-0956-2); "High Tech Drug Delivery Systems", 1984, Intl Res Dev (ISBN: 0-88694-622-0); Swsrbrick, Jsmes, "Current Concepts in Phsrmsceuticsl Sciences: Dossge Form Design &
Biosvsilsbility", 1985, Lea & Febiger (ISBN: 0-318-79917-0); Sprowls, Joseph B., Editor, "Prescription Pharmacy: Dosage Formulstion & Phsrmsceuticsl Adjuncts, 2nd ed.", 1970, Lippincott (ISBN: 0-397-52050-6); snd Poldermsn, J., Editor, "Formulstion & Prepsrstion of Dossge Forms: Proceedings of the 37th Internstionsl Congress of Phsrmaceutical Sciences of F.I.P., The Hsgue, Netherlsnds, September, 1977", Elsevier (ISBN: 0-444-80033-6). Specific Embodiments:
In snother embodiment, the inventive composition is in the form of sn enteric costed tsblet dossge form. In this embodiment, the formulstion is formed into a hsrd tsblet by conventionsl mesns snd the tsblet is costed with the enteric costing in accordsnce with conventionsl techniques.
In s preferred embodiment, the inventive compound is in the form of 3n enteric costed powder dossge form. In this embodiment, the formulstion is filled into s hsrd or soft-shell cspsule or their equivslent end the cspsule is costed with the enteric costing in sccordsnce with conventionsl techniques.
In one embodiment the inventive composition is in the form of a liquid suspension of enteric costed psrticles of s compound of the invention. In this embodiment, a suspension of the inhibitor in a liquid is filled into a hard or soft-shell capsule or their equivslent snd the cspsule is costed with the enteric costing in sccordsnce with conventionsl techniques. As slternstives to the foregoing embodiments the cspsule or other dossge contsiner is itself constructed of sn enteric protection resgent or component, or otherwise is integral to the contsiner.
In snother embodiment enteric protectsnts sre used to sdminister a compound of the invention to the colon. The delivery system is a tsblet comprised of three lsyers: 1) a core contsining the sctive compound of the invention; 2) a non-swelling, erodible polymer lsyer surrounding the core (with the combinstion of core snd erodible polymer lsyer being referred to ss the "dusl mstrix tsblet"); snd 3) sn enteric costing applied to the dual matrix tablet. The composition and function of the components of such a colon targeted delivery system are further described in U.S. Patent 5,482,718, which is incorporated herein by reference in its entirety at this location, in particular column 2, line 29, to column 4, line 12, are incorporated herein with specifidty. Another embodiment of the invention is directed toward enteric protected emulsion, suspension, tablet, coated tablet, hard cspsule, soft gelstin cspsule, microencspsulstion, sustsined relesse, liquid, semisolid, suppositorie, snd serosol dossge forms of the compounds of the invention. "Theory snd Practice of Industrisl Phsrmscy," 3rd ed. Les & Febiger, Philsdelphis, 1986 (ISBN 0-8121-0977-5), describes esch of these stsndsrd dossge forms in detsil at the following locations: emulsion and suspension dossge forms (pp. 100-122), tsblets (pp. 293-345), costed tsblet (pp. 346-373), hsrd cspsules (pp. 374-397), soft gelstin cspsules (pp. 398-411), microencspsulstion (pp. 412-430), sustsined relesse dossge forms (pp. 430- 456), liquids (pp. 457-478), phsrmsceuticsl suspensions (pp. 479-501), emulsions (pp. 502-533), semisolids (pp. 534-563), suppositories (pp. 564-587), snd phsrmsceuticsl serosols (pp. 589-618).
Alternstive embodiments include enteric protected sustsined release, controlled release, psrticulste, microencspsulsted, multipsrticulste, micropsrticulste, colloidsl, nsssl, inhslstion, oral mucossl, colonic, dermsl, trsnsdermsl, oculsr, topicsl, snd veterinsry dossge forms of the compounds of the invention. Esch of these dossge form technologies is described in detsil in "Drugs snd the Phsrmsceuticsl Sciences", Edited by Jsmes Swsrbrick, Msrcel Dekker, New York.
Msterisls:
Conventionsl enteric protectsnt polymers or mixtures of polymers for use herein include insoluble st s pH below sbout 5.5, i.e., thst which is generally found in the stomsch, but sre soluble st pH sbout 5.5 or sbove, i.e., thst present in the smsll intestine snd the lsrge intestine. The effectiveness of psrticulsr enteric protectsnt msterisls csn be messured using known USP procedures.
Exemplsry enteric protectsnt polymers employsble in this embodiment include cellulose scetste phthslste, methyl scrylste-methscrylic scid copolymers, cellulose scetste succinste, hydroxypropylmethylcellulose phthslste, polyvinyl scetste phthslste, snd methyl methscrylste-methscrylic scid copolymers. Another exsmple is sn snionic csrboxylic copolymers bssed on methscrylic scid snd methscrylste, commercislly svsilsble ss Eudragit(r). Typicsl exsmples include cellulose scetste phthslste ("CAP"), cellulose scetste trimellitste, hydroxypropyl methylcellulose phthslste ("HPMCP"), hydroxypropyl methylcellulose phthslste succinste, polyvinyl scetste phthslste ("PVAP"), methscrylic scid, and methacrylic acid esters. More typically the protectsnt is selected from, PVAP snd /or HPMCP, psrticulsrly PVAP. PVAP is known under the trademsrk Sureteric(r), msnufsctured by Colorcon, Inc. The enteric protectsnt msterisls msy be spplied to the vehicle with or without conventionsl plssticizers, such ss scetylsted mono glycerides, propylene glycol, glycerol, glyceryl triscetste, polyethylene glycol, triethyl citrste, tributyl citrste, diethyl phthslste, or dibutyl phthslste using methods known to those skilled in the srt.
Exemplsry Embodiments of Enteric Protection:
Embodiment 1: Enteric Protected GS 4104 Cspsules
In this exemplsry embodiment, GS 4104 (compound 262, Exsmple 116, phosphste sslt form, 131.4 mg/cspsule, 100 mg free bsse equivslent)) is mixed with Croscsrmellose Sodium (2.6 mg/cspsule) in a size 4 white opsque hsrd gelstin cspsule shells (cspsule composition: gelstin NF, titsnium dioxide USP) 3nd the cspsule is entericslly costed.
The following enteric costing formulstions sre spplied to the cspsule by procedures known to those in the srt.
Ingredients % w/w
Prepsrstion A:
Hydroxypropyl methylcellulose phthslste ("HPMCP") 5.0 Triscetin 0.5
Alcohol USP 7.9
Wster 15.5
Preparation B:
HPMCP 10.0
Titanium dioxide 0.2
Dimethyl polysiloxsne 0.05
Triethyl citrste 1.0
Alcohol USP 72.75
Wster 16.00
Prepsrstion C:
Cellulose scetste phthslste ("CAP") 8.5
Diethyl phthslste 1.5
Titsnium dioxide 0.2
Acetone 44.9
Denshired slcohol 44.9 Prepsration D:
Polyvinyl scetste phthslste ("PVAP") 5.0
Acetylsted glycerides 0.8
Methylene chloride 47.1 Denshired slcohol 47.1
Prepsrstion E:
Methscrylic scid or methscrylic 8.0 scid ester (Eudragit (r) S or L, msnufsctured by Rohm Phsrms, GMBH, Wetterstsdt, West Germsny)
Acetone 46.0
Anhydrous slcohol 46.0
Plssticizer q.s.
Typicslly the enteric polymer (with or without plssticizer) is dissolved in the solvents described under esch formulstion to form a suspension/ solution. Optionslly, sn opscifer such ss titsnium dioxide is 3dded. The vehicle is sprayed with the costing suspension /solution in s suitsble vessel under conditions such thst sn entericslly-protected costing is lsid down on the vehicle without dissolving or disrupting the vehicle. Approximstely 1-50%, typicslly 1-15%, more typicslly, 5-10% by weight of the finished costed vehicle of the enteric polymer costing will be useful for sdequste enteric protection.
Embodiment 2: Enteric Protected Tsblet In snother exemplsry embodiment a core tsblet is encssed within sn enteric costing. Optionslly, s subcosting is used.
Core Tsblets:
Core tsblets of the present invention msy be formed by combining (s) the sctive ingredient with phsrmsceuticslly-scceptsble excipients in a mixture including for exsmple: a diluent, a binder, s disintegrant, snd optionslly one or more ingredients selected from a group consisting of: compression sids, flsvors, flsvor enhsncers, sweeteners, dyes, pigments, buffer systems, snd preservstives; (b) lubricsting the mixture with a lubricsnt; snd (c) compressing the resultsnt lubricsted mixture into s desired tsblet form using vsrious tsbleting techniques svsilsble to those skilled in the srt. The term "tsblet" ss used herein is intended to encompsss compressed or formed phsrmsceuticsl dossge formulstions of all shapes snd sizes. Typicsl diluents employsble in this embodiment include lsctose or microcrystslline cellulose.
Typicsl binders employsble in this embodiment include, but sre not limited to, povidone. Povidone is svsilsble under the trade name "Avicel" from ISP Corporation. The disintegrant msy be one of several modified stsrches, or modified cellulose polymers. Typicslly, croscsrmellose sodium is used. Croscsrmellose sodium NF Type A is commercially svsilsble under the trade name "Ac-di-sol".
Typical lubricants include magnesium stearate, stesric scid, hydrogensted vegetsble oil or t3lc.
Flsvoring sgents include those described in Remington's Phsrmsceuticsl Sciences, 18th Edition, Msck Publishing Compsny, 1990, pp. 1288-1300.
Typicsl sweeteners include sscchsrin, Aspartame, or edible mono- or disaccharides such as glucose or sucrose.
Dyes and pigments include those described in the Handbook of Phsrmsceuticsl Excipients, pp. 81-90, 1986 by the Americsn Phsrmsceuticsl Associstion & the Phsrmsceutical Society of Great Britain.
Typicsl preservstives include methyl paraben, propyl paraben, cetylpyridinium chloride, snd the sslts thereof, sorbic scid snd the sslts thereof, thimerossl, or benzslkonium chloride.
Enteric Costing:
Eudrsgit L-30-D(r), a methscrylic scid copolymer, msnufsctured by Rohm Phsrms GmbH, Weiterstsdt, West Germsny, is a suitable enteric polymer. Eudrsgit L-30-D(r) hss a ratio of free csrboxyl groups to ester groups of spproximstely 1:1 snd is freely soluble st pH 5.5 snd sbove. In general, the grester the percentsge of Eudrsgit L-30-D(r) contsined in the enteric costing, the more proximsl the relesse of sctive in the lower gsstrointestinsl trsct. The locstion in the lower gsstrointestinsl trsct st which the costing relesses the compound csn be msnipulsted by one skilled in the srt through control of the composition snd thickness of the spplied enteric costing.
Typicslly s plssticizer, such ss those set forth above, is included.
Other additives such ss tslc or silics msy be used ss detsckifiers to improve the coating process.
Subcoating:
Optionslly s stsbility enhsncing subcost on the core tsblet is used to minimize interaction between the compound of this invention snd the enteric costing. This slso permits utilizstion of a single 10-300 micron thick enteric film without sffecting product stsbility. This subcost inhibits migrstion of sctive ingredient from the core tsblet into the enteric costing, thus improving shelf life and product stability, but the subcoat rapidly dissolves in intestinal fluid once the exterior enteric coating has been bresched.
Typicsl subcosting polymers employsble in this embodiment include hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose, or polyvinylpyrrolidone.
Exsmples
General
The following Exsmples refer to the Schemes.
Some Exsmples hsve been performed multiple times. In repested Exsmples, resction conditions such 3S time, tempersture, concentration snd the like, snd yields were within normal experimentsl ranges. In repested Exsmples where significsnt modificstions were msde, these hsve been noted where the results vsried significsntly from those described. In Exsmples where different stsrting msterisls were used, these sre noted. When the repested Exsmples refer to s "corresponding" anslog of s compound, such ss s "corresponding ethyl ester", this intends thst sn otherwise present group, in this csse typicslly a methyl ester, is tsken to be the ssme group modified as indicated. For example, the "corresponding ethyl ester of compound 1" is
Figure imgf000291_0001
500
Example 1
Epoxy alcohol 1: Prepared from shikimic acid by the procedure of McGowan snd Berchtold, "J. Org. Chem.", 46:2381 (1981). Example 2
Epoxy allyl ether 2: To a solution of epoxy alcohol 1 (2.37g, 14.08 mmol) in dry benzene (50 mL) was added thallium(I)ethoxide (1.01 mL) in one portion. After 2 hr the reaction was concentrated in vαcuo and the residue dissolved in acetonitrile. Allyl iodide (3.0 mL) was added and the mixture wss stirred in the dark for 16 h. The solids were filtered thru a celite psd snd wsshed with chloroform. Concentrstion in vαcuo followed by flash chromstography (40% EtOAc in hexsne) gsve 1.24 g (42%) of 2 ss 3 psle viscous oil. lH NMR (300 MHz, CDCI3): δ 6.75 (IH, m); 6.10-5.90 (IH, m, -CH=, allyl); 5.40-5.15 (2H, m, =CH2, allyl); 4.47-4.43 (IH, m); 4.30-4.15 (2H, m, -CH2-, allyl); 3.73 (3H, s); 3.55-3.50 (IH, m); 3.45-3.40 (IH, m); 3.15-3.00 (IH, dm, / = 19.5 Hz), 2.50-2.35 (IH, dm, / = 2.7, 19.5 Hz). Exsmple 3
Azido alcohol 3: Epoxide 2 (1.17 g, 5.57 mmol), sodium azide (1.82 g) and ammonium chloride (658 mg) were refluxed in MeOH/H2θ (8:1) (35 mL) for 18 h. The reaction wss then concentrated in vacuo snd the residue psrtitioned between ethyl ether snd wster. The orgsnic lsyer wss wsshed with brine snd dried. Concentration in vacuo gsve 3 ss a psle oil 1.3 g (92%) which wss used without further purificstion. ^H NMR (300 MHz, CDCI3): δ 6.95-6.85 (IH, m); 6.00-5.85 (IH, m, XH=, silyl); 5.35-5.25 (2H, m, =CH2, slh/l); 4.25-4.10 (2H, m, -CH2-, allyl); 4.12 (IH, bt, / =4.2 Hz); 3.95-3.75 (2H, m); 3.77 (3H, s); 2.85 (IH, dd, / =5.3, 18.3 Hz); 2.71 (IH, bs); 2.26 (IH, dd, / =7.2, 18.3 Hz).
Example 4
Aziridine 4: To a solution of alcohol 3 (637 mg, 2.52 mmol) in CH2CI2 (20 mL) cooled to 0°C was added DMAP (few crystsls) snd triethyl smine (442 μL). MsCl (287 μL) wss then sdded snd the resction stirred for 2 h st 0°C. Volstiles were removed snd the residue psrtitioned between ethyl ether snd wster. The orgsnic lsyer wss wsshed with ssturated bicsrbonste, brine snd then dried. Concentration in vαcuo gave 881 mg of crude mesylste. ^H NMR (300 MHz, CDCI3): δ 6.87-6.84 (IH, s); 6.00-5.85 (IH, m, -CH=, silyl); 5.40- 5.25 (2H, m, =CH2, allyl); 4.72 (IH, dd, / = 3.9, 8.5 Hz); 4.32 (IH, bt, / = 3.9 Hz); 4.30-4.15 (2H, m, -CH2-, allyl); 3.77 (3H, s); 3.14 (3H, s); 2.95 (IH, dd, / = 5.7, 18.6 Hz); 2.38 (IH, dd, / = 6.7, 18.6 Hz).
The crude mesylate wss dissolved in dry THF (20 mL) snd trested with Ph3P (727 mg). After stirring for 3 h st room tempersture, wster (15 mL) snd solid N3HCO3 (1.35 g) wss sdded 3nd the mixture stirred overnight st room tempersture. The resction wss then concentrated in vαcuo snd the residue psrtitioned between EtOAc, ssturated bicsrbonste snd brine. The organic layer wss sepsrsted snd dried over MgSθ4. Concentration in vαcuo 3nd flssh chromstography of the residue gsve the sziridine 4 170 mg (33%) ss s psle yellow oil. αH NMR (300 MHz, CDCI3): δ 6.82-6.80 (IH, m); 6.04-5.85 (IH, m, -CH=, silyl); 5.35-5.20 (2H, m, =CH2, allyl); 4.39 (IH, bd, / =2.4 Hz); 4.20-4.05 (2H, m, -CH2-allyl); 3.73 (3H, s); 2.90-2.80 (IH, bd, / =18.9 Hz); 2.65- 2.40 (2H, m).
Exairφle 5
N-acetyl aziridine 5: Aziridine 4 (170 mg, 0.814 mmol) was dissolved in CH2CI2 (2 mL) and pyridine (4 mL) and cooled to 0°C. Acetyl chloride (87 μL) was then sdded snd the resction stirred st 0°C for 1 h. Volstiles were removed in vacuo 3nd the residue psrtitioned between ethyl ether, ssturated bicsrbonste snd brine. The orgsnic lsyer was separated and dried over MgSθ4. Concentration gave crude 5 196 mg (96%) which wss used without further purificstion. IH NMR (300 MHz, CDCI3): δ 6.88-6.86 (IH, m); 6.00-5.85 (IH, m, -CH=, allyl); 5.40-5.20 (2H, m, =CH2, allyl); 4.45-4.40 (IH, m); 4.16 (2H, d, / =6.0 Hz, -CH2-, allyl); 3.76 (3H, s); 3.00-2.95 (2H, m); 2.65 (IH, bd, / =18.5 Hz); 2.14 (3H, s).
Example 6
Azido allyl ether 6: Aziridine 5 (219 mg, 0.873 mmol), sodium azide (426 mg) and ammonium chloride (444 mg) in dry DMF (7 mL) was heated st 65°C under srgon overnight. The resction wss poured into ssturated bicsrbonste /brine and extracted with ethyl ether several times. The combined ether lsyers were wsshed with brine 3nd dried. Concentration followed by flssh chromstography (EtOAc only) gsve the szido smine 77 mg (35%) which wss dissolved in CH2CI2 (1 mL) snd pyridine (1 mL) snd cooled to 0°C. Acetyl chloride (38 μL) wss sdded snd sfter 45 min solid NsHCθ3 wss sdded snd the volstiles removed under vscuum. The residue wss psrtitioned between EtOAc snd brine. The orgsnic lsyer wss dried over MgSθ4 snd concentrated in vacuo. Flssh chromstography (EtOAc only) gsve 6 90 mg (99%). *H NMR (500 MHz, CDCI3): δ 6.86 (IH, bt, / =2.2 Hz); 5.95-5.82 (IH, m, CH=, silyl); 5.68 (IH, bd, / =7.3 Hz); 5.35-5.20 (2H, m, =CH2, allyl); 4.58- 4.52 (IH, m); 4.22-4.10 (2H, m); 4.04 (IH, dd, / =5.9, 12.5 Hz); 3.77 (3H, s); 3.54- 3.52 (IH, m); 2.89 (IH, dd, / = 5.9, 17.6 Hz); 2.32-2.22 (IH, m); 2.06 (3H, s).
Example 7 Azido diol 7: To a solution of olefin 6 (90 mg, 0.306 mmol) in acetone
(3 mL) snd wster (258 μL) wss 3dded N-methyl morpholine-N-oxide (39 mg) snd Osθ4 (73 μL of a 2.5 % w/w in -butsnol). The resction wss then stirred st room temperature for 3 dsys. Solid sodium hydrosulfite wss sdded snd sfter stirring for 20 min the resction wss filtered thru a celite psd snd wsshed with copious smounts of scetone. Concentration in vαcuo followed by flssh chromstography (10% MeOH in CH2CI2) gsve the diol 7 50 mg (50%). IH NMR (300 MHz, CD3CN): δ 6.80-6.70 (IH, m); 4.20-4.15 (IH, bm); 3.95-3.80 (IH, m); 3.80-3.25 (6H, m); 3.70 (3H, s); 3.10 (IH, bs); 2.85 (IH, bs); 2.85-2.75 (IH, m); 2.30-2.15 (IH, m); 2.16 (IH, bs); 1.92 (3H, s). Exsmple 8
Amino acid diol 8: A solution of the diol 7 (23 mg, 0.07 mmol) in THF (1 mL) was trested with sq. KOH (223 μL, of 0.40 M solution) 3t room tempersture. After stirring for 1.5 h the resction wss scidified to pH=4 with .Amberlite IR-120 (plus) ion exchsnge resin. The resin wss filtered snd wsshed with MeOH. Concentration in vacuo gsve the crude csrboxylic scid which wss dissolved in ethsnol (1.5 mL). To this solution wss sdded Lindlsr's cstslyst (20 mg) snd the resction stirred over s hydrogen stmosphere (1 stm vis a bslloon) for 20 h. The resction mixture wss filtered thru a celite psd snd wsshed with hot ethsnol snd wster. The ethsnol wss removed under vscuum snd the resulting squeous lsyer lyophilized to give 3 mixture of the desired smino scid 8 3nd the stsrting szide 7 3S a white powder. Compound 8: *H NMR (500 MHz, D2O): δ 6.5 (IH, s); 4.24-4.30 (2H, m); 4.25-4.18 (IH, m); 3.90-3.55 (5H, complex m); 2.96-2.90 (IH, m); 2.58-2.50 (IH, complex m); 2.12 (3H, s).
Example 9
Compound 62: A suspension of Quinic scid (60 g), cyclohexsnone (160 mL) snd toluenesulfonic scid (600 mg) in benzene (450 mL) wss refluxed with Desn-Stsrk for 14 hrs. The resction mixture wss cooled to room tempersture snd poured into sstursted N3HCO3 solution (150 mL). The squeous lsyer wss extracted with CH2CI2 (3x). The combined orgsnic lsyers were wsshed with wster (2x), brine (lx), snd dried over Ns2Sθ4. Concentration gsve s whited solid, which wss recrystsllized from ether (75 g, 95%): lH NMR (CDCI3) δ 4.73 (dd, J = 6.1, 2.5 Hz, 1 H), 4.47 (ddd, J = 7.0, 7.0, 3.0 Hz, IH), 4.30 (ddd, J = 5.4, 2.6, 1.4 Hz, 1 H), 2.96 (s, IH), 2.66 (d, J = 11.7 Hz, IH), 2.40-2.15 (m, 3 H), 1.72-1.40 (m, 10 H).
Exsmple 10
Compound 63: To a solution of Isctone 62 (12.7 g, 50 mmol) in methsnol (300 mL) wss sdded sodium methoxide (2.7 g, 50 mmol) in one portion. The mixture wss stirred st room tempersture for 3 hrs, snd quenched with scetic scid (3 mL) snd stirred for 10 min. The mixture wss poured into sstursted NH4CI solution (300 mL), 3nd extracted with CH2CI2 (3x). The combined orgsnic phsse wss wsshed with brine (lx), snd dried over MgSθ4. Purificstion by flssh column chromstography (Hexsne/EtOAc = 1/1 to 1/2) gsve diol (11.5 g, 80%) snd stsrting msterisl (1.2 g, 10%): H
NMR (CDCI3) δ 4.47 (ddd, J = 7.4, 5.8, 3.5 Hz, 1 H), 4.11 (m, 1 H), 3.98 (m, 1 H), 3.81 (s, 3 H), 3.45 (s, 1 H), 2.47 (d, J = 3.3 Hz, 1 H), 2.27 (m, 2 H), 2.10 (dd, J = 11.8, 4.3 Hz, 1 H), 1.92-1.26 (m, 10 H).
Example 11
Compound 64: To a mixture of diol 63 (1.100 g, 3.9 mmol), molecule sieves (3 A, 2.2 g) and pyridine (1.1 g) in CH2CI2 (15 mL) was added PCC (3.3 g, 15.6 mmol) in one portion. The mixture was stirred 3t room tempersture for 26 hrs, 3nd diluted with ether (30 mL). The suspension wss filtered through s psd of celite, snd wsshed with ether (2x20 mL). The combined ether wss wsshed with brine (2x), snd dried over MgSθ4. Concentration snd purificstion wss by flssh column chromstogrsphy (Hexsne /EtOAc = 3/1) gsve the ketone (0.690 g, 67%): H NMR (CDCI3) δ 6.84 (d, J = 2.8 Hz, 1 H), 4.69 (ddd, J = 6.4, 4.9, 1.6 Hz, 1 H), 4.30 (d, J = 5.0 Hz, 1 H), 3.86 (s, 3 H), 3.45 (d, J = 22.3 Hz, 1 H), 2.86 (m, 1 H), 1.69-1.34 (m, 10 H).
Example 12 Compound 28: To a solution of ketone 64 (0.630 g, 2.4 mmol) in
MeOH (12 mL) at 0°C was added NaBH4 in 30 min. The mixture wss stirred for sdditionsl 1.5 hrs 3t 0°C, snd quenched with 15 mL of sstursted NH4CI solution. The solution wss extracted with CH2CI2 (3x), snd the combined orgsnic extract wss dried over MgSθ4. Purificstion by flssh column chromstogrsphy (Hexsne/EtOAc = 2/1) gsve the slcohol (0.614 g, 97%): lH NMR (CDCI3) δ 6.94 (d, J = 0.5 Hz, 1 H), 4.64 (ddd, J = 9.8, 6.7, 3.2 Hz, 1 H), 4.55 (dd, J = 7.1, 4.2 Hz, 1 H), 4.06 (m, 1 H), 3.77 (s, 3 H), 3.04 (dd, J = 16.5, 2.1 Hz, 1 H), 2.73 (d, J = 10.2 Hz, 1 H), 1.94 (m, 1 H), 1.65-1.29 (m, 10 H).
Exsmple 13 Compound 66: Alcohol 28 (2.93 g, 10.9 mmol) snd toluenesulfonic scid (1.5 g) were dissolved in scetone (75 mL), snd the mixture wss stirred st room tempersture for 15 hrs. The resction wss quenched with wster (30 mL), snd bssified with concentrated NH3-H2O until PH = 9. Acetone wss removed under reduced pressure, snd the wster phsse wss extracted with CH2CI2 (3x). The combined orgsnic extrscts were wsshed with brine (lx), snd dried over Ns2Sθ4. Concentration gsve the desired product: H NMR (CDCI3) δ 7.01 (m, 1 H), 4.73 (m, 1 H), 4.42 (m, 1 H), 3.97 (m, 1 H), 3.76 (s, 3 H), 2.71-2.27 (m, 2 H), 2.02 (s, 3 H), 1.98 (s, 3 H).
Exsmple 14 Compound 67: To a solution of alcohol 66 (10.9 mmol) in CH2CI2 (60 mL) 3t 0°C wss sdded pyridine (4.4 mL, 54.5 mmol), followed by sddition of trimethylscetyl chloride (2.7 mL, 21.8 mmol). The mixture wss wsrmed to room tempersture snd stirred for 14 hrs. The mixture wss diluted with CH2CI2, and washed with water (2x), brine (lx), and dried over MgSθ4. Purification by flssh column chromstogrsphy (Hexsne/EtOAc = 9/1) gsve the diester (2.320 g, 68%): *H NMR (CDCI3) δ 6.72 (m, 1 H), 5.04 (m, 1 H), 4.76 (m, 1 H), 4.40 (m, 1 H), 3.77 (s, 3 H), 2.72-2.49 (m, 2 H), 1.37 (s, 3 H), 1.35 (s, 3 H), 1.23 (s, 9 H).
Exapple 15 Compound 68: Diester 67 (2.32 g, 2.3 mmol) was dissolved in acetone/H2θ (1/1, 100 mL) snd hested 3t 55°C for 16 hrs. Solvents were removed, wster (2 x 50 mL) wss sdded snd evsporated. Concentration with toluene (2 x 50 mL) gsve diol, which wss used without further purificstion: !H NMR (CDCI3) δ 6.83 (m, 1 H), 5.06 (m, 1 H), 4.42 (m, 1 H), 4.09 (m, 1 H), 3.77 (s, 3 H), 2.68-2.41 (m, 2 H), 1.22 (s, 9 H).
Example 16
Compound 69: To a solution of diol 68 (0.410 g, 1.5 mmol) in THF (8 mL) at 0°C wss added triethylamine (0.83 mL, 6.0 mmol), followed by slow addition of thionyl chloride (0.33 mL, 4.5 mmol). The mixture was wsrmed to room tempersture snd stirred for 3 hrs. The mixture wss diluted with CHCI3, snd wsshed with wster (3x), brine (lx), and dried over MgSθ4. Purification by flash column chromatography (Hexanes/ EtOAc = 5/1) gave 3 exo/endo mixture (0.430 g, 90°/.): lH NMR (CDCI3) δ 6.89-6.85 (m, 1 H), 5.48- 4.84 (m, 3 H), 3.80, 3.78 (s, 3 H), 2.90-2.60 (m, 2 H), 1.25, 1.19 (s, 9 H). Exsmple 17
Compound 70: The mixture of sulfone 69 (0.400 g, 1.3 mmol) snd sodium szide (0.410 g, 6.29 mmol) in DMF (10 mL) wss stirred for 20 hrs.
The resction mixture wss then diluted with ethyl scetste, wsshed with sstursted NH4CI solution, wster, brine, snd dried over MgSθ4. Concentration gsve the szide (0.338 g, 90%): H NMR (CDCI3) δ 6.78 (m, 1
H), 5.32 (m, 1 H), 4.20 (m, 1 H), 3.89 (m, 1 H), 3.78 (s, 3 H), 3.00-2.60 (m, 2 H),
1.21 (s, 9 H). Exsmple 18
Compound 71: To a solution of alcohol 70 (0.338 g, 1.1 mmol) in CH2CI2 (11 mL) 3t 0°C wss sdded triethylsmine (0.4 mL, 2.9 mmol), followed by slow sddition of methylsulfonic chloride (0.18 mL, 2.3 mmol). The mixture wss stirred st OX for 30 min., snd diluted with CH2CI2. The orgsnic lsyer wss wsshed with wster (2x), brine, snd dried over MgSθ4. Purificstion by flssh column chromstogrsphy (Hexsne/EtOAc = 3/1) gave the desired compound (0.380 g, 82%): H NMR (CDCI3) δ 6.82 (m, 1 H), 5.44 (m, 1 H), 4.76 (dd, J = 7.3, 1.4 Hz, 1 H), 4.48 (m, 1 H), 3.80 (s, 3 H), 3.11 (s, 3 H), 2.82-2.61 (m, 2 H), 1.21 (s, 9 H).
Example 19
Compound 72: The mixture of azide 71 (0.380 g, 0.94 mmol) snd triphenylphosphine (0.271 g, 1.04mmol) in THF (19 mL) wss stirred for 2 hrs. The resction wss quenched with wster (1.9 mL) snd triethylsmine (0.39 mL, 2.82 mmol), snd the mixture wss stirred for 14 hrs. Solvents were removed under reduced pressure, 3nd the mixture wss used for next step. To a solution of sbove mixture in CH2CI2 (20 mL) 3t OX wss sdded pyridine (0.68 mL, 8.4 mmol), followed by slow sddition of scetyl chloride (0.30 mL, 4.2 mmol). The mixture wss stirred st 0°C for 5 min., snd diluted with ethyl scetste. The mixture wss wsshed with wster (2x), brine (lx), dried over MgSθ4. Purificstion by flash column chromatography (Hexanes/ EtOAc = 3/1) gsve the sziridine (0.205 g, 83%): H NMR (CDCI3) δ 7.19 (m, 1 H), 5.58 (m, 1 H), 3.77 (s, 3 H), 3.14 (m, 2 H), 2.85 (dd, J = 7.0, 1.6 Hz, 1 H), 2.34 (m, 1 H), 2.16 (s, 3 H), 1.14 (s, 9 H). Exsmple 20
Compound 73: The mixture of sziridine 72 (0.200 g, 0.68 mmol), sodium szide (0.221 g, 3.4 mmol), snd ammonium chloride (0.146 g, 2.7 mmol) in DMF (10 mL) was stirred at room temperature for 14 hrs. Then the mixture wss diluted with ethyl scetste, snd wsshed with wster (5x), brine (lx), snd dried over MgSθ4. Purificstion by flssh column chromstogrsphy (hexsnes/ EtOAc = 2/1) gsve desired product snd descetyl smine (0.139 g). The mixture wss dissolved in scetic snhydride (2 mL), snd stirred for 2 hrs. Excess snhydride wss removed under reduced pressure, snd give the desired product (149 mg): IH NMR (CDCI3) δ 6.76 (m, 1 H), 5.53 (d, J = 8.5 Hz, 1 H), 5.05 (m, 1 H), 4.31 (m, 1 H), 4.08 (m, 1 H), 3.79 (s, 3 H), 2.91 (m, 1 H), 2.51 (m, 1 H), 1.99 (s, 3 H), 1.20 (s, 9 H). Example 21
Compound 74: A solution of potsssium hydroxide in MeOH/H2θ (0.5 M, 4.4 mL, 2.2 mmol) wss sdded to ester 73 (149 mg, 0.44 mmol) 3nd the mixture wss stirred st room tempersture for 3 hrs. The mixture wss cooled to OX, snd scidified with Amberlite (scidic) to PH = 3-4. The mixture wss filtered, snd wsshed with MeOH. Concentration gsve the csrboxylic scid ss a white solid (73 mg, 69%): iH NMR (CD3OD) δ 6.62 (m, 1 H), 4.15 (m, 1 H), 3.95-3.72 (m, 2 H), 2.84 (dd, J = 6.7, 1.4 Hz, 1 H), 2.23 (m, 1 H), 1.99 (s, 3 H).
Example 22 Compound 75: The mixture of azide 74 (8 mg) and Pd-C (Lindlsr) (15 mg) in ethsnol (2 mL) wss stirred under hydrogen for 16 hrs. The mixture wss filtered through celite, wsshed with hot MeOH-H2θ (1/1). Concentration gsve a solid. The solid was dissolved in wster, snd psssed through 3 short C-8 column, snd wsshed with wster. Concentration gsve s white solid (6 mg): *H NMR (D2O) δ 6.28 (m, 1 H), 4.06-3.85 (m, 3 H), 2.83 (dd, J =17.7, 5.4 Hz, 1 H), 2.35 (m, 1 H), 2.06 (s, 3 H).
Exsmple 23
Compound 76: Csrboxylic scid 74 (68 mg, 0.28 mmol) snd diphenyldiszomethsne (61 mg, 0.31 mmol) were dissolved in ethsnol (12 mL), snd stirred for 16 hrs. The resction wss quenched with scetic scid (0.5 mL), snd the mixture wss stirred for 10 min. Solvents were removed under reduced pressure. Purificstion by flssh column chromstogrsphy (EtOAc) gsve the ester (56 mg, 50°/.): Iji NMR (CD3OD) δ 7.36-7.23 (m, 10 H), 6.88 (s, 1 H), 6.76 (s, 1 H), 4.21 (m, 1 H), 3.93-3.79 (m, 2 H), 2.89 (dd, J = 17.7, 5.0 Hz, 1 H), 2.34 (m, 1 H), 2.00 (s, 3 H).
Exsmple 24
Compound 77: To s solution of slcohol 76 (20 mg, 0.05 mmol) in CH2CI2 (1 mL) wss sdded pyridine (40 μL, 0.5 mmol), followed by sddition of scetic snhydride (24 μL, 0.25 mmol). The mixture wss stirred for 24 hrs, snd solvents snd resgents were removed under reduced pressure. Purificstion by flssh column chromstogrsphy (Hexsne/EtOAc = 1/2) gsve the diester (20 mg, 91%): iH NMR (CDCI3) δ 7.40-7.27 (m, 10 H), 6.95 (s, 1 H), 6.87 (m, 1 H), 5.60 (m, 1 H), 5.12 (ddd, J = 16.4, 10.2, 5.9 Hz, 1 H), 4.28 (dd, J = 20.0, 9.4 Hz, 1 H), 4.15 (m, 1 H), 2.93 (dd, J = 17.8, 5.2 Hz, 1 H), 2.57 (m, 1 H), 2.09 (s, 3 H), 2.01 (s, 3 H). Example 25
Compound 78: The mixture of diester 77 (20 mg, 0.045 mmol), snisole (50 μL, 0.45 mmol), snd TFA (1 mL) in CH2CI2 (1 mL) wss stirred for 20 min. Solvents snd resgents were removed under reduced pressure. Purificstion by flssh column chromstogrsphy (EtOAc to EtOAc/AcOH = 100/1) gsve the csrboxylic scid (6 mg): iH NMR (CDCI3) δ 6.85 (m, 1 H), 5.54 (m, 1 H), 5.12 (m, 1 H), 4.31-4.03 (m, 2 H), 2.89 (m, 1 H), 2.60-2.41 (m, 1 H), 2.11 (s, 3 H), 2.03 (s, 3 H).
Exsmple 26 Compound 79: The mixture of szide 78 (6 mg, 0.02 mmol) snd PdX
(Lindlsr) (15 mg) in EtOH/H2θ (2.2 mL, 10/1) wss stirred under hydrogen for 3 hrs. The mixture wss filtered through a psd of celite, wsshed with hot MeOH/H2θ (1/1). Evaporation gsve a white solid. The solid wss dissolved in wster, 3nd psssed through s C-8 column. Evsporstion of wster gsve a white powder (3 mg): iH NMR (D2O) δ 6.32 (m, 1 H), 5.06 (m, 1 H), 4.06 (t, J = 10.4 Hz, 1 H), 3.84 (m, 1 H), 2.83 (m, 1 H), 2.42 (m, 1 H), 2.06 (s, 3 H), 2.00 (s, 3 H).
Exsmple 27
Compound 80: To s solution of slcohol 76 (35 mg, 0.086 mmol), Boc- glycine (30 mg, 0.172 mmol), and catalytic amount DMAP in CH2CI2 (1 mL) was sdded DCC (35 mg, 0.172 mmol). The mixture was stirred for 30 min, and filtered 3nd wsshed with CHCI3. The CHCI3 solution wss wsshed with wster (2x). Concentration gsve a white solid. Purificstion by flssh column chromstography (Hexsne/EtOAc = 1/2) gsve product (30 mg): ^H NMR (CDCI3) δ 7.39-7.26 (m, 10 H), 6.95 (s, 1 H), 6.86 (m, 1 H), 5.77 (m, 1 H), 5.27 (m, 1 H), 4.99 (m, 1 H), 4.18-4.01 (m, 2 H), 3.94-3.84 (m, 2 H), 2.96 (dd, J = 7.8, 5.9 Hz, 1 H), 2.57 (m, 1 H), 2.02 (s, 3 H), 1.45 (s, 9 H).
Exsmple 28
Compound 81: The mixture of diester 80 (30 mg, 0.05 mmol), snisole (150 μL), snd TFA (1 mL) in CH2CI2 (1 mL) was stirred for 3 hrs. Solvents and resgents were evsporsted . The mixture was dissolved in water, snd wsshed with CHCI3 (3x). Wster phsse wss evsporsted to gsve s white solid (15 mg): iH NMR (CD3OD) δ 6.73 (m, 1 H), 5.25-5.15 (m, 1 H), 4.35 (m, 1 H), 4.17 (m, 1 H), 3.82 (m, 2 H), 2.93 (dd, J = 17.7, 5.6 Hz, 1 H), 2.42 (m, 1 H), 1.97 (s, 3 H). Example 29
Compound 82: The mixture of azide 81 (15 mg, 0.05 mmol) snd PdX (Lindlsr) (30 mg) in EtOH/H2θ (4 mL, 1/1) wss stirred under hydrogen for 3 hrs. The mixture wss filtered through a pad of celite, snd wsshed with hot MeOH/H2θ (1/1). Concentration gsve a glsss-like solid. The solid wss dissolved in wster, snd psssed through C-8 column. Evsporation of wster gsve the smino 3cid: H NMR (D2O) δ 6.68 (m, 1 H), 5.28 (m, 1 H), 4.29 (m, 1 H), 4.08-3.79 (m, 3 H), 2.85 (m, 1 H), 2.41 (m, 1 H), 2.04 (s, 3 H).
Example 30 bis-Boc guanidinyl methyl ester 92: Treated according to the procedure of Kim and Qian, "Tetrahedron Lett.", 34:7677 (1993). To a solution of smine 91 (42 mg, 0.154 mmol), bis-Boc thiourea (43 mg, 0.155 mmol) snd triethylsmine (72 μL) in dry DMF (310 μL) cooled to 0°C wss sdded mercury chloride (46 mg, 0.170 mmol) in one portion. After 30 min the resction wss wsrmed to room tempersture snd stirred for sn sdditionsl 2.5 h. The resction mixture wss then filtered through a celite psd, concentrated snd purified by flssh column chromstogrsphy (100% ethyl scetste) to give 70 mg (89%) of 92 ss a colorless fosm. ΪH NMR (CDCI3, 300 MHz): δ 11.37 (s, IH); 8.60 (d, IH, / = 7.8 Hz); 6.83 (t, IH, / = 2.1 Hz); 6.63 (d, IH, / = 8.4 Hz); 4.76 (d, IH, / = 7.0 Hz); 4.71 (d, IH, / = 7.0 Hz); 4.45-4.10 (complex m, 2H); 3.76 (s, 3H); 3.39 (s, 3H); 2.84 (dd, IH, / = 5.4, 17.4 Hz); 2.45-2.30 (m, IH); 1.92 (s, 3H); 1.49 (s, 18H).
Example 31 bis-Boc guanidinyl carboxylic acid 93: To a solution of ester 92 (70 mg, 0.136 mmol) in THF (3 mL) cooled to 0°C was sdded aq. KOH (350 μL of a 0.476 M solution). The reaction was then wsrmed to room tempersture snd stirred for 2 h. The resction wss then scidified to pH = 4.5 with Amberlite IR-120 (plus) scidic resin. The resin wss then filtered snd wsshed with ethsnol snd H2O. Concentration in vαcuo gsve 66 mg (97%) of csrboxylic 3dd 93 ss a white solid. *H NMR (CDCI3, 300 MHz): δ 11.40 (br s, IH); 8.67 (d, IH, / = 7.8 Hz); 6.89 (s, IH); 6.69 (br d, IH, / = 8.4 Hz); 4.77 (d, IH, / = 7.2 Hz); 4.70 (d, IH, / = 7.2 Hz); 4.40-4.15 (m, 2H); 3.39 (s, 3H); 2.84 (dd, IH, / = 4.8, 17.1 Hz); 2.45-2.30 (m, IH); 1.95 (s, 3H); 1.49 (s, 9H); 1.48 (s, 9H).
Exsmple 32 Guanidine carboxylic acid TFA salt 94: To a solution of bis-Boc gusnidinyl csrboxylic scid 93 (23 mg, 0.046 mmol) in CH2CI2 (1 mL) cooled to 0°C wss sdded nest trifluoroscetic 3cid (500 μL). After 30 min the resction wss wsrmed to room tempersture snd stirred for sn sdditionsl 1.25 h. Volstiles were removed under vscuum snd the residue co-evsporated with seversl portions of H2O to give a psle orsnge solid. The residue wss purified by reverse phsse Ci8 chromstogrsphy using H2O ss sn eluent. Fractions contsining the desired product were pooled snd lyophilized to give 15 mg of 93 3S s white powder. H NMR (D2O, 500 MHz): δ 6.82 (t, IH, / = 2.0 Hz); 4.51^.47 (m, IH); 3.93 (dd, IH, / = 9.0, 11.2 Hz); 3.87-3.80 (sppsrent ddd, IH); 2.88 (m, IH); 2.48-2.45 (complex m); 2.07 (s, 3H). 13C NMR (D2O): δ 176.1; 170.0; 157.1; 139.2; 129.5; 69.4; 56.2; 50.9; 30.3; 22.2.
Exsmple 33
Synthesis of 102: A solution of azido allyl ether 6 (24 mg, 0.082 mmol) in ethanol (1 mL) was treated with hydrogen gas (1 atm) over Lindlar's cstslyst (30 mg) for 1.5 h. The resction mixture wss filtered through a celite psd snd wsshed with hot ethsnol. Concentrstion in vαcuo gsve a psle solid which wss dissolved in THF (1.5 mL) and treated with squeous KOH (246 μL of s 0.50 M solution). After stirring 3t smbient tempersture for 2 h the resction wss scidified to pH = 4.0 with Amberlite IR-120 (plus) scidic resin, filtered 3nd wsshed with ethsnol snd H2O. Concentrstion in vαcuo gsve sn orsnge solid which wss purified by s Ci8 column chromstogrsphy eluting with H2O. Fractions containing the product were pooled and lyophilized to give a 2 to 1 mixture of 102 and the fully saturated compound 103 as a white powder. !H NMR data for compound 102: H NMR (D2O, 500 MHz): δ: 7.85 (s, IH); 4.29 (br d, IH, / = 9.2 Hz); 4.16 (dd, IH, / = 11.6, 11.6 Hz); 3.78 - 3.72 (m, 2H); 3.62 (appsrent ddd, IH); 2.95 (sppsrent dd, IH); 2.58 - 2.52 (m, IH); 2.11 (s, 3H); 1.58 (q, 2H, / = 7.3 Hz); 0.91 (t, 3H, / = 7.3 Hz).
Exsmple 34
Synthesis of 115: A solution of smino acid 114 (10.7 mg, 0.038 mmol) in water (1.3 mL) cooled to 0°C was adjusted to pH = 9.0 with 1.0 M NaOH. Benzyl formimidate hydrochloride (26 mg, 0.153 mmol) wss then sdded in one portion snd the resction stirred between 0 - 5°C for 3 h while msintsining the pH between 8.5 - 9.0 with 1.0 M NsOH. The resction wss then concentrated in vαcuo snd the residue applied to a Ci8 column and eluted with wster. Fractions contsining the product were pooled snd lyophilized to give the formsmidine csrboxylic scid 115 (10 mg) ss a white powder. lH NMR (D2O, 300 MHz, mixture isomers): δ 7.83 (s, IH); [6.46(s) & 6.43 (s); 1 H total]; 4.83 (d, IH, / = 7.3 Hz); 4.73 (d, IH, / = 7.3 Hz); 4.50 - 4.35 (m, IH); 4.10 - 4.05 (m, IH); [4.03 - 3.95 (m) & 3.80 - 3.65 (m), 1 H totsl]; 3.39 (s, 3H); 2.90 - 2.75 (m, IH); 2.55 - 2.30 (m, IH); [2.03 (s) & 2.01 (s), 3H totsl]. Exsmple 35
Compound 123: To a solution of slcohol 63 (5.842 g, 20.5 mmol) snd DMAP (200 mg) in pyridine (40 mL) wss sdded tosyl chloride (4.3 g, 22.6 mmol). The mixture wss stirred st room tempersture for 40 hrs, snd pyridine wss removed under reduced pressure. The resction wss quenched with wster, 3nd extrscted with EtOAc (3x). The combined orgsnic extracts were wsshed with wster, brine, snd dried over MgSθ4. Purificstion by flssh column chromstogrsphy (Hexsnes/ EtOAc = 2/1) gsve the tosylste (8.04 g, 89%): iH NMR (CDCI3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2 H), 4.78 (m, 1 H), 4.43 (m, 1 H), 4.06 (m, 1 H), 3.79 (s, 3 H), 2.44 (s, 3 H), 2.43-1.92 (m, 4 H), 1.61-1.22 (m, 10 H).
Exsmple 36
Compound 124: To a solution of slcohol 123 (440 mg, 1.0 mmol) in pyridine (3 mL) wss sdded POCI3 (100 μL, 1.1 mmol). The mixture wss stirred 3t room temperature for 12 hrs, 3nd quenched with sstursted NH4CI solution. The wster phsse wss extracted with ether (3x). The combined ether lsyers were wsshed with wster (2x), 2 N HCl solution (2x), brine, snd dried over MgSθ4. Purificstion by flssh column chromstogrsphy (Hexsne/EtOAc = 2/1) gsve a mixture of the desired product 124 snd some inpurity (350 mg, 83%, 2/1). Exsmple 37
Compound 1: To a solution of the known scetonide of methyl shikimste (877 mg, 3.85 mmol, "Tetrshedron Lett.", 26:21 (1985)) in dichloromethβne (15 mL) st -10°C wss sdded methsnesulfonyl chloride (330 μL, 4.23 mmol) followed by the dropwise sddition of triethylsmine (640 μL, 4.62 mmol). The solution wss stirred 3t -10°C for 1 h then st 0°C for 2 h, st which time methsnesulfonyl chloride (30 μL), triethylsmine (64 μL) wss sdded. After 1 h cold wster wss sdded, the orgsnic phsse wss sepsrated, wsshed with wster, dried (MgSO-t), snd evsporated. The crude product wss chromstographed on silics gel (1/1-hexsne/ethyl scetste) to provide mesylste 130 (1.1 g, 93%) ss sn oil. Mesylste 130 (990 mg, 3.2 mmol) wss dissolved in tetrahydrofuran (5 mL) snd wss trested with 1M HCl (5 mL). The solution wss stirred 3t room tempersture for 19 h, diluted with wster (5 mL) snd stirred sn sdditionsl 7 h. Evsporstion of the orgsnic solvent precipitsted sn oily residue which wss extracted into ethyl scetste. The combined orgsnic extrscts were wsshed with brine, dried (MgSθ4), snd evsporated. Addition of CH2CI2 to the crude residue precipitsted s white solid which wss filtered snd wsshed with CH2CI2 to sfford diol 131 (323 mg, 38%). To a psrtisl suspension of diol 131 (260 mg, 0.98 mmol) in THF (5 mL) st 0°C wss sdded DBU (154 μL, 1.03 mmol). The solution wss stirred 3t 0°C for 3 h snd then wss wsrmed to room tempersture stirring for 5 h. The solvent wss evsporated snd the crude residue wss psrtitioned between ethyl scetste (40 mL) snd 5% citric scid (20 mL). The orgsnic phsse wss wsshed with brine. Aqueous phsses were bsck extracted with ethyl scetste (15 mL) snd the combined orgsnic extrscts were dried (MgSθ4) snd evsporated to sfford the epoxide (117 mg, 70%) ss s white solid which gsve sn *H NMR spectrum consistent with structure 1 prepsred by literature method.
Example 38
Alcohol 51: To a solution of protected alcohol (PG=methoxymethyl) (342 mg, 1.15 mmol) in CH2CI2 (10 mL) at 0°C was sdded trifluoroscetic scid (8 mL). After 5 min st 0°C, the solution wss stirred 1 h st room temperature snd wss evsporated. The crude product wss purified on silics gel (ethyl scetste) to sfford slcohol 51 (237 mg, 82%) ss sn oil: *H NMR (300 MHz, CDCI3) δ 2.11 (s, 3H), 2.45 (m, IH), 2.97 (dd, IH, / = 3.8, 18.8), 3.66 (m, 2H), 3.78 (s, 3H), 4.40 (br s, IH), 5.22 (br s, IH), 6.19 (br s, IH), 6.82 (m, IH). Exsmple 39
Methyl ether 150: To a solution of slcohol 51 (46 mg, 0.18 mmol) snd methyl iodide (56 μL, 0.90 mmol) in THF (0.7 mL) st 0°C wss sdded NsH ss s 60% mineral oil dispersion (8 mg, 0.20 mmol). The solution wss stirred 3t 0°C for 2.5 h, snd a second portion of NsH (2 mg) wss sdded. After sn sdditionsl 1 h st 0°C snd 4 h at room temperature the solution wss cooled to 0°C snd 5% citric scid (0.5 mL) wss sdded. The mixture wss extracted with ethyl scetste (4X2mL) snd the combined orgsnic extrscts were dried (MgSθ4), snd evsporated. Purificstion of the crude residue on silics gel (ethyl scetste) gsve methyl ether 150 (12 mg, 25%) ss s solid: H NMR (300 MHz, CDCI3) δ 2.07 (s, 3H), 2.23-2.34 (m, IH), 2.89 (spp ddd, IH), 3.43 (s, 3H), 3.58 (m, IH), 3.78 (s, 3H), 4.13 (m, IH), 4.40 (m, IH), 5.73 (d, IH, / = 7.6), 6.89 (m, IH). Example 40
Amino acid 151: To a solution of methyl ether 150 (12 mg, 0.45 mmol) in THF(1 mL)/w3ter (100 μL) wss sdded polymer support PI13P (75 mg, 3 mmol P/g resin). The mixture wss stirred st room tempersture for 19 h. The resin wss filtered, wsshed seversl times with THF snd the combined filtrate snd wsshings were evsporated to provide 8 mg of a crude residue. The residue wss dissolved in THF (0.5 mL), snd 0.5 M KOH (132 μL)/w3ter (250 μL) wss sdded. The solution wss stirred st room temperature for 1.25 h snd the pH wss sdjusted to 3-4 with IR120 ion exchsnge resin. The resin wss filtered snd wss stirred with 1M HCl. After filtration, the resin wss subjected to the ssme treatment with 1M HCl until the acidic washes no longer tested positive for amine with ninhydrin. The combined resin washings were evsporated and the residue was purified on C-18 reverse phase silica eluting with water to afford after lyophilization, amino acid 151 (1.8 mg, 15%) 3S a white solid: H NMR (300 MHz, D2O) δ 2.09 (s, 3H), 2.48- 2.59 (app qt, IH), 2.94 (dd, IH, / = 5.7, 17.4), 3.61 (m, IH), 4.14-4.26 (m, 2H), 6.86 (br s, IH).
Example 41
Amino acid allyl ether 153: To a solution of azide 6 ( 16 mg, 0.054 mmol) in THF (0.50 mL) and H2O (35 μL) was sdded polystyrene supported PPh3 (50 mg). The resction wss stirred st ambient temperature for 24 h, filtered through s sintered glsss funnel 3nd wsshed with hot methsnol. Concentrstion in vαcuo gsve the crude amino ester which was dissolved in THF (1.0 mL) and treated with aqueous KOH (220 μL of a 0.5 M solution). After stirring at ambient temperature for 2 h Amberlite IR-120 (plus) scidic resin wss sdded until the solution attsined pH = 4.5 . The resin wss filtered 3nd wsshed with ethsnol snd H2O. Concentration in vαcuo gave 3 psle orsnge solid which wss purified by reverse phsse Ci8 chromstogrsphy using H2O ss sn eluent. Fractions contsining the desired product were pooled snd lyophilized to give the smino scid ss s white powder. iH NMR (D2O, 300 MHz): δ 6.51 (br t, IH); 6.05-5.80 (m, IH, -CH=, silyl); 5.36-5.24 (m, 2H, =CH2, silyl); 4.35-4.25 (m, IH); 4.25 - 4.05 (m, 2H, -CH2-, allyl); 4.02-3.95 (m, IH); 3.81- 3.70 (m, IH); 2.86-2.77 (apparent dd, IH); 2.35-2.24 (complex m, IH); 2.09 (s, 3H). Example 42
Epoxide 161: MCPBA (690 mg) was added to a solution of olefin 160 (532 mg, 1.61 mmol, prepsred by Exsmple 14, crude mesylste wss filtered through silics gel using 30% EtOAc/Hexsnes prior to use) in dichloromethsne (15 mL) cooled to 0°C. The mixture wss wsrmed to room tempersture snd stirred overnight. The bulk of the solvent wss removed under vscuum snd the mixture diluted with ethyl scetste. The orgsnic lsyer wss wsshed with squeous sodium bisulfite, sstursted sodium bicsrbonste, brine snd dried over MgSθ4. Concentrstion in vacuo followed by flssh column chromstogrsphy of the residue (30% hexsnes in ethyl scetste) gsve 437 mg (78%) of 161 ss a psle oil. XH NMR (CDCI3, 300 MHz): [1:1 mixture of disstereomers] δ [4.75 (dd, / = 3.9, 8.2 Hz) & 4.71 (dd, / = 3.9, 8.4 Hz), IH total]; 4.37 (m, IH); 4.25-4.00 (m, 2H); 3.78 (s, 3H); [3.68 (dd, / = 5.7, 11.7 Hz) & 3.51 (dd, / = 6.6, 11.7 Hz), IH total]; [3.17 (s) & 3.16 (s), 3H total]; [2.99 (m) & 2.93 (m), IH total]; [2.83 (t, / = 4.1 Hz) & 2.82 (t, / = 4.5 Hz), IH total]; 2.70-2.60 (m, IH); 2.45-2.30 (m, IH). Example 43
Diol 162: The epoxide 161 (437 mg, 1.23 mmol) was gently reluxed for
1 h in THF (20 mL) 3nd H2O (10 mL) contsining 5 drops of 70% HCIO4.
Solid NsHCθ3 wss sdded and the mixture concentrated in vαcuo. The residue was dissolved in EtOAc, wsshed with brine snd dried. Concentrstion in vαcuo gsve the crude diol 162 ss s psle oil in qusntitstive yield. Used without sny purificstion for the next resction.
Exsmple 44
Aldehyde 163: Oxidstion of diol 162 was carried out according to the procedure of Vo-Quang and co-workers, "Synthesis", 68 (1988). To 3 slurry of silics gel (4.3 g) in dichloromethsne (30 mL) wss added a solution of NaIθ4
(4.4 mL of 3 0.65 M aqueous solution). To this slurry was added a solution of the crude diol 162 (520 mg) in EtOAc (5 mL) and dichloromethane (15 mL).
After 1 h the solids were filtered snd wsshed with 20% hexsnes /EtOAc.
Concentrstion gsve sn oily residue which was dissolved in EtOAc snd dried over MgSθ4. Concentrstion in vαcuo gsve the sldehyde 163 3S a psle oil which wss used immediately for the next reaction. ^H NMR (CDCI3, 300
MHz): δ 9.69 (s, IH); 6.98 (m, IH); 4.72 (dd, IH, / = 3.7, 9.1 Hz); 4.53 (d, IH, / =
18.3 Hz); 4.45 (d, IH, / = 18.3 Hz); 4.31 (m, IH); 4.26-4.18 (m, IH); 3.79 (s, 3H);
3.19 (s, 3H); 3.05 (dd, IH, / = 5.7, 18.6 Hz); 2.20-2.45 (m, IH). Example 45 Alcohol 164: The crude aldehyde 163 was treated with N3CNBH3 sccording to the procedure of Borch snd co-workers, "J. Amer. Chem. Soc", 93:2897 (1971) to give 269 mg (65%) of the slcohol 164 after flash chromstogrsphy (40% hexsnes in ethyl scetste). *H NMR (CDCI3, 300 MHz): δ 6.91 (m, IH); 4.75 (dd, IH, / = 3.9, 8.7 Hz); 4.34 (br t, IH, / = 4.1 Hz); 4.25-4.15 (m, IH); 3.85-3.70 (m, 4H); 3.77 (s, 3H); 3.16 (s, 3H); 2.95 (dd, IH, / = 5.7, 18.6 Hz); 2.37 (dd, IH, / = 7.1, 18.6 Hz); 2.26 (br s, IH).
Exsmple 46
Aziridine 165: The slcohol 164 (208 mg, 0.62 mmol) wss scetylsted in the ususl msnner (AcCl, pyridine, dichloromethsne, cst. DMAP) to give the scetste (241 mg, 100%). The crude scetste (202 mg, 0.54mmol) wss trested st room tempersture with Ph3P (155 mg) in THF (12 mL) for 2 h. H2O (1.1 mL) snd triethylsmine (224 μL) were then 3dded snd the solution stirred overnight. The resction mixture wss concentrated and the residue partitioned between ethyl scetste snd sstursted bicarbonate/brine. The organic layer was dried, concentrated in vacuo snd purified by flssh chromstography (10% MeOH in EtOAc) to give 125 mg (90%) of aziridine 165 as a white solid. H NMR (CDCI3, 300 MHz): δ 6.80 (m, IH); 4.44 (br s, IH); 4.23 (t, 2H, / = 4.8 Hz); 3.82-3.65 (m, 2H); 3.74 (s, 3H); 2.85 (br d, IH, / = 19.2 Hz); 2.65-2.40 (m, 3H); 2.09 (s, 3H); 1.25 (br s, IH).
Exsmple 47
N-Boc aziridine 166: Boc anhydride (113 mg, 0.52 mmol) was added to a solution of aziridine 165 (125 mg, 0.49 mmol), triethylamine (70 μL), DMAP (cat. amount) in dichloromethane (7 mL). After 1 h the reaction wss concentrated snd the residue subjected to flssh chromatography (40% EtOAc in hexanes) to give 154 mg (88%) of the N Boc sziridine 166 ss s psle oil. ^H NMR (CDCI3, 300 MHz): δ 6.82 (m, IH); 4.47 (br m, IH); 4.23 (t, 2H, / = 4.7 Hz); 3.81 (t, 2H, / = 4.7 Hz); 3.75 (s, 3H); 3.00 (br d, IH, / = 18.0 Hz); 2.90-2.85 (m, 2H); 2.65-2.55 (m, IH); 2.10 (s, 3H); 1.44 (s, 9H). Exsmple 48
Azido ester 167: Aziridine 166 (154 mg, 0.43 mmol), sodium szide (216 mg), snd ammonium chloride (223 mg) was heated at 100°C in DMF (5 mL) for 18 h. The cooled reaction mixture was partitioned between ethyl ether and brine. The ether layer was washed with H2O, brine and dried over MgSθ4. Concentration gave a crude residue which was treated with 40% TFA in dichloromethsne st room tempersture. After 2 h the resction wss concentrated in vacuo to give s psle oil which wss passed through a short column of silics gel eluting with EtOAc The product wss then scylsted in the ususl msnner (AcCl, pyridine, dichloromethsne, cst. DMAP) to give the szido ester 167 ss s psle yellow oil 16 mg (11% for 3 steps) sfter flssh chromstogrsphy (5% MeOH in chloroform). H NMR (CDCI3, 300 MHz): δ 6.85 (m, IH); 5.80 (br d, IH, / = 7.8 Hz); 4.55 (m, IH); 4.25-4.10 (m, 3H); 3.90-3.85 (m, 2H); 3.78 (s, 3H); 3.55 (m, IH); 2.90 (dd, IH, / = 5.4, 17.0 Hz); 2.45-2.25 (m, IH); 2.10 (s, 3H); 2.05 (s, 3H). Exsmple 49
Amino acid 168: To a solution of ester 167 (16 mg, 0.047 mmol) in THF (1 mL) cooled to 0°C was added aq. KOH (208 μl of a 0.476 M solution). The reaction was then warmed to room temperature and stirred for 2 h. The reaction wss then scidified to pH = 4.0 with Amberlite IR-120 (plus) 3cidic resin. The resin wss then filtered snd wsshed with ethsnol and H2O.
Concentration in vacuo gsve s 14 mg (100%) of the szido csrboxylic scid ss s white solid. The szido acid was dissolved in ethanol (2 mL) snd trested with hydrogen gss (1 stm) over Lindlsr's cstslyst (15 mg) for 16 h sccording to the procedure of Corey snd co-workers, "Synthesis", 590 (1975). The resction mixture wss filtered through s celite psd snd wsshed with hot ethsnol snd H2O. Concentrstion in vacuo gsve s psle orsnge solid which wss purified by 3 Ci8 column chromstogrsphy eluting with H2O. The fractions containing the product were pooled and lyophilzed to give 9.8 mg of 168 as s white powder. iH NMR (D2O, 500 MHz): δ: 6.53 (br s, IH); 4.28 (br m, IH); 4.08 (dd, IH, / = 11.0, 11.0 Hz); 3.80-3.65 (complex m, 4H); 3.44 (m, IH); 2.84 apparent dd, IH); 2.46-2.39 (complex m, IH); 2.08 (s, 3H).
Example 50
Epoxy MOM ether 19 (PG=methoxymethyl): Prepared in 74% from epoxy slcohol 1 according to the procedure of Mordini and co-workers, "J. Org. Chem.", 59:4784 (1994). iH NMR (CDCI3, 300 MHz): δ 6.73 (m, IH); 4.87 (s, 2H); 4.59 (t, IH, / = 2.4 Hz); 3.76 (s, 3H); 3.57 (m, IH); 3.50-3.40 (m, IH); 3.48 (s, 3H); 3.10(d, / = 19.5 Hz); 2.45 (m, IH).
Example 51
Aziridine 170: Prepared in 77% overall from epoxide 19 (PG=methoxymethyl) according to the general protocol described in Exsmples 3 3nd 4: H NMR (CDC13, 300 MHz): δ 6.85 (m, IH); 4.78 (s, 2H); 4.54 (m, IH); 3.73 (s, 3H); 3.41 (s, 3H); 2.87 (d, IH, / = 18.9 Hz); 2.70-2.45 (m, 3H).
Example 52 Azido ester 22 (PG=methoxymethyl): The aziridine 170 (329 mg, 1.54 mmol), NaN3 (446 mg) and NH4CI (151 mg) wss hested 3t 65°C in DMF (20 mL) for 18 h. The cooled resction mixture wss psrtitioned between ethyl ether snd brine. The ether lsyer wss wsshed with H2O, brine snd dried over MgSθ4. Concentrstion in vacuo gsve the crude szido smine 3S 3 psle oil which wss tsken up in CH2CI2 (15 mL) snd trested with pyridine (4 mL) snd AcCl (150 μL). Aqueous work up followed by flssh chromstogrsphy of the residue gsve 350 mg (76%) of szido ester 22 (PG=methoxymethyl) ss s psle oil. *H NMR (CDCI3, 300 MHz): δ 6.78 (s, IH); 6.39 (br d, IH, / = 7.8 Hz); 4.72 (d, IH, / = 6.9 Hz); 4.66 (d, IH, / = 6.9 Hz); 4.53 (br d, IH, / = 8.4 Hz); 4.00-3.90 (m, IH); 3.80-3.65 (m, IH); 3.75 (s, 3H); 3.37 (s, 3H); 2.85 (dd, IH, / = 5.4, 17.7 Hz); 2.35-2.20 (m, IH); 2.04 (s, 3H).
Example 53
Amino acid 114: The azide 22 (PG=methoxymethyl) (39 mg, 0.131 mmol) was trested with hydrogen gss st 1 atmosphere over Lindlar's cstslyst (39 mg) in ethsnol for 2.5 h sccording to the procedure of Corey snd co- workers, "Synthesis", 590 (1975). The resction mixture wss filtered through a celite pad, wsshed with hot ethsnol snd concentrated to give the crude smine 33 mg (92%) ss a pale foam. The amine in THF (1 mL) was treated with aq. KOH (380 μL of a 0.476 M solution). After 1 h the reaction was acidified to pH = 4.0 with Amberlite IR-120 (plus) acidic resin. The resin was then filtered, washed with H2O and concentrated to give a pale solid which wss purified by 3 Ci8 column chromstogrsphy eluting with H2O. The fractions contsining the product were pooled snd lyophilzed to give 20 mg of 114 ss s white powder. l NMR (D20, 300 MHz): δ 6.65 (s, IH); 4.87 (d, IH, / = 7.5 Hz); 4.76 (d, IH, / = 7.5 Hz); 4.47 (br d, IH, / = 8.7 Hz); 4.16 (dd, IH, / = 11.4, 11.4 Hz); 3.70-3.55 (m, IH); 3.43 (s, 3H); 2.95 (dd, IH, / = 5.7, 17.4 Hz); 2.60-2.45 (m, IH); 2.11 (s, 3H).
Example 54
Amino acid 171: To solid amino acid 114 (4 mg, 0.015 mmol) was added 40% TFA in CH2CI2 (1 mL, cooled to 0°C prior to addition). After stirring st room tempersture for 1.5 h the resction mixture wss concentrated to give 3 white foam. Co-evsporstion from H2O seversl times followed by lyophilizstion gsve a white solid, 5.5 mg of 117 ss the TFA sslt. *H NMR (D20, 300 MHz): δ 6.85 (m, IH); 4.45 (m, IH); 4.05 (dd, IH, / = 11.4, 11.4 Hz); 3.65-3.55 (m, IH); 3.00-2.90 (m, IH); 2.60-2.45 (m, IH); 2.09 (s, 3H).
Exsmple 55
Acetonide 180: To 3 suspension of shikimic scid (25 g, 144 mmol, Aldrich) in methsnol (300 mL) wss sdded p-toluenesulfonic scid (274 mg, 1.44 mmol, 1 mol%) snd the mixture wss hested to reflux for 2h. After sdding more p-toluenesulfonic scid (1 mol%) the resction wss refluxed for 26h snd wss evsporated. The crude methyl ester (28.17 g) wss suspended in scetone (300 mL) snd wss trested with dimethoxypropsne (35 mL, 288 mmol) 3nd was stirred at room temperature for 6h and then was evsporated. The crude product W3S dissolved in ethyl acetate (400 mL) and was washed with sstursted NsHCθ3 (3X125 mL) snd sstursted NsCl. The orgsnic phsse wss dried (MgSO-i), filtered, snd evsporated to sfford crude scetonide 180 (~29.4 g) which wss used directly: *H NMR (CDCI3) δ 6.91 (t, IH, / = 1.1), 4.74 (t, IH, / = 4.8), 4.11 (t, IH, / = 6.9), 3.90 (m, IH), 2.79 (dd, IH, / = 4.5, 17.4), 2.25 (m, 2H), 1.44 (s, 3H), 1.40 (s, 3H). Example 56
Mesylate 130: To a solution of acetonide 180 (29.4 g, 141 mmol) in CH2CI2, (250 mL) at 0°C was added triethylamine (29.5 mL, 212 mmol) followed by the addition of methanesulfonyl chloride (13.6 mL, 176 mmol) over 3 period of 10 min. The resction wss stirred st 0°C for 1 h snd ice cold wster (250 mL) wss sdded. After transfer to a sepsratory funnel, the orgsnic phsse wss wsshed with wster, 5% citric scid (300 mL), sstursted N3HCO3 (300 mL) snd wss dried (MgSθ4), filtered, 3nd evsporated. The crude product wss filtered through s short plug of silics gel on a fritted glsss funnel eluting with ethyl scetste. The filtrate wss evaporated to afford mesylate 130 (39.5 g, 91%) as a viscous oil which was used directly in the next step: !H NMR (CDCI3) δ 6.96 (m, IH), 4.80 (m, 2H), 4.28 (dd, IH, / = 6.6, 7.5), 3.79 (s, 3H), 3.12 (s, 3H), 3.01 (dd, IH, / = 5, 17.7), 2.56-2.46 (m, IH).
Example 57
Diol 131: To a solution of mesylate 130 (35.85 g, 117 mmol) in methanol (500 mL) wss sdded p-toluenesulfonic acid (1.11 g, 5.85 mmol, 5 mol%) snd the solution was refluxed for 1.5 h and was evaporated. The residue was redissolved in methsnol (500 mL) snd wss refluxed 3n sdditionsl 4 h. The solvent wss evsporated snd the crude oil wss triturated with diethyl ether (250 mL). After completing the crystsllizstion overnight st 0°C, the solid wss filtered 3nd wss wsshed with cold diethyl ether, snd dried to sfford diol 131 (24.76 g) ss s white solid. Evsporation of the filtrate snd crystsllization of the residue from methsnol/ diethyl ether gsve 3n sdditionsl 1.55 g. Obtsined 26.3 g (85%) of diol 131: H NMR (CD3OD) δ 6.83 (m, IH), 4.86 (m, IH), 4.37 (t, IH, / = 4.2), 3.87 (dd, IH, / = 4.2, 8.4), 3.75 (s, 3H), 3.13 (s, 3H), 2.98-2.90 (m, IH), 2.53-2.43 (m, IH).
Exsmple 58
Epoxy alcohol 1: A suspension of diol 131 (20.78g, 78 mmol) in tetrahydrofuran (400 mL) at 0°C was treated with 1, 8- disz3bicyclo[5.4.0]undec-7-ene (11.7 mL, 78 mmol) snd wss stirred st room tempersture for 9 h st which time the resction wss complete. The resction wss evsporated snd the crude residue wss dissolved in CH2CI2 (200 mL) snd wss wsshed with sstursted NsCl (300 mL). The aqueous phase wss extracted with CH2CI2 (2X200 mL). The combined orgsnic extrscts were dried (MgSθ4), filtered, snd evsporated. The crude product wss purified on silics gel (ethyl scetste) to sfford epoxy slcohol 1 (12 g, 90%) ss a white solid whose *H NMR spectrum wss consistent with thst reported in the literature: McGowsn, D. A.; Berchtold, G. A., "J. Org. Chem.", 46:2381 (1981).
Example 59
Methoxymethyl ether 19 (PG=methoxymethyl): To a solution of epoxy alcohol 1 (4 g, 23.5 mmol) in CH2C12 (100 mL) was sdded N, N'- diisopropylethylamine (12.3 mL, 70.5 mmol) followed by chloromethyl methyl ether (3.6 mL, 47 mmol, distilled from tech. grade). The solution wss refluxed for 3.5 h snd the solvent wss evsporated. The residue wss psrtitioned between ethyl acetate (200 mL) and wster (200 mL). The squeous phsse wss extracted with ethyl scetste (100 mL). The combined orgsnic extrscts were wsshed with ssturated NsCl (100 mL), dried (MgSθ4), filtered, snd evsporated to sfford 4.9 g of a solid residue which wss of suitsble purity to use directly in the next step: mp 62-65°(crude); mp 64-66°C (diethyl ether/hexsne); iH NMR (CDCI3) δ 6.73 (m, IH), 4.87 (s, 2H), 4.59 (m, IH), 3.75 (s, 3H), 3.57 (m, IH), 3.48 (m overlspping s, 4H), 3.07 (dd, IH, / = 1.2, 19.8), 2.47 (dq, IH, / = 2.7, 19.5). Ethyl Ester Analog of Compound 19: To a solution of the corresponding ethyl ester of compound 1 ( 12.0g, 0.065 mol) in CH2CI2 (277 mL) at room tempersture wss sdded diisopropylethyl smine (34.0 mL, 0.13 mol) followed by chloromethyl methyl ether (10.0 mL, 0.19 mol). The resction mixture wss then gently refluxed for 2 h, cooled, concentrsted in vacuo, snd psrtitioned between EtOAc snd wster. The orgsnic lsyer wss sepsrsted snd wsshed successively with dil. HCl, sstursted bicsrb, brine snd dried over MgSθ4. Concentrstion in vacuo followed by flssh chromstogrsphy on silics gel (50% hexsnes in EtOAc) gsve 13.3 g (90%) of the corresponding ethyl ester of compound 19 ss s colorless liquid. *H NMR( 300 MHz, CDCI3) δ 6.73-6.71 (m, IH); 4.87 (s, 2H); 4.61-4.57 (m, IH); 4.21 (q, 2H, / = 7.2 Hz); 3.60-3.55 (m, IH); 3.50-3.45 (m, IH); 3.48 (s, 3H); 3.12-3.05 (m, IH); 2.52-2.42 (m, IH); 1.29 (t, 3H, / = 7.2 Hz).
Example 60 Alcohol 181: To a solution of methoxymethyl ether 19
(PG=methoxymethyl) (4.9 g, 22.9 mmol) in 8/l-MeOH/H20 (175 mL, v/v) was sdded sodium szide (7.44 g, 114.5 mmol) and ammonium chloride (2.69 g, 50.4 mmol) and the mixture was refluxed for 15 h. The reaction wss diluted with wster (75 mL) to dissolve precipitsted sslts snd the solution wss concentrsted to remove methsnol. The resulting squeous phsse contsining s precipitsted oily residue wss diluted to s volume of 200 mL with wster snd wss extracted with ethyl scetste (3X100 mL). The combined orgsnic extrscts were wsshed with sstursted NsCl (100 mL), dried (M Sθ4), filtered snd evsporated. The crude wss purified on silica gel (1/1-hexane/ ethyl scetste) to sfford slcohol 181 (5.09 g, 86%) ss s psle yellow oil. Subsequent prepsrations of alcohol 181 provided material which was of sufficient purity to use in the next step without further purification: lH NMR (CDCI3) δ 6.86 (m, IH), 4.79 (s, 2H), 4.31 (br t, IH, / = 4.2), 3.90-3.75, 3.77 (m overlspping s, 5H), 3.43 (s, 3H), 2.92 (d, IH, / = 6.6), 2.87 (dd, IH, / = 5.4, 18.6), 2.21-2.30 (m, IH).
Example 61
Mesylate 184: To a solution of alcohol 181 (6.47 g, 25.2 mmol) in CH2CI2 (100 mL) at 0°C was added first triethyl amine (4.4 mL, 31.5 mmol) then methanesulfonyl chloride (2.14 mL, 27.7 mmol). The resction wss stirred st 0°C for 45 min then wss wsrmed to room tempersture stirring for 15 min. The resction was evaporated and the residue was partitioned between ethyl acetste (200 mL) snd wster (100 mL). The orgsnic phsse wss wsshed with wster (100 mL), sstursted NsHCθ3 (100 mL), sstursted NsCl (100 mL). The wster wsshes were extracted with 3 single portion of ethyl scetste which wss wsshed with the ssme NsHCθ3/NsCl solutions. The combined orgsnic extrscts were dried (MgSθ4), filtered, snd evsporated. The crude product wss of suitsble purity to be used directly in the next step: *H NMR (CDC13) δ 6.85 (m, IH), 4.82 (d, IH, / = 6.9), 4.73 (d, IH, / = 6.9), 4.67 (dd, IH, / = 3.9, 9.0), 4.53 (br t, IH, / = 4.2), 3.78 (s, 3H), 3.41 (s, 3H), 3.15 (s, 3H), 2.98 (dd, IH, / = 6.0, 18.6), 2.37 (m, IH); 13C NMR (CDCI3) δ 165.6, 134.3, 129.6, 96.5, 78.4, 69.6, 55.8, 55.7, 52.1, 38.2, 29.1.
Exsmple 62
Aziridine 170: To s solution of mesylste 184 (8.56 g, 25 mmol) in THF (150 mL) 3t OX wss sdded Ph3P (8.2 g, 31 mmol), initially adding a third of the amount while cooling and then after removing the ice bath adding the remainder of the PI13P over a period of 10-15 min. After complete addition of the PI13P the reaction was stirred at room temperature for 3 h with the formation of a white precipitate. To this suspension was added triethyl amine (5.2 mL, 37.5 mmol) and wster (10 mL) snd the mixture wss stirred st room tempersture for 12 h. The resction was concentrated to remove THF snd the residue wss psrtitioned between CH2CI2 (200 mL) snd sstursted NsCl (200 mL). The aqueous phase was extracted with several portions of CH2CI2 3nd the combined orgsnic extrscts were dried (N32SU4), filtered, snd evsporsted to afford a crude product which was purified on silica gel (10% MeOH/EtOAc) to sfford sziridine 170 (4.18 g, 78%) as an oil which typically contsined trsce smounts of triphenylphosphine oxide impurity: *H NMR (CDCI3) δ 6.81 (m, IH), 4.78 (s, 2H), 4.54 (m, IH), 3.73 (s, 3H), 3.41 (s, 3H), 2.87 (spp dd, IH), 2.64 (br s, IH), 2.56-2.47 (m, 2H), NH signsl wss not sppsrent; 13C NMR (CDCI3) δ 166.9, 132.5, 128.0, 95.9, 69.5, 55.2, 51.6, 31.1, 27.7, 24.1.
Exsmple 63
Amine 182: To a solution of aziridine 170 (3.2 g, 15 mmol) in DMF (30 mL) was applied a vacuum on a rotary evaporator (40°C) for several minutes to degas the solution. To the solution was added sodium azide (4.9 g, 75 mmol) and ammonium chloride (1.6 g, 30 mmol) and the mixture was hested st 65-70°C for 21 h. The resction mixture wss cooled to room tempersture, diluted with ethyl acetate (~100 mL) and was filtered. The filtrate wss evsporsted snd the residue wss psrtitioned between diethyl ether (100 mL) snd sstursted NsCl (100 mL). The orgsnic phsse wss wsshed 3gsin with sstursted N3CI (100 mL), dried (MgSθ4), filtered, snd W3S evsporated. Additionsl crude product wss obtsined from the squeous wsshings by extrsction with ethyl scetste snd trested in the ssme msnner ss described sbove. The crude product wss purified on silics gel (5%MeOH/CH2θ2) to sfford smine 182 (2.95 g) ss sn oil which contsined a smsll smount of triphenylphosphine oxide impurity from the previous step: !H NMR (CDCI3) δ 6.82 (t, IH, / = 2.3), 4.81 (d, IH, / = 7.2), 4.77 (d, IH, / = 6.9), 4.09-4.04 (m, IH), 3.76 (s, 3H), 3.47 snd 3.44 (m overlspping s, 4H), 2.94- 2.86 (m, 2H), 2.36-2.24 (m, IH); 13c NMR (CDCI3) δ 165.9, 137.3, 128.2, 96.5, 79.3, 61.5, 55.7, 55.6, 51.9, 29.5.
Exsmple 64
N-Trityl aziridine 183: Amine 182 (2.59 g, 10.2 mmol) was dissolved in 5% HCl/MeOH (30 mL) and the solution was stirred for 3 h at room temperature. Additional 5% HCl/MeOH (10 mL) was added stirring 1 h and the solvent was evaporated to afford 2.52 g of the HCl salt as a tan solid after high V3cuum. To a suspension of the HCl sslt in CH2CI2 (50 mL) st 0°C wss sdded triethylsmine (3.55 mL, 25.5 mmol) followed by the sddition of solid trityl chloride (5.55 g, 12.8 mmol) in one portion. The mixture wss stirred st 0°C for 1 h snd then wss wsrmed to room temperature stirring for 2 h. The reaction was cooled to 0°C, triethylamine (3.6 mL, 25.5 mmol) was added 3nd methsne sulfonyl chloride (0.97 mL, 12.5 mmol) was added, stirring the resulting mixture for 1 h at 0°C and for 22 h at room temperature. The reaction wss evsporsted and the residue was partitioned between diethyl ether (200 mL) and water (200 mL). The organic phase was washed with wster (200 mL) snd the combined squeous phsses were extracted with diethyl ether (200 mL). The combined orgsnic extrscts were wsshed with wster (100 mL), sstursted NsCl (200 mL) snd were dried (Ns2Sθ4), filtered, 3nd evsporsted. The crude product wss purified on silics gel (1/1- hex3ne/CH2Cl2) to afford N-trityl aziridine 183 (3.84 g, 86%) as a white foam: IH NMR (CDCI3) δ 7.4-7.23 (m, 16H), 4.32 (m, IH), 3.81 (s, 3H), 3.06 (dt, IH, / = 1.8, 17.1), 2.94-2.86 (m, IH), 2.12 (m, IH), 1.85 (t, IH, / = 5.0). Example 65
Compound 190: A solution of N-trityl aziridine 183 (100 mg, 0.23 mmol), cyclohexanol (2 mL) 3nd boron trifluoride etherste (42 μL, 0.35 mmol) wss hested st 70°C for 1.25 h snd wss evsporsted. The residue wss dissolved in pyridine (2 mL) snd wss trested with scetic snhydride (110 μL, 1.15 mmol) snd cstslytic DMAP. After stirring for 3 h st room tempersture the resction wss evsporsted. The residue wss psrtitioned between ethyl scetste snd 5% citric scid. The squeous phsse wss extracted with ethyl scetste snd the combined orgsnic extrscts were wsshed with sstursted NsHCθ3, snd sstursted NsCl. The orgsnic phsse wss dried (MgSθ4), filtered, snd evsporsted. The crude product wss purified on silics gel (1/1- hexsne /ethyl scetste) to sfford compound 190 (53 mg, 69%) ss s solid: mp 105-107°C (ethyl scetste/hexane); iH NMR (CDCI3) δ 6.78 (m, IH), 6.11 (d, IH, / = 7.4), 4.61 (m, IH), 4.32-4.23 (m, IH), 3.76 (s, 3H), 3.44-3.28 (m, 2H), 2.85 (dd, IH, / = 5.7, 17.6), 2.28-2.17 (m, IH), 2.04 (s, 3H), 1.88-1.19 (m, 10H).
Exsmple 66
Compound 191: To s solution of compound 190 (49 mg, 0.15 mmol) in THF wss sdded triphenylphosphine (57 mg, 0.22 mmol) snd wster (270 μL) snd the solution wss hested 3t 50°C for 10 h. The resction wss evsporsted snd the residue W3S dissolved in ethyl scetste, dried (Ns2Sθ4), filtered snd evsporsted. The crude product was purified on silica gel (1/1- methsnol/ethyl scetste) to afford the amine (46 mg) as a pale yellow solid. The 3 solution of the amine in THF (1.5 mL) was added 1.039N KOH solution (217 μL) and water (200 μL). The mixture was stirred at room tempersture for 1 h snd wss then cooled to 0°C snd 3cidified to pH 6-6.5 with LR 120 ion exchange resin. The resin wss filtered, wsshed with methsnol snd the filtrate wss evsporsted. The solid residue wss dissolved in wster snd wss psssed through a column (4X1 cm) of C-18 reverse phsse silics gel eluting with wster snd then 2.5% scetonitrile/wster. Product fractions were combined snd evsporsted snd the residue wss dissolved in wster snd lyophilized to sfford amino acid 191 (28 mg ) as a white solid: !H NMR (D20) δ 6.47 (br s, IH), 4.80 (br d, IH), 4.00 (dd, IH, / = 8.9, 11.6), 3.59-3.50 (m, 2H), 2.87 (dd, IH, / = 5.5, 17.2), 2.06 (s, 3H), 1.90-1.15 (series of m, 10H); Anal. C3lcd for Ci5H24N2θ4»H2θ: C, 57.31; H, 8.34; N, 8.91. Found: C, 57.38; H, 8.09; N, 8.77. Exsmple 67 bis-Boc guanidino ester 201: Treated sccording to the procedure of Kim snd Qisn, "Tetrshedron Lett.", 34:7677 (1993). To a solution of smine 200 (529 mg, 1.97 mmol, prepsred by the method of Exsmple 109, bis-Boc thioures (561 mg, 2.02 mmol) snd Et3N (930 μL) in dry DMF (5.0 mL) cooled to 0°C wss sdded HgC-2 (593 mg, 2.18 mmol) in one portion. The heterogeneous resction mixture wss stirred for 45 min 3t 0°C snd then st room tempersture for 15 min, sfter which the resction wss diluted with EtOAc snd filtered through a psd of celite. Concentrstion in vαcuo followed by flssh chromstogrsphy of the residue on silics gel (10% hexsnes in ethyl scetste) gsve 904 mg (90%) of 201 ss a psle oil. :H NMR (CDC13, 300 MHz): δ 11.39 (s, IH); 8.63 (d, IH, / = 7.8 Hz); 6.89 (t, IH, / = 2.4 Hz); 6.46 (d, IH, / = 8.7 Hz); 4.43-4.32 (m, IH); 4.27-4.17 (m, IH); 4.13-4.06 (m, IH); 3.77 (s, 3H); 3.67- 3.59 (m, IH); 2.83 (dd, IH, / = 5.1, 17.7 Hz); 2.45-2.33 (m, IH); 1.95 (s, 3H); 1.65- 1.50 (m, 2H); 1.45 (s, 18H); 0.90 (t, 3H, / = 7.5 Hz).
Exsmple 68
Carboxylic acid 202: To a solution of methyl ester 201 (904 mg, 1.77 mmol) in THF (10 mL) wss sdded squeous KOH (3.45 mL of a 1.039 N solution). The reaction mixture was stirred at room temperature for 17 h, cooled to 0°C and acidified to pH 4.0 with Amberlite IR-120 (H+) acidic resin. The resin was filtered and washed with water and methanol. Concentration in vαcuo g3ve the free scid ss a psle fosm which was used without further purification in the next resction.
Exsmple 69 Guanidine carboxylic acid 203: To a solution of bis-Boc guanidnyl scid
202 (crude from previous resction) in CH2CI2 (40 mL) cooled to 0°C wss sdded nest trifluoroscetic scid (25 mL). The resction mixture wss stirred st 0°C for 1 h snd then st room tempersture for 2 h. Concentrstion in vαcuo gsve 3 psle orsnge solid which wss purified by Ci8 reverse phsse chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 495 mg (68%, 2 steps) of the gusnidine csrboxylic acid 203 as the trifluoroscetic acid salt. iH NMR (D2O, 300 MHz): δ 6.66 (s, IH); 4.29 (bd, IH, / = 9.0 Hz); 4.01 (dd, IH, / = 10.8, 10.8 Hz); 3.87-3.79 (m, IH); 3.76-3.67 (m, IH); 3.60-3.50 (m, IH); 2.83 (dd, IH, / = 5.1, 17.4 Hz); 2.47-2.36 (m, IH); 2.06 (s, 3H); 1.65-1.50 (m, 2H); 0.90 (t, 3H, / = 7.2 Hz). Anal. Cslcd for C15H23O N4F3: C, 43.69; H, 5.62; N, 13.59. Found: C, 43.29; H, 5.90; N, 13.78.
Figure imgf000316_0001
Formamidine carboxylic acid 204: A solution of amino acid 102 (25 mg, 0.10 mmol, prepared by the method of Example 110) in water (500 μL) st 0 - 5°C wss sdjusted to pH 8.5 with 1.0 N NsOH. Benzyl formimidste hydrochloride (45 mg, 0.26 mmol) wss sdded in one portion snd the resction mixture wss stirred for 3 h 3t this tempersture while msintsining the pH st 8.5 - 9.0 with 1.0 N NsOH. The resction wss then concentrsted in vacuo snd purified by Ci8 reverse phsse chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 4.0 mg (13%) of the formamidine carboxylic acid 204. IH NMR (D20, 300 MHz): δ 7.85 (s, IH); 6.53 (bd, IH, / = 7.8 Hz); 4.32-4.25 (bm, IH); 4.10-3.97 (m, IH); 3.76- 3.67 (m, 2H); 3.57-3.49 (m, IH); 2.86-2.81 (m, IH); 2.55-2.40 (m, IH); 2.04 (s, 3H); 1.65-1.50 (m, 2H); 0.90 (t, 3H, / = 7.4 Hz). Example 71
Amino acid 206: To a solution of amino methyl ester 205 (84 mg, 0.331 mmol, prepared by Example 107) in THF (1.0 mL) was added aqueous KOH (481 μL of a 1.039 N solution). The resction mixture wss stirred st room tempersture for 2.5 h snd scidified to pH 6.5 with Amberlite IR-120 (H+) scidic resin. The resin wss filtered snd wsshed with wster snd methsnol. Concentrstion in vacuo gsve the amino acid as a white solid which was purified by Ci8 reverse phase chromatography eluting with water. Fractions contsining the desired product were pooled snd lyophilized to give 59 mg (74%) of the amino acid 206. iH NMR (CD3OD, 300 MHz): δ 6.60 (bd, IH, / = 1.8 Hz); 4.01-3.95 (m, IH); 3.71-3.60 (m, 2H); 3.50-3.42 (m, IH); 3.05-2.85 (m, 2H); 2.39-2.28 (m, IH); 1.70-1.55 (m, 2H); 0.95 (t, 3H, / = 7.5 Hz).
Example 72
Trifluoroacetamide 207: To a degsssed solution of smino scid 206 (59 mg, 0.246 mmol) in dry methsnol (1.0 mL) under srgon wss sdded Et3N (35 μL) followed by methyl trifluoroscetste (35 μL). The resction wss stirred for one week st room tempersture snd concentrsted. Anslysis by ^H NMR showed thst resction wss 40% complete. The crude resction product wss redissolved in dry methsnol (1.0 mL), methyl trifluoroscetste (1.0 mL) snd Et3N (0.5 mL) snd stirred st room tempersture for 5 dsys. The resction wss then concentrsted in vacuo and dissolved in 50% aqueous THF (2.0 mL), scidified to pH 4 with Amberlite IR-120 (H+) acidic resin and filtered. Concentrstion gsve the crude trifluoroacetsmide csrboxylic scid which wss used without further purificstion for the next resction.
Exsmple 73 Amino acid 208: A solution of azide 207 (crude from previous resction) in THF (2.0 mL) snd wster (160 μL) wss trested with polymer supported triphenyl phosphine (225 mg) st room tempersture. After stirring for 20 h the polymer wss filtered snd wsshed with methsnol. Concentrstion in vacuo gsve s psle solid which wss purified by Cis reverse phsse chromstography eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 6.5 mg (9 %) of the trifluoroscetsmide amino acid 208. iH NMR (D20, 300 MHz): δ 6.59 (bs, IH); 4.40-4.30 (m, IH); 4.26 (t, IH, / = 10.1 Hz); 3.80-3.66 (m, 2H); 3.56-3.47 (m, IH); 2.96 (bdd, IH, / = 5.4, 17.7 Hz); 2.58-2.45 (m, IH); 1.62 - 1.50 (m, 2H); 0.89 (t, 3H, / = 7.5 Hz).
Example 74
Methylsulfonamide methyl ester 209: Methanesulfonyl chloride (19 μL) wss sdded to s solution of smine 205 (58 mg, 0.23 mmol, prepsred by Exsmple 107), Et3N (97 μL) snd s cstslytic 3mount of DMAP (few crystsls) in CH2CI2 (1.0 mL) st 0°C. After 30 min the resction mixture wss wsrmed to room tempersture 3nd stirred for sn sdditionsl 1 h. Concentrstion in vacuo followed by flssh chromstogrsphy of the residue on silics gel (50% hexsnes in ethyl scetste) gsve 61 mg (79%) of the sulfonamide 209. !H NMR (CDCI3, 300 MHz): δ 6.87 (t, IH, / = 2.3 Hz); 5.08 (d, IH, / = 7.5 Hz); 4.03-3.90 (m, IH); 3.78 (s, 3H); 3.75-3.45 (m, 4H); 3.14 (s, 3H); 2.95 (dd, IH, / = 5.2, 17.3 Hz); 2.42- 2.30 (m, IH); 1.75-1.55 (m, 2H); 0.95 (t, 3H, / = 7.5Hz).
Example 75
Amino ester 210: A solution of szide 209 (61 mg, 0.183 mmol) in THF (2.0 mL) snd wster (118 μL) wss trested with polymer supported triphenyl phosphine (170 mg) at room temperature. After stirring for 17.5 h the polymer was filtered and washed with methanol. Concentration in vacuo followed by flash chromstogrsphy of the residue through s short silics gel column (100% methsnol) gsve 45 mg (80%) of the smino ester 210 3S s psle foam. IH NMR (CDCI3, 300 MHz): δ 6.85 (s, IH); 3.94 (bd, IH, / = 7.8 Hz); 3.77 (s, 3H); 3.74-3.60 (m, 2H); 3.55-3.45 (m, IH); 3.25-3.15 (m, IH); 3.11 (s, 3H); 2.94- 2.85 (m, IH); 2.85 (bs, 2H); 2.22-2.10 (m, IH); 1.70-1.56 (m, 2H); 0.94 (t, 3H, / = 7.5 Hz).
Exsmple 76
Amino acid 211: A solution of methyl ester 210 (21 mg, 0.069 mmol) in THF (200 μL) was treated with aqueous KOH (135 μL of a 1.039 N solution). The resction mixture wss stirred st room tempersture for 40 min snd neutralized to pH 7.0 with Amberlite IR-120 (H+) acidic resin. The resin was filtered snd wsshed with wster snd methsnol. Concentrstion in vacuo gsve the smino scid 3S s psle solid which wss purified by Ci8 reverse phsse chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 3.5 mg (17%) of the smino scid 211. H NMR (D20, 300 MHz): δ 6.60 (d, IH, / = 1.8 Hz); 4.30-4.20 (m, IH); 3.84-3.75 (m, IH); 3.68-3.58 (m, IH); 3.60-3.40 (m, 2H); 3.20 (s, 3H); 2.96-2.88 (m, IH); 2.55-2.45 (m, IH); 1.72-1.59 (m, 2H); 0.93 (t, 3H, / = 7.4 Hz). Example 77
Bis-Boc guanidino ester 212: Treated according to the procedure of Kim and Qisn, "Tetrshedron Lett." 34:7677 (1993). To s solution of smine 210 (31 mg, 0.101 mmol), bis-Boc thioures (28.5 mg, 0.103 mmol) snd Et3N (47 μL) in dry DMF (203 μL) cooled to 0°C wss sdded HgCl2 (30 mg, 0.11 mmol) in one portion. The heterogeneous resction mixture was stirred for 30 min at 0°C snd then at room temperature for 30 min, after which the resction wss diluted with EtOAc snd filtered through a pad of celite. Concentration in vacuo followed by flash chromatography of the residue on silica gel (40% hexsnes in ethyl scetste) gsve 49 mg (89%) of 212 ss a psle oil. IH NMR (CDC13, 300 MHz): δ 11.47 (s, IH); 8.66 (d, IH, / = 8.4 Hz); 6.87 (s, IH); 6.01 (bs, IH); 4.50-4.35 (m, IH); 4.04 (bd, IH, / = 8.4 Hz); 3.76 (s, 3H); 3.70-3.60 (m, IH); 3.53-3.45 (m, 2H); 3.02 (s, 3H); 2.85 (dd, IH, / = 5.3, 17.3 Hz); 2.42-2.30 (m, IH); 1.66-1.55 (m, 2H); 1.49 (s, 9H); 1.48 (s, 9H); 0.93 (t, 3H, / = 7.3 Hz).
Exsmple 78 Carboxylic acid 213: To a solution of methyl ester 212 (49 mg, 0.090 mmol) in THF (1.0 mL) was added aqueous KOH (260 μL of a 1.039 N solution). The resction mixture wss stirred st room tempersture for 16 h, cooled to 0°C snd scidified to pH 4.0 with Amberlite IR-120 (H+) scidic resin. The resin wss filtered snd wsshed with water and methanol. Concentrstion in vαcuo gsve the free scid ss s psle fosm which wss used without further purificstion in the next reaction.
Example 79
Guanidine carboxylic acid 214: To a solution of bis-Boc guanidnyl scid 213 (crude from previous resction) in CH2CI2 (2.0 mL) cooled to 0°C wss sdded nest trifluoroscetic 3cid (2.0 mL). The resction mixture wss stirred st 0°C for 1 h snd then 3t room tempersture for 1 h. Concentrstion in vacuo gsve 3 psle orange solid which wss purified by Ci8 reverse phsse chromstography eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 10 mg (25%, 2 steps) of the gusnidine csrboxylic scid 214. iH NMR (D20, 300 MHz): δ 6.60 (bs, IH); 4.22 (bd, IH, / = 9.0 Hz); 3.82-3.66 (m, 2H); 3.65-3.54 (m, IH); 3.43 (bt, IH, / = 9.9 Hz); 3.15 (s, 3H); 2.82 (dd, IH, / = 5.0, 17.5 Hz); 2.48-2.30 (m, IH); 1.71-1.58 (m, 2H); 0.93 (t, 3H, / = 7.3 Hz).
Exsmple 80 Propionamide methyl ester 215: Propionyl chloride (96 μL, 1.1 mmol) was added to a solution of amine 205 (178 mg, 0.70 mmol, prepared by Exsmple 107) snd pyridine (1.5 mL) in CH2CI2 (2.0 mL) cooled to 0°C. After 30 min st 0°C the resction wss concentrsted snd psrtitioned between ethyl scetste snd brine. The orgsnic lsyer wss sepsrated and washed sequentislly with sstursted sodium bicsrbonste, brine 3nd dried over MgSθ4.
Concentrstion in vacuo followed by flssh chromatography of the residue on silica gel (40% hexsnes in ethyl scetste) gsve 186 mg (86%) of the propionsmide methyl ester 215 ss a pale yellow solid. l NMR (CDCI3, 300 MHz): δ 6.86 (t, IH, / = 2.3 Hz); 5.72 (bd, IH, / = 7.8 Hz); 4.52-4.49 (m, IH); 4.25- 4.15 (m, IH); 3.77 (s, 3H); 3.65-3.37 (complex m, 3H); 2.87 (dd, IH, / = 5.7, 17.7 Hz); 2.28 (q, 2H, / = 7.5 Hz); 2.25-2.20 (m, IH); 1.65-1.50 (m, 2H); 1.19 (t, 3H, / = 7.5 Hz); 0.92 (t, 3H, / = 7.5 Hz).
Example 81
Amino methyl ester 216: A solution of azide 215 (186 mg, 0.60 mmol) in THF (5.0 mL) and water (400 μL) was treated with polymer supported triphenyl phosphine (560 mg) at room temperature. After stirring for 21 h the polymer was filtered and washed with methanol. Concentrstion in vacuo gsve the crude amino ester 216 which was used without any further purification for the next step. Example 82 Amino acid 217: A solution of methyl ester 216 (crude from previous reaction) in THF (500 μL) was treated with squeous KOH (866 μL of s 1.039 N solution). The resction mixture wss stirred st room tempersture for 3 h snd neutralized to pH 7.0 with Amberlite IR-120 (H+) acidic resin. The resin was filtered 3nd wsshed with wster snd methsnol. Concentrstion in vacuo gsve the smino scid ss a psle solid which wss purified by Ci8 reverse phsse chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 49 mg (31% 2 steps) of the smino scid 217. iH NMR (D20, 300 MHz): δ 6.54 (s, IH); 4.25 (bd, IH, / = 8.7 Hz); 4.13 (dd, IH, / = 9.0, 11.3 Hz); 3.74-3.60 (m, IH); 3.61-3.40 (m, 2H); 2.85 (dd, IH, / = 5.9, 17.1 Hz); 2.55-2.40 (m, IH); 2.35 (q, 2H, / = 7.5 Hz); 1.65-1.45 (m, 2H); 1.13 (t, 3H, / = 7.5 Hz); 0.88 (t, 3H, / = 7.5 Hz).
Exsmple 83
(mono methyl) bis-Boc guanidino ester 218: To a solution of amine 200 (51 mg, 0.19 mmol) snd mono methyl bis-Boc thioures (36 mg, 0.19 mmol) in dry DMF (1.0 mL) , wss sdded l-(3-Dimethylsminopropyl)-3- ethylcsrbodiimide hydrochloride (38 mg) snd Et3N (56 μL) st room tempersture. After 1.5 h st room tempersture HgCl2 (-75 mg, excess) wss sdded in one portion. The heterogeneous resction mixture wss stirred for 45 min, diluted with ethyl acetate and filtered through a pad of celite. The filtrate wss diluted with sdditionsl ethyl scetste snd wsshed with dilute HCl, sstursted sodium bicsrbonste, brine snd dried over MgSθ4. Concentrstion in vαcuo followed by flssh chromatography of the residue on silica gel (10% methanol in ethyl acetate) gave 13 mg (16%) of the (mono methyl) bis-Boc gusnidino ester 218 ss s colorless fosm. iH NMR (CDCI3, 300 MHz): δ 6.84 (s, IH); 6.20 (bd, IH, / = 5.1 Hz); 5.45 (bs, IH); 4.25-4.40 (bm, IH); 4.20-4.05 (bm, 2H); 3.76 (s, 3H); 3.60-3.50 (m, IH); 3.43-3.30 (m, IH); 2.90 (dd, IH, / = 5.4, 17.7 Hz); 2.77 (d, 3H, / = 4.8 Hz); 2.35-2.25 (m, IH); 1.96 (s, 3H); 1.60-1.50 (m, 2H); 1.47 (s, 9H); 0.91 (t, 3H, / = 7.2 Hz). Exsmple 84
(mono methyl) bis-Boc guanidino acid 219: To a solution of methyl ester 218 (13 mg, 0.031 mmol) in THF (500 μL) was added aqueous KOH (60 μL of a 1.039 N solution). The resction mixture wss stirred st room tempersture for 1 h snd then gently refluxed for 1 h. The resction wss cooled to 0°C snd scidified to pH 6.0 with Amberlite IR-120 (H+) scidic resin. The resin wss filtered and washed with water and methanol. Concentrstion in vacuo gsve the free scid 219 which wss used without further purificstion in the next resction.
Exsmple 85
(mono methyl) guanidino amino acid 220: To a solution of (mono methyl) bis-Boc gusnidnyl scid 219 (crude from previous resction) in CH2CI2 (1.0 mL) cooled to 0°C wss sdded nest trifluoroscetic scid (1.0 mL). The resction mixture wss stirred st 0°C for 1 h snd then st room tempersture for 1 h. Concentrstion in vacuo gsve s psle solid which wss purified by Cl8 reverse phsse chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 4.4 mg (33%, 2 steps) of the gusnidine csrboxylic scid 220. iH NMR (D20, 300 MHz): δ 6.52 (bs, IH); 4.27 (bd, IH, / = 8.4 Hz); 4.01 (dd, IH, / = 9.2, 10.3 Hz); 3.86-3.75 (m, IH); 3.75- 3.67 (m, IH); 3.60-3.49 (m, IH); 2.85 (s, 3H); 2.80 (dd, IH, / = 5.1, 17.7 Hz); 2.47- 2.37 (m, IH); 2.04 (s, 3H); 1.64-1.50 (m, 2H); 0.90 (t, 3H, / = 7.2 Hz). Exsmple 86
(R)-methyl propyl ester 221: BF3»Et2θ (63 μL, 0.51 mmol) wss sdded to s solution of N-trityl aziridine 183 (150 mg, 0.341 mmol) in (R)-(-)-2- butsnol (1.2 mL) under srgon with stirring st room tempersture. The psle solution wss hested st 70°C for 2 h snd then concentrsted in vacuo to give a brown residue which was dissolved in dry pyridine (2.0 mL) and treated with acetic anhydride (225 μL) and a catalytic amount of DMAP (few crystals) 3t 0°C. The resction wss sllowed to wsrm to room tempersture snd stirred for 2 h, concentrated in vacuo and partitioned between ethyl acetste snd brine. The orgsnic lsyer wss sepsrsted snd wsshed sequentislly with dilute HCl, saturated sodium bicarbonate, brine and dried over MgSθ4.
Concentration in vacuo followed by flash chromatography of the residue on silica gel (50% hexanes in ethyl acetste) gsve 75 mg (72%) of the (R)-methyl propyl ester 221 ss a pale solid. H NMR (CDCI3, 300 MHz): δ 6.79 (t, IH, / = 2.2 Hz); 6.14 (d, IH, / = 7.3 Hz); 4.55 (bd, IH, / = 8.7 Hz); 4.33-4.23 (m, IH); 3.77 (s, 3H); 3.56-3.45 (m, IH); 3.40-3.27 (m, IH); 2.85 (dd, IH, / = 5.5, 17.5 Hz); 2.30- 2.15 (m, IH); 2.04 (s, 3H); 1.5901.40 (m, 2H); 1.10 (d, 3H, / = 6.0 Hz); 0.91 (t, 3H, / = 7.4 Hz).
Exsmple 87
(R)-methyl propyl amino ester 222: PI13P (95 mg, 0.36 mmol) was sdded in one portion to s solution of szide 221 (75 mg, 0.24 mmol) snd wster (432 μL) in THF (3.0 mL). The psle yellow solution was then heated at 50°C for 10 h, cooled 3nd concentrsted in vacuo to give s psle solid. Purificstion by flssh chromstogrsphy on silics gel (50% methsnol in ethyl scetste) gsve 66 mg (97%) of the smino ester 222 ss a pale solid. Example 88
Amino acid 223: A solution of methyl ester 222 (34 mg, 0.12 mmol) in THF (1.0 mL) was trested with squeous KOH (175 μL of s 1.039 N solution). The resction mixture wss stirred st room tempersture for 3 h snd scidified to pH 6.0 with Amberlite IR-120 (H+) scidic resin. The resin wss filtered snd wsshed with wster snd methsnol. Concentrstion in vacuo gsve the smino scid ss s psle solid which wss purified by Cis reverse phsse chromstogrsphy eluting with wster. Fractions containing the desired product were pooled and lyophilized to give 11.5 mg (36%) of the smino scid 223. !H NMR (D2O, 300 MHz): δ 6.52 (bs, IH); 4.28 (bd, IH, / = 8.7 Hz); 4.04 (dd, IH, / = 8.8, 11.5 Hz); 3.74-3.65 (m, IH); 3.50-3.60 (m, IH); 2.90 (dd, IH, / = 5.5, 17.2 Hz); 2.50-2.40 (m, 1H0; 2.10 (s, 3H); 1.60-1.45 (m, 2H); 1.14 (d, 3H, / = 6.2 Hz); 0.91 (t, 3H, / = 7.4 Hz).
Exsmple 89 bis-Boc guanidino ester 224: Treated sccording to the procedure of Kim and Qian, "Tetrshedron Lett.", 34:7677 (1993). To a solution of amine 222 (32 mg, 0.113 mmol), bis-Boc thiourea (32 mg, 0.115 mmol) and Et3N (53 μL) in dry DMF (350 μL) cooled to 0°C was added HgC-2 (34 mg, 0.125mmol) in one portion. The heterogeneous reaction mixture was stirred for 45 min at 0°C and then at room temperature for 1 h, after which the reaction was diluted with EtOAc and filtered through a pad of celite. Concentration in vacuo followed by flash chromatography of the residue on silics gel (20% hexsnes in ethyl scetste) gsve 57 mg (96%) of 224 ss s colorless fosm. iH NMR (CDCI3, 300 MHz): δ 11.40 (s, IH); 8.65 (d, IH, / = 7.8 Hz); 6.82 (s, IH); 6.36 (d, IH, / = 8.7 Hz); 4.46-4.34 (m, IH); 4.20-4.10 (m, IH); 4.10-3.95 (m, IH); 3.76 (s, 3H); 2.79 (dd, IH, / = 5.4, 17.7 Hz); 2.47-2.35 (m, IH); 1.93 (s, 3H); 1.60- 1.45 (m, 2H); 1.49 (s, 18H); 1.13 (d, 3H, / = 6.0 Hz); 0.91 (t, 3H, / = 7.5 Hz).
Exsmple 90
Carboxylic acid 225: To a solution of methyl ester 224 (57 mg, 0.11 mmol) in THF (1.5 mL) was added aqueous KOH (212 μL of 3 1.039 N solution). The resction mixture wss stirred st room tempersture for 16 h, cooled to 0°C and acidified to pH 4.0 with Amberlite IR-120 (H+) acidic resin. The resin wss filtered snd wsshed with wster and methanol. Concentrstion in vacuo gsve the free scid 3S s psle fosm which was used without further purification in the next reaction. Example 91
Guanidine carboxylic acid 226: To a solution of bis-Boc gusnidnyl scid 225 (crude from previous resction) in CH2CI2 (4.0 mL) cooled to 0°C wss sdded nest trifluoroscetic scid (4.0 mL). The resction mixture wss stirred 3t 0°C for 1 h snd then st room tempersture for 2 h. Concentrstion in vacuo gsve s psle orsnge solid which wss purified by Cis reverse phsse chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 18.4 mg (40%, 2 steps) of the gusnidine csrboxylic scid 226. l NMR (D20, 300 MHz): δ 6.47 (s, IH); 4.28 (bd, IH, / = 8.4 Hz); 3.93-3.74 (m, 2H); 3.72-3.63 (m, IH); 2.78 (dd, IH, / = 4.8, 17.4 Hz); 2.43-2.32 (m, IH); 1.58-1.45 (m, 2H); 1.13 (d, 3H, / = 6.0 Hz); 0.90 (t, 3H, / = 7.4 Hz).
Exsmple 92
(Diethyl) methyl ether ester 227: BF3«Et2θ (6.27 mL, 51 mmol) wss 3dded to a solution of N-trityl sziridine 183 (15 g, 34 mmol) in 3-pent3nol (230 mL) under srgon with stirring st room temperature. The pale solution was hested st 70-75°C for 1.75 h snd then concentrated in vαcuo to give a brown residue which was dissolved in dry pyridine (2.0 mL) and treated with acetic anhydride (16 mL, 170 mmol) and a catalytic amount of DMAP 200 mg. The reaction was stirred at room temperature for 18 h, concentrated in vαcuo and partitioned between ethyl acetste snd 1M HCl. The orgsnic lsyer wss sepsrated snd wsshed sequentislly with saturated sodium bicarbonste, brine snd dried over MgSθ4. Concentration in vαcuo followed by flash chromstogrsphy of the residue on silics gel (50% hexsnes in ethyl scetste) gsve 7.66 g of the (Diethyl) methyl ether ester which wss recrystsllized from ethylscetate/hexane to afford 227 (7.25 g, 66%) as colorless needles: IH NMR (CDCI3, 300 MHz): δ 6.79 (t, IH, / = 2.1 Hz); 5.92 (d, IH, / = 7.5 Hz); 4.58 (bd, IH, / = 8.7 Hz); 4.35-4.25 (m, IH); 3.77 (s, 3H); 3.36-3.25 (m, 2H); 2.85 (dd, IH, / = 5.7, 17.4 Hz); 2.29-2.18 (m, IH); 2.04 (s, 3H); 1.60-1.45 (m, 4H); 0.91 (t, 3H, / = 3.7 Hz); 0.90 (t, 3H, / = 7.3 Hz).
Exsmple 93 (Diethyl) methyl ether amino ester 228: Ph3P (1.21 g, 4.6 mmol) was sdded in one portion to a solution of szide 227 (1 g, 3.1 mmol) snd wster (5.6 mL) in THF (30 mL). The psle yellow solution wss then hested st 50°C for 10 h, cooled and concentrated in vαcuo . The squeous oily residue wss psrtitioned between EtOAc snd sstursted NsCl. The orgsnic phsse wss dried (MgSθ4), filtered, 3nd evsporsted. Purificstion by flssh chromstogrsphy on silics gel (50% methsnol in ethyl scetste) gsve 830 mg (90%) of the smino ester 228 ss a pale white solid. *H NMR (CDC13, 300 MHz): δ 6.78 (t, IH, / = 2.1 Hz); 5.68 (bd, IH, / = 7.8 Hz); 4.21-4.18 (m, IH); 3.75 (s, 3H); 3.54-3.45 (m, IH); 3.37-3.15 (m, 2H); 2.74 (dd, IH, / = 5.1, 17.7 Hz); 2.20-2.07 (m, IH); 2.03 (s, 3H); 1.69 (bs, 2H, -NH2); 1.57-1.44 (m, 4H); 0.90 (t, 3H, / = 7.5 Hz); 0.89 (t, 3H, / = 7.5 Hz).
Example 94
Amino acid 229: A solution of methyl ester 228 (830 mg, 2.8 mmol) in THF (15 mL) was treated with squeous KOH (4 mL of a 1.039 N solution). The reaction mixture was stirred at room temperature for 40 min snd scidified to pH 5.5-6.0 with Dowex 50WX8 scidic resin. The resin wss filtered snd wsshed with wster snd methsnol. Concentrstion in vαcuo gsve the smino 3cid 3S a psle solid which wss purified by Cis reverse phsse chromstography eluting with wster and then with 5% CH3CN/water. Fractions contsining the desired product were pooled snd lyophilized to give 600 mg (75%) of the amino acid 229. iH NMR (D20, 300 MHz): δ 6.50 (t, IH, / = 2.1 Hz); 4.30-4.26 (m, IH); 4.03 (dd, IH, / = 9.0, 11.7 Hz); 3.58-3.48 (m, 2H); 2.88 (dd, IH, / = 5.4, 16.8 Hz); 2.53-2.41 (m, IH); 1.62-1.40 (m, 4H); 0.90 (t, 3H, / = 7.5 Hz); 0.85 (t, 3H, / = 7.5 Hz).
Example 95 t-amyl ether ester 230: BF3»Et2θ (43 μL, 0.35 mmol) was added to 3 solution of N-trityl sziridine 183 (104 mg, 0.24 mmol) in t-amyl slcohol (2.5 mL) under srgon with stirring 3t room tempersture. The psle solution wss hested st 75°C for 3 h snd then concentrsted in vαcuo to give a brown residue which was dissolved in dry pyridine (2.0 mL) and treated with acetic snhydride (250 μL) snd a catalytic amount of DMAP (few crystals). The resction wss stirred st room tempersture for 1.5 h, concentrsted in vαcuo 3nd psrtitioned between ethyl acetate and brine. The organic layer wss sepsrsted snd wsshed sequentislly with dilute HCl, sstursted sodium bicsrbonste, brine snd dried over MgSθ4. Concentrstion in vαcuo followed by flssh chromstogrsphy of the residue on silics gel (50% hexsnes in ethyl scetste) gsve 27 mg (35%) of the t-smyl ether ester 230 ss s psle orsnge oil. H NMR (CDC13, 300 MHz): δ 6.72 (t, IH, / = 2.1 Hz); 5.83 (d, IH, / = 7.2 Hz); 4.71 (bd, IH, / = 8.1 Hz); 4.45-4.35 (m, IH); 3.75 (s, 3H); 3.27-3.17 (m, IH); 2.84 (dd, IH, / = 5.7, 17.4 Hz); 2.27-2.15 (m, IH); 2.05 (s, 3H); 1.57-1.47 (m, 2H); 1.19 (s, 3H); 1.15 (s, 3H); 0.90 (t, 3H, / = 7.5 Hz).
Exsmple 96 t-amyl ether amino ester 231: PI13P (35 mg, 0.133 mmol) was 3dded in one portion to a solution of szide 230 (27 mg, 0.083 mmol) snd wster (160 μL) in THF (1.5 mL). The psle orsnge solution was then heated at 50°C for 10 h, cooled and concentrsted in vαcuo to give a psle solid. Purificstion by flssh chromstogrsphy on silics gel (50% methsnol in ethyl acetate) gave 20 mg (82%) of the amino ester 231 as a pale oil.
Example 97 Amino acid 232: A solution of methyl ester 231 ( 20 mg, 0.068 mmol) in THF (1.0 mL) was treated with aqueous KOH (131 μL of a 1.039 N solution). The reaction mixture was stirred at room temperature for 2.5 h snd scidified to pH 5.0 with Amberlite IR-120 (H+) acidic resin. The resin was filtered snd wsshed with wster snd methsnol. Concentrstion in vαcuo gsve the smino scid ss a psle solid which wss purified by Cis reverse phsse chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 8.6 mg (45%) of the smino scid 232. IH NMR (D20, 300 MHz): δ 6.47 (bs, IH); 4.42 (bd, IH, / = 8.1 Hz); 3.97 (dd, IH, / = 8.4, 11.4 Hz); 3.65-3.54 (m, IH); 2.88 (dd, IH, / = 5.5, 17.3 Hz); 2.51- 2.39 (m, IH); 2.08 (s, 3H); 1.61-1.46 (m, 2H); 1.23 (s, 3H); 1.18 (s, 3H), 0.86 (t, 3H, / = 7.5 Hz).
Example 98 n-Propyl thio ether ester 233: BF3*Et2θ (130 μL, 1.06 mmol) was sdded to s solution of N-trityl aziridine 183 (300mg, 0.68 mmol) in 1-propanethiol (8.0 mL) under srgon with stirring st room tempersture. The psle solution wss then hested st 65°C for 45 min, concentrsted snd psrtitioned between ethyl scetste snd brine. The orgsnic lsyer wss sepsrsted snd wsshed with ssturated sodium bicsrbonate, brine and dried over MgSθ4. Concentration in vαcuo followed by flssh chromatography of the residue on silica gel (30% hexsnes in ethyl scetste) gsve 134 mg (73%) of the n-propyl thio ether ester 233 3S 3 psle oil. lH NMR (CDC13, 300 MHz): δ 6.87 (t, IH, / = 2.4 Hz); 3.77 (s, 3H); 3.48-3.38 (m, IH); 3.22-3.18 (m, IH), 2.93 (dd, IH, / = 5.4, 17.4 Hz); 2.80 (t, IH, / = 9.9 Hz); 2.51 (t, 2H, / = 7.2 Hz); 2.32-2.20 (m, IH); 1.96 (bs, 2H, -NH2), 1.69-1.56 (m, 2H); 1.00 (t, 3H, / = 7.2 Hz). Example 99 n-Propyl thio ether azido ester 234: To a solution of amine 233 (134 mg, 0.50 mmol) in pyridine (1.5 mL) cooled to 0°C was added nest scetyl chloride (60 μL, 0.84 mmol). After stirring for 1 h the resction mixture wss wsrmed to room tempersture and stirred for an additionsl 15 min. The resction wss concentrsted and partitioned between ethyl acetate and brine and wsshed sequentislly with dilute HCl, wster, sstursted sodium bicsrbonste, brine snd dried over MgSθ4. Concentrstion in vacuo followed by flssh chromstogrsphy of the residue on silics gel (30% hexsnes in ethyl scetste) gsve 162 mg (100%) of the n-Propyl thio ether szido ester 234 ss a psle yellow solid. lU NMR (CDC13, 300 MHz): δ 6.90 (t, IH, / = 2.7 Hz); 5.87 (bd, IH, / = 7.8 Hz); 4.07-3.98 (m, IH); 3.77 (s, 3H); 3.65-3.55 (m, IH); 2.95-2.85 (m, IH); 2.60-2.45 (m, 2H); 2.30-2.18 (m, IH); 2.08 (s, 3H); 1.65-1.53 (m, 2H); 0.98 (t, 3H, / = 7.2 Hz).
Example 100 π-Propyl thio ether amino ester 235: The azide 234 (130 mg, 0.416 mmol) in ethyl acetate (10 mL) was hydrogensted (1 stmosphere) over Lindlsr's cstslyst (150 mg) for 18 h at room temperature. The cstslyst wss then filtered through a celite pad snd washed with hot ethyl scetste snd methsnol. Concentrstion in vαcuo followed by flssh chromstogrsphy of the orsnge residue gsve 62 mg (53%) of the n-propyl thio ether amino ester 235. IH NMR (CDC13, 300 MHz): δ 6.88 (t, IH, / = 2.7 Hz); 5.67 (bd, IH, / = 8.7 Hz); 3.76 (s, 3H); 3.75-3.65 (m, IH); 3.45-3.35 (bm, IH); 3.05-2.95 (m, IH); 2.87-2.78 (m, IH); 2.56-2.40 (m, 2H); 2.18-2.05 (m, IH); 2.09 (s, 3H); 1.65-1.50 (m, 2H); 1.53 (bs, 2H, -NH2); 0.98 (t, 3H, / = 7.2 Hz). Example 101
Compound 240: A suspension of Quinic acid (103 g), 2,2- dimethoxypropsne (200 mL) and toluenesulfonic acid (850 mg) in acetone (700 mL) was stirred st room tempersture for 4 dsys. Solvents snd excess resgents were removed under reduced pressure. Purificstion by flssh column chromstogrsphy (Hexsnes/EtOAc = 2/1-1.5/1) gsve Isctone 240 (84 g, 73%): XH NMR (CDCI3) δ 4.72 (dd, J = 2.4, 6.1 Hz, 1 H), 4.50 (m, 1 H), 4.31 (m, 1 H), 2.67 (m, 2 H), 2.4-2.2 (m, 3 H), 1.52 (s, 3 H), 1.33 (s, 3 H). Performing the resction st reflux temperstures for 4 h sfforded lactone 240 in 71% yield after aqueous work-up (ethyl acetate/wster partition) and recrystallization of the crude product from ethyl scetste/hexsne.
Exsmple 102
Compound 241: To s solution of Isctone 240 (43.5 g, 203 mmol) in methsnol (1200 mL) wss sdded sodium methoxide (4.37 M, 46.5 ml, 203 mmol) in one portion. The mixture wss stirred st room temperature for 3 hrs, snd quenched with scetic scid (11.62 mL). Methsnol wss removed under reduced pressure. The mixture wss diluted with wster, snd extracted with EtOAc (3x). The combined orgsnic phsse was washed with water (lx) and brine (lx), and dried over MgSθ4. Purification by flash column chromtography (Hexanes/ EtOAc = 1/1 to 1/4) gave diol (43.4g, 87%): *H NMR (CDCI3) δ 4.48 (m, 1 H), 4.13 (m, 1 H), 3.99 (t, J = 6.4 Hz, 1 H), 3.82 (s, 3 H), 3.34 (s, 1 H), 2.26 (d, J = 3.8 Hz, 2 H), 2.08 (m, 1 H), 1.91 (m, 1 H), 1.54 (s, 3 H), 1.38 (s, 3 H). Alternatively, treatment of lactone 240 with catalytic sodium ethoxide (1 mol%) in ethanol gave the corresponding ethyl ester in 67% sfter crystsllizstion of the crude product from ethyl scetste/hexsne. The residue obtsined from the mother liquor (consisting of stsrting msterisl snd product) wss subjected sgsin to the ssme resction conditions, sffording sdditionsl product sfter recrystsllizstion. Overall yield was 83%.
Example 103
Compound 242: To a solution of diol 241 (29.8 g, 121 mmol) and 4- (N,N-dimethylamino)pyridine (500 mg) in pyridine (230 mL) was sdded tosyl chloride (27.7 g, 145 mmol). The mixture wss stirred st room temperature for 3 dsys, snd pyridine was removed under reduced pressure. The mixture was diluted with wster, snd extracted with EtOAc (3x). The combined orgsnic phsse wss wsshed with water (2x) and brine (lx), and dried over MgSθ4. Concentration and purification by flash column chromatography (Hexsnes/EtOAc = 2/1-1/1) gave tosylate 242 (44.6 g, 92%): H NMR (CDCI3) δ 7.84 (d, J = 8.4 Hz, 2 H), 7.33 (d, J = 8.1 Hz, 2 H), 4.76 (m, 1 H), 4.42 (m, 1 H), 4.05 (dd, J = 5.5, 7.5 Hz, 1 H), 3.80 (s, 3 H), 2.44 (s, 3 H), 2.35 (m, 1 H), 2.24 (m, 2 H), 1.96 (m, 1 H), 1.26 (s, 3 H), 1.13 (s, 3 H). The corresponding ethyl ester of compound 241 was treated with methanesulfonyl chloride and triethylamine in CH2CI2 at 0°C to afford the mesylste derivstive in qusntitstive yield sfter squeous work-up. The mesylste wss used directly without sny further purificstion.
Exsmple 104
Compound 243: To a solution of tosylste 242 (44.6 g, 111.5 mmol) in CH2C12 (450 mL) st -78X wss sdded pyridine (89 mL), followed by slow sddition of SO2CI2 (26.7 mL, 335 mmol). The mixture wss stirred st -78X for 5 hrs, snd methsnol (45 mL) W3S sdded dropwise. The mixture wss wsrmed to room tempersture snd stirred for 12 hrs. Ethyl ether wss sdded, snd the mixture wss wsshed with wster (3x) snd brine (lx), snd dried over MgSθ4. Concentrstion gsve the intermediste ss s oil (44.8 g). To a solution of the intermediste (44.8 g, 111.5 mmol) in MeOH (500 mL) wss sdded TsOH (1.06 g, 5.6 mmol). The mixture wss refluxed for 4 hrs. The resction mixture wss cooled to room tempersture, and methanol was removed under reduced pressure. Fresh methanol (500 mL) was added, and the whole mixture was refluxed for another 4 hrs. The reaction mixture was cooled to room temperature, and methanol was removed under reduced pressure. Purification by flssh column chromstogrsphy (Hexsnes/EtOAc = 3/1-1/3) gsve 3 mixture of the two isomers (26.8 g). Recrystslizstion from EtOAc /Hexsnes sf forded the pure desired product 243 (20.5 g, 54%): iH NMR (CDCI3) δ 7.82 (d, J = 8.3 Hz, 2 H), 7.37 (d, J = 8.3 Hz, 2 H), 6.84 (m, 1 H), 4.82 (dd, J = 5.8, 7.4 Hz, 1 H), 4.50 (m, 1 H), 3.90 (dd, J = 4.4, 8.2 Hz, 1 H), 3.74 (s, 3 H), 2.79 (dd, J = 5.5, 18.2 Hz, 1 H), 2.42 (dd, J = 6.6, 18.2 Hz, 1 H). The corresponding mesylste-ethyl ester derivstive of compound 242 wss trested in the ssme msnner as described. Removsl of the acetonide protecting group was sccomplished with scetic scid in refluxing ethsnol to sfford the diol in 39% yield by direct precipitstion with ether from the crude resction mixture.
Exsmple 105
Compound 1: To a solution of diol 243 (20.0 g, 58.5 mmol) in THF (300 mL) st 0°C wss sdded DBU (8.75 mL, 58.5 mmol). The resction mixture wss wsrmed to room tempersture, snd stirred for 12 hrs. Solvent (THF) wss removed under reduced pressure. Purificstion by flssh column chromstography (Hexsnes/EtOAc = 1/3) gsve epoxide 1 (9.72 g, 100%): *H NMR (CDCI3) δ 6.72 (m, 1 H), 4.56 (td, J = 2.6, 10.7 Hz, 1 H), 3.76 (s, 3 H), 3.56 (m, 2 H), 3.0 (d, J = 21 Hz, 1 H), 2.50 (d, J = 20 Hz, 1 H), 2.11 (d, 10.9 Hz, 1 H). The corresponding mesylste-ethyl ester derivstive of compound 243 wss trested in the ssme msnner as described, affording the epoxide in nesrly qusntitstive yield.
Example 106
Aziridine 244: A solution of silyl ether 4 (223 mg, 1.07 mmol) snd Lindlsr's cstslyst (200 mg) in sbsolute ethsnol (8.0 mL) wss trested with hydrogen gss (1 stmosphere) 3t room tempersture for 50 min. The cstslyst wss then filtered through a celite psd snd wsshed with hot methanol. Concentration in vαcuo gsve -230 mg of 244 ss psle yellow oil which wss used for the next resction without sny further purificstion. Example 107
Azido amine 205: Crude aziridine 244 (230 mg ), sodium azide (309 mg, 4.75 mmol) snd ammonium chloride (105 mg, 1.96 mmol) in dry DMF (10 mL) wss hested at 70°C for 16 h under an argon atmosphere. The reaction was cooled, filtered through a fritted glass funnel to remove solids and psrtitioned between ethyl acetate and brine. The organic layer wss sepsrated snd dried over MgSθ4. Concentration in vαcuo followed by flash chromatography of the residue on silics gel (10% hexsnes in ethyl scetste) gsve 154 mg (57%, 2 steps) of 205 ss a yellow viscous oil of sufficient purity for the next reaction. Example 108
N-acetyl azide 245: Acetyl chloride (70 μl, 0.98 mmol) was sdded to a solution of smine 205 (154 mg, 0.61 mmol) 3nd pyridine (1.3 mL) in CH2CI2 (4.0 mL) cooled to 0°C. After 1.5 h st 0°C the resction wss concentrsted snd psrtitioned between ethyl acetste snd brine. The orgsnic layer was separated and washed sequentially with saturated sodium bicarbonate, brine and dried over MgSθ4. Concentrstion in vαcuo followed by flssh chromstogrsphy of the residue on silics gel (ethyl acetate) gave 167 mg (93%) of 245 as 3 psle yellow solid.
Exsmple 109 Amino ester 200: Triphenyl phosphine (1.7 g, 6.48 mmol) wss sdded in seversl portions to a solution of 245 (1.78 g, 6.01 mmol) in THF (40 mL) snd wster (1.5 mL). The resction wss then stirred at room temperature for 42.5 h. Volstiles were removed under vsccum snd the crude solid sbsorbed onto silics gel snd purified by flssh chromstogrsphy on silics gel (100% ethyl acetate then 100% methanol) to give 1.24 g {77%) of 200 as a pale solid. Exsmple 110
Amino acid 102: To a solution of methyl ester 200 (368 mg, 1.37 mmol) in THF (4.0 mL) cooled to 0°C was added aqueous NaOH (1.37 mL of a 1.0 N solution). The reaction mixture was stirred at 0°C for 10 min, room temperature for 1.5 h snd then acidified to pH 7.0-7.5 with Amberlite IR-120 (H+) acidic resin. The resin wss filtered snd washed with water snd methsnol. Concentrstion in vacuo gsve the smino scid ss s white solid which wss purified by Ci8 reverse phsse chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 290 mg (83%) of smino scid 102.
Exsmple 111
Amine hydrochloride 250: Amine 228 (15.6 mg, 0.05 mmol) wss trested with 0.1 N HCl and was evaporated. The residue was dissolved in water and was filtered through a small column of C-18 reverse phase silica gel. The hydrochloride sslt 250 (12 mg) wss obtained as a solid after lyophilizstion: !H NMR (D20) δ 6.86 (s, IH), 4.35 ( br d, / = 9.0), 4.06 (dd, IH, / = 9.0, 11.6), 3.79 (s, 3H), 3.65-3.52 (m, 2H), 2.97 (dd, IH, / = 5.5, 17.2), 2.58-2.47 (m, IH), 2.08 (s, 3H), 1.61-1.41 (m, 4H), 0.88 (t, 3H, / = 7.4), 0.84 (t, 3H, / = 7.4).
Exsmple 112 Bis-Boc-guanidine 251: To a solution of amine 228 (126 mg, 0.42 mmol), N, N'- bis- rt-butoxycarbonylthiourea (127 mg, 0.46 mmol), and triethylamine (123 μL, 0.88 mmol) in DMF (4 mL) at 0°C was added HgCl2 (125 mg, 0.46 mmol). The mixture was stirred at 0°C for 30 min and at room temperature for 1.5 h. The reaction was diluted with ethyl acetate and filtered through celite. The solvent was evsporsted snd the residue wss psrtitioned between ethyl scetste 3nd wster. The orgsnic phsse wss wsshed with sstursted NsCl, dried (MgSθ4), filtered snd the solvent wss evsporated. The crude product wss purified on silics gel (2/1, 1/1-hexsne/ethyl scetste) to sfford bis-Boc-gusnidine 251 (155 mg, 69%) as a solid: iH NMR (CDC13) δ 11.40 (s, IH), 8.66 (d, IH, / = 7.9), 6.8 (s, IH), 6.22 (d, IH, / = 8.9), 4.43-4.34 (m, IH), 4.19-4.08 (m, IH), 4.03 (m, IH), 3.76 (s, 3H), 3.35 (m, IH), 2.79 (dd, IH, / = 5.4, 17.7), 2.47-2.36 (m, IH), 1.92 (s, 3H), 1.50, 1.49 (2s, 18H), 0.89 (m, 6H).
Example 113
Guanidino-acid 252: To a solution of bis-Boc-guanidine 251 (150 mg, 0.28 mmol) in THF (3 mL) was added 1.039N KOH solution (337 μL) and W3ter (674 μL). The mixture W3S stirred for 3 h, sdditionsl 1.039N KOH solution (67 μL) wss sdded snd stirring wss continued for 2 h. The resction wss filtered to remove a smsll smount of dsrk precipit3te. The filtrate wss cooled to 0°C snd wss scidified with IR 120 ion exchsnge resin to pH 4.5-5.0. The resin wss filtered snd wsshed with methsnol. The filtrate wss evsporsted to s residue which wss dissolved in CH2CI2 (3 mL), cooled to 0°C, snd wss trested with trifluoroscetic scid (3 mL). After stirring 10 min. st 0°C, the resction was stirred at room temperature for 2.5 h. The solvents were evsporsted snd the residue wss dissolved in wster snd wss chromstogrsphed on a short column (3X1.5 cm) of C-18 reverse phsse silics gel eluting initislly with wster snd then 5% scetonitrile/wster. Product fractions were combined snd evaporated. The residue was dissolved in water and lyophilized to afford guanidino-acid 252 (97 mg, 79%) as a white solid. Example 114
Azido acid 260: To a solution of methyl ester 227 (268 mg, 0.83 mmol) in THF (7.0 mL) was added aqueous KOH (1.60 mL of a 1.039 N solution) at room temperature. After stirring for 19 h at room temperature the resction wss scidified to pH 4.0 with Amberlite IR-120 (H+) acidic resin. The resin was filtered 3nd wsshed with wster snd ethanol. Concentration in vαcuo gsve the crude azido acid 260 as a pale orange foam which was used for the next reaction without any further purification.
Example 115
Azido ethyl ester 261: To a solution of carboxylic acid 260 (crude from previous resction, sssume 0.83 mmol), ethyl alcohol (150 μL), and catslytic DMAP in CH2CI2 (6.0 mL) wss sdded DCC (172 mg, 0.83 mmol) in one portion st room tempersture. After seversl minutes a precipitate formed snd sfter sn sdditionsl 1 h of stirring the resction wss filtered snd wsshed with CH2CI2. Concentrstion in vαcuo sfforded a psle solid which wss purified by flssh chromstogrsphy on silics gel (50% hexsnes in ethyl scetste) to give 272 mg (96%, smsll smount of DCU impurity present) of 261 ss s white solid. When DCC wss replsced by diisopropyl carbodiimide than the yield of 261 was 93% but the chromatographic purification eliminated ures impurities present when DCC wss used. Exsmple 116 Amino ethyl ester 262: Triphenyl phosphine (342 mg, 1.30 mmol) wss sdded in one portion to a solution of 261 (272 g, 0.80 mmol) in THF (17 mL) 3nd wster (1.6 mL). The resction wss then hested st 50°C for 10 h, cooled snd concentrsted in vαcuo to give a psle white solid. Purificstion of the crude solid by flssh chromstogrsphy on silics gel (50% methsnol in ethyl scetate) gave 242 mg (96%) of the smino ethyl ester 262 ss a psle solid. The smino ethyl ester is dissolved in 3N HCl snd lyophilized to give the corresponding wster soluble HCl sslt form. l NMR (D20, 300 MHz): δ 6.84 (s, IH); 4.36-4.30 (br m, IH); 4.24 (q, 2H, / = 7.2 Hz); 4.05 (dd, IH, / = 9.0, 11.7 Hz); 3.63-3.50 (m, 2H); 2.95 (dd, IH, / = 5.7, 17.1 Hz); 2.57-2.45 (m, IH); 1.60-1.39 (m, 4H); 1.27 (t, 3H, / = 7.2 Hz); 0.89-0.80 (m, 6H).
Exsmple 117 bis-Boc guanidino ethyl ester 263: Treated according to the procedure of Kim and Qisn, "Tetrshedron Lett." 34:7677 (1993). To s solution of smine 262 (72 mg, 0.23 mmol), bis-Boc thioures (66 mg, 0.24mmol) snd Et3N (108 μL) in dry DMF (600 μL) cooled to 0°C wss sdded HgCl (69 mg, 0.25mmol) in one portion. The heterogeneous resction mixture was stirred for 1 h at 0°C snd then st room tempersture for 15 min, sfter which the resction wss diluted with EtOAc snd filtered through a psd of celite. Concentrstion in vαcuo followed by flssh chromstogrsphy of the residue on silics gel (20% hexsnes in ethyl scetste) gsve 113 mg (89%) of 263 as a colorless foam. iH NMR (CDCI3, 300 MHz): δ 11.41 (s, IH); 8.65 (d, IH, / = 8.1 Hz); 6.83 (s, IH); 6.22 (d, IH, / = 9.0 Hz); 4.46-4.34 (m, IH); 4.21 (q, 2H, / = 6.9 Hz); 4.22-4.10 (m, IH); 4.04^.00 (m, IH); 3.36 (quintet, IH, / = 5.7 Hz); 2.78 (dd, IH, / = 5.4, 17.7 Hz); 2.46-2.35 (m, IH); 1.94 (s, 3H); 1.60-1.40 (m, 4H); 1.49 (s, 9H); 1.50 (s, 9H); 1.30 (t, 3H, / = 6.9 Hz); 0.93-0.84 (m, 6H).
Example 118
Guanidino ethyl ester 264: To a solution of bis-Boc guanidnyl ethyl ester 263 (113 mg, 0.20 mmol) in CH2CI2 (5.0 mL) cooled to 0°C wss sdded nest trifluoroscetic acid (5.0 mL). The reaction mixture wss stirred st 0°C for 30 min snd then st room tempersture for 1.5 h. The resction wss then concentrsted in vαcuo to give a psle orsnge solid which wss purified by Cis reverse phsse chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 63 mg (66%) of the gusnidine ethyl ester 264 ss white solid. lH NMR (D20, 300 MHz): δ 6.82 (s, IH); 4.35-4.31 (m, IH); 4.24 (q, 2H, / = 7.1 Hz); 3.95-3.87 (m, IH); 3.85-3.76 (m, IH); 3.57-3.49 (m, IH); 2.87 (dd, IH, / = 5.1, 17.7 Hz); 2.46-2.34 (m, IH); 2.20 (s, 3H); 1.60-1.38 9M, 4H); 1.28 (t, 3H, / = 7.1 Hz); 0.90-0.80 (m, 6H).
Example 119
Enzyme Inhibition: Using the methods of screening in vitro activity described sbove, the following sctivities were observed (+ 10-100 μm, ++ 1-10 μm, +++ < 1.0 μm):
Figure imgf000333_0001
Example 120 Compounds A.113.b.4.i and A.113.x.4.i were incubated separately in enzyme asssy buffey and tested for activity as described in Example 119.
Activity was >100μm for both. When esch compound was separately incubated in rat plasma prior to testing as described in Example 119, activity of both wss similsr to compound A.113.3.4.
Example 121
Studies were conducted under the supervision of Dr. Robert Sidwell at the Institute for Antiviral Research of Utah State University to determine the comparative anti-influenzs A activity of compound 203 (example 69), GG167 3nd ribsvirin in vivo in mice by i.p. or p.o. routes of sdministrstion.
GG167 snd ribsvirin sre known snti-influenzs virus compounds.
Figure imgf000334_0001
GG167
Mice: Femsle 13-15 g specific-psthogen free BALB/c mice were obtsined from Simonsen Lsborstories (Gilroy, CA). They were qusrantined 24 hr prior to use, snd msintsined on Wsyne Lsb Blox snd tsp wster. Once infected, the drinking wster contsined 0.006% oxytetracycline (Pfizer, New York, NY) to control possible secondsry bscterial infections.
Virus: Influenza A/NWS/33 (H1N1) was obtained from K.W. Cochran, University of Michigsn (Ann Arbor, MI). A virus pool wss prepsred by infecting confluent monolsyers of Madin Dsrby csnine kidney (MDCK) cells, incubsting them st 37X in 5% CO2, snd harvesting the cells st 3 to 5 dsys when the viral cytopsthic effect wss 90 to 100%. The virus stock wss smpuled 3nd stored at -80X until used.
Compounds: Compound 203 and GG167 were dissolved in sterile physiological ssline for this study.
Arterial Oxygen Saturation (Saθ2) Determinations: Ssθ2 wss determined using the Ohmeds Biox 3740 pulse oximeter (Oh eds, Louisville, OH). The ear probe attachment was used, the probe placed on the thigh of the animsl, with the slow instrument mode selected. Resdings were msde sfter s 30 second stsbilizstion time on esch animal. Use of this device for measuring effects of influenza virus on arterial oxygen saturation hss been described by Sidwell et al., "Antimicrob. Agents Chemother." 36:473-476 (1992).
Experiment Design for Intraperitoneal Administration Study: Groups of eleven mice infected intranasally with an approximate 95% lethal dose of virus received esch dose of test compound. Doses of both 203 snd GG167 were 50, 10, 2 snd 0.5 mg/kg/ day. Treatments were i.p. twice daily for 5 dsys beginning 4 hr pre-virus exposure. Eight of the infected, trested mice 3t esch dossge snd 16 infected, ssline-trested controls were ssssyed for S3O2 level on dsys 3 through 10; desths were recorded dsily in these snimsls for 21 dsys. The remsining three snimsls in esch group as well as six saline- trested control mice were killed on dsy 6 snd their lungs removed, weighed, sssigned a consolidstion score bssed on extent of plum color in the lungs (0=normsl, 4=100% of lung sffected). Since no toxicity hsd been seen st s dose of 300 mg/kg/dsy of 203 snd literature reports indicste GG167 to be similsrly nontoxic, toxicity controls were not included in this study.
Experiment Design for Oral Administration Study: Groups of 11 mice were infected intrsnssslly with sn spproximste 95% lethsl dose of virus snd trested with 250, 50, or 10 mg/kg/dsy of 203 or GG167 or with 100, 32 or 10 mg/kg/dsy of ribsvirin. Treatment was by oral gavage (p. o.) twice daily for 5 dsys beginning 4 hr pre-virus exposure. Eight of the snimsls in esch group were held for 21 dsys, with desths noted dsily and Saθ2 levels determined on days 3-10. The remaining 3 infected mice in each group were killed on day 6 snd their lungs removed, weighed, sssigned s consolidstion score of 0 (normsl) to 4 (100% lung sffected). Fifteen infected mice were trested with ssline only snd held 21 dsys with Ssθ2 determined as sbove, and 6 sdditionsl infected, ssline trested mice were killed on dsy 6 for lung ssssy. Three normsl controls were held 21 dsys, with Saθ2 determined in parallel with the sbove, snd sn sdditionsl 3 normal animals were killed on day 6 for lung weight and score.
Experiment Design for Low Dose Oral Administration Study: Groups of 8 mice infected intranasally with an approximate 90% lethal concentration of virus received each dosage of compound. Doses of each compound were 10, 1, and 0.1 mg/kg/ day. Treatments were p.o. twice daily for 5 days beginning 4 hr pre-virus exposure. Eight of the infected, treated mice st esch dossge snd 16 infected, saline-treated controls were asssyed for Ssθ2 level on dsys 3 through 11; desths were recorded dsily in these snimsls for 21 dsys.
Statistical Evaluation: Incresse in survivor number wss evslusted by chi squsre snslysis with Ystes' correction. Mean survival time increases snd differences in S3O2, lung weight snd lung virus titers were analyzed by est. Lung score differences were evaluated by ranked sum analysis. In all cases, differences between drug-treated and saline-treated controls were studied. The results of the i.p. dosing experiment are summarized in Table I snd in Figures 1 snd 2. While in this model both compounds were significsntly inhibitory at the high dose used, 203 treatment also resulted in significsnt survivors at a dose of 10 mg/kg/day. Saθ2 decline was psrticulsrly inhibited by both compounds st the 50 mg/kg/dsy dose, snd again GG167 sppesred to slso prevent this decline at 10 and even 2 mg/kg/day. The lung score dsts appesr to show the ssme trend of GG167 being effective st more thsn one dose. Some erraticism wss seen in lung weights, with lungs tsken from the mice receiving the highest dose of GG167 hsving a grester mesn weight thsn the ssline-trested controls.
The p.o. dosing study is summsrized in Tsble II, with dsily S3O2 vslues shown in Figures 3-5. Oral trestment with all three drugs in this model was significantly inhibitory to the influenza virus infection, preventing death, lowering lung scores and infection-associated lung weights, and inhibiting the ususl decline in Ssθ2-
The p.o. low dose study results are summarized in Table III and in Figures 6-8. In this experiment, the infection was lethal to 14 of 16 saline- trested snimsls, the mean survival time being 9.6 days in this group. While all three compounds exhibited some degree of inhibitory effect on the virus infection, 262 (the ethyl ester prodrug) was the most effective st every dose ss evidenced by number of survivors, mesn survival time, and prevention of Saθ2 decline. Tsble III shows the mean Saθ2% for all assay time taken together.
The daily values for esch compound sre graphically represented in Figures 6 through 8. Figure 6 illustrates the Saθ2 dats with the highest concentrations of esch compound; Figure 7 shows the vslues at the median dose of each compound, snd the Saθ2 values for the low dose of each compound are compered in Figure 8.
Table III and Figs. 6-8 indicate thst while all three compounds were active orally 3gsinst an experimentally induced influenzs A (H1N1) virus infection, 262 wss considered most effective. It wss not determined whether the improved sntiviral potency of 262 was unaccompanied with a concomitant incressed animal toxicity, but this is unlikely since its greater efficscy is expected to be a result of its elevated oral bioavailability. Table I. Comparison of the Effect of 203 and GG167 Administered i.p.a to Influenza A (HlNl) Virus-Infected Mice
Infected. Treated
Mean Lung Parameters'1
Dosage Surv/ Mean Surv. Mean Saθ2c Weight
Cnmpnund ('mg/kcr/Hay'i Total Timek (days) /o Score rrg
203 50 8/8** >21.0** 87.2** 0.7* 173*
10 3/8* 10.8 84.7 2.5 217
2 0/7 12.6 84.4 2.0 203
0.5 0/8 11.1 85.2* 2.0 230
GG167 50 8/8** >21.0** 87.6** 0.7* 230
10 7/8** 15.0 87.5** 1.7 170*
2 1/8 12.6 86.0** 1.3 213
0.5 0/8 12.3 84.5 2.3 227
Saline . 0/16 11,0 82.9 2,0 220
Table II. Comparison of the Effect of Orally Administered3 203, GG167 and Ribavirin on Influenza A (HlNl) Virus Infections in Mice.
Infected. Treated
Mean Lung Parameters'
Dosage Surv/ Mean Surv.b Mean Saθ2 Weight
Compound (mg/k /rlav'i Total Time (άavs) % Score (ma)
203 250 8/8** >21.0** 87.9* 0.8** 160**
50 8/8** >21.0** 87.9* 1.3* 200
10 4/8* 12.8* 87.7* 1.3* 240
GG167 250 8/8** >21.0** 88.6* 0.3** 163**
50 8/8** >21.0** 88.0* 1.5* 187*
10 5/7* 10.5 85.2 1.5* 250
Ribavirin 100 8/8** >21.0** 88.2* 0.3** 140**
32 6/8* 13.0 88.0* 0.8** 163**
10 3/8 11.0 86.4 2.2 267
Saline . 1/16 10.9 84.5 2,4 203 Table III. Comparison of the Effect of Orally Administered3 260, 262 and GG167 on Influenza A (HlNl) Virus Infections in Mice.
Dosage Surv/ /o Mean Surv. Mean Saθ2c
Compound mg/kg/dav*) total Survivors Timek ("days") (%)
260 10 6/8** 75** 13.5** 87.6*
1 3/5 38 11.8 86.8
0.1 0/8 0 10.0 84.3
262 10 8/8*** 100*** >21.0** 88.1**
1 7/8*** 88*** 14.0** 87.4*
0.1 2/8 25 11.1** 85.7
GG167 10 5/8* 63* 12.3** 86.9
1 2/8 25 11.7** 85.7
0.1 0/8 0 9.8 83.5
Saline 0 2/16 13 9.6 83.8
Footnotes for Tables I-III aBid x 5 beginning 4 hr pre-virus exposure.
" Animals dying on or before day 21. cMean of values determined on days 3-10.
"Determined on day 6.
*P<0.05, **P<0.01. ***P<0.001 compared to saline-treated controls
Surprisingly, the foregoing demonstrates that in this model the oral or i.p. administration of GG167 wss effective in prscticsl therspeutic doses 3t reducing mortality in influenzs-infected mice, despite the conclusion of Rysn et al. ("Antimicrob. Agents Chemother.", 38(10):2270-2275) [1994]) that "it is likely that the relatively poor in vivo activity seen with GG167 in mice following intraperitonesl administration, despite good bioavsi bility, is due to its rspid clesrance from the plssms, permitting poor penetrstion into respiratory secretions, coupled with its inability to penetrate and persist inside cells....Similarly, the poor efficacy following oral dosing is probably a consequence of poor oral biosvsilsbility in sddition to these other fsctors." (p.2274). These observstions sre consistent with Von Izstein et al., WO 91/16320, WO 92/06691 and U.S. patent 5,360,817, which cover or are directed specifically to GG167. These pstent documents sre devoid of sny tesching or suggestion to sdminister GG167 by sny other route thsn intrsnsssl. However, intransssl sdministrstion is believed to be inconvenient snd costly in some circumstsnces. It would be sdvsntageous if more facile routes of sdministrstion could be employed for GG167 and its related compounds set forth in WO 91/16320, WO 92/06691 and U.S. pstent 5,360,817.
Thus, sn embodiment of this invention is s method for the trestment or prophylsxis of influenzs virus infection in a host comprising administering to the host, by a route other thsn topicslly to the respiratory system, a therspeuticslly effective dose of sn sntivirslly sctive compound hsving formuls (X) or (Y)
Figure imgf000339_0001
(x) (y) where in general formuls (x), A is oxygen, carbon or sulphur, and in general formula (y), A is nitrogen or csrbon;
R1 denotes COOH, P(0)(OH)2, Nθ2, SOOH, SO3H, tetrszol, CH2CHO,
CHO or CH(CHO)2,
R2 denotes H, OR6, F, Cl, Br, CN, NHR6, SR6, or CH2X, wherein X is
NHR6, hslogen or OR6 and R6 is hydrogen; an acyl group having 1 to 4 carbon atoms; a linear or cyclic slkyl group hsving 1 to 6 csrbon atoms, or a halogen-substituted anslogue thereof; sn silyl group or sn unsubstituted aryl group or an aryl substituted by a halogen, an OH group, an NO2 group, an NH2 group or a
COOH group, R3 3nd R^' are the same or different, and each denotes hydrogen, CN,
NHR6, N3, SR6, =N-OR6, OR6, guanidino, 6 ■
Figure imgf000340_0001
R4 denotes NHR6, SR6, OR6, COOR6, Nθ2, C(R )3, CH2COOR6, CH2NO2 or CH2NHR6, snd R5 denotes CH2YR6, CHYR6CH2YR6 or CHYR6CHYR6CH2YR6, where Y is O, S, NH or H, and successive Y moieties in an group are the ssme or different, snd pharmsceuticslly scceptsble sslts or derivstives thereof, provided thst in general formula (x) (i) when R or ' is OR6 or hydrogen, and A is oxygen or sulphur, then said compound cannot have both
(a) an R2 that is hydrogen snd
(b) sn R4 thst is NH-scyl, snd
(ii) R6 represents a covalent bond when Y is hydrogen, and that in general formuls (y),
(i) when or Rβ' is OR6 or hydrogen, snd A is nitrogen, then ssid compound csnnot hsve both
(3) sn R2 thst is hydrogen, snd (b) an R4 that is NH-acyl, and (ii) R6 represents a covalent bond when Y is hydrogen.
The compounds of formulas x and y are more fully described in WO 91/16320, at page 3, line 23 to psge 7, line 1, WO 92/06691 snd U.S. pstent 5,360,817, x 3nd y are described therein as "I" snd "la", respectively. For the purposes herein, administration by a route "other than topicslly to the respiratory trsct mesns" does not exclude sdministrstion of compound by buccsl or sublingusl routes, snd does not exclude incidentsl sdsorption of compound in the esophsgus during orsl, buccsl or sublingusl sdministrstion, provided however, thst such as buccal, oral, sublingual or esophageal sdsorption is not incidentsl to sdministrstion to the lungs or nsssl pssssges by inhslers or the like. Ususliy, compound is sdministered ss a formed article, a slurry or a solution. In typicsl embodiments of this invention, the compound is GG167, the host is sn snimsl other than mice (such as ferrets or humans), the route of administration is orsl, snd the objective of trestment end prophylsxis is reduction in mortslity. Optionslly, a prodrug of the compound of formuls (X) or (Y) is employed, slthough ss shown sbove it is not necesssry to do so to schieve sntivirsl effect by orsl sdministrstion. As prodrugs of GG167 snd its co-disclosed compounds, sny of the esters, smides or other prodrugs described elsewhere herein for the compounds of this invention sre suitsble for use with the snslogous groups of the compounds of formuls (X) 3nd (Y), e.g., csrboxyl esters or smides.
The therspeuticslly effective dose of GG167 snd its relsted compounds, when sdministered by orsl or other non-nsssl sdministration routes, will be determined by the ordinsrily skilled clinicisn in light of the considerstions set forth in connection with dosing the compounds of this invention. For the most psrt the principsl considerstions sre the route of sdministrstion and the host species. In general, larger doses will be required as one proceeds from intravenous to subcutaneous to orsl sdministrstion routes, snd in sccord with conventionsl phsrmscologic scsling principles ss one proceeds to lsrger animals. Determination of therapeuticslly sctive doses is well within the ordinsry skill in the srt, but in genersl the doses will be substsntislly the ssme as those employed for the compounds of this invention.
Example 122 Each of the reactions shown in Table 50 were preformed according to
Scheme 50. The preformed reactions are indicated with a "/". Unless otherwise indicsted in Table 50, steps AA, AB and AC were preformed according to Examples 92, 93 and 94, respectively, and step AD was preformed sccording to the combinstion of Exsmples 112 snd 113. Scheme 50
Figure imgf000342_0001
400 401
Figure imgf000342_0002
402 403
AD
Figure imgf000342_0003
gCOgH 404
Table 50
Figure imgf000343_0001
Figure imgf000344_0001
Table 50 (continued)
Figure imgf000345_0001
Table 50 (notes) a) ester hydrolysis prior to azide reduction b) azide reduction using PI13P at room temperature c) ester hydrolysis using aqueous KOH/MeOH d) azide reduction using polymer-support PI 3P at room temperature e) isolated as the HCl salt f) szide reduction using Ph P in MeOH/THF/H20 g) disstereomeric mixture, msjor disstereomer indicsted h) szide reduction slso performed with Me3P i) sziridine opening performed 3t 55°C j) C-slkylsted products were isolsted
Figure imgf000346_0001
405 406
k) slcohol wss not evsporsted prior to scylstion
1) disstereomeric mixture, sepsrsted by chromstography /recrystsllizstion
Example 123
Trifluroacetamide 340: To a solution of amine 228 (100 mg, 0.34 mmol) in CH2CI2 (3.5 mL) at 0°C was added pyridine (41 μL, 0.51 mmol) and trifluro3cetic snhydride (TFAA) (52 μL, 0.37 mmol) snd the solution wss stirred for 45 min st which time sdditionsl TFAA (0.5 eq) wss sdded. After 15 min the resction wss evsporsted under reduced pressure snd the residue wss psrtitioned between ethyl scetste snd 1M HCl. The orgsnic phsse wss wsshed with sstursted NsHCθ3, ssturated NsCl, snd wss dried (MgSθ4), filtered, snd evsporsted. The residue wss chromstogrsphed on silics gel (2/1-hexsne/ethyl scetste) to sfford trifluoroscetsmide 340 (105 mg, 78%): iH NMR (CDCI3) δ 8.64 (d, IH, / = 7.7), 6.81 (s, IH), 6.48 (d, IH, / = 8.2), 4.25- 4.07 (m, 3H), 3.75 (s, 3H), 3.37 (m, IH), 2.76 (dd, IH, / = 4.5, 18.7), 2.54 (m, IH), 1.93 (s, 3H), 1.48 (m, 4H), 0.86 (m, 6H).
Exsmple 124 N-Methyl trifluoroacetamide 341: To a solution of trifluroacetsmide
340 (90 mg, 0.23 mmol) in DMF (2 mL) st 0°C wss sdded sodium hydride (10 mg, 60% dispersion in mineral oil, 0.25 mmol). After 15 min st 0°C, methyl iodide (71 μL, 1.15 mmol) wss added and the reaction was stirred for 2 h at 0°C snd for 1 h st room tempersture. Acetic scid (28 μL) wss sdded wss the solution wss evsporsted. The residue wss psrtitioned between ethyl scetste snd wster. The orgsnic phase was washed with saturated NaCl, dried (MgSθ4), filtered, snd evsporsted. The residue wss chromstogrsphed on silics gel (1/1-hexsne/ethyl scetste) to sfford N-methyl trifluoroscetsmide
341 (81 mg, 87%) 3s 3 colorless glass: :H NMR (CDCI3) δ 6.80 (s, IH), 6.26 (d, IH, / = 9.9), 4.67 (m, IH), 4.32 (m, IH), 4.11 (m, IH), 3.78 (s, 3H), 3.32 (m, IH), 3.07 (br s, 3H), 2.60 (m, 2H), 1.91 (s, 3H), 1.48 (m, 4H), 0.87 (m, 6H).
Example 125
N-Methyl amine 342: To a solution of N-methyl trifluoroscetsmide 341 (81 mg, 0.20 mmol) in THF (3 mL) wss sdded 1.04 N KOH (480 μL, 0.50 mmol) snd the mixture wss stirred st room tempersture for 14 h. The resction wss scidified with IR 120 ion exchsnge resin to pH~4. The resin was filtered, washed with THF, snd the filtrate wss evsporsted. The residue was dissolved in 10% TFA/water (5 mL) 3nd wss evsporsted. The residue wss psssed through 3 column (1.5X2.5 cm) of C-18 reverse phsse silics gel eluting with wster. Product fractions were pooled and lyophilized to afford N- methyl amine 342 (46 mg, 56%) as a white solid: H NMR (D2O) δ 6.80 (s, IH), 4.31 (br d, IH, / = 8.8), 4.09 (dd, IH, / = 8.9, 11.6), 3.53 (m, 2H), 2.98 (dd, IH, / = 5.4, 16.9), 2.73 (s, 3H), 2.52-2.41 (m, IH), 2.07 (s, 3H), 1.61-1.39 (m, 4H), 0.84 (m, 6H). Example 126
Compound 346: To a solution of epoxide 345 (13.32 g, 58.4 mmol) in 8/l-MeOH/H 0 (440 mL, v/v) was sdded sodium azide (19.0 g, 292.0 mmol) and ammonium chloride (2.69 g, 129.3 mmol) and the mixture was refluxed for 15h. The reaction was cooled, concentrated under reduced pressure and psrtitioned between EtOAc and H2O. The organic layer was washed successively with S3td. bicsrb, brine snd dried over MgSθ4. Concentrstion in vαcuo followed by flssh chromstogrsphy on silics gel (30% EtOAc in hexsnes) gsve 11.81 g (75%) of szido slcohol 346 as a viscous oil. H NMR( 300 MHz, CDCI3) δ 6.90-6.86 (m, IH); 4.80 (s, 2H); 4.32 (bt, IH, / = 4.2 Hz); 4.22 (q, 2H, / = 7.2 Hz); 3.90-3.74 (overlapping m, 2H); 3.44 (s, 3H); 2.90 (d, IH, J = 6.9 Hz); 2.94-2.82 (m, IH); 2.35-2.21 (m, IH); 1.30 (t, 3H, / = 7.2 Hz).
Example 127
Compound 347: To a solution of ethyl ester 346 (420 mg, 1.55 mmol) in dry THF (8.0 mL) cooled to -78°C was sdded DIBAL (5.1 mL of a 1.0 M solution in toluene) dropwise vis syringe. The bright yellow resction mixture wss stirred st -78°C for 1.25 h snd then slowly hydrolyzed with the slow sddition of MeOH (1.2 mL). Volstiles were removed under reduced pressure snd the residue partitioned between EtOAc and cold dilute HCl. The organic layer was separated and the aqueous layer back extracted with EtOAc. The organic lsyers were combined snd washed successively with sstd. bicsrb, brine snd dried over MgSθ4. Concentrstion in vacuo followed by flssh chromstogrsphy on silics gel (20% hexsnes in EtOAc) gsve 127 mg (36%) of the diol 347 ss a colorless viscous oil. H NMR( 300 MHz, CDC13) δ 5.83-5.82 (m, IH); 4.78 (s, 2H); 4.21 (bt, IH, / = 4.4 Hz); 4.06 (bs, 2H); 3.85-3.65 (overlspping m, 2H); 3.43 (s, 3H); 3.18 (d, IH, / = 8.1 Hz); 2.51 (dd, IH, / = 5.5, 17.7 Hz); 2.07-1.90 (m, IH); 1.92 (bs, IH).
Example 28
Methyl ester 600: Prepsred in 51% overall yield from D-(-)-quinic 3dd sccording to the procedure of Frost, J.W., et. al. "J. Org. Chem." 61:3897 (1996).
Example 129
Ketone 601: To a slurry of diol 600 (15.0 g, 46.9 mmol), pyridine (13.7 mL), celite (equal volume to PCC) in dichloromethane (200 mL) was added PCC (40.5 g, 187.9 mmol) in portions snd the resction wss stirred st room tempersture for 21 h. Excess PCC wss destroyed with the sddition of excess 2-propsnol. After stirring for sn sdditionsl 30 min the resction mixture was diluted with diethyl ether, filtered through a pad of celite and washed with ethyl scetste. The orgsnic lsyer wss then psssed through a short column of silics gel snd eluted with ethyl scetste. Concentrstion under reduced pressure gsve a yellow solid which was recrystallized from methanol /ethyl scetste /hexsnes to give 10.9 g (74%) of ketone 601 ss a crystalline powder. HRMS (FAB): Calcd for Cι4H22θ8 (MLi+) 325.1474, found 325.1471.
Exsmple 130
Olefin 602: To a slurry of butyltriphenylphosphonium bromide (16.6 g, 41.6 mmol) in dry THF (150 mL) cooled to 0°C was added n-BuLi (26.0 mL of a 1.61 M solution in hexane) dropwise. After stirring at 0°C for 20 min the mixture was warmed to room temperature, stirred for 5 min and recooled to 0°C. To this bright orange solution wss sdded a solution of 601 (6.0 g, 18.9 mmol) in dry THF (75.0 mL) vis csnnuls. The resction mixture wss wsrmed to room tempersture, stirred for 10 min snd then gently refluxed for 2.5 h. The resction mixture wss cooled, sstursted N3HCO3 wss sdded snd diluted with ethyl scetste. The orgsnic lsyer wss sepsrated, wsshed with brine snd dried over MgSθ4- Concentrstion under reduced pressure followed by flssh column chromstogrsphy on silics gel (30% hexsnes in ethyl scetste) gsve 5.5 g (81%) of 602 ss a viscous pale oil consisting of a 4:1 mixture of olefin isomers.
Exsmple 131 Triethylsilyl ether 603: To a solution of 602 (5.5 g, 15.37 mmol) in dichloromethane (125 mL) cooled to 0°C wss sdded 2,6-lutidine (3.6 mL) followed by the dropwise sddition of triethylsilyl trifluoromethsnesulfonate (5.35 mL, 23.66 mmol). The reaction mixture wss slowly wsrmed to room tempersture snd stirred for 15 h. Volstiles were removed under reduced pressure snd the crude residue wss psrtitioned between diethyl ether snd wster. The orgsnic lsyer wss wsshed with dilute HCl, sstursted N3HCO3, brine snd dried over MgSθ4. Concentrstion under reduced pressure followed by flssh column chromstogrsphy on silics gel (20% ethyl scetste in hexsnes) gsve 6.78 g (93%) of 603 ss s mobile liquid.
Exsmple 132
Butyl cyciohexyl ester 604: To s degsssed solution of olefin 603 (6.78 g, 14.34 mmol) in ethsnol (140 mL) wss sdded 10% psllsdium on csrbon (5.0 g). The resction mixture wss then stirred under an atmosphere of hydrogen gas (1 atm vis bslloon) st room tempersture for 22 h. The resction wss filtered through 3 celite psd snd wsshed with hot methsnol. Concentrstion under reduced pressure followed by flssh column chromstogrsphy on silics gel (10% ethyl scetate in hexanes) gave 5.44 g (80%) of 604 as a colorless oil.
Example 133
Alcohol 605: A solution of tetrabutylammonium fluoride (17.1 mL of a 1.0 M solution in THF) wss sdded dropwise to s solution of 604 (5.44 g, 11.46 mmol) in THF (50 mL) st room tempersture. After 45 min the bulk of the THF wss removed under reduced pressure snd the crude resction wss psrtitioned between diethyl ether snd wster. The orgsnic lsyer wss wsshed with sstursted ammonium chloride, water, brine and dried over MgSθ4. Concentration under reduced pressure followed by flash column chromatography on silics gel (20% ethyl scetste in hexanes ) gave 3.18 g {77%) of 605 3S s colorless viscous oil. Exsmple 134
Olefin 606: To a solution of slcohol 605 (3.18 g, 8.82 mmol) in pyridine (39 mL) snd dry dichloromethsne (35 mL) cooled to -78°C wss sdded sulfuryl chloride (1.07 mL, 13.32 mmol) dropwise vis syringe. The resction mixture wss slowly wsrmed to -40°C over s 30 min period 3nd msintsined between -40° - - 30°C for 30 min. The resction wss recooled to -78°C snd methsnol (1.0 mL) wss sdded. The resction wss then slowly wsrmed to room tempersture over a 3 h period snd then diluted with diethyl ether. The orgsnic lsyer wss wsshed sequentislly with wster, dilute HCl, wster, sstursted N3HCO3, brine snd dried over MgSθ4. Concentrstion under reduced pressure followed by flssh column chromstogrsphy on silics gel (25% ethyl scetste in hexsnes) gsve 2.73 g (90%) of 606 ss s colorless viscous oil which is contsminsted with -3% of the isomeric cyclohexene csrboxylste.
Exsmple 135
Diol 607: A solution of 606 (2.73 g, 7.97 mmol) in dichloromethsne (58 mL) wss trested with 40% squeous trifluoroscetic scid (37 mL) st room tempersture for 14 h. Volstiles were removed under reduced pressure snd the residue wss psrtitioned between diethyl ether snd wster. The orgsnic lsyer wss csutiously wsshed with sstursted NsHCθ3, wster, brine snd dried over MgSθ4. Concentration under reduced pressure followed by flash column chromstogrsphy on silics gel (10% hexsnes in ethyl scetste) gsve 1.36 g (75%) of 607 3S a viscous oil.
Exsmple 136
Mesylates 608 and 609: To a solution of diol 607 (1.06 g, 4.64 mmol) and triethyl smine (1.31 mL) in dichloromethsne (25 mL) cooled to -78°C wss sdded dropwise methsnesulfonyl chloride (360 μL, 4.64 mmol). The resction was stirred at -78°C for 1 h and then slowly warmed to 0°C over a 1 h period. After sn sdditionsl 1 h st this tempersture, the resction wss diluted with diethyl ether snd wsshed with wster, sstursted NsHCθ3, brine 3nd dried over MgSθ4. Concentrstion under reduced pressure followed by flssh column chromstogrsphy on silics gel (20% ethyl scetste in hexsnes) gsve 1.23 g (87%) of 608 snd 609 as an inseparable mixture in a 6:1 ratio, respectively. Example 137
Epoxide 610: To a solution of a 6 to 1 mixture of 608 and 609 (1.23 g, 4.02 mmol) in dry THF (20 mL) cooled to 0°C was added DBU (601 μL, 4.02 mmol). The ice bsth wss removed snd the resction stirred st room tempersture for 18 h. The resction wss diluted with diethyl ether snd wsshed with wster, brine snd dried over MgSθ4. Concentrstion under reduced pressure followed by flssh column chromatography on silica gel (20% ethyl scetste in hexsnes) gsve 490 mg (58%) of pure epoxide 610 ss s mobile liquid snd 100 mg (13%) of methyl-3-butyl benzoste 611 ss sn oil. Ansl. Cslcd for Cι2Hi8θ3: C, 68.55; H, 8.63. Found: C, 68.29; H, 8.52.
Exsmple 138
Azido alcohols 612 and 613: A solution of 610 (490 mg, 2.33 mmol), sodium azide (764 mg, 11.75 mmol) and ammonium chloride (281 mg, 5.25 mmol) in methanol/water (8:1, 17.0 mL) was gently refluxed for 15 h. The cooled reaction mixture was concentrated under reduced pressure snd psrtitioned between diethyl ether snd wster. The orgsnic lsyer wss wsshed with brine snd dried over MgSθ4. Concentration under reduced pressure followed by flash column chromatography on silics gel (20% ethyl scetste in hexsnes) gsve 562 mg (95%) of 612 snd 613 ss an inseparable mixture in a 2:1 ratio, respectively.
Exsmple 139
Azido mesylates 614 and 615: To a solution of 612 and 613 (642 mg, 2.54 mmol), triethyl amine (1.8 mL) and catalytic DMAP in dichloromethane (15 mL) cooled to 0°C was added dropwise methanesulfonyl chloride (232 μL, 3.00 mmol). The reaction wss stirred st 0°C for 1.5 h snd then st room tempersture for 30 min. The resction was diluted with diethyl ether and washed with water, dilute HCl, sstursted NsHCθ3, brine snd dried over MgSθ4. Concentrstion under reduced pressure gsve a yellow liquid which was passed through s short plug of silics gel eluting with 25% ethyl scetste in hexsnes to give 840 mg (100%) of 614 snd 615 as an inseparable mixture.
Exsmple 140 Aziridine 616: To a solution of 614 and 615 (840 mg, 2.53 mmol) in dry
THF (20 mL) was added triphenyl phosphine (750 mg) in portions at room tempersture. After 2.5 h triethyl smine (550 μL) snd wster (5.50 mL) were sdded 3nd the resction stirred st room tempersture for 16 h. Volstiles were removed under reduced pressure snd the residue diluted with ethyl scetste. The orgsnic lsyer wss wsshed with wster, sstursted NsHCθ3, brine end dried over MgSθ4. Concentrstion under reduced pressure followed by flssh column chromstogrsphy on silics gel (5% methsnol in ethyl scetste) gsve 375 mg (71%) of 616 ss a viscous oil.
Exsmple 141 Azido amine 617: A solution of 616 (354 mg, 1.70 mmol), sodium azide (555 mg, 8.54 mmol) and ammonium chloride (182 mg, 3.40 mmol) in dry DMF (8.0 mL) was heated 3t 80°C for 17 h. The bulk of the DMF wss removed under reduced pressure and the residue partitioned between diethyl ether snd wster. The orgsnic lsyer was washed with water, brine and dried over MgSθ4. Concentration under reduced pressure gave a yellow liquid which wss psssed through 3 short plug of silics gel eluting with ethyl scetste to give 380 mg (86%) of 617 ss a yellow liquid which wss used immedistely for the next resction.
Example 142
N-acetyl azide 618: The crude amine 617 (380 mg, 1.51 mmol) in dry pyridine (3.0 mL) and dichloromethsne (7.0 mL) was treated with scetyl chloride (173 μL, 2.40 mmol) st 0°C. After 40 min the resction wss wsrmed to room tempersture snd stirred for 5 min. Volstiles were removed under reduced pressure and the residue was partitioned between diethyl ether snd wster. The orgsnic lsyer wss washed with dilute HCl, saturated N3HCO3, brine snd dried over MgSθ4. Concentrstion under reduced pressure followed by flash column chromatography on silica gel (20% hexanes in ethyl scetste) gsve 349 mg of sn off-white solid which wss recrystsllized from ethyl scetste snd hexsnes to give 304 mg (68%) of 618 ss colorless needles.
Exsmple 143
N-acetyl amino ester 619: A solution of 618 (292 mg, 0.99 mmol) and triphenyl phosphine (393 mg, 1.50 mmol) in water (1.8 mL) and THF (15 mL) was hested st 50°C for 10 h. The resction wss evsporsted to dryness, spplied to s silics gel column and eluted with 40% methanol in ethyl acetate to give 250 mg (93%) of 619 as a pale gummy solid.
Example 144 Amino acid 620: A solution of 619 (142 mg, 0.53 mmol) in THF (2.0 mL) was trested st room tempersture with squeous KOH (770 μL of 3 1.039 M solution) for 3.5 h snd then scidified to pH = 3.0 with Amberlite IR-120 (H+) ion-exchsnge resin. The resction wss filtered snd the resin wsshed with wster snd methsnol. Concentrstion under reduced pressure gsve s psle solid which wss purified by Cg reverse phsse column chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd evsporsted to give 87 mg (65%) of 620 ss a colorless powder.
Exsmple 145 Azido propyl ester 265: To s solution of csrboxylic scid 260 (55 mg,
0.18 mmol), 1-propsnol (67μL, 0.89 mmol), and cstslytic DMAP in CH2CI2 (1.0 mL) wss sdded diisopropyl csrbodiimide (31μL, 0.19 mmol) dropwise at room temperature. After stirring for 1 h the reaction was concentrated and purified by flssh chromstogrsphy on silics gel (50% hexsnes in ethyl scetste) to give 53 mg (85%) of 265 ss a colorless crystslline solid.
Exsmple 146
Amino propyl ester 266: Triphenyl phosphine (65 mg, 0.25 mmol) wss sdded in one portion to a solution of 265 (53 mg, 0.15 mmol) in THE (4.0mL) and water (300μL). The reaction was then heated at 50°C for 10 h, cooled and concentrsted in vαcuo to give a psle white solid. Purificstion of the crude solid by flssh chromstogrsphy on silics gel (50% methsnol in ethyl scetste) gsve a psle oil which wss evsporsted from 3 N HCl to give a solid which wss purified by Cis reverse phsse column chromstogrsphy eluting with wster. Fractions contsining the desired product were pooled snd lyophilized to give 41 mg {75%) of 266 ss a colorless powder.
Example 147
Sulfide 700 was made from shikimic scid according to a literature procedure (Robert H. Rich, Brisn M. Lswrence, Psul A. Bsrtlett, "J. Org. Chem.", 59:693-694 (1994). Example 148
Sulfoxide 701: To a solution of sulfide 700 (16.0 g, 32.7 mmol) in CH2CI2 (750 mL) at -45°C was dropwise added 3 solution of m- diloroperoxybenzoic scid (8.5 g, 57-86%) in CH2CI2 (250 mL) over 3 period of 0.5 h. The resction wss stirred st -40°C for 1 h, then st room tempersture for 0.5 h. The resction mixture was evaporsted to solid begsn to precipitste out, snd then diluted with hexsne. The solid wss removed by filtration and the filtrate wss evsporsted. The residue wss dissolved in ethyl scetste snd wsshed with sstursted N3HCO3, dried (MgSθ4), filtered snd evsporsted. The crude product wss purified by chromstogrsphy on silics gel (ethyl scetste /hexsne) to give sulfoxide 701 (14.2 g, 86%, s mixture of disstereomers, ratio = 2.2:1) 3s a colorless solid.
Example 149 Vinyl Chloride 702: The sulfoxide 701 (14.0 g, 27.7mmol) wss refluxed in xylene (180 mL) for 50 min. The resction mixture wss cooled to room tempersture snd evsporsted. The residue wss chromstogrsphed to sfford vinyl chloride 702 (7.6 g, 79%) 3s sn oil.
Example 150
Triol 703: To a solution of vinyl chloride 702 (7.3 g, 20.9 mmol) in anhydrous methsnol (80 mL) st room tempersture wss added sodium methoxide (0.3 mL, 25%, 1.3 mmol). The reaction was stirred at room temperature for 1 h, then quenched with HCI/CH3OH (1.0 mL, 1.4M, 1.4 mmol). The resction mixture W3S evsporsted snd the residue was treated with ethyl acetste /hexsne to give triol 703 (4.6 g, 99%) ss a colorless solid. Anal. Calcd for
Figure imgf000354_0001
C, 42.36; H, 4.89; Cl, 16.75. Found: C, 42.29; H, 4.90; Cl, 16.56.
Exsmple 151
Acetonide 704: The mixture of triol 703 (4.6 g, 20.7 mmol), 2,2- dimethoxypropane (4.0 mL, 32.5 mmol) snd acetone (50 mL) was stirred at room temperature for 1.5 h. The resction mixture was evaporated, and fresh 2,2-dimethoxypropane (1.5 mL, 12.2 mmol) snd acetone (30 mL) were added. The reaction wss stirred for snother 1.5 h. The resction mixture wss evsporsted, snd the crude product wss filtered through a short plug of silics gel. The filtrste wss evsporsted to give scetonide 704 (5.4 g, 99%) ss sn oil, Anal. Cslcd for
Figure imgf000355_0001
C, 49.45; H, 5.85; Cl, 13.27. Found: C, 49.67; H, 5.82; Cl, 13.60.
Example 152
Mesylate 705: To a solution of acetonide 704 (2.63 g, 10.0 mmol) in CH2CI2 (30 mL) st 0°C wss sdded triethylsmine (2.23 mL, 16 mmol), followed by methsnesulfonyl chloride (1.16 mL, 15 mmol). The resction wss stirred st 0°C for 1 h, then evsporsted. The residue wss psrtitioned between ethyl scetste snd wster. The squeous phsse wss extracted with ethyl scetste. The combined orgsnic phsses were dried (MgSθ4), filtered and evaporated. The crude product was filtered through a short plug of silics gel. The filtrste wss evsporsted to give mesylste 705 (3.4 g, 100%) as an oil.
Example 153
3-Pentyl Ketal 706: The mixture of mesylate 705 (3.4 g, 10.0 mmol) and perchloric scid (30 mg, 70%, 0.2 mmol) in 3-pentsnone (40 mL) wss stirred st 45°C for 2 h. The resction wss evsporsted snd fresh 3-pentsnone (40 mL) wss sdded. The resction wss stirred for snother 0.5 h, then evsporsted. The crude product wss filtered through a short plug of silics gel. The filtrste wss evsporsted to sfford 3-pentyl ketsl 706 (3.7 g, 100%) as an oil.
Exsmple 154
Mesylate Alcohol 707: To a solution of ketal 706 (1.68 g, 4.55 mmol) in CH2CI2 (20 mL) at -5°C was added borane-methyl sulfide complex (0.7 mL,
10M, 7.0 mmol), followed by trimethylsilyl trifluoromethsnesulfonste (0.82 mL, 4.6 mmol). The resulted mixture was stirred at 0°C for 1 h, then very slowly added sstursted N3HCO3 (1 drop/ 10 min. for the first 5 drops, 1 mL).
The resulted mixture wss filtered through a short plug of silics gel. The filtrste wss evsporsted snd the residue wss purified by chromstogrsphy on silics gel (ethyl scetste /hexsne) to give s mixture of regio-isomers 707 snd
708 (1.2 g, 71%, 8/9 = 3/2) ss an oil.
Example 155 Epoxide 709: A mixture of 707 and 708 (1.95 g, 5.26 mmol) was mixed with KHCO3 (1.0 g, 10 mmol) in methanol (15 mL) 3nd wster (10 mL). The resction wss stirred at 50°C for lh, then evaporated to remove methsnol. The remsined mixture wss extrscted with ethyl scetste. The combined extrscts wss dried (MgSθ4), filtered, evsporsted. The residue wss chromstogrsphed to give epoxide 709 (0.88 g, 61%) ss sn oil.
Example 156
Azide Alcohol 710: The mixture of epoxide 709 (0.95 g, 3.46 mmol), sodium azide (0,65 g, 10 mmol) and ammonium chloride (0,40 g, 7.5 mmol) in methanol (40 mL) and wster (10 mL) wss stirred st 65°C for 18 h. The resction mixture wss diluted with wster snd evsporsted to remove methsnol, then extrscted with ethyl scetste. The orgsnic extrscts were dried (MgSθ4), filtered snd evsporsted. The crude product was crystallized from hexane/ ethyl scetste to sfford szide slcohol 710 (0,8 g, 73%) ss s colorless solid. Anal. Calcd for C13H20CIN3O4: C, 49.14; H, 6.34; N, 13.22; Cl, 11.16. Found: C, 49.14; H, 6.47; N, 13.21; Cl, 11.38.
Example 157
Azide mesylate 711: To a solution of azide alcohol 710 (1.0 g, 3.15 mmol) in CH2CI2 (20 mL) at 0°C was sdded triethylsmine (1.1 mL, 8.0 mmol), followed by methanesulfonyl chloride (0.5 mL, 6.5 mmol). The resulted mixture was stirred at 0°C for 0.5 h, then at room temperature for another 0.5 h. The reaction was added 2 drops of water, then diluted with hexane and filtered through a short plug of silica gel. The filtrste wss evsporated to give szide mesylste 711 (1.27 g, 100%) ss sn oil.
Exsmple 158
Azido phenethyl ester 800: To s solution of 260 (63 mg, 0.20 mmol), phenethyl slcohol (26 μL, 0.22 mmol), snd DMAP (7.8 mg) in 1/1- CH2CI2/THF (2 mL) wss sdded diisopropylcsrbodiimide (34 μL, 0.22 mmol) at room temperature. After stirring 4 h the solvent wss evaporated 3nd the residue wss chromstogrsphed on silics gel (1/1-hexane/ethyl acetate) to afford 800 (60 mg) as an oil which contained a trace of phenethyl slcohol. This msterisl wss used directly in the next step without sny further purificstion.
Exsmple 159 Amino phenethyl ester 801: Triphenyl phosphine (55 mg, 0.21 mmol) wss sdded in one portion to a solution of 800 (60 mg, 0.14 mmol) in THF (2 mL) snd wster (252 μL). The resction wss then hested st 50°C for 10 h, cooled snd evsporated. The residue wss purified by silics gel chromstogrsphy (1/1-ethyl scetste /methsnol) to afford 53 mg of an oil which was dissolved in 0.1N HCl (1 mL) snd evsporsted. The residue wss dissolved in wster snd psssed through a column of CJS reverse phsse silics gel to sfford sfter lyophilizstion 801 (41 mg, 69%) ss s white solid.
Exsmple 160
Azido butyl ester 802: To a solution of 260 (60 mg, 0.19 mmol), n- butsnol (87 μL, 0.95 mmol), snd DMAP (4 mg) in 2/1- CH2C12/THF (3 mL) wss sdded diisopropylcsrbodiimide (33 μL, 0.21 mmol) st room tempersture.
After stirring 2 h the solvent wss evsporsted and the residue was chromatographed on silics gel (1/1-hexsne/ethyl acetate) to afford 802 (48 mg, 68%) 3S sn oil.
Exsmple 161
Amino butyl ester 803: Triphenyl phosphine (51 mg, 0.19 mmol) wss sdded in one portion to a solution of 802 (48 mg, 0.13 mmol) in THF (1.5 mL) snd wster (234 μL). The resction wss then hested at 50°C for 10 h, cooled and evsporsted. The residue wss dissolved in ethyl scetste, dried (Ns2Sθ4), filtered snd evsporsted. Purificstion of the residue by silics gel chromstogrsphy (1/1-ethyl acetate /methsnol) afforded 38 mg of an oil which was dissolved in 0.1N HCl (2 mL) and evaporsted. The residue wss dissolved in wster snd psssed through a column of Cis reverse phsse silics gel to sfford sfter lyophilizstion 803 (23 mg, 47%) ss a white solid.
Exsmple 162 l-Phenyl-3-pentanol 804: To a solution of ethylmagnesium bromide
(75 mmol) in ether (325 mL) 3t 0°C wss sdded hydrocinnsmsldehyde (6.71 g, 50 mmol) in ether (50 mL). The solution wss stirred for 1 h snd W3S sllowed to W3rm to room tempersture. The resction solution wss poured into ice- wster (1000 mL) snd the mixture wss acidified to pH=3 with cone. HCl. The layers were separated and the aqueous phase wss extracted with ether. The combined organic extrscts were wsshed with ssturated NaHCθ3, brine, snd were dried (MgSθ4), filtered, evsporsted. The crude product wss distilled under high vscuum (bp 90-93°C) to sfford 804 (5.3 g, 64%) ss s colorless oil.
Exsmple 163 l,5-diphenyl-3-pentanol 805: To a solution of phenethylmagnesium bromide (25 mL, 0.9M in THF) in ether (100 mL) 3t 0°C was added hydrocinnsmsldehyde (3.0 g, 22.5 mmol) in ether (30 mL). The solution wss stirred for 5 min snd wss sllowed to wsrm to room tempersture stirring for 1 h. The resction solution wss poured into ice-wster (200 mL) snd the mixture wss scidified to pH=3 with cone. HCl. The lsyers were sepsrated snd the squeous phsse wss extrscted with ether. The combined orgsnic extracts were wsshed with sstursted NsHCθ3, brine, snd were dried (MgSθ4), filtered, evsporsted. Chromstography on silica gel (4/1- hexsne/ethyl scetste) gsve s psle yellow oil (3.74 g) which solidified upon cooling. Recrystsllizstion from hexsne gsve 805 (1.35 g, 25%) ss white needles.
Exsmple 164 l,3-diphenyl-2-propanol 806: To a solution of l,3-diphenyl3cetone (17.08 g, 81.2 mmol) in ethsnol (100 mL) st 0°C wss sdded N3BH4 (3.07 g, 81.2 mmol) snd the mixture wss stirred for 2 h. The resction wss scidified to pH=3 with IN HCl snd ethsnol wss evsporsted. The resction wss diluted with wster 3nd the squeous phsse wss extrscted with seversl portions of ethyl scetste. The combined orgsnic extrscts were wsshed with sstursted NsHCθ3, brine, dried (MgSθ4), filtered snd evsporsted to sfford 806 (17 g, 99%) ss 3 psle yellow oil.
Exsmple 165
Ether 807: To a solution of 183 (200 mg, 0.46 mmol) snd 804 (1 mL) wss sdded BF3 #OEt2 (85 μL, 0.69 mmol) snd the solution wss hested st 75- 80°C for 1.25 h. After cooling to room tempersture the resction wss diluted with pyridine (5 mL) cooled to 0°C, snd trested with acetic anhydride (1.25 mL) and DMAP (50 mg). The reaction was stirred at 0°C for 15 min. and then st room tempersture for 14 h. The solvent wss evsporsted snd the residue wss psrtitioned between ethyl scetste snd IN HCl snd the orgsnic phsse wss wsshed sgsin with IN HCl. The combined squeous wsshes were extrscted with ethyl scetste, snd the combined orgsnic extrscts were wsshed with sstursted NaHCθ3, brine, dried (MgSθ4), filtered and evsporsted. The residue wss chromstographed on silics gel (1/1-hexane/ethyl acetste) to sfford 807 (116 mg mg, 63%) ss a mixture of disstereomers which wss rechromstographed (2/1-hexsne/ethyl scetste). Fractions contsining the fsster eluting diastereomer were combined to sfford 807a (44 mg) as a solid which wss recrystsllized (hexsne/ethyl scetste): mp 131-133°C. The slower eluting disstereomer was obtained as a solid which wss recrystsllized (hexsne/ethyl scetste) to sfford 807b (41 mg) ss needles: mp 111-H2°C.
Exsmple 166
Azidoesters 807a and 807b were trested with triphenylphosphine in s similsr msnner as described in Example 93 to afford amino esters 808a and 808b, which were treated with aqueous potassium hydroxide ss described in Exsmple 94 to sfford amino acids 809a and 809b.
Exsmple 167
Ether 810: A solution of 183 (200 mg, 0.46 mmol) snd 805 (750 mg, 3.1 mmol, mp 43-45°C) wss formed by gentle nesting. To this solution wss sdded BF3»OEt2 (85 μL, 0.69 mmol) snd the solution was heated st 70-75°C for 1.5 h. After cooling to room tempersture the resction was diluted with pyridine (2 mL) cooled to 0°C, and treated with acetic anhydride (660 μL, 7.0 mmol) and catalytic DMAP. The reaction was stirred at 0°C for several min 3nd then st room tempersture for 16 h. The solvent was evaporated and the residue W3S psrtitioned between ethyl scetste and IN HCl and the orgsnic phsse wss wsshed sgsin with IN HCl. The combined squeous wsshes were extrscted with ethyl scetste, snd the combined orgsnic extrscts were wsshed with ssturated NsHCθ3, brine, dried (MgSθ4), filtered and evaporated. The residue was chromstogrsphed on silics gel (l/l-hexsne/ethyl scetste) to sfford 3 solid residue which wss recrystsllized (hexsne/ethyl acetate) to afford 810 (63 mg, 28%) as needles: mp 139-140°C
Example 168
Azidoester 810 was treated with triphenylphosphine in a similsr msnner ss described in Exsmple 93 to sfford smino ester 811, which wss trested with squeous potsssium hydroxide as described in Example 94 to afford amino acid 812.
Example 169
Ether 813: To a solution of 183 (100 mg, 0.23 mmol) snd 806 (1 mL) wss added BF3«OEt2 (42 μL, 0.35 mmol) and the solution was heated 3t 70- 75°C for 1.25 h. After cooling to room tempersture the resction wss diluted with pyridine (5 mL) cooled to 0°C, snd trested with scetic snhydride (680 μL, 7.2 mmol) snd cstslytic DMAP. The resction wss stirred st 0°C for several min. end then st room tempersture for 15 h. The solvent wss evsporsted snd the residue wss psrtitioned between ethyl scetste snd IN HCl snd the orgsnic phsse wss wsshed sgsin with IN HCl. The combined squeous wsshes were extrscted with ethyl scetste, snd the combined orgsnic extrscts were wsshed with sstursted N3HCO3, brine, dried (MgSθ4), filtered snd evsporsted. The residue was chromatographed (1/1-hexane/ethyl scetste) to sfford 813 (57 mg, 55%) ss a pale yellow solid: mp 132-133°C (needles from hexane /ethyl acetste)
Exsmple 170
Azidoester 813 wss trested with triphenylphosphine in 3 similsr manner as described in Exsmple 93 to sfford smino ester 817, which wss trested with squeous potsssium hydroxide ss described in Exsmple 94 to sfford smino scid 815.
Example 171 N-Boc aziridine 817: To a solution of 816 (700 mg, 3.1 mmol, prepsred in 3 similsr msnner from quinic scid ss described for methyl ester derivstive 170) in CH2CI2 (10 mL) wss sdded di-terf-butyldicsrbonste (1.0 g, 4.6 mmol) in CH2CI2 (5 mL) and catalytic DMAP (10 mol%). After stirring for 45 min at room temperature the solvent was evaporsted snd the residue wss directly purified by silics gel chromstogrsphy (3/1 -hexane /ethyl acetste) to sfford 817 (880 mg, 87%) ss sn oil.
Example 172
Alcohol 818: To s solution of 817 (826 mg, 2.52 mmol) in DMF (20 mL) wss 3dded smmonium formste (1.59 g, 25.2 mmol) snd the mixture wss hested st 130°C for 1 h. After a second sddition of smmonium formste (1.59 g, 25.2 mmol) the resction was heated for 1.5 h and was evaporated. The residue was partitioned between ethyl acetste snd sstursted NsHCθ3. The orgsnic phsse wss wsshed with brine, dried (MgSθ4), filtered snd evsporsted. The residue was purified by silica gel chromatography (1/2- hexane /ethyl scetste) to sfford 818 (556 mg, 64%) as a pale yellow solid.
Example 173
Acetate 819: To a solution of 818 (500 mg, 1.45 mmol) in pyridine (10 mL) was sdded DMAP (20 mg, 0.16 mmol) end scetic snhydride (216 μL, 2.3 mmol). The solution wss stirred for 1 h st room tempersture snd wss evsporated. The residue wss purified by silics gel chromstography (1/1- hexsne/ethyl scetste) to sfford 819 (557 mg, 94%) ss a solid.
Example 174 N-Trityl aziridine 820: A solution of 819 (459 mg, 1.18 mmol) in 1.24
M HCl in ethyl acetate (20 mL) wss stirred at room temperature for 2.5 h. The solvent was evaporated to afford a white solid which was placed under high vacuum overnight. To a solution of the solid (315 mg) in CH2CI2 (10 mL) at 0°C wss sdded trityl chloride (346 mg, 1.24 mmol) snd Et3N (354 μL, 2.54 mmol). The solution wss stirred for 1.75 h st which time Et3N (354 μL, 2.54 mmol) snd methanesulfonyl chloride (105 μL, 1.36 mmol) were added. The resction mixture wss stirred st 0°C for 1.5 h snd wss wsrmed to room tempersture stirring for 5 h. The solvent was evaporated and the residue was partitioned between ether and water. The orgsnic phsse wss wsshed with wster snd the combined squeous wsshes were extrscted with ether. The combined orgsnic extrscts were wsshed with brine, dried (MgSθ4), filtered snd evsporsted. Purificstion of the residue by silics gel chromstogrsphy (CH2CI2) afforded 820 (440 mg, 83%) as a white foam.
Example 175
Pentyl ether 821: To a solution of 820 (100 mg, 0.21 mmol) in 3- pentsnol (2 mL) wss sdded BF3«OEt2 (39 μL, 0.32 mmol) and the solution was heated st 75-80°C for 1.5 h. After evsporstion of the solvent, the residue wss dissolved in pyridine (2 mL) and was treated with acetic anhydride (100 μL, 1.05 mmol) and DMAP. The reaction was stirred at room temperature for 14 h, evsporsted snd the residue wss psrtitioned between ethyl scetste snd IN HCl. The squeous phsse wss extrscted with ethyl scetste snd the combined orgsnic extrscts were wsshed with sstursted NsHCθ3, brine, dried (MgSθ4), filtered snd evsporsted. The residue wss chromstogrsphed on silica gel (1/1-ethyl acetste /CH2CI2) to sfford 821 (46 mg, 62%) ss s solid.
Example 176
Hydroxy acid 822: To a solution of 821 (42 mg, 0.12 mmol) in THF (2 mL) was added IN KOH (260 μL, 0.27 mmol) and the mixture was stirred at room tempersture for 5.5 h. The solution wss acidified with Amberlite IR120 ion exchange resin (pH 3) and the resin wss filtered snd wsshed with THF. Sovent wss evsporsted to sfford s residue which wss dissolved in water and chroma tographed on Cg reverse phase silica gel eluting with wster. The wster wss evsporsted snd the residue was evaporated from methanol to give 822 (29 mg, 85%) as a solid.
Example 177
Methyl ether 823: To a solution of 816 (200 mg, 0.88 mmol) in methanol (5 mL) wss sdded BF3»OEt2 (120 μL, 0.97 mmol). The solution wss refluxed for 2 h, evsporsted, snd the residue was dissolved in pyridine (4 mL) and wss trested with scetic snhydride (415 μL, 4.4 mmol). After stirring for 1 h st room tempersture the solvent wss evaporated and the residue was psrtitioned between ethyl acetate and 5% citric acid. The organic phase wss wsshed with sstursted N3HCO3, brine, dried ( gSθ4), filtered, snd evsporsted. The residue wss purified by silics gel chromstogrsphy (10% methsnol in CH2CI2) to sfford 823 (76 mg, 29%) ss a white solid.
Exsmple 178
Hydroxy acid 824: A solution of 823 (33 mg, 0.11 mmol) in 2.5M HCl in ethyl acetate (2 mL) W3S stirred for 2.5 h st room tempersture snd wss evsporsted. The residue wss dissolved in THF (2 mL) and was treated with IN KOH (154 μL, 0.16 mmol) snd wster (300 μL). The resction wss stirred 3t room tempersture for 6 h snd was acidified with Dowex 50WX8 ion exchange resin. The resin was filtered and the filtrate was evaporated to sfford a residue which wss dissolved in wster snd chromstographed on Cis reverse phase silics gel. After lyophilizstion, 824 (24 mg, 95%) wss isolsted ss s white solid. Exsmple 179
Methyl ether 825: To s solution of 820 (80 mg, 0.17 mmol) in methsnol (2 mL) wss sdded BF3»OEt2 (32 μL, 0.26 mmol). The solution wss refluxed for 2 h, evsporsted, snd the residue wss dissolved in pyridine (2 mL). To the solution wss sdded scetic snhydride (80 μL, 0.85 mmol) 3nd cstslytic DMAP. After stirring 14 h, the solvent wss evsporsted snd the residue wss chromstogrsphed on silics gel (ethyl acetate) to afford 825 (46 mg, 90%) ss a white solid.
Exsmple 180
Hydroxy acid 826: To a solution of 825 (46 mg, 0.15 mmol) in THF (2 mL) was added IN KOH (433 μL, 0.45 mmol) and the mixture was stirred at room temperature for 5 h. The solution was acidified with Dowex 50WX8 ion exchange resin and the resin was filtered snd wsshed with methsnol. Sovent wss evsporsted to afford a residue which was dissolved in water snd psssed through a column of Cis reverse phsse silica eluting with water. The solvent was evaporated to give 826 (33 mg, 96%) ss a white solid.
Example 181
Methyl ether 827: To a solution of 816 (612 mg, 0.27 mmol) in methanol (25 mL) wss added BF3»OEt2 (370 μL, 3.0 mmol). The solution was refluxed for 2 h, evaporated, and the residue was dissolved in CH2CI2 (5 mL) and was trested with di-tert-butyldicarbonate (880 mg, 4.1 mmol) in CH2CI2 (3 mL) and Et3N (570 μL, 4.1 mmol). After stirring for 5 h at room temperature the solvent wss evsporated and the residue was partitioned between ethyl scetste snd wster. The orgsnic phsse wss wsshed with wster, brine, dried (MgSθ4), filtered, snd evaporated. The residue was purified by silica gel chromstogrsphy (2/1-hexsne/ethyl scetste) to sfford 827 (630 mg, 65%) ss 3n oil.
Example 182
N-Trityl aziridine 828: A solution of 827 (574 mg, 1.6 mmol) in 2.5 M HCl in ethyl acetate (20 mL) was stirred at room temperature for 5 h. The solvent was evsporsted to afford a white solid (400 mg). To a suspension of the solid in CH2CI2 (5 mL) at 0°C was added trityl chloride (490 mg, 1.6 mmol) and Et3N (278 μL, 3.6 mmol). The solution was stirred for 2 h at which time Et3N (278 μL, 3.6 mmol) and methanesulfonyl chloride (136 μL, 1.76 mmol) were sdded. The resction mixture wss stirred st 0°C for 1 h snd wss wsrmed to room tempersture stirring for 4 h. The solvent wss evsporsted snd the residue wss psrtitioned between ether snd wster. The orgsnic phsse wss wsshed with wster snd the combined squeous wsshes were extrscted with ether. The combined orgsnic extrscts were wsshed with brine, dried (MgSθ4), filtered snd evsporsted. Purificstion of the residue by silics gel chromstogrsphy (CH2CI2) afforded 828 (170 mg, 25%) as a white fosm.
Example 183
Bis-methyl ether 829: To a solution of 828 (60 mg, 0.14 mmol) in methsnol (2 mL) wss sdded BF3»OEt2 (26 μL, 0.21 mmol). The solution wss refluxed for 1 h, evsporated, and the residue was dissolved in pyridine (1 mL) and W3S trested with acetic anhydride (66 μL, 0.70 mmol). After stirring for 18 h at room temperature the solvent wss evsporsted snd the residue wss psrtitioned between ethyl scetste snd IN HCl. The orgsnic phsse wss wsshed with saturated NaHCθ3, brine, snd wss dried (MgSθ4), filtered, snd evsporsted. The residue was purified by silica gel chromstogrsphy (10% methsnol in CH2CI2) to afford 829 (13 mg, 34%) as a white solid.
Example 184
Carboxylic acid 830: To a solution of 829 (13 mg, 0.048 mmol) in THF (1 mL) was sdded IN KOH (69 μL, 0.072 mmol) snd the mixture wss stirred st room tempersture for 48 h. The solution wss scidified with Dowex 50WX8 ion exchsnge resin snd the resin wss filtered 3nd wsshed with methsnol. Sovent was evaporated to afford a residue which was dissolved in wster snd psssed through s column of Cis reverse phsse silics to give sfter lyophilizstion 830 (8 mg, 68%) ss s white solid.
Exsmple 185
Lactone 900: A solution of quinic acid (20 kg, 104 mol; [α]D-43.7° (c = 1.12, water); Merck Index 11th ed., 8071: [α]D -42° to -44° (wster)), 2,2- dimethoxypropsne (38.0 kg, 365 mol) snd p-toluenesulfonic scid monohydrate (0.200 kg, 1.05 mol) in scetone (80 kg) wss hested st reflux for two hours. The resction wss quenched by sddition of 21% sodium ethoxide in ethsnol (0.340 kg, 1.05 mol) snd most of the solvent wss distilled in vacuo. The residue wss psrtitioned between ethyl scetste (108 kg) and water (30 kg). The aqueous layer was back-extracted with ethyl scetste (13 kg) snd the combined orgsnic layers were wsshed with 5% squeous sodium bicsrbonste (14 kg). Most of the ethyl scetste wss distilled in vacuo to lesve 3 psle yellow solid residue of 900 which wss used directly in the next step.
Example 186 Hydroxy ester 901: A solution of the crude Isctone 900 (from 104 mol
(-)-quinic scid) in sbsolute ethsnol (70 kg) wss trested with 20% sodium ethoxide in ethsnol (0.340kg, 1.05 mol). After two hours st room temperature, scetic acid (0.072 kg, 1.2 mol) was added and the solvent was distilled in vacuo. Ethyl acetate (36 kg) was added and the distillation continued to nesr dryness. The tsn solid residue composed of s cs. 5:1 mixture of 901:900 wss dissolved in ethyl scetste (9 kg) st reflux snd hexsne (9 kg) wss sdded. Upon cooling, a white crystslline solid formed which was isolated by filtration to afford a ca. 6.5:1 mixture of 901:900 (19.0 kg, 70% yield).
Example 187
Mesyl ester 902: A solution of a ca. 6.5:1 mixture (18.7 kg, ca. 72 mol) of hydroxy ester 901 and lactone 900 in dichloromethane (77 kg) wss cooled to 0-10°C snd trested with methsnesulfonyl chloride (8.23 kg, 71.8 mol), followed by slow sddition of triethylsmine (10.1 kg, 100 mol). An sdditionsl portion of methsnesulfonyl chloride (0.84 kg, 7.3 mol) wss sdded. After one hour, wster (10 kg) snd 3% hydrochloric scid (11 kg) were sdded. The lsyers were sepsrsted snd the orgsnic lsyer wss washed with water (9 kg), then distilled in vαcuo to leave a semi-solid residue composed of a cs. 6.5:1 mixture of mesyl ester 902 snd mesyl Isctone 903. The residue wss dissolved in ethyl scetste (11 kg) snd cooled to -10° to -20°C for two hours. Mesyl Isctone 903 crystsllized snd wss sepsrated by filtration snd wsshed with cold ethyl scetse (11 kg). The filtrste wss concentrsted to sfford mesyl ester 902 ss sn orsnge resin (20.5 kg, 84.3% yield).
Example 188 Mesyl acetonide 904: A solution of mesyl ester 902 (10.3 kg, 30.4 mol) and pyridine (10.4 kg, 183 mol) in dichloromethane (63 kg) was cooled to -20° to -30°C and treated portionwise with sulfuryl chloride (6.22 kg, 46 mol). After the exothermic reation subsided, the resulting slurry wss quenched with ethsnol (2.4 kg), wsrmed to 0°C, snd wsshed successively with 16% sulfuric scid (35 kg), wster (15 kg) snd 5% squeous sodium bicsrbonate (1 kg). The organic layer contsining a C3. 4:1:1 mixture of 904:905:906 wss concentrated in vαcuo 3nd ethyl scetste (14 kg) wss added. The allylic mesylste 905 wss selectively removed by trestment of the ethyl scetste solution with pyrrolidine (2.27 kg, 31.9 mol) snd tetrskis(triphenylphosphine)psllsdium(0) (0.0704 kg, O.Oόlmol) st ambient temperature for five hours, followed by wsshing with 16% sulfuric scid (48 kg). The orgsnic layer was filtered through a pad of silica gel (11 kg) and eluted with ethyl acetate (42 kg). The filtrate was concentrated in vαcuo to leave a thick orange oil composed of a ca. 4:1 mixture of 904:906. The residue was dissolved in ethyl acetate (5.3 kg) at reflux and hexane (5.3 kg) wss sdded. Upon cooling, mesyl 3cetonide 904 crystsllized snd wss sepsrated by filtration snd wsshed with 14% ethyl scetste in hexsne (2.1 kg). After drying in vαcuo, 904 was obtained ss psle yellow needles (4.28 kg, 43.4% yield), mp 102-3°C.
Exsmple 189
Pentyl ketal 907: A solution of acetonide 904 (8.9 kg, 27.8 mol), 3- pentsnone (24 kg, 279 mol) snd 70% perchloric acid (0.056 kg, 0.39 mol) was stirred for 18 hours. The volatiles were distilled in vαcuo at ambient tempersture snd fresh 3-pentanone (30 kg, 348 mol) was added gradually as the distillation progressed. The reaction mixture was filtered, toluene (18 kg) was added, and the resulting solution was washed successively with 6% aqueous sodium bicsrbonste (19 kg), wster (18 kg) snd brine (24 kg) . The orgsnic lsyer wss concentrsted in vαcuo and toluene (28 kg) was added graduslly ss the distillstion progressed. When on more distilled, the residusl orsnge oil wss composed of pentyl ketsl 907 (9.7 kg, 100% yield) snd toluene (cs. 2 kg).
Example 190
Pentyl ether 908: A solution of ketal 907 (8.6 kg, 25 mol) in dichloromethane (90 kg) was cooled to -30° to -20°C and treated with borane- methyl sulfide complex (2.1 kg, 27.5 mol) snd trimethylsilyl trifluoromethanesulfonste (7.2 kg, 32.5 mol). After one hour, 10% aqueous sodium bicarbonste solution (40 kg) wss slowly added. The mixture was wsrmed to smbient tempersture snd stirred for 12 hours. The orgsnic lsyer wss filtered snd concentrsted in vacuo to lesve a ca. 8:1 mixture of 908:909 as a gray wsxy solid (7.8 kg, 90% yield).
Exsmple 191 Epoxide 910: A cs. 8:1 mixture of isomeric pentyl ethers 908:909 (7.8 kg, 22.3 mol) in ethsnol (26 kg) wss trested with a solution of potassium hydrogen csrbonste (3.52 kg, 35 mol) in wster (22 kg). After nesting st 55°- 65°C for two hours, the solution was cooled and twice extracted with hexanes (31 kg, then 22 kg). Unreacted 909 remained in the aqueous ethanol lsyer. The combined hexsne extrscts were filtered snd concentrsted in vacuo to lesve epoxide 910 as a flocculent white crystalline solid (3.8 kg, 60% yield), mp=54-6°C.
Example 192 Hydroxy azide 911: A mixture of epoxide 910 (548 g, 2.0 mol), sodium azide (156 g, 2.4 mol) and ammonium chloride (128.4 g, 2.4 mol) in water (0.265 L) and ethsnol (1.065 L) wss hested at 70°-75°C for eight hours. Aqueous sodium bicarbonate (0.42 L of 8% solution) was added and the ethanol was distilled in vacuo. The aqueous residue was extracted with ethyl scetste (1 L) snd the extrsct wss wsshed with wster (0.5 L). The wster wssh wss bsck-extracted with ethyl scetste (0.5 L). The combined orgsnic extracts were wsshed with brine (0.5 L), dried over snhydrous sodium sulfste, filtered and concentrated in vacuo to leave a ca. 10:1 mixture of isomeric hydroxy azides 911:912 (608 g, 102% yield) as a dark brown oil.
Example 193
Aziridine 913: A ca. 10:1 mixture of hydroxy azides 911:912 (608 g, 2.0 mol) was three times co-evaporated in vacuo from anhydrous acetonitrile (3 x 0.3 L) snd then dissolved in anhydrous acetonitrile (1 L). A solution of anhydrous triphenylphosphine (483 g, 1.84 mol) in anhydrous tetrahydrofuran (0.1 L) and anhydrous acetonitrile (0.92 L) was 3dded dropwise over two hours. The mixture was heated at reflux for six hours then concentrated in vacuo to leave a golden paste composed of aziridine 913, triphenylphosphine oxide snd traces of triphenylphosphine. The psste wss triturated with diethyl ether (0.35 L). Most of the insoluble triphenylphosphine oxide wss removed by filtration snd wsshed with diethyl ether (1.5 L). The filtrste wss concentrsted in vacuo to lesve 3 dsrk brown oil which wss dissolved in 20% squeous methsnol snd extracted three times with hexsnes (3 x 1 L) to remove triphenylphosphine. The hexsne extrscts were bsck-extracted with 20% squeous methsnol (0.5 L) snd the combined squeous methsnol lsyers were concentrsted in vacuo. The residue wss twice co-evsporsted in vacuo from snhydrous scetonitrile (2 x 0.5 L) to lesve s dsrk brown oil composed of sziridene 913 (490 g, 96.8 % yield) snd triphenylphosphine oxide (c3. 108 g) which wss used directly in the next step.
Exsmple 194
Acetamido azide 915: A mixture of aziridine 913 (490 g, 1.93 mol) and triphenylphosphine oxide (c3. 108 g), sodium szide (151 g, 2.33 mol) snd smmonium chloride (125 g, 2.33 mol) in dimethylformsmide (1.3 L) wss hested st 80°-85°C for five hours. Sodium bicsrbonste (32.8 g, 0.39 mol) snd wster (0.66 L) were sdded. The amino azide 914 was isolated from the reaction mixture by six extractions with hexsnes (6 x 1 L). The combined hexsne extrscts were concentrsted in vacuo to ca. 4.5 L total volume and dichloromethsne (1.04 L) wss sdded. Aqueous sodium bicsrbonste (4.2 L of 8% solution, 3.88 mol) wss added, followed by acetic anhydride (198 g, 1.94 mol). After stirring for one hour at ambient temperature, the aqueous layer wss discsrded. The orgsnic phsses were concentrsted in vacuo to 1.74 kg totsl weight 3nd dissolved with ethyl scetste (0.209 L) st reflux. Upon cooling, scetsmido szide 915 crystsllized and was isolated by filtration. After washing with cold 15% ethyl acetate in hexane (1 L) and drying in vacuo at ambient tempersture, pure 915 wss obtsined as off-white crystals (361 g, 55% yield), mp 126-132°C.
Example 195 Acetamido amine 916: A mixture of azide 915 (549 g, 1.62 mol) and
Lindlar cstslyst (50 g) in sbs. ethsnol (3.25 L) was stirred for eighteen hours while hydrogen (1 atm.) wss bubbled through the mixture. Filtration through Celite snd concentrstion of the filtrste vacuo afforded 916 as 3 fosm which solidified on stsnding (496 g, 98% yield).
Example 196
Phosphate salt of 916: A solution of acetamido amine 916 (5.02 g, 16.1 mmol) in acetone (75 mL) st reflux wss trested with 85% phosphoric sdd (1.85 g, 16.1 mmol) in sbs. ethsnol (25 mL). Crystsllizstion commenced immedistely 3nd 3fter cooling to 0°C for 12 hours the precipitste was collected by filtration to afford 916»H3Pθ4 as long colorless needles (4.94 g, 75% yield; [α]D -39.9° (c=l, water)), mp 203-4°C.
Example 197
Hydrochloride salt of 916: A solution of acetamido amine 916 (2.8 g, 8.96 mmol) in sbs. ethsnol (9 mL) wss trested with 2.08 M hydrogen chloride in ethsnol (8.6 mL, 17.9 mmol). Most of the ethsnol wss evsporsted in vacuo 3nd the oily residue wss stirred with ethyl scetste (20 mL) until solid formed. Hexsnes (20 mL) were grsduslly sdded to the stirred mixture. After one hour st smbient tempersture, the solid was collected by filtration, wsshed with diethyl ether and dried in vacuo. This afforded 916* HCl as an off-white solid (2.54 g, 81°/.. yield; [α]D -43° (c=0.4, water)), mp 206°C.
Example 198
Aziridine 712: To a solution of azide mesylate 711 (1.27 g, 3.15 mmol) in anhydrous THF (10 mL) at room temperature was added triphenylphosphine (1.0 g, 3.8 mmol) in four portion. The reaction was stirred at room temperature for 3.5 h, then cooled to 0°C, and triethylsmine (0.53 mL, 3.8 mmol) and water (0.5 mL) were added. The resulted mixture was stirred st room tempersture for 3 h, then st 45°C for another 3 h. The reaction mixture wss evsporsted snd the residue wss psrtitioned between ethyl scetste snd wster. The squeous phsse was extracted with ethyl acetste. The combined extrscts were wsshed with brine, dried (MgSθ4), filtered snd evsporated. The residue wss chromstogrsphed and treated with ethyl ether /hexsne (to remove most of the triphenylphosphine oxide) to sfford desired sziridine 712 (0.56 g, 65%, with cs. 15% of triphenylphosphine oxide) Exsmple 199
N-Acetyl Azide 713: The mixture of aziridine 712 (0.56g, 17 mmol), sodium azide (0,65 g, 10.0 mmol) 3nd smmonium chloride (0.4 g, 7.5 mmol) in DMF (5.0 mL) wss stirred st 65°C for 18 h. The resction mixture wss diluted with hexsne (20 mL) snd filtered through a short plug of silics gel (eluted with ethyl acetste/hexsne). The filtrste was evaporsted. The residue wss dissolved in pyridine (5.0 mL), 3nd scetic snhydride (1.0 mL) wss sdded. The resulted mixture wss stirred 3t room tempersture for 14 h, snd then evsporated. The residue wss dissolved in ethyl scetste snd wsshed with sstursted NsHCθ3, 3nd brine. The orgsnic phsse W3S dried (MgSθ4), filtered snd evsporsted. The residue wss chromstogrsphed snd crystsllized from ethyl scetste /hexsne to give N-scetyl szide 713 (20 mg, 3.3%) ss 3 solid. iH NMR (CDCI3): 5.68 (d, IH, J=7.9), 4.31 (d, IH, J=5.2), 4.09 (m, IH), 3.94 (m, IH), 3.83 (s, 3H), 3.65 (m, IH), 2.82 (ddd, IH, J=0.9, 5.2, 17.7), 2.55 (ddd, IH, J=1.5, 7.3, 17.7), 2.06 (s, 3H), 1.62 (m, 4H), 0.96 (m, 6H).
All literature snd pstent citations sbove are hereby expressly incorporated by reference in their entirety 3t the locations of their citation. Spedfically cited sections or psges of the sbove cited works sre incorporated by reference with specificity. The invention hss been described in detsil sufficient to sllow one of ordinsry skill in the art to make and use the subject matter of the following clsims. It is apparent that certain modificstions of the methods snd compositions of the following clsims csn be msde within the scope and spirit of the invention.

Claims

What is claimed is:
1. A composition comprising a compound of formula (I) or (II):
Figure imgf000371_0001
0) CD wherein
Al is -C(Jl)=, -N= or -N(0)=;
A2 is -C(Ji)2-, -N(J╬╣)-, -N(0)(J╬╣)-, -S-, -S(O)-, -S(0)2- or -O-;
Ei is -(CRiRi)miWi;
Gi is N3, -CN, -OH, -OR6a, -N╬╕2, or -(CR╬╣R╬╣)m╬╣W2; Ti is -NR1W3, H, -R3, -R5, a heterocycle, or is taken together with Ui or Gi to form a group having the structure
Figure imgf000371_0002
Ul is H, -R3 or -X1W6;
Jl and Jla are independently Ri, Br, Cl, F, I, CN, NO2 or N3; J2 and J2a sre independently H or Ri;
Rl is independently H or slkyl of 1 to 12 carbon atoms;
R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
R3 is independently F, Cl, Br, I, -CN, N3, -N0 , -OR a, -ORi, -N(R╬╣)2, -N(R!)(R6b), -N(R6b)2, -SRi, -SR6a, -S(0)R╬╣, -S(0)2R╬╣, -S(0)OR!, -S(0)OR a, -S(0)2OR╬╣, -S(0)2OR6a, -C(0)OR╬╣, -C(0)R6c, -C(0)OR a, -OC(0)R╬╣, -N(R╬╣)(C(0)R╬╣), -N(R6 )(C(0)R╬╣), -N(R╬╣)(C(0)OR╬╣), -N(-Rsb)(C(0)OR╬╣), -C(0)N(R╬╣)2, -C(0)N(R6b)(R1), -C(0)N(R6b)2, -C(NR╬╣)(N(R╬╣)2), -C(N(R6b))(N(R╬╣)2), -C(N(R1))(N(R1)(R6b)), -C(N(R6b))(N(R1)(R6b)), -C(N(R1))(N(R6b)2), -C(N(R6b))(N(R6b)2), -N(R╬╣)C(N(R1))(N(R1)2), -N(R╬╣)C(N(R╬╣))(N(R╬╣)(R6b)), -N(R╬╣)C(N(R6b))(N(R1)2), -N(R6b)C(N(R1))(N(R╬╣)2), -N(R6b)C(N(R6b))(N(R1)2), -N(R6b)C(N(R1))(N(R╬╣)(R6b)), -N(R1)C(N(R6b))(N(R1)(R6b)), -N(R╬╣)C(N(R╬╣))(N(R6b)2), -N(R6b)C(N(R6b))(N(R╬╣)(R6b)), -N(R6b)C(N(R1))(N(R6b)2), -N(R╬╣)C(N(R6b))(N(R6b)2), -N(R6b)C(N(R6b))(N(R6b)2), =0, =S, =N(R╬╣), =N(R6b) or W5;
R4 is independently slkyl of 1 to 12 csrbon atoms, alkenyl of 2 to 12 carbon 3toms, or slkynyl of 2 to 12 csrbon stoms;
R5 is independently R4 wherein esch R4 is substituted with 0 to 3 R3 groups;
R5a is independently slkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon 3toms, or slkynylene of 2-12 csrbon stoms 3ny one of which slkylene, slkenylene or slkynylene is substituted with 0-3 R3 groups; R6s is independently H or sn ether- or ester-forming group; R^t, is independently H, s protecting group for smino or the residue of s csrboxyl-containing compound;
R6c is independently H or the residue of an amino-containing compound;
Wi is a group comprising an acidic hydrogen, a protected acidic group, or 3n R6c amide of the group comprising an acidic hydrogen;
W2 is a group comprising a basic heterostom or s protected bssic heterostom, or an R6b amide of the basic heteroatom; W3 is W4 or W5;
W4 is R5 or -C(0)R5, -C(0)W5, -SO2R5, or -SO2W5; W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
W6 is -R5, -W5, -R5aW5, -C(0)OR6s, -C(0)R6o -C(0)N(R6b)2, -C(NR6b)(N(R6b)2), -C(NR6b)(N(H)(R6b)), -C(N(H)(N(R6b)2), -C(S)N(R6b)2, or -C(0)R2;
Xl is 3 bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH2)-, -N(N(H)(W6))-, -N(N(W6)2)-, -N(H)N(W6)-, -S-, -SO-, or -SO2-; and each mi is independently sn integer from 0 to 2; provided, however, thst compounds sre excluded wherein: (3) Ai is -CH= or -N= snd A2 is -CH2-;
(b) Ei is COOH, P(0)(OH)2, SOOH, SO3H, or tetrszol;
(c) Gi is CN, N(H)R20, N3, SR20, OR20, gusnidino, -N(H)CN N-R20 . NR20 - NΓÇö O Γûá _NH J-R20 . O 20 R20 R20R20
Figure imgf000373_0001
(d) Ti is -NHR20;
(e) R20 is H; sn scyl group hsving 1 to 4 csrbon stoms; a linesr or cyclic slkyl group hsving 1 to 6 csrbon stoms, or 3 hslogen-substituted snslogue thereof; sn silyl group or an unsubstituted aryl group or an aryl substituted by a hslogen, sn OH group, sn NO2 group, sn NH2 group or COOH group;
(f) Ji is H snd J╬╣a is H, F Cl, Br or CN; (g) J2 is H snd J23 is H, CN or N3;
(h) Ui is CH2YR20s, CHYR2╬╕sCH2YR2╬╕3 or
CHYR20sCHYR20aCH2YR20a; (i) R203 is H or scyl hsving 1 to 4 csrbon stoms; (j) Y is O, S, H or NH; (k) 0 to 2 YR2O3 are H, snd
(1) successive Y moieties in a Ui group sre the ssme or different, snd when Y is H then R20s i a covslent bond, snd provided thst if Gi is N3 then Ui is not -CH2OCH2PI1. and the pharmaceutically acceptable salts and solvates thereof; further excluded sre compounds of the formuls II wherein: (s) A2 is O;
(b) Ei is COOH, P(0)(OH)2, N02, SOOH, SO3H, tetrazole, CH2CHO, CHO, CH(CHO)2 or where Ei is COOH, P(0)(OH)2, SOOH or SO3H, an ethyl, methyl or pivaloyl ester thereof;
(c) Gi is hydrogen, N(R20a)2, SR20a or OR20a;
(d) Ti is -NHC(O)R20b, where R20b is sn unsubstituted or halogen-substituted linear or cyclic alkyl group of 1 to 6 carbon atoms, or SR20a, OR20a, COOH or alkyl /aryl ester thereof, N02, C(R20a)3, CH2COOH or alkyl/aryl ester thereof, CH2N02 or CH2NHR20b; (e) R2t)a is hydrogen; an acyl group having 1 to 4 csrbon atoms; a linear or cyclic alkyl group having 1 to 6 csrbon atoms, or a halogen-substituted analogue thereof; or an unsubstituted aryl group or an aryl substituted by a hslogen, sn silyl group, 3n OH group, sn NO2 group, sn
NH2 group or 3 COOH group;
(f) Ji is H snd Jιa is H, OR20a, F, Cl, Br, CN, NHR^a, SR20a or CH2X wherein X is NHR2« , hslogen or OR2«a;
(g) J2 is H or J2a is hydrogen, N(R 0a)2, SR 0a or OR20a; (h) Ui is CH2YR20a, CHYR 0CH2YR20 or
CHYR 0aCHYR20aCH2YR2┬░a where Y is O, S or H, snd successive Y moieties in Ui are the same or different and R20a represents a covalent bond when Y is hydrogen; snd and pharmscologicslly scceptsble salts or derivatives thereof; and the salts, solvates, resolved enantiomers snd purified disstereomers thereof.
2. A composition comprising a compound of clsim 1 and an enteric protectant.
3. A composition comprising an enterically protected compound of clsim 1.
4. A composition comprising an enteric protectant and a compound of the formula:
Figure imgf000374_0001
wherein:
Ei is -C02H, -CO2R5, - 02R5aW5 or -CO2W5; Gi is -N(Ru)2, -N(Rn)C(N(R╬╣╬╣))(N(Rn)2), or -C(Rii)2-N(R╬╣╬╣)2;
Ti is -NH(C(0)CH3), -NH(C(0)CH2F), -NH(C(0)CHF2), or -NH(C(0)CF3);
Ui is -OR4, -SR4, NHR4 or N(R4)2; each Ri is independently H or alkyl of 1 to 12 carbon atoms; esch R2 is independently R3 or R4 wherein esch R4 is independently substituted with 0 to 3 R3 groups; esch R3 is independently F, Cl, Br, I, -CN, N3, -N02, -OR a, -ORi, -N(R╬╣)2, -N(R!)(R6b), -N(R6b)2, -SRj, -SR6a, -S(0)R╬╣, -S(0)2R╬╣, -S(0)OR╬╣, -S(0)OR6a, -S(0)2OR╬╣, -S(0)2OR6a/ -C(0)OR!, -C(0)R6C, -C(0)OR6a/ -OC(0)R╬╣, -N(R╬╣)(C(0)R╬╣), -N(R6b)(C(0)R╬╣), -N(R!)(C(0)OR╬╣), -N(R6b)(C(0)OR╬╣), -C(0)N(R╬╣)2, -C(0)N(R6b)(R1), -C(0)N(R6b)2, -C(NR1)(N(R1)2), -C(N(R6b))(N(R!)2), -C(N(R1))(N(R1)(R6b)), -C(N(R6b))(N(R1)(R6b)), -C(N(R╬╣))(N(R6b)2), -C(N(R6b))(N(R6b)2), -N(R╬╣)C(N(R╬╣))(N(R1)2), -N(R╬╣)C(N(R╬╣))(N(R1)(R6b)), -N(R1)C(N(R6b))(N(R1)2), -N(R6b)C(N(R1))(N(R1)2), -N(R6b)C(N(R6b))(N(R1)2), -N(R6b)C(N(R╬╣))(N(R1)(R6b)), -N(R1)C(N(R6b))(N(R╬╣)(R6b)), -N(R1)C(N(R1))(N(R6b)2), -N(R6b)C(N(R6b))(N(R1)(R6b)), -N(R6b)C(N(R╬╣))(N(R6b)2), -N(R1)C(N(R6b))(N(R6b)2), -N(R6b)C(N(R6b))(N(R6b)2)/ =0, =S, =N(R╬╣), =N(R6b) or W5;
R4 is independently slkyl of 1 to 12 csrbon stoms, alkenyl of 2 to 12 carbon stoms, or slkynyl of 2 to 12 csrbon stoms; 3nd
R5 is independently R4 wherein esch R4 is substituted with 0 to 3 R3 groups; R5a is independently slkylene of 1 to 12 csrbon stoms, slkenylene of 2 to 12 csrbon stoms, or slkynylene of 2-12 csrbon stoms sny one of which slkylene, slkenylene or alkynylene is substituted with 0-3 R3 groups R a is independently H or 3n ether- or ester-forming group; R6b is independently H, a protecting group for amino or the residue of a csrboxyl-contsining compound;
R6C is independently H or the residue of an smino-contsining compound;
W5 is csrbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups; snd R11 is independently H or R5.
5. The composition comprising a compound of clsim 4 wherein El is C(0)0CH2CH3; Gi is NH2; Ti is NH(C(0)CH3); snd Ui is OCH(CH2CH3)2.
6. A composition comprising sn entericslly protected compound of the formuls:
Figure imgf000376_0001
7. The composition of claim 6 comprising a compound of the formula:
H3C 1r CH3 Q
H3C 0 N H2 and an enteric coating.
8. A method of inhibiting the activity of neuraminidase comprising the step of contacting a sample suspected of containing neuraminidase with a composition comprising an enterically protected composition of claim 1.
9. The method of clsim 8 wherein the neuraminidase is influenza neuraminidase in vivo.
10. A method for the treatment or prophylaxis of influenza infection in a host comprising administering to the host a therapeutically effective amount of a composition comprising an enterically protected compound of claim 1.
PCT/US1998/019355 1997-09-17 1998-09-15 Compounds containing six-membered rings, processes for their preparation, and their use as medicaments WO1999014185A1 (en)

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NZ502988A NZ502988A (en) 1997-09-17 1998-09-15 5-Acetamido-4-amino-2-propionyloxy-6-isopropoxy-1-cyclohexene useful for treating influenza
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