USRE38333E1 - Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability - Google Patents

Antiviral phosphonomethoxy nucleotide analogs having increased oral bioavailability Download PDF

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USRE38333E1
USRE38333E1 US10/159,888 US15988802A USRE38333E US RE38333 E1 USRE38333 E1 US RE38333E1 US 15988802 A US15988802 A US 15988802A US RE38333 E USRE38333 E US RE38333E
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pmpa
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Murty N. Arimilli
Kenneth C. Cundy
Joseph P. Dougherty
Choung U. Kim
Reza Oliyai
Valentino J. Stella
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Gilead Sciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • the present invention relates to intermediates for phosphonomethoxy nucleotide analogs, in particular intermediates suitable for use in the efficient oral delivery of such analogs.
  • Z is independently —OC(R 2 ) 2 OC(O)X(R) a , an ester, an amidate or —H, but at least one Z is —OC(R 2 ) 2 OC(O)X(R) a ;
  • A is the residue of an antiviral phosphonomethoxy nucleotide analog
  • X is N or O
  • R 2 independently is —H, C 1 -C 12 alkyl, C 5 -C 12 aryl, C 2 -C 12 alkenyl, C 2 -C 12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or —OR 3 in which R 3 is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or C 5 -C 12 aryl;
  • R independently is —H, C 1 -C 12 alkyl, C 5 -C 12 aryl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 7 -C 12 alkyenylaryl, C 7 -C 12 alkynylaryl, or C 6 -C 12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, —N(R 4 ) 2 or —OR 3 , where R 4 independently is —H or C 1 -C 8 alkyl, provided that at least one R is not H; and
  • a is 1 when X is 0 , or 1 or 2 when X is N;
  • N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be —OR 3 or (c) both N-linked R groups can be —H;
  • B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl of their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl;
  • R is independently —H, C 1 -C 12 alkyl, C 5 -C 12 aryl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 7 -C 12 alkenylaryl, C 7 -C 12 alkynylaryl, or C 6 -C 12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or —OR 3 in which R 3 is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or C 5 -C 12 aryl;
  • R 1 is hydrogen, —CH 3 , —CH 2 OH, —CH 2 F, —CH ⁇ CH 2 , or —CH 2 N 3 , or R 1 and R 8 are joined to form —CH 2 —;
  • R 2 independently is hydrogen or C 1 -C 6 alkyl
  • R 8 is hydrogen or —CHR 2 —O—C(O)—OR, or R 8 is joined with R 1 to form —CH 2 —;
  • inventions of this invention include a method for preparing a compound of formula (1a) which comprises reacting the diacid of a phosphonomethoxy nucleotide analog with LC(R 2 ) 2 OC(O)X(R) a wherein L is a leaving group.
  • a method for preparing a compound of formula (1) comprises reacting a compound of formula (4)
  • NMP, DMF and DMPU mean, respectively, N-methylpyrrolidinone, dimethylformamide and N,N′-dimethylpropyleneurea.
  • Heterocycle means aromatic and nonaromatic ringed moieties.
  • Heterocyclic moieties typically comprise one ring or two fused rings, where the ring(s) is 5- or 6-membered and typically contains 1 or 2 noncarbon atoms such as oxygen, nitrogen or sulfur, usually oxygen or nitrogen.
  • Alkyl as used herein, unless stated to the contrary, is C 1 -C 12 hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in the form of normal, secondary, tertiary or cyclic structures.
  • Examples are —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 ) CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 3 , —CH (CH 3 )CH 2 CH 2 CH 3 , —CH(CH 2 CH 3 ) 2 , —C(CH 3 2 CH 2 CH 3 , —CH(CH 3 )CH(CH 3 ) 2 , —CH 2 CH 2 CH(CH 3 ) 2 , —CH 2 CH (CH 3 )CH 2 CH 3 , —CH 2 C(CH 3 ) 3 , —CH 2 CH 2 CH 2 CH 2 CH 3 , —CH(CH 3 ) CH 2 CH 2 CH 3 , —CH(CH 2 CH 3 )(CH 2 CH 3 )(CH 2 CH 3
  • Alkenyl as used herein, unless stated to the contrary, is C 1 -C 12 hydrocarbon containing normal, secondary, tertiary or cyclic structures. Examples are —CH ⁇ CH 2 , —CH ⁇ CHCH 3 , —CH 2 CH ⁇ CH 2 , —C( ⁇ CH 2 )(CH 3 ), —CH ⁇ CHCH 2 CH 3 , —CH 2 CH ⁇ CHCH 3 , —CH 2 CH 2 CH ⁇ CH 2 , —CH ⁇ C(CH 3 ) 2 , —CH 2 C( ⁇ CH 2 ) (CH 3 ), —C( ⁇ CH 2 )CH 2 CH 3 , —C(CH 3 ) 2 , —CH 2 C( ⁇ CH 2 ) (CH 3 )CH ⁇ CH 2 , —C ⁇ CHCH 2 CH 2 CH 3 , —CHCH ⁇ CHCH 2 CH 3 , —CHCH ⁇ CHCH 2 CH 3 , —CHCH ⁇ CHCH 2 CH 3 , —CHCH ⁇ CHCH 2 CH
  • Alkynyl as used herein, unless stated to the contrary, is C 1 -C 12 hydrocarbon containing normal, secondary, tertiary, or cyclic structures. Examples are —CCH, —CCCH 3 , —CH 2 CCH, —CCCH 2 CH 3 , —CH 2 CCCH 3 , —CH 2 CH 2 CCH, CH(CH 3 )CCH, —CCCH 2 CH 2 CH 3 , —CH 2 CCCH 2 CH 3 , —CH 2 CH 2 CCCH 3 and —CH 2 CH 2 CH 2 CCH.
  • Salt(s) include those derived by combination of appropriate anions such as inorganic or organic acids.
  • Suitable acids include those having sufficient acidity to form a stable salt, preferably acids of low toxicity.
  • Exemplary organic sulfonic acids include C 6 -C 16 aryl sulfonic acids, C 6 -C 16 heteroaryl sulfonic acids and C 1 -C 16 alkyl sulfonic acids such as phenyl ⁇ -naphthyl, ⁇ -naphthyl, (S)-camphor, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acids.
  • Exemplary organic carboxylic acids include C 1 -C 16 alkyl, C 6 -C 16 aryl carboxylic acids and C 4 -C 16 heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic and 2-phenoxybenzoic. Salts also include the invention compound salts with one or more amino acids.
  • amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically in 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.
  • Salts are usually biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells. Salts that are biologically toxic are generally used with synthetic intermediates of invention compounds.
  • the salts of invention compounds may be crystalline or noncrystalline.
  • A is the residue of a phosphonomethoxy nucleotide analog.
  • the parental compounds have the structure AOCH 2 P (O)(OH) 2 . They are well known and have demonstrated antiviral activity. Per se, they are not part of this invention.
  • A has the structure BQ wherein B is a purine or pyrimidine base or the aza and/or deaza analogs thereof and Q is a cyclic or acyclic aglycon. B is linked to Q through the purine 9 or pyrimidine 1 positions. Examples of these analogs can be found in U.S. Pat. Nos.
  • A will have the structure BCH 2 CH(CH 3 )—or BCH 2 CH 2 —.
  • a is an integer of 1 or 2. If X is N then a is 2 and one R is usually H and the other is not H. If X is O then a is 1.
  • B generally is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl. Ordinarily, B is adenin-9-yl or 2,6-diaminopurin-9-yl.
  • one Z optionally comprises an ester or an amidate. Suitable esters or amidates have been described, e.g., WO 95/07920.
  • esters are phenyl, benzyl, o-ethoxyphenyl, p-ethoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-ethylmorpholino, C 1 -C 8 O-alkyl and C 1 -C 8 NH-alkyl.
  • every compound of the invention will contain at least one —C(R 2 ) 2 OC(O)X(R) a moiety.
  • R 2 independently is —H, C 1 -C 12 alkyl, C 5 -C 12 aryl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 7 -C 12 alkenylaryl, C 7 -C 12 alkynylaryl, or C 6 -C 12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or —OR 3 in which R 3 is C 1 -C 12 alkyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl or C 5 -C 12 aryl.
  • R 2 is usually H or C 1 -C 6 alkyl, and typically only one R 2 is other than H. In most embodiments R 2 is H in both instances.
  • the carbon atom to which R 2 is bonded is capable of chiral substitution, in which case R 2 is in the (R), (S) or racemic configuration.
  • R 2 is other than H the compounds of this invention are chirally enriched or pure at this site. In general, however, manufacturing is somewhat less expensive if chirality at the R 2 carbon can be avoided.
  • R 2 is H when it is desired to help minimize the cost of synthesis.
  • X is O or N, typically O.
  • X is O then a is 1.
  • R independently is —H, C 1 -C 12 alkyl, C 5 -C 12 aryl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 7 -C 12 alkyenylaryl, C 7 -C 12 alkynylaryl, or C 6 -C 12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, —N(R 4 ) 2 or —OR 3 , where R 4 independently is —H or C 1 -C 8 alkyl, provided that at least one R is not H.
  • R is C 1 -C 6 secondary or normal alkyl which is unsubstituted or substituted with OR 3 .
  • X is N then a is 2.
  • one R is usually other than H.
  • two N-linked R groups are joined to form a carbocycle or O-containing heterocycle, typically containing 3 to 5 carbon atoms in the ring.
  • R is unsaturated, but not aryl, the site of unsaturation is not critical and is in the Z or E configuration.
  • the alkenyl chains of naturally occurring unsaturated fatty acids would be suitable as R groups, for example.
  • R also includes cycloalkenyl or cycloalkynyl containing 1 or 2 unsaturated bonds, typically 1 unsaturated bond. When R is unsaturated, usually it is alkenyl or alkynyl without aryl substitution.
  • R is substituted with halo, cyano, azido, nitro or OR 3 , typically R will contain 1 of these substituents. If substituted with 2 of these substituents, they are same or different. Generally, substituents found on R are OR 3 .
  • An exemplary R group containing an OR 3 substituent is —CH 2 C (CH 2 OCH 3 )(CH 3 ) 2 .
  • R contains an aryl group
  • the aryl group generally is bonded directly to X or is linked to X by methylene or ethylene.
  • the aryl group may contain —N ⁇ or —O— as a ring atom.
  • the aryl group contains 5 or 6 carbons. If substituted, the aryl moiety is substituted with halo or OR 3 in the ortho, meta or para positions, with R 3 in this instance being typically C 1 -C 3 .
  • Aryl groups containing 5 carbons are typically 2-, 3- or 4-pyridyl. In general, only one substituent group will be found on the aryl moiety if it is substituted at all.
  • Exemplary aromatic and nonaromatic heterocyclic groups as used herein includes by way of example and not limitation the heterocycles described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc”, 82: 5566 (1960).
  • heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azoicyl, 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 or 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, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or b-carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • R includes the structure —C 2 -C 6 R 5 C 2 -C 6 where each C 2 -C 6 independently is a 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl moiety, e.g., ethylene, ethyl, propylene, propyl, isopropylene, isopropyl, cyclohexyl, etc., and R 5 is —O— or —NR 6 — where R 6 is linear, branched or cyclic alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • Embodiments include compounds where R 4 is —H or —CH 3 .
  • R includes the structure —C 2 -C 12 R 9 , where each C 2 -C 12 independently is a 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon linear, branched or cyclic alkyl moiety, and R 9 is
  • N-piperidino 2-pyridyl, 3-pyridyl or 4-pyridyl.
  • R also includes —C(CH 2 (X) 0-1 R 7 ) 3 , —CH[C(CH 2 (X) o-1 R 7 ) 3 ] 2 and —CH 2 (C(X) o-1 R 7 ) 3 , where R 7 is 1, 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl or R 7 is 5 or 6 carbon aryl.
  • R 7 is 1, 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl or R 7 is 5 or 6 carbon aryl.
  • one or two X are typically present, usually 1, X is usually oxygen and R 7 is typically methyl, ethyl, isopropyl, propyl or butyl, usually methyl.
  • R usually is phenyl, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, i-butyl, t-butyl, pentyl or 3-pentyl.
  • R 1 is a substituent found in prior art phosphonomethoxy nucleotide analogs.
  • R 1 typically is any of hydrogen, —CH 3 , —CH 2 OH, —CH 2 F, —CH ⁇ CH 2 , —CH 2 N 3 or R 1 and R 8 are joined to form —CH 2 —.
  • R 1 is usually H or methyl. If R 1 and R 8 are joined to form methylene, B typically is cytosin-1-yl.
  • R 3 is C 1 -C 12 alkyl, but typically is C 1 -C 6 alkyl.
  • Compounds of structure (1) typically are those in which B is adenin-9-yl, R 1 is methyl or H, R 8 is —CHR 2 —O—C(O)—OR and R, R 2 and R 3 are set forth above.
  • the compounds of this invention are optionally enriched or resolved at the carbon atom chiral center linked to R 1 in accordance with prior findings associating optimal antiviral activity with the configuration at this site.
  • R 1 is methyl the compounds will be in (R) configuration at this center and will be substantially free of the (S) enantiomer.
  • R and each R 2 are independently chosen and R 2 is C 1 -C 6 alkyl.
  • Exemplary embodiments include the compounds named in Table B. Each compound in Table B is depicted as a compound having the formula (8)
  • Exemplary embodiments include the following numbered groups of compounds.
  • the group 3 compound defined in Table A and named 1.4.1.1 in compound group 1 has the structure: 3-deazaadenin-9-yl—CH 2 —CH(CH 3 )—O—CH 2 —P(O)(OH)—O—CH 2 —O—C(O)—OCH(CH 3 ) 2 .
  • the group 15B compound defined in Table a and named 1.16.1.1 in compound group 3, as named under group 8, has the structure:
  • R 9 is N-morpholino, in moieties 11-20, R 9 is 2-pyridyl and in moieties 21-25, R 9 is 3-pyridyl.
  • R 9 is 4-pyridyl, in moieties 6-9 R 9 is N-morpholino an din moieties 9-13, R 9 is N-piperidyl.
  • the compounds of this invention are, to varying degrees, chemically stable. It is preferable that the compounds be chemically stable in order to ensure an adequate shelf-life and proper biodistribution upon oral administration.
  • embodiments are selected that have a t 1 ⁇ 2 at pH 7.4 of greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours and preferably in addition posses at t 1 ⁇ 2 at pH 2.0 of greater than 1, 10 or 100 hours.
  • the t-butyl carbonate found in Table 1 has a t 1 ⁇ 2 that is less stable than these parameters and therefor is not preferred.
  • the optimal compounds of this invention should have bioavailability in beagle dogs (as set forth in more detail below) that exceeds about 20%, preferably, about 30%.
  • the carbamates and carbonates of this invention are prepared from the diacids of the phosphonomethoxy nucleotide analogs and the synthon LCH(R 2 )OC(O)X(R) a .
  • L is a leaving group such as Cl, although it will be appreciated that any of the conventional leaving groups used in organic chemistry in nucleophilic substitution reactions can be successfully employed in place of chloro.
  • leaving groups include halides, such as Cl, Br and I, and sulfonic acid esters such as methane, benzene or toluene sulfonic acid esters.
  • the synthon is prepared by reacting LCH(R 2 )OC (O)L with HOR for preparation of the carbonate synthon or HNR 2 for the preparation of the carbamate synthon.
  • the synthon is then reacted with the nucleotide analog of choice, typically PMPA, to form the desired carbamate or carbonate adducts.
  • the carbamates are prepared by reacting the synthon with the nucleotide analog under typical conditions of nucleophilic attack, for example in Et 3 N/DMF at room temperature.
  • the carbonates are formed by reacting the appropriate synthon with the nucleotide analog in the presence of an organic base, typically an amine base.
  • masked leaving groups such as thioesters, which may be activated by, for example, oxidation, and coupled directly to the phosphonic acid moiety may be used.
  • Intermediates may be made with other leaving groups in this way, for example diphenylphosphinic acids, and others known in the chemistry of formacetals and glycosylation.
  • N,O-dialkylhydroxylamines are known in the literature, and may be prepared by alkylation of hydroxylamine, or by reductive amination of aldehydes or ketones with alkyl hydroxylamines.
  • the dialkylhydroxylamines may be acylated with the appropriately substituted haloalkyl chloroformate under conditions analogous to those used to prepare the unsubstituted chloromethyl carbamates. Phosphonates may then be alkylated with the haloalkyl.
  • O-alkyl carbamates to give the prodrugs under conditions used for the carbonates and carbamates. Leaving groups other than chloride may of course by used throughout.
  • the carbonate compounds of this invention are prepared by reacting L—CHR 2 —O—C(O)—OR with (4) to yield a compound of formula ( 1 ).
  • the reaction typically proceeds in two concurrent steps in which the monoester forms first, and then the diester as the reaction proceeds longer. In this situation monoester is not typically isolated as an intermediate.
  • the monoester intermediate is recovered from the early reaction and the reaction is then completed with for example a second L—CHR 2 —O—C (O)—OR reagent, thereby resulting in substitution with a second ester different from the first.
  • the reaction is conducted in the presence of an organic base in an organic solvent at a reaction temperature of about 4-100° for about 4-72 hours.
  • organic bases include triethylamine or Hunig base.
  • suitable organic solvents include DMF, DMPU, or NMP.
  • the monoester or diester products are purified by standard methods including flash column chromatography or salting out.
  • Suitable salts for purification and/or formulation will final product include the sulfuric acid, phosphoric acid, lactic acid, fumaric or citric acid salts or complexes of the diester or monoester compounds of structures (1) or (1a).
  • the compounds of this invention are useful in the treatment or prophylaxis of one or more vital infections in man or animals, including infections caused by DNA viruses, RNA viruses, herpesviruses (CMV, HSV 1, HSV 2, VZV, and the like), retroviruses, hepadnaviruses, (e.g. HBV), papillomavirus, hantavirus, adenoviruses and HIV.
  • Other infections to be treated with the compounds herein include MSV, RSV, SIV, FIV, MuLV, and other retroviral infections of rodents and other animals.
  • the prior art describes the antiviral specificity of the nucleotide analogs, and the parental drug specificity is shared by the compounds of this invention.
  • Dosages, viral targets, and suitable administration routes to best attack the site of infection are well known in the art for the parental drugs. Determination of proper doses is a straightforward matter for the clinician, taking into account the molecular weight of the compounds of this invention and, when administering them orally, their bioavailability in animals or as deduced in clinical trials with humans.
  • Oral dosages of the compounds of this invention in humans for antiviral therapy will range about from 0.5 to 60 mg/Kg/day, usually about from 1 to 30 mg/Kg/day and typically about from 1.5 to 10 mg/Kg/day.
  • the compounds of this invention also are useful as intermediates in the preparation of detectable labels for oligonucleotide probes.
  • the compounds are hydrolyzed to yield the diacid, diphosphorylated and incorporated into an oligonucleotide by conventional enzymatic or chemical means.
  • the incorporated base from the compound of the invention will be capable of participating in base pairing and thus will not interfere substantially with the binding of the oligonucleotide to its complementary sequence (E. De Clercq Rev. Med. Virol. 3: 85-96 1993).
  • the compound of the invention optionally is incorporated into the oligonucleotide as the 3′ terminal base, an innocuous position and a conventional site for oligonculeotide labeling.
  • the aglycon donated by the nucleotide analog that is incorporated into the oligonucleotide is detected by any means, such as NMR or by binding to antibodies specific for the nucleotide analog.
  • Compounds of the invention and their pharmaceutically, i.e. physiologically, acceptable salts are administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and dpidural).
  • suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and dpidural).
  • the compounds of this invention are administered orally, but if an embodiment is not sufficiently orally bioavailable it can be administered by any of the other routes noted above.
  • the active ingredients While it is possible for the active ingredients to be administered as pure compounds it is preferable to present them as pharmaceutical formulations.
  • the formulations of the present invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
  • the formulations include those suitable for topical or systemic administration, including oral, rectal, nasal, buccal, sublingual, vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
  • the formulations are in unit dosage form and are prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.01 to 10% w/w (including active ingredient(s) in a range between 0.1% and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 3% w/w and most preferably 0.5 to 2% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane, 1,3-diol, mannnitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhances include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the emulsifying wax, and the wax together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters.
  • Crodamol CAP may be used, the last three being preferred esters.
  • high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • a suitable carrier especially an aqueous solvent for the active ingredient.
  • the active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0.1 to 10%, and in others about 1.0% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for a nasal or inhalational administration wherein the carrier is a solid include a powder having a particle size for example in the range of 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc).
  • Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration are sterile and include aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited above, or an appropriate fraction thereof, of an active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administrating the composition to cats, dogs, horses, rabbits and other animals and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • Compounds of the invention can be used to provide controlled release pharmaceutical formulations containing a matrix or absorbent material and as active ingredient one or more compounds of the invention in which the release of the active ingredient can be controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the compound.
  • Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
  • PMPA is prepared as follows: (S)-Glycidol is reduced to (R)-1,2-propanediol by catalytic hydrogenation, which is then reacted with diethyl carbonate to afford (R)-1,2-propylene carbonate.
  • the carbonate is reacted with adenine and catalytic amounts of a base such as sodium hydroxide to give (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine which, without isolation, is reacted with lithium alkoxide (alkyl containing 1, 2, 3, 4, 5 or 6 carbon atoms, e.g., n-hexoxide, n-pentoxide, n-butoxide, i-butoxide, t-butoxide, n-propoxide, i-propoxide, ethoxide, methoxide) and diethyl-p-toluenesulfonyl-oxymethylphosphonate (prepared by reacting diethyl phosphite and paraformaldehyde, and tosylating the product in situ).
  • a base such as sodium hydroxide
  • the process uses a small amount of a base such as NaOH at step 1, which increases the reaction rate about 10-fold compared to the same reaction lacking the base.
  • Step 1 also uses hydrogen gas instead of using a reagent such as NCO 2 NH 4 to generate hydrogen in situ.
  • the process uses lithium alkoxide at step 4b, which is mildly exothermic on addition to the reaction mixture.
  • the use of a highly reactive base such as NaH results in an exothermic reaction that generates hydrogen gas in a reaction is difficult to control.
  • the use of NaH thus requires more labor and care to use than lithium alkoxide.
  • Lithium alkoxide bases also give a product that has an improved by-product profile compared to that obtained using NaH, e.g., lower amounts of starting material or overalkylated products usually result from the use of lithium alkoxide.
  • the scale of the following method is proportionately reduced or increased if desired.
  • the scheme and process steps depict synthesis of (R)-PMPA and (R)-bis(POC) PMPA.
  • Step 1 (R)-1,2-Propanediol: (S)-Glycidol (1.0 kg, 13.5 moles) is added to a rector containing (i) an inert, e.g., nitrogen, atmosphere and (ii) a stirred suspension of 5% palladium on activated carbon (50% wet) catalyst (100 g) in denatured ethyl alcohol containing 2 mole % sodium hydroxide (7.85 kg EtOH and 54 g of 16.7% NaOH solution). The contents of the inerted reactor containing catalyst and the ethanol solution is usually cooled to about 0° C. (usually about ⁇ 5 to 5° C.) before the (S)-glycidol is added.
  • an inert e.g., nitrogen, atmosphere
  • a stirred suspension of 5% palladium on activated carbon 100 g
  • denatured ethyl alcohol containing 2 mole % sodium hydroxide 7.85 kg EtOH and 54 g of 16.7% NaOH
  • Hydrogen gas at not more than 20 psi is then introduced to the inerted reaction vessel containing reactants at a temperature of no more than 25° C.
  • the mixture is agitated for approximately 4-5 hours, until hydrogen consumption stops. Reaction completion is monitored by TLC (trace or no (S)-glycidol remaining).
  • the mixture is then filtered e.g., diatomaceous earth (about 150 g), to remove solids and the filtrate is concentrated in vacuo at no more than 50° C., until volatile collection stops or is very slow, to obtain an oil containing the crude product.
  • the crude product is used directly in the next step.
  • Title compound yield is about 100%.
  • Step 2 Diethyl carbonate (1.78 kg, 15.1 moles) and sodium ethoxide in denatured ethyl alcohol (210 g of 21% w/w sodium ethoxide in ethanol) are added to (R)-1,2-propanediol (1.0 kg theoretical based on the quantity of (S)-glycidol used in step 1 above), and the solution is heated to 80 to 150° C. to distill off the ethanol. If necessary to achieve reaction completion, additional diethyl carbonate (0.16 kg) is added to the reaction mixture, followed by distillation to remove ethanol.
  • Reaction completion is monitored by TLC showing a trace or no detectable (R)-1,2-propanediol.
  • the residue is fractionally distilled at 120° C. and 10-17 mm Hg, to yield the title compound as a colorless liquid.
  • the product purity is typically 96% or greater purity by GC analysis.
  • Step 3 Diethyl-p-toluenesulfonyloxymethylphosphonate: In a reactor containing an inert atmosphere, e.g., nitrogen, a mixture of diethyl phosphite (0.80 kg), paraformaldehyde (0.22 kg), and triethylamine (0.06 kg) in toluene (0.11 kg) is heated at 87° C. for about 2 hours, then refluxed for about 1 hour, until the reaction is complete as monitored by TLC showing a trace or no detectable diethyl phosphite. During the reaction, the inert atmosphere is maintained. Toluene is necessary to moderate the reaction, which may otherwise explode.
  • an inert atmosphere e.g., nitrogen
  • Reaction completion is optionally confirmed by 1 H NMR (diethyl phosphite peak at ⁇ 8.4-8.6 ppm no longer detected).
  • the solution is cooled to about 1° C. (typically about ⁇ 2 to 4° C.) and p-toluenesulfonyl chloride (1.0 kg) is added and then triethylamine (0.82 kg) at about 5° C. is slowly added (exothermic addition) while maintaining the temperature at no more than about 10° C. (typically 0 to 10° C.).
  • the resulting mixture is warmed to 22° C., and stirred for at least about 5 hours (typically about 4.5 to 6.0 hours), until the reaction is complete as shown by TLC (trace or no p-toluenesulfonyl chloride detectable) and optionally confirmed by 1 H NMR (p-toluenesulfonyl chloride doublet at ⁇ 7.9 ppm no longer detected).
  • the solids are removed by filtration and washed with toluene (0.34 kg). The combined washings and filtrate are washed either twice with water (1.15 kg per wash), or optionally with a sequence of water (1.15 kg), 5% aqueous sodium carbonate (3.38 kg), and then twice with water (1.15 kg).
  • the reactor contents are briefly agitated, allowed to settle and the lower aqueous layer is then discarded. If the reaction results in an emulsion, brine (0.23 kg of water containing 0.8 kg NaCl) may be added to the first organic/water mixture, followed by agitating the reactor contents, allowing the solids to settle, discarding the lower aqueous layer, adding 1.15 kg water, agitating, allowing solids to settle and again discarding the lower aqueous layer.
  • the organic phase is distilled in vacuo at nor more than 50° C. (to LOD at 110° C. of no more than 10% and water content, by KF titration, no more than 0.3%), affording a yield of about 60-70% of the title compound as an oil of about 85-95% purity, exclusive of toluene.
  • Step 4 (R)-9-[2-(Diethylphosphonomethoxy)propyl]adenine: In a reactor containing an inert atmosphere, e.g., nitrogen, a mixture of adenine (1.0 kg), sodium hydroxide (11.8 g), (R)-1,2-propylene carbonate (0.83 kg), and N,N-dimethylformamide (6.5 kg) is heated to about 130° C. (typically about 125-138° C.) for about 18-30 hours until the reaction is complete as optionally monitored by area normalized HPLC showing no more than about 0.5% adenine remaining.
  • an inert atmosphere e.g., nitrogen
  • the resulting mixture is cooled to about 25° C., typically about 20-30° C., and contains the stage I intermediate, (R)-9-(2-hydroxypropyl)adenine, which may precipitate out at this point.
  • lithium t-butoxide (3.62 kg), 2.0 M in tetrahydrofuran is added to the stage I intermediate, to produce the lithium salt of (R)-9-(2-hydroxypropyl)adenine in a mildly exothermic addition.
  • the slurry is treated with diethyl p-toluenesulfonyloxymethylphosphonate (1.19 kg) and the mixture is heated to a temperature of about 32° C., typically about 30-45° C., and is stirred for at least about 2 hours (typically about 2-3 hours) during which time the mixture becomes homogeneous. More diethyl p-toluenesulfonyloxymethylphosphonate (1.43 kg) is added and the mixture is stirred at a temperature of about 32° C. (typically about 30-45° C.) for at least about 2 hours (typically about 2-3 hours).
  • Additional lithium t-butoxide (0.55 kg), 2.0 M in tetrahydrofuran ad diethyl p-toluenesulfonyloxymethylphosphonate (0.48 kg) are added twice more, each time followed by stirring the mixture, which is at a temperature of about 32° C. for at least about 2 hours. Reaction completion is optionally monitored by area normalized HPLC showing nor more than about 10% of stage I intermediate remaining. If the reaction is incomplete, additional lithium t-butoxide (0.33 kg), 2.0 M in tetrahydrofuran and diethyl p-toluenesulfonyloxymethylphosphonate (0.24 kg) are added and the reaction mixture is maintained at a temperature of about 32° C.
  • the mixture is then cooled to about 25° C. (typically about 20-40° C.) and glacial acetic acid (0.5 kg) is then added.
  • the resulting mixture is concentrated in vacuo at a final maximum mixture temperature of about 80° C. under about 29 in Hg vacuum.
  • the residue is cooled to about 50° C. (typically about 40-60° C.) and water (1.8 kg) is added and the reaction is rinsed forward with additional water (1.8 kg).
  • the solution is continuously extracted with dichloromethane (about 35 kg) for 12-48 hours with periodic additions of glacial acetic acid (0.2 kg) to the aqueous phase after about 5 hours and after about 10 hours of continuous extraction time.
  • Extraction completion is optionally confirmed by area normalized HPLC as shown by no more than about 7% of (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine remaining in the aqueous phase.
  • the combined dichloromethane extracts are concentrated initially at atmospheric pressure then in vacuo at an extract temperature of no more than about 80° C. to give the title compound as a viscous orange oil.
  • the title compound yield is about 40-45% by weight normalized HPLC and its purity is typically 60-65% by area normalized HPLC.
  • the actual weight of the title compound after concentration is approximately 1.6 times the theoretical weight (or 3.8 times the expected yield). The additional observed weight is attributed to impurities and/or solvents remaining after the continuous extraction and concentration.
  • Step 5 (R)-9-[2-(Phosphonomethoxy)propyl]adenine, crude: Bromotrimethylsilane (1.56 kg) is added to a reactor containing a mixture of crude (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (1.0 kg calculated based on adenine input from step 4 above) and acetonitrile (0.9 kg) with cooling to maintain a temperature no higher than about 50° C. The lines are rinsed forward with acetonitrile (0.3 kg) and the mixture is refluxed at about 60-75° C. for about 2-4 hours with moderate agitation to avoid splashing the reactor contents.
  • Reaction completion is monitored by area normalized HPLC showing no more than about 3% total of monoethyl PMPA and diethyl PMPA remaining. If the reaction is incomplete, additional bromotrimethylsilane (0.04 kg) is charged into the reactor and the reaction is refluxed for at least about 1 hour with moderate agitation. The volatiles are removed by distillation at no higher than about 70° C. initially at atmospheric pressure and then in vacuo (about 24-27 in Hg) at no higher than about 70° C. The reactor is then cooled to about 20° C. (typically about 15-25° C.) and water (1.9 kg) is added (exothermic addition) to the residue with the temperature maintained at no higher than about 50° C. The mixture is cooled to 20° C.
  • the isolated aqueous phase is then filtered through a 1 ⁇ m cartridge filter, diluted with water (3.2 kg), heated to about 40° C. (typically about 35-50° C.) and adjusted to pH about 1.1 (typically about 0.9-1.3) with aqueous sodium hydroxide (about 0.15 kg NaOH as a 50% solution) while the temperature is maintained at about 45° C.
  • PMPA seed crystals are added to the mixture and the pH is adjusted to about 2.8 (typically about 2.6-3.0) with a 50% aqueous sodium hydroxide solution (about 0.15 kg NaOH required) while the temperature is maintained at about 45° C. (typically about 35-50° C.).
  • the solution is cooled to about 22° C. (typically about 15-25° C.) over about 3-20 hours with slow to moderate agitation that avoids splashing the contents, during which time the product should precipitate, beginning at about 35° C.
  • the pH of the slurry is adjusted to about 3.2 (typically about 3.1-3.3), usually using 50% aqueous sodium hydroxide or concentrated hydrochloric acid, if necessary.
  • the slurry is cooled to approximately 5° C., typically about 0-10° C., and slowly agitated for at least about 3 hours in that temperature range.
  • the solids are collected by filtration, washed sequentially with cold water (0.35 kg) and acetone (0.3 kg) giving crude PMPA as a damp solid typically of about 97% purity.
  • the product is heated to about 50° C. and dried in vacuo to a water content of less than 10%.
  • the quantity of diethyl PMPA is calculated from the quantity of adenine used in the preceding step of the synthesis (assuming 100% yield) and not from the net weight of the crude diethyl PMPA, which may contain other compounds.
  • Step 6 (R)-9-[2-Phosphonomethoxy)propyl]adenine, pure: A suspension of the crude PMPA (1.00 kg corrected for water content) (Step 5 product) in water is heated to about 100° C. (typically about 95-110° C). with moderate to high agitation until all solids dissolve, and the resulting solution is clarified by filtration while hot, rinsing forward using additional hot water (1 kg, about 95-110° C.). The filtrate is heated to 100° C. prior to cooling, first to about 30° C. (typically about 20-25° C.) over about 3-5 hours with slow agitation, then cooling is continued to about 10° C. (typically about 5-15° C.). After holding at about 10° C.
  • the solids are collected by filtration and washed sequentially with cold water (1.5 kg, about 0-10° C.) and then acetone (1 kg).
  • the wet cake is dried in vacuo at about 50° C. (typically about 40-60° C.) to a water content of about 5.9% (typically about 3.9-7.9%), affording pure PMPA monohydrate.
  • the product purity is typically 98% or greater by both area normalized and weight normalized HPLC. If the chemical purity is unsatisfactory, the product may be repurified by a repeat of this step.
  • Preparation C PMPA (0.50 g) was recrystallized from approximately 7.5 mL boiling H 2 O (15:1 wt. ratio). Upon cooling to room temperature, the PMPA was filtered on a coarse frit fit with TyvekTM. The filter cake was rinsed with ice-cold H 2 O and acetone then sucked to dryness to afford a fluffy white solid (Preparation D). The filtrate was also concentrated to afford a white solid (Preparation E).
  • Step 7 Bis(POC)PMPS fumarate: In a reactor with an inert atmosphere, e.g., nitrogen, a mixture of 1-methyl-2-pyrrolidinone (4.12 kg), PMPA monohydrate (1.00 kg), triethylamine (0.996 kg), are agitated for about 15-45 min., typically about 30 min, and then chloromethyl-2-propyl carbonate (2.50 kg) is added and the mixture is heated to about 55-65° C., typically about 60° C. and agitated without splashing the contents for about 3-6 hours, typically about 4 hours, until the reaction is complete, as optionally indicated by HPLC (no more than 15% mono(POC)PMPA present).
  • an inert atmosphere e.g., nitrogen
  • the mixture is diluted with isopropyl acetate (10.72 kg), cooled to about 15-30° C., typically about 25° C., as rapidly as possible, and while holding the reactor contents at a of about 15-30° C., typically about 25° C., the mixture is agitated for about 20-60 minutes, typically about 30 minutes.
  • the solids are removed by filtration and washed with isopropyl acetate (4.44 kg).
  • the combined organic phases at about 15-30° C., typically about 25° C. are extracted twice with water (3.28 kg)using moderate agitation for about 1-10 min. to avoid forming an emulsion followed by allowing the phases to separate.
  • the combined aqueous phases are back-extracted twice with isopropyl acetate (3.56 kg) (about 15-30° C., typically about 25° C.). All organic phases are combined and washed with water (2.20 kg) (about 15-30° C., typically about 25° C.) using moderate agitation for about 1-10 min. to avoid forming an emulsion, then the combined organic phases, which are at about 25-43° C., but at no more than 45° C., are concentrated in vacuo (about 26.5-28′′ Hg) to approximately 30% of the original volume (about 10-12 L/kg PMPA monohydrate).
  • the concentration of the organic phase is resumed at about 20-38° C., but no higher than 40° C. under a vacuum (about 28′′ Hg) until a pale yellow oil remains.
  • the oil is dissolved in a warmed solution (about 45-55° C., typically about 50° C.) of fumaric acid (0.38 kg) in 2-propanol (6.24 kg) with vigorous agitation until solids dissolve, about 0.5-2.0 hours.
  • the warm solution is then optionally filtered using an in-line 1 ⁇ m filter while minimizing cooling of the solution.
  • the filtrate at about 34-50° C., typically at about 40° C. is agitated using the minimum agitation needed to obtain a homogeneous solution.
  • the resulting solution is cooled to about 30-33° C., typically about 32° C., over about 30 minutes using minimal agitation, optionally seeded with a small quantity of bis(POC)PMPA fumarate (about 100 mg), and cooled to about 12-18° C., typically about 15° C., over about 1-2 hours, typically over about 1 hour. Seed crystals may not be needed if crystal formation begins before seed crystals are added. Crystals may form over a range of about 12-33° C. as the solution is cooled.
  • Crystallization will occur at lower temperatures if the solution is further chilled, e.g., to about ⁇ 10° C. to about 11° C. Agitation is discontinued when crystal formation begins. The mixture is allowed to stand at about 15° C. for at least about 12 hours, typically about 12-30 hours. The resulting slurry is filtered (Tyvek) and the filter cake is washed with a premixed solution of isopropyl acetate (0.70 kg) in butyl ether (2.44 kg) (1:4 v/v).
  • the filter cake which is at no more than 40° C., is dried in vacuo for about 1 to 3 days and the dried product is optionally milled (Fitzmill M5A fitted with a 0.050′′ screen), affording bis(POC)PMPA fumarate as white, fine powder-like crystals of about 97.0 to 99.5% purity.
  • Butyl chloromethyl carbonate A solution of butyl alcohol (50 mmol) and chloromethyl chlorofomrate (4.5 mL, 50 mmol) in diethyl ether (200 mL) was cooled to 0° C. under argon. Pyridine (5.7 mL, 50 mmol) was added dropwise with stirring over 5 min. The solution was stirred at 0° C. for 15 min, then allowed to warm to room temperature and stirred for three additional hours. The ether solution was filtered, washed with 1 M HCl, and then twice with water, dried over MgSO 4 , filtered, and concentrated on a rotary evaporator to give butyl chloromethyl carbonate (7 g, 85%).
  • Dibutyl PMPA carbonate Anhydrous PMPA (4 g, 13 mmol) and DIEA (10.5 mL, 60 mmol) were placed in anhydrous DMF (40 mL). Butyl chloromethyl carbonate (40 mmol) was then added and the suspension stirred at room temperature for 48 hr. The reaction was then heated to 50° C. for 18 hr. The DMF was removed on a rotary evaporator, and the reaction partitioned between CH 2 Cl 2 (250 mL) and water (250 mL). The CH 2 Cl 2 layer was washed once with saturated aqueous NaHCO 3 , dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator.
  • the CH 2 Cl 2 layer was dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was taken up in methylene chloride and applied to a silica gel column (25 g SiO 2 ). It was eluted with 100 mL CH 2 Cl 2 , 50 mL each 3,6,9,12,15,18% (v/v) isopropanol in methylene chloride, and then with 200 mL 21% ispropanol in methylene chloride. Appropriate fractions were pooled and evaporated to give the desired product.
  • the solution stability of PMPA carbonates was studied at pH 7.4 at 37° C. in 10 mM buffer (NaH 2 PO 4 and Na 2 HPO 4 ) with the total ionic strength adjusted to 0.15 M with KCl.
  • the assays were performed by adding 200 ⁇ L of a PMPA carbonate stock solution (about 1 mg/mL in DMSO) to 10 mL of pre-equilibrated buffer at 37° C. Samples were removed at specific times points and analyzed by HPLC. The chemical t 1 ⁇ 2 is expressed in terms of the number of hours required to hydrolyze 50% of the carbonate at the specified pH.
  • PMPA (9-[(R)-2-(phosphonomethoxy)propyl]adenine) and PMPA carbonates were examined to determine the effect of dose on the pharmacokinetics of PMPA in beagle dogs, in particular the bioavailability of PMPA following oral administration to beagle dogs.
  • TAAHP Tetrabutylammonium hydrogen phosphate
  • Fluka Fluka (Ronkonkoma, N.Y.).
  • Acetonitrile was obtained from Baxter (Muskegon, Mich.).
  • Dibasic potassium phosphate, monobasic potassium phosphate, and sodium acetate trihydrate were obtained from Mallinckrodt (Paris, Ky.).
  • Chloroacetaldehyde and trifluoroacetic acid (TFA) were from Aldrich (Milwaukee, Wis.).
  • the intravenous formulations used as standards were isotonic aqueous solutions containing 50 mg/mL PMPA.
  • Compound was added to 10 mL of WFI (water for injection from Abbott Laboratory) and 1N NaOH was added to adjust the pH to 7.4.
  • the solutions were diluted to 15 mL with WFI and sterile filtered with a 0.2 ⁇ m filter.
  • the PMPA dose was 10 mg/kg (0.2 mL/kg).
  • the intravenous formulation for a 1 mg/kg dose was prepared as described above except only 75 mg of PMPA was added to WFI and the final concentration was 5 mg/mL. The dose was 1 mg/kg (0.2 mL/kg). Oral formulations of carbonates were prepared in 20-40% PEG 400/50 mM citric acid and were adjusted to pH 2.2. Doses ranged from 6.2-10 mg eq of PMPA/kg and are shown in Table 1.
  • pentagastrin pretreatment dogs were given a single intramuscular injection of pentagastrin (Peptavlon 0.25 mg/mL, Ayerst Laboratories, Inc., Philadelphia, Pa.) at a dose of 6 ⁇ g/kg, 20 minutes prior to dosing. Water was provided ad lib.
  • Each formulation was administered as a single dose to five male beagle dogs. Individual vials of each formulation were provided for each animal. The intravenous formulation was administrated via a cephalic vein. The oral suspension was administered by gavage, followed by two 10 mL water washes. At least one week washout period was allowed between administrations.
  • Plasma samples (4.0 mL) were collected by direct jugular access from each animal into heparinized tubes. Animals remained conscious throughout the sample collection period. Blood was processed immediately for plasma by centrifugation at 2000 rpm for 10 minutes. Plasma samples were frozen and maintained at ⁇ 20° C. until analyzed.
  • Urine samples were collected over 0-24 and 24-48 hours time periods. Urine samples from 0-24 and 24-48 hours were divided into aliquots and mixed based on the volume collected and analyzed to determine amount of PMPA recovered from urine during 0-48 hours.
  • PMPA in Plasma and Urine was determined as follows.
  • PMEA (9-(2-phosphono-methoxyethyl)adenine; adefovir) was used as the internal standard for both analyses.
  • the total concentration of PMPA in dog plasma or urine samples was determined by derivatizing PMPA and PMEA with chloroacetaldehyde to yield a highly fluorescent N 1 ,N 6 -ethenoadenine derivative as described (Russell, J. et al. (1991) Determination of 9-[(2-Phosophonylmethoxy)-ethyl]Adenine in Rat Urine by High-Performance Liquid Chromatography with Fluorescence Detection. J. Chromatogr. (Netherlands) 572, 321-326).
  • Plasma 200 ⁇ L
  • internal standard 200 ⁇ L of 10 ⁇ g/mL PMEA providing a final PMEA concentration of 1 ⁇ g/mL
  • Samples were then evaporated to dryness under reduced pressure at room temperature (Savant SpeedVac).
  • the samples were derivatized for analysis as follows. Dried plasma samples or urine samples were reconstituted or mixed in 200 ⁇ L derivatization cocktail (0.34% chloroacetaldehyde in 100 mM sodium acetate, pH 4.5), vortexed, and centrifuged for 10 minutes at 14,000 rpm in an Eppendorf Centrifuge 5402. Supernatant was then transferred to a clean screw capped tube and incubated at 95° C. for 40 minutes. Derivatized samples were quenched on ice and evaporated to dryness under reduced pressure at room temperature. Dried samples were reconstituted in 200 ⁇ L Mobile Phase A (see below), vortexed and centrifuged for 10 minutes at 14,000 rpm in an Eppendorf Centrifuge 5402. The supernatant was then transferred to autoinjector vials for HPLC analysis.
  • derivatization cocktail 0.34% chloroacetaldehyde in 100 mM sodium acetate, pH 4.5
  • the plasma and urine samples were analyzed by HPLC with Fluorescence Detection as follows.
  • the HPLC system comprised a Model P4000 solvent delivery system with a Model AS3000 autoinjector and a Model F2000 Fluorescence detector (Thermo Separation, San Jose, Calif.).
  • the column was a Zorbax RX-C18 (5 ⁇ m, 150 ⁇ 4.6 mm) (MAC-MOD, Chadds Ford, N.Y.) equipped with a Brownless RP-18 Newguard guard column (7 ⁇ m, 15 ⁇ 3.2 mm) (Alltech, Deerfield, Ill.).
  • the mobile phases used were: A, 2% acetonitrile in 25 mM potassium phosphate buffer with 5 mM TBAP, pH 6.0; B, 65% acetonitrile in 25 mM potassium phosphate buffer with 5 mM TBAHP, pH 6.0.
  • the flow rate was 1.5 mL/min and the column temperature was maintained at 35° C. by a column oven.
  • the gradient profile was 100% A until 2.0 min, then a linear gradient to 100% B by 13.0 minutes, returning immediately to 100% A.
  • Detection was by fluorescence with excitation at 236 nm and emission at 420 nm, and the injection volume was 50 ⁇ L. Total cycle time between injections was 25 min. Data was acquired and stored by a Peak Pro data acquisition system (Beckman, Palo Alto, Calif.).
  • Vss CL ⁇ MRT; where Vss is the apparent volume of distribution at steady state. MRT is the mean residence time.
  • Bioavailability ⁇ ⁇ ( % ) AUC ⁇ ⁇ ( 0 - ⁇ ) ⁇ ⁇ oral ⁇ ⁇ or ⁇ ⁇ ⁇ prodrug AUC ⁇ ⁇ ( 0 - ⁇ ) ⁇ ⁇ intravenous ⁇ 100
  • Dog liver was obtained fresh from Pharmakon USA (Waverly, Pa.). Liver homogenate was prepared following a standard protocol. Dog liver was rinsed three times with ice-code 50 mM sodium/potassium phosphate buffer and homogenized with a Tekmar Tissumizer homogenizer (VWR 33995-060). The homogenate was centrifuged at 9000 g (11,000 rpm for Eppendorf Centrifuge 5402; Brinkman Instruments, Westbury, N.Y.) at 4° C. for 20 minutes. The supernatant was designated at the S9 fraction. The concentration of protein in the S9 fraction was determined using a Bio-Rad Protein Assay Kit II, with bovine serum albumin as standard.
  • Esterase activity was determined using o-nitrophenyl butyreate as substrate and activity was calculated based on the increase in absorbance at 420 nm after a 1 min incubation. The homogenates were stored as 1.0 mL aliquots at ⁇ 70° C.
  • Dog intestinal segments (jejunum/ileum) were obtained fresh from Pharmakon USA (Waverly, Pa.) and intestinal homogenate was prepared as described for liver. The intestinal homogenates were stored as 1.0 mL aliquots at ⁇ 70° C.
  • Human intestinal homogenate (S9) was obtained from Keystone Skin Bank (Exton, Pa.) at concentration of 20 mg protein/mL.
  • PMPA (9-[(R)-2-(phosphonomethoxy)propyl]adenine) and PMPA carbonates were examined to determine their activity against HIV-1.
  • the antiviral activity of the carbonates 5 a, 5 c-g against HIV-1 (IIIB) was determined in MT-2 cells and the IC 50 (50% inhibitory concentration) and CC 50 (concentration to kill 50% of the cells) values were measured.
  • the carbonate prodrugs exhibited increased potency (about 2.5-500 fold) compared to PMPA (Table 2). Although cytotoxicity of the prodrugs also increased, the selectivity indices were improved compared to PMPA.
  • the increased activity can be attributed to increased cellular uptake of the prodrugs followed by effective intracellular conversion to PMPA, which undergoes subsequent phosphorylation to the antivirally active diphosphate metabolite.
  • the t-butyl carbonate 5 d exhibited only 2.5 fold increased activity over PMPA with reduced selectivity possibly due to chemical instability.
  • the antiviral activity data indicate good permeability of alkyl methyl carbonate prodrugs into cells, possibly due to their increased lipophilicity.
  • IC 50 a CC 50 b compound ( ⁇ M) ( ⁇ M) SI c 2 0.5 250 500 5a 0.002 40 20000 5c ⁇ 0.001 30 30000 5d 0.2 10 50 5e ⁇ 0.001 3 3000 5f 0.003 50 16600 5g ⁇ 0.001 40 40000 a IC 50 — 50% Inhibitory concentration; b CC 50 — Concentration to kill 50% of the cells; c SI — Selectivity Index (CC 50 /IC 50 ); n.d — not determined; DMSO used as control.

Abstract

Novel compounds are provided that comprise esters of antiviral phosphonomethoxy nucleotide analogs with carbonates and/or carbamates having the structure —OC(R2)2OC(O)X(R)a, wherein R2 independently is H, C1-C12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro or OR3 in which R3 is C1-C12 alkyl; X is N or O; R is independently H, C1-C12 alkyl, aryl, alkenyl, alkynyl, alkyenylaryl, alkynylaryl, alkaryl, arylalkynyl, arylalkenyl or arylalkyl which is unsubstituted or is substituted with halo, azido, nitro, —O—, —N═, —NR4—, —N(R4)2— or OR3, R4 independently is —H or C1-C8 alkyl, provided that at least one R is not H; and a is 1 or 2, with the proviso that when a is 2 and X is N, (a) two R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, or (b) one R additionally can be OR3. The compounds are useful as intermediates for the preparation of antiviral compounds or oligonucleotides, or are useful for administration directly to patients for antiviral therapy of prophylaxis. Embodiments are particularly useful when administered orally.

Description

CROSS REFERENCED TO RELATED APPLICATIONS
This application is a division of U.S. patent application Ser. No. 09/187,763, filed Nov. 6, 1998, now U.S. Pat. No. 5,977,089, which is a continuation of U.S. patent application Ser. No. 08/900,746, filed Jul. 25, 1997, now U.S. Pat. No. 5,922,695, which is a continuation-in-part application of U.S. Provisional Patent Application Ser. No. 60/022,708, filed Jul. 26, 1996, abandoned, which is incorporated herein by reference in its entirety.
BACKGROUND OF THE INVENTION
The present invention relates to intermediates for phosphonomethoxy nucleotide analogs, in particular intermediates suitable for use in the efficient oral delivery of such analogs.
Such analogs per se and various technologies for oral delivery of these and other therapeutic compounds are known. See WO 91/19721, WO 94/03476, WO 94/03466, WO 92/13869, U.S. Pat. No. 5,208,221, 5,124,051, DE 41 38 584 A1, WO 94/10539, WEJ7368583647920, WO 95 79/07919, WO 92/09611, WO 92/01698, WO 91/19721, WO 88/05438, EP 0 632 048, EP 0 481 214, EP 0 369 409, EP 0 269 947, U.S. Pat. Nos. 3,524,846 and 5,386,030, Engel, Chem. Rev. 77: 349-367 1997, Farquhar et al., J. Pharm. Sci. 72: 324-325 1983, Starrett et al., Antiviral Res. 19: 267-273 1992, Safadi et al., Pharmaceutical Research 10(9): 1350-1355 1993, Sakamoto et al., Chem. Pharm. Bull. 32(6): 2241-2248 1984, and Davidsen et al., J. Med. Chem. 37(26): 4423-4429 1994.
SUMMARY OF THE INVENTION
In accordance with this invention, compounds are provided having formula (1a)
Figure USRE038333-20031125-C00001
wherein Z is independently —OC(R2)2OC(O)X(R)a, an ester, an amidate or —H, but at least one Z is —OC(R2)2 OC(O)X(R)a;
A is the residue of an antiviral phosphonomethoxy nucleotide analog;
X is N or O;
R2 independently is —H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or —OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12 aryl;
R independently is —H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkyenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, —N(R4)2 or —OR3, where R4 independently is —H or C1-C8 alkyl, provided that at least one R is not H; and
a is 1 when X is 0 , or 1 or 2 when X is N;
with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form a carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be —OR3 or (c) both N-linked R groups can be —H;
and the salts, hydrates, tautomers and solvates thereof.
Further embodiments of the compounds of this invention are compounds of formula (1)
Figure USRE038333-20031125-C00002
wherein B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl of their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl;
R is independently —H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or —OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12 aryl;
R1 is hydrogen, —CH3, —CH2OH, —CH2F, —CH═CH2, or —CH2N3, or R1 and R8 are joined to form —CH2—;
R2 independently is hydrogen or C1-C6 alkyl; and
R8 is hydrogen or —CHR2—O—C(O)—OR, or R8 is joined with R1 to form —CH2—;
and the salts, hydrates, tautomers and solvates thereof.
Other embodiments of this invention include a method for preparing a compound of formula (1a) which comprises reacting the diacid of a phosphonomethoxy nucleotide analog with LC(R2)2OC(O)X(R)a wherein L is a leaving group.
In particular embodiments of this invention, a method for preparing a compound of formula (1) is provided which comprises reacting a compound of formula (4)
Figure USRE038333-20031125-C00003
with LC(R2)2OC(O)X(R)a.
DETAILED DESCRIPTION OF THE INVENTION
The abbreviations NMP, DMF and DMPU mean, respectively, N-methylpyrrolidinone, dimethylformamide and N,N′-dimethylpropyleneurea.
Heterocycle means aromatic and nonaromatic ringed moieties. Heterocyclic moieties typically comprise one ring or two fused rings, where the ring(s) is 5- or 6-membered and typically contains 1 or 2 noncarbon atoms such as oxygen, nitrogen or sulfur, usually oxygen or nitrogen.
“Alkyl” as used herein, unless stated to the contrary, is C1-C12 hydrocarbon containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms in the form of normal, secondary, tertiary or cyclic structures. Examples are —CH3, —CH2CH3, —CH2CH2CH3, —CH(CH3)2, —CH2CH2CH2CH3, —CH2CH(CH3)2, —CH(CH3) CH2CH3, —C(CH3)3, —CH2CH2CH2CH2CH3, —CH (CH3)CH2CH2CH3, —CH(CH2CH3)2, —C(CH3 2CH2CH3, —CH(CH3)CH(CH3)2, —CH2CH2CH(CH3)2, —CH2CH (CH3)CH2CH3, —CH2C(CH3)3, —CH2CH2CH2CH2CH2CH3, —CH(CH3) CH2CH2CH2CH3, —CH(CH2CH3)(CH2CH2CH3) —C(CH3)2CH2CH2CH3, —CH(CH3)CH(CH3)CH2CH3, —CH(CH3)CH2CH(CH3)2, —C(CH3)(CH2CH3)2, —CH (CH2CH3)(CH(CH3)2, —C(CH3)2CH(CH3)2, —CH(CH3C (CH3)3, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclopentyl, cyclobutylmethyl, 1-cyclopropyl-1-ethyl, 2-cyclopropyl-1-ethyl, cyclohexyl, cyclopentylmethyl, 1-cyclobutyl-1-ethyl, 2-cyclobutyl-1-ethyl, 1-cyclopropyl-1-propyl, 2-cyclopropyl-1-propyl, 3-cyclopropyl-1-propyl, 2-cyclopropyl-2-propyl, and 1-cyclopropyl-2-propyl.
“Alkenyl” as used herein, unless stated to the contrary, is C1-C12 hydrocarbon containing normal, secondary, tertiary or cyclic structures. Examples are —CH═CH2, —CH═CHCH3, —CH2CH═CH2, —C(═CH2)(CH3), —CH═CHCH2CH3, —CH2CH═CHCH3, —CH2CH2CH═CH2, —CH═C(CH3)2, —CH2C(═CH2) (CH3), —C(═CH2)CH2CH3, —C(CH3)2, —CH2C(═CH2) (CH3)CH═CH2, —C═CHCH2CH2CH3, —CHCH═CHCH2CH3, —CHCH2CH═CHCH3, —CHCH2CH2CH═CH2, —C(═CH2)CH2CH2CH3, —C(CH3)═CH2CH2CH3, —CH(CH3)CH═CHCH3, —CH(CH3)CH2CH═CH2, —CH2CH═C(CH3)2, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
“Alkynyl” as used herein, unless stated to the contrary, is C1-C12 hydrocarbon containing normal, secondary, tertiary, or cyclic structures. Examples are —CCH, —CCCH3, —CH2CCH, —CCCH2CH3, —CH2CCCH3, —CH2CH2CCH, CH(CH3)CCH, —CCCH2CH2CH3, —CH2CCCH2CH3, —CH2CH2CCCH3 and —CH2CH2CH2CCH.
Salt(s) include those derived by combination of appropriate anions such as inorganic or organic acids. Suitable acids include those having sufficient acidity to form a stable salt, preferably acids of low toxicity. For example, one may form invention salts from acid addition of certain organic and inorganic acids, e.g., HF, CHl, HBr, HI, H2SO4, H3PO4, or from organic sulfonic acids, organic carboxylic acids to basic centers, typically a mines. Exemplary organic sulfonic acids include C6-C16 aryl sulfonic acids, C6-C16 heteroaryl sulfonic acids and C1-C16 alkyl sulfonic acids such as phenyl α-naphthyl, β-naphthyl, (S)-camphor, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pentyl and hexyl sulfonic acids. Exemplary organic carboxylic acids include C1-C16 alkyl, C6-C16 aryl carboxylic acids and C4-C16 heteroaryl carboxylic acids such as acetic, glycolic, lactic, pyruvic, malonic, glutaric, tartaric, citric, fumaric, succinic, malic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicyclic and 2-phenoxybenzoic. Salts also include the invention compound salts with one or more amino acids. Many amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically in 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. Salts are usually biologically compatible or pharmaceutically acceptable or non-toxic, particularly for mammalian cells. Salts that are biologically toxic are generally used with synthetic intermediates of invention compounds. The salts of invention compounds may be crystalline or noncrystalline.
A is the residue of a phosphonomethoxy nucleotide analog. The parental compounds have the structure AOCH2P (O)(OH)2. They are well known and have demonstrated antiviral activity. Per se, they are not part of this invention. In general, A has the structure BQ wherein B is a purine or pyrimidine base or the aza and/or deaza analogs thereof and Q is a cyclic or acyclic aglycon. B is linked to Q through the purine 9 or pyrimidine 1 positions. Examples of these analogs can be found in U.S. Pat. Nos. 4,659,825, 4,724,233, 5,142,051 and 5,130,427, EP 369,409, EP 398,231, EP 494,370, EP 454,427, EP 270,885, EP 269,947, EP 452,935, WO 93/07157, WO 94/03567, and WO 96/23801. Typically, A will have the structure BCH2CH(CH3)—or BCH2CH2—.
The designation “a” is an integer of 1 or 2. If X is N then a is 2 and one R is usually H and the other is not H. If X is O then a is 1.
B generally is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl. Ordinarily, B is adenin-9-yl or 2,6-diaminopurin-9-yl. In formula (1a) compounds, one Z optionally comprises an ester or an amidate. Suitable esters or amidates have been described, e.g., WO 95/07920. Exemplary esters are phenyl, benzyl, o-ethoxyphenyl, p-ethoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, N-ethylmorpholino, C1-C8 O-alkyl and C1-C8 NH-alkyl. However, every compound of the invention will contain at least one —C(R2)2OC(O)X(R)a moiety.
R2 independently is —H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or —OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12 aryl. R2 is usually H or C1-C6 alkyl, and typically only one R2 is other than H. In most embodiments R2 is H in both instances. The carbon atom to which R2 is bonded is capable of chiral substitution, in which case R2 is in the (R), (S) or racemic configuration. In most, embodiments, if R2 is other than H the compounds of this invention are chirally enriched or pure at this site. In general, however, manufacturing is somewhat less expensive if chirality at the R2 carbon can be avoided. Thus, R2 is H when it is desired to help minimize the cost of synthesis.
X is O or N, typically O. The carbamates (where X=N) tend to be more stable in biological environments than the carbonates. When X is O then a is 1.
R independently is —H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkyenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro, —N(R4)2 or —OR3, where R4 independently is —H or C1-C8 alkyl, provided that at least one R is not H. In general, R is C1-C6 secondary or normal alkyl which is unsubstituted or substituted with OR3. When X is N then a is 2. In the latter case one R is usually other than H. Alternatively, two N-linked R groups are joined to form a carbocycle or O-containing heterocycle, typically containing 3 to 5 carbon atoms in the ring. When R is unsaturated, but not aryl, the site of unsaturation is not critical and is in the Z or E configuration. The alkenyl chains of naturally occurring unsaturated fatty acids would be suitable as R groups, for example. R also includes cycloalkenyl or cycloalkynyl containing 1 or 2 unsaturated bonds, typically 1 unsaturated bond. When R is unsaturated, usually it is alkenyl or alkynyl without aryl substitution.
If R is substituted with halo, cyano, azido, nitro or OR3, typically R will contain 1 of these substituents. If substituted with 2 of these substituents, they are same or different. Generally, substituents found on R are OR3. An exemplary R group containing an OR3 substituent is —CH2C (CH2OCH3)(CH3)2.
When R contains an aryl group, the aryl group generally is bonded directly to X or is linked to X by methylene or ethylene. The aryl group may contain —N═ or —O— as a ring atom. In general, the aryl group contains 5 or 6 carbons. If substituted, the aryl moiety is substituted with halo or OR3 in the ortho, meta or para positions, with R3 in this instance being typically C1-C3. Aryl groups containing 5 carbons are typically 2-, 3- or 4-pyridyl. In general, only one substituent group will be found on the aryl moiety if it is substituted at all. Exemplary aromatic and nonaromatic heterocyclic groups as used herein includes by way of example and not limitation the heterocycles described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc”, 82: 5566 (1960).
Examples of heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azoicyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3-H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, b-carbonlinyl, 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 isatinolyl.
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 or 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, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or b-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
R includes the structure —C2-C6R5C2-C6 where each C2-C6 independently is a 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl moiety, e.g., ethylene, ethyl, propylene, propyl, isopropylene, isopropyl, cyclohexyl, etc., and R5 is —O— or —NR6— where R6 is linear, branched or cyclic alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms.
Embodiments include compounds where R4 is —H or —CH3.
R includes the structure —C2-C12R9, where each C2-C12 independently is a 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon linear, branched or cyclic alkyl moiety, and R9 is
Figure USRE038333-20031125-C00004
N-piperidino, 2-pyridyl, 3-pyridyl or 4-pyridyl.
R also includes —C(CH2(X)0-1R7)3, —CH[C(CH2(X)o-1R7)3]2 and —CH2(C(X)o-1R7)3, where R7 is 1, 2, 3, 4, 5 or 6 carbon linear, branched or cyclic alkyl or R7 is 5 or 6 carbon aryl. In these embodiments, one or two X are typically present, usually 1, X is usually oxygen and R7 is typically methyl, ethyl, isopropyl, propyl or butyl, usually methyl.
R usually is phenyl, methyl, ethyl, 1-propyl, 2-propyl, n-butyl, i-butyl, t-butyl, pentyl or 3-pentyl.
R1 is a substituent found in prior art phosphonomethoxy nucleotide analogs. R1 typically is any of hydrogen, —CH3, —CH2OH, —CH2F, —CH═CH2, —CH2N3 or R1 and R8 are joined to form —CH2—. R1 is usually H or methyl. If R1 and R8 are joined to form methylene, B typically is cytosin-1-yl.
R3 is C1-C12 alkyl, but typically is C1-C6 alkyl.
Compounds of structure (1) typically are those in which B is adenin-9-yl, R1 is methyl or H, R8 is —CHR2—O—C(O)—OR and R, R2 and R3 are set forth above.
The compounds of this invention are optionally enriched or resolved at the carbon atom chiral center linked to R1 in accordance with prior findings associating optimal antiviral activity with the configuration at this site. Thus, where R1 is methyl the compounds will be in (R) configuration at this center and will be substantially free of the (S) enantiomer.
Other embodiments include structure (10) and (11) compounds where R and each R2 are independently chosen and R2 is C1-C6 alkyl.
Figure USRE038333-20031125-C00005
Exemplary embodiments include the compounds named in Table B. Each compound in Table B is depicted as a compound having the formula (8)
Figure USRE038333-20031125-C00006
Compounds named in Table B are designated by numbers assigned to B, R, R1 and R2 according to the following convention, B.R.R1.R2 , using the numbered structures depicted in Table A. Thus, the compound named 1,2,3,4 specifies adenin-9-yl at B, —CH2CH3 at both R groups, —CH2OH at R1 and —(CH2)2CH3 at both R2 groups.
TABLE A
B R1
1 adenin-9-yl 1 —CH3
2 guanin-9-yl 2 —H
3 2,6-diaminopurin-9-yl 3 —CH2OH
4 2-aminopurin-9-yl 4 —CH2F
5 cytosin-1-yl 5 —CH═CH2
6 —CH2N3
R R2
1 —CH3 1 —H
2 —C2H5 2 —CH3
3 —(CH2)2CH3 3 —C2H5
4 —CH(CH3)2 4 —(CH2)2CH3
5 —(CH2)3CH3 5 —CH(CH3)2
6 —CH2CH(CH3)2 6 —(CH2)3CH3
7 —CH(CH3)CH2CH3 7 —CH2CH(CH3)2
8 —C(CH3)3 8 —C(CH3)3
9 —(CH2)4CH3 9 —(CH2)4CH3
10 —CH(CH3)CH2CH2CH3 10 —(CH2)5CH3
11 —CH(CH2)3)2
12 —C(CH3)2CH2CH3
13 —CH(CH3)CH(CH3)2
14 —CH2CH2CH(CH3)2
15 —CH2CH(CH3)CH2CH3
16 —CH2CH2CH2CH2CH2CH3
17 —CH(CH3)CH2CH2CH2CH3
18 —CH(CH2CH3)CH2CH2CH3
19 —C(CH3)2CH2CH2CH3
20 —CH(CH3)CH(CH3)CH2CH3
21 —CH(CH3)CH2CH(CH3)2
22 —C(CH3)(CH2CH3)2
23 —CH(CH2CH3)CH(CH3)2
24 —CH2C6H5
25 —C6H5
TABLE B
1.1.1.1 1.1.1.2 1.1.1.3 1.1.1.4 1.1.1.5 1.1.1.6 1.1.1.7 1.1.1.8 1.1.1.9 1.1.1.10 1.1.2.1 1.1.2.2 1.1.2.3
1.1.2.4 1.1.2.5 1.1.2.6 1.1.2.7 1.1.2.8 1.1.2.9 1.1.2.10 1.1.3.1 1.1.3.2 1.1.3.3 1.1.3.4 1.1.3.5 1.1.3.6
1.1.3.7 1.1.3.8 1.1.3.9 1.1.3.10 1.1.4.1 1.1.4.2 1.1.4.3 1.1.4.4 1.1.4.5 1.1.4.6 1.1.4.7 1.1.4.8 1.1.4.9
1.1.4.10 1.1.5.1 1.1.5.2 1.1.5.3 1.1.5.4 1.1.5.5 1.1.5.6 1.1.5.7 1.1.5.8 1.1.5.9 1.1.5.10 1.1.6.1 1.1.6.2
1.1.6.3 1.1.6.4 1.1.6.5 1.1.6.6 1.1.6.7 1.1.6.8 1.1.6.9 1.1.6.10 1.2.1.1 1.2.1.2 1.2.1.3 1.2.1.4 1.2.1.5
1.2.1.6 1.2.1.7 1.2.1.8 1.2.1.9 1.2.1.10 1.2.2.1 1.2.2.2 1.2.2.3 1.2.2.4 1.2.2.5 1.2.2.6 1.2.2.7 1.2.2.8
1.2.2.9 1.2.2.10 1.2.3.1 1.2.3.2 1.2.3.3 1.2.3.4 1.2.3.5 1.2.3.6 1.2.3.7 1.2.3.8 1.2.3.9 1.2.3.10 1.2.4.1
1.2.4.2 1.2.4.3 1.2.4.4 1.2.4.5 1.2.4.6 1.2.4.7 1.2.4.8 1.2.4.9 1.2.4.10 1.2.5.1 1.2.5.2 1.2.5.3 1.2.5.4
1.2.5.5 1.2.5.6 1.2.5.7 1.2.5.8 1.2.5.9 1.2.5.10 1.2.6.1 1.2.6.2 1.2.6.3 1.2.6.4 1.2.6.5 1.2.6.6 1.2.6.7
1.2.6.8 1.2.6.9 1.2.6.10 1.3.1.1 1.3.1.2 1.3.1.3 1.3.1.4 1.3.1.5 1.3.1.6 1.3.1.7 1.3.1.8 1.3.1.9 1.3.1.10
1.3.2.1 1.3.2.2 1.3.2.3 1.3.2.4 1.3.2.5 1.3.2.6 1.3.2.7 1.3.2.8 1.3.2.9 1.3.2.10 1.3.3.1 1.3.3.2 1.3.3.3
1.3.3.4 1.3.3.5 1.3.3.6 1.3.3.7 1.3.3.8 1.3.3.9 1.3.3.10 1.3.4.1 1.3.4.2 1.3.4.3 1.3.4.4 1.3.4.5 1.3.4.6
1.3.4.7 1.3.4.8 1.3.4.9 1.3.4.10 1.3.5.1 1.3.5.2 1.3.5.3 1.3.5.4 1.3.5.5 1.3.5.6 1.3.5.7 1.3.5.8 1.3.5.9
1.3.5.10 1.3.6.1 1.3.6.2 1.3.6.3 1.3.6.4 1.3.6.5 1.3.6.6 1.3.6.7 1.3.6.8 1.3.6.9 1.3.6.10 1.4.1.1 1.4.1.2
1.4.1.3 1.4.1.4 1.4.1.5 1.4.1.6 1.4.1.7 1.4.1.8 1.4.1.9 1.4.1.10 1.4.2.1 1.4.2.2 1.4.2.3 1.4.2.4 1.4.2.5
1.4.2.6 1.4.2.7 1.4.2.8 1.4.2.9 1.4.2.10 1.4.3.1 1.4.3.2 1.4.3.3 1.4.3.4 1.4.3.5 1.4.3.6 1.4.3.7 1.4.3.8
1.4.3.9 1.4.3.10 1.4.4.1 1.4.4.2 1.4.4.3 1.4.4.4 1.4.4.5 1.4.4.6 1.4.4.7 1.4.4.8 1.4.4.9 1.4.4.10 1.4.5.1
1.4.5.2 1.4.5.3 1.4.5.4 1.4.5.5 1.4.5.6 1.4.5.7 1.4.5.8 1.4.5.9 1.4.5.10 1.4.6.1 1.4.6.2 1.4.6.3 1.4.6.4
1.4.6.5 1.4.6.6 1.4.6.7 1.4.6.8 1.4.6.9 1.4.6.10 1.5.1.1 1.5.1.2 1.5.1.3 1.5.1.4 1.5.1.5 1.5.1.6 1.5.1.7
1.5.1.8 1.5.1.9 1.5.1.10 1.5.2.1 1.5.2.2 1.5.2.3 1.5.2.4 1.5.2.5 1.5.2.6 1.5.2.7 1.5.2.8 1.5.2.9 1.5.2.10
1.5.3.1 1.5.3.2 1.5.3.3 1.5.3.4 1.5.3.5 1.5.3.6 1.5.3.7 1.5.3.8 1.5.3.9 1.5.3.10 1.5.4.1 1.5.4.2 1.5.4.3
1.5.4.4 1.5.4.5 1.5.4.6 1.5.4.7 1.5.4.8 1.5.4.9 1.5.4.10 1.5.5.1 1.5.5.2 1.5.5.3 1.5.5.4 1.5.5.5 1.5.5.6
1.5.5.7 1.5.5.8 1.5.5.9 1.5.5.10 1.5.6.1 1.5.6.2 1.5.6.3 1.5.6.4 1.5.6.5 1.5.6.6 1.5.6.7 1.5.6.8 1.5.6.9
1.5.6.10 1.6.1.1 1.6.1.2 1.6.1.3 1.6.1.4 1.6.1.5 1.6.1.6 1.6.1.7 1.6.1.8 1.6.1.9 1.6.1.10 1.6.2.1 1.6.2.2
1.6.2.3 1.6.2.4 1.6.2.5 1.6.2.6 1.6.2.7 1.6.2.8 1.6.2.9 1.6.2.10 1.6.3.1 1.6.3.2 1.6.3.3 1.6.3.4 1.6.3.5
1.6.3.6 1.6.3.7 1.6.3.8 1.6.3.9 1.6.3.10 1.6.4.1 1.6.4.2 1.6.4.3 1.6.4.4 1.6.4.5 1.6.4.6 1.6.4.7 1.6.4.8
1.6.4.9 1.6.4.10 1.6.5.1 1.6.5.2 1.6.5.3 1.6.5.4 1.6.5.5 1.6.5.6 1.6.5.7 1.6.5.8 1.6.5.9 1.6.5.10 1.6.6.1
1.6.6.2 1.6.6.3 1.6.6.4 1.6.6.5 1.6.6.6 1.6.6.7 1.6.6.8 1.6.6.9 1.6.6.10 1.7.1.1 1.7.1.2 1.7.1.3 1.7.1.4
1.7.1.5 1.7.1.6 1.7.1.7 1.7.1.8 1.7.1.9 1.7.1.10 1.7.2.1 1.7.2.2 1.7.2.3 1.7.2.4 1.7.2.5 1.7.2.6 1.7.2.7
1.7.2.8 1.7.2.9 1.7.2.10 1.7.3.1 1.7.3.2 1.7.3.3 1.7.3.4 1.7.3.5 1.7.3.6 1.7.3.7 1.7.3.8 1.7.3.9 1.7.3.10
1.7.4.1 1.7.4.2 1.7.4.3 1.7.4.4 1.7.4.5 1.7.4.6 1.7.4.7 1.7.4.8 1.7.4.9 1.7.4.10 1.7.5.1 1.7.5.2 1.7.5.3
1.7.5.4 1.7.5.5 1.7.5.6 1.7.5.7 1.7.5.8 1.7.5.9 1.7.5.10 1.7.6.1 1.7.6.2 1.7.6.3 1.7.6.4 1.7.6.5 1.7.6.6
1.7.6.7 1.7.6.8 1.7.6.9 1.7.6.10 1.8.1.1 1.8.1.2 1.8.1.3 1.8.1.4 1.8.1.5 1.8.1.6 1.8.1.7 1.8.1.8 1.8.1.9
1.8.1.10 1.8.2.1 1.8.2.2 1.8.2.3 1.8.2.4 1.8.2.5 1.8.2.6 1.8.2.7 1.8.2.8 1.8.2.9 1.8.2.10 1.8.3.1 1.8.3.2
1.8.3.3 1.8.3.4 1.8.3.5 1.8.3.6 1.8.3.7 1.8.3.8 1.8.3.9 1.8.3.10 1.8.4.1 1.8.4.2 1.8.4.3 1.8.4.4 1.8.4.5
1.8.4.6 1.8.4.7 1.8.4.8 1.8.4.9 1.8.4.10 1.8.5.1 1.8.5.2 1.8.5.3 1.8.5.4 1.8.5.5 1.8.5.6 1.8.5.7 1.8.5.8
1.8.5.9 1.8.5.10 1.8.6.1 1.8.6.2 1.8.6.3 1.8.6.4 1.8.6.5 1.8.6.6 1.8.6.7 1.8.6.8 1.8.6.9 1.8.6.10 1.9.1.1
1.9.1.2 1.9.1.3 1.9.1.4 1.9.1.5 1.9.1.6 1.9.1.7 1.9.1.8 1.9.1.9 1.9.1.10 1.9.2.1 1.9.2.2 1.9.2.3 1.9.2.4
1.9.2.5 1.9.2.6 1.9.2.7 1.9.2.8 1.9.2.9 1.9.2.10 1.9.3.1 1.9.3.2 1.9.3.3 1.9.3.4 1.9.3.5 1.9.3.6 1.9.3.7
1.9.3.8 1.9.3.9 1.9.3.10 1.9.4.1 1.9.4.2 1.9.4.3 1.9.4.4 1.9.4.5 1.9.4.6 1.9.4.7 1.9.4.8 1.9.4.9 1.9.4.10
1.9.5.1 1.9.5.2 1.9.5.3 1.9.5.4 1.9.5.5 1.9.5.6 1.9.5.7 1.9.5.8 1.9.5.9 1.9.5.10 1.9.6.1 1.9.6.2 1.9.6.3
1.9.6.4 1.9.6.5 1.9.6.6 1.9.6.7 1.9.6.8 1.9.6.9 1.9.6.10 1.10.1.1 1.10.1.2 1.10.1.3 1.10.1.4 1.10.1.5
1.10.1.6 1.10.1.7 1.10.1.8 1.10.1.9 1.10.1.10 1.10.2.1 1.10.2.2 1.10.2.3 1.10.2.4 1.10.2.5 1.10.2.6
1.10.2.7 1.10.2.8 1.10.2.9 1.10.2.10 1.10.3.1 1.10.3.2 1.10.3.3 1.10.3.4 1.10.3.5 1.10.3.6 1.10.3.7
1.10.3.8 1.10.3.9 1.10.3.10 1.10.4.1 1.10.4.2 1.10.4.3 1.10.4.4 1.10.4.5 1.10.4.6 1.10.4.7 1.10.4.8
1.10.4.9 1.10.4.10 1.10.5.1 1.10.5.2 1.10.5.3 1.10.5.4 1.10.5.5 1.10.5.6 1.10.5.7 1.10.5.8 1.10.5.9
1.10.5.10 1.10.6.1 1.10.6.2 1.10.6.3 1.10.6.4 1.10.6.5 1.10.6.6 1.10.6.7 1.10.6.8 1.10.6.9 1.10.6.10
1.11.1.1 1.11.1.2 1.11.1.3 1.11.1.4 1.11.1.5 1.11.1.6 1.11.1.7 1.11.1.8 1.11.1.9 1.11.1.10 1.11.2.1
1.11.2.2 1.11.2.3 1.11.2.4 1.11.2.5 1.11.2.6 1.11.2.7 1.11.2.8 1.11.2.9 1.11.2.10 1.11.3.1 1.11.3.2
1.11.3.3 1.11.3.4 1.11.3.5 1.11.3.6 1.11.3.7 1.11.3.8 1.11.3.9 1.11.3.10 1.11.4.1 1.11.4.2 1.11.4.3
1.11.4.4 1.11.4.5 1.11.4.6 1.11.4.7 1.11.4.8 1.11.4.9 1.11.4.10 1.11.5.1 1.11.5.2 1.11.5.3 1.11.5.4
1.11.5.5 1.11.5.6 1.11.5.7 1.11.5.8 1.11.5.9 1.11.5.10 1.11.6.1 1.11.6.2 1.11.6.3 1.11.6.4 1.11.6.5
1.11.6.6 1.11.6.7 1.11.6.8 1.11.6.9 1.11.6.10 1.12.1.1 1.12.1.2 1.12.1.3 1.12.1.4 1.12.1.5 1.12.1.6
1.12.1.7 1.12.1.8 1.12.1.9 1.12.1.10 1.12.2.1 1.12.2.2 1.12.2.3 1.12.2.4 1.12.2.5 1.12.2.6 1.12.2.7
1.12.2.8 1.12.2.9 1.12.2.10 1.12.3.1 1.12.3.2 1.12.3.3 1.12.3.4 1.12.3.5 1.12.3.6 1.12.3.7 1.12.3.8
1.12.3.9 1.12.3.10 1.12.4.1 1.12.4.2 1.12.4.3 1.12.4.4 1.12.4.5 1.12.4.6 1.12.4.7 1.12.4.8 1.12.4.9
1.12.4.10 1.12.5.1 1.12.5.2 1.12.5.3 1.12.5.4 1.12.5.5 1.12.5.6 1.12.5.7 1.12.5.8 1.12.5.9 1.12.5.10
1.12.6.1 1.12.6.2 1.12.6.3 1.12.6.4 1.12.6.5 1.12.6.6 1.12.6.7 1.12.6.8 1.12.6.9 1.12.6.10 1.13.1.1
1.13.1.2 1.13.1.3 1.13.1.4 1.13.1.5 1.13.1.6 1.13.1.7 1.13.1.8 1.13.1.9 1.13.1.10 1.13.2.1 1.13.2.2
1.13.2.3 1.13.2.4 1.13.2.5 1.13.2.6 1.13.2.7 1.13.2.8 1.13.2.9 1.13.2.10 1.13.3.1 1.13.3.2 1.13.3.3
1.13.3.4 1.13.3.5 1.13.3.6 1.13.3.7 1.13.3.8 1.13.3.9 1.13.3.10 1.13.4.1 1.13.4.2 1.13.4.3 1.13.4.4
1.13.4.5 1.13.4.6 1.13.4.7 1.13.4.8 1.13.4.9 1.13.4.10 1.13.5.1 1.13.5.2 1.13.5.3 1.13.5.4 1.13.5.5
1.13.5.6 1.13.5.7 1.13.5.8 1.13.5.9 1.13.5.10 1.13.6.1 1.13.6.2 1.13.6.3 1.13.6.4 1.13.6.5 1.13.6.6
1.13.6.7 1.13.6.8 1.13.6.9 1.13.6.10 1.14.1.1 1.14.1.2 1.14.1.3 1.14.1.4 1.14.1.5 1.14.1.6 1.14.1.7
1.14.1.8 1.14.1.9 1.14.1.10 1.14.2.1 1.14.2.2 1.14.2.3 1.14.2.4 1.14.2.5 1.14.2.6 1.14.2.7 1.14.2.8
1.14.2.9 1.14.2.10 1.14.3.1 1.14.3.2 1.14.3.3 1.14.3.4 1.14.3.5 1.14.3.6 1.14.3.7 1.14.3.8 1.14.3.9
1.14.3.10 1.14.4.1 1.14.4.2 1.14.4.3 1.14.4.4 1.14.4.5 1.14.4.6 1.14.4.7 1.14.4.8 1.14.4.9 1.14.4.10
1.14.5.1 1.14.5.2 1.14.5.3 1.14.5.4 1.14.5.5 1.14.5.6 1.14.5.7 1.14.5.8 1.14.5.9 1.14.5.10 1.14.6.1
1.14.6.2 1.14.6.3 1.14.6.4 1.14.6.5 1.14.6.6 1.14.6.7 1.14.6.8 1.14.6.9 1.14.6.10 1.15.1.1 1.15.1.2
1.15.1.3 1.15.1.4 1.15.1.5 1.15.1.6 1.15.1.7 1.15.1.8 1.15.1.9 1.15.1.10 1.15.2.1 1.15.2.2 1.15.2.3
1.15.2.4 1.15.2.5 1.15.2.6 1.15.2.7 1.15.2.8 1.15.2.9 1.15.2.10 1.15.3.1 1.15.3.2 1.15.3.3 115.3.4
1.15.3.5 1.15.3.6 1.15.3.7 1.15.3.8 1.15.3.9 1.15.3.10 1.15.4.1 1.15.4.2 1.15.4.3 1.15.4.4 1.15.4.5
1.15.4.6 1.15.4.7 1.15.4.8 1.15.4.9 1.15.4.10 1.155.1 1.15.5.2 1.15.5.3 1.15.5.4 1.15.5.5 1.15.5.6
1.15.5.7 1.15.5.8 1.15.5.9 1.15.5.10 1.15.6.1 1.15.6.2 1.15.6.3 1.15.6.4 1.15.6.5 1.15.6.6 1.15.6.7
1.15.6.8 1.15.6.9 1.15.6.10 1.16.1.1 1.16.1.2 1.16.1.3 1.16.1.4 1.16.1.5 1.16.1.6 1.16.1.7 1.16.1.8
1.16.1.9 1.16.1.10 1.16.2.1 1.16.2.2 1.16.2.3 1.16.2.4 1.16.2.5 1.16.2.6 1.16.2.7 1.16.2.8 1.16.2.9
1.16.2.10 1.16.3.1 1.16.3.2 1.16.3.3 1.16.3.4 1.16.3.5 1.16.3.6 1.16.3.7 1.16.3.8 1.16.3.9 1.16.3.10
1.16.4.1 1.16.4.2 1.16.4.3 1.16.4.4 1.16.4.5 1.16.4.6 1.16.4.7 1.16.4.8 1.16.4.9 1.16.4.10 1.16.5.1
1.16.5.2 1.16.5.3 1.16.5.4 1.16.5.5 1.16.5.6 1.16.5.7 1.16.5.8 1.16.5.9 1.16.5.10 1.16.6.1 1.16.6.2
1.16.6.3 1.16.6.4 1.16.6.5 1.16.6.6 1.16.6.7 1.16.6.8 1.16.6.9 1.16.6.10 1.17.1.1 1.17.1.2 1.17.1.3
1.17.1.4 1.171.5 1.17.1.6 1.17.1.7 1.171.8 1.17.1.9 1.17.1.10 1.17.2.1 1.17.2.2 1.17.2.3 1.17.2.4
1.17.2.5 1.17.2.6 1.17.2.7 1.17.2.8 1.17.2.9 1.17.2.10 1.17.3.1 1.17.3.2 1.17.3.3 1.17.3.4 1.17.3.5
1.17.3.6 1.17.3.7 1.17.3.8 1.17.3.9 1.17.3.10 1.17.4.1 1.17.4.2 1.17.4.3 1.17.4.4 1.17.4.5 1.17.4.6
1.17.4.7 1.17.4.8 1.17.4.9 1.17.4.10 1.17.5.1 1.17.5.2 1.17.5.3 1.17.5.4 1.17.5.5 1.17.5.6 1.17.5.7
1.17.5.8 1.17.5.9 1.17.5.10 1.17.6.1 1.17.6.2 1.17.6.3 1.17.6.4 1.17.6.5 1.17.6.6 1.17.6.7 1.17.6.8
1.17.6.9 1.17.6.10 1.18.1.1 1.18.1.2 1.18.1.3 1.18.1.4 1.18.1.5 1.18.1.6 1.18.1.7 1.18.1.8 1.18.1.9
1.18.1.10 1.18.2.1 1.18.2.2 1.18.2.3 1.18.2.4 1.18.2.5 1.18.2.6 1.18.2.7 1.18.2.8 1.18.2.9 1.18.2.10
1.18.3.1 1.18.3.2 1.18.3.3 1.18.3.4 1.18.3.5 1.18.3.6 1.18.3.7 1.18.3.8 1.18.3.9 1.18.3.10 1.18.4.1
1.18.4.2 1.18.4.3 1.18.4.4 1.18.4.5 1.18.4.6 1.18.4.7 1.18.4.8 1.18.4.9 1.18.4.10 1.18.5.1 1.18.5.2
1.18.5.3 1.18.5.4 1.18.5.5 1.18.5.6 1.18.5.7 1.18.5.8 1.18.5.9 1.18.5.10 1.18.6.1 1.18.6.2 1.18.6.3
1.18.6.4 1.18.6.5 1.18.6.6 1.18.6.7 1.18.6.8 1.18.6.9 1.18.6.10 1.19.1.1 1.19.1.2 1.19.1.3 1.19.1.4
1.19.1.5 1.19.1.6 1.19.1.7 1.19.1.8 1.19.1.9 1.19.1.10 1.19.2.1 1.19.2.2 1.19.2.3 1.19.2.4 1.19.2.5
1.19.2.6 1.19.2.7 1.19.2.8 1.19.2.9 1.19.2.10 1.19.3.1 1.19.3.2 1.19.3.3 1.19.3.4 1.19.3.5 1.19.3.6
1.19.3.7 1.19.3.8 1.19.3.9 1.19.3.10 1.19.4.1 1.19.4.2 1.19.4.3 1.19.4.4 1.19.4.5 1.19.4.6 1.19.4.7
1.19.4.8 1.19.4.9 1.19.4.10 1.19.5.1 1.19.5.2 1.19.5.3 1.19.5.4 1.19.5.5 1.19.5.6 1.19.5.7 1.19.5.8
1.19.5.9 1.19.5.10 1.19.6.1 1.19.6.2 1.19.6.3 1.19.6.4 1.19.6.5 1.19.6.6 1.19.6.7 1.19.6.8 1.19.6.9
1.19.6.10 1.20.1.1 1.20.1.2 1.20.1.3 1.20.1.4 1.20.1.5 1.20.1.6 1.20.1.7 1.20.1.8 1.201.9 1.20.1.10
1.20.2.1 1.20.2.2 1.20.2.3 1.20.2.4 1.20.2.5 1.20.2.6 1.20.2.7 1.20.2.8 1.20.2.9 1.20.2.10 1.20.3.1
1.20.3.2 1.20.3.3 1.20.3.4 1.20.3.5 1.20.3.6 1.20.3.7 1.20.3.8 1.20.3.9 1.20.3.10 1.20.4.1 1.20.4.2
1.20.4.3 1.20.4.4 1.20.4.5 1.20.4.6 1.20.4.7 1.20.4.8 1.20.4.9 1.20.4.10 1.20.5.1 1.20.5.2 1.20.5.3
1.20.5.4 1.20.5.5 1.20.5.6 1.20.5.7 1.20.5.8 1.20.5.9 1.20.5.10 1.20.6.1 1.20.6.2 1.20.6.3 1.20.6.4
1.20.6.5 1.20.6.6 1.20.6.7 1.20.6.8 1.20.6.9 1.20.6.10 1.21.1.1 1.21.1.2 1.21.1.3 1.21.1.4 1.21.1.5
1.21.1.6 1.21.1.7 1.21.1.8 1.21.1.9 1.21.1.10 1.21.2.1 1.21.2.2 1.21.2.3 1.21.2.4 1.21.2.5 1.21.2.6
1.21.2.7 1.21.2.8 1.21.2.9 1.21.2.10 1.21.3.1 1.21.3.2 1.21.3.3 1.21.3.4 1.21.3.5 1.21.3.6 1.21.3.7
1.21.3.8 1.21.3.9 1.21.3.10 1.21.4.1 1.21.4.2 1.21.4.3 1.21.4.4 1.21.4.5 1.21.4.6 1.21.4.7 1.21.4.8
1.21.4.9 1.21.4.10 1.21.5.1 1.21.5.2 1.21.5.3 1.21.5.4 1.21.5.5 1.21.5.6 1.21.5.7 1.21.5.8 1.21.5.9
1.21.5.10 1.21.6.1 1.21.6.2 1.21.6.3 1.21.6.4 1.21.6.5 1.21.6.6 1.21.6.7 1.21.6.8 1.21.6.9 1.21.6.10
1.22.1.1 1.22.1.2 1.22.1.3 1.22.1.4 1.22.1.5 1.22.1.6 1.22.1.7 1.22.1.8 1.22.1.9 1.22.1.10 1.22.2.1
1.22.2.2 1.22.2.3 1.22.2.4 1.22.2.5 1.22.2.6 1.22.2.7 1.22.2.8 1.22.2.9 1.22.2.10 1.22.3.1 1.22.3.2
1.22.3.3 1.22.3.4 1.22.3.5 1.22.3.6 1.22.3.7 1.22.3.8 1.22.3.9 1.22.3.10 1.22.4.1 1.22.4.2 1.22.4.3
1.22.4.4 1.22.4.5 1.22.4.6 1.22.4.7 1.22.4.8 1.22.4.9 1.22.4.10 1.22.5.1 1.22.5.2 1.22.5.3 1.22.5.4
1.22.5.5 1.22.5.6 1.22.5.7 1.22.5.8 1.22.5.9 1.22.5.10 1.22.6.1 1.22.6.2 1.22.6.3 1.22.6.4 1.22.6.5
1.22.6.6 1.22.6.7 1.22.6.8 1.22.6.9 1.22.6.10 1.23.1.1 1.23.1.2 1.23.1.3 1.23.1.4 1.23.1.5 1.23.1.6
1.23.1.7 1.23.1.8 1.23.1.9 1.23.1.10 1.23.2.1 1.23.2.2 1.23.2.3 1.23.2.4 1.23.2.5 1.23.2.6 1.23.2.7
1.23.2.8 1.23.2.9 1.23.2.10 1.23.3.1 1.23.3.2 1.23.3.3 123.3.4 1.23.3.5 1.23.3.6 1.23.3.7 1.23.3.8
1.23.3.9 1.23.3.10 1.23.4.1 1.23.4.2 1.23.4.3 1.23.4.4 1.23.4.5 1.23.4.6 1.23.4.7 1.23.4.8 1.23.4.9
1.23.4.10 1.23.5.1 1.23.5.2 1.23.5.3 1.23.5.4 1.23.5.5 1.23.5.6 1.23.5.7 1.23.5.8 1.23.5.9 1.23.5.10
1.23.6.1 1.23.6.2 1.23.6.3 1.23.6.4 1.23.6.5 1.23.6.6 1.23.6.7 1.23.6.8 1.23.6.9 1.23.6.10 1.24.1.1
1.24.1.2 1.24.1.3 1.24.1.4 1.24.1.5 1.24.1.6 1.24.1.7 1.24.1.8 1.24.1.9 1.24.1.10 1.24.2.1 1.24.2.2
1.24.2.3 1.24.2.4 1.24.2.5 1.24.2.6 124.2.7 1.24.2.8 1.24.2.9 1.24.2.10 1.24.3.1 1.24.3.2 1.24.3.3
1.24.3.4 1.24.3.5 1.24.3.6 1.24.3.7 1.24.3.8 1.24.3.9 1.24.3.10 1.24.4.1 1.24.4.2 1.24.4.3 1.24.4.4
1.24.4.5 1.24.4.6 1.24.4.7 1.24.4.8 1.24.4.9 1.24.4.10 1.24.5.1 1.24.5.2 1.24.5.3 1.24.5.4 1.24.5.5
1.24.5.6 1.24.5.7 1.24.5.8 1.24.5.9 1.24.5.10 1.24.6.1 1.24.6.2 1.24.6.3 1.24.6.4 1.24.6.5 1.24.6.6
1.24.6.7 1.24.6.8 1.24.6.9 1.24.6.10 1.25.1.1 1.25.1.2 1.25.1.3 1.25.1.4 1.25.1.5 1.25.1.6 1.25.1.7
1.25.1.8 1.25.1.9 1.25.1.10 1.25.2.1 1.25.2.2 1.25.2.3 1.25.2.4 1.25.2.5 1.25.26 1.25.2.7 1.25.2.8
1.25.2.9 1.25.2.10 1.25.3.1 1.25.3.2 1.25.3.3 1.25.3.4 1.25.3.5 1.25.3.6 1.25.3.7 1.25.38 1.25.3.9
1.25.3.10 1.25.4.1 1.25.4.2 1.25.4.3 1.25.4.4 1.25.4.5 1.25.4.6 1.25.4.7 1.25.48 1.25.4.9 1.25.4.10
1.25.5.1 1.25.5.2 1.25.5.3 1.25.5.4 1.25.5.5 1.25.5.6 1.25.5.7 1.25.5.8 1.25.5.9 1.25.5.10 1.25.6.1
1.25.6.2 1.25.6.3 1.25.6.4 1.25.6.5 1.25.6.6 1.25.6.7 1.25.6.8 1.25.6.9 1.25.6.10 2.1.1.1 2.1.1.2 2.1.1.3
2.1.1.4 2.1.1.5 2.1.1.6 2.1.1.7 2.1.1.8 2.1.1.9 2.1.1.10 2.1.2.1 2.1.2.2 2.1.2.3 2.1.2.4 2.1.2.5 2.1.2.6
2.1.2.7 2.1.2.8 2.1.2.9 2.1.2.10 2.1.3.1 2.1.3.2 2.1.3.3 2.1.3.4 2.1.3.5 2.1.36 2.1.3.7 2.1.38 2.1.3.9
2.1.3.10 2.1.4.1 2.1.4.2 2.1.4.3 2.1.4.4 2.1.4.5 2.1.4.6 2.1.4.7 2.1.4.8 2.1.4.9 2.1.4.10 2.1.5.1 2.1.5.2
2.1.5.3 2.1.5.4 2.1.5.5 2.1.5.6 2.1.5.7 2.1.5.8 2.1.5.9 2.1.5.10 2.1.6.1 2.1.6.2 2.1.6.3 2.1.6.4 2.1.6.5
2.1.6.6 2.1.6.7 2.1.6.8 2.1.6.9 2.1.6.10 2.2.1.1 2.2.1.2 2.2.1.3 2.2.1.4 2.2.1.5 2.2.1.6 2.2.1.7 2.2.1.8
2.2.1.9 2.2.1.10 2.2.2.1 2.2.2.2 2.2.2.3 2.2.2.4 2.2.2.5 2.2.2.6 2.2.2.7 2.2.2.8 2.2.2.9 2.2.2.10 2.2.3.1
2.2.3.2 2.2.3.3 2.2.3.4 2.2.3.5 2.2.3.6 2.2.3.7 2.2.3.8 2.2.3.9 2.2.3.10 2.2.4.1 2.2.4.2 2.2.4.3 2.2.4.4
2.2.4.5 2.2.4.6 2.2.4.7 2.2.4.8 2.2.4.9 2.2.4.10 2.2.5.1 2.2.5.2 2.2.5.3 2.2.5.4 2.2.5.5 2.2.5.6 2.2.5.7
2.2.5.8 2.2.5.9 2.2.5.10 2.2.6.1 2.2.6.2 2.2.6.3 2.2.6.4 2.2.6.5 2.2.6.6 2.2.6.7 2.2.6.8 2.2.6.9 2.2.6.10
2.3.1.1 2.3.1.2 2.3.1.3 2.3.1.4 2.3.1.5 2.3.1.6 2.3.1.7 2.3.1.8 2.3.1.9 2.3.1.10 2.3.2.1 2.3.2.2 2.3.2.3
2.3.2.4 2.3.2.5 2.3.2.6 2.3.2.7 2.3.2.8 2.3.2.9 2.32.10 2.3.3.1 2.3.3.2 2.3.3.3 2.3.3.4 2.3.3.5 2.3.3.6
2.3.3.7 2.3.3.8 2.3.3.9 2.3.3.10 2.3.4.1 2.3.4.2 2.3.4.3 2.3.4.4 2.3.4.5 2.3.4.6 2.3.4.7 2.3.4.8 2.3.4.9
2.3.4.10 2.3.5.1 2.3.5.2 2.3.5.3 2.3.5.4 2.3.5.5 2.3.5.6 2.3.5.7 2.3.5.8 2.3.5.9 2.3.5.10 2.3.6.1 2.3.6.2
2.3.6.3 2.3.6.4 2.3.6.5 2.3.6.6 2.3.6.7 2.3.6.8 2.3.6.9 2.3.6.10 2.4.1.1 2.4.1.2 2.4.1.3 2.4.1.4 2.4.1.5
2.4.1.6 2.4.1.7 2.4.1.8 2.4.1.9 2.4.1.10 2.4.2.1 2.4.2.2 2.4.2.3 2.4.2.4 2.4.2.5 2.4.2.6 2.4.2.7 2.4.2.8
2.4.2.9 2.4.2.10 2.4.3.1 2.4.3.2 2.4.3.3 2.4.3.4 2.4.3.5 2.4.3.6 2.4.3.7 2.4.3.8 2.4.3.9 2.4.3.10 2.4.4.1
2.4.4.2 2.4.4.3 2.4.4.4 2.4.4.5 2.4.4.6 2.4.4.7 2.4.4.8 2.4.4.9 2.4.4.10 2.4.5.1 2.4.5.2 2.4.5.3 2.4.5.4
2.4.5.5 2.4.5.6 2.4.5.7 2.4.5.8 2.4.5.9 2.4.5.10 2.4.6.1 2.4.6.2 2.4.6.3 2.4.6.4 2.4.6.5 2.4.6.6 2.4.6.7
2.4.6.8 2.4.6.9 2.4.6.10 2.5.1.1 2.5.1.2 2.5.1.3 2.5.1.4 2.5.1.5 2.5.1.6 2.5.1.7 2.5.1.8 2.5.1.9 2.5.1.10
2.5.2.1 2.5.2.2 2.5.2.3 2.5.2.4 2.5.2.5 2.5.2.6 2.5.2.7 2.5.2.8 2.5.2.9 2.5.2.10 2.5.3.1 2.5.3.2 2.5.3.3
2.5.3.4 2.5.3.5 2.5.3.6 2.5.3.7 2.5.3.8 2.5.3.9 2.5.3.10 2.5.4.1 2.5.4.2 2.5.4.3 2.5.4.4 2.5.4.5 2.5.4.6
2.5.4.7 2.5.4.8 2.5.4.9 2.5.4.10 2.5.5.1 2.5.5.2 2.5.5.3 2.5.5.4 2.5.5.5 2.5.5.6 2.5.5.7 2.5.5.8 2.5.5.9
2.5.5.10 2.5.6.1 2.5.6.2 2.5.6.3 2.5.6.4 2.5.6.5 2.5.6.6 2.5.6.7 2.5.6.8 2.5.6.9 2.5.6.10 2.6.1.1 2.6.1.2
2.6.1.3 2.6.1.4 2.6.1.5 2.6.1.6 2.6.1.7 2.6.1.8 2.6.1.9 2.6.1.10 2.6.2.1 2.6.2.2 2.6.2.3 2.6.2.4 2.6.2.5
2.6.2.6 2.6.2.7 2.6.2.8 2.6.2.9 2.6.2.10 2.6.3.1 2.6.3.2 2.6.3.3 2.6.3.4 2.6.3.5 2.6.3.6 2.6.3.7 2.6.3.8
2.6.3.9 2.6.3.10 2.6.4.1 2.6.4.2 2.6.4.3 2.6.4.4 2.6.4.5 2.6.4.6 2.6.4.7 2.6.4.8 2.6.4.9 2.6.4.10 2.6.5.1
2.6.5.2 2.6.5.3 2.6.5.4 2.6.5.5 2.6.5.6 2.6.5.7 2.6.5.8 2.6.5.9 2.6.5.10 2.6.6.1 2.6.6.2 2.6.6.3 2.6.6.4
2.6.6.5 2.6.6.6 2.6.6.7 2.6.6.8 2.6.6.9 2.6.6.10 2.7.1.1 2.7.1.2 2.7.1.3 2.7.1.4 2.7.1.5 2.7.1.6 2.7.1.7
2.7.1.8 2.7.1.9 2.7.1.10 2.7.2.1 2.7.2.2 2.7.2.3 2.7.2.4 2.7.2.5 2.7.2.6 2.7.2.7 2.7.2.8 2.7.2.9 2.7.2.10
2.7.3.1 2.7.3.2 2.7.3.3 2.7.3.4 2.7.3.5 2.7.3.6 2.7.3.7 2.7.3.8 2.7.3.9 2.7.3.10 2.7.4.1 2.7.4.2 2.7.4.3
2.7.4.4 2.7.4.5 2.7.4.6 2.7.4.7 2.7.4.8 2.7.4.9 2.7.4.10 2.7.5.1 2.7.5.2 2.7.5.3 2.7.5.4 2.7.5.5 2.7.5.6
2.7.5.7 2.7.5.8 2.7.5.9 2.7.5.10 2.7.6.1 2.7.6.2 2.7.6.3 2.7.6.4 2.7.6.5 2.7.6.6 2.7.6.7 2.7.6.8 2.7.6.9
2.7.6.10 2.8.1.1 2.8.1.2 2.8.1.3 2.8.1.4 2.8.1.5 2.8.1.6 2.8.1.7 2.8.1.8 2.8.1.9 2.8.1.10 2.8.2.1 2.8.2.2
2.8.2.3 2.8.2.4 2.8.2.5 2.8.2.6 2.8.2.7 2.8.2.8 2.8.2.9 2.8.2.10 2.8.3.1 2.8.3.2 2.8.3.3 2.8.3.4 2.8.3.5
2.8.3.6 2.8.3.7 2.8.3.8 2.8.3.9 2.8.3.10 2.8.4.1 2.8.4.2 2.8.4.3 2.8.4.4 2.8.4.5 2.8.4.6 2.8.4.7 2.8.4.8
2.8.4.9 2.8.4.10 2.8.5.1 2.8.5.2 2.8.5.3 2.8.5.4 2.8.5.5 2.8.5.6 2.8.5.7 2.8.5.8 2.8.5.9 2.8.5.10 2.8.6.1
2.8.6.2 2.8.6.3 2.8.6.4 2.8.6.5 2.8.6.6 2.8.6.7 2.8.6.8 2.8.6.9 2.8.6.10 2.9.1.1 2.9.1.2 2.9.1.3 2.9.1.4
2.9.1.5 2.9.1.6 2.9.1.7 2.9.1.8 2.9.1.9 2.9.1.10 2.9.2.1 2.9.2.2 2.9.2.3 2.9.2.4 2.9.2.5 2.9.2.6 2.9.2.7
2.9.2.8 2.9.2.9 2.9.2.10 2.9.3.1 2.9.3.2 2.9.3.3 2.9.3.4 2.9.3.5 2.9.3.6 2.9.3.7 2.9.3.8 2.9.3.9 2.9.3.10
2.9.4.1 2.9.4.2 2.9.4.3 2.9.4.4 2.9.4.5 2.9.4.6 2.9.4.7 2.9.4.8 2.9.4.9 2.9.4.10 2.9.5.1 2.9.5.2 2.9.5.3
2.9.5.4 2.9.5.5 2.9.5.6 2.9.5.7 2.9.5.8 2.9.5.9 2.9.5.10 2.9.6.1 2.9.6.2 2.9.6.3 2.9.6.4 2.9.6.5 2.9.6.6
2.9.6.7 2.9.6.8 2.9.6.9 2.9.6.10 2.10.1.1 2.10.1.2 2.10.1.3 2.10.1.4 2.10.1.5 2.10.1.6 2.10.1.7 2.10.1.8
2.10.1.9 2.10.1.10 2.10.2.1 2.10.2.2 2.10.2.3 2.10.2.4 2.10.2.5 2.10.2.6 2.10.2.7 2.10.2.8 2.10.2.9
2.10.2.10 2.10.3.1 2.10.3.2 2.10.3.3 2.10.3.4 2.10.3.5 2.10.3.6 2.10.3.7 2.10.3.8 2.10.3.9 2.10.3.10
2.10.4.1 2.10.4.2 2.10.4.3 2.10.4.4 2.10.4.5 2.10.4.6 2.10.4.7 2.10.4.8 2.10.4.9 2.10.4.10 2.10.5.1
2.10.5.2 2.10.5.3 2.10.5.4 2.10.5.5 2.10.5.6 2.10.5.7 2.10.5.8 2.10.5.9 2.10.5.10 2.10.6.1 2.10.6.2
2.10.6.3 2.10.6.4 2.10.6.5 2.10.6.6 2.10.6.7 2.10.6.8 2.10.6.9 2.10.6.10 2.11.1.1 2.11.1.2 2.11.1.3
2.11.1.4 2.11.1.5 2.11.1.6 2.11.1.7 2.11.1.8 2.11.1.9 2.11.1.10 2.11.2.1 2.11.2.2 2.11.2.3 2.11.2.4
2.11.2.5 2.11.2.6 2.11.2.7 2.11.2.8 2.11.2.9 2.11.2.10 2.11.3.1 2.11.3.2 2.11.3.3 2.11.3.4 2.11.3.5
2.11.3.6 2.11.3.7 2.11.3.8 2.11.3.9 2.11.3.10 2.11.4.1 2.11.4.2 2.11.4.3 2.11.4.4 2.11.4.5 2.11.4.6
2.11.4.7 2.11.4.8 2.11.4.9 2.11.4.10 2.11.5.1 2.11.5.2 2.11.5.3 2.11.5.4 2.11.5.5 2.11.5.6 2.11.5.7
2.11.5.8 2.11.5.9 2.11.5.10 2.11.6.1 2.11.6.2 2.11.6.3 2.11.6.4 2.11.6.5 2.11.6.6 2.11.6.7 2.11.6.8
2.11.6.9 2.11.6.10 2.12.1.1 2.12.1.2 2.12.1.3 2.12.1.4 2.12.1.5 2.12.1.6 2.12.1.7 2.12.1.8 2.12.1.9
2.12.1.10 2.12.2.1 2.12.2.2 2.12.2.3 2.12.2.4 2.12.2.5 2.12.2.6 2.12.2.7 2.12.2.8 2.12.2.9 2.12.2.10
2.12.3.1 2.12.3.2 2.12.3.3 2.12.3.4 2.12.3.5 2.12.3.6 2.12.3.7 2.12.3.8 2.12.3.9 2.12.3.10 2.12.4.1
2.12.4.2 2.12.4.3 2.12.4.4 2.12.4.5 2.12.4.6 2.12.4.7 2.12.4.8 2.12.4.9 2.12.4.10 2.12.5.1 2.12.5.2
2.12.5.3 2.12.5.4 2.12.5.5 2.12.5.6 2.12.5.7 2.12.5.8 2.12.5.9 2.12.5.10 2.12.6.1 2.12.6.2 2.12.6.3
2.12.6.4 2.12.6.5 2.12.6.6 2.12.6.7 2.12.6.8 2.12.6.9 2.12.6.10 2.13.1.1 2.13.1.2 2.13.1.3 2.13.1.4
2.13.1.5 2.13.1.6 2.13.1.7 2.13.1.8 2.13.1.9 2.13.1.10 2.13.2.1 2.13.2.2 2.13.2.3 2.13.2.4 2.13.2.5
2.13.2.6 2.13.2.7 2.13.2.8 2.13.2.9 2.13.2.10 2.13.3.1 2.13.3.2 2.13.3.3 2.13.3.4 2.13.3.5 2.13.3.6
2.13.3.7 2.13.3.8 2.13.3.9 2.13.3.10 2.13.4.1 2.13.4.2 2.13.4.3 2.13.4.4 2.13.4.5 2.13.4.6 2.13.4.7
2.13.4.8 2.13.4.9 2.13.4.10 2.13.5.1 2.13.5.2 2.13.5.3 2.13.5.4 2.13.5.5 2.13.5.6 2.13.5.7 2.13.5.8
2.13.5.9 2.13.5.10 2.13.6.1 2.13.6.2 2.13.6.3 2.13.6.4 2.13.6.5 2.13.6.6 2.13.6.7 2.13.6.8 2.13.6.9
2.13.6.10 2.14.1.1 2.14.1.2 2.14.1.3 2.14.1.4 2.14.1.5 2.14.1.6 2.14.1.7 2.14.1.8 2.14.1.9 2.14.1.10
2.14.2.1 2.14.2.2 2.14.2.3 2.14.2.4 2.14.2.5 2.14.2.6 2.14.2.7 2.14.2.8 2.14.2.9 2.14.2.10 2.14.3.1
2.14.3.2 2.14.3.3 2.14.3.4 2.14.3.5 2.14.3.6 2.14.3.7 2.14.3.8 2.14.3.9 2.14.3.10 2.14.4.1 2.14.4.2
2.14.4.3 2.14.4.4 2.14.4.5 2.14.4.6 2.14.4.7 2.14.4.8 2.14.4.9 2.14.4.10 2.14.5.1 2.14.5.2 2.14.5.3
2.14.5.4 2.14.5.5 2.14.5.6 2.14.5.7 2.14.5.8 2.14.5.9 2.14.5.10 2.14.6.1 2.14.6.2 2.14.6.3 2.14.6.4
2.14.6.5 2.14.6.6 2.14.6.7 2.14.6.8 2.14.6.9 2.14.6.10 2.15.1.1 2.15.1.2 2.15.1.3 2.15.1.4 2.15.1.5
2.15.1.6 2.15.1.7 2.15.1.8 2.15.1.9 2.15.1.10 2.15.2.1 2.15.2.2 2.15.2.3 2.15.2.4 2.15.2.5 2.15.2.6
2.15.2.7 2.15.2.8 2.15.2.9 2.15.2.10 2.15.3.1 2.15.3.2 2.15.3.3 2.15.3.4 2.15.3.5 2.15.3.6 2.15.3.7
2.15.3.8 2.15.3.9 2.15.3.10 2.15.4.1 2.15.4.2 2.15.4.3 2.15.4.4 2.15.4.5 2.15.4.6 2.15.4.7 2.15.4.8
2.15.4.9 2.15.4.10 2.15.5.1 2.15.5.2 2.15.5.3 2.15.5.4 2.15.5.5 2.15.5.6 2.15.5.7 2.15.5.8 2.15.5.9
2.15.5.10 2.15.6.1 2.15.6.2 2.15.6.3 2.15.6.4 2.15.6.5 2.15.6.6 2.15.6.7 2.15.6.8 2.15.6.9 2.15.6.10
2.16.1.1 2.16.1.2 2.16.1.3 2.16.1.4 2.16.1.5 2.16.1.6 2.16.1.7 2.16.1.8 2.16.1.9 2.16.1.10 2.16.2.1
2.16.2.2 2.16.2.3 2.16.2.4 2.16.2.5 2.16.2.6 2.16.2.7 2.16.2.8 2.16.2.9 2.16.2.10 2.16.3.1 2.16.3.2
2.16.3.3 2.16.3.4 2.16.3.5 2.16.3.6 2.16.3.7 2.16.3.8 2.16.3.9 2.16.3.10 2.16.4.1 2.16.4.2 2.16.4.3
2.16.4.4 2.16.4.5 2.16.4.6 2.16.4.7 2.16.4.8 2.16.4.9 2.16.4.10 2.16.5.1 2.16.5.2 2.16.5.3 2.16.5.4
2.16.5.5 2.16.5.6 2.16.5.7 2.16.5.8 2.16.5.9 2.16.5.10 2.16.6.1 2.16.6.2 2.16.6.3 2.16.6.4 2.16.6.5
2.46.6.6 2.16.6.7 2.16.6.8 2.16.6.9 2.16.6.10 2.17.1.1 2.17.1.2 2.17.1.3 2.17.1.4 2.17.1.5 2.17.1.6
2.17.1.7 2.17.1.8 2.17.1.9 2.17.1.10 2.17.2.1 2.17.2.2 2.17.2.3 2.17.2.4 2.17.2.5 2.17.2.6 2.17.2.7
2.17.2.8 2.17.2.9 2.17.2.10 2.17.3.1 2.17.3.2 2.17.3.3 2.17.3.4 2.17.3.5 2.17.3.6 2.17.3.7 2.17.3.8
2.17.3.9 2.173.10 2.17.4.1 2.17.4.2 2.17.4.3 2.17.4.4 2.17.4.5 2.17.4.6 2.17.4.7 2.17.4.8 2.17.4.9
2.17.4.10 2.17.5.1 2.17.5.2 2.17.5.3 2.17.5.4 2.17.5.5 2.17.5.6 2.17.5.7 2.17.5.8 2.17.5.9 2.17.5.10
2.17.6.1 2.17.6.2 2.17.6.3 2.17.6.4 2.17.6.5 2.17.6.6 2.17.6.7 2.17.6.8 2.17.6.9 2.17.6.10 2.18.1.1
2.18.1.2 2.18.1.3 2.18.1.4 2.18.1.5 2.18.1.6 2.18.1.7 2.18.1.8 2.18.1.9 2.18.1.10 2.18.2.1 2.18.2.2
2.18.2.3 2.18.2.4 2.18.2.5 2.18.2.6 2.18.2.7 2.18.2.8 2.18.2.9 2.18.2.10 2.18.3.1 2.18.3.2 2.18.3.3
2.18.3.4 2.18.3.5 2.18.3.6 2.18.3.7 2.18.3.8 2.18.3.9 2.18.3.10 2.18.4.1 2.18.4.2 2.18.4.3 2.18.4.4
2.18.4.5 2.18.4.6 2.18.4.7 2.18.4.8 2.18.4.9 2.18.4.10 2.18.5.1 2.18.5.2 2.18.5.3 2.18.5.4 2.18.5.5
2.18.5.6 2.18.57 2.18.5.8 2.18.5.9 2.18.5.10 2.18.6.1 2.18.6.2 2.18.6.3 2.18.6.4 2.18.6.5 2.18.6.6
2.18.6.7 2.18.6.8 2.18.6.9 2.18.6.10 2.19.1.1 2.19.1.2 2.19.1.3 2.19.1.4 2.19.1.5 2.19.1.6 2.19.1.7
2.19.1.8 2.191.9 2.19.1.10 2.19.2.1 2.19.2.2 2.19.2.3 2.19.2.4 2.19.2.5 2.19.2.6 2.19.2.7 2.19.2.8
2.19.2.9 2.19.2.10 2.19.3.1 2.19.3.2 2.19.3.3 2.19.3.4 2.19.3.5 2.19.3.6 2.19.3.7 2.19.3.8 2.19.3.9
2.19.3.10 2.19.4.1 2.19.4.2 2.19.4.3 2.19.4.4 2.19.4.5 2.19.4.6 2.194.7 2.19.4.8 21.9.4.9 2.19.4.10
2.19.5.1 2.19.5.2 2.19.5.3 2.19.5.4 2.19.5.5 2.19.5.6 2.19.5.7 2.19.5.8 2.19.5.9 2.19.5.10 2.19.6.1
2.19.6.2 2.19.6.3 2.19.6.4 2.19.6.5 2.19.6.6 2.19.6.7 2.19.6.8 2.19.6.9 2.19.6.10 2.20.1.1 2.20.1.2
2.20.1.3 2.20.1.4 2.20.1.5 2.20.1.6 2.20.1.7 2.20.1.8 2.20.1.9 2.20.1.10 2.20.2.1 2.20.2.2 2.20.2.3
2.20.2.4 2.20.2.5 2.20.2.6 2.20.2.7 2.20.2.8 2.20.2.9 2.20.2.10 2.20.3.1 2.20.3.2 2.20.3.3 2.20.3.4
2.20.3.5 2.20.3.6 2.20.3.7 2.20.3.8 2.20.3.9 2.20.3.10 2.20.4.1 2.20.4.2 2.20.4.3 2.20.4.4 2.20.4.5
2.20.4.6 2.20.4.7 2.20.4.8 2.20.4.9 2.20.4.10 2.20.5.1 2.20.5.2 2.20.5.3 2.20.5.4 2.20.5.5 2.20.5.6
2.20.5.7 2.20.5.8 2.20.5.9 2.20.5.10 2.20.6.1 2.20.6.2 2.20.6.3 2.20.6.4 2.20.6.5 2.20.6.6 2.20.6.7
2.20.6.8 2.20.6.9 2.20.6.10 2.21.1.1 2.21.1.2 2.21.1.3 2.21.1.4 2.21.1.5 2.21.1.6 2.21.1.7 2.21.1.8
2.21.1.9 2.21.1.10 2.21.2.1 2.21.2.2 2.21.2.3 2.21.2.4 2.21.2.5 2.21.2.6 22.1.2.7 2.21.2.8 2.21.2.9
2.21.2.10 2.21.3.1 2.21.3.2 2.21.3.3 2.21.3.4 2.21.3.5 2.21.3.6 2.21.3.7 2.21.3.8 2.21.3.9 2.21.3.10
2.21.4.1 2.21.4.2 2.21.4.3 2.21.4.4 2.21.4.5 2.21.4.6 2.21.4.7 2.21.4.8 2.21.4.9 2.21.4.10 2.21.5.1
2.21.5.2 2.21.5.3 2.21.5.4 2.21.5.5 2.21.5.6 2.21.5.7 2.21.5.8 2.21.5.9 2.21.5.10 2.21.6.1 2.21.6.2
2.21.6.3 2.21.6.4 2.21.6.5 2.21.6.6 2.21.6.7 2.21.6.8 2.21.6.9 2.21.6.10 2.22.1.1 2.22.1.2 2.22.1.3
2.22.1.4 2.22.1.5 2.22.1.6 2.22.1.7 2.22.1.8 2.22.1.9 2.22.1.10 2.22.2.1 2.22.2.2 2.22.2.3 2.22.2.4
2.22.2.5 2.22.2.6 2.22.2.7 2.22.2.8 2.22.2.9 2.22.2.10 2.22.3.1 2.22.3.2 2.22.3.3 2.22.3.4 2.22.3.5
2.22.3.6 2.22.3.7 2.22.3.8 2.22.3.9 2.22.3.10 2.22.4.1 2.22.4.2 2.22.4.3 2.22.4.4 2.22.4.5 2.22.4.6
2.22.4.7 2.22.4.8 2.22.4.9 2.22.4.10 2.22.5.1 2.22.5.2 2.22.5.3 2.22.5.4 2.22.5.5 2.22.5.6 2.22.5.7
2.22.5.8 2.22.5.9 2.22.5.10 2.22.6.1 2.22.6.2 2.22.6.3 2.22.6.4 2.22.6.5 2.22.6.6 2.22.6.7 2.22.6.8
2.22.6.9 2.22.6.10 2.23.1.1 2.23.4.2 2.23.1.3 2.23.1.4 2.23.1.5 2.23.1.6 2.23.1.7 2.23.1.8 2.23.1.9
2.23.1.10 2.23.2.1 2.23.2.2 2.23.2.3 2.23.2.4 2.23.2.5 2.23.2.6 2.23.2.7 2.23.2.8 2.23.2.9 2.23.2.10
2.23.3.1 2.23.3.2 2.23.3.3 2.23.3.4 2.23.3.5 2.23.3.6 2.23.3.7 2.23.3.8 2.23.3.9 2.23.3.10 2.23.4.1
2.23.4.2 2.23.4.3 2.23.4.4 2.23.4.5 2.23.4.6 2.23.4.7 2.23.4.8 2.23.4.9 2.23.4.10 2.23.5.1 2.23.5.2
2.23.5.3 2.23.5.4 2.23.5.5 2.23.5.6 2.23.5.7 2.23.5.8 2.23.5.9 2.23.5.10 2.23.6.1 2.23.6.2 2.23.6.3
2.23.6.4 2.23.6.5 2.23.6.6 2.23.6.7 2.23.6.8 2.23.6.9 2.23.6.10 2.24.1.1 2.24.1.2 2.24.1.3 2.24.1.4
2.24.1.5 2.24.1.6 2.24.1.7 2.24.1.8 2.24.1.9 2.24.1.10 2.24.2.1 2.24.2.2 2.24.2.3 2.24.2.4 2.24.2.5
2.24.2.6 2.24.2.7 2.24.2.8 2.24.2.9 2.24.2.10 2.24.3.1 2.24.3.2 2.24.3.3 2.24.3.4 2.24.3.5 2.24.3.6
2.24.3.7 2.24.3.8 2.24.3.9 2.24.3.10 2.24.4.1 2.24.4.2 2.24.4.3 2.24.4.4 2.24.4.5 2.24.4.6 2.24.4.7
2.24.4.8 2.24.4.9 2.24.4.10 2.24.5.1 2.24.5.2 2.24.5.3 2.24.5.4 2.24.5.5. 2.24.5.6 2.24.5.7 2.24.5.8
2.24.5.9 2.24.5.10 2.24.6.1 2.24.6.2 2.24.6.3 2.24.6.4 2.24.6.5 2.24.6.6 2.24.6.7 2.24.6.8 2.24.6.9
2.24.6.10 2.25.1.1 2.25.1.2 2.25.1.3 2.25.1.4 2.25.1.5 2.25.1.6 2.25.1.7 2.25.1.8 2.25.1.9 2.25.1.10
2.25.2.1 2.25.2.2 2.25.2.3 2.25.2.4 2.25.2.5 2.25.2.6 2.25.2.7 2.25.2.8 2.25.2.9 2.25.2.10 2.25.3.1
2.25.3.2 2.25.3.3 2.25.3.4 2.25.3.5 2.25.3.6 2.25.3.7 2.25.3.8 2.25.3.9 2.25.3.10 2.25.4.1 2.25.4.2
2.25.4.3 2.25.4.4 2.25.4.5 2.25.4.6 2.25.4.7 2.25.4.8 2.25.4.9 2.25.4.10 2.25.5.1 2.25.5.2 2.25.5.3
2.25.5.4 2.25.5.5 2.25.5.6 2.25.5.7 2.25.5.8 2.25.5.9 2.25.5.10 2.25.6.1 2.25.6.2 2.25.6.3 2.25.6.4
2.25.6.5 2.25.6.6 2.25.6.7 2.25.6.8 2.25.6.9 2.25.6.10 3.1.1.1 3.1.1.2 3.1.1.3 3.1.1.4 3.1.1.5 3.1.1.6
3.1.1.7 3.1.1.8 3.1.1.9 3.1.1.10 3.1.2.1 3.1.2.2 3.1.2.3 3.1.2.4 3.1.2.5 3.1.2.6 3.1.2.7 3.1.2.8 3.1.2.9
3.1.2.10 3.1.3.1 3.1.3.2 3.1.3.3 3.1.3.4 3.1.3.5 3.1.3.6 3.1.3.7 3.1.3.8 3.1.3.9 3.1.3.10 3.1.4.1 3.1.4.2
3.1.4.3 3.1.4.4 3.1.4.5 3.1.4.6 3.1.4.7 3.1.4.8 3.1.4.9 3.1.4.10 3.1.5.1 3.1.5.2 3.1.5.3 3.1.5.4 3.1.5.5
3.1.5.6 3.1.5.7 3.1.5.8 3.1.5.9 3.1.5.10 3.1.6.2 3.1.6.2 3.1.6.3 3.1.6.4 3.4.6.5 3.1.6.6 3.1.6.7 3.1.6.8
3.1.6.9 3.1.6.10 3.2.1.1 3.2.1.2 3.2.1.3 3.2.1.4 3.2.1.5 3.2.1.6 3.2.1.7 3.2.1.8 3.2.1.9 3.2.1.10 3.2.2.1
3.2.2.2 3.2.2.3 3.2.2.4 3.2.2.5 3.2.2.6 3.2.2.7 3.2.2.8 3.2.2.9 3.2.2.10 3.2.3.1 3.2.3.2 3.2.3.3 3.2.3.4
3.2.3.5 3.2.3.6 3.2.3.7 3.2.3.8 3.2.3.9 3.2.3.10 3.2.4.1 3.2.4.2 3.2.4.3 3.2.4.4 3.2.4.5 3.2.4.6 3.2.4.7
3.2.4.8 3.2.4.9 3.2.4.10 3.2.5.1 3.2.5.2 3.2.5.3 3.2.5.4 3.2.5.5 3.2.5.6 3.2.5.7 3.2.5.8 3.2.5.9 3.2.5.10
3.2.6.1 3.2.6.2 3.2.6.3 3.2.6.4 3.2.6.5 3.2.6.6 3.2.6.7 3.2.6.8 3.2.6.9 3.2.6.10 3.3.1.1 3.3.1.2 3.3.1.3
3.3.1.4 3.3.1.5 3.3.1.6 3.3.1.7 3.3.1.8 3.3.1.9 3.3.1.10 3.3.2.1 3.3.2.2 3.3.2.3 3.3.2.4 3.3.2.5 3.3.2.6
3.3.2.7 3.3.2.8 3.3.2.9 3.3.2.10 3.3.3.1 3.3.3.2 3.3.3.3 3.3.3.4 3.3.3.5 3.3.3.6 3.3.3.7 3.3.3.8 3.3.3.9
3.3.3.10 3.3.4.1 3.3.4.2 3.3.4.3 3.3.4.4 3.3.4.5 3.3.4.6 3.3.4.7 3.3.4.8 3.3.4.9 3.3.4.10 3.3.5.1 3.3.5.2
3.3.5.3 3.3.5.4 3.3.5.5 3.3.5.6 3.3.5.7 3.3.5.8 3.3.5.9 3.3.5.10 3.3.6.1 3.3.6.2 3.3.6.3 3.3.6.4 3.3.6.5
3.3.6.6 3.3.6.7 3.3.6.8 3.3.6.9 3.3.6.10 3.4.1.1 3.4.1.2 3.4.1.3 3.4.1.4 3.4.1.5 3.4.1.6 3.4.1.7 3.4.1.8
3.4.1.9 3.4.1.10 3.4.2.1 3.4.2.2 3.4.2.3 3.4.2.4 3.4.2.5 3.4.2.6 3.4.2.7 3.4.2.8 3.4.2.9 3.4.2.10 3.4.3.1
3.4.3.2 3.4.3.3 3.4.3.4 3.4.3.5 3.4.3.6 3.4.3.7 3.4.3.8 3.4.3.9 3.4.3.10 3.4.4.1 3.4.4.2 3.4.4.3 3.4.4.4
3.4.4.5 3.4.4.6 3.4.4.7 3.4.4.8 3.4.4.9 3.4.4.10 3.4.5.1 3.4.5.2 3.4.5.3 3.4.5.4 3.4.5.5 3.4.5.6 3.4.5.7
3.4.5.8 3.4.5.9 3.4.5.10 3.4.6.1 3.4.6.2 3.4.6.3 3.4.6.4 3.4.6.5 3.4.6.6 3.4.6.7 3.4.6.8 3.4.6.9 3.4.6.10
3.5.1.1 3.5.1.2 3.5.1.3 3.5.1.4 3.5.1.5 3.5.1.6 3.5.1.7 3.5.1.8 3.5.1.9 3.5.1.10 3.5.2.1 3.5.2.2 3.5.2.3
3.5.2.4 3.5.2.5 3.5.2.6 3.5.2.7 3.5.2.8 3.5.2.9 3.5.2.10 3.5.3.1 3.5.3.2 3.5.3.3 3.5.3.4 3.5.3.5 3.5.3.6
3.5.3.7 3.5.3.8 3.5.3.9 3.5.3.10 3.5.4.1 3.5.4.2 3.5.4.3 3.5.4.4 3.5.4.5 3.5.4.6 3.5.4.7 3.5.4.8 3.5.4.9
3.5.4.10 3.5.5.1 3.5.5.2 3.5.5.3 3.5.5.4 3.5.5.5 3.5.5.6 3.5.5.7 3.5.5.8 3.5.5.9 3.5.5.10 3.5.6.1 3.5.6.2
3.5.6.3 3.5.6.4 3.5.6.5 3.5.6.6 3.5.6.7 3.5.6.8 3.5.6.9 3.5.6.10 3.6.1.1 3.6.1.2 3.6.1.3 3.6.1.4 3.6.1.5
3.6.1.6 3.6.1.7 3.6.1.8 3.6.1.9 3.6.1.10 3.6.2.1 3.6.2.2 3.6.2.3 3.6.2.4 3.6.2.5 3.6.2.6 3.6.2.7 3.6.2.8
3.6.2.9 3.6.2.10 3.6.3.1 3.6.3.2 3.6.3.3 3.6.3.4 3.6.3.5 3.6.3.6 3.6.3.7 3.6.3.8 3.6.3.9 3.6.3.10 3.6.4.1
3.6.4.2 3.6.4.3 3.6.4.4 3.6.4.5 3.6.4.6 3.6.4.7 3.6.4.8 3.6.4.9 3.6.4.10 3.6.5.1 3.6.5.2 3.6.5.3 3.6.5.4
3.6.5.5 3.6.5.6 3.6.5.7 3.6.5.8 3.6.5.9 3.6.5.10 3.6.6.1 3.6.6.2 3.6.6.3 3.6.6.4 3.6.6.5 3.6.6.6 3.6.6.7
3.6.6.8 3.6.6.9 3.6.6.10 3.7.1.1 3.7.1.2 3.7.1.3 3.7.1.4 3.7.1.5 3.7.1.6 3.7.1.7 3.7.1.8 3.7.1.9 3.7.1.10
3.7.2.1 3.7.2.2 3.7.2.3 3.7.2.4 3.7.2.5 3.7.2.6 3.7.2.7 3.7.2.8 3.7.2.9 3.7.2.10 3.7.3.1 3.7.3.2 3.7.3.3
3.7.3.4 3.7.3.5 3.7.3.6 3.7.3.7 3.7.3.8 3.7.3.9 3.7.3.10 3.7.4.1 3.7.4.2 3.7.4.3 3.7.4.4 3.7.4.5 3.7.4.6
3.7.4.7 3.7.4.8 3.7.4.9 3.7.4.10 3.7.5.1 3.7.5.2 3.7.5.3 3.7.5.4 3.7.5.5 3.7.5.6 3.7.5.7 3.7.5.8 3.7.5.9
3.7.5.10 3.7.6.1 3.7.6.2 3.7.6.3 3.7.6.4 3.7.6.5 3.7.6.6 3.7.6.7 3.7.6.8 3.7.6.9 3.7.6.10 3.8.1.1 3.8.1.2
3.8.1.3 3.8.1.4 3.8.1.5 3.8.1.6 3.8.1.7 3.8.1.8 3.8.1.9 3.8.1.10 3.8.2.1 3.8.2.2 3.8.2.3 3.8.2.4 3.8.2.5
3.8.2.6 3.8.2.7 3.8.2.8 3.8.2.9 3.8.2.10 3.8.3.1 3.8.3.2 3.8.3.3 3.8.3.4 3.8.3.5 3.8.3.6 3.8.3.7 3.8.3.8
3.8.3.9 3.8.3.10 3.8.4.1 3.8.4.2 3.8.4.3 3.8.4.4 3.8.4.5 3.8.4.6 3.8.4.7 3.8.4.8 3.8.4.9 3.8.4.10 3.8.5.1
3.8.5.2 3.8.5.3 3.8.5.4 3.8.5.5 3.8.5.6 3.8.5.7 3.8.5.8 3.8.5.9 3.8.5.10 3.8.6.1 3.8.6.2 3.8.6.3 3.8.6.4
3.8.6.5 3.8.6.6 3.8.6.7 3.8.6.8 3.8.6.9 3.8.6.10 3.9.1.1 3.9.1.2 3.9.1.3 3.9.1.4 3.9.1.5 3.9.1.6 3.9.1.7
3.9.1.8 3.9.1.9 3.9.1.10 3.9.2.1 3.9.2.2 3.9.2.3 3.9.2.4 3.9.2.5 3.9.2.6 3.9.2.7 3.9.2.8 3.9.2.9 3.9.2.10
3.9.3.1 3.9.3.2 3.9.3.3 3.9.3.4 3.9.3.5 3.9.3.6 3.9.3.7 3.9.3.8 3.9.3.9 3.9.3.10 3.9.4.1 3.9.4.2 3.9.4.3
3.9.4.4 3.9.4.5 3.9.4.6 3.9.4.7 3.9.4.8 3.9.4.9 3.9.4.10 3.9.5.1 3.9.5.2 3.9.5.3 3.9.5.4 3.9.5.5 3.9.5.6
3.9.5.7 3.9.5.8 3.9.5.9 3.9.5.10 3.9.6.1 3.9.6.2 3.9.6.3 3.9.6.4 3.9.6.5 3.9.6.6 3.9.6.7 3.9.6.8 3.9.6.9
3.9.6.10 3.10.1.1 3.10.1.2 3.10.1.3 3.10.1.4 3.10.1.5 3.10.1.6 3.10.1.7 3.10.1.8 3.10.1.9 3.10.1.10
3.10.2.1 3.10.2.2 3.10.2.3 3.10.2.4 3.10.2.5 3.10.2.6 3.10.2.7 3.10.2.8 3.10.2.9 3.10.2.10 3.10.3.1
3.10.3.2 3.10.3.3 3.10.3.4 3.10.3.5 3.10.3.6 3.10.3.7 3.10.3.8 3.10.3.9 3.10.3.10 3.10.4.1 3.10.4.2
3.10.4.3 3.10.4.4 3.10.4.5 3.10.4.6 3.10.4.7 3.10.4.8 3.10.4.9 3.10.4.10 3.10.5.1 3.10.5.2 3.10.5.3
3.10.5.4 3.10.5.5 3.10.5.6 3.10.5.7 3.10.5.8 3.10.5.9 3.10.5.10 3.10.6.1 3.10.6.2 3.10.6.3 3.10.6.4
3.10.6.5 3.10.6.6 3.10.6.7 3.10.6.8 3.10.6.9 3.10.6.10 3.11.1.1 3.11.1.2 3.11.4.3 3.11.4.4 3.11.1.5
3.11.1.6 3.11.1.7 3.11.1.8 3.11.1.9 3.11.1.10 3.11.2.1 3.11.2.2 3.11.2.3 3.11.2.4 3.11.2.5 3.11.2.6
3.11.2.7 3.11.2.8 3.11.2.9 3.11.2.10 3.11.3.1 3.11.3.2 3.11.3.3 3.11.3.4 3.11.3.5 3.11.3.6 3.11.3.7
3.11.3.8 3.11.3.9 3.11.3.10 3.11.4.1 3.11.4.2 3.11.4.3 3.11.4.4 3.11.4.5 3.11.4.6 3.11.4.7 3.11.4.8
3.11.4.9 3.11.4.10 3.11.5.1 3.11.5.2 3.11.5.3 3.11.5.4 3.11.5.5 3.11.5.6 3.11.5.7 3.11.5.8 3.11.5.9
3.11.5.10 3.11.6.1 3.11.6.2 3.11.6.3 3.11.6.4 3.11.6.5 3.11.6.6 3.11.6.7 3.11.6.8 3.11.6.9 3.11.6.10
3.12.1.1 3.12.1.2 3.12.1.3 3.12.1.4 3.12.1.5 3.12.1.6 3.12.1.7 3.12.1.8 3.12.1.9 3.12.1.10 3.12.2.1
3.12.2.2 3.12.2.3 3.12.2.4 3.12.2.5 3.12.2.6 3.12.2.7 3.12.2.8 3.12.2.9 3.12.2.10 3.12.3.1 3.12.3.2
3.12.3.3 3.12.3.4 3.12.3.5 3.12.3.6 3.12.3.7 3.12.3.8 3.12.3.9 3.12.3.10 3.12.4.1 3.12.4.2 3.12.4.3
3.12.4.4 3.12.4.5 3.12.4.6 3.12.4.7 3.12.4.8 3.12.4.9 3.12.4.10 3.12.5.1 3.12.5.2 3.12.5.3 3.12.5.4
3.12.5.5 3.12.5.6 3.12.5.7 3.12.5.8 3.12.5.9 3.12.5.10 3.12.6.1 3.12.6.2 3.12.6.3 3.12.6.4 3.12.6.5
3.12.6.6 3.12.6.7 3.12.6.8 3.12.6.9 3.12.6.10 3.13.1.1 3.13.1.2 3.13.1.3 3.13.1.4 3.13.1.5 3.13.1.6
3.13.1.7 3.13.1.8 3.13.1.9 3.13.1.10 3.13.2.1 3.13.2.2 3.13.2.3 3.13.2.4 3.13.2.5 3.13.2.6 3.13.2.7
3.13.2.8 3.13.2.9 3.13.2.10 3.13.3.1 3.13.3.2 3.13.3.3 3.13.3.4 3.13.3.5 3.13.3.6 3.13.3.7 3.13.3.8
3.13.3.9 3.13.3.10 3.13.4.1 3.13.4.2 3.13.4.3 3.13.4.4 3.13.4.5 3.13.4.6 3.13.4.7 3.13.4.8 3.13.4.9
3.13.4.10 3.13.5.1 3.13.5.2 3.13.5.3 3.13.5.4 3.13.5.5 3.13.5.6 3.13.5.7 3.13.5.8 3.13.5.9 3.13.5.10
3.13.6.1 3.13.6.2 3.13.6.3 3.13.6.4 3.13.6.5 3.13.6.6 3.13.6.7 3.13.6.8 3.13.6.9 3.13.6.10 3.14.1.1
3.14.1.2 3.14.1.3 3.14.1.4 3.14.1.5 3.14.1.6 3.14.1.7 3.14.1.8 3.14.1.9 3.14.1.10 3.14.2.1 3.14.2.2
3.14.2.3 3.14.2.4 3.14.2.5 3.14.2.6 3.14.2.7 3.14.2.8 3.14.2.9 3.14.2.10 3.14.3.1 3.14.3.2 3.14.3.3
3.14.3.4 3.14.3.5 3.14.3.6 3.14.3.7 3.14.3.8 3.14.3.9 3.14.3.10 3.14.4.1 3.14.4.2 3.14.4.3 3.14.4.4
3.14.4.5 3.14.4.6 3.14.4.7 3.14.4.8 3.14.4.9 3.14.4.10 3.14.5.1 3.14.5.2 3.14.5.3 3.14.5.4 3.14.5.5
3.14.5.6 3.14.5.7 3.14.5.8 3.14.5.9 3.14.5.10 3.14.6.1 3.14.6.2 3.14.6.3 3.14.6.4 3.14.6.5 3.14.6.6
3.14.6.7 3.14.6.8 3.14.6.9 3.14.6.10 3.15.1.1 3.15.1.2 3.15.1.3 3.15.1.4 3.15.1.5 3.15.1.6 3.15.1.7
3.15.1.8 3.15.1.9 3.15.1.10 3.15.2.1 3.15.2.2 3.15.2.3 3.15.2.4 3.15.2.5 3.15.2.6 3.15.2.7 3.15.2.8
3.15.2.9 3.15.2.10 3.15.3.1 3.15.3.2 3.15.3.3 3.15.3.4 3.15.3.5 3.15.3.6 3.15.3.7 3.15.3.8 3.15.3.9
3.15.3.10 3.15.4.1 315.4.2 3.15.4.3 3.15.4.4 3.15.4.5 3.15.4.6 3.15.4.7 3.15.4.8 3.15.4.9 3.15.4.10
3.15.5.1 3.15.5.2 3.15.5.3 3.15.5.4 3.15.5.5 3.15.5.6 3.15.5.7 3.15.5.8 3.15.5.9 3.15.5.10 3.15.6.1
3.15.6.2 3.15.6.3 3.15.6.4 3.15.6.5 3.15.6.6 3.15.6.7 3.15.6.8 3.15.6.9 3.15.6.10 3.16.1.1 3.16.1.2
3.16.1.3 3.16.1.4 3.16.1.5 3.16.1.6 3.16.1.7 3.16.1.8 3.16.1.9 3.16.1.10 3.16.2.1 3.16.2.2 3.16.2.3
3.16.2.4 3.16.2.5 3.16.2.6 3.16.2.7 3.16.2.8 3.16.2.9 3.16.2.10 3.16.3.1 3.16.3.2 3.16.3.3 3.16.3.4
3.16.3.5 3.16.3.6 3.16.3.7 3.16.3.8 3.16.3.9 3.16.3.10 3.16.4.1 3.16.4.2 3.16.4.3 3.16.4.4 3.16.4.5
3.16.4.6 3.16.4.7 3.16.4.8 3.16.4.9 3.16.4.10 3.16.5.1 3.16.5.2 3.16.5.3 3.16.5.4 3.16.5.5 3.16.5.6
3.16.5.7 3.16.5.8 3.16.5.9 3.16.5.10 3.16.6.1 3.16.6.2 3.16.6.3 3.16.6.4 3.16.6.5 3.16.6.6 3.16.6.7
3.16.6.8 3.16.6.9 3.16.6.10 3.17.1.1 3.17.1.2 3.17.1.3 3.17.1.4 3.17.1.5 3.17.1.6 3.17.1.7 3.17.1.8
3.17.1.9 3.17.1.10 3.17.2.1 3.17.2.2 3.17.2.3 3.17.2.4 3.17.2.5 3.17.2.6 3.17.2.7 3.17.2.8 3.17.2.9
3.17.2.10 3.17.3.1 3.17.3.2 3.17.3.3 3.17.3.4 3.17.3.5 3.17.3.6 3.17.3.7 3.17.3.8 317.3.9 3.17.3.10
3.17.4.1 3.17.4.2 3.17.4.3 3.17.4.4 3.17.4.5 3.17.4.6 3.17.4.7 3.17.4.8 3.17.4.9 3.17.4.10 3.17.5.1
3.17.5.2 3.17.5.3 3.17.5.4 3.17.5.5 3.17.5.6 3.17.5.7 3.17.5.8 3.17.5.9 3.17.5.10 3.17.6.1 3.17.6.2
3.17.6.3 3.17.6.4 3.17.6.5 3.17.6.6 3.17.6.7 3.17.6.8 3.17.6.9 3.17.6.10 3.18.1.1 3.18.1.2 3.18.1.3
3.18.1.4 3.18.1.5 3.18.1.6 3.18.1.7 3.18.1.8 3.18.1.9 3.18.1.10 3.18.2.1 3.18.2.2 3.18.2.3 3.18.2.4
3.18.2.5 3.18.2.6 3.18.2.7 3.18.2.8 3.18.2.9 3.18.2.10 3.18.3.1 3.18.3.2 3.18.3.3 3.18.3.4 3.18.3.5
3.18.3.6 3.18.3.7 3.18.3.8 3.18.3.9 3.18.3.10 3.18.4.1 3.18.4.2 3.18.4.3 3.18.4.4 3.18.4.5 3.18.4.6
3.18.4.7 3.18.4.8 3.18.4.9 3.18.4.10 3.18.5.1 3.18.5.2 3.18.5.3 3.18.5.4 3.18.5.5 3.18.5.6 3.18.5.7
3.18.5.8 3.18.5.9 3.18.5.10 3.18.6.1 3.18.6.2 3.18.6.3 3.18.6.4 3.18.6.5 3.18.6.6 3.18.6.7 3.18.6.8
3.18.6.9 3.18.6.10 3.19.1.1 3.19.1.2 3.19.1.3 3.19.1.4 3.19.1.5 3.19.1.6 3.19.1.7 3.19.1.8 3.19.1.9
3.19.1.10 3.19.2.1 319.2.2 3.19.2.3 3.19.2.4 3.19.2.5 3.19.2.6 3.19.2.7 3.19.2.8 3.19.2.9 3.19.2.10
3.19.3.1 3.19.3.2 3.19.3.3 3.19.3.4 3.19.3.5 3.19.3.6 3.19.3.7 3.19.3.8 3.19.3.9 3.19.3.10 3.19.4.1
3.19.4.2 3.19.4.3 3.19.4.4 3.19.4.5 3.19.4.6 3.19.4.7 3.19.4.8 3.19.4.9 3.19.4.10 3.19.5.1 3.19.5.2
3.19.5.3 3.19.5.4 3.19.5.5 3.19.5.6 3.19.5.7 3.19.5.8 3.19.5.9 3.19.5.10 3.19.6.1 3.19.6.2 3.19.6.3
3.19.6.4 3.19.6.5 3.19.6.6 3.19.6.7 3.19.6.8 3.19.6.9 3.19.6.10 3.20.1.1 3.20.1.2 3.20.1.3 3.20.1.4
3.20.1.5 3.20.1.6 3.20.1.7 3.20.1.8 3.20.1.9 3.20.1.10 3.20.2.1 3.20.2.2 3.20.2.3 3.20.2.4 3.20.2.5
3.20.2.6 3.20.2.7 3.20.2.8 3.20.2.9 3.20.2.10 3.20.3.1 3.20.3.2 3.20.3.3 3.20.3.4 3.20.3.5 3.20.3.6
3.20.3.7 3.20.3.8 3.20.3.9 3.20.3.10 3.20.4.1 3.20.4.2 3.20.4.3 3.20.4.4 3.20.4.5 3.20.4.6 3.20.4.7
3.20.4.8 3.20.4.9 3.20.4.10 3.20.5.1 3.20.5.2 3.20.5.3 3.20.5.4 3.20.5.5 3.20.5.6 3.20.5.7 3.20.5.8
3.20.5.9 3.20.5.10 3.20.6.1 3.20.6.2 3.20.6.3 3.20.6.4 3.20.6.5 3.20.6.6 3.20.6.7 3.20.6.8 3.20.6.9
3.20.6.10 3.21.1.1 3.21.1.2 3.21.1.3 3.21.1.4 3.21.1.5 3.21.1.6 3.21.1.7 3.21.1.8 3.21.1.9 3.21.1.10
3.21.2.1 3.21.2.2 3.21.2.3 3.21.2.4 3.21.2.5 3.21.2.6 3.21.2.7 3.21.2.8 3.21.2.9 3.21.2.10 3.21.3.1
3.21.3.2 3.21.3.3 3.21.3.4 3.21.3.5 3.21.3.6 3.21.3.7 3.21.3.8 3.21.3.9 3.21.3.10 3.21.4.1 3.21.4.2
3.21.4.3 3.21.4.4 3.21.4.5 3.21.4.6 3.21.4.7 3.21.4.8 3.21.4.9 3.21.4.10 3.21.5.1 3.21.5.2 3.21.5.3
3.21.5.4 3.21.5.5 3.21.5.6 3.21.5.7 3.21.5.8 3.21.5.9 3.21.5.10 3.21.6.1 3.21.6.2 3.21.6.3 3.21.6.4
3.21.6.5 3.21.6.6 3.21.6.7 3.21.6.8 3.21.6.9 3.21.6.10 3.22.1.1 3.22.1.2 3.22.1.3 3.22.1.4 3.22.1.5
3.22.1.6 3.22.1.7 3.22.1.8 3.22.1.9 3.22.1.10 3.22.2.1 3.22.2.2 3.22.2.3 3.22.2.4 3.22.2.5 3.22.2.6
3.22.2.7 3.22.2.8 3.22.2.9 3.22.2.10 3.22.3.1 3.22.3.2 3.22.3.3 3.22.3.4 3.22.3.5 3.22.3.6 3.22.3.7
3.22.3.8 3.22.3.9 3.22.3.10 3.22.4.1 3.22.4.2 3.22.4.3 3.22.4.4 3.22.4.5 3.22.4.6 3.22.4.7 3.22.4.8
3.22.4.9 3.22.4.10 3.22.5.1 3.22.5.2 3.22.5.3 3.22.5.4 3.22.5.5 3.22.5.6 3.22.5.7 3.22.5.8 3.22.5.9
3.22.5.10 3.22.6.1 3.22.6.2 3.22.6.3 3.22.6.4 3.22.6.5 3.22.6.6 3.22.6.7 3.22.6.8 3.22.6.9 3.22.6.10
3.23.1.1 3.23.1.2 3.23.1.3 3.23.1.4 3.23.1.5 3.23.1.6 3.23.1.7 3.23.1.8 3.23.1.9 3.23.1.10 3.23.2.1
3.23.2.2 3.23.2.3 3.23.2.4 3.23.2.5 3.23.2.6 3.23.2.7 3.23.2.8 3.23.2.9 323.2.10 3.23.3.1 3.23.3.2
3.23.3.3 3.23.3.4 323.3.5 3.23.3.6 3.23.3.7 3.23.3.8 3.23.3.9 3.23.3.10 3.23.4.1 3.23.4.2 3.23.4.3
3.23.4.4 3.23.4.5 323.4.6 3.23.4.7 3.23.4.8 3.23.4.9 3.23.4.10 3.23.5.1 3.23.5.2 323.5.3 3.23.5.4
3.23.5.5 3.23.5.6 3.23.5.7 3.23.5.8 3.23.5.9 3.23.5.10 3.23.6.1 3.23.6.2 3.23.6.3 3.23.6.4 3.23.6.5
3.23.6.6 3.23.6.7 3.23.6.8 3.23.6.9 3.23.6.10 3.24.1.1 3.24.1.2 3.24.1.3 3.24.1.4 3.24.1.5 3.24.1.6
3.24.1.7 3.24.1.8 3.24.1.9 3.24.1.10 3.24.2.1 3.24.2.2 3.24.2.3 3.24.2.4 3.24.2.5 3.24.2.6 3.24.2.7
3.24.2.8 3.24.2.9 3.24.2.10 3.24.3.1 3.24.3.2 3.24.3.3 3.24.3.4 3.24.3.5 3.24.3.6 3.24.3.7 3.24.3.8
3.24.3.9 3.243.10 3.24.4.1 3.24.4.2 3.24.4.3 3.24.4.4 3.24.4.5 3.24.4.6 3.24.4.7 3.244.8 3.24.4.9
3.24.4.10 3.24.5.1 3.24.5.2 3.24.5.3 3.24.5.4 3.24.5.5 3.24.5.6 3.24.5.7 3.24.5.8 3.24.5.9 3.24.5.10
3.24.6.1 3.24.6.2 3.24.6.3 3.24.6.4 3.24.6.5 3.24.6.6 3.24.6.7 3.24.6.8 3.24.6.9 3.24.6.10 3.25.1.1
3.25.1.2 3.25.1.3 3.25.1.4 3.25.1.5 3.25.1.6 3.25.1.7 3.25.1.8 3.25.1.9 3.25.1.10 3.25.2.1 3.25.2.2
3.25.2.3 3.25.2.4 3.25.2.5 3.25.2.6 3.25.2.7 3.25.2.8 3.25.2.9 3.25.2.10 3.25.3.1 3.25.3.2 3.25.3.3
3.25.3.4 3.25.3.5 3.25.3.6 3.25.3.7 3.25.3.8 3.25.3.9 3.25.3.10 3.25.4.1 3.25.4.2 3.25.4.3 3.25.4.4
3.25.4.5 3.25.4.6 3.25.4.7 3.25.4.8 3.25.4.9 3.25.4.10 3.25.5.1 3.25.5.2 3.25.5.3 3.25.5.4 3.25.5.5
3.25.5.6 3.25.5.7 3.25.5.8 3.25.5.9 3.25.5.10 3.25.6.1 3.25.6.2 3.25.6.3 3.25.6.4 3.25.6.5 3.25.6.6
3.25.6.7 3.25.6.8 3.25.6.9 3.25.6.10 4.1.1.1 4.1.1.2 4.1.1.3 4.1.1.4 4.1.1.5 4.1.1.6 4.1.1.7 4.1.1.8 4.1.1.9
4.1.1.10 4.1.2.1 4.1.2.2 4.1.2.3 4.1.2.4 4.1.2.5 4.1.2.6 4.1.2.7 4.1.2.8 4.1.2.9 4.1.2.10 4.1.3.1 4.1.3.2
4.1.3.3 4.1.3.4 4.1.3.5 4.1.3.6 4.1.3.7 4.1.3.8 4.1.3.9 4.1.3.10 4.1.4.1 4.1.4.2 4.1.4.3 4.1.4.4 4.1.4.5
4.1.4.6 4.1.4.7 4.1.4.8 4.1.4.9 4.1.4.10 4.1.5.1 4.1.5.2 4.1.5.3 4.1.5.4 4.1.5.5 4.1.5.6 4.1.5.7 4.1.5.8
4.1.5.9 4.1.5.10 4.1.6.1 4.1.6.2 4.1.6.3 4.1.6.4 4.1.6.5 4.1.6.6 4.1.6.7 4.1.6.8 4.1.6.9 4.1.6.10 4.2.1.1
4.2.1.2 4.2.1.3 4.2.1.4 4.2.1.5 4.2.1.6 4.2.1.7 4.2.1.8 4.2.1.9 4.2.1.10 4.2.2.1 4.2.2.2 4.2.2.3 4.2.2.4
4.2.2.5 4.2.2.6 4.2.2.7 4.2.2.8 4.2.2.9 4.2.2.10 4.2.3.1 4.2.3.2 4.2.3.3 4.2.3.4 4.2.3.5 4.2.3.6 4.2.3.7
4.2.3.8 4.2.3.9 4.2.3.10 4.2.4.1 4.2.4.2 4.2.4.3 4.2.4.4 4.2.4.5 4.2.4.6 4.2.4.7 4.2.4.8 4.2.4.9 4.2.4.10
4.2.5.1 4.2.5.2 4.2.5.3 4.2.5.4 4.2.5.5 4.2.5.6 4.2.5.7 4.2.5.8 4.2.5.9 4.2.5.10 4.2.6.1 4.2.6.2 4.2.6.3
4.2.6.4 4.2.6.5 4.2.6.6 4.2.6.7 4.2.6.8 4.2.6.9 4.2.6.10 4.3.1.1 4.3.1.2 4.3.1.3 4.3.1.4 4.3.1.5 4.3.1.6
4.3.1.7 4.3.1.8 4.3.1.9 4.3.1.10 4.3.2.1 4.3.2.2 4.3.2.3 4.3.2.4 4.3.2.5 4.3.2.6 4.3.2.7 4.3.2.8 4.3.2.9
4.3.2.10 4.3.3.1 4.3.3.2 4.3.3.3 4.3.3.4 4.3.3.5 4.3.3.6 4.3.3.7 4.3.3.8 4.3.3.9 4.3.3.10 4.3.4.1 4.3.4.2
4.3.4.3 4.3.4.4 4.3.4.5 4.3.4.6 4.3.4.7 4.3.4.8 4.3.4.9 4.3.4.10 4.3.5.1 4.3.5.2 4.3.5.3 4.3.5.4 4.3 5.5
4.3.5.6 4.3.5.7 4.3.5.8 4.3.5.9 4.3.5.10 4.3.6.1 4.3.6.2 4.3.6.3 4.3.6.4 4.3.6.5 4.3.6.6 4.3.6.7 4.3.6.8
4.3.6.9 4.3.6.10 4.4.1.1 4.4.1.2 4.4.1.3 4.4.1.4 4.4.1.5 4.4.1.6 4.4.1.7 4.4.1.8 4.4.1.9 4.4.1.10 4.4.2.1
4.4.2.2 4.4.2.3 4.4.2.4 4.4.2.5 4.4.2.6 4.4.2.7 4.4.2.8 4.4.2.9 4.4.2.10 4.4.3.1 4.4.3.2 4.4.3.3 4.4.3.4
4.4.3.5 4.4.3.6 4.4.3.7 4.4.3.8 4.4.3.9 4.4.3.10 4.4.4.1 4.4.4.2 4.4.4.3 4.4.4.4 4.4.4.5 4.4.4.6 4.4.4.7
4.4.4.8 4.4.4.9 4.4.4.10 4.4.5.1 4.4.5.2 4.4.5.3 4.4.5.4 4.4.5.5 4.4.5.6 4.4.5.7 4.4.5.8 4.4.5.9 4.4.5.10
4.4.6.1 4.4.6.2 4.4.6.3 4.4.6.4 4.4.6.5 4.4.6.6 4.4.6.7 4.4.6.8 4.4.6.9 4.4.6.10 4.5.1.1 4.5.1.2 4.5.1.3
4.5.1.4 4.5.1.5 4.5.1.6 4.5.1.7 4.5.1.8 4.5.1.9 4.5.1.10 4.5.2.1 4.5.2.2 4.5.2.3 4.5.2.4 4.5.2.5 4.5.2.6
4.5.2.7 4.5.2.8 4.5.2.9 4.5.2.10 4.5.3.1 4.5.3.2 4.5.3.3 4.5.3.4 4.5.3.5 4.5.3.6 4.5.3.7 4.5.3.8 4.5.3.9
4.5.3.10 4.5.4.1 4.5.4.2 4.5.4.3 4.5.4.4 4.5.4.5 4.5.4.6 4.5.4.7 4.5.4.8 4.5.4.9 4.5.4.10 4.5.5.1 4.5.5.2
4.5.5.3 4.5.5.4 4.5.5.5 4.5.5.6 4.5.5.7 4.5.5.8 4.5.5.9 4.5.5.10 4.5.6.1 4.5.6.2 4.5.6.3 4.5.6.4 4.5.6.5
4.5.6.6 4.5.6.7 4.5.6.8 4.5.6.9 4.5.6.10 4.6.1.1 4.6.1.2 4.6.1.3 4.6.1.4 4.6.1.5 4.6.1.6 4.6.1.7 4.6.1.8
4.6.1.9 4.6.1.10 4.6.2.1 4.6.2.2 4.6.2.3 4.6.2.4 4.6.2.5 4.6.2.6 4.6.2.7 4.6.2.8 4.6.2.9 4.6.2.10 4.6.3.1
4.6.3.2 4.6.3.3 4.6.3.4 4.6.3.5 4.6.3.6 4.6.3.7 4.6.3.8 4.6.3.9 4.6.3.10 4.6.4.1 4.6.4.2 4.6.4.3 4.6.4.4
4.6.4.5 4.6.4.6 4.6.4.7 4.6.4.8 4.6.4.9 4.6.4.10 4.6.5.1 4.6.5.2 4.6.5.3 4.6.5.4 4.6.5.5 4.6.5.6 4.6.5.7
4.6.5.8 4.6.5.9 4.6.5.10 4.6.6.1 4.6.6.2 4.6.6.3 4.6.6.4 4.6.6.5 4.6.6.6 4.6.6.7 4.6.6.8 4.6.6.9 4.6.6.10
4.7.1.1 4.7.1.2 4.7.1.3 4.7.1.4 4.7.1.5 4.7.1.6 4.7.1.7 4.7.1.8 4.7.1.9 4.7.1.10 4.7.2.1 4.7.2.2 4.7.2.3
4.7.2.4 4.7.2.5 4.7.2.6 4.7.2.7 4.7.2.8 4.7.2.9 4.7.2.10 4.7.3.1 4.7.3.2 4.7.3.3 4.7.3.4 4.7.3.5 4.7.3.6
4.7.3.7 4.7.3.8 4.7.3.9 4.7.3.10 4.7.4.1 4.7.4.2 4.7.4.3 4.7.4.4 4.7.4.5 4.7.4.6 4.7.4.7 4.7.4.8 4.7.4.9
4.7.4.10 4.7.5.1 4.7.5.2 4.7.5.3 4.7.5.4 4.7.5.5 4.7.5.6 4.7.5.7 4.7.5.8 4.7.5.9 4.7.5.10 4.7.6.1 4.7.6.2
4.7.6.3 4.7.6.4 4.7.6.5 4.7.6.6 4.7.6.7 4.7.6.8 4.7.6.9 4.7.6.10 4.8.1.1 4.8.1.2 4.8.1.3 4.8.1.4 4.8.1.5
4.8.1.6 4.8.1.7 4.8.1.8 4.8.1.9 4.8.1.10 4.8.2.1 4.8.2.2 4.8.2.3 4.8.2.4 4.8.2.5 4.8.2.6 4.8.2.7 4.8.2.8
4.8.2.9 4.8.2.10 4.8.3.1 4.8.3.2 4.8.3.3 4.8.3.4 4.8.3.5 4.8.3.6 4.8.3.7 4.8.3.8 4.8.3.9 4.8.3.10 4.8.4.1
4.8.4.2 4.8.4.3 4.8.4.4 4.8.4.5 4.8.4.6 4.8.4.7 4.8.4.8 4.8.4.9 4.8.4.10 4.8.5.1 4.8.5.2 4.8.5.3 4.8.5.4
4.8.5.5 4.8.5.6 4.8.5.7 4.8.5.8 4.8.5.9 4.8.5.10 4.8.6.1 4.8.6.2 4.8.6.3 4.8.6.4 4.8.6.5 4.8.6.6 4.8.6.7
4.8.6.8 4.8.6.9 4.8.6.10 4.9.1.1 4.9.1.2 4.9.1.3 4.9.1.4 4.9.1.5 4.9.1.6 4.9.1.7 4.9.1.8 4.9.1.9 4.9.1.10
4.9.2.1 4.9.2.2 4.9.2.3 4.9.2.4 4.9.2.5 4.9.2.6 4.9.2.7 4.9.2.8 4.9.2.9 4.9.2.10 4.9.3.1 4.9.3.2 4.9.3.3
4.9.3.4 4.9.3.5 4.9.3.6 4.9.3.7 4.9.3.8 4.9.3.9 4.9.3.10 4.9.4.1 4.9.4.2 4.9.4.3 4.9.4.4 4.9.4.5 4.9.4.6
4.9.4.7 4.9.4.8 4.9.4.9 4.9.4.10 4.9.5.1 4.9.5.2 4.9.5.3 4.9.5.4 4.9.5.5 4.9.5.6 4.9.5.7 4.9.5.8 4.9.5.9
4.9.5.10 4.9.6.1 4.9.6.2 4.9.6.3 4.9.6.4 4.9.6.5 4.9.6.6 4.9.6.7 4.9.6.8 4.9.6.9 4.9.6.10 4.10.1.1 4.10.1.2
4.10.1.3 4.10.1.4 4.10.1.5 4.10.1.6 4.10.1.7 4.10.1.8 4.10.1.9 4.10.1.10 4.10.2.1 4.10.2.2 4.10.2.3
4.10.2.4 4.10.2.5 4.10.2.6 4.10.2.7 4.10.2.8 4.10.2.9 4.10.2.10 4.10.3.1 4.10.3.2 4.10.3.3 4.10.3.4
4.10.3.5 4.10.3.6 4.10.3.7 4.10.3.8 4.10.3.9 4.10.3.10 4.10.4.1 4.10.42 4.10.4.3 4.10.4.4 4.10.4.5
4.10.4.6 4.10.4.7 4.10.4.8 4.10.4.9 4.10.4.10 4.10.5.1 4.10.5.2 4.10.5.3 4.10.5.4 4.10.5.5 4.10.5.6
4.10.5.7 4.10.5.8 4.10.5.9 4.10.5.10 4.10.6.1 4.10.6.2 4.10.6.3 4.10.6.4 4.10.6.5 4.10.6.6 4.10.6.7
4.10.6.8 4.10.6.9 4.10.6.10 4.11.1.1 4.11.1.2 4.11.1.3 4.11.1.4 4.11.1.5 4.11.1.6 4.11.1.7 4.11.1.8
4.11.1.9 4.11.1.10 4.112.1 4.11.2.2 4.11.2.3 4.11.2.4 4.11.2.5 4.11.2.6 4.11.2.7 4.11.2.8 4.11.2.9
4.11.2.10 4.11.3.1 4.11.3.2 4.11.3.3 4.11.3.4 4.11.3.5 4.11.3.6 4.11.3.7 4.11.3.8 4.11.3.9 4.11.3.10
4.11.4.1 4.11.4.2 4.11.4.3 4.11.4.4 4.11.4.5 4.11.4.6 4.11.4.7 4.11.4.8 4.11.4.9 4.11.4.10 4.11.5.1
4.11.5.2 4.11.5.3 4.11.5.4 4.11.5.5 4.11.5.6 4.11.5.7 4.11.5.8 4.11.5.9 4.11.5.10 4.11.6.1 4.11.6.2
4.11.6.3 4.11.6.4 4.11.6.5 4.11.6.6 4.11.6.7 4.11.6.8 4.11.6.9 4.11.6.10 4.12.1.1 4.12.1.2 4.12.1.3
4.12.1.4 4.12.1.5 4.12.1.6 4.12.1.7 4.12.1.8 4.12.1.9 4.12.1.10 4.12.2.1 4.12.2.2 4.12.2.3 4.12.2.4
4.12.2.5 4.12.2.6 4.12.2.7 4.12.2.8 4.12.2.9 4.12.2.10 4.12.3.1 4.12.3.2 4.12.3.3 4.12.3.4 4.12.3.5
4.12.3.6 4.12.3.7 4.12.3.8 4.12.3.9 4.12.3.10 4.12.4.1 4.12.4.2 4.12.4.3 4.12.4.4 4.12.4.5 4.12.4.6
4.12.4.7 4.12.4.8 4.12.4.9 4.12.4.10 4.12.5.1 4.12.5.2 4.12.5.3 4.12.5.4 4.12.5.5 4.12.5.6 4.12.5.7
4.12.5.8 4.12.5.9 4.12.5.10 4.12.6.1 4.12.6.2 4.12.6.3 4.12.6.4 4.12.6.5 4.12.6.6 4.12.6.7 4.12.6.8
4.12.6.9 4.12.6.10 4.13.1.1 4.13.1.2 4.13.1.3 4.13.1.4 4.13.1.5 4.13.1.6 4.13.1.7 4.13.1.8 4.13.1.9
4.13.1.10 4.13.2.1 4.13.2.2 4.13.2.3 4.13.2.4 4.13.2.5 4.13.2.6 4.13.2.7 4.13.2.8 4.13.2.9 4.13.2.10
4.13.3.1 4.13.3.2 4.13.3.3 4.13.3.4 4.13.3.5 4.13.3.6 4.13.3.7 4.13.3.8 4.13.3.9 4.13.3.10 4.13.4.1
4.13.4.2 4.13.4.3 4.13.4.4 4.13.4.5 4.13.4.6 4.13.4.7 4.13.4.8 4.13.4.9 4.13.4.10 4.13.5.1 4.13.5.2
4.13.5.3 4.13.5.4 4.13.5.5 4.13.5.6 4.13.5.7 4.13.5.8 4.13.5.9 4.13.5.10 4.13.6.1 4.13.6.2 4.13.6.3
4.13.6.4 4.13.6.5 4.13.6.6 4.13.6.7 4.13.6.8 4.13.6.9 4.13.6.10 4.14.1.1 4.14.1.2 4.14.1.3 4.14.1.4
4.14.1.5 4.14.1.6 4.14.1.7 4.14.1.8 4.14.1.9 4.14.1.10 4.14.2.1 4.14.2.2 4.14.2.3 4.14.2.4 4.14.2.5
4.14.2.6 4.14.2.7 4.14.2.8 4.14.2.9 4.14.2.10 4.14.3.1 4.14.3.2 4.14.3.3 4.14.3.4 4.14.3.5 4.14.3.6
4.14.3.7 4.14.3.8 4.14.3.9 4.14.3.10 4.14.4.1 4.14.4.2 4.14.4.3 4.14.4.4 4.14.4.5 4.14.4.6 4.14.4.7
4.14.4.8 4.14.4.9 4.14.4.10 4.14.5.1 4.14.5.2 4.14.5.3 4.14.5.4 4.14.5.5 4.14.5.6 4.14.5.7 4.14.5.8
4.14.5.9 4.14.5.10 4.14.6.1 4.14.6.2 4.14.6.3 4.14.6.4 4.14.6.5 4.14.6.6 4.14.6.7 4.14.6.8 4.14.6.9
4.14.6.10 4.15.1.1 4.15.1.2 4.15.1.3 4.15.1.4 4.15.1.5 4.15.1.6 4.15.1.7 4.15.1.8 4.15.1.9 4.15.1.10
4.15.2.1 4.15.2.2 4.15.2.3 4.15.2.4 4.15.2.5 4.15.2.6 4.15.2.7 4.15.2.8 4.15.2.9 4.15.2.10 4.15.3.1
4.15.3.2 4.15.3.3 4.15.3.4 4.15.3.5 4.15.3.6 4.15.3.7 4.15.3.8 4.15.3.9 4.15.3.10 4.15.4.1 4.15.4.2
4.15.4.3 4.15.4.4 4.15.4.5 4.15.4.6 4.15.4.7 4.15.4.8 4.15.4.9 4.15.4.10 4.15.5.1 4.15.5.2 4.15.5.3
4.15.5.4 4.15.5.5 4.15.5.6 4.15.5.7 4.15.5.8 4.15.5.9 4.15.5.10 4.15.6.1 4.15.6.2 4.15.6.3 4.15.6.4
4.15.6.5 4.15.6.6 4.15.6.7 4.15.6.8 4.15.6.9 4.15.6.10 4.16.1.1 4.16.1.2 4.16.1.3 4.16.1.4 4.16.1.5
4.16.1.6 4.16.1.7 4.16.1.8 4.16.1.9 4.16.1.10 4.16.2.1 4.16.2.2 4.16.2.3 4.16.2.4 4.16.2.5 4.16.2.6
4.16.2.7 4.16.2.8 4.16.2.9 4.16.2.10 4.16.3.1 4.16.3.2 4.16.3.3 4.16.3.4 4.16.3.5 4.16.3.6 4.16.3.7
4.16.3.8 4.16.3.9 4.16.3.10 4.16.4.1 4.16.4.2 4.16.4.3 4.16.4.4 4.16.4.5 4.16.4.6 4.16.4.7 4.16.4.8
4.16.4.9 4.16.4.10 4.16.5.1 4.16.5.2 4.16.5.3 4.16.5.4 4.16.5.5 4.16.5.6 4.16.5.7 4.16.5.8 4.16.5.9
4.16.5.10 4.16.6.1 4.16.6.2 4.16.6.3 4.16.6.4 4.16.6.5 4.16.6.6 4.16.6.7 4.16.6.8 4.16.6.9 4.16.6.10
4.17.1.1 4.17.1.2 4.17.1.3 4.17.1.4 4.17.1.5 4.17.1.6 4.17.1.7 4.17.1.8 4.17.1.9 4.17.1.10 4.17.2.1
4.17.2.2 4.17.2.3 4.17.2.4 4.17.2.5 4.17.2.6 4.17.2.7 4.17.2.8 4.17.2.9 4.17.2.10 4.17.3.1 4.17.3.2
4.17.3.3 4.17.3.4 4.17.3.5 4.17.3.6 4.17.3.7 4.17.3.8 4.17.3.9 4.17.3.10 4.17.4.1 4.17.4.2 4.17.4.3
4.17.4.4 4.17.4.5 4.17.4.6 4.17.4.7 4.17.4.8 4.17.4.9 4.17.4.10 4.17.5.1 4.17.5.2 4.17.5.3 4.17.5.4
4.17.5.5 4.17.5.6 4.17.5.7 4.17.5.8 4.17.5.9 4.17.5.10 4.17.6.1 4.17.6.2 4.17.6.3 4.17.6.4 4.17.6.5
4.17.6.6 4.17.6.7 4.17.6.8 4.17.6.9 4.17.6.10 4.18.1.1 4.18.1.2 4.18.1.3 4.18.1.4 4.18.1.5 4.18.1.6
4.18.1.7 4.18.1.8 4.18.1.9 4.18.1.10 4.18.2.1 4.18.2.2 4.18.2.3 4.18.2.4 4.18.2.5 4.18.2.6 4.18.2.7
4.18.2.8 4.18.2.9 4.18.2.10 4.18.3.1 4.18.3.2 4.18.3.3 4.18.3.4 4.18.3.5 4.18.3.6 4.18.3.7 4.18.3.8
4.18.3.9 4.18.3.10 4.18.4.1 4.18.4.2 4.18.4.3 4.18.4.4 4.18.4.5 4.18.4.6 4.18.4.7 4.18.4.8 4.18.4.9
4.18.4.10 4.18.5.1 4.18.5.2 4.18.5.3 4.18.5.4 4.18.5.5 4.18.5.6 4.18.5.7 4.18.5.8 4.18.5.9 4.18.5.10
4.18.6.1 4.18.6.2 4.18.6.3 4.18.6.4 4.18.6.5 4.18.6.6 4.18.6.7 4.18.6.8 4.18.6.9 4.18.6.10 4.19.1.1
4.19.1.2 4.19.1.3 4.19.1.4 4.19.1.5 4.19.1.6 4.19.1.7 4.19.1.8 4.19.1.9 4.19.1.10 4.19.2.1 4.19.2.2
4.19.2.3 4.19.2.4 4.19.2.5 4.19.2.6 4.19.2.7 4.19.2.8 4.19.2.9 4.19.2.10 4.19.3.1 4.19.3.2 4.19.3.3
4.19.3.4 4.19.3.5 4.19.3.6 4.19.3.7 4.19.3.8 4.19.3.9 419.3.10 4.19.4.1 4.19.4.2 4.19.4.3 4.19.4.4
4.19.4.5 4.19.4.6 4.19.4.7 4.19.4.8 4.19.4.9 4.19.4.10 4.19.5.1 4.19.5.2 4.19.5.3 4.19.5.4 4.19.5.5
4.19.5.6 4.19.5.7 4.19.5.8 4.19.5.9 419.5.10 4.19.6.1 4.19.6.2 4.19.6.3 4.19.6.4 4.19.6.5 4.19.6.6
4.19.6.7 4.19.6.8 4.19.6.9 4.19.6.10 4.20.1.1 4.20.1.2 4.20.1.3 4.20.1.4 4.20.1.5 4.20.1.6 4.20.1.7
4.20.1.8 4.20.1.9 4.20.1.10 4.20.2.1 4.20.2.2 4.20.2.3 4.20.2.4 4.20.2.5 4.20.2.6 4.20.2.7 4.20.2.8
4.20.2.9 4.20.2.10 4.20.3.1 4.20.3.2 4.20.3.3 4.20.3.4 4.20.3.5 4.20.3.6 4.20.3.7 4.20.3.8 4.20.3.9
4.20.3.10 4.20.4.1 4.20.4.2 4.20.4.3 4.20.4.4 4.20.4.5 4.20.4.6 4.20.4.7 4.20.4.8 4.20.4.9 4.20.4.10
4.20.5.1 4.20.5.2 4.20.5.3 4.20.5.4 4.20.5.5 4.20.5.6 4.20.5.7 4.20.5.8 4.20.5.9 4.20.5.10 4.20.6.1
4.20.6.2 4.20.6.3 4.20.6.4 4.20.6.5 4.20.6.6 4.20.6.7 4.20.6.8 4.20.6.9 4.20.6.10 4.21.1.1 4.21.1.2
4.21.1.3 4.21.1.4 4.21.1.5 4.21.1.6 4.21.1.7 4.21.1.8 4.21.1.9 4.21.1.10 4.21.2.1 4.21.2.2 4.21.2.3
4.21.2.4 4.21.2.5 4.21.2.6 4.21.2.7 4.21.2.8 4.21.2.9 4.21.2.10 4.21.3.1 4.21.3.2 4.21.3.3 4.21.3.4
4.21.3.5 4.21.3.6 4.21.3.7 4.21.3.8 4.21.3.9 4.21.3.10 4.21.4.1 4.21.4.2 4.21.4.3 4.21.4.4 4.21.4.5
4.21.4.6 4.21.4.7 4.21.4.8 4.21.4.9 4.21.4.10 4.21.5.1 4.21.5.2 4.21.5.3 4.21.5.4 4.21.5.5 4.21.5.6
4.21.5.7 4.21.5.8 4.21.5.9 4.21.5.10 4.21.6.1 4.21.6.2 4.21.6.3 4.21.6.4 4.21.6.5 4.21.6.6 4.21.6.7
4.21.6.8 4.21.6.9 4.21.6.10 4.22.1.1 4.22.1.2 4.22.1.3 4.22.1.4 4.22.1.5 4.22.1.6 4.22.1.7 4.22.1.8
4.22.1.9 4.22.1.10 4.22.2.1 4.22.2.2 4.22.2.3 4.22.2.4 4.22.2.5 4.22.2.6 4.22.2.7 4.22.2.8 4.22.2.9
4.22.2.10 4.22.3.1 4.22.3.2 4.22.3.3 4.22.3.4 4.22.3.5 4.22.3.6 4.22.3.7 4.22.3.8 4.22.3.9 4.22.3.10
4.22.4.1 4.22.4.2 4.22.4.3 4.22.4.4 4.22.4.5 4.22.4.6 4.22.4.7 4.22.4.8 4.22.4.9 4.22.4.10 4.22.5.1
4.22.5.2 4.22.5.3 4.22.5.4 4.22.5.5 4.22.5.6 4.22.5.7 4.22.5.8 4.22.5.9 4.22.5.10 4.22.6.1 4.22.6.2
4.22.6.3 4.22.6.4 4.22.6.5 4.22.6.6 4.22.6.7 4.22.6.8 4.22.6.9 4.22.6.10 4.23.1.1 4.23.1.2 4.23.1.3
4.23.1.4 4.23.1.5 4.23.1.6 4.23.1.7 4.23.1.8 4.23.1.9 4.23.1.10 4.23.2.1 4.23.2.2 4.23.2.3 4.23.2.4
4.23.2.5 4.23.2.6 4.23.2.7 4.23.2.8 4.23.2.9 4.23.2.10 4.23.3.1 4.23.3.2 4.23.3.3 4.23.3.4 4.23.3.5
4.23.3.6 4.23.3.7 4.23.3.8 4.23.3.9 4.23.3.10 4.23.4.1 4.23.4.2 4.23.4.3 4.23.4.4 4.23.4.5 4.23.4.6
4.23.4.7 4.23.4.8 4.23.4.9 4.23.4.10 4.23.5.1 4.23.5.2 4.23.5.3 4.23.5.4 4.23.5.5 4.23.5.6 4.23.5.7
4.23.5.8 4.23.5.9 4.23.5.10 4.23.6.1 4.23.6.2 4.23.6.3 4.23.6.4 4.23.6.5 4.23.6.6 4.23.6.7 4.23.6.8
4.23.6.9 4.23.6.10 4.24.1.1 4.24.1.2 4.24.1.3 4.24.1.4 4.24.1.5 4.24.1.6 4.24.1.7 4.24.1.8 4.24.1.9
4.24.1.10 4.24.2.1 4.24.2.2 4.24.2.3 4.24.2.4 4.24.2.5 4.24.2.6 4.24.2.7 4.24.2.8 4.24.2.9 4.24.2.10
4.24.3.1 4.24.3.2 4.24.3.3 4.24.3.4 4.24.3.5 4.24.3.6 4.24.3.7 4.24.3.8 4.24.3.9 4.24.3.10 4.24.4.1
4.24.4.2 4.24.4.3 4.24.4.4 4.24.4.5 4.24.4.6 4.24.4.7 4.24.4.8 4.24.4.9 4.24.4.10 4.24.5.1 4.24.5.2
4.24.5.3 4.24.5.4 4.24.5.5 4.24.5.6 4.24.5.7 4.24.5.8 4.24.5.9 4.24.5.10 4.24.6.1 4.24.6.2 4.24.6.3
4.24.6.4 4.24.6.5 4.24.6.6 4.24.6.7 4.24.6.8 4.24.6.9 4.24.6.10 4.25.1.1 4.25.1.2 4.25.1.3 4.25.1.4
4.25.1.5 4.25.1.6 4.25.1.7 4.25.1.8 4.25.1.9 4.25.1.10 4.25.2.1 4.25.2.2 4.25.2.3 4.25.2.4 4.25.2.5
4.25.2.6 4.25.2.7 4.25.2.8 4.25.2.9 4.25.2.10 4.25.3.1 4.25.3.2 4.25.3.3 4.25.3.4 4.25.3.5 4.25.3.6
4.25.3.7 4.25.3.8 4.25.3.9 4.25.3.10 4.25.4.1 4.25.4.2 4.25.4.3 4.25.4.4 4.25.4.5 4.25.4.6 4.25.4.7
4.25.4.8 4.25.4.9 4.25.4.10 4.25.5.1 4.25.5.2 4.25.5.3 4.25.5.4 4.25.5.5 4.25.5.6 4.25.5.7 4.25.5.8
4.25.5.9 4.25.5.10 4.25.6.1 4.25.6.2 4.25.6.3 4.25.6.4 4.25.6.5 4.25.6.6 4.25.6.7 4.25.6.8 4.25.6.9
4.25.6.10 5.1.1.1 5.1.1.2 5.1.1.3 5.1.1.4 5.1.1.5 5.1.1.6 5.1.1.7 5.1.1.8 5.1.1.9 5.1.1.10 5.1.2.1 5.1.2.2
5.1.2.3 5.1.2.4 5.1.2.5 5.1.2.6 5.1.2.7 5.1.2.8 5.1.2.9 5.1.2.10 5.1.3.1 5.1.3.2 5.1.3.3 5.1.3.4 5.1.3.5
5.1.3.6 5.1.3.7 5.1.3.8 5.1.3.9 5.1.3.10 5.1.4.1 5.1.4.2 5.1.4.3 5.1.4.4 5.1.4.5 5.1.4.6 5.1.4.7 5.1.4.8
5.1.4.9 5.1.4.10 5.1.5.1 5.1.5.2 5.1.5.3 5.1.5.4 5.1.5.5 5.1.5.6 5.1.5.7 5.1.5.8 5.1.5.9 5.1.5.10 5.1.6.1
5.1.6.2 5.1.6.3 5.1.6.4 5.1.6.5 5.1.6.6 5.1.6.7 5.1.6.8 5.1.6.9 5.1.6.10 5.2.1.1 5.2.1.2 5.2.1.3 5.2.1.4
5.2.1.5 5.2.1.6 5.2.1.7 5.2.1.8 5.2.1.9 5.2.1.10 5.2.2.1 5.2.2.2 5.2.2.3 5.2.2.4 5.2.2.5 5.2.2.6 5.2.2.7
5.2.2.8 5.2.2.9 5.2.2.10 5.2.3.1 5.2.3.2 5.2.3.3 5.2.3.4 5.2.3.5 5.2.3.6 5.2.3.7 5.2.3.8 5.2.3.9 5.2.3.10
5.2.4.1 5.2.4.2 5.2.4.3 5.2.4.4 5.2.4.5 5.2.4.6 5.2.4.7 5.2.4.8 5.2.4.9 5.2.4.10 5.2.5.1 5.2.5.2 5.2.5.3
5.2.5.4 5.2.5.5 5.2.5.6 5.2.5.7 5.2.5.8 5.2.5.9 5.2.5.10 5.2.6.1 5.2.6.2 5.2.6.3 5.2.6.4 5.2.6.5 5.2.6.6
5.2.6.7 5.2.6.8 5.2.6.9 5.2.6.10 5.3.1.1 5.3.1.2 5.3.1.3 5.3.1.4 5.3.1.5 5.3.1.6 5.3.1.7 5.3.1.8 5.3.1.9
5.3.1.10 5.3.2.1 5.3.2.2 5.3.2.3 5.3.2.4 5.3.2.5 5.3.2.6 5.3.2.7 5.3.2.8 5.3.2.9 5.3.2.10 5.3.3.1 5.3.3.2
5.3.3.3 5.3.3.4 5.3.3.5 5.3.3.6 5.3.3.7 5.3.3.8 5.3.3.9 5.3.3.10 5.3.4.1 5.3.4.2 5.3.4.3 5.3.4.4 5.3.4.5
5.3.4.6 5.3.4.7 5.3.4.8 5.3.4.9 5.3.4.10 5.3.5.1 5.3.5.2 5.3.5.3 5.3.5.4 5.3.5.5 5.3.5.6 5.3.5.7 5.3.5.8
5.3.5.9 5.3.5.10 5.3.6.1 5.3.6.2 5.3.6.3 5.3.6.4 5.3.6.5 5.3.6.6 5.3.6.7 5.3.6.8 5.3.6.9 5.3.6.10 5.4.1.1
5.4.1.2 5.4.1.3 5.4.1.4 5.4.1.5 5.4.1.6 5.4.1.7 5.4.1.8 5.4.1.9 5.4.1.10 5.4.2.1 5.4.2.2 5.4.2.3 5.4.2.4
5.4.2.5 5.4.2.6 5.4.2.7 5.4.2.8 5.4.2.9 5.4.2.10 5.4.3.1 5.4.3.2 5.4.3.3 5.4.3.4 5.4.3.5 5.4.3.6 5.4.3.7
5.4.3.8 5.4.3.9 5.4.3.10 5.4.4.1 5.4.4.2 5.4.4.3 5.4.4.4 5.4.4.5 5.4.4.6 5.4.4.7 5.4.4.8 5.4.4.9 5.4.4.10
5.4.5.1 5.4.5.2 5.4.5.3 5.4.5.4 5.4.5.5 5.4.5.6 5.4.5.7 5.4.5.8 5.4.5.9 5.4.5.10 5.4.6.4 5.4.6.2 5.4.6.3
5.4.6.4 5.4.6.5 5.4.6.6 5.4.6.7 5.4.6.8 5.4.6.9 5.4.6.10 5.5.1.1 5.5.1.2 5.5.1.3 5.5.1.4 5.5.1.5 5.5.1.6
5.5.1.7 5.5.1.8 5.5.1.9 5.5.1.10 5.5.2.1 5.5.2.2 5.5.2.3 5.5.2.4 5.5.2.5 5.5.2.6 5.5.2.7 5.5.2.8 5.5.2.9
5.5.2.10 5.5.3.1 5.5.3.2 5.5.3.3 5.5.3.4 5.5.3.5 5.5.3.6 5.5.3.7 5.5.3.8 5.5.3.9 55.3.10 5.5.4.1 5.5.4.2
5.5.4.3 5.5.4.4 5.5.4.5 5.5.4.6 5.5.4.7 5.5.4.8 5.5.4.9 5.5.4.10 5.5.5.1 5.5.5.2 5.5.5.3 5.5.5.4 5.5.5.5
5.5.5.6 5.5.5.7 5.5.5.8 5.5.5.9 5.5.5.10 5.5.6.1 5.5.6.2 5.5.6.3 5.5.6.4 5.5.6.5 55.6.6 5.5.6.7 5.5.6.8
5.5.6.9 5.5.6.10 5.6.1.1 5.6.1.2 5.6.1.3 5.6.1.4 5.6.1.5 5.6.1.6 5.6.1.7 5.6.1.8 5.6.1.9 5.6.1.10 5.6.2.1
5.6.2.2 5.6.2.3 5.6.2.4 5.6.2.5 5.6.2.6 56.2.7 5.6.2.8 5.6.2.9 5.6.2.10 5.6.3.1 5.6.3.2 5.6.3.3 5.6.3.4
5.6.3.5 5.6.3.6 5.6.3.7 5.6.3.8 5.6.3.9 5.6.3.10 5.6.4.1 5.6.4.2 5.6.4.3 5.6.4.4 5.6.4.5 5.6.4.6 5.6.4.7
5.6.4.8 5.6.4.9 5.6.4.10 5.6.5.1 5.6.5.2 5.6.5.3 5.6.5.4 5.6.5.5 5.6.5.6 5.6.5.7 5.6.5.8 5.6.5.9 5.6.5.10
5.6.6.1 5.6.6.2 5.6.6.3 5.6.6.4 5.6.6.5 5.6.6.6 5.6.6.7 5.6.6.8 5.6.6.9 5.6.6.10 5.7.1.1 5.7.1.2 5.7.1.3
5.7.1.4 5.7.1.5 5.7.1.6 5.7.1.7 5.7.1.8 5.7.1.9 5.7.1.10 5.7.2.1 5.7.2.2 5.7.2.3 5.7.2.4 5.7.2.5 5.7.2.6
5.7.2.7 5.7.2.8 5.7.2.9 5.7.2.10 5.7.3.1 5.7.3.2 5.7.3.3 5.7.3.4 5.7.3.5 5.7.3.6 5.7.3.7 5.7.3.8 5.7.3.9
5.7.3.10 5.7.4.1 5.7.4.2 5.7.4.3 5.7.4.4 5.7.4.5 5.7.4.6 5.7.4.7 5.7.4.8 5.7.4.9 5.7.4.10 5.7.5.1 5.7.5.2
5.7.5.3 5.7.5.4 5.7.5.5 5.7.5.6 5.7.5.7 5.7.5.8 5.7.5.9 5.7.5.10 5.7.6.1 5.7.6.2 5.7.6.3 5.7.6.4 5.7.6.5
5.7.6.6 5.7.6.7 5.7.6.8 5.7.6.9 5.7.6.10 5.8.1.1 5.8.1.2 5.8.1.3 5.8.1.4 5.8.1.5 5.8.1.6 5.8.1.7 5.8.1.8
5.8.1.9 5.8.1.10 5.8.2.1 5.8.2.2 5.8.2.3 5.8.2.4 5.8.2.5 5.8.2.6 5.8.2.7 5.8.2.8 5.8.2.9 5.8.2.10 5.8.3.1
5.8.3.2 5.8.3.3 5.8.3.4 5.8.3.5 5.8.3.6 5.8.3.7 5.8.3.8 5.8.3.9 5.8.3.10 5.8.4.1 5.8.4.2 5.8.4.3 5.8.4.4
5.8.4.5 5.8.4.6 5.8.4.7 5.8.4.8 5.8.4.9 5.8.4.10 5.8.5.1 5.8.5.2 5.8.5.3 5.8.5.4 5.8.5.5 5.8.5.6 5.8.5.7
5.8.5.8 5.8.5.9 5.8.5.10 5.8.6.1 5.8.6.2 5.8.6.3 5.8.6.4 5.8.6.5 5.8.6.6 5.8.6.7 5.8.6.8 5.8.6.9 5.8.6.10
5.9.1.1 5.9.1.2 5.9.1.3 5.9.1.4 5.9.1.5 5.9.1.6 5.9.1.7 5.9.1.8 5.9.1.9 5.9.1.10 5.9.2.1 5.9.2.2 5.9.2.3
5.9.2.4 5.9.2.5 5.9.2.6 5.9.2.7 5.9.2.8 5.9.2.9 5.9.2.10 5.9.3.1 5.9.3.2 5.9.3.3 5.9.3.4 5.9.3.5 5.9.3.6
5.9.3.7 5.9.3.8 5.9.3.9 5.9.3.10 5.9.4.1 5.9.4.2 5.9.4.3 5.9.4.4 5.9.4.5 5.9.4.6 5.9.4.7 5.9.4.8 5.9.4.9
5.9.4.10 5.9.5.1 5.9.5.2 5.9.5.3 5.9.5.4 5.9.5.5 5.9.5.6 5.9.5.7 5.9.5.8 5.9.5.9 5.9.5.10 5.9.6.1 5.9.6.2
5.9.6.3 5.9.6.4 5.9.6.5 5.9.6.6 5.9.6.7 5.9.6.8 5.9.6.9 5.9.6.10 5.10.1.1 5.10.1.2 5.10.1.3 5.10.1.4
5.10.1.5 5.10.1.6 5.10.1.7 5.10.1.8 5.10.1.9 5.10.1.10 5.10.2.1 5.10.2.2 5.10.2.3 5.10.2.4 5.10.2.5
5.10.2.6 5.10.2.7 5.10.2.8 5.10.2.9 5.10.2.10 5.10.3.1 5.10.3.2 5.10.3.3 5.10.3.4 5.10.3.5 5.10.3.6
5.10.3.7 5.10.3.8 5.10.3.9 5.10.3.10 5.10.4.1 5.10.4.2 5.10.4.3 5.10.4.4 5.10.4.5 5.10.4.6 5.10.4.7
5.10.4.8 5.10.4.9 5.10.4.10 5.10.5.1 5.10.5.2 5.10.5.3 5.10.5.4 5.10.5.5 5.10.5.6 5.10.5.7 5.10.5.8
5.10.5.9 5.10.5.10 5.10.6.1 5.10.6.2 5.10.6.3 5.10.6.4 5.10.6.5 5.10.6.6 5.10.6.7 5.10.6.8 5.10.6.9
5.10.6.10 5.11.1.1 5.11.1.2 5.11.1.3 5.11.1.4 5.11.1.5 5.11.1.6 5.11.1.7 5.11.1.8 5.11.1.9 5.11.1.10
5.11.2.1 5.11.2.2 5.11.2.3 5.11.2.4 5.11.2.5 5.11.2.6 5.11.2.7 5.11.2.8 5.11.2.9 5.11.2.10 5.11.3.1
5.11.3.2 5.11.3.3 5.11.3.4 5.11.3.5 5.11.3.6 5.11.3.7 5.11.3.8 5.11.3.9 5.11.3.10 5.11.4.1 5.11.4.2
5.11.4.3 5.11.4.4 5.11.4.5 5.11.4.6 5.11.4.7 5.11.4.8 5.11.4.9 5.11.4.10 5.11.5.1 5.11.5.2 5.11.5.3
5.11.5.4 5.11.5.5 5.11.5.6 5.11.5.7 5.11.5.8 5.11.5.9 5.11.5.10 5.11.6.1 5.11.6.2 5.11.6.3 5.11.6.4
5.11.6.5 5.11.6.6 5.11.6.7 5.11.6.8 5.11.6.9 5.11.6.10 5.12.1.1 5.12.1.2 5.12.1.3 5.12.1.4 5.12.1.5
5.12.1.6 5.12.1.7 5.12.1.8 5.12.1.9 5.12.1.10 5.12.2.1 5.12.2.2 5.12.2.3 5.12.2.4 5.12.2.5 5.12.2.6
5.12.2.7 5.12.2.8 5.12.2.9 5.12.2.10 5.12.3.1 5.12.3.2 5.12.3.3 5.12.3.4 5.12.3.5 5.12.3.6 5.12.3.7
5.12.3.8 5.12.3.9 5.12.3.10 5.12.4.1 5.12.4.2 5.12.4.3 5.12.4.4 5.12.4.5 5.12.4.6 5.12.4.7 5.12.4.8
5.12.4.9 5.12.4.10 5.12.5.1 5.12.5.2 5.12.5.3 5.12.5.4 5.12.5.5 5.12.5.6 5.12.5.7 5.12.5.8 5.12.5.9
5.12.5.10 5.12.6.1 5.12.6.2 5.12.6.3 5.12.6.4 5.12.6.5 5.12.6.6 5.12.6.7 5.12.6.8 5.12.6.9 5.12.6.10
5.13.1.1 5.13.1.2 5.13.1.3 5.13.1.4 5.13.1.5 5.13.1.6 5.13.1.7 5.13.1.8 5.13.1.9 5.13.1.10 5.13.2.1
5.13.2.2 5.13.2.3 5.13.2.4 5.13.2.5 5.13.2.6 5.13.2.7 5.13.2.8 5.13.2.9 5.13.2.10 5.13.3.1 5.13.3.2
5.13.3.3 5.13.3.4 5.13.3.5 5.13.3.6 5.13.3.7 5.13.3.8 5.13.3.9 5.13.3.10 5.13.4.1 5.13.4.2 5.13.4.3
5.13.4.4 5.13.4.5 5.13.4.6 5.13.4.7 5.13.4.8 5.13.4.9 5.13.4.10 5.13.5.1 5.13.5.2 5.13.5.3 5.13.5.4
5.13.5.5 5.13.5.6 5.13.5.7 5.13.5.8 5.13.5.9 5.13.5.10 5.13.6.1 5.13.6.2 5.13.6.3 5.13.6.4 5.13.6.5
5.13.6.6 5.13.6.7 5.13.6.8 5.13.6.9 5.13.6.10 5.14.1.1 5.14.1.2 5.14.1.3 5.14.1.4 5.14.1.5 5.14.1.6
5.14.1.7 5.14.1.8 5.14.1.9 5.14.1.10 5.14.2.1 5.14.2.2 5.14.2.3 5.14.2.4 5.14.2.5 5.14.2.6 5.14.2.7
5.14.2.8 5.14.2.9 5.14.2.10 5.14.3.1 5.14.3.2 5.14.3.3 5.14.3.4 5.14.3.5 5.14.3.6 5.14.3.7 5.14.3.8
5.14.3.9 5.14.3.10 5.14.4.1 5.14.4.2 5.14.4.3 5.14.4.4 5.14.4.5 5.14.4.6 5.14.4.7 5.14.4.8 5.14.4.9
5.14.4.10 5.14.5.1 5.14.5.2 5.14.5.3 5.14.5.4 5.14.5.5 5.14.5.6 5.14.5.7 5.14.5.8 5.14.5.9 5.14.5.10
5.14.6.1 5.14.6.2 5.14.6.3 5.14.6.4 5.14.6.5 5.14.6.6 5.14.6.7 5.14.6.8 5.14.6.9 5.14.6.10 5.15.1.1
5.15.1.2 5.15.1.3 5.15.1.4 5.15.1.5 5.15.1.6 5.15.1.7 5.15.1.8 5.15.1.9 5.15.1.10 5.15.2.1 5.15.2.2
5.15.2.3 5.15.2.4 5.15.2.5 5.15.2.6 5.15.2.7 5.15.2.8 5.15.2.9 5.15.2.10 5.15.3.1 5.15.3.2 5.15.3.3
5.15.3.4 5.15.3.5 5.15.3.6 5.15.3.7 5.15.3.8 5.15.3.9 5.15.3.10 5.15.4.1 5.15.4.2 5.15.4.3 5.15.4.4
5.15.4.5 5.15.4.6 5.15.4.7 5.15.4.8 5.15.4.9 5.15.4.10 5.15.5.1 5.15.5.2 5.15.5.3 5.15.5.4 5.15.5.5
5.15.5.6 5.15.5.7 5.15.5.8 5.15.5.9 5.15.5.10 5.15.6.1 5.15.6.2 5.15.6.3 5.15.6.4 5.15.6.5 5.15.6.6
5.15.6.7 5.15.6.8 5.15.6.9 5.15.6.10 5.16.1.1 5.16.1.2 5.16.1.3 5.16.1.4 5.16.1.5 5.16.1.6 5.16.1.7
5.16.1.8 5.16.1.9 5.16.1.10 5.16.2.1 5.16.2.2 5.16.2.3 5.16.2.4 5.16.2.5 5.16.2.6 5.16.2.7 5.16.2.8
5.16.2.9 5.16.2.10 5.16.3.1 5.16.3.2 5.16.3.3 5.16.3.4 5.16.3.5 5.16.3.6 5.16.3.7 5.16.3.8 5.16.3.9
5.16.3.10 5.16.4.1 5.16.4.2 5.16.4.3 5.16.4.4 5.16.4.5 5.16.4.6 5.16.4.7 5.16.4.8 5.16.4.9 5.16.4.10
5.16.5.1 5.16.5.2 5.16.5.3 5.16.5.4 5.16.5.5 5.16.5.6 5.16.5.7 5.16.5.8 5.16.5.9 5.16.5.10 5.16.6.1
5.16.6.2 5.16.6.3 5.16.6.4 5.16.6.5 5.16.6.6 5.16.6.7 5.16.6.8 5.16.6.9 5.16.6.10 5.17.1.1 5.17.1.2
5.17.1.3 5.17.1.4 5.17.1.5 5.17.1.6 5.17.1.7 5.17.1.8 5.17.1.9 5.17.1.10 5.17.2.1 5.17.2.2 5.17.2.3
5.17.2.4 5.17.2.5 5.17.2.6 5.17.2.7 5.17.2.8 5.17.2.9 5.17.2.10 5.17.3.1 5.17.3.2 5.17.3.3 5.17.3.4
5.17.3.5 5.17.3.6 5.17.3.7 5.17.3.8 5.17.3.9 5.17.3.10 5.17.4.1 5.17.4.2 5.17.4.3 5.17.4.4 5.17.4.5
5.17.4.6 5.17.4.7 5.17.4.8 5.17.4.9 5.17.4.10 5.17.5.1 5.17.5.2 5.17.5.3 5.17.5.4 5.17.5.5 5.17.5.6
5.17.5.7 5.17.5.8 5.17.5.9 5.17.5.10 5.17.6.1 5.17.6.2 5.17.6.3 5.17.6.4 5.47.6.5 5.17.6.6 5.17.6.7
5.17.6.8 5.17.6.9 5.17.6.10 5.18.1.1 5.18.1.2 5.18.1.3 5.18.1.4 5.18.1.5 5.18.1.6 5.18.1.7 5.18.1.8
5.18.1.9 5.18.1.10 5.18.2.1 5.18.2.2 5.18.2.3 5.18.2.4 5.18.2.5 5.18.2.6 5.18.2.7 5.18.2.8 5.18.2.9
5.18.2.10 5.18.3.1 5.18.3.2 5.18.3.3 5.18.3.4 5.18.3.5 5.18.3.6 5.18.3.7 5.18.3.8 5.18.3.9 5.18.3.10
5.18.4.1 5.18.4.2 5.18.4.3 5.18.4.4 5.18.4.5 5.18.4.6 5.18.4.7 5.18.4.8 5.18.4.9 5.18.4.10 5.18.5.1
5.18.5.2 5.18.5.3 5.18.5.4 5.18.5.5 5.18.5.6 5.18.5.7 5.18.5.8 5.18.5.9 5.18.5.10 5.18.6.1 5.18.6.2
5.18.6.3 5.18.6.4 5.18.6.5 5.18.6.6 5.18.6.7 5.18.6.8 5.18.6.9 5.18.6.10 5.19.1.1 5.19.1.2 5.19.1.3
5.19.1.4 5.19.1.5 5.19.1.6 5.19.1.7 5.19.1.8 5.19.1.9 5.19.1.10 5.19.2.1 5.19.2.2 5.19.2.3 5.19.2.4
5.19.2.5 5.19.2.6 5.19.2.7 5.19.2.8 5.19.2.9 5.19.2.10 5.19.3.1 5.19.3.2 5.19.3.3 5.19.3.4 5.19.3.5
5.19.3.6 5.19.3.7 5.19.3.8 5.19.3.9 5.19.3.10 5.19.4.1 5.19.4.2 5.19.4.3 5.19.4.4 5.19.4.5 5.19.4.6
5.19.4.7 5.19.4.8 5.19.4.9 5.19.4.10 5.19.5.1 5.19.5.2 5.19.5.3 5.19.5.4 5.19.5.5 5.19.5.6 5.19.5.7
5.19.5.8 5.19.5.9 5.19.5.10 5.19.6.1 5.19.6.2 5.19.6.3 5.19.6.4 5.19.6.5 5.19.6.6 5.19.6.7 5.19.6.8
5.19.6.9 5.19.6.10 5.20.1.1 5.20.1.2 5.20.1.3 5.20.1.4 5.20.1.5 5.20.1.6 5.20.1.7 5.20.1.8 5.20.1.9
5.20.1.10 5.20.2.1 5.20.2.2 5.20.2.3 5.20.2.4 5.20.2.5 5.20.2.6 5.20.2.7 5.20.2.8 5.20.2.9 5.20.2.10
5.20.3.1 5.20.3.2 5.20.3.3 5.20.3.4 5.20.3.5 5.20.3.6 5.20.3.7 5.20.3.8 5.20.3.9 5.20.3.10 5.20.4.1
5.20.4.2 5.20.4.3 5.20.4.4 5.20.4.5 5.20.4.6 5.20.4.7 5.20.4.8 5.20.4.9 5.20.4.10 5.20.5.1 5.20.5.2
5.20.5.3 5.20.5.4 5.20.5.5 5.20.5.6 5.20.5.7 5.20.5.8 5.20.5.9 5.20.5.10 5.20.6.1 5.20.6.2 5.20.6.3
5.20.6.4 5.20.6.5 5.20.6.6 5.20.6.7 5.20.6.8 5.20.6.9 5.20.6.10 5.21.1.1 5.21.1.2 5.21.1.3 5.21.1.4
5.21.1.5 5.21.1.6 5.21.1.7 5.21.1.8 5.21.1.9 5.21.1.10 5.21.2.1 5.21.2.2 5.21.2.3 5.21.2.4 5.21.2.5
5.21.2.6 5.21.2.7 5.21.2.8 5.21.2.9 5.21.2.10 5.21.3.1 5.21.3.2 5.21.3.3 5.21.3.4 5.21.3.5 5.21.3.6
5.21.3.7 5.21.3.8 5.21.3.9 5.21.3.10 5.21.4.1 5.21.4.2 5.21.4.3 5.21.4.4 5.21.4.5 5.21.4.6 5.21.4.7
5.21.4.8 5.21.4.9 5.21.4.10 5.21.5.1 5.21.5.2 5.21.5.3 5.21.5.4 5.21.5.5 5.21.5.6 5.21.5.7 5.21.5.8
5.21.5.9 5.21.5.10 5.21.6.1 5.21.6.2 5.21.6.3 5.21.6.4 5.21.6.5 5.21.6.6 5.21.6.7 5.21.6.8 5.21.6.9
5.21.6.10 5.22.1.1 5.22.1.2 5.22.1.3 5.22.1.4 5.22.1.5 5.22.1.6 5.22.1.7 5.22.1.8 5.22.1.9 5.22.1.10
5.22.2.1 5.22.2.2 5.22.2.3 5.22.2.4 5.22.2.5 5.22.2.6 5.22.2.7 5.22.2.8 5.22.2.9 5.22.2.10 5.22.3.1
5.22.3.2 5.22.3.3 5.22.3.4 5.22.3.5 5.22.3.6 5.22.3.7 5.22.3.8 5.22.3.9 5.22.3.10 5.22.4.1 5.22.4.2
5.22.4.3 5.22.4.4 5.22.4.5 5.22.4.6 5.22.4.7 5.22.4.8 5.22.4.9 5.22.4.10 5.22.5.1 5.22.5.2 5.22.5.3
5.22.5.4 5.22.5.5 5.22.5.6 5.22.5.7 5.22.5.8 5.22.5.9 5.22.5.10 5.22.6.1 5.22.6.2 5.22.6.3 5.22.6.4
5.22.6.5 5.22.6.6 5.22.6.7 5.22.6.8 5.22.6.9 5.22.6.10 5.23.1.1 5.23.1.2 5.23.1.3 5.23.1.4 5.23.1.5
5.23.1.6 5.23.1.7 5.23.1.8 5.23.1.9 5.23.1.10 5.23.2.1 5.23.2.2 5.23.2.3 5.23.2.4 5.23.2.5 5.23.2.6
5.23.2.7 5.23.2.8 5.23.2.9 5.23.2.10 5.23.3.1 5.23.3.2 5.23.3.3 5.23.3.4 5.23.3.5 5.23.3.6 5.23.3.7
5.23.3.8 5.23.3.9 5.23.3.10 5.23.4.1 5.23.4.2 5.23.4.3 5.23.4.4 5.23.4.5 5.23.4.6 5.23.4.7 5.23.4.8
5.23.4.9 5.23.4.10 5.23.5.1 5.23.5.2 5.23.5.3 5.23.5.4 5.23.5.5 5.23.5.6 5.23.5.7 5.23.5.8 5.23.5.9
5.23.5.10 5.23.6.1 5.23.6.2 5.23.6.3 5.23.6.4 5.23.6.5 5.23.6.6 5.23.6.7 5.23.6.8 5.23.6.9 5.23.6.10
5.24.1.1 5.24.1.2 5.24.1.3 5.24.1.4 5.24.1.5 5.24.1.6 5.24.1.7 5.24.1.8 5.24.1.9 5.24.1.10 5.24.2.1
5.24.2.2 5.24.2.3 5.24.2.4 5.24.2.5 5.24.2.6 5.24.2.7 5.24.2.8 5.24.2.9 5.24.2.10 5.24.3.1 5.24.3.2
5.24.3.3 5.24.3.4 5.243.5 5.24.3.6 5.24.3.7 5.24.3.8 5.24.3.9 5.24.3.10 5.24.4.1 5.24.4.2 5.24.4.3
5.24.4.4 524.4.5 5.24.4.6 5.24.4.7 5.24.4.8 5.24.4.9 5.24.4.10 5.24.5.1 5.24.5.2 5.24.5.3 5.24.5.4
5.24.5.5 5.24.5.6 5.24.5.7 5.24.5.8 5.24.5.9 5.24.5.10 5.24.6.1 5.24.6.2 5.24.6.3 5.24.6.4 5.24.6.5
5.24.6.6 5.24.6.7 5.24.6.8 5.24.6.9 5.24.6.10 5.25.1.1 5.25.1.2 5.25.1.3 5.25.1.4 5.25.1.5 5.25.1.6
5.25.1.7 5.25.1.8 5.25.1.9 5.25.1.10 5.25.2.1 5.25.2.2 5.25.2.3 5.25.2.4 5.25.2.5 5.25.2.6 5.25.2.7
5.25.2.8 5.25.2.9 5.25.2.10 5.25.3.1 5.25.3.2 5.25.3.3 5.25.3.4 5.25.3.5 5.25.3.6 5.25.3.7 5.25.3.8
5.25.3.9 5.25.3.10 5.25.4.1 5.25.4.2 5.25.4.3 5.25.4.4 5.25.4.5 5.25.4.6 5.25.4.7 5.25.4.8 5.25.4.9
5.25.4.10 5.25.5.1 5.25.5.2 5.25.5.3 5.25.5.4 5.25.5.5 5.25.5.6 5.25.5.7 5.25.5.8 5.25.5.9 5.25.5.10
5.25.6.1 5.25.6.2 5.25.6.3 5.25.6.4 5.25.6.5 5.25.6.6 5.25.6.7 5.25.6.8 5.25.6.9 5.25.6.10
Exemplary embodiments include the following numbered groups of compounds.
1 Each compound named in Table B having only one carbonate moiety and a hydroxyl group linked to the phosphorus atom in place of the second carbonate moiety, i.e., B—CH2—CHR1—O—CH2—P(O)(OH)—O—CHR2—O-C(O)—OR. Thus, the group 1 compound named 1.4.1.1 in Table B has the structure: adenin-9-yl-—CH2—CH (CH3)—O—CH2—P(O)(OH)—O—CH2—O—C(O)—OCH(CH3)2.
2 Compounds named in Table B having only one carbonate moiety and having only the R1 moiety, #3 (—CH2OH), which is modified such that R8 of formula (1) compounds is joined with R1 to form —CH2—. Thus, the group 2 compound named 1.4.3.1 in Table B has the structure: adenin-9-yl—CH2—CH(CH2—⋄)—O—CH2—P(O)(O—⋄)—O—CH2—O—C(O)—OCH(CH3)2, where the symbols ⋄ indicate a covalent bond that links the oxygen and carbon atoms together.
3 Compounds named in Table B and compounds named by compound groups 1 and 2 where each purine base listed in Table A is the 3-deaza analog, e.g., 3-deazaadenin-9-yl. Thus, the group 3 compound defined in Table A and named 1.4.1.1 in Table B has the structure: 3-deazaadenin-9-yl—CH2—CH(CH3)—O—CH2—P(O)(—O—CH2—O—C (O)—OCH(CH3)2)2. The group 3 compound defined in Table A and named 1.4.1.1 in compound group 1 has the structure: 3-deazaadenin-9-yl—CH2—CH(CH3)—O—CH2—P(O)(OH)—O—CH2—O—C(O)—OCH(CH3)2.
4 Compounds named in Table B and compounds named by compound groups 1 and 2 where each purine based listed in Table A is the 1-deaza analog, e.g., 1-deazaadenin-9-yl. Thus, the group 4 compound defined in Table A and named 1.4.1.1 in Table B has the structure: 1-deazaadenin-9-yl-CH2—CH(CH3)—O—CH2—P(O)(—O—CH2—O—C (O)—OCH(CH3(2)2. The group 3 compound defined in Table A and named 1.4.1.1 in compound group 1 has the structure:
5 Compounds named in Table B and compounds named by compound groups 1 and 2 where each purine based listed in Table A is the 8 -aza analog, e.g., 8-azaadenin-9-yl.
6 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
1 -cyclopropyl (cyclopropyl replaces —CH3, which is R moiety 1 in
Table A)
2 —CH2-cyclopropyl
3 —(CH2)2-cyclopropyl
4 —(CH2)3-cyclopropyl
5 —(CH2)4-cyclopropyl
6 -cyclobutyl
7 —CH2-cyclobutyl
8 —(CH2)2-cyclobutyl
9 —(CH2)3-cyclobutyl
10 —(CH2)4-cyclobutyl
11 -cyclopentyl
12 —CH2-cyclopentyl
13 —(CH2)2-cyclopentyl
14 —(CH2)3-cyclopentyl
15 —(CH2)4-cyclopentyl
16 -cyclohexyl
17 —CH2-cyclohexyl
18 —(CH2)2-cyclohexyl
19 —(CH2)3-cyclohexyl
20 —(CH2)4-cyclohexyl
21 —CH(CH3)2-cyclopropyl
22 —CH(CH3)2-cyclobutyl
23 —CH(CH3)2-cyclopentyl
24 —CH(CH3)2-cyclohexyl
25 —(CH2)0-4-cyclooctyl.
Thus, the group 6 compound defined in Table A and named 1.16.1.1 in Table B has the structure
adenin-9-yl-CH2—CH(CH3)—O—CH2—P(O)(—O—CH2—O—C(O)—O—cyclohexyl)2. The group 6 compound defined in Table A and named 1.16.1.1 in compound group 1 has the structure:
adenin-9-yl-CH2—CH(CH3)—O—CH2—P(O)(OH)—O—CH2—O—C(O)—O-cyclohexyl. The group 6 compound defined in Table A and named 1.16.1.1 in compound group 3 has the structure.
7 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
1 7 carbon alkyl*
2 8 carbon alkyl
3 9 carbon alkyl
4 10 carbon alkyl
5 11 carbon alkyl
6 12 carbon alkyl
7 —(CH2)2C6H5
8 —(CH2)3C6H5
9 —(CH2)4C6H5
10 —C(CH3)2CH(CH3)2
11 —CH(CH3)C(CH3)3
12 —(CH2)2CH(C2H6)CH2CH3
13 —(CH2)2CH(C2H5)CH2)2CH3
14 —(CH2)2CH(C2)5)(CH2)3CH3
15 —(CH2)3CH(C2H5)CH3
16 —(CH2)3CH(C2H5)CH2CH3
17 —(CH2)3CH(C2H5)(CH2)2CH3
18 —CH2CH(C2H5)CH2CH3
19 —CH2CH(C2H5)(CH2)2CH3
20 —CH2CH(C2H5)(CH2)3CH3
21 —(CH2)2CH(C3H7)CH2CH3
22 —(CH2)2CH(C3H7)(CH2)2CH3
23 —(CH2)2CH(C3H7)(CH2)3CH3
24 —CH2CH═CH2
25 —CH═CHCH3.
8 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
1 —(CH2)2OCH3
2 —(CH2)3OCH3
3 —(CH2)4OCH3
4 —(CH2)5OCH3
5 —(CH2)6OCH3
6 —(CH2)2OCH2CH3
7 —(CH2)3OCH2CH3
8 —(CH2)4O(CH2)2CH3
9 —(CH2)5O(CH2)2CH3
10 —(CH2)6O(CH2)2CH3
11 —(CH2)2O(CH2)2CH3
12 —(CH2)3O(CH2)2CH3
13 —(CH2)4O(CH2)2CH3
14 —(CH2)5O(CH2)2CH3
15 —(CH2)6O(CH2)2CH3
16 —(CH2)2OCH(CH3)2
17 —(CH2)3OCH(CH3)2
18 —(CH2)4OCH(CH3)2
19 —(CH2)5OCH(CH3)2
20 —(CH2)6OCH(CH3)2
21 —(CH2)2O(CH2)3CH3
22 —(CH2)2OCH2CH(CH3)2
23 —(CH2)2OC(CH3)3
24 —(CH2)2OC5H11
25 —(CH2)2OC6H13.
9 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
1 —CH(CH3)CH2OCH3
2 —CH(CH3)(CH2)2OCH3
3 —CH(CH3)(CH2)3OCH3
4 —CH(CH3)(CH2)4OCH3
5 —CH(CH3)CH2OCH2CH3
6 —CH(CH3)(CH2)2OCH2CH3
7 —CH(CH3)(CH2)3OCH2CH3
8 —CH(CH3)(CH2)4OCH2CH3
9 —CH(CH3)CH2O(CH2)2CH3
10 —CH(CH3)(CH2)2O(CH2)2CH3
11 —CH(CH3)(CH2)3O(CH2)2CH3
12 —CH(CH3)(CH2)4O(CH2)2CH3
13 —CH(CH3)CH2OCH(CH3)2
14 —CH(CH3)(CH2)2OCH(CH3)2
15 —CH(CH3)(CH2)3OCH(CH3)2
16 —CH(CH3)(CH2)4OCH(CH3)2
17 —CH(CH3)CH2OC4H9
18 —CH(CH3)(CH2)2OC4H9
19 —CH(CH3)(CH2)3OC4H9
20 —CH(CH3)(CH2)4OC4H9
21 —CH(CH3)CH2OC5H11
22 —CH(CH3)(CH3)(CH2)2OC5H11
23 —CH(CH3)(CH3)(CH2)3OC5H11
24 —CH(CH3)(CH3)(CH2)4OC5H11
25 —CH(CH3)CH2OC6H13.
10 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
1 —CH(CH3)(CH2)2OC6H13
2 —CH(CH3)(CH2)3OC6H13
3 —CH(CH3)(CH2)4OC6H13
4 —CH2CH(CH3)OCH3
5 —(CH2)2CH(CH3)OCH3
6 —(CH2)3CH(CH3)OCH3
7 —(CH2)4CH(CH3)OCH3
8 —CH2CH(CH3)OCH2CH3
9 —(CH2)2CH(CH3)OCH2CH3
10 —(CH2)3CH(CH3)OCH2CH3
11 —(CH2)4CH(CH3)OCH2CH3
12 —CH2CH(CH3)OCH2CH3
13 —(CH2)2CH(CH3)O(CH2)2CH3
14 —(CH2)3CH(CH3)O(CH2)3CH3
15 —(CH2)4CH(CH3)O(CH2)4CH3
16 —CH2CH(CH3)OCH(CH3)2
17 —(CH2)2CH(CH3)OCH(CH3)2
18 —(CH2)3CH(CH3)OCH(CH3)2
19 —(CH2)4CH(CH3)OCH(CH3)2
20 —CH2CH(CH3)OC4H9
21 —(CH2)2CH(CH3)OC4H9
22 —(CH2)3CH(CH3)OC4H9
23 —(CH2)4CH(CH3)OC4H9
24 —CH2CH(CH3)OC5H11
25 —(CH2)2CH(CH3)OC5H11
11 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
1 —(CH2)3CH(CH3)OC5H11
2 —(CH2)4CH(CH3)OC5H11
3 —CH2CH(CH3)OC6H13
4 —(CH2)2CH(CH3)OC6H13
5 —(CH2)3CH(CH3)OC6H13
6 —(CH2)4CH(CH3)OC6H13
7 —(CH2)2OCH(CH3C2H5
8 —(CH2)2OCH(CH3)(CH2)2CH3
9 —(CH2)2OCH(CH3)CH(CH3)2
10 —(CH2)2OCH(CH3)(CH2)3CH3
11 —(CH2)2OCH(CH3)C(CH3)3
12 —(CH2)2OCH(CH3)CH(CH3)CH2CH3
13 —(CH2)2OCH(CH3)CH2CH(CH3)2
14 —(CH2)3OCH(CH3C2H5
15 —(CH2)3OCH(CH3(CH2)2CH3
16 —(CH2)3OCH(CH3)CH(CH3)2
17 —(CH2)3OCH(CH3)(CH2)3CH3
18 —(CH2)3OCH(CH3)C(CH3)3
19 —(CH2)3OCH(CH3)CH(CH3)CH2CH3
20 —(CH2)3OCH(CH3)CH2CH(CH3)2
21 —(CH2)4OCH(CH3)C2H5
22 —(CH2)4OCH(CH3)(CH2)2CH3
23 —(CH2)4OCH(CH3)CH(CH3)2
24 —(CH2)4OCH(CH3)(CH2)3CH3
25 —(CH2)4OCH(CH3)C(CH3)3
12 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table a are replaced with the following groups:
1 —(CH2)2O(CH2)3CH3
2 —(CH2)2O(CH2)4CH3
3 —(CH2)2O(CH2)5CH3
4 —(CH2)3O(CH2)3CH3
5 —(CH2)3O(CH2)4CH3
6 —(CH2)3O(CH2)5CH3
7 —(CH2)2OC6H5
8 —(CH2)2OC6H5
9 —(CH2)2OC6H5
10 —CH(C2H5)CH2OCH3
11 —CH(C2H5)CH2OC2H5
12 —CH(C2H5)CH2O(CH2)2CH3
13 —CH(C2H5)CH2OCH2(CH3)2
14 —CH(C2H5)CH2O(CH2)3CH3
15 —CH(C2H5)CH2OCH(CH3)C2H5
16 —CH(C2H5)CH2OCH2CH(CH3)2
17 —CH(C2H5)CH2OC(CH3)3
18 —CH(C2H5)CH2O(CH2)4CH3
19 —CH(C2H5)CH2O(CH2)2CH(CH3)2
20 —CH(C2H5)CH2O(CH2)5CH3
21 —CH(C2H5)CH2O(CH2)3CH(CH3)2
22 —CH2CH(C2H5)OCH3
23 —CH2CH(C2H5)OC2H5
24 —CH2CH(C2H5)OC3H7
25 —CH2CH(C2H5)OC4H9.
13 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table a are replaced with the following groups:
1 —(CH2)2O-cyclopropyl
2 —(CH2)2O-cyclobutyl
3 —(CH2)2O-cyclopentyl
4 —(CH2)2O-cyclohexyl
5 —(CH2)2OCH2-cyclopropyl
6 —(CH2)2OCH2-cyclobutyl
7 —(CH2)2OCH2-cyclopentyl
8 —(CH2)2OCH2-cyclohexyl
9 —(CH2)2O—(CH2)2cyclopropyl
10 —(CH2)2O—(CH2)2cyclobutyl
11 —(CH2)2O—(CH2)2cyclopentyl
12 —(CH2)2O—(CH2)2cyclohexyl
13 —(CH2)3O-cyclopropyl
14 —(CH2)3O-cyclobutyl
15 —(CH2)3O-cyclopentyl
16 —(CH2)3O-cyclohexyl
17 —(CH2)3OCH2-cyclopropyl
18 —(CH2)3OCH2-cyclobutyl
19 —(CH2)3OCH2-cyclopentyl
20 —(CH2)3OCH2-cyclohexyl
21 —CH(CH3)CH2O-cyclopropyl
22 —CH(CH3)CH2O-cyclobutyl
23 —CH(CH3)CH2O-cyclopentyl
24 —CH(CH3)CH2O-cyclohexyl
25 —CH(CH3)CH2OCH2-cyclohexyl.
14 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
1 —C(CH2OCH3)3
2 —C(C2H5)2(CH2OCH3)
3 —CH(C2H5)CH2OCH3)
4 —CH2(CH2OCH3)
5 —C(CH3)2(CH2OCH3)
6 —CH(CH3)(CH2OCH3)
7 —C(CH2OC2H5)3
8 —C(C2H5)2(CH2OC2H5)
9 —CH(C2H5)(CH2OC2H5)
10 —CH(C4H9)(CH2OCH3)
11 —CH2C(CH2OCH3)3
12 —CH2C(C2H5)2(CH2OCH3)
13 —CH2CH(C2H5)(CH2OCH3)
14 —CH(CH2OCH3)2
15 —CH2C(CH2OCH3)3
16 —CH2CH(CH2OCH3)2
17 —C(CH2OC2H5)3
18 —CH(CH2OC2H5)2
19 —CH2C(CH2OC2H5)3
20 —CH2CH(CH2OC2H5)2
21 —C(C2H5)2(CH2OC3H7)
22 —CH(C3H7)(CH2OCH3)
23 —C(C3H7)2(CH2OCH3)
24 —CH(C3H7)(CH2OC2H5)
25 —C(C3H7)2(CH2OC2H5)
15 The following groups of compounds A-J.
A Compounds named in groups 8-14 where the oxygen atom (—O—) in the R moiety is replaced with —NH—.
B Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with —N(CH3)—.
C Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with —N(C2H5)—.
D Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with —N(CH2CH2CH3)—.
E Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with —N(CH(CH3)2—.
F Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with n-butyl substituted nitrogen (—N(CH2)3CH3)—).
G Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with i-butyl substituted nitrogen.
H Compounds named in groups 8-14 where the oxygen atom in the R moiety is replaced with t-butyl substituted nitrogen.
I Compound named in groups 8-14 where the oxygen atom in the R moiety is replaced with linear, branched or cyclic 6 carbon alkyl substituted nitrogen.
Thus, the group 15B compound defined in Table A and named 1.1.1.1 in compound group 8 has the structure:
adenin-9-yl-CH2—CH(CH3)—O—CH2—P(O)(—O—CH2—O—C(O)—O—(CH2)2N(CH3)2)2. The group 15B compound defined in Table A and named 1.1.1.1 in compound group 1, as named under group 8, has the structure:
adenin-9-yl-CH2-—CH(CH3)—O—CH2—P(O)(OH)—O—CH2—O—C(O)—O—(CH2)2N(CH3)2.
The group 15B compound defined in Table a and named 1.16.1.1 in compound group 3, as named under group 8, has the structure:
3-deazaadenin-9-yl-CH2—CH(CH3)—O—(CH2—P(O) (—O—CH2—O—C(O)—O—(CH2)2N(CH3)2)2.
16 Compounds named in Table B and compounds named by compound groups 1-5 where R moieties 1-25 listed in Table A are replaced with the following groups:
1 —(CH2)2R9
2 —(CH2)3R9
3 —(CH2)4R9
4 —(CH2)5R9
5 —(CH2)6R9
6 —(CH2)7R9
7 —(CH2)8R9
8 —CH(CH3)CH2R9
9 —CH(CH3)(CH2)2R9
10 —CH(CH3)(CH2)3R9
11 —(CH2)2R9
12 —(CH2)3R9
13 —(CH2)4R9
14 —(CH2)5R9
15 —(CH2)6R9
16 —(CH2)7R9
17 —(CH2)8R9
18 —CH(CH3)CH2R9
19 —CH(CH3)(CH2)2R9
20 —CH(CH3)(CH2)4R9
21 —(CH2)2R9
22 —(CH2)3R9
23 —(CH2)4R9
24 —(CH2)5R9
25 —(CH2)6R9
In moieties 1-10, R9 is N-morpholino, in moieties 11-20, R9 is 2-pyridyl and in moieties 21-25, R9 is 3-pyridyl.
17 Compounds named in Table B and compounds named by compound groups 1-5 when R moieties 1-25 listed in Table a are replaced with the following groups:
1 —(CH2)2R9
2 —(CH2)3R9
3 —(CH2)4R9
4 —(CH2)5R9
5 —(CH2)6R9
6 —(CH2)2CH(CH3)R9
7 —(CH2)3CH(CH3)R9
8 —(CH2)4CH(CH3)R9
9 —(CH2)2R9
10 —(CH2)3R9
11 —(CH2)4R9
12 —(CH2)5R9
13 —(CH2)6R9
14 —(CH2)6CH3
15 —(CH2)7CH3
16 —(CH2)8CH3
17 —(CH2)9CH3
18 —(CH2)10CH3
19 —(CH2)11CH3
20 —(CH2)4CH(CH3)2
21 —(CH2)5CH(CH3)2
22 —(CH2)6CH(CH3)2
23 —(CH2)7CH(CH3)2
24 —(CH2)8CH(CH3)2
25 —(CH2)9CH(CH3)2.
In moieties 1-5, R9 is 4-pyridyl, in moieties 6-9 R9 is N-morpholino an din moieties 9-13, R9 is N-piperidyl.
18 The following groups of compounds A-J.
A Compounds named in Table B and compounds named by groups 1-17 where compound (8) is replaced with compound (9)
Figure USRE038333-20031125-C00007
where one R2 is as specified in Table A and the other R2 is —CH3.
B Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is —CH2CH3.
C Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is —(CH2)2CH3.
D Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is —CH(CH2)2.
E Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is —(CH2)3(CH3.
F Compounds named in Table b and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table a and the other R2 is —(CH2)4CH.
G Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is —CH2CH(CH3)2.
H Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is —C(CH3)3.
I Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is —C5H11.
J Compounds named in Table B and compounds named by compound groups 1-17 where compound (8) is replaced with compound (9) where one R2 is as specified in Table A and the other R2 is —C6H13.
Thus, the group 18A compound defined in Table A and named 1.4.2.3 in Table B has the structure:
adenin-9-yl-CH2—CH2—O—CH(CH3)—P(O)(—O—C (C2H5)(CH3)—O—C(O)—O—CH(CH3)2)2. The group 18A compound defined in Table A and named 1.1.1.1 in compound group 3, as named under compound group 8, has the structure:
3-deazaadenin-9-yl-CH—2—CH(CH3)—O—CH2—P(O)(—O—CH(CH3)—O—C(O)—O—(CH2)2OCH3)2.
19 Compounds named in Table B and compounds named by compound groups 1-18 where compound (8) and compound (9) are replaced with compound (10) and (11) respectively
Figure USRE038333-20031125-C00008
where both R moieties are the same. Thus, the group 19 compound defined in Table A and named 1.4.1.1 in Table B has the structure:
adenin-9-yl-CH2—CH3—O—CH(CH3)—P(O)(—O—CH2—O—C(O)—N—CH(CH3)2)2. The group 19 compound defined in Table A and named 1.4.1.1 in compound group 1 has the structure:
adenin-9-yl-CH2—CH(CH3)—O—CH2—P(O)(OH)—O—CH2—O—C(O)—N—CH(CH3)2. The group 19 compound defined in Table A and named 1.1.1.1 in compound group 3, as named under compound group 8, has the structure:
3-deazaadenin-9-yl-CH2—CH(CH3)—O—CH2P(O)(—O—CH2—O—C(O)—N—(CH2)2OCH3)2.
The compounds of this invention are, to varying degrees, chemically stable. It is preferable that the compounds be chemically stable in order to ensure an adequate shelf-life and proper biodistribution upon oral administration. In general, embodiments are selected that have a t ½ at pH 7.4 of greater than 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours and preferably in addition posses at t ½ at pH 2.0 of greater than 1, 10 or 100 hours. For example, the t-butyl carbonate found in Table 1 has a t ½ that is less stable than these parameters and therefor is not preferred. In addition, the optimal compounds of this invention should have bioavailability in beagle dogs (as set forth in more detail below) that exceeds about 20%, preferably, about 30%.
Synthetic Methods
The carbamates and carbonates of this invention are prepared from the diacids of the phosphonomethoxy nucleotide analogs and the synthon LCH(R2)OC(O)X(R)a. L is a leaving group such as Cl, although it will be appreciated that any of the conventional leaving groups used in organic chemistry in nucleophilic substitution reactions can be successfully employed in place of chloro. In particular, leaving groups include halides, such as Cl, Br and I, and sulfonic acid esters such as methane, benzene or toluene sulfonic acid esters. The synthon is prepared by reacting LCH(R2)OC (O)L with HOR for preparation of the carbonate synthon or HNR2 for the preparation of the carbamate synthon. The synthon is then reacted with the nucleotide analog of choice, typically PMPA, to form the desired carbamate or carbonate adducts. The carbamates are prepared by reacting the synthon with the nucleotide analog under typical conditions of nucleophilic attack, for example in Et3N/DMF at room temperature. The carbonates are formed by reacting the appropriate synthon with the nucleotide analog in the presence of an organic base, typically an amine base. In addition, masked leaving groups such as thioesters, which may be activated by, for example, oxidation, and coupled directly to the phosphonic acid moiety may be used. Intermediates may be made with other leaving groups in this way, for example diphenylphosphinic acids, and others known in the chemistry of formacetals and glycosylation.
Figure USRE038333-20031125-C00009
Compounds where X=N and R=OR3 may be prepared by alkylation with the appropriate haloalkyl, O-alkyl carbamate. N,O-dialkylhydroxylamines are known in the literature, and may be prepared by alkylation of hydroxylamine, or by reductive amination of aldehydes or ketones with alkyl hydroxylamines. The dialkylhydroxylamines may be acylated with the appropriately substituted haloalkyl chloroformate under conditions analogous to those used to prepare the unsubstituted chloromethyl carbamates. Phosphonates may then be alkylated with the haloalkyl. O-alkyl carbamates to give the prodrugs under conditions used for the carbonates and carbamates. Leaving groups other than chloride may of course by used throughout.
In a typical method, the carbonate compounds of this invention are prepared by reacting L—CHR2—O—C(O)—OR with (4) to yield a compound of formula (1).
Figure USRE038333-20031125-C00010
The reaction typically proceeds in two concurrent steps in which the monoester forms first, and then the diester as the reaction proceeds longer. In this situation monoester is not typically isolated as an intermediate.
In order to make a diester than contains different carbonate or carbamate functionalities the monoester intermediate is recovered from the early reaction and the reaction is then completed with for example a second L—CHR2—O—C (O)—OR reagent, thereby resulting in substitution with a second ester different from the first.
One optionally conducts the carbonate synthesis reactions using at least about 1.0 and typically 2 equivalents of L—CHR2—O—C(O)—OR. The reaction is conducted in the presence of an organic base in an organic solvent at a reaction temperature of about 4-100° for about 4-72 hours. Exemplary suitable organic bases include triethylamine or Hunig base. Exemplary suitable organic solvents include DMF, DMPU, or NMP.
The monoester or diester products are purified by standard methods including flash column chromatography or salting out. Suitable salts for purification and/or formulation will final product include the sulfuric acid, phosphoric acid, lactic acid, fumaric or citric acid salts or complexes of the diester or monoester compounds of structures (1) or (1a).
Utilities
The compounds of this invention are useful in the treatment or prophylaxis of one or more vital infections in man or animals, including infections caused by DNA viruses, RNA viruses, herpesviruses (CMV, HSV 1, HSV 2, VZV, and the like), retroviruses, hepadnaviruses, (e.g. HBV), papillomavirus, hantavirus, adenoviruses and HIV. Other infections to be treated with the compounds herein include MSV, RSV, SIV, FIV, MuLV, and other retroviral infections of rodents and other animals. The prior art describes the antiviral specificity of the nucleotide analogs, and the parental drug specificity is shared by the compounds of this invention. Dosages, viral targets, and suitable administration routes to best attack the site of infection are well known in the art for the parental drugs. Determination of proper doses is a straightforward matter for the clinician, taking into account the molecular weight of the compounds of this invention and, when administering them orally, their bioavailability in animals or as deduced in clinical trials with humans. Oral dosages of the compounds of this invention in humans for antiviral therapy will range about from 0.5 to 60 mg/Kg/day, usually about from 1 to 30 mg/Kg/day and typically about from 1.5 to 10 mg/Kg/day.
The compounds of this invention also are useful as intermediates in the preparation of detectable labels for oligonucleotide probes. The compounds are hydrolyzed to yield the diacid, diphosphorylated and incorporated into an oligonucleotide by conventional enzymatic or chemical means. The incorporated base from the compound of the invention will be capable of participating in base pairing and thus will not interfere substantially with the binding of the oligonucleotide to its complementary sequence (E. De Clercq Rev. Med. Virol. 3: 85-96 1993). However, if it does interfere with binding of the oligonucleotide containing the analog to the complementary sequence, the compound of the invention optionally is incorporated into the oligonucleotide as the 3′ terminal base, an innocuous position and a conventional site for oligonculeotide labeling. The aglycon donated by the nucleotide analog that is incorporated into the oligonucleotide is detected by any means, such as NMR or by binding to antibodies specific for the nucleotide analog.
Pharmaceutical Formulations
Compounds of the invention and their pharmaceutically, i.e. physiologically, acceptable salts (hereafter collectively referred to as the active ingredients), are administered by any route appropriate to the condition to be treated, suitable routes including oral, rectal, nasal, topical (including ocular, buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and dpidural). Generally, the compounds of this invention are administered orally, but if an embodiment is not sufficiently orally bioavailable it can be administered by any of the other routes noted above.
While it is possible for the active ingredients to be administered as pure compounds it is preferable to present them as pharmaceutical formulations. The formulations of the present invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers and optionally other therapeutic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient.
The formulations include those suitable for topical or systemic administration, including oral, rectal, nasal, buccal, sublingual, vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration. The formulations are in unit dosage form and are prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
For infections of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.01 to 10% w/w (including active ingredient(s) in a range between 0.1% and 5% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc), preferably 0.2 to 3% w/w and most preferably 0.5 to 2% w/w. When formulated into an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.
If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane, 1,3-diol, mannnitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhances include dimethyl sulphoxide and related analogs.
The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the emulsifying wax, and the wax together with the oil and fat make up the emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
Emulgents and emulsion stabilizers suitable for use in the formulation of the present invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is suitably present in such formulations in a concentration of 0.01 to 20%, in some embodiments 0.1 to 10%, and in others about 1.0% w/w.
Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
Formulations suitable for a nasal or inhalational administration wherein the carrier is a solid include a powder having a particle size for example in the range of 1 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc). Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents. Inhalational therapy is readily administered by metered dose inhalers.
Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations suitable for parenteral administration are sterile and include aqueous and non-aqueous injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials with elastomeric stoppers, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited above, or an appropriate fraction thereof, of an active ingredient.
In addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The present invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
Veterinary carriers are materials useful for the purpose of administrating the composition to cats, dogs, horses, rabbits and other animals and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
Compounds of the invention can be used to provide controlled release pharmaceutical formulations containing a matrix or absorbent material and as active ingredient one or more compounds of the invention in which the release of the active ingredient can be controlled and regulated to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the compound. Controlled release formulations adapted for oral administration in which discrete units comprising one or more compounds of the invention can be prepared according to conventional methods.
All citations found herein are incorporated by reference.
The following examples further illustrate the invention but are not to be construed as limiting the invention.
EXAMPLES Example 1
Figure USRE038333-20031125-C00011
Process Summary
PMPA is prepared as follows: (S)-Glycidol is reduced to (R)-1,2-propanediol by catalytic hydrogenation, which is then reacted with diethyl carbonate to afford (R)-1,2-propylene carbonate. The carbonate is reacted with adenine and catalytic amounts of a base such as sodium hydroxide to give (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine which, without isolation, is reacted with lithium alkoxide (alkyl containing 1, 2, 3, 4, 5 or 6 carbon atoms, e.g., n-hexoxide, n-pentoxide, n-butoxide, i-butoxide, t-butoxide, n-propoxide, i-propoxide, ethoxide, methoxide) and diethyl-p-toluenesulfonyl-oxymethylphosphonate (prepared by reacting diethyl phosphite and paraformaldehyde, and tosylating the product in situ). The resulting (R)-9-[2-diethylphosphonomethoxypropyl]adenine is deesterified with bromotrimethylsilane to give crude PMPA, which is then purified by precipitation from water with pH adjustment. The product is further purified by recrystallization with water to afford PMPA monohydrate.
The process uses a small amount of a base such as NaOH at step 1, which increases the reaction rate about 10-fold compared to the same reaction lacking the base. Step 1 also uses hydrogen gas instead of using a reagent such as NCO2NH4 to generate hydrogen in situ. The process uses lithium alkoxide at step 4b, which is mildly exothermic on addition to the reaction mixture. The use of a highly reactive base such as NaH, results in an exothermic reaction that generates hydrogen gas in a reaction is difficult to control. The use of NaH thus requires more labor and care to use than lithium alkoxide. Lithium alkoxide bases also give a product that has an improved by-product profile compared to that obtained using NaH, e.g., lower amounts of starting material or overalkylated products usually result from the use of lithium alkoxide.
The scale of the following method is proportionately reduced or increased if desired. The scheme and process steps depict synthesis of (R)-PMPA and (R)-bis(POC) PMPA. One can practice the method using chirally impure starting materials such as (R,S)-glycidol to obtain a chiral mixture of intermediates, e.g. a chiral mixture of 1,2-propylene carbonate, PMPA or bis(POC)PMPA.
Step 1. (R)-1,2-Propanediol: (S)-Glycidol (1.0 kg, 13.5 moles) is added to a rector containing (i) an inert, e.g., nitrogen, atmosphere and (ii) a stirred suspension of 5% palladium on activated carbon (50% wet) catalyst (100 g) in denatured ethyl alcohol containing 2 mole % sodium hydroxide (7.85 kg EtOH and 54 g of 16.7% NaOH solution). The contents of the inerted reactor containing catalyst and the ethanol solution is usually cooled to about 0° C. (usually about −5 to 5° C.) before the (S)-glycidol is added. Hydrogen gas at not more than 20 psi is then introduced to the inerted reaction vessel containing reactants at a temperature of no more than 25° C. The mixture is agitated for approximately 4-5 hours, until hydrogen consumption stops. Reaction completion is monitored by TLC (trace or no (S)-glycidol remaining). The mixture is then filtered e.g., diatomaceous earth (about 150 g), to remove solids and the filtrate is concentrated in vacuo at no more than 50° C., until volatile collection stops or is very slow, to obtain an oil containing the crude product. The crude product is used directly in the next step. Title compound yield is about 100%.
Step 2. (R)-1,2-Propylene carbonate: Diethyl carbonate (1.78 kg, 15.1 moles) and sodium ethoxide in denatured ethyl alcohol (210 g of 21% w/w sodium ethoxide in ethanol) are added to (R)-1,2-propanediol (1.0 kg theoretical based on the quantity of (S)-glycidol used in step 1 above), and the solution is heated to 80 to 150° C. to distill off the ethanol. If necessary to achieve reaction completion, additional diethyl carbonate (0.16 kg) is added to the reaction mixture, followed by distillation to remove ethanol. Reaction completion is monitored by TLC showing a trace or no detectable (R)-1,2-propanediol. The residue is fractionally distilled at 120° C. and 10-17 mm Hg, to yield the title compound as a colorless liquid. The product purity is typically 96% or greater purity by GC analysis.
Step 3. Diethyl-p-toluenesulfonyloxymethylphosphonate: In a reactor containing an inert atmosphere, e.g., nitrogen, a mixture of diethyl phosphite (0.80 kg), paraformaldehyde (0.22 kg), and triethylamine (0.06 kg) in toluene (0.11 kg) is heated at 87° C. for about 2 hours, then refluxed for about 1 hour, until the reaction is complete as monitored by TLC showing a trace or no detectable diethyl phosphite. During the reaction, the inert atmosphere is maintained. Toluene is necessary to moderate the reaction, which may otherwise explode. Reaction completion is optionally confirmed by 1H NMR (diethyl phosphite peak at δ 8.4-8.6 ppm no longer detected). The solution is cooled to about 1° C. (typically about <2 to 4° C.) and p-toluenesulfonyl chloride (1.0 kg) is added and then triethylamine (0.82 kg) at about 5° C. is slowly added (exothermic addition) while maintaining the temperature at no more than about 10° C. (typically 0 to 10° C.). The resulting mixture is warmed to 22° C., and stirred for at least about 5 hours (typically about 4.5 to 6.0 hours), until the reaction is complete as shown by TLC (trace or no p-toluenesulfonyl chloride detectable) and optionally confirmed by 1H NMR (p-toluenesulfonyl chloride doublet at δ 7.9 ppm no longer detected). The solids are removed by filtration and washed with toluene (0.34 kg). The combined washings and filtrate are washed either twice with water (1.15 kg per wash), or optionally with a sequence of water (1.15 kg), 5% aqueous sodium carbonate (3.38 kg), and then twice with water (1.15 kg). After each wash, the reactor contents are briefly agitated, allowed to settle and the lower aqueous layer is then discarded. If the reaction results in an emulsion, brine (0.23 kg of water containing 0.8 kg NaCl) may be added to the first organic/water mixture, followed by agitating the reactor contents, allowing the solids to settle, discarding the lower aqueous layer, adding 1.15 kg water, agitating, allowing solids to settle and again discarding the lower aqueous layer. The organic phase is distilled in vacuo at nor more than 50° C. (to LOD at 110° C. of no more than 10% and water content, by KF titration, no more than 0.3%), affording a yield of about 60-70% of the title compound as an oil of about 85-95% purity, exclusive of toluene.
Step 4. (R)-9-[2-(Diethylphosphonomethoxy)propyl]adenine: In a reactor containing an inert atmosphere, e.g., nitrogen, a mixture of adenine (1.0 kg), sodium hydroxide (11.8 g), (R)-1,2-propylene carbonate (0.83 kg), and N,N-dimethylformamide (6.5 kg) is heated to about 130° C. (typically about 125-138° C.) for about 18-30 hours until the reaction is complete as optionally monitored by area normalized HPLC showing no more than about 0.5% adenine remaining. The resulting mixture is cooled to about 25° C., typically about 20-30° C., and contains the stage I intermediate, (R)-9-(2-hydroxypropyl)adenine, which may precipitate out at this point. After cooling, lithium t-butoxide (3.62 kg), 2.0 M in tetrahydrofuran is added to the stage I intermediate, to produce the lithium salt of (R)-9-(2-hydroxypropyl)adenine in a mildly exothermic addition. The slurry is treated with diethyl p-toluenesulfonyloxymethylphosphonate (1.19 kg) and the mixture is heated to a temperature of about 32° C., typically about 30-45° C., and is stirred for at least about 2 hours (typically about 2-3 hours) during which time the mixture becomes homogeneous. More diethyl p-toluenesulfonyloxymethylphosphonate (1.43 kg) is added and the mixture is stirred at a temperature of about 32° C. (typically about 30-45° C.) for at least about 2 hours (typically about 2-3 hours). Additional lithium t-butoxide (0.55 kg), 2.0 M in tetrahydrofuran ad diethyl p-toluenesulfonyloxymethylphosphonate (0.48 kg) are added twice more, each time followed by stirring the mixture, which is at a temperature of about 32° C. for at least about 2 hours. Reaction completion is optionally monitored by area normalized HPLC showing nor more than about 10% of stage I intermediate remaining. If the reaction is incomplete, additional lithium t-butoxide (0.33 kg), 2.0 M in tetrahydrofuran and diethyl p-toluenesulfonyloxymethylphosphonate (0.24 kg) are added and the reaction mixture is maintained at a temperature of about 32° C. for at least about 2 hours to achieve reaction completion. The mixture is then cooled to about 25° C. (typically about 20-40° C.) and glacial acetic acid (0.5 kg) is then added. The resulting mixture is concentrated in vacuo at a final maximum mixture temperature of about 80° C. under about 29 in Hg vacuum. The residue is cooled to about 50° C. (typically about 40-60° C.) and water (1.8 kg) is added and the reaction is rinsed forward with additional water (1.8 kg). The solution is continuously extracted with dichloromethane (about 35 kg) for 12-48 hours with periodic additions of glacial acetic acid (0.2 kg) to the aqueous phase after about 5 hours and after about 10 hours of continuous extraction time. Extraction completion is optionally confirmed by area normalized HPLC as shown by no more than about 7% of (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine remaining in the aqueous phase. The combined dichloromethane extracts are concentrated initially at atmospheric pressure then in vacuo at an extract temperature of no more than about 80° C. to give the title compound as a viscous orange oil. The title compound yield is about 40-45% by weight normalized HPLC and its purity is typically 60-65% by area normalized HPLC. The actual weight of the title compound after concentration is approximately 1.6 times the theoretical weight (or 3.8 times the expected yield). The additional observed weight is attributed to impurities and/or solvents remaining after the continuous extraction and concentration.
Step 5. (R)-9-[2-(Phosphonomethoxy)propyl]adenine, crude: Bromotrimethylsilane (1.56 kg) is added to a reactor containing a mixture of crude (R)-9-[2-(diethylphosphonomethoxy)propyl]adenine (1.0 kg calculated based on adenine input from step 4 above) and acetonitrile (0.9 kg) with cooling to maintain a temperature no higher than about 50° C. The lines are rinsed forward with acetonitrile (0.3 kg) and the mixture is refluxed at about 60-75° C. for about 2-4 hours with moderate agitation to avoid splashing the reactor contents. Reaction completion is monitored by area normalized HPLC showing no more than about 3% total of monoethyl PMPA and diethyl PMPA remaining. If the reaction is incomplete, additional bromotrimethylsilane (0.04 kg) is charged into the reactor and the reaction is refluxed for at least about 1 hour with moderate agitation. The volatiles are removed by distillation at no higher than about 70° C. initially at atmospheric pressure and then in vacuo (about 24-27 in Hg) at no higher than about 70° C. The reactor is then cooled to about 20° C. (typically about 15-25° C.) and water (1.9 kg) is added (exothermic addition) to the residue with the temperature maintained at no higher than about 50° C. The mixture is cooled to 20° C. and washed with dichloromethane (1.7 kg) by agitating for about 30 minutes. The isolated aqueous phase is then filtered through a 1 μm cartridge filter, diluted with water (3.2 kg), heated to about 40° C. (typically about 35-50° C.) and adjusted to pH about 1.1 (typically about 0.9-1.3) with aqueous sodium hydroxide (about 0.15 kg NaOH as a 50% solution) while the temperature is maintained at about 45° C. PMPA seed crystals are added to the mixture and the pH is adjusted to about 2.8 (typically about 2.6-3.0) with a 50% aqueous sodium hydroxide solution (about 0.15 kg NaOH required) while the temperature is maintained at about 45° C. (typically about 35-50° C.). The solution is cooled to about 22° C. (typically about 15-25° C.) over about 3-20 hours with slow to moderate agitation that avoids splashing the contents, during which time the product should precipitate, beginning at about 35° C. The pH of the slurry is adjusted to about 3.2 (typically about 3.1-3.3), usually using 50% aqueous sodium hydroxide or concentrated hydrochloric acid, if necessary. The slurry is cooled to approximately 5° C., typically about 0-10° C., and slowly agitated for at least about 3 hours in that temperature range. The solids are collected by filtration, washed sequentially with cold water (0.35 kg) and acetone (0.3 kg) giving crude PMPA as a damp solid typically of about 97% purity. The product is heated to about 50° C. and dried in vacuo to a water content of less than 10%. The quantity of diethyl PMPA is calculated from the quantity of adenine used in the preceding step of the synthesis (assuming 100% yield) and not from the net weight of the crude diethyl PMPA, which may contain other compounds.
Step 6. (R)-9-[2-Phosphonomethoxy)propyl]adenine, pure: A suspension of the crude PMPA (1.00 kg corrected for water content) (Step 5 product) in water is heated to about 100° C. (typically about 95-110° C). with moderate to high agitation until all solids dissolve, and the resulting solution is clarified by filtration while hot, rinsing forward using additional hot water (1 kg, about 95-110° C.). The filtrate is heated to 100° C. prior to cooling, first to about 30° C. (typically about 20-25° C.) over about 3-5 hours with slow agitation, then cooling is continued to about 10° C. (typically about 5-15° C.). After holding at about 10° C. for at least about 3 hours, the solids are collected by filtration and washed sequentially with cold water (1.5 kg, about 0-10° C.) and then acetone (1 kg). The wet cake is dried in vacuo at about 50° C. (typically about 40-60° C.) to a water content of about 5.9% (typically about 3.9-7.9%), affording pure PMPA monohydrate. The product purity is typically 98% or greater by both area normalized and weight normalized HPLC. If the chemical purity is unsatisfactory, the product may be repurified by a repeat of this step.
Optional recrystallization: 0.75 g of PMPA (preparation A) was recrystallized from H2O (11.3 mL, 15:1 wt. ratio) by heating the suspension to 95-100° C. Upon cooling to room temperature, the crystallized PMPA was chilled in a freezer. After 3 h the crystals were filtered on a coarse frit fit with Tyvek™, the filter cake rinsed with ice-cold H2O and acetone, and air dried to constant weight to give a fluffy white solid (Preparation B). Recovery was 0.64 g (85.3%), HPLC showed 98.5-98.9% pure PMPA. No 14.7 min impurity was observed. Recrystallized liquors (1039-91-23) showed 71.4% pure PMPA with a major impurity of 4.8 min (26.9%), possibly solvent. 14.7 min impurity=0.05%.
Preparation B PMPA was recrystallized again from 9.6 mL (15:1 wt. ratio) H2O heated to 95-100° C. Upon cooling to room temperature, the crystallized PMPA was chilled in a freezer overnight. The PMPA was filtered through a coarse frit fit with Tyvek™ and the filter cake was rinsed with ice-cold H2O and acetone, then sucked dry to constant weight to afford a fluffy, white solid (Preparation C). Recovery was 0.52 g (81.3%). HPLC (JH52807, JH52810) showed 99.3-99.5% pure PMPA. The largest impurity at 19 min=0.22%. Recrystallized liquors showed 64.9% pure PMPA with 0.01% 14.7 min impurity and 0.09% 19 min impurity.
Preparation C PMPA (0.50 g) was recrystallized from approximately 7.5 mL boiling H2O (15:1 wt. ratio). Upon cooling to room temperature, the PMPA was filtered on a coarse frit fit with Tyvek™. The filter cake was rinsed with ice-cold H2O and acetone then sucked to dryness to afford a fluffy white solid (Preparation D). The filtrate was also concentrated to afford a white solid (Preparation E).
Recovery: Filter cake: 0.41 g (82%), Filtrate: 0.08 g=0.49 g combined (98%). HPLC analysis showed the filtrate (Preparation E) was 99.9% pure. PMPA prepared in this fashion is used to manufacture the compounds of this invention.
Step 7. Bis(POC)PMPS fumarate: In a reactor with an inert atmosphere, e.g., nitrogen, a mixture of 1-methyl-2-pyrrolidinone (4.12 kg), PMPA monohydrate (1.00 kg), triethylamine (0.996 kg), are agitated for about 15-45 min., typically about 30 min, and then chloromethyl-2-propyl carbonate (2.50 kg) is added and the mixture is heated to about 55-65° C., typically about 60° C. and agitated without splashing the contents for about 3-6 hours, typically about 4 hours, until the reaction is complete, as optionally indicated by HPLC (no more than 15% mono(POC)PMPA present). The mixture is diluted with isopropyl acetate (10.72 kg), cooled to about 15-30° C., typically about 25° C., as rapidly as possible, and while holding the reactor contents at a of about 15-30° C., typically about 25° C., the mixture is agitated for about 20-60 minutes, typically about 30 minutes. The solids are removed by filtration and washed with isopropyl acetate (4.44 kg). The combined organic phases at about 15-30° C., typically about 25° C., are extracted twice with water (3.28 kg)using moderate agitation for about 1-10 min. to avoid forming an emulsion followed by allowing the phases to separate. The combined aqueous phases are back-extracted twice with isopropyl acetate (3.56 kg) (about 15-30° C., typically about 25° C.). All organic phases are combined and washed with water (2.20 kg) (about 15-30° C., typically about 25° C.) using moderate agitation for about 1-10 min. to avoid forming an emulsion, then the combined organic phases, which are at about 25-43° C., but at no more than 45° C., are concentrated in vacuo (about 26.5-28″ Hg) to approximately 30% of the original volume (about 10-12 L/kg PMPA monohydrate). After a polishing filtration using an in-line 1 μm filter, the concentration of the organic phase is resumed at about 20-38° C., but no higher than 40° C. under a vacuum (about 28″ Hg) until a pale yellow oil remains. The oil is dissolved in a warmed solution (about 45-55° C., typically about 50° C.) of fumaric acid (0.38 kg) in 2-propanol (6.24 kg) with vigorous agitation until solids dissolve, about 0.5-2.0 hours. The warm solution is then optionally filtered using an in-line 1 μm filter while minimizing cooling of the solution. The filtrate at about 34-50° C., typically at about 40° C., is agitated using the minimum agitation needed to obtain a homogeneous solution. The resulting solution is cooled to about 30-33° C., typically about 32° C., over about 30 minutes using minimal agitation, optionally seeded with a small quantity of bis(POC)PMPA fumarate (about 100 mg), and cooled to about 12-18° C., typically about 15° C., over about 1-2 hours, typically over about 1 hour. Seed crystals may not be needed if crystal formation begins before seed crystals are added. Crystals may form over a range of about 12-33° C. as the solution is cooled. Crystallization will occur at lower temperatures if the solution is further chilled, e.g., to about −10° C. to about 11° C. Agitation is discontinued when crystal formation begins. The mixture is allowed to stand at about 15° C. for at least about 12 hours, typically about 12-30 hours. The resulting slurry is filtered (Tyvek) and the filter cake is washed with a premixed solution of isopropyl acetate (0.70 kg) in butyl ether (2.44 kg) (1:4 v/v). The filter cake, which is at no more than 40° C., is dried in vacuo for about 1 to 3 days and the dried product is optionally milled (Fitzmill M5A fitted with a 0.050″ screen), affording bis(POC)PMPA fumarate as white, fine powder-like crystals of about 97.0 to 99.5% purity.
Example 2 Preparation of Alkyl Chloromethylcarbonates
Figure USRE038333-20031125-C00012
A solution of the alcohol (73 mmol) and chloromethyl chloroformate (Fluka, 6.23 mL, 70 mmol) in diethyl ether was cooled to 0° C. under argon. Pyridine (5.7 mL, 70 mmol) was added dropwise with stirring over 10 minutes. The solution was stirred at 0° C. for one hour, then allowed to warm to room temperature and stirred for three additional hours. The ether solution was filtered, washed with 1 M HCl, dried over MgSO4, filtered and concentrated on a rotary evaporator. Brief application of 0.1 torr vacuum gave the alkyl chloromethyl carbonates in 85-95% yields. Ethyl chloromethyl carbonate is somewhat volatile, and cannot be left on the rotovap too long, or the yield suffers (87-35%).
Example 3 Preparation of the Bis-ethyl Oxymethyl Carbonate of PMPA
Figure USRE038333-20031125-C00013
R=Et. Anhydrous PMPA (5 g, 16 mmol) and DIEA (Hunig's base) (11.5 mL, 66 mmol) were placed in anhydrous DMF (50 mL). The chloromethyl carbonate (49 mmol) was then added and the suspension heated to 50° C. under argon with rapid mechanical stirring. After 1 hr the reaction was clear and the temperature was lowered to 35° C. and the reaction stirred for 48 hr. The DMF was removed on a rotary evaporator, and the reaction partitioned between CH2Cl2 and water. The CH2Cl2 layer was dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was taken up in methylene chloride and applied to a silica gel column (150 g SiO2). It was eluted with 500 mL each 0,3,6,9,12,15,18% (v/v) isopropanol in methylene chloride, and then with 2000 mL 21%. Appropriate fractions were pooled and evaporated to give the desired product.
Example 4 Preparation of the Bis-n-butyl Oxymethyl Carbonate of PMPA
Figure USRE038333-20031125-C00014
Butyl chloromethyl carbonate. A solution of butyl alcohol (50 mmol) and chloromethyl chlorofomrate (4.5 mL, 50 mmol) in diethyl ether (200 mL) was cooled to 0° C. under argon. Pyridine (5.7 mL, 50 mmol) was added dropwise with stirring over 5 min. The solution was stirred at 0° C. for 15 min, then allowed to warm to room temperature and stirred for three additional hours. The ether solution was filtered, washed with 1 M HCl, and then twice with water, dried over MgSO4, filtered, and concentrated on a rotary evaporator to give butyl chloromethyl carbonate (7 g, 85%).
Dibutyl PMPA carbonate. Anhydrous PMPA (4 g, 13 mmol) and DIEA (10.5 mL, 60 mmol) were placed in anhydrous DMF (40 mL). Butyl chloromethyl carbonate (40 mmol) was then added and the suspension stirred at room temperature for 48 hr. The reaction was then heated to 50° C. for 18 hr. The DMF was removed on a rotary evaporator, and the reaction partitioned between CH2Cl2 (250 mL) and water (250 mL). The CH2Cl2 layer was washed once with saturated aqueous NaHCO3, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was taken up in methylene chloride and applied to a silica gel column (150 g SiO2). It was eluted with 1000 mL CH2Cl2, 500 mL each 0,3,6,9,12,15,18% (v/v) isopropanol in methylene chloride, and then with 2000 mL 21% isopropanol in methylene chloride. Appropriate fractions were pooled and evaporated to give the desired product.
Example 5 Synthesis of Bis-n-propyl Oxyethyl Carbonate of PMPA
Figure USRE038333-20031125-C00015
Preparation of propyl-1-chloroethyl carbonate. A solution of propyl alcohol (70 mmol) and 1-chloroethyl chloroformate (7.6 ml, 70 mmol) in diethyl ether (200 mL) was cooled to 0° C. under argon. Pyridine (70 mmol) was added dropwise with stirring over 5 min. The solution was stirred at 0° C. for 15 min, then allowed to warm to room temperature and stirred for 4.5 additional hours. The ether solution was filtered, washed with 1 M HCl, and then twice with water, dried over MgSO4, filtered, and concentrated on a rotary evaporator to give propyl-1-chloroethyl carbonate (9.8 g, 84%). Anhydrous PMPA (0.3 g, 1 mmol) and DIEA (0.7 mL, 4 mmol) were placed in anhydrous DMF (2 mL) under argon. Propyl-1-chloroethyl carbonate (3 mmol) was then added and the suspension stirred at 50° C. for 20 hr. The DMF was removed on a rotary evaporator, and the reaction partitioned between CH2Cl2 and water. The CH2Cl2 layer was dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was taken up in methylene chloride and applied to a silica gel column (25 g SiO2). It was eluted with 100 mL CH2Cl2, 50 mL each 3,6,9,12,15,18% (v/v) isopropanol in methylene chloride, and then with 200 mL 21% ispropanol in methylene chloride. Appropriate fractions were pooled and evaporated to give the desired product.
Example 6 Synthesis of Chloromethyl Isopropyl Carbonate
To a cold solution (approximately 10° C.) of chloromethylchloroformate (65 mL) in diethyl ether (1.4 L) was added isopropanol (56 mL) followed by a dropwise addition of pyridine (60 mL). After the addition the cold bath was removed and the reaction mixture was stirred for 18 h. The reaction mixture was poured into a separation funnel containing cold water (100 mL). The ether layer was separated and washed with water (100 mL×2) and then dried over Na2SO4. Evaporation of the solvent furnished the chloromethyl isopropyl carbonate (107 g, 95%). Chloromethyl isobutyl carbonate, chloromethyl neopentyl carbonate, chloromethyl tert butyl carbonate and chloromethyl 3-pentyl carbonate are prepared in a similar manner.
Example 7 Synthesis of Bis Isopropyl Oxymethyl Carbonate of PMPA
To a stirred suspension of PMPA (7.26 g, 0.026 mmol) in DMF (100 mL) at 50° C. was added Et3N (10.8 mL, 0.0778 mmol). The reaction mixture became homogeneous and chloromethyl isopropyl carbonate (12.1 g, 0.0778 mol) was added to the reaction mixture and stirring continued at 50° C. (oil bath temperature) for 20 h. The solvents were removed under reduced pressure and the crude was chromatographed on a silica gel column. Elution with 10% isopropanol in CH2Cl2 removed all the non polar impurities. Further elution wit the same solvent mixture furnished the prodrug, 1.3 g (approximately 10%).
Example 8 Synthesis of Bis Isopropyl Oxymethyl Carbonate of PMPA
To a stirred suspension of PMPA (1 g, 3.57 mmol) in DMF (5 mL) were added Et3N (1.5 mL, 10.71 mmol) and chloromethyl isopropyl carbonate (1.67 g, 10.71 mmol). The reaction mixture was then diluted with ethyl acetate (100 mL) and filtered. The filtrate was washed with water (2×50 mL) and finally with brine (10 mL). The crude obtained after removal of the solvent was dried under vacuum. The resulting oil was dissolved in isopropanol (7 mL) and citric acid (260 mg) was added. The mixture was stirred for 16 hr at room temperature and then cooled to 0° C. The product was crystallized and crystals were filtered and dried. Mp 76-81° C.
Example 9 Preparation of Chloromethylcarbamates
Figure USRE038333-20031125-C00016
A solution of the amine (24 mmol), DIEA (30 mmol), and DMAP (0.5 mmol) in methylene chloride (5 mL), was added dropwise to a cold (0° C.) solution of chloromethyl chloroformate (25 mmol) in methylene chloride (45 mL) over 5 min. The solution was allowed to warm to room temperature over 1.5 hr. The solution was diluted into ethyl acetate (100 mL), and washed with saturated sodium bicarbonate, 1 M HCl, and saturated sodium chloride. It was then dried over magnesium sulfate, filtered, and evaporated to give the desired chloromethyl carbamate.
Example 10 Synthesis of Bis Morpholino Oxymethyl Carbamate of PMPA
Figure USRE038333-20031125-C00017
Anhydrous PMPA (0.3 g, 1 mmol) and DIEA (1 mL, 6 mmol) were placed in anhydrous DMF (2 mL). Chloromethyl morpholino carbamate (3 mmol) was then added and the suspension stirred at room temperature for 3 days. The reaction was partitioned between CH2Cl2/isopropanol and 0.1 M citrate buffer (pH 6). The CH2Cl2 layer was washed with water, dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was taken up in methylene chloride and applied to a silica gel column (5 g SiO2). It was eluted wit 25 mL each 0,3,6,9,12,15,18% (v/v) isopropanol in methylene chloride, and then with 100 mL 21% isopropanol in methylene chloride. Appropriate fractions were pooled and evaporated to give the desired product.
Example 11 Synthesis of Bis Piperidino Oxymethyl Carbamate of PMPA
Figure USRE038333-20031125-C00018
Anhydrous PMPA (0.3 g, 1 mmol) and DIEA (0.7 mL, 4 mmol) were placed in anhydrous DMF (2 mL). Chloromethyl piperidino carbamate (3 mmol) was then added and the suspension stirred at room temperature for 3 days. More DIEA (4 mmol) and chloromethyl piperidino carbamate (100 μl) were added, and the reaction stirred for 27 hr. The reaction was partitioned between CH2Cl2/isopropanol and 0.1 M citrate buffer (pH 6). The CH2Cl2 layer was dried over magnesium sulfate, filtered, and concentrated on a rotary evaporator. The residue was taken up in methylene chloride and applied to a silica gel column (5 g SiO2). It was eluted with 25 mL each 0,3,6,9,12,15,18% (v/v) isopropanol in methylene chloride, and then with 100 mL 21% isopropanol in methylene chloride. Appropriate fractions were pooled and evaporated to give the desired product.
Example 12 Other Carbamate Intermediates
To a solution of chloromethylchloroformate (4.16 mL) in CH2Cl2 (30 mL) were added tert butyl amine (4.9 mL) and proton sponge (10 g). The reaction mixture was stirred for 18 h and then it was poured into a separation funnel containing cold 0.5N HCl (100 mL). The CH2Cl2 layer was separated and washed with water (100 mL×2) and then dried over Na2SO4. Evaporation of the solvent furnished the chloromethyl tert butyl carbamate (8 g). Chloromethyl n-butyl carbamate (R=n butyl) and chloromethyl dimethyl carbamate (R=Me) were prepared in the same fashion.
Example 13 Other Oxymethyl Alkyl Carbamate Prodrugs of PMPA
To a stirred suspension of PMPA (4.51 g, 0.016 mmol) in DMF (50 mL) was added Et3N (6.7 mL, 0.048 mmol). The reaction mixture became homogeneous and chloromethyl tert butyl carbamate (8 g, 0.048 mol) was added to the reaction mixture and stirring continued at room temperature for 3 days. The solvents were removed under reduced pressure and the crude wash chromatographed on a silica gel column. Elution with 10% isopropanol in CH2Cl2 removed all the less polar impurities. Further elution with the same solvent mixture furnished the prodrug (1.25 g). The n-butyl and methyl carbamates were prepared in the same fashion from the intermediates of the preceding example.
Example 14 Chemical Stability of PMPA Carbonates
The solution stability of PMPA carbonates was studied at pH 7.4 at 37° C. in 10 mM buffer (NaH2PO4 and Na2HPO4) with the total ionic strength adjusted to 0.15 M with KCl. The assays were performed by adding 200 μL of a PMPA carbonate stock solution (about 1 mg/mL in DMSO) to 10 mL of pre-equilibrated buffer at 37° C. Samples were removed at specific times points and analyzed by HPLC. The chemical t ½ is expressed in terms of the number of hours required to hydrolyze 50% of the carbonate at the specified pH.
Example 15 Oral Bioavailability of PMPA and PMPA Carbonates in Beagle Dogs
PMPA (9-[(R)-2-(phosphonomethoxy)propyl]adenine) and PMPA carbonates were examined to determine the effect of dose on the pharmacokinetics of PMPA in beagle dogs, in particular the bioavailability of PMPA following oral administration to beagle dogs.
PMPA monohydrate was synthesized by Gilead Sciences. Tetrabutylammonium hydrogen phosphate (TBAHP) was obtained from Fluka (Ronkonkoma, N.Y.). Acetonitrile was obtained from Baxter (Muskegon, Mich.). Dibasic potassium phosphate, monobasic potassium phosphate, and sodium acetate trihydrate were obtained from Mallinckrodt (Paris, Ky.). Chloroacetaldehyde and trifluoroacetic acid (TFA) were from Aldrich (Milwaukee, Wis.).
The intravenous formulations used as standards were isotonic aqueous solutions containing 50 mg/mL PMPA. Compound was added to 10 mL of WFI (water for injection from Abbott Laboratory) and 1N NaOH was added to adjust the pH to 7.4. The solutions were diluted to 15 mL with WFI and sterile filtered with a 0.2 μm filter. The PMPA dose was 10 mg/kg (0.2 mL/kg).
The intravenous formulation for a 1 mg/kg dose was prepared as described above except only 75 mg of PMPA was added to WFI and the final concentration was 5 mg/mL. The dose was 1 mg/kg (0.2 mL/kg). Oral formulations of carbonates were prepared in 20-40% PEG 400/50 mM citric acid and were adjusted to pH 2.2. Doses ranged from 6.2-10 mg eq of PMPA/kg and are shown in Table 1.
Two groups of five adult male beagle dogs were used. The mean body weight at the time of the first does was 9.6±0.4 Kg (range 9.2-10.2). The dogs were fasted 12-18 hours prior to dosing and until 6 hours post-dose. For pentagastrin pretreatment, dogs were given a single intramuscular injection of pentagastrin (Peptavlon 0.25 mg/mL, Ayerst Laboratories, Inc., Philadelphia, Pa.) at a dose of 6 μg/kg, 20 minutes prior to dosing. Water was provided ad lib.
Each formulation was administered as a single dose to five male beagle dogs. Individual vials of each formulation were provided for each animal. The intravenous formulation was administrated via a cephalic vein. The oral suspension was administered by gavage, followed by two 10 mL water washes. At least one week washout period was allowed between administrations.
Blood samples (4.0 mL) were collected by direct jugular access from each animal into heparinized tubes. Animals remained conscious throughout the sample collection period. Blood was processed immediately for plasma by centrifugation at 2000 rpm for 10 minutes. Plasma samples were frozen and maintained at ≦−20° C. until analyzed.
Urine samples were collected over 0-24 and 24-48 hours time periods. Urine samples from 0-24 and 24-48 hours were divided into aliquots and mixed based on the volume collected and analyzed to determine amount of PMPA recovered from urine during 0-48 hours.
PMPA in Plasma and Urine was determined as follows. PMEA (9-(2-phosphono-methoxyethyl)adenine; adefovir) was used as the internal standard for both analyses. The total concentration of PMPA in dog plasma or urine samples was determined by derivatizing PMPA and PMEA with chloroacetaldehyde to yield a highly fluorescent N1,N6-ethenoadenine derivative as described (Russell, J. et al. (1991) Determination of 9-[(2-Phosophonylmethoxy)-ethyl]Adenine in Rat Urine by High-Performance Liquid Chromatography with Fluorescence Detection. J. Chromatogr. (Netherlands) 572, 321-326).
Sample Extraction for PMPA in plasma and urine was performed as follows. Plasma (200 μL) and internal standard (200 μL of 10 μg/mL PMEA providing a final PMEA concentration of 1 μg/mL) were mixed with 400 μL of acetonitrile containing 0.1% TFA to precipitate protein. Samples were then evaporated to dryness under reduced pressure at room temperature (Savant SpeedVac). Urine samples (20 μL) and internal standard (30 μL of 10 μg/mL PMEA providing a final PMEA concentration of 1.5 μg/mL) were used directly for derivatization without drying.
The samples were derivatized for analysis as follows. Dried plasma samples or urine samples were reconstituted or mixed in 200 μL derivatization cocktail (0.34% chloroacetaldehyde in 100 mM sodium acetate, pH 4.5), vortexed, and centrifuged for 10 minutes at 14,000 rpm in an Eppendorf Centrifuge 5402. Supernatant was then transferred to a clean screw capped tube and incubated at 95° C. for 40 minutes. Derivatized samples were quenched on ice and evaporated to dryness under reduced pressure at room temperature. Dried samples were reconstituted in 200 μL Mobile Phase A (see below), vortexed and centrifuged for 10 minutes at 14,000 rpm in an Eppendorf Centrifuge 5402. The supernatant was then transferred to autoinjector vials for HPLC analysis.
The plasma and urine samples were analyzed by HPLC with Fluorescence Detection as follows. The HPLC system comprised a Model P4000 solvent delivery system with a Model AS3000 autoinjector and a Model F2000 Fluorescence detector (Thermo Separation, San Jose, Calif.). The column was a Zorbax RX-C18 (5 μm, 150×4.6 mm) (MAC-MOD, Chadds Ford, N.Y.) equipped with a Brownless RP-18 Newguard guard column (7 μm, 15×3.2 mm) (Alltech, Deerfield, Ill.). The mobile phases used were: A, 2% acetonitrile in 25 mM potassium phosphate buffer with 5 mM TBAP, pH 6.0; B, 65% acetonitrile in 25 mM potassium phosphate buffer with 5 mM TBAHP, pH 6.0. The flow rate was 1.5 mL/min and the column temperature was maintained at 35° C. by a column oven. The gradient profile was 100% A until 2.0 min, then a linear gradient to 100% B by 13.0 minutes, returning immediately to 100% A. Detection was by fluorescence with excitation at 236 nm and emission at 420 nm, and the injection volume was 50 μL. Total cycle time between injections was 25 min. Data was acquired and stored by a Peak Pro data acquisition system (Beckman, Palo Alto, Calif.).
The pharmacokinetic parameters for intravenous and oral formulations of PMPA and PMPA carbonates were assessed using non-compartmental methods. Intravenous data were analyzed using PCNONLIN Model 201 (5); oral data were analyzed using Model 200. Additional pharmacokinetic parameters were calculated as follows:
CL=Dose/AUC(0−∞); where CL is the total plasma clearance.
Vss=CL×MRT; where Vss is the apparent volume of distribution at steady state. MRT is the mean residence time.
The initial plasma concentration (Co) was determined by extrapolation of log transformed data to zero time. Bioavailability was expressed as Bioavailability   ( % ) = AUC   ( 0 - ∞ )   oral   or     prodrug AUC   ( 0 - ∞ )   intravenous × 100 Urinary  recovery  was  expressed  as Uninary   Recovery   ( % ) = amount   ( mg )   of   PMPA   in   urine   ( 0 –48   hr ) amount   ( mg )   of   PMPA     dosed × 100
Figure USRE038333-20031125-M00001
Oral bioavailability of t-Bu, 3-pentyl, isopropyl, Et carbonate parameters were compared by unpaired t-tests (Stat View® Version 4.0, Software for the Statistical Analysis. Abacus Concepts, Inc., Berkeley, Calif.). A P value of ≦0.05 was considered significant.
Biological t½:
Dog liver was obtained fresh from Pharmakon USA (Waverly, Pa.). Liver homogenate was prepared following a standard protocol. Dog liver was rinsed three times with ice-code 50 mM sodium/potassium phosphate buffer and homogenized with a Tekmar Tissumizer homogenizer (VWR 33995-060). The homogenate was centrifuged at 9000 g (11,000 rpm for Eppendorf Centrifuge 5402; Brinkman Instruments, Westbury, N.Y.) at 4° C. for 20 minutes. The supernatant was designated at the S9 fraction. The concentration of protein in the S9 fraction was determined using a Bio-Rad Protein Assay Kit II, with bovine serum albumin as standard. Esterase activity was determined using o-nitrophenyl butyreate as substrate and activity was calculated based on the increase in absorbance at 420 nm after a 1 min incubation. The homogenates were stored as 1.0 mL aliquots at −70° C.
Intestinal Homogenate:
Dog intestinal segments (jejunum/ileum) were obtained fresh from Pharmakon USA (Waverly, Pa.) and intestinal homogenate was prepared as described for liver. The intestinal homogenates were stored as 1.0 mL aliquots at −70° C.
Human intestinal homogenate (S9) was obtained from Keystone Skin Bank (Exton, Pa.) at concentration of 20 mg protein/mL.
Study Design:
Enzymatic stability studies involving plasma and intestinal homogenate were performed with 90% biological fluids.
Stability Measurement:
One blank (drug free) incubation was performed for each biological fluid. All biological fluid tubes (open) were pre-incubated without PMPA prodrugs in a shaker bath at 37° C. and 100 oscillation/min for 5 minutes. PMPA prodrugs was added to the test incubations (final concentration: 20 μg/mL, mixed and maintained at 37° C. and 100 oscillations/min. Samples (50 μL) were withdrawn at 0, 30, and 60 minutes and the reaction was quenched with 100 μL of 0.1% trifluoroacetic acid (TFA) in acetonitrile. Quenched samples were centrifuged for 5 minutes at 14,000 rpm in an Eppendorf Centrifuge 5402, and the supernatant was used for HPLC analysis.
Calculations:
For each incubation, the observed rate constant for degradation was calculated by plotting the log of the peak area of PMPA prodrugs versus time of incubation (min). The slope was the observed rate constant (kobs). The half life was calculated according to the following equation: t1 / 2 ( min ) = 0.693 k obs
Figure USRE038333-20031125-M00002
If the observed rate constant for degradation was less than 0.01 min−1, then t½ was expressed as stable.
The results of the beagle study are shown below in Table 1.
TABLE 1
PMPA Prodrug Summary
Biological t½ (min) Urinary
Chemical (Dog) % of PMPA IV (1 mg/kg) AUC Recovery
PRODRUGS t½ (hr) Log PC (Human) Mono- (% as
CARBONATES pH 7.4 pH 2.0 pH 7.4 Intestine Plasma Liver PMPA ester Prodrug other PMPA)
Figure USRE038333-20031125-C00019
(Dose mg e.g.
PMPA/Kg)
Bis-t-Bu COM PMPA 0.4 0.4 1.93 26.6 21.2 14.9 36.2 ± 6.76 — — — 34.9 ±
(<5)   14.0
Figure USRE038333-20031125-C00020
Bis-IBu COM PMPA 9 >150 2.0 15 <5 <5 24.5 ± 8.82 — — — TBD
(<5)
Figure USRE038333-20031125-C00021
Bis-neoPentylICOM PMPA 6 >150 3.2 <5 <5 <5 18.9 ± 6.57 — — — TBD
(<5)
Figure USRE038333-20031125-C00022
Bis-nBuCOM PMPA 6 >150 2.7 <5 <5 <5 17.3 ± 2.57 — — — TBD
(<5)
Figure USRE038333-20031125-C00023
Bis-3-PentylCOM PMPA 8 >150 3.2 30 15 <5 33.9 ± 9.02 — — — TBD
(<5)
Figure USRE038333-20031125-C00024
Bis-EtCOM PMPA 7 0.6 23.3 16.6 <5 29.3 ± 3.4 −2 0 0 TBD
(<5)
Figure USRE038333-20031125-C00025
Bis-EtCOE PMPA 4 62.4 42.6 <5 NA NA NA NA NA
Figure USRE038333-20031125-C00026
Bis-Methoxy diMeCOM PMPA 9 1.0 Stable 77.6 100.8 NA NA NA NA NA
(30)
Figure USRE038333-20031125-C00027
Bis-isopropylCOM PMPA 9 1.25 52.6 20.5 <5 35.8 ± 14.7 3.1 ± 0 0 TBD
(<5) 0.67
Figure USRE038333-20031125-C00028
Figure USRE038333-20031125-C00029
Bis-tBuNCOM PMPA 0.4 107.5 99.5 166.5 8.86 ± 2.38 — 9.97 ± —
  2.52
Figure USRE038333-20031125-C00030
Bis-di-n-proNCOM PMPA 13 Stable Stable 76 NA NA NA NA NA
Figure USRE038333-20031125-C00031
Example 16 Antiviral Activity of PMPA and PMPA Carbonates in Tissue Culture
PMPA (9-[(R)-2-(phosphonomethoxy)propyl]adenine) and PMPA carbonates were examined to determine their activity against HIV-1. The antiviral activity of the carbonates 5a, 5c-g against HIV-1 (IIIB) was determined in MT-2 cells and the IC50 (50% inhibitory concentration) and CC50 (concentration to kill 50% of the cells) values were measured. The carbonate prodrugs exhibited increased potency (about 2.5-500 fold) compared to PMPA (Table 2). Although cytotoxicity of the prodrugs also increased, the selectivity indices were improved compared to PMPA. The increased activity can be attributed to increased cellular uptake of the prodrugs followed by effective intracellular conversion to PMPA, which undergoes subsequent phosphorylation to the antivirally active diphosphate metabolite. The t-butyl carbonate 5d exhibited only 2.5 fold increased activity over PMPA with reduced selectivity possibly due to chemical instability. The antiviral activity data indicate good permeability of alkyl methyl carbonate prodrugs into cells, possibly due to their increased lipophilicity. The partition coefficient values support this hypothesis, with all prodrugs being more lipophilic (logP=0.6-3.2) compared to PMPA (logP=−2.5).
Figure USRE038333-20031125-C00032
TABLE 2
Antiretroviral activity of PMPA and PMPA prodrugs against HIV-1.
IC50 a CC50 b
compound (μM) (μM) SIc
2  0.5 250   500
5a 0.002 40 20000
5c <0.001 30 30000
5d 0.2 10   50
5e <0.001  3  3000
5f 0.003 50 16600
5g <0.001 40 40000
aIC50 — 50% Inhibitory concentration;
bCC50 — Concentration to kill 50% of the cells;
cSI — Selectivity Index (CC50/IC50);
n.d — not determined;
DMSO used as control.

Claims (5)

We claim:
1. A method for preparing a compound of formula (1)
Figure USRE038333-20031125-C00033
comprising reacting a compound of formula (4)
Figure USRE038333-20031125-C00034
with LC(R2)2OC(O)X(R)a wherein,
B is guanin-9-yl, adenin-9-yl, 2,6-diaminopurin-9-yl, 2-aminopurin-9-yl or their 1-deaza, 3-deaza, or 8-aza analogs, or B is cytosin-1-yl;
X is N or O;
R is independently —H, C1-C12 alkyl, C5-C12 aryl, C2-C12 alkenyl, C2-C12 alkynyl, C7-C12 alkenylaryl, C7-C12 alkynylaryl, or C6-C12 alkaryl, any one of which is unsubstituted or is substituted with 1 or 2 halo, cyano, azido, nitro or —OR3 in which R3 is C1-C12 alkyl, C2-C12 alkenyl, C2-C12 alkynyl or C5-C12 aryl;
R1 is hydrogen, —CH3, —CH2OH, —CH2F, —CH═CH2, or —CH2N3, or R1 and R8 are joined to form —CH2—;
R2 independently is hydrogen or C1-C6 alkyl provided that at least one R2 is hydrogen;
L is a leaving group;
R8 is hydrogen or —CHR2—O—C(O)—OR, or R8 is joined with R1 to form —C2— —CH2; and
a is 1 when X is O, or 1 or 2 when X is N,
with the proviso that when a is 2 and X is N, (a) two N-linked R groups can be taken together to form N-containing carbocycle or oxygen-containing heterocycle, (b) one N-linked R additionally can be —OR3 or (c) both N-linked R groups can be H.
2. The method of claim 1 comprising conducting the reaction using at least about 1.0 equivalent of L—CHR2 —O—C(O)—OR.
3. The method of claim 1 comprising conducting the reaction in the presence of an organic base in an organic solvent at a reaction temperature of about 4-100° C. for about 4-72 hours.
4. The method of claim 1 wherein the compound of formula ( 1 ) is recovered by forming a salt, precipitating the salt and recovering the precipitated salt.
5. The method of claim 4 wherein the salt is formed from sulfuric acid, phosphoric acid, lactic acid, or citric acid.
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US6043230A (en) 2000-03-28
US5922695A (en) 1999-07-13
US5977089A (en) 1999-11-02

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