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EP1879657A2 - Utilisation de composes d'amelioration de la capacite de traitement d'une telomerase - Google Patents

Utilisation de composes d'amelioration de la capacite de traitement d'une telomerase

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Publication number
EP1879657A2
EP1879657A2 EP06722450A EP06722450A EP1879657A2 EP 1879657 A2 EP1879657 A2 EP 1879657A2 EP 06722450 A EP06722450 A EP 06722450A EP 06722450 A EP06722450 A EP 06722450A EP 1879657 A2 EP1879657 A2 EP 1879657A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
alkynyl
alkenyl
independently
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06722450A
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German (de)
English (en)
Inventor
Miroslav Hajek
Nadezda Matulova
Ivan Votruba
Antonin Holy
Eva Tloustova
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Czech Academy of Sciences CAS
Institute of Organic Chemistry and Biochemistry CAS
Original Assignee
Czech Academy of Sciences CAS
Institute of Organic Chemistry and Biochemistry CAS
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Application filed by Czech Academy of Sciences CAS, Institute of Organic Chemistry and Biochemistry CAS filed Critical Czech Academy of Sciences CAS
Publication of EP1879657A2 publication Critical patent/EP1879657A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • telomerase Human telomerase is a large cellular ribonucleoprotein complex (Morin GB, Cell, 1989, 59, 521-9; Wenz C, et al., EMBO J 2001,20:3526-34; and Collins K,
  • telomerase As a functional catalytic reverse transcriptase prompted studies of inhibiting telomerase with established HIV reverse transcriptase inhibitors, such as the chain terminating 3'- azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC) (Nakamura TM, et al., Science, 1997, 277, 955-9; Blackburn EH, Annu Rev Biochem, 1992, 61, 113-29; and Cech TR, et al., Biochemistry (Moscow), 1997, 62, 1202-5).
  • ZTT chain terminating 3'- azido-3'-deoxythymidine
  • ddC 2',3'-dideoxycytidine
  • nucleosides are transformed in vivo in the form of triphosphates, which inhibit reverse transcriptases by acting as competitive substrates for the enzyme and terminate DNA synthesis de novo.
  • AZT-TP inhibits the activity of telomerase to ⁇ 50% at 30 ⁇ mol/L.
  • Other nucleotide-based inhibitors both purine and pyrimidine derivatives, have been evaluated against telomerase with effective IC 5 O values in the micro-molar range.
  • Fletcher reported the use of deazadeoxypurines as inhibitors of telomerase with one compound, 6-thio-7-deaza-2'- deoxyguanosine 5 '-triphosphate showing an IC 5O value of 60 nmol/L.
  • telomere activity has previously been shown to inhibit telomerase activity (see Morin GB, Cell, 1989, 59, 521-9; Strahl C, Blackburn EH., MoI Cell Biol, 1996, 16, 53-65; Pai RB 5 et al., Cancer Res, 1998, 58, 1909-13; Fletcher TM, et al., Bioorg Chem, 2001, 29, 36-55; Tendian SW 5 Parker WB.
  • S- HPMPC cidofovir, CDV 5 Vistide ®
  • i?)-PMPA tenofovir, TDV, Viread ®
  • PMEA adefovir, ADV, Hepsera ®
  • the invention provides the use of an acyclic nucleoside purine of formula I:
  • X is OH or -N(R*) 2 wherein R 1 independently is, H;
  • R 1 are joined together to form a saturated or unsaturated C 2 -C 5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom; wherein one of the foregoing R groups can be substituted with halo, - CN or -N 3 ;
  • W is H or NH 2 ;
  • Y independently is, OH, -OR 2 , -OCH(R 3 )OC(O)R 2 , a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate, -NHR 2 , or -N(R 2 ) 2 ;
  • R 2 independently is unsubstituted alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl; alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl wherein H is substituted by halo, carboxy, hydroxyl, cyano, nitro, N- morpholino, or amino; or alkyl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl in which a -CH 2 - moiety has been substituted by NH, S, or O;
  • Z is C 1 -C 6 alkyl, optionally substituted with one or more hydroxy; and R 3 is H or R 2 ; or a prodrug, diphosphate, pharmaceutically acceptable salt, or other phosphorus- substituted derivative thereof, in the manufacture of a medicament for enhancing the processivity of a telomerase.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, or a prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention also provides a method of increasing the number of mitotic cycles of cells continually growing in tissue cultures comprising contacting the cells with a compound of formula I, or a prodrug or a salt thereof.
  • the invention also provides a method of increasing mitotic cell division of non- dividing cells comprising contacting the cells in vitro or in vivo with a compound of formula I, or a prodrug or salt thereof.
  • the invention also provides the use of a compound of formula I, or a prodrug or pharmaceutically acceptable salt thereof to prepare a medicament for increasing the number of mitotic cycles of cells continually growing.
  • the invention also provides the use of a compound of formula I, or a prodrug or pharmaceutically acceptable salt thereof to prepare a medicament for increasing mitotic cell division of non-dividing cells.
  • the invention also provides novel compounds of formula I described herein as well as prodrugs and pharmaceutically acceptable salts thereof.
  • Figure 1 Illustrates the structure of PME, PMEO, PMP, and HPMP purines and pyrimidines.
  • Figure 2 Illustrates the inhibition of HL-60 telomerase by PMEGpp as measured in Example 1.
  • Figure 3 Illustrates the eenhancement of telomerase processivity by 6- Me 2 PMEDAPp ⁇ (A) and (S)-PMP App measured in Example 1.
  • Figure 4 Illustrates inhibition of HL-60 telomerase by guanine derivatives PMEGpp (1), (i ⁇ )-PMPGpp (2), (i?)-HPMPGpp (3), (S)-PMPGpp (4) and (B) illustrates inhibition by adenine and 2,6-diaminopurine derivatives PMED APpp (5), (S)-HPMPApp (6), PMEO-D APypp (7) and (i?)-6-cyprPMPDAPpp (8).
  • the enzyme activity was measured in HL-60 cell extract in the presence of 125 ⁇ mol/L dNTPs.
  • Figure 5 Illustrates telomere length changes in cell line CCRF-CEM following treatment of 10 ⁇ M and 20 ⁇ M (S)-PMPA (see Example T).
  • ANP acyclic nucleoside phosphonate
  • ANPpp ANP diphosphate
  • TRAP telomeric repeat amplification protocol
  • PMEG 9-[2-(phosphonomethoxy)ethyl]guanine
  • ⁇ -PMPG (R)-9-[2- (phosphonomethoxy)propyl] guanine
  • PMEDAP 2,6-diamino-9-[2- (phosphonomethoxy)ethyl]purine
  • S)-PMPG (S)-9-[2-(phosphonomethoxy)- propyl]guanine
  • S)-HPMPA (S)-9-[(3-hydroxy-2-phosphonomethoxy)- propyl]adenine
  • PMEO-DAPy 2,4-diamino-6
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically-active compound.
  • Prodrug moiety refers to a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and
  • Enzymes which are capable of an enzymatic activation mechanism with the phosphonate compounds include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
  • Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
  • a prodrug moiety may include an active metabolite or drug itself.
  • acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Set 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
  • a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
  • Aryl esters of phosphorus groups are reported to enhance oral bioavailability (De Lombaert et al. (1994) J Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-or para-position may accelerate the hydrolysis.
  • Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g., esterases, oxidases, etc., which in turn undergoes cleavage at the benzylic C-O bond to generate the phosphoric acid and the quinone methide intermediate.
  • enzymes e.g., esterases, oxidases, etc.
  • this class of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc. Perkin Trans. /72345; Glazier WO 91/19721.
  • Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier WO 91/19721).
  • Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs.
  • These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesterification or reduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996) J Med. Chem. 39: 4958).
  • Cyclic phosphonate esters have also been described as prodrugs of phosphorus-containing compounds (Erion et al., US Patent No. 6312662).
  • Examples of pharmaceutically acceptable salts include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth (for example, magnesium), ammonium and NX 4 + (wherein X is C 1 -C 4 alkyl).
  • Pharmaceutically acceptable salts of a compound having an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and succinic acids
  • organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids
  • inorganic acids such as
  • salts of a compound having a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NX 4 + (wherein X is independently selected from H or a C 1 -C 4 alkyl group).
  • a suitable cation such as Na + and NX 4 + (wherein X is independently selected from H or a C 1 -C 4 alkyl group).
  • salts of active ingredients will typically be pharmaceutically acceptable, i.e. they will be salts derived from a pharmaceutically acceptable acid or base.
  • “Alkyl” is branched or unbranched hydrocarbon containing normal, secondary, or tertiary carbon atoms.
  • Examples are methyl (Me,-CH3), ethyl (Et,-CH2CH3), 1-propyl (n-Pr, n-pr ⁇ pyl,-CH2CH2CH3), 2-pro ⁇ yl (
  • Aryl means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Alkyl refers to an alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan- 1 -yl, , naphthylmethyl, 2-naphthylethan- 1 -yl, naphthobenzyl, 2-naphthophenylethan- 1 - yl and the like.
  • the arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.
  • Arylalkenyl refers to an alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with an aryl radical.
  • Arylalkynyl refers to an alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Heterocycle or “Heterocyclo” as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc.
  • heterocycle includes a “carbocycle” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).
  • a heteroatom e.g. O, N, or S
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), 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
  • treatment or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms "racemic mixture” and “racemate” refer to an equirnolar mixture of two enantiomeric species, devoid of optical activity.
  • Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group "PG" will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PG groups do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency.
  • Suitable amino acids whose residues can be represented by Y in Formula I include the following: Glycine; Aminopolycarboxylic acids, e.g., aspartic acid, ⁇ -hydroxyaspartic acid, glutamic acid, ⁇ -hydroxyglutamic acid, ⁇ -methylaspartic acid, ⁇ -methylglutamic acid, ⁇ , ⁇ -dimethylaspartic acid, ⁇ -hydroxyglutamic acid, ⁇ , ⁇ - dihydroxy glutamic acid, ⁇ -phenylglutamic acid, ⁇ -methyleneglutamic acid, 3- aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid; Amino acid amides such as glutamine and asparagine; Polyamino- or polybasic- monocarboxylic acids such as arginine, lysine, ⁇ -aminoalanine, ⁇ -aminobutyrine, ornithine, citruline, homoarg
  • Diaminodicarboxylic acids such as ⁇ , ⁇ '-diaminosuccinic acid, ⁇ , ⁇ '-diaminoglutaric acid, ⁇ , ⁇ '-diaminoadipic acid, ⁇ , ⁇ '-diaminopimelic acid, ⁇ , ⁇ '-diamino- ⁇ -hydroxypimelic acid, ⁇ , ⁇ '-diaminosuberic acid, ⁇ , ⁇ '-diaminoazelaic acid, and ⁇ , ⁇ '- diaminosebacic acid; Imino acids such as proline, hydroxyproline, allohydroxyproline, ⁇ -methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2-carboxylic acid; A mono- or di-alkyl (typically Ci-Cs branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, nor
  • Aliphatic ⁇ -amino- ⁇ -hydroxy acids such as serine, ⁇ -hydroxyleucine, ⁇ -hydroxynorleucine, ⁇ -hydroxynorvaline, and ⁇ -amino- ⁇ -hydroxystearic acid; ⁇ - Amino, ⁇ -, ⁇ -, ⁇ - or ⁇ -hydroxy acids such as homoserine, ⁇ -hydroxynorvaline, ⁇ -hydroxynorvaline and ⁇ -hydroxynorleucine residues; canavine and canaline; ⁇ -hydroxyornithine; 2-hexosaminic acids such as D-glucosaminic acid or D- galactosaminic acid; ⁇ -Amino- ⁇ -thiols such as penicillamine, ⁇ -thiolnorvaline or ⁇ -thiolbutyrine; Other sulfur containing amino acid residues including cysteine; homocystine, ⁇ -phenylmethionine, methionine, S-allyl-L-c
  • Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond.
  • Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000 MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
  • Peptidolytic enzymes for cleaving polypeptide conjugates are well known, and in particular include carboxypeptidases.
  • Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C- terminal sequences.
  • Such enzymes and their substrate requirements in general are well known.
  • a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its ⁇ -amino group to the phosphorus or carbon atoms of the compounds herein.
  • This peptide can be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond.
  • Suitable dipeptidyl groups include AA, AR, AN, AD, AC, AE, AQ, AG, AH, AI, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, C
  • Dipeptide or tripeptide species can be selected on the basis of known transport properties and/or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types.
  • Dipeptides and tripeptides lacking an ⁇ -amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., (1992) Pharm Res. 9:969-978).
  • Transport competent peptides can thus be used to enhance bioavailability of the compounds.
  • Dior tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be utilized in the compounds.
  • Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N.
  • di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine.
  • tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A
  • di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids are poor substrates for endopeptidase
  • peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P.
  • Similar considerations can also be applied to the selection of peptides that are either relatively resistant or relatively susceptible to hydrolysis by cytosolic, renal, hepatic, serum or other peptidases.
  • Such poorly cleaved polypeptide amidates are immunogens or are useful for bonding to proteins in order to prepare immunogens.
  • a specific acyclic nucleoside purine is a compound of formula 1 :
  • n 2 or 3;
  • R 1 independently is H
  • R 1 are joined together to form a saturated or unsaturated C 2 -C 5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom; wherein one of the foregoing R 1 groups can be substituted with halo,- CN or-N 3 , but either one or two R 1 groups are not H;
  • Y independently is, OH,-OR 2 ,-OCH(R 3 )OC(0)R 2 , a monophosphate, a diphosphate, an amino acid amidate, a polypeptide amidate,-NHR 2 , or-N(R 2 ) 2 ;
  • R 2 independently is unsubstituted alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl; alkyl, aryl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl wherein H is substituted by halo, carboxy, hydroxyl, cyano, nitro, N- morpholino, or amino; or alkyl, alkenyl, alkynyl, alkaryl, alkynylaryl or alkenylaryl in which a-CH 2 - moiety has been substituted by NH, S 3 or O;
  • R 3 is H or R 2 ; or a prodrug, diphosphate, or other phosphorus-substituted derivative thereof.
  • Another specific acyclic nucleoside purine of formula I is a compound of the following formula:
  • Another specific acyclic nucleoside purine is a compound of the following formula:
  • each R 1 independently is H, C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl, or C 3 -C8cycloalkyl; or optionally both R 1 are joined together to form a saturated or unsaturated C 2 -C 5 heterocycle containing one or two N heteroatoms and optionally an additional O or S heteroatom.
  • R 1 independently is H, methyl, or cyclopropyl.
  • a specific value for each R 1 independently is H.
  • a specific value for each R 1 independently is methyl.
  • R 1 A specific value for one R 1 is H and the other R 1 is cyclopropyl.
  • a specific value for W is H.
  • a specific value for W is NH 2 .
  • a specific value for X is OH.
  • a specific value for Z is -CH 2 -CH 2 -, -CH 2 -CH(CH 3 )-, Or-CH 2 -CH(CH 2 OH)-.
  • n 2
  • n 3
  • a specific value for Z is an S-enantiomer Of-CH 2 -CH(CH 3 )-, or - CH 2 -CH(CH 2 OH)-.
  • a specific compound of formula I is 6-Me 2 PMED APpp or a pharmaceutically acceptable salt or a prodrug thereof.
  • a specific compound of formula I is (S)-PMP App or a pharmaceutically acceptable salt or prodrug thereof.
  • a specific compound of formula I is (S)-PMPA or a pharmaceutically acceptable salt or prodrug thereof.
  • a specific compound of formula I is 6-Me 2 PMED APpp or a prodrug thereof.
  • a specific compound of formula I is (S)-PMP App or a prodrug thereof.
  • a specific compound of formula I is (S)-PMPA or a prodrug thereof.
  • the compounds may have chiral centers, e.g., chiral carbon or phosphorus atoms.
  • the compounds thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds include enriched or resolved optical isomers at any or all asymmetric, chiral atoms.
  • the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
  • racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases
  • the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
  • the compounds can also exist as tautomeric isomers in certain cases. All though only one delocalized resonance structure may be depicted, all such forms are contemplated within the scope of the invention.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • the invention also provides salts of compounds of Formula (I), especially pharmaceutically acceptable non-toxic salts containing, for example, Na + , Li + , K + '
  • Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic acid. Monovalent salts are preferred if a water soluble salt is desired.
  • Metal salts typically are prepared by reacting the metal hydroxide with a compound of this invention. Examples of metal salts which are prepared in this way are salts containing Li + , Na + , and K + . A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.
  • compositions herein comprise compounds in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the salts formed with one or more amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, arginine or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.
  • the compounds of this invention can be formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • the formulations both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • 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 a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in- water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet can 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 molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffmic 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, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non- staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present invention comprise one or more compounds together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as cellulose, microcrystalline cellulose, starch,
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyetliylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution, hi addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as ole
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight: weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment of inflammation as described below.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • Compounds can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provided compositions comprising one or more compounds formulated for sustained or controlled release.
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against existing inflammation, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about .01 to about 5 mg/kg body weight per day. More typically, from about .05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
  • One or more compounds can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
  • Active ingredients of the invention can also be used in combination with other active ingredients. Such combinations are typically selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. It is also possible to combine any compound with one or more other active ingredients in a unitary dosage form for simultaneous or sequential administration to a patient.
  • the combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.
  • the combination therapy may provide "synergy” or a "synergistic effect", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.
  • the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radiolabeled (e.g., C ⁇ or BP) compound, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • an animal such as rat, mouse, guinea pig, monkey, or to man
  • sufficient time for metabolism to occur typically about 30 seconds to 30 hours
  • isolating its conversion products from the urine, blood or other biological samples typically isolating its conversion products from the urine, blood or other biological samples.
  • the metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis.
  • the invention also relates to methods of making the novel compounds herein.
  • the compounds are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive Organic Synthesis.
  • reaction conditions such as temperature, reaction time, solvents, work-up procedures, and the like, will be those common in the art for the particular reaction to be performed.
  • the cited reference material, together with material cited therein, contains detailed descriptions of such conditions.
  • temperatures will be -100°C to 200°C
  • solvents will be aprotic or protic
  • reaction times will be 10 seconds to 10 days.
  • Work-up typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
  • a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents ( " Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302).
  • Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, ⁇ - methyl- ⁇ -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography.
  • addition of chiral carboxylic or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair
  • a diastereomeric pair Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched xanthene.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, ⁇ -methoxy- ⁇ -(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • chiral esters such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, ⁇ -methoxy- ⁇ -(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric diastereomers.
  • Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111).
  • a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. ofChromatogr. 513:375-378).
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • Example 1 The invention will now be illustrated by the following non-limiting Examples.
  • Example 1 The invention will now be illustrated by the following non-limiting Examples.
  • the eluate was evaporated at 30 0 C, dissolved in 0.05 M triethylammonium bicarbonate and purified by chromatography on POROS ® 50HQ anion exchanger (Applied Biosystems, Foster City, CA, USA) in the linear concentration gradient of triethylammonium bicarbonate (0.05 - 0.4 mol/L). Peak corresponding to ANPpp (triethylammonium salt) was collected, evaporated in vacuo at room temperature and then converted to the ANPpp sodium salt on DOWEXTM 50X8 (Na + ) (SERVA Electrophoresis GmbH, Heidelberg, Germany).
  • Human acute promyelocytic leukaemia HL-60 cells (ATCC CCL 240) were cultured in RPMI- 1640 medium supplemented with 10% (v/v) heat-inactivated fetal calf serum, antibiotics (200 ⁇ g/mL of streptomycin and 200 units/mL of penicillin G), 10 mM ⁇ -mercaptoethanol, and vitamin B 12 at 37 0 C in a humidified atmosphere containing 5% CO 2 . After harvesting in log-phase growth, cells were pelleted, washed in PBS, and frozen at-70 0 C.
  • Extracts with telomerase activity were prepared and analyzed as described by Kim NW, et al., Science, 1994, 266, 2011-5, with some modifications. Briefly, the cells were thawed and incubated on ice for 30 min in CHAPS lysis buffer containing 0.5% CHAPS, 10 mM HEPES-NaOH (pH 7.5), 1 mM MgCl 2 , 1 mM EGTA, 5 mM ⁇ -mercaptoethanol, 2 mM Pefabloc-SC, 10% glycerol plus 1 ⁇ L (40 U) of Protector RNase inhibitor. 200 ⁇ L of CHAPS lysis buffer was used to lyse one million cells.
  • telomerase activity was not affect in the HL-60 cells.
  • Cell debris was pelleted for 20 min at 16 000 x g at 4 0 C. The supernatant was removed, aliquoted, frozen on dry ice, and stored at -70 0 C. The protein concentration of the supernatant was determined by the Bradford assay.
  • Telomerase activity was determined using the TRAP assay as described by Kim NW, Wu F., Nucleic Acids Res, 1997, 25, 2595-7 with the modifications described below. In the present study, the sensitivity of the TRAP assay was increased by prolongation of incubation time from 10 to 15 min and increasing the number of PCR cycles from 27 to 33. The dependence of the amount of amplified telomerase product versus number of PCR cycle was linear in the range of 30 to 35 cycles (data not shown). An aliquot of 800 pmol of TS substrate primer
  • TRAP reactions contained Taq polymerase reaction buffer (50 mM KCl, 10 mM Tris-HCl (pH 9.0 at 25 0 C), 1.5 mM MgCl 2 , 0.1% Triton X ® -100), dNTPs (30, 60 and 125 ⁇ mol/L), 18 pmol of end-labeled TS substrate primer, an appropriate amount of studied ANPpp, ANPp and ANP respectively. Reaction was started by cell extract addition (0.15 ⁇ g protein).
  • Each TRAP reaction mixture was placed in a thermocycler block preheated to 30 0 C and incubated at 30 0 C for 15 min and then heated at 95 0 C for 2 min (for one cycle) to stop telomerase reaction.
  • 10 ⁇ L of mixture containing 6 pmol ACX reverse primer (5 t -GCGCGG[CTTACC] 3 CTAACC-3 l ) (SEQ ID NO:2), 3 pmol NT internal control primer, 0.01 amol TSNT internal control and 1.25 U Taq DNA polymerase the reaction was cycled 33 times at 94 0 C for 20 s, 52 0 C for 30 s, 72 0 C for 20 s.
  • telomerase activity was very dependent on telomerase itself.
  • a number of inactivation experiments were performed. Aliquot of cell lysate was incubated with RNase A (50 ⁇ g/mL) at 37 0 C for 30 min. Proteinase K and heat-inactivated cell extracts were prepared by incubating of the cell extract with proteinase K (50 ⁇ g/mL) at 37 0 C for 30 min and heating 10 ⁇ L extract at 75 0 C for 10 min prior to assaying 3 ⁇ L by TRAP assay respective.
  • HL-60 cell extract showed telomerase activity with the characteristic primer extension-binding pattern on the autoradigraphs.
  • telomere products were analyzed on a denaturating 15% polyacrylamide-7 M urea sequencing gel at 1,900 V for 2 h with Tris-borate-EDTA. Dried gels were exposed to a Phosphorlmager storage screen and the amount of reaction products was evaluated using TYPHOONTM 9410 imagerUmageQuantTM software (Molecular Dynamics, Sunnyvale, CA, USA).
  • TYPHOONTM 9410 imagerUmageQuantTM software Molecular Dynamics, Sunnyvale, CA, USA.
  • the TRAP assay signals of the telomerase ladders were normalized to the signal of the corresponding internal standard after background substraction. The signal intensity of the bands from ANPpp, ANPp and ANP- treated samples was expressed as a percentage of the signal intensity detected in the control. Their relative intensities were calculated with the ImageQuant software. All results were expressed as mean ⁇ SD of the four independent determinations.
  • 6-Me 2 PMEDAPp ⁇ P.E. d N.D. N.D. a Values are means ⁇ SD of the four independent determinations; b not determined; c no inhibition; d processivity enhancement.
  • the guanine derivative PMEGpp is the most potent telomerase inhibitor among all acyclic nucleotide analogues studied with the IC 50 12.7 + 0.5 ⁇ mol/L at 125 ⁇ M dNTPs (Table 1, Fig. 2). Its inhibitory potency towards telomerase is comparable to that of ddGTP (IC 50 8.1 ⁇ 0.4 ⁇ mol/L at 125 ⁇ M dNTPs), which is known to be one of the most effective nucleotide analogue based telomerase inhibitors.
  • PMEGpp inhibits telomerase activity by 50% when it is present in the range 0.07 to 0.11 of the dGTP concentration only, depending on the dNTPs concentration. The PMEG monophosphate and PMEG itself do not show at 125 ⁇ M dNTPs any effect on telomerase activity up to the concentration of 300 ⁇ M PMEG and/or PMEGp, respectively.
  • PMEApp with pyrimidine derivatives PMETpp and PMECpp, which inhibit retroviral reverse transcriptases show no significant inhibitory potency towards telomerase.
  • the inhibition is observed with PMEO-D APypp; this open ring ANP is considered to be PMED APpp analogue (Fig.
  • the most potent inhibitor among the PMP type analogues is the guanine derivative (i?)-PMPGpp, which inhibits the enzyme activity with the IC 50 at 5 to 8 times lower concentration compared to that of the natural substrate dGTP.
  • (S)- PMPGpp is dramatically less inhibitory than its (iJ)-enantiomer: its IC 5O exceeds almost 5 times that of (i?)-PMPGpp. This indicates that absolute configuration plays a significant role in inhibition of telomerase and that the enzyme can distinguish between the (R)- and (5)-enantiomers.
  • (S)-PMPApP increases processivity of the enzyme (Fig.
  • telomerase active site has been shown to be related to that of other reverse transcriptases (Nugent CI, Lundblad V., Genes Dev, 1998, 12, 1073-85), (i?)-PMPApp and PMEApp, nucleotide analogues known to be chain-terminating inhibitors of retroviral reverse transcriptases (Holy A., Curr Pharm Des, 2003, 9, 2567-92), do not inhibit telomerase activity.
  • RNA template of one subunit could be used primarily for substrate binding, while the second template would be copied during telomere repeats addition (Kelleher C, et al., Trends Biochem Sci, 2002, 27, 572-9).
  • So-called DNA anchor site which is distinct from the catalytic site, could be affected by both (,S)-PMPApP and/or 6-Me 2 PMED APpp and might thereby facilitate processivity during the synthesis of telomere repeats.
  • Example 2 Using a procedure similar to that described above, (S)-PMPA was found to increase telomere length in CCRF-CEM cells in vivo for about 1 kb when supplied in the growth medium for 5 weeks at concentrations 10 and 20 ⁇ M (see Figure 5). This data is consistent with the fact that (,S)-PMPA diphosphate does not inhibit telomerase activity and was shown to increase the processivity of telomerase in vitro at 125 ⁇ M dNTPs.
  • (S)-PMPA was also shown to enhance the processivity of telomerase in CCRF-CEM T lymphoblastoid cell extracts (human acute lymphoblastic leukemia, ATCC CCL 119), in human cervix carcinoma HeLa S3 (ATCC CCL 2.2) cell extracts, in mouse lymphocytic leukemia L 1210 cells and in T-cell spontaneous leukemia/lymphoma (inbred Sprague-Dawley rat strain - see Otova B, et al., Folia Biol (Praha), 2002, 48, 213-26).

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Abstract

L'invention concerne l'utilisation de phosphonates de nucléoside acyclique et leurs dérivés dans la préparation d'un médicament destiné à améliorer la capacité de traitement d'une télomérase.
EP06722450A 2005-04-25 2006-04-25 Utilisation de composes d'amelioration de la capacite de traitement d'une telomerase Withdrawn EP1879657A2 (fr)

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Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1831225A2 (fr) 2004-11-19 2007-09-12 The Regents of the University of California Pyrazolopyrimidines anti-inflammatoires
DK2004654T3 (da) 2006-04-04 2013-07-22 Univ California Pyrazolopyrimidin derivater til anvendelse som kinase antagonister
FR2908133B1 (fr) * 2006-11-08 2012-12-14 Centre Nat Rech Scient Nouveaux analogues de nucleotides comme molecules precurseurs d'antiviraux
WO2009046448A1 (fr) 2007-10-04 2009-04-09 Intellikine, Inc. Entités chimiques et leurs utilisations thérapeutiques
US8193182B2 (en) 2008-01-04 2012-06-05 Intellikine, Inc. Substituted isoquinolin-1(2H)-ones, and methods of use thereof
KR101897881B1 (ko) 2008-01-04 2018-09-12 인텔리카인, 엘엘씨 특정 화학 물질, 조성물 및 방법
WO2009114874A2 (fr) 2008-03-14 2009-09-17 Intellikine, Inc. Inhibiteurs de kinases (benzothiazole) et procédés d’utilisation associés
EP2252293B1 (fr) 2008-03-14 2018-06-27 Intellikine, LLC Inhibiteurs de kinases, et procédés d utilisation associés
WO2010006072A2 (fr) 2008-07-08 2010-01-14 The Regents Of The University Of California Modulateurs de mtor et leurs utilisations
AU2009268611B2 (en) 2008-07-08 2015-04-09 Intellikine, Llc Kinase inhibitors and methods of use
US8703778B2 (en) 2008-09-26 2014-04-22 Intellikine Llc Heterocyclic kinase inhibitors
DK2358720T3 (en) 2008-10-16 2016-06-06 Univ California Heteroarylkinaseinhibitorer fused-ring
US8476282B2 (en) 2008-11-03 2013-07-02 Intellikine Llc Benzoxazole kinase inhibitors and methods of use
CA2760791C (fr) 2009-05-07 2017-06-20 Intellikine, Inc. Composes heterocycliques et leurs utilisations
WO2011047384A2 (fr) 2009-10-16 2011-04-21 The Regents Of The University Of California Procédés d'inhibition de l'activité ire1
ES2593256T3 (es) 2010-05-21 2016-12-07 Infinity Pharmaceuticals, Inc. Compuestos químicos, composiciones y métodos para las modulaciones de cinasas
US8901133B2 (en) 2010-11-10 2014-12-02 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
EP3581574A1 (fr) 2011-01-10 2019-12-18 Infinity Pharmaceuticals, Inc. Composition pour administration orale à utiliser dans le traitement du cancer, d'une maladie inflammatoire ou d'une maladie auto-immune
WO2012148540A1 (fr) 2011-02-23 2012-11-01 Intellikine, Llc Combinaison d'inhibiteurs des kinases et utilisations associées
JP6027611B2 (ja) 2011-07-19 2016-11-16 インフィニティー ファーマシューティカルズ， インコーポレイテッド 複素環式化合物及びその使用
CN103930422A (zh) 2011-07-19 2014-07-16 无限药品股份有限公司 杂环化合物及其用途
CN103998442B (zh) 2011-08-29 2016-09-14 无限药品股份有限公司 杂环化合物及其用途
WO2013077921A2 (fr) 2011-09-02 2013-05-30 The Regents Of The University Of California Pyrazolo[3,4-d]pyrimidines substituées et utilisations de celles-ci
JP6113185B2 (ja) 2011-12-22 2017-04-12 ジェロン・コーポレーションＧｅｒｏｎ Ｃｏｒｐｏｒａｔｉｏｎ テロメラーゼ基質およびテロメア長作用因子としてのグアニンアナログ
US8940742B2 (en) 2012-04-10 2015-01-27 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
US8828998B2 (en) 2012-06-25 2014-09-09 Infinity Pharmaceuticals, Inc. Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors
CN103665043B (zh) 2012-08-30 2017-11-10 江苏豪森药业集团有限公司 一种替诺福韦前药及其在医药上的应用
CN104995192A (zh) 2012-09-26 2015-10-21 加利福尼亚大学董事会 Ire1的调节
NZ708563A (en) 2012-11-01 2019-02-22 Infinity Pharmaceuticals Inc Treatment of cancers using pi3 kinase isoform modulators
US9481667B2 (en) 2013-03-15 2016-11-01 Infinity Pharmaceuticals, Inc. Salts and solid forms of isoquinolinones and composition comprising and methods of using the same
CN105246902B (zh) * 2013-03-15 2018-05-04 加利福尼亚大学董事会 无环核苷膦酸二酯
NZ713498A (en) 2013-04-08 2017-07-28 Univ Texas Mercaptopurine ribonucleoside analogues for altering telomerase mediated telomere
EP3964507A1 (fr) 2013-10-04 2022-03-09 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations
WO2015051241A1 (fr) 2013-10-04 2015-04-09 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations
JP6701088B2 (ja) 2014-03-19 2020-05-27 インフィニティー ファーマシューティカルズ， インコーポレイテッド Ｐｉ３ｋ−ガンマ媒介障害の治療で使用するための複素環式化合物
WO2015160975A2 (fr) 2014-04-16 2015-10-22 Infinity Pharmaceuticals, Inc. Polythérapies
EA036391B1 (ru) 2014-09-15 2020-11-05 Дзе Риджентс Оф Дзе Юниверсити Оф Калифорния Нуклеотидные аналоги
WO2016054491A1 (fr) 2014-10-03 2016-04-07 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations
EP3350183B1 (fr) 2015-09-14 2025-04-02 Twelve Therapeutics, Inc. Formes solides de dérivés d'isoquinolinone, leur procédé de fabrication, compositions les comprenant et méthodes d'utilisation de celles-ci
WO2017048956A1 (fr) 2015-09-15 2017-03-23 The Regents Of The University Of California Analogues nucléotidiques
WO2017161116A1 (fr) 2016-03-17 2017-09-21 Infinity Pharmaceuticals, Inc. Isotopologues de composés isoquinolinone et quinazolinone et leurs utilisations comme inhibiteurs de la kinase pi3k
WO2017214269A1 (fr) 2016-06-08 2017-12-14 Infinity Pharmaceuticals, Inc. Composés hétérocycliques et leurs utilisations
BR112018077021A2 (pt) 2016-06-24 2019-04-02 Infinity Pharmaceuticals, Inc. terapias de combinação
TW201829412A (zh) 2016-12-22 2018-08-16 美商默沙東藥廠 抗病毒之替諾福韋（tenofovir）之脂系酯前藥
CN108948084B (zh) * 2017-05-19 2020-10-20 浙江司太立制药股份有限公司 替诺福韦双-l-氨基酸酯及其制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6057305A (en) * 1992-08-05 2000-05-02 Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic Antiretroviral enantiomeric nucleotide analogs
EP0618214A1 (fr) * 1993-04-01 1994-10-05 Merrell Dow Pharmaceuticals Inc. Dérivés phosphonates insaturés de purines et de pyrimidines
AU5466500A (en) * 1999-06-04 2000-12-28 Jessie L.S. Au Methods and compositions for modulating drug activity through telomere damage
CA2747954C (fr) * 1999-12-03 2014-02-25 The Regents Of The University Of California Composes de phosphonate
WO2002069949A2 (fr) * 2001-03-06 2002-09-12 Prendergast Patrick T Polytherapie pour la reduction de la toxicite d'agents chimiotherapeutiques
EP1418241A1 (fr) * 2002-11-08 2004-05-12 PrimaGen Holding B.V. Procédé de quantifier le rapport de deux séquences d'acides nucléiques
EP1732569B1 (fr) * 2004-01-21 2009-10-14 Gilead Sciences, Inc. Utilisation d'adefovir ou de tenofovir pour inhiber les virus semblables a mmtv impliques dans le cancer du sein et la cirrhose biliaire primaire

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006114064A2 *

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