WO1998017647A1 - Composes de piperidine - Google Patents

Composes de piperidine Download PDF

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Publication number
WO1998017647A1
WO1998017647A1 PCT/US1997/018193 US9718193W WO9817647A1 WO 1998017647 A1 WO1998017647 A1 WO 1998017647A1 US 9718193 W US9718193 W US 9718193W WO 9817647 A1 WO9817647 A1 WO 9817647A1
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WIPO (PCT)
Prior art keywords
compound
independently
group
carbon atoms
substituted
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PCT/US1997/018193
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English (en)
Inventor
Choung U. Kim
Matthew A. Williams
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Gilead Sciences, Inc.
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Filing date
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Application filed by Gilead Sciences, Inc. filed Critical Gilead Sciences, Inc.
Priority to AU49795/97A priority Critical patent/AU743333B2/en
Priority to EP97912680A priority patent/EP0938475A1/fr
Priority to CA002268756A priority patent/CA2268756A1/fr
Priority to JP10519416A priority patent/JP2001502690A/ja
Publication of WO1998017647A1 publication Critical patent/WO1998017647A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms

Definitions

  • Neuraminidase (also known as sialidase, acylneuraminyl hydrolase, and EC 3.2.1.18) is an enzyme common among animals and a number of microorganisms. It is a glycohydrolase that cleaves terminal alpha- ketosidically linked sialic acids from glycoproteins, glycolipids and oligiosaccharides. Many of the microorganisms containing neuraminidase are pathogenic to man and other animals including fowl, horses, swine and seals. Organisms having N-acetylneuraminidases include bacteria such as Vibrio cholerae, C. perfringens and Streptococcus sp. and viruses such as influenza virus, and parainfluenza virus.
  • Influenza neuraminidase has been implicated in the pathogenicity of influenza viruses. It is thought to help the elution of newly synthesized virons from infected cells and assist in the movement of the virus (through its hydrolase activity) through the mucus of the respiratory tract.
  • a principal object of the invention is inhibition of bacteria and viruses, in particular influenza viruses.
  • an object is inhibition of glycolytic enzymes such as neuraminidase, in particular the selective inhibition of viral or bacterial neuraminidases.
  • An additional object of the invention is to provide neuraminidase inhibitors that have a retarded rate of urinary excretion, that enter into nasal or pulmonary secretions from the systemic circulation, that have sufficient oral bioavailability to be therapeutically effective, that possess elevated potency, that exhibit clinically acceptable toxicity profiles and have other desirable pharmacologic properties.
  • Another object is to provide improved and less costly methods for synthesis of neuraminidase inhibitors.
  • a still further object is to provide improved methods for administration of known and novel neuraminidase inhibitors.
  • An additional object is to provide compositions useful in preparing polymers, surfactants or immunogens and for use in other industrial processes and articles.
  • El is -(CRiRi)mlWi;
  • Gi is N3, -CN, -OH, -OR ⁇ a, -NO2, or -(CRi Ri) m lW2;
  • T is -NR1W3, or a heterocycle;
  • Jla are independently Ri, Br, Cl, F, I, CN, NO2 or N3;
  • J2 and J2a are independently H or Ri;
  • Rl is independently H or alkyl of 1 to 12 carbon atoms;
  • R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR ⁇ a, -ORi, -N(R ⁇ ) 2 ,
  • R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
  • R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
  • R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
  • R6a is independently H or an ether- or ester-forming group;
  • R ⁇ b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound
  • R ⁇ c is independently H or the residue of an amino-containing compound
  • Wi is a group comprising an acidic hydrogen, a protected acidic group, or an R6 C amide of the group comprising an acidic hydrogen
  • W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6 amide of the basic heteroatom;
  • W3 is W4 or W5;
  • W4 is R5 or -C(0)R5, -C(0)Ws, -SO2R5, or -SO2W5;
  • W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
  • W 6 is -R5, -W 5 , -R5aW 5 , -C(0)OR 6a , -C(0)R6 -C(0)N(R 6 b)2, -C(NR 6 b)(N(R6b)2), -C(NR 6 b)(N(H)(R 6 b)), -C(N(H)(N(R 6 b)2), -C(S)N(R 6 b)2, or -C(0)R2; and each mi is independently an integer from 0 to 2; provided, however, that compounds are excluded wherein J ⁇ a is H, each J2 is H, J 2a is H and Ti is -N(H)(Ac) and:
  • Ei is -C0 2 H or -C0 2 CH 3 , Gi is -OBoc, and W6 is Boc;
  • Ei is -C0 2 H or -C0 2 CH 3 , Gi is -OH, and W6 is H;
  • Ei is -C0 2 H, -C0 2 CH 3 or -C ⁇ 2Bn
  • Gi is -OH, and W6 is Boc
  • Ei is -CONH 2
  • Gi is -OH
  • W6 is Boc or H
  • Ei is -C0 H or -C0 2 CH 3 , Gi is OH, and W6 is Bn; or
  • Ei is -C0 2 H or -C0 2 CH 3 ,
  • W6 is -CH 2 CH(OH)CH 2 (OH);
  • Zi is W ⁇ and the other Zi is Gi;
  • Ei is -(CRiRi)miWi; Gi is -OH, -OR 6a , or -(CRiRl) m lW2;
  • Ti is -NR1W3 or a heterocycle;
  • Ji and J ⁇ a are independently Ri, Br, Cl, F, I, CN, NO2 or N3;
  • J2 is H or Ri
  • Rl is independently H or alkyl of 1 to 12 carbon atoms;
  • R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR6 a , -ORi, -N(R ⁇ ) 2 ,
  • R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
  • R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
  • R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to
  • alkynylene 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
  • R6 a is independently H or an ether- or ester-forming group
  • R 6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound
  • R ⁇ c is independently H or the residue of an amino-containing compound
  • Wi is a group comprising an acidic hydrogen, a protected acidic group, or an R6c amide of the group comprising an acidic hydrogen;
  • W2 is H or a group comprising a basic heteroatom or a protected basic heteroatom, or an R ⁇ b amide of the basic heteroatom;
  • W3 is W4 or W5;
  • W4 is R5 or -C(0)R5, -C(0)Ws, -SO2R5, or -SO2W5;
  • W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
  • W 6 is -R5, -W5, -R5aW 5 , -C(0)OR 6a , -C(0)R 6c , -C(0)N(R 6 b)2,
  • each mi is independently an integer from 0 to 2; and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
  • a compound or composition of the invention that further comprises a pharmaceutically- acceptable carrier.
  • the activity of neuraminidase is inhibited by a method comprising the step of treating a sample suspected of containing neuraminidase with a compound or composition of the invention.
  • Another embodiment of the invention provides a method for inhibiting the activity of neuraminidase comprising the step of contacting a sample suspected of containing neuraminidase with the composition embodiments of the invention.
  • compositions of the Invention exclude compounds heretofore known. However, as will be further apparent below, in other embodiments, it is within the invention to use for antiviral purposes known compounds heretofore only produced and used as intermediates in the preparation of antiviral compounds. With respect to the United States, the compounds or compositions herein exclude compounds that are anticipated under 35 USC ⁇ 102 or obvious under 35 USC ⁇ 103. In particular, the claims herein shall be construed as excluding the compounds which are anticipated by or not possessing novelty over WO 96/26933 (September 6, 1996); Nishimura, Y. et al., "J. Am. Chem. Soc.” 110:7249-7250 (1988); and "Bull. Chem. Soc.
  • the compounds of this invention are those in which W6 is not -CH2OH, -CH2OAC, or -CH2 ⁇ CH2Ph.
  • the compounds of this invention are those in which Ei is not -CH2OH, -CH2OTMS, or -CHO.
  • the compounds of this invention are those in which W6 is not polyhydroxyalkane, especially -CH(OH)CH(OH)CH2 ⁇ H.
  • W6 is a branched chain group R5 as described below or a carbocycle which is substituted with at least one group R5. Whenever a compound described herein is substituted with more than one of the same designated group, e.g., "Ri" or “R6a” / then it will be understood that the groups may be the same or different, i.e., each group is independently selected.
  • Heterocycle as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A., “Principles of Modern Heterocyclic Chemistry” (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and "J. Am. Chem. Soc", 82:5566 (1960).
  • heterocycles include by way of example and not limitation pyridyl, thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2- pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5- pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6- pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4- thiazolyl, or 5- thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2- pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3- imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ - carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Alkyl as used herein, unless stated to the contrary, is C1-C12 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH3CH
  • compositions of the invention comprise compounds of either formula:
  • Jl and Jla are independently Rl, Br, Cl, F, I, CN, N ⁇ 2 or N3, typically Rl or F, more typically H or F, more typically yet H.
  • J2 and J2a are independently H or Rl, typically H.
  • One Zi of Formula X is W ⁇ and the other is Gi.
  • Z 2 of Formula X is H or W ⁇ , typically H.
  • E ⁇ is -(CRiRi)miWi.
  • Rl is H or alkyl of 1 to 12 carbon atoms, usually H or an alkyl of 1 to 4 or 5 to 10 carbon atoms, still more typically, H or an alkyl of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, more typically yet, H or an alkyl of 1 to 3 carbon atoms selected from methyl, ethyl, n-propyl, and i-propyl.
  • Ri is H.
  • ml is an integer of 0 to 2, typically 0 or 1, most typically 0.
  • m2 is an integer of 0 to 1.
  • m3 is an integer of 1 to 3.
  • Wi is a group comprising an acidic hydrogen, a protected acidic group or an R6c amide of the group comprising an acidic hydrogen which, within the context of the invention, means a group having a hydrogen atom that can be removed by a base yielding an anion or its corresponding salt or solvate.
  • the general principles of acidity and basicity of organic materials are well understood and are to be understood as defining Wi. They will not be detailed here. However, a description appears in Streitwieser, A. and Heathcock, C. H. "Introduction to Organic Chemistry, Second Edition” (Macmillan, New York, 1981), pages 60-64.
  • Exemplary Wl are -CO2H, -C ⁇ 2R6a, -OSO3H, -SO3H, -SO2H, -OPO3H2, -P0 3 (R 6a )2, -PO3H2, -P0 3 (H)(R 6a ), and -OP0 3 (R6a)2- El typically is Wl, and Wl typically is -CO2H, -C ⁇ 2R6a, -CO2R4 or CO2R1, and most typically is CO2R14 wherein R14 is normal or terminally secondary Cl-C alkyl.
  • Wi may also be a protected acidic group, which, within the context of the invention means an acidic group as described above that has been protected by one of the groups commonly used in the art for such groups and are described below under R ⁇ a- More typically, protected Wi is -CO2R1,-
  • Exemplary Ei groups are listed in Tables 3a through 3b.
  • Gi of Formula X is -OH, OR6a, or -(CRiRi) m lW2
  • Gl of Formula IX is -N3, -CN, -OH, OR6a, - O2 or -(CRlRl) m lW2, wherein Ri and ml are defined above.
  • Gi of Formula (IX) is -(CR ⁇ R ⁇ ) m ⁇ W2 and Gl of Formula (X) is H.
  • W2 of Formula (X) is H or a group comprising a basic heteroatom, a protected basic heteroatom or an R b amide of the basic heteroatom.
  • W2 of Formula (IX) is a group comprising a basic heteroatom, a protected basic heteroatom or an R ⁇ b amide of the basic heteroatom.
  • W2 generally comprises a basic heteroatom, which, within the context of the invention means an atom other than carbon which is capable of protonation, typically by an acidic hydrogen having an acidity in the range described above for Wl.
  • the basic principles of basicity are described in Streitwieser and Heathcock (op. cit.) and provide meaning for the term basic heteroatom as will be understood by those ordinarily skilled in the art.
  • Basic heteroatoms include the heteroatoms common in organic compounds which have an un-shared, non-bonding, n-type, or the like, electron pair.
  • typical basic heteroatoms include the oxygen, nitrogen, and sulfur atoms of groups such as alcohols, amines, amidines, guanidines, sulfides, and the like, frequently, amines, amidines and guanidines.
  • W2 is amino or an amino alkyl (generally lower alkyl Cl to C ) group such as aminomethyl, aminoethyl or aminopropyl; an amidinyl, or an amidinoalkyl group such as amidinomethyl, amidinoethyl, or amidinopropyl; or guanidinyl, or a guanidinoalkyl group such as guanidinomethyl, guanidinoethyl, or guanidinopropyl (in each instance wherein the alkyl group serves to bridge the basic substituent to the carbocyclic ring).
  • an amino alkyl generally lower alkyl Cl to C
  • an amidinyl, or an amidinoalkyl group such as amidinomethyl, amidinoethyl, or amidinopropyl
  • guanidinyl, or a guanidinoalkyl group such as guanidinomethyl, guanidinoethyl, or guanidinopropy
  • W2 is amino, amidino, guanidino, heterocycle, heterocycle substituted with 1 or 2 amino or guanidino groups (usually 1), or an alkyl of 2 to 3 carbon atoms substituted with amino or guanidino, or such alkyl substituted with an amino and a second group selected from the group consisting of hydroxy and amino.
  • Such groups are described in detail in Greene (op. cit.) as set forth below.
  • Such groups include by way of example and not limitation, amides, carbamates, amino acetals, imines, enamines, N-alkyl or N-aryl phosphinyls, N-alkyl or N-aryl sulfenyls or sulfonyls, N-alkyl or N-aryl silyls, thioethers, thioesters, disulfides, sulfenyls, and the like.
  • the protecting group R6b will be cleavable under physiological conditions, typically it will be cleavable in vivo where, for example, the basic heteroatom forms an amide with an organic acid or an amino acid such as a naturally occurring amino acid or a polypeptide as described below for the R6a group.
  • Gl of Formula (X) is H and Gl of Formula (IX) is selected from the group consisting of:
  • Ti is -NR1W3, -R3, -R5 or heterocycle.
  • Ti is -NR1W3 or heterocycle.
  • Ti is selected from the group consisting of:
  • W3 is W4 or W5, wherein W4 is R5 or -C(0)Rs, -C(0)W5, -SO2R5, or -SO2W5. Typically, W3 is -C(0)Rs or W5.
  • R2 is independently R3 or R4 as defined below, with the proviso that each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR ⁇ a, -ORi, -N(R ⁇ ) 2 , -N(R ⁇ )(R ⁇ b), -N(R ⁇ b)2, -SRi, -SR 6a , -S(0)R ⁇ , -S(0) 2 R ⁇ , -S(0)OR ⁇ , -S(0)OR6 a , -S(0) 2 OR ⁇ , -S(0) 2 OR 6a , -C(0)OR ⁇ , -C(0)R6 C , -C(0)OR ⁇ a , -OC(0)R ⁇ ,
  • R4 is alkyl of 1 to 12 carbon atoms, and alkynyl or alkenyl of 2 to 12 carbon atoms.
  • the alkyl R4's are typically of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms and the alkenyl and alkynyl R4's are typically of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms.
  • R4 ordinarily is alkyl (as defined above).
  • R4 alkenyl groups are of 2, 3 or 4 carbon atoms.
  • R4 is alkynyl it is typically ethynyl (-C ⁇ CH), 1-prop-l- ynyl (-C ⁇ CCH3), l-prop-2-ynyl (-CH2C ⁇ CH), 1-but-l-ynyl (-C ⁇ CCH2CH3), 1-but- 2-ynyl (-CH2C ⁇ CCH3), l-but-3-ynyl (-CH2CH2C ⁇ CH), 2-but-3-ynyl (CH(CH3)C ⁇ CH), 1-pent-l-ynyl (-C ⁇ CCH2CH2CH3), l-pent-2-ynyl (-CH2C ⁇ CCH2CH3), l-pent-3-ynyl (-CH2CH2C ⁇ CCH3) or l-pent-4-ynyl (-CH2CH2CH2C ⁇ CH). More typically, R4 alkyn
  • R5 is R4, as defined above, or R4 substituted with 0 to 3 R3 groups.
  • R5 is an alkyl of 1 to 4 carbon atoms substituted with 0 to 3 fluorine atoms.
  • R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups.
  • R5 a 's are of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms when alkylene and of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms when alkenylene or alkynylene.
  • Each of the typical R4 groups is a typical R5 a group with the proviso that one of the hydrogen atoms of the described R4 group is removed to form the open valence to a carbon atom through which the second bond to the R5a is attached.
  • Rl4 is normal or terminally secondary Cl-C6 alkyl.
  • W5 is a carbocycle or heterocycle, with the proviso that each W5 is independently substituted with 0 to 3 R2 groups.
  • W5 carbocycles and Ti and W5 heterocycles are stable chemical structures. Such structures are isolatable in measurable yield, with measurable purity, from reaction mixtures at temperatures from -78°C to 200°C.
  • Each W5 is independently substituted with 0 to 3 R2 groups.
  • Ti and W5 are a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. More typically, Ti or W5 has 3 to 10 ring atoms, still more typically, 3 to 7 ring atoms, and ordinarily 3 to 6 ring atoms.
  • the Ti and W5 rings are saturated when containing 3 ring atoms, saturated or monounsaturated when containing 4 ring atoms, saturated, or mono- or diunsaturated when containing 5 ring atoms, and saturated, mono- or diunsaturated, or aromatic when containing 6 ring atoms.
  • Unsaturation of the W$ rings include internal and external unsaturation wherein the external incorporates a ring atom.
  • W5 When W5 is carbocyclic, it is typically a 3 to 7 carbon monocycle or a 7 to 12 carbon atom bicycle. More typically, W5 monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. W5 bicyclic carbocycles typically have 7 to 12 ring atoms arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, still more typically, 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l- enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, 1- cyclohex-2-enyl, l-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
  • a Ti or W5 heterocycle is typically a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S). More typically, Ti and W5 heterocyclic monocycles have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S), still more typically, 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system, still more typically, 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
  • Ti and W5 heterocycles are selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, or pyrrolyl.
  • the heterocycle of Ti and W5 is bonded through a carbon atom or nitrogen atom thereof. Still more typically Ti heterocycles are bonded by a stable covalent bond through a nitrogen atom thereof to the cyclohexene ring of the compositions of the invention and W5 heterocycles are bonded by a stable covalent bond through a carbon or nitrogen atom thereof to the cyclohexene ring of the compositions of the invention. Stable covalent bonds are chemically stable structures as described above.
  • W5 optionally is selected from the group consisting of:
  • W 6 is -R5, -W5, -R5aW5, -C(0)OR6a, -C(0)R6c, -C(0)N(R6b)2, -C(NR 6 b)(N(R6b)2), -C(NR 6 b)(N(H)(R 6 b)), -C(N(H)(N(R 6 b)2), -C(S)N(R 6 b)2, or -C(0)R2, typically W ⁇ is -R5, -W5, or -R5aW5; in some embodiments, W6 is Rl, -C(0)-Rl, -CHR1W7, -CH(Ri) a W7, -CH(W7)2, (where, W7 is monovalent a is 0 or 1, but is 0 when W7 is divalent) or -C(0)W7.
  • W6 is -CHR1W7 or -C(0)W7, or W6 is -(CH2)mlCH((CH 2 )m3R3)2; -(CH2)mlC((CH2)m3R3)3; -(CH2)mlCH((CH2)m3R5aW5)2; -(CH2)mlCH((CH 2 )m3R3)((CH2)m3R5aW5);
  • W7 is R3 or R 5 , but typically is alkyl of 1 to 12 carbons substituted with 0 to 3 R3 groups, the latter typically selected from the group consisting of -NRl(R ⁇ b)/ -N(R6b)2/ -OR ⁇ a, or SR ⁇ a- More typically, W7 is -ORi or an alkyl of 3 to 12 carbon atoms substituted with ORi. In general, W6 is Rl-, -CHR1W7, H
  • each Rl and R ⁇ b are typically H, and W2 is typically selected from the group consisting of:
  • W6 is one of:
  • R7 is H, -CH3, -CH2CH3, -CH2CH2CH3, -OCH3, -OAc (-0-C(0)CH3), -OH, -NH2, or -SH, typically H, -CH3 or -CH2CH3.
  • Another embodiment of the invention is directed toward compounds of formula (XX) or (XXa):
  • a 3 is N, N(O) or N(S);
  • Z 3 is H, W 6 , Gi or R 3a; Ei is -(CR ⁇ R ⁇ ) m iWi;
  • Gl is N3, -CN, -OH, -OR6a, -NO2 or -(CRiRi) m lW2; Ti is -NR1W3 or a heterocycle;
  • Jl is Rl, Br, Cl, F, I, CN, NO2 or N3; J2 is H or Ri;
  • J 3 is Ji if Xi is a bond; and J 3 is J 2 if Xi is -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW 6 )-, -N(NH 2 )-, -N(N(H)(W 6 ))-, -N(N(W 6 )2h -N(H)N(W 6 )-, -S-, -SO-, or -SO2-;
  • Rl is independently H or alkyl of 1 to 12 carbon atoms;
  • R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3 , -N0 2 , -OR 6a , -ORi, -N(R ⁇ ) 2 , -N(R ⁇ )(R6b), -N(R6b)2, -SRi, -SR 6a , -S(0)R ⁇ , -S(0) 2 R ⁇ , -S(0)OR ⁇ , -S(0)OR6 a , -S(0) 2 OR ⁇ , -S(0) 2 OR 6a , -C(0)OR ⁇ , -C(0)R 6c , -C(0)OR 6a , -OC(0)R ⁇ , -N(R ⁇ )(C(0)R ⁇ ), -N(R6b)(C(0)R ⁇ ), -N(R ⁇ )(C(0)OR ⁇ ), -N(R 6b )(C(0)OR ⁇ ), -C(0)OR ⁇ ), -C(0)N(R ⁇ ) 2 , -C(0)N(R 6b
  • R3a is independently -CN, N 3 , -NO, -N0 , -OR 6a , -ORi, -N(R ⁇ ) / -N(R ⁇ )(R 6 ), -N(R 6b ) 2 , -SRi, -SR6 a , -S(0)R ⁇ , -S(0) 2 R ⁇ , -S(0)OR ⁇ , -S(0)OR6 a , -S(0) 2 OR ⁇ , -S(0) 2 OR 6a , -C(0)OR ⁇ , -C(0)R 6c , -C(0)OR 6a , -OC(0)R ⁇ , -N(R ⁇ )(C(0)R ⁇ ), -N(R 6b )(C(0)R ⁇ ), -N(R ⁇ )(C(0)OR ⁇ ), -N(R 6b )(C(0)OR ⁇ ), -C(0)N(R ⁇ ) 2 , -C(0)N(R6b)(R ⁇ ), -C(0)OR ⁇ ), -
  • R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
  • R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups
  • R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
  • R6a is independently H or an ether- or ester-forming group
  • R 6b s independently H, a protecting group for amino or the residue of a carboxyl-containing compound
  • R 6C is independently H or the residue of an amino-containing compound
  • Wl is a group comprising an acidic hydrogen, a protected acidic group, or an R6c amide of the group comprising an acidic hydrogen
  • W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R amide of the basic heteroatom;
  • W3 is W4 or W5;
  • W4 is R5 or -C(0)R5, -C(0)W5, -SO2R5, or -SO2W5;
  • W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
  • W 6 is -R 5 , -W5, -R5aW 5 , -C(0)OR 6a , -C(0)R 6c , -C(0)N(R 6 b)2, -C(NR 6 b)(N(R 6 b)2), -C(NR6b)(N(H)(R 6 b)), -C(N(H)(N(R 6 b)2), -C(S)N(R 6 b)2, or -C(0)R 2 ;
  • Xi is a bond, -O-, -N(H)-, -N(W6)-, -N(OH)-, -N(OW6)-, -N(NH2)-,
  • each mi is independently an integer from 0 to 2; provided, however, that compounds of formula (XX) are excluded wherein A 3 is N, each Ji, J 2 , J 2a and J 3 is H and Ti is -N(H)(Ac) and:
  • Ei is -C0 2 H or -C0 2 CH 3
  • G 2 is -OBoc
  • Ei is -C0 2 H or -C0 2 CH 3 , G 2 is -OH, and Z 3 is H;
  • Ei is -C0 2 H, -C0 2 CH 3 or -C ⁇ 2Bn G 2 is -OH, and Z 3 is Boc;
  • Ei is -CONH 2 , G 2 is -OH, and Z 3 is Boc or H;
  • Ei is -C0 2 H or -C0 2 CH 3 ,
  • G 2 is OH, and Z 3 is Bn; or
  • Ei is -C0 2 H or -C0 2 CH 3
  • G 2 is -OH
  • Z 3 is -CH 2 CH(OH)CH 2 (OH);
  • Ei is -(CRiRi) m iWi;
  • Gi is N3, -CN, -OH, -OR 6a , -NO2, or -(CRiRl) m lW 2 ;
  • Ti is -NR1W3, a heterocycle, or is taken together with Gl to form a group having the structure
  • Ui is -X1W6; Jl and J ⁇ a are independently Rl, Br, Cl, F, I, CN, NO2 or N3;
  • J2 and J2a are independently H or Ri;
  • Rl is independently H or alkyl of 1 to 12 carbon atoms;
  • R2 is independently R3 or R4 wherein each R4 is independently substituted with 0 to 3 R3 groups;
  • R3 is independently F, Cl, Br, I, -CN, N 3/ -N0 , -OR 6a , -ORi, -N(R ⁇ ) 2 ,
  • R4 is independently alkyl of 1 to 12 carbon atoms, alkenyl of 2 to 12 carbon atoms, or alkynyl of 2 to 12 carbon atoms;
  • R5 is independently R4 wherein each R4 is substituted with 0 to 3 R3 groups;
  • R5a is independently alkylene of 1 to 12 carbon atoms, alkenylene of 2 to 12 carbon atoms, or alkynylene of 2-12 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R3 groups;
  • R a is independently H or an ether- or ester-forming group;
  • R6b is independently H, a protecting group for amino or the residue of a carboxyl-containing compound
  • R6c is independently H or the residue of an amino-containing compound
  • Wl is a group comprising an acidic hydrogen, a protected acidic group, or an R6c amide of the group comprising an acidic hydrogen
  • W2 is a group comprising a basic heteroatom or a protected basic heteroatom, or an R6b amide of the basic heteroatom;
  • W3 is W4 or W5;
  • W4 is R5 or -C(0)R5, -C(0)W5, -SO2R5, or -SO2W5;
  • W5 is carbocycle or heterocycle wherein W5 is independently substituted with 0 to 3 R2 groups;
  • W 6 is -R5, -W5, -R5aW 5 , -C(0)OR 6a , -C(0)R 6c , -C(0)N(R 6 b)2, -C(NR6b)(N(R6b)2), -C(NR 6 b)(N(H)(R 6 b)), -C(N(H)(N(R 6 b)2), -C(S)N(R 6 b)2, or -C(0)R 2 ;
  • Xl is a bond, -O-, -N(H)-, -N(W ⁇ )-, -S-, -SO-, or -SO2-; and each mi is independently an integer from 0 to 2; and the salts, solvates, resolved enantiomers and purified diastereomers thereof.
  • a 3 is N or N(O), more typically A 3 is N.
  • one of Z 3 and G 2 is Gi or R 3a and the other is W 6 or -XiW ⁇ - More typically, Z 3 is W or R 3a and G 2 is Gi or -XiW ⁇ - More typically yet, Z 3 is W and G 2 is Gi; or Z 3 is R 3a and G 2 is -X ⁇ W 6 - J 3 is Ji if Xi is a bond; and J 3 is J 2 if Xi is -O-, -N(H)-, -N(W6)-, -N(OH)-,
  • An embodiment of the invention comprises a compound of the formula (XXI) or (XXIa):
  • An embodiment of the invention comprises a compound of the formula (XXII) or (XXIIa):
  • An embodiment of the invention comprises a compound of the formula (XXIII) or (XXIIIa):
  • An embodiment of the invention comprises a compound of the formula (XXIV) or (XXIVa):
  • Z 2 is H or W ⁇ .
  • Z 2 is H.
  • An embodiment of the invention comprises a compound of the formula (XXV) or (XX Va):
  • An embodiment of the invention comprises a compound of the formula (XXVI) or (XXVIa):
  • An embodiment of the invention comprises a compound of the formula (XXVII) or (XXVIIa): (XXVIIa)
  • An embodiment of the invention comprises a compound of the formula (XXVIII) or (XXVIIIa):
  • An embodiment of the invention comprises a compound of the formula (XXIX) or (XXIXa):
  • An embodiment of the invention comprises a compound of the formula (XXX) or (XXXa):
  • Groups R 6a and R 6b are not critical functionalities and may vary widely. When not H, their function is to serve as intermediates for the parental drug substance. This does not mean that they are biologically inactive. On the contrary, a principal function of these groups is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs are absorbed more effectively than the parental drug they in fact often possess greater potency in vivo than the parental drug. When not hydrogen, R a and R6b are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting pro-functionality products, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
  • chemical intermediates it is not particularly important that the resulting pro-functionality products, e.g. alcohols, be physiologically acceptable, although in general it
  • R 6a is H or an ether- or ester-forming group.
  • "Ether-forming group” means a group which is capable of forming a stable, covalent bond between the parental molecule and a group having the formula:
  • V a is a tetravalent atom typically selected from C and Si
  • Vb is a trivalent atom typically selected from B, Al, N, and P, more typically N and P
  • Vc is a divalent atom typically selected from O, S, and Se, more typically S
  • Vl is a group bonded to V a , Vb or V by a stable, single covalent bond, typically Vl is W6 groups, more typically Vl is H, R2, W5, or -R5aW5, still more typically H or R2
  • V3 is a group bonded to V a by a stable, triple covalent bond, typically V3 is
  • Ester-forming group means a group which is capable of forming a stable, covalent bond between the parental molecule and a group having the formula:
  • V a , Vb, and Vl are as described above;
  • Vd is a pentavalent atom typically selected from P and N;
  • Ve is a hexavalent atom typically S;
  • Protecting groups for -OH functions are embodiments of "ether- or ester-forming groups". Particularly of interest are ether- or ester-forming groups that are capable of functioning as protecting groups in the synthetic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed under R6 C below. R6 is capable of protecting hydroxyl or thio groups such that hydrolysis from the parental molecule yields hydroxyl or thio.
  • R6 a In its ester-forming role, R6 a typically is bound to any acidic group such as, by way of example and not limitation, a -CO2H or -C(S)OH group, thereby resulting in -C ⁇ 2R ⁇ a- R ⁇ a for example is deduced from the enumerated ester groups of WO 95/07920.
  • R6 a examples include
  • C 3 -Ci2 heterocycle (described above) or C6-C ⁇ 2 aryl.
  • aromatic groups optionally are polycyclic or monocyclic. Examples include phenyl, spiryl, 2- and 3-pyrrolyl, 2- and 3-thienyl, 2- and 4-imidazolyl, 2-, 4- and 5-oxazolyl, 3- and 4-isoxazolyl, 2-, 4- and 5-thiazolyl, 3-, 4- and 5- isothiazolyl, 3- and 4-pyrazolyl, 1-, 2-, 3- and 4-pyridinyl, and 1-, 2-, 4- and 5- pyrimidinyl,
  • Such groups include 2-, 3- and 4-alkoxyphenyl (C ⁇ -C ⁇ 2 alkyl), 2-, 3- and 4-methoxyphenyl, 2-, 3- and 4-ethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethoxyphenyl, 2- and 3-carboethoxy-4-hydroxyphenyl, 2- and 3-ethoxy-4- hydroxyphenyl, 2- and 3-ethoxy-5-hydroxyphenyl, 2- and 3-ethoxy-6- hydroxyphenyl, 2-, 3- and 4-O-acetylphenyl, 2-, 3- and 4- dimethylaminophenyl, 2-, 3- and 4-methylmercaptophenyl, 2-, 3- and 4- halophenyl (including 2-, 3- and 4-fluorophenyl and 2-, 3- and 4- chlorophenyl), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-,
  • triglycerides such as ⁇ -D- ⁇ -diglycerides (wherein the fatty acids composing glyceride lipids generally are naturally occurring saturated or unsaturated C6-26 C6-18 or C ⁇ -io fatty acids such as linoleic, lauric, myristic, palmitic, stearic, oleic, palmitoleic, linolenic and the like fatty acids) linked to acyl of the parental compounds herein through a glyceryl oxygen of the triglyceride; phospholipids linked to the carboxyl group through the phosphate of the phospholipid; phthalidyl (shown in Fig.
  • hydroxyl groups of the compounds of this invention optionally are substituted with one of groups III, IV or V disclosed in WO 94/21604, or with isopropyl.
  • Table A lists examples of R 6a ester moieties that for example can be bonded via oxygen to -C(0)0- and -P(0)(0-) 2 groups.
  • R6c amidates also are shown, which are bound directly to -C(O)- or
  • -P(0)2- Esters of structures 1-5, 8-10 and 16, 17, 19-22 are synthesized by reacting the compound herein having a free hydroxyl with the corresponding halide (chloride or acyl chloride and the like) and N ,N-dicyclohexyl-N-morpholine carboxamidine (or another base such as DBU, triethylamine, CsC0 3 , N,N- dimethylaniline and the like) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone).
  • halide chloride or acyl chloride and the like
  • N ,N-dicyclohexyl-N-morpholine carboxamidine or another base such as DBU, triethylamine, CsC0 3 , N,N- dimethylaniline and the like
  • DMF or other solvent such as acetonitrile or N-methylpyrrolidone
  • the esters of structures 5-7, 11, 12, 21, and 23-26 are synthesized by reaction of the alcohol or alkoxide salt (or the corresponding amines in the case of compounds such as 13, 14 and 15) with the monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
  • # - chiral center is (R), (S) or racemate.
  • R6a also includes "double ester" forming profunctionalities such as
  • R37 and R38 are bulky groups such as branched alkyl, ortho-substituted aryl, meta- substituted aryl, or combinations thereof, including normal, secondary, iso- and tertiary alkyls of 1-6 carbon atoms.
  • An example is the pivaloyloxymethyl group.
  • R6a groups are alkylacyloxymethyl esters and their derivatives, including -CH(CH 2 CH 2 OCH 3 )OC(0)C(CH 3 ) 3 ,
  • ester typically chosen is one heretofore used for antibiotic drugs, in particular the cyclic carbonates, double esters, or the phthalidyl, aryl or alkyl esters.
  • R a 6c and R ⁇ b groups optionally are used to prevent side reactions with the protected group during synthetic procedures, so they function as protecting groups (PRT) during synthesis.
  • PRT protecting groups
  • the PRT groups do not need to be, and generally are not, the same if the compound is substituted with multiple PRT. In general, PRT will be used to protect carboxyl, hydroxyl or amino groups.
  • the R ⁇ a protected acidic group is an ester of the acidic group and R ⁇ a is the residue of a hydroxyl-containing functionality.
  • an R6c amino compound is used to protect the acid functionality.
  • the residues of suitable hydroxyl or amino-containing functionalities are set forth above or are found in WO 95/07920.
  • the residues of amino acids, amino acid esters, polypeptides, or aryl alcohols are described on pages 11-18 and related text of WO 95/07920 as groups LI or L2.
  • WO 95/07920 expressly teaches the amidates of phosphonic acids, but it will be understood that such amidates are formed with any of the acid groups set forth herein and the amino acid residues set forth in WO 95/07920.
  • Typical R6a esters for protecting Wl acidic functionalities are also described in WO 95/07920, again understanding that the same esters can be formed with the acidic groups herein as with the phosphonate of the '920 publication.
  • Typical ester groups are defined at least on WO 95/07920 pages 89- 93 (under R 31 or R 35 ), the table on page 105, and pages 21-23 (as R).
  • esters of unsubstituted aryl such as phenyl or arylalkyl such benzyl, or hydroxy-, halo-, alkoxy-, carboxy- and /or alkylestercarboxy- substituted aryl or alkylaryl, especially phenyl, ortho-ethoxyphenyl, or C 1 -C 4 alkylestercarboxyphenyl (salicylate C 1 -C 12 alkylesters).
  • the protected acidic groups Wi are useful as prodrugs for oral administration. However, it is not essential that the Wi acidic group be protected in order for the compounds of this invention to be effectively administered by the oral route.
  • the compounds of the invention having protected groups in particular amino acid amidates or substituted and unsubstituted aryl esters are administered systemically or orally they are capable of hydrolytic cleavage in vivo to yield the free acid.
  • One or more of the acidic hydroxyls are protected. If more than one acidic hydroxyl is protected then the same or a different protecting group is employed, e.g., the esters may be different or the same, or a mixed amidate and ester may be used.
  • Typical R 6a hydroxy protecting groups described in Greene include Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, f-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, f-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2-Methoxyethoxy methyl, 2,2,2-Trichloroethoxymethyl, Bis (2- chloroethoxy )methyl, 2- (Trimethy lsily l)ethoxymethy 1, Tetrahy dropy rany 1, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-Methoxytetrahydropyranyl, 4-Methoxytetrahydr
  • R 6a hydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, still more typically, trialkylsilyl ethers, tosylates and acetates.
  • Typical 1,2-diol protecting groups are described in Greene at pages 118-142 and include Cyclic Acetals and Ketals (Methylene, Ethylidene, 1- ⁇ -Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2-Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene, Cyclohexylidene, Cycloheptylidene, Benzylidene, p-Methoxybenzylidene, 2,4-Dimethoxybenzylidene, 3,4-Dimethoxybenzylidene, 2-Nitrobenzylidene); Cyclic Ortho Esters (Methoxymethylene, Ethoxymethylene, Dimethoxymethylene, 1-Methoxyethylidene, 1-Eth
  • Tetraisopropyldisiloxanylidene and Tetra-f-butoxydisiloxane-l,3-diylidene
  • Cyclic Carbonates Cyclic Boronates, Ethyl Boronate and Phenyl Boronate.
  • 1,2-diol protecting groups include those shown in Table B, still more typically, epoxides, acetonides, cyclic ketals and aryl acetals.
  • R ⁇ is C1-C6 alkyl
  • R6b is H, a protecting group for amino or the residue of a carboxyl- containing compound, in particular H, -C(0)R4, an amino acid, a polypeptide or a protecting group not -C(0)R4, amino acid or polypeptide.
  • Amide-forming R6b are found for instance in group Gl.
  • R ⁇ b i an amino acid or polypeptide it has the structure Ri5NHCH(Ri6)C(0)-, where R15 is H, an amino acid or polypeptide residue, or R5, and Ri6 is defined below.
  • Rl6 is lower alkyl or lower alkyl (Ci-C ⁇ ) substituted with amino, carboxyl, amide, carboxyl ester, hydroxyl, C 6 -C 7 aryl, guanidinyl, imidazolyl, indolyl, sulfhydryl, sulfoxide, and /or alkylphosphate.
  • Ri6 is generally the side group of a naturally-occurring amino acid such as H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH(CH 3 ) 2 , -CHCH 3 -CH 2 -CH 3 , -CH 2 -C 6 H 5 , -CH 2 CH 2 -S-CH 3 , -CH 2 OH, -CH(OH)-CH 3 , -CH 2 -SH, -CH2-C6H 4 OH, -CH 2 -CO- NH 2 , -CH2-CH2-CO-NH2, -CH 2 -COOH, -CH 2 -CH 2 -COOH, -(CH 2 ) 4 -NH 2 and -(CH2) 3 -NH-C(NH2)-NH2- Ri6 also includes l-guanidinoprop-3-yl, benzyl, 4- hydroxybenzyl, imidazol-4-yl, indol-3-yl,
  • R6b are residues of carboxylic acids for the most part, but any of the typical amino protecting groups described by Greene at pages 315-385 are useful. They include Carbamates (methyl and ethyl, 9-fluorenylmethyl, 9(2- sulfo)fluoroenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-f-buthyl-[9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, 4-methoxyphenacyl); Substituted Ethyl (2,2,2-trichoroethyl, 2-trimethylsilylethyl, 2-phenylethyl, l-(l-adamantyl)-l-methylethyl, l,l-dimethyl-2-haloethyl, l,l-dimethyl-2,2- dibromoethyl, l,l
  • Another protecting group, also useful as a prodrug at the Gl site, particularly for amino or -NH(Rs), is:
  • R 6c is H or the residue of an amino-containing compound, in particular an amino acid, a polypeptide, a protecting group, -NHSO2R4, NHC(0)R4, -N(R4)2, NH2 or -NH(R4)(H), whereby for example the carboxyl or phosphonic acid groups of Wl are reacted with the amine to form an amide, as in -C(0)R6c/ -P(0)(R6c)2 or -P(0)(OH)(R 6c ).
  • R6c has the structure R l7 C(0)CH(Ri 6 )NH-, where R 1 7 is OH, OR6a, OR5, an amino acid or a polypeptide residue.
  • Amino acids are low molecular weight compounds, on the order of less than about 1,000 MW, that contain at least one amino or imino group and at least one carboxyl group. Generally the amino acids will be found in nature, i.e., can be detected in biological material such as bacteria or other microbes, plants, animals or man. Suitable amino acids typically are alpha amino acids, i.e. compounds characterized by one amino or imino nitrogen atom separated from the carbon atom of one carboxyl group by a single substituted or unsubstituted alpha carbon atom. Of particular interest are hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkylamino acids and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parental drug. Typically, the residue does not contain a sulfhydryl or guanidino substituent.
  • Naturally-occurring amino acid residues are those residues found naturally in plants, animals or microbes, especially proteins thereof. Polypeptides most typically will be substantially composed of such naturally- occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline.
  • R(fo and R6 C are single amino acid residues or polypeptides they usually are substituted at R3, W6, Wl and /or W2, but typically only Wl or W2-
  • These conjugates are produced by forming an amide bond between a carboxyl group of the amino acid (or C-terminal amino acid of a polypeptide for example) and W2-
  • conjugates are formed between Wl and an amino group of an amino acid or polypeptide.
  • Wl amino acid
  • Wl amino acid
  • Wl amino acid
  • the ⁇ -amino or ⁇ -carboxyl group of the amino acid or the terminal amino or carboxyl group of a polypeptide are bonded to the parental functionalities, i.e., carboxyl or amino groups in the amino acid side chains generally are not used to form the amide bonds with the parental compound (although these groups may need to be protected during synthesis of the conjugates as described further below).
  • carboxyl-containing side chains of amino acids or polypeptides it will be understood that the carboxyl group optionally will be blocked, e.g. by R ⁇ a, esterified with R 5 or amidated with R c - Similarly, the amino side chains Ri6 optionally will be blocked with R6b or substituted with
  • esters or amide bonds with side chain amino or carboxyl groups like the esters or amides with the parental molecule, optionally are hydrolyzable in vivo or in vitro under acidic (pH ⁇ 3) or basic (pH >10) conditions. Alternatively, they are substantially stable in the gastrointestinal tract of humans but are hydrolyzed enzymatically in blood or in intracellular environments.
  • the esters or amino acid or polypeptide amidates also are useful as intermediates for the preparation of the parental molecule containing free amino or carboxyl groups.
  • the free acid or base of the parental compound for example, is readily formed from the esters or amino acid or polypeptide conjugates of this invention by conventional hydrolysis procedures.
  • any of the D, L, meso, threo or erythro (as appropriate) racemates, scalemates or mixtures thereof may be used.
  • D isomers are useful.
  • L isomers are more versatile since they can be susceptible to both non-enzymatic and enzymatic hydrolysis, and are more efficiently transported by amino acid or dipeptidyl transport systems in the gastrointestinal tract.
  • Suitable amino acids whose residues are represented by R ⁇ b and R ⁇ c include the following: Glycine;
  • Aminopolycarboxylic acids e.g., aspartic acid, ⁇ -hydroxyaspartic acid, glutamic acid, ⁇ -hydroxyglutamic acid, ⁇ -methylaspartic acid, ⁇ - methylglutamic acid, ⁇ , ⁇ -dimethylaspartic acid, ⁇ -hydroxyglutamic acid, ⁇ , ⁇ - dihydroxyglutamic acid, ⁇ -phenylglutamic acid, ⁇ -methyleneglutamic acid, 3- aminoadipic acid, 2-amino ⁇ imelic acid, 2-aminosuberic acid and 2- aminosebacic acid;
  • Amino acid amides such as glutamine and asparagine; Polyamino- or polybasic-monocarboxylic acids such as arginine, lysine, ⁇ -aminoalanine, ⁇ -aminobutyrine, ornithine, citruline, homoarginine, homocitrulline, hydroxylysine, allohydroxylsine and diaminobutyric acid; Other basic amino acid residues such as histidine; Diaminodicarboxylic acids such as ⁇ , ⁇ '-diaminosuccinic acid, ⁇ , ⁇ '- diaminoglutaric acid, , ⁇ '-diaminoadipic acid, ⁇ , ⁇ '-diaminopimelic acid, ⁇ , ⁇ '- diamino- ⁇ -hydroxypimelic acid, oc, ⁇ '-diaminosuberic acid, ⁇ , ⁇ '- diaminoazelaic acid, and ⁇ , ⁇ '-diaminosebac
  • Imino acids such as proline, hydroxyproline, allohydroxyproline, ⁇ - methylproline, pipecolic acid, 5-hydroxypipecolic acid, and azetidine-2- carboxylic acid;
  • a mono- or di-alkyl (typically Ci - Cs branched or normal) amino acid such as alanine, valine, leucine, allylglycine, butyrine, norvaline, norleucine, heptyline, ⁇ -methylserine, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxyvaleric acid, ⁇ -amino- ⁇ -methyl- ⁇ -hydroxycaproic acid, isovaline, -methylglutamic acid, ⁇ -aminoisobutyric acid, ⁇ - aminodiethylacetic acid, ⁇ -aminodiisopropylacetic acid, ⁇ -aminodi-n- propylacetic acid, ⁇ -aminodiisobutylacetic acid, ⁇ -aminodi-n-butylacetic acid, -aminoethylisopropylacetic acid, -amino
  • Aliphatic ⁇ -amino- ⁇ -hydroxy acids such as serine, ⁇ -hydroxyleucine, ⁇ - hydroxynorleucine, ⁇ -hydroxynorvaline, and ⁇ -amino- ⁇ -hydroxystearic acid; ⁇ - Amino, ⁇ -, ⁇ -, ⁇ - or ⁇ -hydroxy acids such as homoserine, ⁇ - hydroxynorvaline, ⁇ -hydroxynorvaline and epsilon-hydroxynorleucine residues; canavine and canaline; ⁇ -hydroxyornithine;
  • 2-hexosaminic acids such as D-glucosaminic acid or D-galactosaminic acid
  • ⁇ -Amino- ⁇ -thiols such as penicillamine, ⁇ -thiolnorvaline or ⁇ - thiolbutyrine
  • cysteine Other sulfur containing amino acid residues including cysteine; homocystine, ⁇ -phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiolhistidine, cystathionine, and thiol ethers of cysteine or homocysteine;
  • Phenylalanine, tryptophan and ring-substituted ⁇ amino acids such as the phenyl- or cyclohexylamino acids ⁇ -aminophenylacetic acid, ⁇ - aminocyclohexylacetic acid and ⁇ -amino- ⁇ -cyclohexylpropionic acid; phenylalanine analogues and derivatives comprising aryl, lower alkyl, hydroxy, guanidino, oxyalkylether, nitro, sulfur or halo-substituted phenyl (e.g., tyrosine, methyltyrosine and o-chloro-, p-chloro-, 3,4-dicloro, o-, m- or p- methyl-, 2,4,6-trimethyl-, 2-ethoxy-5-nitro-, 2-hydroxy-5-nitro- and p-nitro- phenylalanine); furyl-, thienyl-, pyrid
  • Polypeptides are polymers of amino acids in which a carboxyl group of one amino acid monomer is bonded to an amino or imino group of the next amino acid monomer by an amide bond.
  • Polypeptides include dipeptides, low molecular weight polypeptides (about 1500-5000MW) and proteins. Proteins optionally contain 3, 5, 10, 50, 75, 100 or more residues, and suitably are substantially sequence-homologous with human, animal, plant or microbial proteins. They include enzymes (e.g., hydrogen peroxidase) as well as immunogens such as KLH, or antibodies or proteins of any type against which one wishes to raise an immune response. The nature and identity of the polypeptide may vary widely.
  • the polypeptide amidates are useful as immunogens in raising antibodies against either the polypeptide (if it is not immunogenic in the animal to which it is administered) or against the epitopes on the remainder of the compound of this invention.
  • Antibodies capable of binding to the parental non-peptidyl compound are used to separate the parental compound from mixtures, for example in diagnosis or manufacturing of the parental compound.
  • the conjugates of parental compound and polypeptide generally are more immunogenic than the polypeptides in closely homologous animals, and therefore make the polypeptide more immunogenic for facilitating raising antibodies against it. Accordingly, the polypeptide or protein may not need to be immunogenic in an animal typically used to raise antibodies, e.g., rabbit, mouse, horse, or rat, but the final product conjugate should be immunogenic in at least one of such animals.
  • the polypeptide optionally contains a peptidolytic enzyme cleavage site at the peptide bond between the first and second residues adjacent to the acidic heteroatom.
  • Such cleavage sites are flanked by enzymatic recognition structures, e.g. a particular sequence of residues recognized by a peptidolytic enzyme.
  • Peptidolytic enzymes for cleaving the polypeptide conjugates of this invention are well known, and in particular include carboxypeptidases.
  • Carboxypeptidases digest polypeptides by removing C-terminal residues, and are specific in many instances for particular C-terminal sequences.
  • Such enzymes and their substrate requirements in general are well known.
  • a dipeptide (having a given pair of residues and a free carboxyl terminus) is covalently bonded through its ⁇ -amino group to the phosphorus or carbon atoms of the compounds herein.
  • Wl is phosphonate it is expected that this peptide will be cleaved by the appropriate peptidolytic enzyme, leaving the carboxyl of the proximal amino acid residue to autocatalytically cleave the phosphonoamidate bond.
  • Suitable dipeptidyl groups are AA, AR, AN, AD, AC, AE, AQ, AG, AH, Al, AL, AK, AM, AF, AP, AS, AT, AW, AY, AV, RA, RR, RN, RD, RC, RE, RQ, RG, RH, RI, RL, RK, RM, RF, RP, RS, RT, RW, RY, RV, NA, NR, NN, ND, NC, NE, NQ, NG, NH, NI, NL, NK, NM, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DG, DH, DI, DL, DK, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, C
  • Tripeptide residues are also useful as R6b or R6c- When Wl is phosphonate, the sequence -X4-pro-X5- (where X4 is any amino acid residue and X5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) will be cleaved by luminal carboxypeptidase to yield X4 with a free carboxyl, which in turn is expected to autocatalytically cleave the phosphonoamidate bond.
  • the carboxy group of X5 optionally is esterified with benzyl.
  • Dipeptide or tripeptide species can be selected on the basis of known transport properties and /or susceptibility to peptidases that can affect transport to intestinal mucosal or other cell types.
  • Dipeptides and tripeptides lacking an ⁇ -amino group are transport substrates for the peptide transporter found in brush border membrane of intestinal mucosal cells (Bai, J.P.F., "Pharm Res.” 9:969-978 (1992). Transport competent peptides can thus be used to enhance bioavailability of the amidate compounds.
  • Di- or tripeptides having one or more amino acids in the D configuration are also compatible with peptide transport and can be utilized in the amidate compounds of this invention. Amino acids in the D configuration can be used to reduce the susceptibility of a di- or tripeptide to hydrolysis by proteases common to the brush border such as aminopeptidase N (EC 3.4.11.2).
  • di- or tripeptides alternatively are selected on the basis of their relative resistance to hydrolysis by proteases found in the lumen of the intestine.
  • tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase A (EC 3.4.11.7)
  • di- or tripeptides lacking amino acid residues on the N-terminal side of hydrophobic amino acids are poor substrates for endopeptidase 24.11 (EC 3.4.24.11)
  • peptides lacking a pro residue at the penultimate position at a free carboxyl terminus are poor substrates for carboxypeptidase P (EC 3.4.17).
  • the compounds of the invention are enriched or resolved optical isomers at any or all asymmetric atoms.
  • the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures.
  • racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
  • stereospecific synthesis is described below. Methods of this type conveniently are used when the appropriate chiral starting material is available and reaction steps are chosen do not result in undesired racemization at chiral sites.
  • One advantage of stereospecific synthesis is that it does not produce undesired enantiomers that must be removed from the final product, thereby lowering overall synthetic yield.
  • a suitable stereospecific synthesis cannot be empirically designed or determined with routine experimentation then those skilled in the art would turn to other methods.
  • One method of general utility is chromotographic resolution of enantiomers on chiral chromatography resins. These resins are packed in columns, commonly called Pirkle columns, and are commercially available. The columns contain a chiral stationary phase. The racemate is placed in solution and loaded onto the column, and thereafter separated by HPLC. See for example, Proceedings Chromatographic Society - International Symposium on Chiral Separations, Sept. 3-4, 1987.
  • Another method entails converting the enantiomers in the mixture to diastereomers with chiral auxiliaries and then separating the conjugates by ordinary column chromatography.
  • This is a very suitable method, particularly when the embodiment contains free carboxyl, amino or hydroxyl that will form a salt or covalent bond to a chiral auxiliary.
  • Chirally pure amino acids, organic acids or organosulfonic acids are all worthwhile exploring as chiral auxiliaries, all of which are well known in the art. Salts with such auxiliaries can be formed, or they can be covalently (but reversibly) bonded to the functional group.
  • pure D or L amino acids can be used to amidate the carboxyl group of embodiments of this invention and then separated by chromatography.
  • Enzymatic resolution is another method of potential value.
  • one prepares covalent derivatives of the enantiomers in the racemic mixture, generally lower alkyl esters (for example of carboxyl), and then exposes the derivative to enzymatic cleavage, generally hydrolysis.
  • an enzyme must be chosen that is capable of stereospecific cleavage, so it is frequently necessary to routinely screen several enzymes. If esters are to be cleaved, then one selects a group of esterases, phosphatases, and lipases and determines their activity on the derivative. Typical esterases are from liver, pancreas or other animal organs, and include porcine liver esterase.
  • the enantiomeric mixture separates from solution or a melt as a conglomerate, i.e., a mixture of enantiomerically-pure crystals, then the crystals can be mechanically separated, thereby producing the enantiomerically enriched preparation.
  • This method is not practical for large scale preparations and is of no value for true racemic compounds.
  • Asymmetric synthesis is another technique for achieving enantiomeric enrichment. For example, a chiral protecting group is reacted with the group to be protected and the reaction mixture allowed to equilibrate. If the reaction is enantiomerically specific then the product will be enriched in that enantiomer.
  • the compounds of the invention can also exist as tautomeric isomers in certain cases.
  • ene-amine tautomers can exist for imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • each compound is depicted as a substituted nucleus in which the nucleus is designated by capital letter and each substituent is designated in order by lower case letter or number.
  • Table 1 are a schedule of nuclei which differ principally by the position of ring unsaturation and the nature of ring substituents. Each nucleus is given a alphabetical designation from Table 1, and this designation appears first in each compound name.
  • Tables 2, 3, 4, and 5 list the selected Qi, Q2, Q 3 and Q4 substituents, again by letter or number designation.
  • each named compound will be depicted by a capital letter designating the nucleus from Table 1, followed by a number designating the Qi substituent, a lower case letter designating the Q2 substituent, a number designating the Q 3 substituent, and a lower case letter or letters designating the Q4 substituent.
  • the structure below has the name shown.
  • A.724.a.4.i A.3.a.4.o; A.4.a.4.o; A.7.a.4.o; A.9.a.4.o; A.103.a.4.o; A.106.a.4.o;
  • A.140.a.4.o A.141.a.4.o; A.142.a.4.o; A.145.a.4.o; A.146.a.4.o; A.147.a.4.o;
  • A..712.y.4. A.713.y ,4.i; A.714.y.4.i; A.715.y.4. i; A.716.y.4.i; A. V17.y.4.i; A.718.y.4.i;
  • A..4.y.4.o A.7.y.4.o; A.9.y.4.o; A.103.y.4.o; A 106.y.4.o; A.107 y.4.o; A.108.y.4.o;
  • a .172.A.4.0 A.173. A.4.o A.174, ,A.4.o; A.175.A.4.o; A.176.A.4.o; A.188.A.4.o;
  • a .189.A.4.0 A.190. A.4.o A.196. ,A.4.o; A.202.A.4.o; A.205.A.4.o; A.206.A.4.o;
  • a .213.A.4.0 A.700. A.4.o A.701, ,A.4.o; A.702.A.4.o; A.703.A.4.o; A.704.A.4.o;
  • a 723.A.4.o; A.724.A.4.o A.172. B.4.i; A.173.B.4 ,i; A.174.B.4.i; A.175.B.4.i; A.176.B.4.i;
  • a 138.B.4.o A.139.B.4.0 A.140.B.4.O A.141.B.4.o; A.142.B.4.o; A.145.B.4.o;

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Abstract

L'invention concerne de nouveaux composés. Ces composés comprennent généralement un groupe acide, un groupe basique, un groupe amino substitué ou N-acyle et un groupe possédant une fraction alkane éventuellement hydroxylée. Elle concerne également des compositions pharmaceutiques contenant ces composés inhibiteurs. Elle concerne également des procédés d'inhibition de neuramidinase dans des spécimens susceptibles de contenir neuraminidase. Elle concerne, de plus, des matériaux antigéniques, des polymères, des anticorps, des conjugués de ces composés comportant des marquages, ainsi que des procédés servant à détecter une activité de neuraminidase.
PCT/US1997/018193 1996-10-21 1997-10-17 Composes de piperidine WO1998017647A1 (fr)

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CA002268756A CA2268756A1 (fr) 1996-10-21 1997-10-17 Composes de piperidine
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Cited By (8)

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WO2000029385A1 (fr) * 1998-11-13 2000-05-25 Gilead Sciences, Inc. Composes 1,4,5,6-tetrahydro-pyridaziniques, leur elaboration et leur utilisation comme inhibiteurs des neuraminidases
WO2001029020A2 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs de la neuraminidase
US6455571B1 (en) 1998-04-23 2002-09-24 Abbott Laboratories Inhibitors of neuraminidases
US6518305B1 (en) 1998-04-23 2003-02-11 Abbott Laboratories Five-membered carbocyclic and heterocyclic inhibitors of neuraminidases
US6518299B1 (en) 2000-10-20 2003-02-11 Biocryst Pharmaceuticals, Inc. Substituted pyrrolidine compounds useful as neuraminidase inhibitors
US6593314B1 (en) 1999-10-19 2003-07-15 Abbott Laboratories Neuraminidase inhibitors
WO2019113462A1 (fr) 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine et dérivés et leurs utilisations anti-virales
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6455571B1 (en) 1998-04-23 2002-09-24 Abbott Laboratories Inhibitors of neuraminidases
US6518305B1 (en) 1998-04-23 2003-02-11 Abbott Laboratories Five-membered carbocyclic and heterocyclic inhibitors of neuraminidases
WO2000029385A1 (fr) * 1998-11-13 2000-05-25 Gilead Sciences, Inc. Composes 1,4,5,6-tetrahydro-pyridaziniques, leur elaboration et leur utilisation comme inhibiteurs des neuraminidases
WO2001029020A2 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs de la neuraminidase
WO2001029020A3 (fr) * 1999-10-19 2001-12-27 Abbott Lab Inhibiteurs de la neuraminidase
US6593314B1 (en) 1999-10-19 2003-07-15 Abbott Laboratories Neuraminidase inhibitors
US6518299B1 (en) 2000-10-20 2003-02-11 Biocryst Pharmaceuticals, Inc. Substituted pyrrolidine compounds useful as neuraminidase inhibitors
US11628181B2 (en) 2014-12-26 2023-04-18 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
WO2019113462A1 (fr) 2017-12-07 2019-06-13 Emory University N4-hydroxycytidine et dérivés et leurs utilisations anti-virales
US11331331B2 (en) 2017-12-07 2022-05-17 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto
US11903959B2 (en) 2017-12-07 2024-02-20 Emory University N4-hydroxycytidine and derivatives and anti-viral uses related thereto

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