Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
  • C07D337/02—Seven-membered rings
  • C07D337/04—Seven-membered rings not condensed with other rings

Definitions

• HTV infection and related disease is a major public health problem worldwide.
• a virally encoded protease (HTV protease) mediates specific protein cleavage reactions during the natural reproduction of the virus. Accordingly, inhibition of HTV protease is an important therapeutic target for treatment of HTV infection and related disease.
• Lam P.; Jadhav, P.; Eyermann, C; Hodge, C; De Lucca, G.; and Rodgers, J.; WO 94/19329, September 1, 1994, discloses substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors.
• HIV protease inhibitors Wong, Y.; Burcham, D.; Saxton, P.; Erickson-Viitanen, S.; Grubb, M.; Quon, C; and Huang, S.-M.; Biopharm. & Drug Disp.. 1994, IS, 535-544, discloses pharmacokinetic evaluation of cyclic urea HIV protease inhibitors in rats and dogs.
• Inhibition of HIV protease is an object of the invention.
• Inhibitors of HIV protease are useful to limit the establishment and progression of infection by HIV as well as in assays for HIV protease, both of which are further objects of the invention.
• Preparation of compositions capable of inhibiting HIV protease is also an object of the invention.
• HIV protease inhibitors having improved antiviral and pharmacokinetic properties, including enhanced activity against development of HTV resistance, improved oral bioavailability, greater potency and extended effective half-life in vivo. It is another object herein to provide compounds useful in diagnostic assays for HTV, for use in the preparation of polymers and for use as surfactants, and in other industrial utilities that will be readily apparent to the artisan.
• Y is independently -O-, -S-, -SO-, -SO_-, -N(R ⁇ , -N(R ⁇ )-S ⁇ 2-, -N(R ⁇ >CO-, or -O-SO2-;
• E and U are independently H, or -(CR ⁇ R ⁇ ) m l-W ⁇ , with the proviso that at least one of E and U is -(CR ⁇ R ⁇ )ml-W ⁇ ;
• G and T are independently -(CR ⁇ R ⁇ )ml-W ⁇ , or -(CRiR ⁇ ) m ⁇ -C(Ri)(W ⁇ )(W2), with the provisos that: when E is -(CR ⁇ R_) m i-W ⁇ , then G is -(CR ⁇ R_) m ⁇ -W ⁇ ; when U is -(CR ⁇ R ⁇ ) m ⁇ -W ⁇ , then T is -(CR ⁇ R ⁇ ) m ⁇ -W ⁇ ; and G and T may be the same or different;
• J and L are independently H, N3, -OR2, -N(R2)(R2), or -N(R2)(R3), wherein R2 is H, or PRT, with the proviso that at least one of J and L is -OR2, or J and L are taken together to form an epoxide or a cyclic protecting group;
• Wi is W2 or W3;
• W2 is carbocycle or heterocycle, with the proviso that each W2 is independently substituted with 0 to 3 R5 groups;
• W3 is alkyl, alkenyl, or alkynyl, with the proviso that each W3 is independently substituted with 0 to 3 R6 groups; Ri is R3 or R6;
• R3 is H or R4;
• R4 is alkyl
• R5 is R6, or R7, with the proviso that each R7 is independently substituted with 0 to 3 R6 groups;
• R6 is -0-(antigenic polypeptide), -N(R3)-(antigenic polypeptide), -C(0)0-
• the invention is also directed to methods of inhibiting the activity of HIV protease comprising contacting the protease with an inhibitory effective amount of a composition of the invention.
• compositions of the invention comprise compounds of the formulas:
• the E, G, T and U groups may be the same or different.
• Y is independently -O-, -S-, -SO-, -SO2-, -N(R ⁇ )-, -N(R_)-S ⁇ 2-, -N(R ⁇ )-CO-, or -O-SO2-.
• compositions of the invention comprise compounds of the formula:
• compositions of the invention comprise compounds of the formula:
• E and U are independently H, or -(CR ⁇ R_) m l-W_, provided that at least one of E and U is -(CR ⁇ R ⁇ ) m ⁇ -W ⁇ .
• E and U are independently groups of the formula -(CR ⁇ R ⁇ ) m ⁇ -W2, more typically, -(CR3R3)ml-W2.
• E and U are not H.
• G and T are independently -(CRiRiJmi-Wi, D r -(CR ⁇ R ⁇ )ml- C(Rl)(W ⁇ )(W2), provided that when E is -(CRlRl)ml-W ⁇ , G is -(CR ⁇ R ⁇ ) m ⁇ -W ⁇ , and when U is -(CRlRl)ml-W ⁇ , T is -(CR ⁇ R ⁇ ) m ⁇ -W_.
• G and T are independently groups of the formula -(CR ⁇ R_)ml-W2, more typically, -(CR 3 R3)ml-W 2 .
• E, G, T and U are all -(CR ⁇ R_) m ⁇ -W ⁇ .
• E, G, T and U are -(CR3R3) m ⁇ -W ⁇ .
• E, G, T and U are -(CR ⁇ R ⁇ )ml-W2.
• E, G, T and U are -( R3R3) m l-W2.
• one of E and U is H and the other is -(CR ⁇ R ⁇ )ml- Wi; and T and G are -(CR ⁇ R ⁇ )ml-W ⁇ .
• one of E and U is H and the other is -(CR3R3) m l-W ⁇ ; and T and G are -(CR3R3) m ⁇ -W ⁇ .
• one of E and U is H and the other is -(CR ⁇ R_) m ⁇ -W2; -nd T and G are -(CR ⁇ R ⁇ )ml- W2- Still more typically, one of E and U is H and the other is -(CR3R3) m l-W2; and T and G are -(CR3R3) m ⁇ -W2. In another embodiment one of E and U is H and the other is -(CR ⁇ R_)ml _
• G is -(CR ⁇ R ⁇ ) m ⁇ -C(R ⁇ )(W ⁇ )(W2), when E is -(CR ⁇ R ⁇ )mi-W ⁇ , then G is -(CR ⁇ R ⁇ ) m ⁇ -W ⁇ , when U is H, then T is -(CR ⁇ R ⁇ ) m ⁇ -C(R ⁇ )(W ⁇ )(W2), and when U is -(CR ⁇ R ⁇ ) m ⁇ -W ⁇ , then T is -(CR ⁇ R ⁇ )n ⁇ i-W ⁇ .
• one of E and U is H and the other is -(CR3R3) m i- Wi, provided that when E is H, then G is -(CR ⁇ R ⁇ ) m ⁇ -C(R ⁇ )(W ⁇ )(W2), when E is -(CR3R3)mi-W ⁇ , then G is -(CR ⁇ R_) m ⁇ -W ⁇ , when U is H, then T is -(CR ⁇ R ⁇ ) m ⁇ -C(R ⁇ )(W ⁇ )(W2), and when U is -(CR3R3) m ⁇ -W ⁇ , then T is -(CR ⁇ R ⁇ )ml-W ⁇ .
• one of E and U is H and the other is -(CR ⁇ R ⁇ )mi-W2, provided that when E is H, then G is -(CR ⁇ R_) m l- C(R ⁇ )(W ⁇ )(W2), when E is -(CR ⁇ R ⁇ ) m ⁇ -W2, then G is -(CR ⁇ R ⁇ )ml-W ⁇ , when U is H, then T is -(CR ⁇ R ⁇ ) m i-C(R ⁇ )(W_)(W2), and when U is -(CR ⁇ R ⁇ ) m ⁇ -W2, then T is -(CR ⁇ R ⁇ ) m ⁇ -W ⁇ .
• one of E and U is H and the other is -( R3R3)ml- 2, provided that when E is H, then G is -(CR ⁇ R_)mi- C(R ⁇ )(W ⁇ )(W2), when E is -(CR3R3)ml-W2, then G is -(CR ⁇ R ⁇ )n ⁇ l-W ⁇ , when U is H, then T is -(CR ⁇ R ⁇ ) m i-C(R ⁇ )(W ⁇ )(W2), and when U is -(CR3R3)ml-W2, then T is -(CR ⁇ R ⁇ ) m ⁇ -W ⁇ .
• E, G, T and U are independently -CR3R3-W2 wherein R3 is H or a 1 to 3 carbon alkyl group and W2 is a monocyclic carbocycle (3 to 6 carbon atoms) or monocyclic heterocycle (3 to 6 ring members, 2 to 5 carbon atoms, and 1 to 2 heteroatoms selected from O, N, and S) provided that W2 is substituted with 0 to 1 -OH, -OMe, -NH2, -N(H)(Me), -N(H)(Et), -N(H)(i- Pr), -N(H)(n-Pr), -N(Me)2, -NO2, or -CN.
• W2 is phenyl, pyridyl, tetrahydrothiophene, sulfur oxidized (sulfoxide or sulfone) tetrahydrothiophene, or thiazole.
• E, G, T and U are independently -CR3R3-W2 wherein W2 is phenyl or thiazole provided that each W2 is independently substituted with 0, 1 or 2 R5 groups as described above.
• E, G, T and U are independently -CHR3-W2 wherein W2 is phenyl or thiazole provided that each W2 is independently substituted with 0 to 1 R5 groups as described above.
• E, G, T and U are independently -CHR3-W2 wherein W2 is phenyl or thiazole provided that each W2 is independently substituted with 0 to 1 R3 groups as described above.
• E, G, T and U are benzyl.
• E, G, T, and U when taken individually, are substituted with no more than 8 R ⁇ groups, typically, no more than 3 R4 or R7 and 6 R ⁇ groups. More typically, each is substituted with 1 or 2 R4 or R7 groups of 1 or 3, or 2 or 3 carbon atoms, respectively, and 0 to 4 R6 groups selected from -OR3, -SR3, -N(R3)(R3), F, CN, -NO2, and heterocycle.
• each is substituted with 0 or 1 R4 of 1 to 3 carbon atoms and 0 or 1 R6 groups selected from -OH, -OMe, -OEt, -NH2, -N(H)(Me) F, CN, -NO2, 1-aziridyl, and 1-azetidyl.
• R3 is H or R4-
• R4 is alkyl.
• R4 is an alkyl of 1 to 6 carbon atoms such as methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl t ⁇ -Pr, n-propyl, -CH2CH2CH3), 2- propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl t ⁇ -Bu, n-butyl, -CH2CH2CH2CH3), 2- methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3).
• 2-methyl-2-propyl (t-Bu, i-butyl, -C(CH3)3) .
• 1-pentyl n- pentyl, -CH2CH2CH2CH2CH3.
• 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-l-butyl (-CH2CH2CH(CH3)2), 2-methyl-l-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3).
• 2-hexyl (-CH(CH3)CH2CH2CH2CH3. 3-hexyl ( ⁇ (CH2CH3)(CH2CH2CH3)), 2-methyl-2- pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2).
• R4 is an alkyl of 1, 2, 3 or 4 carbon atoms. Still more typically, R4 is an alkyl of 1, 2 or 3 carbon atoms selected from methyl, ethyl, n- propyl, and i-propyl.
• R5 is R ⁇ or R7, provided that each R7 is independently substituted with 0 to 3 R6 atoms or groups. R6 and R7 are as defined below.
• R5 is R ⁇ , unsubstituted R7 or mono-, di- and trihaloalkyls of 1 to 6 carbon atoms, more typically, mono- di-, and trifluoro-n-alkyls of 1, 2 or 3 carbon atoms, still more typically monofluoromethyl, difluoromethyl, or trifluoromethyl.
• R ⁇ is -0-(antigenic polypeptide), -N(R3)-(antigenic polypeptide), -C(0)0-
• R ⁇ is -0-(antigenic polypeptide), -N(R3)- (antigenic polypeptide), -C(0)0-(antigenic polypeptide), -C(0)N(R3)-(antigenic polypeptide), F, Cl, Br, I, -CN, N3, -NO2, -OR3, -N(R3)(R3), -SR3, -0-C(0)R4, -N(R3)-C(0)R4, -C(0)N(R3)(PRT), -C(0)N(PRT) 2 , -C(0)N(R3)2, - O)OR3.
• R ⁇ groups are selected from -OR3, -SR3, -N(R3)(R3), F, CN, -NO2, and heterocycle.
• R ⁇ groups are selected from -OH, -OMe, -OEt, -O-i-Pr, -NH2. -N(H)(Me), F, CN, -NO2, 1-aziridyl, and 1-azetidyl.
• R ⁇ is carbocycle or heterocycle, it is typically a monocycle having 3 or 4 ring atoms, more typically, it is a heterocycle having 2 to 3 carbon atoms and 1 heteroatom selected from O, S, and N, still more typically, it is aziridyl, or azetidyl, more typically yet, it is 1-aziridyl, or 1-azetidyl.
• Other heterocycles or carbocycles suitable for R ⁇ , and their substitution sites, are described below under W2.
• Wi is W2 or W3.
• W2 is carbocycle or heterocycle.
• Carbocycles and heterocycles within the context of W2 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 W2 is independently substituted with 0 to 3 R ⁇ groups.
• W2 is a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. More typically, W2 has ' 3 to 10 ring atoms, still more typically, 3 to 7 ring atoms.
• W2 is a carbocyclic or heterocyclic monocycle with 3 to 6 ring atoms.
• the carbocycles or heterocycles are typically saturated if they have 3 ring atoms, saturated or monounsaturated if they have 4 ring atoms, saturated, or mono- or diunsaturated if they have 5 ring atoms, and saturated, mono- or diunsaturated, or aromatic if they have 6 or more ring atoms.
• W2 When W2 is carbocyclic, it is typically a 3 to 7 carbon monocycle or a 7 to 10 carbon atom bicycle. More typically, W2 monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. More typically, W2 bicyclic carbocycles have 7 to 10 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, and naphthyl.
• W2 When W2 is a heterocycle, it 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, W2 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).
• W2 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.
• Heterocycles include by way of example and not limitation those described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A.
• 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
• W2 heterocycles are selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, or pyrrolyl.
• the W2 heterocycle is bonded to -(CR ⁇ R ⁇ )ml- through a ring carbon or heteroatom and, where the heterocycle is polycyclic, through a
• W2 is 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, positon 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
• the heterocycle of W2 is 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.
• Ordinary and typical W2's are selected from those shown in Table 2.
• W2 is phenyl, thiazole, tetrahydrothiophene, and sulfur oxidized tetrahydrothiophene structures.
• R7 is alkyl, alkenyl, or alkynyl. Typically, R7 is a group of 1 to 8 carbon atoms. When R7 is alkyl it is typically selected from those described above with respect to R4 and the corresponding 7 and 8 carbon homologs.
• R7 alkenyl groups are of 2 to 6 carbon atoms, still more typically, 2, 3 or 4 carbon atoms.
• R7 is alkynyl it is a group of 2 to 8 carbon atoms, typically ethynyl (-CCH), 1-prop-l-ynyl (-CCCH3), l-prop-2-ynyl (-CH2CCH), 1-but-l-ynyl (-CCCH2CH3), l-but-2-ynyl (-CH2CCCH3), l-but-3-ynyl (- CH2CH2CCH), 2-but-3-ynyl (CH(CH3)CCH), 1-pent-l-ynyl (-CCCH2CH2CH3), l-pent-2-ynyl (-CH2CCCH2CH3), l-pent-3-ynyl
• R7 alkynyl groups are of 2 to 6 carbon atoms. Still more typically, 2, 3 or 4 carbon atoms.
• W3 is alkyl, alkenyl, or alkynyl provided that each W3 is independently substituted with 0 to 2 R groups.
• W3 is an alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms, or alkynyl of 2 to 8 carbon atoms. Such groups are described above with respect to R7. More typically, W3 is an alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, or alkynyl of 2 to 6 carbon atoms. Still more typically, W3 is an alkyl of 1 to 3 carbon atoms, alkenyl of 2 to 3 carbon atoms, or alkynyl of 2 to 3 carbon atoms.
• Each ml is an integer from 0 to 3, typically 0 to 2, and more typically 0 or 1.
• E, G, T, or U contains a W2 heterocycle group and ml is 0, then W2 is typically bonded through a carbon atom of W2 as described above.
• Y is -O-, and both G and T are hydroxy protecting groups as described below.
• Y is -O-, and one or both of G and T are not a hydroxy protecting group.
• Y is -O- and one or both of G and T are benzyl, then one or both of the benzyls is substituted in such a way as to render it not useful as a hydroxy protecting group, e.g. not useful in the method described in Greene (cited below).
• substitutions include by way of example and not limitation, incorporation of a protonatable group in the meta position of the benzene ring of a benzyl group to render the group non-removable by conventional debenzylation methods or to render the group cleavable, but only n under conditions that do not result in cleavage of conventional benzyl protecting groups.
• groups include R ⁇ groups containing sulfur, nitrogen or oxygen.
• Typical benzyls of this type indude meta amino, sulfhydryl, and hydroxyl substituted benzyls.
• G and T optionally are selected to be stable in add or base deprotecting conditions used heretofore to remove OH protecting groups.
• J and L are independently H, N3, -OR2, -N(R2)(R2), or -N(R2)(R3) provided that at least one of J and L is -OR2.
• J and L are taken together to form an epoxide, or a cyclic protecting group.
• one of J and L is -OH.
• the other of J and L is typically, -OH, -NH2, -N(R3)(H) or H. More typically, the other of J and L is -OH.
• one of J and L is -OR8 and the other is H, -OR2, -N(R2)(R2), or -N(R2)(R3).
• R ⁇ is -( 3R3)m2- C(0)(R 9 ), -(CR 3 R3)m2-P(0)(R9)(R9), or -(CR3R3)m2-S(0) 2 (R9)
• R9 is W_, -OW_, -N(R3)(W ⁇ ), -N(W ⁇ )(W ⁇ ), or -SWi
• m2 is an integer from 0 to 2, typically 0 to 1.
• R3 is typically H or an alkyl group of 1, 2 or 3 carbon atoms as described above with respect to R4.
• R2 is H, or a cydic protecting group.
• J or L is -OR2, -N(R2)(R2), or -N(R2)(R3), R2 is H, or PRT.
• PRT protecting groups
• cyclic protecting groups and corresponding cleavage reactions are described in "Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (Greene) and will not be detailed here.
• these protecting groups are groups that can be removed from the molecule of the invention without irreversibly changing the covalent bond structure or oxidation/ reduction state of the remainder of the molecule.
• PRT of a -OPRT or -N(R3)(PRT) group can be removed to form a -OH or -N(R3)(H) group, respectively, without affecting other covalent bonds in the molecule.
• more than one PRT group can be removed at a time, or they can be removed sequentially.
• the PRT are the same or different. Determination of whether a group is a protecting group is made in the conventional manner, illustrated by the work of Kocienski, Section 1.1, page 2, and Greene Chapter 1, pages 1-9, both cited herein.
• a group is a protecting group if when, based on mole ratio, 90% of that protecting group has been removed by a deprotection reaction, no more than 50%, preferably 25%, more preferably 10%, of the deprotected product molecules of the invention have undergone changes to their covalent bond structure or oxidation/reduction state other than those occasioned by the removal of the protecting group.
• the mole ratios are determined when all of the groups of that type are removed.
• a group is a protecting group if when, based on mole ratio determined by conventional techniques, 90% of that protecting group has been removed by a conventional deprotection reaction, no more than 50%, preferably 25%, more preferably 10%, of the deprotected product molecules of the invention have undergone irreversible changes to their covalent bond structure or oxidation/ reduction state other than those occasioned by the removal of the protecting group.
• Typical hydroxy protecting groups are described in Greene at pages 14-118 and indude Ethers (Methyl); Substituted Methyl Ethers (Methoxymethyl, Methylthiomethyl, t-Butylthiomethyl, (Phenyldimethylsilyl)methoxymethyl, Benzyloxymethyl, p-Methoxybenzyloxymethyl, (4-Methoxyphenoxy)methyl, Guaiacolmethyl, f-Butoxymethyl, 4-Pentenyloxymethyl, Siloxymethyl, 2- Methoxyethoxymethyl, 2,2,2-Trichloroethoxymethyl, Bis(2-chloroethoxy)methyl, 2-(Trimethylsilyl)ethoxymethyl, Tetrahydropyranyl, 3-Bromotetrahydropyranyl, Tetrahydropthiopyranyl, 1-Methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4- Methoxytetrahydrothiopyranyl, 4-
• hydroxy protecting groups indude subtituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic add esters, still more typically, trialkylsilyl ethers, tosylates and acetates.
• Typical 1,2- and 1,3-diol protecting groups are described in Greene at pages 118-142 and indude Cyclic Acetals and Ketals (Methylene, Ethylidene, l-t- Butylethylidene, 1-Phenylethylidene, (4-Methoxyphenyl)ethylidene, 2,2,2- Trichloroethylidene, Acetonide (Isopropylidene), Cyclopentylidene,
• Tetraisopropyldisiloxanylidene) Derivative Tetra-.-butoxydisiloxane-l,3- diylidene Derivative, Cyclic Carbonates, Cyclic Boronates, Ethyl Boronate, Phenyl Boronate).
• 1,2- and 1,3-diol protecting groups include those shown in Table 3, still more typically, epoxides and acetonides.
• Typical amino protecting groups are described in Greene at pages 315-385 and include Carbamates (Methyl and Ethyl, 9-Fluorenylmethyl, 9(2- Sulfo)fluoroenylmethyl, 9-(2,7-Dibromo)fluorenylmethyl, 2,7-Di-.-buthyl-[9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl, 4-Methoxyphenacyl); Substituted Ethyl (2,2,2-Trichoroethyl, 2-Trimethylsilylethyl, 2-Phenylethyl, 1-(1- Adamantyl)-l-methylethyl, l,l-Dimethyl-2-haloethyl, l,l-Dimethyl-2,2- dibromoethyl, l,l-Dimethyl-2,2,2-trichloroethyl, l-
• Methoxyphenylazo)benzyl 1-Methylcyclobutyl, 1-Methylcyclohexyl, 1-Methyl-l- cyclopropylmethyl, l-Methyl-l-(3,5-dimethoxyphenyl)ethyl, l-Methyl-l-(p- phenylazophenyl)ethyl, 1-Methyl-l-phenylethyl, l-Methyl-l-(4-pyridyl)ethyl, Phenyl, p-(Phenylazo)benzyl, 2,4,6-Tri-.-butylphenyl, 4- (Trimethylammonium)benzyl, 2,4,6-Trimethylbenzyl); Amides (N-Formyl, N- Acetyl, N-Choroacetyl, N-Trichoroacetyl, N-Trifluoroacetyl, N -Phenylacet
• amino protecting groups include carbamates and amides, still more typically, N-acetyl groups.
• Bundgaard pages 1 to 92 describe prodrugs and their biological cleavage reactions for a number of functional group types.
• Prodrugs for carboxyl and hydroxyl groups are detailed in Bundgaard at pages 3 to 10, for amides, imides and other NH-acidic compounds at pages 10 to 27, amines at pages 27 to 43, and cyclic prodrugs, as for example when J and L are taken together, at pages 62 to 70.
• the compounds of this invention contains 0 to 6 R ⁇ groups, typically 0 to 3 R ⁇ groups.
• Y is independently -N(R ⁇ , -N(R ⁇ )-S ⁇ 2-, or -N(R ⁇ CO-;
• E and U are independently H, or -(CR ⁇ R ⁇ ) m ⁇ -W ⁇ , with the proviso that at least one of E and U is -(CR ⁇ R ⁇ )ml-W ⁇ ;
• G and T are independently -(CR ⁇ R ⁇ )ml-W ⁇ / or -(CR ⁇ R ⁇ )mi-C(R ⁇ )(W ⁇ )(W2), with the proviso that: when E is -(CR ⁇ R ⁇ )mi-W ⁇ , then G is -(CR ⁇ R ⁇ )mi-W ⁇ , and when U is -(CRlRl)ml-W ⁇ , then T is -(CRiRi)ml-W ⁇ and G and T may be the same or different;
• J and L are independently H, N3, -OR2, -N(R2)(R2), or -N(R2)(R3), wherein R2 is H, or PRT with the proviso that at least one of J and L is -OR2; or J and L are taken together to form an epoxide, or a cyclic protecting group; Wi is W2 or W3;
• W2 is carbocycle or heterocycle, with the proviso that each W2 is independently substituted with 0 to 3 R5 groups;
• W3 is alkyl, alkenyl, or alkynyl, with the proviso that each W3 is independently substituted with 0 to 3 R ⁇ groups;
• Rl is R3 or R ⁇ ;
• R3 is H or R4;
• R4 is alkyl;
• R5 is R ⁇ , or R7, with the proviso that each R7 is independently substituted with 0 to 3 R ⁇ groups;
• R ⁇ is -0-(antigenic polypeptide), -N(R3)-(antigenic polypeptide), -C(0)0- (antigenic polypeptide), -C(0)N(R3)-(antigenic polypeptide), F, Cl, Br, I, -CN, N3, -NO2, -OR3, -N(R3)(R 3 ), -SR3, -0-C(0)R4, -N(R 3 )-C(0)R4, -C(0)N(R3)(PRT), -C(0)N(PRT)2, -C(0)N(R3)2, -C(0)OR3, -OPRT, -N(PRT) 2 , -C(NR3)(N(R3)2), - -C(N(PRT))(N(R3)(PRT)), -C(N(R3))(N(R3)(PRT)), -C(N(R3))(N(PRT) 2 ), -C(N(PRT)2),
• R7 is alkyl, alkenyl, or alkynyl
• Each ml is independently an integer from 0 to 3; and with the proviso that the compound, taken as a whole, contains 0 to 16 R ⁇ groups, and that each E, G, T, and U, taken individually, contain 0 to 8 R ⁇ groups.
• Y is -N(R3)-, more typically, Y is -N(H)-.
• E, G, J, L, T, discussed above, are also preferred in each of these embodiments.
• Formulas herein that do not depict stereochemistry are intended to include all possible stereochemistries.
• formulas I, ⁇ , and III do not depict stereochemistry for the sulfoxide or groups E, G, J, L, T, and U. All possible stereochemistries of these groups are intended. Table 1 lists specifically each of these intended stereochemistries for groups E, G, J, L, T and V.
• Table 1 may be redundant, being identical to one another by symmetry options.
• the designation ⁇ indicates that the group is projected behind the plane of the page and the designation ⁇ indicates that the group projects above the plane of the page.
• structure "a" in Table 10 is ⁇ Qb, ⁇ O-
• One preferred stereochemistry is that shown in structure "k" of Table 10, ⁇ Qb, ⁇ O-Qc, ⁇ Qd, ⁇ Qe, ⁇ O-Qf, ⁇ Qg or ⁇ E, ⁇ O-G, ⁇ j, ⁇ L, ⁇ O-T, ⁇ U.
• group Q a is -S(O)- (structure "b” from Table 11) then, depending on the choice of the remaining substituents and the ring substituent stereochemistries, an additional stereocenter is introduced.
• Each of the two possible sulfoxide diastereomers is intended, neither being uniquely preferred.
• the compounds of the invention can exist as optical isomers at any asymmetric atoms.
• the chiral centers designated by "*" in the depictions can exist as stereoisomers.
• racemic and diasteromeric mixtures of these isomers which may exist for certain compounds, as well as the individual optical isomers isolated or synthesized, being resolved or substantially (>90%) free of their enantiomeric or diastereomeric partners, are all within the scope of the invention.
• the 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.
• the compounds of the invention can also exist as tautomeric isomers in certain cases.
• ene-amine tautomers can exist for imidazole, guanine, amidine, and tetrazole systems and all the possible tautomeric forms of either are within the scope of the invention.
• compositions of this invention optionally comprise pharmaceutically acceptable non-toxic salts of the compounds herein, containing, for example, x ⁇ Na + , Li + , K + / Ca ++ and Mg ++ .
• Such salts may include those derived by combination of appropriate cations such as alkali and alkaline earth metal ions or ammonium and quaternary amino ions with an acid anion moiety, typically a carboxylic add, phenol, or the like.
• 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 predpitated from the solution of a more soluble salt by addition of the suitable metal compound.
• salts may be formed from acid addition of certain organic and inorganic adds, e.g., HC1, HBr, H2SO4 amino acids such as glutamic acid or aspartic acid, lysine, hydroxylysine, arginine or histidine, or organic sulfonic adds, with basic centers, typically amines, pyridine, or the like.
• organic and inorganic adds e.g., HC1, HBr, H2SO4 amino acids such as glutamic acid or aspartic acid, lysine, hydroxylysine, arginine or histidine, or organic sulfonic adds, with basic centers, typically amines, pyridine, or the like.
• Oxidation and alkylation of amine groups of the compositions of the invention to form N-oxides and quaternary ammonium salts, respectively, is also contemplated within the scope of the invention.
• compositions of the invention are depicted by the structures of formulas I, ⁇ , and HI.
• the compounds in the Table 14 exemplary list are designated by an alphanumerical format in which the first field is the seven membered ring structure of formulas I, II or III as numbered in Table 10.
• the second field represents Qa
• the third field represents Qb
• the fourth field represents Qc
• the fifth field represents Qd
• the sixth field represents Qe
• the seventh field represents Qf
• the eight field represents Qg, each attached by a covalent bond to the ring system as depicted in Table 10. Fields are separated by periods.
• the ring structures of Table 10 have labels Q a , Qb, Qc Qd, Qe, Qf, and Q g as shown.
• the groups shown in Table 11 are Q a groups.
• Table 12 are the Qb, Qc, Qf and Qg groups.
• the groups shown in Table 13 are the
• the first letter from left to right is one of the ring systems shown in
• Table 10 designated a-z and A-Y. This is the cyclic structure which is substituted by the 7 substituents spedfied by the remaining 7 designation codes.
• the second letter encodes the Q a group of the Table 10 structures specified in the first code letter.
• the Q a groups are listed in Table 11, where they are shown with flanking Qi sites.
• the Qi sites are located at the ring carbon atoms occupied by the Qg and Qb substituents.
• Qi is not a depiction of a group or bond but is only intended to show orientation of Q a -
• the third letter encodes the Qb group of the Table 10 ring structure specified by the first letter in the compound code. Refer to Table 12 and select the encoded Qb group.
• the "Q2" designation in the Table 12 groups depicts the site at which the Qb group is bonded to the ring carbon atom; Q2 does not stand for any group or bond, but instead (like Q_) is only intended to aid in determining the substitution site.
• the fourth letter (or combination of letters not separated by a period) encodes the Q c group of the designated ring structure. Again, refer to Table 12 to select the encoded group.
• Q2 has the same meaning as with Qb except that the bonding site is the oxygen atom shown in the Table 10 structure encoded by the first letter.
• the fifth letter encodes Qd- It is determined by reference to Table 13 in the same general fashion as was done for Q a , Qb and Q c .
• Q3 in Table 13 similarly is the designation of ring carbon atom site, but does not represent a bond or group in its own right.
• the seventh and eight letters encode Qf and Qg, respectively. They are decoded from Table 12 in the same fashion as Qb and Q c .
• aw.b.b.e.a k c.aA.aw.b.b.e.aA kx.aA.aw.b.b.e.aG kx aA.aw.b.b.m.a k.c.aA .aw.b.b.m.aA kx.aA.aw.b.b.m.aG k.c.aA. aw.b.b.ao.a k. c.aA.aw.b.b.o.aA kx.aA.aw.b.b.o.aG kx, aA.aw.b.b.E.a k.c.aA.
• caG.R.b.b.aw.a k caG.Rb.b.aw.aA kx.aG.Rb.b.aw.aG k. caG.Rb.b.aA.a k. c.aG.Rb.b.aA.aA k caG.R.b.b.aA.aG k.caG.R.b.b.aG.a k. caG.R.b.b.aG.aA k. caG.Rb.b.aG.aG k. caG.Rb.b.aG.aG k c.aG.aw.a.b.a.a kx.aG.aw.a.b.a.aA k.
• caG.aw.b.b.Ra k caG.aw.b.b.RaA kx.aG.aw.b.b.RaG k. c.aG.aw.b.b.aw.a k. c.aG.aw.b.b.aw.aA k.caG.aw.b.b.aw.aG k. caG.aw.b.b.aA.a k caG.aw.b.b.aA.aA kx.aG.aw.b.b.aA.aG k.
• caG.aA.a.b.e.aG kx.aG.aA.a.b.m.a k caG.aA.a.b.m.aA k
• caG.aA.a.b.o.aG k caG.aA.a.b.E.a k.caG.aA.a.b.E.aA k. caG.aA.a.b.E.aG k. caG.aA.a.b.E.aG k.
• caG.aA.b.a.o.aG k caG.aA.b.a.E.a kx.aG.aA.b.a.E.aA k, c.aG.aA.b.a.E.aG k. c.aG.aA.b.a.Ra k. caG.aA.b.a.R.aA kx.aG.aA.b.a.RaG k. c.aG.aA.b.a.aw.a k.
• compositions comprising compound(s) of this invention plus one or more pharmaceutically-acceptable carriers.
• One or more compounds of the invention are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient.
• 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 oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) administration.
• 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) which is incorporated by reference herein. 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 invention suitable for oral administration are prepared as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
• the active ingredient may also be presented as a bolus, electuary or paste.
• a tablet is made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
• the tablets may optionally are 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 paraffinic or a water- miscible ointment base.
• the active ingredients may be formulated in a cream with an oil-in-water cream base.
• the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, 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.
• 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.
• 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, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
• Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
• the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active lOtr compound in most oils likely to be used in pharmaceutical emulsion formulations is very low.
• the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
• Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and /or liquid paraffin or other mineral oils are used.
• Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
• the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
• Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
• Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
• Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to 500 microns (including particle sizes in a range between 20 and 500 microns in increments of 5 microns such as 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
• Suitable formulations wherein the carrier is a liquid, for administration as for example a nasal spray or as nasal drops include aqueous or oily solutions of the active ingredient.
• Formulations suitable for aerosol administration may be prepared according to conventional methods and may be delivered with other therapeutic agents.
• Formulations suitable for inhalation therapy are prepared as aerosols or powders having a particle size small enough to dose the alveoli. Such powders and aerosols are prepared by any of the methods common in the art. Ordinarily aerosols are aqueous aerosols.
• Formulations suitable for vaginal administration may be presented as l ⁇ (> pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
• Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried
• sterile liquid carrier for example water for injections
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
• Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
• formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• the 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.
• controlled release formulations in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
• Effective dose of active ingredient depends on the nature of the condition being treated, the method of treatment, pharmaceutical formulation, and the like. It can be expected to be from about 0.001 to about 30 mg/kg body weight per day. Particular dose ranges are determined by the methods common in the art.
• Such methods include dose escalation studies involving animal models such as l ⁇ SIV in monkeys or HIV IN SOD mouse systems. Studies of this type take into account effectiveness and toxicity of a particular dose among other variables commonly studied in the art.
• Active ingredients of the invention are also used in combination with other active ingredients heretofore employed or useful in the treatment of HIV, including nucleotide or nucleoside analogues such as PMEA, PMPA, PMEDAP, PMPDAP, DDI, AZT, DDC, D4T, D4AP, bis(POM) PMEA and the like. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. Metabolites of the Compounds of the Invention
• the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of structure I, II, or HI with a mammal for a period of time sufficient to yield a metabolic product of the compound.
• a radiolabeled (e.g. C* or H ⁇ ) compound of structure I, II, or HI typically are identified by preparing a radiolabeled (e.g. C* or H ⁇ ) compound of structure I, II, or HI, administering it parenterally in a detectable dose (e.g.
• metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
• the conversion products are useful in diagnostic assays for therapeutic dosing of the compounds of structure I, ⁇ , or HI - even if they possess no HIV protease inhibitory activity of their own.
• Particular compounds are products of cytochrome-mediated oxidation. These include oxidation of aryl groups to phenolic groups and amino to hydroxyl. They are identified by incubating the compounds described herein with liver cytochrome preparations in conventional fashion.
• the compounds of this invention or the biologically active substances lot produced from these compounds by hydrolysis or metabolism in vivo, are used as immunogens to prepare antibodies capable of binding specifically to the compounds or their metabolic products which retain immunologically recognized epitopes (sites of antibody binding).
• the immimogenic compositions therefore are useful as intermediates in the preparation of antibodies for use in diagnostic, quality control, or the like methods or in assays for the compounds or their novel metabolic products.
• the hydrolysis products of interest include products of the hydrolysis of protected acidic groups (such as carboxylic acids and phenols), hydroxy groups, and basic groups (such as amines).
• protected acidic groups such as carboxylic acids and phenols
• hydroxy groups such as hydroxy groups
• basic groups such as amines.
• the metabolic products described above may retain a substantial degree of immunological cross reactivity with the compounds of the invention.
• the antibodies of this invention will be capable of binding to the inhibitor compounds of the invention without binding to the non-inhibitory protected compounds; alternatively the metabolic products, will be capable of binding to the non-inhibitory protected compounds and /or the metabolitic products without binding to the inhibitory compounds of the invention, or will be capable of binding specifically to any one or all three.
• the antibodies desirably will not substantially cross-react with naturally- occurring materials (other than naturally produced metabolites as discussed above).
• Substantial cross-reactivity is reactivity under specific assay conditions for specific analytes such that it interferes with
• the immunogens of this invention contain the compound presenting the desired epitope in association with an immunogenic substance such as an antigenic polypeptide.
• an immunogenic substance such as an antigenic polypeptide.
• association means covalent bonding to form an immunogenic conjugate (when applicable) or a mixture of non-covalently bonded materials, or a combination of the above.
• Immunogenic substances include adjuvants such as Freund's adjuvant, immunogenic proteins such as viral, bacterial, yeast, plant and animal polypeptides, in particular keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor, and immimogenic polysaccharides.
• the compound having the structure of the desired epitope is covalently conjugated to an immunogenic polypeptide or polysaccharide by the use of a polyfunctional (ordinarily bifunctional) cross-linking agent.
• a polyfunctional (ordinarily bifunctional) cross-linking agent for the manufacture of hapten immunogens are conventional per se. and any of the methods used heretofore for conjugating haptens to immunogenic polypeptides or the like are suitably employed here as well, taking into account the functional groups on the precursors or hydrolytic products which are available for cross-linking and the likelihood of producing antibodies specific to
• polypeptide is conjugated to a site on the compound of the invention distant from the epitope to be recognized.
• the conjugates are prepared in conventional fashion.
• the conjugates comprise a compound of the invention attached by a bond or a linking group of 1-100, typically, 1-25, more typically 1-10 carbon atoms to the immunogenic substance.
• the conjugates are separated from starting materials and by products using chromatography or the like, and then are sterile filtered and vialed for storage.
• the compounds of this invention are cross-linked for example through any one or more of the following groups: a hydroxyl group of E, G, J, L, T, or U; a carboxyl group of E, G, T, or T; a carbon atom of the compound of formulas I, ⁇ , or HI in substitution of H and/or an amine group of E, G, J, L, T, or U.
• Animals are typically immunized against the immunogenic conjugates or derivatives by combining 1 mg or 1 ⁇ g of conjugate (for rabbits or mice, respectively) with 3 volumes of Freund's complete adjuvant and injecting the solution intradermally at multiple sites.
• the animals are boosted with 1/5 to 1/10 the original amount of conjugate in Freund's complete adjuvant (or other suitable adjuvant) by subcutaneous injection at multiple sites.
• 7 to 14 days later animals are bled and the serum is assayed for the desired antibody titer. Animals are boosted until the titer plateaus.
• the animal is boosted with the conjugate in which the precursor or product is linked to a different protein, through a different cross-linking agent or both.
• aggregating agents such as alum are used to enhance the immune response.
• monoclonal antibodies are prepared by recovering immune lymphoid cells (typically spleen cells or lymphocytes from lymph node tissue) from immunized animals and immortalizing the cells in conventional fashion, e.g., by fusion with myeloma cells or by Epstein-Barr virus transformation and screening for clones expressing the desired antibody.
• immune lymphoid cells typically spleen cells or lymphocytes from lymph node tissue
• immortalizing the cells in conventional fashion, e.g., by fusion with myeloma cells or by Epstein-Barr virus transformation and screening for clones expressing the desired antibody.
• the hybridoma technique described originally be Kohler and Milstein, Eur. J. Immunol. (1976) 6:511 has been widely applied to produce hybrid cell lines that secrete high levels of monoclonal antibodies against many specific antigens. It is possible to fuse cells of one species with another. However, it is preferably that the source of the immunized antibody producing cells and the myelom
• the hybrid cell lines are maintained in culture in vitro.
• HO this invention are selected or maintained in a hypoxanthine-aminopterin thymidine (HAT) medium.
• HAT hypoxanthine-aminopterin thymidine
• the secreted antibody is recovered from culture by conventional methods such as precipitation, ion exchange chromatography, affinity chromatography, or the like.
• the antibodies described herein are also recovered from hybridoma cell cultures by conventional methods for purification of IgG or IgM as the case may be that heretofore have been used to purify immunoglobulins from pooled plasma, e.g., ethanol or polyethylene glycol precipitation procedures.
• the purified antibodies are sterile filtered, and optionally are conjugated to a detectable marker such as an enzyme or spin label for use in diagnostic assays of test samples.
• the antibodies of this invention are obtained from any animal species, but ordinarily are from murine or rat. Once a monoclonal antibody having the desired specificity and affinity is obtained, other conventional modifications of the antibodies are within the scope of this invention. For example, the complementarity determining regions of an animal antibody, together with as much of the framework domain as is needed, are substituted into an antibody of another animal species or class to produce a cross-class or cross-species chimeric antibody. Fragments or other amino acid sequence variants of monoclonal antibodies also are encompassed within the meaning of antibody as that term is used herein, for example, Fab, Fab' or (Fab')2 fragments, single chain antibodies, bi or polyspe ⁇ fic antibodies, and the like.
• the antibodies of this invention are from any suitable class or isotype, e.g. IgG, IgM, IgA, IgD or IgE. They may or may not participate in complement binding or ADCC.
• hybridomas which are capable of binding to the immunogen are screened for the ability to bind to the hapten itself in typical test samples (plasma, serum and the like) with the requisite degree of affinity.
• the desired affinity will depend upon the use intended for the antibody, but should be adequate to function in a conventional competitive-type ELISA or radioimmunoassays, or in conventional EMIT immunoassays.
• the antibodies of this invention are used in such assays together with a labeled form of the compounds of the invention.
• the antibody is labeled.
• Suitable labels are well-known and include radioisotopes, enzymes, stable free radicals, fluorophors, chemiluminescent moieties and other detectable groups heretofore employed to prepare covalent conjugates for use in assays.
• Methods for linking the labels to ligand amino groups, or amino acid side chains or termini of polypeptides are known and are suitable for use herein. Other suitable linking methods will be apparent to the ordinary artisan.
• Ill Labels are conveniently bound to the thiepanes herein at the same sites used for bonding to antigenic polypeptides.
• the antibodies and labeled ligands herein optionally are assembled into kits for use in therapeutic drug monitoring or evaluation, or for process quality control, and used in the conventional manner.
• the invention also relates to methods of detecting HTV protease in a sample suspected of containing HIV protease comprising the steps of: treating a sample suspected of containing HTV protease with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label.
• compositions of the invention are inhibitors of HIV protease. As such frequently the compositions will bind to locations on the surface or in a cavity of HIV protease having a geometry unique to HIV protease. Compositions binding HTV protease may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, the substantially irreversibly binding compositions become probes for the detection of HTV protease.
• compositions of the invention are screened for inhibitory activity against
• compositions are first screened for inhibition of HTV protease in vitro and compositions showing inhibitory activity are then screened for activity in vivo.
• Compositions having in vitro Ki (inhibitory constants) of less then about 5 X 10"6 M, typically less than about 5 X 10"* 7 M and more typically less than about 5 X 10"8 M are excellent candidates for in vivo screening.
• compositions of the invention bind HIV protease. Accordingly, they are useful in any of the assay methods described. They are also inhibitors of HTV
• protease and as a result are useful as negative controls and analytical standards in any of the described methods of assay for HTV protease activity.
• a composition which inhibits HIV protease is useful for suppressing HIV protease in an assay which detects HIV protease activity, thereby acting as a negative control or analytical standard.
• Another aspect of the invention relates to methods of inhibiting the activity of HIV protease comprising the step of treating a sample suspected of containing HTV protease with a composition of the invention.
• samples suspected of containing HIV protease include natural or man-made materials such as living organisims; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells; and the like.
• biological material samples blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like
• laboratory samples food, water, or air samples
• bioproduct samples such as extracts of cells; and the like.
• samples can be contained in any medium including water and organic solvent ⁇ water mixtures.
• samples include living organisms such as mammals and man made materials such as bioproduct samples, more typically, samples include humans.
• the treating step of the invention can involve adding the composition of the invention to the sample or it can involve adding a precursor of the composition to the sample.
• the addition step comprises any method of administration as described above.
• the activity of HIV protease after application of the composition can be observed by any method including direct and indirect methods of detecting HTV protease activity. Quantitative, qualitative, and semiquantitative methods of determining HIV protease activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
• the compounds of the invention are polyfunctional. As such they represent a unique class of monomers for the synthesis of polymers.
• the polymers could include polyamides and polyesters.
• Polyamides and polyesters are materials of well known utility and the present monomers provide access to polymers having unique pendent functionalities.
• Polymers are prepared from the compounds of the invention by conventional techniques. Polyesters are prepared from the compounds having a carboxylic acid group and an alcohol or other leaving group. Alternatively, a diol composition of the invention is reacted with a diacid monomer. Polyamides are prepared from the compounds of the invention containing one or more amine groups.
• the compounds of the invention are also a unique class of polyfunctional surfactants.
• the sulfur group Q a and the groups comprising E, G, T, and U having a chain of carbon atoms are spatially separated by the 7-membered ring structure and thus have the properties of bi-functional surfactants. As such they have useful surfactant, surface coating, emulsion modifying, rheology modifying and surface wetting properties.
• the compounds of the invention are useful as a unique class of phase transfer agents.
• the compounds of the invention are useful in phase transfer catalysis and liquid/liquid ion extraction (LIX).
• the compounds of the invention optionally contain asymmetric carbon atoms in groups E, G, T, or U. As such, they are a unique class of chiral auxiliaries for use in the synthesis or resolution of other optically active materials.
• a racemic mixture of carboxylic acids can be resolved into its component enantiomers by: 1) forming a mixture of diastereomeric esters with a compound of the invention having one or more -OH groups; 2) separating the diastereomers; and 3) hydrolyzing the ester structure. Racemic acids are also separated by amide formation with an amine function of the molecule of the invention. Further, such a method can be used to resolve the compounds of the invention themselves if optically active acids, bases or alcohols are used instead of racemic starting materials.
• the invention also relates to methods of making the compositions of the invention.
• the compositions are prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in "Compendium of Organic Synthetic Methods" (John Wiley & Sons, New York), Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G. Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B.
• compositions of the invention are provided below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods.
• reaction conditions such as temperature, reaction time, solvents, workup procedures, and the like, will be those common in the art for the particular reaction to be performed.
• the incorporated 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.
• Workup typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer containing the product.
• Oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20°C) or at temperatures corresponding to the boiling point of solvents used in the reaction, although for metal hydride reductions frequently the temperature is reduced to 0°C to -100°C.
• Solvents are typically protic for sodium borohydride reductions and may be either protic or aprotic for oxidations. More typically, oxidations of hydroxy groups pendant on the thiepane ring to form corresponding carbonyls are carried out in refluxing toluene. Reaction times are adjusted to achieve desired conversions.
• Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0°C to -100°C) are also common. More typically, Claisen-Schmidt condensations are carried out in refluxing toluene. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled reactions). Standard synthetic techniques such as azeotropic removal of reaction by ⁇ products and use of anhydrous reaction conditions (e.g. inert gas environments) are common in the art and will be applied when applicable.
• anhydrous reaction conditions e.g. inert gas environments
• the starting thiepane diols for these preparations are available from D- mannitol and D-sorbitol by literature methods.
• the enantiomeric series (illustrated as diols 1) is available in analogous fashion from L-mannonolactone and L-glucuronolactone after sodium borohydride reduction by the method of H.L. Frush, H.S. Isbell, J. Am. Chem. Soc. 78, 2844-2846 (1956).
• Diols 5, 6 or 7 are individually alkylated by methods such as the Williamson ether synthesis described in March Advanced Organic Chemistry Org. 2nd, reaction 0-14 p 357 and Feuer and Hooz, pp446-450, 460-468 in The Chemistry of the Ether Linkage, S. Patai Ed., Inters ⁇ ence Pub., New York, NY (1967) or arylated C. Paradisi "Arene Substitution via Nucleophilic Addition to Electron Deficient Arenes" p423-450 in Comprehensive Organic Synthesis V4 sect 2.1, Trost and Fleming Ed., Pergamon Press, (1991); J.B. Hynes, J. Heterocyclic
• Monoethers may be etherified with the different groups to provide unsymetrically substituted diethers 8.
• Kb Diols 5-7 may also be acylated with a variety of methods to form esters or carbamates 8.
• the acetonide may be retained to the end and removed after sulfur oxidation. This sequence is advantageous for those stereochemical relationships (idito) which favor sulfur participation and resulting ring contraction, J. Kuszmann and P. Sohar., Carb Res. 56, 105-115 (1977).
• the diols 9 are converted to the corresponding epoxides 11 by methods such as those described in O. Mitsunobu "Synthesis of Alcohols and Ethers" p25- 31 in Vol. 1 sect 1.1.3.2 of Comprehensive Organic Synthesis, Trost and Fleming Ed., Pergamon Press (1991); D. R Hicks and B. Fraser-Reid, Synthesis 203 (1974); and O. Mitsunobu et al. Chem. Lett. 1613 (1980)).
• the initial thiepane diols 1 may also be oxidized to the diastereotopic sulfones 16, 17 or 18 by methods described earlier.
• the epoxy derivatives 25 are converted to azido alcohols 26 or 27 or amino alcohols 28 or 29 by methods such as those discussed in O. Mitsunobu "Synthesis of Amines and Ammonium Salts" p65-101 in Vol. 6 sect 1.3 of Comprehensive Organic Synthesis, Trost and Fleming Ed., Pergamon Press (1991).
• epoxides are also reduced by methods such as those discussed in S. Murai "Reduction of Epoxides" p871-893 in Vol. 8 sect 4.4 of Comprehensive Organic Synthesis, Trost and Fleming Ed., Pergamon Press (1991) and Y. Fort et al. Tet. Lett. 26, 3111 (1985) to provide the monoalcohol analogs 30 and 31.
• Azido alcohols 26 or 27 after adjustment of the sulfur oxidation state are reduced to the corresponding amino alcohols 28 or 29 by methods such as those listed in RC. Larock, p 409-410 in Comprehensive Organic Transformations, VCH Publishers, New York, NY (1989).
• the acetonide of dimethyl L-tartrate 32 is converted into the diketone 33 by the method of I. Kikkawa and T. Yorifuji, Synthesis 877-880 (1980).
• the bis- silyl enol ether 34 is prepared by the methods of H. Emde et al., Liebigs Ann. Chem. 1643 (1981); S. Torkelson and C. Ainsworth, Synthesis 431 (1977); or other methods as discussed in T. H. Chan "Enol Ethers" p 595-628 in Vol. 2 sect 2.3 of Comprehensive Organic Synthesis, Trost and Fleming Ed., Pergamon Press (1991).
• the bis-enol ether 34 is cydized via SC12 according to the method of M. Muehlstaedt, D. Martinez and P. Schneider, J. Prakt. Chemie. 315, 940-948 (1973) to diketone 15 which is reduced to diol 5 as discussed before.
• Alternatively 34 is halogenated by methods such as J. Org. Chem. 39, 1785 (1974), J. Org. Chem. 52, 3346 (1987) and Synthesis 194 (1976) to the bis haloketone and cyclized with sulfide reagents such as NaHS or Na2S to give the cyclic i/r diketone 15.
• Tet. Lett. 4771 (1967) is converted by the method of I. Kikkawa and T. Yorifuji, Synthesis 877-880 (1980) to the keto alcohol 36.
• Activation with tosylate and displacement by sulfide provides the thiepane bisacetonide 38.
• Diol 7 obtained as described in Scheme 1 is monoalkylated to ether 40, either directly or via a monoprotected intermediate. After oxidation to the sulfone 41, the equatorial alcohol is eliminated via methanesulfonylchloride and triethyl amine in methylene chloride to vinyl sulfone 42. Michael addition of various nudeophiles such as amines, thiols or carbon based nudeophiles sud as cuprates provides structures such as 43 or its stereoisomers.
• Diol 5 is activated by acylation or alkylation to 45 followed by oxidation to the corresponding sulfone 46.
• Base induced elimination provides the divinyl sulfone 47.
• Other diol stereoisomers may be oxidized to the sulfone first and then dehydrated to the desired sulfone 47.
• Nudeophilic addition with amines, or thiols gives 48, or 50.
• Alkoxy nudeophiles will provide O-linked structures such as 64 (Scheme 12). With some nudeophiles, the elimination and Michael addition may occur in the same pot to provide the adducts directly from 46.
• Acetonide removal provides the sulfone diol 49, or 51.
• An alternative route to the divinyl sulfone 47 involves condensation of sulfone 54 with L-tartaric ester-derived dialdehyde 55 followed by dehydration.
• diastereomers of diol 62 can be oxidized to the corresponding diketone and reduced to the desired stereochemistry. After activation of the hydroxyls to structures 63, ring dosure to structures 8 will occur. Oxidation to sulfones 64 and deprotection provides the sulfone diols 11.
• the dialdehyde 61 is a versatile intermediate which can be olefinated to the diene 65 or epoxidized to 66, directly or via 65.
• Regioselectivity of the epoxide opening and ring dosure reactions can be moderated by the steric and electronic characteristics of the R" substituent as well as by solvent and counter ion effects.
• Thiepane 67 can be converted to diol sulfones in a variety of routes, retaining the extra alkoxy substituents or eliminating them to olefin or saturated side chains as illustrated in structures 8 or 68.
• Divinyl sulfone 68 can be further elaborated by conjugate addition reactions similar to those described in Scheme 8 or by conjugate redudion to provide saturated structures such as 64 (Scheme 11).
• the tartrate derived silyl enol ether may be condensed with thionyl chloride to give the diketosulfoxide 70 which can be reduced to thiepane diol 5 l£0 or oxidized to the sulfone 71 and then reduced and eliminated to give the divinyl sulfone 47.
• the readion of silyl enolethers with thionyl chloride is described in B. Zwanenburg, "Phosphorus, Sulfur and Silica" 43, 1-24 (1989).
• Chiral 102 is readily available by routes described in CR. Johnson, P.A. Pie, L. Su, M.J. Heeg, J.P. Adam., Synlett 338 (1992) and L. Dumortier, P. Liu, S. Dobbelarere, J. Van der Eycken, M. Vanderwalle., Synlett, 243 (1992).
• Another preparation of 104 is described by H-J Altenbach in Antibiotics and Antiviral Compounds, Chemical Synthesis and Modification, Eds.; K. Krohn, H.A. Kirst, H. Maag: VCH Publishning Inc., p. 359 (1993).
• Alternatively 42 is deprotected in 50%TFA/30%methanol/20%water for 30 minutes to provide the vinyl sulfone diol 207.
• Treatment of 207 with various primary amines in refluxing solvents such as ethanol or toluene provides the aminosulfones 208.
• Monoalcohols 209 or 41 are oxidized to the keto sulfones 210.
• Enamine formation to the vinylogous sulfonamides 211 will occur under dehydrating conditions such as azeotropic removal of water, or treatment with drying agents such as molecular sieves or magnesium sulfate. Reduction of the enamine provides the aminosulfones 212.
• Reductive cleavage of the N-O bond affords the diol 218 which is dehydrated to the exocyclic divinylsulfone 219.
• Michael addition of N,S,0 or C based nudeophiles provides the aminosulfones 220.
• R" is not hydrogen
• hydrogenolysis or dehydration/redudion may afford the corresponding amionosulfones 220.
• Deprotection provides the aminodiols 221.
• the bisisoxazolidines 217 can be built sequentially by the condensation of known nitrones 222, S. Saito et al., Synlett, 282-284 (1994) with divinylsulfones 216 to provide the monocydic isoxazolidine 223. Deprotection of the protected primary alcohol function is followed by oxidation to the aldehyde 224. Condensation with an N-substituted hydroxylamine provides the nitrone 225 which can then undergo an intramolecular cycloaddition reaction to 217 optionally deprotected to sulfone diol 226.
• the starting tartrate esters 251 are available from natural L-tartaric acid by literature methods, L.T. Rossaano, Tet. Lett., 36, 4967 (1995). Treatment with N,0-dimethylhydroxylamine, S. Nahm, Tet. Lett., 39,
• diketones 255 may be available directly from bis- amides 252 via acylation of thio 1,3-dianions, E.M. Kaiser, Tet. Lett., 3341 (1967); S. Patai, Ed., "The Syntheses of Sulphones, Sulphoxides and Cyclic Sulphides", J. Wiley & Sons, New York, NY (1994).
• Keto amides 254 are also available in sequential fashion starting from diols 258, S. Terashima, Tet. Lett. 23, 4107 (1982) and L.J. Rubin, J. Am. Chem. Soc. 74, 425 (1952).
• Tartrate esters 251 are reduced to dialdehydes 262 with DIBAL, A. Krief, Tetrahedron, 45, 3039 (1989). Alkylation of metalated sulfer reagents 253 provide alcohols 263 or diols
• aldehydes 265 H. Iida, J. Org. Chem., 52, 3337 (1987) and T. Mukaiyama, Tetrahedron, 46, 265 (1990).
• Treatment of aldehydes 265 with metalated sulfer reagents 253 allow access to the mono protected diols 266.
• Protecting group removal followed by oxidation provide aldehyde intermediates 263.
• epoxide opening can be performed seqentially via basic hydrolysis of intermediates 275.
• a stepwise route toward intermediate 279 also allow access to thiepane 256.
• Wittig olefination of aldehydes 265 provide (Z)-olefins 276. Directed epoxidation followed by nucleophilic opening affords alcohols 278.
• aldehydes 279 which can be converted to oxiranes 275 by repeating the initial two step sequence described in Scheme 31.
• Lithium aluminum hydride reduction, G.R. Newkome, J. Org. Chem., 52, 5480 (1987) give allylic alcohols 281 which undergo Sharpless asymmetric epoxidation, T. Katsuki, J. Org. Chem., 47, 1373 (1982) to provide 282.
• O-alkylation, arylation or acylation provide the bis-hydroxymethyl thiepanes 286.
• sulfones 257 Interconversion of the free hydroxyls to suitable leaving groups (e.g. mesylates, tosylates, halides, etc), nucleophilic displacement and sulfide oxidation afford sulfones 257.
• suitable leaving groups e.g. mesylates, tosylates, halides, etc
• Epoxides 284 can also be assembled in stepwise fashion following the general protocol described in Scheme 32.
• An optional method to stereoselectively prepare bis-(Z)-olefins 273 involve a formyl to ethynyl conversion as described by E.J. Corey, Tet. Lett. 3769 (1972).
• Treatment of dialdehydes 262 with CBr 4 and PPI. 3 afford intermediate bis-vinylidene dibromides which undergo elimination and metal halogen exchange upon treatment with alkyllithium bases.
• the resultant terminal alkynes can be isolated, remetalated, and homologated to provide bis-alkynes 290 or obtained directly by alkylation of the intermediate alkynyllithium.
• Wittig salt 296 can be prepared according to the procedure described in Scheme 37.
• Olefination of 296 provide 276 which is elaborated to compounds 278 according to Scheme 32.
• O-alkylation, arylation or acylation of the secondary alcohol, followed by deprotection of the primary alcohol afford compounds which can be subjected to the above sequence (halogenation, Wittig olefination) allowing entry to compounds 275.
• reaction products from one another and/or from starting materials.
• the desired products of each step or series of steps are separated and/or purified (hereinafter separated) to the desired degree of homogeneity by techniques common in the art.
• separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
• Chromatography can involve any number of methods including, for example, size exclusion or ion exchange chromatography, high, medium, or low pressure liquid chromatography, small scale and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
• reagents selected to bind to or render otherwise separable a desired product, unreacted starting material, reaction by product, or the like.
• reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, or the like.
• the reagents can be acids in the case of a basic material, bases in the case of an acidic material, binding reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (liX), or the like.
• Cis dihydroxylation of 408 provides a single diastereomer 409 which may be deprotected and adjusted to the cis diol diastereomer 413.
• Cyclization of 409 into the cis protecting group provides the oxazolidinone 410 which allows activation of the remaining hydroxyl and displacement via neighboring group participation to the symmetrical 411.
• Hydrolysis of the carbamate rings provide the trans diols 412. Final adjustment of sulfur oxidation state may be accomplished at this point if not earlier.
• Scheme 64 An alternative preparation of bis-olefins 457 is as follows. Condensation of aldehydes 462 with amines 463 provide imines 464. Nucleophilic addition of a vinyl group (e.g. vinyllithium, grignard, cuprate, etc.) afford the allylic amines 465 which are resolved to provide optically active 466, J.D. Morrison, Ed., Asymmetric Synthesis, Vol 1, Academic Press, Inc., New York, NY (1983). Alternatively, amines 466 may be available directly from imine 464 via stereoselective organometallic addition. Coupling of amines 466 with an appropriate acylating reagent (e.g. CDI, phosgene, etc.) afford bis olefins 457.
• an appropriate acylating reagent e.g. CDI, phosgene, etc.
• compositions described in the Examples are uniquely designated as indicated in Tables 101, 107 and 108 based on the following formula:

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