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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
  • C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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  • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
  • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/36—Sulfur atoms
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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  • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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  • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
  • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
  • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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  • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the invention relates to 4-amino-3-hydroxycarboxylic acid derivatives. It concerns the compounds of formula I
• a and B independently are a bond or an optionally substituted aminoacyl moiety
• R 1 is hydrogen; an amino protecting group; or a group of formula R 6 Y- wherein
• R 6 is hydrogen or an optionally substituted alkyl, alkenyl, alkinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group;
• Y is -CO-; -NHCO-; -NHCS-; -SO 2 -; -O-CO-; or -O-CS-;
• R 2 is the side chain of a natural amino acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl,
• R 3 is an optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group;
• R 4 is a group of formula -OR 7 or -NHR 7 wherein
• R 7 has the significance indicated above for R 6 ;
• X is -S- or -NR 5 - wherein
• R 5 is hydrogen, methyl, formyl or acetyl
• One approach for effecting retroviral inhibition is the use of an inhibitor of a viral proteinase essential for processing viral polypeptide precursors by proteolytic maturation, e.g. the HIV proteinase.
• the compounds of the present invention are antivirally active. They inhibit the HIV proteinase.
• R 1 preferably is 2-pyridylmethoxycarbonyl, benzyl-CH(OH)-carbonyl, phenoxymethylcarbonyl or an amino protecting group such as
• A preferably is an optionally substituted aminoacyl moiety, preferably an optionally substituted ⁇ -aminoacyl moiety such as alanine, leucine, isoleucine, asparagine, valine, tert-butylglycine, tert-leucine or histidine. It preferably is the optionally protected moiety of a natural ⁇ -amino acid, preferably of an amino acid which is a normal constitutive part of proteins. It especially is L-valine.
• R 2 preferably is the side chain of a natural amino acid,
• ⁇ -amino acid preferably of an amino acid which is a normal constitutive part of proteins. It is e.g. isopropyl,
• aminocarbonylmethyl methyl, 1-methylpropyl, benzyl, 4-hydroxybenzyl or isobutyl, preferably benzyl.
• B preferably is an optionally substituted aminoacyl moiety, preferably an optionally substituted ⁇ -aminoacyl moiety, such as
• R 4 preferably is a group -NHR 7 ; it preferably is isopropylamino, tert-butylamino, 1- or 2-naphthylmethylamino, or 2-, 3- or 4-pyridylmethyl-amino; it especially is benzylamino or benzimidazolylmethylamino,
• R 3 preferably is an optionally substituted arylalkyl group, especially benzyl.
• the aryl part of arylalkyl optionally is substituted by, preferably, alkoxy or 1 to 4 carbon atoms, such as methoxy, or halogen of atomic number of from 9 to 35, such as bromine; it preferably is monosubstituted, preferably in 3 or 4 position; it especially is
• X preferably is a group -NR 5 - as defined above. It especially is the imino group.
• R 6 preferably is an optionally substituted alkyl, arylalkyl or heteroarylalkyl group, especially alkyl; when it is optionally substituted heteroarylalkyl it preferably is pyridylalkyl, especially 2-pyridylmethyl; when it is optionally substituted arylalkyl it preferably is
• Y preferably is -CO- or -O-CO-, especially -CO-.
• R 7 preferably is an optionally substituted alkyl, arylalkyl or heteroarylalkyl group, preferably phenylalkyl of altogether 7 to 10 carbon atoms such as benzyl, or a pyridylalkyl, indolylalkyl or
• Rs preferably is hydrogen or methyl, especially hydrogen.
• a salt is e.g. an acid addition salt such as a hydrochloride.
• the compounds of formula I normally have several chiral centers and can therefore exist in a variety of stereoisomers.
• the invention provides all stereoisomers as well as racemic mixtures.
• the isomers may be resolved or separated by conventional techniques, e.g. chromatographically.
• the carbon atom in 4 position preferably has the S configuration.
• An optionally substituted aminoacyl moiety preferably is unsubstituted. When it is substituted it e.g. is substituted by alkyl of 1 to 4 carbon atoms, such as in O-tert-butyl-L-serinoyl or in
• 2-aminobutanoyl It preferably is in the L optically active form. It preferably is an ⁇ -aminoacyl moiety, such as valine or tert-leucine.
• Optionally substituted alkyl preferably is alkyl of 1 to 5 carbon atoms, preferably of 1 to 4 carbon atoms, e.g. methyl, ethyl, isopropyl or tert-butyl; it is especially of 1 or 4 carbon atoms.
• the substituent is e.g. phenoxy, hydroxy or optionally protected amino.
• Optionally substituted arylalkyl is e.g. phenylalkyl of altogether 7 to 10 carbon atoms, such as benzyl or 2-phenylethyl; it is optionally substituted by e.g. hydroxy, such as in benzyl-CH(OH)- or
• phenyl-CH(CH 2 OH)- or is e.g. naphthylalkyl of 1 to 4 carbon atoms in the alkylene part.
• An amino protecting group preferably is benzyloxycarbonyl or tert-butoxycarbonyl.
• Optionally substituted heteroarylalkyl preferably is pyridylalkyl, especially 2-pyridylmethyl.
• heteroarylalkyl may be mono- or polycyclic, such as e.g. pyridyl, naphthyl, 9-fluorenylmethoxycarbonyl (FMOC) or benzimidazolyl.
• the alkylene part of arylalkyl or heteroarylalkyl may be substituted by e.g. hydroxy.
• heterocyclylalkyl group is a saturated heterocyclic group having one or more heteroatoms selected from nitrogen, oxygen and sulfur. It preferably has 5 or 6 ring constitutent atoms, and preferably up to 3 heteroatoms.
• Cycloalkylalkyl preferably is cyclohexylalkyl; it preferably is of 1 to 4 carbon atoms in the alkylene part.
• a subgroup of compounds of formula I is the compounds of formula I wherein A and B independently are a bond, the aminoacyl moiety of a natural amino acid, the D-enantiomer thereof, or tert-butylglycine, and the other substituents are as defined above.
• a further subgroup is the compounds of formula I wherein R 1 A- is an optionally substituted and optionally N-terminal protected natural aminoacyl moiety, -BR 4 is a natural aminoacyl moiety optionally esterified or amidated at the C-terminus , R 2 is the side chain of a natural amino acid, R 3 is an alkyl, alkenyl, cycloalkyl, aryl or arylalkyl group such as naphthylmethyl and X is as defined above.
• a further subgroup is the compounds of formula I wherein R 1 is benzylyoxycarbonyl, 2-pyridylmethoxycarbonyl, phenyllactoyl or
• A is L-valine or L-tert-leucine
• R 2 is benzyl
• X is -NH-
• R 3 is benzyl, 3- or 4-methoxybenzyl or 4-bromobenzyl
• B is L-valine
• R 4 is benzylamino or benzimidazol-2-ylmethylamino
• the carbon atom in 4 position has the S configuration.
• R 1s is hydrogen; phenylalkyloxycarbonyl of altogether 8 to 10 carbon atoms; alkyloxycarbonyl of altogether 2 to 10 carbon atoms;
• FMOC 9-fluorenylmethoxycarbonyl
• a s is a bond; a natural ⁇ -aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; O-tert-butyl-L-serine; or
• R 2s is alkyl of 3 or 4 carbon atoms or phenylalkyl of altogether 7 to
• X a is -S- or -NR 5s - wherein Rs is hydrogen or methyl;
• R 3s is alkyl of 3 to 5 carbon atoms; cycloalkyl of 5 to 7 carbon atoms
• B s is a bond; a natural o-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; or aminocyclopropan-1-carbonyl;
• R 4s is hydroxy; an alkoxy or alkylamino group of 1 to 5 carbon atoms;
• a further subgroup is the compounds of formula Ip 1
• A, B, R 2 and X are as defined above;
• R 1p with the exception of hydrogen has the significance indicated above for R 1 ;
• R 3p with the exception of optionally substituted cycloalkyl has the
• R 4P is hydroxy or a group of formula -OR 7 or -NHR 7 as defined above;
• a further subgroup is the compounds Ip 2 , i.e. the compounds of formula I as defined above with the exception that R 4 is hydroxy or a group of formula -OR 7 or -NHR 7 as defined above.
• the compounds of the invention may be prepared by a process which comprises
• -BR 4 is other than hydroxy [b 1 ], or
• R 1 is other than hydrogen or HY- [b 2 ],
• R 1 ' is hydrogen or HY- and
• the process of the invention can be carried out in conventional manner.
• Process variant a) is effected e.g. in an inert solvent such as an ether, e.g. tetrahydrofuran, or acetonitrile.
• the temperature preferably is between about -50°C and the boiling temperature of the reaction mixture, preferably between about -20°C and about 80oC.
• the compound of formula III is an appropriate amine or mercaptan.
• a further reactive form preferably is a salt of a mercaptan, e.g. an alkali metal salt such as the potassium salt.
• Process variant b) is effected using conditions known for coupling amino acids.
• the reaction preferably is effected in an inert solvent, such as an amide, e.g. dimethylformamide, or an ether, e.g. tetrahydrofuran.
• the temperature preferably is between about room temperature and the boiling temperature of the reaction mixture, preferably about room temperature.
• Deprotection conveniently is effected by hydrolysis, preferably under acidic conditions for removing e.g. a hydroxy or amino protecting group such as tert-butoxycarbonyl, preferably with trifluoroacetic acid, or hydrogenolytically for removing e.g. benzyloxycarbonyl.
• Saponification is effected preferably with aqueous sodium hydroxide solution for removing e.g. alkoxy.
• the temperature preferably is between about -20°C and about 60°C, it conveniently is about room temperature.
• An organic solvent such as dichloromethane or tetrahydrofuran conveniently is used.
• the resultant compounds of formula I can be isolated from the reaction mixture and purified according to known methods, e.g.
• the starting materials and intermediates are either known or can be prepared according to known methods or analogously to known methods or methods described in the Examples.
• Ph phenyl
• Pr n-propyl
• tLeu a tert-leucine moiety -NHCH[-C(CH 3 ) 3 ]CO-;
• Example 1a 4(S)-[(N-tert-Butoxycarbonyl-L-valinoyl)amino]- 2-benzylthio-3-hydroxy-5-phenylpentanoic acid ethyl ester
• Example_2a H- ⁇ [2-Benzylamino-4(S)-[(H-benzyloxycarbonyl-L-valinoyl)- amino]-3-hydroxy-5-phenyl]pentanoyl)-L-leucine benzylamide
• N-hydroxysuccinimidyloxy are added to a solution of 0.1 g of compound of Example 119 in 4 ml of dioxane. The mixture is stirred for 6 days at room temperature, the solvent is evaporated and the residue is chromatographed on silicagel (solvent: cyclohexane/ethyl acetate 1:1). The title compound is obtained (m.p. 59-63°).
• Example 3a N-([2-Benzylamino-4(S)-[(N-benzyloxycarbonyl-L-valinoyl)amino]- 3-hydroxy-6-methyl]heptanoyl)-L-phenylalanine methylester
• N-benzyloxycarbonyl-L-histidinoyl hydrazide an intermediate of formula R 1 A-Q wherein Q is -NHNH 2
• a solution of 80 mg of sodium nitrite in 2 ml of water is added at 5°, the mixture is stirred for 5 minutes and quenched with 8 ml of saturated Na 2 CO 3 solution.
• the resulting white solid is washed twice with water, dissolved in 4 ml of dimethylformamide and added to a solution of 150 mg of compound of Example 119 in 3 ml of
• the compounds used as starting materials can be prepared e .g. as follows:
• step b) 1.7 g of product of step a) are dissolved in 50 ml of dichloromethane , 10 ml of trifluoroacetic acid are added, the mixture is stirred for 4 hours and the solvent is removed. The residue is dissolved in ethyl acetate and washed with a saturated solution of sodium bicarbonate, then brine. The organic layer is dried, the solvent removed and the title compound (compound G) is obtained (oil):
• Inhibition of peptide cleavage by HIV-proteinase is measured as described in A.Richards et al., J.Biol.Chem. 265 (1990) 7733-7736 and L.H.Philip et al., Biochem.Biophys.Res.Commun. 171 (1990) 439-444.
• the peptide H-Lys-Ala-Arg-Val-Leu-N ⁇ h-Glu-Ala-Nle-NH 2 (where Nph is p-nitrophenylalanine and Nle is norleucine) is used as substrate for recombinant HIV-1 or HIV-2 proteinase. Cleavage, occurs between the Leu and Nph residues. The reaction is followed spectrophotometrically by the decrease in extinction at 300 nm which is observed upon cleavage.
• the compounds exhibit K i values of from about 3 nM to about 1 ⁇ M for HIV-1, and of from about 30 nM to about 10 uM for HIV-2.
• Inhibition of the HIV-1 (HTLV III B )-induced cytopathic effect is measured in MT4 cells as described in R.Pauwels et al., J.Virol.Methods 20 (1988) 309-321. Briefly, an HTLV-1 transformed T4 cell line, MT4, which has been shown previously to be highly susceptible to HIV infection, serves as the target cell line. Inhibition of HIV-induced cytopathic effect is used as the end point. The viability of both HIV- and mock-infected cells is assessed spectrophotometrically via the in situ reduction of
• the compounds of the invention in free form and, where salt forms exist, in pharmaceutically acceptable salt form are therefore indicated for use as pharmaceuticals, particularly as agents against HIV-proteinase, e.g. in the prophylaxy and treatment of retroviral infections.
• the effective dosage will, of course, vary depending on the particular compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained when the compounds are administered at a daily dosage of from about 0.02 mg/kg to about 50 mg/kg animal body weight, suitably given in divided dosages two to four times daily. For most larger mammals the total daily dosage is from about 1 mg to about 3500 mg, e.g. from about 1 mg to about 500 mg or about 10 mg to about 100 mg.
• the compounds may be administered in similar manner to known standards for use in such indications.
• the compounds are also indicated for use in treating non-human animals infected with a retrovirus, such as cats infected with feline leukemia virus, feline infectious peritonitis virus, calicivirus, rabies virus, feline immunodeficiency virus, feline parvovirus (panleukopenia virus), and feline chlamydia.
• a retrovirus such as cats infected with feline leukemia virus, feline infectious peritonitis virus, calicivirus, rabies virus, feline immunodeficiency virus, feline parvovirus (panleukopenia virus), and feline chlamydia.
• corresponding 4-methoxy position isomer are the preferred compounds as anti HIV-proteinase agents. It is indicated that for this indication these compounds may be administered to larger mammals, for example humans, by similar modes of administration at similar or lower dosages than employed with standards for such indications.
• the invention therefore also concerns a method of treating retroviral diseases, especially diseases caused by HIV which comprises administering to a subject in need of such treatment a prophylactically or therapeutically effective amount of a compound of formula I in free form or, where salt forms exist, in pharmaceutically acceptable salt, e.g. acid addition salt form, as well as a compound of formula I in free form or, where salt forms exist, in pharmaceutically acceptable salt form for use as a pharmaceutical, especially as an agent against HIV-proteinase.
• the compounds may be admixed with conventional pharmaceutically acceptable diluents and carriers and, optionally, other excipients and administered e.g. orally in such forms as tablets or capsules.
• the compounds may alternatively be administered parenterally or intravenously.
• concentrations of active substance will, of course, vary depending i.a. on the compound employed, the treatment desired and the nature of the form.
• the invention thus also includes a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula I in free form or, where salt forms exist, in pharmaceutically acceptable salt, e.g. acid addition salt form, together with at least one pharmaceutically acceptable carrier or diluent.
• It further concerns a process for the preparation of a medicament against retroviral diseases which comprises mixing a compound of formula I in free form or, where salt forms exist, in pharmaceutically acceptable salt, e.g. acid addition salt form, together with a pharmaceutically acceptable carrier or diluent, and the use of such a compound in the manufacture of a medicament against retroviral diseases.

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• 1992
  • 1992-06-30 IL IL102362A patent/IL102362A0/xx unknown
  • 1992-06-30 EP EP92913821A patent/EP0594656A1/de not_active Withdrawn
  • 1992-06-30 MX MX9203836A patent/MX9203836A/es unknown
  • 1992-06-30 JP JP5501937A patent/JPH07501786A/ja active Pending
  • 1992-06-30 WO PCT/EP1992/001471 patent/WO1993001166A1/en not_active Application Discontinuation
  • 1992-06-30 AU AU21944/92A patent/AU2194492A/en not_active Abandoned
  • 1992-06-30 CA CA002109326A patent/CA2109326A1/en not_active Abandoned
  • 1992-07-01 IE IE214392A patent/IE922143A1/en not_active Application Discontinuation
  • 1992-07-03 TW TW081105274A patent/TW221686B/zh active

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