WO1993001166A1 - 4-amino-3-hydroxycarboxylic acid derivatives - Google Patents

4-amino-3-hydroxycarboxylic acid derivatives Download PDF

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Publication number
WO1993001166A1
WO1993001166A1 PCT/EP1992/001471 EP9201471W WO9301166A1 WO 1993001166 A1 WO1993001166 A1 WO 1993001166A1 EP 9201471 W EP9201471 W EP 9201471W WO 9301166 A1 WO9301166 A1 WO 9301166A1
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formula
carbon atoms
group
compound
hydrogen
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PCT/EP1992/001471
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French (fr)
Inventor
Andreas Billich
Brigitte Charpiot
Philip Lehr
Dieter Scholz
Hubert Gstach
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Sandoz Ltd.
Sandoz-Patent-Gmbh
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Priority claimed from GB919114261A external-priority patent/GB9114261D0/en
Priority claimed from GB919123721A external-priority patent/GB9123721D0/en
Priority claimed from GB929203884A external-priority patent/GB9203884D0/en
Application filed by Sandoz Ltd., Sandoz-Patent-Gmbh filed Critical Sandoz Ltd.
Priority to EP92913821A priority Critical patent/EP0594656A1/en
Priority to JP5501937A priority patent/JPH07501786A/en
Publication of WO1993001166A1 publication Critical patent/WO1993001166A1/en

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    • 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
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    • 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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    • 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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    • 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
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    • 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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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.

Abstract

The invention concerns the compounds of formula (I) wherein A and B independently are a bond or optionally substituted aminoacyl; R1 is hydrogen; an amino protecting group; or a group of formula R6Y- wherein R6 is hydrogen or an optionally substituted alkyl, alkenyl, alkinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group; and Y is -CO-; -NHCO-; NHCS-; -SO2-; -O-CO-; or -O-CS-; R2 is the side chain of a natural amino acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl, 2-thienylmethyl or styrylmethyl; R3 is an optionally substituted alkyl, alkenyl, alkinyl, cyloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group; R4 is a group of formula -OR7 or -NHR7 wherein R7 has the significance indicated above for R6; and X is -S- or -NR5- wherein R5 is hydrogen, methyl, formyl or acetyl; in free form and, where such forms exist, in salt form. They can be obtained by a process comprising epoxide ring opening, appropriate substitution and/or deprotection or saponification. They have antiviral activity, particularly HIV-1 proteinase inhibiting activity, and are thus indicated for use in the treatment of retroviral diseases.

Description

4-AMINO-3-HYDROXYCARBOXYLIC ACID DERIVATIVES
The invention relates to 4-amino-3-hydroxycarboxylic acid derivatives. It concerns the compounds of formula I
Figure imgf000003_0001
wherein
A and B independently are a bond or an optionally substituted aminoacyl moiety;
R1 is hydrogen; an amino protecting group; or a group of formula R6Y- wherein
R6 is hydrogen or an optionally substituted alkyl, alkenyl, alkinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group; and
Y is -CO-; -NHCO-; -NHCS-; -SO2-; -O-CO-; or -O-CS-; R2 is the side chain of a natural amino acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl,
2-thienylmethyl or styrylmethyl;
R3 is an optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group;
R4 is a group of formula -OR7 or -NHR7 wherein
R7 has the significance indicated above for R6; and
X is -S- or -NR5- wherein
R5 is hydrogen, methyl, formyl or acetyl;
in free form and, where such forms exist, in salt form,
hereinafter briefly named "a compound of the invention".
To date, there is a definite need for finding compounds which effectively inhibit retroviruses in a human infected by such a virus, and thus treat or prevent diseases caused thereby, such as acquired
immunodeficiency syndrome (AIDS).
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.
R1 preferably is 2-pyridylmethoxycarbonyl, benzyl-CH(OH)-carbonyl, phenoxymethylcarbonyl or an amino protecting group such as
tert-butorycarbonyl or benzyloxycarbonyl; it especially is
benzyloxycarbonyl.
A preferably is an optionally substituted aminoacyl moiety, preferably an optionally substituted α-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 α-amino acid, preferably of an amino acid which is a normal constitutive part of proteins. It especially is L-valine. R2 preferably is the side chain of a natural amino acid,
preferably of an α-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 α-aminoacyl moiety, such as
phenylalanine, valine, leucine, isoleucine, alanine or asparagine. It preferably is the optionally substituted moiety of a natural o-amino acid, preferably of an amino acid which is a normal constitutive part of proteins. It especially is L-valine.
R4 preferably is a group -NHR7; it preferably is isopropylamino, tert-butylamino, 1- or 2-naphthylmethylamino, or 2-, 3- or 4-pyridylmethyl-amino; it especially is benzylamino or benzimidazolylmethylamino,
particularly benzimidazol-2-ylmethylamino.
R3 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
monosubstituted in 3 or 4 position by methoxy.
X preferably is a group -NR5- as defined above. It especially is the imino group.
R6 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
benzyl-CH(OH)-; when it is substituted alkyl it preferably is
phenoxymethyl.
Y preferably is -CO- or -O-CO-, especially -CO-.
R7 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
benzimidazolylalkyl group of 1 to 4 carbon in the alkylene part; it preferably is benzyl, 2-, 3- or 4-pyridylmethyl or benzimidazolylmethyl, especially benzyl or benzimidazolylmethyl, particularly
benzimidazol-2-ylmethyl.
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 α-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(CH2OH)-, 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.
Aryl, heteroaryl and the aryl parts of arylalkyl or
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.
A heterocyclyl group and the heterocyclyl part of a
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 R1A- is an optionally substituted and optionally N-terminal protected natural aminoacyl moiety, -BR4 is a natural aminoacyl moiety optionally esterified or amidated at the C-terminus , R2 is the side chain of a natural amino acid, R3 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 R1 is benzylyoxycarbonyl, 2-pyridylmethoxycarbonyl, phenyllactoyl or
phenoxymethylcarbonyl, A is L-valine or L-tert-leucine, R2 is benzyl, X is -NH-, R3 is benzyl, 3- or 4-methoxybenzyl or 4-bromobenzyl, B is L-valine and R4 is benzylamino or benzimidazol-2-ylmethylamino, and the carbon atom in 4 position has the S configuration.
A further subgroup is the compounds of formula Is
Figure imgf000007_0001
wherein R1s is hydrogen; phenylalkyloxycarbonyl of altogether 8 to 10 carbon atoms; alkyloxycarbonyl of altogether 2 to 10 carbon atoms;
quinolylcarbonyl or quinolylsulfonyl; pyridylmethoxycarbonyl;
aminocaproyl optionally protected by tert-butoxycarbonyl;
9-fluorenylmethoxycarbonyl (FMOC); phenyllactoyl; isovalerianoyl;
phenoxymethylcarbonyl; palmitoyl; or 4-hydroxyphenylpropionyl;
As is a bond; a natural α-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; O-tert-butyl-L-serine; or
L-2-aminobutanoyl;
R2s is alkyl of 3 or 4 carbon atoms or phenylalkyl of altogether 7 to
9 carbon atoms;
Xa is -S- or -NR5s- wherein Rs is hydrogen or methyl;
R3s is alkyl of 3 to 5 carbon atoms; cycloalkyl of 5 to 7 carbon atoms
optionally monosubstituted by hydroxy; phenyl; phenylalkyl of
altogether 7 to 9 carbon atoms optionally monosubstituted in the phenyl ring by hydroxy, alkoxy of 1 to 3 carbon atoms, halogen of atomic number of from 9 to 35, or phenyl; a pyridylalkyl, indolylalkyl or naphthylalkyl group of 1 to 3 carbon atoms in the alkylene part; or phenylalkenyl of 2 to 4 carbon atoms in the alkenylene part;
Bs is a bond; a natural o-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; or aminocyclopropan-1-carbonyl;
R4s is hydroxy; an alkoxy or alkylamino group of 1 to 5 carbon atoms;
phenylalkylamino of altogether 7 to 9 carbon atoms optionally
monosubstituted in the phenyl ring or in the alkylene part by hydroxy, or monosubstituted in the phenyl ring by halogen of atomic number of from 9 to 35; benzimidazolylalkoxy or benzimidazolylalkylamino of 1 to 3 carbon atoms in the alkylene part optionally mono- or disubstituted in the aryl part by halogen of atomic number of from 9 to 35 or nitro; organ indolylalkylamino, pyridylalkylamino or morpholinylalkylamino moiety of 1 to 3 carbon atoms in the alkylene part; and
the configuration in 4 position is S,
in free form and, where such forms exist, in salt form. In a subgroup of compounds of formula Is, when As or Bs is a natural α-aminoacyl moiety it is valine, tryptophane, phenylalanine, asparagine, isoleucine, glutamine, leucine, alanine or histidine; in a further subgroup, when R1s is phenylalkyloxycarbonyl it is
benzyloxycarbonyl.
A further subgroup is the compounds of formula Ip1
Figure imgf000009_0001
wherein
A, B, R2 and X are as defined above;
R1p with the exception of hydrogen has the significance indicated above for R1;
R3p with the exception of optionally substituted cycloalkyl has the
significance indicated above for R3; and
R4P is hydroxy or a group of formula -OR7 or -NHR7 as defined above;
in free form and, where such forms exist, in salt form.
A further subgroup is the compounds Ip2, i.e. the compounds of formula I as defined above with the exception that R4 is hydroxy or a group of formula -OR7 or -NHR7 as defined above.
The compounds of the invention may be prepared by a process which comprises
a) submitting an epoxide of formula II
Figure imgf000010_0001
wherein the substituents are as defined above,
to ring opening in the presence of a compound of formula III
H - XR3 III wherein the substituents are as defined above, where indicated in a further reactive form; or b) for the preparation of the compounds of formula I wherein
-BR4 is other than hydroxy [b1], or
R1 is other than hydrogen or HY- [b2],
appropriately substituting a corresponding compound of formula I wherein -CO-BR4 is carboxy or R1 is hydrogen or HY-, e.g.
b1) substituting a corresponding compound of formula Ia
Figure imgf000010_0002
wherein the substituents are as defined above, or
b2) substituting a corresponding compound of formula Ib
Figure imgf000010_0003
wherein R1' is hydrogen or HY- and
the other substituents are as defined above; and where indicated deprotecting or saponifying a resultant compound of formula I in protected or esterified form, and recovering the resultant compounds of formula I in free form or, where such forms exist, in salt form.
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.
chromatographically. The compounds of formula II can be prepared e.g. in accordance with the following reaction scheme:
Figure imgf000012_0001
In the above reaction scheme the substituents are as defined above The single reaction steps may be carried out according to reaction conditions conventionally employed in such reactions, whereby the various intermediates can, where appropriate, be reacted further without isolation.
Insofar as they are not particularly described above or in the Examples, 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.
The following Examples illustrate the invention. The carbon atom in the 4 position in formula I has the S configuration. All temperatures are in degrees Centigrade. The abbreviations for amino acids follow the
international (IUPAC) rules. All NMR spectra are in CDCl3 unless indicated otherwise; the shifts are in ppm relative to trimethylsilane .
Other abbreviations have the following meaning:
BOC = tert-butoxycarbonyl;
Bu = n-butyl;
Bz = benzyl;
ch = hydrochloride;
cHex = cyclohexyl;
d. = decomposition;
dch = dihydrochloride;
depr. = deprotection;
Et = ethyl;
Ex. = Example;
FMOC = 9-fluorenylmethoxycarbonyl;
iBu = isobutyl = 2-methylpropyl;
iPr = isopropyl;
Me = methyl;
m.p. = melting point;
OEt = ethoxy;
OMe = methoxy;
Ph = phenyl;
Phe = a phenylalanine moiety;
Pr = n-propyl;
s. = sublimation;
sap. = saponification;
Su = the N-hydroxysuccinimide ester moiety;
tBu = tert-butyl;
tch = trihydrochloride;
tLeu = a tert-leucine moiety -NHCH[-C(CH3)3]CO-;
Z = benzyloxycarbonyl. Example 1; 2-Benzylamino-4(S)-[(N-benzyloxycarbonyl-L-valinoyl)amino]- 3-hydroxy-5-phenylpentanoic acid ethyl ester
[Formula I: R1 = Z; A =L-Val; R2, R3 = Bz; X = -NH-; B = a bond;
R4 = OEt]
[Process variant a), ring opening]
400 mg of 4(S)-[(N-benzyloxycarbonyl-L-valinoyl)amino]-2,3-epoxy- 5-phenylpentanoic acid ethyl ester (an intermediate of formula II;
compound A hereafter) are dissolved in 6 ml of tetrahydrofuran. 185 μl of benzylamine (an intermediate of formula III) are added and the solution is kept at 60° for 2 days. The solvent is evaporated and the residue chromatographed on silicagel (solvent: toluene/ethyl acetate 2:1). The title compound is obtained (m.p. 52-55°).
Example 1a: 4(S)-[(N-tert-Butoxycarbonyl-L-valinoyl)amino]- 2-benzylthio-3-hydroxy-5-phenylpentanoic acid ethyl ester
[Formula I: R1 = BOC; A = L-Val; R2,R3 = Bz;
X = -S-; B = a bond; R4 =OEt]
[Process variant a), ring opening]
1.15 g of benzylmercaptan (an intermediate of formula III) potassium salt are dissolved in 20 ml of acetonitrile and cooled to -50°. 2 g of 4(S)-[(H-tert-butoxycarbonyl-L-valinoyl)amino]-2,3-epoxy-5-phenylpentanoic acid ethyl ester (an intermediate of formula II; compound C hereafter) dissolved in 10 ml of acetonitrile are added and the mixture is kept at -20° for 48 hours. After neutralization with acetic acid the mixture is filtered, the solvent evaporated and the residue chromatographed on silicagel (solvent: toluene/ethyl acetate 4:1). The title compound is obtained (sirup):
1H-NMR: 1.27 (t,3H); 1.42 (s,9H); 2.67-3.15 (AB,2H); 3.24 (d,1H); 3.47
(d,1H); 3.70 (AB,2H); 3.84 (dd,1H); 4.17 (q,2H); 4.22 (q,1H); 4.78 (q,1H); 7.15-7.40 (m,10H); Example 2: N-{[2-Benzylamino-4(S)-[(H-benzyloxycarbonyl-L-valinoyl)amino] 3-hydroxy-5-phenyl]pentanoyl)-L-valine benzylamide
[Formula I: R1 = Z; A,B = L-Val; R2,R3 - Bz; X = -NH-; R4 = NHBz]
[Process variant b1), substitution]
230 mg of compound of Example 4a are dissolved in 5 ml of dimethylformamide. 87 mg of L-valine benzylamide (an intermediate of formula H-BR4), 57 mg of hydroxybenzotriazole and 104 mg of
dicyclohexylcarbodiimide are added at room temperature. After 24 hours stirring at room temperature the solution is filtered, the solvent evaporated and the residue chromatographed on silicagel (solvent: gradient toluene/ethyl acetate 1:1 to 1:3). The title compound is obtained
(amorphous; m.p. 81-84°).
Example_2a: H-{[2-Benzylamino-4(S)-[(H-benzyloxycarbonyl-L-valinoyl)- amino]-3-hydroxy-5-phenyl]pentanoyl)-L-leucine benzylamide
[Formula I: R1 = Z; A = L-Val; R2,R3 = Bz; X = -NH-; B = L-Leu;
R4 = NHBz]
[Process variant b1), substitution]
220 mg of compound of Example 4a in 10 ml of a mixture of dry tetrahydrofuran and dimethylformamide (1:1) are protected from light and stirred at room temperature in the presence of 195 mg of 1-benzotriazolyl-oxy-tris-(dimethylamino)phosphonium hexafluorophosphate and 49 μl of
N-methylmorpholine for 15 minutes. 106 mg of L-leucine benzylamide (an intermediate of formula H-BR4) are then added and the reaction mixture is stirred at room temperature overnight. The solvent is removed, water is added and the crude product extracted with ethyl acetate. The organic layers are dried, the solvent evaporated and the residue chromatographed on silicagel (solvent: gradient toluene/ethyl acetate 3:2 to 1:1). The title compound is obtained (m.p. 190-201°). Example 3: N-{[Benzylamino-4(S)-[(N-benzyloxycarbonyl-O-tert-butyl- L-serinoyl)amino]-3-hydroxy-5-phenyl]pentanoyl}-L-valine benzylamide
[Formula I: R1 = Z; A = O-tBu-L-Ser; R2,R3 = Bz; X = -NH-; B = L-Val;
R4 = NHBz]
[Process variant b2), substitution]
0.35 g of N-benzyloxycarbonyl-O-tert-butyl-L-serine-N-hydroxy-succinimide ester (an intermediate of formula R1A-Q wherein Q is
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
[Formula I: R1 = Z; A = L-Val; R2 = iBu; X = -NH-; R3 = Bz; B = L-Phe;
R4 = OMe]
[Process variant b2), substitution]
96 mg of compound of Example 118 are dissolved in 2 ml of tetrahydrofuran. 82 mg of N-benxyloxycarbonyl-L-valine-p-nitrophenyl ester
(an intermediate of formula R1A-Q wherein Q is p-nitrophenyloxy) and 200 mg of K2CO3 are added and the reaction mixture is stirred for 3 days. The solution is filtered and the solvent evaporated. The residue is dissolved in ethyl acetate; the solution is washed with aqueous 0.1 N HCl, saturated
NaHCO3 solution, dried and the solvent evaporated. The residue is
chromatographed on silicagel (solvent: toluene/ethyl acetate 1:1), the title compound obtained (oil):
1H-NMR: 0.90-1.00 (2d,12H); 1.20-1.40 (m,1H); 1.50-1.80 (m,2H); 2.20
(oct,1H); 3.05-3.20 (m,3H); 3.55 (bs,1H); 3.75 (s,3H); 3.84 (d,1H); 3.97 (dd,1H); 4.08-4.17 (m,1H); 4.90 (dd,1H); 5.08-5.20 (m,2H); 6.60 (d,1H); 7.10-7.38 (m,15H); 8.10 (d,1H); Example 3b: N-{[2-Benzylamino-4(S)-[(H-benzyloxycarbonyl-L-histidinoyl)- amino]-3-hydroxy-5-phenyl]pentanoyl}-L-valine benzylamide
[Formula I: R1 = Z; A = L-His; R2,R3 = Bz; X = -NH-; B = L-Val;
R4 = NHBz]
[Process variant b2), substitution]
300 mg of N-benzyloxycarbonyl-L-histidinoyl hydrazide (an intermediate of formula R1A-Q wherein Q is -NHNH2) are added at 5° to 4 ml of 1 N HCl solution. 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 Na2CO3 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
dimethylformamide. The mixture is stirred for 6 hours at room temperature, the solvent is evaporated and the residue is chromatographed on silicagel
(solvent: ethyl acetate). The title compound is obtained (resin):
1H-NMR (DMSO): 0.88 and 0.89 (2d,J=6Hz,6H); 2.04 (oct, J=6Hz,1H); 2.61-2.68
(m,1H); 2.73-2.90 (m,3H); 3.42-3.56 (m,3H); 4.22-4.38 (m,5H); 5.03 (s,2H); 5.13 (b,1H); 6.72 (s,1H); 7.10-7.35 (m,20H); 7.39 (d,J=9Hz,1H); 7.48 (s,1H); 7.65 (d,J=9Hz,1H); 8.26 (t, J=6Hz,1H); Example_3c: N-([2-Benzylamino-3-hydroxy-5-phenyl-4(S)-[(H-2-quinolyl- carbonyl-L-asparaginoyl)amino]]pentanoyl}-L-valine benzylamide
[Formula I: R1 = quinolin-2-ylcarbonyl; A = L-Asn; R2,R3 = Bz;
X = -NH-; B = L-Val; R4 = NHBz]
[Process variant b2), substitution]
55 mg of diphenylphosphoryl azide and 20 mg of N-methylmorpholine are added to a solution of 100 mg of compound of Example 119 and 57 mg of N-(2-quinolylcarbonyl)-L-asparagine (an intermediate of formula R1A-Q wherein Q is -OH) in 3 ml of dimethylformamide. The mixture is stirred for 2 days at room temperature, the solvent is evaporated and the residue is chromatographedon silicagel. The title compound is obtained: 1H-NMR: 0.92 and 0.95 (2d,6H); 1.70 (b,1H); 2.16-2.24 (m,1H); 2.82 (dd,2H); 2.92 and 3.01 (ABX,2H); 3.34 (d,1H); 3.57 and 3.66 (AB,2H); 3.86-3.90 (m,1H); 4.26 (dd,1H); 4.31-4.46 (m,3H);
4.89-4.95 (m,1H); 6.68-6.72 (m,1H); 6.95-7.00 (m,1H); 7.09-7.30 (m,17H); 7.65-7.68 (m,1H); 7.79-7.82 (m,1H); 7.86-7.93 (m,2H); 8.16-8.21 (m,2H); 8.31 (d,1H); 8.73 (d,1H);
Example 4: N-[2-Benzylamino-4(S)-(N-benzyloxycarbonyl-L-serinoyl)amino- 3-hydroxy-5-phenylpentanoyl]-L-valine benzylamide
[Formula I: R1 = Z; A = L-Ser; R2,R3 = Bz; X = -NH-; B = L-Val;
R4 = NHBz]
[Deprotection]
2 ml of trifluoroacetic acid are added to a solution of 55 mg of compound of Example 3 in 2 ml of dichloromethane. The mixture is stirred for 16 hours at room temperature, the solvent is evaporated, toluene is added and evaporated (twice), the residue is solved in dichloromethane, washed with 0.1 N NaOH, dried over MgSO4, concentrated in vacuo and chromatographed on silicagel (solvent: cyclohexane/ethyl acetate 1:2). The title compound is obtained (m.p. 76-81°).
Example 4a: [2-Benzylamino-4(S)-(N-benzyloxycarbonyl-L-valinoyl)amino]- 3-hydroxy-5-phenylpentanoic acid
[Formula I: R1 = Z; A = L-Val; R2,R3 = Bz; X = -NH-; B = a bond;
R4 = OH]
[Saponification]
330 mg of compound of Example 1 are dissolved in 3 ml of tetrahydrofuran. 627 μl of IN aqueous sodium hydroxide solution are added and the reaction mixture is stirred for 10 hours at room temperature. Neutralization with dilute aqueous HCl solution leads to a white
precipitate which is filtered off and dried. The title compound is obtained (m.p. 187-193°).
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Example 29:
1H-NMR: 0.70 (d,3H); 0.82 (d,3H); 0.87 (d,3H); 0.92 (d,3H); 1.80 (sext,1H); 2.01 (sext,1H); 2.97 (d,2H); 3.22
(d,1H); 3.55 (AB,2H); 3.72 (s,3H); 3.75-3.90 (m,2H); 4.15-4.23 (m,2H); 4.40 (dq,2H); 5.10 (bs,3H); 6.45 (bd,1H); 6.63 (bt,1H); 6.82 (d,1H); 7.08-7.40 (m,19H); 8.18 (d,1H);
Example 31:
1H-NMR: 0.72 (d,3H); 0.78 (d,3H); 0.84 (d,3H); 0.90 (d,3H); 2.08 (m,2H); 2.85 (AB,2H); 3.24 (d,1H); 3.62
(dd,2H); 3.84 (m,2H); 4.40 (AB,2H); 4.61 (dd,1H); 5.08 (bs,3H); 6.28 (d,1H); 6.52 (t,1H); 6.64 (d,1H); 7.12-7.41 (m,20H);
Example 32 (CDCl3/CD3OD 9:1):
1H-NMR: 0.87 (d,3H); 0.93 (2d,6H); 0.97 (d,3H); 2.2-2.3 (m,2H); 2.83-2.96 (m,2H); 3.33 (d,1H); 3.88 (dd,1H);
4.25-4.33 (m,3H); 4.52 (s,2H); 6.94-6.99 (m,1H); 7.08-7.18 (5H); 7.2-7.36 (5H); 7.6-7.7 (m,2H); 7.8-7.85 (m,1H); 7.91 (dd,1H); 8.14 (dd,1H); 8.36 (d+m,2H); 8.60 (d,1H);
13C-NMR: 17.55, 17.695, 19.27, 19.353, 29.98, 30.07, 37.18, 44.32, 51.89, 52.4, 58.813, 59.36, 63.506, 71.78,
118.59, 122.26, 122.36, 126.18, 127.21, 127.634, 128.146, 128.178, 128.283, 128.389, 129.013, 129. 368, 129.69, 130.226, 137.13, 137.61, 137.76, 138.75, 146.38, 148.59, 148.67, 156.88, 165.11, 171. 59, 171.66, 173.67;
Example 36:
1H-NMR: 0.73, 0.86, 0.89 and 0.95 (4d, J=6Hz,12H); 2.07 and 2.23 (2oct, J=6Hz,2H); 2.96 (d,J=6.7Hz,2H); 3.25
(d,J=8Hz,1H); 3.59 (q,J=12Hz,2H); 3.84-3.93 (m,2H); 4.16-4.22 (m,2H); 4.35 and 4.45 (ABX,
JAB=15Hz,JAX=JBX=6Hz,2H); 4.92 (b,1H); 5.19 and 5.24 (AB,J=13Hz,2H); 5.21-5.26 (m,1H); 6.50-6.62 (m,2H); 7.15-7.35 (m,17H); 7.68 (t,J=6Hz,1H); 8.09 (d,J=9Hz,1H); 8.53 (d,J=5Hz,1H);
Example 37:
1H-HMR: 0.86 (s,9H); 1.86 and 1.94 (2d,J=7Hz,6H); 2.00 (b,1H); 2.25 (oct,J=7Hz,1H); 2.97 (d,J=8Hz,2H); 3.29
(d,J=8Hz,1H); 3.52-3.63 (m,2H); 3.73 (d,J=8Hz,1H); 3.90 (d,J=6.4Hz,1H); 4.12 (q,J=7Hz,1H); 4.29
(dd,J=7 and 9Hz,1H); 4.33 and 4.51 (ABX,JAB=15Hz,JAX=5.4Hz,JBX=6Hz,2H); 5.01 and 5.10 (AB,J=12Hz,2H);
5.08 (b,1H); 5.31 (d,J=8Hz,1H); 6.48 (d,J=7Hz,1H); 6.90-7.03 (m,1H); 7.08-7.39 (m,20H); 8.13
(d,J=9Hz,1H);
Example 38:
1H-HMR: 0.91 and 0.97 (2d,J=7Hz,6H); 1.23 (t,J=6Hz,3H); 1.72 (b,1H); 2.32 (oct,J=7Hz,1H); 2.86 (m,2H); 3.30
(d,J=8.5Hz,1H); 3.56 and 3.71 (AB,J=13.6Hz,2H); 3.74 (dd,J=2 and 16Hz,1H); 4.12-4.22 (m,2H); 4.34-4.49
(m,2H); 6.58 (d,J=9Hz,1H); 6.96-7.18 (m,11H); 7.60-7.65 (m,1H); 7.78-7.96 (m,2H); 8.15-8.38 (m,3H);
8.63 (d,J=8.6Hz,1H);
Example 40 :
1H-NMR: a) diastereoisomer a: 0.69 (d,3H); 0.82 (d,3H); 0.88 (d,3H); 0.94 (d,3H); 1.70 (m, 1H exchangeable);
2.03 (m,1H); 2.30 (m,1H); 2.90-3.00 (2dd,2H); 3.30 (d,1H,J=6.7Hz); 3.65 (dd,2H); 4.15 (m,1H); 4.25
(q,1H); 4.40 (dd,2H); 4.65 (p,1H exchangeable); 5.09 (s,2H); 5.13 (d,1H exchangeable); 6.59 (d,1H exchangeable); 7.10-7.40 (m,16H); 7.6 (ddd,1H); 8.08 (d,1H exchangeable); 8.43 (dd,1H, J=3.6Hz); 8.49
(d,1H,J=1.7Hz);
b) diastereoisomer b: 0.78 (d,3H); 0.79 (d,3H); 0.88 (d,3H); 0.94 (d,3H); 1.70 (m, IH exchangeable);
1.90 (m,1H); 2.25 (m,1H); 2.92 (m,2H); 3.10 (d,1H); 3.54 (AB,JAB=12.5Hz,2H); 3.62 (d,1H); 3.80 (t,1H);
4.28 (dd,1H); 4.40 (d,2H); 4.60 (dd,1H); 5.15 (AB,JAB=12.5Hz,2H); 5.45 (d,1H exchangeable); 6.50 (d,1H exchangeable); 7.05 (m, 1H exchangeable); 7.10-7.40 (m,16H); 7.59 (ddd,1H); 8.45 (dd,1H); 8.50 (d,1H); Example 42:
1H-NMR: a) diastereoisomer a: 0.73 (d,3H); 0.87 (d,3H); 0.98 (s,9H); 1.70-2.00 (m,H exchangeable); 2.00-2.18
(m,1H); 2.85-3.00 (m,2H); 3.25 (d,J=8.5Hz,1H); 3.56 (s,2H); 3.88 (m,1H); 3.90-4.10 (m,1H); 4.10-4.50
(m,4H); 5.05 (s,2H); 5.22 (d,1H exchangeable); 6.44-6.54 (t,1H exchangeable); 6.80 (d,1H); 7.10-7.45
(m,20H); 8.34 (d, 1H exchangeable);
b) diastereoisomer b: 0.72 (d,3H); 0.79 (d,3H); 1.05 (s,9H); 1.80-2.00 (m,1H); 2.80-3.00 (m,2H); 3.12
(d,J=9.4Hz,1H); 3.54 (s,2H); 3.66 (d,1H); 4.00-4.10 (dd,1H); 4.40-4.55 (m,4H); 4.70-4.95 (dd,2H); 5.21
(d,1H exchangeable); 7.00-7.40 (m,20H);
13C-NMR: diastereoisomer b: 17.65, 19.42, 26.81, 31.05, 35.5, 38.36, 43.58, 51.32, 53, 60.92, 64.5, 66.97, 72.5,
77.2, 126.38-129.34 (C aromatic), 136.02, 137.86, 138.01, 138.73, 156.38, 169.91, 171.43, 174.14;
Example 43:
1H-NMR: [0.8 (d,diastereoisomer a); 0.90 (d, diastereoisomers a+b), 0.95 (d, diastereoisomer b), 6H]; [1.23 (s, diastereoisomer a), 1.38 (diastereoisomer b), 9H]; 2.10-2.20 (m,1H); 2.70-2.80 (m,2H); 3.20-4.60 (8H);
7.00-7.30 (m, 11H); 7.55-7.70 (m,1H); 8.35-8.45 (m,2H);
Example 44:
1H-NMR (DMSO): 0.88 (d,3H); 0.94 (d,3H); 1.33 (s,9H); 2.20-2.30 (m,1H); 2.80-2.90 (m,2H); 3.30 (d,1H); 3.60-3.80
(2d,2H); 3.80-3.90 (m,1H); 3.90-4.10 (m,1H); 4.40 (m,1H); 4.50 (m,2H); 7.00-7.40 (m,12H); 7.60 (ddd,1H);
8.45 (m,1H);
Example 45:
1H-NMR: 0.85 (d,3H); 0.93 (d,3H); 1.28 (s,9H); 2.20-2.30 (m,1H); 2.80-3.00 (m,2H); 3.38 (d,1H); 3.50-4.60 (m, 8H);
7.10-7.40 (m,12H); 8.50-8.60 (m,2H);
Example 46:
1H-NMR: 0.96 (s,9H); 1.39 and 1.42 (2s,9H); 2.80-3.00 (m,2H); 3.12 and 3.24 (2d,1H); 3.50-4.10 (m,8H); 4.30-4.40
(m,2H); 7.10-7.50 (m,15H);
Example 51:
1H-NMR: 0.73 (s,9H); 0.95 and 0.98 (2d,J=7Hz,6H); 1.65 (bs,1H); 2.30 (oct, J=7Hz,1H); 2.89 and 3.15 (ABX,
JAB=14Hz,JAX=4Hz,JBX=7.5Hz,2H); 2.94-3.08 (m,3H); 3.29 (d,J=7.5Hz,1H); 3.60 (d,J=7.5Hz,1H); 3.60 and 3.65 (AB,JAB=12.5Hz,2H); 3.89 (dd,J=3.5Hz,J=7.5Hz,1H); 3.95-4.01 (m,1H); 4.22-4.33 (m,3H); 4.52-4.58 (m,1H); 5.13 (b,1H); 5.95 (bm,1H); 6.79 (t,J=6Hz,1H); 6.88 (d,J=7.5Hz,1H); 7.14-7.33 (m,20H); 8.01 (d,J=9Hz,1H);
Example 53:
1H-NMR: 0.63, 0.89, 0.93, 0.95 (4d, J=7Hz,12H); 2.05 (dsp, J=3Hz,J=7Hz,1H); 2.19 (oct, J=7Hz,1H); 2.91-3.02
(m,2H); 3.20 (d,J=8Hz,1H); 3.55 and 3.58 (AB,JAB=13Hz,2H); 3.88 (d,J=8Hz,1H); 3.91 (d,J=3Hz,1H); 4.18 (dd,J=6Hz,J=7Hz,1H); 4.35 (q,J=7.5Hz,1H); 4.42 (dd,J=2Hz,J=6Hz,2H); 6.45 (t,J=6Hz,1H); 7.03
(d,J=10Hz,1H); 7.18-7.35 (m,15H); 8.08 (d,J=8Hz,1H);
Example 56:
1H-NMR: 0.78 (d,3H); 0.83 (d,3H); 0.97 (d,3H); 1.00 (d,3H); 1.98 (sext,1H); 2.35 (sext,1H); 2.95 (ABX,2H); 3.38
(d,1H); 3.65-3.76 (m,2H); 3.79 (s,3H); 3.84 (m,1H); 3.99 (m,1H); 4.17 (m,1H); 4.24 (dd,1H); 4.62 (ABX,2H); 5.11 (AB,2H); 5.19 (d,1H); 6.80-7.41 (m,20H); 7.96 (d,1H); 8.20 (bs,1H);
Example 59:
1H-NMR (CDCl3/CD3OD 9:1): 0.76 (d,3H); 0.83 (d,3H); 0.97 (2d,6H); 1.94 (sext,1H); 2.20 (sext,1H); 2.78-2.92
(m,2H); 3.38 (d,1H); 3.58 (AB,2H); 3.79 (s,3H); 3.84 (d,1H); 3.90 (m,1H); 4.22 (d,1H); 4.25 (dd,1H); 4.61 (AB,2H); 5.10 (AB,2H);.6.82 (d,2H); 7.02-7.60 (m,16H);
Example 66 (DMSO) :
1H-NMR: 0.75 (d,6H); 0.87 (d,3H); 0.90 (d,3H); 1.80-2.00 (m,1H); 2.00-2.15 (m,1H); 2.50-2.70 (m,1H); 2.70-2.85
(m,1H); 3.00-3.20 (d,1H); 3.30-3.50 (m,2H); 3.50-3.60 (m,1H); 3.83 (t,1H); 4.20-4.40 (2m,2H);
4.40-4.65 (2dd,2H); 5.00-5.15 (AB,JAB=12.4Hz,2H); 5.35 (d,1H exchangeable); 7.00-7.45 (m,19H); 7.52
(d, 1H exchangeable); 7.60 (d,1H exchangeable); 7.90 (d,1H exchangeable);
13C-NMR: 17.85, 18.25, 19.3, 29.92, 30.38, 37.04, 51.3, 51.8, 58, 60.75, 63.79, 65.5, 71.06, 74.1, 11??.2,
118.35, 121.1, 121.8, 124.8-129.16 (C aromatic); 136.9, 138.9, 140.1, 151.8, 156.2, 170.78, 171.3,
173.2;
Example 67 (DMSO):
1H-NMR: 0.74 (d,6H); 0.87 (d,3H); 0.89 (d,3H); 1.80-2.20 (m,2H); 2.40-2.70 (m,1H); 2.70-2.95 (m,1H); 3.10
(d,1H); 3.30-3.50 (m,2H); 3.50-3.60 (m,1H); 3.75-3.85 (t,1H); 4.20-4.40 (m,2H); 4.40-4.65 (m,2H);
4.90-5.10 (AB, JAB=12.5Hz,2H); 5.36 (d, 1H exchangeable); 7.05-7.25 (m,9H); 7.25-7.6 (m,9H+1H
exchangeable); 7.86 (d,1H exchangeable); 8.65 (t,1H exchangeable); 12.17 (s,1H exchangeable); 13C-NMR: 17.84, 18.29, 19.26, 19.3, 29.86, 30.33, 37.04, 50.37, 51.73, 58.05, 60.75, 63.6, 65.5, 70.96,
111.19, 118.35, 119.68, 121.07, 121.86, 125.825, 127.7, 127.765, 127.99, 128.31, 129.15, 130.31, 130.87, 134.11, 136.93, 138.9, 139.56, 143, 151.8, 156.2, 162.3, 170.7, 171.3, 173.2;
Example 73:
1H-NMR: 1.80 (bs,1H); 2.99 (d,J=8Hz,2H); 3.16 (d, J=9Hz,1H); 3.41 and 3.50 (AB, J=13Hz,2H); 3.78 (d, J=10Hz,1H);
4.12 (q,J=8Hz,1H); 4.33 and 4.40 (ABX, JAB=14Hz, JAX=JBX=6Hz,2H); 5.00-5.28 (m,3H); 5.40 (d, J=10Hz,1H);
6.98-7.42 (m,20H); 7.84 (t, J=5.5Hz,1H);
Example 74:
1H-NMR: 0.92 (d,6H); 1.20-1.38 (m,2H); 1.40 (s,9H); 1.53-1.72 (m,1H); 3.01-3.22 (m,2H); 3.10 (d,1H); 3.45 and
3.60 (AB,2H); 3.75 (d,1H); 3.78 (s,3H); 3.80-3.95 (m,1H); 4.80-4.95 (m,1H); 7.02-7.38 (m,10H); Example 76:
1H-NMR: 0.92 (d,6H); 1.30 (t,3H); 1.30-1.41 (m,2H); 1.65 (sept,1H); 3.35 (dd,1H); 3.65 and 3.85 (AB,2H);
3.67-3.73 (m,1H); 3.80-3.92 (m,1H); 4.22 (q,2H); 4.65 (d,1H); 7.20-7.35 (m,5H);
Example 77:
1H-NMR: 1.28 (t,3H); 1.38 (s,9H); 1.72 (bs,1H); 2.80-3.03 (m,2H); 3.33 (d,1H); 3.60 and 3.80 (AB,2H); 3.72
(d,1H); 4.04 (q,1H); 4.18 (q,2H); 4.80 (d,1H); 7.15-7.40 (m,10H);
Example 78:
1H-NMR: 0.82 (2d,6H); 1.08 (t,3H); 2.10 (sext,1H); 2.95 (m,2H); 3.90 (m,2H); 4.05 (d,1H); 4.10 (q,2H); 4.28
(dt,1H); 5.12 (s,2H); 6.65 (d,2H); 6.78 (t,1H); 7.08-7.42 (m,15H);
Example 81:
1H-NMR: 0.64 (d,3H); 0.82 (t,3H); 1.85 (sext,1H); 2.61-2.83 (m,2H); 3.24 (d,H); 3.62-3.80 (m,2H); 3.94 (d,1H);
4.21 (q,2H); 4.25-4.41 (m,2H); 5.07 (d,1H); 5.10 (s,2H); 5.97 (d,1H); 7.00-7.61 (m,14H); 7.78 (m,1H);
7.81 (d,1H); 8.24 (d,1H);
Example 82:
1H-NMR: 0.78 (d,3H); 0.84 (d,3H); 1.21 (t,3H); 1.95 (sext,1H); 2.60-3.08 (m,6H); 3.10 (d,1H); 3.62 (dd,1H);
3.75 (dd,1H); 4.17 (q,2H); 4.23 (dq,1H); 5.12 (s,2H); 5.17 (m,1H); 6.17 (d,1H); 6.95-7.40 (m,14H);
7.58 (d,1H); 8.39 (bs,1H);
Example 83:
1H-NMR: 0.75 (d,3H); 0.87 (d,3H); 1.26 (t,3H); 2.17 (sext,1H); 2.84 (AB,2H); 3.22 (d,1H); 3.43-3.81 (m,3H);
3.90 (dd,1H); 4.18 (q,2H); 4.45 (dd,1H); 5.10 (s,2H); 5.20 (d,1H); 6.41 (d,1H); 7.08-7.40 (m,11H);
7.69 (d,1H); 8.50 (m,2H);
Example 84:
1H-NMR: 0.78 (d,3H); 0.85 (d,3H); 1.22 (t,3H); 2.00 (sext,1H); 2.75-3.00 (m,5H); 3.12 (dd,1H); 3.28 (d,1H);
3.65 (dd,1H); 3.91 (dq,1H); 4.08 (dd,1H); 4.18 (q,2H); 5.10 (s,2H); 5.38 (d,1H); 7.10-7.39 (m,12H);
7.64 (dt,1H); 8.15 (d,1H); 8.22 (m,1H);
Example 91:
1H-NMR: 0.80 (d,3H); 0.92 (d,3H); 1.34 (t,3H); 2.15 (m,4H); 2.82-3.22 (m,5H); 3.84 (m,2H); 4.23 (dq,2H);
4.70 (dd,1H); 5.10 (s,2H); 5.20 (d,1H); 6.01 (dt,1H); 6.40 (d,1H); 7.00-7.40 (m,16H);
Example 93:
1H-NMR: 1.27 (t,3H); 1.42 (s,9H); 2.67-3.15 (AB,2H); 3.24 (d,1H); 3.47 (d,1H); 3.70 (AB,2H); 3.84 (dd,1H);
4.17 (q,2H); 4.22 (q,1H); 4.78 (q,1H); 7.15-7.40 (m,10H);
Example 97:
1H-NMR: 0.72 (d,3H); 0.80 (s,9H); 0.87 (d,3H); 2.18 (sext,1H); 2.88-3.16 (m,5H); 3.62 (AB,2H); 3.76 (d,1H);
3.81 (s,3H); 4.00 (dd,1H); 4.45 (bq,1H); 5.11 (s,2H); 5.08-5.18 (m,1H); 6.58 (d,1H); 6.83 (d,2H); 7.15-7.40 (m,12H); 7.80 (bt,1H);
Example 98:
1H-NMR: 1.27 (s,9H); 2.80-3.12 (m,2H); 3.38 (d,1H); 3.63 (d,1H); 3.69 (s,3H); 3.81-3.94 (m,1H); 4.46 (bq,1H);
4.90 (d,1H); 7.03-7.40 (m,10H);
Example 106:
1H-NMR: 0.83 (s,9H); 0.95 and 1.01 (2d,J=7Hz,6H); 1.59 (bs,1H); 2.32 (oct,J=7Hz,1H); 2.96-3.06 (m,2H); 3.31
(d,J=7.5Hz,1H); 3.61 and 3.65 (AB,J=14Hz,2H); 3.77 (d,J=7.5Hz,1H); 3.92 (d,J=7.5Hz,1H); 4.06-4.12 (m,1H); 4.28 (dd,J=6Hz and 9Hz,1H); 4.35 and 4.58 (ABX,JAB=15Hz,JAX=6.5Hz,JBX=5Hz,2H); 4.40 and 4.47 (AB,J=15Hz,2H); 4.98 (bs,1H); 5.98 (d,J=7.5Hz,1H); 6.73 (t,J=6Hz,1H); 6.90-6.97 (m,3H); 7.02-7.07 (m,1H); 7.13-7.37 (m,17H); 8.09 (d,J=9Hz,1H);
Example 108:
1H-NMR: 0.84 (s,9H); 0.85 (s,3H); 0.88 and 0.92 (2d,6H); 1.20-1.41 (m,25H); 1.48-1.62 (m,1H); 1.92 (bs,1H);
2.01-2.21 (m,2H); 2.28 (oct,1H); 3.00 (d,J=8.5Hz,2H); 3.26 (d,J=8Hz,1H); 3.58-3.65 (m,2H); 3.83-3.98 (m,2H); 4.02-4.18 (m,1H); 4.23-4.39 (m,2H); 4.48-4.60 (m,1H); 5.03 (bs,1H); 5.90 (d,J=7Hz,1H); 6.32 (d,J=7.5Hz,1H); 7.03 (t,1H); 7.10-7.37 (m,15H); 8.08 (d,J=9Hz,1H);
Example 114:
1H-HMR: 0.83 (s,9H); 0.92 and 0.97 (2d,J=7Hz,6H); 2.24 (oct,J=7Hz,1H); 2,95 and 3.01
(ABX,JAB=14Hz,JAX=7Hz,JBX=8Hz,2H); 3.23 (d,J=8Hz,1H); 3.56 and 3.63 (AB,JAB=13Hz,2H); 3.92
(d,J=8Hz,1H); 4.23 (dd,J=3Hz and 9Hz,1H); 4.29 (q,J=8.5Hz,1H); 4.42 and 4.45
(ABX,JAB=14Hz,JAX=JBX=6Hz,2H); 5.10 (bs,1H); 6.72 (bm,1H); 7.18-7.36 (m,15H); 8.05 (d,J=9Hz,1H);
Example 116:
1H-NMR: 0.58 and 0.87 (2d, J=7Hz,6H); 1.28 (t, J=7Hz,3H); 1.50 (b,3H); 2.09-2.24 (m,1H); 2.97 (d, J=8Hz,2H);
3.08 (d,J=4Hz,1H); 3.22 (d,J=8Hz,1H); 3.54-3.83 (m,4H); 4.23 (dq,J=3 and 8Hz,2H); 7.08-7.38 (m,10H);
7.51 (d,J=8Hz,1H);
Example 118:
1H-HMR: 0.88 (d,6H); 1.38 (t,2H); 1.70 (sept,1H); 3.00-3.20 (m,2H); 3.20 (d,1H); 3.22-3.35 (m,1H); 3.58
(AB,2H); 3.67 (dd,1H); 3.71 (s,3H); 4.82 (dd,1H); 7.15-7.35 (m,10H); 7.90 (d,1H);
Example 120:
1H-NMR (CDCl3/CD3OD 9:1): 0.97 (d,3H); 1.04 (d,3H); 2.26 (sext,1H); 2.48-2.81 (AB,2H); 3.21 (m,1H); 3.43
(d,1H); 3.69 (d,2H); 3.74 (dd,1H); 4.30 (d,1H); 4.42 (AB,2H); 7.08-7.38 (m,12H)
Example 130:
1H-NMR (DMSO): 0.68 (d,3H); 0.76 (d,3H); 1.87 (sext,1H); 2.70,2.80 (2dd,2H); 4.34 (q,1H); 5.07 (s,2H);
7.08-7.60 (m,15H); 7.70 (d,1H);
Example 138 (DMSO) :
1H-NMR: 0.79 and 0.81 (2d, J=8Hz,6H); 2.02-2.18 (m,1H); 2.64-2.86 (m,2H); 3.80-4.16 (m,3H); 4.24-4.58 (m,2H);
6.90-7.03 (m,1H); 7.04-7.30 (m,4H); 7.30-7.54 (m,5H); 7.70-7.82 (m,1H); 7.82-7.98 (m,1H); 8.12-8.39
(m,4H); 8.58-8.70 (m,1H);
13C-NMR: 18.27, 19.24, 30.06, 37.46, 50.34, 51.28, 61.12, 62.32, 65.68, 70.98, 74.2, 120.6, 126, 127.9,
128.2, 128.4, 129.3, 130.9, 131.16, 136.9, 137.24, 138.8, 156.23, 171.56, 173.3;
The compounds used as starting materials can be prepared e .g. as follows:
A: 4(S)-[(N-Benzyloxycarbonyl-L-valinoyl)amino]-2,3-epoxy-5-phenyl- pentanoic acid ethyl eater
[Formula II: R1 = Z; A = L-Val; R2 = Bz; B = a bond; R4 = OEt;
configuration at 4 position: S] a) Acylation:
3.2 g of L-phenylalaninol (an intermediate of formula III) are added to a solution of 7.44 g of N-benzyloxycarbonyl-L-valin-p-nitro-phenylester (an intermediate of formula R1A-Q. wherein Q is
p-nitrophenyloxy) in 50 ml of dimethylformamide. 2 g of triethylamine are added and the reaction mixture is stirred at room temperature for 3 days. After evaporation of the solvent the residue is dissolved in dichloromethane and carefully washed repeatedly with 0.1 N NaOH, then once with water and dried. The solution is filtered, the solvent evaporated and the residue chromatographed on silicagel (solvent: dichloromethane/methanol 95:5). N-Benzyloxycarbonyl-L-valinoyl-L-phenylalaninol (an intermediate of formula IV) (m.p. 154-156º) is obtained. b) Oxidation and Wittig reaction:
3.12 ml of oxalylchloride are dissolved in 40 ml of dry
dichloromethane and cooled to -55°. 2.81 ml of dimethylsulfoxide are carefully added dropwise and then 6.98 g of product of step a) dissolved in 40 ml of dichloromethane and 3.125 ml of dimethylsulfoxide are added at -50°. The reaction mixture is stirred at -60º for one hour, reacted with triethylamine and stirred until it reaches room temperature. After dilution with 200 ml of dichloromethane the mixture is washed with aqueous 1N HCl solution, dried and the solvent evaporated. The residue is dissolved in toluene, 6.32 g of ethoxycarbonylmethylenetriphenylphosphorane are added and the reaction mixture is heated to 80° for 1 hour. After evaporation of the solvent the residue is chromatographed on silicagel (solvent: toluene/ethyl acetate 4:1). 4(S)-[(N-Benzyloxycarbonyl-L-valinoyl)amino]-5-phenylpent-2(E)-enoic acid ethyl ester (an intermediate of formula VI) (m.p. 161-165°) is obtained. c) Epoxidation:
3 g of product of step b) are dissolved in 30 ml of
dichloromethane. 1.373 g of m-chloroperbenzoic acid are added and the reaction mixture is stirred for 5 days. After evaporation of the solvent the residue is chromatographed on silicagel (solvent: toluene/ethyl acetate 4:1). The title compound (compound A) (an intermediate of formula IIa) is obtained (m.p. 164-167°).
The following intermediates of formula II are obtained in analogous manner (the configuration in 4 position is S):
Compound R1 A R2 B R4 m.p.
B BOC bond iBu bond OEt NMRa)
C BOC bond Bz bond OEt 55-61°
D Z L-Val 2-phenylethyl bond OEt NMRb)
E Z L-Val Bz L-Val NHBz 166-175°
F Z L-Val Bz bond OH NMRc) a)1H-NMR: 0.97 (2d,6H); 1.29 (t,3H); 1.44 (s,9H); 1.40-1.53 (m,2H); 1.63-1.80 (m,1H); 3.25 (bs,1H); 3.35
(bs,1H); 4.10 (bq,1H); 4.22 (dq,2H);
b)1H-NMR: 0.87 (d,3H); 0.98 (d,3H); 1.28 (t,3H); 1.82-2.06 (m,2H); 2.20 (sext,1H); 2.60-2.78 (m,2H);
3.21-3.37 (m,2H); 3.95 (dd,1H); 4.21 (q,2H); 4.38-4.50 (m,1H); 5.07-5.20 (m,3H); 5.92 (d,1H); 7.10-7.42 (m,10H);
c)1H-NMR: 0.70 (d,3H); 0.76 (d,3H); 1.70-1.90 (m,1H); 2.60-2.90 (m,2H); 3.00-3.15 (m,1H); 3.18-3.20
(m,1H); 3.60-4.30 (m,2H); 5.10 (s,2H); 7.00-7.50 (m,11H); 7.86 (d,1H).
G: D,L-tert-Leucine benzylamide
[Formula H - BR4: B = D,L-tLeu; R4 = NHBz]
a) To a solution of 1 g of N-(tert-butoxycarbonyl)-D,L-tert-leucine in
60 ml of dichloromethane are added at room temperature 980 mg of
dicyclohexylcarbodiimide, 550 mg of N-hydroxysuccinimide, 0.53 ml of
N-methylmorpholine and 0.57 ml of benzylamine. After 24 hours stirring at room temperature the solution is filtered, the solvent evaporated and the residue chromatographed on silicagel (solvent: toluene/ethyl acetate 5:1).
N-(tert-Butoxycarbonyl)-D,L-tert-leucine benzylamide is obtained (solid):
1H-NMR: 0.98 (s,9H); 1.4 (s,9H); 3.89 (d,1H); 4.3-4.6 (2dd,2H); 5.35
(d,1H); 6.55 (m,1H); 7.2-7.4 (m,5H). 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):
1H-NMR: 0.98 (s,9H); 3.05 (s,1H); 4.4 (s,2H); 7.2-7.4 (m,5H);
13C-NMR (CDCl3 + drops CD3OD): 26.35, 34.05, 63.87, 127.3, 127.74, 128.5,
138.04, 173.7.
The following intermediates of formula H - BR4, which may suitably be in protected form, are obtained in analogous manner:
Compound B R4 m.p.
H L-Val 3-pyridyl- oil; NMRa)
methylamino
I L-Val 2-pyridyl- oil; NMRb)
methylamino
J L-Val 4-pyridyl- oil; NMRc)
methylamino
K L-Val 4-Br-benzylamino 71-75°
L -NHC(-CH2CH2-)CO- NHBz oil; NMRd) Compound B R4 m.p.
M L-Val benzimidazol- oil; NMRe)
2-ylmethylamino
N L-Val 2-(4-OH-phenyl)- oil; NMRf)
ethylamino
O L-Val 2-(4-morpholinyl)- oil; NMRg)
ethylamino
P L-Val benzimidazol- oil; NMRh)
2-ylmethoxy
Q L-Val 5-NO2-benzimidazol- oil; NMRi)
2-ylmethoxy
R L-Val 5, 6-diCl-benzimidoil; NMRj)
azol-2-ylmethoxy
S L-Val 2-(indol-3-yl)- 81-86°
ethylamino a)1H-NMR: 0.82 (d,J=7Hz,3H); 1.00 (d, J=7Hz,3H); 2.30-2.50 (m,1H); 3.31
(d,J=3.6Hz,1H); 4.40-4.60 (ddd,2H); 7.25-7.35 (m,2H); 7.60-7.70 (ddd,1H); 7.80-7.90 (m,1H); 8.53 (dd,J=4.8 and 1.6Hz,1H); 8.55 (d,J=2.25Hz,1H);
b)1H-NMR: 0.88 (d, J=7Hz,3H) ; 0.99 (d, J=7Hz,3H); 2.00-2.20 (m,1H); 3.30
(d,J=4.8Hz,1H); 4.54 (s,2H); 7.10-7.40 (m,2H); 7.60-7.70
(ddd,1H); 8.20-8.30 (m,1H); 8.30 (d,1H);
c)1H-NMR: 0.88 (d,J=7Hz,3H); 0.95 (d, J=7Hz,3H); 2.10-2.30 (m,1H); 3.23
(d,J=4.6Hz,1H); 4.46 (s,2H); 7.25 (d,2H); 8.45 (d,2H); d) 1H- NMR: 0.75-0.90 (m,2H); 1.45-1.55 (m,2H); 4.40-4.50 (d,2H); 7.20-7.40
(m,5H); 7.90-8.10 (bs,1H);
e) 1H-NMR (DMSO) 0.80 (d,3H); 0.89 (d,3H); 1.85-2.10 (m,1H); 3.06 (d,1H);
4.51 (s,2H); 7.10-7.20 (m,2H); 7.45-7.55 (m,2H); 8.50 (bs,1H);
f)1H-NMR (DMSO) 0.74 (d,3H); 0.81 (d,3H); 1.82 (sext,1H); 2.58 (t,2H);
2.88 (d,1H); 3.14-3.30 (m,2H); 6.67 (d,2H); 7.00 (d,2H); 7.82 (bt,1H);
g)1H-NMR (CDCI3/D2O): 0.78 (d,3H); 1.84 (sext,1H); 2.31-2.42 (m,6H); 2.95
(d,1H); 3.18-3.31 (m,2H); 3.54-3.62 (m,4H);
h)1H-NMR: 0.84 (d,3H); 0.89 (d,3H); 1.80-2.00 (sext,1H); 3.00-3.50
(d,J=4.6Hz,1H); 5.30 (s,2H); 7.00-7.20 (m,2H); 7.40-7.60 (m,2H); i)1H-NMR: 0.84 (d,3H); 0.89 (d,3H); 1.80-2.00 (m,1H); 3.26 (d,J=5.4Hz,1H);
5.37 (s,2H); 7.74 and 7.67 (2d,J=9Hz,1H); 8.00-8.20 (2dd,1H); 8.40 and 8.47 (2d,1H);
j)1H-NMR: 0.83 (d,3H); 0.89 (d,3H); 1.80-2.00 (m,1H); 3.24 (d,J=5.4Hz,1H);
5.36 (s,2H); 7.74 (s,2H); T: N-Benzyloxycarbonyl-L-tert-leucine-N-hydroxysuccinimide ester
[Formula R1A - Q: R1 = Z; A = L-tLeu;
Q = N-hydroxysuccinimid-2-yloxy]
2.6 g of N-hydroxysuccinimide and 4.6 g of dicyclohexylcarbodiimide are added to a solution of 6 g of N-benzyloxycarbonyl-L-tert-leucine in 70 ml of dioxane. The mixture is stirred for 12 hours at room temperature, the solvent is evaporated, the residue is suspended in ethyl acetate, the urea is removed by filtration and the solvent is evaporated.
The title compound (compound T) is obtained:
1H-NMR: 1.10 (s,9H); 2.84 (s,4H); 4.52 (d, J=10Hz,1H); 5.03-5.12 (m,2H);
5.34 (d,J=10Hz,1H); 7.26-7.40 (m,5H).
The following intermediate of formula R1A - Q is obtained in analogous manner:
Compound R1 A Q m.p.
U 2-pyridyl- L-Val Su white solid;
methoxycarbonyl NMRa)
a)1H-NMR: 1.09 and 1.11 (2d, J=7Hz, 6H); 2.38 (oct, J=7Hz, 1H); 2.82 and
2.84 (2s, 4H); 4.62 (dd, J=5Hz, J=7.5HZ, 1H); 5.28 (s,2H);
7.25-7.42 (m,3H); 7.72-7.81 (m,1H).
The compounds of formula I in free form and, where salt forms exist, in pharmaceutically acceptable salt, e.g. acid addition salt form, possess interesting pharmacological properties. They are therefore indicated for use as pharmaceuticals. In particular, they exhibit antiviral activity, especially HIV-1 protease inhibiting activity, whereby they show only low or inexistent inhibiting effect against human proteases such as renin or pepsin.
This activity can be shown in the following tests:
1. HIV-proteinase inhibition
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.
Briefly, the peptide H-Lys-Ala-Arg-Val-Leu-Nρh-Glu-Ala-Nle-NH2 (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.
In this test the compounds exhibit Ki values of from about 3 nM to about 1 μM for HIV-1, and of from about 30 nM to about 10 uM for HIV-2.
2. Inhibition of cellular HIV-induced cytopathic effect
Inhibition of the HIV-1 (HTLV IIIB)-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
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The comparison of the effects of various concentrations of the compound on HIV-versus mock-infected cells allows the determination of minimum toxic (MTC) and minimum virus-inhibitory (MIC) concentrations. In this test the compounds exhibit IC50 values of from about 5 nM to about 350 nM. Thus the compounds of Examples 56 and 59 exhibit
IC50 values of, respectively, 49 nM and 12 nM against HIV-1 strains, and the compound of Example 37 is effective with an IC50 value of 150 nM.
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. For this use 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. Exact dosages, forms and modes of
administration of the compounds to non-human animals would be apparent to one of ordinary skill in the art, e.g. a veterinarian.
The compounds of Examples 29, 36, 37, 51, 56, 59, 66, 67 and 106, especially of Examples 56 and 59, i.e. N-{[4(S)-[(N-benzyloxycarbonyl-L-valinoyl)amino]-3-hydroxy-2-(3-methoxybenzylamino)-5-phenyl]pentanoyl}-L-valine-N-(methyl-2-benzimidazolyl)amide and, respectively, the
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. The 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 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.
It further concerns a compound of formula I in free form or, where salt forms exist, in pharmceutically acceptable salt, e.g. acid addition salt form, for use as a pharmaceutical, particularly for use in the treatment of retroviral diseases.

Claims

C L A I M S
1. A compound of formula I
Figure imgf000044_0001
wherein
A and B independently are a bond or an optionally substituted aminoacyl moiety;
R1 is hydrogen; an amino protecting group; or a group of formula R6Y- wherein
R6 is hydrogen or an optionally substituted alkyl, alkenyl, alkinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group; and
Y is -CO-; -NHCO-; -NHCS-; -SO2-; -O-CO-; or -O-CS-;
R2 is the side chain of a natural amino acid; an alkyl, arylalkyl,
heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl,
2-thienylmethyl or styrylmethyl;
R3 is an optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group;
R4 is a group of formula -OR7 or -NHR7 wherein
R7 has the significance indicated above for R6; and
X is -S- or -NR5- wherein
R5 is hydrogen, methyl, formyl or acetyl;
in free form or, where such forms exist, in salt form.
2. A compound according to claim 1 of formula Is
Figure imgf000045_0001
wherein
R1s is hydrogen; phenylalkyloxycarbonyl of altogether 8 to 10 carbon
atoms; alkyloxycarbonyl of altogether 2 to 10 carbon atoms;
quinolylcarbonyl or quinolylsulfonyl; pyridylmethoxycarbonyl;
aminocaproyl optionally protected by tert-butoxycarbonyl;
9-fluorenylmethoxycarbonyl (FMOC); phenyllactoyl; isovalerianoyl;
phenoxymethylcarbonyl; palmitoyl; or 4-hydroxyphenylpropionyl;
A, is a bond; a natural α-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; O-tert-butyl-L-serine; or
L-2-aminobutanoyl;
R2s is alkyl of 3 or 4 carbon atoms or phenylalkyl of altogether 7 to
9 carbon atoms;
Xs is -S- or -NR5s- wherein R5s is hydrogen or methyl;
R3s is alkyl of 3 to 5 carbon atoms; cycloalkyl of 5 to 7 carbon atoms
optionally monosubstituted by hydroxy; phenyl; phenylalkyl of
altogether 7 to 9 carbon atoms optionally monosubstituted in the phenyl ring by hydroxy, alkoxy of 1 to 3 carbon atoms, halogen of atomic number of from 9 to 35, or phenyl; a pyridylalkyl, indolylalkyl or naphthylalkyl group of 1 to 3 carbon atoms in the alkylene part; or phenylalkenyl of 2 to 4 carbon atoms in the alkenylene part;
Bs is a bond; a natural α-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; or aminocyclopropan-1-carbonyl;
R4s is hydroxy; an alkoxy or alkylamino group of 1 to 5 carbon atoms;
phenylalkylamino of altogether 7 to 9 carbon atoms optionally
monosubstituted in the phenyl ring or in the alkylene part by hydroxy, or monosubstituted in the phenyl ring by halogen of atomic number of from 9 to 35; benzimidazolylalkoxy or benzimidazolylalkylamino of 1 to 3 carbon atoms in the alkylene part optionally mono- or disubstituted in the aryl part by halogen of atomic number of from 9 to 35 or nitro; or an indolylalkylamino, pyridylalkylamino or morpholinylalkylamino moiety of 1 to 3 carbon atoms in the alkylene part; and
the configuration in 4 position is S,
in free form or, where such forms exist, in salt form.
3. A compound according to claim 1 of formula I wherein R1 is
benzylyoxycarbonyl, 2-pyridylmethoxycarbonyl, phenyllactoyl or
phenoxymethylcarbonyl, A is L-valine or L-tert-leucine, R2 is benzyl, X is -NH-, R3 is benzyl, 3- or 4-methoxybenzyl or 4-bromobenzyl, B is L-valine and R4 is benzylamino or benzimidazol-2-ylmethylamino, and the carbon atom in 4 position has the S configuration, in free form or, where such forms exist, in salt form.
4. A compound according to claim 1 of formula Ip1
Figure imgf000046_0001
wherein
A, B, R2 and X are as defined in claim 1;
R1p with the exception of hydrogen has the significance indicated in
claim 1 for R1;
R3p with the exception of optionally substituted cycloalkyl has the
significance indicated in claim 1 for R3; and
R4p is hydroxy or a group of formula -OR7 or -NHR7 as defined in claim 1; in free form or, where such forms exist, in salt form.
5. A compound according to claim 1 of formula I as defined in claim 1 with the exception that R4 is hydroxy or a group of formula -OR7 or -NHR7 as defined in claim 1, in free form or, where such forms exist, in salt form.
6. The compound according to claim 1 of formula I wherein the
configuration at the carbon atom in 4 position is S, R1 is
benzyloxycarbonyl, A is L-valine, R2 is benzyl, X is -NH-, B is L-valine, R4 is benzimidazol-2-ylmethylamino and R3 is 3-methoxybenzyl, or the correspondig 4-methoxy position isomer, in free form or, where such forms exist, in salt form.
7. The compound according to claim 1 of formula I wherein the
configuration at the carbon atom in 4 position is S, R2 is benzyl,
X is -NH-, B is L-valine, and R1, A, R3 and R4 respectively are either
- benzyloxycarbonyl, L-valine, 4-methoxybenzyl and benzylamino, or
- 2-pyridylmethoxycarbonyl, L-valine, benzyl and benzylamino, or
- benzyloxycarbonyl, L-tert-leucine, benzyl and benzylamino, or
- D-phenyllactoyl, L-tert-leucine, benzyl, and benzylamino, or
- benzyloxycarbonyl, L-valine, benzyl and benzimidazol-2-ylmethylamino, or
- benzyloxycarbonyl, L-valine, 4-bromobenzyl and benzimidazol-2-yl- methylamino, or
- phenoxymethylcarbonyl, L-tert-leucine, benzyl and benzylamino,
in free form or, where such forms exist, in salt form.
8. A compound according to any one of claime 1 to 7 in free form or, where salt forms exist, in pharmaceutically acceptable salt form, for use as a pharmaceutical.
9. A process for the preparation of a compound according to claim 1 which comprises
a) submitting an epoxide of formula II
Figure imgf000047_0001
wherein the substituents are as defined in claim 1,
to ring opening in the presence of a compound of formula III H - XR3 III wherein the substituents are as defined in claim 1, where indicated in a further reactive form; or b) for the preparation of a compound of formula I wherein
-BR4 is other than hydroxy [b1], or
Ri is other than hydrogen or HY- [b2],
appropriately substituting a corresponding compound of formula I wherein -CO-BR4 is carboxy or R1 is hydrogen or HY-, e.g.
b1) substituting a corresponding compound of formula la
Figure imgf000048_0001
wherein the substituents are as defined in claim 1, or
b2) substituting a corresponding compound of formula Ib
Figure imgf000048_0002
wherein R1' is hydrogen or HY- and
the other substituents are as defined in claim 1;
and where indicated deprotecting or saponifying a resultant compound of
formula I in protected or esterified form,
and recovering the resultant compound of formula I in free form or, where such forms exist, in salt form.
10. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 in free form or, where salt forms exist, in
pharmaceutically acceptable salt form, together with at least one
pharmaceutically acceptable carrier or diluent.
PCT/EP1992/001471 1991-07-02 1992-06-30 4-amino-3-hydroxycarboxylic acid derivatives WO1993001166A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP92913821A EP0594656A1 (en) 1991-07-02 1992-06-30 4-amino-3-hydroxycarboxylic acid derivatives
JP5501937A JPH07501786A (en) 1991-07-02 1992-06-30 4-Amino-3-hydroxycarboxylic acid derivative

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
GB919114261A GB9114261D0 (en) 1991-07-02 1991-07-02 New organic compounds,process for production thereof and their use
GB9114261.2 1991-07-02
GB9123721.4 1991-11-07
GB919123721A GB9123721D0 (en) 1991-11-07 1991-11-07 New organic compounds,process for production thereof and their use
GB929203884A GB9203884D0 (en) 1992-02-24 1992-02-24 New organic compounds,process for production thereof and their use
GB9203884.3 1992-02-24

Publications (1)

Publication Number Publication Date
WO1993001166A1 true WO1993001166A1 (en) 1993-01-21

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Country Status (9)

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EP (1) EP0594656A1 (en)
JP (1) JPH07501786A (en)
AU (1) AU2194492A (en)
CA (1) CA2109326A1 (en)
IE (1) IE922143A1 (en)
IL (1) IL102362A0 (en)
MX (1) MX9203836A (en)
TW (1) TW221686B (en)
WO (1) WO1993001166A1 (en)

Cited By (5)

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Publication number Priority date Publication date Assignee Title
EP0615969A1 (en) * 1993-03-12 1994-09-21 Sandoz Ltd. 2,4-Diamino-3-hydroxycarboxylic acid derivatives
WO1996000718A1 (en) * 1994-06-28 1996-01-11 Bayer Aktiengesellschaft Amino acid derivatives and their use as pesticides
EP0911318A2 (en) * 1994-06-28 1999-04-28 Bayer Ag Amino acid derivatives and their use as pesticides
WO2000064863A1 (en) * 1999-04-27 2000-11-02 Novartis Ag Use of 2,4-diamino-3-hydroxycarboxylic acid derivatives as proteasome inhibitors
WO2011075634A1 (en) * 2009-12-18 2011-06-23 Janssen Pharmaceutica Nv Bicyclic derivatives useful as inhibitors of dpp-1

Families Citing this family (7)

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Publication number Priority date Publication date Assignee Title
DE69333270T2 (en) 1992-03-11 2004-08-05 Narhex Ltd. AMINE DERIVATIVES OF OXO AND HYDROXY SUBSTITUTED CARBON HYDROGEN
US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
WO1993018006A1 (en) * 1992-03-11 1993-09-16 Narhex Limited Amine derivatives of oxo- and hydroxy-substitued hydrocarbons
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons
WO2003006021A1 (en) * 2001-07-10 2003-01-23 Elan Pharmaceuticals, Inc. Alpha-hydroxyamide statine derivatives for the treatment of alzh eimer's disease
US7351738B2 (en) * 2002-11-27 2008-04-01 Elan Pharmaceuticals, Inc. Substituted ureas and carbamates

Citations (1)

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EP0412350A2 (en) * 1989-08-05 1991-02-13 Bayer Ag Renininhibitors, procedure for their preparation and use as medicaments

Patent Citations (1)

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EP0412350A2 (en) * 1989-08-05 1991-02-13 Bayer Ag Renininhibitors, procedure for their preparation and use as medicaments

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5538997A (en) * 1993-03-12 1996-07-23 Sandoz Ltd. 2,4-diamino-3-hydroxycarboxylic acid derivatives
AU672867B2 (en) * 1993-03-12 1996-10-17 Sandoz Ltd. 4-amino-3-hydroxycarboxylic acid and their use as anitvirals
EP0615969A1 (en) * 1993-03-12 1994-09-21 Sandoz Ltd. 2,4-Diamino-3-hydroxycarboxylic acid derivatives
CN1122021C (en) * 1994-06-28 2003-09-24 拜尔公司 Amino acid derivatives and their use as pesticides
WO1996000718A1 (en) * 1994-06-28 1996-01-11 Bayer Aktiengesellschaft Amino acid derivatives and their use as pesticides
EP0911318A2 (en) * 1994-06-28 1999-04-28 Bayer Ag Amino acid derivatives and their use as pesticides
EP0911318A3 (en) * 1994-06-28 1999-08-04 Bayer Ag Amino acid derivatives and their use as pesticides
WO2000064863A1 (en) * 1999-04-27 2000-11-02 Novartis Ag Use of 2,4-diamino-3-hydroxycarboxylic acid derivatives as proteasome inhibitors
CN100357267C (en) * 1999-04-27 2007-12-26 诺瓦提斯公司 Use of 2,4-diamino-3-hydroxycarboxylic acid derivatives as proteasome inhibitors
WO2011075634A1 (en) * 2009-12-18 2011-06-23 Janssen Pharmaceutica Nv Bicyclic derivatives useful as inhibitors of dpp-1
CN102753524A (en) * 2009-12-18 2012-10-24 詹森药业有限公司 Bicyclic derivatives useful as inhibitors of dpp-1
JP2013514991A (en) * 2009-12-18 2013-05-02 ヤンセン ファーマシューティカ エヌ．ベー． Bicyclic derivatives useful as inhibitors of DPP-1
US8552032B2 (en) 2009-12-18 2013-10-08 Janssen Pharmaceutica Nv Bicyclic derivatives useful as inhibitors of DPP-1
AU2010330792B2 (en) * 2009-12-18 2015-10-08 Janssen Pharmaceutica Nv Bicyclic derivatives useful as inhibitors of DPP-1

Also Published As

Publication number Publication date
CA2109326A1 (en) 1993-01-03
EP0594656A1 (en) 1994-05-04
AU2194492A (en) 1993-02-11
IL102362A0 (en) 1993-01-14
IE922143A1 (en) 1993-01-13
TW221686B (en) 1994-03-11
MX9203836A (en) 1993-01-01
JPH07501786A (en) 1995-02-23

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