IE922143A1 - 4-amino-3-hydroxycarboxylic acid derivatives - Google Patents
4-amino-3-hydroxycarboxylic acid derivativesInfo
- Publication number
- IE922143A1 IE922143A1 IE214392A IE922143A IE922143A1 IE 922143 A1 IE922143 A1 IE 922143A1 IE 214392 A IE214392 A IE 214392A IE 922143 A IE922143 A IE 922143A IE 922143 A1 IE922143 A1 IE 922143A1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- compound
- carbon atoms
- group
- hydrogen
- Prior art date
Links
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Classifications
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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
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—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
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—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
- 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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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/40—Acylated substituent nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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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-AMIND-3-HWRQXYCARBQXYLIC ACID DERIVATIVES The invention relates to 4-amino-3-hydroxycarboxylic acid derivatives. It concerns the compounds of formula I R2 XR3 I 3 I RiA - NH - CH - CH - CH - CO - BR4 I | 2 I OH wherein A and B independently are a bond or an optionally substituted aminoacyl moiety; Ri is hydrogen; an amino protecting group; or a group of formula R6Ywherein Rg 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-; -2- 900-9710 R2 is the side chain of a natural amino acid; an alkyl, aryiaikyl, heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl, 2-thienylmethyl or styryImethyl; R3 is an optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, aryiaikyl, heteroaryl or heteroarylalkyl group; R4 is a group of formula -OR7 or -NHR7 wherein R7 has the significance indicated above for Rg; 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.
Ri preferably is 2-pyridylmethoxycarbonyl, benzyl-CH(OH)-carbonyl, phenoxymethylcarbonyl or an amino protecting group such as tert-butoxycarbonyl 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. -3- 900-9710 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 α-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 -4- 900-9710 preferably is benzyl, 2-, 3- or 4-pyridylmethyl or benzimidazolylmethyl, especially benzyl or benzimidazolylmethyl, particularly benzimidazol-2-ylmethyl.
R5 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(0Η2ΟΗ)-, 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 -5900-9710 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 R2A- 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 Ri 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 R2 s Xs R3 a I 3 I RlsAs - NH - CH - CH - CH - CO - B3R4a j 2 l OH Is wherein -6- 900-9710 Ris 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; R23 is alkyl of 3 or 4 carbon atoms or phenylalkyl of altogether 7 to 9 carbon atoms; Xs is -S- or -NRss- wherein Rse is hydrogen or methyl; R3a 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; Ba is a bond; a natural α-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; or aminocyclopropan-l-carbonyl; R4a 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 and, where such forms exist, in salt form. -7- 900-9710 In a subgroup of compounds of formula Is, when As or B9 is a natural α-aminoacyl moiety it is valine, tryptophane, phenylalanine, asparagine, isoleucine, glutamine, leucine, alanine or histidine; in a further subgroup, when Rla is phenylalkyloxycarbonyl it is benzyloxycarbonyl.
A further subgroup is the compounds of formula Ip3 r2 XR3p 1 3 1 RloA - NH - CH - CH - CH - CO - 4 1 2 1 OH wherein A, B, R2 and X are as defined above; Rip with the exception of hydrogen has the significance indicated above for Rx; 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. -8- 900-9710 The compounds of the invention may be prepared by a process which comprises a) submitting an epoxide of formula II R2 I RjA - NH - CH - CH - CH - CO - BR4 \ / II 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 [bi], or Ri is other than hydrogen or HY- [b2], appropriately substituting a corresponding compound of formula I wherein -CO-BR4 is carboxy or Ri is hydrogen or HY-, e.g. bi) substituting a corresponding compound of formula Ia R2 xr3 I I RXA - NH - CH - CH - CH - COOH Ia I OH wherein the substituents are as defined above, or b2) substituting a corresponding compound of formula Ib R2 XR3 I I Rl'A - NH - CH - CH - CH - CO - BR4 Ib OH wherein Rx' is hydrogen or HY- and the other substituents are as defined above; -9- 900-9710 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 80°C. 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. -10900-9710 The compounds of formula II can be prepared e.g. in accordance with the following reaction scheme: R2 I H2N - CH - CH2OH acylation V R2 I RlA - NH - CH - CH2OH III IV R2 RXA - NH - CH oxidation V R2 RXA - NH - CH - CHO Wittig reaction V R2 I Rj_A - NH - CH - CH = CH - COOC2H5 saponification + coupling VI V r2 RlA - NH - CH - CH = CH - CO - BR4 VII epoxidation R2 CH - CH - COOC2H5 \ / Ila RiA - NH - CH - CH - CH - CO - BR4 \ / II -11- 900-9710 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. -12900-9710 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 CDC13 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 = cyciohexyl; 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. -13- 900-9710 R-rample 1: 2-Benzylamino-4 (S) - [ (N-benzyloxycarbonyl-L-valinoyl) amino] 3-hydroxy-5-phenylpentanoic acid ethyl ester [Formula I: Ri = 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-epoxy5-phenylpentanoic acid ethyl ester (an intermediate of formula II; compound A hereafter) are dissolved in 6 ml of tetrahydrofuran. 185 μΐ 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 la: 4(S)-[(N-tert-Butoxycarbonyl-L-valinoyl)amino]2-benzylthio-3-hydroxy-5-phenylpentanoic acid ethyl ester [Formula I: Ri = 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°. g of 4(S)-[ (N-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,lH); 3.47 (d,lH); 3.70 (AB,2H); 3.84 (dd,lH); 4.17 (q,2H); 4.22 (q,lH); 4.78 (q,IH); 7.15-7.40 (m,10H); -14- 900-9710 Example 2: N-{[2-Benzylamino-4(S)-[(N-benzyloxycarbonyl-L-valinoyl)amino]3-hydroxy-5-phenyl]pentanoyl)-L-valine benzylamide [Formula I: Ri = Z; A,B = L-Val; R2,R3 = Bz; X = -NH-; R4 = NHBz] [Process variant bi), 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) - [ (N-benzyloxycarbonyl-L-valinoyl) amino]-3-hydroxy-5-phenyl]pentanoyl}-L-leucine benzylamide [Formula I: Rx = Z; A = L-Val; R2,R3 = Bz; X = -NH-; B = L-Leu; R4 = NHBz] [Process variant bi), 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-benzotriazolyloxy-tris-(dimethylamino)phosphonium hexafluorophosphate and 49 μΐ 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°). -15- 900-9710 Example 3: N-{[Benzylamino-4(S)-[(N-benzyloxycarbonyl-O-tert-butylL-eerinoyl)amino]-3-hydroxy-5-phenyl]pentanoyl)-L-valine benzylamide [Formula I: Ri = 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-H-hydroxysuccinimide ester (an intermediate of formula RiA-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)-[(H-benzyloxycarbonyl-L-valinoyl)amino]3-hydroxy-6-methyl]heptanoyl}-L-phenylalanine methylester [Formula I: Ri = Z; A = L-Val; R2 = iBu; X = -NH-; R3 = Bz; B = L-Phe; R4 = OMe] [Process variant b2), substitution] mg of compound of Example 118 are dissolved in 2 ml of tetrahydrofuran. 82 mg of N-benzyloxycarbonyl-L-valine-p-nitrophenyl ester (an intermediate of formula RiA-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 NaHCOs 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,lH); 1.50-1.80 (m,2H); 2.20 (oct,lH); 3.05-3.20 (m,3H); 3.55 (bs,lH); 3.75 (s,3H); 3.84 (d,lH); 3.97 (dd,lH); 4.08-4.17 (m,lH); 4.90 (dd,lH); 5.08-5.20 (m,2H); 6.60 (d,1H,; 7.10-7.38 (m,15H); 8.10 (d,1H); -16- 900-9710 Example 3b: N-{[2-Benzylamino-4(S)-[(H-benzyloxycarbonyl-L-histidinoyl)amino]-3-hydroxy-5-phenyl]pentanoyl}-L-valine benzylamide [Formula I: Ri = 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 RiA-Q wherein Q is -NHNH2) are added at 5° to 4 ml of 1 N HCl solution. A solution of SO 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,IH); 2.61-2.68 (m,lH); 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,IH); 6.72 (S,1H); 7.10-7.35 (m,20H); 7.39 (d, J=9Hz,IH); 7.48 (s,lH); 7.65 (d,J=9Hz,IH); 8.26 (t, J=6Hz,lH); Example 3c: N-f[2-Benzylamino-3-hydroxy-5-phenyl-4(S)—[(N-2-quinolylcarbonyl-L-aaparaginoyl)amino]]pentanoyl}-L-valine benzylamide [Formula I: Ri = quinolin-2-ylcarbonyl; A = L-Asn; R2,R3 = Bz; X = -NH-; B = L-Val; R4 = NHBz] [Process variant b2), substitution] 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 RiA-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: -17- 900-9710 1H-NMR: 0.92 and 0.95 (2d,6H); 1.70 (b,lH); 2.16-2.24 (m,IH); 2.82 (dd,2H); 2.92 and 3.01 (ABX,2H); 3.34 (d,lH); 3.57 and 3.66 (AB,2H); 3.86-3.90 (m,lH); 4.26 (dd,lH); 4.31-4.46 (m,3H); 4.89-4.95 (m,lH); 6.68-6.72 (m,lH); 6.95-7.00 (m,lH); 7.09-7.30 (m,17H); 7.65-7.68 (m,IH); 7.79-7.82 (m,IH); 7.86-7.93 (m,2H); 8.16-8.21 (m,2H); 8.31 (d,lH); 8.73 (d,lH); Example 4: N-[2-Benzylamino-4(S)-(N-benzyloxycarbonyl-L-serinoyl)amino3-hydroxy-5-phenylpentanoyl]-L-valine benzylamide [Formula I: Ri = Z; A = L-Ser; R2/R3 = Bz; X = -NH-; B = L-Val; R4 = NHBz] [Deprotection] 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 confound is obtained (m.p. 76-81°).
Example 4a: [2-Benzylamino-4(S)-(N-benzyloxycarbonyl-L-valinoyl)amino]3 hydroxy-5-phenylpentanoic acid [Formula I: Ri = 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 μΐ 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°). -18- 900-9710 Η Φ d d e CQ d O CF o i—| fO d Ό Φ d •H OJ -U X3 O Φ H rt <0 •H d o Ψ4 d o •H -l—l d Φ > d • H Φ £ UH O m n c O £ o a M a) Λ 4-) Cn c •rt O O MH Φ £ ft to 4-) « G Φ (0 υ -η O 1-1 rt ro > e? • · SB o O o O o O o o © O © © © O o O o o O •n« co M4 co C-> O cn Γ- O Γ- 00 CF CF O © m rH cn O CN rH co i—1 cn • cn όη 00 m cn CN 00 m in m CO rH I iH 1 rH CN rH Ό rH oo | rH | rH rH rH rH I rH rH rH CF | rH iH 1 o 1 CD 1 CO 1 CO LD OO 1 CF m 1 CF 1 in I in m cn 1 ττ 1 CO OO 1 O 1 m CF Γ— CF 00 rH o O CN rH cn r- oo cn r— m cn CN Γ— CN oo M4 in rH rH rH CN rH rH rH rH rH iH i—1 iH rH rH rH r—1 iH •G 43 u a Ό £ 43 43 43 43 Φ rtj Φ Φ Φ φ Φ N N u 43 43 43 (0 <0 Φ rO 43 43 43 43 43 43 t0 tO (O to ro ro ro H σ) rH ro 73 Ί3 φ a h H « nj 3 3 33 H rt m !> !? t> 7 T ’T t> ‘r t> !> > Jq Jq Jq Jq «l-q « Jq Jq rfl id Jq Jq r r r r « « « « N NN « «so NN N « « « is N N N XS tS 9 N « « η ft υ a « ? ? SS 7 7 SS 7 7 s 1 SS 7 7 SS 7 7 s s s s s s s 7 7 7 7 i 7 7 N N N N N N N N N N N N N N N N Μ N « CQ CQ CQ CQ ffl « CQ CQ « « CQ CQ CQ CQ CQ CQ CQ | rrt Q 8*1 .3 a rrt (0 3 33 33 3 φ § rrt 1 rc S 335333 3 !> s> «> f s> > !> ? 7 Η CN | 1 Λ Jq 1 rtS « « rtS « 1 l-q rtS « 1 1 id >d ά Jq Jq Jq Jq Jq Jq M H M N Μ M M Μ M N N N Μ Μ *9 Μ tfl m r- co σι o cn n t1 tn ie r~ oo σι o ι-t cn rt H rrt rrt i—I rt rt rt CN O') CN -19- 900-9710 α. e CO 4-> CO C Φ nJ U -H Ο M M nJ CM > • · SB Λ. Λ. co O O o o o o S y, Ο 00 Ο ο o CO • < r* «31 O cm 2 S co 1X5 1X5 CM r—Ί i-H Ow r—1 00 10 00 co ι—1 ι—1 ΟΟ 00 | 1 1 1 1 | I *%·>». 1 1 1 ·«. | 00 Γ- n CM CTi σ> CM η h <τ» CO r—1 00 CM •H <0 Γ- in c** C** ·Η ·Η r-1 in 00 •Η Γ-* T—1 W i—1 Ο Ο ι—1 τ—1 Ο Ή O £>£>£) nJ nJ nJ X) XJ X3 XI XI X) X) rn nJ nJ rn nJ nJ rn nJ nJ nJ XI nJ x: u x x nJ nJ Η Η Η ft ft ft Η ft <3 3 Η Η Η Η ft ft ft ft rt Ί3 nJ r—I ft Ή ft !> tf * Τ ί !> t> f> *| *| *| *1 Sf if if XXX χ ι-3 η3 j_q XXX X X § N BQ ± ' e tt?? N N BQ BQ M BQ N BQ N CQ ITT TTT <0 X N CQ N CQ N CQ N BQ N OQ N N M CQ CQ OQ M CQ N N CQ CQ N CQ N BQ N BQ N BQ 3 3 3 9 3 fH ft 3 fH ft X m fH ft j3 /3 3 T 33 T r rH >1 3 T * !> > t? *r *r *r X X X g V X X X X X X XXX H X X fM 1 X 1 X CS CN rf*l CO CN Μ Μ M σ» O r-Η CN Nmm ro BOC bond Bz -S- Bz L-Val NHBz a) b) 55-62° 40f) Z L-Val Bz -NH- Bz L-Val 3-pyridyl- a) b) a NMRh) ; methylamino b 77-82°; NMRh> -20- 900-9710 α. e CO -P CO a Φ nj a • H o P P nJ 04 > e? B? α •r| § 43 43, 43, 43, ·% co •K o Og 0¾ Pq p^ o o O o> ~ o CM • s « w y y y o m β co o P 43 o o TT m o q ® S s O »—1 co CO m p^ co o rH Γ- r- «-Η OO «"H rH OO a> § oo Γ- CM 1 oo OO ·*. » ·«. •K I 1 I ί 1 t -U S 1 1 t OO 1 1 «-Ι ι—1 T—1 rH r*« r-1 OO m o •H co co OO co CM -H Ή Ή •H to i—1 OO CM CM 00 x: oo to σι »—1 00 OO O O o o rd «Η r-1 3 rH fl X3 £> £) £> X5 X3 XQ X) X3 43 Λ X) 43 X3 X) S' X3 _ _ r—«. r—«. s, nJ nJ nJ nJ nJ nJ nJ nJ (TJ CXJ nJ nJ nJ nJ nJ nJ •H 43 M -t-i ans r3 JJ I Q M O I ►J 1 2 cn fl ι -3 1 2 CN fl I ι—I 8m N pa N BQ N BQ N BQ •Η 43 ·Η Λ ·Η 43 felj & 8 & ϊ α a ι ι Η a a co CN hQ ? hQ fl 3d I t-fl 4J N r-l N N fl Ο,Γ fl >1 2 r3 H fl ι—1 r-l fl fl H fl H fl H J? t> 'T ϊ> T* Jq Jq Jq hQ G) Jq Jq Jq N NN a a a is I I ii ι ι —. 5*1 r-l Λ fl Φ Qc >i 2 o a 43 Μ φ Q< a ι 1 H —, N 5 a Q fl 1 T Φ CN Q * xq Qj 1 P’ T 1 CN cn co g gg g ί g -21- 900-9710 α, e CO 4_> CO C CD (fl α -η Ο M Μ Π3 CM > • s. •M. 43 43 43 o O o o o o © © o © p< o ι—I [**· O m o © Tl« 00 ι—1 © o in © co kO m O o O CO r· CN Γ* O o kO o in in m kO g OO τ—1 CN in ι—1 τ—1 ι—1 00 00 CN CN r—1 00 un τ—1 in r—1 1 1 1 00 | 1 1 1 1 1 1 1 1 1 | | • > • v 1 • K co m in I o OO r- 1—1 TT in o in O r—1 <—1 I-) OO o CN o CN ko r- OO o o in r*· in in H •H in ♦H CN OO 1"f Γ—ί τ—1 CN CN 1"< 1"< o o i—( o Α A (fl (0 A (fl A (fl A ifl A Tfl Λ Λ Ό Ό (fl (fl (fl (fl A A XI A (fl (0(0 A XJ (fl (fl (fl (fl (fl (fl (fl I CM I CM mi N A N A H ? H ? H ? ? ? ? A A A A A A β1 ! y > S> ‘r τ A A Ό Ό Ό Ό A 1fl Ό fl fl β β h > β N 0 N N >1 N N 03 0 0 s 0 I 0 | 1 f-H s 1 A A M 1 M N U V T V V •H Λ0 •H 0 1 03 0 w· * «r A A w * N N N N N N N 03 03 a 03 03 03 co gg g g g g ^gg S gg ggggggg N N aa a I A I A A A A A M Cti Φ Oj 0) 0 I I CM CM 9 «S3 fH (0 A Η a fl 3 A fl fl fl 'fl 3 3 T S3 9 9 s> If if if > if if if A g if T 1 A A A A A A A AAA A A I § ^ A 1 F-1 fl £ 0 •H M g M M M M N M M Μ Μ M M M >i 43 QiX) M M 1 CM a a 00 σι O A CM m * vn vo a 00 0 o A m m ΙΌ VO VO VO vo vo vo vo vo VO VO A A r~ a a -22- 900-9710 οε CO 4-1 co C Φ σ> ο ·Η ο Μ Oj η? e? as LT) r* <τ» tO tO CM to ° 2 Π- ct~ tO tO 0 0 oo r- in CX 0 43 1 1 43 •H •H 43 1 I 1 1 1 I 0 t-ι Aa If) CO S CO CO CM 00 o to O 1 '"H o M i—) 2 in tO § Φ Φ OO oo to cn -H in • H co S § M s <Τι O CO Λ Λ Λ Λ <τ$ nJ nJ nJ nj +J 4J +J +J 4-) Μ Μ M W H OOOOO Λ Λ Χ5 XJ 43 43 43 nJ co ro co nJ nJ Φ rcJ σ, ro ~(5 XI Γ0 rt 4-1 4J 4-1 4J +J U U U Μ M OOOOO 4-1 4J 88 XI X* « s o o *2 *3 *2 *2 *2 *o 0 0 0 0 53555 5 5 5 5555 a 55552 555 55555 55 5 55 «SS85 * I I fH I H ^Φ Λ 4JH N N N N N oa co n co a §3333 τ ύ j xj xa j .9 I CN N aa SO cu i τ* o 5 Φ I CN 51 t) Η H 55Λ V MV * n a » N N OQ $ 1 W I (—I 1 >1 1 Λ Λ XI N N N N ft· Φ OQ 03 OQ OQ 1 CN a H 0 H 0 33 rt 3 3 33 «r > t ‘r τ Ja Ja i-3 i-3 Jia Jia Jia Λ h3 ? i-3 03 03 03 M 03 03 03 03 03 03 03 03 03 03 03 00 O fH CN cn rt· m ic 00 σι O r4 CN r- r* 00 00 00 00 00 00 00 00 00 00 σι σι σι n «r σι σ ? λ| ΛΪ -23- 900-9710 (X e u o β CM s ** © © © in o o m 2 in • V 2 o © 00 m in co n· CM r- 2 o o a Γ* in k£> m CM f—1 CM OO rH τ—1 1-4 Ή ♦ ». cr» co 1 I 1 I I | 1 * «* 1 1 CO 1 | oo r- LO o CO Γ- ι-1 ι-I r—1 B"1 Φ •Η o in 00 co CM r* -Η O o M Ο σι 00 iH i-H Ο M ι—1 υ n . Q 43 X3 43 43 Xi 43 43 43 43 M 43 43 43 Om nJ CM Φ ~ nJ co nJ (fl (0 nJ (fl (fl nJ (fl (0 (fl (fl Ά (fl nJ (fl xj Ό Ό © ra ra © a S 3 3 > 5» 3 33 3 3A A 2 N N bo bo gg ι ι N N BQ CQ !> CM N N 00 BQ BQ Q I 11 w w o s3 si w n •rl u I N W 03 00 I * 2 CM fl I H Ϊ N 3 N N ι-t Η ι—I •2 >2 2 ‘r *r *r J h5 p3 N BQ I ? h3 NN N BQ BQ I ± 1 V) 1 S Ψ S ? ? ? SS ? s^ ? N N N H N N N N N N N N N N 00 BO 00 00 B0 00 00 BO B0 BO BO B0 BO BQ s 9 9 9 3 Η H >1 © 3 3 rM rt 3 H rt H ft 33 rM © 33 44 1 §> g 5? t? > 1? «r 'f v &§ V V rQ 3 A 3 A A A A A A A A P A A 1 pH SS •tr « CM 44 M M M M fr0 a a ft m Ρ» 00 at O fH CM CO in to σι at σ» at o o O o o o o rH H rM A a »H 8*iJ, ο 43 a Q 44 CM O 3 fl I ·Η ·Η O -24- 900-9710 CO 4-) CO C Φ nJ Ο -d Ο d d nJ CM > a •d CO Λ co co co co Φ k o o o OJ 9 0 ZJ o M 43 o CM m • o O o o CO Cd z m cs cn r—d 43 n 43 43 Φ 2 i—l CM CM CL CL CL CL 1 4-) z 1 40 • k. 1 A 1 o 1 μι d d d 43 i-H i—1 -H σν i—1 Ή 00 pTj I— r—I OO cn © o o O O OO •H •Η X3 in g •Η -H cn 5] .|-H Ή i—1 r*· i-H c gs o o » o o i—l 9: o o CM r-H CM nJ nj M 0 0 0 0 0 0 0ee . CL CL CL CL CL CL CL CL CL CL CL CL CL Φ Φ · Φ Φ Φ Φ Φ Φ nJ nJ nJ nJ nJ Ό TJ Cl Ό TJ T> Ό Ό Ό co • • co co • co co CL CL CL CL o—*. I·—·. • —‘ Φ «-ftk. >—k. nj nJ nj X X) d XI X) d x n x x XI X XI XI XI co co X X co XI X CL CL Φ Φ k, -*"»k x—kk k. z«s -k <«~-k O*»k nJ T5 nJ nJ n nJ nJ nj nj nj nJ nJ nJ nJ nJ nJ nJ nJ nj nJ I i *» II CS is n f · T i-4 (S’ id 3 N ? h4 •d 4J P ?* i fo i i—I id i—I i—I ££££ H +J ·Η 4J d ω η ω N N fcl 1 fel Oc Oc 1 1 9 co cs o SSS ? i-4 N 3,d f & ο Λ I )-4 Μ N 04 04 ££ i T N N β 04 •gS o +j 3i Ό Ό 5 fl rt 9 a ac > > > 6i3 „ ►j 3 3 I I I . h4 1-4 i-4 i-4 r h4 3 553 I id : Μ Μ N N N Μ M 04 04 04 04 04 OQ 04 I I I I I ± £ £ £ £ £ W £ TTT ι T I I t4 N N 04 N N M 04 04 04 -H 04 04 04 M N I? 'S 9 ’S 3 2 > a s> 9 a a s 9 I CS N 0Q 333 553 I id i d/a5 H 2^·.+ 9 §s & N N d Β I 04 6b Oc I cn CS I CN If Oc N N -d 04 04 3 £ 33Ϊ N CO ? i-5 N N N CO CO CO HS HS HS EH HS HS Dd 04 04 Dd 04 M M N &0 M rH CM O' cn m kO r* CO σι o fM CS m w· m VO > OO σν O i-H i-M rri rH rM rM rH τ-M id CS CM cs cs cs cs CM CM CM CM cn fM H iH Fd rd fM id fH rd id M fH Ή fM -25- 900-9710 CO 4-) co c Φ ft a •H o J-l Ul ft CM > ffl Λ o o © o o o o o o o © o m in in cn CM CM c*» co o m o o »—1 © CM o f4 cn cn O o o o o r—1 in o co CM CM CM r—1 i-M CM CM CM CM CM τ—1 m OO CM 10 | | I 1 I I I ♦ < 1 I 1 1 I 4 1 1 X 0 ft o CM O 10 r- 00 »-1 CM oo o *—1 o CM r-1 o CM O »-H cn oo •H O cn •H cn m 2 oo cn in CM CM CM »—I r-4 i—1 1—1 o CM i—1 i—1 os r-4 CM Om On G. G. CM CM ft ft ft ft ft ft ft co co co co co CO co ___ ___( X) X3 X» ΧΪ • Λ • XI XI Xi • Xi X) • Λ x> . 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Ν Λ X N N BQ Οι Φ BQ BQ CN BQ n m n n X BQ BQ BQ BQ h <8 Ν N BQ BQ N N N BQ BQ BQ rt 3333 •r τ 'r *r XXXX X BS X n BQ rt X V *? a I O X 1 X M N N N N N er » 3M M N M M M M N N K CN « 3 fM CN cn W» m IO r* 00 cn O fH CM CO m C0 r* 00 cn o co cn cn CO «η CO rn cn * «e w· F m rH X X fH X fH X fH X fH fH fM fH fH X fH fM X fH Λ 8 -26- 900-9710 (X e co 4-> co G Φ nJ o Ή o M Ul nJ Oh > oo ι LO ss 03 Sa o o o n moo CM CO oo η h in I I I Γ- TT ’ύ* co cm m (X nJ co m oo o r-* © 1 Γ— CM o i-H LO o O CM 1 ι-1 o Γ- τ—1 Γ- CM CM « 1 Ι LO 1 ··. in CO i-H m o LO ι—ί • V X τ—1 JX CM ι—1 o X Ό CM Ό *» £ LO • cn CX o • .—.J—L nJ CM Γ— X3 Xi Λ CO • m ·«· 1 b. nJ nJ nJ nJ o X oo ι—1 cn Ό «<. O O X CM τ—1 • [— 1 g TJ CM « B •K 1 Η O H ►in o X O 40 B CM N •p 0 • i-H •sa •H H CM ruS N CM CJ © Φ ·- a © -H φ ra c x> •Η 43 ra o 4J O raf rj> e c-~ in O oo co • • LO CM 1 • X m X CM CM ·>.
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Ο ΓΟ -33- 900-9710 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-phenylpentanoic acid ethyl eater [Formula II: Ri = 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-nitrophenylester (an intermediate of formula RiA-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. 154-156°) 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 -60* 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 IN 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 -34- 900-9710 (solvent: toluene/ethyl acetate 4:1). 4(S)-[(N-BenzylozycarbonylL-valinoyl)amino]-5-phenylpent-2(E)-enoic acid ethyl ester (an intermediate of formula VI) (m.p. 161-165°) is obtained. c) Epoxidation: 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 Ila) is obtained (m.p. 164-167°). -35- 900-9710 c o • H 4-) ft Ml Cn •H Ψ4 CJ o o Φ 0! M Φ CJ a « o ¢7) o Γ—J ft CJ ft CJ •H Ό Φ a •H ft 4-) XJ o Φ Ml ft a •H CM s e? I LO in N OQ t) & ?CM in r— i—l I N Ό ·β rt § § τ τ T x x x BM m CO JJ co X • fc ι-H • fc .«fc. ·» o ^-fc. ac Ό CM X CM ·—" • f"4 *fc CO fc S, CM 1 w σι 00 Xi • ,—1 OO m • Γ- co in • • fc CM CM • fc • 1 X co O co X 10 fc i—l • fc • 3 •fc —fc CM S' ac r-4 • < o ·. CM m s. ac • r-4 • 1—t in • «—fc •fc 1 co X o 4-) r- 1 »—l oo X o o fc • Φ • o Ό i—l CO m • 1 '-f· co co • fc 10 <0 o «—. • fc OO CM X «—fc • ι-H • r-4 X Γ— CM CM • fc. s. fc • fc .—u • fc 3 .«-fc ac X CM ac o r-4 CM in o i-H fc • σ» fc e. ft* • S' 1 CM CO co 1 in 10 co o o • O • 10 in I—1 • ft* • • 1 CM CM r- o 1 • fc I CM «-fc • χ o • OO X «-fc o i—l • CM X • i—l K cd Γ- • fc cr fc ··. s. • fc X ^-fc σ> ·«. X i—l X ·· ^-fc. co CM o CM co ac •fc • cn ·» ·*—" CM 4-) • CO —«* r-4 -- ft* cr • fc 1 ft* Ό OO >*fc o o • CM X Γ- r-4 i—1 • i—l • • CM i—4 •fc r-4 in • fc CM Ό ,—L • ··. Ό • fc • ·, X ft* «μ» *-* «^. «^ co X X X • ν co m co CM 4-)J—. ·. σ> •i fc ac Ό • Ό 6, r-4 - co •fc • fc CM cr OO fc .«fc 10 o • £ σ\ .«-» X r* co τ—1 • X o • • o CM i—l o ft* • o fc 1 ^-.fc i—1 ·ν S' s. • fc o ac • fc «—fc. 10 <0 ft* X X • CO Γ- CM co co Ό • ·. •fc ΓΟ ft* CM fc. Ό • • Ό • fc ·—— ac -*-* co Γ— --- «-fc. ι—1 1 | X r- Γ- i—l o o i—4 σι CO ΟΟ CM i-H r- fc . X5 • • • • S, o o CO r- o I 1 Ϊ 1 33 1 33 1 33 r4 i-4 r4 «fc «fc nJ Δ 0 -36900-9710 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 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 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): XH-NMR: 0.98 (s,9H); 3.05 (s,lH); 4.4 (s,2H); 7.2-7.4 (m,5H); 13C-NMR (CDC13 + drops CD30D): 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 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> -37900-9710 Compound m.p.
M N P Q R S L-Val L-Val L-Val L-val L-Val L-Val L-Val benzimidazol2-ylmethy lamino 2-(4-OH-phenyl)ethylamino 2- (4-morpholinyl)ethylamino benzimidazol2-ylmethoxy -MO2"benzimidazol2-ylmethoxy ,6-diCl-benzimidazol-2-ylmethoxy 2-(indol-3-yl)ethylamino oil; NMRe> oil; NMRf> oil; NMR9> Oil; NMRh> oil; NMR1» oil; NMRl) 81-86’ 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,lH); 4.40-4.60 (ddd,2H); 7.25-7.35 (m,2H); 7.60-7.70 (ddd,lH); 7.80-7.90 (m,IH); 8.53 (dd,J=4.8 and 1.6Hz,IH); 8.55 (d,J=2.25Hz,IH); b>1H-NMR: 0.88 (d,J=7Hz,3H); 0.99 (d,J=7Hz,3H); 2.00-2.20 (m,lH); 3.30 (d,J=4.8Hz,IH); 4.54 (s,2H); 7.10-7.40 (m,2H); 7.60-7.70 (dddzlH); 8.20-8.30 (m,lH); 8.30 (d,lH); C>1H-NMR: 0.88 (d,J=7Hz,3H); 0.95 (d,J=7Hz,3H); 2.10-2.30 (m,lH); 3.23 (d,J=4.6Hz,lH); 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,lH); ®>1H-NMR (DMSO): 0.80 (d,3H); 0.89 (d,3H); 1.85-2.10 (m,lH); 3.06 (d,IH); 4.51 (s,2H); 7.10-7.20 (m,2H); 7.45-7.55 (m,2H); 8.50 (bs,lH) ; f)1H-NMR (DMSO): 0.74 (d,3H); 0.81 (d,3H); 1.82 (sext,lH); 2.58 (t,2H); 2.88 (d,lH); 3.14-3.30 (m,2H); 6.67 (d,2H); 7.00 (d,2H); 7.82 (bt,lH); 9>1H-NMR (CDCI3/D2O): 0.78 (d,3H); 1.84 (sext,lH); 2.31-2.42 (m, 6H); 2.95 (d,lH); 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,lH); 3.00-3.50 (d,J=4.6Hz,lH); 5.30 (s,2H); 7.00-7.20 (m,2H); 7.40-7.60 (m,2H); 1>1H-NMR: 0.84 (d,3H); 0.89 (d,3H); 1.80-2.00 (m,lH); 3.26 (d,J=5.4Hz,IH); .37 (s,2H); 7.74 and 7.67 (2d,J=9Hz,1H); 8.00-8.20 (2dd,lH); 8.40 and 8.47 (2d,lH); 3>1H-NMR: 0.83 (d,3H); 0.89 (d,3H); 1.80-2.00 (m,IH); 3.24 (d,J=5.4Hz,IH); .36 (s,2H); 7.74 (s,2H); -38900-9710 T: N-Benzyloxycarbonyl-L-tert-leucine-N-hydroxysuccinimide e3ter [Formula RiA - Q: Ri = 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,IH); 5.03-5.12 (m,2H); .34 (d,J=10Hz,lH); 7.26-7.40 (m,5H).
The following intermediate of formula R]A - Q is obtained in analogous manner: Compound Ri 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, IH); 2.82 and 2.84 (2s,4H); 4.62 (dd, J-5Hz, J=7.5Hz, IH); 5.28 (s,2H); 7.25-7.42 (m,3H); 7.72-7.81 (m, IH). -39- 900-9710 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-Nph-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 μΜ for HIV-1, and of from about 30 nM to about 10 μΜ 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 HIVversus mock-infected cells allows the determination of minimum toxic (MTC) and minimum virus-inhibitory (MIC) concentrations. -40- 900-9710 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-benzyloxycarbonylL-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 -41- 900-9710 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 prophyiactically 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 (13)
1. A compound of formula I R 2 xr 3 R X A - NH - CH - CH - CH - CO - BR 4 I 4 | 2 1 OH wherein A and B independently are a bond or an optionally substituted aminoacyl moiety; R x is hydrogen; an amino protecting group; or a group of formula RgYwherein Rg is hydrogen or an optionally substituted alkyl, alkenyl, alkinyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl group; and 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, 2-thienyImethyl or styrylmethyl; R 3 is an optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group; R 4 is a group of formula -OR7 or -NHR7 wherein R 7 has the significance indicated above for R 6 ; 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. -43900-9710
2. A compound according to claim 1 of formula Is R23 RlaA s - NH - CH CH - CH - CO - B 3 R 4s I 2 1 IS OH wherein R ls 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 3 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; R 2s is alkyl of 3 or 4 carbon atoms or phenylalkyl of altogether 7 to 9 carbon atoms; X 3 is -S- or -NR5 3 - wherein R 5a is hydrogen or methyl; R 3s 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; B s is a bond; a natural α-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; or aminocyclopropan-l-carbonyl; R 4s 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 -44900-9710 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 Ri is benzylyoxycarbonyl, 2-pyridylmethoxycarbonyl, phenyllactoyl or phenoxymethylcarbonyl, 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 and R 4 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 Ipi 4 12 1 R lp A - NH - CH - CH - CH - CO - BR 4p IPl OH wherein A, B, R 2 and X are as defined in claim 1; Ri p with the exception of hydrogen has the significance indicated in claim 1 for Ri; R 3p with the exception of optionally substituted cycloalkyl has the significance indicated in claim 1 for R 3 ; and R 4p 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 R 4 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. -45- 900-9710
6. The compound according to claim 1 of formula I wherein the configuration at the carbon atom in 4 position is S, Ri is benzyloxycarbonyl, A is L-valine, R 2 is benzyl, X is -NH-, B is L-valine, R 4 is benzimidazol-2-ylmethylamino and R 3 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, R 2 is benzyl, X is -NH-, B is L-valine, and Ri, A, R 3 and R 4 respectively are either - benzyloxycarbonyl, L-valine, 4-methoxybenzyl and benzylamino, or - 2-pyridyimethoxycarbonyl, 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-ylmethylamino, 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 R 2 I RiA - NH - CH - CH - CH - CO - BR 4 \ / II wherein the substituents are as defined in claim 1, to ring opening in the presence of a compound of formula III -46- 900-9710 Η - XR 3 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 -BR 4 is other than hydroxy [bi], or Ri is other than hydrogen or HY- [b 2 ], appropriately substituting a corresponding compound of formula I wherein -CO-BR 4 is carboxy or Ri is hydrogen or HY-, e.g. bi) substituting a corresponding compound of formula Ia R 2 XR 3 I I RiA - NH - CH - CH - CH - COOH Ia I OH wherein the substituents are as defined in claim 1, or b 2 ) substituting a corresponding compound of formula lb R 2 xr 3 I I Rl'A - NH - CH - CH - CH - CO - BR 4 lb OH wherein Ri' 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. 6300/VA3207/RE4476 - 47
11. A process for the preparation of a compound of formula I as defined in claim 1 substantially as described herein with reference to the Examples. 5
12. A compound of formula I as defined in claim 1 whenever prepared by a process as claimed in claim 9 or claim 11.
13. A pharmaceutical composition comprising a compound as claimed in claim 12.
Applications Claiming Priority (3)
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 |
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 |
Publications (1)
Publication Number | Publication Date |
---|---|
IE922143A1 true IE922143A1 (en) | 1993-01-13 |
Family
ID=27265743
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE214392A IE922143A1 (en) | 1991-07-02 | 1992-07-01 | 4-amino-3-hydroxycarboxylic acid derivatives |
Country Status (9)
Country | Link |
---|---|
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) |
Families Citing this family (12)
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 |
US5538997A (en) * | 1993-03-12 | 1996-07-23 | Sandoz Ltd. | 2,4-diamino-3-hydroxycarboxylic acid derivatives |
IL110898A0 (en) * | 1993-09-10 | 1994-11-28 | Narhex Australia Pty Ltd | Polar-substituted hydrocarbons |
HU223083B1 (en) * | 1994-06-28 | 2004-03-29 | Bayer Ag. | Fungicidal amino-acid-derivatives, process for their preparation and their use |
DE19501175A1 (en) * | 1994-06-28 | 1996-01-04 | Bayer Ag | Amino acid derivatives |
AU4555800A (en) * | 1999-04-27 | 2000-11-10 | Novartis Ag | Use of 2,4-diamino-3-hydroxycarboxylic acid derivatives as proteasome inhibitors |
EP1404328A1 (en) * | 2001-07-10 | 2004-04-07 | Elan Pharmaceuticals, Inc. | Alpha-hydroxyamide statine derivatives for the treatment of alzheimer's disease |
WO2004050609A1 (en) * | 2002-11-27 | 2004-06-17 | Elan Pharmaceutical, Inc. | Substituted ureas and carbamates |
US8552032B2 (en) * | 2009-12-18 | 2013-10-08 | Janssen Pharmaceutica Nv | Bicyclic derivatives useful as inhibitors of DPP-1 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE4004820A1 (en) * | 1989-08-05 | 1991-04-25 | Bayer Ag | RENININHIBITORS, METHOD FOR THE PREPARATION AND THEIR USE IN MEDICINAL PRODUCTS |
-
1992
- 1992-06-30 CA CA002109326A patent/CA2109326A1/en not_active Abandoned
- 1992-06-30 IL IL102362A patent/IL102362A0/en unknown
- 1992-06-30 AU AU21944/92A patent/AU2194492A/en not_active Abandoned
- 1992-06-30 JP JP5501937A patent/JPH07501786A/en active Pending
- 1992-06-30 MX MX9203836A patent/MX9203836A/en unknown
- 1992-06-30 WO PCT/EP1992/001471 patent/WO1993001166A1/en not_active Application Discontinuation
- 1992-06-30 EP EP92913821A patent/EP0594656A1/en not_active Withdrawn
- 1992-07-01 IE IE214392A patent/IE922143A1/en not_active Application Discontinuation
- 1992-07-03 TW TW081105274A patent/TW221686B/zh active
Also Published As
Publication number | Publication date |
---|---|
CA2109326A1 (en) | 1993-01-03 |
JPH07501786A (en) | 1995-02-23 |
TW221686B (en) | 1994-03-11 |
EP0594656A1 (en) | 1994-05-04 |
AU2194492A (en) | 1993-02-11 |
WO1993001166A1 (en) | 1993-01-21 |
MX9203836A (en) | 1993-01-01 |
IL102362A0 (en) | 1993-01-14 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
FC9A | Application refused sect. 31(1) |