WO2002079234A1 - Peptides and their use as inhibitors of hepatitis c virus ns3 protease - Google Patents
Peptides and their use as inhibitors of hepatitis c virus ns3 protease Download PDFInfo
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- WO2002079234A1 WO2002079234A1 PCT/EP2002/003435 EP0203435W WO02079234A1 WO 2002079234 A1 WO2002079234 A1 WO 2002079234A1 EP 0203435 W EP0203435 W EP 0203435W WO 02079234 A1 WO02079234 A1 WO 02079234A1
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- KRRBFUJMQBDDPR-UHFFFAOYSA-N tetrabutylazanium;cyanide Chemical compound N#[C-].CCCC[N+](CCCC)(CCCC)CCCC KRRBFUJMQBDDPR-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- ORQXBVXKBGUSBA-QMMMGPOBSA-N β-cyclohexyl-alanine Chemical compound OC(=O)[C@@H](N)CC1CCCCC1 ORQXBVXKBGUSBA-QMMMGPOBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/021—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0819—Tripeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1021—Tetrapeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1027—Tetrapeptides containing heteroatoms different from O, S, or N
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/02—Linear peptides containing at least one abnormal peptide link
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- This invention relates to compounds which can act as inhibitors of the hepatitis C virus (HCV) NS3 protease, to uses of such compounds and to their preparation.
- HCV hepatitis C virus
- HCV hepatitis C virus
- NANB-H sporadic non-A, non-B hepatitis
- Some 1% of the human population of the planet is -believed to be affected. Infection by the virus can result in chronic hepatitis and cirrhosis of the liver, and may lead to hepatocellular carcinoma.
- NS3 protease is located in the N-terminal domain of the NS3 protein, and is considered a prime drug target since it is responsible for an intramolecular cleavage at the NS3/4A site and for downstream intermolecular processing at the NS4A/4B, NS4B/5A and NS5A/5B junctions.
- peptides in particular hexapeptides, showing degrees of activity in inhibiting the NS3 protease.
- the aim of the present invention is to provide further compounds which exhibit similar, and if possible improved, activity.
- peptidic phenethylamides and related compounds are effective inhibitors of NS3 protease. Although not wishing to be bound by any particular theory, the inventors believe that these compounds are non-covalent inhibitors of serine protease which may be involved in a partial bond with the serine hydroxyl group of the enzyme. This distinguishes the compounds of the invention from compounds previously suggested as serine protease inhibitors and which rely on formation of a covalent bond with the serine hydroxyl group.
- the inventors have found that by including a phenethylamide or analogous group at the C-terminus the activity of hexapeptide inhibitors may be improved.
- molecules containing less than six amino acids retain useful activity because of the presence of the phenethylamide, or analogous, group at the C-terminus.
- Q is selected from the group consisting of: wherein X is -CH,- or -0-;
- Y is a group of formula -C(R a ) 2 - where each R a is independently selected from hydrogen, hydroxyl, carboxylic acid, lower alkyl (such as methyl) , aryl (such as phenyl) , heteroaryl, aralkyl or heteroaralkyl, or the two R a groups together form a cycloalkyl group containing 3 to 7, preferably 3 to 5 carbon atoms;
- Z is a substituted or unsubstituted aryl or heteroaryl group
- R 2 is a lower alkyl group, optionally substituted with one or more fluorine atoms, or is -CH 2 SH;
- R 3 is an optionally substituted alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group containing from 2 to 16 carbon atoms, or together with R c forms a ring including the nitrogen atom which bears R c ;
- R c is hydrogen or a lower alkyl group or together with R 3 forms a ring;
- R 4 is an alkyl, alkenyl, aralkyl, heteroaralkyl, aryl or heteroaryl group containing from 2 to 16 carbon atoms or is an acidic group;
- R 5 is selected from (R 6 ) 2 NCO-, R 7 CO-, ROCO- , R 7 NHC0- , R 7 CO.CO-, R 7 S(0) 2 - and R 8 pep where "pep" is an amino acid, di- or tri- peptide;
- each R 6 is selected from hydrogen and optionally substituted, optionally interrupted lower alkyl or lower alkenyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups, or the two R 6 taken together form a four to seven membered ring optionally containing one or more other heteroatoms in addition to the nitrogen atoms to which the R 6 groups are bonded;
- R 7 is an optionally substituted, optionally interrupted alkyl, alkenyl, aralkyl, heteroaralkyl, aryl or heteroaryl group containing from 1-18 preferably 1 to 14 carbon atoms, particularly, 1-8 carbon atoms;
- R 8 is a group of formula (R e ) 2 NCO-, R 7 C0- , R 7 OCO- , R 7 NHCO- , R 7 C0C0-, and R 7 S(0) 2 -;
- pep if present is an amino acid, di, or tri peptide of formula C-B-A;
- A is selected from naturally and non-naturally occurring amino acids having a hydrophobic side chain containing 1-20 carbon atoms;
- B may be absent, in which case C will also be absent, but if present is selected from naturally or non-naturally occurring amino acids having a side chain which includes an acidic functionality;
- C may be absent, either by itself or together with B, but if present may be selected from naturally or non- naturally occurring amino acids containing an acidic functionality;
- R 13 is a group containing up to 25 carbon atoms, 0-5 oxygen atoms, 0-3 nitrogen atoms, 0-2 sulphur atoms and up to 9 other heteroatoms which may be the same or different ;
- R 17 is hydrogen, a lower alkyl, lower alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, hydroxyl, alkoxy, aryloxy, aralkoxy, heteroaralkoxy, thioether, sulfonyl or sulfoxide group;
- R 18 is a group containing up to 25 carbon atoms, 0-5 oxygen atoms, 0-3 nitrogen atoms, 0-2 sulphur atoms and up to 9 other heteroatoms which may be the same or different.
- lower alkyl and lower alkoxy are intended groups having from 1 to 10, preferably 1 to 6, most preferably 1 to 4 carbon atoms.
- Lower alkenyl groups have from 2 to 10, preferably 2 to 6 carbon atoms.
- aryl as used herein implies an aromatic ring optionally fused, e.g. benzofused, with one to three cycloalkyl, aromatic, heterocyclic or heteroaromatic rings .
- Preferred groups containing a carbocyclic aromatic radical have from 6 to 14 more preferably 6 to 10 carbon atoms . Examples of such groups include phenyl and naphthyl .
- the terra "heteroaryl” as used herein implies a heteroaromatic ring which is optionally fused with one to three cycloalkyl , aromatic, heterocyclic or heteroaromatic rings .
- Heteroaryl groups in general , include a 3 to 7 membered heterocyclic aromatic ring consisting of one or more carbon atoms and from one to four heteroatoms selected from nitrogen, oxygen and sulphur .
- Lower alkyl and lower alkoxy groups as defined above may, optionally, carry one or more aryl or heteroaryl substituent .
- the result is an aralkyl , heteroaralkyl , aralkyloxy or he ' teroaralkyloxy group .
- aralkyl - and heteroaralkyl groups include , but are not limited to, those of formula :
- aralkyloxy- and heteroaralkyloxy- groups include but are not limited to, those of formula :
- aralkyl, heteroaralkyl, aralkyloxy- and heteroaralkyloxy- groups generally include from 2 to 20, say from 4 to 15 carbon atoms.
- Optional substituents are not particularly limited but may be selected from the following list: lower alkyl or alkenyl, aryl, heteroaryl, lower alkoxy, aryloxy or aralkyloxy, heteroaryloxy or heteroaralkyloxy, amino, nitro, halo, hydroxy, carboxylic acid, acyl, formyl, sulphonamide, acylsulphonamide, ester, amide, cyano, and trihalomethyl groups.
- an optional substituent may itself optionally be interrupted and/or be substituted by another substituent.
- R is hydrogen, or an alkyl, e.g. lower alkyl, alkenyl, e.g. lower alkenyl, aryl, heteroaryl, aralkyl or heteroaralkyl group.
- this amino acid is chosen to be identical to, or to mimic, the amino acid found at the so-called PI position at the trans-cleavage sites of the natural substrates for HCV NS3 serine protease .
- R 2 is a lower alkyl group, optionally substituted with one or more fluorine atoms, or is the side chain of cysteine (-CH 2 SH) .
- R 1 groups are -CH 2 -CHF 2 (the side chain of difluoroaminobutyric acid) , -CH 2 CF 3 (the side chain of trifluoroaminobutyric acid) and -CH 2 CH 3 (the side chain of aminobutyric acid) .
- X is -CH 2 - or -0-;
- Y is a group of formula -C(R a ) 2 - where each R a is independently selected from hydrogen, hydroxyl, carboxylic acid, lower alkyl (such as methyl) , aryl (such as phenyl), heteroaryl aralkyl or heteroaralkyl, or the two R a groups together form a cycloalkyl group containing 3 to 7, preferably 3 to 5 carbon atoms.
- Preferred combinations -X-Y- are -0-CH 2 - and -CH 2 CH 2 -, of which the latter is the more preferred.
- Z is a substituted or unsubstituted aryl or heteroaryl group.
- it is an optionally substituted phenyl group, although other preferred possibilities include optionally substituted indolyl, thienyl, naphthyl, and pyridyl groups .
- substituents on phenyl are the halogens, especially chlorine and fluorine, carboxylic acid (possibly in the form of an ester, e.g. lower alkyl ester), acylsulphonamide, and tetrazole.
- halogens especially chlorine and fluorine
- carboxylic acid possibly in the form of an ester, e.g. lower alkyl ester
- acylsulphonamide tetrazole.
- Another preferred substituent has the formula:
- W is selected from -CH 2 -, -O-, and -NH- and V is selected from -CH 2 - and -CHR b - where R b is an optionally substituted lower alkyl, lower alkenyl, aralkyl,. heteroaralkyl, aryl, or heteroaryl group.
- R b is an optionally substituted lower alkyl, lower alkenyl, aralkyl,. heteroaralkyl, aryl, or heteroaryl group.
- W and V together form a carbon carbon double bond, preferably with a trans configuration.
- the acidic group is preferably at the 4- position of the phenyl group (i.e. para to the remainder of the molecule.
- the substituent - W-V-C0 2 H is however preferably at the 3- position, although substitution at the 4- position is also possible.
- Substitution by halogens, particularly fluorine and chlorine is preferably at the position (s) ortho- to the rest of the molecule - i.e. at the 2- and/or 6- position.
- Particularly preferred compounds have an acidic group (carboxylic acid, tetrazole, acylsulphonamide) at the 4- position and either 2 fluorines (at positions 2- and 6-) or a chlorine in the 2- position.
- the compounds of the invention include an "N-terminal portion" linked to the "C-terminal portion” .
- This is chosen such that the molecule as a whole is capable of binding to the NS3 protease of HCV, and in particular in the SI binding pocket of the enzyme.
- the extent to which the compounds bind to the NS3 serine protease is reflected by their IC 5Q s in inhibition assays, for instance as described herein.
- the IC S0 is lOOuM or less, particularly lO ⁇ M or less and, ideally lOOnM or less.
- activity in an inhibition assay should not be thought of as the sole indicator of usefulness.
- a molecule having relatively 1 low activity may be useful for another reason - e.g. because of its small size or relative lack of peptidic character which render it resistant to degradation when taken orally.
- R 3 there are generally two possibilities for R 3 . The first is that it is a side chain whose distal end is free. Alternatively, together with Rc it forms a ring which includes the adjacent nitrogen atom.
- R 3 is a side chain it is generally an optionally substituted (e.g. by fluorine or carboxylic acid group) alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, containing from 2 to 16 ⁇ carbon atoms.
- Preferred R 3 groups are unsubstituted hydrocarbons, in particular alkyl groups, such as the side chains of alanine (-CH 3 ) , valine (-CH(CH 3 ) 2 ), leucine (-CH 2 CH (CH 3 ) 2 ) , isoleucine (-
- R together with R° form a ring including a nitrogen atom
- the ring is desirably 4 to 7 membered, particularly 5- membered and may be saturated or unsaturated.
- the ring is substituted, for instance by one or more lower alkyl, lower alkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl groups. Substituents present on adjacent ring carbons may together form a further 4 to 7 membered ring.
- substituents in the ring include, among others, hydroxyl, alkoxy (such as lower alkoxy) , aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy thioether, aryl-, or alkyl-, sulfonyl and aryl-, or alkyl-, sulfoxide groups.
- the amino acid residue including the ring is a proline residue of formula:
- R d is hydrogen or, more preferably is one of the substituents discussed above - i.e. it is preferably selected from lower alkyl, lower alkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl groups, a hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy, thioether, sulfonyl and sulfoxide groups.
- substituents are phenyl, cyclohexyl, benzyl ether, benzyl thioether, and the thioethers, sulfones and sulfoxides formed with phenyl, cyclohexyl or n-propyl groups.
- R° is preferably hydrogen or, as described above may form a ring with R 3 . Less preferably it may be a lower alkyl group, especially methyl.
- R 4 is an alkyl, alkenyl, aralkyl, heteroaralkyl, aryl or heteroaryl group containing from 2 to 16 carbon atoms.
- it is a lower alkyl group, for instance the side chain of alanine (-CH 3 ) , leucine (-CH 2 -CH (CH 3 ) 2 ) , isoleucine (-CH (CH 3 ) .(C 2 H S ) , or valine (-CH(CH 3 ) 2 ), a cyclopentyl or t-butyl group.
- the side chain of valine is preferred.
- R 4 may be an acidic group, e.g. a carboxyalkyl group containing from 2 to 8 carbon atoms, such as the side chain of aspartic acid (- CH 2 COOH) or, more preferably, glutamic acid (-CH 2 CH 2 COOH) .
- R s is selected from (R s ) 2 NCO-, R 7 CO-, R 7 OCO- , R 7 NHCO-, R 7 CO.CO-, R 7 S(0) 2 - and R 8 pep where "pep" is an amino acid, di- or tri- peptide.
- Each R 6 independently, is selected from hydrogen and optionally substituted, optionally interrupted lower alkyl or lower alkenyl, aryl, heteroaryl, aralkyl or heteroaralkyl groups, or the two R ⁇ taken together form a four to seven membered ring optionally containing one or more other heteroatoms in addition to the nitrogen atoms to which the R 6 groups are bonded.
- R 7 is an optionally substituted, optionally interrupted alkyl, alkenyl, aralkyl, heteroaralkyl, aryl or heteroaryl group containing from 1-18 preferably 1 to 14 carbon atoms, particularly, 1-8 carbon atoms.
- R 8 is a group of formula (R 6 ) 2 NC0-, R 7 CO- , R 7 0C0-, R 7 NHCO-, R 7 COCO-, andR 7 S(O) 2 -
- pep if present is an amino acid, di, or tri peptide of formula C-B-A
- A is selected from naturally and non-naturally occurring amino acids having a hydrophobic side chain containing 1-20 carbon atoms.
- Possibilities include leucine, methionine, isoleucine or, more preferably, diphenylalanine .
- B may be absent. If it is, then C will also be absent Where present, B is selected from naturally or non- naturally occurring amino acids having a side chain which includes an acidic functionality. Preferred examples are glutamic and aspartic acid, with the former being particularly preferred.
- C may be absent, either by itself or together with B. Where present it may be selected from naturally or non- naturally occurring amino acids containing an acidic functionality. Aspartic acid is preferred, although glutamic acid is another possibility.
- pep is absent and the compounds are tripeptides.
- Preferred R s groups are those of formula R 6 OCO- .
- Preferred R 7 groups are t-butyl and isobutyl .
- the present invention is concerned with dipeptides, and pharmaceutically acceptable salts and esters thereof. At the C-terminus, these resemble the tri- and higher peptides described above. However, instead of a third amino acid (providing the side group R 4 in formula (1), the molecules contain a "cap".
- One preferred group of compounds includes dipeptides of the following formula:
- X, Y, Z and R 2 are as defined above. Preferred examples of these groups described above are also preferred in this embodiment.
- X and Y are preferably both -CH 2 - and R 2 is preferably -CH 3 CHF 2 or -CH 2 SH.
- R 13 is a group containing up to 25, preferably 4-21, particularly 4-16 carbon atoms and 0-5 oxygen atoms, 0-3 nitrogen atoms, 0 to 2 sulphur atoms, and up to 9 other heteroatoms, such as halogen atoms) which may be the same or different.
- Preferred R 13 groups contain an acidic functionality, preferably a carboxylic acid group which may be in prodrug form - e.g. esterified.
- Substituent groups R 13 preferably include a relatively hydrophobic portion such as a cycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl group each of which may, optionally, be substituted.
- Preferred examples of the group R 13 include indolines of formula:
- R is hydrogen, an optionally branched, optionally interrupted and optionally substituted lower alkyl or lower alkenyl group, or an optionally. substituted aralkyl or heteroaralkyl group and R 1S is hydrogen or an optionally substituted and optionally interrupted lower alkoxy, aryloxy or heteroaryloxy group.
- R 1S is , -C0 2 H, optionally in the form of a lower alkyl ester.
- R 1S is an aralkyl group it is preferably an optionally substituted benzyl or thienylmethyl group.
- Preferred substituents in the aryl group include halogens, especially chlorine, lower alkoxy (e.g. OMe) and aryloxy (e.g. PhO-) groups, cyano, and carboxylic acid groups.
- Carboxylic acid groups, optionally in the form of lower alkyl esters are especially preferred.
- R ls groups include:
- the carboxylic acid group may be esterified for instance as a lower alkyl ester such as a methyl ester.
- the carboxylic acid group may be amidated, e.g. as -CONH 2 .
- R 13 groups are listed under the heading “R 3 " at Table 7. Each R 13 exemplified may be used in conjunction with any of the groups “R 2 " and “R 1 n listed in the table.
- Another preferred group of dipeptides includes proline, or a proline derivative at the P2 position.
- Compounds in this category have the formula:
- X, Y, Z and R 2 are as defined above. Preferred examples of these groups, described above are also preferred in this embodiment.
- X and Y are preferably both -CH 2 - and R 2 is preferably CH 2 CHF 2 or CH 2 SH.
- Z is preferably 2, 6-difluoro-4-carboxy-phenyl- .
- R 17 is hydrogen or more preferably is a lower alkyl, lower alkenyl, aryl, heteroaryl, aralkyl or heteroaralkyl group, a hydroxyl, alkoxy, aryloxy, heteroaryloxy, aralkoxy, heteroaralkoxy thioether, sulfonyl or sulfoxide group.
- Particularly preferred substituents are phenyl, cyclohexyl, benzyl ether, benzyl thioether, and the thioethers, sulfones and sulfoxides formed with phenyl, cyclohexyl or n-propyl groups. Miscellaneous examples of this group can be found at table 6.
- R 18 is a group containing up to 25, preferably 4-21, particularly 4 to 16 carbon atoms and 0 to 5 oxygen atoms, 0-3 nitrogen atoms, 0-2 sulphur atoms and up to 9 other heteroatoms, such as halogen atoms, which may be the same or different.
- suitable R ,1 i 8 S groups include the following :
- R 19 is an alkyl group, preferably a lower alkyl group, including branched especially ⁇ -branched alkyl groups such as isopropyl or t-butyl groups, a C 3 -C 7 cycloalkyl group, or an optionally substituted aryl group.
- Preferred substituents include C ⁇ . g alkoxy, halogen or -CF 3 .
- R 18 group has the formula:
- each R e is independently selected from hydrogen, lower alkyl (especially methyl), lower alkenyl, lower alkoxy, optionally substituted aryl, heteroaryl, aralkyl or heteroaralkyl groups (such as those substituted with halogen, -CF 3 or lower alkyl or alkoxy groups) or two R e taken together result in the formation of a three to seven membered aliphatic or aromatic ring which . optionally contains at least one heteroatom. In the case where two R e taken together result in the formation of a ring containing unsaturation, especially an aromatic ring, then other R e may be absent.
- the carboxylic acid group in any of this preferred class of compounds may be esterified for instance as a lower alkyl ester such as a methyl ester.
- the -OH group of the carboxyl acid group may also optionally be replaced by an -S0 2 NH- group, especially by Ph-S0 2 -NH-.
- the present invention provides a compound or derivative according to the first aspect, for use in any therapeutic method, preferably for use in inhibiting the HCV NS3 protease, and/or for use in treating or preventing hepatitis C or a related condition.
- related condition is meant a condition which is or can be caused, directly or indirectly, by the hepatitis C virus, or with which the HCV is in any way associated.
- the present invention provides the use of a compound or derivative according to the first aspect in the .manufacture of a medicament for the treatment or prevention of hepatitis C or a related condition.
- a fifth aspect of the invention provides a pharmaceutical composition which includes one or more compounds or derivatives according to the first aspect .
- composition may also include pharmaceutically acceptable adjuvants such as carriers, buffers, stabilisers and other excipients. It may additionally include other therapeutically active agents, in particular those of use in treating or preventing hepatitis C or related conditions.
- the pharmaceutical composition may be in any suitable form, depending on the intended method of administration. It may for example be in the form of a tablet, capsule or liquid for oral administration, or of a solution or suspension for administration parenterally.
- a method of inhibiting HCV NS3 protease activity, and/or of treating or preventing hepatitis C or a related condition the method involving administering to a human or animal (preferably mammalian) subject suffering from the condition a therapeutically or prophylactically effective amount of a composition according to the fourth aspect of the invention, or of a compound or derivative according to the first aspect.
- Effective amount means an amount sufficient to cause a benefit to the subject or at least to cause a change in the subject's condition.
- the dosage rate at which the compound, derivative or composition is administered will depend on the nature of the subject, the nature and severity of the condition, the administration method used, etc. Appropriate values can be selected by the trained medical practitioner. Preferred daily doses of the compounds are likely to be of the order of about 1 to 100 mg.
- the compound, derivative or composition may be administered alone or in combination with other treatments, either simultaneously or sequentially. It may be administered by any suitable route, including orally, intravenously, cutaneously, subcutaneously, etc. Intravenous administration is preferred. It may be administered directly to a suitable site or in a manner in which it targets a particular site, such as a certain type of cell - suitable targeting methods are already known.
- a seventh aspect of the invention provides a method of preparation of a pharmaceutical composition, involving admixing one or more compounds or derivatives according to the first aspect of the invention with one or. more pharmaceutically acceptable adjuvants, and/or with one or more other therapeutically or prophylactically active agents.
- the resulting compound may subsequently be extended towards the N-terminus by conventional methods of synthesis employing protected amino acids, peptides or "capped" amino acids.
- the invention provides, according to an eighth aspect, a method as described above for preparing a compound according to the first or second aspect .
- BEMP 2-tert. -butylimino-2-diethylamino-1, 3-dimethyl- perhydro-1,3, 2-diazaphosphorine;
- Boc tert-butyloxycarbonyl [Me3CO(0)]; i-Boc: isobutyloxycarbonyl [Me 2 CHCH 2 CO (O) ] ;
- DCM dichloromethane
- DIEA diisopropylethyl amine
- Dif ' L-diphenylalanine
- DMSO dimethylsulfoxide
- EDC l-ethyl-3- (3 ' -dimethylaminopropyl) carbodiimide hydrochloride
- Et 2 0 diethyl ether
- Fmoc fluorenylmethyloxycarbonyl
- HATU [O-7-azabenzotriazol-l-yl) -1,1,3,3- tetramethyluronium hexafluorophosphate] ;
- HOBt N-hydroxybenzotriazole
- KHMDS potassium bis (trimethylsilyl) amide
- LDA lithium diisopropyl amide
- mCPBA meta chloroperoxybenzoic acid
- Me methyl
- NBS N-bromosuccineamide
- NMM N-methyl morpholine
- Ph phenyl
- pip piperidine
- PPTs pyridinium-para-toluenesulfonate
- TFA trifluoroacetic acid
- TIPS triisopropylsilane
- TMEDA N,N,N' ,N' -tetramethyl-ethylendiamine
- NMR Nuclear magnetic resonance
- Mass spectral data were obtained on a Perkin Elmer API 100 in negative or positive ionization mode.
- Organic extracts were usually dried over sodium sulfate, the drying agent was removed by filtration and the solvents evaporated on a rotary evaporator under reduced pressure .
- Flash chromatography was carried out on silca gel according to Still's published procedure (W.C. Still et al . , J. Org. Chem. 1978, 43, 2923) or on Flash chromatography systems with prepacked columns (Biotage corporation) .
- Preparative RP-HPLC was carried out with a Waters Delta Prep 4000 separation module, equipped with a Waters 486 absorption detector.
- a SymmetryPrep C18 column (7 micron, 100 A, 19 x 150 mm, Waters) was routinely used. Compounds were eluted with gradients of water (solvent A) and acetonitrile (solvent B) both containing 0.1% TFA (v/v) at 17 mL/min.
- an amine H 2 N-X-Y-Z - i.e. a P' building block - (either commercially available or prepared as laid out in the experimental section)
- an amino acid containing R 2 - i.e. a Pi building block - using well known peptide coupling techniques.
- a compound Q- can be coupled using peptide coupling techniques to give a compound of formula (I) .
- the compound can be elongated with another amino acid using the methods described. This deprotection and coupling procedure is repeated until the desired compound is obtained.
- 3,5-Difluorobenzoic acid 25 g, 0.158 mol was dissolved in DCM (150 mL) and dioxane (50 L) . The mixture was transferred into a stainless steel autoclave. Concentrated sulfuric acid (3.6 mL) was added, followed by isobutene (100 mL) . The mixture was kept in the autoclave for 5 days . Excess isobutene and the solvents were removed under reduced pressure, the mixture diluted with EtOAc and washed with water, saturated aqueous sodium hydrogen carbonate and brine .
- nitrostyrene was dissolved in isopropanol (215 mL) and chloroform (1 1) .
- Silica gel 172 g was added followed by sodium borohydride (11.0 g, 292 mmol) in 10 portions. After 30 min TLC indicated complete consumption of the starting material . After acidification with hydrochloric acid (100 mL, 1 N) the silica gel was removed by filtration and washed thoroughly with chloroform. The combined filtrates' were washed with water and brine, dried and evaporated.
- TMEDA 25.68 mmol, 3.9 ml, 1.2 eq
- BuLi 2.2 M in hexane, 11.67 ml, 1.2 eq
- THF 70 mL
- a solution of the foregoing ketal (21.4 moT, 3.98g) in THF (40 mL) was added dropwise over 10 min.
- the solution was stirred for lh at -78 °C, then trimethylborate (64.2 mmol, 6.67g) was added in one portion.
- the aldehyde 11 (304 mg) was 90% pure as judged by ⁇ -NMR and taken directly to the Henry aldol reaction.
- amino acids used like 2-aminobutanoic acid or 2- amino-4,4,4-trifluorobutanoic acid are commercially available.
- Example 15 Synthesis of N- (Isobutyloxycarbonyl) -valine (21) -Valine (5.86 g, 50 mmol) was dissolved in a mixture of water (200 mL) containing sodium carbonate (10.6 g, 100 mmol) . The solution was cooled to 0° C, then a solution of isobutylchloroformate (6.76 g, 49.5 mmol) in dioxane (100 mL) was added dropwise over 50 min. The ice-bath was removed and the reaction stirred overnight . Dioxane was evaporated, the aqueous phase was extracted once with diethylether and the brought to pH 2 by addition of hydrochloric acid. Extraction with DCM (3x, 150 mL each) , drying of the organic phase (sodium sulfate) and evaporation gave 21 (14.2 g) as a colorless solid. ⁇ -NMR
- Example 16 Synthesis of N- (Isobutyloxycarbonyl) - ⁇ -tert- butyl-gluta ate (22) Using the conditions described in example 15, ( ⁇ -O-tert.-
- 0-tert-butyl-N,N' -diisopropylisourea 4 (10.55 g, 52.7 mmol) was added to a solution of 3-Methyl-2-thiophene- carboxylicc acid in DCM (45 ml) .
- the reaction mixture was slowly warmed to reflux and maintained at reflux for 8 hours.
- Another 10.55 g of 4 was added and reflux was continued for an additional 10 hours.
- Step 1 N2- [ (9-Fluorenyl) methoxycarbonyl] -NI- [2- (2 , 4- dichloropenyl) ethyl] -L-cysteinamide (40)
- Trityl chloride resin (Novabiochem, loading 2.05 mmol of active chlorine) was washed once with DCM and then added to a solution of 40 in DCM containing 7% TFA
- the foregoin resin was acylated with a premixed solution of Fmoc-L-leucine (4.23 g, 12.35 mmol), EDC (2.30 g, 12.35 mmol) and HOBt (1.62 g, 12.35 mmol) in DCM (40 mL) for 3 h. After drainage the resin was washed with DCM (1 x 25 mL) , DMF (2 x 20 - 25 mL) , DMF/DCM (1 x 25 mL) , DCM (3 x 20 - 25 mL) , methanol and diethylether (1 x 25 mL each) .
- Step 5 Synthesis of 165 To 30 mg of resin 43 (ca. 0.029 mmol of compound) was added DCM (1 mL) , followed by diisopropylethylamine (0.2 mL) and isobutyl chloroformate (0.038 mL, 0.29 mmol). The resin was agitated for 5 h. Prior to cleavage, the resin was washed with DMF (3 x 1 mL) and DCM (3 x 1 mL) and then treated with a solution of 50% TFA / 45% DCM/ 5% water (1.5 mL) containing TIPS (0.02 mL) for 30 min at room temperature.
- Step 1 N2- [ (9-Fluorenyl)methoxycarbonyl] -NI [2- phenylethyl] -L-cysteinamide
- the foregoing resin (450 mg) was acylated with Fmoc-L- leucine (239 mg 0.68 mmol) and then treated with 20% piperidine/DMF to cleave the Fmoc protecting group.
- Step 4 Analogous to the procedure described in example 19, step 4, the foregoing resin (270 mg) was acylated with Fmoc- ( ⁇ -O-tert .-butyl) -L-glutamic acid (77 mg, 0.18 mmol) and then treated with 20% piperidine/DMF to cleave the Fmoc protecting group.
- Step 5 Analogous to the procedure described in example 19, step 4, the foregoing resin (270 mg) was acylated with Fmoc- ( ⁇ -O-tert .-butyl) -L-glutamic acid (77 mg, 0.18 mmol) and then treated with 20% piperidine/DMF to cleave the Fmoc protecting group.
- step 5 the foregoing resin was acylated with N- (benzyloxycarbonyloxy) succinimide (90 mg, 0.36 mmol) in DCM (1 mL) and DIEA (0.5 mL) . After agitating the mixture overnight the resin was drained and washed as described. After cleavage from the resin, 101 was isolated by preparative RP-HPLC (gradient: 65% A, 3 min isocratic, then in 9 min to 35% A; RT 10.2 min) .
- the resin (160 mg) obtained in example 21 (steps 1 to 3 , ca. 0.021 mmol of compound) was acylated with FmocValOH ( 36 mg, 0.105 mmol) analogous to the procedure described in example 19, step 4, and then treated with 20% piperidine/DMF to cleave the Fmoc protecting group.
- the resulting resin was then suspended in DCM (1 mL) and DIEA (0.5 mL) .
- Step 1 N2- [ (9-Fluorenyl)methoxycarbonyl] -NI- [2- (2- chloropenyl) ethyl] -L-cysteinamide
- step 1 from coupling of Fmoc-S-trityl-L-cysteine (14.0 g, 23.9 mmol) and 2- (2-chlorophenyl)ethyl amine (31.07 mmol) and subsequent deprotection with TFA and TES.
- Step 2 Analogous to the procedure described in example 19, step
- step 4 The resin (20 g) obtained in example 23, step 4 was acylated with 1-naphthalensulfonyl chloride (50 mg, 0.22 mmol) under identical conditions described in example 23, step 5. After cleavage and lyophilization 252 was obtained as a colorless powder.
- Step 1 N2- [ (9-Fluore ⁇ yl) methoxycarbonyl] -NI- [2- (4- carboxymethyl-phenyl) ethyl] -L-cysteinamide
- the title compound was obtained analogous to the procedure described in to example 19, step 1 from coupling of Fmoc-S-trityl-L-cysteine and amine hydrochloride 5b and subsequent deprotection with TFA and
- Step 2 - 5 The procedures are identical to the ones described in example 19, using 20 mg of resin, but in step 3 (2S, 4S) - Fmoc-L-cyclohexyl-alanine was used instead of Fmoc-Leu- OH.
- the crude product obtained after cleavage (22 mg ⁇ .033 mmol) was dissolved in methanol (1 mL) and cooled to 0 °C. After 5 minutes 1 ml of 1 N NaOH (30 equiv) was added and reaction mixture was left at room temperature. After 90 min solution was concentrated in vacuo and ethyl acetate was added. The organic layer was washed with 1 N HCI (3x) , brine and dried. Evaporation of the solvent and freeze drying from acetonitrile/water gave 409 (8 mg,
- Example 27 Synthesis of compound 177 and 178 Step 1: Synthesis of resin 44 A solution of Fmoc-S-trityl-L-cysteine (10.0 g, 17.1 mmol) , in DCM containing 15% trifluoroacetic acid (TFA) and 5%TES (total volume 150 mL) was stirred at room temperature. After 10 min the reaction was evaporated to dryness, the solid residue was washed three times with 150 mL n-pentane and then dried under high vacuum. 4.46 g of Fmoc-L-cysteine was obtained as a colorless solid. This material was dissolved in DCM (20 mL) containing 7% TFA.
- TFA trifluoroacetic acid
- Trityl chloride resin (Novabiochem, loading 2.05 mmol of active chlorine) was added in one portion. The solution was slowly agitated overnight (orbital shaker, or slow stirring on a magnetic stirrer) . The resin was isolated on a sintered glass funnel, washed with DCM (5 x 40 mL) , methanol (1 x 40 mL) and again with DCM and dried overnight in vacuo.
- Step 5 Synthesis of 177 Resin 47 was treated with a solution of 50% TFA / 45%
- the acylating reagent cyclopentylmethyloxycarbonyl-N- hydroxysuccinimide was prepared in si tu by addition of cyclopentanol (50 mg, 0.5 mmol) and triethylamine (152 mg, 1.5 mmol) to a solution of N,N' -disuccinimidyl carbonate (128 mg, 0.5 mmol) in anhydrous acetonitrile (2 mL) (see A. K. Gosh et al, Tetrahedron Letters 1992, 33,
- Pentapeptide 49 (50 mg, 0.051 mmol) was dissolved in DMF (0.8 mL) .
- HATU 21 mg, 0.056 mmol
- amine 50 (20 mg,
- reaction mixture was stirred at room temperature for 8 hours, diluted with DCM and extracted with HCI (I N), - NaOH (1 N) , brine.
- the oily residue was dissolved in CHC1 3 (5 mL) and the solution was cooled in an ice bath. 1.25 mL of 4-AMP were added and the mixture was stirred at room temperature for 1 h.
- the solvent was evaporated under vacuo and the residue was purified by flash column chromatography on silica gel, eluting with PE/EtOAc (80/20 v/v and then 20/80 v/v) to give 51 (330 mg, 60%) .
- the powder was purified by preparative RP-HPLC: Symmetry Waters column (C18, 30 x 50 mm) , flow 40 ml/min, gradient linear from 80% to 38% A over 13 minutes, then isocratic (RT 14.6 minutes), 48 mg Of 539 (57%).
- the dipeptide 54 (30 mg, 0.054 mmol) was dissolved in DCM/DMF (1:1, 2mL) .
- K ⁇ values of peptide inhibitors were calculated from substrate titration experiments performed in the presence of increasing amounts of inhibitor. Experimental data sets were simultaneously fitted to eq.l using a multicurve fit macro with the help of a Sigmaplot software :
- V (V m participateS)/(K m (l+K t /T.)+S); (eq.l)
- K ⁇ values were derived from IC50 values, calculated using a four-parameter logistic function, according to eq.2:
- Example 47 HCV NS3 protease domain / NS4A cofactor peptide assay (Assay B)
- NS3 protease domain (residues 1027-1206 of the HCV polyprotein) complexed to a modified form of the NS4A peptide, spanning residues 21-34 of the NS4A cofactor in addition to a solubilizing lys-tag, Pep 4AK [KKKGSWIVGRIILSGR(NH 2 ) ] were used.
- peptide 4AB [DEMEECASHLPYK] based on the sequence of the NS4A/NS4B cleavage site of the HCV polyprotein, was added .
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Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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EP02757728A EP1392721A1 (en) | 2001-03-29 | 2002-03-26 | Peptides and their use as inhibitors of hepatitis c virus ns3 protease |
US10/473,443 US7119073B2 (en) | 2001-03-29 | 2002-03-26 | Peptides and their use as inhibitors of hepatitis C virus ns3 protease |
CA002442540A CA2442540A1 (en) | 2001-03-29 | 2002-03-26 | Peptides and their use as inhibitors of hepatitis c virus ns3 protease |
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GBGB0107924.3A GB0107924D0 (en) | 2001-03-29 | 2001-03-29 | Inhibitor of hepatitis C virus NS3 protease |
GB0107924.3 | 2001-03-29 |
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WO2002079234A1 true WO2002079234A1 (en) | 2002-10-10 |
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PCT/EP2002/003435 WO2002079234A1 (en) | 2001-03-29 | 2002-03-26 | Peptides and their use as inhibitors of hepatitis c virus ns3 protease |
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US (1) | US7119073B2 (en) |
EP (1) | EP1392721A1 (en) |
CA (1) | CA2442540A1 (en) |
GB (1) | GB0107924D0 (en) |
WO (1) | WO2002079234A1 (en) |
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Also Published As
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GB0107924D0 (en) | 2001-05-23 |
US7119073B2 (en) | 2006-10-10 |
CA2442540A1 (en) | 2002-10-10 |
US20040142876A1 (en) | 2004-07-22 |
EP1392721A1 (en) | 2004-03-03 |
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