CA2109326A1 - 4-amino-3-hydroxycarboxylic acid derivatives - Google Patents
4-amino-3-hydroxycarboxylic acid derivativesInfo
- Publication number
- CA2109326A1 CA2109326A1 CA002109326A CA2109326A CA2109326A1 CA 2109326 A1 CA2109326 A1 CA 2109326A1 CA 002109326 A CA002109326 A CA 002109326A CA 2109326 A CA2109326 A CA 2109326A CA 2109326 A1 CA2109326 A1 CA 2109326A1
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- carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
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- 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
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- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
- C07C323/59—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton with acylated amino groups bound to the carbon skeleton
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- C07C323/50—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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- 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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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
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- C07D213/02—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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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/36—Sulfur atoms
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/14—Radicals substituted by nitrogen atoms
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- 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
- C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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.
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
W O 93/01166 PC~r/EP92/01471 21~g326 .,. ~
~ - ~. ..
~ .
. ~ - . ,- `~
The isnlYnti~n ralates to 4-arIiu~-3-h~4~ey~rbq~lic~acid derivacav~s. It~c~c ~ ~he conFxn~ad- of ~ormula I:~
RlA - NH - ~H o C~ R~
w~er~in A and B independently~are~a bond or a~ optionaIly~Jubstituted:ami~oacyl~
Rl i hydÆog~n: an am m o protect~g group: or a group of formula R~Y~
wherein .
R6 i~ hydrogen or a~ optionally `~ubstitut~d alk~ l, a1k-nyl,~alkinyl, aryl, arylalkyl,:het~roa~yl, h~t~roarylalkyl,~ heterocycIyl~or~
het~rocy~1~lalkyl grou~; a~d Y i~ -CO-; -N-~0~ :-S0~ o- ~ : OE -O-C8-;
, ~ ;,, ,j ,.
~',`' ~, SUBSTITUTE~ SHE~
W ~ ~3/01166 PCT/EP92/01471 R~ is the ~ide chai~ of a natural ~ no acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethyl~ilylmethyl, 2-th~enylmethyl or styrylmethyl; `;:
R3 is an op~ionally sub~tituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group~
R4 i~ a group of fonmula -OR7 or -NHR7 wherein R7 has the ~ignificance indicated above for R6, and X i~ -S- or -NR5- wherein R5 i3 hydroge~, methyl, formyl or acetyl;
i~ f~ee foDm and, wher~ quch fo~ms exi~t, in salt ~o~m, hersina~ter briefly named ~a compound of the in~ention~
To dat~, there iq a definite need for ~indi~g compound~ which -~
effectively inhibit retroviru3e3 in a hu~an infeoted by such a viru~, and thus treat or pr~vent di~ea~e~ cau~ed thereby, such as acquired immunode~îcien~y ~yndr~me 5AIDSI.
: One approaeh for effecting retro~iral i~hibition i~ the use of an inhibitor of a ~ir l proteina9e~e5~-ntial for pr~ces~ing viral polypeptid~
precursors by p~oteolytic maturation, ~.g. the HrV proteina~s.
Th~ compound~ of the pres~nt inventio~ ar~ anti~irally activ~
They inhi~it the ~IV proteina3e.
Rl preferably iJ 2-pyrid~lm~tho y carbo~yl, be~zyl-CHlOH)-carbonyl, phenoxym~thylcasbo~yl Q~ a~ ami~o protecting group:Juch a~
tert-butoy ca~bony1 or benzyloxyca~bony1; it e~p~ci-1ly i~
be~zylo~ycarbo~yl.
A prefeEably is a~ optio~ally s~ ~titu~d a~i~oacyl moi-ty, p~erably a~ optionally ~ub:Jtitut2d ~-a¢1Doacyl ~ci~ty ~uch a~ alani~e, leucin~, i801euei~, a~paragine~ ~alins, tert-bu~ylglyci~, tert-l~ucin~ or :~
.
hiYtidi~. It pra~ra~l~ is the op~ionally prot~ct~d ~ i~ty of a ~atural ;
~-amino acid, preferably of a~ amino wid whic~ i~ a no~mal constitutiv~
part of pro~si~s. Xt ~p~cially is L vali~eO
.: . ~
:
, SOBSTITUTE SHEET ::
~ - ~. ..
~ .
. ~ - . ,- `~
The isnlYnti~n ralates to 4-arIiu~-3-h~4~ey~rbq~lic~acid derivacav~s. It~c~c ~ ~he conFxn~ad- of ~ormula I:~
RlA - NH - ~H o C~ R~
w~er~in A and B independently~are~a bond or a~ optionaIly~Jubstituted:ami~oacyl~
Rl i hydÆog~n: an am m o protect~g group: or a group of formula R~Y~
wherein .
R6 i~ hydrogen or a~ optionally `~ubstitut~d alk~ l, a1k-nyl,~alkinyl, aryl, arylalkyl,:het~roa~yl, h~t~roarylalkyl,~ heterocycIyl~or~
het~rocy~1~lalkyl grou~; a~d Y i~ -CO-; -N-~0~ :-S0~ o- ~ : OE -O-C8-;
, ~ ;,, ,j ,.
~',`' ~, SUBSTITUTE~ SHE~
W ~ ~3/01166 PCT/EP92/01471 R~ is the ~ide chai~ of a natural ~ no acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethyl~ilylmethyl, 2-th~enylmethyl or styrylmethyl; `;:
R3 is an op~ionally sub~tituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group~
R4 i~ a group of fonmula -OR7 or -NHR7 wherein R7 has the ~ignificance indicated above for R6, and X i~ -S- or -NR5- wherein R5 i3 hydroge~, methyl, formyl or acetyl;
i~ f~ee foDm and, wher~ quch fo~ms exi~t, in salt ~o~m, hersina~ter briefly named ~a compound of the in~ention~
To dat~, there iq a definite need for ~indi~g compound~ which -~
effectively inhibit retroviru3e3 in a hu~an infeoted by such a viru~, and thus treat or pr~vent di~ea~e~ cau~ed thereby, such as acquired immunode~îcien~y ~yndr~me 5AIDSI.
: One approaeh for effecting retro~iral i~hibition i~ the use of an inhibitor of a ~ir l proteina9e~e5~-ntial for pr~ces~ing viral polypeptid~
precursors by p~oteolytic maturation, ~.g. the HrV proteina~s.
Th~ compound~ of the pres~nt inventio~ ar~ anti~irally activ~
They inhi~it the ~IV proteina3e.
Rl preferably iJ 2-pyrid~lm~tho y carbo~yl, be~zyl-CHlOH)-carbonyl, phenoxym~thylcasbo~yl Q~ a~ ami~o protecting group:Juch a~
tert-butoy ca~bony1 or benzyloxyca~bony1; it e~p~ci-1ly i~
be~zylo~ycarbo~yl.
A prefeEably is a~ optio~ally s~ ~titu~d a~i~oacyl moi-ty, p~erably a~ optionally ~ub:Jtitut2d ~-a¢1Doacyl ~ci~ty ~uch a~ alani~e, leucin~, i801euei~, a~paragine~ ~alins, tert-bu~ylglyci~, tert-l~ucin~ or :~
.
hiYtidi~. It pra~ra~l~ is the op~ionally prot~ct~d ~ i~ty of a ~atural ;
~-amino acid, preferably of a~ amino wid whic~ i~ a no~mal constitutiv~
part of pro~si~s. Xt ~p~cially is L vali~eO
.: . ~
:
, SOBSTITUTE SHEET ::
R2 prefer~bly iq the 9ide chain of a natural a~ino acid, :
preferably of an -amlno acid, preferably of an amino acid which i~ a normal constitutiv~ part of prot~in~. It i9 e.g. i30propyl, :;
aminocarbonylmathyl, methyl, l-methylpropyl~ benzyl, 4-hydroxybenzyl or isobutyl, preferably benzyl.
B pr~ferably i9 an optio~ally ~ubstituted aminoacyl moi~ty, preferably an optionally 9ub3tituted a-amlnoacyl moiety, ~uch as phenylalanine, valine, leucine, i~oleucine, aIanin~or a~paragine~ It ;:-preferably i~-th~ optionally~9ub5tituted moiety b~ ~a ~Dà-toral^~o~no acid, pre~erably of an amdno:~acid which i9 a normal constit~tiie-part of :
proteins. It ~speoially is L-valin~
R4 preferably i~ a group -NHR7; it preferably i~ i~opropylamino, t~rt-butylamino, l- or 2-naphthylmethyla~ino, or 2-, 3-~or 4-pyridylmethyl- ~:
ami~o; it esp~cially is benzyla~ino or benz~midazolylm~thylamdno, pa~scular~y benz~mi~zol-2-yl~ethylamino.
E~3 pre~erably~i~ an optionally sub3tituted arylalkyl ~roup, ,~,~
e~pecially-be~zyl. The aryl part of a~lalkyl optionally:i3 9ub~tituted by, prefe~ably, alkoxy or 1 to 4 ca~bon atom9, 9uch a~ methoxy, or halogen of atomic number of fr~m~9 to 35, ~uch a~3 bromine, it prefQrably i9 -"
mono~ub titutet, preferably in 3 or 4 po~ition: it:esp cLally is ~:
monosubstitu~ed in 3 or 4 po~ition ~ methoxy.
: X pref~r~ly~is a ~roup -NR5- a9 defined aboYe. ~t especially~is th~ o group.
R6 pr~ferably ~i~ an optionally ~ tituted alkyl, a2ylalkyl or heteroa~ylalkyl g~oup,: e~pecially alkyl; wh~r~ it ~ optionally ~ubstituted~
heteroarylalkyl it pr~ferably i~ :pyridylalkyl, e~p-ci~lly 2-pyridyL~ethyl; ~. -~hen it i~ optio~aliy s~tituted arylalkyl it p~f~rably i8 `
benzyl-CH~O~ he~ it i~ sub~tituted alkyl it pr~f~rably phenox~m~thyl. :
Y pre~æ~ably i~-CO; or ~CO-, e~pecia1ly -CO~
R~ preferably i~ an optionally~ 3ub~tit~sted alkyl, :arylalkyl or .
het~roarylalkyl ~roup, pr~f-rably phenylalkyl o~ altog~ther 7 to 10 carbon~
a~ uch aa be~zyl, or a pyridylallcyl, indolylalkyl or benz~udazolylalkyl group of ~1 to 4 carbo~ in thQ alkylQn- part:; it "`''~',' ''`
SUBSTITlJTE SHEET
WC? ~3/01166 . PCI/EP92~01471 21~g32~ ':
preferably is benzyl, 2-, 3- or 4-pyridyLmethyl or benzLmldazolylmethyl, e~pecially benzyl or benzimidazolylmethyl, particularly benz~mida201-2-ylmethyl.
R5 preferably i~ hydrogen or methyl, e~p~cially hydrogen. ~.
'.
alt i9 e.g. an acid addition 3alt such as a hydroshloride. ~i ~ The compou~d of fo~ula I ~ormally have ~v~ral chiral cente~
.~ ~ and can thereforQ eai~t i~ a ~ariety:~.of~3tereoisom~r.~. Th@ inventionpro~ides all ~te~eoi30mer~ a3 well a~ racemic m~x*ur~. The i3~mer~ ~ay b~
resolved or 3eparated by conventional techniqus~, e.g. chromatographically. ~.... `~
The carbon atom in 4 po~ition preferably has the S configuration. ""~
An optionally sub3tituted ami~oacyl moiety pref-r~ly i~
un~ub~tituted. When it i3 sub~ti~uted it ~.g. i sub~titu~ed by alkyl of 1 `~
~o 4 ~arbon atcms, ~u~h a~ iD O-t~rt-butyl-~-serinoyl~o~
2-aml~obutanoyl. It preferably i~:in the L optically~aetive foD~. :It :
preferably i~:an ~-aminoacyl: i~ty, ~ueh a9 valinR: or tert-leuoine.
~tionally ~ub3titut~d alkyl;;pr~ferably is~alkyl o~ 1 to S carbon atoma, p~eferably of 1 to 4 carbon~atoms, ~.g. mathyl,~ethyl, ~sopropyl o~
tert-butyl: it i9 especially of~l or 4 carbon a~o~ The s~bstituent i~
e.g. pheno ~ hydrosy:or optionally pro~ectQd amino.
Cptio~a11y ~ubstitut~d arylalkyl~i~ e.g. phanyl-lkyl of altog~th~r ~:
7 to 10 oarbo~ at~m~, ~u~:a~ benzyl or 2-ph~yl~thyl; it i~ optionally ~ub~tituted by e.g. hydro~y~ such a~ iD benzyl-CH~OH~- or :~
ph~nyl-CH(CH20~-, or i~ e.g. ~aphthylalkyl o~ l to~4 carbon atom~ iD t he~
alkylQn~ part.
An aEi~o protectinq qroup p~æf~ably i~ be~zyloxyca~bo~yl or t~xt-butoxycaEbonyl.
Optio~ally ~b~titut~d het~roarylalkyl prsferably i~ pyridylalkyl, : :
especially 2~pyridy~met~yl. : :::
A~yl, h~@roa~yl and the aryl parts of arylalkyl or hQteroa~ylalkyl may be m~o- or polycyc1ic, -QUCh a~ e.g. pyrityl, naphthyl,~
s~luoranyL~n~thoal:yG~rborly~ OC) sr b~zi~ olylD :Th~ alkyle~ part of SlJ13STlTUTE SHE~ - ~ ~
W O 93/01166 P ~ /EP92/01471 2 ~L O 9 3 2 6 o5 arylalkyl or heteroarylalkyl may be ~bstituted by e~g. hydroxy.
A heterocyclyl group and the heterocyclyl part o~ a ~:
heterocyclylalkyl group i~ a ~aturated heterocyclic group having one or more heteroatom~ ~elacted ~rom nitrogen, oxygen and ~ulfur. It preferably ~ :
ha~ 5 or 6 ring constitutent atom~, and preferably :up to 3 heteroatoms.: :~
Cycloalkylalkyl preferably i~ cyclohexylalkyl it preferably i~ of 1 ~o 4 carbon atom~ in the alkylene part.
~ .!A ~ubg~oup of~.compound~ of fon~ula I i~ the compound~ of:forIuIa 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 o~her ~.
~ubstituent~ are a~ defined above.
~ further ~ubgroup i~ the compound~ of formula I Nher-in RlA- is .. -~
an optionally ~3tituted and optio~lally N-terminal~prct~cted~natural a~noacyl moiety, -3R~ i9 a natural amin~acyl moi-ty optionally esteriFied or amidated at the C-terminus , R2 i ~th~ sid~ chai~ of a natural~amino acid,~R3 is~an alkyl, alkenyl, cycloalkyl, aryl or;~arylalkyl~group ~uch as naphthylmethyl and X i~ as defined~above.
: : A urther subgroup i~ the col~pounds of formula I wherei~Rl is ~`
~benzylyoxycarbo~yl,, 2-pyridylmethoxy~arbonyl, Phenyllac~oyl or phenoxymethylcarbo~yl, A is L-valin~or~L-tert-leucin-,~R2~ i8 ~benzyl, X i~
-NH-, R3 is~be~zyL, 3- or 4-m~t~oxyb~nzyl or 4-~Éomob~n~yl,~ L-vali~Q
and R~ ~is~b~zylaxino~or ben~imi~azol-2-ylmethylamino,~and thè carbon~atam ~ ,',`'a", !'.
in 4 po~ition ha3 the:S~configura~ion.
fur~h~er ~ubgroup i~ he compound~ of formula Is ; R2,~ X,R3, Rl,A~ ~ NH -~H - :fH~ o - B,~ , :OH:
wherein ~ j -: ~ ~ SlJBSTlTUTE S,H"E',~
W ~ 93/~1166 PCT/EP92/01471 ~.,, " J J `'J'; J
-6- `~
'.''' ~'''~
R~ hydrogen; phenylalkyloxycarbonyl of altogether 8 to 10 carbon :.
atoms; alkyloxycarbonyl of altogether 2 to 10 carbon atom~
quinolylcarbonyl or quinolyl~ulfonyl; pyridylmethoxycarbonyl; :~
aminocaproyl optionally protected by tert-butoxycarbonyl; . ; : ~ ~
9-fluorenylmethoxycarbonyl (F~OC); phenyllactoyl: i~oval~rianoyl; ~ ~`phenoxymethylcarbonyl; palm~toyl; or 4-hydroxyphenylpropionyl;
Ag is a bond; a natural a-ami~oacyl moiety; the corr~9pondin~ D optical i~omer form: L- or D-tert-leuci~e; 0- ert-butyl-L-c~rine: or - -L-2-aminobutanoyl;
R2~ i9 alkyl of 3 or 4 car~on ato~ or~phe~ylalkyl of altogsther 7 to ~ :
9 carbon atom~
X~ i3 -S- or -NR5,- wherein Rs, i~ hydroge~ o~ methyl;
R3, is alkyl of 3 to 5 carbon atom3; oycloalkyl of 5 to 7 ca~bon atoms optionally mono~ tituted b3~ hydro~y; pib~yl: phenylalkyl of altogether 7 to 9 oarbo~ atom~optio~ally monosub~tituted in the phenyl ring by hydroxr, alkoxy of 1 to 3 ca~bon at ~ , halogen of atomic number of from 9 to 35, or ph~nyl; a pyridylalkyl, in~ol~lalkyl or naphthylalkyl group of } to 3 carbon atom~ in:the:alkylene part: or phenylalk~nyl of 2 to 4 carbon ato~3 in th~ alkenyl~ne part;
B, i~ a bond; a natura~ ~-a~inoacyl ~oi~ty; th~ corr~sponding D optical i~omer f~D~; L- or D-tert-leucine; or aminocyclopropan-~ carbony~
R4~ is hydroxy; an alkosy o~ alkylami~o group o~ 1 to 5 carbon~atom~; ~
phenylalkylamino o altog~t~er 7 ~o 9 carban:atomJ optionally~ ~p:
P monos~bstituted i~ th~ ph~n~l ring or in th~ alkylene part by~hydroxy, or nosub~tituted in the ph~nyl ring b~:halog~n of ato~ic numbeL of fr~ 9 to 35; benzImidazolylal~oz~ or beazi~idazolylalkylamino of ~ to 3 carbo~ atcm~ i~ the alkylena part optionally ~o- or di~ub~tituted in ~he a~yl part by halog~ of~ atomic numb~r Or fr~m 9 ~o 35 ~r nitro;
or an indolylalkylzEi~o, p~ridylalkylamino or rp~olinylalkylami~o ;
moiety of 1 to 3 car~o~ atcm~ in the alkyl~ne part; a~d ~he co~figuratio~ i~ 4~po~i~ion i~ S, i~ fre~ fonm a~d, wh~re ~uch fo~m~ exi~t~ alt form.
: -SUBSTITUTE~ SHEET ~:
WO 93/01166 PCr/EP92/01471 2~09~26 In a subgroup of compound~ of fonmula I , when ~ or B, i3 a natural ~-~minoacyl moiety it i9 valine, tryptophane, phenylalanine, asparagine, i~oleucine, glutamine, leucine, alanine or hi~tidine: in a further subgroup, when Rl~ is phenylalkyloxycarbonyl it i~
benzyloxycarbonyl.
. ,; ~:,.
A further ~ubgroup i~ the compounds of foDmula Ipl .!
' ' ~..', R2 - X~3 p R~pA -NH - CH - CH CH CO - ~R4p ~ Ipl ;,.;;
OH
wherein A, B, R2 and X are a3 defined abo~e;
Rlp with the exception of hydrogen has the ~i~nificance~indicated above :~ ;
for R~
R3p with t:he exception of optîonally ~ tituted cyc}oalkyl has the significance indicated above for R3; and~
R4p i~ hyd~o~y or a group of formula -OR7~or -NHR7 a~ defined above~
in free fonm and, wher~ ~uch form~ exi t, ;in salt fonm.
A further subgroup i~ the: compound~ Ip2, i.e. the oo~ounds of formula I a~ defi~d abo~e with the e2ception that R4: i~ hydro~cy or a gro~p -~
of formula -OR7 or -NHR7 as defined above.
SlJ113~TITUTE SHEET
., '.. ` ~. .`~;~.
WO 93~01166 PCI`/EPg2/01471 ~ ' ! ' ' 2 1 0 ~ 3 2 6 -8;
; ~
The compound~ of the invention may be prepared by a proceq3 which - ~`
comprise3 ' ~`' ' . a) submltting an epo~ide of fon~ula II
.
RlA - NH - CH - C - CH - C0 - BR4 II
O "
wherein the ~ tituent~ are as~ dafined abo~e, to r~g oyening in the pre~ence of~a compo~und o~ formula III
H - XR3 III ~ :
wherein the 3ub3ti uents ar~ as d~fined above, where indicated in a further reactive form; or ~ -b) for the preparation of ~he compo ~ d~:of fo~mula I wherein :~
-3R4 L3 other than~hydroxY tbll, ~
: ~Rl i~ other~ tha~ hydrogen or HY- lb2~]~
approprlately sdb~ti~utiGg~;a~:corresponding c~mpound of fo ~ a~I wh~ein : : CO-~R6 i~ carboxy or R~ i~ hydroge~or HY-, e.g.
blj 3u~stituti~g a corresponding com~ou~d of formula Ia : : R2 ~ ~:XR3 Rl~ - NH ~ :CH - CH -~COO~ ~ ; Ia ii~
wher~i~ th~ subJtituen~ ar~ a~ defined;abo~, or b2~ sub~tltuting ~ corx~spondin~ compouat of for~ul~ Ib :
Rl'A - N~} - CH~ -~ CH - Ctl~- C0 - BR~ : :Ib OH :
wherei~ Rl' i5 hydro~en or HY- and th~ other 9ub9tituent3 are aJ d~fi~ed abo~e;
~ .. .
, ; .: .~
....
SUBSTqTlJTE Sl IEFI
W O ~3/01166 PCT/EP~2/01471 2109326 ~
.~ .,: ,, and wh re indicated deprotecting or ~apoDi~yiag a resultant compound of .
formul~ I in protected or e terified form, and recovering th~ reGultant compounds of formula I in free form or, wher~
~uch form~ exi~t, in salt f onm.
Th~ proceq~ o~ the invention can be carr~ed out in conv~tional manner~ T -~
P~ocs~ ~ariant a) is effect~d e.g. in an inert ~olY~nt ~u~h aQ a~
,- ~
ether~ e.q. tetrahydrofuran, or acetonitrile. The temperature preferably i9 between about -50C and the boiling temperature of the reaction mixture, pzeferably betwe~ about 20~C a~d about 80~$. The c~mpound of for~ula III `
i3 a~ appropriate amin~ or mercapta~. A ~urthe~ reactive form prefexably is a qalt of a mercapta~, s.g. an alkali m~tal salt such a~ the pota ~ium 3alt. .`,Prnce~s Yariant b) is ef~cted u~ing condition~ known ~or coupling ami~o acid~. Th~ reactio~ pref~rably i8 effe~ed in:an ine~t ~olvent~ ~uch a~ an amide,~e.g. dim~thylfor1alide,~ or an ether,:~.g~ tet:rahydrofuran. ~:The temperature prefe~ably i~ betw~en~about ro~ temperature a~d the boiling temperatur~ o~ the reaction~mi~ture, pre~e~ably about room temp~ratur~
De~Q~tio~ con~e~ tly i9 effe~ted by hydroly~i~, preferably undeE acidic cond~tio~ ~or removing e.g. a:hydroxy~or amlno protecting group such a3 t~rt~-buto~arbonyl, pref~r~ly ~itb trifluoroacetic acid, or hydrog~no}yt~cally for removing e.g. ba~zyloxycasbonyl.~ SapoDific~tion iJ ;~
effected pre~rably ~ith aqueou~ sodiu~ hydrox~d~ ~olutio~ for recovlng .g~ alkoxy. .The temp~aturB pre~erably i~b~tween about -20~C~a~d about 60C, it conve~ien~ about room temp~rature. ~a organic ~olvent ~uch ~ ;
a~ diehlor~th~e or tetrahydrofuran con~enie~t1y is u3ed.
Th~ r~sultan~ compousd9 of fo ~ a I can b~i30lated frw~ the ; 'i'`''',`',.7 r~actio~ mis~urQ and purified accoEding to know~ m~thods~ ~.g.
chromAtographically.
~ ";! ~
c~ TlTuTE SHEET
W0~3/01166 PCI~ /01471 ~; ~
210!~326 ` ~;
1 0 ' 1 ;
The compound~ of formula II ~-an be prepared e.g. in accorda~ce with the following reaction scheme: ~:
R2 ~.
I
H2N ~ CH - CH20H III
.
acylation V: , RlA ~ NH - C11 - CH20~ rv . ,S. ~ .
oxidation .,~ .
V
~2 . .
RlA NH Cl~ - C~0 V
.~ : :
: Nittig reaction :
.~A~ - N~ Cl~ - CH ~- C~ CO~)C2h5 ~ ~ ;: VI ~ ~
apo~ification ~ ~:
epoxida~ior~
I coupli~
R1A~- NE1 - CH~- C~ - ~H - C0 - 9R~
~: ~ ~ YII
r : ~poxidal:iosa~ : :
12 : ~ : : ~; ~ R;~; , .
RlA - N}~ - CH - CH - CH - ~2 H5 RlA - NH - CH ~ CH - CH lt? CO - BR
0 IIa 0 II
SUB5TlTlJT SHE~
W ~ 93/01166 PCT/EPg2/014?71 2 ;1 (~ ~ 3 ~
-11- ' ' ',,'';
In the above reaction 3cheme the sub~tituento? are as defined above. ~ :~
The single reactio~ stepq may be carried out accordi~g to r~action condition3 conventionally employed in quch rea~tion~, whereby the various intermediateQ
can, where appropriate, be reacted further without i~?olation. ;~
Insofar a~ they are not particularly de3cribed abov~ or i~ the Ex~mpleq, the ~?tarting material3 and intermQdiate3 are either known or can be prepared according to known method~ or analogou~}y? to known ~ethod~ or method3 de~cribed in the ~xample~
' '~ ';
~;',~'' ~ ''''~ ' .~
~"'.,.`,';.',.' ".'''~;' . ' ' . '.:~, ' . .
-: ' .,.'',~
::;.4~
~'''' `.'`; '',~
~ ,,~, ,,:.
SlJBSTlTUTE SHEE~
210~3~6 -12- :~
' The following Examples illu trate the invention, The carbon atom in the 4 position in fonmula I haQ the S confi~ura~io~. All temperatures are in degree~ Centigrade. The abbreviation9 for amino acids follow the ~ . -.
international tIUP~C) rule3. All NMR ~pectra are in CDCl3 unles3 indicated otherwise; the shiftQ are in ppm relative to trimethyl3ilane. ~;
.....
Other abbre~iation~ have the fo1lowing meaning:
. ., . . . ~ -BOC - tert-butoxycar~onyl; :
3u ~ n butyl; ~ -~
Bz ~ benzyl;
ch - hydrochloride;
cHex ~ cyclohexyl;
d. ~ decompo~ition;
dch - dihydrochloride; ::
d~pr. ~ deprotection~
~t ~ ethyl;
Ex. ~ Exampl~
FMOC o 9-fluorenylmethoxycarbonyl;
iBu - i~obutyl ~ 2-methylpropyl~
i~r ~ i~oprspyl;
Me - methyl: ~ :
m.p. a mel~ing point;
.. . .
OEt - ethoxy;
OMe ~ metho2y;
Ph ~ phenyl;
Ph~ ~ a phe~ylalanin~ moi~ty~
Pr - n-propyl;
ubl~matio~
~ap. ~ saponif~catio~ . C.
Su ~ the N-hydro~y3ucoini~id e~ter moiety;
t~u Y tert-butyl;
tch D trihydrochloride;
tL~u ~ a tert-}~ucin~ i-ty N~CH[ C~CH3)3]CO~
Z - be~zyloxycarbonyl.
TlTl ITI~ .C~ T
WO 93/01 l66 PCr~l :P92/01471 211)9~2~ ~
~a~le l: 2~ 4(5~-[(l~-~nzv o~carbonYl-L~ no~lami n i ester `~
. ~
[Formula I: Rl = Z; A - L Val; R2, R3 ~ Bz; X ~ -NH; B D a bond; .
R4 - OEt ]
[Proce.~ variant a), ring operling] :~
400 mg of 4(S)-t(~-benz~lo~carboQ~ )a~ol-2~3-epo~
5-phe31ylpe~tan~ic a~d et~yl *~r ~an intermedia~ o~ ~ormula II;
com~?ound ~ her~a~ter~ are di~olved in 6 ml of tetrahy~o uran. l~5 ~l o~
" ,,, , . ~ . r ~ " ",-i,, ~ ,;~ .,, ,;`~ . -;
be~z~ia~in~ (an itltermediate of ~on~lula III) are added asid the ~olu~iorl i8 ''.
kept at 6bo for 2 day~. The ~olvent i~ evaporated and th~ rèsidu~
chromatographed on silicagel (solvent: toluene/ethyl aceta'ce ?.:l). The title ca~o~d i~ obtained (m.p. 52-55)o `~
'". ','~ ;, tFormula I: Rl ~ B0C; A - L-Val: R2,R3 ~ Bz;
X Y -S-; B -- a bos1d; R4 ~0Et ]
[Proce.~ v~ria~t a)~ ring opening~
1.1~ g of ~e=capt~ ~a~ int~rm~diate of for~nula III) p~ta~s~u~ ~lt are ~30l~d in 2~ ml of a~etonit~ile and cooled to -~û.
2 g of ~1~5~ [(1~t~ b~to~~ o]-2,3~5~
penta~oic acid eth~ t~ (an inte~mediate of for~ula II; com~ou~d C ~ -h~reafter~ olved ~in lO ~L of ac~tonitrile ar~ a~d~d a~d th~ tu~
kept at -200 ~or 4~ hour~. After IlQutrali~atio~ ~dith acetic acid th~
mi$~ur~ i filt~ed~ th~ solv~s~ avaporated and the r~du~ chromatog~aphed on silicag~ olv~t: tolu@n~/~thyl acetate 4~ Th~ ~tl~
obtain~ up~
H-~: 1.27 (t,3E~: 1.42 (~,9H); 2.67-3.lS~AB,2H); 3.24 ~d?l}l); 3.47 :`~
(d,lH); 3.70 ~ ~B,2H): 3.84 (dd,l~); 4.17 (q,2H); 4o22 (~ ; 4~781 (q~ ; 7 .15-1. 40 ~:(m, 10H); : .
~, SUBSTITUTE SHEET :~
210932~
Es~le 2~ 2-BenzylalQin~4(s?~ o~ on~l-L valinovl~a~ino]-[For~ula I: Rl 5 Z; A,B - L-Val; R2,R3 ~ Bz: X - -NH-; R4 = NHBz [Proce~s ~Tarian~ bl ), 3ubstitution]
230 mg of ca~ d of ~le 4a are digqolved in 5 ml of dimethyl~ormamldeO 87 mg of L-vali~ benz~a~ide 5a~ ~ntermediate of formula ~-BR~), 57 mg of hydro~ybënzotriazole an~ 104~mg of dicyciob~xylcàrbodi ~ de are add~d at:roQm t~mpérature. Af~ër 24 hour~
~tirring at room temperature the ~olution i9 filt~r:ed, the ~olv~t evaporated and the residue chro~atographed on ~ilicagel ~Qolvent: gradient ~ i toLue~e/ethyl acetate 1:1 to 1:3). Th~ title coæpoun~ i~ obtained (amorphous; m.p. 81-84).
",:
~Fo~ula I: Rl ~ Z; A ~ L-Val: R2:,R3 ~ 8z; X ~ -N~-; 3 - L-Leu~
R4 - NXB2) :,. .
[Proce3~ variant bl), sub~titution]
220 mg of ~a2poo~d o~ ~$aqplo ~a~in 10 ml of a mlxture o~ dry .~
tetrahydrofuran and dim~thylfor~amit ~ are protected;from light and ~ . ;
3tirred at r~m te~perature in th~ pres~nce:of 195 mg o~ l-benzotriazolyl~
o~ tri~-~dimethylamino)pho~phonium hexafluoropho3phat~ and 49 ~1 of~
N-methylmorpholine for~l5 mi~ute3. 106 mg o L~ C1D~ ben~ylaoidn ~an interm~diat~ of fo~mula H-~R4) ar~ th~n add~d a~d th~ r~actio~ mixture i~
st~rred at roo~ t~mp~2ratur~ oYernight~ The 30lven~ r~mo~ed, water i~
added and t-he C~ud~ product ~xtractQâ ~ith ~thyl acetat~.~ The orga~c layers ar~ dri~d, th~ 901vent e~aporat~d a~d th~ resi~u~ chramatographed on silicagel (~ol~ent:: gradient tolue~e/2khyl:aceta~3:2 to:l:1). The titl~
OoE~O~ i9 obtained ~m.p. 190-201~
:~, ' --":'' .''".
~ .. "
~ ,. ~ , ....
gl ll~C TITUTE SHEFr ;: ~ ~
WO 93/011~6 PCI/EP92/01471 21~326 ~ ~
l~pl~ 3: N-l [~e~zYl~ino-4 ~S)-l t~ ylo~carbo~ rl~tert-bllt l- :
nzylalni ~Fonnula I: Rl - Z, A - 0-tBu-L-Se~; R2,R3 ~ Bz, X ~ -NH~ L-Val;
R4 :s NHBz] ; ~ :
[Prsces3 variant b2), substitution]
- 0.35 g of ~-benzylo~ca~o~yl~tert-b~
~uccini~id~ e~ter (an intermediata of formula R1A~Q wher~in Q i~:
N-hydroxy~uccinimidyloacy): ar~ added to a ~olutio~ of O.l"g of c~t of ~ple 119 in 4 ml o~ dioxane. The ml~CtUE2 i~l ~tirred for 6 day~` at room temperature, the ~olvent i~ evaporated and the r~idue i9 chromato~raphed on ~ilicagel (.olv~nt: cyclohe~asle/ethyl acetat~ 1:1). The titl~ c~spou~
i~ obtained ~m.p. 59-63).
~ i~ ;.,i.s~, [Formula I: Rl ~ Z; A 8 ~-Val; R2 ~ iBu; X - -N~-, R3 - Bz; B ~ L-Phe;
R4 ~ OMe ]
[Proce~s variant b2), 3ubstitutior~]
96 mg of c~po~d of E~pl 118~ are dis~olvo~ i~ 2 ml of tetrahydrofuran. 8~ m~ of ~ ~Ditrcph~l 2st~r ~an inte~med~ate o~ formula RlA Q wherein 9 i~ p-nit~ophenyloa~) and 200 mg o~ K2C03 ar~ added a~d the reaction mixture i~ ~tirr~d for 3 days. The solu~io~ i~ filtared a~d th~ qolv~nt ~vapo~ated. Th~ residu~ sol~d i~ ethyl acetate; the ~olutio~ i9 ~ashed with aqueou~ Q.1 a~ HCl, ~aturated . ~``
Na~CO3 ~olution, ~i~d a~d th~ 301~n~ evapo~ated. Th~ r~idu~
chromatographed on ~ilicagel ~(901v~t: tolueras/ethyl acetat~ 1:1):, th~
ti~I~ ca~ obtainsd (oil) ~
0 . 90-1. 00 (2d, 12H~; 1. 20~1. 40 (m, lH~ 0-1. 80 (m, 2H); 2 . 20 (oct,lH); 3.05~3.20 (m,3H); 3.55 (b~,lK); 3.75 (~,3H); 3.84 (d, lH~; 3 . 97 (dd, lH); 4 . 08-4 . 17 (m, lH); 4 . 90 (dd, lH); 5 . 08-~ . 20 (m, 2~); 6 ~ 60 (d, lH); 7 . 10-7 . 38 ~ 15H); 8 . 10 (d, 1~
. . ~.
:~'.'' .
~' ~
SUE~STITUTE St IEI~T
WO ~3/01166 PCI`/EP92/01471 2l932li3 le 3b: ~_~yl~-[Fermula I: Rl = Z; A - L-Hi3; R2, R3 - Bz: X ~ -NH-; B - L-Val:
R4 - NHBz ]
[ProceY~ variant b2), ~ubqtitution]
300 mg of ~-ben2ylo~a~0~l-L-hi~tid~oyl hydra~ ~an intermediate o~ fon~ula RlA-Q wherein Q i~ -NHN~2) are add~d at S~ to 4 ml of 1 N HCl ~oLution. A ~olutio~ of 80 mg of 90dium nitrlt~ in 2 ~ml of -~
water i4 added at 5~, the mixture i~ 9tirred for 5 minute~and ~enched with ~ ml of saturated Na2C03 ~olution. The reRulting white solid i~
wa~hed twice with water, dis301Yed in 4 ml of dimethylforma~de and add~d to a qolutios~ of 150 mg of c~po~ d of ~s~pl~ ll9 in 3 ~ of dlmethylfosmamide. The m~xture i9 stirrecl for 6 hours at room temperature, the ~olvent is evaporated and the re~idue i~ chromatographed Oll 3ilica9~l ~solvent: e~hyl acetat~. Th~ titl~ Co po ~ i~ obtai~ed ~re~in)~
~N~R ~DM~0): Q.88 a~d 0.89 ~2d,J-6Hz,6H); 2.04 (Qct~J~6Hz~H); 2.~1-2~68 i (m~l~); 2.73-2.9~ ~m,3~); 3.42-3.56 i~,3H3: 4.22-4:.38 (m,5H):: 5.03 (s,2H); 5:.13 (b,l~): 6.72 1~,lH): 7.10-7.35 (~,20H); 7.39 ~d~J~9Hz,lH); 7.48 (~,lH); 7.65 (d,~gHz,lHj;
8 . 26 (t, Jo6HZr 1}1) ~
~ ~ ,"
~ "'' ~' ,`
[Fon~ula I: Rl ~ quinoli~-2-ylear~onyl; A 8 L-Asn; R2,R3 ~ Bz~
X w -N~; B - L~ z]
[Proce8~ vaEian~ b2), ~ub8titution~
~ "
SS mg of diphenylpho9phoryl azid~ and 20 mg ~f ~-m~thylmsrpholin~
are added l:o a ~olutio~ Qf 100 mg of c~ of B~l~ 1~9 a~d 57 mg o~
1~(2 W lrlc ~ 7l~ ~ a ~ (an i~t-r~ diat- o~ formula;RlA-Q
wh~r~ OH~ in 3 ml o~ di~e~hylformami~ 0 T~ mistur~ tirred for ..
2 day~ at ~o~ temp~ra~u~, th~ solvent i~ evaporat~d a~d th~:re~idu~
chromatograph~do~ ~ilic8g~1. Th~ t~tl~ ao pou~d i~ obtain~d~
SllBsTlTlJTF~ r~r WO ~3/01166 PCT/EP92~0147l : ;
2109321~ - `
.~ -H-NMR: 0.92 and 0.95 (2d,6H); 1.70 ~b,lH), 2.16-2.24 ~m,lH): 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), 4.8g-4.95 (m,lH); 6.6~6.72 ~m,lH); 6.95-7.00 (m,lH~; 7.0g-7.30 (m~17H~; 7.6S-7.68 (M~ lH); 7.79-7.82 (m,lH); 7.86-7.93 (m,2H); :~
8.16-8.21 (m,2H); 8.31 (d~1~); 8~73 (d,lH);
~sample 4:
3-hYdro~y-~-phen~ent~o91]-L-valIa~ ~ z~la~ida [Formula I: Rl - Z;~ A - L-Ber; R2,R3 ~ Bs; X ~ -N~: B ~ L~Val;
R4 ~ N B z] ;~
~Deprotection]
2 ml of tri~luoroacetie aeid ar~ added to a solution of 55 mg o~
co~pou~d of k~a~pl~ 3 in 2 m~ of dichlorom~thane. The mixtur~ is stirr2d for 16 hours at room t~mpe~ature, the 901~e~t i~ evaporat~d, tolu~De i9 added and eva~ora~ed ~twice), the r~sidu~ is 301ved in di~hloromethan2, wa3hed with 0.1 N NaOH, driet over MgSO4, co~c~ntra~ed~i~ vacuo and chromatograph~d on ilicag~ olvent cyclohe~a~e/ethyl acetate 1::2),~
The ~itle c~poqDd i9 obtaln~d (m.p. 76-a1).
Es~G~le:4a 3-~v~gosY~ be~ylwta~oi~ a~id : ~
~Formula l: Rl 2~ -Val, R2~R3 - Bz; X - -NN-: 9~- bo~d;
tSapo~ification~
330 m~ of ~ of ~ pl~ 1 are di~olved in 3 ml of tetrahydrQfura~. 627 pl o~lN aqueo~s ~odi _ b~dkQYid~ solueion are addet a~d:the~reaction mhx~u~ is~ tir~ed ~o~ 10 hou~ at ~o~m;~t~mpera~ur~
~NeutralizatioQ ~ith dilut~ agu~ou~ ~Cl ~olu~ion l~ad~ ~o ~ whit~
pr~cipitat~ which i3 ~iltexet off:and dried. The gi~1~ ccspoDn~
obtained ~m.p. 1~7-lg3 ~ ~TITI ITC C!UIE I T .
21 0 9 ~ 2 ~ PCI/EP92/01471 o o o~ o ~ o~ O o .~
~n o ~ ~ ~17 ~ ~ ~ ~ a~ ~ ~ u~ ~ ~ cO ~ u~ ~ ~7 .. E~ o ~ c~ ~D ~ 0 a~ ~ ~ ~ OD O U> Cr) ~-~ s~
.~0 ,4 ~ R .4 .R .~ n ., N ~
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H I ~ ~ N N N N ~
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:
WO 93/01166 2 ~ O ~ ~ 2 ~ PCr/EP92/0147~
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SUBSTITUTE SHEET ~ :
WO 93~01166 21 0 9 ~ 2 6 PCI/EP92/01471 .
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SUBSTITUTE~ SHE~ET
wo ~3/011~6 2 1 0 ~ 3:2 ~
1~ o~ N O ~ ~ 3 ~ T U~ o ~
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:
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t~ N ~ ~ sq m ~ 3~
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5UB~;TITUTE SHEET
WO 93/01166 210 9 3 2 6 PCII~/EP92/01471 a~ ~ o`D NU~ o ',''''`'"'"~
O S.l ._ ,_ ~ _ ~ ,_ ~ ~ ,-, ., . ~.
., ., ~ ,, , ., . : , ,, ~ : . r .~ ~ -~ 8 ~ N
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SlJE~STlTUTE SHEFI ~: :
W~ 93/C11166 2 1 û 9 3 2 6 PCr/EP92/01471 - 23_ o ~ ~ ~ ~ ~ ~ ~
~:: ,.,~ `.`" .,' C~ ~ ~
G~ ¦ ~ N ~ U
. ''`''''.'.. ~'~
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N C~ S ~
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~ SLJBSTITUTE SHEET ` ~
WO 93/01166 2 1 û 9 3 2 6 P~/EP92/01471 ,c~
o ~ o ~ o o o o o o ~ o~ o o O~ ~ CL ~ ,,"~
I ~ ", ,.';
æ
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ta~ ~ ~a ~ ~ ~ l~j N ~ N
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~1 IQ~TITI ITF ~
W~ 93/01166 PCI/EP92/01~71 ~ .
21~9326 iil ~
2. ~
o o o o o o ~ . ~, L~-) u~ N N ~ ~ r) O U~) o o r-l o o ~ ~ o o z o o C~ O
. N C~ I ~I N N ~1 ~ N ~ 0 C`~
C~ O N ~ ~ ~ I N CD O _!O C~3 ~: ~1 O a~
~ , O ~ O æ
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o~ ~ ~ ~
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SLJBSTIT(ITE SIHEET : :~
",~ .?
WO 93~01166 211~ 9 '3 2 B P~/I~P92/01471 .
.
o O ~ ~ o a~
~ ~ ~ O N I _I o l~
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_ ~ -` ','-.. ~'','~' '` ' ,~. ", ':,' `''~' ~'','' - ''.... ~.: "':
' ::. ``
SIJE~STITUlE SHE~
WO 93/01166 ~ PCI/El'92/01471 2109326 ;
~ .
~ . .
- 2~
U~
V ~ ~ : .
N ~ ' ~ 3 ~ X C~ N
X c~ ¢i æ
c~ . o ~ ~o ~ o ,.c~ ~ ul : :
~æ ~ o ~ ~ 1~ w ~ ~ ~ ~
I N
~-- o ~ ~ C~ N ~: N
o 1 0 o ~ N ,~
~ o ~ æ 3: ~ X ~ 1~
preferably of an -amlno acid, preferably of an amino acid which i~ a normal constitutiv~ part of prot~in~. It i9 e.g. i30propyl, :;
aminocarbonylmathyl, methyl, l-methylpropyl~ benzyl, 4-hydroxybenzyl or isobutyl, preferably benzyl.
B pr~ferably i9 an optio~ally ~ubstituted aminoacyl moi~ty, preferably an optionally 9ub3tituted a-amlnoacyl moiety, ~uch as phenylalanine, valine, leucine, i~oleucine, aIanin~or a~paragine~ It ;:-preferably i~-th~ optionally~9ub5tituted moiety b~ ~a ~Dà-toral^~o~no acid, pre~erably of an amdno:~acid which i9 a normal constit~tiie-part of :
proteins. It ~speoially is L-valin~
R4 preferably i~ a group -NHR7; it preferably i~ i~opropylamino, t~rt-butylamino, l- or 2-naphthylmethyla~ino, or 2-, 3-~or 4-pyridylmethyl- ~:
ami~o; it esp~cially is benzyla~ino or benz~midazolylm~thylamdno, pa~scular~y benz~mi~zol-2-yl~ethylamino.
E~3 pre~erably~i~ an optionally sub3tituted arylalkyl ~roup, ,~,~
e~pecially-be~zyl. The aryl part of a~lalkyl optionally:i3 9ub~tituted by, prefe~ably, alkoxy or 1 to 4 ca~bon atom9, 9uch a~ methoxy, or halogen of atomic number of fr~m~9 to 35, ~uch a~3 bromine, it prefQrably i9 -"
mono~ub titutet, preferably in 3 or 4 po~ition: it:esp cLally is ~:
monosubstitu~ed in 3 or 4 po~ition ~ methoxy.
: X pref~r~ly~is a ~roup -NR5- a9 defined aboYe. ~t especially~is th~ o group.
R6 pr~ferably ~i~ an optionally ~ tituted alkyl, a2ylalkyl or heteroa~ylalkyl g~oup,: e~pecially alkyl; wh~r~ it ~ optionally ~ubstituted~
heteroarylalkyl it pr~ferably i~ :pyridylalkyl, e~p-ci~lly 2-pyridyL~ethyl; ~. -~hen it i~ optio~aliy s~tituted arylalkyl it p~f~rably i8 `
benzyl-CH~O~ he~ it i~ sub~tituted alkyl it pr~f~rably phenox~m~thyl. :
Y pre~æ~ably i~-CO; or ~CO-, e~pecia1ly -CO~
R~ preferably i~ an optionally~ 3ub~tit~sted alkyl, :arylalkyl or .
het~roarylalkyl ~roup, pr~f-rably phenylalkyl o~ altog~ther 7 to 10 carbon~
a~ uch aa be~zyl, or a pyridylallcyl, indolylalkyl or benz~udazolylalkyl group of ~1 to 4 carbo~ in thQ alkylQn- part:; it "`''~',' ''`
SUBSTITlJTE SHEET
WC? ~3/01166 . PCI/EP92~01471 21~g32~ ':
preferably is benzyl, 2-, 3- or 4-pyridyLmethyl or benzLmldazolylmethyl, e~pecially benzyl or benzimidazolylmethyl, particularly benz~mida201-2-ylmethyl.
R5 preferably i~ hydrogen or methyl, e~p~cially hydrogen. ~.
'.
alt i9 e.g. an acid addition 3alt such as a hydroshloride. ~i ~ The compou~d of fo~ula I ~ormally have ~v~ral chiral cente~
.~ ~ and can thereforQ eai~t i~ a ~ariety:~.of~3tereoisom~r.~. Th@ inventionpro~ides all ~te~eoi30mer~ a3 well a~ racemic m~x*ur~. The i3~mer~ ~ay b~
resolved or 3eparated by conventional techniqus~, e.g. chromatographically. ~.... `~
The carbon atom in 4 po~ition preferably has the S configuration. ""~
An optionally sub3tituted ami~oacyl moiety pref-r~ly i~
un~ub~tituted. When it i3 sub~ti~uted it ~.g. i sub~titu~ed by alkyl of 1 `~
~o 4 ~arbon atcms, ~u~h a~ iD O-t~rt-butyl-~-serinoyl~o~
2-aml~obutanoyl. It preferably i~:in the L optically~aetive foD~. :It :
preferably i~:an ~-aminoacyl: i~ty, ~ueh a9 valinR: or tert-leuoine.
~tionally ~ub3titut~d alkyl;;pr~ferably is~alkyl o~ 1 to S carbon atoma, p~eferably of 1 to 4 carbon~atoms, ~.g. mathyl,~ethyl, ~sopropyl o~
tert-butyl: it i9 especially of~l or 4 carbon a~o~ The s~bstituent i~
e.g. pheno ~ hydrosy:or optionally pro~ectQd amino.
Cptio~a11y ~ubstitut~d arylalkyl~i~ e.g. phanyl-lkyl of altog~th~r ~:
7 to 10 oarbo~ at~m~, ~u~:a~ benzyl or 2-ph~yl~thyl; it i~ optionally ~ub~tituted by e.g. hydro~y~ such a~ iD benzyl-CH~OH~- or :~
ph~nyl-CH(CH20~-, or i~ e.g. ~aphthylalkyl o~ l to~4 carbon atom~ iD t he~
alkylQn~ part.
An aEi~o protectinq qroup p~æf~ably i~ be~zyloxyca~bo~yl or t~xt-butoxycaEbonyl.
Optio~ally ~b~titut~d het~roarylalkyl prsferably i~ pyridylalkyl, : :
especially 2~pyridy~met~yl. : :::
A~yl, h~@roa~yl and the aryl parts of arylalkyl or hQteroa~ylalkyl may be m~o- or polycyc1ic, -QUCh a~ e.g. pyrityl, naphthyl,~
s~luoranyL~n~thoal:yG~rborly~ OC) sr b~zi~ olylD :Th~ alkyle~ part of SlJ13STlTUTE SHE~ - ~ ~
W O 93/01166 P ~ /EP92/01471 2 ~L O 9 3 2 6 o5 arylalkyl or heteroarylalkyl may be ~bstituted by e~g. hydroxy.
A heterocyclyl group and the heterocyclyl part o~ a ~:
heterocyclylalkyl group i~ a ~aturated heterocyclic group having one or more heteroatom~ ~elacted ~rom nitrogen, oxygen and ~ulfur. It preferably ~ :
ha~ 5 or 6 ring constitutent atom~, and preferably :up to 3 heteroatoms.: :~
Cycloalkylalkyl preferably i~ cyclohexylalkyl it preferably i~ of 1 ~o 4 carbon atom~ in the alkylene part.
~ .!A ~ubg~oup of~.compound~ of fon~ula I i~ the compound~ of:forIuIa 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 o~her ~.
~ubstituent~ are a~ defined above.
~ further ~ubgroup i~ the compound~ of formula I Nher-in RlA- is .. -~
an optionally ~3tituted and optio~lally N-terminal~prct~cted~natural a~noacyl moiety, -3R~ i9 a natural amin~acyl moi-ty optionally esteriFied or amidated at the C-terminus , R2 i ~th~ sid~ chai~ of a natural~amino acid,~R3 is~an alkyl, alkenyl, cycloalkyl, aryl or;~arylalkyl~group ~uch as naphthylmethyl and X i~ as defined~above.
: : A urther subgroup i~ the col~pounds of formula I wherei~Rl is ~`
~benzylyoxycarbo~yl,, 2-pyridylmethoxy~arbonyl, Phenyllac~oyl or phenoxymethylcarbo~yl, A is L-valin~or~L-tert-leucin-,~R2~ i8 ~benzyl, X i~
-NH-, R3 is~be~zyL, 3- or 4-m~t~oxyb~nzyl or 4-~Éomob~n~yl,~ L-vali~Q
and R~ ~is~b~zylaxino~or ben~imi~azol-2-ylmethylamino,~and thè carbon~atam ~ ,',`'a", !'.
in 4 po~ition ha3 the:S~configura~ion.
fur~h~er ~ubgroup i~ he compound~ of formula Is ; R2,~ X,R3, Rl,A~ ~ NH -~H - :fH~ o - B,~ , :OH:
wherein ~ j -: ~ ~ SlJBSTlTUTE S,H"E',~
W ~ 93/~1166 PCT/EP92/01471 ~.,, " J J `'J'; J
-6- `~
'.''' ~'''~
R~ hydrogen; phenylalkyloxycarbonyl of altogether 8 to 10 carbon :.
atoms; alkyloxycarbonyl of altogether 2 to 10 carbon atom~
quinolylcarbonyl or quinolyl~ulfonyl; pyridylmethoxycarbonyl; :~
aminocaproyl optionally protected by tert-butoxycarbonyl; . ; : ~ ~
9-fluorenylmethoxycarbonyl (F~OC); phenyllactoyl: i~oval~rianoyl; ~ ~`phenoxymethylcarbonyl; palm~toyl; or 4-hydroxyphenylpropionyl;
Ag is a bond; a natural a-ami~oacyl moiety; the corr~9pondin~ D optical i~omer form: L- or D-tert-leuci~e; 0- ert-butyl-L-c~rine: or - -L-2-aminobutanoyl;
R2~ i9 alkyl of 3 or 4 car~on ato~ or~phe~ylalkyl of altogsther 7 to ~ :
9 carbon atom~
X~ i3 -S- or -NR5,- wherein Rs, i~ hydroge~ o~ methyl;
R3, is alkyl of 3 to 5 carbon atom3; oycloalkyl of 5 to 7 ca~bon atoms optionally mono~ tituted b3~ hydro~y; pib~yl: phenylalkyl of altogether 7 to 9 oarbo~ atom~optio~ally monosub~tituted in the phenyl ring by hydroxr, alkoxy of 1 to 3 ca~bon at ~ , halogen of atomic number of from 9 to 35, or ph~nyl; a pyridylalkyl, in~ol~lalkyl or naphthylalkyl group of } to 3 carbon atom~ in:the:alkylene part: or phenylalk~nyl of 2 to 4 carbon ato~3 in th~ alkenyl~ne part;
B, i~ a bond; a natura~ ~-a~inoacyl ~oi~ty; th~ corr~sponding D optical i~omer f~D~; L- or D-tert-leucine; or aminocyclopropan-~ carbony~
R4~ is hydroxy; an alkosy o~ alkylami~o group o~ 1 to 5 carbon~atom~; ~
phenylalkylamino o altog~t~er 7 ~o 9 carban:atomJ optionally~ ~p:
P monos~bstituted i~ th~ ph~n~l ring or in th~ alkylene part by~hydroxy, or nosub~tituted in the ph~nyl ring b~:halog~n of ato~ic numbeL of fr~ 9 to 35; benzImidazolylal~oz~ or beazi~idazolylalkylamino of ~ to 3 carbo~ atcm~ i~ the alkylena part optionally ~o- or di~ub~tituted in ~he a~yl part by halog~ of~ atomic numb~r Or fr~m 9 ~o 35 ~r nitro;
or an indolylalkylzEi~o, p~ridylalkylamino or rp~olinylalkylami~o ;
moiety of 1 to 3 car~o~ atcm~ in the alkyl~ne part; a~d ~he co~figuratio~ i~ 4~po~i~ion i~ S, i~ fre~ fonm a~d, wh~re ~uch fo~m~ exi~t~ alt form.
: -SUBSTITUTE~ SHEET ~:
WO 93/01166 PCr/EP92/01471 2~09~26 In a subgroup of compound~ of fonmula I , when ~ or B, i3 a natural ~-~minoacyl moiety it i9 valine, tryptophane, phenylalanine, asparagine, i~oleucine, glutamine, leucine, alanine or hi~tidine: in a further subgroup, when Rl~ is phenylalkyloxycarbonyl it i~
benzyloxycarbonyl.
. ,; ~:,.
A further ~ubgroup i~ the compounds of foDmula Ipl .!
' ' ~..', R2 - X~3 p R~pA -NH - CH - CH CH CO - ~R4p ~ Ipl ;,.;;
OH
wherein A, B, R2 and X are a3 defined abo~e;
Rlp with the exception of hydrogen has the ~i~nificance~indicated above :~ ;
for R~
R3p with t:he exception of optîonally ~ tituted cyc}oalkyl has the significance indicated above for R3; and~
R4p i~ hyd~o~y or a group of formula -OR7~or -NHR7 a~ defined above~
in free fonm and, wher~ ~uch form~ exi t, ;in salt fonm.
A further subgroup i~ the: compound~ Ip2, i.e. the oo~ounds of formula I a~ defi~d abo~e with the e2ception that R4: i~ hydro~cy or a gro~p -~
of formula -OR7 or -NHR7 as defined above.
SlJ113~TITUTE SHEET
., '.. ` ~. .`~;~.
WO 93~01166 PCI`/EPg2/01471 ~ ' ! ' ' 2 1 0 ~ 3 2 6 -8;
; ~
The compound~ of the invention may be prepared by a proceq3 which - ~`
comprise3 ' ~`' ' . a) submltting an epo~ide of fon~ula II
.
RlA - NH - CH - C - CH - C0 - BR4 II
O "
wherein the ~ tituent~ are as~ dafined abo~e, to r~g oyening in the pre~ence of~a compo~und o~ formula III
H - XR3 III ~ :
wherein the 3ub3ti uents ar~ as d~fined above, where indicated in a further reactive form; or ~ -b) for the preparation of ~he compo ~ d~:of fo~mula I wherein :~
-3R4 L3 other than~hydroxY tbll, ~
: ~Rl i~ other~ tha~ hydrogen or HY- lb2~]~
approprlately sdb~ti~utiGg~;a~:corresponding c~mpound of fo ~ a~I wh~ein : : CO-~R6 i~ carboxy or R~ i~ hydroge~or HY-, e.g.
blj 3u~stituti~g a corresponding com~ou~d of formula Ia : : R2 ~ ~:XR3 Rl~ - NH ~ :CH - CH -~COO~ ~ ; Ia ii~
wher~i~ th~ subJtituen~ ar~ a~ defined;abo~, or b2~ sub~tltuting ~ corx~spondin~ compouat of for~ul~ Ib :
Rl'A - N~} - CH~ -~ CH - Ctl~- C0 - BR~ : :Ib OH :
wherei~ Rl' i5 hydro~en or HY- and th~ other 9ub9tituent3 are aJ d~fi~ed abo~e;
~ .. .
, ; .: .~
....
SUBSTqTlJTE Sl IEFI
W O ~3/01166 PCT/EP~2/01471 2109326 ~
.~ .,: ,, and wh re indicated deprotecting or ~apoDi~yiag a resultant compound of .
formul~ I in protected or e terified form, and recovering th~ reGultant compounds of formula I in free form or, wher~
~uch form~ exi~t, in salt f onm.
Th~ proceq~ o~ the invention can be carr~ed out in conv~tional manner~ T -~
P~ocs~ ~ariant a) is effect~d e.g. in an inert ~olY~nt ~u~h aQ a~
,- ~
ether~ e.q. tetrahydrofuran, or acetonitrile. The temperature preferably i9 between about -50C and the boiling temperature of the reaction mixture, pzeferably betwe~ about 20~C a~d about 80~$. The c~mpound of for~ula III `
i3 a~ appropriate amin~ or mercapta~. A ~urthe~ reactive form prefexably is a qalt of a mercapta~, s.g. an alkali m~tal salt such a~ the pota ~ium 3alt. .`,Prnce~s Yariant b) is ef~cted u~ing condition~ known ~or coupling ami~o acid~. Th~ reactio~ pref~rably i8 effe~ed in:an ine~t ~olvent~ ~uch a~ an amide,~e.g. dim~thylfor1alide,~ or an ether,:~.g~ tet:rahydrofuran. ~:The temperature prefe~ably i~ betw~en~about ro~ temperature a~d the boiling temperatur~ o~ the reaction~mi~ture, pre~e~ably about room temp~ratur~
De~Q~tio~ con~e~ tly i9 effe~ted by hydroly~i~, preferably undeE acidic cond~tio~ ~or removing e.g. a:hydroxy~or amlno protecting group such a3 t~rt~-buto~arbonyl, pref~r~ly ~itb trifluoroacetic acid, or hydrog~no}yt~cally for removing e.g. ba~zyloxycasbonyl.~ SapoDific~tion iJ ;~
effected pre~rably ~ith aqueou~ sodiu~ hydrox~d~ ~olutio~ for recovlng .g~ alkoxy. .The temp~aturB pre~erably i~b~tween about -20~C~a~d about 60C, it conve~ien~ about room temp~rature. ~a organic ~olvent ~uch ~ ;
a~ diehlor~th~e or tetrahydrofuran con~enie~t1y is u3ed.
Th~ r~sultan~ compousd9 of fo ~ a I can b~i30lated frw~ the ; 'i'`''',`',.7 r~actio~ mis~urQ and purified accoEding to know~ m~thods~ ~.g.
chromAtographically.
~ ";! ~
c~ TlTuTE SHEET
W0~3/01166 PCI~ /01471 ~; ~
210!~326 ` ~;
1 0 ' 1 ;
The compound~ of formula II ~-an be prepared e.g. in accorda~ce with the following reaction scheme: ~:
R2 ~.
I
H2N ~ CH - CH20H III
.
acylation V: , RlA ~ NH - C11 - CH20~ rv . ,S. ~ .
oxidation .,~ .
V
~2 . .
RlA NH Cl~ - C~0 V
.~ : :
: Nittig reaction :
.~A~ - N~ Cl~ - CH ~- C~ CO~)C2h5 ~ ~ ;: VI ~ ~
apo~ification ~ ~:
epoxida~ior~
I coupli~
R1A~- NE1 - CH~- C~ - ~H - C0 - 9R~
~: ~ ~ YII
r : ~poxidal:iosa~ : :
12 : ~ : : ~; ~ R;~; , .
RlA - N}~ - CH - CH - CH - ~2 H5 RlA - NH - CH ~ CH - CH lt? CO - BR
0 IIa 0 II
SUB5TlTlJT SHE~
W ~ 93/01166 PCT/EPg2/014?71 2 ;1 (~ ~ 3 ~
-11- ' ' ',,'';
In the above reaction 3cheme the sub~tituento? are as defined above. ~ :~
The single reactio~ stepq may be carried out accordi~g to r~action condition3 conventionally employed in quch rea~tion~, whereby the various intermediateQ
can, where appropriate, be reacted further without i~?olation. ;~
Insofar a~ they are not particularly de3cribed abov~ or i~ the Ex~mpleq, the ~?tarting material3 and intermQdiate3 are either known or can be prepared according to known method~ or analogou~}y? to known ~ethod~ or method3 de~cribed in the ~xample~
' '~ ';
~;',~'' ~ ''''~ ' .~
~"'.,.`,';.',.' ".'''~;' . ' ' . '.:~, ' . .
-: ' .,.'',~
::;.4~
~'''' `.'`; '',~
~ ,,~, ,,:.
SlJBSTlTUTE SHEE~
210~3~6 -12- :~
' The following Examples illu trate the invention, The carbon atom in the 4 position in fonmula I haQ the S confi~ura~io~. All temperatures are in degree~ Centigrade. The abbreviation9 for amino acids follow the ~ . -.
international tIUP~C) rule3. All NMR ~pectra are in CDCl3 unles3 indicated otherwise; the shiftQ are in ppm relative to trimethyl3ilane. ~;
.....
Other abbre~iation~ have the fo1lowing meaning:
. ., . . . ~ -BOC - tert-butoxycar~onyl; :
3u ~ n butyl; ~ -~
Bz ~ benzyl;
ch - hydrochloride;
cHex ~ cyclohexyl;
d. ~ decompo~ition;
dch - dihydrochloride; ::
d~pr. ~ deprotection~
~t ~ ethyl;
Ex. ~ Exampl~
FMOC o 9-fluorenylmethoxycarbonyl;
iBu - i~obutyl ~ 2-methylpropyl~
i~r ~ i~oprspyl;
Me - methyl: ~ :
m.p. a mel~ing point;
.. . .
OEt - ethoxy;
OMe ~ metho2y;
Ph ~ phenyl;
Ph~ ~ a phe~ylalanin~ moi~ty~
Pr - n-propyl;
ubl~matio~
~ap. ~ saponif~catio~ . C.
Su ~ the N-hydro~y3ucoini~id e~ter moiety;
t~u Y tert-butyl;
tch D trihydrochloride;
tL~u ~ a tert-}~ucin~ i-ty N~CH[ C~CH3)3]CO~
Z - be~zyloxycarbonyl.
TlTl ITI~ .C~ T
WO 93/01 l66 PCr~l :P92/01471 211)9~2~ ~
~a~le l: 2~ 4(5~-[(l~-~nzv o~carbonYl-L~ no~lami n i ester `~
. ~
[Formula I: Rl = Z; A - L Val; R2, R3 ~ Bz; X ~ -NH; B D a bond; .
R4 - OEt ]
[Proce.~ variant a), ring operling] :~
400 mg of 4(S)-t(~-benz~lo~carboQ~ )a~ol-2~3-epo~
5-phe31ylpe~tan~ic a~d et~yl *~r ~an intermedia~ o~ ~ormula II;
com~?ound ~ her~a~ter~ are di~olved in 6 ml of tetrahy~o uran. l~5 ~l o~
" ,,, , . ~ . r ~ " ",-i,, ~ ,;~ .,, ,;`~ . -;
be~z~ia~in~ (an itltermediate of ~on~lula III) are added asid the ~olu~iorl i8 ''.
kept at 6bo for 2 day~. The ~olvent i~ evaporated and th~ rèsidu~
chromatographed on silicagel (solvent: toluene/ethyl aceta'ce ?.:l). The title ca~o~d i~ obtained (m.p. 52-55)o `~
'". ','~ ;, tFormula I: Rl ~ B0C; A - L-Val: R2,R3 ~ Bz;
X Y -S-; B -- a bos1d; R4 ~0Et ]
[Proce.~ v~ria~t a)~ ring opening~
1.1~ g of ~e=capt~ ~a~ int~rm~diate of for~nula III) p~ta~s~u~ ~lt are ~30l~d in 2~ ml of a~etonit~ile and cooled to -~û.
2 g of ~1~5~ [(1~t~ b~to~~ o]-2,3~5~
penta~oic acid eth~ t~ (an inte~mediate of for~ula II; com~ou~d C ~ -h~reafter~ olved ~in lO ~L of ac~tonitrile ar~ a~d~d a~d th~ tu~
kept at -200 ~or 4~ hour~. After IlQutrali~atio~ ~dith acetic acid th~
mi$~ur~ i filt~ed~ th~ solv~s~ avaporated and the r~du~ chromatog~aphed on silicag~ olv~t: tolu@n~/~thyl acetate 4~ Th~ ~tl~
obtain~ up~
H-~: 1.27 (t,3E~: 1.42 (~,9H); 2.67-3.lS~AB,2H); 3.24 ~d?l}l); 3.47 :`~
(d,lH); 3.70 ~ ~B,2H): 3.84 (dd,l~); 4.17 (q,2H); 4o22 (~ ; 4~781 (q~ ; 7 .15-1. 40 ~:(m, 10H); : .
~, SUBSTITUTE SHEET :~
210932~
Es~le 2~ 2-BenzylalQin~4(s?~ o~ on~l-L valinovl~a~ino]-[For~ula I: Rl 5 Z; A,B - L-Val; R2,R3 ~ Bz: X - -NH-; R4 = NHBz [Proce~s ~Tarian~ bl ), 3ubstitution]
230 mg of ca~ d of ~le 4a are digqolved in 5 ml of dimethyl~ormamldeO 87 mg of L-vali~ benz~a~ide 5a~ ~ntermediate of formula ~-BR~), 57 mg of hydro~ybënzotriazole an~ 104~mg of dicyciob~xylcàrbodi ~ de are add~d at:roQm t~mpérature. Af~ër 24 hour~
~tirring at room temperature the ~olution i9 filt~r:ed, the ~olv~t evaporated and the residue chro~atographed on ~ilicagel ~Qolvent: gradient ~ i toLue~e/ethyl acetate 1:1 to 1:3). Th~ title coæpoun~ i~ obtained (amorphous; m.p. 81-84).
",:
~Fo~ula I: Rl ~ Z; A ~ L-Val: R2:,R3 ~ 8z; X ~ -N~-; 3 - L-Leu~
R4 - NXB2) :,. .
[Proce3~ variant bl), sub~titution]
220 mg of ~a2poo~d o~ ~$aqplo ~a~in 10 ml of a mlxture o~ dry .~
tetrahydrofuran and dim~thylfor~amit ~ are protected;from light and ~ . ;
3tirred at r~m te~perature in th~ pres~nce:of 195 mg o~ l-benzotriazolyl~
o~ tri~-~dimethylamino)pho~phonium hexafluoropho3phat~ and 49 ~1 of~
N-methylmorpholine for~l5 mi~ute3. 106 mg o L~ C1D~ ben~ylaoidn ~an interm~diat~ of fo~mula H-~R4) ar~ th~n add~d a~d th~ r~actio~ mixture i~
st~rred at roo~ t~mp~2ratur~ oYernight~ The 30lven~ r~mo~ed, water i~
added and t-he C~ud~ product ~xtractQâ ~ith ~thyl acetat~.~ The orga~c layers ar~ dri~d, th~ 901vent e~aporat~d a~d th~ resi~u~ chramatographed on silicagel (~ol~ent:: gradient tolue~e/2khyl:aceta~3:2 to:l:1). The titl~
OoE~O~ i9 obtained ~m.p. 190-201~
:~, ' --":'' .''".
~ .. "
~ ,. ~ , ....
gl ll~C TITUTE SHEFr ;: ~ ~
WO 93/011~6 PCI/EP92/01471 21~326 ~ ~
l~pl~ 3: N-l [~e~zYl~ino-4 ~S)-l t~ ylo~carbo~ rl~tert-bllt l- :
nzylalni ~Fonnula I: Rl - Z, A - 0-tBu-L-Se~; R2,R3 ~ Bz, X ~ -NH~ L-Val;
R4 :s NHBz] ; ~ :
[Prsces3 variant b2), substitution]
- 0.35 g of ~-benzylo~ca~o~yl~tert-b~
~uccini~id~ e~ter (an intermediata of formula R1A~Q wher~in Q i~:
N-hydroxy~uccinimidyloacy): ar~ added to a ~olutio~ of O.l"g of c~t of ~ple 119 in 4 ml o~ dioxane. The ml~CtUE2 i~l ~tirred for 6 day~` at room temperature, the ~olvent i~ evaporated and the r~idue i9 chromato~raphed on ~ilicagel (.olv~nt: cyclohe~asle/ethyl acetat~ 1:1). The titl~ c~spou~
i~ obtained ~m.p. 59-63).
~ i~ ;.,i.s~, [Formula I: Rl ~ Z; A 8 ~-Val; R2 ~ iBu; X - -N~-, R3 - Bz; B ~ L-Phe;
R4 ~ OMe ]
[Proce~s variant b2), 3ubstitutior~]
96 mg of c~po~d of E~pl 118~ are dis~olvo~ i~ 2 ml of tetrahydrofuran. 8~ m~ of ~ ~Ditrcph~l 2st~r ~an inte~med~ate o~ formula RlA Q wherein 9 i~ p-nit~ophenyloa~) and 200 mg o~ K2C03 ar~ added a~d the reaction mixture i~ ~tirr~d for 3 days. The solu~io~ i~ filtared a~d th~ qolv~nt ~vapo~ated. Th~ residu~ sol~d i~ ethyl acetate; the ~olutio~ i9 ~ashed with aqueou~ Q.1 a~ HCl, ~aturated . ~``
Na~CO3 ~olution, ~i~d a~d th~ 301~n~ evapo~ated. Th~ r~idu~
chromatographed on ~ilicagel ~(901v~t: tolueras/ethyl acetat~ 1:1):, th~
ti~I~ ca~ obtainsd (oil) ~
0 . 90-1. 00 (2d, 12H~; 1. 20~1. 40 (m, lH~ 0-1. 80 (m, 2H); 2 . 20 (oct,lH); 3.05~3.20 (m,3H); 3.55 (b~,lK); 3.75 (~,3H); 3.84 (d, lH~; 3 . 97 (dd, lH); 4 . 08-4 . 17 (m, lH); 4 . 90 (dd, lH); 5 . 08-~ . 20 (m, 2~); 6 ~ 60 (d, lH); 7 . 10-7 . 38 ~ 15H); 8 . 10 (d, 1~
. . ~.
:~'.'' .
~' ~
SUE~STITUTE St IEI~T
WO ~3/01166 PCI`/EP92/01471 2l932li3 le 3b: ~_~yl~-[Fermula I: Rl = Z; A - L-Hi3; R2, R3 - Bz: X ~ -NH-; B - L-Val:
R4 - NHBz ]
[ProceY~ variant b2), ~ubqtitution]
300 mg of ~-ben2ylo~a~0~l-L-hi~tid~oyl hydra~ ~an intermediate o~ fon~ula RlA-Q wherein Q i~ -NHN~2) are add~d at S~ to 4 ml of 1 N HCl ~oLution. A ~olutio~ of 80 mg of 90dium nitrlt~ in 2 ~ml of -~
water i4 added at 5~, the mixture i~ 9tirred for 5 minute~and ~enched with ~ ml of saturated Na2C03 ~olution. The reRulting white solid i~
wa~hed twice with water, dis301Yed in 4 ml of dimethylforma~de and add~d to a qolutios~ of 150 mg of c~po~ d of ~s~pl~ ll9 in 3 ~ of dlmethylfosmamide. The m~xture i9 stirrecl for 6 hours at room temperature, the ~olvent is evaporated and the re~idue i~ chromatographed Oll 3ilica9~l ~solvent: e~hyl acetat~. Th~ titl~ Co po ~ i~ obtai~ed ~re~in)~
~N~R ~DM~0): Q.88 a~d 0.89 ~2d,J-6Hz,6H); 2.04 (Qct~J~6Hz~H); 2.~1-2~68 i (m~l~); 2.73-2.9~ ~m,3~); 3.42-3.56 i~,3H3: 4.22-4:.38 (m,5H):: 5.03 (s,2H); 5:.13 (b,l~): 6.72 1~,lH): 7.10-7.35 (~,20H); 7.39 ~d~J~9Hz,lH); 7.48 (~,lH); 7.65 (d,~gHz,lHj;
8 . 26 (t, Jo6HZr 1}1) ~
~ ~ ,"
~ "'' ~' ,`
[Fon~ula I: Rl ~ quinoli~-2-ylear~onyl; A 8 L-Asn; R2,R3 ~ Bz~
X w -N~; B - L~ z]
[Proce8~ vaEian~ b2), ~ub8titution~
~ "
SS mg of diphenylpho9phoryl azid~ and 20 mg ~f ~-m~thylmsrpholin~
are added l:o a ~olutio~ Qf 100 mg of c~ of B~l~ 1~9 a~d 57 mg o~
1~(2 W lrlc ~ 7l~ ~ a ~ (an i~t-r~ diat- o~ formula;RlA-Q
wh~r~ OH~ in 3 ml o~ di~e~hylformami~ 0 T~ mistur~ tirred for ..
2 day~ at ~o~ temp~ra~u~, th~ solvent i~ evaporat~d a~d th~:re~idu~
chromatograph~do~ ~ilic8g~1. Th~ t~tl~ ao pou~d i~ obtain~d~
SllBsTlTlJTF~ r~r WO ~3/01166 PCT/EP92~0147l : ;
2109321~ - `
.~ -H-NMR: 0.92 and 0.95 (2d,6H); 1.70 ~b,lH), 2.16-2.24 ~m,lH): 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), 4.8g-4.95 (m,lH); 6.6~6.72 ~m,lH); 6.95-7.00 (m,lH~; 7.0g-7.30 (m~17H~; 7.6S-7.68 (M~ lH); 7.79-7.82 (m,lH); 7.86-7.93 (m,2H); :~
8.16-8.21 (m,2H); 8.31 (d~1~); 8~73 (d,lH);
~sample 4:
3-hYdro~y-~-phen~ent~o91]-L-valIa~ ~ z~la~ida [Formula I: Rl - Z;~ A - L-Ber; R2,R3 ~ Bs; X ~ -N~: B ~ L~Val;
R4 ~ N B z] ;~
~Deprotection]
2 ml of tri~luoroacetie aeid ar~ added to a solution of 55 mg o~
co~pou~d of k~a~pl~ 3 in 2 m~ of dichlorom~thane. The mixtur~ is stirr2d for 16 hours at room t~mpe~ature, the 901~e~t i~ evaporat~d, tolu~De i9 added and eva~ora~ed ~twice), the r~sidu~ is 301ved in di~hloromethan2, wa3hed with 0.1 N NaOH, driet over MgSO4, co~c~ntra~ed~i~ vacuo and chromatograph~d on ilicag~ olvent cyclohe~a~e/ethyl acetate 1::2),~
The ~itle c~poqDd i9 obtaln~d (m.p. 76-a1).
Es~G~le:4a 3-~v~gosY~ be~ylwta~oi~ a~id : ~
~Formula l: Rl 2~ -Val, R2~R3 - Bz; X - -NN-: 9~- bo~d;
tSapo~ification~
330 m~ of ~ of ~ pl~ 1 are di~olved in 3 ml of tetrahydrQfura~. 627 pl o~lN aqueo~s ~odi _ b~dkQYid~ solueion are addet a~d:the~reaction mhx~u~ is~ tir~ed ~o~ 10 hou~ at ~o~m;~t~mpera~ur~
~NeutralizatioQ ~ith dilut~ agu~ou~ ~Cl ~olu~ion l~ad~ ~o ~ whit~
pr~cipitat~ which i3 ~iltexet off:and dried. The gi~1~ ccspoDn~
obtained ~m.p. 1~7-lg3 ~ ~TITI ITC C!UIE I T .
21 0 9 ~ 2 ~ PCI/EP92/01471 o o o~ o ~ o~ O o .~
~n o ~ ~ ~17 ~ ~ ~ ~ a~ ~ ~ u~ ~ ~ cO ~ u~ ~ ~7 .. E~ o ~ c~ ~D ~ 0 a~ ~ ~ ~ OD O U> Cr) ~-~ s~
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SUBSTITUTE SHEET ~ :
WO 93~01166 21 0 9 ~ 2 6 PCI/EP92/01471 .
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wo ~3/011~6 2 1 0 ~ 3:2 ~
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WO 93/01166 210 9 3 2 6 PCII~/EP92/01471 a~ ~ o`D NU~ o ',''''`'"'"~
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W~ 93/C11166 2 1 û 9 3 2 6 PCr/EP92/01471 - 23_ o ~ ~ ~ ~ ~ ~ ~
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WO 93/01166 2 L O 9 ~ 2 ~ Pcr/EP92/o147l . .
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a v o ~ o .. u~ o u~ . o ~ r~ ~ .. a~ ~
o~ a: o c~ ~ o u~ ,: ~ :
,~ o ~ r- ,~ o--c~ a ~ ~ o ~--. .
::~: ::
!~LIBSTITUTE SHE~
WO 93/01166 PC~/EPg2/01471 2109~26 The compou~d3 u ed ae ~tarting material~ ~an be prepared e.g. as follows: :
A: 4 (S)~ rlo~carbon~l-L~
De~lta~lOiC aeid et~ r ~.. . . - ~ , [Formula II: Rl - Z; ~ = L-Val; R2 ~ B~; B Y a bond; R4 ~ OEt;
configuratlonat 4po~ition: Sl a) ~a~
.. . .
3.2 g of L ph~ylal~o1 (an inter~ediate o~ fo=l~la I$I) a~
dded to a ~olution of 7.44 g of ll~ a~
phenyla~ter (an .int~nnediate of formula RlA-Q ~rher~i~ Q i~ :
p-ni~roph~nyloxy~ in 50 ml of dimethylforma~ide. 2 g of triethyla~ine ars added and the reaction ~xture i~ ~tirred a~ room temperatur~ ~or 3 daysc After ev~poratio~ of the ~olvent the rs~3idue i~ di~olYed in dichloro-metharle and carefully wa~h~d rep~atedly with O.l N NaO}II then onc~ with water and dried. The solutio~ fill:~r~d, 'che .olve~t evaporat~d a~d the re~idue chromatographed on ~ilitag~ olY~t: diehloro~tha~/m~tha~ol 95:5~ y~onyl~ p~lala~i~ol (a~ i~termadiat~ o~ -fGrmula IVJ (m.p~ lS4-lS6~) ia obtainedv ~) ~o ,:~
3.12 ml of ~al~ blorid~ ar~ olv@d in 40 ml o' dry dichloromethane and cooletl to -55. 2.81 ml of dim~th~lsulfoxida are caref7~lly ~dded dropwi~3Q and th~n 6.~8 g of p~ct o ~t~p a) d~ssol~d in 40 ml of dichlorQmet2~ane nd 3.l25 ~al of di~t~qls~lfo:~dQ ar~ added at -50. Th~ r~a~io~ misture i9 tLr~ed at -60 ~or o~ hour, reacted w~th t i~tbSrl~i~ a~d ~ti~r~d un~il it r~a~he~ ro~ tamp~ratur~, After dilution with 200 ml o~ dic~loram~thane th~ mixtur~ i3 ~a~h~d ~ith ~ ou~
1~ HCl solutiol d alld th~ 301v~ vaporatsd. The r~sidu~
~issol~ed ial tolue~e/ 6032 g of ~tb~l~la~st~p~l~
ar~ add~d alld the reaction m~xtur~ i~ heat2d to 80~ fox 1 hou~. Aft~
evaporatio~ of the ~ol~e~t th~ re~idue i3 chEomatographed o~ ~ilica~l WO 93/01166 PCI/EP92/0147l (solvent: toluene/ethyl acetate 4 :1) . 4 ts)~ o~ rbon~
I.-Yalinoyl)~o]-5~phen~ nt-2(~g)~0ic aeid 8thy1 ~ r ~an intermediate :
of formula VI) (m.p. 161-165~ obtained.
c) Epo~ldatlon:
.: .
3 g of pr~:t of ~tQp b) are di~solved in 30 ml of dichlorometha~le. 1.373 g of ~ hlorop~oie ac~d arg added and the reactio~ mixture i~ tirred for 5 day~. ~fter ~vaporatio~ of the 901~tc!nt th~ re3idue i~ chromatographed on 9ilicagel (~ol~ent: tolu~e/~hyl acetat~ 4:1) . Th~ title ca~o~d ~e~ou~d a) ~an intermediat~ of formula IIa) i~ obtair~ed (m.pO 164 167). - ;`
' ,-- `'.-~ ~''`''' ' ` ' . ~`: ';
~'.-'~'' ``,';
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W~ 93~01166 P~/EI~2/01~71 .~ '.?~ . .~ . ...
O
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~ tta ~ :'' : .
TlTLlTE~ SHEE~T
W(:~ 9~/~1166 PCI/EP92/01471 21~9326 G:
[Fonnula H - BR4: B 3 D,L-tLeu; R4 3 NHBz~
a1 To a ~olution of 1 g of ~-tt~-buto~carbonyl)-D~L t~rt le~ e in 60 ml of dichloromethane are added at room temperature 980 mg of dicyclohex~lcarbodiimide, 550 mg of ~-hydro2qr~uccinamide~ 0.53 mi o~
N-methyL~aorpholine and 0.57 ml of ~la~ ter 24 how:~ stirring at roo~ t~erature the solution i~ filtered, the 301Y~n~ evap3ratad and th~
residu~ chro~aatog~aph~d o~ ~ilica~l (~ol~ent: toluQnet~thyl acetat~ 5 ~-(t~rt B~to~ca~o~l)oD,L-tert-leuQ~n~ ~l~dQ i~ obtained (solid):
H~ 0.98 (s,9Hj; 1.4 (~,9H); 3.89 (d,lH); 4.3-4.6 (2dd~2H); 5.35 (d, lH): 6 . 55 (m, lH~; 7 . 2-7 . 4 (m, 5EI) .
b3 1.7 g of pr~ct of stQp a) ar~ solvQd in 5~ ml of dichlo~o - .
methan~, 10 ml of trî~ ic acid ar~ added, th~ mixtur~ i9 ~tirr~d for 4 hour~ a~d th~ ~olv~nt i3 remov~d~ The re~idu~ L~ olved i~ ethyl ace~ate and ~a~hed with a ~aturated ~olut~on of 30dil.$B bica~o~at~, th~
b~ ae. The o~ganic layer i~ dried, the 301vert r@moved and th~
c~potmd ~o~d G) i~ obtai~d ~oil) 9 H~ 0 . 98 (~, 9~1); 3 . ûS ~ 4 . 4 (9, 2}~); 7 . 2~ (~, 5H);
13c-~ ~CDCl3 + drop~ C~30D): 26035, 34,05, 63.87, 127.3, 127.74~ 128.5, ~ .l38.04 3.7.
Th~ follo~ g ixlterm~ata~ of fo~mula H ~hich ~y ~tably b~ in protect~d form, ase ob~ai~d i~ a~alogou~ mil~aE~
~ 4 m.p.
~ ~
oil: X~R
~V~ 4~Eid~ oil; I~R~
~ld~O ~ ' L-~ ~o 71-75 ~:
. ~i~2~a2-)C~ ~ oil~
,- , : . .:
.5~ 6TITlJTE SHEET
WO 93/01166 PCI/EPg2/01471 3 7~
: . . -, . . . . . , ~
Ca~pou~d B R~ m. p .
- ~ L-Val ~llz~dLazolo oil; NMR~
2~sth71~illo L--~al 2~ -ph~yl~- oiL, N~
e~hyla~iDo o I. Val 2 (~ oil; ~g~
P L--Val ~ida~ol oil NpDRh 3 - . ~ - L~ 5~ Dzi~ida2~1 oil; ~ ) ~
2~ et~Q~ -,. -R L-l~al 5,6~Cl-~2Dz~ad~ oil; 2~gRi) . . a201 2-~l~bc~
L-~al 2--(i~1-3~1) ~ 8 6 O
eth~l~aino H~ 0.82 (d,J~7Hz,3H~; 1.00 ~d,J~7H~,3H3: 2.30-2.50 5~i,1H); 3.31(d, ~3 . 6~z, lH); 4 . 40~4 . 60 (ddd, 2~); 7 . 25-7 . 35 (m~ 2~); 7 . 50 ~7 . 70 (ddd, lH); 7 . 80-7 . 90 (m, lH); 8 ~ 53 ~dd, J~4 . 8 and l . 61~z, 1~1); 8 . 55(d, J~2 . 25~z, lH);
b)lH-~: 0.88 (d,J~7~z,3~); 0.99 ~d,J~7Hz,3H); 2.0Q-2.20 (~a,lH); 3.30 (d,J~4.8Hz,lH); 4.54 (~J2H): 7.10-7.40 (m,2E~); 7.60-7.70 ~ddd, 1~?; ~ . 20-B . 30 (m, l}l); 8 . 30 (d, lEI~
lH N~: Q.88 ~d,J~7Hz,3H); 0.95 ~d,~7Hz~3H); 2.10-2.30 ~m,l~J, 3.23 ~-(d,J84.6~1Z,lH); 4.46 (J,2H); 7.25 (d~2H); 8.45 (d,2H~;
d) lH_~ 0,75-0.9O ~2H); 1.45-1.55 (Dl~2~); 4.40~4.50 (dr2~); 7.20-7.40 (m, 5H): 7 . ~0-8 .10 ~b~, 1~);
)lH NMR (D~SO): 0.80 (d,3H); 0.89 (d,3~1); 1.85-2.10 (~,l~J; 3.06 ~d,l~);
4 . 51 ~J, 2H~; ~ . 10~7 . 20 (~, 2H~; 7 . 45 -7 . 55 (I&~ 2~ . 50 ~b3, lH); ~ :.
H-N~R (D~SO): 0.74 (c~,3H~; 0.~1 (d,3~); l.B2 ~s~sct,l~); 2.58 (t~2H);
2~88 (d91~1); 3.14-~.30 (~,2~); 6.67 (d,2~); 7.00 (d,2 7. 82 (bt, 1~);
5) lH-~ ~Cl3/D20~: 0078 (d,3H) ~ 1.84 (~ext,lH~; 2.31-2.42 ~m,6~); 2.95 (d~ lH~; 3 . 18 3 . 31 :~m, 2~); 3 0 54-3 . 52 ~m, 4}~
h)lH-~o 0.84 Id,3H); 0.89 (d,3H); 1.80-2.00 (~ )" 3.00-3.50 (d,J~4.6Hz,l~); 5.30 ~,2H); 7.90-7.20 ~,2~; 7.40-7.60 (m,2~
1) lH_~3~ 0.84 ~d,3H); 0.89 (dj3H); 1.80-2.00 ~m"l~); 3~26 ~d~oe5~4E~z~l.EI);
5 . 37 (~, 211): 7 . 74 and 7 . 67 (2d, J-9Hz, lH): 8 0 00-8 . 20 (2dd, 1H) ~ : :
_ t ", ~ :
210~326 - 2~
o ~ . . --~ I ~ c .:
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o o c~ ~ ~ oo u~ ~ o -- :
O ~ ~C ~D O ~O CD ~0 ~ O 0 O _ O O _ ¢ ~40 ~ ~ : ~ O
~.. . i `:
- SU~35Tl~UrE SHEET
WO 93/01166 2 L O 9 ~ 2 ~ Pcr/EP92/o147l . .
--2 ~ -o ~ .
OD
CO ~ U~
o ~ N ~
~ X ~ ~_ ~ N
U) ~ ~ O X O `~
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~ N ~ N un _ X ~ a ~ o ~ D ~ O O ;:- ' V N t_ --5:
O 11 1 ~ 3 tr~ O ~ ~: ~¢ 0 0 q E3 ~ : 11 ~ O I N IU --I 0 1 .
O ~ o ~n F O ~
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o â~ O
n s~ a ~ æ ~ :
--~9 0------~ O ~ a ~ ~P ~D o ~
X ~ X ~ X 3 i ~ X ~
~ ~:
$UBSTIl-IJTE SHEET : ~:
WO 93/01166 PCr/EP92~01471 2109'~2(i.
. .
~ N N
~ ~O O O ~ `~ ` ~ V
_ IJ O ~
o o o : , :
~ S ~ O tr~ ~ ) O
~ ~ . t~ ~ ~ ~ ~ ~ O ~ ::
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~ _~ o ~ ~ n ~o ~ n ,~
N ~, ~ ~ _I a C~ ~
~ ~ ~ o ~ ~--~--~ :o--~ o ~ t~ c~l o ~ t SUB~TITlJ~E SHEET
WO 93/01166 pcr/Eps2/ol47l 3 2 1 0 '~ 3 '~ 6 ` `
, r~ GD
O O O ~ N
. ~r7 ~ ~ t-- a~ ~ N
O _ :s: o ~
og ~ N ~ o ~ ~ o U~ O ~ ~ :~:
O C~ E~ W ~ ~ N Ir) ¦¦ 5 N ~ ' O ~ ~ O _I N C`~ ~ u~ ~I C~
~ In ll e ~ ~ N ~ t::
o ~ ~ ~ ~ ~ ~ ~ N IJ`) N ._ ' '`.-o ~ x -- ~ x ~
--a ~ o ~ o U') C ~ N OC~ N
N ~ ~ O O N
ro .~ ~ U ~ ~ t t~
CD u~ 0 ~ N I
0 ~ ~: ~ ~ ~ ~ ~ 0 ~ 5 ~ ~
Il ~ H
~ O O ~ O ~ U~ ~ ~ ,:
0 . . cs~ o ~ ~ o o~ ~ :`;
O o ~ o 3 --~ ~ ~1 ~ ~ Pa N
O ~ ~ ~ o ~ ~ ~ P O O ~ ~ ~ ~ O O ~ ~ I O
- ~ ~ :
:
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- 32~
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~0 ~
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o~ a~ .. ~ . . . -D . . ~i:
N S~l~ 0 N I 3: ~ r-l ~ ~ :
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O O ~ : '' O ~ o ~ I
a v o ~ o .. u~ o u~ . o ~ r~ ~ .. a~ ~
o~ a: o c~ ~ o u~ ,: ~ :
,~ o ~ r- ,~ o--c~ a ~ ~ o ~--. .
::~: ::
!~LIBSTITUTE SHE~
WO 93/01166 PC~/EPg2/01471 2109~26 The compou~d3 u ed ae ~tarting material~ ~an be prepared e.g. as follows: :
A: 4 (S)~ rlo~carbon~l-L~
De~lta~lOiC aeid et~ r ~.. . . - ~ , [Formula II: Rl - Z; ~ = L-Val; R2 ~ B~; B Y a bond; R4 ~ OEt;
configuratlonat 4po~ition: Sl a) ~a~
.. . .
3.2 g of L ph~ylal~o1 (an inter~ediate o~ fo=l~la I$I) a~
dded to a ~olution of 7.44 g of ll~ a~
phenyla~ter (an .int~nnediate of formula RlA-Q ~rher~i~ Q i~ :
p-ni~roph~nyloxy~ in 50 ml of dimethylforma~ide. 2 g of triethyla~ine ars added and the reaction ~xture i~ ~tirred a~ room temperatur~ ~or 3 daysc After ev~poratio~ of the ~olvent the rs~3idue i~ di~olYed in dichloro-metharle and carefully wa~h~d rep~atedly with O.l N NaO}II then onc~ with water and dried. The solutio~ fill:~r~d, 'che .olve~t evaporat~d a~d the re~idue chromatographed on ~ilitag~ olY~t: diehloro~tha~/m~tha~ol 95:5~ y~onyl~ p~lala~i~ol (a~ i~termadiat~ o~ -fGrmula IVJ (m.p~ lS4-lS6~) ia obtainedv ~) ~o ,:~
3.12 ml of ~al~ blorid~ ar~ olv@d in 40 ml o' dry dichloromethane and cooletl to -55. 2.81 ml of dim~th~lsulfoxida are caref7~lly ~dded dropwi~3Q and th~n 6.~8 g of p~ct o ~t~p a) d~ssol~d in 40 ml of dichlorQmet2~ane nd 3.l25 ~al of di~t~qls~lfo:~dQ ar~ added at -50. Th~ r~a~io~ misture i9 tLr~ed at -60 ~or o~ hour, reacted w~th t i~tbSrl~i~ a~d ~ti~r~d un~il it r~a~he~ ro~ tamp~ratur~, After dilution with 200 ml o~ dic~loram~thane th~ mixtur~ i3 ~a~h~d ~ith ~ ou~
1~ HCl solutiol d alld th~ 301v~ vaporatsd. The r~sidu~
~issol~ed ial tolue~e/ 6032 g of ~tb~l~la~st~p~l~
ar~ add~d alld the reaction m~xtur~ i~ heat2d to 80~ fox 1 hou~. Aft~
evaporatio~ of the ~ol~e~t th~ re~idue i3 chEomatographed o~ ~ilica~l WO 93/01166 PCI/EP92/0147l (solvent: toluene/ethyl acetate 4 :1) . 4 ts)~ o~ rbon~
I.-Yalinoyl)~o]-5~phen~ nt-2(~g)~0ic aeid 8thy1 ~ r ~an intermediate :
of formula VI) (m.p. 161-165~ obtained.
c) Epo~ldatlon:
.: .
3 g of pr~:t of ~tQp b) are di~solved in 30 ml of dichlorometha~le. 1.373 g of ~ hlorop~oie ac~d arg added and the reactio~ mixture i~ tirred for 5 day~. ~fter ~vaporatio~ of the 901~tc!nt th~ re3idue i~ chromatographed on 9ilicagel (~ol~ent: tolu~e/~hyl acetat~ 4:1) . Th~ title ca~o~d ~e~ou~d a) ~an intermediat~ of formula IIa) i~ obtair~ed (m.pO 164 167). - ;`
' ,-- `'.-~ ~''`''' ' ` ' . ~`: ';
~'.-'~'' ``,';
, . . . . . ...
W~ 93~01166 P~/EI~2/01~71 .~ '.?~ . .~ . ...
O
~ -~
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.~ æ~ ~ 3 .
. ' ' E3 ~ In 3 . .:' . .'~ :~' o~ C . ~
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O ~ ~ N ~ N ~ N ~--L~ CC9 ~ 0 H ~
a~ ~. z ~ :C
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c~ ~ `~
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~ ~ c~
a~ Q a~ ~
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o U~ C~ ~ ~ ~
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~ tta ~ :'' : .
TlTLlTE~ SHEE~T
W(:~ 9~/~1166 PCI/EP92/01471 21~9326 G:
[Fonnula H - BR4: B 3 D,L-tLeu; R4 3 NHBz~
a1 To a ~olution of 1 g of ~-tt~-buto~carbonyl)-D~L t~rt le~ e in 60 ml of dichloromethane are added at room temperature 980 mg of dicyclohex~lcarbodiimide, 550 mg of ~-hydro2qr~uccinamide~ 0.53 mi o~
N-methyL~aorpholine and 0.57 ml of ~la~ ter 24 how:~ stirring at roo~ t~erature the solution i~ filtered, the 301Y~n~ evap3ratad and th~
residu~ chro~aatog~aph~d o~ ~ilica~l (~ol~ent: toluQnet~thyl acetat~ 5 ~-(t~rt B~to~ca~o~l)oD,L-tert-leuQ~n~ ~l~dQ i~ obtained (solid):
H~ 0.98 (s,9Hj; 1.4 (~,9H); 3.89 (d,lH); 4.3-4.6 (2dd~2H); 5.35 (d, lH): 6 . 55 (m, lH~; 7 . 2-7 . 4 (m, 5EI) .
b3 1.7 g of pr~ct of stQp a) ar~ solvQd in 5~ ml of dichlo~o - .
methan~, 10 ml of trî~ ic acid ar~ added, th~ mixtur~ i9 ~tirr~d for 4 hour~ a~d th~ ~olv~nt i3 remov~d~ The re~idu~ L~ olved i~ ethyl ace~ate and ~a~hed with a ~aturated ~olut~on of 30dil.$B bica~o~at~, th~
b~ ae. The o~ganic layer i~ dried, the 301vert r@moved and th~
c~potmd ~o~d G) i~ obtai~d ~oil) 9 H~ 0 . 98 (~, 9~1); 3 . ûS ~ 4 . 4 (9, 2}~); 7 . 2~ (~, 5H);
13c-~ ~CDCl3 + drop~ C~30D): 26035, 34,05, 63.87, 127.3, 127.74~ 128.5, ~ .l38.04 3.7.
Th~ follo~ g ixlterm~ata~ of fo~mula H ~hich ~y ~tably b~ in protect~d form, ase ob~ai~d i~ a~alogou~ mil~aE~
~ 4 m.p.
~ ~
oil: X~R
~V~ 4~Eid~ oil; I~R~
~ld~O ~ ' L-~ ~o 71-75 ~:
. ~i~2~a2-)C~ ~ oil~
,- , : . .:
.5~ 6TITlJTE SHEET
WO 93/01166 PCI/EPg2/01471 3 7~
: . . -, . . . . . , ~
Ca~pou~d B R~ m. p .
- ~ L-Val ~llz~dLazolo oil; NMR~
2~sth71~illo L--~al 2~ -ph~yl~- oiL, N~
e~hyla~iDo o I. Val 2 (~ oil; ~g~
P L--Val ~ida~ol oil NpDRh 3 - . ~ - L~ 5~ Dzi~ida2~1 oil; ~ ) ~
2~ et~Q~ -,. -R L-l~al 5,6~Cl-~2Dz~ad~ oil; 2~gRi) . . a201 2-~l~bc~
L-~al 2--(i~1-3~1) ~ 8 6 O
eth~l~aino H~ 0.82 (d,J~7Hz,3H~; 1.00 ~d,J~7H~,3H3: 2.30-2.50 5~i,1H); 3.31(d, ~3 . 6~z, lH); 4 . 40~4 . 60 (ddd, 2~); 7 . 25-7 . 35 (m~ 2~); 7 . 50 ~7 . 70 (ddd, lH); 7 . 80-7 . 90 (m, lH); 8 ~ 53 ~dd, J~4 . 8 and l . 61~z, 1~1); 8 . 55(d, J~2 . 25~z, lH);
b)lH-~: 0.88 (d,J~7~z,3~); 0.99 ~d,J~7Hz,3H); 2.0Q-2.20 (~a,lH); 3.30 (d,J~4.8Hz,lH); 4.54 (~J2H): 7.10-7.40 (m,2E~); 7.60-7.70 ~ddd, 1~?; ~ . 20-B . 30 (m, l}l); 8 . 30 (d, lEI~
lH N~: Q.88 ~d,J~7Hz,3H); 0.95 ~d,~7Hz~3H); 2.10-2.30 ~m,l~J, 3.23 ~-(d,J84.6~1Z,lH); 4.46 (J,2H); 7.25 (d~2H); 8.45 (d,2H~;
d) lH_~ 0,75-0.9O ~2H); 1.45-1.55 (Dl~2~); 4.40~4.50 (dr2~); 7.20-7.40 (m, 5H): 7 . ~0-8 .10 ~b~, 1~);
)lH NMR (D~SO): 0.80 (d,3H); 0.89 (d,3~1); 1.85-2.10 (~,l~J; 3.06 ~d,l~);
4 . 51 ~J, 2H~; ~ . 10~7 . 20 (~, 2H~; 7 . 45 -7 . 55 (I&~ 2~ . 50 ~b3, lH); ~ :.
H-N~R (D~SO): 0.74 (c~,3H~; 0.~1 (d,3~); l.B2 ~s~sct,l~); 2.58 (t~2H);
2~88 (d91~1); 3.14-~.30 (~,2~); 6.67 (d,2~); 7.00 (d,2 7. 82 (bt, 1~);
5) lH-~ ~Cl3/D20~: 0078 (d,3H) ~ 1.84 (~ext,lH~; 2.31-2.42 ~m,6~); 2.95 (d~ lH~; 3 . 18 3 . 31 :~m, 2~); 3 0 54-3 . 52 ~m, 4}~
h)lH-~o 0.84 Id,3H); 0.89 (d,3H); 1.80-2.00 (~ )" 3.00-3.50 (d,J~4.6Hz,l~); 5.30 ~,2H); 7.90-7.20 ~,2~; 7.40-7.60 (m,2~
1) lH_~3~ 0.84 ~d,3H); 0.89 (dj3H); 1.80-2.00 ~m"l~); 3~26 ~d~oe5~4E~z~l.EI);
5 . 37 (~, 211): 7 . 74 and 7 . 67 (2d, J-9Hz, lH): 8 0 00-8 . 20 (2dd, 1H) ~ : :
8 . 40 a2ld B . 47 ~2d, 1H);
U.B3 ~d~38); 0.89 (d~3H); 1.80-2000 (~,~PO): 3.24 (d,J-5.4Hz9lH) f 5.36 (~,2~); 7.7~ (3,2~);
".
.~e IR~TITI ITI~ ~ue~T
W O 93~01166 PCT/EP92/01471 21~9~26 ~38- : :
T~
[FoDmula RlA - Q: Rl ;~ Z: A 8 L-tL~u;
Q - N-hydroxy~uccinLmid-2-yloxy]
2.6 g of ~-h~drQsy~u~cL~lmld~ and 4.6 g of dicyclohexylcarbodio `; ~:
Lmide ar~ added to a ~olution of 6 g of ~-benz~1~2ycarboD~l L-tert-leuci~e ~-~in 70 ml o~ dioxa~e. The mixtur~ i9 ~tirred for 12 hou~q at room temperature, tha 301~e~t i~ evaporat~d, the re~idue i9 su~pended i~ ~thyl ace~ate, the u~ea i3 rem~ved by filtratlon a~d the solv~nt ~ evaporated.
The ti~l~ co~po~ud (compo~ d T) i obtai~d~
H~NMR: 1.10 ~9H): 2,84 ~,4~ .52 ~d,J~lOHz,lH); 5.03 5.12 (m,2X); ~ :
5.34 (d,J~lOHz,1~); 7.26-7.40 ~,5H).
The following intermediat~ of fonmula RlA - Q i8 obtained i~
analo~ous mann~r:
. .
~o~o ~ ~1 ~ Q mOp.
~ 2-pyrid~ Val S~ whit~ ~olid;
a)lH-N~R: 1.09 a~d 1.11 (2d, J-7Hæ, 6H); 2~38 ~oct, J~7Hz, lH~; 2.82 a~d .
2,B4 (2~,4H~; 4.62 (dd~ ~-SHz, J~7.5~z, 1~); 5.28 ~s,2H);
7.25-7.42 ~m, 3a); 7 . 72-7.81 ~f lH).
` ~'''.'~'' ~'`".'` ~
W O g3/0116~ PCT~P92/01471 2109326 `~;, -39- .
The compound3 of fonmula I in free fonm and, where ~alt fo~m~
exist, in pharmaceutically cc~pt~ble alt, e.g. acid addition ~alt fonm, po~qe~ intereqting pharmacological propertie3. They are therefor@
i~dica~ed for u~e a~ pharmaceuticala. In particular~ they exhi~it antiviral activity, esp~cially HIV-l protea9e inhibiting activity, whereby they ~how only low or inexi3tent i~hibiting ~ff~ct again~t human protea~e~
qUCh ~3 ~enin or pep~in.
Thi~ activ ty ca~ b~ show~ in the followin~ ~sts~
.. . .
Inhibition of peptide cleaYage by HIV-proteinase i9 mea~ured as de~cribed in A.Richards et al., J.31ol.Ch~m. 265 ~l990) 7733-7736 and L.H.Philip et al., l~59~ 5l~llL__ ~m~un. l7l (1990) 439-444.
Bri~fly, the peptide ~-Ly~-Ala-Arg-V~l Leu~Nph~Glu Ala~ N~2 (where ~ph i~ p-nitroph~nylalani~e and ~la i3 norleuc:in~ us~d a~ ~ub~tra~e for recombi~ant HIV l or HXV-2 pEot*in 3~. Cllaa~ag~,occ~r~ bet~e~n the Leu a~d Nph Eesidues. The r~ction i~ follow1ad sp~ ophotc~wtrically by the decr~as~ in e~tinction at 300 nm which i~ ob3~d upor~ cleavaga~
In thi3 teat th~ com~ound~ ~xhibit ~ values of ~rom about 3 ~ to abou~ 1 ~M ~or HIV-l, and of fE~m ~bout 30 ~ to about lO ~ for HI~2.
2 ~
.
I~hibitio~ of th~ HI~ TL~ B)-~ducQd cytopathic ~ffeet is mea~ured l~ ~T4 cell~ a~ d~3cribed in R.Pauw~l~ et al., J.Vlrol,~ t:o:~ 20 (1988~ 309-321. Briefly~ an ~TLV-l transformed T4 cell lt~a~ ~T4, which has bee~ ~how~ pre~iously to b~ highly su~ceptibl~ to ~IY i~ectis~ ser~e~
a3 th~ target c~ll li~e. I ~ bitio~ of HIV-iaduced cytop~t~ic e~f~ct i~
u~d a3 th3 en~ poi~t. Th~ viability o~ both ~V- aQd ek~i~feGted c~
i3 as~sed ~p~ctrophoto~t~ically via th~ u reduetio~ of 3~(4,5;dimethylthiazol-20yl);-2i5~diph~nyltetrazolium br~mid~ T)~ Ths compari~on o~ ~h~ ~ffect~ of ~ariou~ coac~ntration~ o~ th~ c~mpound o~ ~IV~
versu~ mock-i~f~eSed cells allo~ the d~tegmina~ion of mi ~ u~ toxic ~TC) ;~
~d mi~i~um ~irus-inhibitory (~c) ~o~c~tra~io~
SUBSTITUTE SHE~
WO 93~01166PCr~EP92/01~71 ..' In this te~t th~ compound~ exhibit ICso value~ of from about 5 nM :~
to about 350 nM. Thus the compound~ of Examples 56 and 59 exhibit IC50 values of, re3pectively~ 49 nM and 12 nM again~t HIV-~ train-~, and ~ .
the compound of Example 37 i-~ effective with an IC50 value of 150 nM.
The compound~ of the invention in free form and, where ~alt fo~m3 exi~t~ in pha~mac~uticalLy acoeptable 3alt form are t~er~fore i~dicated for ~;~
u~e as pharmac~uti~al~,.partiCUlarly a~ agQnt~ again~t ~V-protai~a~ .g. ~ ~-in tha prophylaxy and traatment of retroviral inections. Fo~ thi~ usa ~h~ .
effectiv~ dosag~ of cour3~, va~y dependi~g on th~ particular compou~d - . .
employed, the moda of admini3tration and th~ treatm~nt desired. How~ver, in general, ~ati~factory re~ult~ are obtain~d when th~ compound~ ar~
admi~istered at a daily dosage of from abo~t 0.02 mgl~g to ~out 50 m~/kg animal body weight, 3uitab1y giv~n i~ divided doqage~ two ~o four ~ime~
daily. For m~t larg~r mamma13 tha total daily do~ag~ i3 from about 1 ~g to about 3500 mg, ~.g. from about 1 m~ to about 500 mg or about lO mg to about lO0 m~. Tha compounds m~y be admi~ ter~d i~ similar ma~r to known sta~dards for u~e in ~uch indicatio~
The c~mpound~ ar~ also indicated for U9~ in treating ~on-human -animals infected ~ith a retrovirus, ~uch a~ cats mfect~d with felin~ ~ :
leukemla viru~ f~line inf~ctious p~ritonitis ~ixU~o cal~civi~u~, rabies ~:
viru~, feli~e ~ unod~iciency viru~, feli~ parvoviru~ (pa~leukopenia viru9), and f~line chlaTydia. Exact dosag~, forms a~d m~d~ of admi~iatra~io~ o~ the co~pounds to non-human a~imal~ would be appare~t to on~ of ordi~ary skill in th~ art, e.g. a ~teri~aria~
:~ .
The compou~d~ o Exam~l~s 29, 36, 37, 519 56r 59, 66~ 67 and lO6,~- :
especially of ~amp~e~ 56 and 59~ . N~l[4ts)-[(~-ben~ylo~ycarbony~
alinoyl3 ~no] -3-hydro~y-2~ t3-methoxybenzylamino) -5-phen~l]p~ntarloyl~-L-ralin~-N-(mQthrl?2~b~hzim~dazolyl1amid~ a~d~ r~pectiv~ly, h~
~or:responding 4-m~tho~ po~ition i~o2ller are th~ prefQrred Gompo~ds as ~:
an'ci HIV-pro~ei~la~ age~. It i~ at~d tha'~G ~or t~ indi.catisn th~
compounà~ may be ad~i~ster~d to larger m~al~ for ea:ample humarl~ by -~::1 I R~::TlTl JTE SHEFI :
W O 93~0l166 PCT/EP92/01471 2109326 -41- .
similar mode~ of adminictration at q ~ lar or lower do3age~ than employed with standard~ for ~uch indication~.
The invention therefore al~o concerns a method of treating retroviral diseas~s, e~pecially di~a~e8 cau4ed by HIY wAich compriseq admini~tering ~o a ~ubject in need of such treatmeQt a prophylactically or therap~utically ~f~ective amount o~ a com~ou~d of fo~mula I in free fo~m or, wh~rs ~alt forms exi3t9 in phaDmaceutically acceptabl~ ~alt, e.g. aeid addition salt fonm, a~ well a~ a compou~d o~ foxmula I i~ fre~ fo~-or~`
where salt fo~ ex~t, in pha~maceutically acc@ptable salt fonm for use a~
a pharmaceutical, e3pecially a~ an agBnt again~t HIV~proteinase.
The compounds m~y be admixed with con~ ntional pha~maceutically accep~able diluent~ and carrier~ and~ optionally9 oth~r excipien~q and admini3tered e.~ orally in ~uch form~ a9 tablet~ o~ cap~ul~. Th~
compound~ may alter~atively be admi~i~tered par@nterally or intravenously, The co~cen~ratio~s of activ~ ~ub~tance will, of cours~, ~ary depending i.a.
on the compound 2~ployed, th~ tr~a ~ ~t da~ir~d and the ~ature of th~ ~or~.
The inv~ntio~ ~hu~ al~o includes a pharmac~utical ~ompo~ition comprising a oompound of formula I in fr~ foDm or, wh~r~ ~alt foEms axi~t, in phanmaceutically acceptabl~ qalt, e.g. acid additlo~ salt foDm, tagether with at leas~ o~e pharmaceutically acc~ptabl~ carri~r or dilu~nt.
It further concern~ a proc~9 ~or tho pr~pa~ation o~ a medicam~nt agai~t xetrov~ral ~9@a3e whiCh c~mpris~g ~ ~g a coMpound of foEmul~
in fre~ form or, wher~ -qalt fo~m~ ex~t~ i~ phaE~aceutically acceptabla ~-salt, ~.g. acid addition ~alt foDm, tog~thar ~ith a pha~maceutically accep~able carrier or di}u~t, a~d ~h~ u9~ of ~uch a c~pound in th~
manufaetusQ of a m~dicame~t agai~3t r~tro~iral di~a~
I~uxther co~ce~ a compo~d of formula I i~ fr~ fonm ~r ~her~
~alt form9 s~i~t~ i~ pharmceutically acc~ptabla ~alt, Q.g. acid additio~
~alt fo~, for u9e a9 a phar~aceuti~al, ~articularly for uqe in the ;-trea~ment of retro~iral di ea3e~
SUBSTlTlJTE Slt OEFr
U.B3 ~d~38); 0.89 (d~3H); 1.80-2000 (~,~PO): 3.24 (d,J-5.4Hz9lH) f 5.36 (~,2~); 7.7~ (3,2~);
".
.~e IR~TITI ITI~ ~ue~T
W O 93~01166 PCT/EP92/01471 21~9~26 ~38- : :
T~
[FoDmula RlA - Q: Rl ;~ Z: A 8 L-tL~u;
Q - N-hydroxy~uccinLmid-2-yloxy]
2.6 g of ~-h~drQsy~u~cL~lmld~ and 4.6 g of dicyclohexylcarbodio `; ~:
Lmide ar~ added to a ~olution of 6 g of ~-benz~1~2ycarboD~l L-tert-leuci~e ~-~in 70 ml o~ dioxa~e. The mixtur~ i9 ~tirred for 12 hou~q at room temperature, tha 301~e~t i~ evaporat~d, the re~idue i9 su~pended i~ ~thyl ace~ate, the u~ea i3 rem~ved by filtratlon a~d the solv~nt ~ evaporated.
The ti~l~ co~po~ud (compo~ d T) i obtai~d~
H~NMR: 1.10 ~9H): 2,84 ~,4~ .52 ~d,J~lOHz,lH); 5.03 5.12 (m,2X); ~ :
5.34 (d,J~lOHz,1~); 7.26-7.40 ~,5H).
The following intermediat~ of fonmula RlA - Q i8 obtained i~
analo~ous mann~r:
. .
~o~o ~ ~1 ~ Q mOp.
~ 2-pyrid~ Val S~ whit~ ~olid;
a)lH-N~R: 1.09 a~d 1.11 (2d, J-7Hæ, 6H); 2~38 ~oct, J~7Hz, lH~; 2.82 a~d .
2,B4 (2~,4H~; 4.62 (dd~ ~-SHz, J~7.5~z, 1~); 5.28 ~s,2H);
7.25-7.42 ~m, 3a); 7 . 72-7.81 ~f lH).
` ~'''.'~'' ~'`".'` ~
W O g3/0116~ PCT~P92/01471 2109326 `~;, -39- .
The compound3 of fonmula I in free fonm and, where ~alt fo~m~
exist, in pharmaceutically cc~pt~ble alt, e.g. acid addition ~alt fonm, po~qe~ intereqting pharmacological propertie3. They are therefor@
i~dica~ed for u~e a~ pharmaceuticala. In particular~ they exhi~it antiviral activity, esp~cially HIV-l protea9e inhibiting activity, whereby they ~how only low or inexi3tent i~hibiting ~ff~ct again~t human protea~e~
qUCh ~3 ~enin or pep~in.
Thi~ activ ty ca~ b~ show~ in the followin~ ~sts~
.. . .
Inhibition of peptide cleaYage by HIV-proteinase i9 mea~ured as de~cribed in A.Richards et al., J.31ol.Ch~m. 265 ~l990) 7733-7736 and L.H.Philip et al., l~59~ 5l~llL__ ~m~un. l7l (1990) 439-444.
Bri~fly, the peptide ~-Ly~-Ala-Arg-V~l Leu~Nph~Glu Ala~ N~2 (where ~ph i~ p-nitroph~nylalani~e and ~la i3 norleuc:in~ us~d a~ ~ub~tra~e for recombi~ant HIV l or HXV-2 pEot*in 3~. Cllaa~ag~,occ~r~ bet~e~n the Leu a~d Nph Eesidues. The r~ction i~ follow1ad sp~ ophotc~wtrically by the decr~as~ in e~tinction at 300 nm which i~ ob3~d upor~ cleavaga~
In thi3 teat th~ com~ound~ ~xhibit ~ values of ~rom about 3 ~ to abou~ 1 ~M ~or HIV-l, and of fE~m ~bout 30 ~ to about lO ~ for HI~2.
2 ~
.
I~hibitio~ of th~ HI~ TL~ B)-~ducQd cytopathic ~ffeet is mea~ured l~ ~T4 cell~ a~ d~3cribed in R.Pauw~l~ et al., J.Vlrol,~ t:o:~ 20 (1988~ 309-321. Briefly~ an ~TLV-l transformed T4 cell lt~a~ ~T4, which has bee~ ~how~ pre~iously to b~ highly su~ceptibl~ to ~IY i~ectis~ ser~e~
a3 th~ target c~ll li~e. I ~ bitio~ of HIV-iaduced cytop~t~ic e~f~ct i~
u~d a3 th3 en~ poi~t. Th~ viability o~ both ~V- aQd ek~i~feGted c~
i3 as~sed ~p~ctrophoto~t~ically via th~ u reduetio~ of 3~(4,5;dimethylthiazol-20yl);-2i5~diph~nyltetrazolium br~mid~ T)~ Ths compari~on o~ ~h~ ~ffect~ of ~ariou~ coac~ntration~ o~ th~ c~mpound o~ ~IV~
versu~ mock-i~f~eSed cells allo~ the d~tegmina~ion of mi ~ u~ toxic ~TC) ;~
~d mi~i~um ~irus-inhibitory (~c) ~o~c~tra~io~
SUBSTITUTE SHE~
WO 93~01166PCr~EP92/01~71 ..' In this te~t th~ compound~ exhibit ICso value~ of from about 5 nM :~
to about 350 nM. Thus the compound~ of Examples 56 and 59 exhibit IC50 values of, re3pectively~ 49 nM and 12 nM again~t HIV-~ train-~, and ~ .
the compound of Example 37 i-~ effective with an IC50 value of 150 nM.
The compound~ of the invention in free form and, where ~alt fo~m3 exi~t~ in pha~mac~uticalLy acoeptable 3alt form are t~er~fore i~dicated for ~;~
u~e as pharmac~uti~al~,.partiCUlarly a~ agQnt~ again~t ~V-protai~a~ .g. ~ ~-in tha prophylaxy and traatment of retroviral inections. Fo~ thi~ usa ~h~ .
effectiv~ dosag~ of cour3~, va~y dependi~g on th~ particular compou~d - . .
employed, the moda of admini3tration and th~ treatm~nt desired. How~ver, in general, ~ati~factory re~ult~ are obtain~d when th~ compound~ ar~
admi~istered at a daily dosage of from abo~t 0.02 mgl~g to ~out 50 m~/kg animal body weight, 3uitab1y giv~n i~ divided doqage~ two ~o four ~ime~
daily. For m~t larg~r mamma13 tha total daily do~ag~ i3 from about 1 ~g to about 3500 mg, ~.g. from about 1 m~ to about 500 mg or about lO mg to about lO0 m~. Tha compounds m~y be admi~ ter~d i~ similar ma~r to known sta~dards for u~e in ~uch indicatio~
The c~mpound~ ar~ also indicated for U9~ in treating ~on-human -animals infected ~ith a retrovirus, ~uch a~ cats mfect~d with felin~ ~ :
leukemla viru~ f~line inf~ctious p~ritonitis ~ixU~o cal~civi~u~, rabies ~:
viru~, feli~e ~ unod~iciency viru~, feli~ parvoviru~ (pa~leukopenia viru9), and f~line chlaTydia. Exact dosag~, forms a~d m~d~ of admi~iatra~io~ o~ the co~pounds to non-human a~imal~ would be appare~t to on~ of ordi~ary skill in th~ art, e.g. a ~teri~aria~
:~ .
The compou~d~ o Exam~l~s 29, 36, 37, 519 56r 59, 66~ 67 and lO6,~- :
especially of ~amp~e~ 56 and 59~ . N~l[4ts)-[(~-ben~ylo~ycarbony~
alinoyl3 ~no] -3-hydro~y-2~ t3-methoxybenzylamino) -5-phen~l]p~ntarloyl~-L-ralin~-N-(mQthrl?2~b~hzim~dazolyl1amid~ a~d~ r~pectiv~ly, h~
~or:responding 4-m~tho~ po~ition i~o2ller are th~ prefQrred Gompo~ds as ~:
an'ci HIV-pro~ei~la~ age~. It i~ at~d tha'~G ~or t~ indi.catisn th~
compounà~ may be ad~i~ster~d to larger m~al~ for ea:ample humarl~ by -~::1 I R~::TlTl JTE SHEFI :
W O 93~0l166 PCT/EP92/01471 2109326 -41- .
similar mode~ of adminictration at q ~ lar or lower do3age~ than employed with standard~ for ~uch indication~.
The invention therefore al~o concerns a method of treating retroviral diseas~s, e~pecially di~a~e8 cau4ed by HIY wAich compriseq admini~tering ~o a ~ubject in need of such treatmeQt a prophylactically or therap~utically ~f~ective amount o~ a com~ou~d of fo~mula I in free fo~m or, wh~rs ~alt forms exi3t9 in phaDmaceutically acceptabl~ ~alt, e.g. aeid addition salt fonm, a~ well a~ a compou~d o~ foxmula I i~ fre~ fo~-or~`
where salt fo~ ex~t, in pha~maceutically acc@ptable salt fonm for use a~
a pharmaceutical, e3pecially a~ an agBnt again~t HIV~proteinase.
The compounds m~y be admixed with con~ ntional pha~maceutically accep~able diluent~ and carrier~ and~ optionally9 oth~r excipien~q and admini3tered e.~ orally in ~uch form~ a9 tablet~ o~ cap~ul~. Th~
compound~ may alter~atively be admi~i~tered par@nterally or intravenously, The co~cen~ratio~s of activ~ ~ub~tance will, of cours~, ~ary depending i.a.
on the compound 2~ployed, th~ tr~a ~ ~t da~ir~d and the ~ature of th~ ~or~.
The inv~ntio~ ~hu~ al~o includes a pharmac~utical ~ompo~ition comprising a oompound of formula I in fr~ foDm or, wh~r~ ~alt foEms axi~t, in phanmaceutically acceptabl~ qalt, e.g. acid additlo~ salt foDm, tagether with at leas~ o~e pharmaceutically acc~ptabl~ carri~r or dilu~nt.
It further concern~ a proc~9 ~or tho pr~pa~ation o~ a medicam~nt agai~t xetrov~ral ~9@a3e whiCh c~mpris~g ~ ~g a coMpound of foEmul~
in fre~ form or, wher~ -qalt fo~m~ ex~t~ i~ phaE~aceutically acceptabla ~-salt, ~.g. acid addition ~alt foDm, tog~thar ~ith a pha~maceutically accep~able carrier or di}u~t, a~d ~h~ u9~ of ~uch a c~pound in th~
manufaetusQ of a m~dicame~t agai~3t r~tro~iral di~a~
I~uxther co~ce~ a compo~d of formula I i~ fr~ fonm ~r ~her~
~alt form9 s~i~t~ i~ pharmceutically acc~ptabla ~alt, Q.g. acid additio~
~alt fo~, for u9e a9 a phar~aceuti~al, ~articularly for uqe in the ;-trea~ment of retro~iral di ea3e~
SUBSTlTlJTE Slt OEFr
Claims (10)
1. A compound of formula I
I
wherein A and B independently are a bond or an optionally substituted aminoacyl moiety;
R1 is a 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-CS-;
R2 is the side chain of a natural amino acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl, 2-thienylmethyl or styrylmethyl;
R3 is an optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group;
R4 is a group of formula -OR7- or -NHR7- wherein R7 has the significance indicated above for R6; and X is -S-, or -NR5- wherein R5 is hydrogen, methyl, formyl or acetyl;
in free form or, where such forms exist, in salt form.
I
wherein A and B independently are a bond or an optionally substituted aminoacyl moiety;
R1 is a 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-CS-;
R2 is the side chain of a natural amino acid; an alkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl group; or trimethylsilylmethyl, 2-thienylmethyl or styrylmethyl;
R3 is an optionally substituted alkyl, alkenyl, alkinyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group;
R4 is a group of formula -OR7- or -NHR7- wherein R7 has the significance indicated above for R6; and X is -S-, or -NR5- wherein R5 is hydrogen, methyl, formyl or acetyl;
in free form or, where such forms exist, in salt form.
2. A compound according to claim 1 of formula Is Is wherein R1s is hydrogen; phenylalkyloxycarbonyl of altogether 8 to 10 carbon atoms; alkyloxycarbonyl of altogether 2 to 10 carbon atoms;
quinolylcarbonyl or quinolylsulfonyl; pyridylmethoxycarbonyl;
aminocaproyl optionally protected by tert - butoxycarbonyl;
9-fluorenylmethoxycarbonyl (FMOC); phenyllactoyl; isovalerianoyl;
phenoxymethylcarbonyl; palmitoyl; or 4- hydroxyphenylpropionyl;
As is a bond; a natural .alpha.-aminoacyl moiety; the corresponding D optical isomer form; L- of D-tert-leucine; O-tert-butyl-L-serine; or L-2-aminobutanoyl;
R2s is alkyl of 3 or 4 carbon atoms or phenylalkyl of altogether 7 to 9 carbon atoms;
Xs is -S- or - NR5s - wherein R5s is hydrogen or methyl;
R3s is alkyl or 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, indolyalkyl or naphthylalkyl group of 1 to 3 carbon atoms in the alkylene part; or phenylalkenyl of 2 to 4 carbon atoms in the alkenylene part;
Bs is a bond; a natural .alpha.-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; or aminocyclopropan-1-carbonyl;
R4s is hydroxy; an alkoxy or alkylamino group of 1 to 5 carbon atoms;
phenylalkylamino of altogether 7 to 9 carbon atoms optionally monosubstituted in the phenyl ring or in the alkylene part by hydroxy, or monosubstituted in the phenyl ring by halogen of atomic number of from 9 to 35; benzimidazolylalkoxy or benzimidazolylalkylamino of 1 to 3 carbon atoms in the alkylene part optionally mono- or disubstituted in the aryl part by halogen of atomic number of from 9 to 35 or nitro;
or an indolyalkylamino, 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.
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 .alpha.-aminoacyl moiety; the corresponding D optical isomer form; L- of D-tert-leucine; O-tert-butyl-L-serine; or L-2-aminobutanoyl;
R2s is alkyl of 3 or 4 carbon atoms or phenylalkyl of altogether 7 to 9 carbon atoms;
Xs is -S- or - NR5s - wherein R5s is hydrogen or methyl;
R3s is alkyl or 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, indolyalkyl or naphthylalkyl group of 1 to 3 carbon atoms in the alkylene part; or phenylalkenyl of 2 to 4 carbon atoms in the alkenylene part;
Bs is a bond; a natural .alpha.-aminoacyl moiety; the corresponding D optical isomer form; L- or D-tert-leucine; or aminocyclopropan-1-carbonyl;
R4s is hydroxy; an alkoxy or alkylamino group of 1 to 5 carbon atoms;
phenylalkylamino of altogether 7 to 9 carbon atoms optionally monosubstituted in the phenyl ring or in the alkylene part by hydroxy, or monosubstituted in the phenyl ring by halogen of atomic number of from 9 to 35; benzimidazolylalkoxy or benzimidazolylalkylamino of 1 to 3 carbon atoms in the alkylene part optionally mono- or disubstituted in the aryl part by halogen of atomic number of from 9 to 35 or nitro;
or an indolyalkylamino, pyridylalkylamino or morpholinylalkylamino moiety of 1 to 3 carbon atoms in the alkylene part; and the configuration in 4 position is S, in free form or, where such forms exist, in salt form.
3. A compound according to claim 1 of formula I wherein R1 is benzylyoxycarbonyl, 2-pyridylmethoxycarbonyl, phenyllactoyl or phenoxymethylcarbonyl, A is L-valine or L-tert-leucine, R2 is benzyl, X is -NH-, R3 is benzyl, 3- or 4-methoxybenzyl or 4-bromobenzyl, B is L-valine and R4 is benzylamino or benzimidazol-2-ylmethylamino, and the carbon atom in 4 position has the S configuration, in free form or, where such forms exits, in salt form.
4. A compound according to claim 1 of formula Ip1 Ip1 wherein A, B, R2 and X are as defined in claim 1;
R1p with the exception of hydrogen has the significance indicated in claim 1 for R1;
R3p with the exception of optionally substituted cycloalkyl has the significance indicated in claim 1 for R3; and R4p is hydroxy or a group of formula -OR7- or -NHR7 as defined in claim 1;
in free form or, where such forms exist, in salt form.
R1p with the exception of hydrogen has the significance indicated in claim 1 for R1;
R3p with the exception of optionally substituted cycloalkyl has the significance indicated in claim 1 for R3; and R4p is hydroxy or a group of formula -OR7- or -NHR7 as defined in claim 1;
in free form or, where such forms exist, in salt form.
5. A compound according to claim 1 of formula I as defined in claim 1 with the exception that R4 is hydroxy or a group of formula -OR7- -NHR7 as defined in claim 1, in free form or, where such forms exists, in salt form.
6. A compound according to claim 1 of formula I wherein the configuration at the carbon atom in 4 position is S, R1 is benzylyoxycarbonyl, A is L-valine, R2 is benzyl, X is -NH-, B is L-valine, R4 is benzimidazol-2-ylmethylamino and R3 is 3- methoxybenzyl, or the corresponding 4-methoxy position isomer, in free form or, where such forms exits, in salt form.
7. A compound according to claim 1 of formula I wherein the configuration at the carbon atom in 4 position is S, R2 is benzyl, X is -NH-, B is L-valine, and R1, A, R3 and R4 respectively are either - benzyloxycarbonyl, L-valine, 4-methoxybenzyl and benzylamino, or - 2-pyridylmethoxycarbonyl, L-valine, benzyl and benzylamino, or - benzyloxycarbonyl, L-tert-leucine, benzyl and benzylamino, or - D-phenyllactoyl, L-tert-leucine, benzyl and benzylamino, or - benzyloxycarbonyl, L-valine, benzyl and benzimidazol-2-ylmethylamino, or - benzyloxycarbonyl, L-valine, 4-bromobenzyl and benzimidazol-2-yl-methylamino, or - phenoxymethylcarbonyl, L-tert-leucine, benzyl and benzylamino, in free form or, where such forms exist, in salt form.
8. A compound according to any one of claims 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
II
wherein the substituents are as defined in claim 1, to ring opening in the presence of a compound of formula III
wherein the substituents are as defined in claim 1, where indicated in a further reactive form; or b) for the preparation of a compound of formula I wherein -BR4 is other than hydroxy [b1], or R1 is other than hydrogen or HY- [b2], appropriately substituting a corresponding compound of formula I wherein -CO-BR4 is carboxy or R1 is hydrogen or HY-, e.g.
b1) substituting a corresponding compound of formula Ia Ia wherein the substituents are as defined in claim 1, or b2) substituting a corresponding compound of formula Ib Ib wherein R1' is hydrogen or HY- and the other substituents are as defined in claim 1;
and where indicated deprotecting or saponifying a resultant compound of formula I in protected or esterified form.
and recovering the resultant compound of formula I i free form or, where such form exist, in salt form.
II
wherein the substituents are as defined in claim 1, to ring opening in the presence of a compound of formula III
wherein the substituents are as defined in claim 1, where indicated in a further reactive form; or b) for the preparation of a compound of formula I wherein -BR4 is other than hydroxy [b1], or R1 is other than hydrogen or HY- [b2], appropriately substituting a corresponding compound of formula I wherein -CO-BR4 is carboxy or R1 is hydrogen or HY-, e.g.
b1) substituting a corresponding compound of formula Ia Ia wherein the substituents are as defined in claim 1, or b2) substituting a corresponding compound of formula Ib Ib wherein R1' is hydrogen or HY- and the other substituents are as defined in claim 1;
and where indicated deprotecting or saponifying a resultant compound of formula I in protected or esterified form.
and recovering the resultant compound of formula I i free form or, where such form 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.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9114261.2 | 1991-07-02 | ||
| 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 |
| GB9123721.4 | 1991-11-07 | ||
| GB9203884.3 | 1992-02-24 | ||
| 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 |
|---|---|
| CA2109326A1 true CA2109326A1 (en) | 1993-01-03 |
Family
ID=27265743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002109326A Abandoned CA2109326A1 (en) | 1991-07-02 | 1992-06-30 | 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 |
|---|---|
| IE922143A1 (en) | 1993-01-13 |
| 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 |
|---|---|---|---|
| FZDE | Discontinued |