GB2323842A - Pyridine derivatives - Google Patents
Pyridine derivatives Download PDFInfo
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- GB2323842A GB2323842A GB9706923A GB9706923A GB2323842A GB 2323842 A GB2323842 A GB 2323842A GB 9706923 A GB9706923 A GB 9706923A GB 9706923 A GB9706923 A GB 9706923A GB 2323842 A GB2323842 A GB 2323842A
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- Prior art keywords
- amino
- phenyl
- mercaptopropylamino
- pyridyloxy
- propionamide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—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 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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
3-Aminopyridine derivatives of formula 1, wherein W is a group of general formula 2 or general formula 3, are inhibitors of T-cell proliferation and protein farnesyl transferase. They are useful as pharmaceutical agents for the treatment of inflammatory and malignant diseases.
Description
r 1 1 2323842
BACKGROUND
The immune response is essential for the defense of the body against invading pathogens. However, an inappropriate activation of the immune system has been implicated in the etiology of some serious disease states. These are characterised by progressive tissue damage with inflammation and invasion of the lesion by leukocytes. Examples of such diseases include inflammatory bowel disease, asthma, psoriasis and rheumatoid arthritis. Current therapeutic regimens for these conditions are often inadequate, and new approaches are required. One aspect of-the present invention is a series of compounds that inhibit the proliferation of T lymphocytes. Because T lymphocytes play a central role in the immune response it is reasonable to suppose that such compounds will prove to be of value in the treatment of irnmunoinflammatory conditions.
Another property exhibited by the compounds of the present invention is the ability to inhibit the enzyme farnesyl protein transferase (EC 2.5.1 p21RAs farnesyl transferase; Mase). Inhibitors of this enzyme have shown promise as agents for the treatment of rumours, particularly those which express variants of the oncogenic protein ras that are constituitively active. Therefore a second use for the compounds of this invention is the treatment of neoplastic: diseases.
DETAILED DESCRIMON OF THE INVENTION The compounds of this invention are pyridine derivatives of general formula 1:
7 1 1 a RI 1 X 5' 1 H2K,T,,-- (C H2) n"- N ', N 0 H Y ', W 2 R2 HS JCH2)p formula 1 in which:
W is a group of general formula 2 or general formula 3:
R 7 N "'Y R 6 1 MS N,(CR 10 R 11)aR 4 1 12 13 5 (CR R)bR formula 2 formula 3 X is a covalent bond; -CH2-; -0-; -NH-; -NMe-; or -S-:
Y is -0-, -S- or -Nle R' is hydrogen; linear or branched lower alkyl (Cl Cs); lower cycloalkyl (C3 - Ca); substituted or unsubstituted phenyl or naphthyl: or substituted or unsubstituted monocyclic: or benzofused heteroaryl:
R is hydrogen; linear or branched lower alkyl (Cl - Q) or Ph(CH2).:
W is hydrogen or linear or branched lower alkyl (Cl - C4):
R and R5 are independently hydm-Cn; linear or branched lower alkyl (Cl Cg); lower 0 6 cycloalkyl (C3 - Cg) which may be benzofused or substituted with COR; substitutedpr 1 2 A unsilbstituted phenyl or naphthyl, substituted or unsubstituted monocyclic or benzofused heteroaryl; COR 6; or R4 and R-' together with the nitrogen atom and the methylene groups to which they are attached fon- n'a saturated heterocycle of up to 8 atoms which may be benzofused or substituted with COR6:
R is OH, 0-alkyl; NH2; NH-alkyl; N(alkyl)2; or NHS 02-alkyl (wherein alkyl includes linear or branched lower alkyl Cl - Cs, lower cycloallql C3 - Q and (cycloalIkyl)alkyl C4- C10); or R6and k7together are -O(CH2)2- to form ay-lactone ring:
IC is selected from linear or branched lower alkyl (Cl - C6) or (CH2).R!; or R7 and R6 together are -(CH2)20- to form ay-lactone ring:
R' is hydrogen or methyl:
R is OH; OCH3; SCH3; SOMe; S02.Me; NHCOMe; optionally substituted phenyl; or COR 6:
R1'D, R' l, R 12 and R 13 are independently hydrogen or lower alkyl or phenyl:
a, b and c are integers in the range 0-4:
m is 0, 1 or 2:
n is 1, 2 or 3.
pis 1 or2.
The compounds of general formula 1 have at least one stereogenic centre and so can exist as stereoisomers (enantiomers and diastereomers). These isomers, as single compounds or as mixtures, are included within the scope of this invention. The compounds also have at least one basic site and so can form salts with acids. These 3 salts, and particularly those salts formed by pharmaceutically acceptable acids (including, but not limited to, acetic acid, citric acid, lactic acid, tartaric acid, hydrochloric acid, sulphuric acid, trifluoroacetic acid) are also included in the scope of the invention. Certain embodiments of general formula I also include acidic sites.
Ilese compounds can form s?lts with bases. Again, these salts (for example the sodium, potassium and ammonium salts) are included within the scope of the invention.
A prefered embodiment of the invention is a compound of formula 1 in which R' is an optionally substituted phenyl group, X is a covalent bond and Y is an oxygen atom, all the other groups being as defined above.
A most prefered embodiment of the invention is a compound selected from:
2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3phenylpropy l)- acetamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy J -Nbenzylacemmide 2{3-(2-An2ino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy J -N-(2phenylethyl)- acetamide 2-{3-(2-Amino-3-m=ptopmpylamino)-6-phenyl-2-pyiidyloxy}-N-(4-phenylbutyl)acetamide 2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -Nburylacetamide 2{3-(2-Am:iino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -Nphenylacemiffide 2(3-(2-Amino-3-mercaptopropylanfino)-6-phenyl-2-pyridyloxy) -N-benzyPNmethyl- acetamide 4 0 4 2(3-(2-Amino-3-mercaptopropylarnino)-6-phenyl-2-pyridyloxy} -N-methyl-N(2_ phenylethyl)acemmide 2{3-(2-Amino-3-meicaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(1 naphthyImethyl)acetamide 2{3-(2-Amino--^)-mercaptopmpylamino)-6-phenyl-2-pyridyloxy) -N-(2naphthyImethyl)acetamide 2{3-(2-Amino-3-meTcaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(2pyridyImethyl)- acetamide 2- ( 3-(2-Amino-3-mercaptopropylarriino)-6-phenyl-2-pyridyloxy) -N-(3pyridyImethyl)- acemnide N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxyacetyl}methionine N(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl) methionine methyl ester N(3-(2-Amino-3-mercaptopropylarnino)-6-phenyl-2-pyridyloxyacetyl} methioninesulphone N-{3-(2-Amino-3-mercaptopropylarnino)-6-phenyl-2-pyridyloxyacetyl}methioninesulphoxide N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl) homophenylalanine N'-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-py, ddyloxyacetyl}glutamine 0 4 N(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl} glutamic acid 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxyacetamido}pentan oic acid Na-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}-Nometh yl- el glutamine N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl) methionineamide 1,rz-{3-(2-An.iino-3-mercaptopropylaniino)-6-phenyl-2-pyridyloxyacetyl)N' methanesulphonylglutamine N{3-(2-Amino-3-mercaptopropylarnino)-6-phenyl-2-pyridyloxyacetyl} methionine methanesulphonimide N(3-(2-Amino-3-mercaptopropylan-fino)-6-phenyl-2-pyridyloxyacetyl) homoserine lactone N{3-(2-Amino-3-mercaptopropylamino)-6-PhenYl-2-PYridYlOxYacc-tYl 1 phenylalanine N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl) serine N( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl 1 aspartic acid N- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-'-?-pyridyloxyacetyl} - homophenylalanineamide N'- ( 3-(2-Amino-3-mercaptopropylaraino)-6-phenyl-2-pyridyloxyacetyl 1 asparagine 6 4 N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyaceryl)homophenylalanine methyl ester N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl) methioninesulpho)dde methyl ester N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl} methionine-N- methylamide l'-Acetyl-N2-{3-(2-amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacet yl}- 2,3-diaminopropionic acid N- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2- pyridyloxyacetyl}methionineN,N-dimethylamide 2(3-(2-Amino-3-mercaptopropylaniino)-6-phenyl-2-pyridyloxy} -N-(4phenylbutyl)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-benzylpropionamide 2- (3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy j -N-(3,4- dichlorobenzyl)propionamide 2(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N- (2thienylmethyl)- propionamide 2(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(4methoxybenzyl)propionamide 2(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(4methybenzyl)- propionamide 0 7 1 2{3-(Z-Amino-3-mercaptOpropybinino)-6-phenyl-2-pyridyloxy} -N-(4chlorobenzyi)- propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3methyloxycarbonylbenzyl)propionamide 2-{3-(2-Amino-3-mereaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4methyloxycarbonylbenzyl)propionarnide 2- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy J -N-(3- carboxybenzy1)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(4- carboxybenzy1)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-Q naphthylmethyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(2naphthylmethyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N(eyclohexylmethyl)propionarnide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-Q- hydroxybenzy1)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2phenylethyl)- propionamide 2(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 propionarnide 1 8 1 2- {3-(2-Amino-3-mercaptopropylaiino)-6-phenyl-2-pyridyloxy J -N-Qphenylethyl)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(1phenylethyl)- -fropionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(4(benzyloxycarbonylamino)benzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3chlorobenzy l)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(3pyridyhnethyl)- propionamide 2(3-(2-Amino-3-mercaptopropylan2ino)-6-phenyl-2-pyridyloxy I -N-(2pyridylmethyl)- propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(4pyridylmeth yl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2fiirylmethyl) - propionamide 2(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-(3hydroxybenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(4hydroxybenzyl)propionarnide 1 9 Af 1 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3bromobenzyi)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy J -N-(3nitrobenzyl)- propionamide 2{3-(2-Amino-3-mercaptopropylanfino)-6-phenyl-2-pyridyloxy} -N-(4(methyloxycarbonyl)cyclohexyhnethyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3methoxybenzyl)propionamide 2(3-(2-Amino-3-m=aptopropylamino)-6-phenyl-2-pyridyloxy} -N-(3methylbenzyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy J -N-(2methylbenzyl)- propionamide 2-(3-(2-Amino-3-mereaptopropylarrfino)-6-phenyl-2-pyridyloxy}-N-(2methoxybenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-(2chlorobenzyl)- propionnmide 2{3-(2-Amino-3-mercaptopropylan-iino)-6-phenyl-2-pyridyloxy) -N-(3(methanesulphonylamihocarbonyl)benzyl)propionamide 2(3-(2-Aminc-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyj -N-(3carboxamido- benzy1)propionamide N-(3-Aminobenzyl)-2-{3-(2-amino-3-mercaptopropylamino)-6-phenyl-2pyridylo xy}- propionamide 1 2(3-(2-An-iino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(3phenylbenzyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(3trifluoromethylbenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N(diphenylmet hyl)- propionamide 22{3-(2-Amino-3-mercap4,.,-?propylamino)-6-phenyl-2-pyridyloxy 1 -N-(3methylarninocarbonylbenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(3dimethylanfinocarbonylbenzyl)propionamide 3 2-{3-(2-Amino-)-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2phenylben zyl)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2bromobenz yl)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-Njq-dibenzylpropionamide 2-{3-(2-Amino-3-mercaptopropylarriino)-6-phenyl-2-pyridyloxy)-N-(1indanyl)- propionamide 2-(3-(2-Amino-3-uie, aptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- nitrobenzyl)- propionamide 11 A 2- (3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(2,3dimethoxybenzyl)propionaiffide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(2ethoxybenzyl)- propionamide 2{3-(2-Amino-3-mercaptopropylaniino)-6-phenyl-2-pyridyloxy} -N-(3acetamidobenzyl)propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3bis(medmesulphonyl)aminobenzyl)propionamide 2-(3-(2-Amino-3-mercaptopropylanfino)-6-phenyl-2-pyridyloxy)-N-isopropylpropionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2bromobenz yl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-tert- butylpropionamide 2-{3-(2-Amino-3-me=ptopropylamino)-6-phenyl-2-pyridyloxy)-N-cyclopentylpropionamide 2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 -IN- cyclohexyl- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N- cyclobutylpropionamide 2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy j -N-(2,6- dichlorobenzyl)propionamide 1 12 A 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3-pentyl)propionamide 2- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(3,5- dimethoxybenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4fluorobenzyl) - propionamide 2{3-(2-Arnino-3-mereaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(4methylbutyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(2,5dimethoxybenzyl)proplonamide 2{3-(2-Amino-3-mercaptopmpylamino)-6-phenyl-2-pyridyloxy} -N-(2trifluoromethoxybenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(2,6dimethoxybenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3-chloro-4fluorobenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylaniino)6-phenyl-2-pyridyloxy} -N-(2-chloro- 4fluorobenzyl)propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2acetamidobenzyl)propionamide 13 k 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-(2methoxyphenyl)ethyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-(1cyclohexenyl)ethyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy J -N-(2cyclohexylethyl)propionamide 2-(3-(2-Amino-3-mei aptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2- dimethylamino6-fluorobenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy J -N-(3fluorobenzyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(2methanesulfonylbenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylarnino)-6-phenyl-2-pyridyloxy)-N-(4methanesulfonylbenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2methylthio- benzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-(3benzothienyl- methyl)propionamide 2{3-(2-Amino-3-m=aptopropylairiino)-6-phenyl-2-pyridyloxy) -N-methyPN- (lphenylethyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(4methanesuffinylbenzyl)propionamide 14 A 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyiidyloxy) -N-phenylpropionamide 2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(2- indanyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N(cyclopentyhnethyl)propionamide 2- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(3methylphenyl)- propionarnide 2{3-(2-Amino-'^)-mercaptopropylan-iino)-6-phenyl-2-pyridyloxy) -N-(4methylphenyl)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyTidyloxy}-N-methyl-N-(3methylbenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-methyl-N-(2methylbenzyl)propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(1-(2methylphenyl)ethyl)propionamide 2(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy j -N-(1-(3methylphenyl)ethyl)propionamide 2-{2-{3-(2-Amino-3-mercaptopmpyi:irnino)-6-phenyl-2pyridyloxy)propionyl}1,2,3,4-tet-,ihydroisoquinoline 1 is 1 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy j -N(Pindanyi)-IN- methylpropionamide 2{3-(2-Amino-3-memaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(2chloroberizyl)- N-methylpropionamide 1{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2,3dimethylbenzyl)propionamide N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl} methionine methyl ester N{2-(3-(2-Amino-3-mercaptopropylarnino)-6-phenyl-2- pyridyloxy)propionyl) methionine N- {2-(3)-(2-Aniino-3-mercaptopropylamino)-6-phenyl-2pyridyloxy)propionyl} - phenylalanine N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl} phenylalanine methyl ester N-{(2S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxy)propion yl}- phenylalanine methyl ester N{(2S)-2-(3-(2-Ainino-3-mercaptopropylamino)-6-phenyl-2pyridyloxy)propiony l} - phenylalanine N-{(2RS)-2-(3-(2-Aniino-3-mercaptopropylamino)-6-phenyl-2pyridyloxy)propi onyl}- phenylalanine methyl ester N- ( (2R5)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxy)propionyl} - phenylalanine 1 16 N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-2phenylacety l) - methionine N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-2phenylace ryll- methionine iX-{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)bi-1Vryl}methionine methyl ester N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)butyryl) methionine methyl ester N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)burpyl I methionine N{2-(3-(2-Aminc>-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)buVryl} methionine N(2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexwoyl} methionine N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoyl I methionine N- (2-(3-(2-Aminc>-3-mercaptopropylaniino)-6-phenyl-2pyridyloxy)hexanoyl} - methionine methyl ester N(2-(3-(2-Amino-3-meicaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoyl} methionine methyl ester 17 4 N(2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoylj methionine methyl ester N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyllmethionine methyl ester N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl}methionine N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl) methionine N-{3-(2-Aminc-3-mercaptopropylamino)-6-(2-chlorophenyl)-2-pyridyloxyacery ll- methionine N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-trifluoromethylphenyl)-2pyridyloxyacetyllmethionine N{3-(2-Amino-3-mereaptopropylamino)-6-(3-methoxyphenyl)-2pyridyloxyacetyl} - methionine N-(3-(2-Amino-3-mercaptopmpylamino)-6-(3-hydroxymethylphenyl)-2pyridyloxyacetyllmethionine N(3-(2-Amino-3-mercaptopropylamino)-6-(3-acetamidophenyl)-2pyridyloxyacety l} - methionine N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-biphenylyl)-2-pyridyloxyacetyl}methionine N- {3-(2-Amino-3-mercaptopropylamino)-6-(4-biphenylyl)-2pyridyloxyacetyl) - methionine is 1 N{3-(2-Amino-3-mercaptopropylamino)-6-(3-methyloxycarbonylphenyl)2pyridyloxyacetyl}methionine N{3-(2-Amino-3-mercaptopropylarriino)-6-(3-methyloxycarbonylphenyl)-2pyridyloxyacetyl}methionine methyl ester N{3-(2-Amino-3-mercaDtopropylamino)-6-(3-carboxyphenyl)-2- pyridyloxyacetyl j - methionine N(3-(2-Amino-3-mercaptopropylaidno)-6-(2,4,6-trimethylphenyl)-2pyridyloxyacetyl)methionine N(3-(2-Amino-3-mercaptopropylardno)-6-(3-biphenylyl)-2- pyridyloxyacetyl} - methionine 2- {3-(2-Amino-3-mercaptopropyLimino)-6-butyl-2-pyridyloxy) -N-(3- phenylpropyi)- acetamide N(3-(2-Amino-3-mercaptopropylamino)-6-(2-naphthyl)-2-pyfidyloxyacetyl} methionine N- {3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxyacetyl} methionine N-{3-(2-Amino-3-mercaptopropylaniino)-6-(2-thienyl)-2pyridyloxyacetyl}methi onine N{3-(2-Amino-3-mercaptopropylamino)-6-(2-benzofuryl)-2- pyridyloxyacetyl} methionine N{3-(2-Amino-3-rn=aptopropylamino)-6-buryl-2-pyridyloxyacetyl} methionine 1 19 N{3-(2-Amino-3-mercaptopropylamino)-6-(1-naphthyl)-2-Pyridyloxyacetyl) methionine N- (3-(2-Amino-3-mercaptopropylamino)-6-(2-thienyl)-2pyridyloxyacetyl}methio nine methyl ester N-{3-(2-Amino-3-mercaptopropylamino)-6-(1-naphthyl)-2-pyridyloxyacetyllmethionine methyl ester N-{3-(2-Amino-3-mercaptopropylamino)-6-butyl-2pyridyloxyacetyl}methionine methyl ester N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-buryl-2-pyridyloxy)propionyl} methionine N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-pyridyloxy)propionyl}methionine N-{2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl}methionine N{2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl) methionine N{2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyI 1 methionine methyl ester N{2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl) methionine methyl ester N(3-(2-Amino-3-mercaptopropylamino)-6-benzyl-2-pyridyloxyacetyl) methionine methyl ester 1 t N-{3-(2-Amino-3-memaptopropylamino)-6-benzyl-2pyridyloxyacetyl}methionine N{3-(2-Amino-3-mercaptopropylamino)-6-phenoxy-2-pyridyloxyacetyl} methionine methyl ester N{3-(2-Amino-3-mercaptopropylamino)-6-phenoxy-2-pyridyloxyacetyl} methionine N- (3-(2-Amino-3-mercaptopmpylamino)-6-phenyl-2-pyridyl 1 alanine-(N- benzyl)amide N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyiidylj-D-e-(Nbenzy1)amide N- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl} -Nmethylalanine-(N- benzy1)amide N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl) glycine-(Nbenzyl)amide N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl}-N-methylglycine( N- benzy1)amide N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl}-N-methylalanine( N- benzyl)aniide N(3-(2-Amino-3-mercaptopropylaniino)-6-phenyl-2-pyridyl} alanine-(N-2Methoxybenzy1)amide N(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl} e-(NIphenylethyl)amide 2-{3-(2-Amino-3-mercaptopmpylaniino)-6-phenyl-2-pyridylthio)-N-benzylpropionamide 21 2{3-(3-Amino-4-mereaptobutylamino)-6-phenyl-2-pyridyloxy) -N(3methyloxycarbonylbenzyl)propionamide 2(3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy)-Nbenzylpropionamide 2-{3-(3-Annin mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(2pyT!dylinethyl)propionamide 2-{3-(3-AminQ4-mercaptobutylaulino)-6-phenyl-2-pyridyloxy)-N-(2methylbenzyl)propionamide 2(3-(3-Amino.mercaptobutylamino)-6-phenyl-2-pyridyloxy} -N-(2chlorobenzyl)propionamide 2{3-(3-Aminc>-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy 1 -N-(3methyloxycarbonylbenzyl)-N-methylpropionarnide N{3-(3-Amino-4-memaptobutylamino)-6-phenyl-2-pyridyloxyacetyl) methionine methyl ester N- (3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2pyridyloxyacetyl)methiorine N{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxygLcetyl} phenylalanine methyl ester N{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxyacetyl I phenylalanine The invention includes medicinal formulations in which a compound as described above is used as an active principal. Such formulations will have as other ingredients 22 such materials as bulking and binding agents and preservatives as are well known in the art. Ibe formulation may be a tablet solution, suspension, cream, suppository or any other form appropriate for the administratiod of the active principal. The administration can be topical, by intravenous, subcutaneous or intramuscular injection, or via the oral, nasal, bucal, rectal or vaginal routes.
The invention includes equally the use of these formulations for the treatment of a pathological condition in a human or other mammal, wherein the pathological condition is either an inflammatory or autoimmune disease such as (but not limited to) ulcerative colitis, Crohn's disease, allergic rhinitis, graft-vs-host disease, conjuncdAtis, asthma, rheumatoid arthritis, osteoarthritis, ARDS, Behcet's disease, transplant rejection, uticaria, allergic dermatitis, allopecia areata, scleroderma, exanthem, eczema, dermatomyositis, acne, diabetes, systemic lupus erythematosis, Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis, chronic bronchitis or psoriasis, or a proliferative disease such as cancer, for example colon, prostate or mammary carcinoma or leukaemia, or neurofibromatosis.
When used to treat these conditions the amount of formulation (and hence the amount of active principal) will be chosen by the treating physician taking into account the age, weight and state of health of the patient as well as any other factors he considers to be relevant. The amount of active principal used will generally be between 0.1mg and 10g per day in a single dose or in divided doses. Preferably the amount will be between 1mg and lg.
The general methods for the synthesis of the compounds of the invention is outlined below. For simplicity, the structural formulae show the case where p=1. The analogues in which p=2 can be prepared in the same way but starting with the appropriate homocysteine derivative in place of cysteine.
The compounds of general formula 1 are prepared from a precursor (formula 4) in which the potentially reactive amino (NH2) and mercapto (SH) groups are masked. Suitable masking groups are well Imown to practitioners of the art- Conveniently, the amino group is protected as its tert-butyl carbamate (BOC) derivative and the 23 mercapto group is protected as its triphenylmethyl (trityl) thioether. In this case both protecting groups can be removed by treating the compound with a strong acid (for example trifluoroacetic acid) in a solvent such as dichloromethane in the presence of a cation scavenger such as triethylsilane.
X H 0 Ir N:)",(CH 2)rl' N N 0 0 S 1 W 0 H X 3C 2 ion H N (CH2)rl' N 0 H Y W ESiH H HS W R 2 CH2C12 formula 4 formula 1 The compound of formula 4 can be prepared by coupling an amine H-W with an acid 0 of formula 5. 17his may be achieved by any of several well known methods for amide bond formation (for example, the use of a carbodiimide or a phosphorus reagent such as BOP).
X H E3W' N (CH 2)n1 N j::;:N 0 H-W Trt, S Y Y k 0 H R 2 R 1 X H B0C N (CH2)n'-, N N 0 H Y Trt, S Y, W 2 formula 5 formula 4 (where BOC " Me3COCO and Trt = PhP Th some embodiments of the invention there will be functionality in W that is incompatible with this reaction. For example, W may include a carboxylic acid f1mcdonal group or a second amine. Either of these would lead to a mixture of products arising from competition between altemative reaction centres. In these cases 24 it will be necessary to use an amine H-W' in which the competing functional group is modified. Such a modification will generally involve the use of a protecting group, and it will often be most convenient if the protecitmig group is cleaved under the same conditions as are used to effect the final deprotetion (formula 4 -+ formula 1). Ocasionally it may be preferable to deprotect W' in a separate operation. The choice of protection strategy for W' will reflect these considerations.
The acid of formula 5 is generally prepared from a suitable ester (formula 6). Conveniently, this will, be a lower allV1 ester such as the methyl or ethyl ester. In this case the acid is released by allcaline hydrolysis using, for example, lithium hydroxide in a mixed waterldioxan solvent systern.
R R 1 1 X X H H N (CH 2) n N LiOH N (CH 2)n. N BOC" N 0 B OC' N 0 Trt-., Y 0Me H20 Trt,, S Y OH S Dioxan R 2 R 2 formula 6 formula 5 The ester of formula 6 can be prepared from an aminopyridine (formula 7) and an aldehyde (formula 8) using conditions Imown to effect such reductive aminations. Typically this will involve mixing the aminopyridine and the aldehyde in a solvent such 0 as methanol containing 1-10% acetic acid, and subsequently treating the mixture with a reducing agent such as sodium cyanoborohydride.
R 1 X 2 rl H2N. N 0 + BOC' rt,' S 0Me R 2 formula 7 formula 8 formula 6 X H MeOH H N (CH) CHO HOAC N (CH2),,N w BOC N 0 NaCNBH3Trk, S Y-JAOMe A2 The aminopyridine of formula 7 can be prepared from the corresponding nitropyridin, M (formula 9) by any of several well known protocols (for example, hydrogenation in the presence of a platinum or palladium catalyst, reaction with zinc in acetic acid, reaction with sodium hydrosulphite) R 1 1 1 "'X 02N, P-JN 0 Y ', R 20Me R 1 X H 2 N N 0 Y 0Me R 2 H-JPd-C formula 9 formula 7 The aldehyde of formula 8 can be prepared from the corresponding alcohol by oxidation or from an appropriate carboxylic: acid derivative by reduction. For the case where n--1 the starting material for these reactions is protected cysteine. 0 H BW' N z Trt,, 5)1 H 0 BOC' N:),,a, OH Trt, S H 0 BW' N::1"lH Trt, S H
B0c, N OH Trt,, S r formula 8 (n--1) One convenient method is to proceed via the NO-dimethyl oxamate [Z = N(Me)OMe] which can be reduced to the aldehyde with lithium aluminium hydride.
For the case where n=2 it is first necessary to homologate the cystrine. This can be achieved via a diazoketone intermediate.
0 26 0 H B0c, N 1 1 1. iBuOCOC1 Tri,, N2 S H 0 2. CH2N N 2 1.A902CPh SOC" OH Et.N, MeOH Trt,, S H BOC N 0Me Trt-., S)"' yo H BOC"N CHO Trt,, S r formula 8 (n--2) It is possible to reverse the order in which the substituents on the pyridine are elaborated. Starting from the nitropyridine of formula 9, hydrolysis to the corresponding acid (formula 10) and coupling with H-W (or H-W') using protocols analogous to those described above leads to the nitropyridine of formula 11.
R 1 X 02N,,C,N 0 Y 0Me R 2 formula 9 R 1 X UOH 02N 0 Y OH R 2 formula 10 X H-W 02N 0 k2- formula 11 The nitro group can then be reduced to give the aminopyridine (formula 12) which is then reacted with the aldehyde as described above to give the protected compound of formula 4.
formula 11 R 1 X 02 N 0 HPd-C 27 1 R 1 X H 2 N J,N 0 Y ---rw W formula 12 R 1 1 1 R X 1 X H MeOH H 1 1 CH.) HOAc N (CH 2)n', IN N + BOC N (CH2)n-1 C ---- BOC N 0 H Y H2N 0 NaCNSH.Trt,.
Y W S S.kw A2 R 2 formula 12 formula 8 formula 4 The nitropyridine of formula 9 can be prepared by two routes. In the first, the group R'-X is introduced into a chloropyridine of formula 13. When X is a heteroatom, (oxygen, nitrogen or sulphur) the second component in the reaction is R'XR and the reaction requires a basic catalyst such as potassium fluoride or sodium carbonate. When X is CH2 or a covalent bond then the reaction is best achieved by a Suzuki coupling. This involves the reaction of the chloropyridine with a boronic acid R'XB(OH)-2(or a boronate ester) in the presence of a palladium catalyst.
cl 1 RIXH, base, or 02N j:::: Y 0 0Me WXB(OH)2, Pd Y k R 2 R 1 X 02N N 0 Y.. 0Me R 2 formula 13 formula 9 The chloropyridine of formula 13 is obtained from 2,6-dichloro-3- nitropyridine and a fragment of formula 14. These react in the presence of a base such as sodium carbonate, sodium hydride or potassium tert- butoxide.
28 cl cl 0 Base 1 J,,IN + HY,)oMe. 02N J::: 1 N 0 02N cl R 2 Y Y L 0Me R 2 formula 14 formula 13 The second route to the nitropyridine of formula 9 involves the alkylation of a pyridone of formula 15 (which can eyist as the tautomeric hydroxypyridine). 1'bis route is mainly of value when Y = 0, although use of the analogous thiopyridone would lead to a product in which Y = S. 7he reaction can be performed under basic conditions, in which case the alkylating agent is a bromide, chloride or sulphonate (formula 16: LG 0 Br, Cl, RSQ). Ile reaction can also be performed under neutral conditions using the Nfitsunobu protocol (Ph3P, MO2WNCO2Et) in which case the alkylating agent is an alcohol (LG = 01.1) R X 0 0N J7N HX + LG,,rk 0Me 0. 02N f: N 0 2 0 R 2 0 0Me R 2 formula 15 formula 16 formula 9 (Y = 0) The pyridone and the alkylating agent will, in most cases, be known in the literature. Otherwise they can be prepared by methods analogous to those described for si compounds.
A variation of this pyridone route starts with a pyridonenitrile of formula 17. For some combinations of R' and X, the nitrile may be more accessible than the nitropyridine. The nitrile can be hydrolysed to the corresponding acid (formula 18) in the presence of strong acids. Ile acid is then subjected to a Curtius rearrangement 29 using diphenylphosphoryl azide and benzyl alcohol to give a protected an- linopyridine of formula 19.
1 R 1 T j X H+ X Ph2P02N3 0 X NC"' NH H02 CJ NrH PhCH20H 0 L N NrH 0 0 [:::r H 0 formula 17 formula 18 formula 19 The use of benzyl alcohol in this reaction results in the amine being protected as its benzyl carbamate. When this is incompatible with the chemistry necessary for the further elaboration of this intermediate to the target compound a different alcohol may be used. The resulting carbamate will be chosen to have the appropriate compatibility with the conditions to be used and to require deprotection conditions which will be compatible with the functionality present when the amine is liberated.
This pyridone can then be allcylated as described above with the fragment of formula 16 to give the pyridine of formula 20.
R 1 1 X 0 11 R 1 0 X 0 N 1 + L " --" N 0 NH G T, 0Me H H R 2 O'T''0Me 0 c:r R 2 formula 19 formula 16 formula 20 The protected aminopyridine of formula 20 can be further elaborated by either of two routes which are analogous to those described above for the nitropyridine of formula 9. The ester can be hydrolysed to the corresponding acid- This is then coupled to the amine corresponding to H- W or H-W. Ile result is the pyridine of formula 21.
R 1 X 0 1 i N N 0 c:ro H 0 ' t k 0Me 2. H-W R formula 20 1. LiOH R 1 0 X 0 k N N 0 c:r H 0,rk,, R 2 formula 21 The amine function is then released. If, as illustrated, the amine is protected as its benzyl carbamate, the deprotection is conveniently performed by hydrogenolysis in the presence of a pallatflurn or platinum catalyst. If a different alcohol was used in the Curtius rearrangement then the conditions for the deprotection will be chosen accordingly. The result is an amine of formula 12 (with Y = 0) which can be taken on as decribed previously.
R 0 H2, Pd-C 0 JL N N 0 c:r H formula 21 X H2N N 0 0,L,, R 2, formula 12 (Y = 0) The alternative route for the elaboration of the protected amine of formula 20 is to deprotect the arnine prior to hydrolysis of the ester. This gives an amine of formula 7 (again with Y = 0) which can be taken on as described above.
R 0 H2. Pd-C 0 JI N J1?N 0 c:r 0 0Me R 2 formula 20 31 X H 2 N N 0 0 --k0Me R 2 formula 7 (Y = 0) 1 These general methods are further illustrated in the following non- limiting examples.
EXAMPLE 1
N-f3-L2-Amino-3-mercautot)roDylamino)-6-phenvl-2-vvridvioxvacetyll.
methionine methvl este CH 3 S 2N N N 0 H 11 0, HS 0"N CH 3 H H IA: 6-Pheny-12-12ddone-3-carbonitrile This was prepared according to the method of Damewood et al. (J.Med.Chern. 1994, 37, 3303). Briefly, a solution of acetophenone (11.6mL, 10Ommol) and dimethylformamide dimethyl acetal (43.8mL, 330mmol) in acetonitrile was heated at reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in dimethylformamide (160mL), cyanoacetamide (7.55... 9Ommol) and sodium methoxide (10.6g, 196mmol) were added, and the mixture was heated at 100C for 5h, then allowed to stand at room temperature overnight. The solution was poured into water (50OmL) and the mixture was acidified to pH 2 with IM HCL The resulting precipitate was collected and dried over P203; yield 17.6g (100%).
32 IB: 6-Phenyl-2-pyddone-3-carboxvlic aci Tle nitrile of Example 1A (17.6g, 9Ommol) was suspended in acetic acid (170mL). 48% EBr (8mL) was added and the mixture was heated at reflux overnight The resulting solution was cooled to room temperature, diluted with water (100m.L), and basified to pH 5 with 10% NaOH (ca. 60OmL). The precipitate was collected, washed with 1M HCl and water, and dried over P205; yield 13.7g (71%).
1C 3-BenzylQUcarbonylamino-6-jphenyl-2-jpyddon To a solution of the acid of Example 1B (8.0g, 37.2mmol) in dioxan (2OOmL) was added triethylamine (6.2mL, 45mmol) and diphenylphosphoryl azide (8.8m.L, 41mmol). 'nie mixture was heated under reflux for 4h. Benzyl alcohol (7.7mL, 74mmol) was added and heating was continued overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was washed with 1M HCL satd. NaHC03, water (twice) and ether (twice); yield 7.2g (60%).
1D: Methyl 2- (3-benzyloxycarbonylarnino-6-phenyl-2-MddyloxyI acetate To an ice-cold solution of the pyridone of Example 1C (96Orng, 3mmol) in dimethylformamide (1OmL) was added NaH (117rng, 80% dispersion, 3.9m=ol). The mixture was allowed to warm to room temperature and stirred for 45min. Methyl bromoacetate (31SpL, 3.3mmol) was added and stirring was continued overnight. The mixture was partitioned between EtOAc and 1M HQ, and the organic layer was washed with 5% KHCO3 and brine, then concentrated in vacuo. The residue was purffied by flash chromatography on silica (eluant EtOAc:pet. ether 25:75); yield 64Orng (54%).
33 1 1E: Methyl 2- ( 3-amino-6-phenyl-2-pvridyloxv 1 acetate To a degassed solution of the compound of Example 1D (640mg, 1.63rnmol) in methanol (SOmL) was added 10% pallafflum-on-carbon (100mg). The mixture was stirred at room temperature under an atmosphere of hydrogen for 2h, then filtered. The catalyst was washed with methanol and the combined filtrates were concentrated in vacuo.. llne residue was dried by azeotropic evaporation with toluene and used without purification; assume 100% yield.
IF: Methyl 2-(3-(2-tert-butyloxvcarbonylan-dno-3tdphenvlmethvlmercgpWMpylamino)=1i-phenyl-2-pydd3LIMI acetate To a solution of the aminopyridine of Example 1E (1.63mmol) and N-BOCStritylcysteinal. (0.73g, 1.63mmol) in methanol (20mL) and acetic acid (0. 2mL) was added sodium cyanoborohydride (113mc,r, 1.79mrnol). The mixture was stirred overnight at room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 25:75); yield 893mg (79%).
IG: 2-f3-(2-tert-BuZIIQnylamino-3-trijphenylmethvlmercapto=pylarnino)6phenyl-2:p, )ddyloxy I acetic acid To a solution of the ester of Example IF (893mg, 1.29mmol) in dioxan (10m. L) and water (1OmL) was added lithium hydroxide hydrate (60mg, 1.42=ol). The mixture was stirred overnight at room temperature then concentrated in vacuo. The residue was partitioned between dichloromethane and 0.5M KHS04. The organic layer was washed with brine, dried overMaSO4and concentrated in vacuo; assume 100% yield- CP 34 IR N-(3-(2-tert-BuiylQxvcarbonvlamino-3iriphenvlrnethylmercaptoj2=ylamino)-612henvl-2]2yddyloxyac=llmcthioninemethvles To an ice-cold solution of the acid of Example IG (0.645=ol), methinoine methyl ester hydrochloride (193mg, 0.968mmol), diisopropylethylamine (0. 28mL, 1.6lmmol) and 1-hydroxybenzotriazole (150mg. 1.1Ommol) in dichloromethane (4OmL) was added WSWI (198mg, 1.03=ol). Ile mixture was allowed to warm to room temperature and stirred for 3 days, then partitioned between EtOAc and water. The organic layer was washed with 1M M04, sateL NaHCO3 and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica, (cluant EtOAc. -petether 30:70 then 40:60), yield 386mg (74%).
11: N-f3-(2-Amino-3-mffapmpr -6-phenvl-2-pdylox_vacetyl 1 methionine 2wpvlamino) methyl ester To a solution of the ester of Example IH (386mg,0.476mmol) in dichloromethane (6mL) was added trifluoroacetic acid (3mL) and triethylsilane (0.38ml, 2.38mmol). 'Me mixture was stirred overnight at room temperature, then diluted with toluene (2mL) and evaporated. The residue was purified by preparative HPLC (gradient water.-acetonitrile 80:20 -+ 20:80; 0. 1% TFA) and lyophilised; yield 155mg (68 %).
MS: calc mle 478.17; found [M+HI'=479 1 EXAMPLE2 (2R)-2-{3-(2-Amino-3-mercar)toDroz)vlamino)-6-1)henvl-2- i)vridvloxy}:L-(3 _- methvloxvcarbonvlbenzvl)r)rovionamide H2 N N N 0 0 O'Y'kN O,CH3 H HS 2A: Methyl (2R)-2-(3-benzvloxycarbonvlamino-6-phenvl-212Vridvloxylp=ionat To an ice-cold stirred suspension of the pyridone of Example 1C (16g, 5Ommol) in dimethylformamide (10OmL) was added sodium hydride (1.85g, 60% dispersion, C 55mmol). The mixture was allowed to warm to room temperature and stirred for 1h.
Methyl (2S)-2-chloropropionate (6.74g, 55mmol) was added and the mixture was rp heated at 80C for 4h then stirred at room temperature overnight and partitioned between EtOAc and 1M HCL The organic layer was washed with 5% KHS04, water (three times) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 15:85); yield 6.Og (30%).
2B: Methyl (2R)-2-(3-amino-6-phenvl-2-pvridyloxylpropionate The pyridone of Example 2A (6.0g, 14.7mmol) was hydrogenated over palladium following the method of Example 1E. The product was used without purification.
1 36 2Q Methyl (2R)-2- ( 3-(2-tert-butvloxy-carbonvlan- no-3triphenylmethylmercaptop= 1o)-6-12henyl-2-p-yddyloxylpiMionate Ile aminopyridine of Example 2B (14.7mmol) was reacted with N-BOC-Stritylcysteinal (7.9g, 17.7=ol) and sodium cyanoborohydride (1.11g, 17. 7mmol) in methanol (100mL) and acetic acid (7.5mL) following the method of Example lF. The product was purified by flash chromatography on silica (eluant EtOAc-pet. ether 15:85); yield 7.91g (76%).
2l): (2R)-2-(3-(2-tert-Bury-loxycarbony_lardmo-3triphcnvlmethylmercgptglnpylamino)-6-12hen41-2-pj!iidyloxylp=ionic aci The ester of Example 2C (7.91,,,,., 11.2mrnol) was hydrolysed with lithium hydroxide hydrate (1.09g, 26mmol) in dioxan (20mL) and water (2OmL) following the method of Example 1 G. The product was purified by flash chromatography on silica (eluant EtOAc -pet. ether 40:60 then Et0Ac50Ac 99: 1); yield 3.74g (72%).
2E: Methyl 3-(aminomethyl)benzoate hydmphlcwide 3-Cyanobenzoic acid (1g, 6.8mmol) was dissolved in ethanol (50mL). The solution was acidified with IM HO (7mL) and hydrogenated over 10% palladium-on-carbon for 4h, then filtered and concentrated in vacuo. The residue was dissolved in methanol and cooled in ice. Thionyl chloride (1. 8mL, 23.8mmol) was added dropwise, then the mixture was allowed to warm to room temperatue and stirred overnight. The solution was concentrated to half its volume and diluted with ether - yield 1.21 g (200mJ-). The resulting precipitate was collected and dried over P-20s, (88%).
37 2R (2R)-2-f3-(2-tert-Bur_vloxvcarbonvlamino-3triphenylmethylmercgjptQffopylamino)-6 12henyl-2-12vrid_vloxvl-N-(3-methyloUcarbonylbenzyl)p=ionamide To an ice-cold solution of the acid of Example 2D (20Orng, 0.29mmol) in dichloromethane (1OmL) were added methyl 3-(aminomethyl)benzoate hydrochloride C7Omg, 0.35mmol), triethylamine; (120pL, 0.87mmol) and benzoniuol-l-yloxy-u-ispyrrolidinciphosphonium hexafluorophosphate (180mg, 0.35mmol). The mixture was allowed to warm to room temperature and stirred for 6h, then concentrated in vactio. The residue was partitioned between EtOAc and 0.3M ICHS04. The organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica (eluant ROAc:pet. ether 30:70 then 40:60); yield 155m. (64%).
0 2G: (2R)-2-(3-(2-Amino-3-mercaptop=ylamin<>)-6-12henyl-2-J2yddyloLcyl-iJ(3methylQ);ycarbonylbennil)Wopionamid To a solution of the compound of Example 20 (40mg, 0.048mmol) in dichloromethane (SmL) was added trifluoroacetic acid (SmL) and then triethylsilane was added dropwise until the yellow colour was discharged. The mixture was stirred at room temperature for 4h, diluted with toluene, and concentrated in vacuo. The residue was dissolved in acetonitrile/Water and filtered to remove triphenylmethane. The filtrate was lyophilised and the residue was purified by preparative 1HPLC (gradient watenacetonitrile 90:10 - 50:50; 0.1% TFA) and lyophilised; yield 19.3mg (81%).
MS: calc mle 494.20; found [M+HI'=495 38 EXAMPLE 3 (2R)-2-f3-(2-Amino-3-mercai)tovrot)vlamino)-6-t)henvl-2Dvridyloxy-N-((1S)-1- Dhenylethvl)DroDionamide H2N rN No H 0" N H HS 3k (2R)-2-f3-(2-tert-Bulyloncarbonylarnino-3tdl2henylmethylmercaptoM]2ylamino)-6-phenyl-2-Uvridyloxy]-N-((IS)-1phenvlethvl)p =-ionamide The acid of Ele 2D (130mg, 0.188mmol) was coupled to (S)-(+ amethylbenzylamine (27.4mg, 0.226mmol) following the method of Example 2F. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield 90mg (60%).
313: (2R)-2-f3-(2-Amino-3-m=aRmp=ylardno) 12henyl-2:Mddy-loNyl-N-((IS)1phmylr,ffiyl)jpmpionamide The compound of Example 3A (9Orng, 0.113mmol) was deprotected following the method of Example 2G. The product was purified by preparative HPLC (gradient water.acetonitrile 90:10 --.> 40:60-, 0.1% TFA) and lyophilised; yield 31.5mg (61%).
MS: calc mle 450.21; found [M+M"=451 39 EXAMPLE 4 (2R)-2-f 3-(2-Amino-3-merca ntop rot) via m ino)-6-i) hen vi-2- pyri dvioxv} -N-(2methoxvbenzvl)Drovionamide H2N N (0 0 CH3 rN 11 H HS 4A: (2R)-2-(3-(2-tert-BunLloncarbonylamino-3-tdphenylmethylmercntopmpvlandno)-:phenyl-2:p3ddvloxvl-N-(2-methoxvl2gnzyl)prppionamide The acid of Example 2D (130rng, 0.188mmol) was coupled to 2- methoxybenzylamine (31mg, 0.226mmol) following the method of Example 2F. The product was purified by flash chromatography on silica (eluant ROAc:pet. ether 35:65); yield 137mg (90%).
4B: (2R):2-(3-(2-Amino-3-mercaRtoRmpvlarnino):-jhenyl-2-pyddylo3yl-N-(2rnethMbenzyl)=ionamid 1he compound of Example 4A (137rng, 0. 169mmol) was deprotected following the method of Example 2G. The product was purified by preparative 1HPLC (gradient wateracetonitrile 85:15 ---.> 50:50-, 0.1% TFA) and lyophilised; yield 46.3mg (59%).
MS: calc mle 466.20; found [M+M'=467 The compounds of the invention are useful as inhibitors of the enzyme farnesyl protein transferase and as inhibitors of T-lymphocyte proliferation. Inhibitors of famesyl protein transferase are known to show good efficacy in animal models of tumour growth and hence can be expected to be useful in the chemotherapy of human cancers. T-lymphocytes are key mediators of the immune response and are believed to play a central role in the etiology of many inflammatory diseases. Hence, inhibitors of Tlymphocyte proliferation are expected to show clinically useful i-inflaMMatOry activity. The utility of the compounds of the invention can be demonstrated using the assays described below.
ASSAY 1: FarneSyl P-mtein Transferase Inhibition.
Inhibition of Farnesyl Protein Transf6rase is determined using a Scintillation Proximity Assay (Amersham). A biotin-tagged peptide substrate and CH)-farnesyl pyrophosphate are incubated with recombinant human enzyme and varying concentrations of the test compound. After a fixed time the reaction is halted, streptavidin-coated. scintillation beads are added, and the product formation is quantified in a scintillation counter. The IC5o is the concentration of test compound required to reduce the amount of product formed by 50%. The compounds of the invention have ICso values below IOpM Typical examples are:
Compound of. Example 1 Example 2 Example 3 Example 4 IC50 (WA) 0.23 0.009 0.027 0.007 ASSAY 2: T-L3=hocyte Proliferation Inhibition.
Human T-lymphocytes are stimulated to proliferate with an anti-CD3 antibody in the presence of varying concentrations of the test compound. After 3 days ["thymidine is addedL The cells are incubated for a ftu-ther 12 hours, then proliferation is quantified by counting the incorporation of radioactivity into the cellular fraction. The 41 1 compounds of the invention inhibit proliferation at concentrations below sopiM. Typical examples are:
Compound of Concenwation (p" Example 1 1
Example 2 0.2
Example 3 0.1
Example 4 0.1
Inhibition (%) 65 98 71 67 ..
42 1
Claims (8)
1 44 pis 1 or
2 2. A compound of Claim 1 in which; R' is an optionally substituted phenyl group; X is a covalent bond, and Y is an oxygen atom, all the other groups being as defined above.
3.
A compound of Claim 1 which is selected from:
2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3phenylpro pyl)- acetamide 2(3-(2-Amino-3-mercaptopropylarnino)-6-phenyl-2-pyridyloxy} -Nbenzylacemmide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2phenyleth yl)- acetamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(4phenylbut yl)- acetamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-Nbutylacetami de 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyj-Nphenylacetam ide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-benzyl-Nmet hyl- acetamide 1 2(3-(2-Amino-3-mercaptopropylarrdno)-6phenyl-2-pyridyloxy) -N-methyPN- (2phenylethyl)acetamide 2{3-(2-Arnino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N(1 naphthylmethyl)acetamide 2-{3-(2-Amino-3-mer aptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- naphthylmethyl)acemmide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2pyridybne thyl)- acetunide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3pyridylmeth yl)- acetamide N{3-(2-Aniino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl) methionine N-{3-(2-Amino-3-mercaptopropylaniino)-6-phenyl-2pyridyloxyacetyl}methioni ne methyl ester N- {3-(2-A rnino-3-mercaptopropylqrnino)-6-phenyl-2-pyridyloxyacetyl} methioninesulphone N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl) methioninesulphoxide N(3-(2-Amino-3-mercaptopropylaniino)-6-phenyl-2-pyridyloxyacetyl) homophenylalanine N'-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxyacetyl}glutamin e 46 N(3-(2-Amino-3-mercaptopropylarriino)-6-phenyl-2-pyridyloxyacetyl} giummic acid 2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetamido J pentanoic acid I,Px-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyll-N'me thyl- glutamine N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl}methionineamide N'(3-(2-Amino-3-mercaptoPropylamino)-6-phenyl-2-pyridyloxyacetyl)-Nmethanesulphonylglutamine N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxyacetyl}methionin e methanesulphonimide N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxyacetyl}homoserin e lactone N{3-(2-Amino-3-mercapmpropylamino)-6-phenyl-2pyridyloxyacetyl)phenylaianin e N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl} serine N(3-(2-Amino-3-mei aptopropylarnino)-6-phenyl-2-pyridyloxyacetyl) aspartic acid N- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl) homophenyLilanineamide N'-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxyacetyl)asparagi ne 47 N(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl) homophenylalanine methyl ester N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl} methioninesulphoyide methyl ester IN{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyacetyl} methionine-N- methylamide N3-Acetyl-N2-{3-(2-amino-3-mereaptopropylamino)-6-phenyl-2pyridyloxyacety l}- 2,3-diaminopropionic acid N{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyiidyloxyacetyl} methionine- N,N-dimethylamide 2- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(4phenylbutyl)- propionamide, 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-benzylpropionamide 2- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(3,4- dichlorobenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(2thienyImethyl)- propionamide 2{3-(2-An2ino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(4methoxybenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(4methybenzyl)- propionamide 48 2- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(4chlorobenzyl)- propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3methyloxycarbonylbenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -i'J-(4methyloxycarbonylbenzyl)propionamide 2(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(3- carboxybenzy1)proplonamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(4- carboxybenzyl)propionamide 2-(3-(2-Amino-3-mei aptopropylamino)-6-phenyl-2-pyridyloxy)-N-(1- naphthylmethyl)propionamide 2-(3-(2-Amino-3-mercaptopmpylamino)-6-phenyl-2-pyridyloxy}-N-(2naphthylmethyl)propionamide 2- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N(cyclohexylmethyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2-hydroxybenzy1)propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2phenylethyl)- propionamide 2{3-(2-Amino-3-mercaptopropyhudno)-6-phenyl-2-pyridyloxy J propionamide 0 49 2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(1 phenylethyl)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(1phenylethyl)- propionamide 2-(3-(2-Amino-3-mercaptopropylaniino)-6-phenyl-2-pyridyloxy)-N-(4(benzyloxycarbonylamino)benzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3chlorobenzy l)- propionanfide 2(-^)-(2-Amino-3-mereaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-(^-)pyridylmethyl)- propionamide 2-(3-(2-Amino-3-mercaptopropylamino)_6-phenyl-2-pyridyloxy}-N-(2pyridylmeth yl)- propionamide 2(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(4pyridylmcthyl)- propionamide 2-{3-(2-Amino-3-memaptopropylamino)6-phenyl-2-pyridyloxy)-N-(2fuxylmethyl) - propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3hydroxybenzyl)propionamide 2-{3-(2-Arnino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(4hydroxybenzyl)propionamide so 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 3 -N-(3bromobenzyi)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3nitrobenz yl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(4(methyloxycarbonyl)cyclohexylmethyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3methoxybenzyl)propionamide 2(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(3methylbenzyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyj -N-(2methylbenzyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-Qmethoxybenzyl)propionamide 2-(3-(2-Amino-3-mei aptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2- chlorobenzyl)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3(methanesulphonylaminocarbonyl)benzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3carboxami do- benzyl)proplonaniide N-(3-Aminobenzyl)-2-(3-(2-amino-3-mercaptopropylamino)-6-phenyl-2pyridylo xy}- propionamide 51 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy J -N-(3phenylbenzyl)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N(3trifluoromethylbenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N(diphenylmet hyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(3methylaminocarbonylbenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-Qdimethylaminocarbonylbenzyl)propionamide 2-{3-(2-Amino-3-mer aptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2- phenylbenzyl)- propionamide 2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2bromobenzyl)- propionamide 2(3-(2-Amino-3-mereaptopropylamino)-6-phenyl-2-pyridyloxy}-NN-dibenzylpropionamide 2- (3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(l- indanyl)- propionamide 2(3-(2-Amino-3-mereaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-(2nitrobenzyl)- propionamide 52 2{3-(2-Amino-3-mercaptopropylaniino)-6-phenyl-2-pyridyloxy) -N-(2,3dimethoxybenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyiidyloxy}-N-(2ethoxybenzy l)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(3acemmidobenzyl)proplonamide 2-{3-(2-Amino-3-me=ptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3bis(methanesulphonyl)aminobenzyl)propionamide 2-{3-(2-Amino-3-meTcaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-isopropylpropionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2bromobenzyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-tert- butylpropionamide 2- {3-(2-Anfino-3-m=ptopropylamino)-6-phenyl-2-pyridyloxyj -N-cyclopentyl- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N- cyclohexylpropionamide 2- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N- cyclobutyl- propionamide 2- ( 3-(2-Aminc-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(2, 6dichlorobenzyl)propionamide 53 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3-pentyl)propionamide 2-{3-(2-Amino-3-memaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3,5dimethoxybenzyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(4fluorobenzy l)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxyJ -N-(4methylbutyl)- propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,5dimethoxybenzyl)proplonamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-(2trifluoromethoxybenzyl)propionamide 2-{3-(2-Amino-3-mei aptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2,6dimethoxybenzyl)propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3-chloro-4fluorobenzyl)propionamide 2-{3-(2-Aminc)-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy]-N-(2-chloro4 - fluorobenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2acetamidobenzyl)propionamide 54 2-(3-(2-Amino-3-mereaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2-(2methoxyphenyl)ethyl)propionamide 2-{3-(2-Anfino-3-mercaptopmpylamino)-6-phenyl-2-pyridyloxy)-N-(2(1cyclohexenyl)ethyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-(2cyclohexylethyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2dimethyla mino6-fluorobenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3fluoroben zyl) propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N(2methanesulfonylbenzyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(4methanesulfonylbenzyl)propionamide 2-(3-(2-Amino-3-merr-aptopropylamino)-6-phenyl-2-pyridyloxy)-N-(2methylth iobenzyl)propionamide 2- ( 3-(2-Arnino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-(3benzothienylmethyl)propionamide 2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-Methyl-N(1phenylethyl)propionamide 2(3-(2-An2ino-3-mercaptopropylainino)-6-phenyl-2-pyridyloxy} -N-(4_ mcthanesWfInYlbcnzYI)Propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy} -N-phenylpropionamide 2-{3-(2-Amino-3-mercaptopropylannino)-6-phenyl-2-pyridyloxy)-N-(2indanyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N(cyclopentylmethyl)propionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(3methylpheny l)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy 1 -N-(4methylphenyl)- propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy) -N-methyPN- (3methylbenzyl)propionamide 2-{3-(2-Amino-3-mei aptopropylamino)-6-phenyl-2-pyridyloxy}-N-methyl-N-(2methylbenzyl)propionamide 2-{3-(2-Amino-3-mereaptopropylamino)-6-phenyl-2-pyridyloxy)-N-(1-(2methylphenyl)ethyl)propionamide 2{3-(2-Amino-3-mercaptopropylamino)-6phenyl-2-pyridyloxy) -N-(l-Qmethylphenyl)ethyl)propionamide 2-{2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxylpropionyll1,2,3,4-ten-ahydroisoquinoline 0 56 2{3-(2-Amino-^)-mercaptopropylamino)-6-phenyl-2-pyridyloxy j -N-(1 indanyl)-N- methylpropionamide 2-(3-(2-Arnino-3-mei aptopropylnrhino)-6-phenyl-2-pyridyloxy}-N-(2- chlorobenzyl)N-methylpropionamide 2-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy}-N-(2,3dimethylbenz,vl)propionamide N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl) methionine methyl ester N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)propionyl}methionine N-(2-(3-(2-Amino-3-mercaptopropylnrnino)-6-phenyl-2-pyridyloxy)propionyl}phenylalanine N-{2-(3-(2-Amino-3-mercaptopropy]2rnino)-6-phenyl-2-pyridyloxy)propionyl}phenylalanine methyl ester N-{(2S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxy)propion yl}- phenylalanine methyl ester N- ( (2S)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxy)propionyl) - phenyLU-mffie N{(2RS)-2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2pyridyloxy)propiony l) - phenylalanine methyl ester N-{(2RS)-2-(3-(2-Amino-3-mercaptopropylamirlo)-6-phenyl-2pyridyloxy)propi onyl}- phenylalanine 1 57 N{2-(3-(2-Amino-3-me=aptopropylamino)-6-phenyl-2-pyridyloxy)-2phenylacetyl} - methionine N-{2-(3-(2-Aniino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)-2phenylac etyl}- methionine N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)butyryllmethionine methyl ester N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)buty71}-' methionine methyl ester N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyiidyloxy)butyryl) methioijne N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)butyryl}methionine N- {2-(3-(2-Amino-3-mercaptopropyl:irnino)-6-phenyl-2pyridyloxy)hexanoyl}- methionine N-(2-(3-(2-Amino-3-mercaptopropylarnino)-6-phenyl-2-pyridyloxy)hexanoyl}methionine N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)hexanoyllmethionine methyl ester N-(2-(3-(2-Amino-3-mex aptopmpyl2rnino)-6-phenyl-2-pyridyloxy)hexanoyl}- methionine methyl ester 0 58 N(2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl) methionine methyl ester N(2-(3-(2-Amino-3-mer,-aptopropylamino)-6-phenyl-2- pyridyloxy)pentanoyl) methionine methyl ester N{2-(3-(2-Amino-3-meicaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl} methionine N{2-(3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyloxy)pentanoyl} methionine N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-chlorophenyl)-2pyridyloxyaceryl}- methionine N-{3-(2-Amino-3-mercaptopropylanfino)-6-(3-trifluoromethylphenyl)-2pyridyloxyacetyljmethionine N-(3-(2-Amino-3-mercaptopropylamino)-6-(3-methoxyphenyl)-2pyridyloxyacety l}- methionine N- {3-(2-Amino-3-mei aptopropylamino)-6-(3-hydroxymethylphenyl)-2- pyridyloxyacetyllmethionine N- (3-(2-Amino-3-mercaptopropylamino)-6-(3-acetamidophenyl)-2pyridyloxyacety l} - methionine N(3-(2-Amino-3-mercaptopropylamino)-6-(2-biphenylyl)-2- pyridyloxyacetyl} methionine N- (3-(2-Amino-3-mercaptopropylmnino)-6-(4-biphenylyl)-2pyridyloxyacetyl) - 9 methionine 59 N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-methyloxycarbonylphenyl)-2pyridyloxyacetyl) methionine N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-methyloxycarbonylphenyl)-2pyridyloxyaceryl}methionine methyl ester N-{3-(2-Amino-3-mercaptopropylamino)-6-(3-carboxyphenyl)-2pyridyloxyacety l}- methionine N-{3-(2-Amino-3-mercaptopropylamino)-6-(2,4,6-trimethylphenyl)2pyridyloxyacetyl}methionine N{3-(2-Amino-3-mercaptopropylamino)-6-(3-biphenylyl)-2- pyridyloxyacetyl} methionine 2- {3-(2-Amino-3-mercaptopropy]2rnino)-6-butyl-2-pyridyloxy} -N-(3- phenylpropyj)- acetamide N{3-(2-Amino-3-mercaptopropylamino)-6-(2-naphthyl)-2-pyridyloxyacetyl) methionine N-{3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxyacetyllmethionine N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-thienyl)-2pyridyloxyacetyl)meth ionine N-{3-(2-Amino-3-mercaptopropylamino)-6-(2-benzofuryl)-2-pyridyloxyacetyl}methionine N{3-(2-Amino-3-mercaptopropylmffio)-6-butyl-2-pyridyloxyacetyl} methionine 0 N- {3-(2-Amino-3.)-mercaptopropylaniino)-6-(1-naphthyl)-2pyridyloxyacetyl} - methionine N-(3-(2-Amino-3-mercaptopropylamino)-6-(2-thienyl)-2pyridyloxyacetyl)meth ionine methyl ester N-{3-(2-Amino-3-mercaptopropylamino)-6-(1-naphthyl)-2-pyridyloxyaceryl}methionine methyl ester N-{3-(2-ATnino-3-mercaptopropylamino)-6-butyl-2pyridyloxyacetyl}methionin e methyl ester N(2-(3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-pyridyloxy)propionyl} methionine N-{2-(3-(2-Amino-3-mercaptopropylamino)-6-butyl-2-pyridyloxy)propionyl}methionine N{2-(3-(2-Amino-3-mercaptopropyjamino)-2-pyridyloxy)-3-phenylpropionylj methionine N-{2-(3-(2-Amino-3-mercaptopropy]2rnino)-2-pyridyloxy)-3-phenylpropionyljmethionine N-{2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyllmethionine methyl ester N-{2-(3-(2-Amino-3-mercaptopropylamino)-2-pyridyloxy)-3-phenylpropionyl}methionine methyl ester N{3-(2-Amino-3-mercaptopropylamino)-6-benzyl-2-pyridyloxyacetyl} methionine methyl ester 1 61 h N{3-(2-Amino-3-mercaptopropylamino)-6-benzyl-2-pyridyloxyacetyl} methiorne N-{3-(2-Amino-3-mercaptopropylamino)-6-pher,oxy-2pyridyloxyacetyllmethion ine' methyl ester N{3-(2-Amino-3-mercaptopropylamino)-6-phenoxy-2-pyridyloxyacetyl} methionine N- (3-(2- Arnino-3-mercaptopropylamino)-6-phenyl-2-pyiidyl j alanine-(N- benzyl)amide N-{3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2 pyridyl}-D-e-(N- benzy1)amide N-{3-(2-Amino-3-mereaptopropylamino)-6-phenyl-2-pyridyl}-N-methylalanine( N- benzy1)amide N- ( 3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl 1 glycine-(Nbenzyl)an2ide N- {3-(2-Amino-3-mercaptopropylamino)-6-phenyl-2-pyridyl) -N- methy1glycine-(N- benzy1)amide N-{3-(2-Amino-3-mercaptc)l)ropylamino)-6-phenyl-2-pyridyl}-Nmethylalanine -(N- benzy1)amide N{3-(2-Aminc-3-mercaptopropylamino)-6-phenyl-2-pyridyl j aL-inine-(N-2methoxybenzy1)amide N-{3-(2-Amino-3-mei aptopropylamino)-6-phenyl-2-pyridyl}alanine-(N-1- phenylethyl)amide 2(3-(2-Amino-3-mercaptopmpylamino)-6-phenyl-2-pyridyltbio 1 -N-benzylpropionamide 0 62 2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N(3methyloxycarbonylbenzyl)proplonamide 2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-benzylpropionamide 2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy)-N-(2pyridyimet hyl)- propionamide 2-(3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(2methylbenz yl)- propionamide 2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-p,yridyloxy}-N-(2chloroben zyl)- propionamide 2-{3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2-pyridyloxy}-N-(3methyloxycarbonylbenzyl)-N-methylpropionamide N{3-(3-Amino-4-mercaptobutyL-xaino)-6-phenyl-2-pyridyloxyacetyl J methionine methyl ester N-{3-(3-Amino-4-mei aptobutylamino)-6-phenyl-2pyridyloxyacetyl}mcthionine N-(3-(3-Amino-4-mercaptobutylamino)-6-phenyl-2pyridyloxyacetyl}phenylalan ine methyl ester N-{-:^)-(3-Amino-4-meic.aptobutylamino)-6-phenyl-2pyridyloxyacetyl}phenyl alanine 4. A medicinal formulation which includes as an active principal a compound of claim 1.
4 63
5. The use of a medicinal formulation which includes as an active principal a compound of Claim 1, 2 or 3 for the treatment of a human or other mammal.
6. The use of a medicinal formulation which includes as an active principal a compound of Claim 1, 2 or 3 f or the treatment of an inf lammatory pathological condition in a human or other mammal.
7. The use of a medicinal formulation which includes as an active principal a compound of Claim 1, 2 or 3 for the treatment of a proliferative pathological condition in a human or other mammal.
8. The use of a compound according to any of claims 1 to 3 for the preparation of a medicament for the treatment of a proliferative or inflammatory pathological condition.
1 64
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9706923A GB2323842A (en) | 1997-04-04 | 1997-04-04 | Pyridine derivatives |
| PCT/GB1998/000997 WO1998045266A1 (en) | 1997-04-04 | 1998-04-03 | 3-aminopyridine derivatives for treatment of inflammatory and malignant diseases |
| AU69271/98A AU6927198A (en) | 1997-04-04 | 1998-04-03 | 3-aminopyridine derivatives for treatment of inflammatory and malignant diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9706923A GB2323842A (en) | 1997-04-04 | 1997-04-04 | Pyridine derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB9706923D0 GB9706923D0 (en) | 1997-05-21 |
| GB2323842A true GB2323842A (en) | 1998-10-07 |
| GB2323842A8 GB2323842A8 (en) | 1998-10-26 |
Family
ID=10810333
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB9706923A Withdrawn GB2323842A (en) | 1997-04-04 | 1997-04-04 | Pyridine derivatives |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU6927198A (en) |
| GB (1) | GB2323842A (en) |
| WO (1) | WO1998045266A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004043926A1 (en) * | 2002-11-11 | 2004-05-27 | Bayer Healthcare Ag | Phenyl or heteroaryl amino alkane derivatives as ip receptor antagonist |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9013997B2 (en) * | 2012-06-01 | 2015-04-21 | Broadcom Corporation | System for performing distributed data cut-through |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW365602B (en) * | 1994-06-10 | 1999-08-01 | Rhone Poulenc Rorer Sa | New farnesyl transferase inhibitors, their preparation and the pharmaceutical compositions which contain them |
| WO1996021456A1 (en) * | 1995-01-12 | 1996-07-18 | University Of Pittsburgh | Inhibitors of prenyl transferases |
| US5631280A (en) * | 1995-03-29 | 1997-05-20 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
-
1997
- 1997-04-04 GB GB9706923A patent/GB2323842A/en not_active Withdrawn
-
1998
- 1998-04-03 AU AU69271/98A patent/AU6927198A/en not_active Abandoned
- 1998-04-03 WO PCT/GB1998/000997 patent/WO1998045266A1/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004043926A1 (en) * | 2002-11-11 | 2004-05-27 | Bayer Healthcare Ag | Phenyl or heteroaryl amino alkane derivatives as ip receptor antagonist |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2323842A8 (en) | 1998-10-26 |
| WO1998045266A1 (en) | 1998-10-15 |
| GB9706923D0 (en) | 1997-05-21 |
| AU6927198A (en) | 1998-10-30 |
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