EP1094812A1 - Angiogenesisinhibitoren - Google Patents
AngiogenesisinhibitorenInfo
- Publication number
- EP1094812A1 EP1094812A1 EP99932289A EP99932289A EP1094812A1 EP 1094812 A1 EP1094812 A1 EP 1094812A1 EP 99932289 A EP99932289 A EP 99932289A EP 99932289 A EP99932289 A EP 99932289A EP 1094812 A1 EP1094812 A1 EP 1094812A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- naphthyl
- represented
- mhz
- mmol
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/52—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/02—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton
- C07C247/04—Compounds containing azido groups with azido groups bound to acyclic carbon atoms of a carbon skeleton being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
- C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D233/44—Nitrogen atoms not forming part of a nitro radical
- C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- 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
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
Definitions
- the present invention relates to nonpeptide compounds having RGD mimetic activity and to the synthesis and biological activity of nonpeptide compounds having RGD mimetic activity. More particularly, the present invention relates to nitroaryl based nonpeptide RGD mimetics and to their synthesis and biological activity.
- the integrins are a class of extracellular proteins that facilitate cell-cell and cell-matrix adhesion (Cheresh, D.A.; Mecham, R.P. Eds.; Academic Press: New York, 1994; Stromblad, S.; Cheresh, D.A. Chem. Biol . 1996, 3, 881)
- These important biological targets are membrane bound, heterodimeric glycoproteins made up of an -subunit and a smaller ⁇ -subunit.
- the relative affinity and specificity for ligand binding is determined by the unique combination of the different ⁇ - and ⁇ - subunits.
- ⁇ IIb ⁇ 3 Of the members of this family of receptors, ⁇ IIb ⁇ 3 , a 5 l r Oi v ⁇ 3 , and ⁇ v ⁇ 5 are the most studied.
- a number of known natural ligands to these integrins such as fibronectin (binds to 5 ⁇ 1 ) , fibrinogen (binds to ⁇ IIb ⁇ 3 ) and vitronectin (binds to Q! v ⁇ 3 ) , contain the key peptide sequence Arg-Gly-Asp (RGD) within their native sequence, which is recognized by most integrins.
- the ⁇ IIb ⁇ 3 integrin was shown to be an excellent target for the inhibition of platelet aggregation and several groups have already disclosed the design and synthesis of potent binders with peptide and nonpeptidal structures (Ojima et al . Bioorg. Med. Chem., 1995, 337; Engleman et al . Ann. Rep. Med. Chem. 1996, 31, 191).
- Antagonists of X v ⁇ 3 are, therefore, envisioned as potential therapeutic agents for the treatment of numerous disease states such as diabetic retinopathy, cancer, osteoporosis and restenosis (Van der Pluijm et al . Bone Mineral Res. 1994, 9, 1021; Helfrich et al . J. Bone Mineral Res. 1992, 7, 335; Horton et al . Ex . Cell Res. 1991, 195, 368; Robey et al . Ann. Rep. Med. Chem. 1993, 28, 227; Choi et al. Surgery 1994, 19, 125; Matsuno et al . Circulation 1994, 90, 2203; Hammes et al . Nature Med. 1996, 2, 529; Friedlander et al. Proc. Natl. Acad. Sci., USA 1996, 93, 9764.
- the first small molecule antagonists of 0C v ⁇ 3 were reported by Kessler et al . (e.g. 1, Figure 1; Gurrath et al .
- the invention is directed to the design, chemical synthesis and biological evaluation of a series of nitroaryl- based RGD mimetics. More particularly, the invention is directed to compounds which combine a novel nitroaryl system with arylether/ ⁇ -aminoacid/guanidine frameworks of the type disclosed in U.S. Patent No. 5,741,796, issued April 21, 1998, incorporated herein by reference, i.e., the "Merck compounds”.
- RGD mimetic represented by the following structure:
- R 1 is selected from the following radical :
- X is a diradical selected from sulfur, -NH- and oxygen.
- R 2 is a radical selected from -C0 2 t-Butyl, -CO-Aryl and -S0 2 - Aryl .
- Preferred Aryls include phenyl , 1-naphthyl, and 2- naphthyl .
- a preferred R 2 radical is -S0 2 -Aryl.
- a preferred RGD mimetic is represented by the following structure:
- RGD mimetics are represented by the following structures :
- nitroaryl precursor having a fluoride group covalently attached to the nitroaryl ring represented by the following structure:
- R 3 is an acid protecting group. Then, the fluoride group is displaced with a nucleophile having a protected guanidine group using nucleophilic aromatic substitution for producing a protected RGD mimetic. Finally, the protected RGD mimetic is deprotected with an acid for producing the RDG mimetic.
- RGD mimetic represented by the following structure:
- R 2 is a radical selected from a group consisting of -C0 2 t-Butyl, and -S0 2 -Aryl.
- Preferred Aryls include phenyl, 1-naphthyl, and 2-naphthyl.
- RGD mimetics were tested against a variety of integrins ( ⁇ v ⁇ 3 , o IIb ⁇ 3 and ⁇ v ⁇ 5 ) for their ability to inhibit cell adhesion and in order to determine their binding selectivity. Selected compounds were also tested for their ability to inhibit angiogenesis in vivo in the CAM (chick chorioallantoic membrane) assay. All compounds were verified to have inhibitory activity and selectivity against the above targets, consistant with their activity as inhibitors of angiogenesis
- Another aspect of the invention is directed to a process for differentially inhibiting ⁇ llb ⁇ 3 mediated cell adhesion over ⁇ v ⁇ 3 mediated cell adhesion.
- Cells that express ⁇ llb ⁇ 3 are contacted with a solution containing selected RGD mimetics.
- the solution has a concentration of such RGD mimetics sufficient for inhibiting ⁇ llb ⁇ 3 mediated cell adhesion.
- ⁇ llb ⁇ 3 mediated cell adhesion is inhibited at least approximately 100 fold more than v ⁇ 3 mediated cell adhesion.
- Preferred RGD mimetics employable for this aspect of the invention are as follows:
- Figure 1 illustrates selected structures of ⁇ v ⁇ 3 antagonists based on the RGD peptide sequence.
- Figure 2 illustrates selected nonpeptide RGD mimetics with high affinity for Oi v ⁇ 3 .
- Figure 3 illustrates targeted nitroaryl ethers (10-21) as RGD mimetics and benzimidazole 22.
- Figure 4 illustrates general structures of nitroarylether RGD mimetics and retrosynthetic analysis.
- Figure 5 illustrates synthesis of amino esters 26, 29a and 29b with the following Reagents and condi tions : (a) 1.1 equivalents of Boc 2 0, 1.0 equivalent of Na 2 C0 3 , 1,4-dioxane, H 2 0, 25°C, 88%; (b) i ) 20% aqueous solution of Cs 2 C0 3 , H20:Me0H (1:2.5), 25°C, 4 hours, 100%, ii ) 1.1 equivalents of BnBr, DMF, 25°C, 14 hours, 88%; (c) 1.5 equivalents of Phi (OCOCF 3 ) 2 , DMF:H 2 0 (1:1), 2.0 equivalents of pyridine, 25°C, 3.5 hours, 41%; (d) 1.1 equivalents of ArS0 2 Cl, 2.25 equivalents of NaOH, dioxane:H 2 0 (1:2), 0 to 25°C, 3 hours, [71% for 27a, 66% for 27b]; (e
- Figure 6 illustrates the synthesis of compounds 10 - 13 with the following Reagents and condi tions : (a) 5.0 equivalents of MeC(OMe) 3 , PhMe, 80°C, 8 hours, 98%; (b) 1.1 equivalents of N 3 (CH 2 ) 2 OTBS, 0.1 equivalents of TBAF, 4 A MS, DMF, 25°C, 4 hours, 73%; (c) 2.0 equivalents of LiOH «H 2 0, 3:1 dioxane:H20 (3:1), 25°C, 4 hours, 99%; (d) 1.0 equivalent of DCC, 0.2 equivalents of 4-DMAP, CH 2 C1 2 , 25°C, 4 hours, 82%; (e) 50% TFA in CH 2 C1 2 , 25°C, 2 hours, 84%; (f) 1.1 equivalents of PhS0 2 Cl or l-NaphS0 2 Cl, 1.3 equivalents of i-Pr2NEt, CH 2 C1 2 , 25°C,4 hours
- Figure 7 illustrates the snthesis of guanidine derivatives 51 - 56 with the following Reagents and condi tions : (a) 1.0 equivalent of BtBMTP, 2.0 equivalents of Et 3 N, 1.0 equivalent of HgCl 2 , DMF, 25°C, 4 hours, 98%; (b) 1.0 equivalent of BtBMTP, DMF, 25°C, 14 hours, 95%; (c) 1.0 equivalent of BtBCT, DMF, 25°C, 14 hours, 60%; (d) 0.2 equivalents of BtBMTP, 0.4 equivalents of Et 3 N, 0.2 equivalents of HgCl 2 , DMF, 25°C, 4 hours, 51%; (e) 0.66 equivalents of o-NH 2 C 6 H 4 NH 2 , 5.5 N aqueous HCl, reflux, 24 hours, 73%; (f) 1.0 equivalent of DmPD»HBr, iPr 2 NEt, DMF, 25°C, 11 hours, 51%.
- Figure 8 illustrates the synthesis of compounds 11 and 14-19 with the following reagents and conditions: (a) 1.2 equivalents of (C0C1) 2 , PhH, DMF, 0°C, 6 hours, 99%; (b) 1.0 equivalent of 29a or 29b, 1.2 equivalents of Et 3 N, CH 2 C1 2 , 0°C, 2 hours, 58 (98%), or 59 (96%); (c) for 60: 2.2 equivalents of NaH, 2.2 equivalents of 51, DMF, 25°C, 8 hours, 66%; for 63:
- Figure 10 illustrates the synthesis of compound 22 with the following Reagents and condi tions : (a) NH 3 , DMF, 25°C, 5 hours, 93%; (b) 10% Pd/C, H 2 , MeOH, 25°C, 8 hours, 90%; (c)
- Figure 11 shows a compilation of data which indicates the effect of nitroaryl ethers on RGD-dependent ligand interaction with integrins.
- concentration necessary for half-maximal inhibition of ligand binding (IC 50 ) is shown.
- the peptide GRGDSPK and compound 1 were included for reference.
- the data have been sorted by IC 50 values (from low to high) on ⁇ v ⁇ 3 .
- the 'cQ' value shows the activity of the NPE relative to the activity of compound 1.
- the >' shows that the IC 50 had not been reached at the maximum concentration tested, 10 ⁇ M.
- Figure 12 shows a compilation of data which indicates the effect of nitroaryl ethers on RGD-dependent cell adhesion to immobilized ligands.
- concentration necessary for half- maximal inhibition of ligand binding IC 50
- 25000 cells were allowed to adhere to immobilized ligands in the presence of the nitroaryl ethers as described herein.
- concentration resulting in half-maximal inhibition of cell adhesion IC 50
- the data have been sorted by IC 50 (from low to high) on ⁇ v ⁇ 3 mediated adhesion of M21 cells.
- FIG. 3 shows the targeted compounds (10-22) .
- the considerations that led to their design were : (a) the Merck findings pointing to the importance of the guanidine/aryl sulfonamide functionalities (Duggan et al . Abstracts of Papers, 211th ACS National Meeting, New La, LA, March 24-28, 1996; American Chemical Society: Washington, DC, 1996, MEDI 234); and (b) the facile entry into such structures from o-nitro-arylfluorides as shown in Figure 4.
- the designed molecules fall within the general structure I ( Figure 4) which can be derived by coupling the central nitrofluoroaromatic system II with fragments III (nucleophile) and IV (aminoacid component) .
- the sulfonamides 29a and 29b were prepared by sulfonylation of the amino group to afford 27a, followed by Hoffmann rearrangement and esterification of the resulting aminoacids (28a and 28b) with isobutylene ( Figure 5) .
- FIG. 6 summarizes the initial approach to compounds 10- 13.
- 4-fluoro-o-nitrobenzoic acid (30) was converted to its methyl ester (31, 98%) by treatment with trimethylorthoacetate at 80°C, and thence reacted with N 3 (CH 2 ) 2 OTBS in DMF in the presence of catalytic amounts of TBAF resulting in the formation of compound 32 (73%; yields are unoptimized) .
- Saponification of 32 (LiOH, 99% yield) furnished carboxylic acid 33 which was condensed with building block 26 in the presence of DCC and 4-DMAP to give key intermedate 34 (82% yield).
- nucleophilic species containing a fully protected guanidine moiety was to be employed in the displacement of the fluoride from the central nitroaryl system.
- nucleophiles 51-56 (Poss et al. Tetrahedron Lett. 1992, 33, 5933; Iwanowicz et al . Synth. Commun. 1993, 23, 1443; Cherkaoui et al . Bull. Soc. Chim. Fr . 1991, 255) were prepared from readily available starting materials and by standard chemistry as outlined in Figure 7.
- the amino compounds 61 and 64 were obtained from 58 and 59 in 73 and 99% yield respectively, by reaction with amine 53 in DMF at ambient temperature.
- Thioether 62 was obtained by exposure of 58 to thiol 54 and NaH (DMF, 25°C, 23% yield) .
- Treatment of componds 60-64 with TFA in CH 2 C1 2 at room temperature resulted in concomitant deprotection of both the guanidine and carboxyl groups in excellent yield (90-99%, after RP-HPLC purification) .
- the piperazine compounds 16 and 19 were prepared in a similar fashion from 58 and 59 respectively by first displacing the fluoride with nucleophile 52, followed by TFA-induced deprotection of the resulting derivatives 65 and 66 as summarized in Figure 8.
- Reverse phase HPLC was performed on a Waters Model 600E HPLC instrument utilizing a Vydac 218TP1022 column with detection at 254 nm using a 90:10 E 40:60 H 2 0:CH 3 CN + 0.1% TFA gradient over 40 minutes.
- NMR spectra were recorded on Bruker DRX-600, AMX-500, AMX-400 or AC-250 instruments and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiples- band, several overlapping signals; b, broad.
- IR spectra were recorded on a Perkin-Elmer 1600 series FT-IR spectrometer.
- High resolution mass spectra (HRMS) were recorded on a VG ZAB- ZSE mass spectrometer under fast atom bombardment (FAB) conditions.
- Electrospray mass spectra were recorded on a Perkin Elmer Science API III mass spectrometer.
- the aqueous phase was extracted with ethyl acetate (2 x 50 mL) .
- the aqueous layer was acidified at 0°C with cone, aqueous HCl (pH ⁇ 1) while the protected amino acid precipitated.
- the resulting solid was collected by filtration and washed with H 2 0 (20 mL) . Overnight drying in an oven at ca. 50°C gave 27a as a colorless solid (14.6 grams, 71%) .
- the crude product was used without further purification.
- Step A To a solution of 3-hydroxypropionic acid (.073 g, 0.16 mmol, 1.0 equiv.) was added DMF (0.5 mL, .32 M), imidazole (26.0 mg, 0.38 mmol, 2.4 equiv.) and TBDPSC1 (.046 mL, 0.19 mmol, 1.2 equiv.) and allowed to stir for 2.5 hour at 25 °C. The solution was then diluted with ether (10 mL) and then washed with a saturated solution of 5% hydrogen chloride (2X 10 mL) , water (2X 10 mL) , brine (IX 5 mL) and then dried over MgS04. The compound was purified by flash column chromatography (silica, 80% ether in light petroleum ether) and carried onto the next step as follows:
- Step B To a solution of phenylenediamine (1.08 g, 0.01 mol) in 5.5 N HCl (10 mL) was added the protected intermediate formed in step A (1.125g, 0.015 mol) at room temperature. The reaction mixture was refluxed for 24 h and then allowed to cool to room temperature. The solvent was removed in vacuo to give a precipitate, which was filtered and washed with ether; and then
- Step C The TBDPS group was removed as follows: A solution of intermediate from Step B (7.481 mmol) in THF (0.1M) was cooled to 0 °C and treated with azeotropically dried (benzene, 3 x 50 L) TBAF (22.44 mmol). The reaction mixture was stirred at 0 °C for 10 h and quenched with saturated aqueous NH 4 C1. the two layers were separated and the aqueous phase was extracted with a mixture of ethyl acetate and ethyl ether. The combined organic phase was washed with brine, dried, and concentrated. Purification by silica gel column chromatography gave the pure compound 55(b) wherein -NH 2 substituent of compound 55 is replaced with -OH.
- the aqueous solution was extracted with diethyl ether (40 mL) and then the pH of the aqueous phase adjusted to 12-13 with 6 N aqueous NaOH.
- the free amine was extracted with ethyl acetate (4 x 50 mL) and the combined organic extracts were washed successiveively with saturated aqueous NaHC0 3 -solution (50 mL) , 5 % aqueous KHS0 4 -solution (50 mL) and brine (50 mL) .
- the organic phase was dried over MgS0 4 , filtrated and the solvent removed in vacuo to give 29a (10.9 grams, 55.5%) as an off- white solid.
- the crude product was used without further purification.
- R f 0.43 (silica gel, 50 % ethyl acetate in hexanes); IR (KBr): n max 3329, 3142, 2977, 2934, 2870, 1724, 1644, 1443, 1412, 1360, 1299, 1103, 1052, 1027, 864, 809, 778 cm “1 ; X H NMR (500 MHz, CDC1 3 ) : d 11.48 (bs, 1 H, NHC0 2 ) , 8.66 (m, 1 H,
- the solution was cooled to 0°C and 5.5 mL of the previously prepared suspension was added by means of a syringe. After 8 hours at 0°C the reaction was stopped by addition of water (10 mL) and diluted with ethyl acetate. The aqueous phase was seperated and extracted with ethyl acetate (3 x 25 mL) . The combined organic extracts were washed successively with H 2 0 (2 x 10 L) and brine (10 mL) and dried over MgS0 4 .
- aqueous phase was extracted with ethyl acetate (3 x 25 mL) .
- the combined organic extracts were washed successiveively with water (2 x 10 mL) and brine (10 mL) and dried over MgS0 4 .
- the residue was purified by flash column chromatography (silica gel, 40 % ethyl acetate in hexanes) to give 62 as a yellowish foam (35 mg, 23%) .
- reaction mixture was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3 x 10 mL) .
- the combined organic extracts were washed successiveively with water (2 x 5 mL) and brine (5 mL) and dried over MgSO 4 .
- the residue was purified by flash column chromatography (silica gel, 50 % ethyl acetate in hexanes) to give 64 as a yellow solid (76 mg, 99%).
- R f 0.16 (silica, 5% methanol in dichloromethane) ; IR (thin film) : n max 3316, 3061, 2978, 1729, 1624, 1504, 1448, 1368, 1309, 1252,
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11088598A | 1998-07-06 | 1998-07-06 | |
US110885 | 1998-07-06 | ||
PCT/US1999/015252 WO2000001383A1 (en) | 1998-07-06 | 1999-07-06 | Angiogenesis inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1094812A1 true EP1094812A1 (de) | 2001-05-02 |
EP1094812A4 EP1094812A4 (de) | 2003-04-16 |
Family
ID=22335452
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99932289A Withdrawn EP1094812A4 (de) | 1998-07-06 | 1999-07-06 | Angiogenesisinhibitoren |
Country Status (14)
Country | Link |
---|---|
EP (1) | EP1094812A4 (de) |
JP (1) | JP2002519377A (de) |
KR (1) | KR20010079497A (de) |
CN (1) | CN1308534A (de) |
AU (1) | AU4862599A (de) |
BR (1) | BR9911885A (de) |
CA (1) | CA2336774A1 (de) |
HU (1) | HUP0104509A3 (de) |
ID (1) | ID28125A (de) |
NO (1) | NO20010085L (de) |
PL (1) | PL345574A1 (de) |
SK (1) | SK242001A3 (de) |
WO (1) | WO2000001383A1 (de) |
ZA (1) | ZA200007405B (de) |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9805655D0 (en) | 1998-03-16 | 1998-05-13 | Celltech Therapeutics Ltd | Chemical compounds |
GB9814414D0 (en) | 1998-07-03 | 1998-09-02 | Celltech Therapeutics Ltd | Chemical compounds |
GB9826174D0 (en) | 1998-11-30 | 1999-01-20 | Celltech Therapeutics Ltd | Chemical compounds |
WO2001079173A2 (en) | 2000-04-17 | 2001-10-25 | Celltech R & D Limited | Enamine derivatives as cell adhesion molecules |
US6486174B2 (en) | 2000-08-07 | 2002-11-26 | 3-Dimensional Pharmaceuticals, Inc. | Tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidines as integrin antagonists |
EP1488455B1 (de) | 2002-03-20 | 2010-08-11 | Koninklijke Philips Electronics N.V. | Elektrolumineszierende anzeigevorrichtungen mit aktiver matrix und deren herstellungsverfahren |
US8586033B2 (en) * | 2003-12-03 | 2013-11-19 | The Scripps Research Institute | Integrin αIIbβ3 specific antibodies and peptides |
EP3381460A4 (de) * | 2015-11-26 | 2019-07-17 | Daiwa Pharmaceutical Co., Ltd | Angiogenesehemmer |
CN109535035A (zh) * | 2019-01-08 | 2019-03-29 | 吉尔生化(上海)有限公司 | 一种n-苄氧羰基-3-氨基-丙氨酸叔丁酯的制备方法 |
CN113773260B (zh) * | 2021-08-26 | 2023-09-22 | 华南师范大学 | 一种类共价有机材料及其制备方法和应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994008962A1 (en) * | 1992-10-14 | 1994-04-28 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
WO1994012181A1 (en) * | 1992-12-01 | 1994-06-09 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
WO1997037655A1 (en) * | 1996-04-10 | 1997-10-16 | Merck & Co., Inc. | αvβ3 ANTAGONISTS |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU701776B2 (en) * | 1994-05-27 | 1999-02-04 | Merck & Co., Inc. | Compounds for inhibiting osteoclast-mediated bone resorption |
-
1999
- 1999-07-06 ID IDW20010172A patent/ID28125A/id unknown
- 1999-07-06 CA CA002336774A patent/CA2336774A1/en not_active Abandoned
- 1999-07-06 WO PCT/US1999/015252 patent/WO2000001383A1/en not_active Application Discontinuation
- 1999-07-06 KR KR1020017000144A patent/KR20010079497A/ko not_active Application Discontinuation
- 1999-07-06 EP EP99932289A patent/EP1094812A4/de not_active Withdrawn
- 1999-07-06 JP JP2000557829A patent/JP2002519377A/ja active Pending
- 1999-07-06 BR BR9911885-8A patent/BR9911885A/pt not_active Application Discontinuation
- 1999-07-06 CN CN99808280A patent/CN1308534A/zh active Pending
- 1999-07-06 PL PL99345574A patent/PL345574A1/xx not_active Application Discontinuation
- 1999-07-06 AU AU48625/99A patent/AU4862599A/en not_active Abandoned
- 1999-07-06 SK SK24-2001A patent/SK242001A3/sk unknown
- 1999-07-06 HU HU0104509A patent/HUP0104509A3/hu unknown
-
2000
- 2000-12-12 ZA ZA200007405A patent/ZA200007405B/xx unknown
-
2001
- 2001-01-05 NO NO20010085A patent/NO20010085L/no not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994008962A1 (en) * | 1992-10-14 | 1994-04-28 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
WO1994012181A1 (en) * | 1992-12-01 | 1994-06-09 | Merck & Co., Inc. | Fibrinogen receptor antagonists |
WO1997037655A1 (en) * | 1996-04-10 | 1997-10-16 | Merck & Co., Inc. | αvβ3 ANTAGONISTS |
Non-Patent Citations (3)
Title |
---|
CHU-BIAO X ET AL: "Design, synthesis and in vitro activities of a series of benzimidazole/benzoxazole glycoprotein IIb/IIIa inhibitors" BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 6, no. 3, 6 February 1996 (1996-02-06), pages 339-344, XP004135090 ISSN: 0960-894X * |
NICOLAOU K C ET AL: "DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NONPEPTIDE INTEGRIN ANTAGONISTS" BIOORGANIC & MEDICINAL CHEMISTRY, ELSEVIER SCIENCE LTD, GB, vol. 6, no. 8, 1998, pages 1185-1208, XP000908906 ISSN: 0968-0896 * |
See also references of WO0001383A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP1094812A4 (de) | 2003-04-16 |
SK242001A3 (en) | 2001-10-08 |
JP2002519377A (ja) | 2002-07-02 |
HUP0104509A2 (hu) | 2002-04-29 |
PL345574A1 (en) | 2001-12-17 |
CA2336774A1 (en) | 2000-01-13 |
HUP0104509A3 (en) | 2002-05-28 |
BR9911885A (pt) | 2001-03-27 |
ID28125A (id) | 2001-05-03 |
CN1308534A (zh) | 2001-08-15 |
ZA200007405B (en) | 2001-09-21 |
AU4862599A (en) | 2000-01-24 |
WO2000001383A1 (en) | 2000-01-13 |
NO20010085D0 (no) | 2001-01-05 |
NO20010085L (no) | 2001-03-05 |
KR20010079497A (ko) | 2001-08-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Nicolaou et al. | Design, synthesis and biological evaluation of nonpeptide integrin antagonists | |
AU702487B2 (en) | Meta-guanidine, urea, thiourea or azacyclic amino benzoic acid derivatives as integrin antagonists | |
DK171888B1 (da) | Benzoe- og phenyleddikesyreamidderivater, farmaceutiske præparater indeholdende forbindelserne, anvendelse af forbindelserne, samt mellemprodukter | |
AU742928C (en) | N-alkanoylphenylalanine derivatives | |
AU761407B2 (en) | New biphenyl and biphenyl-analogous compounds as integrin antagonists | |
JP4177484B2 (ja) | 置換されたジアミノカルボン酸 | |
CA2250464A1 (en) | Meta-substituted phenylene derivatives and their use as alphavbeta3 integrin antagonists or inhibitors | |
US6806365B2 (en) | N-alkanoylphenylalamine derivatives | |
CA2238175A1 (en) | D-amino acid derived inhibitors of cysteine and serine proteases | |
EP1094812A1 (de) | Angiogenesisinhibitoren | |
CZ280651B6 (cs) | Farmakologicky účinné hydrazinové deriváty a způsob jejich výroby | |
EP1330430A2 (de) | Integrinrezeptor-inhibitoren | |
CA2075547A1 (en) | Trifluoromethyl-containing pseudopeptides | |
CA2210746A1 (en) | Platelet aggregation inhibitors | |
US5424426A (en) | Dithiolanylglycine-containing HIV protease inhibitors of the hydroxyethylene isostere type | |
MXPA00012759A (en) | Angiogenesis inhibitors | |
CZ20004656A3 (cs) | RGD mimetická látka, způsob její produkce a způsob pro diferenční inhibování buněčné adheze | |
WO2003051795A2 (de) | Harzgebundene isonitrile | |
Suhs | New guanidinium compounds for the molecular recognition of carboxylates and contributions to the synthesis of bivalent NPY Y1 receptor antagonists | |
JPS6052698B2 (ja) | チオウレア及びウレア誘導体の製造法 | |
MXPA00001743A (es) | Derivados de n-alcanoilfenilalanina | |
IE870109L (en) | Substituted peptide compounds | |
NO314800B1 (no) | N<alfa>-2-(4-nitrofenylsulfonyl)etoksykarbonylaminosyrer og fremgangsmåte for fremstilling av disse | |
HRP930500A2 (en) | Benzoic-acid phenylacetic-acid new derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20001213 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
AX | Request for extension of the european patent |
Free format text: AL PAYMENT 20000107;LT PAYMENT 20000107;LV PAYMENT 20000107;MK PAYMENT 20000107;RO PAYMENT 20000107;SI PAYMENT 20000107 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: MERCK PATENT GMBH Owner name: THE SCRIPPS RESEARCH INSTITUTE |
|
RIC1 | Information provided on ipc code assigned before grant |
Free format text: 7C 07D 235/14 A, 7C 07C 235/52 B, 7C 07C 247/04 B, 7C 07C 271/22 B, 7C 07C 279/08 B, 7C 07C 311/19 B, 7C 07D 233/48 B, 7C 07D 235/30 B, 7C 07D 295/20 B, 7A 61K 31/435 B |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 20030226 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20040203 |