Synthetic routes have been developed to access 4‐substituted 1(2H)‐isoquinolinones from readily a... more Synthetic routes have been developed to access 4‐substituted 1(2H)‐isoquinolinones from readily available precursors. This is achieved via electrophilic trapping of di‐ and monolithium anions derived from alkyllithium exchange of 4‐bromo‐1(2H)‐isoquinolinones and corresponding 4‐bromo‐1‐methoxyisoquinolines, respectively. Products derived from the latter are then hydrolyzed to the target 4‐substituted 1(2H)‐isoquinolinones. The methodology has potential application to access 4‐substituted 1(2H)‐isoquinolinones with additional substituents in either ring.
Screening of a compound library for inhibitors of the fibroblast growth factor (FGFr) and platele... more Screening of a compound library for inhibitors of the fibroblast growth factor (FGFr) and platelet-derived growth factor (PDGFr) receptor tyrosine kinases led to the development of a novel series of ATP competitive pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. The initial lead, 1-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3- tert-butylurea (4b, PD-089828), was found to be a broadly active tyrosine kinase inhibitor. Compound 4b inhibited the PDGFr, FGFr, EGFr, and c-src tyrosine kinases with IC50 values of 1.11, 0.13, 0.45, and 0.22 microM, respectively. Subsequent SAR studies led to the synthesis of new analogs with improved potency, solubility, and bioavailability relative to the initial lead. For example, the introduction of a [4-(diethylamino)butyl]amino side chain into the 2-position of 4b afforded compound 6c with enhanced potency and bioavailability. Compound 6c inhibited PDGF-stimulated vascular smooth muscle cell proliferation with an IC50 of 0.3 microM. Furthermore, replacement of the 6-(2,6-dichlorophenyl) moiety of 4b with a 6-(3',5'-dimethoxyphenyl) functionality produced a highly selective FGFr tyrosine kinase inhibitor 4e. Compound 4e inhibited the FGFr tyrosine kinase with an IC50 of 0.060 microM, whereas IC50s for the inhibition of the PDGFr, FGFr, EGFr, c-src, and InsR tyrosine kinases for this compound (4e) were all greater than 50 microM.
Aus dem Dichloran-thrachjnon (I) werden über die Nitroverbindung (II) das Amino-Derivat (III) und... more Aus dem Dichloran-thrachjnon (I) werden über die Nitroverbindung (II) das Amino-Derivat (III) und das Hydroxy-Derivat (IV) hergestellt. (IR-, 'HNMR-Daten).
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The Synthesis of Symmetrical (2-Indolyl)ethynes and Reduced Congeners via Palladium-Catalyzed Cou... more The Synthesis of Symmetrical (2-Indolyl)ethynes and Reduced Congeners via Palladium-Catalyzed Couplings of 2-Bromoindole Precursors. -The target compounds (VII), (IX), and (X) are inactive towards tyrosine kinase. -(SERCEL, A. D.;
Aufgrund der pharmakologischen Eigenschaften des Alkaloids Canthin-6-on (I) werden Synthesewege z... more Aufgrund der pharmakologischen Eigenschaften des Alkaloids Canthin-6-on (I) werden Synthesewege zu diesem sowie zu ähnlichen Verbindungen beschrieben. Tryptophan (II) reagiert mit dem Acetal (III) in Gegenwart von Essigs äure und liefert nach Behandlung mit Bichromat das Methoxymethyl-Derivat (IV), das mit HBr zum Carbinol (Va) gespalten und dann durch Braunstein zum Harmanaldehyd (Vb) oxidiert wird. Mit Malons äure (VIa) erh ält man aus (Vb) in Gegenwart von Piperidin das Canthinon (I), das auch über eine Kondensation mit Ma1onester(VIb) zum Ester (VIIa) und dessen Hydrolyse zur Carbons äure (VIIb) nach Decarboxylierung entsteht. Ferner werden die Amide (VIIc) hergestellt. Mit Bernsteins äurealdehyd (VIII) erh ält man aus (II) das Kondensat (IX), das mit Hg(II)-acetat zu (I) oxidiert wird. Indol-3-essigester (X) reagiert mit Bemsteins äureanhydrid (XI) zum 1-substituierten Indol (XIIa), dessen S äurechlonid (XIIb) in Gegenwart von Aluminiumchlorid zu (XIII) cyclisiert wird. Mit Ammoniak entsteht das Amid (XIIc), mit Pyridiniumperbromid das Dehydrierungs produkt (XIV). Ferner werden das Monoxim (XVa) und dessen Acetat (XVb) hergestellt. Aus (IV) entsteht mit Oxalester (XVI) das Cyclisierungsprodukt (XVII). (IR-, UV-, NMR-, MS-Spektren).
... SCC-100000577 Lalgudi S. Harikrishnan a * , Terri L. Boehm b & HD Hollis Showalter b page... more ... SCC-100000577 Lalgudi S. Harikrishnan a * , Terri L. Boehm b & HD Hollis Showalter b pages 519-525. ... The reduction of this logic to practice is shown is Scheme 2. 3-Hydroxy pyridine 4 was protected as its MOM ether 5 [11]11. Winkle, MR and Ronald, RC 1982. J. Org. Chem. ...
Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibitors of the plateletde... more Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibitors of the plateletderived growth factor receptor (PDGFR), further structure-activity relationships for analogues (particularly 5-substituted derivatives) are reported. The data are consistent with a binding model (constructed from the homology-modeled structure of the catalytic subunit of the PDGFR using protein kinase A as the template) in which the ligand binds in the relatively narrow ATP site, with the phenyl ring pointing toward the interior of the pocket and the 5-position of the benzimidazole ring toward the mouth of the pocket. The narrow binding pocket allows a maximum torsion angle between the phenyl and benzimidazole rings of about 40°, consistent with that calculated (43.6°) for the minimum-energy conformation of the unsubstituted free ligand. The inactivity of 7-or 2′-substituted analogues is consistent with the greater torsion angle (and thus larger ligand cross-section) of such substituted analogues. There is substantial bulk tolerance for 5-substituents, which protrude out of the mouth of the hydrophobic pocket, with the most effective analogues being those bearing weak bases. On the basis of this model, 5-OR derivatives bearing cationic side chains were prepared as soluble analogues, and these showed sub-micromolar potencies against the isolated PDGFR enzyme. They were also moderately effective inhibitors of autophosphorylation of PDGFR in rat aortic vascular smooth muscle cells, with IC 50 s in the range 0.1-1 µM.
7-Substituted 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas are inhibitors of fibrobl... more 7-Substituted 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas are inhibitors of fibroblast growth factor receptor-1 (FGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2). 3-(3,5-Dimethoxyphenyl) and 3-phenyl analogues were prepared from 7-acetamido-2-tert-butylureas by alkylation with benzyl omega-iodoalkyl ethers, debenzylation, and amination, followed by selective cleavage of the 7-N-acetamide. 3-(2,6-Dichlorophenyl) analogues were prepared from the 7-fluoro-2-amine by displacement with substituted alkylamines, followed by selective acylation of the resulting substituted naphthyridine-2,7-diamines with alkyl isocyanates. The 3-(3,5-dimethoxyphenyl) derivatives were low nanomolar inhibitors of both FGFR and VEGFR and were highly selective (>100-fold) over PDGFR and c-Src. Variations in the base strength or spatial position of the 7-side chain base had only small effects on the potency (<5-fold) or selectivity (<20-fold). The 3-(2,6-dichlorophenyl)-2-urea derivatives were slightly less active against VEGFR and less selective, being more effective against PDGFR (ca. 10-fold) and c-Src (ca. 500-fold). The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridines were generally more potent than the corresponding pyrido[2,3-d]pyrimidines against both VEGFR and FGFR (2- to 20-fold), with only slightly increased PDGFR and c-Src activity. The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine 2-ureas were also low nanomolar inhibitors of the growth of human umbilical vein endothelial cells (HUVECs) stimulated by serum, FGF, or VEGF, at concentrations that did not affect the growth of representative tumor cell lines, and were more (3- to 65-fold) potent than the corresponding pyrido[2,3-d]pyrimidines.
While engaged in therapeutic intervention against a number of proliferative diseases, we have dis... more While engaged in therapeutic intervention against a number of proliferative diseases, we have discovered the 2-aminopyrido[2, 3-d]pyrimidin-7(8H)-ones as a novel class of potent, broadly active tyrosine kinase (TK) inhibitors. An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. From the lead structure 2, a series of analogues bearing variable substituents at the C-2 position and methyl or ethyl at N-8 was made. Compounds of this series were competitive with ATP and displayed submicromolar to low nanomolar potency against a panel of TKs, including receptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGFr; epidermal growth factor, EGFr) and nonreceptor (c-Src) classes. One of the more thoroughly evaluated members was 63 with IC50 values of 0.079 microM (PDGFr), 0.043 microM (bFGFr), 0.044 microM (EGFr), and 0.009 microM (c-Src). In cellular studies, 63 inhibited PDGF-mediated receptor autophosphorylation in a number of cell lines at IC50 values of 0.026-0.002 microM and proliferation of two PDGF-dependent lines at 0.3 microM. It also caused inhibition of soft agar colony formation in three cell lines that overexpress the c-Src TK, with IC50 values of 0.33-1.8 microM. In in vivo studies against a panel of seven xenograft tumor models with known and/or inferred dependence on the EGFr, PDGFr, and c-Src TKs, compound 63 produced a tumor growth delay of 10.6 days against the relatively refractory SK-OV-3 ovarian xenograft and also displayed activity against the HT-29 tumor. In rat oral bioavailability studies, compound 63 plasma concentrations declined in a biexponential manner, and systemic plasma clearance was high relative to liver blood flow. Finally, in rat metabolism studies, HPLC chromatography identified two metabolites of 63, which were proved by mass spectrometry and synthesis to be the primary amine (58) and N-oxide (66). Because of the excellent potency of 63 against selected TKs, in vitro and in vivo studies are underway for this compound in additional tumor models dependent upon PDGFr, FGFr, and c-Src to assess its potential for advancement to clinical trials.
Approaches toward the preparative-scale synthesis of target 3,4-dihydro-1(2H)-isoquinolinones 1–3... more Approaches toward the preparative-scale synthesis of target 3,4-dihydro-1(2H)-isoquinolinones 1–3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large-scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high-temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)-isoquinolinone (9). Catalytic hydrogenation of 9 provided the desired 3,4-dihydro-5-methyl-1(2H)-isoquinolinone (2) in 65 % overall yield. Similar reduction of a commercially available 5-hydroxy-1(2H)-isoquinolinone precursor 10 followed by an O-alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4-dihydro-1(2H)-isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.
Chemical-ionization (CI) mass spectra are described for methyl esters of eight clinically signifi... more Chemical-ionization (CI) mass spectra are described for methyl esters of eight clinically significant penicillins and their breakdown products. These substances give spectra with very few fragment ions and contain easily discernible protonated molecule ions. The main cleavage reaction is postulated to involve a retro 2 + 2 DIELS-ALDER-type fragmentation of the 13-lactam ring liberating one fragment (m/e=174) that is characteristic of the penicillin nucleus and a second fragment that is molecule specific, as it contains the elements of the side chain. The other fragment ions, though interesting, are of minor intensity. The free acids, on the other hand, fragment more extensively because of their relative instability and lack of volatility. These spectra resemble electron impact spectra more closely and, though they encode more structural information, are less reproducible from run to run. The ease with which the esters can be made and the relative simplicity of their CI mass spectra make this method significant for the identification and characterization of 3-lactam antibiotics.
A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the know... more A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the known quinazolones 19 and 23, via conversion to the corresponding thiones, S-methylation to the thioethers, N-1-alkylation, and coupling with 3-bromoaniline. C-3-Substituted pyrroloquinazolines were prepared by Mannich base chemistry. A series of compounds bearing solubilizing side chains at these positions has been prepared and evaluated for inhibition of the tyrosine kinase activity of the isolated epidermal growth factor receptor (EGFR) and of its autophosphorylation in EGF-stimulated A431 cells. Several analogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both assays. A model for the binding of the general class of 4-anilinoquinazolines to the EGFR was constructed from structural information (particularly for the catalytic subunit of the cAMP-dependent protein kinase) and structure-activity relationships (SAR) in the series. In this model, the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions of quinazoline and related pyridopyrimidine inhibitors) occupies the entrance of the ATP binding pocket of the enzyme, with the pyrrole nitrogen located at the bottom of the cleft and the pyrrole C-3 position pointing toward a pocket corresponding to the ribose binding site of ATP. This allows considerable bulk tolerance for C-3 substituents and lesser but still significant bulk tolerance for N-1 substituents. The observed high selectivity of these compounds for binding to EGFR over other similar tyrosine kinases is attributed to the 4-anilino ring binding in an adjacent hydrophobic pocket which has an amino acid composition unique to the EGFR. The SAR seen for inhibition of the isolated enzyme by the pyrazolo- and pyrroloquinazolines discussed here is fully consistent with this binding model. For the N-1-substituted compounds, inhibition of autophosphorylation in A431 cells correlates well with inhibition of the isolated enzyme, as seen previously for related pyridopyrimidines. However, the C-3-substituted pyrroloquinazolines show unexpectedly high potencies in the autophosphorylation assay, making them of particular interest.
While engaged in therapeutic intervention against a number of proliferative diseases, we have dis... more While engaged in therapeutic intervention against a number of proliferative diseases, we have discovered the 2-aminopyrido[2, 3-d]pyrimidin-7(8H)-ones as a novel class of potent, broadly active tyrosine kinase (TK) inhibitors. An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. From the lead structure 2, a series of analogues bearing variable substituents at the C-2 position and methyl or ethyl at N-8 was made. Compounds of this series were competitive with ATP and displayed submicromolar to low nanomolar potency against a panel of TKs, including receptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGFr; epidermal growth factor, EGFr) and nonreceptor (c-Src) classes. One of the more thoroughly evaluated members was 63 with IC50 values of 0.079 microM (PDGFr), 0.043 microM (bFGFr), 0.044 microM (EGFr), and 0.009 microM (c-Src). In cellular studies, 63 inhibited PDGF-mediated receptor autophosphorylation in a number of cell lines at IC50 values of 0.026-0.002 microM and proliferation of two PDGF-dependent lines at 0.3 microM. It also caused inhibition of soft agar colony formation in three cell lines that overexpress the c-Src TK, with IC50 values of 0.33-1.8 microM. In in vivo studies against a panel of seven xenograft tumor models with known and/or inferred dependence on the EGFr, PDGFr, and c-Src TKs, compound 63 produced a tumor growth delay of 10.6 days against the relatively refractory SK-OV-3 ovarian xenograft and also displayed activity against the HT-29 tumor. In rat oral bioavailability studies, compound 63 plasma concentrations declined in a biexponential manner, and systemic plasma clearance was high relative to liver blood flow. Finally, in rat metabolism studies, HPLC chromatography identified two metabolites of 63, which were proved by mass spectrometry and synthesis to be the primary amine (58) and N-oxide (66). Because of the excellent potency of 63 against selected TKs, in vitro and in vivo studies are underway for this compound in additional tumor models dependent upon PDGFr, FGFr, and c-Src to assess its potential for advancement to clinical trials.
Das Nitro-styryl-imidazol (Ia) liefert die N-Derivate (Ib) und (Ic) neben den Isomeren (IIb) und ... more Das Nitro-styryl-imidazol (Ia) liefert die N-Derivate (Ib) und (Ic) neben den Isomeren (IIb) und (IIc). (Ib) und (Ic) werden zu den Alkoholen (III) abgebaut und diese nach Oxidation zu den Aldehyden (IV) in die Cyanhydrin-silylether (V) umgewandelt. (Ie) kann ferner an der Nitrogruppe direkt reduziert und acyliert werden und dann in (VIIa) mit (VIIb) übergef ührt werden, jedoch ist das Diamin (VIII) so nicht zug änglich. Ein weiterer Versuch zur Synthese von (VIII) geht von (IXa) aus, das über (IXb) zu den Olefinen (X) und zum Epoxid (XI) f ührt, aus dem die Azidalkohole (XII) und (XIII) erhalten werden k önnen. Die Verbindungen sollen f ür die Synthese des Diazepin-Systems (XIV) im therapeutisch interessanten Pentostatin (XV) eingesetzt werden. (IR-, UV-, NMR-Daten).
A series of 4-acylamino-a-oximinobenzeneacetic acids, and 1,2-dihydro-6-methyl-aoximino-2-oxo-3-p... more A series of 4-acylamino-a-oximinobenzeneacetic acids, and 1,2-dihydro-6-methyl-aoximino-2-oxo-3-pyridineacetic acid were prepared and coupled to 7-aminocephalosporanic acid and its 3'-(1-methyltetrazol-5-yl)thiolo analogue. Several coupling methods and oxime protecting groups were thoroughly examined. The best coupling procedure employed dimethylchloroformimini um chloride, and the tetrahydropyranyl (THP) group was selected for oxime protection. The cephalosporins prepared were tested and compared to cefuroxime and cefotaxime. The corresponding a-keto acids, and 0-methyl oximes were also examined. A great deal of attention has been given in recent years, to several new and therapeutically significant antibiotics, in which a ,3-lactam nucleus is appended to a Z-a-oximino acid. Early entries in this area were nocardicin A' (1) and cefuroximez) (2), followed more recently, by the very potent cefotaxime3) (3) and its derivatives". These compounds possess especially good Gram-negative activity and are resistant to most 8-lactamases". In all known examples, the E (anti)-isomers were not found to be active. While the free oxime (=NOH) of 1 is essential for good activity (KAMIYA, private communication), the 0-substituted oximes (=NOCH3) of cefuroxime and cefotaxime are preferred and slightly more active than their unsubstituted dcrivativese,14>.
The 1,4-dichloroanthraquinones (I) are coupled with the hydrazines (II), yielding the pyrazole de... more The 1,4-dichloroanthraquinones (I) are coupled with the hydrazines (II), yielding the pyrazole derivatives (III). These react with the amines (IV) to form the substitution products (V). The synthesis of some representatives of (II) and of the fused pyrazoles (X) is also described. Ethylation of (III) (X, R1: -H) produces the isomers (VIII) and (IX). The sulfonates (XII) undergo substitution reactions with the compounds (XIII), yielding the derivatives (XIV). (UV-, IR-, 1H-NMR-data).
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Synthetic routes have been developed to access 4‐substituted 1(2H)‐isoquinolinones from readily a... more Synthetic routes have been developed to access 4‐substituted 1(2H)‐isoquinolinones from readily available precursors. This is achieved via electrophilic trapping of di‐ and monolithium anions derived from alkyllithium exchange of 4‐bromo‐1(2H)‐isoquinolinones and corresponding 4‐bromo‐1‐methoxyisoquinolines, respectively. Products derived from the latter are then hydrolyzed to the target 4‐substituted 1(2H)‐isoquinolinones. The methodology has potential application to access 4‐substituted 1(2H)‐isoquinolinones with additional substituents in either ring.
Screening of a compound library for inhibitors of the fibroblast growth factor (FGFr) and platele... more Screening of a compound library for inhibitors of the fibroblast growth factor (FGFr) and platelet-derived growth factor (PDGFr) receptor tyrosine kinases led to the development of a novel series of ATP competitive pyrido[2,3-d]pyrimidine tyrosine kinase inhibitors. The initial lead, 1-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3- tert-butylurea (4b, PD-089828), was found to be a broadly active tyrosine kinase inhibitor. Compound 4b inhibited the PDGFr, FGFr, EGFr, and c-src tyrosine kinases with IC50 values of 1.11, 0.13, 0.45, and 0.22 microM, respectively. Subsequent SAR studies led to the synthesis of new analogs with improved potency, solubility, and bioavailability relative to the initial lead. For example, the introduction of a [4-(diethylamino)butyl]amino side chain into the 2-position of 4b afforded compound 6c with enhanced potency and bioavailability. Compound 6c inhibited PDGF-stimulated vascular smooth muscle cell proliferation with an IC50 of 0.3 microM. Furthermore, replacement of the 6-(2,6-dichlorophenyl) moiety of 4b with a 6-(3',5'-dimethoxyphenyl) functionality produced a highly selective FGFr tyrosine kinase inhibitor 4e. Compound 4e inhibited the FGFr tyrosine kinase with an IC50 of 0.060 microM, whereas IC50s for the inhibition of the PDGFr, FGFr, EGFr, c-src, and InsR tyrosine kinases for this compound (4e) were all greater than 50 microM.
Aus dem Dichloran-thrachjnon (I) werden über die Nitroverbindung (II) das Amino-Derivat (III) und... more Aus dem Dichloran-thrachjnon (I) werden über die Nitroverbindung (II) das Amino-Derivat (III) und das Hydroxy-Derivat (IV) hergestellt. (IR-, 'HNMR-Daten).
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The Synthesis of Symmetrical (2-Indolyl)ethynes and Reduced Congeners via Palladium-Catalyzed Cou... more The Synthesis of Symmetrical (2-Indolyl)ethynes and Reduced Congeners via Palladium-Catalyzed Couplings of 2-Bromoindole Precursors. -The target compounds (VII), (IX), and (X) are inactive towards tyrosine kinase. -(SERCEL, A. D.;
Aufgrund der pharmakologischen Eigenschaften des Alkaloids Canthin-6-on (I) werden Synthesewege z... more Aufgrund der pharmakologischen Eigenschaften des Alkaloids Canthin-6-on (I) werden Synthesewege zu diesem sowie zu ähnlichen Verbindungen beschrieben. Tryptophan (II) reagiert mit dem Acetal (III) in Gegenwart von Essigs äure und liefert nach Behandlung mit Bichromat das Methoxymethyl-Derivat (IV), das mit HBr zum Carbinol (Va) gespalten und dann durch Braunstein zum Harmanaldehyd (Vb) oxidiert wird. Mit Malons äure (VIa) erh ält man aus (Vb) in Gegenwart von Piperidin das Canthinon (I), das auch über eine Kondensation mit Ma1onester(VIb) zum Ester (VIIa) und dessen Hydrolyse zur Carbons äure (VIIb) nach Decarboxylierung entsteht. Ferner werden die Amide (VIIc) hergestellt. Mit Bernsteins äurealdehyd (VIII) erh ält man aus (II) das Kondensat (IX), das mit Hg(II)-acetat zu (I) oxidiert wird. Indol-3-essigester (X) reagiert mit Bemsteins äureanhydrid (XI) zum 1-substituierten Indol (XIIa), dessen S äurechlonid (XIIb) in Gegenwart von Aluminiumchlorid zu (XIII) cyclisiert wird. Mit Ammoniak entsteht das Amid (XIIc), mit Pyridiniumperbromid das Dehydrierungs produkt (XIV). Ferner werden das Monoxim (XVa) und dessen Acetat (XVb) hergestellt. Aus (IV) entsteht mit Oxalester (XVI) das Cyclisierungsprodukt (XVII). (IR-, UV-, NMR-, MS-Spektren).
... SCC-100000577 Lalgudi S. Harikrishnan a * , Terri L. Boehm b & HD Hollis Showalter b page... more ... SCC-100000577 Lalgudi S. Harikrishnan a * , Terri L. Boehm b & HD Hollis Showalter b pages 519-525. ... The reduction of this logic to practice is shown is Scheme 2. 3-Hydroxy pyridine 4 was protected as its MOM ether 5 [11]11. Winkle, MR and Ronald, RC 1982. J. Org. Chem. ...
Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibitors of the plateletde... more Following an earlier discovery of 1-phenylbenzimidazoles as ATP-site inhibitors of the plateletderived growth factor receptor (PDGFR), further structure-activity relationships for analogues (particularly 5-substituted derivatives) are reported. The data are consistent with a binding model (constructed from the homology-modeled structure of the catalytic subunit of the PDGFR using protein kinase A as the template) in which the ligand binds in the relatively narrow ATP site, with the phenyl ring pointing toward the interior of the pocket and the 5-position of the benzimidazole ring toward the mouth of the pocket. The narrow binding pocket allows a maximum torsion angle between the phenyl and benzimidazole rings of about 40°, consistent with that calculated (43.6°) for the minimum-energy conformation of the unsubstituted free ligand. The inactivity of 7-or 2′-substituted analogues is consistent with the greater torsion angle (and thus larger ligand cross-section) of such substituted analogues. There is substantial bulk tolerance for 5-substituents, which protrude out of the mouth of the hydrophobic pocket, with the most effective analogues being those bearing weak bases. On the basis of this model, 5-OR derivatives bearing cationic side chains were prepared as soluble analogues, and these showed sub-micromolar potencies against the isolated PDGFR enzyme. They were also moderately effective inhibitors of autophosphorylation of PDGFR in rat aortic vascular smooth muscle cells, with IC 50 s in the range 0.1-1 µM.
7-Substituted 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas are inhibitors of fibrobl... more 7-Substituted 3-aryl-1,6-naphthyridine-2,7-diamines and related 2-ureas are inhibitors of fibroblast growth factor receptor-1 (FGFR-1) and vascular endothelial growth factor receptor-2 (VEGFR-2). 3-(3,5-Dimethoxyphenyl) and 3-phenyl analogues were prepared from 7-acetamido-2-tert-butylureas by alkylation with benzyl omega-iodoalkyl ethers, debenzylation, and amination, followed by selective cleavage of the 7-N-acetamide. 3-(2,6-Dichlorophenyl) analogues were prepared from the 7-fluoro-2-amine by displacement with substituted alkylamines, followed by selective acylation of the resulting substituted naphthyridine-2,7-diamines with alkyl isocyanates. The 3-(3,5-dimethoxyphenyl) derivatives were low nanomolar inhibitors of both FGFR and VEGFR and were highly selective (>100-fold) over PDGFR and c-Src. Variations in the base strength or spatial position of the 7-side chain base had only small effects on the potency (<5-fold) or selectivity (<20-fold). The 3-(2,6-dichlorophenyl)-2-urea derivatives were slightly less active against VEGFR and less selective, being more effective against PDGFR (ca. 10-fold) and c-Src (ca. 500-fold). The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridines were generally more potent than the corresponding pyrido[2,3-d]pyrimidines against both VEGFR and FGFR (2- to 20-fold), with only slightly increased PDGFR and c-Src activity. The 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine 2-ureas were also low nanomolar inhibitors of the growth of human umbilical vein endothelial cells (HUVECs) stimulated by serum, FGF, or VEGF, at concentrations that did not affect the growth of representative tumor cell lines, and were more (3- to 65-fold) potent than the corresponding pyrido[2,3-d]pyrimidines.
While engaged in therapeutic intervention against a number of proliferative diseases, we have dis... more While engaged in therapeutic intervention against a number of proliferative diseases, we have discovered the 2-aminopyrido[2, 3-d]pyrimidin-7(8H)-ones as a novel class of potent, broadly active tyrosine kinase (TK) inhibitors. An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. From the lead structure 2, a series of analogues bearing variable substituents at the C-2 position and methyl or ethyl at N-8 was made. Compounds of this series were competitive with ATP and displayed submicromolar to low nanomolar potency against a panel of TKs, including receptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGFr; epidermal growth factor, EGFr) and nonreceptor (c-Src) classes. One of the more thoroughly evaluated members was 63 with IC50 values of 0.079 microM (PDGFr), 0.043 microM (bFGFr), 0.044 microM (EGFr), and 0.009 microM (c-Src). In cellular studies, 63 inhibited PDGF-mediated receptor autophosphorylation in a number of cell lines at IC50 values of 0.026-0.002 microM and proliferation of two PDGF-dependent lines at 0.3 microM. It also caused inhibition of soft agar colony formation in three cell lines that overexpress the c-Src TK, with IC50 values of 0.33-1.8 microM. In in vivo studies against a panel of seven xenograft tumor models with known and/or inferred dependence on the EGFr, PDGFr, and c-Src TKs, compound 63 produced a tumor growth delay of 10.6 days against the relatively refractory SK-OV-3 ovarian xenograft and also displayed activity against the HT-29 tumor. In rat oral bioavailability studies, compound 63 plasma concentrations declined in a biexponential manner, and systemic plasma clearance was high relative to liver blood flow. Finally, in rat metabolism studies, HPLC chromatography identified two metabolites of 63, which were proved by mass spectrometry and synthesis to be the primary amine (58) and N-oxide (66). Because of the excellent potency of 63 against selected TKs, in vitro and in vivo studies are underway for this compound in additional tumor models dependent upon PDGFr, FGFr, and c-Src to assess its potential for advancement to clinical trials.
Approaches toward the preparative-scale synthesis of target 3,4-dihydro-1(2H)-isoquinolinones 1–3... more Approaches toward the preparative-scale synthesis of target 3,4-dihydro-1(2H)-isoquinolinones 1–3 are presented. Compounds 1 and 2 were prepared via a Schmidt rearrangement on easily obtained indanone precursors, but in low overall yield. A better method to make this class of compounds is exemplified by the large-scale synthesis of 2 via a Curtius rearrangement sequence. Thus, high-temperature thermal cyclization of an in situ formed styryl isocyanate from precursor 8 in the presence of tributylamine gave the corresponding 1(2H)-isoquinolinone (9). Catalytic hydrogenation of 9 provided the desired 3,4-dihydro-5-methyl-1(2H)-isoquinolinone (2) in 65 % overall yield. Similar reduction of a commercially available 5-hydroxy-1(2H)-isoquinolinone precursor 10 followed by an O-alkylation/amination sequence gave target 3 in good overall yield. The route proceeding via the Curtius rearrangement is recommended for large scale synthesis of other 3,4-dihydro-1(2H)-isoquinolinones. Only when deactivating substituents or sensitive functionality within the benzenoid ring render the high temperature ring closure of the intermediate isocyanate inefficient might a Schmidt rearrangement protocol be the method of choice.
Chemical-ionization (CI) mass spectra are described for methyl esters of eight clinically signifi... more Chemical-ionization (CI) mass spectra are described for methyl esters of eight clinically significant penicillins and their breakdown products. These substances give spectra with very few fragment ions and contain easily discernible protonated molecule ions. The main cleavage reaction is postulated to involve a retro 2 + 2 DIELS-ALDER-type fragmentation of the 13-lactam ring liberating one fragment (m/e=174) that is characteristic of the penicillin nucleus and a second fragment that is molecule specific, as it contains the elements of the side chain. The other fragment ions, though interesting, are of minor intensity. The free acids, on the other hand, fragment more extensively because of their relative instability and lack of volatility. These spectra resemble electron impact spectra more closely and, though they encode more structural information, are less reproducible from run to run. The ease with which the esters can be made and the relative simplicity of their CI mass spectra make this method significant for the identification and characterization of 3-lactam antibiotics.
A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the know... more A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the known quinazolones 19 and 23, via conversion to the corresponding thiones, S-methylation to the thioethers, N-1-alkylation, and coupling with 3-bromoaniline. C-3-Substituted pyrroloquinazolines were prepared by Mannich base chemistry. A series of compounds bearing solubilizing side chains at these positions has been prepared and evaluated for inhibition of the tyrosine kinase activity of the isolated epidermal growth factor receptor (EGFR) and of its autophosphorylation in EGF-stimulated A431 cells. Several analogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both assays. A model for the binding of the general class of 4-anilinoquinazolines to the EGFR was constructed from structural information (particularly for the catalytic subunit of the cAMP-dependent protein kinase) and structure-activity relationships (SAR) in the series. In this model, the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions of quinazoline and related pyridopyrimidine inhibitors) occupies the entrance of the ATP binding pocket of the enzyme, with the pyrrole nitrogen located at the bottom of the cleft and the pyrrole C-3 position pointing toward a pocket corresponding to the ribose binding site of ATP. This allows considerable bulk tolerance for C-3 substituents and lesser but still significant bulk tolerance for N-1 substituents. The observed high selectivity of these compounds for binding to EGFR over other similar tyrosine kinases is attributed to the 4-anilino ring binding in an adjacent hydrophobic pocket which has an amino acid composition unique to the EGFR. The SAR seen for inhibition of the isolated enzyme by the pyrazolo- and pyrroloquinazolines discussed here is fully consistent with this binding model. For the N-1-substituted compounds, inhibition of autophosphorylation in A431 cells correlates well with inhibition of the isolated enzyme, as seen previously for related pyridopyrimidines. However, the C-3-substituted pyrroloquinazolines show unexpectedly high potencies in the autophosphorylation assay, making them of particular interest.
While engaged in therapeutic intervention against a number of proliferative diseases, we have dis... more While engaged in therapeutic intervention against a number of proliferative diseases, we have discovered the 2-aminopyrido[2, 3-d]pyrimidin-7(8H)-ones as a novel class of potent, broadly active tyrosine kinase (TK) inhibitors. An efficient route was developed that enabled the synthesis of a wide variety of analogues with substitution on several positions of the template. From the lead structure 2, a series of analogues bearing variable substituents at the C-2 position and methyl or ethyl at N-8 was made. Compounds of this series were competitive with ATP and displayed submicromolar to low nanomolar potency against a panel of TKs, including receptor (platelet-derived growth factor, PDGFr; fibroblast growth factor, FGFr; epidermal growth factor, EGFr) and nonreceptor (c-Src) classes. One of the more thoroughly evaluated members was 63 with IC50 values of 0.079 microM (PDGFr), 0.043 microM (bFGFr), 0.044 microM (EGFr), and 0.009 microM (c-Src). In cellular studies, 63 inhibited PDGF-mediated receptor autophosphorylation in a number of cell lines at IC50 values of 0.026-0.002 microM and proliferation of two PDGF-dependent lines at 0.3 microM. It also caused inhibition of soft agar colony formation in three cell lines that overexpress the c-Src TK, with IC50 values of 0.33-1.8 microM. In in vivo studies against a panel of seven xenograft tumor models with known and/or inferred dependence on the EGFr, PDGFr, and c-Src TKs, compound 63 produced a tumor growth delay of 10.6 days against the relatively refractory SK-OV-3 ovarian xenograft and also displayed activity against the HT-29 tumor. In rat oral bioavailability studies, compound 63 plasma concentrations declined in a biexponential manner, and systemic plasma clearance was high relative to liver blood flow. Finally, in rat metabolism studies, HPLC chromatography identified two metabolites of 63, which were proved by mass spectrometry and synthesis to be the primary amine (58) and N-oxide (66). Because of the excellent potency of 63 against selected TKs, in vitro and in vivo studies are underway for this compound in additional tumor models dependent upon PDGFr, FGFr, and c-Src to assess its potential for advancement to clinical trials.
Das Nitro-styryl-imidazol (Ia) liefert die N-Derivate (Ib) und (Ic) neben den Isomeren (IIb) und ... more Das Nitro-styryl-imidazol (Ia) liefert die N-Derivate (Ib) und (Ic) neben den Isomeren (IIb) und (IIc). (Ib) und (Ic) werden zu den Alkoholen (III) abgebaut und diese nach Oxidation zu den Aldehyden (IV) in die Cyanhydrin-silylether (V) umgewandelt. (Ie) kann ferner an der Nitrogruppe direkt reduziert und acyliert werden und dann in (VIIa) mit (VIIb) übergef ührt werden, jedoch ist das Diamin (VIII) so nicht zug änglich. Ein weiterer Versuch zur Synthese von (VIII) geht von (IXa) aus, das über (IXb) zu den Olefinen (X) und zum Epoxid (XI) f ührt, aus dem die Azidalkohole (XII) und (XIII) erhalten werden k önnen. Die Verbindungen sollen f ür die Synthese des Diazepin-Systems (XIV) im therapeutisch interessanten Pentostatin (XV) eingesetzt werden. (IR-, UV-, NMR-Daten).
A series of 4-acylamino-a-oximinobenzeneacetic acids, and 1,2-dihydro-6-methyl-aoximino-2-oxo-3-p... more A series of 4-acylamino-a-oximinobenzeneacetic acids, and 1,2-dihydro-6-methyl-aoximino-2-oxo-3-pyridineacetic acid were prepared and coupled to 7-aminocephalosporanic acid and its 3'-(1-methyltetrazol-5-yl)thiolo analogue. Several coupling methods and oxime protecting groups were thoroughly examined. The best coupling procedure employed dimethylchloroformimini um chloride, and the tetrahydropyranyl (THP) group was selected for oxime protection. The cephalosporins prepared were tested and compared to cefuroxime and cefotaxime. The corresponding a-keto acids, and 0-methyl oximes were also examined. A great deal of attention has been given in recent years, to several new and therapeutically significant antibiotics, in which a ,3-lactam nucleus is appended to a Z-a-oximino acid. Early entries in this area were nocardicin A' (1) and cefuroximez) (2), followed more recently, by the very potent cefotaxime3) (3) and its derivatives". These compounds possess especially good Gram-negative activity and are resistant to most 8-lactamases". In all known examples, the E (anti)-isomers were not found to be active. While the free oxime (=NOH) of 1 is essential for good activity (KAMIYA, private communication), the 0-substituted oximes (=NOCH3) of cefuroxime and cefotaxime are preferred and slightly more active than their unsubstituted dcrivativese,14>.
The 1,4-dichloroanthraquinones (I) are coupled with the hydrazines (II), yielding the pyrazole de... more The 1,4-dichloroanthraquinones (I) are coupled with the hydrazines (II), yielding the pyrazole derivatives (III). These react with the amines (IV) to form the substitution products (V). The synthesis of some representatives of (II) and of the fused pyrazoles (X) is also described. Ethylation of (III) (X, R1: -H) produces the isomers (VIII) and (IX). The sulfonates (XII) undergo substitution reactions with the compounds (XIII), yielding the derivatives (XIV). (UV-, IR-, 1H-NMR-data).
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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Papers by Hollis Showalter