Showing papers on "Bicyclic molecule published in 1997"

Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors

Abstract: Substituted heteroaromatic compounds, and in particular substituted bicyclic heteroaromatic compounds in which one ring is a pyridine or pyrimidine of formula (I) are protein tyrosine kinase inhibitors. The compounds are described as are methods for their preparation, pharmaceutical compositions including such compounds and their use in medicine, for example in the treatment of cancer and psoriasis.

Quinazoline derivatives as antitumor agents

Abstract: The invention concerns quinazoline derivatives of formula (I), wherein X1 is a direct link or a group such as CO, C(R2)2 and CH(OR2); wherein Q1 is phenyl, naphthyl or a 5- or 6-membered heteroaryl moiety and Q1 optionally bears up to 3 substituents; wherein m is 1 or 2 and each R1 may be a group such as hydrogen, halogeno and trifluoromethyl; and wherein Q2 may be phenyl or a 9- or 10-membered bicyclic heterocyclic moiety and Q2 optionally bears up to 3 substituents; or a pharmaceutically acceptable salt thereof; processes for their preparation, pharmaceutical compositions containing them and the use of their receptor tyrosine kinase inhibitory properties in the treatment of proliferative disease such as cancer.

4-aminoquinazoline derivatives

Abstract: Disclosed are novel 4-aminoquinazoline derivatives of the formula (See formula I) (wherein Z is NR3R4 in which R3 is H and R4 is Q2 or phenyl substituted with (R5)q or Z is (See formula II) the dotted line represents an optional double bond; R5 is a substituent such as halo, amino, alkyl, alkoxy, etc.; R6 is a substituent such as hydroxyl, amino, sulfo, alkoxy, carboxyl, etc.; q is 0-3; o is 0-2; Q2 is a 9- or 10-membered bicyclic heterocyclic moiety; Q1 is Ar-Y-X in which Ar is mono- or bicyclic (hetero)aryl, X is alkenylene, alkynylene or bond and Y is (CH2)p where p is 0-5; R1 is a substituent such as trifluoromethyl; n is 0-3; m is 1-2) and their pharmaceutically acceptable salts. Those compounds and the salts are useful for the treatment of hyperproliferative disorders and conditions in mammals.

Dual Metalloprotease Inhibitors: Mercaptoacetyl-Based Fused Heterocyclic Dipeptide Mimetics as Inhibitors of Angiotensin-Converting Enzyme and Neutral Endopeptidase

Abstract: A series of 7,6- and 7,5-fused bicyclic thiazepinones and oxazepinones were generated and incorporated as conformationally restricted dipeptide surrogates in mercaptoacyl dipeptides. These compounds are potent inhibitors of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP) both in vitro and in vivo. Compound 1a, a 7,6-fused bicyclic thiazepinone, demonstrated excellent blood pressure lowering in a variety of animal models characterized by various levels of plasma renin activity and significantly potentiated urinary sodium, ANP, and cGMP excretion in a cynomolgus monkey assay. On the basis of its potency and duration of action, compound 1a (BMS-186716) was advanced into clinical development for the treatment of hypertension and congestive heart failure.

Dysiherbaine: A New Neurotoxic Amino Acid from the Micronesian Marine Sponge Dysidea herbacea

Abstract: A new amino acid, dysiherbaine (1), was isolated from a Micronesian sponge Dysidea herbacea. The structure was determined by using FABMS, ESIMS, FABMS/CID/MS, and one- and two-dimensional NMR experiments of 1 and its dimethyl derivative 3 to be a novel diamino dicarboxylic acid, which consisted of a cis-fused hexahydrofuro[3,2-b]pyran ring substituted with a 3-[2-aminopropanoic acid] side chain. The relative configuration of the bicyclic portion of 1 was determined by 3JH,H analysis and difference NOE experiments, and that of the acyclic side chain was assigned by additional 2,3JC,H analysis, measured by hetero half-filtered TOCSY (HETLOC) and phase sensitive HMBC experiments. Systemic administration of 1 induced neurotoxic symptoms in mice which were reminiscent of neuroexcitatory amino acids such as domoic acid. Dysiherbaine inhibited bindings of [3H]-kainic acid (KA) and [3H]-1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), but not [3H]CGS-19755, an N-methyl-d-asparatic acid (NMDA) receptor...

Substituted 4-hydroxy-phenylalcanoic acid derivatives with agonist activity to ppar-gamma

Abstract: A compound having formula (I), wherein A is selected from the group consisting of: (i) phenyl, wherein said phenyl is optionally substituted by one or more halogen atoms, C1-6alkyl, C1-3alkoxy, C1-3fluoroalkoxy, nitrile, or -NR7R8 where R?7 and R8? are independently hydrogen or C?1-3?alkyl; (ii) a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur; and (iii) a fused bicyclic ring (a), wherein ring C represents a heterocyclic group as defined in point (ii) above, which bicyclic ring is attached to group B via a ring atom of ring C; B is selected from the group consisting of: (iv) C1-6alkylene; (v) -MC1-6alkylene or C1-6alkyleneMC1-6alkylene, wherein M is O, S, or -NR?2? wherein R2 represents hydrogen or C?1-3? alkyl; (vi) a 5- or 6-membered heterocyclic group containing at least one nitrogen heteroatom and optionally at least one further heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted by C1-3 alkyl; and (vii) Het-C1-6alkylene, wherein Het represents a heterocyclic group as defined in point (vi) above; Alk represents C1-3alkylene; R?1? represents hydrogen or C?1-3?alkyl; Z is selected from the group consisting of: (viii) -(C1-3alkylene) phenyl, which phenyl is optionally substituted by one or more halogen atoms; and (ix) -NR?3R4?, wherein R3 represents hydrogen or C?1-3?alkyl, and R?4? represents -Y-(C=O)-T-R5, or -Y-(CH(OH))-T-R5.

Antirheumatic agents: novel methotrexate derivatives bearing a benzoxazine or benzothiazine moiety.

Abstract: Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H-1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro. Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68) were comparable to that of MTX in these in vitro assays. Compounds 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In addition, 3d (MX-68) completely suppressed this progression at the dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.

Substituted 6,5-hetero-bicyclic derivatives

Abstract: This invention relates to compounds of formula (I), wherein the dashed lines represent optional double bonds; A is nitrogen or CR7; B is -NR?1R2, -CR1R2R10-C(=CR2R11)R1, -NHCR1R2R10, -OCR1R2R10, -SCR1R2R10, -CR2R10NHR1, -CR2R10OR1, -CR2R10SR1? or -COR2; J and K are each independently nitrogen or carbon and both J and K are not nitrogens; D and E are each selected, independently, from nitrogen, CR4, C=O, C=S, sulfur, oxygen, CR?4R6 and NR8?; G is nitrogen or carbon; and their use for the prevention or inhibition of a disorder that can be treated by antagonizing CRF.

Qinoline derivatives inhibiting the effect of growth factors such as vegf

Abstract: The invention relates to the use of compounds of formula (I) wherein: R2 represents hydroxy, halogeno, C?1-3?alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; n is an integer from 0 to 5; Z represents -O-, -NH-, -S- or -CH2-; G?1? represents phenyl or a 5-10 membered heteroaromatic cyclic or bicyclic group; Y?1, Y2, Y3 and Y4? each independently represents carbon or nitrogen; R1 represents fluoro or hydrogen; m is an integer from 1 to 3; R3 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl; C?1-3?alkyl, -NR?4R5? (wherein R?4 and R5? can each be hydrogen or C?1-3?alkyl), or a group R?6-X1?- wherein X1 represents -CH?2?- or a heteroatom linker group and R?6? is an alkyl, alkenyl or alkynyl chain optionally substituted by for example hydroxy, amino, nitro, alkyl, cycloalkyl, alkoxyalkyl, or an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring, which alkyl, alkenyl or alkynyl chain may have a heteroatom linker group, or R6 is an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans, processes for the preparation of such derivatives, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula (I). The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

Asymmetric Sulfoxidation Catalyzed by a Vanadium-Containing Bromoperoxidase.

Abstract: A vanadium-containing bromoperoxidase (VBrPO) from the alga Corallina officinalis has been shown to catalyze the stereoselective oxidation of some aromatic bicyclic sulfides to the corresponding (S)-sulfoxides in high (up to 91%) ee. Hydrogen peroxide was found to have a large effect on the catalyzed reaction, most likely due to an inhibition of VBrPO. High optical and chemical yields were found to be favored by a continuous slow addition of hydrogen peroxide to keep a low excess. The reaction gives no overoxidation to sulfone, and its stereochemistry is the opposite as compared to that previously found with the heme-containing chloroperoxidase (CPO) from Caldariomyces fumago.

Tyrosine Kinase Inhibitors. 12. Synthesis and Structure−Activity Relationships for 6-Substituted 4-(Phenylamino)pyrimido[5,4-d]pyrimidines Designed as Inhibitors of the Epidermal Growth Factor Receptor

Abstract: A series of 6-substituted 4-anilinopyrimido[5,4-d]pyrimidines has been prepared and shown to be potent inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). These compounds are structurally related to the pyrido[3,2-d]- and pyrido[3,4-d]-pyrimidines previously shown to be EGFR inhibitors. Their structure-activity relationships (SAR) for inhibition of the isolated enzyme more closely resemble those of the [3,2-d] than the [3,4-d] pyridopyrimidine isomers. This suggests the requirement of an aza atom in the 7- but not the 5-position (i.e., a carbon atom in the 5-position) for the enhanced potency shown by 6-N-methylated derivatives in each series. X-ray crystal structures were determined for the three NHMe derivatives 2, 3, and 5c in the pyrido[9,2-d]-, pyrido[3,4-d]-, and pyrimido[5,4-d]-pyrimidine series, respectively. These show that a carbon rather than a nitrogen atom at the 5-position leads to significant conformational changes in the molecule (a longer C5a-C4 bond and a 30 degrees out-of-plane rotation of the phenyl group), due to the requirement to relieve nonbonding interactions between the C5 and N9 protons. Pyrimido[5,4-d]pyrimidine analogues bearing bulky, weakly basic solubilizing side chains linked to the 6-position through a secondary amine generally retained potency both against the isolated enzyme and for inhibition of autophosphorylation of EGFR in intact A431 cells. This agrees with a recent binding model that suggests this general class of compounds binds to EGFR with the 6-position located in an area of comparative bulk tolerance at the entrance to the ATP-binding pocket. While these solubilized pyrimido[5,4-d]pyrimidine analogues were less potent than the NHMe derivative 5c in the isolated enzyme assay, some were considerably superior to 5c (and among the most potent ever reported) as inhibitors of EGFR autophosphorylation in cellular assays.

Cbi analogues of cc-1065 and the duocarmycins

Abstract: 132 CBI analogues of CC-1 065 and the duocarmycins having dimeric monocyclic, bicyclic, and tricyclic heteroaromatics substituents were synthesized by a parallel route. The resultant analogues were evaluated with respect to their catalytic and cytotoxic activities. The relative contribution of the various dimeric monocyclic, bicyclic, and tricyclic heteroaromatics substituents within the DNA binding domain were characterized. Several of the resultant CBI analogues of CC-1065 and the duocarmycins were characterized as having enhanced catalytic and cytotoxic activities and were identified as having utility as anti-cancer agents.

Total synthesis of dysidiolide

Abstract: The cdc25A protein phosphatase inhibitor dysidiolide (1) has been synthesized enantioselectively, starting from the enantiomerically pure ketal enone 2 and using a cationic rearrangement as the key step to produce the fully substituted bicyclic core of the natural product. Once the central portion of 1 was established, elaboration of the side chains was accomplished expediently via steps that included (1) vinyl cuprate displacement of an iodide to complete the C-1 side chain, (2) a highly diastereoselective oxazaborolidine-catalyzed (CBS) reduction to form carbinol 11, and (3) photochemical oxidation of 11 to generate the γ-hydroxybutenolide functionality of 1. Additionally, this synthesis proves the absolute stereochemistry of dysidiolide (1).

Substituted 6,6-hetero-bicyclic derivatives

Abstract: This invention relates to compounds of formula (I), wherein A, B, D, E, K, G, R?3 and R5? are defined as in the specification, and to the pharmaceutically acceptable salts of such compounds. Compounds (I) are corticotropin releasing factor (hormone) CRF (CRH) antagonists.

Intramolecular Cyclization of 2,7- or 2,8-Bis-unsaturated Esters Mediated by (η2-Propene)Ti(O-i-Pr)2. Facile Construction of Mono- and Bicyclic Skeletons with Stereoselective Introduction of a Side Chain. A Synthesis of d-Sabinene

Abstract: tert-Butyl 2-en-7-ynoate 6 was treated with (η2-propene)Ti(O-i-Pr)2 (3), generated in situ from Ti(O-i-Pr)4 or Ti(O-i-Pr)3Cl and i-PrMgCl, in ether at −50 to −20 °C to afford the product 8 in good yield. The presence of the intermediate titanabicycle 7 was verified by bis-deuterolysis with excess D2O. When the titanabicycle 7 was treated with 1.1 equiv of i-PrOD and then worked up as usual, the monodeuterated product 10 was obtained with high site selectivity and stereoselectivity. Other electrophiles such as aldehydes and ketones also reacted with the titanabicycle in a highly stereoselective manner to give cyclopentanes having a stereo-defined side chain. On the contrary, treatment of the corresponding ethyl ester, ethyl 8-(trimethylsilyl)-(E)-2-octen-7-ynoate (28), with 3 under the same conditions followed by the addition of 1.1 equiv of s-BuOH afforded 2-(trimethylsilyl)-1-bicyclo[3.3.0]octen-3-one (32) in 80% yield. Quenching the same reaction mixture with i-PrOD, EtCHO, and Et2CO in place of s-BuOH ...

A Template for Stabilization of a Peptide α-Helix: Synthesis and Evaluation of Conformational Effects by Circular Dichroism and NMR

Abstract: The bicyclic diacid 1 was designed as a semi-rigid template for the hydrogen-bonding pattern of a peptide α-helix. The protected precursor 7 was synthesized in eight steps from tert-butyl 3,5-dimet...

4-Substituted pyrrolopyrimidine compounds as tyrosin kinase inhibitors

Abstract: Novel 4-substituted 7H-pyrrolo[2,3-d]pyrimidine derivatives, useful as tyrosine kinase inhibitors, encompassed by following formula (I) wherein X is -CH 2 -, -NH-(CH 2 ) n -, -O-(CH 2 ) n - or -S-(CH 2 ) n - in which n is zero or 1; A is a mono- or bicyclic ring chosen from phenyl, pyridine, tetralin, indan, 2-oxindole, quinoline, isoquinoline and indole; R is hydrogen, C 1 -C 4 alkyl or benzyl; each of R 1 and R 2 , independently, is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, NR 5 R 6 in which each of R 5 and R 6 independently is hydrogen or C 1 -C 4 alkyl, phenyl unsubstituted or substituted by one to three substituents chosen from halogen, trifluoromethyl, C 1 -C 4 alkyl and C 1 -C 4 alkoxy; each of R 3 and R 4 , independently, is hydrogen, C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkoxycarbonyl, nitro, cyano or trifluoromethyl; and the pharmaceutically acceptable salts thereof are provided.

Controlled formation of organic layers on semiconductor surfaces

Abstract: It has been shown that well-defined, ordered organic layers can be formed on the silicon (100) surface. This is achieved through the interaction of unsaturated C=C bonds with the oriented dimers of the reconstructed Si(100)-(2×1) surface. In this article, we present an investigation of the structure and chemical bonding of organic films prepared using different organic precursors. Data were obtained using scanning tunneling microscopy, Fourier-transform infrared spectroscopy, and x-ray photoelectron spectroscopy. The molecules investigated are cyclopentene, 3-pyrroline, and norbornadiene, representing prototypical cyclic, heterocyclic, and bicyclic unsaturated organic molecules, respectively. Each molecule has at least one unsaturated C=C bond.

Synthesis of conduritols and related compounds

Abstract: New and stereospecific syntheses for all conduritol isomers have been developed starting from appropriate 1.3-cyclohexadiene derivatives. Oxygen functionalities were introduced by photooxygenation. Application of the ene-reaction of singlet oxygen to 1.4-cyclohexadiene and its derivatives afforded diene system which can be easily trapped by second mol of singlet oxygen to give 49 and 50. Thiourea reduction of the peroxide linkages followed by oxidation gave the corresponding pent01 derivatives. Furthermore, reaction of unsaturated endoperoxides with 1.2.4.5- temine derivatives 59-63 afforded new bicyclic endoperoxides with unusual structures.

Heteroaromatic analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors

Abstract: A new series of heteroaromatic GBR 12935 [1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)-piperazine] (I) and GBR 12909 [1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine] (2) analogs was synthesized and evaluated as dopamine transporter (DAT) ligands. Analogs 5-16, in which the benzene ring in the phenylpropyl side chain of the GBR molecule had been replaced with a thiophene, furan, or pyridine ring, exhibited high affinity and selectivity for the DAT vs serotonin transporter (SERT) and stimulated locomotor activity in rats in a manner similar to the parent compound 2. In cocaine and food self-administration studies in rhesus monkeys, both thiophene-containing (6 and 8) and pyridine-containing (14 and 16) derivatives displayed potency comparable to 2 in decreasing the cocaine-maintained responding at the doses tested (0.8, 1.7, and 3 mg/kg). However, these compounds did not produce the degree of separation between food- and cocaine-maintained responding that was seen with 2. Among the bicyclic fused-ring congeners 17-38, the indole-containing analog of 2, 22, showed the greatest affinity for binding to the DAT, with IC50 = 0.7 nM, whereas the corresponding indole-containing derivative of 1, 21, displayed the highest selectivity (over 600-fold) at this site vs the SERT site.

Fused bicyclic pyrimidine derivatives

Abstract: The invention relates to compounds of formula (I) and to pharmaceutically acceptable salts thereof, wherein R1, R2 and Z are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula (I) and to methods of using said compounds in the treatment of hyperproliferative diseases such as cancer.

New pharmaceutically active compounds

Abstract: The present invention relates to novel compounds which are protein kinase C inhibitors, methods for their preparation, intermediates therefor and pharmaceutical compositions comprising them. More particularly, the present invention relates to compounds of formula (I), wherein one of Ar1 and Ar2 is optionally substitute d bicyclic heteroaryl or optionally substituted tricyclic heteroaryl and the other is optionally substituted heteroaryl or optionally substituted aryl; X is O or S; and R is H, OH, NH2 or C1-6 alkyl (itself optionally substituted by amino or hydroxy); or a salt or solvate thereof, or a solvate of a salt thereof; and the use of such compounds in medical therapies.

[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives as high-affinity, selective 5-HT1A receptor ligands.

Abstract: A series of 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4(1H)-one and 3-substituted 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4(3H)-one derivatives was prepared and evaluated for in vitro 5-HT1A receptor affinity by radioligand binding assays; the selectivity for 5-HT1A receptors rather than α1-adrenoceptors was also examined (ratio of the IC50 α1 to IC50 5-HT1A). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the substituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT1A ligands. The most effective derivative for displacing [3H]-8-OH-DPAT from rat hippocampal membranes was the 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0.3 nM) with selectivity of 24 for the 5-HT1A over the α1-adrenoceptor. Compound 73, where the 2-methoxyphenyl on the N4 piperazine ring was replaced with a pyrimidine group, showed the be...