Showing papers on "Bicyclic molecule published in 1995"

Carbocyclic nucleosides containing bicyclic rings, oligonucleotides therefrom, process for their preparation, their use and intermediates

Abstract: Compounds of the formulae I and Ia and their racemates ##STR1## in which A is --CH 2 -- or --CH 2 CH 2 --, R 1 is hydrogen or a protective group, R 2 is hydrogen or a protective group or a radical forming a phosphorus-containing nucleotide bridge group and B is a purine or pyrimidine radical or an analogue thereof, can be used as antiviral active ingredients or for the preparation of biologically active oligonucleotides.

Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family

Abstract: Epidermal growth-factor inhibitors of formula (I), wherein: 1) Y and Z are both C (carbon), both N or one N and the other C, in which case the ring structure is a linearly fused 6,6 (5 or 6) tricycle, or 2) one of Y and Z is C=C, C=N, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a nonlinear 6,6 (5 or 6) tricycle, or 3) one of Y and Z is N, O or S, whereupon the other one of Y or Z is simply a bond between the two aromatic rings, then the ring structure is a fused 6,5 (5 or 6) tricycle; A, B, D and E can all be carbon, or up to two of them can be nitrogen, whereupon the remaining atoms must be carbon, or any two contiguous positions in A-E can be a single heteroatom, N, O or S, forming a five membered fused ring, in which case one of the two remaining atoms must be carbon, and the other can be either carbon or nitrogen. X = O, S, NH or NR9, such that R9 = lower alkyl, OH, NH?2?, lower alkoxy or lower monoalkylamino m = 0-3, and Ar is phenyl, thienyl, furanyl, pyrrolyl, pyridyl, pyrimidyl, imidazolyl, pyrazinyl, oxazolyl, thiazolyl, naphthyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, isoquinolinyl and quinazolinyl.

Tetracyclic derivatives, process of preparation and use

Abstract: A compound of formula (I) ##STR1## and salts and solvates thereof, in which: R 0 represents hydrogen, halogen or C 1-6 alkyl; R 1 represents hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-3 alkyl, arylC 1-3 alkyl or heteroarylC 1-3 alkyl; R 2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic ring ##STR2## attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and R 3 represents hydrogen or C 1-3 alkyl, or R 1 and R 3 together represent a 3- or 4-membered alkyl or alkenyl chain. A compound of formula (I) is a potent and selective inhibitor of cyclic guanosine 3', 5'-monophosphate specific phosphodiesterase (cGMP specific PDE) having a utility in a variety of therapeutic areas where such inhibition is beneficial, including the treatment of cardiovascular disorders.

Bicyclic fibrinogen antagonists

Abstract: This invention relates to compounds of formula (I), wherein A1 to A5 form an accessible substituted seven-membered ring, which may be saturated or unsaturated, optionally containing up to two heteroatoms chosen from the group of O, S and N wherein S and N may be optionally oxidized; D1 to D4 form an accessible substituted six membered ring, optionally containing up to two nitrogen atoms; R is at least one substituent chosen from the group of R7, or Q-C?1-4?alkyl, Q-C2-4alkenyl, Q-C2-4alkynyl, preferably substituted by an acidic function; R* is H, Q-C1-6alkyl, Q-C1-6oxoalkyl, Q-C2-6alkenyl or Q-C2-4alkynyl, C3-6cycloalkyl, Ar or Het, optionally substituted by one or more substituents; and R?6? is preferably a substituent containing a basic nitrogen moiety; or a pharmaceutically acceptable salt thereof, which are effective for inhibiting platelet aggregation, pharmaceutical compositions for effecting such activity, and a method for inhibiting platelet aggregation.

1-(Fluorobenzyl)-4-amino-1H-1,2,3-triazolo[4,5-c]pyridines : synthesis and anticonvulsant activity

Abstract: A series of (fluorobenzyl)triazolo[4,5-c]pyridines was synthesized and tested for activity against maximal electroshock-induced seizures in rodents. The most promising compound, 14 (BW 534U87), which is a carbon-nitrogen isoster of a purine anticonvulsant, has a profile in rodents that suggests 14 will be free of emesis and useful in the treatment of seizure disorders for which phenytoin is presently indicated.

Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors

Abstract: Novel hydrosoluble 3-arylidene-2-oxindole derivatives, having tyrosine kinase inhibitor activity, encompassed by general formula (I), wherein m is zero, 1 or 2; A is a bicyclic ring chosen from tetralin, naphthalene, quinoline and indole; R1 is hydrogen, C1-C6 alkyl or C2-C6 alkanoyl; one of R2 and R3 independently is hydrogen and the other is a substituent selected from: a C1-C6 alkyl group substituted by 1, 2 or 3 hydroxy groups; -SO3R4 in which R4 is hydrogen or C1-C6 alkyl unsubtituted or substituted by 1, 2 or 3 hydroxy groups; -SO2NHR5 in which R5 is as R4 defined above or a -(CH2)n-N(C1-C6 alkyl)2 group in which n is 2 or 3; -COOR6 in which R6 is C1-C6 alkyl unsubtituted or substituted by phenyl or by 1, 2 or 3 hydroxy groups or phenyl; -CONHR7 in which R7 is hydrogen, phenyl or C1-C6 alkyl substituted by 1, 2 or 3 hydroxy groups or by phenyl; -NHSO2R8 in which R8 is C1-C6 alkyl or phenyl unsubtituted or substituted by halogen or by C1-C4 alkyl; -N(R9)2, -NHR9 or -OR9 wherein R9 is C2-C6 alkyl substituted by 1, 2 or 3 hydroxy groups; -NHCOR10, -OOCR10 or -CH2OOCR10 in which R10 is C1-C6 alkyl substituted by 1, 2 or 3 hydroxy groups; -NHCONH2; -NH-C(NH2)=NH; -C(NH2)=NH; -CH2NHC(NH2)=NH; -CH2NH2; -OPO(OH)2; -CH2OPO(OH)2; -PO(OH)2; or (a), (b), (c), or (d) group, wherein p is 1, 2 or 3 and Z is -CH2-, -O- or (e), in which R11 is hydrogen or is as R9 defined above; and the pharmaceutically acceptable salts thereof, are disclosed.

Classification and Structure-Activity Relationships of Fluoroquinolones

Abstract: Fluoroquinolones are potent broad spectrum antibacterial agents. Two classifications have been described: chemical and biological. Quinolones can be classified into 4 groups according to their chemical structures: monocyclic, bicyclic, tricyclic and tetracyclic derivatives. Each group can be subdivided into subgroups if a fluorine atom is fixed at the 6-position. The biological classification recognised 4 groups. Groups 1 and 2 are composed of compounds showing limited spectra (Enterobacteriaceae) and groups 3 and 4 contain compounds displaying broad antibacterial spectra. Compounds that are highly metabolised fall into groups 1 and 3 and those poorly metabolised (< 5%) into groups 2 and 4. The structure of fluoroquinolones may help to predict antibacterial activity, pharmacokinetics, physicochemical properties, toxicity and adverse events.

Tri-substituted phenyl derivatives useful as PDE IV inhibitors

Abstract: Compounds of general formula (1) are described wherein =W- is (1) =C(Y)- where Y is a halogen atom, or an alkyl or -XRa group where X is -O-, -S(O)?m?-[where m is zero or an integer of value 1 or 2], or -N(R?b?)- where Rb is a hydrogen atom or an optionally substituted alkyl group or, (2) =N; L is a -XR, [where R is an optionally substituted alkyl, alkenyl, cycloalkyl or cycloalkenyl group], -C(R?11)=C(R1)(R2?) or [-CH(R11)]nCH(R1)(R2) group where R11 is a hydrogen or a fluorine atom or a methyl group, and R?1 and R2?, which may be the same or different, is each a hydrogen or fluorine atom or an optionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio, -CO?2 R?8, [where R8 is a hydrogen atom or an optionally substituted alkyl, aralkyl, or aryl group], -CONR9R10 [where R?9 and R10?, which may be the same or different are as defined for R8], -CSNR9R10, -CN or -NO?2?group, or R?1 and R2? together with the C atom to which they are attached are linked to form an optionally substituted cycloalkyl or cycloalkenyl group and n is zero or the integer 1; Z is (1) a group -C(R?3)(R4)C(R5)(R6)(R7) or -C(R?4)=C(R5)(R6?) where R3 is a hydrogen or a fluorine atom or an optionally substituted straight or branched alkyl group; R4 is a group selected from -XaL1R12 [where Xa is as defined above for X, L1 is a linker group and R12 is a hydrogen atom or a cycloaliphatic, heterocycloaliphatic, or monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms], -Alk1R12 [where Alk1 is an optionally substituted straight or branched alkenyl or alkynyl chain optionally containing one or more -O- or -S- atoms or -N(Rb)-, carbocyclic or heteroatom-containing groups], -CH?2L?1R12a [where R12a is as defined for R12 but is not a hydrogen atom]; -XaR12a; or -C(Xb)R12a [where Xb is an oxygen or sulphur atom]; R5 is a -(CH?2?)pAr group where p is zero or an integer 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms; R?6? is a hydrogen or a fluorine atom or an optionally substituted alkyl group; R7 is a hydrogen or a fluorine atom or an ORc group where Rc is a hydrogen atom or an optionally substituted alkyl or alkenyl group, or an alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group; or Z is (2) a group -C(R?4)C(R5)(R6)(R7?) where R4 is a group =CH?2?, or =CH(L?1)?n-R12; and the salts, solvates, hydrates, prodrugs and N-oxides thereof. Compounds according to the invention are phosphodiesterase type IV inhibitors and are useful in the prophylaxis and treatment of disease such as asthma where an unwanted inflammatory response or muscular spasm is present.

Inhibition of E-Selectin-, ICAM-1-, and VCAM-1-Mediated Cell Adhesion by Benzo[b]thiophene-, Benzofuran-, Indole-, and Naphthalene-2-carboxamides: Identification of PD 144795 as an Antiinflammatory Agent

Abstract: It was previously reported that 3-alkoxybenzo[b]thiophene-2-carboxamides exemplified by 1, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide, decreased the adherence of neutrophils to activated endothelial cells by inhibiting the upregulation of the adhesion molecules E-selectin and ICAM-1 on the surface of the endothelium. This finding is extended here to a series of 3-thiobenzo[b]thiophene-2-carboxamides and also heterocyclic analogs of 1, including benzofurans, indoles, and naphthalenes. The compounds that inhibited the expression of E-selectin and ICAM-1 had the same effect on the expression of VCAM-1. PD 144795, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide 1-oxide (44), the sulfoxide analog of 1, was orally active in several models of inflammation. The in vitro and in vivo activity of PD 144795 resided predominately in the S-enantiomer.

Effect of bridge region variation on antifolate and antitumor activity of classical 5-substituted 2,4-diaminofuro[2,3-d]pyrimidines

Abstract: Variation of the bridge linking the heterocyclic ring and p-aminobenzoyl-L-glutamate portions of our previously descibed classical 2,4-diaminofuro[2,3-d]pyrimidines 1 and 2 are reported as inhibitors of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and as antitumor agents. Specifically -CH 2 CH 2 - and -CH 2 NHCH 2 - bridged analogues, N-[4-[2-(2,4-diamino-furo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (3) and N-[4-[[N-[(2,4-diaminofuro[2,3-d]pyrimidin-5-yl)methyl]amino]methyl]benzoyl]-L-glutamic acid (4), respectively, were synthesized. Compound 3 was obtained via a Wittig reaction of the tributylphosphonium salt of 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine (5) and methyl 4-formylbenzoate (6) followed by reduction and coupling with the diethyl ester of L-glutamic acid. Compound 4 was synthesized by the nucleophilic displacement of 5 with diethyl N-[4-(aminomethyl)benzoyl]-L-glutamate (15) and saponification. Both analogues were evaluated in vitro as inhibitors of DHFRs from (recombinant) human, human CCRF-CEM cells, and Lactobacillus casei. Compound 3 showed moderate activity (IC 50 10 -6 -10 -7 M). Compound 4 was essentially inactive (IC 50 10 -5 M, CCRF-CEM). The compounds were also evaluated against TS from (recombinant) human and L. casei and were of low activity (IC 50 10 -5 M). The three-atom-bridged analogue 4 was somewhat more inhibitory to human TS than methotrexate (MTX). Compound 3 inhibited the growth of tumor cells in culture (IC 50 10 -7 M) while 4 showed a low level of growth inhibitory activity. The inhibition of the growth of leukemia CCRF-CEM cells by both compounds parallels their inhibition of CCRF-CEM DHFR. Analogue 3 was a good substrate for human folylpolyglutamate synthetase (FPGS) derived from CCRF-CEM cells (K m 8.5 μM). Further evaluation of the growth inhibitory activity of 3 against the MTX-resistant subline of CCRF-CEM cells (R30dm) with decreased FPGS indicated that poly-γ-glutamylation was important for its action. Protection studies with 3 in the FaDu squamous cell carcinoma cell line indicated that inhibition was completely reversed by leucovorin [(6R,S-5-formyltetrahydrofolate] or by a combination of thymidine and hypoxanthine, suggesting an antifolate effect directed at DHFR

Lta4 hydrolase inhibitors

Abstract: The present invention provides compounds of the formula Ar1-Q-Ar2-Y-R-Z and pharmaceutically acceptable salts thereof wherein Ar?1 and Ar2? are optionally substituted aryl moieties, Z is an optionally substituted nitrogen-containing moiety which may be an acyclic, cyclic or bicyclic amine or an optionally substituted monocyclic or bicyclic nitrogen-containing heteroaromatic moiety; Q is a linking group capable of linking two aryl groups; R is an alkylene moiety; Y is a linking moiety capable of linking an aryl group to an alkylene moiety and wherein Z is bonded to R through a nitrogen atom. The compounds and pharmaceutical compositions of the present invention are useful in the treatment of inflammatory diseases which are mediated by LTB?4? production, such as psoriasis, ulcerative colitis, IBD and asthma.

Post‐Translational Heterocyclic Backbone Modifications in the 43‐Peptide Antibiotic Microcin B17

Abstract: Microcin B17 (McB17), the first known gyrase inhibitor of peptidic nature, is produced by ribosomal synthesis and post-translational modification of the 69-residue precursor protein by an Escherichia coli strain. To elucidate the chemical structure of the mature 43-residue peptide antibiotic, fermentation and purification protocols were established and optimized which allowed the isolation and purification of substantial amounts of highly pure McB17 (non-labelled, 15N-labelled and 13C/15N-labelled peptide. By ultraviolet-absorption spectroscopy, HPLC-electrospray mass spectrometry and GC-mass spectrometry, amino acid analysis, protein sequencing, and, in particular, multidimensional NMR, we could demonstrate and unequivocally prove that the enzymic modification of the precursor backbone at Gly-Cys and Gly-Ser segments leads to the formation of 2-aminomethylthiazole-4-carboxylic acid and 2-aminomethyl-oxazole-4-carboxylic acid, respectively. In addition, two bicyclic modifications 2-(2-aminomethyl-oxazolyl)thiazole-4-carboxylic acid and 2-(2-aminomethylthiazolyl)oxazole-4-carboxylic acid were found that consist of directly linked thiazole and oxazole rings derived from one Gly-Ser-Cys and one Gly-Cys-Ser segment. Analogous to the thiazole and oxazole rings found in antitumor peptides of microbial and marine origin, these heteroaromatic ring systems of McB17 presumably play an important role in its gyrase-inhibiting activity, e.g. interacting with the DNA to trap the covalent protein-DNA intermediate of the breakage-reunion reaction of the gyrase.

Purealidins J-R, new bromotyrosine alkaloids from the Okinawan marine sponge Psammaplysilla purea

Abstract: Nine new bromotyrosine alkaloids, purealidins J-R (1-9), have been isolated from the Okinawan marine sponge Psammaplysilla purea and the structures were elucidated on the basis of spectroscopic data. A hydroxy group as C-1 of purealidins M-O (4-6) may be biosynthetically derived from ring-opening of a spirocyclohexadienyl-isoxazole unit of purealidin J (1), aerophobin-1 (10), and purealidin L (3), respectively. Purealidins N (5), P (7), and Q (8) were cytotoxic to tumor cell lines, while purealidins J (1), K (2), P (7), and Q (8) showed moderate inhibitory activity against epidermal growth factor (EGF) receptor kinase.

Bridged bicyclic aromatic compounds and their use in modulating gene expression of retinoid receptors

Abstract: Bridged bicyclic aromatic compounds are provided having the structure ##STR1## wherein R1, R2, R3, R4, R5 and n are as defined herein. The novel compounds are useful for modulating gene expression of retinoic acid receptors, vitamin D receptors and thyroid receptors. Pharmaceutical compositions and methods for modulating gene expression are provided as well.

Enhanced D1 affinity in a series of piperazine ring substituted 1-piperazino-3-arylindans with potential atypical antipsychotic activity.

Abstract: A study of the effect of aromatic substitution on D1 and D2 affinity in a series of previously reported trans-1-piperazino-3-phenylindans shows similar structure-activity relationships for the two receptor sites. 6-Substituted derivatives have affinity for both receptors, and 6-chloro-or 6-fluoro-substituted derivatives show preference for D1 receptors. D1 affinity and selectivity are significantly increased in a series of new piperazine ring substituted derivatives. Potent D1 and D2 antagonism in vivo are confined to derivatives with relatively small substituents in the 2-position of the piperazine ring (e.g. 2-methyl,2,2-dimethyl, 2-spirocyclobutyl or 2-spirocyclopentyl). Consequently, the effect of aromatic substitution is examined in a series of 1-(2,2-dimethylpiperazino)-3-arylindans. All these compounds except the 4-, 5-, 7- and 4'-chloro-substituted derivatives have potent D1 affinity (IC50's below 10 nM) and the majority of the compounds antagonize SK&F 38393-induced circling in 6-OHDA-lesioned rats with ED50 values about 1 mumol/kg. In vitro all compounds show preference for D1 receptors, but in vivo they are equally effective as D1 and D2 antagonists. The compounds have high affinity for 5-HT2 receptors and selected compounds show high affinity for alpha 1 adrenoceptors. Furthermore, a subgroup consisting of (-)-38, (-)-39, (-)-41, and (-)-54 does not induce catalepsy in rats. These compounds have the potential of being "atypical" antipsychotics and have consequently been selected for further studies. The non-receptor-blocking enantiomers are shown to be inhibitors of DA and NE uptake in accordance with previous observations in compounds unsubstituted in the piperazine ring. Two compounds, (+)-38 and (+)-40, block DA uptake with IC50 values below 10 nM. Finally, the observed structure-activity relationships are discussed in relation to previously published pharmacophore models for D2 and 5-HT2 receptors. It is concluded that the piperazine substituents might induce a different binding mode at the dopamine receptor sites, perhaps only at the D1 receptor site.

Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same

Abstract: Compounds of the general formula (1) ##STR1## are described wherein Y is halogen or --OR 1 , where R 1 is a substituted or unsubstituted alkyl; X is --O--, --S-- or --N(R 8 )--, where R 8 is hydrogen or alkyl; R 2 is substituted or unsubstituted alkyl, alkenyl, cycloalkyl or cycloalkenyl; R 3 is hydrogen, halogen or --OR 9 , where R 9 is hydrogen or substituted or unsubstituted alkyl, alkenyl, alkoxyalkyl, or alkanoyl, or formyl, carboxamido or thiocarboxamido; R 4 and R 5 , which may be the same or different, are each --(CH 2 ) n Ar, where Ar is a monocyclic or bicyclic aryl group or monocyclic or bicyclic heteroaryl and n is integer of 0 to 3; R 6 is hydrogen or substituted or unsubstituted alkyl; R 7 is hydrogen or substituted or unsubstituted alkyl; and the salts, solvates, hydrates and N-oxides thereof. Compounds according to the invention are potent, selective and orally active PDE IV inhibitors and are useful in the prophylaxis and treatment of asthma and other diseases.

Synthesis and investigation of a hindered, chiral, bicyclic guanidine

Abstract: Chiral amidines and guanidines have potential as enantioselective catalysts for reactions of nitroalkanes, through formation of hydrogen-bonded complexes with nitronate anions. With this in mind, the bicyclic guanidine 9 was synthesized from amino-alcohol 12 , employing pyrrole formation as a protection method for the amino-nitrogen. Low enantioselectivities were obtained when 9 was used as catalyst for conjugate additions of nitroalkanes. However, other applications are suggested by its hindered, chiral and strongly basic nature.

Photoinduced ring opening metathesis polymerization (PROMP) of strained bicyclic olefins with ruthenium complexes of the type [(η6‐arene1)Ru(η6‐arene2)]2+ and [Ru(Nc‐R)6]2+

Abstract: Upon UV irradiation, the complexes [(η6-arene1)Ru(η6-arene2)]2+ (toluene-4-sulfonate or trifluormethane-sulfonate as counter ion; examples for arene: benzene, toluene, mesitylene, hexamethylbenzene, anisole, biphenyl, naphthalene) and [Ru(NC-R)6]2+ (tosylate or triflate as counter iron; R = methyl, ethyl, phenyl) are transformed into active catalysts for ring opening metathesis polymerization (ROMP) of strained bicyclic olefins. The photoinduced ring opening metathesis polymerization (PROMP) is most efficient with sandwich complexes having high quantum yields for the photochemically induced solvation of [(η6-arene1)Ru(η6-arene2)]2+ to [Ru(solvent)6]2+. With most of the complexes no (or only low) catalytic activity is observed in the absence of light. After the photolysis step, the mechanism of the polymerzation is identical to ROMP reactions with thermally activated ruthenium catalysts. Good yields and high molecular weights are obtained with a catalyst concentration of 0.1–1%. A mechanistic model for the initiation is presented. © 1995 John Wiley & Sons, Inc.

N-substituted oxazolo[5,4-b]pyridin-2(1H)-ones: a new class of non-opiate antinociceptive agents.

Abstract: A series of 1-(aminoalkyl)- and 1-[(4-aryl-1-piperazinyl)alkyl]oxazolo[5,4-b]pyridin-2(1H)-one derivatives of oxazolo[5,4-b]pyridin-2(1H)-one, incorporating modifications to the length of the alkyl side chain and to the amino or 4-aryl-1-piperazinyl substituents, were tested for safety and analgesic efficacy in mice and rats. Some compounds with 4-(substituted or nonsubstituted phenyl)-1-piperazinyl substituents and a 3-4-carbon alkyl side chain had significantly greater analgesic activity than that of the oxazolo[4,5-b]pyridin-2(3H)-one analogs. To reduce the metabolic N-dealkylation of the piperazine observed in our previous work on oxazolo[4,5-b]-pyridin-2(3H)-ones, analogs of the most active compounds with steric hindrance on the alkyl side chain were prepared and tested. The compound with the maximal combination of safety and analgesic efficacy was 1-[[4-(4-fluorophenyl)-1-piperazinyl]propyl]oxazolo[5,4-b]pyridin- 2(1H)-one (compound 3b), with ED50 values of 5.6 mg/kg po (mouse, phenylquinone writhing test) and 0.5 mg/kg po (rat, acetic acid writhing test). Compound 3b is a potent, rapid-acting, non-opioid, nonantiinflammatory analgesic with low acute toxicity and sustained effect.

Aromatic amino ethers as pain relieving agents

Abstract: The present invention relates to compounds of formula (I), wherein A is an optionally substituted phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, thienyl, thiazolyl, oxazolyl, thiadiazolyl having at least two adjacent ring carbon atoms or a bicyclic ring system, provided that the -CH(R?3)N(R2)B-R1? and -OCH(R4-)-D linking groups are positioned in a 1,2 relationship to one another on ring carbon atoms and the ring atom positioned ortho to the -OCHR4 - linking group (and therefore in the 3-position relative to the -CHR3NR2- linking group) is not substituted; B is an optionally substituted ring system; D is an optionally substituted ring system; R1 is a variety of group as defined in the description; R2 is hydrogen, C?1-6?alkyl, C2-6alkenyl, C2-6alkynyl, phenylC1-3alkyl or 5- or 6-membered heteroarylC1-3alkyl; R?3? is hydrogen or C?1-4?alkyl; R?4? is hydrogen or C?1-4?alkyl; and N-oxides of NR?2? where chemically possible; and S-oxides of sulphur containing rings were chemically possible; and pharmaceutically acceptable salts and in vivo hydrolysable esters and amides thereof. Process for their preparation, intermediates in their preparation, their use as therapeutic agents and pharmaceutical compositions containing them.

Controlled Synthesis of Bicyclic "Eight-Shaped" Poly(chloroethyl vinyl ether)s

Abstract: The synthesis of bicyclic eight-shaped poly(chloroethyl vinyl ether)s of controlled molar masses and narrow polydispersities has been achieved in very good yield. The strategy used is derived from the one reported for the synthesis of monomacrocyclic poly(vinyl ether)s and polystyrene. The procedure consists in the preparation of a linear tetrafunctional precursor bearing two series of antagonist functions, namely, α,α'-distyrenyl-ω,ω'-diacetal-poly(CEVE). The synthesis and the characterization of this polymer by controlled living cationic polymerization of chloroethyl vinyl ether are first described. In a second step, performed in highly diluted conditions, the acetal ends of the precursor are selectively activated by an electrophilic catalyst in order to form carbocationic-like termini which rapidly add on the styrenyl function of the chain. The presence of two functions of each type on a poly(CEVE) chain allows the formation of two rings per chain. The structural investigation of the cyclized polymer by SEC and NMR supports that bicyclic eight-shaped poly(CEVE) can be prepared cleanly and almost quantitatively by this cyclization procedure based on unimolecular end-to-end coupling reactions