61380-07-2

Thiofentanyl is a potent analgesic and anesthetic drug that belongs to the microreceptor agonist group and is mainly used in animal's anesthesia. We present an optimized synthesis route for synthesis of thiofentanyl using nanocatalysts such as MCM-41-SO3H and SBA-15-Ph-PrSO3H as green, heterogeneous and recyclable catalysts according to the strategy. The intermediate 2-(thiophen-2-yl) ethyl methanesulfonate (1) easily obtained after conversion of the alcohol functional group into the mesylate leaving group using methanesulfonyl chloride (97% yield). The alkylation of commercially available 4-piperidone monohydrate hydrochloride with 2-(thiophen-2-yl) ethyl methanesulfonate in the presence of phase transfer catalyst was then carried out giving N-[2-(2-thienyl) ethyl]-4-piperidone (2) with 90% yield. N-[2-(2-thienyl)ethyl]-4-piperidone was then reacted with aniline in the presence of MCM-41-SO3H catalyst giving the imine derivative which reduced with sodium triacetoxyborohydride to N-phenyl-1-(2-(thiophen-2-yl)ethyl) piperidine-4-amine (ANTP) (4) with 80% yield. ANTP was finally acylated using propionyl chloride to achieve thiofentanyl (5) with 90% yield. High yields, mild reaction conditions, decreased reaction times, and convenient workup were the advantages of this method compared to the previous work.

The first continuous flow process was developed to synthesize N-methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N-methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their precursors. Up to 10.6 g (88% yield) of an N-methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.

The invention belongs to the technical field of 1,2,5-oxadiazole derivatives, and particularly relates to a 1,2,5-oxadiazole derivative or a pharmaceutically acceptable salt thereof which is used as an indoleamine 2,3-dioxygenase inhibitor. The structure of the 1,2,5-oxadiazole derivative or the pharmaceutically acceptable salt thereof used as the IDO inhibitor is shown in the following formula I.The invention provides a general formula compound I with a novel structure. Experimental results show that some compounds have excellent IDO inhibitory activity and permeation performance at the sametime. The compound is expected to be marketed as a tumor molecular immunotherapeutic drug for cancer treatment.

Abstract: The present work describes the design, synthesis, molecular docking, biological evaluation, and assessment of structure–activity relationship of new derivatives based upon the molecular skeleton of the drug pioglitazone, a compound which is currently used for the management of type 2 diabetes mellitus. Pioglitazone has several side effects such as weight gain, edema, congestive heart failure, and bladder cancer. Therefore, there is a strong demand for identification of new lead candidates in the treatment of type 2 diabetes mellitus. A series of 24 compounds were prepared and evaluated for their peroxisome proliferator-activated receptor-γ (PPARγ) binding affinity assay and the IC50 values were determined. Among these compounds, six compounds exhibited promising IC50 values as compared to standard drugs pioglitazone and rosiglitazone. Furthermore, in order to confirm the target of these molecules, molecular docking study was carried out with peroxisome proliferator-activated receptor-γ (PPARγ) protein. Molecular modeling studies suggested that these compounds appropriately interact in the active sites of receptor. Graphical abstract: [Figure not available: see fulltext.].

The invention discloses a preparation method of alfentanil and sufentan and compounds used for preparation of sufentanil and alfentan. Specifically, the method for preparation of a compound shown as formula V includes: carrying out BOC reaction on a compound shown as formula IV to obtain the compound shown as formula V in the specification. The method can conveniently, efficiently and safely prepare an intermediate product for synthesis of alfentanil and sufentan, i.e. the compound shown as formula V. And then, the compound shown as formula V can be effectively used for preparation of alfentanil and sufentan.

The invention relates to a substituted piperidine amide derivative as shown in a general formula (I) or a stereisomer and pharmaceutically acceptable salt thereof, a preparation method of the derivative, medicinal combination as well as application of the derivative to the aspects of local anaesthesia or analgesia. The definition of each group of the general formula (I) is consistent with that of the description. (The general formula (I) is as shown in the description).

The invention provides compounds that bind with high affinities to the μ-, δ- and κ- opioid receptors and α2 - adrenoreceptor. In addition to providing these compounds with novel pharmacological binding properties, the invention also describes detailed novel methods for the preparation of representative compounds and a scheme for the synthesis of related compounds that bind to the opioid receptors and/or α2 - adrenoreceptor.

The alternate and optimized syntheses of the parent opioid fentanyl and its analogs are described. The routes presented exhibit high-yielding transformations leading to these powerful analgesics after optimization studies were carried out for each synthetic step. The general three-step strategy produced a panel of four fentanyls in excellent yields (73-78%) along with their more commonly encountered hydrochloride and citric acid salts. The following strategy offers the opportunity for the gram-scale, efficient production of this interesting class of opioid alkaloids.

The present invention relates to new substituted 4-amino-piperidine opioid receptor modulators, pharmaceutical compositions thereof, and methods of use thereof

Compounds represented by the formulas wherein each symbol is as defined in the specification, and a prodrug thereof have a superior renin inhibitory activity, and are useful as agents for the prophylaxis or treatment of hypertension, various organ damages attributable to hypertension and the like.

Several 3-acylindoles with high affinity for the CB2 cannabinoid receptor and selectivity over the CB1 receptor have been prepared. A variety of 3-acyl substituents were investigated, and the tetramethylcyclopropyl group was found to lead to high affinity CB2 agonists (5, 16). Substitution at the N1-indole position was then examined. A series of aminoalkylindoles was prepared and several substituted aminoethyl derivatives were active (23-27, 5) at the CB2 receptor.Astudy of N1 nonaromatic side chain variants provided potent agonists at the CB2 receptor (16, 35-41, 44-47, 49-54, and 57-58). Several polar side chains (alcohols, oxazolidinone) were well-tolerated for CB2 receptor activity (41, 50), while others (amide, acid) led to weaker or inactive compounds (55 and 56). N1 aromatic side chains also afforded several high affinity CB2 receptor agonists (61, 63, 65, and 69) but were generally less potent in an in vitro CB2 functional assay than were nonaromatic side chain analogues.

An improved process for the synthesis of sufentanil with an overall yield of 26% is described. The reactive and high yielding N-debenzylation of the piperidine intermediate 7 using a mixture of Pd/C and Pd(OH)2 was applied to other drug intermediates affording free amines in short reaction times. The deuterium-labeled sufentanil and the metabolite desmethylsufentanil were synthesized applying the optimized process.

Various vinylheterocycles compounds have been prepared in excellent yields through β-elimination of the corresponding sulfonate esters with 50% aq NaOH under phase transfer catalysis conditions without organic solvent. The new approach provides an economic and environmentally friendly solution to removal of hazardous bases as well as toxic and expensive dipolar aprotic solvents.

The present invention relates to a process for the preparation of piperidine derivatives including sufentanil and its pharmaceutically acceptable salts, such as it citrate salt

Structure-activity relationships (SAR) were analyzed within a library of diverse yet simple compounds prepared as histamine H3 antagonists. The libraries were constructed with a variety of low molecular weight pyrrolidines, selected from (R)-2-methylpyrrolidine, (S)-2-methylpyrrolidine, and pyrrolidine.

The present invention provides novel compounds of Formula (I), which are CB2 selective ligands useful for the treatment of pain.

Compounds of the general formula (I): (I)wherein m, n, R1, R2, R3 and R4 are as described in the specification. Further included are pharmaceutical compositions comprising the compounds, processes for their preparation, as well as the use of the compounds for the preparation of a medicament for the treatment of 5-HT2A receptor-related disorders or medical conditions.

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A piperidine derivative such as sufentanil is formed in a process which includes the step of condensing a piperidone with a primary amine so as to form a 4-amino-4-carboxyamino-piperidine.

The present invention is concerned with novel imidazo[1,2-a](pyrrolo, thieno or furano)[3,2-d]azepines of formula STR1 the pharmaceutically acceptable addition salts and stereochemically isomefic forms thereof, wherein each of the dotted lines independently represents an optional bond; R1 represents hydrogen, C1-4 alkyl, halo, ethenyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl, hydroxy C1-4 alkyl, formyl, hydroxycarbonyl or hydroxycarbonyl C1-4 alkyl; R2 represents hydrogen, C1-4 alkyl, ethenyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl, C1-4 alkyl substituted with hydroxycarbonyl or C1-4 alkyloxycarbonyl, hydroxy C1-4 alkyl, formyl or hydroxycarbonyl; R3 represents hydrogen, C1-4 alkyl, hydroxy C1-4 alkyl, phenyl or halo; L represents hydrogen; C1-6 alkyl; C1-6 alkyl substituted with one substituent selected from the group consisting of hydroxy, halo, C1-4 alkyloxy, hydroxycarbonyl, C1-4 alkyloxycarbonyl, C1-4 alkyloxycarbonyl C1-4 alkyloxy, hydroxycarbonyl C1-4 alkyloxy, C1-4 alkyloxycarbonylamino, C1-4 alkylaminocarbonyl, C1-4 alkylaminocarbonylamino, C1-4 alkylaminothiocarbonylamino, aryl, aryloxy and arylcarbonyl; C1-6 alkyl substituted with both hydroxy and aryloxy; C3-6 alkenyl; C3-6 alkenyl substituted with aryl; L represents a radical of formula --Alk--Y--Het1 (a-1), --Alk--NH--CO--Het2 (a-2) or --Alk--Het3 (a-3); which are useful antiallergic compounds. Compositions comprising said compounds, methods of using, and processes for preparing the same.

Compounds of the formulae:and wherein:, R1, R2, R3 and R4 are independently hydrogen, lower alkyl of one to six carbon atoms, aryl or substituted aryl;, are advantageously converted to isocyanurate compounds, 2-(2-thienyl)ethylamine compounds and thieno[3,2-c]pyridine derivatives and the pharmaceutically acceptable salts thereof, particularly ticlopidine hydrochloride.

This invention relates to 2-aryl-2-cyano-2-(heterocyclylalkyl)ethyl-1,2,4-triazoles of the formula STR1 wherein Ar is an optionally substituted aryl group, Het is an optionally substituted five or six membered saturated or unsaturated heterocyclic ring containing one, two or three heteroatoms selected from oxygen, nitrogen and sulfur, or is a bicyclic unsaturated ring system containing up to ten atoms including one heteroatom selected from oxygen, nitrogen and sulfur, R is hydrogen or alkyl, n is zero or an integer of at least one, and the agronomically acceptable enantiomorphs, geometric isomers, acid addition salts and metal salt complexes thereof.

The design, synthesis, and biological activity of a series of -Arg2-enkephalin-derived tetrapeptide amides and tripeptide aralkylamides are reported.These polar analogues were designed to be excluded from the central nervous system with their action thus limited to peripheral opioid receptors.The effects of the nature of the aromatic ring, aryl ring substitution, and aralkylamine chain length on activity were investigated; in a number of cases the N-terminal amino group of Tyr1 was converted to a guanidino group to further increase hydrophilicity.The peptides were all synthesized by classical solution methodology.The opioid activit y of the peptides was assessed in vitro on the guinea pig ileum and their antinociceptive activity was determined in vivo in chemically induced writhing models (peripheral activity) and in the hot-plate test (central activity), in rodents.That the analgesic effects were predominantly mediated in the periphery was demonstrated by antagonism of antinociception by the peripheral opioid antagonist N-methylnalorphine and by comparison of the activities in the writhing and hot-plate tests.As a class, the tetrapeptides were more potent than the tripeptides; Nα-amidination generally increased activity.A number of compounds exhibited very potent opioid activity and had the desired pharmacological profile, indicating a high degree of peripheral selectivity.

Novel para-[thienyl and furyl(alkyl or alkenyl)amino]-benzoic acids, esters, pharmaceutically acceptable salts and pharmaceutical compositions thereof and a method of lowering serum-lipid levels in mammals therewith.

Aryloxyalkylaminobenzoic acids and esters as hypolipemic compounds.

Novel para-[aryl(alkyl or alkenyl)amino]benzoic acids, esters, pharmaceutically acceptable salts and pharmaceutical compositions thereof and a method of lowering serum lipid levels in mammals therewith.

Novel N-(4-piperidinyl)-N-phenylamides and -carbamates having very potent analgesic activity, methods of preparing same and useful intermediates therefor.

Novel N-(4-piperidinyl)-N-phenylamides and -carbamates having very potent analgesic activity, methods of preparing same and useful intermediates therefor.