132875-61-7

The invention discloses a synthetic method of an anesthetic analgesic drug. According to the synthetic method, 4-piperidinecarboxylic acid is used as a raw material and subjected to alkylation, bromination, methylation, acylation and the like to prepare the anesthetic analgesic drug. The method avoids the usage of highly toxic cyanide, so the safety and controllability of operation are improved; the method avoids an elimination reaction in reaction process, thereby accelerating reaction speed and shortening reaction time; and the method reduces reaction temperature, shortens the reaction time,and is more suitable for industrial production.

The invention relates to a method for producing N-phenyl-N-(4-piperidinyl)amide salts, particularly pharmaceutically tolerable addition salts of the compound Remifentanil, in that a compound of the formula (III) is reacted with an acrylic acid alkyl ester of the formula CH2═CH—C(O)—OR: where independently of each other R denotes low-molecular alkyl, preferably (C1-4)alkyl, preferably methyl or ethyl, R1 denotes low-molecular alkyl, preferably (C1-4)alkyl, preferably methyl or ethyl; and HX denotes an inorganic or organic acid, wherein the components are optionally reacted in the presence of a catalyst, preferably at a higher temperature, thereby obtaining the salt of the compound of formula (I).

An alternate process for synthesizing opiate or opioid analgesics and anesthetics, and intermediates thereof is provided. In particular, a process of synthesizing synthetic opiate or opioid compounds such as, for example, remifentanil, carfentanil, sufentanil, fentanyl, and alfentanil are disclosed.

A two-step sequence involving an Ugi four-component reaction was developed for the preparation of 4-aminopiperidine-4-carboxylic acid derivatives. This strategy has led to the successful preparation of two drugs carfentanil and remifentanil in shorter times and better yields than previously described methods.

A process for preparing remifentanil by conversion of the nitrile group of a cyanopiperidinyl propanoate derivative to an ester group. Advantageously, with this process the number of steps for preparing remifentanil from commercial products is significantly reduced, compared to the processes known in the art.

The present invention relates to a crystalline polymorphic form of remifentanil hydrochloride. The invention also describes methods of preparing a polymorphic form of remifentanil hydrochloride.

A process for synthesizing remifentanil or carfentanil, as well as intermediates for use in the preparation of synthetic opiate or opioid compounds. The process comprising reacting a 4-amino 4-carbamyl piperidine with a base in a closed reaction chamber at elevated temperature and pressure to form to intermediate which may be esterified with an alcohol, alkylated, and acylated to produce a synthetic opiate or opioid compound.

Active compound combinations of compounds of group A, particularly opioids, and compounds of group B, particularly anti-muscarine agents and other substances suitable for treatment of an increased urge to urinate or urinary incontinence. Related pharmaceutical formulations and methods of treatment of an increased urge to urinate or urinary incontinence are also provided.

In an effort to discover a potent ultrashort-acting μ opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated.One series of compounds displayed potent μ opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action.These analgetics, 4-(methoxycarbonyl)-4--1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for μ opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood.Compounds in this series were all shown to be potent μ agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially.The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s).The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized id discussed.It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.