Neurokinin NKi receptor antagonists

Aroylpyridine-2-carboxylic acids 104 were used as the starting compounds for the preparation of 7-methyl-l,7-naphthyridin-8(7//)-one derivatives 105, which are new strong neurokinin NKi-receptor antagonists (1995JMC3106). 

Drug-drug interactions See Neurokinin NKi receptor antagonists below. 

Neurokinin receptors NK2 receptor agonists (e.g. GR64349) have an anxiogenic profile in animal models while the antagonists (GR100679) have an anti-anxiety effect. However, NKi receptor antagonists have also been reported to have antianxiety activity in the social interaction test (File 1997). 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

To obtain neurokinin-1 (NKi) receptor antagonists. Cooper and co-workers [410] synthesized a series of variously substituted indoles by means of a Fischer indole synthesis on a solid phase. Thus, EUman resin [411], based on Kenner s safety-catch Hnker [318], was first reacted with 4-(4-chlorobenzoyl)butyric acid affording (598) and then treated with differently substituted phenyUiydrazines, affording the required indoles (599). These compounds were then cleaved from the resin using bromoacetonitrile, and subsequently coupled in solution with the desired amines under standard conditions (600) (Scheme 125). 

SCHEME 2.19. Merck synthesis of neurokinin-1 (NKi) receptor antagonist 120. 

Pseudoephedrine was used as a chiral auxiliary in Merck s synthesis of neurokinin-1 (NKj receptor antagonists 226. NKi receptor antagonists have been shown to prevent acute delayed chemotherapy-induced nausea and vomiting. The enolate of (f ,f )-pseudoephedrine amide 222 was formed by reaction with LiHMDS in the presence of TMEDA, and subsequent reaction with ot,p-unsaturated ester afforded the desired product 224 in 56% yield with the required diastereoisomer as the major product. Following reduction of the ester functionality, the chiral auxiliary was removed via acid induced cyclisation to afford lactone 225. This was transformed into NKi receptor antagonist 226 in eight steps (Scheme 14.77). 

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