To examine the utility of human papillomavirus (HPV) DNA testing for the screening of cervical cancer and its precursors, a prospective cohort study was performed in which a total of 8156 women with a median age of 36 years were enrolled. Two smear samples scraped from the uterine cervix were served for Papanicolaou test and HPV DNA testing (Hybrid Capture-II system). HPV-positive samples were further examined for HPV subtype using a DNA microarry chip. Women with cytologic abnormality or those with high-risk HPV DNA were further examined by colposcopy to determine histologic diagnosis. High-risk HPV DNA was detected in 11% of the general population, with higher prevalence of specific types, including 52, 16, 58, 51, 56, and 18. As expected, younger women were likely to have increased frequency of HPV infection. Notably, HPV DNA testing detected all 45 cases of cervical intraepithelial neoplasia (CIN) 3, while cytologic findings were negative in 6 of these cases. It is of particular interest that CIN was commonly associated with multiple HPV types, while invasive cancers had a single type of HPV. In terms of both sensitivity and positive predictive value in detecting the CIN, HPV DNA testing is superior to cytology. However, most importantly, HPV DNA testing in combination with cytology significantly improved the efficacy to CIN screening.

Novel N-[[dialkylamino)ethoxy]benzyl]benzamide derivatives (II-1-51), derived from the structural modification of metoclopramide (I), were synthesized and examined for their pharmacological activities. Among them, N-[4-[2-(dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide (II-34) which exhibited well balanced gastrointestinal prokinetic and antiemetic activities was selected as a new type of gastrointestinal prokinetic agent.

Metoclopramide (1a), possessing a dopamine D 2 receptor antagonist and weak serotonin 5-HT 4 receptor agonist activities, 1a) is used clinically as a gastrointestinal prokinetic and an antiemetic agent. 1b) However, its clinical application is limited due to its side effects, such as extrapyramidal syndrome, parkinsonism and elevated serum prolactin levels, caused by blockage of the dopamine D 2 receptor.We previously reported that the introduction of a methylenephenoxy group between the benzamide moiety and the terminal aminoalkyl groups of 1a led to the discovery of itopride (2), with an appropriate dopamine D 2 receptor antagonist activity and a distinctive acetylcholine esterase inhibitory activity.2) On the other hand, we suggested that amphoteric-ionization would be a useful approach to discovering a new drug, and actually succeeded in finding selective histamine H 1 antagonists by applying this method to classical antihistaminics.3) We initially applied the amphoteric-ionization to 1a in order to find a new type of gastrointestinal prokinetic agent. Although we preliminarily synthesized an amphoteric-ionized compound (3) by the introduction of an alkanecarboxylic acid moiety onto the terminal nitrogen atom of 1a, it had no significant gastrointestinal prokinetic activity. Cisapride (1b), 4) which has a conformationally restricted amino moiety in comparison with 1a, has been found to show more potent gastrointestinal prokinetic activity than 1a. We therefore expected that some kind of conformational restriction of 3 would lead to an increased gastrointestinal prokinetic activity, and designed a series of [[(4-amino-5-chloro-2-methoxybenzoyl)amino]cycloamino]alkanecarboxylic acid derivatives (4).In this paper, we describe the synthesis and gastrointestinal prokinetic activity of a series of [[(4-amino-5-chloro-2-methoxybenzoyl)amino]cycloamino]alkanecarboxylic acids (4). We also discuss conformational effects on gastrointestinal prokinetic activity and the evaluation of ester prodrugs of 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetic acid (19), which exhibited the most excellent gastrointestinal prokinetic activity.Chemistry New amphoteric compounds (19-24, 32a-c, 38, 43d-f) and prodrugs (44-60) of compound 19 were synthesized as shown in Charts 2-6.As shown in Chart 2, benzamides (19-24) with 1- 19-24, 32a-c, 43d-f

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We recently reported the synthesis and gastrointestinal prokinetic activity of novel benzamide derivatives with amphoteric side chains.1) Among them, 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetic acid (1a) exhibited the most excellent gastro-and colon-prokinetic activities by intravenous administration to conscious dogs without significant dopamine D 2 receptor antagonist activity. However, 1a showed only weak gastrointestinal prokinetic activity after oral administration due to its low lipophilicity. After the evaluation of several ester prodrugs of 1a, the butyl ester (1b) was consequently selected as a promising gastrointestinal prokinetic agent without significant side effects.As described previously, 1) compound 1b was prepared by esterification of 1a with butyl bromide in a large amount of N,N-dimethylformamide (DMF). The key intermediate 6 was obtained in four steps and an overall yield of 48% from commercially available 4-amino-1-benzylpiperidine (2). A compound 1a was prepared in four steps and an overall yield of 40% from commercially available 4-amino-5-chloro-2-methoxybenzoic acid (7) as shown in Chart 2.Although the previous route was quite adequate for the synthesis with a wide variety of 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidinealkanecarboxylic acids or the assorted ester prodrugs of 1a, the overall yield (14%) of 1b from 2 was not sufficient and a number of steps (9 steps) were required. We have therefore developed a new and facile synthetic route for a high overall yield with only short steps. In this paper, we describe a new and efficient route for the synthesis of 1b.In a new synthetic route, the key intermediate, butyl 4-amino-1-piperidineacetate (16), was prepared as shown in Chart 3. The amino group of 2 was protected with di-tertbutyl dicarbonate (Boc 2 O) in acetonitrile (CH 3 CN) to give compound 112) in 90% yield. Debenzylation of 11 with Pearlman's catalyst 3) and cyclohexene in ethyl alcohol (EtOH) afforded a secondary amine (12) 2) in 92% yield. Alkylation of 12 with butyl chloroacetate (14), 4) which was derived from chloroacetyl chloride (13) and butyl alcohol (nBuOH) in 92% yield, was accomplished using triethylamine (Et 3 N) as a base in DMF to give compound 15 in 93% yield. Since the usage of potassium carbonate (K 2 CO 3 ) as a base in this step produced a great deal of the byproduct, butyl 4-tertbutoxycarbonylamino-1-piperidinecarboxylate, we changed the base from K 2 CO 3 to Et 3 N. Next, the deprotection with hydrogen chloride-isopropyl alcohol solution of 15 followed by the removal of acid using Et 3 N gave a primary amine (16) quantitatively. Compound 7 was converted into the activated ester with ethyl chlorocarbonate (ClCO 2 Et) in anhydrous tetrahydrofuran (THF) and then amidated with 16 to give the desired ester (1b) in good (84%) yield.In conclusion, we have established an efficient route for the synthesis of 1b, a novel promising gastro-and colon-prokinetic agent. The new route shortened the total steps of the synthesis of 1b and cons...