The discovery of a series of nonpeptide arginine vasopressin V(2) receptor agonists is described. After identifying the aniline derivative 8 as our lead compound from the metabolites of compound 7 that showed antidiuretic activity by po administration to Brattleboro rats, improvements in the in vitro potency involving evaluations of the structural requirements for agonist action and optimizing the structure of the benzoyl moiety have been intensively undertaken. These studies led to compounds 16g, 19a, and 23b,h,i that show potent agonist activity for the V(2) receptor.

This paper describes a novel series of nonpeptide vasopressin V2 receptor antagonists. It has been demonstrated that the 1-[4-(benzoylamino)benzoyl]-2,3,4,5-1H-benzazepines and 1-[4-(benzoylamino)benzoyl]-2,3,4,5-1H-1,5-benzodiazepines show a high affinity for V2 (and V1a) receptors. Among the 1-[4-(benzoylamino)benzoyl]-2,3,4,5-1H-benzazepine series, compounds with an alkylamino group on the benzazepine ring have been shown to have oral activity. A lipophilic group at the ortho position on the terminal benzoyl ring is important for both high V2 receptor affinity and oral activity. On the basis of these favorable properties, clinical testing of 31b has begun for use as an oral and iv aquaretic agent.

1 We discovered the ®rst nonpeptide arginine-vasopressin (AVP) V 2 -receptor agonist, OPC-51803. Pharmacological properties of OPC-51803 were elucidated using HeLa cells expressing human AVP receptor subtypes (V 2 , V 1a and V 1b ) and compared with those of 1-desamino-8-D-arginine vasopressin (dDAVP), a peptide V 2 -receptor agonist. 2 OPC-51803 and dDAVP displaced [3 H]-AVP binding to human V 2 -and V 1a -receptors with K i values of 91.9+10.8 nM (n=6) and 3.12+0.38 nM (n=6) for V 2 -receptors, and 819+39 nM (n=6) and 41.5+9.9 nM (n=6) for V 1a -receptors, indicating that OPC-51803 was about nine times more selective for V 2 -receptors, similar to the selectivity of dDAVP. OPC-51803 scarcely displaced [3 H]-AVP binding to human V 1b -receptors even at 10 74 M, while dDAVP showed potent anity to human V 1b -receptors with the K i value of 13.7+3.2 nM (n=4). 3 OPC-51803 concentration-dependently increased cyclic adenosine 3', 5'-monophosphate (cyclic AMP) production in HeLa cells expressing human V 2 -receptors with an EC 50 value of 189+14 nM (n=6). The concentration-response curve for cyclic AMP production induced by OPC-51803 was shifted to the right in the presence of a V 2 -antagonist, OPC-31260. ] i in HeLa cells expressing human V 1a -and V 1b -receptors in a concentration-dependent fashion. 5 From these results, OPC-51803 has been con®rmed to be the ®rst nonpeptide agonist for human AVP V 2 -receptors without agonistic activities for V 1a -and V 1b -receptors. OPC-51803 may be useful for the treatment of AVP-de®cient pathophysiological states and as a tool for AVP researches.

The 4-dimethylaminopyridine (DMAP) (1)-catalyzed acylation of an alcohol with acid anhydrides 2 is one of the most fundamental and widely used organic transformation for the synthesis of esters. [1] The currently accepted mechanism underlying the catalytic cycle in the presence of an auxiliary base (B:) is depicted in Scheme 1. [2] The first key step of this cycle is the establishment of equilibrium between DMAP and its acylpyridinium salt composed of the acylpyridinium ion 3 and its counteranion, carboxylate 4. The second key step is the irreversible nucleophilic attack of alcohol 5 on the carbonyl group of the acylpyridinium ion via the transition state TS-I. It has been proposed that the rate-determining step of the catalytic cycle is the second key step. Therefore, the efficiency of the DMAP-catalyzed acylation depends not only on the concentration of the acylpyridinium salt, but also on the kinetics of the second step via TS-I.In the rate-determining TS-I, it has been postulated that the carboxylate ion 4 of the acylpyridinium salt plays a crucial role as a general base catalyst in the deprotonation of the alcohol hydroxy group. [3,4] Steglich and Hçfle found that the acylation of a tertiary alcohol with acetic anhydride proceeded faster than acylation by acetyl chloride in the presence of excess DMAP. [3a] Kattnig and Albert also found that the acylation of 1-and 2-propanol with acetic anhydride in the presence of catalytic amounts of DMAP proceeded faster than that with acetyl chloride in the presence of K 2 CO 3 as the auxiliary base. [5] These results supported that the acetate, which was more basic than chloride, functioned better as a general base to accelerate the nucleophilic attack of the alcohol on the acylpyridinium ion. Wakselman observed that the acetylation of tBuOH proceeded only in the presence of the N-acetyl-dimethylaminopyridinium salt with acetate as the counteranion, and the reaction did not proceed if acetate were substituted for other counteranions, such as BF 4 À .[6] Apart from improving the reaction efficiency, we found that a carboxylate ion also affected the regiochemical outcome of the acylation of glucose derivative 6 in the presence of a DMAP-related nucleophilic catalyst 7 (Scheme 2). [7] Although the acylation of 6 with isobutyric anhydride proceeded at the secondary C4 OH group with high regioselectivity to yield 8, this regioselectivity was dramatically reduced upon substitution with isobutyryl chloride, Scheme 1. Catalytic cycle of the DMAP-catalyzed acylation with acid anhydride.Scheme 2. Regioselectivities of the acylation reactions of 6 with isobutyric anhydride or isobutyryl chloride in the presence of catalyst 7.