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We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimization of S1 and S4 ligands. Incorporating the interaction with S1-β pocket enhanced in vitro factor Xa inhibitory activity to less than 1 nM. Many zwitter ionic compounds showed long duration of action and potent inhibitory activity and high AUC values in oral administration tests to monkeys.

We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 μM) and in vivo antithrombotic efficacy.

A series of cis-1,2-diaminocyclohexane derivatives possessing a 6-6 fused ring for the S1 moiety were synthesized as novel factor Xa (fXa) inhibitors. The synthesis, structure-activity relationship (SAR), and physicochemical properties are reported herein, together with the discovery of compound 45c, which has potent anti-fXa activity, good physicochemical properties and pharmacokinetic (PK) profiles, including a reduced negative food effect.

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A series of 2-(biphenylmethyl)glutaric acid amide derivatives were synthesized and evaluated for NEP inhibitory activity. The mode of inhibitor-enzyme interactions of the most potent compound 3a, with a thiazolylacetic acid group at the P2' position, was evaluated by a computer analysis.

A series of glutaric acid amide derivatives were synthesized and tested for NEP inhibitory activity. Compounds 14a, 14b, 16a and 22, with a biphenylmethyl group at P′1 position, showed potent inhibitory activity.

Addition-elimination reactions of lithium enolates 2 of N-acyloxazolidinones with 2-methylene-3-phenoxyalkanoates 3 and 10 proceeded diastereoselectively and regiospecifically to give chiral N-[(E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones 4 and 12a, which are useful intermediates for the synthesis of enzyme inhibitors.

The desired 5,6-dihydro-4H-pyrrolo[3,4-d]thiazole (VII) is readily prepared via a Mitsunobu reaction of diol (IV) with sulfonamide (V).

We have been researching orally active factor Xa inhibitor for a long time. We explored the new diamine linker using effective ligands to obtain a new attractive original scaffold 2-aminomethylphenylamine derivative. Compound 1D showed very strong in vitro and in vivo factor Xa inhibitory activity, as well as favorable PK profiles in po administration to monkeys.

The palladium(0)-catalyzed reactions of lithium enolates 1 of N-acyloxazolidinones with 3-acetoxy-2-methylenealkanoates 2, easily prepared via DABCO-catalyzed coupling of corresponding aldehydes with acrylates, proceeded diastereoselectively and regioselectively to give chiral N-[(E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones3, useful intermediates of metallopeptidase inhibitors.

Addition-elimination reactions of lithium enolates 2 of N-acyloxazolidinones with 2-methylene-3-phenoxyalkanoates 3 and 10 proceeded diastereoselectively and regiospecifically to give chiral N-[(E)-4-alkoxycarbonyl-4-pentenoyl]oxazolidinones 4 and 12a, which are useful intermediates for the synthesis of enzyme inhibitors.

A series of cis-1,2-diaminocyclohexane derivatives were synthesized with the aim of optimizing previously disclosed factor Xa (fXa) inhibitors. The exploration of 5-6 fused rings as alternative S1 moieties resulted in two compounds which demonstrated improved solubility and reduced food effect compared to the clinical candidate, compound A. Herein, we describe the synthesis and structure-activity relationship (SAR), together with the physicochemical properties and pharmacokinetic (PK) profiles of some prospective compounds.

There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.

A method for synthesizing 2, 3-(ring fused)-5-(5-tetrazolyl)-4H-pyrimidin-4-one derivative from ethyl 2-(2-tert-butyl-2H-tetrazol-5-yl)-3-(dimethylamino)acrylate (DMTE) (4a) and amino-heterocycles is described. The structure of DMTE, which was prepared from ethyl (2-tert-butyl-2H-tetrazol-5-yl)acetate (3a) with dimethylformamide diethylacetal, was determined by X-ray analysis to be Z form. The reaction of 2-amino-5-methyloxazole (6) with DMTE in acetic acid gave the oxazolo[3, 2-a]pyrimidine derivative (8), heating of which in concentrated sulfuric acid afforded the desired tetrazole derivative (20). Pyrimido[2, 1-b]benzothiazole (21), pyrazolo[1, 5-a]pyrimidine (22 and 23) and [1, 2, 4]triazolo[1, 5-a]pyrimidine (24) derivatives were prepared in a similar manner.

In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.

There have been few reports on synthetic methods for cis-1,2-diaminocyclohexane bearing a third ring substituent. Starting from 3-cyclohexenecarboxylic acid, we developed efficient methods for synthesizing the 3,4-diaminocyclohexanecarboxylic acid derivatives 2-5. We also evaluated their anti-Xa and anticoagulant activities. Among the compounds, acid 2a and amide 2b exhibited the most potent in vitro anti-fXa activity, indicating that the position and stereochemistry of a polar functional group on the cyclohexane ring greatly affected the in vitro anti-fXa activity.

This paper describes the synthesis of orally available potent fXa inhibitors 2 and 3 by modification of the piperazine part of lead compound 1. Carbonyl derivative 3 showed potent fXa activity but not sulfonyl derivative 2. Among the compounds synthesized, cyclohexane derivatives 3g and 3h and cycloheptane derivative 3j had potent anticoagulant activity as well as anti-fXa activity. Synthetic study of the optical isomers of 3g demonstrated that (-)-3g had more potent activity.

Di- and tri-substituted [(4-oxo-4H-1-benzopyran-7-yl)oxy]acetic acids, and 4-oxo-3-phenyl-4H-furo[2,3-h]-[1]benzopyran-8-carboxylic acid were synthesized and tested for natriuretic and uricosuric activities. Among the compounds tested, 3,5-disubstituted [(4-oxo-4H-1-benzopyran-7-yl)oxy]acetic acids (6c-f, h, n and x) showed potent natriuretic and uricosuric activities, whereas 4-oxo-3-phenyl-4H-furo[2,3-h][1]benzopyran-8-carboxylic acid (6dd) possessed only potent natriuretic activity. The structure-activity relationships are also discussed.

The improved routes to prepare tetrahydrothiazolo[5,4-c]-pyridine-2-carboxylic acid lithium salts (2 and 3) were developed. Route A is consisted of the improved preparation of thiazolopyridine intermediates, and Route B is applicable for a large scale synthesis of tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid derivatives. The methods we developed may serve as facile means for preparing thiazolopyridine and tetrahydrothiazolopyridine derivatives.

Thermal cyclization of ethyl 2-(2-tert-butyl-2H-tetrazol-5-yl)-3-(4-chloroanilino) acrylate (5) did not afford the intended 4-quinolinone derivative (6), but yielded 2,5-dihydro-3H-pyrazolo [4,3-c]-quinolin-3-one (7). The reaction mechanism is thought to have been double cyclization of the nitrile imine intermediate (C)

A series of 1-imidazolylalkyl-substituted or 5-thiazolylalkyl-substituted tetrahydronaphthalenecarboxylic acid and indancarboxylic acid derivatives were prepared and tested for the inhibitory activities of thromboxane A2 (TXA2) production in vitro and ex vivo. Most of the compounds showed potent TXA2 synthetase inhibitory activities in vitro and had long duration of inhibition of TXA2 production in rats when orally or intravenously administrated. The imidazole analogues had slightly less potency in vitro than the thiazole analogues, but the activities of the imidazole analogues in ex vivo models were equal or superior to the activities of the thiazole analogues. 6-(1-Imidazolyl-methyl)-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid hydrochloride hemihydrate (47a, DP-1904) was chosen for clinical studies.

Basic N-heteroaromatic derivatives (1, 2, 4-triazole, thiazole and pyrimidine derivatives) having a 2-[4-(carboxy)phenoxy]ethyl moiety or a 4-[2-(carboxy)vinyl]benzyl moiety were prepared, and evaluated for ability to inhibit thromboxane A2 (TXA2) synthesis. Among the compounds prepared in this study, the 5-substituted thiazole derivatives 14d, 27 and 28 were more potent inhibitors of TXA2 production than the corresponding imidazole derivatives, and the 1-substituted 1H-1, 2, 4-triazole derivatives 14a and 15a were almost as potent as the corresponding imidazole derivatives.