Discovery of Novel, Potent, and Selective Small-Molecule CCR5 Antagonists as Anti-HIV-1 Agents:  Synthesis and Biological Evaluation of Anilide Derivatives with a Quaternary Ammonium Moiety

Shiraishi, Masayuki; Aramaki, Yoshio; Seto, Masaki; H, Ito; Nishikawa, Yoshinori; Kanzaki, Naoyuki; Okamoto, Masato; Sawada, Hideki; Nishimura, Osamu; Baba, Masanori; Fujino, Masahiko

doi:10.1021/jm9906264

Cited by 184 publications

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“…The synthesized compounds, benzocycloheptene 2, the benzoxepine 19, and a variety of tertiary amine derivatives 20-25 7) were evaluated for their inhibitory effects on chemokine binding to CCR5-expressing CHO cells. Binding assays were performed in the presence of […”

Section: Resultsmentioning

confidence: 99%

“…The 4-oxocyclohexyl 23 and 3-pentyl 24 derivatives were comparable to tetrahydropyran-4-yl 19, which was about twice as active as the benzocycloheptene 2. Since quaternary ammonium compound 1 exhibited similar potency to the corresponding 1-benzoxepine compound 26 (IC 50 ϭ1.4 nM), 7) differences in the atom at the 5-postion of the benzocycloheptene ring were considered to have little effect on CCR5 antagonistic activity. However, in contrast, changes in the atom at the 5-postion of the tertiary amine derivatives, was found to affect activity.…”

Section: Resultsmentioning

confidence: 99%

“…Benzothiepine-1,1-dioxide 8 was obtained by m-chloroper- benzoic acid (mCPBA)-oxidation of 7. Alkaline hydrolysis of the esters (7,8) afforded carboxylic acids (9a, 9b), which were coupled with 4-[N-methyl-N-(tetrahydropyran-4-yl)-aminomethyl]aniline 10 7) to provide the desired products (11a, 11b). Oxidation of benzothiepine 11a using mCPBA gave benzothiepine-1-oxide derivative 11c.…”

Section: Chemistrymentioning

confidence: 99%

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Synthesis of 1-Benzothiepine and 1-Benzazepine Derivatives as Orally Active CCR5 Antagonists

Aramaki

Seto

Okawa

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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The b-chemokine receptor CCR5, a G-protein-coupled seven-transmembrane domain receptor, has been shown to act as a major co-receptor for fusion and entry of macrophagetropic (M-tropic or R5) HIV-1 into the host cells.1-4) Although combination chemotherapy and Highly Active AntiRetroviral Therapy (HAART) have achieved long-term suppression of viral replication in HIV-1-infected individuals, 5) CCR5 presents an attractive target for the inhibition of Mtropic HIV-1 replication.N, ]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride 1 has previously been reported as a novel and highly potent non-peptide CCR5 antagonist with a IC 50 value of 1.4 nM in the binding assay. 6,7)Compound 1 has been selected as a clinical candidate for development as a subcutaneous injectable agent since it exhibited poor oral absorption owing to the quaternary ammonium moiety. However, in the course of the investigation of quaternary ammonium derivatives, it was found that the chemical precursor of 1, benzocycloheptene derivative 2 containing a tertiary amine moiety, exhibited CCR5 antagonistic activity with an IC 50 value of 0.95 mM in the binding assay. In addition, since 2 exhibited considerably better oral absorption than quaternary ammonium derivative 1, 2 was used as a starting point to develop orally active small molecule CCR5 antagonists. In order to improve the potency of tertiary amine derivatives, conversion of the benzocycloheptene ring of lead compound 2 to other condensed-heterocycle rings such as 1-benzothiepine and 1-benzazepine was investigated, and the synthesis of these derivatives is described. ChemistryThe synthetic routes to the 1-benzothiepine, 1-benzothiepine-1-oxide and 1-benzothipine-1,1-dioxide derivatives are outlined in Chart 1. The benzothiepine ring was constructed by intramolecular Friedel-Crafts reaction of 4, which was prepared by the alkylation of p-bromothiophenol 3 with ethyl 4-bromobutyrate and subsequent alkaline hydrolysis. The resulting bromide 5 was condensed with 4-methylphenylboronic acid by Suzuki coupling reaction to give the ketone 6. Subsequent methoxycarbonylation gave the b-keto-ester, which was reduced using sodium borohydride, and dehydrated via mesylation to give the a,b-unsaturated esters 7. Benzothiepine-1,1-dioxide 8 was obtained by m-chloroper- * To whom correspondence should be addressed. e-mail: Aramaki_Yoshio@takeda. Laboratories, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd; and b Pharmaceutical Discovery Center, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd.; 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Received October 31, 2003; accepted December 3, 2003; published online December 8, 2003 Quaternary ammonium benzocycloheptene compound 1 has previously been reported as a clinical candidate for an injectable CCR5 antagonist. In order to develop an orally active CCR5 antagonist, derivatives of tertiary amine benzocycloheptene 2, the chemical precursor to 1, were investigated. The benzocycloheptene ring was conv...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

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Synthesis of 1-Benzothiepine and 1-Benzazepine Derivatives as Orally Active CCR5 Antagonists

Aramaki

Seto

Okawa

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…9) The compound 1, which we first reported as a small molecule CCR5 antagonist, exhibited highly potent anti-HIV-1 activity. 10,11) However, its oral absorption was very poor because of its polar quaternary ammonium moiety. In order to develop an orally active CCR5 antagonist, chemical modification of the tertiary amine derivative was performed, which led to the discovery of the orally active 1-benzothiepine 1,1-dioxide (3) and 1-benzazepine (4) derivatives.…”

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Orally Active CCR5 Antagonists as Anti-HIV-1 Agents 2: Synthesis and Biological Activities of Anilide Derivatives Containing a Pyridine N-Oxide Moiety

Seto

Aramaki

et al. 2004

Chem. Pharm. Bull.

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In order to develop orally active CCR5 antagonists, we investigated 1-benzoxepine derivatives containing new polar substituents, such as phosphonate, phosphine oxide or pyridine N-oxide moieties, as replacements for the previoiusly reported quaternary ammonium moiety. Among these compounds, the 2-(a a-hydroxybenzyl)pyridine N-oxide 5e exhibited moderate CCR5 antagonistic activity and had an acceptable pharmacokinetic profile in rats. Subsequent chemical modification was performed and compound (S)-5f possessing the (S)-configuration hydroxy group was found to be more active than the (R)-isomer. Replacement of the 1-benzoxepine ring with a 4-methylphenyl group by a 1-benzazepine ring with a 4-[2-(butoxy)ethoxy]phenyl group enhanced the activity in the binding assay. In addition, introduction of a 3-trifluoromethyl group on the phenyl group of the anilide moiety led to greatly increased activity in the HIV-1 envelope-mediated membrane fusion assay. In particular, compound (S)-5s showed the most potent CCR5 antagonistic activity (IC 50 ‫2.7؍‬ nM) and inhibitory effect (IC 50 ‫4.5؍‬ nM) in the fusion assay, together with good pharmacokinetic properties in rats.Key words CCR5 antagonist; HIV-1; 2-(a-hydroxybenzyl)pyridine N-oxide; (S)-configuration; 1-benzazepine Fig. 1 we describe the search for the new polar substituents, especially the 2-(a-hydroxybenzyl)pyridine N-oxides. ChemistryGeneral synthetic methods to the target compounds are outlined in Charts 6-8. The phosphonate 5a and phosphine oxide 5b were prepared by condensation of the carboxylic acid 19a with the aniline derivatives 8a, b (Chart 6). The target compounds 5c-s with the pyridine N-oxide moieties were synthesized by condensation of the carboxylic acids 19a, b, 23 with aniline derivatives 8c-m, followed by mchloroperbenzoic acid (mCPBA) oxidation (Charts 7, 8).The aniline derivative 8a was prepared according to Chart 1. The nitro compound 7 with a cyclic phosphonate moiety was synthesized by the reaction of 1,3-propanediol with the acid chloride, which was generated from the phosphonic acid 6. Catalytic hydrogenation of the nitro compound 7 gave the key aniline 8a.The aniline derivatives 8b-d, containing a cyclic phosphine oxide or pyridyl moiety, were synthesized according to Chart 2. Nitration of 9a-c 14) gave the corresponding nitro compounds 10a-c.15) The key anilines 8b-d 15) were prepared by catalytic hydrogenation of the nitro compounds 10a-c.The 4-[hydroxyl(pyridin-2-yl)methyl]anilines 8e, 8j-l were synthesized by coupling reaction of 2-lithiopyridine with the corresponding benzaldehydes 11a-d and subsequent catalytic hydrogenation of the resulting nitro compounds 12a-d (Chart 3).The optically active aniline derivatives (S)-8e and (R)-8e were obtained by optical resolution of 8e utilizing a chiral high-performance liquid chromatography (HPLC) (Chart 3). The absolute configuration was determined by X-ray crystallographic analysis (Fig. 2) of the m-bromobenzanilide (R)-13, which was prepared from the aniline (R)-8e (Chart 4).The synthetic method ...

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“…[16][17][18][19][20][21][22] Our laboratories have previously described the discovery of TAK-779, an anilide derivative with a quaternary ammonium moiety, as a small-molecule CCR5 antagonist. 23,24) Continued screening of Takeda compound libraries using […”

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confidence: 99%

CCR5 Antagonists as Anti-HIV-1 Agents. 1. Synthesis and Biological Evaluation of 5-Oxopyrrolidine-3-carboxamide Derivatives

Imamura

Ishihara

Hattori

et al. 2004

CHEMICAL & PHARMACEUTICAL BULLETIN

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Discovery of Novel, Potent, and Selective Small-Molecule CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and Biological Evaluation of Anilide Derivatives with a Quaternary Ammonium Moiety

Cited by 184 publications

References 28 publications

Synthesis of 1-Benzothiepine and 1-Benzazepine Derivatives as Orally Active CCR5 Antagonists

Synthesis of 1-Benzothiepine and 1-Benzazepine Derivatives as Orally Active CCR5 Antagonists

Orally Active CCR5 Antagonists as Anti-HIV-1 Agents 2: Synthesis and Biological Activities of Anilide Derivatives Containing a Pyridine N-Oxide Moiety

CCR5 Antagonists as Anti-HIV-1 Agents. 1. Synthesis and Biological Evaluation of 5-Oxopyrrolidine-3-carboxamide Derivatives

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