Novel 2,7-substituted (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: Peroxisome proliferator-activated receptor γ partial agonists with protein-tyrosine phosphatase 1B inhibition

998

Chem. Pharm. Bull. 63, 998–1014 (2015)

Vol. 63, No. 12

Regular Article

Novel 2,7-Substituted (S)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic

Acids: Peroxisome Proliferator-Activated Receptor γ Partial Agonists

with Protein–Tyrosine Phosphatase 1B Inhibition

Kazuya Otake, Satoru Azukizawa, Shigemitsu Takeda, Masaki Fukui, Arisa Kawahara,

Tatsuya Kitao, and Hiroaki Shirahase*

Drug Discovery Research Department, Kyoto Pharmaceutical Industries, Ltd.; 38, Nishinokyo Tsukinowa-cho,

Nakagyo-ku, Kyoto 604–8444, Japan.

Received June 24, 2015; accepted August 27, 2015

A novel series of 2,7-substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were syn-

thesized and biologically evaluated. (S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-

yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butylamine salt (13jE) was identiﬁed as

a potent human peroxisome proliferator-activated receptor γ (PPARγ)-selective agonist (EC₅₀=85nM) and

human protein–tyrosine phosphatase 1B (PTP-1B) inhibitor (IC₅₀=1.0µM). Compound 13jE partially acti-

vated PPARγ, but not PPARα or PPARδ, and antagonized farglitazar, a full PPARγ agonist. C_maxafter the

oral administration of 13jE at 10mg/kg was 28.6µg/mL (53µ^M) in male Sprague-Dawley (SD) rats. Repeated

administration of 13jE and rosiglitazone for 14d at 10mg/kg/d decreased plasma glucose and triglyceride lev-

els signiﬁcantly in male KK-A^ymice. Rosiglitazone, but not 13jE, signiﬁcantly increased the plasma volume

and liver weight. In conclusion, 13jE showed stronger hypoglycemic and hypolipidemic effects and weaker

hemodilution and hepatotoxic effects than rosiglitazone, suggesting that its safer efﬁcacy may be due to its

partial PPARγ agonism and PTP-1B inhibition.

Key words peroxisome proliferator-activated receptor gamma; partial agonist; diabetes; adverse effect; pro-

tein–tyrosine phosphatase 1B inhibitor; insulin resistance

Thiazolidinedione (TZD) derivatives such as rosiglitazone tance; thus, PTP-1B inhibitors have been focused on as insulin

(Fig. 1) have been used clinically as anti-diabetic drugs. Rosi- sensitizers.^27–29)Indeed, one of the PPARα/γ agonists with

glitazone is known to enhance insulin sensitivity by the acti- PTP-1B inhibitory activity has been reported to show effec-

vation of peroxisome proliferator-activated receptor γ (PPARγ), tive anti-diabetic activities with high safety,³⁰⁾probably due to

causing the reduction of blood glucose levels in type 2 dia- its partial PPARγ activation and PTP-1B inhibition. However,

betic patients^1–3); however, it induces edema and increases the it may not be a true partial PPARγ agonist, since it does not

risks of weight gain and congestive heart failure.^4–7)

antagonize a full PPARγ agonist. Furthermore, its risk of

Thus, many efforts have been made to develop a PPARα/γ carcinogenesis by both PPARα and PPARγ activation has not

dual agonist and a partial PPARγ agonist. PPARα is expressed been examined. In the present study, we found that (S)-2-(2-

in the liver and related to fatty acid metabolism⁸⁾; ﬁbrates, furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-

PPARα agonists, have been used as anti-hyperlipidemic yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic

acid

drugs, and reported to improve insulin resistance and show tert-butylamine salt (13jE, Fig. 1) is a true partial PPARγ

hypoglycemic effects in diabetic animals and patients.^9–11)agonist with PTP-1B inhibitory activity, and shows safer anti-

PPARα agonists have a body-weight-reducing effect, and diabetic effects than rosiglitazone in KK-A^ymice.

show no hemodilution effects.¹²⁾The combination of PPARα

and PPARγ agonists has been expected to show synergistic

Chemistry

anti-diabetic effects with high safety.^13,14)However, the de-

The synthesis of 2,7-substituted-1,2,3,4-tetrahydroisoquino-

velopment of PPARα/γ dual agonists including muraglitazar, line-3-carboxylic acid derivatives from methyl 2-tert-butoxy-

were suspended due to the risk of cardiovascular events, car- carbonyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxyl-

cinogenicity and the potential risks of liver injury and/or renal ate (1)²³⁾is outlined in Chart 1. The hydroxyl group at the

dysfunction^15–17): Overactivation of PPAR with both PPARα 7-position of 1 was alkylated with oxazole derivatives 2a–c

and PPARγ agonist activity may lead to carcinogenesis and and 3c–j in the presence of K₂CO₃and tetraethylammonium

to adverse effects in the liver, heart and kidney.^14,18–21)Thus, ﬂuoride hydrate to give 4a–c and 5c–j, and then the tert-

PPARγ partial agonists, such as INT-131, have been researched butoxycarbonyl (Boc) group at the 2-position was removed

and studied clinically.²²⁾They showed higher efﬁcacy with with HCl/HCO₂H to give 6a–c and 7c–j, respectively. Ac-

lower toxicity in experimental diabetic animals; however, none ylation of 6a–c and 7c–j was performed with carboxylic acids

of them has been successfully developed.

8A, D–G and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

We have reported a PPARγ agonist and PPARα/γ dual ago- hydrochloride (EDC·HCl), or acyl chlorides 9B, C and tri-

nist with protein–tyrosine phosphatase 1B (PTP-1B) inhibitory ethylamine (Et₃N), to give corresponding amides 10aA–cA,

activity.^23–26)PTP-1B is known to regulate the insulin signal 11cA–jA, gB–gE and jE–jG. Hydrolysis of the ester group

negatively and its overexpression is involved in insulin resis- with aqueous LiOH afforded 12aA–cA, 13cA–jA, gB–gF and

*To whom correspondence should be addressed. e-mail: shirahase@kyoto-pharm.co.jp

Vol. 63, No. 12 (2015)

Chem. Pharm. Bull.

999

Fig. 1. Chemical Structures of PPARγ Agonists

jE–jG, which were isolated as tert-butylamine salt or calcium 26h–j. The ester group was transformed to a chloromethyl

salt.

group by reduction with LiAlH₄and then chlorinated with

2-(2-Substituted-5-methyloxazol-4-yl)ethyl methanesulfo- SOCl₂to give 3h–j.

nates 2a–c were prepared according to the previously reported

Carboxylic acids 8A, D and E were purchased, 8G was

procedure,²⁵⁾as shown in Route A in Chart 2. Acylation of prepared according to the literature³⁵⁾and 3-(5-ﬂuorofuryl)-

L-aspartic acid β-methyl ester 15 with acyl chlorides 14a–c acrylic acid (8F) was synthesized from ethyl 5-bromofuran-

afforded 2-acyl ^L-aspartic acid β-methyl esters. The carboxylic 2-carboxylate (27), as shown in Chart 3. Compound 28 was

acid group was transformed to an acetyl group by the Dakin– prepared by the Heck reaction from 27 and ethyl ester was

West reaction with acetic anhydride and bases, which was hydrolyzed. The carboxylic acid group was converted to ﬂuo-

treated with phosphorous oxychloride to give oxazole deriva- rine with Selectﬂuor and NaHCO_3,followed by deprotection of

tives 16a–c. The ester group of 16a–c was reduced by LiAlH₄the tert-butoxycarbonyl group with triﬂuoroacetic acid (TFA)

or NaBH₄to give alcohols 17a–c, and then methanesulfonyl- to give 8F.

ated to afford 2a–c.

The synthesis of non-carboxylic acid-type derivatives 32–34

2-Substituted-4-chloromethyl-5-methyloxazoles 3c–j were is outlined in Chart 4. The hydroxyl group of 1 was protected

synthesized via Routes B and C in Chart 2. In Route B, alde- with a benzyl group, and then the ester group was converted

hydes 18c, d,³¹⁾e, f³²⁾and g,³³⁾which were purchased or pre- to Weinreb’s amide 29 via carboxylic acid, and then trans-

pared according to the literature, were treated with HCl gas formed to an acetyl group with MeMgI, followed by deprotec-

and diacetyl monoxime (19) to give oxazole N-oxides 20c–g, tion of the benzyl group to give 30. Compound 30 was alkyl-

followed by treatment with phosphorous oxychloride to af- ated with 3j at the 7-position, subjected to removal of the Boc

ford 4-chloromethyloxazole derivatives (3c–g).³⁴⁾In Route C, group, and acylated with 3-furylacrylic acid via acid chloride

carboxylic acids 24h³⁵⁾and j³²⁾were prepared according to the to give 32. Reduction of the acetyl group of 32 afforded hy-

literature, and 1,3,4-trimethyl-3-cyclopentenecarboxylate (24i) droxyethyl derivative 33 as a diastereomixture (d.r.=71:29).

was synthesized from 1,4-dichloro-2,3-dimethyl-but-2-ene Separately, 30 was treated with diethylaminosulfur triﬂuoride

(21).³⁶⁾Diethyl malonate was alkylated with 21 and formed a (DAST) to give 31. Diﬂuoroethyl derivative 34 was synthe-

cyclopentene ring 22. The diester group was hydrolyzed and sized from 31 in a similar manner as for the synthesis of 32.

decarboxlated to give monocarboxylic acid 23. Carboxylic

acid was esteriﬁed and then methylated with lithium diisopro-

Results and Discussion

pylamide (LDA) and methyl iodide (MeI), followed by hydro-

In the present study, (S)-2-(2,4-hexadienoyl)-7-[2-(5-methyl-

lysis, affording 24i. Compounds 24h–j were amidated with 2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-

25³⁷⁾via acyl chloride, followed by cyclization with I₂, tri- carboxylic acid (35, Fig. 1), a PPARγ full agonist with a

phenylphosphine (PPh₃) and Et₃N to give oxazole derivatives weak PTP-1B inhibitory activity, was chemically modiﬁed

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Chem. Pharm. Bull.

Vol. 63, No. 12 (2015)

(i) K₂CO₃, tetraethylammonium ﬂuoride hydrate, toluene, (ii) HCl, HCO₂H, (iii) 8A, D–G, EDC·HCl, CH₂Cl₂, (iv) 9B, C, Et₃N, CH₂Cl₂, (v) LiOHaq., THF–MeOH, (vi)

tert-BuNH₂, MeOH, i-Pr₂O, (vii) KHCO₃, CaCl₂, THF, H₂O.

Chart 1. Synthesis of 2,7-Substituted-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acids

at the 2-, 3- and 7-positions. Then, PPARγ agonist activ- tion and 14% maximal inhibition. The introduction of three

ity was determined as the transactivation activity in COS-1 methyl groups at the 2-, 4- and 6-positions (12cA) slightly

cells transfected with full-length human PPARγ1 plasmid, enhanced the partial agonist activity of 12aA. Furthermore,

and human retinoid X receptor alpha (RXRα) plasmid with the shortening of the alkoxy chain (13cA) increased the af-

reporter plasmid pGL3-PPREx4-tk-luc, EC₅₀and the maximal ﬁnity. These results suggest that appropriate bulkiness and

activation level relative to the maximal level induced by far- steric hindrance near the 2-position of the oxazole ring in a

glitazar, a PPARγ full agonist (10⁻⁷M) (Fig. 1). The antagonist side chain at the 7-position of a tetrahydroisoquinoline ring

activity against farglitazar (10⁻⁷M) was also determined. The are needed to exhibit the partial agonist property. The short-

effects of the compounds on PTP-1B activities were examined ening of the alkoxy chain was shown to increase the afﬁnity

using a human PTP-1B enzyme. For some compounds, plasma to PPARγ protein. In the structural study, other partial PPARγ

concentrations after oral administration at 10mg/kg were de- agonists with a carboxyl group interacted with PPARγ protein

termined in male Sprague-Dawley (SD) rats, and anti-diabetic differently from a full PPARγ agonist, leading to insufﬁcient

effects were investigated in KK-A^ymice, a type 2 diabetic PPARγ activation.³⁸⁾Conformational change of the phenyloxa-

animal. All animal experiments in the present study were zole moiety by the introduction of 2 or 3 methyl groups may

conducted according to the guidelines for animal experiments lead to conformational change of the whole molecule, thereby

of our institute and the guidelines for animal experimentation changing the interaction with PPARγ protein.

approved by the Japanese Association of Laboratory Animal

Science.

In the second experiments, the phenyl ring at the 2-position

of oxazole in 13cA was replaced by bulky aliphatic moieties,

In the ﬁrst experiments, methyl groups were introduced on which bind to the oxazole ring via quaternary carbon (Table

the phenyl ring of compound 35 (12aA–cA and 13cA) (Table 1). The seven synthesized compounds all showed partial

1). Interestingly, the introduction of two methyl groups at the agonist activity (EC₅₀: 117–237nM, max: 52–71%). Among

2- and 5-positions (12bA) markedly increased the afﬁnity, the compounds, 13gA with an adamantyl group and 13jA

and slightly decreased the maximal level of PPARγ activation. with an indanyl group showed higher afﬁnity than the other

However, its antagonistic activity against farglitazar was not compounds. The oral absorption of 13jA was much higher

observed. The introduction at the 2- and 6-positions (12aA) than that of 13gA (C_max: 11.0 and 1.2µg/mL, respectively). An

brought typical partial agonist activity: 66% maximal activa- adamantyl ring may be easily metabolized after oral adminis-

Vol. 63, No. 12 (2015)

Chem. Pharm. Bull.

1001

(i) Et₃N, CH₂Cl₂, (ii) Ac₂O, N-methylmorpholine, DMAP, toluene, (iii) POCl₃, toluene, (iv) NaBH₄, MeOH, THF or LiAlH₄, THF, (v) MsCl, Et₃N, CH₂Cl₂, (vi) HCl (g),

AcOEt, (vii) POCl₃, toluene, (viii) diethyl malonate, LiH, THF, (ix) KOH aq., MeOH, (x) pyridine, (xi) K₂CO₃, MeI, DMF, THF, (xii) i-Pr₂NH, n-BuLi in hexane, MeI,

THF, (xiii) LiOH aq., MeOH, THF, (xiv) (COCl)₂, DMF, 25, i-Pr₂NEt, CH₂Cl₂, (xv) I₂, PPh₃, Et₃N, CH₂Cl₂, (xvi) LiAlH₄, THF, (xvii) SOCl₂, CH₂Cl₂.

Chart 2. Synthesis of 2-(2-Substituted-5-methyloxazol-4-yl)ethyl Methanesulfonates and 2-Substituted-4-chloromethyl-5-methyloxazole Derivatives

(i) tert-Butyl acrylate, Pd(OAc)₂, P(o-tol)₃, i-Pr₂NEt, LiCl, DMF, (ii) LiOHaq., THF–MeOH, (iii) Selectﬂuor, NaHCO₃, Et₂O, H₂O, (iv) TFA, CH₂Cl₂.

Chart 3. Synthesis of 3-(5-Fluorofuryl)acrylic Acid

tration of 13gA.

in SD rats. The tetrahydroisoquinoline with an un-ionized

The substituent at the 2-position of 13gA and jA was re- moiety at the 3-position may be a useful scaffold for PPARγ

placed by various chains (Table 2). Hexanoyl, hexenoyl and antagonist.

hexynoyl chains did not affect the partial agonist activity of

Compound 13jE with potent PPARγ partial agonist activity

13gA. A furylacryloyl chain enhanced the afﬁnity by about and good oral absorption was chosen for further biological

2-fold and showed the lowest maximal levels (13gE, gF). evaluation (Table 4). Compound 13jE did not activate PPARα

The oral absorptions of these adamantyl derivatives were and PPARδ, even at 10⁻⁵M. Compound 13jE inhibited PTP-1B

all lower than that of 13gA. Among the indan derivatives, a activity (IC₅₀=1.0 µM). In KK-A^ymice, 13jE more potently re-

furylacryloyl group moderately enhanced the partial agonist duced the plasma glucose and triglyceride levels than rosigli-

activity and markedly increased the oral absorption (13jE). A tazone, while rosiglitazone but not 13jE showed hemodilution

(5-ﬂuorofuryl)acryloyl group reduced the afﬁnity (13jF) and a and hepatomegalysis (Table 5). The PPARγ agonist activity

cyclopropylacryloyl group enhanced the afﬁnity and slightly of 13jE was lower than that of rosiglitazone. Its hypoglyce-

reduced the oral absorption (13jG).

mic effect is likely mediated by partial PPARγ activation and

Finally, the carboxyl group of 13jE was replaced by an PTP-1B inhibition, resulting in high efﬁcacy with no PPARγ-

un-ionized polar group: acetyl (32), hydroxyethyl (33) and related adverse effects.

diﬂuoroethyl (34) groups markedly decreased the maximal

In conclusion, 2,7-substituted 1,2,3,4-tetrahydroisoquino-

levels and enhanced the inhibitory activity (Table 3). Unlike line-3-carboxylic acid derivatives were demonstrated to be

a carboxyl group, un-ionized polar groups may not interact good scaffolds for a PPARγ selective partial agonist with

fully with PPARγ protein, resulting in insufﬁcient recruitment PTP-1B inhibitory activity, and a furylacryloyl moiety and

of coactivators. These compounds were not orally absorbed an indan ring are suitable for partial agonist activity and oral

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Chem. Pharm. Bull.

Vol. 63, No. 12 (2015)

(i) K₂CO₃, BnBr, DMF, (ii) LiOHaq., THF–MeOH, (iii) N,O-dimethylhydroxyamine, Et₃N, EDC·HCl, CH₂Cl₂, (iv) MeMgI in THF, THF, (v) Pd–C, H₂, MeOH, (vi)

DAST, CH₂Cl₂, (vii) 3j, K₂CO₃, tetraethylammonium ﬂuoride hydrate, toluene, (viii) HCl, HCO₂H, (ix) 2-furylacrylic acid, (COCl)₂, DMF, CH₂Cl₂, then Et₃N, (x) NaBH₄,

MeOH, THF.

Chart 4. Synthesis of Non-carboxylic Acid-Type Derivatives

absorption. Compound 13jE is a potential candidate of a safe phenyl)-5-methyloxazol-4-ylethoxy]-1,2,3,4-tetrahydroiso-

1

and efﬁcacious anti-diabetic drug, and its clinical development quinoline-3-carboxylate (4b) Yield 99%. H-NMR (CDCl₃)

is desirable.

δ: 1.45, 1.51 (total 9H, s, s), 2.35 (3H, s), 2.37 (3H, s), 2.59 (3H,

s), 2.96 (2H, t, J=6.6Hz), 3.04–3.21 (2H, m), 3.60, 3.62 (total

3H, s, s), 4.21 (2H, t, J=6.6Hz), 4.37–4.50 (1H, m), 4.60–4.76

Experimental

General Procedures Melting points were measured on (1.5H, m), 5.07–5.13 (0.5H, m), 6.61–6.75 (2H, m), 6.98–7.15

a melting point apparatus (Yamato MP-21; Yamato Scientiﬁc (3H, m), 7.69–7.74 (1H, m).

1

Co., Ltd., Tokyo, Japan) and are uncorrected. H-NMR spectra

Methyl (S)-2-tert-Butoxycarbonyl-7-[2-(2,4,6-dimethyl-

were obtained on a nuclear magnetic resonance spectrometer phenyl)-5-methyloxazol-4-ylethoxy]-1,2,3,4-tetrahydroiso-

at 90MHz (R-1900; Hitachi High-Technologies Corporation, quinoline-3-carboxylate (4c) Quant. ¹H-NMR (CDCl₃) δ:

Tokyo, Japan) or 400MHz (JNM-AL-400; JEOL Ltd., Tokyo, 1.35–1.70 (9H, m), 2.20 (6H, s), 2.29 (3H, s), 2.33 (3H, s), 2.96

Japan) using tetramethylsilane (TMS) as an internal standard. (2H, t, J=6.8Hz), 3.00–3.25 (2H, m), 3.61 (3H, s), 4.22 (2H, t,

IR spectra were recorded with an infrared spectrometer (FT- J=6.6Hz), 4.30–5.20 (3H, m), 6.60–6.80 (2H, m), 6.90 (2H, s),

IR8200PC; Shimadzu Corporation, Kyoto, Japan). MS spectra 7.02 (1H, d, J=8.4 Hz).

were obtained on a QTRAP LC-MS/MS system (API2000;

Methyl (S)-2-tert-Butoxycarbonyl-7-[2-(2,4,6-dimethyl-

Applied Biosystems, Foster, U.S.A.). Column chromatography phenyl)-5-methyloxazol-4-ylmethoxy]-1,2,3,4-tetrahy-

was performed on silica gel (Daisogel No.1001W; Daiso Co., droisoquinoline-3-carboxylate (5c) Yield 94%. ¹H-NMR

Ltd., Osaka, Japan). Reactions were monitored by TLC (TLC (CDCl₃) δ: 1.45, 1.52 (total 9H, s, s), 2.23 (6H, s), 2.31 (3H,

silica gel 60F₂₅₄; Merck, Darmstadt, Germany).

s), 2.39 (3H, s), 3.05–3.25 (2H, m), 3.60, 3.63 (total 3H, s, s),

Methyl (S)-2-tert-Butoxycarbonyl-7-[2-(2,6-dimethylphe- 4.40–4.53 (1H, m), 4.62–4.79 (1.5H, m), 4.99 (2H, s), 5.10–5.15

nyl)-5-methyloxazol-4-ylethoxy]-1,2,3,4-tetrahydroisoquin- (0.5H, m), 6.76–6.88 (2H, m), 6.90 (2H, s), 7.01–7.07 (1H, m).

oline-3-carboxylate (4a) A mixture of 1 (1.42g, 4.62mmol),

Methyl (S)-2-tert-Butoxycarbonyl-7-[2-(1-ethyl-1-methyl-

crude 2a (2.13g), tetraethylammonium ﬂuoride hydrate propan-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetra-

(300mg) and K₂CO₃(1.91g 13.8mmol) in toluene (50mL) was hydroisoquinoline-3-carboxylate (5d) Quant. ¹H-NMR

stirred at 85°C for 14h. AcOEt (100mL) was added to the (CDCl₃) δ: 0.78 (6H, J=7.6Hz), 0.98 (9H, s), 1.29, 1.52 (total

reaction mixture, and the mixture was washed with water and 9H, s, s), 1.45 (3H, s), 1.56–1.69 (2H, m), 1.72–1.84 (2H,

saturated brine and dried over Na₂SO₄. The solvent was evap- m), 2.29 (3H, s), 3.02–3.21 (2H, m), 3.61, 3.63 (total 3H, s,

orated under reduced pressure. The obtained residue was puri- s), 4.38–4.76 (2.5H, m), 4.86, 4.87 (total 2H, s, s), 5.05–5.14

ﬁed by silica gel column chromatography to give 4a (2.47g, (0.5H, m), 6.68–6.83 (2H, m), 6.98–7.05 (1H, m).

1

quant.) as an oil. H-NMR (CDCl₃) δ: 1.45, 1.52 (total 9H, s,

Methyl

(S)-2-tert-Butoxycarbonyl-7-[2-(1-methylcyclo-

s), 2.23 (6H, s), 2.35 (3H, s), 2.97 (2H, t, J=6.6Hz), 3.05–3.20 pentan-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahy-

(2H, m), 3.60, 3.63 (total 3H, s, s), 4.23 (2H, t, J=6.6Hz), droisoquinoline-3-carboxylate (5e) Yield 92%. ¹H-NMR

4.38–4.50 (1H, m), 4.60–4.75 (1.5H, m), 5.06–5.13 (0.5H, m), (CDCl₃) δ: 1.39 (3H, s), 1.45, 1.52 (total 9H, s, s), 1.61–1.79

6.60–6.75 (2H, m), 6.98–7.03 (1H, m), 7.06 (2H, d, J=7.6Hz), (6H, m), 2.15–2.24 (2H, m), 2.30 (3H, s), 3.05–3.20 (2H, m),

7.20 (1H, t, J=7.6 Hz).

Compounds 4b and c and 5c–j were prepared according to m), 4.84 (2H, s), 5.08–5.15 (0.5H, m), 6.72–6.82 (2H, m),

the procedure for the synthesis of 4a. 7.00–7.06 (1H, m).

Methyl (S)-2-tert-Butoxycarbonyl-7-[2-(2,5-dimethyl- Methyl (S)-2-tert-Butoxycarbonyl-7-[2-(1-methylcyclo-

3.61, 3.63 (total 3H, s, s), 4.40–4.52 (1H, m), 4.62–4.78 (1.5H,

Vol. 63, No. 12 (2015)

Chem. Pharm. Bull.

1003

Table 1. Chemical Structure, Molecular Weight, PPARγ Agonist and Antagonist Activity and Plasma Concentration in Male SD Rats of 7-Substituted-

2-hexadienoyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid Derivatives

PPARγ^b)

Max^c)(%)

Plasma levels^e)

Compound

R¹

n

M.W.^a)

472.53

EC₅₀(nM)

1062

IC₅₀(nM)

Max^d)(%)

—

C_max(µg/mL) AUC (µg·h/mL)

35

2

105

>1000

39

177

12aA

12bA

2

1

500.59

514.61

500.59

466.57

454.55

478.58

516.63

462.54

490.59

512.60

357.43

972

156

518

301

237

131

230

117

184

142

122

70

66

—

>1000

94

14

<10

22

—

87

62

51

52

55

68

63

62

71

69

119

—

12cA

—

13cA

62

21

0.32

2.9

3.4

2.8

1.2

9.4

3.4

13dA

124

227

177

314

45

30

6.0

13eA

25

14.2

9.0

13fA

15

13gA

35

5.5

13hA

30

52.9

114.5

74.9

—

13iA

476

622

>1000

17

11.9

13jA

26

11.0

—

Rosiglitazone

—

a) Molecular weight as the free form. b) n=3. c) The activation level induced by farglitazar (10⁻⁷M) was taken as 100%. d) The maximal inhibitory effects against the re-

sponse induced by farglitazar (10⁻⁷M). e) Plasma levels after oral administration at 10mg/kg in male SD rats, n=3.

hexyl-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahy- 4.40–4.52 (1H, m), 4.64–4.77 (1.5H, m), 4.84 (2H, s), 5.08–5.15

droisoquinoline-3-carboxylate (5f) Yield 98%. ¹H-NMR (0.5H, m), 6.70–6.84 (2H, m), 7.00–7.07 (1H, m).

(CDCl₃) δ: 1.27 (3H, s), 1.32–1.60 (17H, m), 2.08–2.21 (2H,

Methyl

(S)-2-tert-Butoxycarbonyl-7-[2-(1-methylcyclo-

m), 2.30 (3H, s), 3.05–3.23 (2H, m), 3.61, 3.63 (total 3H, s, s), pent-3-en-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetra-

1

4.38–4.52 (1H, m), 4.60–4.80 (1.5H, m), 4.86 (2H, s), 5.06–5.18 hydroisoquinoline-3-carboxylate (5h) Yield 99%. H-NMR

(0.5H, m), 6.72–6.86 (2H, m), 6.98–7.06 (1H, m).

(CDCl₃) δ: 1.45, 1.46, 1.52 (total 12H, s, s, s), 2.31 (3H, s),

Methyl (S)-2-tert-Butoxycarbonyl-7-{[2-(adamantan-1-yl)- 2.34–2.44 (2H, m), 2.95–3.22 (4H, m), 3.61, 3.63 (total 3H,

5-methyloxazol-4-yl]methoxy}-1,2,3,4-tetrahydroisoquino- s, s), 4.40–4.52 (1H, m), 4.64–4.78 (1.5H, m), 4.84 (2H, s),

line-3-carboxylate (5g) Yield 98%. ¹H-NMR (CDCl₃) δ: 5.07–5.15 (0.5H, m), 5.66 (2H, s), 6.70–6.84 (2H, m), 7.00–7.06

1.45, 1.52 (total 9H, s, s), 1.70–1.81 (6H, m), 1.98–2.10 (9H, (1H, m).

br), 2.30 (3H, s), 3.03–3.22 (2H, m), 3.61, 3.63 (total 3H, s, s),

Methyl (S)-2-tert-Butoxycarbonyl-7-[2-(1,4,5-trimethyl-

1004

Chem. Pharm. Bull.

Vol. 63, No. 12 (2015)

Table 2. Chemical Structure, Molecular Weight, PPARγ Agonist and Antagonist Activity and Plasma Concentration in Male SD Rats of 2,7-Disubstitut-

ed-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid Derivatives

PPARγ^b)

Max^c)(%)

Plasma levels^e)

Compound

13gA

R¹

R²

M.W.^a)

516.63

520.66

EC₅₀(nM)

117

IC₅₀(nM)

314

Max^d)(%)

35

C_max(µg/mL) AUC (µg·h/mL)

63

60

61

1.2

5.5

13gB

117

139

108

170

27

30

0.22

0.12

0.92

0.69

13gC

518.64

13gD

13gE

516.63

542.62

154

48

59

48

27

14

32

29

0.23

0.13

0.81

13gF^f)

560.61

70

52

82

32

—

13jA

13jE

13jF

13jG

512.60

538.59

556.58

512.60

122

85

69

65

62

55

622

202

120

214

26

20

30

11.0

74.9

28.6

20.4

8.5

367.9

229.5

97.4

193

87

a) Molecular weight as the free form. b) n=3. c) The activation level induced by farglitazar (10⁻⁷M) was taken as 100%. d) The maximal inhibitory effects against the re-

sponse induced by farglitazar (10⁻⁷M). e) Plasma levels after oral administration at 10mg/kg in male SD rats, n=3. f ) Calcium salt.

Table 3. Chemical Structure, Molecular Weight, PPARγ Agonist and Antagonist Activity and Plasma Concentration in Male SD Rats of 3,7-Substituted-

2-furylacryloyl-1,2,3,4-tetrahydroisoquinoline Derivatives

PPARγ^b)

Max^c)(%)

Plasma levels^e)

Compound

R³

M.W.^a)

538.59

EC₅₀(nM)

85

IC₅₀(nM)

202

Max^d)(%)

20

C_max(µg/mL) AUC (µg·h/mL)

13jE^{f )}

65

28.6

367.9

32

33

34

536.62

538.63

558.62

30

120

62

21

38

24

169

1597

2221

63

54

62

0.07

0.04

—

a) Molecular weight as the free form. b) n=3. c) The activation level induced by farglitazar (10⁻⁷M) was taken as 100%. d) The maximal inhibitory effects against the re-

sponse induced by farglitazar (10⁻⁷M). e) Plasma levels after oral administration at 10mg/kg in male SD rats, n=3. f ) t-BuNH₂salt.

cyclopent-3-en-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-

Methyl (S)-2-tert-Butoxycarbonyl-7-[2-(2-methylindane-

tetrahydroisoquinoline-3-carboxylate (5i) Yield 97%. 2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroiso-

1

¹H-NMR (CDCl₃) δ: 1.44, 1.52 (total 9H, s, s), 1.45 (3H, s), quinoline-3-carboxylate (5j) Yield 93%. H-NMR (CDCl₃)

1.61 (6H, s), 2.25–2.33 (5H, m), 2.95–3.22 (4H, m), 3.61, 3.63 δ: 1.45, 1.52 (total 9H, s, s), 1.50 (3H, s), 2.32 (3H, s), 2.93–3.22

(total 3H, s, s), 4.40–4.51 (1H, m), 4.64–4.79 (1.5H, m), 4.84 (4H, m), 3.55–3.66 (5H, m), 4.41–4.51 (1H, m), 4.64–4.79

(2H, s), 5.07–5.14 (0.5H, m), 6.70–6.85 (2H, m), 6.97–7.05 (1H, (1.5H, m), 4.85 (2H, s), 5.07–5.15 (0.5H, m), 6.70–6.85 (2H,

m).

m), 6.98–7.06 (1H, m), 7.11–7.23 (4H, m).

Vol. 63, No. 12 (2015)

Chem. Pharm. Bull.

1005

Table 4. PPARγ, PPARα and PPARδ Transactivation Effects and PPARγ Inhibition and PTP-1B Inhibition of Compound 13jE and Rosiglitazone

PPARγ^a)

PPARα^a)

PPARδ^a)

PTP-1B^a)

Compound

EC₅₀(nM)

Max^b)(%)

IC₅₀(nM)

Max^c)(%)

EC₅₀(nM)

IC₅₀(µM)

13jE

Rosiglitazone

85

70

65

202

20

—

>1000

1.0

119

>1000

>30

a) n=3. b) The activation level induced by farglitazar (10⁻⁷M) was taken as 100%. c) The maximal inhibitory effects against the response induced by farglitazar (10⁻⁷M).

Table 5. Effects of Repeated Administration of Compound 13jE and Rosiglitazone in Male KK-A^yMice

KK-A^ymice (10mg/kg, 14d)

Compound

Glucose % decrease^a)

TG % decrease^a)

Plasma volume % increase^b)

Liver weight % increase^b)

13jE

45.0 7.2**

31.8 4.5**

41.0 3.7**

35.4 8.6*

0.7 7.5

29.1 9.0

Rosiglitazone

13.1 3.9*

60.8 15.6**

Mean S.E. *p<0.05, **p<0.01. The mean value in control mice were taken as 100%. a) 13jE; n=6, rosiglitazone; n=11. b) 13jE; n=6, rosiglitazone; n=5.

Methyl

(S)-7-[2-(2,6-Dimethylphenyl)-5-methyloxazol- boxylate (7d) Yield 92%. ¹H-NMR (CDCl₃) δ: 0.77 (6H,

4-ylethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate J=7.3Hz), 1.29 (3H, s), 1.56–1.69 (2H, m), 1.72–1.85 (2H,

(6a) To a solution of 4a (2.45g, 4.70mmol) in formic acid m), 1.97–2.07 (1H, br), 2.29 (3H, s), 2.87 (1H, dd, J=15.9,

(5mL) was added 8.6^Mhydrogen chloride solution in 2-pro- 10.2Hz), 3.02 (1H, dd, J=15.9, 4.6Hz), 3.71 (1H, dd, J=10.2,

panol (1.64mL, 14.1mmol) under ice-cooling, and the mixture 4.6Hz), 3.77 (3H, s), 3.99–4.10 (2H, m), 4.87 (2H, s), 6.65

was stirred at room temperature for 15min. The reaction (1H, d, J=2.4Hz), 6.79 (1H, dd, J=8.3, 2.4Hz), 7.00 (1H, d,

mixture was neutralized with saturated aqueous NaHCO₃J=8.3 Hz).

solution and extracted with AcOEt. The organic layer was

Methyl (S)-7-[2-(1-Methylcyclopentan-1-yl)-5-methyloxa-

washed with brine and dried over Na₂SO₄. The solvent was zol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-carbox-

evaporated under reduced pressure to give 6a (1.90g, 92% ylate (7e) Yield 89%. ¹H-NMR (CDCl₃) δ: 1.39 (3H, s),

1

yield) as an oil. H-NMR (CDCl₃) δ: 2.22 (6H, s), 2.35 (3H, s), 1.61–1.78 (6H, m), 2.10–2.24 (2H, m), 2.30 (3H, s), 2.89 (1H,

2.86 (1H, dd, J=15.6, 10.2Hz), 2.95–3.04 (3H, m), 3.71(1H, dd, dd, J=15.9, 10.2Hz), 3.04 (1H, dd, J=15.9, 4.4Hz), 3.72–3.77

J=10.2, 4.6Hz), 3.77 (3H, s), 4.03 (1H, d, J=15.6Hz), 4.07 (1H, (1H, m), 3.78 (3H, s), 4.05 (1H, d, J=16.1), 4.11 (1H, d,

d, J=15.6Hz), 4.23 (2H, t, J=6.6Hz), 6.58 (1H, d, J=2.4Hz), J=16.1Hz), 4.84 (2H, s), 6.67 (1H, d, J=2.4Hz), 6.80 (1H, dd,

6.73 (1H, dd, J=8.6, 2.4Hz), 6.99 (1H, d, J=8.6Hz), 7.06 (2H, J=8.6, 2.4Hz), 7.01 (1H, d, J=8.6 Hz).

d, J=7.3Hz), 7.20 (1H, t, J=7.3 Hz).

Compounds 6b and c and 7c–j were prepared according to zol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-carbox-

the procedure for the synthesis of 6a.

ylate (7f) Yield 95%. ¹H-NMR (CDCl₃) δ: 1.28 (3H, s),

Methyl (S)-7-[2-(2,5-Dimethylphenyl)-5-methyloxazol- 1.32–1.63 (8H, m), 2.08–2.18 (2H, m), 2.30 (3H, s), 2.87 (1H,

Methyl (S)-7-[2-(1-Methylcyclohexyl-1-yl)-5-methyloxa-

4-ylethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate dd, J=15.9, 10.5Hz), 3.02 (1H, dd, J=15.9, 4.4Hz), 3.67–3.77

1

(6b) Yield 98%. H-NMR (CDCl₃) δ: 2.34 (3H, s), 2.36 (3H, (1H, m), 3.77 (3H, s), 4.00–4.10 (2H, m), 4.86 (2H, s), 6.67

s), 2.59 (3H, s), 2.86 (1H, dd, J=16.1, 10.5Hz), 2.92–3.04 (3H, (1H, d, J=2.4Hz), 6.80 (1H, dd, J=8.3, 2.4Hz), 7.01 (1H, d,

m), 3.70 (1H, dd, J=10.5, 4.6Hz), 3.76 (3H, s), 4.03 (1H, d, J=8.3 Hz).

J=16.4Hz), 4.07 (1H, d, J=16.4Hz), 4.21 (2H, t, J=6.6Hz),

Methyl (S)-7-{[2-(Adamantan-1-yl)-5-methyloxazol-4-yl]-

6.57 (1H, d, J=2.7Hz), 6.72 (1H, dd, J=8.5, 2.7Hz), 6.99 (1H, methoxy}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (7g)

1

d, J=8.5Hz), 7.06–7.14 (2H, m), 7.69–7.73 (1H, m).

Yield 92%. H-NMR (CDCl₃) δ: 1.71–1.83 (6H, m), 1.95–2.10

Methyl (S)-7-[2-(2,4,6-Dimethylphenyl)-5-methyloxazol- (10H, br), 2.30 (3H, s), 2.87 (1H, dd, J=15.9, 10.2Hz), 3.02

4-ylethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1H, dd, J=15.9, 4.6Hz), 3.72 (1H, dd, J=10.2, 4.6Hz), 3.74

1

(6c) Yield 91%. H-NMR (CDCl₃) δ: 2.19 (6H, s), 2.29 (3H, (3H, s), 4.00–4.12 (2H, m), 4.84 (2H, s), 6.66 (1H, d, J=2.7Hz),

s), 2.33 (3H, s), 2.90–3.10 (4H, m), 3.68 (1H, d, J=5.5Hz), 6.79 (1H, dd, J=8.5, 2.7Hz),, 7.01 (1H, d, J=8.5 Hz).

3.77 (3H, s), 4.06 (2H, s), 4.22 (2H, t, J=7.3Hz), 6.59 (1H,

Methyl (S)-7-[2-(1-Methylcyclopent-3-en-1-yl)-5-methyl-

d, J=2.4Hz), 6.60–6.85 (1H, m), 6.88 (2H, s), 7.00 (1H, d, oxazol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-car-

1

J=8.1 Hz).

boxylate (7h) Yield 94%. H-NMR (CDCl₃) δ: 1.46 (3H, s),

Methyl (S)-7-[2-(2,4,6-Dimethylphenyl)-5-methyloxazol- 1.86–2.03 (1H, br), 2.31 (3H, s), 2.35–2.44 (2H, m), 2.87 (1H,

4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate dd, J=15.9, 10.5Hz), 2.95–3.08 (3H, m), 3.72 (1H, dd, J=10.2,

(7c) Quant. ¹H-NMR (CDCl₃) δ: 1.60–1.85 (1H, br), 2.22 4.6Hz), 3.78 (3H, s), 4.03–4.12 (2H, m), 4.84 (2H, s), 5.67 (2H,

(6H, s), 2.30 (3H, s), 2.39 (3H, s), 2.88 (1H, dd, J=15.6, s), 6.66 (1H, d, J=2.4Hz), 6.80 (1H, dd, J=8.3, 2.4Hz), 7.01

10.5Hz), 3.03 (1H, dd, J=15.6, 4.6Hz), 3.72 (1H, dd, J=10.5, (1H, d, J=8.3 Hz).

4.6Hz), 3.77 (3H, s), 4.02–4.10 (2H, m), 4.99 (2H, s), 6.71 (1H,

d, J=2.4Hz), 6.85 (1H, dd, J=8.3, 2.4Hz), 6.90 (2H, s), 7.02 methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-

(1H, d, J=8.3 Hz).

3-carboxylate (7i) Yield 94%. ¹H-NMR (CDCl₃) δ: 1.44

Methyl (S)-7-[2-(1,4,5-Trimethylcyclopent-3-en-1-yl)-5-

Methyl (S)-7-[2-(1-Ethyl-1-methylpropan-1-yl)-5-methyl- (3H, s), 1.61 (6H, s), 2.25–2.34 (5H, m), 2.95–3.03 (2H, m),

oxazol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-car- 3.20–3.35 (2H, m), 3.83 (3H, s), 4.17–4.25 (1H, m), 4.36 (1H,

1006

Chem. Pharm. Bull.

Vol. 63, No. 12 (2015)

d, J=16.1Hz), 4.55 (1H, d, J=16.1Hz), 4.84 (2H, s), 6.72 m), 7.00–7.07 (1H, m), 7.27–7.39 (1H, m).

(1H, d, J=2.0Hz), 6.87 (1H, dd, J=8.5, 2.0Hz), 7.05 (1H, d,

J=8.5 Hz).

Methyl (S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(1-methylcyclo-

pentan-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahy-

1

Methyl (S)-7-[2-(2-Methylindane-2-yl)-5-methyloxazol- droisoquinoline-3-carboxylate (11eA) Yield 99%. H-NMR

4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (CDCl₃) δ: 1.39 (3H, s), 1.60–1.78 (6H, m), 1.82–1.89 (3H, m),

1

(7j) Yield 79%. H-NMR (CDCl₃) δ: 1.50 (3H, s), 1.51–1.70 2.15–2.24 (2H, m), 2.31 (3H, s), 3.06–3.30 (2H, m), 3.60 (3H,

(1H, br), 2.32 (3H, s), 2.83–3.05 (4H, m), 3.55–3.65 (2H, m), s), 4.55 (0.3H, d, J=15.0Hz), 4.68–5.00 (4H, m), 5.55 (0.7H,

3.69–3.75 (1H, m), 3.78 (3H, s), 4.01–4.12 (2H, m), 4.85 (2H, s), dd, J=5.9, 3.4Hz), 6.06–6.38 (3H, m), 6.73–6.86 (2H, m),

6.66 (1H, d, J=2.4Hz), 6.80 (1H, dd, J=8.3, 2.4Hz), 7.01 (1H, 7.04–7.09 (1H, m), 7.27–7.38 (1H, m).

d, J=8.3Hz), 7.14–7.24 (4H, m).

Methyl (S)-7-[2-(2,6-Dimethylphenyl)-5-methyloxazol- hexyl-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahy-

4-ylethoxy]-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroiso- droisoquinoline-3-carboxylate (11fA) Yield 89%. H-NMR

quinoline-3-carboxylate (10aA) To solution of 6a (CDCl₃) δ: 1.28 (3H, s), 1.32–1.63 (8H, m), 1.82–1.91 (3H, m),

Methyl (S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(1-methylcyclo-

1

a

(1.88g, 4.47mmol) in CH₂Cl₂(40mL) was added (2E,4E)- 2.08–2.20 (2H, m), 2.31 (3H, s), 3.00–3.30 (2H, m), 3.60 (3H,

5-methylhexadienoic acid (601mg, 5.36mmol) and EDC·HCl s), 4.55 (0.3H, d, J=17.3Hz), 4.67–4.98 (4H, m), 5.50–5.59

(1.03g, 5.37mmol) at room temperature and the mixture was (0.7H, m), 6.05–6.40 (3H, m), 6.72–6.86 (2H, m), 7.04–7.09

stirred for 1.5h. The reaction mixture was washed with water (1H, m), 7.27–7.38 (1H, m).

and saturated brine and dried over Na₂SO₄. The solvent was

Methyl

(S)-7-{[2-(Adamantan-1-yl)-5-methyloxazol-4-yl]-

evaporated under reduced pressure, and the obtained residue methoxy}-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroiso-

was puriﬁed by silica gel column chromatography to give 10a quinoline-3-carboxylate (11gA) Yield 86%. ¹H-NMR

1

(1.88g, 82% yield) as an oil. H-NMR (CDCl₃) δ: 1.81–1.89 (CDCl₃) δ: 1.72–1.82 (6H, m), 1.83–1.89 (3H, m), 1.97–2.10

(3H, m), 2.23 (6H, s), 2.35 (3H, s), 2.98 (2H, t, J=6.6Hz), (9H, m), 2.30 (3H, s), 3.00–3.30 (2H, m), 3.60 (3H, s), 4.55

3.03–3.27 (2H, m), 3.60 (3H, s), 4.24 (2H, t, J=6.6Hz), 4.53 (0.3H, d, J=17.3Hz), 4.67–4.98 (4H, m), 5.51–5.58 (0.7H, m),

(0.25H, d, J=17.3Hz), 4.71 (0.75H, d, J=15.6Hz), 4.77 (0.75H, 6.05–6.38 (3H, m), 6.71–6.86 (2H, m), 7.02–7.09 (1H, m),

d, J=15.6Hz), 4.87–4.98 (0.5H, m), 5.53 (0.75H, dd, J=5.8, 7.27–7.37 (1H, m).

3.4Hz), 6.05–6.35 (3H, m), 6.64–6.78 (2H, m), 7.00–7.09 (3H,

Methyl

(S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(1-methylcy-

m), 7.21 (1H, t, J=7.6Hz), 7.27–7.36 (1H, m).

clopent-3-en-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-

Compounds 10bA and cA and 11cA–jA were prepared ac- tetrahydroisoquinoline-3-carboxylate (11hA) Yield 93%.

cording to the procedure for the synthesis of 10aA.

¹H-NMR (CDCl₃) δ: 1.47 (3H, s), 1.80–1.90 (3H, m), 2.25–2.45

Methyl (S)-7-[2-(2,5-Dimethylphenyl)-5-methyloxazol- (5H, m), 2.95–3.30 (4H, m), 3.60 (3H, s), 4.55 (0.3H, d,

4-ylethoxy]-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroiso- J=17.3Hz), 4.68–4.98 (4H, m), 5.51–5.58 (0.7H, m), 5.67 (2H,

quinoline-3-carboxylate (10bA) Yield 81%. ¹H-NMR s), 6.07–6.40 (3H, m), 6.72–6.86 (2H, m), 7.02–7.10 (1H, m),

(CDCl₃) δ: 1.80–1.89 (3H, m), 2.35 (3H, s), 2.36 (3H, s), 2.59 7.27–7.38 (1H, m).

(3H, s), 2.97 (2H, t, J=6.6Hz), 3.02–3.28 (2H, m), 3.59 (3H, s),

Methyl (S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(1,4,5-trimethyl-

4.22 (2H, t, J=6.6Hz), 4.53 (0.25H, d, J=17.6Hz), 4.70 (0.75H, cyclopent-3-en-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-

d, J=15.4Hz), 4.77 (0.75H, d, J=15.4Hz), 4.88–4.97 (0.5H, m), tetrahydroisoquinoline-3-carboxylate (11iA) Yield 96%.

5.53 (0.75H, dd, J=5.8, 3.4Hz), 6.06–6.34 (3H, m), 6.64–6.78 ¹H-NMR (CDCl₃) δ: 1.44 (3H, s), 1.61 (6H, s), 1.85–1.90 (3H,

(2H, m), 6.99–7.15 (3H, m), 7.27–7.36 (1H, m), 7.73 (1H, s).

m), 2.27–2.32 (5H, m), 2.95–3.31 (4H, m), 3.60 (3H, s), 4.55

Methyl (S)-7-[2-(2,4,6-Dimethylphenyl)-5-methyloxazol- (0.3H, d, J=17.6Hz), 4.69–4.98 (4H, m), 5.51–5.58 (0.7H, m),

4-ylethoxy]-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroiso- 6.07–6.38 (3H, m), 6.74–6.86 (2H, m), 7.02–7.10 (1H, m),

quinoline-3-carboxylate (10cA) Quant. ¹H-NMR (CDCl₃) 7.29–7.40 (1H, m).

δ: 1.85 (3H, d, J=4.8Hz), 2.20 (6H, s), 2.29 (3H, s), 2.34 (3H,

Methyl

(S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(2-methylin-

s), 2.97 (2H, t, J=6.8Hz), 3.00–3.25 (2H, m), 3.60 (3H, s), dane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahy-

1

4.24 (2H, t, J=6.8Hz), 4.50–5.10 (2H, m), 5.40–5.65 (1H, m), droisoquinoline-3-carboxylate (11jA) Yield 91%. H-NMR

6.00–6.55 (3H, m), 6.60–6.85 (2H, m), 6.89 (2H, s), 7.04 (1H, (CDCl₃) δ: 1.50 (3H, s), 1.80–1.90 (3H, m), 2.32 (3H,

d, J=8.4Hz), 7.15–7.55 (1H, m).

m), 2.94–3.30 (4H, m), 3.55–3.64 (5H, m), 4.55 (0.3H, d,

Methyl (S)-7-[2-(2,4,6-Dimethylphenyl)-5-methyloxazol- J=16.8Hz), 4.67–4.98 (4H, m), 5.50–5.58 (0.7H, m), 6.05–6.40

4-ylmethoxy]-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydro- (3H, m), 6.72–6.86 (2H, m), 7.02–7.10 (1H, m), 7.13–7.24 (4H,

isoquinoline-3-carboxylate (11cA) Yield 95%. ¹H-NMR m), 7.27–7.40 (1H, m).

(CDCl₃) δ: 1.83–1.90 (3H, m), 2.22 (6H, s), 2.31 (3H, s),

Compounds 11gE and F and 11jE–G were prepared ac-

2.40 (3H, s), 3.03–3.32 (2H, m), 3.60 (3H, s) 4.55 (0.3H, d, cording to the procedure for the synthesis of 10aA using cor-

J=17.6Hz), 4.68–5.03 (4H, m), 5.51–5.57 (0.7H, m), 6.07–6.36 responding carboxylic acid.

(3H, m), 6.80–6.93 (4H, m), 7.03–7.10 (1H, m), 7.27–7.39 (1H,

m).

Methyl

(S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol-

4-yl]methoxy}-2-(2-hexynoyl)-1,2,3,4-tetrahydroisoquino-

Methyl (S)-7-[2-(1-Ethyl-1-methylpropan-1-yl)-5-methyl- line-3-carboxylate (11gD) Quant. ¹H-NMR (CDCl₃)

δ

oxazol-4-yl]methoxy-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tet- (ppm): 1.01 (1.5H, t, J=7.5Hz), 1.07 (1.5H, t, J=7.5Hz),

rahydroisoquinoline-3-carboxylate (11dA) Yield 87%. 1.56–1.70 (2H, m), 1.72–1.81 (6H, m), 2.00–2.11 (9H, m),

¹H-NMR (CDCl₃) δ: 0.78 (6H, J=7.6Hz), 1.29 (3H, s), 2.30, 2.31 (total 3H, s, s), 2.35 (1H, t, J=7.1Hz), 2.41 (1H,

1.56–1.68 (2H, m), 1.73–1.90 (5H, m), 2.30 (3H, s), 3.00–3.30 t, J=7.1Hz), 3.05–3.32 (2H, m), 3.63, 3.64 (total 3H, s, s),

(2H, m), 3.59 (3H, s), 4.54 (0.3H, d, J=17.6Hz), 4.66–4.96 (4H, 4.49 (0.5H, d, J=17.8Hz), 4.49 (0.5H, d, J=17.6Hz), 4.64

m), 5.50–5.58 (0.7H, m), 6.05–6.37 (3H, m), 6.70–6.84 (2H, (0.5H, d, J=16.3Hz), 4.83, 4.86 (total 2H, s, s), 4.94 (0.5H,

Vol. 63, No. 12 (2015)

Chem. Pharm. Bull.

1007

d, J=17.6Hz), 5.08 (0.5H, d, J=16.3Hz), 5.35–5.42 (1H, m), for the synthesis of 11gB.

6.74–6.86 (2H, m), 7.03–7.09 (1H, m). Methyl (S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol-

Methyl (S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol- 4-yl]methoxy}-2-(2-hexenoyl)-1,2,3,4-tetrahydroisoquino-

4-yl]methoxy}-2-(2-furylacryloyl)-1,2,3,4-tetrahydroiso- line-3-carboxylate (11gC) Quant. ¹H-NMR (CDCl₃)

δ

quinoline-3-carboxylate (11gE) Yield 98%. ¹H-NMR (ppm): 0.91–1.00 (3H, m), 1.45–1.57 (2H, m), 1.72–1.82

(CDCl₃) δ (ppm): 1.73–1.82 (6H, m), 2.00–2.10 (9H, m), (6H, m), 2.01–2.10 (9H, m), 2.13–2.27 (2H, m), 2.31 (3H, s),

2.31 (3H, s), 3.05–3.35 (2H, m), 3.61 (3H, s), 4.59 (0.3H, d, 3.02–3.30 (2H, m), 3.61 (3H, s), 4.53 (0.3H, d, J=17.6Hz),

J=17.1Hz), 4.78–5.07 (4H, m), 5.55–5.63 (0.7H, m), 6.45–6.51 4.68–4.96 (4H, m), 5.50–5.56 (0.7H, m), 6.14 (0.3H, d,

(1H, m), 6.56–6.62 (1H, m), 6.45–6.51 (1H, m), 6.74–6.94 (3H, J=15.2Hz), 6.37 (0.7H, d, J=15.2Hz), 6.75–7.08 (4H, m).

m), 7.03–7.12 (1H, m), 7.44–7.55 (1H, m).

(S)-7-[2-(2,6 -Dimethylphenyl)-5 -methyloxazol-

Methyl (S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol- 4-ylethoxy]-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroiso-

4-yl]methoxy}-2-[2-(5-ﬂuorofuryl)acryloyl]-1,2,3,4-tetrahy- quinoline-3-carboxylic Acid tert-Butylamine Salt (12aA)

1

droisoquinoline-3-carboxylate (11gF) Yield 92%. H-NMR To a solution of 10aA (1.88g, 3.65mmol) in tetrahydrofuran

(CDCl₃) δ (ppm): 1.70–1.80 (6H, m), 1.97–2.09 (9H, m), (THF)–MeOH (3:1, 20mL) was added 1^Maqueous lithium

2.31 (3H, s), 3.05–3.35 (2H, m), 3.62 (3H, s), 4.59 (0.3H, d, hydroxide solution (11.0mL, 11.0mmol), and the mixture was

J=17.3Hz), 4.77–5.07 (4H, m), 5.51–5.61 (1.7H, m), 6.45–6.58 stirred at room temperature for 1h. The mixture was acidiﬁed

(1.3H, m), 6.72–6.88 (2.7H, m), 7.03–7.12 (1H, m), 7.34–7.43 with 10% citric acid in water and extracted with AcOEt. The

(1H, m).

organic layer was washed with saturated brine and then dried

Methyl (S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2- over Na₂SO₄. The solvent was evaporated under reduced pres-

yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroiso- sure and the obtained residue was dissolved in MeOH (5mL).

quinoline-3-carboxylate (11jE) Quant. ¹H-NMR (CDCl₃) After dropwise addition of tert-butylamine (0.77mL, 7.33),

δ: 1.50 (3H, s), 2.32 (3H, s), 2.94–3.35 (4H, m), 3.56–3.66 (5H, diisopropyl ether (100mL) was added, and the mixture was

m), 4.59 (0.3H, d, J=17.4Hz), 4.77–4.93 (3.5H, m), 4.95–5.09 stirred at room temperature for 1h. The precipitated crystals

(0.5H, m), 5.55–5.62 (0.7H, m), 6.42–6.50 (1H, m), 6.55–6.61 were collected by ﬁltration to give 12aA (2.14g, quant) as a

1

(1H, m), 6.69 (0.3H, d, J=15.1Hz), 6.75–6.87 (2H, m), 6.91 white solid, mp 135–137°C. H-NMR (CDCl₃) δ: 1.02 (9H,

(0.7H, d, J=15.1Hz), 7.05–7.10 (1H, m), 7.14–7.23 (4H, m), s), 1.78, 1.84 (total 3H, d, d, J=6.6, 5.8Hz), 2.22 (6H, s), 2.35

7.42–7.56 (2H, m).

(3H, s), 2.87–3.05 (3H, m), 3.12–3.30 (1H, m), 4.10–4.25 (2H,

Methyl (S)-2-[2-(5-Fluorofuryl)acryloyl-7-[2-(2-methyl- m), 4.45 (0.5H, d, J=17.8Hz), 4.55–4.77 (1.5H, m), 4.95–5.09

indane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahy- (1H, m), 5.95–6.40 (3H, m), 6.56–6.72 (2H, m), 6.90–7.00 (1H

1

droisoquinoline-3-carboxylate (11jF) Yield 72%. H-NMR m), 7.06 (2H, d, J=7.3Hz), 7.12–7.25 (2H, m). IR attenuated

(CDCl₃) δ: 1.51 (3H, s), 2.33 (3H, s), 2.95–3.35 (4H, m), total reﬂectance (ATR) cm⁻¹: 1652, 1623, 1589, 1538, 1392.

3.56–3.65 (5H, m), 4.58 (0.3H, d, J=18.1Hz), 4.75–4.89 (3.5H, MS m/z: 501 [M+H]⁺.

m), 4.94–5.06 (0.5H, m), 5.54–5.60 (1.7H, m), 6.45–6.55 (1.3H,

m), 6.74–6.86 (2.7H, m), 7.02–7.09 (1H, m), 7.13–7.23 (4H, m), cording to the procedure for the synthesis of 12aA.

7.34–743 (1H, m). (S)-7-[2-(2, 5 -Dimethylphenyl)-5 -methyloxazol-

Methyl (S)-2-(2-Cyclopropylacryloyl)-7-[2-(2-methyl- 4-ylethoxy]-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroiso-

Compounds 12bA and cA and 13cA–jA were prepared ac-

indane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetra- quinoline-3-carboxylic Acid tert-Butylamine Salt (12bA)

1

hydroisoquinoline-3-carboxylate (11jG) Quant. ¹H-NMR Quant. A white solid. mp 134–135°C. H-NMR (CDCl₃) δ:

(CDCl₃) δ: 0.57–0.72 (2H, m), 0.83–1.00 (2H, m), 1.50 (3H, s), 0.99 (9H, s), 1.78, 1.84 (total 3H, d, d, J=6.8, 6.6Hz), 2.34

2.32 (3H, s), 2.93–3.30 (4H, m), 3.56–3.65 (5H, m), 4.53 (0.3H, (3H, s), 2.36 (3H, s), 2.59 (3H, s), 2.88–3.05 (3H, m), 3.12–3.26

d, J=17.6Hz), 4.66–5.00 (4H, m), 5.45–5.58 (0.7H, m), 6.24 (1H, m), 4.13–4.21 (2H, m), 4.45 (0.5H, d, J=17.3Hz),

(0.3H, d, J=14.9Hz), 6.35–6.53 (1.7H, m), 6.70–6.88 (2H, m), 4.59–4.72 (1.5H, m), 4.96–5.04 (1H, m), 5.95–6.35 (3H, m),

7.00–7.10 (1H, m), 7.13–7.27 (5H, m), 7.34–743 (1H, m).

Methyl

(S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol- (1H, s). IR (ATR) cm⁻¹: 1650, 1621, 1585, 1506, 1378. MS m/z:

4-yl]methoxy}-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline- 501 [M+H]⁺.

3-carboxylate (11gB) To solution of 7g (500mg,

(S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(2,4,6-trimethyl-

6.57–6.71 (2H, m), 6.92–7.00 (1H m), 7.05–7.26 (3H, m), 7.72

a

1.15mmol) in CH₂Cl₂(5mL) was added triethylamine phenyl)-5-methyloxazol-4-ylethoxy]-1,2,3,4-tetrahydroiso-

(0.24mL, 1.72mmol) and hexanoyl chloride (0.17mL, quinoline-3-carboxylic Acid tert-Butylamine Salt (12cA)

1.27mmol) under ice-cooling, and the mixture was stirred Yield 72%. A white solid. mp 130–132°C. ¹H-NMR (CDCl₃) δ:

for 15min under ice-cooling. To the reaction mixture was 0.98 (9H, s), 1.60–2.05 (3H, m), 2.20 (6H, s), 2.29 (3H, s), 2.34

added water and extracted with CHCl₃. The organic layer (3H, s), 2.75–3.40 (4H, m), 4.19 (2H, t, J=6.8Hz), 4.45–5.25

was washed with water and dried over Na₂SO₄. The solvent (3H, m), 5.80–7.40 (12H, m). IR (ATR) cm⁻¹: 1652, 1623, 1592,

was evaporated under reduced pressure, and the obtained 1540, 1504, 1394. MS m/z: 515 [M+H]⁺.

residue was puriﬁed by silica gel column chromatography

to give 11gB (0.62g, quant.) as an oil. H-NMR (CDCl₃) δ: phenyl)-5-methyloxazol-4-ylmethoxy]-1,2,3,4-tetrahydro-

0.86–0.96 (3H, m), 1.29–1.40 (4H, m), 1.55–1.62 (0.6H, m), isoquinoline-3-carboxylic Acid tert-Butylamine Salt (13cA)

(S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(2,4,6-trimethyl-

1

1.65–1.81 (8H, m), 2.01–2.10 (9H, m), 2.30, 2.30 (total 3H, Yield 63%. A white solid. mp 135–138°C. H-NMR (CDCl₃)

s, s), 2.44–2.52 (1.4H, m), 3.00–3.31 (2H, m), 3.61 (3H, s), δ: 1.01 (9H, s), 1.78, 1.84 (total 3H, d, d, J=6.6, 6.3Hz), 2.22

4.45 (0.3H, d, J=17.1Hz), 4.65 (1.4H, s), 4.80–4.86 (2.3H, m), (6H, s), 2.30 (3H, s), 2.38, 2.39 (total 3H, s, s), 2.90–3.07 (1H,

5.46–5.51 (0.7H, m), 6.73–6.85 (2H, m), 7.03–7.10 (1H, m).

Compound 11gC was prepared according to the procedure (1.5H, m), 4.91–5.08 (3H, m), 5.95–6.35 (3H, m), 6.72–6.84

m), 3.15–3.32 (1H, m), 4.49 (0.5H, d, J=17.1Hz), 4.55–4.75

1008

Chem. Pharm. Bull.

Vol. 63, No. 12 (2015)

(2H, m), 6.89 (2H, s), 6.95–7.04 (1H, m), 7.16–7.25 (1H, m). IR (CDCl₃) δ: 1.03 (9H, s), 1.43 (3H, s), 1.61 (6H, s), 1.78, 1.85

(ATR) cm⁻¹: 1652, 1623, 1592, 1536, 1504, 1392. MS m/z: 501 (total 3H, d, d, J=6.6, 6.6Hz), 2.23–2.33 (5H, m), 2.92–3.04

[M+H]⁺.

(3H, m), 3.15–3.31 (1H, m), 4.49 (0.5H, d, J=17.6Hz),

(S)-7-[2-(1-Ethyl-1-methylpropan-1-yl)-5-methyloxazol- 4.65–4.85 (3.5H, m), 4.97–5.08 (1H, m), 5.96–6.37 (3H, m),

4-yl]methoxy-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahy- 6.66–6.79 (2H, m), 6.95–7.05 (1H, m), 7.15–7.26 (1H, m).

droisoquinoline-3-carboxylic Acid tert-Butylamine Salt IR (ATR) cm⁻¹: 1652, 1625, 1554, 1504, 1378. MS m/z: 491

1

(13dA) Yield 70%. A white solid. mp 120–123°C. H-NMR [M+H]⁺.

(CDCl₃) δ: 0.78 (6H,, J=7.6Hz), 0.98 (9H, s), 1.29, 1.28

(S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(2-methylindane-2-

(total 3H, s), 1.56–1.69 (2H, m), 1.75–1.88 (5H, m), 2.29 yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroiso-

(3H, s), 2.92–3.07 (1H, m), 3.15–3.30 (1H, m), 4.47 (0.5H, d, quinoline-3-carboxylic Acid tert-Butylamine Salt (13jA)

1

J=17.8Hz), 4.65–4.75 (1.5H, m), 4.82, 4.83 (total 2H, s, s), Yield 65%. A white solid. mp 150–155°C (dec.). H-NMR

4.99–5.12 (1H, m), 5.96–6.37 (3H, m), 6.65–6.78 (2H, m), (CDCl₃) δ: 1.02 (9H, s), 1.49, 1.50 (total 3H, s, s), 1.78, 1.84

6.93–7.00 (1H, m), 7.16–7.25 (1H, m). IR (ATR) cm⁻¹: 1652, (total 3H, d, d, J=6.6, 6.4Hz), 2.30, 2.31 (total 3H, s, s),

1627, 1560, 1504, 1384. MS m/z: 467 [M+H]⁺.

2.90–3.06 (3H, m), 3.15–3.31 (1H, m), 3.60 (2H, d, J=15.9Hz),

(S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(1-methylcyclopentan- 4.47 (0.5H, d, J=17.4Hz), 4.64–4.76 (1.5H, m), 4.80, 4.81 (total

1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroiso- 2H, s, s), 5.00–5.10 (1H, m), 5.95–6.37 (3H, m), 6.66–6.79

quinoline-3-carboxylic Acid tert-Butylamine Salt (13eA) (2H, m), 6.94–7.03 (1H, m), 7.12–7.26 (5H, m). IR (ATR) cm⁻¹:

1

Yield 74%. A white solid. mp 130–133°C. H-NMR (CDCl₃) 1652, 1625, 1554, 1504, 1380. MS m/z: 513 [M+H]⁺.

δ: 0.99 (9H, s), 1.38, 1.39 (total 3H, s), 1.60–1.88 (9H, m),

Compounds 13gB–E and 13jE and F were prepared accord-

2.13–2.24 (2H, m), 2.29, 2.30 (total 3H, s, s), 2.91–3.07 (1H, ing to the procedure for the synthesis of 12aA.

m), 3.15–3.30 (1H, m), 4.47 (0.5H, d, J=17.3Hz), 4.63–4.77

(S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol-4-yl]-

(1.5H, m), 4.80, 4.81 (total 2H, s, s), 5.04 (0.5H, d, J=17.3Hz), methoxy}-2-hexanoyl-1,2,3,4-tetrahydroisoquinoline-3-car-

5.08–5.13 (0.5H, m), 5.96–6.37 (3H, m), 6.64–6.78 (2H, m), boxylic Acid tert-Butylamine Salt (13gB) Yield 76%. A

1

6.93–7.02 (1H, m), 7.15–7.26 (1H, m). IR (ATR) cm⁻¹: 1652, white solid. mp 124–126°C. H-NMR (CDCl₃) δ: 0.86–0.95

1623, 1592, 1538, 1506, 1394. MS m/z: 465 [M+H]⁺.

(3H, m), 1.03 (9H, s), 1.25–1.39 (4H, m), 1.58–1.69 (2H, m),

(S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(1-methylcyclohexyl- 1.25–1.39 (4H, m), 1.72–1.81 (6H, br), 2.03 (6H, s), 2.03–2.10

1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroiso- (3H, br), 2.29, 2.30 (total 3H, s, s), 2.31–2.48 (2H, m),

quinoline-3-carboxylic Acid tert-Butylamine Salt (13fA) 2.92–3.06 (1H, m), 3.13–3.33 (1H, m), 4.45–4.70 (2H, m), 4.80,

1

Yield 70%. A white solid. H-NMR (CDCl₃) δ (ppm): 1.01 4.82 (total 2H, s, s), 4.94–5.05 (1H, m), 6.66–6.80 (2H, m),

(9H, s), 1.28 (3H, s), 1.32–1.65 (8H, m), 1.79, 1.85 (total 3H, d, 6.95–7.04 (1H, m). IR (ATR) cm⁻¹: 1635, 1548, 1504, 1382.

d, J=6.3, 6.6Hz), 2.06–2.18 (2H, m), 2.30 (3H, s), 2.90–3.08 MS m/z: 521 [M+H]⁺.

(1H, m), 3.11–3.29 (1H, m), 4.48 (0.5H, d, J=17.1Hz),

(S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol-4-yl]-

4.62–4.71 (1.5H, m), 4.81, 4.83 (total 2H, s, s), 4.96–5.12 (1H, methoxy}-2-(2-hexenoyl)-1,2,3,4-tetrahydroisoquinoline-3-

m), 5.96–6.37 (3H, m), 6.66–6.81 (2H, m), 6.93–7.05 (1H, m), carboxylic Acid tert-Butylamine Salt (13gC) Yield

7.15–7.26 (1H, m). IR (ATR) cm⁻¹: 1652, 1625, 1554, 1502, 79%. A white solid. mp 141–143°C. ¹H-NMR (CDCl₃) δ

1378. MS m/z: 479 [M+H]⁺.

(ppm): 0.86–0.98 (3H, m), 1.03 (9H, s), 1.38–1.55 (2H, m),

(S)-7-{[2-(Adamantan-1-yl)-5-methyloxazol-4-yl]- 1.72–1.81 (6H, br), 2.02–2.25 (11H, m), 2.29, 2.29 (total 3H,

methoxy}-2-[(2E,4E)-hexadienoyl]-1,2,3,4-tetrahydroiso- s, s), 2.95–3.07 (1H, m), 3.15–3.33 (1H, m), 4.47 (0.5H, d,

quinoline-3-carboxylic Acid tert-Butylamine Salt (13gA) J=17.3Hz), 4.62–4.76 (1.5H, m), 4.80, 4.82 (total 2H, s, s),

1

Yield 82%. A white solid. mp 154–156°C. H-NMR (CDCl₃) 4.96–5.09 (1H, m), 6.25, 6.35 (total 1H, d, d, J=15.1, 15.2 Hz),

δ: 0.99 (9H, s), 1.72–1.89 (9H, m), 2.03 (6H, s), 2.03–2.10 (3H, 6.67–6.85 (3H, m), 6.95–7.04 (1H, m). IR (ATR) cm⁻¹: 1658,

br), 2.29 (3H, s), 2.90–3.07 (1H, m), 3.13–3.31 (1H, m), 4.47 1621, 1548, 1504, 1384. MS m/z: 519 [M+H]⁺.

(0.5H, d, J=17.4Hz), 4.58–4.78 (1.5H, m), 4.80, 4.81 (total 2H,

(S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol-4-yl]-

s, s), 4.99–5.13 (1H, m), 5.96–6.38 (3H, m), 6.66–6.78 (2H, m), methoxy}-2-(2-hexynoyl)-1,2,3,4-tetrahydroisoquinoline-3-

6.95–7.04 (1H, m), 7.15–7.26 (1H, m). IR (ATR) cm⁻¹: 1652, carboxylic Acid tert-Butylamine Salt (13gD) Yield 67%.

1623, 1592, 1540, 1506, 1392. MS m/z: 517 [M+H]⁺.

A white solid. mp 133–135°C. H-NMR (CDCl₃) δ (ppm):

1

(S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(1-methylcyclopent-3- 0.89–1.05 (12H, m), 1.54–1.69 (2H, m), 1.72–1.81 (6H, br),

en-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahy- 2.02 (6H, s), 2.03–2.10 (3H, br), 2.25–2.35 (4H, m), 2.37 (1H,

droisoquinoline-3-carboxylic Acid tert-Butylamine Salt t, J=7.1Hz), 2.95–3.10 (1H, m), 3.13–3.35 (1H, m), 4.46 (0.5H,

1

(13hA) Yield 59%. A white solid. mp 134–137°C. H-NMR d, J=17.6Hz), 4.69–4.84 (2.5H, m), 4.89–4.95 (0.5H, m),

(CDCl₃) δ: 1.01 (9H, s), 1.46, 1.46 (total 3H, s), 1.78, 1.85 (total 4.97–5.12 (1H, m), 6.65–6.80 (2H, m), 6.94–7.04 (1H, m). IR

3H, d, d, J=6.8, 6.8Hz), 2.30, 2.31 (total 3H, s, s), 2.35–2.44 (ATR) cm⁻¹: 1627, 1554, 1506, 1378. MS m/z: 517 [M+H]⁺.

(2H, m), 2.93–3.08 (3H, m), 3.15–3.31 (1H, m), 4.47 (0.5H, d,

(S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol-4-yl]-

J=17.6Hz), 4.59–4.85 (3.5H, m), 4.99–5.12 (1H, m), 5.66 (1H, methoxy}-2-(2-furylacryloyl)-1,2,3,4-tetrahydroiso-

s), 5.96–6.37 (3H, m), 6.66–6.79 (2H, m), 6.93–7.02 (1H, m), quinoline-3-carboxylic Acid tert-Butylamine Salt (13gE)

7.15–7.26 (1H, m). IR (ATR) cm⁻¹: 1652, 1625, 1592, 1560, Yield 60%. A white solid. mp 140–142°C. δ (ppm): 1.01

1540, 1504, 1382. MS m/z: 463 [M+H]⁺.

(9H, s), 1.72–1.81 (6H, br), 1.97–2.10 (9H, br), 2.29 (3H,

(S)-2-[(2E,4E)-Hexadienoyl]-7-[2-(1,4,5-trimethylcyclo- s), 2.94–3.10 (1H, m), 3.13–3.35 (1H, m), 4.52 (0.5H, d,

pent-3-en-1-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetra- J=17.3Hz), 4.69–4.85 (3.5H, m), 5.00–5.13 (1H, m), 6.37–6.58

hydroisoquinoline-3-carboxylic Acid tert-Butylamine Salt (2H, m), 6.67–7.03 (1H, m), 7.35–7.50 (2H, m). IR (ATR) cm⁻¹:

1

(13iA) Yield 63%. A white solid. mp 114–116°C. H-NMR 1648, 1608, 1554, 1504, 1382. MS m/z: 543 [M+H]⁺.

Vol. 63, No. 12 (2015)

Chem. Pharm. Bull.

1009

(S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5- m), 5.12–5.21 (0.3H, m), 5.86–5.60 (1H, m), 6.67–6.92 (4H, m),

methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline- 6.96–7.06 (1H, m), 7.15–7.27 (1H, m). IR (ATR) cm⁻¹: 1648,

3-carboxylic Acid tert-Butylamine Salt (13jE) Yield 63%. 1608, 1569, 1544, 1502, 1427, 1384. MS m/z: 561 [M+H]⁺.

1

A white solid. mp 165–170°C (dec.). H-NMR (CDCl₃) δ: 0.97

Methyl [5-Methyl-2-(2,6-dimethylphenyl)oxazol-4-yl]ace-

(9H, s), 1.50 (3H, s), 2.30 (3H, s), 2.90–3.08 (3H, m), 3.15–3.31 tate (16a) To a suspension of the 2,6-dimethylbenzoyl chlo-

(1H, m), 3.60 (2H, d, J=15.9Hz), 4.49 (0.5H, d, J=17.4Hz), ride 14a (11.8g, 70mmol) and 15 (18.4g, 100mmol) in CH₂Cl₂

4.66–4.84 (3.5H, m), 5.02–5.20 (1H, m), 6.35–6.57 (2H, m), (450mL) was added triethylamine (27.8mL, 200mmol)

6.67–7.02 (4H, m), 7.12–7.24 (4H, m), 7.30–7.46 (3H, m). dropwise at −10°C, and stirred at the same temperature for

IR (ATR) cm⁻¹: 1650, 1616, 1556, 1504, 1376. MS m/z: 539 2h. The reaction mixture was washed with water, 6^MHCl

[M+H]⁺. Anal. Calcd for C₂₉H₃₈N₂O₅·C₄H₁₁N·0.5H₂O: C, and saturated brine, and dried over Na₂SO₄. The solvent was

69.66; H, 6.82; N, 6.77. Found: C, 69.54; H, 7.00; N, 6.58.

(S)-2-[2-(5-Fluorofuryl)acryloyl-7-[2-(2-methylindane-

evaporated under reduced pressure to give a crude oil (16.8g).

The crude oil (16.8g), acetic anhydride (18.4mL, 195mmol),

2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroiso- N-methylmorpholine (21.1mL, 192mmol) and 4-dimethyl-

quinoline-3-carboxylic Acid tert-Butylamine Salt (13jF) aminopyridine (1.21g, 9.90mmol) were dissolved in toluene

1

Yield 64%. A white solid. mp 168–171°C (dec.). H-NMR (250mL) and stirred at 70–80°C for 1.5h. After cooling to

(CDCl₃) δ: 1.00 (9H, s), 1.49, 1.50 (total 3H, s, s), 2.30, room temperature, the reaction mixture was neutralized with

2.30 (total 3H, s, s), 2.90–3.08 (3H, m), 3.14–3.32 (1H, m), saturated aqueous NaHCO₃solution and separated into two

3.53–3.65 (2H, m), 4.49 (0.5H, d, J=17.7Hz), 4.70–4.84 (3.5H, layers. The organic layer was washed with water and saturated

m), 5.01–5.12 (1H, m), 5.45–5.55 (1H, m), 6.36–6.48 (1H, m), brine, and dried over Na₂SO₄. The solvent was evaporated

6.60–6.79 (2H, m), 6.96–7.02 (1H, m), 7.12–7.30 (5H, m). under reduced pressure to give a crude solid (16.6g).

IR (ATR) cm⁻¹: 1652, 1569, 1542, 1506, 1376. MS m/z: 557

To a solution of the crude solid (16.6g) in toluene (200mL)

was added POCl₃(10.0mL, 107mmol), which was reﬂuxed for

[M+H]⁺.

(S)-2-(2-Cyclopropylacryloyl)-7-[2-(2-methylindane- 1.5h. After cooling, the mixture was poured into cold water,

2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroiso- neutralized with K₂CO₃and extracted with AcOEt. The or-

quinoline-3-carboxylic Acid tert-Butylamine Salt (13jG) ganic layer was washed with water and saturated brine, dried

1

Yield 65%. A white solid. mp 148–156°C (dec.). H-NMR over Na₂SO₄and then evaporated under reduced pressure. The

(CDCl₃) δ: 0.50–0.65 (2H, m), 0.77–0.95 (2H, m), 1.04 (9H, s), obtained residue was puriﬁed by silica gel column chroma-

1

1.49, 1.50 (total 3H, s, s), 2.30, 2.31 (total 3H, s, s), 2.92–3.07 tography to give 16a (2.25g, 12.3% yield) as an oil. H-NMR

(3H, m), 3.05–3.32 (1H, m), 3.54–3.65 (2H, m), 4.46 (0.5H, d, (CDCl₃) δ: 2.24 (6H, s), 2.35 (3H, s), 3.60 (2H, s), 3.73 (3H, s),

J=17.6Hz), 4.64–4.87 (3.5H, m), 4.94–5.08 (1H, m), 6.45–6.53 7.07 (2H, d, J=7.6Hz), 7.21 (1H, t, J=7.6 Hz).

(2H, m), 6.67–6.80 (2H, m), 6.95–7.05 (1H, m), 7.12–7.27 (4H,

m). IR (ATR) cm⁻¹: 1654, 1610, 1550, 1504, 1382. MS m/z: 513 dure for the synthesis of 16a.

[M+H]⁺.

Methyl [5-Methyl-2-(2,5-dimethylphenyl)oxazol-4-yl]ace-

Compounds 16b, c were prepared according to the proce-

1

(S)-7-{[2-(Adamantann-1-yl)-5-methyloxazol-4-yl]- tate (16b) Yield 32%. H-NMR (CDCl₃) δ: 2.34 (3H, s), 2.36

methoxy}-2-[2-(5-fluorofuryl)acryloyl]-1,2,3,4-tetrahy- (3H, s), 2.59 (3H, s), 3.58 (2H, s), 3.73 (3H, s), 7.06–7.16 (2H,

droisoquinoline-3-carboxylic Acid Calcium Salt (13gF) m), 7.73 (1H, s).

To a solution of 11gE (1.82g, 3.17mmol) in 1,4-dioxane

Methyl [5-Methyl-2-(2,4,6-trimethylphenyl)oxazol-4-yl]-

1

(38mL) was added 1^Maqueous lithium hydroxide solution acetate (16c) Yield 65%. H-NMR (CDCl₃) δ: 2.20 (6H, s),

(9.5mL, 9.5mmol) dropwise, and the mixture was stirred at 2.29 (3H, s), 2.31 (3H, s), 3.57 (2H, s), 3.72 (3H, s), 6.82 (2H,

room temperature for 2h. The mixture was acidiﬁed with 2^Ms).

HCl and extracted with AcOEt. The organic layer was washed

2-[5-Methyl-2-(2,6-dimethylphenyl)oxazol-4-yl]ethanol

with water and saturated brine, and then dried over Na₂SO₄. (17a) To a suspension of 16a (2.25g, 8.68mmol) and NaBH₄

The solvent was evaporated under reduced pressure, and the (1.35g, 35.7mmol) in THF (70mL) was added methanol

obtained residue was puriﬁed by silica gel column chroma- (10mL) dropwise at 60°C and stirred for 30min. After cool-

tography to give the free form of 11gF (1.65g) as a crude oil. ing, the mixture was poured into cold water and extracted

To a solution of the free form of 11gF (500mg, 0.89mmol) with AcOEt. The organic layer was washed with saturated

in THF (25mL) was added 0.1^Maqueous KHCO₃(9.0mL, brine, dried over Na₂SO₄and then evaporated under reduced

0.9mmol), and the mixture was stirred at room temperature pressure. The obtained residue was puriﬁed by silica gel col-

for 1h. The solvent was evaporated under reduced pressure, umn chromatography to give 17a (1.60g, 80 yield) as an oil.

and the obtained residue was dissolved in 10% MeCN in ¹H-NMR (CDCl₃) δ: 2.26 (6H, s), 2.32 (3H, s), 2.74 (2H, t,

water and passed through an ODS silica gel (Fuji Silysia, J=4.4Hz), 3.25–3.40 (1H, br), 3.88–3.95 (2H, m), 7.08 (2H, d,

Kasugai, Japan) column chromatograph. Fractions contain- J=7.6Hz), 7.22 (1H, t, J=7.6 Hz).

ing the compound were collected and MeCN was evaporated

under reduced pressure. To the obtained residue was added the synthesis of 17a.

1^Maqueous CaCl₂solution (1.0mL, 1.0mmol) dropwise, 2-[5-Methyl-2-(2,5-dimethylphenyl)oxazol-4-yl]ethanol

Compound 17b was prepared according to the procedure for

1

and the mixture was stirred at room temperature for 3h. (17b) Yield 42%. H-NMR (CDCl₃) δ: 2.33 (3H, s), 2.36 (3H,

The precipitated crystals were collected by ﬁltration to give s), 2.60 (3H, s), 2.73 (2H, t, J=5.6Hz), 3.55–3.70 (1H, br), 3.93

11gF (390mg, 76% yield) as a white solid. mp 160–166°C. (2H, t, J=5.6Hz), 7.07–7.15 (2H, m), 7.74 (1H, s).

¹H-NMR (DMSO-d₆) δ: 1.65–1.75 (6H, br), 1.86–2.05 (9H,

2-[5-Methyl-2-(2,4,6-trimethylphenyl)oxazol-4-yl]ethanol

br), 2.27 (3H, s), 2.73–2.95 (1H, m), 3.25–3.40 (1H, m), 4.52 (17c) To a solution of 16c (3.60g, 13.2mmol) in THF (75mL)

(0.7H, d, J=18.3Hz), 4.56–4.69 (0.7H, br), 4.70–4.95 (3.3H, was added lithium aluminum hydride (500mg, 13.2mmol)

1010

Chem. Pharm. Bull.

Vol. 63, No. 12 (2015)

portionwise below 10°C, and stirred at the same tempera- obtained residue was puriﬁed by silica gel column chromatog-

1

ture for 1h. To the reaction mixture was added cold water raphy to give 22 (3.55g, 51% yield) as a yellow oil. H-NMR

(100mL) and AcOEt (100mL). The precipitate was removed (CDCl₃) δ: 1.24 (6H, t, J=7.1), 1.59 (6H, s), 2.92 (4H, s), 4.18

by ﬁltration, and the ﬁltrate was separated into two layers. (4H, q, J=7.1 Hz).

The organic layer was washed with saturated brine, dried over

3,4-Dimethylcyclopent-3-enecarboxylic Acid (23) To a

Na₂SO₄and then evaporated under reduced pressure to give solution of 22 (3.55g, 14.8mmol) in MeOH (70mL) was added

1

17c (3.07g, 95% yield) as an oil. H-NMR (CDCl₃) δ: 2.22 potassium hydroxide (KOH) (5.85g, 88.6mmol) in water

(6H, s), 2.30 (6H, s), 2.72 (2H, t, J=5.7Hz), 2.80–3.20 (1H, br), (25mL) at room temperature and the mixture was stirred at

3.92 (2H, t, J=5.7Hz), 6.90 (2H, s).

2-[5-Methyl-2-(2,6-dimethylphenyl)oxazol-4-yl]ethyl duced pressure. The obtained residue was acidiﬁed with conc.

Methanesulfonate (2a) To solution of 17a (1.60g, HCl and extracted with AcOEt. The organic layer was washed

50°C for 5h. The reaction mixture was evaporated under re-

a

6.92mmol) and triethylamine (1.16mL, 8.30mmol) in CH₂Cl₂with saturated brine and dried over Na₂SO₄. The solvent was

(30mL) was added methanesulfonyl chloride (0.59mL, evaporated under reduced pressure.

7.61mmol) at 0°C and stirred for 15min. The reaction mixture

The obtained residue was dissolved in pyridine (25mL) and

was washed with water and saturated brine, and dried over stirred at 110°C for 3h. After cooling to room temperature,

Na₂SO₄. The solvent was evaporated under reduced pressure the reaction mixture was acidiﬁed with 6^MHCl and extracted

to give a crude 2a (2.13g) as an oil. The crude 2a was used in with AcOEt. The organic layer was washed with saturated

subsequent reactions without further puriﬁcation.

Compounds 2b and c were prepared according to the proce- under reduced pressure. The obtained residue was puriﬁed

dure for the synthesis of 2a. by silica gel column chromatography to give 23 (1.62g, 78%

brine and dried over Na₂SO₄. The solvent was evaporated

1

4-Chloromethyl-5-methyl-2-(2,4,6-trimethylphenyl)oxa- yield) as an oil. H-NMR (CDCl₃) δ: 1.60 (6H, s), 2.55–2.71

zole (21c) To a solution of mesitylaldehyde (15.8g, 416mmol) (4H, m), 3.03–3.14 (1H, m), 9.60–12.40 (1H, br).

in AcOEt (40mL) was added 19 (10g, 98.9mmol) and HCl gas

1,3,5-Trimethylcyclopent-3-enecarboxylic Acid (24i) To

was bubbled through the solution at 0°C for 0.5h. The mixture a solution of 23 (1.41g, 10.1mmol) in DMF (30mL) was added

was stirred at the same temperature for 1.5h. To the reaction K₂CO₃(4.17g, 30.2mmol) and MeI (1.00mL, 16.1mmol) at

mixture was added i-Pr₂O and precipitated crystals were col- room temperature and the mixture was stirred for 15h. To the

lected by ﬁltration to give a crude 20c (13.8 g).

reaction mixture was added water and extracted with Et₂O.

To a solution of the crude 20c (13.8g) in CHCl₃(140mL) The organic layer was washed with saturated brine and dried

was added POCl₃(6.9mL, 74.8mmol), which was reﬂuxed for over Na₂SO₄. The solvent was evaporated under reduced pres-

3h. After cooling, the mixture was poured into cold water and sure to give a crude oil (2.01g).

extracted with AcOEt. The organic layer was washed with 1^M

To a solution of diisopropylamine (2.12mL, 15.1mmol) in

NaOH and saturated brine, dried over Na₂SO₄and then evapo- THF (50mL) was added 2.6^Mn-BuLi in hexane (5.83mL,

rated under reduced pressure. The obtained residue was puri- 15.2mmol) at −78°C and the mixture was stirred at the

ﬁed by silica gel column chromatography to give 3c (4.39g, same temperature for 15min, and then the crude oil (2.01g)

1

29% yield) as an oil. H-NMR (CDCl₃) δ: 2.25 (6H, s), 2.30 in THF (20mL) was added dropwise at −78°C. The mixture

(3H, s), 2.41 (3H, s), 4.57 (2H, s), 6.90 (2H, s).

Compounds 3d–g were prepared according to the procedure added to it. The mixture was stirred and slowly warmed to

for the synthesis of 3c. room temperature for 2h. To the reaction mixture was added

was stirred for 15min and MeI (0.65mL, 10.4mmol) was

4-Chloromethyl-2-(1-ethyl-1-methylpropyl)-5-methyl- water and extracted with Et₂O. The organic layer was washed

1

oxazole (3d) 21% yield. H-NMR (CDCl₃) δ: 0.77 (6H, t, with saturated brine and dried over Na₂SO₄. The solvent was

J=7.3Hz), 1.21 (3H, s), 1.56–1.66 (2H, m), 1.72–1.83 (2H, m), evaporated under reduced pressure to give a crude oil (2.12g).

2.30 (3H, s), 4.47 (2H, s).

To a solution of the crude oil (2.12mmol) in THF (45mL)

4-Chloromethyl-2-(1-methyl-cyclopentan-1-yl)-5-methyl- and MeOH (15mL) was added 1^Maqueous LiOH solution

1

oxazole (3e) 24% yield. H-NMR (CDCl₃) δ: 1.37 (3H, s), (20.0mL, 20.0mmol) at room temperature for 2h and the

1.59–1.79 (6H, m), 1.71–1.78 (2H, m), 2.30 (2H, s), 4.47 (2H, s). mixture was stirred at 40°C for 2h. The reaction mixture

4-Chloromethyl-2-(1-methyl-cyclohexan-1-yl)-5-methyl- was evaporated under reduced pressure. The obtained residue

1

oxazole (3f) 8.7% yield. H-NMR (CDCl₃) δ: 1.27 (3H, s), was acidiﬁed with citric acid and extracted with AcOEt. The

1.35–1.62 (8H, m), 2.07–2.18 (2H, m), 2.31 (2H, s), 4.48 (2H, organic layer was washed with water and saturated brine, and

s).

then dried over Na₂SO₄. The obtained residue was puriﬁed

4-Chloromethyl-2-(Adamantan-1-yl)-5-methyloxazole by silica gel column chromatography to give 24i (1.27g, 82%

1

(3g) 11% yield. H-NMR (CDCl₃) δ: 1.70–1.80 (6H, m), 2.01 yield, 3 steps) as an oil.

(6H, s), 2.03–2.09 (3H, br), 2.29 (3H, s), 4.47 (2H, s).

Methyl 5-Methyl-2-(Cyclopent-3-enyl)oxazole-4-carbox-

Diethyl

3,4-Dimethylcyclopent-3-ene-1,1-dicarboxylate ylate (26h) To a solution of 24h (34.0g, 0.27mmol) in

(22) To a solution of diethyl malonate (4.57g 28.5mmol) CH₂Cl₂(370mL) was added (COCl)₂(23.2mL, 270mmol) and

in N,N-dimethylformamide (DMF) (100mL) was added LiH DMF (3mL) at room temperature, which was stirred for 1h.

(567mg, 71.3mmol) portionwise at room temperature, the To the reaction mixture was added 25 (37.7g, 230mmol) and i-

mixture was stirred for 1h and then 21 in DMF (10mL) was Pr₂NEt (99mL, 580mmol) at 0°C and stirred for 1h. The reac-

added dropwise at the same temperature for 5d. The reaction tion mixture was washed with 10% citric acid in water, dried

mixture was poured into water and extracted with AcOEt. over Na₂SO₄and then evaporated under reduced pressure. The

The organic layer was washed with saturated brine, dried solution of the obtained residue in CH₂Cl₂(140mL) was added

over Na₂SO₄and then evaporated under reduced pressure. The dropwise to a solution of I₂(164g, 650mmol), PPh₃(171g,

Vol. 63, No. 12 (2015)

Chem. Pharm. Bull.

1011

650mmol) and Et₃N (183mL, 1.31mol) in CH₂Cl₂(1.0L) at (1H, d, J=3.4Hz), 7.32 (1H, d, J=15.8 Hz).

0°C and stirred for 0.5h. The reaction mixture was poured 5-(2-tert-Butoxycarbonylvinyl)furan-2-carboxylic Acid

into water and extracted with CH₂Cl₂. The organic layer was To a solution of 22 (110g, 414mmol) in THF (550mL) and

dried over Na₂SO₄and then evaporated under reduced pres- MeOH (550mL) was added 1^Maqueous LiOH solution

sure. To the obtained residue was added i-Pr₂O, precipitated (500mL, 500mmol), and the mixture was stirred at room

crystals were ﬁltered out and the ﬁltrate was puriﬁed by silica temperature for 1h. The mixture was acidiﬁed with 10%

gel column chromatography to give 26h (29.9g, 61% yield) as citric acid in water and extracted with AcOEt. The organic

1

an oil. H-NMR (CDCl₃) δ: 1.48 (3H, s), 2.38–2.47 (2H, m), layer was washed with saturated brine and then dried over

2.60 (3H, s), 2.99–3.06 (2H, m), 3.89 (3H, s), 5.66 (2H, s).

Compounds 26i and j were prepared according to the proce- sure and n-hexane was added to the obtained residue. The

dure for the synthesis of 26h. precipitated crystals were collected by ﬁltration to give

Methyl

Na₂SO₄. The solvent was evaporated under reduced pres-

5-Methyl-2-(1,3,4-trimethylcyclopent-3-enyl)- 5-(2-tert-butoxycarbonylvinyl)furan-2-carboxylic acid (83.3g,

1

oxazole-4-carboxylate (26i) Fifty percent yield. ¹H-NMR 84% yield) as a white solid. H-NMR (CDCl₃) δ: 1.52 (9H, s),

(CDCl₃) δ: 1.45 (3H, s), 1.61 (6H, s), 2.30 (2H, d, J=14.9Hz), 6.54 (1H, d, J=15.9Hz), 6.68 (1H, d, J=3.4Hz), 7.33 (1H, d,

2.60 (3H, s), 3.01 (2H, d, J=14.9Hz), 3.89 (3H, s).

J=3.4Hz), 7.35 (1H, d, J=15.9 Hz).

Methyl 5-Methyl-2-(1-methylindan-2-yl)oxazole-4-car-

tert-Butyl 3-(5-Fluorofuryl)acrylate To a solution of

1

boxylate (26j) 46% yield. H-NMR (CDCl₃) δ: 1.51 (3H, s), 5-(2-tert-butoxycarbonylvinyl)furan-2-carboxylic acid (83.3g,

2.61 (3H, s), 2.99 (2H, d, J=16.0Hz), 3.62 (2H, d, J=16.0Hz), 350mmol) in Et₂O (420mL) and water (840mL) was added

3.89 (3H, s), 7.12–7.26 (4H, m).

NaHCO₃(70.6g, 840mmol), and the mixture was stirred

4-Chloromethyl-5-methyl-2-(cyclopent-3-en-1-yl)oxazole at room temperature for 0.5h. Then, Selectﬂuor (149g,

(3h) To a suspension of lithium aluminum hydride (5.84g, 420mmol) was added portionwise to the reaction mixture. The

150mmol) in THF (500mL) was added a solution of 16h mixture was stirred for 1.5h and separated into two layers.

(29.9g, 140mmol) in THF (100mL) below 25°C, and stirred The organic layer was washed with water and saturated brine,

at the same temperature for 1h. To the reaction mixture was and then dried over Na₂SO₄. The solvent was then evaporated

added cold water and AcOEt. The precipitate was removed by under reduced pressure and the obtained residue was puri-

ﬁltration and the ﬁltrate was separated into two layers. The ﬁed by silica gel column chromatography to give tert-butyl

1

organic layer was washed with saturated brine, dried over 3-(5-ﬂuorofuryl)acrylate (43.2g, 58% yield) as an oil. H-NMR

Na₂SO₄and then evaporated under reduced pressure to give a (CDCl₃) δ: 1.51 (9H, s), 5.53 (1H, dd, J=7.1, 3.6Hz), 6.11 (1H,

crude 17h (25.3 g).

To a solution of the crude 17h (25.3g) in CH₂Cl₂(250mL)

d, J=15.6Hz), 6.41–6.50 (1H, m), 7.16 (1H, dd, J=15.6, 2.7Hz).

3-(5-Fluorofuryl)acrylic Acid (8F) To a solution of tert-

was added SO₂Cl₂(11.4g, 160mmol) dropwise below 30°C. butyl 3-(5-ﬂuorofuryl)acrylate (20.0g, 94.2mmol) in CH₂Cl₂

The mixture was poured into water, neutralized with NaHCO₃(200mL) was added TFA (70mL, 942mmol) at 0°C and the

and extracted with CH₂Cl₂. The organic layer was dried over mixture was stirred for 1.5h. The solvent was evaporated

Na₂SO₄and then evaporated under reduced pressure. The ob- under reduced pressure and the obtained residue was puriﬁed

tained residue was puriﬁed by silica gel column chromatogra- by silica gel column chromatography to give a crude 8F. n-

1

phy to give 3h (22.9g, 79% yield) as an oil. H-NMR (CDCl₃) Hexane was added to the crude 8F and the precipitated crys-

δ: 1.45 (3H, s), 2.31 (3H, s), 2.36–2.46 (2H, m), 2.94–3.04 (2H, tals were collected by ﬁltration to give 8F (9.50g, 65% yield)

1

m), 4.47 (2H, s), 5.66 (2H, s).

as a white solid. H-NMR (CDCl₃) δ: 5.59 (1H, dd, J=6.8,

4-Chloromethyl-5-methyl-2-(1,3,4-trimethylcyclopent- 3.4Hz), 6.17 (1H, d, J=15.6Hz), 6.56–6.63 (1H, m), 7.16 (1H,

3-enyl)oxazole (3i) 99% yield. ¹H-NMR (CDCl₃) δ: 1.43 dd, J=15.6, 2.7Hz).

(3H, s), 1.61 (6H, s), 2.28 (2H, d, J=14.9Hz), 2.31 (3H, s), 2.98

(2H, d, J=14.9Hz), 4.48 (2H, s).

7-Benzyl-2-tert-butoxycarbonyl-tetrahydroisoquinoline-

3-carboxylic Acid To a solution of 1 (20.0g) in DMF

4-Chloromethyl-5-methyl-2-(1-methylindan-2-yl)oxazole (200mL) was added K₂CO₃(13.5g, 97.6mmol) and BnBr

1

(3j) Quant. H-NMR (CDCl₃) δ: 1.49 (3H, s), 2.32 (3H, s), (7.7mL, 65.1mmol) at room temperature, which was stirred

2.98 (2H, d, J=16.0Hz), 3.59 (2H, d, J=16.0Hz), 4.47 (2H, s), for 16h. To the reaction mixture was added water and extract-

7.13–7.26 (4H, m)

ed with AcOEt. The organic layer was washed with water and

Ethyl 5-(2-tert-Butoxycarbonylvinyl)furan-2-carboxylate saturated brine, dried over Na₂SO₄and then evaporated under

(28) Compound 27 (121g, 556mmol), tert-butyl acrylate reduced pressure.

(500mL, 3.43mol), Pd(OAc)₂(12.5g, 55.6mmol), tri(o-tolyl)-

The obtained residue was dissolved in THF (330mL) and

phosphine (67.7g, 222mmol), i-Pr₂NEt (284mL, 1.67mol) and MeOH (110mL), and 1^Maqueous lithium hydroxide solu-

LiCl (70.8g, 1.67mol) were dissolved in DMF (1.1L) under a tion (110mL, 0.11mol) was added to the solution at room

nitrogen atmosphere and stirred at 130°C for 0.5h. After cool- temperature. The mixture was stirred for 18h. The reaction

ing to room temperature, water and Et₂O were added to the mixture was evaporated under reduced pressure, acidiﬁed

reaction mixture, and passed through Celite. The ﬁltrate was with 10% citric acid in water and extracted with AcOEt. The

separated into two layers, and the organic layer was washed organic layer was washed with saturated brine and dried over

with 10% citric acid in water, water and saturated brine, dried Na₂SO₄. The solvent was evaporated under reduced pressure.

over Na₂SO₄and then evaporated under reduced pressure. The n-Hexane was added to the obtained residue and precipitated

obtained residue was puriﬁed by silica gel column chroma- crystals were collected by ﬁltration to give 7-benzyl-2-tert-bu-

1

tography to give 28 (110.2g, 74% yield) as an oil. H-NMR toxycarbonyl-tetrahydroisoquinoline-3-carboxylic acid (25.7g,

1

(CDCl₃) δ: 1.38 (3H, t, J=7.6Hz), 1.52 (9H, s), 4.37 (2H, q, 91% yield) as a white solid. H-NMR (CDCl₃) δ: 1.42, 1.51

J=7.6Hz), 6.48 (1H, d, J=15.8Hz), 6.62 (1H, d, J=3.4Hz), 7.16 (9H, s, s), 3.00–3.25 (2H, m), 4.43 (1H, dd, J=16.6, 7.8Hz),

1012

Chem. Pharm. Bull.

Vol. 63, No. 12 (2015)

4.64 (1H, dd, J=16.6, 7.8Hz), 4.70–4.78 (0.5H, m), 5.01 2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroiso-

(2H, s), 5.05–5.12 (0.5H, m), 6.70–6.83 (2H, m), 7.05 (1H, d, quinoline (32) To

solution of (S)-3-acetyl-2-tert-

J=8.3Hz), 7.27–7.44 (5H, m).

butoxycarbonyl-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-

a

7-Benzyloxy-2-tert-butoxycarbonyl-N-methoxy-N-meth- yl]methoxy-1,2,3,4-tetrahydroisoquinoline (955mg, 1.85mmol)

yl-tetrahydroisoquinoline-3-carboxamide (29) To a solu- in formic acid (3mL) was added 8.6^Mhydrogen chloride

tion of 7-benzyl-2-tert-butoxycarbonyl-tetrahydroisoquinoline- solution in 2-propanol (0.65mL, 5.55mmol) under ice-cooling,

3-carboxylic acid (25.0g, 65.2mmol) in CH₂Cl₂(250mL) was and the mixture was stirred at room temperature for 15min.

added N,O-dimethylhydroxylamine (7.63g, 78.2mmol), Et₃N The reaction mixture was neutralized with saturated aque-

(11.8mL, 84.8mmol) and EDC·HCl (16.3g, 84.8mmol) under ous NaHCO₃solution and extracted with AcOEt. The or-

ice-cooling, and the mixture was stirred at room temperature ganic layer was washed with saturated brine and dried over

for 2h. The reaction mixture was washed with 10% citric Na₂SO₄. The solvent was evaporated under reduced pressure,

acid in water, and water and saturated brine, and dried over and Et₂O was added to the obtained residue and the mixture

Na₂SO₄. The solvent was evaporated under reduced pressure was stirred at room temperature for 1h. The precipitated

and the obtained residue was puriﬁed by silica gel column crystals were collected by ﬁltration to give (S)-3-acetyl-7-[2-

chromatography to give 29 (9.11g, 33% yield) as an oil. (2-methylindane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-

¹H-NMR (CDCl₃) δ: 1.45, 1.50 (total 9H, s, s), 2.85–3.05 (1H, tetrahydroisoquinoline hydrochloride (0.699mg, 92% yield) as

m), 3.07–3.18 (4H, m), 3.76, 3.83 (total 3H, s, s), 4.45–4.90 a white solid.

(2.5H, m), 5.03 (2H, s), 5.18–5.26 (0.5H, m), 6.75–6.85 (2H,

m), 7.00–7.06 (1H, m), 7.27–7.44 (5H, m).

To a solution of 2-furylacrylic acid (150mg, 1.09mmol)

in CH₂Cl₂(7mL) was added (COCl)₂(0.093mL, 1.09mmol)

3-Acetyl-2-tert-butoxycarbonyl-7-benzyloxy-tetrahy- and DMF (1 drop) at room temperature, and stirred for

droisoquinoline To a solution of 29 (5.0g, 11.7mmol) in 0.5h. To the reaction mixture was added (S)-3-acetyl-7-[2-

THF (100mL) was added 3.0^MMeMgI in Et₂O (19.5mL, (2-methylindane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-

58.5mmol) at 0°C and the mixture was stirred at room tem- tetrahydroiso quinoline hydrochloride (340mg, 0.720mmol)

perature for 12h. To the reaction mixture was added 10% and Et₃N (0.51mL, 3.62mol) at 0°C and stirred at room tem-

citric acid in water at 0°C and extracted with AcOEt. The perature for 2h. To the reaction mixture was added AcOEt,

organic layer was washed with saturated brine and dried over washed with water and saturated brine, dried over Na₂SO₄and

Na₂SO₄. The solvent was evaporated under reduced pressure then evaporated under reduced pressure. The obtained residue

and the obtained residue was puriﬁed by silica gel column was puriﬁed by silica gel column chromatography to give 32

1

chromatography to give 3-acetyl-2-tert-butoxycarbonyl-7-ben- (240mg, 76% yield) as a white solid. mp 51–52°C. H-NMR

zyloxy-tetrahydroisoquinoline (4.07g, 91% yield) as an oil. (CDCl₃) δ: 1.50 (3H, s), 2.00, 2.10 (total 3H, s, s), 2.32 (3H,

¹H-NMR (CDCl₃) δ: 1.45, 1.52 (total 9H, s, s), 1.99, 2.06 (total s), 2.94–3.29 (4H, m), 3.61 (2H, d, J=15.6Hz), 4.65–4.97 (4H,

3H, s, s), 2.95–3.15 (2H, m), 4.40–4.55 (1.5H, m), 4.60–4.72 m), 5.27–5.35 (1H, m), 6.44–6.51 (1H, m), 6.55–6.62 (1H,

(1.0H, m), 4.84–4.90 (0.5H, m), 5.03 (2H, s), 6.70–6.85 (2H, m), 6.77–6.95 (3H, m), 7.05–7.24 (5H, m), 7.33–7.57 (2H, m).

m), 7.01–7.07 (1H, m), 7.29–7.44 (5H, m).

IR (ATR) cm⁻¹: 1718, 1648, 1604, 1558, 1400. MS m/z: 537

3-Acetyl-2-tert-butoxycarbonyl-7-hydroxy-tetrahydroiso- [M+H]⁺.

quinoline (30) 3-Acetyl-2-tert-butoxycarbonyl-7-benzyloxy-

1-{(S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-

tetrahydroisoquinoline (4.07g, 10.7mmol) in MeOH (80mL) methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydroisoquinoline-

was hydrogenated at 0.4MPa in the presence of 10% Pd–C 3-yl}ethanol (33) To a solution of 32 (120mg, 0.224mmol)

(814mg) at room temperature for 2h. After removal of the in THF (1mL) and MeOH (1mL) was added NaBH₄(10mg,

catalyst by ﬁltration, the ﬁltrate was evaporated under reduced 0.268mmol) under ice-cooling, and the mixture was stirred

pressure to give crude 30 (2.93g) as an oil. Crude 30 was used for 0.5h. To the reaction mixture was added water and ex-

in subsequent reactions without further puriﬁcation.

tracted with CHCl₃. The organic layer was dried over Na₂SO₄

2-tert-Butoxycarbonyl-3-(1,1-difluoroethyl)-7-hydroxy- and then evaporated under reduced pressure. The obtained

tetrahydroisoquinoline (31) To a solution of 30 (2.0g, residue was puriﬁed by silica gel column chromatography

6.86mmol) in CH₂Cl₂(20mL) was added DAST (2.70mL, to give 33 (107mg, 76% yield) as a white solid. The diaste-

20.6mmol) at 0°C. The mixture was stirred at room tem- reomeric ratio was 71:29, which was determined using an

perature for 18h, and then DAST (2.70mL, 20.6mmol) was HPLC equipment consisted of a pump (LC-8A; Shimadzu

again added to the mixture. The reaction mixture was stirred Corporation, Kyoto, Japan), a UV detector (SPD-10Avp; Shi-

at room temperature for 18h, poured into saturated NaHCO₃madzu Corporation), and a Cosmosil 5C18-AR-II column

solution and extracted with AcOEt. The organic layer was (5 µm, 4.6mm×150mm; Nacalai Tesque, Inc., Kyoto, Japan).

washed with saturated brine and dried over Na₂SO₄. The sol- As the eluent, 0.01^MKH₂PO₄aq.–MeCN (4:6) was used. mp

1

vent was evaporated under reduced pressure and the obtained 67–69°C. H-NMR (CDCl₃) δ: 1.16 (3H, m), 1.51 (3H, s), 2.30

residue was puriﬁed by silica gel column chromatography to (3H, s), 2.70–2.85 (1H, m), 2.88–3.37 (4H, m), 3.54–3.90 (3H,

1

give 31 (620mg, 29% yield) as a solid. H-NMR (CDCl₃) δ: m), 4.08–4.90 (4.5H, m), 5.25–5.37 (0.5H, m), 6.42–6.62 (2H,

1.45–1.65 (12H, m), 2.88–3.07 (2H, m), 4.07–4.20 (1H, m), m), 6.75–7.12 (4H, m), 7.14–7.24 (4H, m), 7.44–7.54 (2H, m).

4.50–5.00 (2H, m), 6.52–6.70 (2H, m), 7.00 (1H, d, J=8.3 Hz).

IR (ATR) cm⁻¹: 1644, 1600, 1583, 1558, 1504, 1484, 1419. MS

(S)-3-Acetyl-2-tert-butoxycarbonyl-7-[2-(2-methyl- m/z: 539 [M+H]⁺.

indane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetrahydro-

Compound 34 was prepared according to the procedure for

isoquinoline was prepared according to the procedure for the the synthesis of 32.

synthesis of 5j.

(S)-3-Difluoroethyl-2-(2-furylacryloyl)-7-[2-(2-methyl-

(S)-3-Acetyl-2-(2-furylacryloyl)-7-[2-(2-methylindane- indane-2-yl)-5-methyloxazol-4-yl]methoxy-1,2,3,4-tetra-

Vol. 63, No. 12 (2015)

Chem. Pharm. Bull.

1013

hydroisoquinoline (34) Yield 56%. A white solid. mp samples were collected by orbital sinus puncture. Plasma con-

1

50–52°C. H-NMR (CDCl₃) δ: 1.40–1.67 (6H, m), 2.32 (3H, centrations of dye were determined and plasma volume was

s), 2.94–3.15 (4H, m), 3.55–3.67 (2H, m), 4.29 (0.5H, d, calculated. The mice were bled to death under deep anesthe-

J=19.2Hz), 4.50–4.70 (1H, m), 4.84–4.94 (2.5H, m), 5.26–5.45 sia, after which the livers were isolated and weighed.

(1H, m), 6.46–6.60 (2H, m), 6.75–6.94 (3H, m), 7.02–7.27

(5H, m), 7.44–7.54 (2H, m). IR (ATR) cm⁻¹: 1648, 1608, 1558,

Conﬂict of Interest The authors declare no conﬂict of

interest.

1506, 1482, 1457, 1400. MS m/z: 559 [M+H]⁺.

PPARγ, PPARα and PPARδ Agonist Activity Full-

length human PPARγ1 plasmid (Open Biosystems, Huntsville,

U.S.A.), human PPARα plasmid (GeneCopoeia Inc., Rock-

ville, U.S.A.) or human PPARδ plasmid (GeneCopoeia Inc.),

and human RXRα plasmid (GeneCopoeia Inc.) with reporter

plasmid pGL3-PPREx4-tk-luc were electroporated into COS-1

cells (Dainippon Sumitomo Pharma Co., Ltd., Osaka, Japan)

using Nucleofector II (AAD-1001S, Lonza Group Ltd., Basel,

Switzerland). The cells were incubated for 24h in the presence

or absence of test compounds in Dulbecco’s modiﬁed Eagle’s

medium (DMEM; Nissui Pharmaceutical Co., Ltd., Tokyo,

Japan) containing 10% fetal bovine serum (FBS) under 5%

CO₂at 37°C. The medium was removed and then luciferase

activities were determined using a commercial kit (PicaGene

LT7.5; TOYO B-Net Co., Ltd., Tokyo, Japan) and a microplate

luminescence reader (Dainippon Sumitomo Pharma Co., Ltd.).

EC₅₀values were determined from the average dose–response

curve using data in three experiments. The maximal activa-

tion level relative to the level activated by farglitazar, a PPARγ

agonist (10⁻⁷M), Wy-14643, a PPARδ agonist (10⁻⁵M), or

GW-501516, a PPARδ agonist (10⁻⁷M), were determined.

PTP-1B Inhibitory Activity PTP-1B inhibitory activities

References

1) Bloomgarden Z. T., Diabetes Care , 28 , 488–493 (2005).

2) Lebovitz H. E., Banerji M. A., Recent Prog. Horm. Res., 56 , 265–

294 (2001).

3) Tack C. J. J., Smits P., Neth. J. Med., 64, 166–174 (2006).

4) Staels B., Cell Metab., 2 , 77–78 (2005).

5) Lehrke M., Lazar M. A., Cell , 123 , 993–999 (2005).

6) Krische D., West. J. Med., 173 , 54–57 (2000).

7) Hussein Z., Wentworth J. M., Nankervis A., Proietto J., Colman P.

G., Med. J. Aust., 181 , 536–539 (2004).

8) Everett L., Galli A., Crabb D., Liver , 20 , 191–199 (2000).

9) Chou C. J., Haluzik M., Gregory C., Dietz K. R., Vinson C.,

Gavrilova O., Reitman M. L., J. Biol. Chem., 277 , 24484–24489

(2002).

10) Kuwabara K., Murakami K., Todo M., Aoki T., Asaki T., Murai M.,

Y a no J., J. Pharmacol. Exp. Ther., 309 , 970–977 (2004).

11) Koh K. K., Han S. H., Quon M. J., Yeal Ahn J., Shin E. K., Diabe-

tes Care , 28 , 1419–1424 (2005).

12) Chaput E., Saladin R., Silvestre M., Edgar A. D., Biochem. Biophys.

Res. Commun., 271 , 445–450 (2000).

13) Yajima K., Hirose H., Fujita H., Seto Y., Fujita H., Ukeda K., Mi-

yashita K., Kawai T., Yamamoto Y ., Ogawa T., Yamada T., Saruta

T., Am. J. Physiol. Endocrinol. Metab., 284 , E966–E971 (2003).

were determined in the absence or presence of test compounds 14) Fiévet C., Fruchart J., Staels B., Curr. Opin. Pharmacol., 6 , 606–

614 (2006).

in 50m^Msodium acetate buffer (pH 5.5) containing the en-

15) Cho N., Momose Y., Curr. Top. Med. Chem., 8 , 1483–1507 (2008).

16) Henke B. R., J. Med. Chem., 47 , 411 8 –4 127 (2004).

17) Nissen S. E., Wolski K., Topol E. J., JAMA , 294 , 2581–2586 (2005).

18) Lai D. Y., J. Environ. Sci. Health C. Environ. Carcinog. Ecotoxicol.

Rev., 22 , 37–55 (2004).

19) Cornwell P . D., De Souza A. T., Ulrich R. G., Mutat. Res., 549 ,

zyme, 1m^Mp-nitrophenylphosphonic acid (pNPP), 1mM di-

thiothreitol and 1m^Methylenediaminetetraacetic acid (EDTA).

The reaction was started by addition of the pNPP and stopped

by the addition of 1^MNaOH after 30min of incubation at

37°C, and the absorbance was determined at 405nm.

Plasma Concentration after Oral Administration in

131–145 (2004).

Male SD Rats Male SD rats (7 weeks old; Japan SLC, Inc.,

Hamamatsu, Japan) were used. The test compound at 10mg/kg

suspended in 0.5% methylcellulose solution was administered

orally and then a blood sample was taken from the external

jugular vein at 0.5, 1, 3, 5 and 8h after administration to rats.

Plasma concentrations of the compounds were determined

using an HPLC equipment consisted of a pump (PU-980;

JASCO, Tokyo, Japan), UV detector (UV-970; JASCO), au-

toinjector (AS-950; JASCO) and STR-ODS-II column (5µm,

4.6mm×150mm; Shimadzu GLC Ltd., Tokyo, Japan).

20) Zungu M., Felix R., Faadiel Essop M., Mitochondrion , 6 , 315–322

(2006).

21) Rubenstrunk A., Hanf R., Hum D. W., Fruchart J. C., Staels B.,

Biochim. Biophys. Acta , 1771 , 1065–1081 (2007).

22) Taygerly J. P., McGee L. R., Rubenstein S. M., Houze J. B., Cush-

ing T. D., Li Y., Motani A., Chen J. L., Frankmoelle W., Ye G.,

Learned M. R., Jaen J., Miao S., Timmermans P . B ., Thoolen M.,

Kearney P ., Flygare J., Beckmann H., Weiszmann J., Lindstrom

M., Walker N., Liu J., Biermann D., Wang Z., Hagiwara A., Iida T.,

Aramaki H., Kitao Y ., Shinkai H., Furukawa N., Nishiu J., Naka-

mura M., Bioorg. Med. Chem., 21 , 979–992 (2013).

Hypoglycemic and Hypotriglyceridemic Effects in Male

KK-A^yMice Male KK-A^ymice (11 weeks old; Clea Japan,

Inc., Tokyo, Japan) were allocated to control and treated

groups (n=5–11). Test compounds were suspended in 0.5%

methylcellulose solution and orally administered once a day

for 4d or 14d. Blood samples were taken from the tail vein

of non-fasted mice 24h after the ﬁnal administration. Plasma

glucose and triglyceride levels in mice administered vehicle

or test compounds were determined using commercial kits

(Wako Pure Chemical Industries, Ltd., Osaka, Japan).

23) Azukizawa S., Kasai M., Takahashi K., Miike T., Kunishiro K.,

Kanda M., Mukai C., Shirahase H., Chem. Pharm. Bull., 56 , 335–

345 (2008).

24) Otake K., Azukizawa S., Takahashi K., Fukui M., Shibabayashi M.,

Kamemoto H., Kasai M., Shirahase H., Chem. Pharm. Bull., 59 ,

876–879 (2011).

25) Otake K., Azukizawa S., Fukui M., Shibabayashi M., Kamemoto

H., Miike T., Kunishiro K., Kasai M., Shirahase H., Chem. Pharm.

Bull., 59 , 1233–1242 (2011).

26) Otake K., Azukizawa S., Fukui M., Kunishiro K., Kamemoto H.,

Kanda M., Miike M., Kasai M., Shirahase H., Bioorg. Med. Chem.,

20 , 1060–1075 (2012).

Plasma volume was determined by the dye dilution method

using Evans blue.³⁹⁾Brieﬂy, mice were injected intravenously

with Evans blue solution (100µg/animal) 48h after the last

administration, anesthetized with diethyl ether and then blood

27) Thareja S., Aggarwal S., Bhardwaj T. R., Kumar M., Med. Res.

Rev., 32 , 459–517 (2012).

1014

Chem. Pharm. Bull.

Vol. 63, No. 12 (2015)

28) Ala P . J., Gonneville L., Hillman M., Becker-Pasha M., Yue E. W.,

5025–5037 (2005).

Douty B., Wayland B., Polam P ., Crawley M. L., McLaughlin E., 34) Brooks D. A., Etgen G. J., Rito C. J., Shuker A. J., Dominianni

Sparks R. B., Glass B., Takvorian A., Combs A. P ., Burn T. C., Hol-

lis G. F., Wynn R., J. Biol. Chem., 281 , 38013–38021 (2006).

29) Wrobel J., Sredy J., Moxham C., Dietrich A., Li Z., Sawicki D. R.,

Seestaller L., Wu L., Katz A., Sullivan D., Tio C., Zhang Z. Y ., J.

Med. Chem., 42 , 3199–3202 (1999).

30) Kubo M., Fukui M., Ito Y ., Kitao T., Shirahase H., Hinoi E., Y o neda

Y., J. Pharmacol. Sci., 124 , 276–285 (2014).

31) Sarel S., Newman M. S., J. Am. Chem. Soc., 78 , 541 6 –5420 (1956).

32) Arasappan A., Venkatraman S., Padilla A. I., Wu W., Meng T., Jin

Y., Wong J., Prongay A., Girijavallabhan V ., Njoroge F. G., Tetrahe-

dron Lett., 48 , 6343–6347 (2007).

33) Augeri D. J., Robl J. A., Betebenner D. A., Magnin D. R., Khanna

A., Robertson J. G., Wang A., Simpkins L. M., Taunk P ., Huang

Q., Han S.-P ., Abboa-Offei B., Cap M., Xin L., Tao L., Tozzo E.,

Welzel G. E., Egan D. M., Marcinkeviciene J., Chang S. Y ., Biller

S. A., Kirby M. S., Parker R. A., Hamann L. G., J. Med. Chem., 48 ,

S. J., Warshawsky A. M., Ardecky R., Paterniti J. R., Tyhonas J.,

Karanewsky D. S., Kauffman R. F., Broderick C. L., Oldham B. A.,

Montrose-Raﬁzadeh C., Winneroski L. L., Faul M. M., McCarthy J.

R., J. Med. Chem., 44 , 2061–2064 (2001).

35) Ma Z., Wang S., Cooper C. S., Fung A. K. L., Lynch J. K., Plagge

F., Chu D. T. W., Tetrahedron Asymmetry , 8 , 883–887 (1997).

36) Müller P ., Pfyffer J., Helv. Chim. Acta , 75 , 745–750 (1992).

37) Judd D. B., Dowle M. D., Middlemiss D., Scopes D. I. C., Ross B.

C., Jack T. I., Pass M., Tranquillini E., Hobson J. E., J. Med. Chem.,

37 , 3108–3210 (1994).

38) Pochetti G., Godio C., Mitro N., Caruso D., Galmozzi A., Scurati

S., Loiodice F., Fracchiolla G., Tortorella P ., Laghezza A., Lavec-

chia A., Novellino E., Mazza F., Crestani M., J. Biol. Chem., 282 ,

1731 4 –17324 (2007).

39) Wilson R. J., Mills I. H., J. Clin. Pathol., 23 , 286–290 (1970).

Article Doi

Novel 2,7-substituted (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids: Peroxisome proliferator-activated receptor γ partial agonists with protein-tyrosine phosphatase 1B inhibition

DOI: 10.1248/cpb.c15-00508

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Full text of DOI:10.1248/cpb.c15-00508

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