Synthesis and biological evaluation of (S)-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acids: A novel series of PPARγ agonists

Article abstract of DOI:10.1248/cpb.56.335

A novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-Benzyl-7-[2-(5- methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (10, KY-021) was identified as a novel peroxisome proliferators-activated receptor (PPAR)γ agonist, which showed potent activity in human PPARγ (EC₅₀=11.8 nM). KY-021 reduced plasma glucose and triglyceride levels at 3 mg/kg/d for 7 d in male KK-A^y mice. KY-021 also decreased plasma triglyceride levels at 0.3-3 mg/kg/d for 6 d, and improved oral glucose tolerance at 1 and 3 mg/kg/d for 7 d in male Zucker fatty rats. Maximal plasma concentration of KY-021 after oral administration at 10 mg/kg was 6.6 μg/ml and 2.1 μg/ml in male ICR mice and male SD rats, respectively. Repeated oral administration of KY-021 at 30 mg/kg/d for 10 weeks had little toxicity in male SD rats. These results demonstrated that KY-021 has great potential as an efficacious and safe drug for diabetes.

Full text of DOI:10.1248/cpb.56.335

March 2008
Chem. Pharm. Bull. 56(3) 335—345 (2008)
335
Synthesis and Biological Evaluation of (S)-1,2,3,4-Tetrahydroisoquinoline-
g
3-carboxylic Acids: A Novel Series of PPAR Agonists
Satoru AZUKIZAWA,a Masayasu KASAI,a Kenji TAKAHASHI,a Tomohiro MIIKE,a Kazuyoshi KUNISHIRO,a
Mamoru KANDA,a Chisato MUKAI,b and Hiroaki SHIRAHASE*,a
a Research Laboratories, Kyoto Pharmaceutical Industries, Ltd.; 38, Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto
604–8444, Japan: and b Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology,
Kanazawa University; Kakuma-machi, Kanazawa, Ishikawa 920–1192, Japan.
Received December 4, 2007; accepted December 24, 2007
A novel series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biolog-
ically evaluated. (S)-2-Benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-car-
boxylic acid (10, KY-021) was identified as a novel peroxisome proliferators-activated receptor (PPAR)g agonist,
which showed potent activity in human PPARg (EC50ꢀ11.8 nM). KY-021 reduced plasma glucose and triglyceride
levels at 3 mg/kg/d for 7 d in male KK-Ay mice. KY-021 also decreased plasma triglyceride levels at 0.3—
3 mg/kg/d for 6 d, and improved oral glucose tolerance at 1 and 3 mg/kg/d for 7 d in male Zucker fatty rats. Max-
imal plasma concentration of KY-021 after oral administration at 10 mg/kg was 6.6 mg/ml and 2.1 mg/ml in male
ICR mice and male SD rats, respectively. Repeated oral administration of KY-021 at 30 mg/kg/d for 10 weeks
had little toxicity in male SD rats. These results demonstrated that KY-021 has great potential as an efficacious
and safe drug for diabetes.
Key words tetrahydroisoquinoline derivative; diabetes; KK-Ay mouse; peroxisome proliferators-activated receptor (PPAR)g ag-
onist; hypoglycemic effect; hypolipidemic effect
Peroxisome proliferators-activated receptors (PPARs) are a interaction with two regions of a PPARg protein.14) However,
subfamily of nuclear hormone receptors, which are ligand- in these compounds, a carboxylic acid moiety, lipophilic
activated transcription factors. There are three subtypes of moiety and benzyl moiety with a lipophilic chain are at-
PPAR: PPARa expressed in the liver and related to fatty acid tached to a central atom (C or N) via a single bond, thus,
metabolism, PPARg expressed in adipocytes and playing a each moiety can bend and/or rotate freely (Fig. 1). We hy-
role in its differentiation, and PPARd expressed in most cell pothesized that in these carboxylic acid-type derivatives, the
types and involved in dyslipidemia, cancer and the central limitation of movement of the three moieties and fixation of
nervous system; therefore, PPARs have been focused on as a their direction may enhance their PPARg agonist activity and
potential target for metabolic diseases such as diabetes, dys- reduce their side effects. In the present study, a tyrosine de-
lipidemia and atherosclerosis.1—3) Fibrates such as clofibrate, rivative was cyclized to a 1,2,3,4-tetrahydroisoquinoline de-
bezafibrate and fenofibrate, which have been long and widely rivative and then various side chains were introduced into the
used as anti-hyperlipidemic drugs, are known to exert their 2nd and 7th positions of the 1,2,3,4-tetrahydroisoquinoline
effect via activation of PPARa. Thiazolidinedione derivatives ring (Fig. 2). Biological activities were evaluated in a series
(glitazones), such as pioglitazone and rosiglitazone, known of 1,2,3,4-tetrahydroisoquinoline derivatives and their struc-
as anti-diabetic drugs, activate PPARg and enhance insulin ture–activity relationships are discussed.
sensitivity.4,5)
Chemistry The general approach to the synthesis of (S)-
Thiazolidinedione derivatives cause edema, increase the 2-substituted-1,2,3,4-tetrahydroisoquinoline-3-carboxylic
risk of weight gain and congestive heart failure, and rarely acid derivatives 19 is outlined in Chart 1. The tetrahydroiso-
show hepatotoxicity.6,7) There have been a great number of quinoline carboxylate 13 was prepared by Pictet–Spengler
attempts to find a novel PPARg agonist that is structurally reaction of 3,5-diiodotyrosine (12)15) followed by esterifica-
different from thiazolidinedione derivatives and has higher tion. Catalytic dehalogenation of 13 and following protection
efficacy and safety. Thiazolidinedione moiety was replaced of the amine with the Boc group afforded ethyl (S)-7-
by oxadiazolidinedione and isoxazolidinedione in YM-440 hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (14).
and JTT-501, respectively (Fig. 1).8,9) Endogenous ligands for Etherification of 14 with methanesulfonate 159,16) in the pres-
PPARg have been reported to be fatty acids and eicosanoids, ence of K2CO3 afforded 16. The Boc group of 16 was re-
such as 15-deoxy-D12,14-prostaglandin J2.2,10) Thus, a number moved with HCl/HCO2H, affording 17. Acylation or alkyla-
of carboxylic acid derivatives have been designed and syn- tion of 17 afforded 2-Acyl or 2-Alkyl tetrahydroisoquinoline
thesized to enhance drug-protein interaction and to modify derivatives 18. Hydrolysis of the esters provided carboxylic
PPAR subtype selectivity (Fig. 1)2,11—13); however, no non- acid derivatives 19.
thiazolidinedione derivatives have been developed success-
fully as new anti-diabetic drugs; therefore, further efforts are Results and Discussion
necessary to identify a structurally new PPARg agonist.
Among benzene-based PPARg agonists with carboxylic
As shown in Fig. 1, some recent PPARg agonists are ben- acid moiety and two lipophilic moieties (Fig. 1), compound 5
zene derivatives with carboxylic acid moiety and two (farglitazar), a tyrosine derivative, has potent and selective
lipophilic moieties, which are postulated to have lipophilic PPARg agonist activity but inevitably causes edema.17) It has
∗ To whom correspondence should be addressed. e-mail: shirahase@kyoto-pharm.co.jp
© 2008 Pharmaceutical Society of Japan

336
Vol. 56, No. 3
Fig. 1. Chemical Structure of PPARg Agonists
Chart 1
relatively high molecular weight (MW: 546.61) and thus is with a more rigid structure, lower molecular weight and
highly lipophilic (log P: 4.2). We synthesized a series of lipophilicity (Fig. 2). In compound 9 lacking a lipophilic
1,2,3,4-tetrahydroisoquinoline derivatives by cyclization of a moiety at the 2nd position of 1,2,3,4-tetrahydroisoquinoline,
tyrosine derivative to find a novel class of PPARg agonist lipophilicity as well as PPARg agonist activity was drasti-

March 2008
337
Fig. 2. Structural Concept of a 1,2,3,4-Tetrahydroisoquinoline-Based PPARg Agonist
Table 1. Insulin-Sensitizing Effects on 3T3-L1 Cells, and Hypoglycemic
and Hypolipidemic Effects in KK-Ay Mice of 1,2,3,4-Tetrahydroisoquino-
line-3-carboxylic Acids with Various Substituents at 2-Position
cally reduced (log P: 1.4, EC50: ꢀ10 mM). Then, two types of
aromatic moieties (benzyl and benzoyl) were introduced into
the 2nd position. Compound 10 with a benzyl moiety showed
potent PPARg agonist activity (EC50: 11.8ꢁ1.8 nM, nꢂ4)
comparable to that of farglitazar (EC50: 8.7ꢁ2.1 nM, nꢂ4),
while it had lower molecular weight and was less lipophilic
than farglitazar (MW: 468.54 vs. 546.61; log P: 3.2 vs. 4.2).
Compound 10 and farglitazar showed similar insulin-sensi-
tizing activities determined as an increasing effect on cellular
triglyceride (TG) levels during insulin-stimulated adipocyte
differentiation in 3T3-L1 cells (EC50: 3.1ꢁ0.9 nM and
2.6ꢁ0.8 nM, respectively, nꢂ4). Compound 11 with a ben-
zoyl moiety showed very weak PPARg agonist activity
(EC50: 1.4ꢁ0.4 mM, nꢂ4). Thus, in the following experi-
ments, a series of derivatives were synthesized by modifica-
tion at the 2nd and 7th positions based on compound 10, and
structure–activity relationships were explored. Insulin-sensi-
tizing activities of the derivatives were determined in com-
parison with compound 10, as described above, in adipocyte
differentiation using 3T3-L1 cells, and expressed as relative
activity to compound 10 (a reciprocal of equipotent concen-
tration ratio). Glucose- and TG-lowering effects of the deriv-
atives and 10 were also examined in KK-Ay mice, a type 2
diabetic model animal, and expressed as a %decrease in glu-
cose and TG in comparison with control mice administered
vehicle.
KK-Ay mouseb)
3T3-L1a)
Compound
R
Activity ratio
Glucose
TG
% decrease % decrease
10
11
1
45**
6
29*
3
0.01
20
21
ꢃ0.01
10 (47**)
6 (47**)
0 (49**)
5.0
9 (49**)
22
23
0.02
0.01
16 (61**)
7 (61**)
8 (54**)
In Table 1, elongation of a benzyl moiety by insertion of
an ethyl chain in compound 20 markedly reduced in vitro ac-
tivity in 3T3-L1 cells. Reduction of benzene to cyclohexane
(compound 21) enhanced in vitro activity but markedly de-
14 (54**)
a) Duplicate assay, relative activity against compound 10 for TG-increasing effect
during insulin-stimulated adipocyte differentiation, expressed as a reciprocal of equipo-
creased glucose-lowering activity: cyclohexyl moiety may tent concentration ratio of test compound/compound 10. b) nꢂ5, % decrease values
of compound 10 in the same experiment are shown in parentheses. ∗ pꢃ0.05,
∗∗ pꢃ0.01, vs. corresponding Control, Student’s t-test.
have been easily metabolized, resulting in a low plasma con-
centration. Replacement of the benzyl group with pyridinyl
(compounds 22, 23) also reduced in vitro activity, suggesting
that a basic nitrogen atom may have disturbed the interaction boxylic acid and two lipophilic moieties was considered to
between the compound and lipophilic region of the protein.
be achieved in the S conformation in cyclic as well as
In Table 2, moving the phenyl oxazole ethoxy moiety from branched molecules. In compounds 27 and 28, the pyridinyl
the 7th to 6th position (compound 24) and shortening the moiety used in 1 (rosiglitazone) and 2 (pioglitazone) was in-
chain at the 7th position (compound 25) remarkably reduced troduced into the 7th position: in vitro and in vivo activity
in vitro and in vivo activity. Compound 26, an R isomer, were markedly reduced. These pyridinyl moieties maintained
showed much less activity than compound 10, an S isomer. the activity in farglitazar-related derivatives.11) In the present
Interestingly, it was reported that the S isomer is more potent type of compounds, movement of the carboxyl moiety and
than the R isomer in tyrosine derivatives and a-alkoxy propi- two lipophilic moieties was limited and their direction was
onic acid derivatives.18,19) The desirable direction of car- fixed; thus, the above pyridinyl chains may not have suitably

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Vol. 56, No. 3
Table 2. Insulin-Sensitizing Effects on 3T3-L1 Cells, and Hypoglycemic Table 4. Insulin-Sensitizing Effects on 3T3-L1 Cells, and Hypoglycemic
and Hypolipidemic Effects in KK-Ay Mice of 2-Benzyl-1,2,3,4-Tetrahy- and Hypolipidemic Effects in KK-Ay Mice of 1,2,3,4-Tetrahydroisoquino-
droisoquinoline-3-carboxylic Acids with Various Substituents at 6- or 7-Po- line-3-carboxylic Acids with Various Substituted Oxazole Rings at 7-Posi-
sition
tion
KK-Ay mouseb)
3T3-L1a)
Activity
ratio
Compound
R
Glucose %
TG
decrease % decrease
KK-Ay mouseb)
3T3-L1a)
Activity
ratio
24
ꢃ0.01
16 (51**)
19 (24)
Compound
R
Glucose
TG
% decrease
% decrease
38
39
0.35
0.1
39** (38**)
42** (56**)
32 (37)
25
26
ꢃ0.01
13 (45**) ꢄ12 (24)
36** (30*)
0.02
8 (42**)
ꢄ2 (40*)
40
41
42
0.16
0.03
0.32
24* (38**)
0.1 (38**)
0 (33**)
17 (36*)
14 (56**)
3 (35*)
27
28
ꢃ0.01 ꢄ13 (38*)
11 (59**)
43
0.06
23* (45**)
14 (32*)
ꢃ0.01
2 (45**) ꢄ13 (29*)
44
45
2.3
10
6 (33*)
ꢄ4 (35*)
11 (33*)
ꢄ35 (35*)
a) Duplicate assay, relative activity against compound 10 for TG-increasing effect
during insulin-stimulated adipocyte differentiation, expressed as a reciprocal of equipo-
tent concentration ratio of test compound/compound 10. b) nꢂ5, % decrease values
of compound 10 in the same experiment are shown in parentheses. ∗ pꢃ0.05,
∗∗ pꢃ0.01, vs. corresponding Control, Student’s t-test.
a) Duplicate assay, relative activity against compound 10 for TG-increasing effect
during insulin-stimulated adipocyte differentiation, expressed as a reciprocal of equipo-
tent concentration ratio of test compound/compound 10. b) nꢂ5, % decrease values
of compound 10 in the same experiment are shown in parentheses. ∗ pꢃ0.05,
∗∗ pꢃ0.01, vs. corresponding Control, Student’s t-test.
Table 3. Insulin-Sensitizing Effects on 3T3-L1 Cells, and Hypoglycemic
and Hypolipidemic Effects in KK-Ay Mice of 1,2,3,4-Tetrahydroisoquino-
line-3-carboxylic Acids with Various Benzyl Analogues at 2-Position
interacted with PPARg protein.
In Table 3, various substituents were introduced to the
benzene ring of the benzyl moiety. At the 4th position,
methyl and trifluoromethyl groups reduced (30, 34), methoxy
and fluoro groups enhanced (29, 32), and the vinyl group did
not alter in vitro activity (31). Methoxy and fluoro groups
may have been involved in hydrogen bond interaction be-
tween compounds and protein. At the 3rd position, fluoro,
trifluoromethyl and acetyl moiety reduced in vitro activity
(33, 35, 36). Acetyl moiety at the 2nd position also reduced
the activity (37). Trifluoromethyl and acetyl moiety may have
reduced the activity by reducing the electron density of the
benzene ring. Compounds 29—33 showed relatively potent
in vivo activities. In Table 4, the effects of substituents at the
2nd position of the oxazole ring were examined. Thiophenyl,
tert-butyl, isopropyl, cyclopropyl, neopentyl and 2-methyl-
propenyl moieties markedly decreased in vitro activity (38—
43). However, 38, 39, 40 and 43 showed hypoglycemic activ-
ity similar to or weaker than that of 10. Butenyl moieties en-
hanced in vitro activity but not in vivo activity (44, 45). In
vitro activity appears dependent on the bulkiness of sub-
KK-Ay mouseb)
3T3-L1a)
Compound
R
Activity
ratio
Glucose
% decrease
TG
% decrease
29
30
31
32
33
34
35
36
37
4-OMe
4-Me
4-vinyl
4-F
20
35** (61**)
40** (61**)
41** (45**)
43** (61**)
31* (35*)
20 (54**)
46** (54**)
18 (24)
24* (54**)
29 (29)
0.12
1.28
4
0.46
0.3
3-F
4-CF3
3-CF3
3-acetyl
2-acetyl
19 (33*)
0 (33*)
0.1
0.01
0.04
26 (33*)
15 (51**)
ꢄ2 (41**)
25 (33*)
15 (34)
ꢄ1 (43**)
a) Duplicate assay, relative activity against compound 10 for TG-increasing effect
during insulin-stimulated adipocyte differentiation, expressed as a reciprocal of equipo-
tent concentration ratio of test compound/compound 10. b) nꢂ5, % decrease values
of compound 10 in the same experiment are shown in parentheses. ∗ pꢃ0.05,
∗∗ pꢃ0.01, vs. corresponding Control, Student’s t-test.

March 2008
339
stituents on the oxazole ring, except for alkenyl groups.
butenyl maintained in vitro activity (51, 52). These findings
In Table 5, aliphatic groups (carbon numbers 3—6) were are interesting, since these compounds with small alkyl
introduced into the 2nd position. Isobutyl, n-butyl, chains at the 2nd position can be regarded as a model of cy-
neopentyl, n-hexyl, allyl, 3-butenyl and 3-methyl-2-butenyl clization of a-alkoxy propionic acid-type PPARg agonists.
markedly reduced (46—50, 53, 54), and propynyl and 2- Among them, compounds with isobutyl, n-butyl, neopentyl,
allyl, propynyl, 2-butenyl and 3-butenyl (46—48, 50—53)
Table 5. Insulin-Sensitizing Effects on 3T3-L1 Cells, and Hypoglycemic
showed hypoglycemic activity similar to or weaker than that
and Hypolipidemic Effects in KK-Ay Mice of 1,2,3,4-Tetrahydroisoquino-
of 10. In Tables 3 and 4, compounds 29, 32, 44 and 45
line-3-carboxylic Acids with Various Aliphatic Chains at 2-Position
showed stronger in vitro activity and weaker hypoglycemic
activity than that of 10; their intestinal absorption or distribu-
tion to a target organ may have been lower than that of 10. In
Tables 3—5, compounds 30, 33, 38, 39, 48 and 53 showed
hypoglycemic effects similar to that of 10 in spite of weaker
KK-Ay mouseb)
3T3-L1a)
Activity
ratio
in vitro activity; they may have been highly absorbed, resist-
ant to metabolism or efficiently distributed to a target organ.
Finally, compound 10 (KY-021) with relatively low molec-
ular weight and lipophilicity, and showing high in vitro activ-
ity and in vivo hypoglycemic effects comparable to those of
farglitazar, was selected and further compared with fargli-
tazar. Oral administration of KY-021 and farglitazar as a di-
etary admixture for 7 d reduced plasma glucose and TG lev-
els at 1 and 3 mg/kg/d in KK-Ay mice (Table 6). KY-021 and
farglitazar dose-dependently lowered plasma TG levels at
0.3—3 mg/kg/d for 6 d in Zucker fatty rats; the effects of KY-
021 were greater than those of farglitazar (Table 7). KY-021
but not farglitazar at 1 and 3 mg/kg/d for 7 d significantly in-
hibited the increase of plasma glucose levels after oral glu-
cose load in male Zucker fatty rats, indicating that KY-021
improved glucose tolerance. After oral administration at
10 mg/kg, the maximal plasma concentration (Cmax) of KY-
021 reached about 7 mg/ml in male ICR mice and 2 mg/ml in
male SD rats, while Cmax of farglitazar was 0.7 mg/ml in mice
and 0.4 mg/ml in rats (Table 8). KY-021 may have been more
efficiently dissolved and absorbed in the intestines than far-
glitazar due to its lower lipophilicity. Repeated administra-
tion of KY-021 and farglitazar at 30 mg/kg/d for 10 weeks
had no severe toxic effects on the general condition, body
weight changes and hematological analyses. However, fargli-
tazar, but not KY-021, significantly increased heart weight
(Control: 0.30ꢁ0.008, farglitazar: 0.34ꢁ0.004**, KY-021:
0.32ꢁ0.008 g/100 g body weight, nꢂ7, meanꢁS.E., ∗∗ pꢃ
Compound
R
Glucose
% decrease
TG
% decrease
46
47
48
0.09
0.09
0.29
17* (45**)
22** (33*)
43** (38**)
1 (29**)
12 (35**)
50** (36**)
49
50
0.21
0.09
12 (47**)
10 (49**)
30 (36*)
28** (38**)
51
52
0.92
1.3
31** (38**)
46** (45**)
16 (36*)
36* (32*)
53
54
0.46
0.06
44** (45**)
9 (45**)
32 (32*)
0 (32*)
a) Duplicate assay, relative activity against compound 10 for TG-increasing effect
during insulin-stimulated adipocyte differentiation, expressed as a reciprocal of equipo-
tent concentration ratio of test compound/compound 10. b) nꢂ5, % decrease values
of compound 10 in the same experiment are shown in parentheses. ∗ pꢃ0.05,
∗∗ pꢃ0.01, vs. corresponding Control, Student’s t-test.
Table 6. Effects of KY-021 and Farglitazar Administered as Dietary Admixtures for 7 d on Plasma Glucose and Triglyceride Levels in Male KK-Ay Mice
KY-021 (mg/kg)
1
Farglitazar (mg/kg)
1
Control
0.3
3
0.3
3
Glu (mg/dl)
TG (mg/dl)
514ꢁ29
510ꢁ57
503ꢁ34
541ꢁ29
424ꢁ34
481ꢁ49
263ꢁ40**
274ꢁ15**
476ꢁ47
507ꢁ42
360ꢁ59*
430ꢁ49
253ꢁ25**
317ꢁ24*
Glu: glucose, TG: triglyceride, MeanꢁS.E. (nꢂ6) ∗ pꢃ0.05, ∗∗ pꢃ0.01 vs. Control.
Table 7. Effects of KY-021 and Farglitazar Administered for 6 d on Plasma TG Levels and for 7 d on Oral Glucose Tolerance in Male Zucker Fatty Rats
KY-021 (mg/kg)
1
Farglitazar (mg/kg)
1
0.3
3
0.3
3
TG (D%)
OGTT-AUC (D%)
24.7ꢁ3.2**
5.9ꢁ10.5
45.3ꢁ3.5**
43.1ꢁ8.4*
66.2ꢁ2.1**
39.6ꢁ6.4**
16.1ꢁ4.0*
4.2ꢁ15.7
12.1ꢁ7.2
15.9ꢁ9.1
30.5ꢁ3.2**
15.9ꢁ10.6
TG (D%): percent decrease in plasma TG levels 24 h after administration on the 6th day in comparison with the mean value of the control group. OGTT-AUC (D%): percent
decrease in the area under the curve in oral glucose tolerance test performed 24 h after administration on the 7th day in comparison with the mean value of the control group.
MeanꢁS.E. (nꢂ7), ∗ pꢃ0.05, ∗∗ pꢃ0.01 vs. Control.

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Vol. 56, No. 3
Table 8. Plasma Concentrations of KY-021 and Farglitazar after Oral Ad- and the organic layer was washed with saturated aqueous sodium hydrogen-
ministration at 10 mg/kg in Non-Fasted Male ICR Mice and Male SD Rats
Mouse Rat
carbonate solution (100 ml) and saturated brine (100 ml) and dried over
Na2SO4. Ethyl acetate was evaporated under reduced pressure to give ethyl
7-hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (11.1 g,
89%) as a solid. 1H-NMR (CDCl3) d: 1.29 (3H, t, Jꢂ7.0 Hz), 2.80—3.00
(2H, m), 3.30—4.10 (5H, m), 4.23 (2H, q, Jꢂ7.0 Hz), 7.46 (1H, s).
Cmax
AUC
Cmax
AUC
Ethyl (S)-7-Hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
To a suspension of 10% Pd–C (350 mg) in MeOH (60 ml) was added 13
(2.80 g, 5.92 mmol) and triethylamine (2.0 ml, 14.3 mmol), and the com-
pound was catalytically hydrogenated under H2 (0.3 MPa) at room tempera-
ture for 3 h. Pd–C was removed by filtration, and MeOH was evaporated
under reduced pressure. Ethyl acetate (10 ml) was added to the obtained
residue. The mixture was washed with saturated brine (100 ml) and dried
over Na2SO4. Ethyl acetate was evaporated under reduced pressure to give
ethyl 7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1.14 g, 89%)
as a solid. 1H-NMR (CDCl3) d: 1.28 (3H, t, Jꢂ7.0 Hz), 2.80—3.10 (3H, m),
3.60—3.80 (1H, m), 3.97 (2H, s), 4.05—4.20 (4H, m), 6.43 (1H, s), 6.50—
6.80 (1H, m), 6.92 (1H, d, Jꢂ8.4 Hz). IR (nujol) cmꢄ1: 1732, 1607, 1516.
Ethyl (S)-2-tert-Butoxycarbonyl-7-hydroxy-1,2,3,4-tetrahydroisoqui-
KY-021
Farglitazar
6.61ꢁ0.45
0.74ꢁ0.08
29.9
5.28
2.13ꢁ0.25
0.38ꢁ0.02
12.6ꢁ1.2
5.04ꢁ0.87
MeanꢁS.E. (nꢂ4), Cmax: mg/ml, AUC: mg·h/ml.
0.01 vs. Control, Student’s t-test) and white adipose tissue
weight (Control: 1.84ꢁ0.15, farglitazar: 3.48ꢁ0.43**, KY-
021: 2.60ꢁ0.36 g/100 g body weight, ∗∗ pꢃ0.01 vs. Con-
trol), suggesting that farglitazar may have a risk for volume
expansion and increase in weight gain. KY-021 is smaller and
less lipophilic than farglitazar, and has a more rigid structure
with carboxylic acid and lipophilic moieties. Therefore, KY-
021 may interact with PPARg protein more specifically and
efficiently than farglitazar; however, further study is needed
to clarify the mode of interaction of KY-021 and protein.
noline-3-carboxylate (14) To
a solution of ethyl 7-hydroxy-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate (1.13 g, 5.11 mmol) in THF (20 ml)
was added di-tert-butyl dicarbonate (1.50 g, 6.87 mmol), and the mixture
was stirred at room temperature for 1 h. Ethyl acetate (30 ml) was added to
the reaction mixture, and the mixture was washed with saturated brine
(20 ml) and dried over Na2SO4. Ethyl acetate was evaporated under reduced
pressure. The obtained residue was purified by column chromatography to
give 14 (1.51 g, 92%) as a solid. 1H-NMR (CDCl3) d: 1.29 (3H, t,
Jꢂ7.0 Hz), 1.47 (9H, s), 3.08 (2H, d, Jꢂ5.2 Hz), 4.21 (2H, q, Jꢂ7.0 Hz),
Conclusion
A series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic
acid derivatives were synthesized to find a useful PPARg 4.41 (1H, d, Jꢂ15.5 Hz), 4.60—5.25 (1H, m), 4.65 (1H, d, Jꢂ15.5 Hz),
5.00—6.00 (1H, br), 6.50—6.80 (2H, m), 6.98 (1H, d, Jꢂ8.1 Hz). IR (nujol)
agonist based on a more rigid structure than benzene de-
rivatives, and (S)-2-benzyl-7-[2-(5-methyl-2-phenyloxazol-4-
yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
(KY-021) has been identified as a novel PPARg agonist. KY-
cmꢄ1: 3260, 1756, 1671, 1615, 1506.
Ethyl (S)-2-tert-Butoxycarbonyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)-
ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (16) A mixture of
14 (1.50 g, 4.67 mmol), 2-(5-methyl-2-phenyloxazol-4-yl)ethyl methanesul-
fonate (15, 2.50 g, 9.28 mmol) and K2CO3 (2.0 g 14.5 mmol) in N,N-di-
methylformamide (DMF) (20 ml) was stirred at 80 °C for 5 h. Ethyl acetate
(100 ml) was added to the reaction mixture, and the mixture was washed
with water and saturated brine and dried over Na2SO4. Ethyl acetate was
evaporated under reduced pressure. The obtained residue was purified by sil-
ica gel column chromatography to give 16 (1.62 g, 68%) as an oil. 1H-NMR
(CDCl3) d: 1.12 (3H, t, Jꢂ7.0 Hz), 1.46, 1.50 (9H, s, s), 2.36 (3H, s), 2.95
(2H, t, Jꢂ6.8 Hz), 2.90—3.30 (2H, m), 4.00—4.40 (4H, m), 4.51, 4.61 (2H,
s, s), 4.70—4.90, 5.00—5.20 (1H, m, m), 6.60—6.90 (2H, m), 7.12 (1H, d,
Jꢂ8.4 Hz), 7.30—7.55 (3H, m), 7.90—8.15 (2H, m). IR (neat) cmꢄ1: 2978,
2930, 1738, 1699, 1614, 1587.
021 showed potent antihyperglycemic and hypolipidemic ef-
fects in male KK-Ay mice, and improved oral glucose toler-
ance in male Zucker fatty rats. KY-021 had excellent oral ab-
sorption in male ICR mice and male SD rats. Repeated oral
administration of KY-021 at 30 mg/kg/d for 10 weeks showed
little toxicity in male SD rats. From these results, KY-021 is
concluded to be a novel 1,2,3,4-tetrahydroisoquinoline-based
PPARg agonist and a promising candidate for an anti-dia-
betic drug.
Ethyl (S)-7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylate (17) To a solution of 16 (5.20 g, 10.3
Experimental
General Melting points were measured on a Yamato MP-21 melting mmol) in formic acid (20 ml) was added saturated hydrogen chloride solu-
point apparatus and are uncorrected. Proton nuclear magnetic resonance
tion in 2-propanol (6.0 ml) under ice-cooling, and the mixture was stirred at
(1H-NMR) spectra were obtained on a Hitachi FT-NMR R-1900 NMR spec- room temperature for 10 min. Ethyl acetate (100 ml) was added to the reac-
trometer, using tetramethylsilane (TMS) as an internal standard. Infrared tion mixture, and the mixture was neutralized with saturated aqueous solu-
(IR) spectra were recorded with a Shimadzu FT-IR8200PC spectrometer. tion of NaHCO3 and separated into two layers. The obtained ethyl acetate
Mass spectra were obtained on an Applied Biosystems API2000 QTRAP
LC/MS/MS system. Daisogel No. 1001W (70—230 mesh, Daiso) was used
layer was washed with brine and dried over Na2SO4. Ethyl acetate was evap-
orated under reduced pressure to give 17 (3.6 g, 86%) as a solid. H-NMR
1
for column chromatography. TLC was performed on pre-coated TLC plates (CDCl3) d: 1.29 (3H, t, Jꢂ7.0 Hz), 2.02 (1H, s), 2.36 (3H, s), 2.80—3.10
with 60F254 (Merck).
(4H, m), 3.50—3.80 (1H, m), 4.00—4.40 (6H, m), 6.50—6.80 (2H, m), 7.00
(S)-7-Hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic (1H, d, Jꢂ8.4 Hz), 7.30—7.50 (3H, m), 7.90—8.10 (2H, m). IR (nujol)
Acid Hydrochloride To a suspension of 3,5-diiodo-L-tyrosine dihydrate
(12, 25.0 g, 53.3 mmol) in concentrated hydrochloric acid (250 ml) was suc-
cmꢄ1: 3476, 1742, 1639, 1611, 1553.
Ethyl (S)-2-Benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-
cessively added 1,2-dimethoxyethane (18 ml) and 37% formalin (20 ml, tetrahydroisoquinoline-3-carboxylate To a solution of 17 (1.40 g, 3.44
242 mmol), and the mixture was warmed to 75 °C over 30 min. To the reac- mmol) in DMF (20 ml) was added sodium hydride (60% oil dispersion,
tion mixture was further added concentrated hydrochloric acid (120 ml), 1,2-
dimethoxyethane (9 ml) and 37% formalin (10 ml, 121 mmol), and the mix-
160 mg, 4.0 mmol) under ice-cooling, and the mixture was stirred at room
temperature for 20 min. Then benzyl bromide (0.40 ml, 3.36 mmol) was
ture was stirred at 75 °C for 18 h. The precipitated crystals were collected by added to the mixture, and stirred 1 h at the same temperature. Ethyl acetate
filtration and washed with 1,2-dimethoxyethane (20 ml) to give 7-hydroxy- (50 ml) was added to the reaction mixture, and the mixture was washed with
6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid hydrochloride water (50 ml) and saturated brine (30 ml) and dried over Na2SO4. Ethyl ac-
1
(12.8 g, 50%). H-NMR (CDCl3) d: 3.00—3.30 (2H, m), 4.05 (2H, s), 4.30 etate was evaporated under reduced pressure, and the obtained residue was
(1H, dd, Jꢂ5.9, 9.5 Hz), 7.71 (1H, s). IR (nujol) cmꢄ1: 1751, 1599, 1578.
purified by silica gel column chromatography to give ethyl 2-benzyl-7-[2-(5-
Ethyl (S)-7-Hydroxy-6,8-diiodo-1,2,3,4-tetrahydroisoquinoline-3-car- methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-car-
boxylate (13) To a suspension of 7-hydroxy-6,8-diiodo-1,2,3,4-tetrahy- boxylate (1.38 g, 81%) as a solid. 1H-NMR (CDCl3) d: 1.21 (3H, t,
droisoquinoline-3-carboxylic acid hydrochloride (12.8 g, 127.1 mmol) in Jꢂ7.0 Hz), 2.34 (3H, s), 2.92 (2H, t, Jꢂ7.0 Hz), 3.05—3.20 (2H, m), 3.60—
ethanol (500 ml) was added concentrated hydrochloric acid (10 ml) and the 4.00 (5H, m), 4.12 (2H, q, Jꢂ7.0 Hz), 4.16 (2H, t, Jꢂ7.0 Hz), 6.51 (1H, d,
mixture was refluxed for 15 h. After evaporation of the solvent under re- Jꢂ2.0 Hz), 6.68 (1H, dd, Jꢂ2.0, 8.4 Hz), 6.99 (1H, d, Jꢂ8.4 Hz), 7.30—
duced pressure, ethyl acetate (300 ml) was added to the obtained residue,
7.50 (8H, m), 7.80—8.10 (2H, m). IR (nujol) cmꢄ1: 1728, 1639, 1614, 1551.

March 2008
341
(S)-2-Benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-
(S)-7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-
tetrahydroisoquinoline-3-carboxylic Acid (10) To a solution of ethyl 2- 1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (20) To
a solution
benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroiso- of ethyl 7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-
quinoline-3-carboxylate (5.20 g, 10.5 mmol) in THF–MeOH (3 : 1, 50 ml)
was added 1 M aqueous lithium hydroxide solution (30 ml), and the mixture
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1.0 g, 1.91 mmol) in THF–
MeOH (3 : 1, 10 ml) was added 2 M aqueous lithium hydroxide solution
was stirred at 50 °C for 2 h. After evaporation of the solvent, the obtained (4.77 ml), and the mixture was stirred at room temperature for 10 h. The sol-
residue was acidified with citric acid. The precipitated crystals were col- vent was evaporated under reduced pressure, and the obtained residue was
lected by filtration. The obtained crude crystals (4.80 g) were recrystallized
acidified with citric acid. The precipitated solid was collected by filtration to
from MeOH to give 10 (2.56 g, 52%) as colorless crystals. mp 154—156 °C
give 20 (0.66 g, 70%) as a colorless solid. mp 104—105 °C. 1H-NMR
(dec.). 1H-NMR (DMSO-d6) d: 2.33 (3H, s), 2.65—3.30 (4H, m), 3.50— (CDCl3) d: 1.70—2.20 (3H, m), 2.35 (3H, s), 2.40—2.70 (4H, m), 2.70—
4.00 (5H, m), 4.00—6.20 (1H, br), 4.13 (2H, t, Jꢂ7.0 Hz), 6.59 (1H, br s),
6.68 (1H, br d, Jꢂ8.4 Hz), 7.01 (1H, d, Jꢂ8.4 Hz), 7.32 (5H, s), 7.35—7.70 Jꢂ7.0 Hz), 3.90—4.30 (4H, m), 5.12 (1H, br s), 6.55—6.80 (2H, m), 6.90—
(3H, m), 7.85—8.10 (2H, m). IR (nujol) cmꢄ1: 1638, 1501. MS m/z: 469 7.25 (6H, m), 7.25—7.55 (3H, m) , 7.80—8.10 (2H, m). IR (nujol) cmꢄ1
[MꢅH]ꢅ. Anal. Calcd for C29H28N2O4: C, 74.34; H, 6.02; N, 5.98. Found: C, 3346, 1616, 1556, 1506. MS m/z: 497 [MꢅH]ꢅ. Anal. Calcd for
74.09; H, 6.07; N, 5.96. C31H34N2O5·H2O: C, 72.35; H, 6.66; N, 5.44. Found: C, 72.11; H, 6.68; N,
3.30 (2H, m), 2.92 (2H, t, Jꢂ6.3 Hz), 3.10 (2H, d, Jꢂ7.0 Hz), 3.65 (1H, t,
:
(R)-2-Benzyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4- 5.41.
tetrahydroisoquinoline-3-carboxylic Acid (26) This compound was pre-
(S)-2-Cyclohexylmethyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-
pared by a similar procedure to that described in the synthesis of 10. A col-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (21) This compound
was prepared by a similar procedure to that described in the synthesis of 20.
1
orless solid, mp 155—157 °C (dec.). H-NMR (DMSO-d6) d: 2.33 (3H, s),
2.95 (1H, t, Jꢂ6.6 Hz), 2.90—3.10 (2H, m), 3.50—4.00 (5H, m), 4.00— A pale yellow solid, mp 112—114 °C. 1H-NMR (CDCl3) d: 0.70—2.10
6.20 (1H, br), 4.13 (2H, t, Jꢂ6.6 Hz), 6.57 (1H, br s), 6.67 (1H, br d,
Jꢂ8.4 Hz), 7.01 (1H, d, Jꢂ8.4 Hz), 7.31 (5H, s), 7.40—7.60 (3H, m), (2H, d, Jꢂ7.2 Hz), 3.70 (1H, t, Jꢂ7.2 Hz), 4.00—4.30 (4H, m), 5.30 (1H,
7.85—8.05 (2H, m). IR (nujol) cmꢄ1: 1636, 1501. MS m/z: 469 [MꢅH]ꢅ.
br s), 6.60—6.90 (2H, m), 7.08 (1H, d, Jꢂ8.4 Hz), 7.30—7.50 (3H, m),
Ethyl (S)-2-Benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]- 7.80—8.10 (2H, m). IR (nujol) cmꢄ1: 3319, 1624, 1506. MS m/z: 475
1,2,3,4-tetrahydroisoquinoline-3-carboxylate To a solution of 17 (1.4 g
[MꢅH]ꢅ. Anal. Calcd for C29H34N2O4·H2O: C, 70.71; H, 7.37; N, 5.69.
3.44 mmol) in CH2Cl2 (14 ml) was added benzoyl chloride (0.48 ml, Found: C, 70.83; H, 7.51; N, 5.66.
(11H, m), 2.36 (3H, s), 2.40—2.55 (2H, m), 2.93 (2H, t, Jꢂ6.4 Hz), 3.16
4.14 mmol) and triethylamine (0.72 ml, 5.17 mmol) under ice-cooling, and
Compounds 22—25 were prepared by a similar procedure to that de-
the mixture was stirred at the same temperature for 15 min. Ethyl acetate scribed in the synthesis of 10.
(100 ml) was added to the reaction mixture, and the mixture was washed
Sodium (S)-7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-2-
successively with 10% aqueous citric acid solution (50 ml), saturated aque- ylmethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (22) A pale yel-
1
ous NaHCO3 solution (50 ml) and then saturated brine (50 ml) and dried
low solid, mp 91—93 °C (dec.). H-NMR (CDCl3) d: 2.32 (3H, s), 2.60—
over Na2SO4. The organic layer was evaporated under reduced pressure. The 3.20 (4H, m), 3.20—3.90 (5H, m), 4.08 (2H, br t, Jꢂ6.5 Hz), 6.15—6.40
obtained residue was purified by silica gel column chromatography to give (1H, m), 6.40—6.70 (1H, m), 7.75—8.20 (3H, m), 7.20—7.65 (4H, m),
ethyl 2-benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahy- 7.75—8.10 (2H, m), 8.25—8.60 (1H, m). IR (nujol) cmꢄ1: 1609, 1575,
droisoquinoline-3-carboxylate (1.16 g, 66%) as a solid. 1H-NMR (CDCl3) d: 1554, 1502. MS m/z: 492 [MꢅH]ꢅ.
0.75—1.15 (3H, m), 2.35 (3H, s), 2.93 (2H, t, Jꢂ6.6 Hz), 3.05—3.25 (2H,
Sodium (S)-7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(pyridin-4-
m), 3.85—4.40 (4H, m), 4.20—4.80 (2H, m), 5.00—5.60 (1H, m), 6.47 (1H, ylmethyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (23) A pale yel-
br s), 6.72 (1H, br d, Jꢂ8.4 Hz), 7.05 (1H, br d, Jꢂ8.4 Hz), 7.30—7.60 (8H, low solid, mp 76—78 °C (dec.). 1H-NMR (DMSO-d6) d: 2.34 (3H, s),
m), 7.80—8.10 (2H, m). IR (nujol) cmꢄ1: 1734, 1638, 1612, 1591.
2.70—3.05 (4H, m), 3.10—3.60 (3H, m), 3.98 (2H, br t, Jꢂ5.7 Hz), 4.10—
(S)-2-Benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4- 4.25 (2H, m), 6.51 (1H, br s), 6.61 (1H, br d, Jꢂ8.7 Hz), 6.94 (1H, br d,
tetrahydroisoquinoline-3-carboxylic Acid (11) To a solution of ethyl 2- Jꢂ8.7 Hz), 7.25—7.65 (5H, m), 7.75—8.00 (2H, m), 8.46 (2H, d,
benzoyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahydroiso- Jꢂ5.2 Hz). IR (nujol) cmꢄ1: 3420, 3177, 1639, 1558, 1504. MS m/z: 492
quinoline-3-carboxylate (1.0 g, 2.01 mmol) in THF–MeOH (3 : 1, 10 ml) was
added 1 M aqueous lithium hydroxide solution (6.0 ml), and the mixture was
[MꢅH]ꢅ.
(RS)-2-Benzyl-6-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-
stirred at room temperature for 1.5 h. The solvent was evaporated under re- tetrahydroisoquinoline-3-carboxylic Acid (24) A colorless solid, mp
1
duced pressure. To the obtained residue was added water (20 ml), and the 151—153 °C (dec.). H-NMR (DMSO-d6) d: 2.35 (3H, s), 2.65—3.25 (4H,
mixture was washed with ethyl acetate (10 ml). The obtained aqueous layer m), 3.40—4.00 (3H, m), 3.90 (2H, s), 4.17 (2H, br t, Jꢂ6.4 Hz), 6.20—
was acidified with hydrochloric acid, and the mixture was extracted twice 10.00 (1H, br), 6.50—7.00 (2H, m), 6.71 (1H, s), 7.30—7.70 (3H, m), 7.32
with diethyl ether (20 ml). The diethyl ether layer was washed with saturated (5H, s), 7.75—8.15 (2H, m). IR (nujol) cmꢄ1: 1634, 1614, 1499. MS m/z:
brine (30 ml) and dried over Na2SO4. Diethyl ether was evaporated under re- 469 [MꢅH]ꢅ. Anal. Calcd for C29H28N2O4: C, 74.34; H, 6.13; N, 5.98.
duced pressure. The obtained residue was recrystallized from MeOH to give Found: C, 74.26; H, 6.13; N, 5.93.
1
11 (0.75 g, 79%) as colorless crystals. mp 96—98 °C. H-NMR (CDCl3) d:
(S)-2-Benzyl-7-[(5-methyl-2-phenyloxazol-4-yl)methoxy]-1,2,3,4-
2.32 (3H, s), 2.87 (2H, t, Jꢂ6.4 Hz), 3.00—3.35 (2H, m), 4.02 (2H, t, tetrahydroisoquinoline-3-carboxylic Acid (25) A pale brown solid, mp
Jꢂ6.4 Hz), 4.40—4.90 (2H, m), 4.90—5.30 (1H, br), 5.00—5.65 (1H, m), 92—95 °C. 1H-NMR (DMSO-d6) d: 2.41 (3H, s), 2.83—3.20 (2H, m),
6.40 (1H, br s), 6.50—6.80 (1H, m), 7.03 (1H, d, Jꢂ8.4 Hz), 7.20—7.60 3.44—4.20 (5H, m), 4.91 (2H, s), 6.73 (1H, br s), 6.77 (1H, d, Jꢂ8.1 Hz),
(8H, m), 7.75—8.05 (2H, m). IR (nujol) cmꢄ1: 1730, 1636, 1551. MS m/z: 7.34 (1H, d, Jꢂ8.1 Hz), 7.34 (5H, s), 7.40—7.68 (3H, m), 7.75—8.10 (2H,
483 [MꢅH]ꢅ.
m). IR (nujol) cmꢄ1: 3462, 1680, 1614, 1556, 1508. MS m/z: 455 [MꢅH]ꢅ.
Ethyl (S)-7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpro- Anal. Calcd for C28H26N2O4: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.61; H,
pyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate To a solution of 17
(1.40 g, 3.44 mmol) in DMF (14 ml) was added 3-phenylpropyl bromide
(0.78 ml, 5.17 mmol) and potassium carbonate (0.95 g, 6.87 mmol), and the
5.70; N, 6.16.
Ethyl (S)-2-Benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-car-
boxylate To a solution of ethyl (S)-7-hydroxy-1,2,3,4-tetrahydroisoquino-
mixture was stirred at 50 °C for 22 h. Water (100 ml) was added to the reac- line-3-carboxylate (8.1 g, 36.6 mmol) and triethylamine (5.6 ml, 40.2 mmol)
tion mixture, and the mixture was extracted twice with ethyl acetate (50 ml). in DMF (80 ml) was added benzyl bromide (4.57 ml, 38.4 mmol), and the
The organic layer was washed with saturated brine (100 ml) and dried over mixture was stirred at room temperature for 3 h. Water (500 ml) was added
Na2SO4. Ethyl acetate was evaporated under reduced pressure. The obtained to the reaction mixture, and the mixture was extracted twice with ethyl ac-
residue was purified by silica gel column chromatography to give ethyl 7-[2- etate (200 ml). The combined ethyl acetate layer was washed with saturated
(5-methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-phenylpropyl)-1,2,3,4-tetrahy- brine (500 ml) and dried over Na2SO4. Ethyl acetate was evaporated under
droisoquinoline-3-carboxylate (1.05 g, 58%) as a powder. 1H-NMR (CDCl3) reduced pressure. The obtained residue was purified by column chromatog-
d: 1.17 (3H, t, Jꢂ7.0 Hz), 1.60—2.05 (2H, m), 2.35 (3H, s), 2.50—2.80 raphy to give ethyl (S)-2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-
(4H, m), 2.94 (2H, t, Jꢂ7.1 Hz), 3.04 (2H, d, Jꢂ5.7 Hz), 3.67 (1H, t,
Jꢂ5.7 Hz), 3.84 (1H, s), 3.94 (1H, s), 4.04 (2H, t, Jꢂ7.1 Hz), 4.16 (2H, q, Jꢂ7.0 Hz), 3.06 (2H, d, Jꢂ5.0 Hz), 3.66 (1H, t, Jꢂ5.0 Hz), 3.78 (2H, s),
carboxylate (10.5 g, 92%) as a solid. 1H-NMR (CDCl3) d: 1.22 (3H, t,
Jꢂ7.0 Hz), 6.50—6.80 (2H, m), 7.07 (1H, d, Jꢂ9.0 Hz), 7.20 (5H, s),
7.10—7.50 (3H, m), 7.80—8.10 (2H, m). IR (nujol) cmꢄ1: 1720, 1647,
1612, 1504.
3.90 (2H, s), 4.13 (2H, q, Jꢂ7.0 Hz), 6.37 (1H, d, Jꢂ2.0 Hz), 6.56 (1H, dd,
Jꢂ2.0, 8.4 Hz), 6.92 (1H, d, Jꢂ8.4 Hz), 7.20—7.50 (5H, m). IR (nujol)
cmꢄ1: 3410, 1717, 1624, 1506.

342
Ethyl (S)-2-Benzyl-7-[2-(N-tert-butoxycarbonyl-N-methylamino)ethoxy]-
Vol. 56, No. 3
mixture, and the mixture was washed with water (50 ml) and saturated brine
1,2,3,4-tetrahydroisoquinoline-3-carboxylate To a solution of ethyl (S)-2- (50 ml) and dried over Na2SO4. Ethyl acetate was evaporated under reduced
benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1.38 g, 4.43 pressure. The obtained residue was purified by silica gel column chromatog-
mmol) in DMF (10 ml) was added sodium hydride (60% oil dispersion,
210 mg, 5.25 mmol) under ice-cooling and the mixture was stirred at room
raphy to give ethyl (S)-2-benzyl-7-[2-(5-ethylpyridin-2-yl)ethoxy]-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate (0.58 g, 41%) as a powder. 1H-NMR
temperature for 30 min. To the obtained mixture was added 2-(N-tert- (CDCl3) d: 1.22 (6H, t, Jꢂ7.2 Hz), 2.61 (2H, q, Jꢂ7.2 Hz), 3.07 (2H, d,
butoxycarbonyl-N-methylamino)ethyl methanesulfonate (1.30 g, 5.13 mmol) Jꢂ5.5 Hz), 3.18 (2H, t, Jꢂ6.6 Hz), 3.72 (1H, t, Jꢂ5.5 Hz), 3.81 (1H, s),
and the mixture was stirred further at the same temperature for 1 h. Ethyl ac- 3.90 (4H, s), 4.13 (2H, q, Jꢂ7.2 Hz), 4.27 (2H, t, Jꢂ6.6 Hz), 6.51 (1H, d,
etate (50 ml) was added to the reaction mixture, and the mixture was washed Jꢂ2.0 Hz), 6.69 (1H, dd, Jꢂ2.0, 8.4 Hz), 6.98 (1H, d, Jꢂ8.4 Hz), 7.10—
with water (50 ml) and saturated brine (30 ml) and dried over Na2SO4. Ethyl 7.50 (7H, m), 8.00—8.20 (1H, m). IR (nujol) cmꢄ1: 1732, 1612, 1504.
acetate was evaporated under reduced pressure. The obtained residue was
Sodium (S)-2-Benzyl-7-[2-(5-ethylpyridin-2-yl)ethoxy]-1,2,3,4-tetrahy-
purified by silica gel column chromatography to give ethyl (S)-2-benzyl-7- droisoquinoline-3-carboxylate (28) To a solution of ethyl (S)-2-benzyl-7-
[2-(N-tert-butoxycarbonyl-N-methylamino)ethoxy]-1,2,3,4-tetrahydroiso- [2-(5-ethylpyridin-2-yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
1
quinoline-3-carboxylate (1.44 g, 69%) as an oil. H-NMR (CDCl3) d: 1.23
(3H, t, Jꢂ7.0 Hz), 1.44 (9H, s), 2.95 (3H, s), 3.08 (2H, d, Jꢂ4.9 Hz), 3.54
(2H, t, Jꢂ5.5 Hz), 3.60—4.30 (7H, m), 6.50 (1H, d, Jꢂ2.0 Hz), 6.68 (1H,
dd, Jꢂ2.0, 8.1 Hz), 7.01 (1H, d, Jꢂ8.1 Hz), 7.20—7.50 (5H, m). IR (neat)
cmꢄ1: 2978, 2932, 1732, 1695, 1614.
(0.94 g, 2.11 mmol) in THF–MeOH (3 : 1, 40 ml) was added 2 M aqueous
sodium hydroxide solution (6.0 ml), and the mixture was stirred at 40 °C for
2 h. The solvent was evaporated under reduced pressure. Water (10 ml) and
then NaCl was added to saturation, and the mixture was extracted three
times with ethyl acetate (30 ml). The ethyl acetate layer was washed with
Ethyl (S)-2-Benzyl-7-(2-methylaminoethoxy)-1,2,3,4-tetrahydroisoqui- saturated brine (10 ml) and dried over Na2SO4. Ethyl acetate was evaporated
noline-3-carboxylate To a solution of ethyl (S)-2-benzyl-7-[2-(N-tert-bu- under reduced pressure. Diisopropyl ether was added to the obtained
toxycarbonyl-N-methylamino)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-car- residue. The solid was collected by filtration to give 28 (0.58 g, 65%) as a
boxylate (1.44 g, 3.07 mmol) in formic acid (7.0 ml) was added saturated hy- pale yellow solid. mp 67—68 °C. 1H-NMR (MeOH-d4) d: 1.22 (6H, t,
drogen chloride solution in 2-propanol (2.0 ml), and the mixture was stirred
at room temperature for 15 min. Ethyl acetate (100 ml) was added to the re- (1H, s), 3.95—4.35 (5H, m), 4.27 (2H, t, Jꢂ6.6 Hz), 6.40—6.75 (2H, m),
action mixture, and the mixture was neutralized with saturated aqueous 6.91 (1H, d, Jꢂ8.4 Hz), 7.20—7.65 (7H, m), 8.20—8.35 (1H, m). IR (nujol)
sodium hydrogencarbonate solution, and then the two layers were separated. cmꢄ1: 1576, 1504. MS m/z: 439 [MꢅH]ꢅ.
Jꢂ7.5 Hz), 2.63 (2H, q, Jꢂ7.5 Hz), 2.90—3.20 (4H, m), 3.72 (1H, s), 3.85
The obtained ethyl acetate layer was washed with saturated brine (50 ml) and
Compounds 29—45 were prepared by a similar procedure to that de-
dried over Na2SO4. Ethyl acetate was evaporated under reduced pressure scribed in the synthesis of 10.
to give ethyl (S)-2-benzyl-7-(2-methylaminoethoxy)-1,2,3,4-tetrahydroiso-
quinoline-3-carboxylate (1.08 g, 95%) as an oil. H-NMR (CDCl3) d: 1.22 1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (29) A colorless solid,
(S)-2-(4-Methoxybenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-
1
(3H, t, Jꢂ7.0 Hz), 2.41 (1H, br s), 2.49 (3H, s), 2.95 (2H, t, Jꢂ5.5 Hz), 3.08
(2H, d, Jꢂ4.9 Hz), 3.60—4.25 (7H, m), 6.52 (1H, d, Jꢂ2.0 Hz), 6.70 (1H,
dd, Jꢂ2.0, 8.4 Hz), 7.00 (1H, d, Jꢂ8.4 Hz), 7.20—7.50 (5H, m). IR (neat)
cmꢄ1: 3332, 1732, 1612, 1504.
mp 146—148 °C (dec.). 1H-NMR (CDCl3) d: 2.35 (3H, s), 2.93 (2H, t,
Jꢂ6.4 Hz), 3.18 (2H, d, Jꢂ6.8 Hz), 3.70—4.10 (5H, m), 3.77 (3H, s), 4.17
(2H, t, Jꢂ6.4 Hz), 4.50 (1H, br s), 6.60 (1H, d, Jꢂ2.0 Hz), 6.65—6.95 (3H,
m), 7.08 (2H, d, Jꢂ8.4 Hz), 7.20—7.60 (5H, m), 7.80—8.10 (2H, m). IR
Ethyl (S)-2-Benzyl-7-{2-[N-methyl-N-(pyridin-2-yl)amino]ethoxy}- (nujol) cmꢄ1: 3288, 1612, 1555, 1514. MS m/z: 499 [MꢅH]ꢅ. Anal. Calcd
1,2,3,4-tetrahydroisoquinoline-3-carboxylate Ethyl (S)-2-benzyl-7-(2- for C30H30N2O5·H2O: C, 69.75; H, 6.24; N, 5.39. Found: C, 69.65; H, 6.25;
methylaminoethoxy)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (1.05 g, N, 5.39.
2.85 mmol) was dissolved in 2-chloropyridine (2.0 ml), and the mixture was
(S)-2-(4-Methylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-
stirred at 140 °C for 16 h. The reaction mixture was purified by silica gel 1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (30) A colorless solid,
column chromatography to give ethyl (S)-2-benzyl-7-{2-[N-methyl-N- mp 136—137 °C (dec.). 1H-NMR (CDCl3) d: 2.32 (3H, s), 2.35 (3H, s), 2.93
(pyridin-2-yl)amino]ethoxy}-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (2H, t, Jꢂ7.0 Hz), 3.17 (2H, d, Jꢂ6.6 Hz), 3.65—4.05 (5H, m), 4.17 (2H, t,
1
(0.50 g, 39%) as an oil. H-NMR (CDCl3) d: 1.22 (3H, t, Jꢂ7.0 Hz), 3.06
Jꢂ7.0 Hz), 4.73 (1H, br s), 6.60 (1H, d, Jꢂ2.0 Hz), 6.77 (1H, dd, Jꢂ2.0,
(2H, d, Jꢂ6.2 Hz), 3.11 (3H, s), 3.60—4.30 (11H, m), 6.40—6.80 (4H, m), 8.8 Hz), 6.95—7.60 (8H, m), 7.85—8.10 (2H, m). IR (nujol) cmꢄ1: 1620,
6.97 (1H, d, Jꢂ8.4 Hz), 7.20—7.50 (6H, m), 8.00—8.20 (1H, m). IR (neat)
1555, 1506. MS m/z: 483 [MꢅH]ꢅ. Anal. Calcd for C30H30N2O4·H2O: C,
71.98; H, 6.44; N, 5.60. Found: C, 71.86; H, 6.44; N, 5.56.
cmꢄ1: 2932, 2905, 1732, 1597, 1560, 1504.
Sodium (S)-2-Benzyl-7-{2-[N-methyl-N-(pyridin-2-yl)amino]ethoxy}-
(S)-7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(4-vinylbenzyl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxylate (27) To a solution of ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (31) A colorless solid,
(S)-2-benzyl-7-{2-[N-methyl-N-(pyridin-2-yl)amino]ethoxy}-1,2,3,4- mp 126—128 °C. 1H-NMR (CDCl3) d: 2.33 (3H, s), 2.70—3.10 (4H, m),
tetrahydroisoquinoline-3-carboxylate (488 mg, 1.10 mmol) in THF–MeOH 3.50—4.00 (3H, m), 3.88 (2H, s), 4.13 (2H, t, Jꢂ6.5 Hz), 5.22 (1H, d,
(3 : 1, 5.0 ml) was added 1 M aqueous sodium hydroxide solution (2.2 ml),
Jꢂ11.0 Hz), 5.77 (1H, d, Jꢂ17.4 Hz), 6.50—7.20 (4H, m), 7.20—7.70 (7H,
and the mixture was stirred at room temperature for 6 h. The solvent was m), 7.80—8.10 (2H, m). IR (nujol) cmꢄ1: 1693, 1622. MS m/z: 495
evaporated under reduced pressure, and the mixture was extracted three [MꢅH]ꢅ. Anal. Calcd for C31H30N2O4·H2O: C, 72.64; H, 6.29; N, 5.47.
times with ethyl acetate (30 ml). The ethyl acetate layer was washed with Found: C, 72.29; H, 6.24; N, 5.48.
saturated brine (10 ml) and dried over Na2SO4. Ethyl acetate was evaporated
(S)-2-(4-Fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-
under reduced pressure. Diethyl ether was added to the obtained residue. 1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (32) A colorless solid,
The solid was collected by filtration to give 27 (356 mg, 74%) as a pale yel- mp 132—134 °C (dec.). 1H-NMR (CDCl3) d: 2.36 (3H, s), 2.94 (2H, t,
low solid. mp 115—118 °C (dec.). 1H-NMR (MeOH-d4) d: 2.95—3.20 (2H, Jꢂ6.4 Hz), 3.15 (2H, d, Jꢂ6.4 Hz), 3.45—4.00 (5H, m), 4.19 (2H, t,
m), 3.07 (3H, s), 3.40—4.20 (9H, m), 6.40—6.70 (4H, m), 6.92 (1H, d, Jꢂ6.4 Hz), 6.60 (1H, d, Jꢂ2.0 Hz), 6.75 (1H, dd, Jꢂ2.0, 8.6 Hz), 6.90—
Jꢂ8.4 Hz), 7.20—7.50 (3H, m), 7.90—8.15 (1H, m). IR (nujol) cmꢄ1: 1597,
1497. MS m/z: 440 [MꢅH]ꢅ.
7.55 (8H, m), 7.90—8.10 (2H, m). IR (nujol) cmꢄ1: 3398, 1614, 1555, 1510.
MS m/z: 487 [MꢅH]ꢅ. Anal. Calcd for C29H27FN2O4·H2O: C, 69.03; H,
Ethyl (S)-2-Benzyl-7-[2-(5-ethylpyridin-2-yl)ethoxy]-1,2,3,4-tetrahy- 5.79; N, 5.55. Found: C, 68.84; H, 5.75; N, 5.45.
droisoquinoline-3-carboxylate To a solution of 5-ethyl-2-pyridineethanol
(1.5 g, 9.92 mmol) and triethylamine (1.68 ml, 12.1 mmol) in CH2Cl2 (40 ml)
was added trifluoromethanesulfonic anhydride (2.0 ml, 11.9 mmol) under
ice-cooling, and the mixture was stirred at room temperature for 30 min. The
(S)-2-(3-Fluorobenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (33) A colorless solid,
mp 155—157 °C (dec.). 1H-NMR (DMSO-d6) d: 2.34 (3H, s), 2.70—3.10
(4H, m), 3.45—4.00 (5H, m), 4.14 (2H, t, Jꢂ6.4 Hz), 6.50—6.80 (2H, m),
reaction mixture was washed with water (30 ml), dried over Na2SO4, and 6.90—7.70 (8H, m), 7.90—8.10 (2H, m). IR (nujol) cmꢄ1: 1624, 1508. MS
then CH2Cl2 was evaporated under reduced pressure to give crude 5-ethyl-2- m/z: 487 [MꢅH]ꢅ. Anal. Calcd for C29H27FN2O4: C, 71.59; H, 5.59; N, 5.76.
pyridineethyl trifluoromethanesulfonate (2.81 g). Separately, to a solution of Found: C, 71.20; H, 5.70; N, 5.75.
ethyl (S)-2-benzyl-7-hydroxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate
(1.0 g, 3.21 mmol) in DMF (10 ml) was added sodium hydride (60% oil dis- benzyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (34) A color-
persion, 200 mg, 5.0 mmol) under ice-cooling and the mixture was stirred at
less solid, mp 106—110 °C. 1H-NMR (DMSO-d6) d: 2.33 (3H, s), 2.88 (2H,
(S)-7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(4-trifluoromethyl-
room temperature for 30 min to give a solution. Crude trifluoromethanesul- d, Jꢂ6.4 Hz), 2.90—3.20 (2H, m), 3.50—4.10 (5H, m), 4.13 (2H, t,
fonate was added to the above solution, and the mixture was stirred at room Jꢂ6.4 Hz), 6.59 (1H, s), 6.69 (1H, d, Jꢂ8.1 Hz), 7.03 (1H, d, Jꢂ8.1 Hz),
temperature for 30 min. Ethyl acetate (100 ml) was added to the reaction 6.55—7.80 (7H, m), 7.80—8.05 (2H, m). IR (nujol) cmꢄ1: 1692, 1620,

March 2008
343
1506. MS m/z: 537 [MꢅH]ꢅ. Anal. Calcd for C30H27F3N2O4·H2O: C, 64.97; 6.17 (1H, d, Jꢂ16.3 Hz), 6.45—6.85 (3H, m), 7.05 (1H, d, Jꢂ8.4 Hz), 7.34
H, 5.27; N, 5.05. Found: C, 64.98; H, 5.30; N, 5.02.
(S)-7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(3-trifluoromethyl-
(5H, s). IR (nujol) cmꢄ1: 3470, 1682, 1614, 1585, 1512. MS m/z: 447
[MꢅH]ꢅ. Anal. Calcd for C27H30N2O4·1.2H2O: C, 69.27; H, 6.98; N, 5.98.
benzyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (35) A color- Found: C, 69.24; H, 6.97; N, 6.03.
less solid, mp 138—140 °C (dec.). 1H-NMR (DMSO-d6) d: 2.33 (3H, s),
(S)-2-Benzyl-7-{2-[2-(3-butenyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4-
2.70—3.20 (4H, m), 3.50—4.30 (7H, m), 6.60 (1H, s), 6.69 (1H, d, tetrahydroisoquinoline-3-carboxylic Acid (45) A colorless solid, mp
Jꢂ8.1 Hz), 7.03 (1H, d, Jꢂ8.1 Hz), 6.30—7.80 (7H, m), 7.80—8.05 (2H, 87—89 °C. 1H-NMR (CDCl3) d: 2.23 (3H, s), 2.49 (2H, t, Jꢂ6.2 Hz),
m). IR (nujol) cmꢄ1: 1692, 1610, 1506. MS m/z: 537 [MꢅH]ꢅ. Anal. Calcd
2.65—2.90 (4H, m), 3.05—3.30 (2H, m), 3.75—4.50 (8H, m), 4.90—5.20
for C30H27F3N2O4·1.5H2O: C, 63.94; H, 5.37; N, 4.97. Found: C, 64.20; H, (2H, m), 5.65—6.10 (1H, m), 6.58 (1H, d, Jꢂ1.7 Hz), 6.75 (1H, dd, Jꢂ1.7,
5.15; N, 4.94.
8.2 Hz), 7.07 (1H, d, Jꢂ8.2 Hz), 7.35 (5H, s). IR (nujol) cmꢄ1: 3442, 1688,
(S)-2-(3-Acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]- 1614, 1578, 1508. MS m/z: 447 [MꢅH]ꢅ.
1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (36) A colorless solid,
Compounds 46—54 were prepared by a similar procedure to that de-
scribed in the synthesis of 20.
(S)-2-Isobutyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-
1
mp 147—150 °C (dec.). H-NMR (DMSO-d6) d: 2.33 (3H, s), 2.56 (3H, s),
2.70—3.20 (4H, m), 3.50—4.30 (5H, m), 3.97 (2H, s), 6.50—6.90 (2H, m),
7.02 (1H, d, Jꢂ8.4 Hz), 7.30—8.00 (9H, m). IR (nujol) cmꢄ1: 1682, 1620, tetrahydroisoquinoline-3-carboxylic Acid (46) A colorless solid, mp
1508. MS m/z: 511 [MꢅH]ꢅ. Anal. Calcd for C31H30N2O5·H2O: C, 70.44; 148—150 °C (dec.). 1H-NMR (CDCl3) d: 0.95 (3H, d, Jꢂ6.7 Hz), 1.01 (3H,
H, 6.10; N, 5.30. Found: C, 70.13; H, 6.18; N, 5.22.
d, Jꢂ7.0 Hz), 1.95—2.15 (1H, m), 2.36 (3H, s), 2.60—2.80 (2H, m), 2.94
(S)-2-(2-Acetylbenzyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]- (2H, t, Jꢂ6.7 Hz), 3.16 (2H, d, Jꢂ6.6 Hz), 3.70 (1H, t, Jꢂ6.6 Hz), 4.11 (2H,
1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (37) A blue solid, mp t, Jꢂ6.1 Hz), 6.60—6.90 (2H, m), 7.25—7.50 (3H, m), 7.49 (1H, d,
81—83 °C (dec.). 1H-NMR (DMSO-d6) d: 2.33 (3H, s), 2.36 (3H, s), 2.70— Jꢂ6.6 Hz), 7.85—8.10 (2H, m). IR (nujol) cmꢄ1: 1620. MS m/z: 435
3.20 (4H, m), 3.30—4.30 (5H, m), 6.57 (1H, d, Jꢂ2.0 Hz), 6.66 (1H, dd, [MꢅH]ꢅ.
Jꢂ2.0, 8.4 Hz), 7.00 (1H, d, Jꢂ8.4 Hz), 7.20—7.75 (7H, m), 7.75—8.10
(S)-2-Butyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic Acid (47) A pale yellow solid, mp
(2H, m). IR (nujol) cmꢄ1: 1668, 1643, 1614, 1504. MS m/z: 511 [MꢅH]ꢅ.
(S)-2-Benzyl-7-{2-[5-methyl-2-(thiophen-2-yl)oxazol-4-yl]ethoxy}- 154—157 °C. 1H-NMR (CDCl3) d: 0.88 (3H, t, Jꢂ6.6 Hz), 1.10—1.95 (4H,
1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (38) A colorless solid, m), 2.36 (3H, s), 2.75—3.40 (6H, m), 3.71 (2H, br t Jꢂ6.1 Hz), 3.95—4.25
mp 112—115 °C (dec.). 1H-NMR (DMSO-d6) d: 2.31 (3H, s), 2.70—3.10 (4H, m), 6.57—7.57 (6H, m), 7.80—8.10 (3H, m). IR (nujol) cmꢄ1: 3382,
(4H, m), 3.39 (2H, s), 3.40—4.00 (4H, m), 4.11 (2H, d, Jꢂ6.2 Hz), 6.59
1722, 1614, 1554, 1506. MS m/z: 435 [MꢅH]ꢅ. Anal. Calcd for
(1H, br s), 6.67 (1H, d, Jꢂ8.4 Hz), 7.01 (1H, d, Jꢂ8.4 Hz), 7.05—7.80 (3H, C26H30N2O4·0.4H2O: C, 70.69; H, 7.03; N, 6.34. Found: C, 70.77; H, 7.02;
m), 7.32 (5H, s). IR (nujol) cmꢄ1: 3423, 1616, 1578, 1510. MS m/z: 475 N, 6.28.
[MꢅH]ꢅ. Anal. Calcd for C27H26N2O4S·0.2H2O: C, 67.90; H, 5.56; N, 5.87.
Found: C, 67.87; H, 5.40; N, 5.93.
(S)-2-(2,2-Dimethylpropyl)-7-[2-(5-methyl-2-phenyloxazol-4-
yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (48) A pale
(S)-2-Benzyl-7-[2-(2-tert-butyl-5-methyloxazol-4-yl)ethoxy]-1,2,3,4- yellow powder, mp 85—88 °C (dec.). 1H-NMR (CDCl3) d: 0.96 (9H, s),
tetrahydroisoquinoline-3-carboxylic Acid (39) A colorless solid, mp 2.35 (3H, s), 2.46, 2.73 (2H, ABq, Jꢂ13.9 Hz), 2.93 (2H, t, Jꢂ6.7 Hz),
137—140 °C (dec.). 1H-NMR (DMSO-d6) d: 1.32 (9H, s), 2.23 (3H, s), 2.83 3.03—3.23 (2H, m), 3.57—3.78 (1H, m), 3.91, 4.18 (1H, ABq, Jꢂ15.4 Hz),
(2H, t, Jꢂ6.6 Hz), 3.18 (2H, d, Jꢂ5.9 Hz), 3.65—4.40 (7H, m), 5.60 (1H, 4.17 (2H, t, Jꢂ6.7 Hz), 5.60—6.05 (1H, br), 6.60 (1H, d, Jꢂ2.0 Hz), 6.73
br s), 6.56 (1H, br s), 6.73 (1H, br d, Jꢂ8.4 Hz), 7.06 (1H, d, Jꢂ8.4 Hz),
(1H, dd, Jꢂ2.0, 8.4 Hz), 7.04 (1H, d, Jꢂ8.4 Hz), 7.30—7.55 (3H, m),
7.20—7.55 (5H, m). IR (nujol) cmꢄ1: 3458, 1682, 1618, 1587, 1510. MS 7.80—8.10 (2H, m). IR (nujol) cmꢄ1: 3391, 3279, 1668, 1645, 1616, 1597,
m/z: 449 [MꢅH]ꢅ. Anal. Calcd for C27H32N2O4·H2O: C, 69.50; H, 7.35; N, 1497. MS m/z: 449 [MꢅH]ꢅ. Anal. Calcd for C27H32N2O4·0.6H2O: C,
6.00. Found: C, 69.59; H, 7.18; N, 6.04.
70.60; H, 7.28; N, 6.25. Found: C, 70.31; H, 7.32; N, 6.05.
(S)-2-Benzyl-7-[2-(2-isopropyl-5-methyloxazol-4-yl)ethoxy]-1,2,3,4-
(S)-2-Hexyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic Acid (40) A colorless solid, mp tetrahydroisoquinoline-3-carboxylic Acid (49) A colorless solid, mp
1
95—99 °C. H-NMR (DMSO-d6) d: 1.21 (6H, m), 2.19 (3H, s), 2.70—3.10 149—152 °C. 1H-NMR (CDCl3) d: 0.70—0.95 (3H, m), 1.05—1.40 (6H,
(5H, m), 3.50—4.20 (5H, m), 6.40—6.85 (2H, m), 7.01 (1H, d, Jꢂ8.1 Hz),
m), 1.50—1.90 (2H, m), 2.36 (3H, s), 2.70—3.30 (2H, m), 2.93 (2H, t,
7.34 (5H, br s). IR (nujol) cmꢄ1: 3456, 1684, 1614, 1576, 1510. MS m/z: 435 Jꢂ6.2 Hz), 3.15 (2H, d, Jꢂ6.4 Hz), 3.75 (1H, t, Jꢂ6.4 Hz), 4.00—4.40 (4H,
[MꢅH]ꢅ.
m), 6.10—6.35 (1H, br), 6.60—6.85 (2H, m), 7.06 (1H, d, Jꢂ8.4 Hz),
(S)-2-Benzyl-7-[2-(2-cyclopropyl-5-methyloxazol-4-yl)ethoxy]-1,2,3,4- 7.30—7.60 (3H, m), 7.80—8.10 (2H, m). IR (nujol) cmꢄ1: 1620. MS m/z:
tetrahydroisoquinoline-3-carboxylic Acid (41) A colorless solid, mp 463 [MꢅH]ꢅ. Anal. Calcd for C28H34N2O4·0.5H2O: C, 71.31; H, 7.48; N,
109—112 °C. 1H-NMR (DMSO-d6) d: 0.70—1.10 (4H, m), 1.80—2.20 (1H, 5.94. Found: C, 71.14; H, 7.38; N, 5.86.
m), 2.16 (3H, s), 2.60—2.85 (2H, m), 2.90—3.15 (2H, m), 3.50—4.20 (5H,
m), 6.50—6.80 (2H, m), 7.03 (1H, d, Jꢂ8.1 Hz), 7.34 (5H, s). IR (nujol)
cmꢄ1: 3470, 1684, 1618, 1583, 1510. MS m/z: 433 [MꢅH]ꢅ. Anal. Calcd
(S)-2-Allyl-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-tetrahy-
droisoquinoline-3-carboxylic Acid (50) A colorless solid, mp 133—
136 °C. 1H-NMR (DMSO-d6) d: 2.35 (3H, s), 2.70—3.15 (4H, m), 3.38 (2H,
for C26H28N2O4·0.2H2O: C, 71.60; H, 6.56; N, 6.42. Found: C, 71.43; H, d, Jꢂ6.2 Hz), 3.55—4.00 (3H, m), 4.16 (2H, t, Jꢂ6.6 Hz), 4.40—5.50 (1H,
6.58; N, 6.31. br) 5.00—5.40 (2H, m), 5.60—6.10 (1H, m), 6.65 (1H, s), 6.69 (1H, d,
(S)-2-Benzyl-7-{2-[2-(2,2-dimethylpropyl)-5-methyloxazol-4- Jꢂ8.1 Hz) 7.01 (1H, d, Jꢂ8.1 Hz), 7.35—7.65 (3H, m), 7.75—8.10 (2H, m).
yl]ethoxy}-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (42) A col-
IR (nujol) cmꢄ1: 3335, 1690, 1618, 1553, 1506. MS m/z: 419 [MꢅH]ꢅ.
orless powder, mp 75—78 °C (dec.). 1H-NMR (CDCl3) d: 0.95 (9H, s), 2.34 Anal. Calcd for C25H26N2O4·1.2H2O: C, 68.23; H, 6.50; N, 6.37. Found: C,
(3H, s), 2.55 (2H, s), 2.60—3.00 (2H, m), 3.00—3.30 (2H, m), 3.80—4.40 68.23; H, 6.50; N, 6.37.
(7H, m), 6.64 (1H, br s), 6.70 (1H, d, Jꢂ8.8 Hz), 7.02 (1H, d, Jꢂ8.8 Hz),
(S)-7-[2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy]-2-(2-propynyl)-1,2,3,4-
7.32 (5H, s), 7.80 (1H, br s). IR (nujol) cmꢄ1: 1722, 1614, 1568, 1506. MS tetrahydroisoquinoline-3-carboxylic Acid (51) A colorless solid, mp
m/z: 463 [MꢅH]ꢅ. Anal. Calcd for C28H34N2O4: C, 72.70; H, 7.41; N, 6.06. 109—111 °C. 1H-NMR (DMSO-d6) d: 2.00—6.40 (1H, br), 2.35 (3H, s),
Found: C, 72.45; H, 7.60; N, 5.92.
2.70—3.10 (4H, m), 3.10—3.25 (1H, m), 3.50—4.00 (5H, m), 4.17 (2H, t,
(S)-2-Benzyl-7-{2-[5-methyl-2-(2-methylpropenyl)oxazol-4-yl]ethoxy}- Jꢂ6.4 Hz), 6.66 (1H, s), 6.70 (1H, d, Jꢂ8.6 Hz), 7.01 (1H, d, Jꢂ8.6 Hz),
1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (43) A colorless solid, 7.30—7.70 (3H, m), 7.85—8.05 (2H, m). IR (nujol) cmꢄ1: 3383, 3306,
1
mp 109—111 °C. H-NMR (DMSO-d6) d: 1.89 (3H, s), 2.11 (3H, s), 2.27 3221, 1692, 1622, 1508. MS m/z: 417 [MꢅH]ꢅ. Anal. Calcd for
(3H, s), 2.79 (2H, t, Jꢂ6.1 Hz), 2.90—3.20 (2H, m), 3.50—4.00 (4H, m), C25H24N2O4·H2O: C, 69.11; H, 6.03; N, 5.45. Found: C, 69.03; H, 6.04; N,
3.93 (2H, s), 4.07 (2H, t, Jꢂ6.1 Hz), 5.99 (1H, s), 6.58 (1H, s), 6.67 (1H, d, 6.43.
Jꢂ8.2 Hz), 6.72 (1H, d, Jꢂ8.2 Hz), 7.33 (5H, s). IR (nujol) cmꢄ1: 3443,
3300, 1695, 1655, 1622, 1543, 1508. MS m/z: 447 [MꢅH]ꢅ. Anal. Calcd for
(S)-2-(2-Butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic Acid (52) A pale yellow solid, mp
C27H30N2O4·H2O: C, 69.81; H, 6.94; N,6.05. Found: C, 69.54; H, 6.91; N, 127—131 °C. 1H-NMR (DMSO-d6) d: 1.67 (3H, d, Jꢂ4.9 Hz), 2.35 (3H, s),
6.03.
2.70—3.10 (4H, m), 3.20—3.50 (2H, m), 3.50—4.00 (3H, m), 4.16 (2H, t,
(S)-2-Benzyl-7-{2-[2-(1-butenyl)-5-methyloxazol-4-yl]ethoxy}-1,2,3,4- Jꢂ6.4 Hz), 4.35—5.20 (1H, br), 5.25—5.90 (2H, m), 6.55—6.90 (2H, m),
tetrahydroisoquinoline-3-carboxylic Acid (44) A pale yellow solid, mp 7.01 (2H, d, Jꢂ8.1 Hz), 7.35—7.70 (3H, m), 7.75—8.10 (2H, m). IR (nujol)
1
98—100 °C. H-NMR (CDCl3) d: 1.07 (3H, t, Jꢂ7.5 Hz), 2.05—2.20 (1H, cmꢄ1: 3447, 3342, 1684, 1620, 1556. MS m/z: 433 [MꢅH]ꢅ. Anal. Calcd
m), 2.26 (3H, s), 2.50—3.00 (3H, m), 3.65—4.45 (7H, m), 5.92 (1H, br s), for C26H28N2O4·H2O: C, 69.31; H, 6.71; N, 6.22. Found: C, 69.10; H, 6.78;

344
Vol. 56, No. 3
7 d in male KK-Ay mice (30 weeks old). On the 7th day, a blood sample was
taken from the tail vein and plasma glucose and TG levels were determined.
In these experiments, plasma glucose and TG values were statistically com-
pared between the treated group and control group using Student’s t-test.
pꢃ0.05 was considered significant.
N, 6.20.
(S)-2-(3-Butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-1,2,3,4-
tetrahydroisoquinoline-3-carboxylic Acid (53) A pale yellow solid, mp
141—143 °C. 1H-NMR (DMSO-d6) d: 2.10—2.40 (2H, m), 2.35 (3H, s),
2.60—3.15 (6H, m), 3.50—4.00 (3H, m), 4.17 (2H, t, Jꢂ6.3 Hz), 4.40—
5.40 (1H, br), 4.85—5.25 (2H, m), 5.55—6.10 (1H, m), 6.50—6.85 (2H, m),
7.01 (1H, d, Jꢂ8.1 Hz), 7.35—7.70 (3H, m), 7.75—8.05 (2H, m). IR (nujol)
cmꢄ1: 3425, 1682, 1612, 1555. MS m/z: 433 [MꢅH]ꢅ. Anal. Calcd for
C26H28N2O4·H2O: C, 69.31; H, 6.71; N, 6.22. Found: C, 69.14; H, 6.65; N,
6.10.
(S)-2-(3-Methyl-2-butenyl)-7-[2-(5-methyl-2-phenyloxazol-4-
yl)ethoxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic Acid (54) A col-
orless solid, mp 132—134 °C. 1H-NMR (DMSO-d6) d: 1.61 (3H, s), 1.72
(3H, s), 2.35 (3H, s), 2.70—3.20 (4H, m), 3.39 (2H, d, Jꢂ7.0 Hz), 3.50—
4.01 (3H, m), 4.16 (2H, t, Jꢂ7.0 Hz), 4.35—5.60 (1H, br), 5.20—5.30
(1H, m), 6.67 (1H, s), 6.71 (1H, d, Jꢂ8.4 Hz), 7.02 (1H, d, Jꢂ8.4 Hz),
7.30—7.70 (8H, m), 7.75—8.10 (2H, m). IR (nujol) cmꢄ1: 3447, 3335,
1670, 1668, 1622, 1556, 1506. MS m/z: 447 [MꢅH]ꢅ. Anal. Calcd for
C27H30N2O4·1.2H2O: C, 69.27; H, 6.98; N, 5.98. Found: C, 69.34; H, 6.95;
N, 5.98.
Determination of Octanol–Water Partition Coefficient Compounds
were dissolved in 1 ml of octanol and mixed with 1 ml of Britton–Robinson
buffer (pH 7.0). The mixed solution was vigorously shaken at room tempera-
ture for 30 min and then centrifuged at 3000 r.p.m. for 10 min at room tem-
perature. Concentrations in the octanol fraction and buffer fraction were de-
termined using HPLC or LC-MS/MS. The HPLC equipment consisted of a
pump (PU-980, JASCO, Tokyo, Japan), UV detector (UV-970, JASCO),
autoinjector (AS-950, JASCO), and Cosmosil-5C18-MS-II column (5 mm,
4.6 mmꢆ150 mm, Nacalai Tesque, Kyoto, Japan). The LC-MS/MS system
with a Develosil-ODS-UG-5 column (5 mm, 2.0 mmꢆ100 mm, NOMURA
Chemical, Seto, Japan) was used (API2000 QTRAP LC/MS/MS system,
Applied Biosystems, Tokyo, Japan). The octanol–water partition coefficent
was calculated as a ratio of the concentration in the octanol fraction to that
in the buffer fraction. Log P was determined as the logarithm of the partition
coefficient.
PPARg Agonist Activity Full-length human PPARg1 plasmid
(GeneCopoeia, Inc., Maryland, U.S.A.), and human RXRa plasmid
(GeneCopoeia, Inc.) with reporter plasmid pGL3-PPREx4-tk-luc and pRL-
tk (Promega Corporation, Madison, WI, U.S.A.) were transfected to CV-1
cells (Dainippon Pharmaceutical Industries, Co., Ltd., Osaka, Japan) using
LipofectAMINE (Invitrogen Corporation, Carlsbad, CA, U.S.A.). The cells
were incubated for 24 h under 5% CO2 at 37 °C. The detached cells were fur-
ther incubated for 48 h in the presence or absence of the test compound in
Dulbecco’s modified Eagle’s medium (DMEM, Nissui Pharmaceutical, Co.,
Ltd., Tokyo, Japan) containing 0.1% fatty acid-free bovine serum albumin.
The medium was removed and then luciferase activities were determined
using a commercial kit (Dual-Luciferase Reporter Assay System, Promega
Corporation) and a microplate luminescence reader (Dainippon Pharmaceu-
tical Industries, Co., Ltd.).
Hypolipidemic Effects and Glucose Tolerance Improving Effects in
Male Zucker Fatty Rats Male Zucker fatty rats (8—12 weeks old, Kiwa
Laboratory Animals, Co., Ltd., Wakayama, Japan) were allocated to control
and treated groups. KY-021 and farglitazar were suspended in 0.5% methyl
cellulose solution and orally administered at 0.3—3 mg/kg for 7 d in male
Zucker fatty rats. A blood sample was taken from the external jugular vein
of non-fasted rats before the final administration and plasma TG was deter-
mined. Glucose (2 g/kg) was orally administered 24 h after the final adminis-
tration of KY-021 and farglitazar to fasted rats. A blood sample was then
taken before and 15, 30, 60, 120 and 180 min after the administration of glu-
cose, and plasma glucose levels were determined. The area under the curve
(AUC) of plasma glucose was measured. Percent decrease in TG and glucose
AUC in rats administered KY-021 and farglitazar was calculated by compari-
son with the mean value in control rats administered vehicle. Plasma TG and
glucose AUC values were statistically compared between the treated group
and control group using Student’s t-test. pꢃ0.05 was considered significant.
Plasma Concentration after Oral Administration of KY-021 and Far-
glitazar in Male ICR Mice and SD Rats Male ICR mice (6 weeks old,
Japan SLC, Inc., Hamamatsu, Japan) and male SD rats (7 weeks old, Japan
SLC, Inc.) were used. KY-021 and farglitazar at 10 mg/kg suspended in
0.5% methyl cellulose solution was orally administered and then a blood
sample was taken from the external jugular vein 0.5, 1, 3, 5 and 8 h after ad-
ministration in rats, and by heart puncture under ether-anesthesia 0.25, 0.5,
1, 3, 5 and 8 h after administration in mice. Plasma concentrations of each
drug were determined using HPLC system consisting of a pump (PU-980,
JASCO, Tokyo, Japan), UV detector (UV-970, JASCO), autoinjector (AS-
950, JASCO), and STR-ODS-II column (5 mm, 4.6 mmꢆ150 mm, Shimadzu
Techno-research, Kyoto, Japan). The maximal concentration (Cmax) and AUC
were calculated.
Toxicity Test of KY-021 Administered at 30 mg/kg for 10 Weeks in
Male SD Rats Male SD rats (6 weeks old, Charles River Japan, Inc.,
Kanagawa, Japan) were allocated to control and treated-groups. KY-021 and
farglitazar were suspended in 0.5% methylcellulose solution and adminis-
tered at 30 mg/kg/d for 10 weeks to the treated group, and vehicle to the
control group. The general condition was observed daily and body weight
was measured. The rats were anesthetized with pentobarbital (50 mg/kg, i.p.)
24 h after the final administration, and bled to death. After euthanasia, tho-
racic and abdominal organs, including periepididymal white adipose tissue,
were isolated and weighed, and hematological tests were performed.
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