Optimization of isochromanone based urotensin II receptor agonists

Article abstract of DOI:10.1016/j.bmc.2010.04.041

A series of novel isochromanone based urotensin II receptor agonists have been synthesized and evaluated for their activity using a functional cell based assay (R-SAT). Several potent and efficacious derivatives were identified with 3-(3,4-dichlorophenyl)-6,7-dimethyl-3-(2-dimethylaminoethyl)isochroman-1-one (28) being the most potent compound showing an EC₅₀-value of 51 nM, thereby being the most potent compound so far within the isochromanone series. In addition, two other heterocyclic systems (isochromanes and tetrahydroisoquinolinones) were investigated and these derivatives were found to be both potent and efficacious. The activity of the isochromane derivatives implies that the carbonyl group of the isochromanone is not necessary for activity. Furthermore it was found that the geometry of the heterocycles was more important for receptor interaction than the composition of the heteroatoms present.

Full text of DOI:10.1016/j.bmc.2010.04.041

Bioorganic & Medicinal Chemistry 18 (2010) 4844–4854
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Optimization of isochromanone based urotensin II receptor agonists
Fredrik Lehmann a, Erika A. Currier c, Roger Olsson b, Jian-Nong Ma c, Ethan S. Burstein c, Uli Hacksell c,
Kristina Luthman a,
*
a Department of Chemistry, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden
b ACADIA Pharmaceuticals AB, Medeon Science Park, SE-205 12 Malmö, Sweden
c ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Boulevard, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 November 2009
Revised 8 April 2010
Accepted 16 April 2010
Available online 1 June 2010
A series of novel isochromanone based urotensin II receptor agonists have been synthesized and evaluated
for their activity using a functional cell based assay (R-SAT). Several potent and efficacious derivatives were
identified with 3-(3,4-dichlorophenyl)-6,7-dimethyl-3-(2-dimethylaminoethyl)isochroman-1-one (28)
being the most potent compound showing an EC50-value of 51 nM, thereby being the most potent
compound so far within the isochromanone series. In addition, two other heterocyclic systems (isochrom-
anes and tetrahydroisoquinolinones) were investigated and these derivatives were found to be both potent
and efficacious. The activity of the isochromane derivatives implies that the carbonyl group of the isochro-
manone is not necessary for activity. Furthermore it was found that the geometry of the heterocycles was
more important for receptor interaction than the composition of the heteroatoms present.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Isochromanone
Isochromane
Tetrahydroisoquinolinone
Urotensin II
UT-receptor
Agonist
GRP14
SAR
1. Introduction
The most active compound in that study was the 6,7-dimethyl deriv-
ative FL68 (2) (Fig. 1).
The urotensin II receptor (UT, previously GRP14)1 and its natu-
ral peptide ligand urotensin II (UII) have over the last years
emerged as a potential therapeutic target.2,3 The UT/UII system
has been proposed to be involved in a variety of diseases, for exam-
ple, type 2 diabetes,4,5 cardiovascular diseases,3,6 and eclampsia.7
There are reports of non-peptidic UT modulators showing activity
in vivo, for example, SB-611812 which attenuates cardiac dysfunc-
tion in rats.8 Although there are examples of both peptide based
and non-peptidergic agonists9,10 and antagonists11,12 there is still
an urgent need for novel potent and selective non-peptidergic UT
modulators to thoroughly investigate the potential of UT as a drug
target.13
We have also investigated a series of similar but non-heterocyclic
derivatives and found that open chain amides were highly
active,9b,d,e and that it was advantageous to introduce substituted
phenyl groups in the 4-position on the benzamide moietyand allow-
ing sterically demanding substituents replacing the B-ring. The most
active compound in that series identified so far is the biphenylcarb-
oxamide N-[3-(dimethylamino)-1-(2-naphthyl)propyl]-4-(4-chlo-
rophenyl)benzamide (pEC50 7.36).9d In the present study we have
continued to explore the SAR around isochromanone based
UT-receptor ligands. This has been done by expanding the series of
In an earlier study9c we reported the initial structure–activity
relationships (SARs) around the isochromanone derivative
AC-7954 (1),9a the first non-peptidic UT receptor agonist reported
(Fig. 1). We found that the introduction of lipophilic substituents
in the aromatic ring denoted A, or large substituents in the 3-posi-
tion (replacements of ring B) of the isochromanone system was ben-
eficial for activity. The activity dropped, however when the alkyl
substituents on the basic nitrogen became larger than methyl.9c
* Corresponding author. Tel.: +46 31 786 9031; fax: +46 31 772 3840.
E-mail address: luthman@chem.gu.se (K. Luthman).
Figure 1. Compounds 1 (AC-7954) and 2 (FL68), examples of isochromanone based
urotensin II receptor agonists.
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.04.041

F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
4845
isochromanones to comprise derivatives with amino, methoxy and
phenyl substituents in the A-ring and larger biphenyl substituents
instead of the B-ring. We have also explored the effects of replacing
the isochromanone by other heterocyclic ring systems such as
isochromane or tetrahydroisoquinolinone, and of further modifying
the size of the substituents around the basic amino function.
2. Results and discussion
2.1. Chemistry
2.1.1. Synthesis of isochromanones
The isochromanone derivatives were synthesized via the dilith-
iation of a 2,N-dimethyl-benzamide followed by the addition of a
ketone and subsequent thermal ring closure (Scheme 1).9c,14 The
appropriate benzamides and b-aminoketones were synthesized
according to methods described below.
Scheme 1. Reagents and conditions: (a) n-BuLi 2.2 equiv, THF; (b) 1,2-dichloro-
benzene,
D. 15–79% yield (20 examples).
2.1.2. Synthesis of benzamides
Benzoic acids 3a–c were prepared by lithiation of the corre-
sponding aromatic bromides followed by the addition of solid car-
bon dioxide. This procedure proceeded smoothly producing the
desired acids in excellent yields (>99%) (Scheme 2). In case of the
4-bis-allylamino derivative 3a, 4-bromo-3-methyl-aniline was first
diallylated with allyl bromide in THF. After carboxylation, the
product was not isolated due to its zwitterionic character. Instead,
the crude product was directly converted to the corresponding
benzamide using standard amide coupling reagents (EDC, DMAP),
affording 4a in 14% yield over two steps.
The other benzoic acids were converted to their corresponding
methyl amides (Scheme 3) via reaction of the corresponding ben-
zoyl chlorides with methyl amine9c generating amides 4b–e in
moderate (49%) to good yields (72–99%).
The 4-phenyl derivative 4f was obtained via a Suzuki arylation
of 4e in 76% yield (Scheme 4).
2.1.3. Synthesis of b-amino ketones
The b-amino ketones 5a–h were produced via a microwave as-
sisted Mannich reaction (Scheme 5).15 In case of the bis-allylamino
derivatives 5f and 5g, they were synthesized by diallylation of the
corresponding 4- or 3-amino-acetophenone using allyl bromide in
THF prior to the Mannich reaction. The allyl-methylamine derivative
5i was obtained in excellent yield (94%) by dissolving 3,40-dichloro-
propiophenone in THF and adding allyl-methylamine (Scheme 5).
Scheme 2. Reagents and conditions: (a) n-BuLi CO2(s), THF, ꢁ78 °C; (b) allyl
bromide, K2CO3, THF, reflux, 24 h; (c) EDC, DMAP, CH3NH2ꢂHCl, THF, rt, 24 h.
2.1.4. Synthesis of isochromanones
A series of 3,4-dihydroisochromanone derivatives (6, 11–28)
was synthesized as previously described (Scheme 1).9c The
2-methylbenzamides 4a–d and 4f were dilithiated using n-BuLi
followed by addition of the appropriate ketone (5a–i). The result-
ing tertiary alcohols were not isolated, instead the crude product
mixtures were heated in 1,2-dichlorobenzene (ꢀ105 °C) to afford
the lactonization.14 The isolated yields of isochromanone deriva-
tives in this two-step reaction ranged between 15–79%, which
were similar to results previously reported for this type of reac-
tions.9a,c,14 All compounds were converted to their HCl or oxalate
salts for analysis and storage.
To study if smaller amino groups resulted in more active com-
pounds the N-allyl group of 6 was removed using a literature pro-
Scheme 3. Reagents and conditions: (a) SOCl2, NEt3, MeNH2, THF rt, 2 h.
cedure16 involving Pd(PPh3)4 to afford a
p-allyl complex which was
reduced by 1,3-dimethylbarbituric acid to afford 7 (Scheme 6).
2.1.5. Synthesis of isochromane derivatives
To investigate whether the carbonyl group in the isochroma-
none derivatives was necessary for activity it was desirable to re-
duce the lactone to acquire the corresponding isochromanes
(Scheme 7). This was accomplished by boron trifluoride etherate
For 2-methyl-1-naphthoic acid (to obtain 4b) other protocols were examined
(e.g., EDC, DMAP) but these failed to give better results and also required more
elaborate purification.

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F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
Scheme 4. Reagents and conditions: (a) Pd(PPh3)4 (5%), Cs2CO3, THF, 150 °C,
30 min.
Scheme 8. Reagents and conditions: (a) n-BuLi 2.2 equiv, THF; (b) H2SO4, 16 h,
29–68%.
Table 1
Results from in vitro testing of UII agonist activity of isochromanone derivatives with
variations in the amine moiety
Scheme 5. Reagents and conditions: (a) CH2O, HNMe2ꢂHCl, dioxane, 200 °C,
10 min; (b) allyl-methylamine, THF, rt, 24 h.
a
Compd
R
R0
R00
pEC50
Efficacyb
133
77 40
1 (AC-7954)
6
7
10
Methyl
Methyl
Methyl
Methyl
Methyl
Allyl
H
—
—
—
5.95 0.12
5.38 0.19
5.71 0.03
5.42 0.13
8
46
9
6
Methyl
Methyl
118
a
Results were determined in R-SAT assays and are expressed as pEC50-values, the
negative of the log EC50 in molarity. Results are the average standard deviations of
2–5 determinations of the EC50 where each compound was tested in eight doses in
triplicate.
Scheme 6. Reagents and conditions: (a) Pd(PPh3)4, 1,3-dimethylbarbituric acid,
CH2Cl2, rt, 16 h, 49%.
b
The % efficacy values are normalized to UII at 100%.
3. Pharmacological testing
Compounds 6–28 were tested for their agonistic properties at
human UII receptors using the functional R-SAT™ assay,18 the re-
sults are shown in Tables 1–4.
4. Structure–activity relationships
4.1. The amine moiety
Scheme 7. Reagents and conditions: (a) BF3OEt2, 30 equiv, NaBH4, THF, ꢁ78 °C,
16 h.
All natural UII peptide isoforms contain the amino acid triad
Trp7-Lys8-Tyr9 which is essential for activity. The amino function
in the Lys side chain has been proposed to form an ionic interaction
with Asp130 in the receptor, and using docking studies it was
implicated that 1 is interacting similarly with the receptor.12a
Guerrini et al. have shown that if the d-amino group of Lys8 in
UII is dimethylated the activity drops by 0.6 log units.12b To inves-
tigate whether the activity of 1 would increase if the tertiary amine
was converted to a secondary amine, compound 7 was synthe-
sized. However the demethylated 7 did not show higher potency
and was found to be considerably less efficacious than 1 (Table
1). In agreement with our previous findings the tertiary amine 6
with a larger allyl substituent also showed low activity (Table 1).
Interestingly, the quaternary ammonium iodide salt 10 showed
in THF followed by sodium borohydride reduction resulting in the
desired products 8a–c in modest yields (26–36%).
2.1.6. Synthesis of tetrahydroisoquinolinone derivatives
The tetrahydroisoquinolinone derivatives (9a–c) were synthe-
sized via the same intermediary tertiary alcohol as the isochroma-
nones,17 but instead of heating to afford the lactonization, the
resulting viscous oil was cooled and concd H2SO4 was added slowly
under vigorous stirring. After 18 h at room temperature the solu-
tion was carefully basified using 1 M NaOH to obtain the tetrahy-
droisoquinolinones in low to moderate yields (29–68%)
(Scheme 8).

F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
4847
Table 2
Table 4
Results from in vitro testing of UII agonist activity of isochromanone derivatives with
variations in the substitution pattern in the aromatic rings
Results from in vitro testing of UII agonist activity of isochromane and tetrahydro-
isoquinolinone derivatives
Efficacyb
a
Compd
R1
R2
pEC50
1 (AC-7954)
H
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
4-Cl-Ph
5.95 0.12 133
6.87 0.03 146 24
8
2c
6,7-Me
6-OMe
5-Me, 6-OMe
6-Bis-allylamino 4-Cl-Ph
6-Ph
Compd
R1
R2
R3
pEC50
Efficacy
11
12
13
14
15
16
17
18
19
20
21
22c
23
24
6.02 0.15 165
5.76 0.02 118
6.14 0.17 132
2
6
7
8a
8b
8c
9a
9b
9c
H
4-Cl-Ph
4-Cl-Ph
2-Naphthyl
—
—
—
—
—
—
Me
Me
i-Pr
6.30 0.49
6.16 0.06
6.58 0.39
5.64 0.06
5.93 0.05
5.65 0.08
110 24
6,7-diMe
6,7-diMe
H
5-OMe
H
47
49
3
2
4-Cl-Ph
4-Cl-Ph
NAd
NAd
152 15
151 30
145 17
7,8-(CH)4
5.94 0.11 124 19
H
H
H
H
H
H
H
H
H
3-Bis-allylamino 5.62 0.01 55 13
4-Bis-allylamino NAd NAd
6.17 0.01 172 13
aResults were determined in R-SAT assays and are expressed as pEC50-values, the
negative of the log EC50 in molarity. Results are the average standard deviations of
2–5 determinations of the EC50 where each compound was tested in eight doses in
triplicate.
3,4-diCl-Ph
3-Br-Ph
5.53 0.02 68
6.03 0.04 127
8
8
4-Br-Ph
4-C„C-Ph
4-OPh-Ph
4-Ph-Ph
NAd
NAd
bThe % efficacy values are normalized to UII at 100%.
5.94 0.26 54
3
NAd NAd
3-Ph-Ph
5.85 0.07 50 11
a
Results were determined in R-SAT assays and are expressed as pEC50-values, the
negative of the log EC50 in molarity. Results are the average standard deviations of
2–5 determinations of the EC50 where each compound was tested in eight doses in
triplicate.
b
The % efficacy values are normalized to UII at 100%.
Data taken from Ref. 9c.
NA = No detectable activity.
c
d
Table 3
As shown in FL68 (2, Fig. 1) introducing methyl substituents in
the aromatic moiety of the isochromanone scaffold is beneficial for
activity.9c To expand these findings and to gain more knowledge
about the topology of the UT-receptor binding site some com-
pounds containing larger and/or more flexible substituents in both
aromatic rings were synthesized. As is apparent from Table 2 the 6-
OMe (11), 5-Me,6-OMe (12) and the 6-bis-allylamino-(13) substi-
tuted compounds were approximately as potent as 1. Thus, bulky
substituents are tolerated as long as they are conformationally
flexible. This means that the inactivity of 14 might be explained
by the rigidity of the biphenyl system, suggesting that this com-
pound stretches too far out in a direction occupied by the receptor.
However, the naphthyl derivative 15 was equipotent with 1 indi-
cating that there is space available in this direction of the binding
pocket.
In the aromatic B-ring (Fig. 1) a derivative containing a 4-phen-
oxyphenyl group (as in 22) was equipotent with a 4-chlorophenyl
substituent (1) (Table 2).10c We therefore synthesized the corre-
sponding 4-biphenyl and 4-(2-phenylethynyl)phenyl derivatives
(23 and 21, respectively) to find that these were devoid of activity.
Hence, also in this position bulky substituents are tolerated as long
as they are flexible. However, the 3-substituted phenyl derivatives
(3-bis-allylaminophenyl (16) and 3-biphenyl (24)) were found to
be approximately equipotent in spite of the lack of flexibility in
24. The most beneficial substitution pattern turned out to be the
3,4-dichlorophenyl group as in derivative 18.
Results from in vitro testing of UII agonist activity of isochromanone derivatives with
variations in the 3-position
Efficacyb
146 24
a
Compd
R1
R2
pEC50
2c
6,7-diMe
6,7-diMe
6,7-diMe
6,7-diMe
6,7-diMe
4-Cl-Ph
6.87 0.03
6.83 0.12
5.54 0.05
5.28 0.01
7.29 0.36
25
26
27
28
2-Naphthyl
3-OMe-Ph
3,5-diOMe-Ph
3,4-diCl-Ph
126
149
0
7
156 10
98
7
a
Results were determined in R-SAT assays and are expressed as pEC50-values, the
negative of the log EC50 in molarity. Results are the average standard deviations of
2–5 determinations of the EC50 where each compound was tested in eight doses in
triplicate.
b
The % efficacy values are normalized to UII at 100%.
Data taken from Ref. 9c.
c
the same potency as 6 but retained most of the efficacy of 1. Taken
together, these results suggest that the dimethylamino group is
most advantageous for activity (Table 1).
4.2. Substitution in the aromatic rings
4.3. Additivity
The 6-phenyl-isochromanone derivative 14 was interesting to
synthesize for comparison with the corresponding highly active
non-heterocyclic derivatives.9b,d,e Interestingly, this compound
was totally devoid of activity (Table 2). This result might be ratio-
nalized by inspecting our previously suggested pharmacophore
model9b which showed a difference in the tilting of the aromatic
rings in 14 compared to that in the open chain amide FL104.
When combining the best features from our previous study9c
(e.g., 6,7-dimethyl substitution in ring A for potency and a 3-meth-
oxy group in ring B for efficacy, or substitution of the 4-Cl-phenyl
group for 2-naphthyl) (Table 3) it becomes clear that the effects are
not additive. For example, the methoxy analogue 26 is substan-

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F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
tially less potent but shows similar efficacy as the parent com-
pound 2. This trend is even more pronounced when considering
the 30,50-dimethoxy analogue 27 which again is less potent but as
efficacious as the parent compound. This lack of additivity is also
seen in the naphthyl derivative 25, which showed no improve-
ments over the 4-Cl-phenyl moiety. However, compound 28 with
6,7-dimethyl groups combined with the 3,4-dichlorophenyl sys-
tem in the 3-position was found to be the most potent compound
in this series so far, indicating that the substitution pattern in both
rings is important, but that it is difficult to predict which combina-
tions that are most advantageous.
Compound 28 was also tested using the R-SAT assay for its
selectivity towards the related somatostatin subreceptors sst-1
and sst-4. The results showed that 28 was selective for UII recep-
tors as it was inactive at sst-1 and acted as a significantly less po-
tent partial agonist at sst-4 (28: maximum effect of 31% at a top
5. Experimental procedures
5.1. General
All chemicals were purchased from Aldrich, Acros, Lancaster or
Maybridge and were used without purification. 1H (400 MHz) and
13C (100 MHz) NMR spectra were recorded in CDCl3 unless other-
wise stated using a JEOL JMN-ECP400 instrument. All reactions
were monitored by TLC (Merck Silica Gel 60 F254) and analyzed un-
der UV (254 nm). In case of flash chromatography, Merck Silica Gel
60 (230–400 mesh) was used. Melting points were recorded on a
Büchi melting point B-545 apparatus and are uncorrected. Elemen-
tal analyses were performed at Kolbe Analytishe Laboratorium,
Mülheim an der Ruhr, Germany. Accurate masses were measured
at Biovitrum using an Agilent MSD-TOF (G1969A) connected to
an Agilent 1100 HPLC system (G1312A, G4061AA, G1367A,
G1316A) with a diode array detector (G1315B). The instrument is
calibrated by Agilent ES-TOF tuning mix and spectra are acquired
in positive electrospray mode.
concentration of 3 lM).
4.4. Other heterocycles
On similar, but non-heterocyclic derivatives it has been found
that open chain amides, esters, ureas and carbamates were active,
but not ether or sulfonamide derivatives.9b In the present study we
therefore wanted to examine if the carbonyl group per se is impor-
tant for receptor activation. To do this, the lactone moiety of iso-
chromanones 1, 2 and 25 was reduced to the corresponding
isochromane derivatives (8a–c).
Somewhat surprisingly, it seems that the carbonyl group of 1 is
not necessary for activity as 8a is equipotent and as efficacious as
its parent compound. Compounds 8b and 8c showed somewhat
lower activity than their respective isochromanone derivatives,
but are still among the most potent compounds identified in this
study. Three tetrahydroisoquinolinone derivatives (9a–c) were
also evaluated for their agonistic effect at the UT-receptor (Table
4). From the results it can be concluded that there is space left in
the binding pocket for substituents in the 2-position of the central
heterocyclic scaffold as 9a–c were about as active as 1 and even
somewhat more efficacious. We therefore conclude that the geom-
etry of the bicyclic systems is more important for activity than the
heteroatoms present in the ring system.
5.2. Allylation of 4-bromo-3-methyl-aniline to obtain N,N-
diallyl-4-bromo-3-methyl-aniline
Cs2CO3 (25.8 g, 79 mmol) and allyl bromide (6.8 mL, 79 mmol)
were added to a solution of 4-bromo-3-methyl-aniline (6.7 g,
36 mmol) in THF (250 mL) and the mixture was heated to reflux
for 48 h. NaOH (1 M) (250 mL) was added and the resulting solu-
tion was extracted twice with EtOAc. The combined organic phases
were washed (water and brine) and concentrated. The resulting
yellow oil was purified using flash chromatography (20% EtOAc
in hexane) to afford 8.8 g (97%) of the title product as a slightly yel-
low oil. 1H NMR d 2.31 (s, 3H), 3.87 (d, 4H, J = 4.8 Hz), 5.12–5.17 (m,
4H), 5.77–5.87 (m, 2H), 6.39 (dd, 1H, J = 4.5, 9.9 Hz), 6.54 (d, 1H,
J = 4.5 Hz), 7.26 (d, 1H, J = 9.9 Hz). 13C NMR d 23.0, 52.9 (2 C:s),
110.9, 111.7, 114.6, 116.2 (2 C:s), 132.5, 133.7 (2 C:s), 138.0, 148.0.
5.3. General procedure for the synthesis of benzoic acids
3b and c
The aryl bromide was dissolved in THF, cooled to ꢁ78 °C and n-
BuLi (1.2 equiv) was added dropwise. To the resulting solution was
added a large excess of solid carbon dioxide and the solution was
slowly heated to rt. The solution was acidified using 1 M HCl and ex-
tracted twice with EtOAc. The combined organic phases were washed
(water and brine) and concentrated to afford the desired product.
Based on the results presented above and those obtained in our
earlier studies9 the SAR of isochromanone and related compounds
so far can be summarized as shown in Figure 2.
The results show that various heterocyclic scaffolds were toler-
ated and more importantly that the carbonyl function of the isochro-
manones is not necessary for activity. It can also be concluded that
the dimethylamino group is superior to either larger or smaller ste-
ric bulk around the amino group. Finally it was also shown that the
substitution pattern in both aromatic rings was of vital importance,
although the best combination of substituents was difficult to
predict.
5.3.1. 2-Methyl-1-naphthoic acid (3b)
1-Bromo-2-methyl-naphthalene (2.2 g, 10 mmol) yielded 1.85 g
(quant) of the title compound as white crystals. Mp 110.1–
111.5 °C. 1H NMR (CD3OD) d 2.51 (s, 3H), 7.74 (d, 1H, J = 8.4 Hz),
7.41–7.51 (m, 2H), 7.78 (d, 1H, J = 8.4 Hz), 7.82 (dd, 1H, J = 1.1,
Figure 2. Summary of the SAR of isochromanone and related compounds.

F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
4849
8.1 Hz), 7.88 (d, 1H, J = 8.4 Hz). 13C NMR (CD3OD) d 18.8, 124.4,
5.4.4. 4-Bromo-2,N-dimethyl-benzamide (4e)
125.1, 126.4, 127.7, 128.0, 128.6, 129.6, 131.6, 131.8, 132.6, 173.3.
4-Bromo-2-methyl-benzoic acid (2.5 g, 11.6 mmol) yielded
2.6 g (99%) of the title compound as light yellow crystals. Mp
113.1–113.6 °C. 1H NMR d 2.38 (s, 3H), 2.95 (d, 3H, J = 5.0 Hz),
5.99 (s, 1H), 7.15–7.18 (m, 1H), 7.27–7.31 (m, 1H), 7.35–7.37 (m,
1H). 13C NMR d 19.5, 26.6, 123.8, 128.2, 128.7, 133.8, 135.3,
138.4, 169.8.
5.3.2. 4-Methoxy-2-methyl-benzoic acid (3c)
4-Bromo-3-methyl-anisole (5.0 g, 25 mmol) yielded 4.6 g
(quant) of the title compound as white crystals. Mp 179.9–
181.2 °C. 1H NMR (CD3OD) d 2.56 (s, 3H), 3.82 (s, 3H), 6.77–6.81
(m, 2H), 7.92 (dd, 1H, J = 2.9, 7.3 Hz). 13C NMR (CD3OD) d 21.1,
54.4, 110.6, 116.6, 121.8, 132.9, 142.9, 162.6, 169.3.
5.4.5. 2,N-Dimethyl-4-phenyl-benzamide (4f)
Compound 4e (0.1 g, 0.44 mmol), phenylboronic acid (0.07 g,
0.6 mmol), Cs2CO3 (0.33 g, 1 mmol) and Pd(PPh3)4 (0.05 g,
0.044 mmol) were dissolved in THF (4 mL) and heated to 150 °C
for 30 min using microwave heating. The reaction mixture was fil-
tered through CeliteÒ and extracted using 1 M NaOH and EtOAc.
The phases were separated and the water phase was extracted
with EtOAc. The organic phases were combined, washed with
water and brine and concentrated. The crude product was purified
using flash chromatography (5% EtOAc in hexane) to yield 75 mg
(76%) of the title compound as a viscous oil. 1H NMR d 2.52 (s,
3H), 3.02 (d, 3H, J = 4.8 Hz), 5.89 (br s, 1H), 7.35–7.47 (m, 5H),
7.57–7.68 (m, 3H). 13C NMR d 20.6, 27.3, 124.9, 127.7 (2 C:s),
127.8, 128.3, 129.3 (2 C:s), 130.3, 132.5, 135.7, 140.8, 143.2, 171.1.
5.3.3. 4-Diallylamino-(2,N-dimethyl)benzamide (4a)
4-Bromo-N,N-diallyl-3-methyl-aniline (8.7 g, 33 mmol) was
dissolved in THF and cooled to ꢁ78 °C and n-BuLi (1.2 equiv) was
added dropwise. To the resulting solution was added a large excess
solid carbon dioxide and the solution was slowly heated to rt.
Aqueous saturated NH4Cl was added to the solution and the mix-
ture was extracted twice with EtOAc. The combined organic phases
were washed (water and brine) and concentrated. The crude prod-
uct (3a) was dissolved in THF and EDC (6.3 g, 33 mmol), DMAP
(0.34 g, 3 mmol) and methylamine (2 M in THF) (20 mL, 40 mmol)
were added and the mixture was stirred for 48 h. NaOH (1 M) was
added and the mixture was extracted twice with EtOAc. The com-
bined organic phases were washed (water and brine) and concen-
trated. The crude oil was purified using flash chromatography
(CH2Cl2/MeOH/triethylamine; 94.9:5:0.1) to afford the title com-
pound (1.1 g, 14%) as slightly brown oil that slowly solidified. 1H
5.5. General procedure for the synthesis of aminoketones 5a–h
The acetophenone, paraformaldehyde and dimethylamine
hydrochloride (1:1:1 counting on the monomer of paraformalde-
hyde) were dissolved in dioxane (10 mL/3 mmol acetophenone)
and heated under microwave irradiation (200 °C for 10 min). The
mixture was poured into saturated aqueous NaHCO3 and extracted
twice with EtOAc. The combined organic phases were washed
(water and brine) and concentrated. The residue was purified using
flash chromatography (CH2Cl2/MeOH/triethylamine; 94.9:5:0.1) to
afford to desired product.
NMR
d 2.43 (s, 3H), 2.96 (d, 3H, J = 5.2 Hz), 3.93 (d, 4H,
J = 4.8 Hz), 5.12–5.18 (m, 4H), 5.71 (br s, 1H), 5.79–5.88 (m, 2H),
6.45–6.48 (m, 2H), 7.21 (d, 1H, J = 1.1 Hz). 13C NMR d 26.9, 30.4,
52.7 (2 C:s), 109.1, 114.4, 116.4 (2 C:s), 123.8, 128.7, 133.5 (2
C:s), 138.5, 149.9, 154.0.
5.4. General procedure for the synthesis of benzamides 4b–e
The benzoic acid was dissolved in THF (75 mL/g), triethylamine
(4 equiv) and SOCl2 (1.2 equiv) were added and the mixture was
stirred for 10 min. Methylamine (1.5 equiv) was added and the
mixture was stirred for an additional 15 min. Then NaOH (1 M)
(twice the volume THF) was added and the resulting mixture
was extracted twice with EtOAc. The combined organic phases
were washed (water and brine) and concentrated to afford the de-
sired product.
5.5.1. 3-Dimethylamino-1-(4-biphenyl)propan-1-one (5a)
4-Phenylacetophenone (1.2 g, 6 mmol), paraformaldehyde
(0.18 g, 6 mmol) and dimethylamine hydrochloride (0.49 g,
6 mmol) yielded 0.63 g (41%) of the title compound as a colorless
oil. 1H NMR d 2.32 (s, 6H), 2.80 (t, 2H, J = 7.2 Hz), 3.20 (t, 2H,
J = 7.2 Hz), 7.38–7.48 (m, 3H), 7.62 (d, 2H, J = 7.2 Hz), 7.69 (d, 2H,
J = 8.8 Hz), 8.04 (d, 2H, J = 8.8 Hz). 13C NMR d 37.2, 45.8 (2 C:s),
54.6, 127.5 (3 C:s), 128.4 (2 C:s), 128.9 (2 C:s), 129.2 (2 C:s),
135.8, 140.0, 145.9, 198.9.
5.4.1. 2,N-Dimethyl-naphthalene-carboxamide (4b)
Compound 3b (2.4 g, 13 mmol) yielded 1.3 g (49%) of the title
compound as an off-white solid. Mp 177.7–178.6 °C. 1H NMR d
2.48 (s, 3H), 3.11 (d, 3H, J = 4.8 Hz), 5.83 (br s, 1H), 7.29 (d, 1H,
J = 8.4 Hz), 7.40–7.49 (m, 2H), 7.76–7.80 (3H). 13C NMR d 19.7,
26.7, 124.6, 125.5, 126.9, 128.0, 128.4, 128.9, 130.2, 131.7, 132.2,
134.0, 170.7.
5.5.2. 3-Dimethylamino-1-(4-(2-phenylethynyl)phenyl)propan-
1-one (5b)
4-(2-Phenylethynyl)acetophenone (1.2 g, 6 mmol), paraformal-
dehyde (0.18 g, 6 mmol) and dimethylamine hydrochloride
(0.49 g, 6 mmol) afforded 0.42 g (24%) of the title compound as a
light brown oil. 1H NMR d 2.35 (s, 6H), 2.83 (t, 2H, J = 6.8 Hz),
3.21 (t, 2H, J = 6.8 Hz), 7.36–7.40 (m, 2H), 7.54–7.57 (m, 3H), 7.62
(d, 2H, J = 8.8 Hz), 7.96 (d, 2H, J = 8.8 Hz). 13C NMR d 36.9, 45.6 (2
C:s), 54.4, 88.8, 93.0, 122.8, 128.3 (2 C:s), 128.5, 128.7 (2 C:s),
129.1, 132.0 (4 C:s), 136.0, 198.3.
5.4.2. 4-Methoxy-2,N-dimethyl-benzamide (4c)
Compound 3c (4.2 g, 25 mmol) yielded 3.2 g (72%) of the title
compound as an off-white solid. Mp 96.1–97.2 °C. 1H NMR d 2.45
(s, 3H), 2.97 (d, 3H, J = 5.1 Hz), 3.80 (s, 3H), 5.70 (br s, 1H), 6.89
(dd, 1H, J = 2.6, 8.0 Hz), 6.73 (d, 1H, J = 2.6 Hz), 7.31 (d, 1H,
J = 8.0 Hz). 13C NMR d 20.4, 26.7, 55.3, 110.8, 116.6, 128.6, 129.0,
138.6, 160.5, 170.5.
5.5.3. 1-(3-Bromophenyl)-3-dimethylamino-propan-1-one (5c)
3-Bromoacetophenone (1.2 g, 6 mmol), paraformaldehyde
(0.18 g, 6 mmol) and dimethylamine hydrochloride (0.49 g,
6 mmol) afforded 0.55 g (34%) of the title compound as a yellow
oil. 1H NMR d 2.28 (s, 6H), 2.74 (t, 2H, J = 7.0 Hz), 3.11 (t, 2H,
J = 7.0 Hz), 7.35 (dd, 1H, J = 6.2, 8.0 Hz), 7.68 (dd, 1H, J = 0.7,
8.0 Hz), 7.87 (d, 1H, J = 6.2 Hz), 8.08 (d, 1H, J = 0.7 Hz). 13C NMR d
37.0, 45.6 (2 C:s), 54.3, 123.1, 126.7, 130.2, 131.2, 136.0, 138.6, 197.8.
5.4.3. 4-Methoxy-2,3,N-trimethyl-benzamide (4d)
4-Methoxy-2,3-dimethyl-benzoic acid (3.6 g, 20 mmol) yielded
3.0 g (78%) of the title compound as white crystals. Mp 169.5–
170.1 °C. 1H NMR d 2.14 (s, 3H), 2.32 (s, 3H), 2.97 (s, 3H), 3.82 (s,
3H), 5.68 (br s, 1H), 6.67 (d, 1H, J = 8.4 Hz), 7.16 (d, 1H,
J = 8.4 Hz). 13C NMR d 11.7, 16.8, 26.8, 55.6, 107.1, 124.9, 126.2,
130.2, 135.9, 158.5, 171.6.

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F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
5.5.4. 1-(4-Bromophenyl)-3-dimethylamino-propan-1-one (5d)
4-Bromoacetophenone (1.2 g, 6 mmol), paraformaldehyde
(0.18 g, 6 mmol) and dimethylamine hydrochloride (0.49 g, 6 mmol)
yielded 0.50 g (31%) of the title compound as a yellow oil. 1H NMR d
2.31 (s, 6H), 2.78 (t, 2H, J = 7.4 Hz), 3.14 (t, 2H, J = 7.4 Hz), 7.60 (d,
2H, J = 8.1 Hz), 7.82 (d, 2H, J = 8.1 Hz). 13C NMR d 36.8, 45.5 (2 C:s),
54.2, 128.4, 129.6 (2 C:s), 132.0 (2 C:s), 135.6, 198.3.
extracted twice with EtOAc. The combined organic phases were
washed with water and brine and concentrated to afford the title
compound as a colorless oil (11.1 g, 94%). 1H NMR d 2.29 (s, 3H),
2.84 (t, 2H, J = 7.2 Hz), 3.06 (d, 2H, J = 6.4 Hz), 3.14 (t, 2H,
J = 7.2 Hz), 5.14–5.22 (m, 2H), 5.80–5.89 (m, 1H), 7.44 (d, 2H,
J = 8.6 Hz), 7.90 (d, 2H, J = 8.6 Hz). 13C NMR d 37.0, 42.4, 52.1,
61.3, 118.1, 129.2 (2 C:s), 129.7 (2 C:s), 135.4, 135.6, 139.7, 198.3.
5.5.5. 1-(3,4-Dichlorophenyl)-3-dimethylamino-propan-1-one
(5e)
5.5.10. 3-(4-Chlorophenyl)-3-(2-trimethylammoniumethyl)
isochroman-1-one iodide (10)
3,4-Dichloroacetophenone (3 g, 16 mmol), paraformaldehyde
(0.48 g, 16 mmol) and dimethylamine hydrochloride (1.3 g, 16 mmol)
afforded 1.4 g (36%) of the title compound as a yellow oil. 1H NMR d
2.27 (s, 6H), 2.73 (t, 2H, J = 7.0 Hz), 3.09 (t, 2H, J = 7.0 Hz), 7.53 (d, 1H,
J = 8.2 Hz), 7.76 (dd, 1H, J = 1.8, 8.2 Hz), 8.02 (d, 1H, J = 1.8 Hz). 13C
NMR d 36.9, 45.6 (2 C:s), 54.1, 127.2, 130.2, 130.8, 133.4, 136.5,
137.7, 196.8.
Compound 1 (AC-7954) (0.13 g, 0.4 mmol) was dissolved in THF
and MeI (0.03 mL, 0.5 mmol) was added. After 3 h, the solvent was
concentrated and the residue crystallized from MeOH/diethyl ether
to yield 0.07 g (37%) of the title compound as a hygroscopic solid.
1H NMR (CD3OD) d 2.75–2.82 (m, 1H), 3.02–3.09 (m, 1H), 3.17–
3.24 (m, 1H), 3.39 (s, 9H), 3.68–3.78 (m, 3H), 7.23–7.31 (m, 4H),
7.45–7.48 (m, 3H), 7.94 (d, 1H, J = 7.7 Hz). 13C NMR (CD3OD) d
36.3, 38.6, 54.3 (3 C:s), 63.4, 84.1, 124.3, 126.8 (2 C:s), 128.0,
128.3, 129.5 (2 C:s), 130.0, 134.6, 134.9, 136.8, 138.5, 164.4. Anal.
Calcd for (C20H23ClINO2): C, 50.9; H, 4.9; N, 3.0. Found: C, 50.6;
H, 5.2; N, 2.9.
5.5.6. 1-(4-Bis-allylaminophenyl)-3-dimethylamino-propan-1-
one (5f)
4-Bis-allylamino-acetophenone (1.3 g, 6 mmol), paraformalde-
hyde (0.18 g, 6 mmol) and dimethylamine hydrochloride (0.49 g,
6 mmol) yielded 0.30 g (18%) of the title compound as a yellow
oil. 1H NMR d 2.54 (s, 6H), 3.13 (t, 2H, J = 7.0 Hz), 3.29 (t, 2H,
J = 7.0 Hz), 3.92 (s, 4H), 5.05–5.14 (m, 4H), 5.74–5.81 (m, 2H),
6.58 (d, 2H, J = 8.8 Hz), 7.78 (d, 2H, J = 8.8 Hz). 13C NMR d 34.2,
44.2 (2 C:s), 52.6 (2 C:s), 53.8, 111.1 (2 C:s), 116.6 (2 C:s), 124.4,
130.6 (2 C:s), 132.4 (2 C:s), 152.6, 194.8.
5.6. General procedure for the synthesis of isochromanones 6,
11–21 and 23–28
The benzamide was dissolved in THF (15 mL/g) and n-BuLi
(2.2 equiv) was added slowly at room temperature. The ketone
was dissolved in THF (15 mL/g) and added to the intense red solu-
tion and the mixture was stirred for 30 min. The reaction was
poured into saturated aqueous NH4Cl (twice the THF volume)
and extracted twice with EtOAc. The combined organic phases
were washed with water and brine and concentrated. The crude
oil was dissolved in 1,2-dichlorobenzene and heated to 105 °C for
48 h. After cooling, the solution was diluted with CH2Cl2 and ap-
plied directly to a flash column. After flash chromatography
(CH2Cl2/MeOH/triethylamine; 94.9:5:0.1) the fractions containing
product were pooled and concentrated and the resulting oil was
dissolved in methanol. After filtration, HClether or 1 equiv of oxalic
acid was added to the filtrate. The resulting solid was recrystallized
from MeOH/diethyl ether to afford the desired compound.
5.5.7. 1-(3-Bis-allylaminophenyl)-3-dimethylamino-propan-1-
one (5g)
Cs2CO3 (33 g, 100 mmol) and allyl bromide (7 mL, 80 mmol)
were added to a solution of 3-acetylaniline (5 g, 37 mmol) in
100 mL DMF and the mixture was heated to 100 °C for 16 h. Brine
(twice the volume of DMF) was added and the resulting mixture
was extracted twice with EtOAc. The combined organic phases were
washed (water and brine) and concentrated to afford 3-acetyl-N,N-
diallylaniline as a yellow oil (6.7 g, 84%). 1H NMR (CD3OD) d 2.56 (s,
3H), 3.96 (d, 4H, J = 4.4 Hz), 5.14–5.19 (m, 4H), 5.80–5.90 (m, 2H),
6.85–6.89 (m, 1H), 7.22–7.28 (m, 2H). The product (1.3 g, 6 mmol)
was then reacted with paraformaldehyde (0.18 g, 6 mmol) and
dimethylamine hydrochloride (0.49 g, 6 mmol) according to the
general procedure to afford 0.25 g (15%) of the title compound as a
yellow oil. 1H NMR d 2.39 (s, 6H), 2.89 (t, 2H, J = 6.6 Hz), 3.23 (t,
2H, J = 6.6 Hz), 3.96 (d, 4H, J = 4.8 Hz), 5.12–5.19 (m, 4H), 5.80–
5.89 (m, 1H), 6.85–6.89 (m, 1H), 7.23–7.28 (m, 3H). 13C NMR d
36.4, 45.1 (2 C:s), 52.9 (2 C:s), 54.2, 111.1, 116.4 (3 C:s), 117.4,
129.3, 133.5 (2 C:s), 137.5, 148.8, 199.1.
5.6.1. 3-(2-(Allylmethylamino)ethyl)-3-(4-chlorophenyl)
isochroman-1-one oxalate (6)
2,N-Dimethyl-benzamide (3.3 g, 22 mmol) and 5i (5.0 g,
21 mmol) yielded 2.4 g (32%) of the title compound as a yellow
oil which was converted to the corresponding oxalate salt, isolated
as a yellow oil. 1H NMR (CD3OD) d 2.51–2.66 (m, 2H), 2.77 (s, 3H),
2.88–2.96 (m, 1H), 3.29–3.35 (m, 1H), 3.60 (d, 1H, J = 16.5 Hz), 3.66
(d, 1H, J = 16.5 Hz), 3.73 (d, 2H, J = 7.3 Hz), 5.46–5.52 (m, 2H), 5.83–
5.94 (m, 1H), 7.25–7.30 (m, 4H), 7.38 (d, 2H, J = 8.8 Hz), 7.48–7.52
(m, 1H), 7.88 (dd, 1H, J = 1.1, 8.0 Hz). 13C NMR (CD3OD) d 35.8, 37.2,
38.9, 50.3, 57.9, 84.2, 124.6, 125.2, 126.6, 126.8 (2 C:s), 127.6,
128.0, 128.7 (2 C:s), 129.3, 133.8, 134.4, 137.6, 139.5, 164.8,
165.9. Anal. Calcd for (C23H24ClNO6ꢂH2O): C, 59.6; H, 5.7; N, 3.0.
Found: C, 59.5; H, 5.9; N, 2.9.
5.5.8. 1-(3,5-Dimethoxyphenyl)-3-dimethylamino-propan-1-
one (5h)
3,5-Dimethoxyacetophenone (2.5 g, 14 mmol), paraformalde-
hyde (0.45 g, 14 mmol) and dimethylamine hydrochloride (1.2 g,
14 mmol) afforded 0.7 g (21%) of the title compound as a yellow
oil. 1H NMR d 2.32 (s, 6H), 2.79 (t, 2H, J = 7.3 Hz), 3.14 (t, 2H,
J = 7.3 Hz), 3.82 (s, 6H), 6.64 (d, 1H, J = 2.2 Hz), 7.08 (d, 2H,
J = 2.2 Hz). 13C NMR d 36.8, 45.4 (2 C:s), 54.3, 55.6 (2 C:s), 105.5,
105.9 (2 C:s), 138.8, 161.0 (2 C:s), 198.6.
5.6.2. 3-(4-Chlorophenyl)-3-(2-dimethylaminoethyl)-6-
methoxy-isochroman-1-one oxalate (11)
Benzamide 4c (0.80 g, 4.4 mmol) and 1-(4-chlorophenyl)-3-
dimethylamino-propan-1-one (0.46 g, 2.2 mmol) yielded 0.86 g
(54%) of the title compound as a yellow oil, which was converted
to the corresponding oxalate salt. Mp 93.5–94.8 °C. 1H NMR
(CD3OD) d 2.43–2.58 (m, 3H), 2.84 (s, 6H), 2.89–2.96 (m, 1H),
3.56 (d, 1H, J = 16.8 Hz), 3.61 (d, 1H, J = 16.8 Hz), 3.82 (s, 3H),
6.82 (d, 1H, J = 1.1 Hz), 6.85 (d, 1H, J = 8.8 Hz), 7.35 (d, 2H,
5.5.9. 3-(Allylmethylamino)-1-(4-chlorophenyl)propan-1-one
(5i)
To a solution of 3,40-dichloro-propiophenone (10 g, 50 mmol) in
THF (250 mL) was added triethylamine (8.6 mL, 60 mmol) and al-
lyl-methylamine (5 mL, 50 mmol) and the solution was stirred
18 h. The reaction was then poured into 1 M NaOH (300 mL) and

F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
4851
J = 9.0 Hz), 7.39 (d, 2H, J = 9.0 Hz), 7.85 (dd, 1H, J = 1.1, 8.8 Hz). 13C
NMR (CD3OD) d 36.3, 37.3, 42.3 (2 C:s), 52.7, 54.8, 83.8, 112.4,
113.5, 116.7, 126.6 (2 C:s), 128.7 (2 C:s), 131.8, 133.9, 139.4,
140.1, 164.9, 165.2. Anal. Calcd for (C22H24ClNO3): C, 58.7; H, 5.4;
N, 3.1. Found: C, 58.6; H, 5.3; N, 3.0.
129.4, 129.5, 131.2, 133.0, 133.2, 135.8, 140.6, 140.7, 164.8. Anal.
Calcd for (C25H24ClNO6): C, 63.9; H, 5.1; N, 3.0. Found: C, 64.0; H,
5.1; N, 2.9.
5.6.7. 3-(3-Bis-allylaminophenyl)-3-(2-dimethylaminoethyl)
isochroman-1-one HCl (16)
5.6.3. 3-(4-Chlorophenyl)-3-(2-dimethylaminoethyl)-6-methoxy-
5-methyl-isochroman-1-one oxalate (12)
2,N-Dimethyl-benzamide (0.40 g, 2.7 mmol) and 5g (0.70 g,
2.7 mmol) yielded 0.3 g (28%) of the title compound as a yellow
oil, which was converted to the corresponding HCl salt. Mp
190.1–191.8 °C. 1H NMR (CD3OD) d 2.60–2.66 (m, 2H), 2.88 (s,
3H), 2.91 (s, 3H), 3.00–3.07 (m, 1H), 3.34–3.41 (m, 1H), 3.69 (d,
1H, J = 16.5 Hz), 3.81 (d, 1H, J = 16.5 Hz), 4.23 (d, 4H, J = 7.0 Hz),
5.24–5.32 (m, 4H), 5.60–5.70 (m, 2H), 7.31–7.35 (m, 1H), 7.38–
7.40 (m, 2H), 7.49–7.57 (m, 4H), 7.65 (s, 1H), 7.89 (d, 1H,
J = 7.4 Hz). 13C NMR (CD3OD) d 36.4, 36.7, 42.3, 42.4, 52.8, 59.3 (2
C:s), 84.0, 119.0 (2 C:s), 121.6 (2 C:s), 124.4, 124.7, 126.0, 127.0,
127.6, 128.1, 129.4, 130.8, 134.5, 137.5, 139.4, 143.6, 164.6. Anal.
(C25H30N2O2ꢂ2HClꢂ2H2O): C, 60.1; H, 7.3; N, 5.6. Found: C, 60.2;
H, 7.3; N, 5.8.
Benzamide 4d (0.80 g, 4.1 mmol) and 1-(4-chlorophenyl)-3-
dimethylamino-propan-1-one (0.43 g, 2.1 mmol) yielded 0.61 g
(79%) of the title compound as a yellow oil, which was converted
to the corresponding oxalate salt. Mp 198.1–199.0 °C. 1H NMR
(DMSO-d6) d 2.13 (s, 3H), 2.38–2.44 (m, 2H), 2.67 (s, 6H), 2.72–
2.79 (m, 1H), 3.08–3.15 (m, 1H), 3.37 (d, 1H, J = 16.9 Hz), 3.75 (d,
1H, J = 16.9 Hz), 3.81 (s, 3H), 6.93 (d, 1H, J = 8.8 Hz), 7.39 (s, 4H),
7.73 (d, 1H, J = 8.8 Hz). 13C NMR (DMSO-d6) d 11.5, 34.5, 37.0,
42.9 (2 C:s), 52.4, 56.4, 83.6, 109.9, 117.4, 123.5, 127.5 (2 C:s),
129.3 (2 C:s), 129.8, 133.0, 138.0, 141.2, 162.1, 164.6, 164.9. Anal.
Calcd for (C23H26ClNO7): C, 59.6; H, 5.6; N, 3.0. Found: C, 59.4; H,
5.7; N, 3.0.
5.6.8. 3-(4-Bis-allylaminophenyl)-3-(2-dimethylaminoethyl)
isochroman-1-one HCl (17)
5.6.4. 6-(Bis-allylamino)-3-(4-chlorophenyl)-3-(2-dimethylamino
ethyl)isochroman-1-one HCl (13)
2,N-Dimethyl-benzamide (0.11 g, 0.7 mmol) and 5f (0.17 g,
0.6 mmol) yielded 0.16 g (65%) of the title compound as a yellow
oil, which was converted to the corresponding HCl salt. Mp
178.0–179.3 °C. 1H NMR (CD3OD) d 2.53–2.62 (m, 2H), 2.86 (s,
3H), 2.88 (s, 3H), 2.98–3.06 (m, 1H), 3.33–3.40 (m, 1H), 3.66 (d,
1H, J = 16.8 Hz), 3.72 (d, 1H, J = 16.8 Hz), 4.14 (d, 4H, J = 6.6 Hz),
5.26–5.30 (m, 4H), 5.67–5.77 (m, 2H), 7.30–7.33 (m, 2H), 7.42–
7.44 (d, 2H, J = 8.4 Hz), 7.51–7.55 (m, 1H), 7.59 (d, 2H, J = 8.4 Hz),
7.88 (dd, 1H, J = 0.7, 8.3 Hz). 13C NMR (CD3OD) d 36.4, 36.8, 42.3,
42.4, 52.8, 58.6 (2 C:s), 84.1, 121.5 (2 C:s), 126.8, 127.1 (3 C:s),
127.3, 127.4, 127.5 (2 C:s), 128.0 (2 C:s), 128.3, 129.3, 134.4,
137.5, 164.7. Anal. Calcd for (C25H30N2O2ꢂ2HClꢂ1.5H2O): C, 61.2;
H, 7.2; N, 5.7. Found: C, 60.9; H, 6.8; N, 5.7.
Benzamide 4a (1.1 g, 4.5 mmol) and 1-(4-chlorophenyl)-3-
dimethylamino-propan-1-one (0.95 g, 4.5 mmol) yielded 0.44 g
(23%) of the title compound which was converted to the corre-
sponding oxalate salt, obtained as a yellow oil. 1H NMR (CD3OD)
d 2.45–2.55 (m, 2H), 2.81 (s, 6H), 2.87–2.94 (m, 1H), 3.24–3.28
(m, 1H), 3.46 (d, 2H, J = 8.5 Hz), 3.49 (d, 2H, J = 8.5 Hz), 3.98 (d,
4H, J = 4.4 Hz), 5.06–5.15 (m, 4H), 5.79–5.87 (m, 2H), 6.48 (d, 1H,
J = 2.2 Hz), 6.56 (dd, 1H, J = 2.2, 9.2 Hz), 7.30 (d, 2H, J = 8.4 Hz),
7.38 (d, 2H, J = 8.4 Hz), 7.66 (d, 1H, J = 9.2 Hz). 13C NMR (CD3OD)
d 36.3, 37.8, 42.3 (2 C:s), 52.3 (2 C:s), 52.8, 83.4, 109.4, 110.8,
110.9, 115.5 (2 C:s), 126.7 (2 C:s), 128.6 (2 C:s), 131.4, 132.5 (2
C:s), 133.6, 139.4, 139.8, 153.4, 165.4, 165.9. Anal. Calcd for
(C27H31ClN2O6ꢂ1.5H2O): C, 59.8; H, 6.3; N, 5.2. Found: C, 60.0; H,
6.2; N, 5.0.
5.6.9. 3-(3,4-Dichlorophenyl)-3-(2-dimethylaminoethyl)
isochroman-1-one HCl (18)
5.6.5. 3-(4-Chlorophenyl)-3-(2-dimethylaminoethyl)-6-phenyl-
isochroman-1-one oxalate (14)
2,N-Dimethyl-benzamide (0.84 g, 5.7 mmol) and 5e (0.7 g,
2.8 mmol) yielded 0.17 g (17%) of the title compound as a yellow
oil, which was converted to the corresponding HCl salt. 1H NMR
(CD3OD) d 2.60–2.85 (m, 9H), 3.13–3.22 (m, 1H), 3.41 (d, 1H,
J = 16.5 Hz), 3.49 (d, 1H, J = 16.5 Hz), 7.18 (d, 1H, J = 7.7 Hz), 7.25–
7.29 (m, 1H), 7.33–7.37 (m, 1H), 7.43 (d, 1H, J = 6.3 Hz), 7.48–
7.53 (m, 2H), 8.02 (d, 1H, J = 7.3 Hz), 12.85 (br s, 1H). 13C NMR
(CD3OD) d 36.2, 36.7, 42.5, 42.6, 52.0, 84.0, 124.8, 126.2, 128.0,
128.3, 128.7, 129.8, 131.3, 131.5, 132.2, 135.2, 138.2, 142.8,
164.0. Anal. Calcd for (C19H20Cl3NO2): C, 57.0; H, 5.0; N, 3.5. Found:
C, 57.1; H, 5.1; N, 3.6.
Benzamide 4f (0.12 g, 0.5 mmol) and 1-(4-chlorophenyl)-3-
dimethylaminopropan-1-one (0.11 g, 0.5 mmol) yielded 0.05 g
(23%) of the title compound which was converted to the corre-
sponding oxalate salt isolated as a yellow oil. 1H NMR (CD3OD) d
2.49–2.59 (m, 2H), 2.84 (s, 6H), 2.86–2.96 (m, 2H), 3.67 (d, 1H,
J = 16.1 Hz), 3.71 (d, 1H, J = 16.1 Hz), 7.32–7.45 (m, 7H), 7.57–
7.65 (m, 4H), 7.97 (d, 1H, J = 8.0 Hz). 13C NMR (CD3OD) d 36.4,
37.3, 42.2 (2 C:s), 57.8, 84.1, 123.2, 126.1, 126.3, 126.8 (2 C:s),
127.0 (2 C:s), 128.4, 128.8 (2 C:s), 128.9 (2 C:s), 130.0, 133.9,
138.2, 139.2, 139.4, 147.4, 164.7, 165.1. Anal. Calcd for
(C27H26ClNO6): C, 65.4; H, 5.3; N, 2.8. Found: C, 65.3; H, 5.2; N, 2.9.
5.6.10. 3-(3-Bromophenyl)-3-(2-dimethylaminoethyl)
isochroman-1-one HCl (19)
5.6.6. 2-(4-Chlorophenyl)-2-(2-dimethylaminoethyl)-1,2-
dihydro-3-oxa-phenanthren-4-one oxalate (15)
2,N-Dimethyl-benzamide (1.3 g, 8.5 mmol) and 5c (2.1 g,
8.5 mmol) yielded 0.7 g (21%) of the title compound as a yellow
oil, which was converted to the corresponding HCl salt, isolated as
a brown oil. 1H NMR (CD3OD) d 2.53–2.61 (m, 2H), 2.85 (s, 3H),
2.88 (s, 3H), 2.94–3.01 (m, 1H), 3.32–3.39 (m, 1H), 3.64 (d, 1H,
J = 16.5 Hz), 3.69 (d, 1H, J = 16.5 Hz), 7.22–7.27 (m, 1H), 7.32–7.35
(m, 2H), 7.40–7.42 (m, 2H), 7.52–7.56 (m, 1H), 7.61 (s, 1H), 7.92 (d,
1H, J = 8.1 Hz). 13C NMR (CD3OD) d 36.5, 37.0, 42.1, 42.4, 52.7, 83.7,
122.8, 123.9, 124.4, 127.6, 127.9, 128.2, 129.4, 130.5, 131.2, 134.5,
137.5, 143.2, 164.7. Anal. Calcd for (C19H21BrClNO2ꢂ2H2O): C, 51.0;
H, 5.6; N, 3.1. Found: C, 49.6; H, 5.6; N, 2.8.
Benzamide 4b (0.5 g, 2.5 mmol) and 1-(4-chlorophenyl)-3-dim-
ethylaminopropan-1-one (0.52 g, 2.5 mmol) yielded 0.35 g (37%) of
the title compound which was converted to the corresponding
oxalate salt isolated as a yellow oil. 1H NMR (DMSO-d6) d 2.40–
2.49 (m, 2H), 2.68 (s, 6H), 2.73–2.80 (m, 1H), 3.11–3.15 (m, 1H),
3.82 (d, 1H, J = 16.9 Hz), 3.88 (d, 2H, J = 16.9 Hz), 7.35 (d, 2H,
J = 8.8 Hz), 7.42–7.48 (m, 3H), 7.53–7.57 (m, 1H), 7.63–7.69 (m,
1H), 7.94 (d, 1H, J = 8.1 Hz), 8.14 (d, 1H, J = 8.4 Hz), 9.02 (d, 1H,
J = 8.4 Hz). 13C NMR (DMSO-d6) d 36.8, 38.3, 43.0 (2 C:s), 52.5,
83.3, 119.5, 125.6, 126.4, 126.8, 127.6 (2 C:s), 129.2 (2 C:s),

4852
F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
5.6.11. 3-(4-Bromophenyl)-3-(2-dimethylaminoethyl)
isochroman-1-one HCl (20)
126.5, 127.2, 127.8, 128.7, 128.8, 129.9, 132.8, 133.0, 135.1, 136.5,
137.8, 144.7, 165.7. Anal. Calcd for (C25H27ClNO2): C, 73.2; H, 6.9; N,
3.4. Found: C, 73.3; H, 6.8; N, 3.5.
2,N-Dimethyl-benzamide (1.3 g, 8.5 mmol) and 5d (2.1 g,
8.5 mmol) yielded 1.4 g (42%) of the title compound as a yellow oil,
which was converted to the corresponding HCl salt, isolated as a
brown oil. 1H NMR (CD3OD) d 2.47–2.61 (m, 2H), 2.86 (s, 6H), 2.91–
2.99 (m, 1H), 3.30–3.37 (m, 1H), 3.63 (d, 1H, J = 16.5 Hz), 3.68 (d,
1H, J = 16.5 Hz), 7.30–7.35 (m, 4H), 7.48 (d, 2H, J = 8.8 Hz), 7.52–
7.55 (m, 1H), 7.91 (d, 1H, J = 7.3 Hz). 13C NMR (CD3OD) d 36.5, 37.1,
42.3, 52.8, 84.1, 122.0, 124.5, 127.0 (2 C:s), 127.6, 127.9, 129.3,
131.8 (2 C:s), 134.5, 137.5, 139.8, 164.8. Anal. (C19H21BrClNO2ꢂH2O):
C, 53.2; H, 5.4; N, 3.3. Found: C, 53.0; H, 5.0; N, 3.2.
5.6.16. 3-(2-Dimethylaminoethyl)-3-(3-methoxyphenyl)-6,7-
dimethyl-isochroman-1-one HCl (26)
2,4,5,N-Tetramethyl-benzamide(0.75 g, 4.3 mmol)and3-dimeth-
ylamino-1-(3-methoxy-phenyl)propan-1-one (0.45 g, 2.1 mmol)
yielded 0.22 g (15%) of the title compound as a yellow oil, which
was converted to the corresponding HCl salt. 1H NMR (CD3OD) d
2.20 (s, 3H), 2.22 (s, 3H), 2.57–2.83 (m, 9H), 3.14–3.22 (m, 1H),
3.33–3.42 (m, 2H), 3.77 (s, 3H), 6.74 (d, 1H, J = 6.2 Hz), 6.86–6.97
(m, 3H), 7.21 (dd, 1H, J = 8.0, 8.1 Hz), 7.73 (s, 1H), 12.60 (br s, 1H).
13C NMR (CD3OD) d 19.4, 20.2, 36.5, 39.0, 42.6, 44.1, 53.5, 55.4, 83.8,
111.0, 113.5, 117.1, 121.9, 129.1, 130.3, 130.7, 134.1, 136.7, 141.8,
144.6, 160.1, 164.8. Anal. Calcd for (C22H27ClNO3): C, 67.8; H, 7.2; N,
3.6. Found: C, 67.9; H, 7.2; N, 3.6.
5.6.12. 3-(2-Dimethylaminoethyl)-3-(4-(2-phenylethynyl)
phenyl)isochroman-1-one HCl (21)
2,N-Dimethyl-benzamide (0.22 g, 1.5 mmol) and 5b (0.41 g,
1.5 mmol) yielded 0.21 g (35%) of the title compound as a yellow
oil, which was converted to the corresponding HCl salt, isolated
as a yellow oil. 1H NMR (CD3OD) d 2.54–2.62 (m, 2H), 2.83 (s,
3H), 2.88 (s, 3H), 2.94–3.02 (m, 1H), 3.29–3.33 (m, 1H), 3.62 (d,
1H, J = 16.5 Hz), 3.70 (d, 1H, J = 16.5 Hz), 7.25–7.32 (m, 5H), 7.43–
7.51 (m, 7H), 7.89 (d, 1H, J = 7.0 Hz). 13C NMR (CD3OD) d 36.5,
37.1, 42.2, 42.5, 52.8, 84.3, 87.9, 89.9, 122.8, 123.2, 124.6, 125.4
(2 C:s), 127.6, 128.0, 128.3 (2 C:s), 128.4, 129.4, 131.3 (2 C:s),
131.7 (2 C:s), 134.5, 137.6, 140.8, 164.9. HRTofMS 395.1884
(C27H25NO2 requires 395.1885).
5.6.17. 3-(3,5-Dimethoxyphenyl)-6,7-dimethyl-3-(2-
dimethylaminoethyl)isochroman-1-one HCl (27)
2,4,5,N-Tetramethyl-benzamide (0.65 g, 3.6 mmol) and 5h
(0.45 g, 1.8 mmol) yielded 0.30 g (43%) of the title compound as a
yellow oil, which was converted to the corresponding HCl salt. Mp
244.5–246.0 °C. 1H NMR (CD3OD) d 2.22 (s, 3H), 2.24 (s, 3H), 2.61–
2.80 (m, 9H), 3.12–3.21 (m, 1H), 3.35 (s, 2H), 3.76 (s, 6H), 6.30 (d,
1H, J = 2.2 Hz), 6.46 (d, 1H, J = 2.2 Hz), 6.90 (s, 1H), 7.75 (s, 1H),
12.65 (br s, 1H). 13C NMR (CD3OD) d 19.4, 20.2, 36.4, 39.0, 42.5,
44.2, 53.5, 55.6 (2 C:s), 83.8, 99.7, 103.2 (2 C:s), 121.8, 129.0,
130.8, 134.0, 136.6, 142.6, 144.5, 161.4 (2 C:s), 164.8. Anal. Calcd
for (C23H29ClNO4): C, 65.8; H, 7.2; N, 3.3. Found: C, 65.7; H, 7.1; N, 3.4.
5.6.13. 3-(2-Dimethylaminoethyl)-3-(4-biphenyl)isochroman-1-
one HCl (23)
2,N-Dimethyl-benzamide (0.30 g, 2.0 mmol) and 5a (0.50 g,
2.0 mmol) yielded 0.38 g (51%) of the title compound as a yellow
oil, which was converted to the corresponding HCl salt, isolated
as a yellow oil. 1H NMR (CD3OD) d 2.59–2.64 (m, 2H), 2.85 (s,
3H), 2.88 (s, 3H), 2.96–3.01 (m, 1H), 3.33–3.40 (m, 1H), 3.66 (d,
1H, J = 16.5 Hz), 3.75 (d, 1H, J = 16.5 Hz), 7.27–7.38 (m, 6H), 7.46–
7.58 (m, 6H), 7.91 (d, 1H, J = 7.7 Hz). 13C NMR (CD3OD) d 36.9,
37.3, 42.2, 42.5, 52.9, 84.5, 124.7, 125.7 (2 C:s), 126.6 (2 C:s),
127.2 (2 C:s), 127.5, 127.6, 128.1, 128.7 (2 C:s), 129.4, 134.5,
137.8, 139.4, 139.8, 140.8, 165.3. HRTofMS 371.1884 (C25H25NO2
requires 371.1885).
5.6.18. 3-(3,4-Dichlorophenyl)-6,7-dimethyl-3-(2-dimethyl
aminoethyl)isochroman-1-one HCl (28)
2,4,5,N-Tetramethyl-benzamide (0.35 g, 2 mmol) and 1-(3,4-
dichlorophenyl)-3-dimethyl-aminopropan-1-one (0.5 g, 2 mmol)
yielded 0.2 g (26%) of the title compound as a yellow oil, which
was converted to the corresponding HCl salt. 1H NMR (CD3OD) d
2.23 (s, 3H), 2.27 (s, 3H), 2.49–2.55 (m, 2H), 2.86 (s, 6H), 2.96–
2.99 (m, 1H), 3.29–3.31 (m, 1H), 3.56 (s, 2H), 7.09 (s, 1H), 7.34
(dd, 1H, J = 2.2, 8.4 Hz), 7.49 (d, 1H, J = 8.4 Hz), 7.59 (d, 1H,
J = 2.2 Hz), 7.68 (s, 1H). 13C NMR (CD3OD) d 18.0, 18.8, 36.3, 36.6,
42.5 (2 C:s), 52.6, 83.5, 121.8, 125.0, 127.3, 128.9, 130.0, 130.8,
132.8, 134.7, 136.1, 136.8, 141.7, 145.1, 164.9. Anal. Calcd for
(C21H27Cl2NOꢂ0.5H2O): C, 57.6; H, 5.8; N, 3.2. Found: C, 58.0; H,
5.4; N, 3.0.
5.6.14. 3-(2-Dimethylaminoethyl)-3-(3-biphenyl)isochroman-1-
one HCl (24)
2,N-Dimethyl-benzamide (0.25 g, 1.0 mmol) and 1-(3-biphenyl)-
3-dimethylamino-propan-1-one (0.15 g, 1.0 mmol) yielded 0.21 g
(57%) of the title compound as a yellow oil, which was converted to
the corresponding HCl salt, isolated as a yellow oil. 1H NMR (CD3OD)
d 2.61–2.65 (m, 2H), 2.85 (s, 3H), 2.87(s, 3H), 2.99–3.02 (m, 1H), 3.32–
3.41 (m, 1H), 3.68 (d, 1H, J = 16.5 Hz), 3.79 (d, 1H, J = 16.5 Hz), 7.29–
7.35 (m, 3H), 7.39–7.44 (m, 4H), 7.48–7.54 (m, 4H), 7.63 (d, 1H,
J = 0.8 Hz), 7.92 (d, 1H, J = 7.7 Hz). 13C NMR (CD3OD) d 36.8, 37.3,
42.2, 42.5, 52.9, 84.6, 123.7, 124.0, 124.7, 126.6, 126.8 (2 C:s), 127.5,
128.0, 128.7, 129.3, 134.5, 137.9, 140.3, 141.2, 141.9, 165.3. HRTofMS
371.1890 (C25H25NO2 requires 371.1885).
5.6.19. 3-(4-Chlorophenyl)-3-(2-methylaminoethyl)
isochroman-1-one HCl (7)
1,3-Dimethylbarbituric acid (0.62 g, 3.9 mmol) and Pd(PPh3)4
(0.09 g, 0.08 mmol) were added to
a solution of 6 (0.28 g,
0.78 mmol) in CH2Cl2, and the mixture was stirred at rt for 18 h.
The mixture was filtered through Celite and concentrated. The
crude product was dissolved in 1 M HCl and washed twice with
EtOAc. The water phase was basified using solid NaOH (pH 14)
and extracted twice with EtOAc. The combined organic phases
were washed with water and brine and concentrated to yield
120 mg (49%) of the title compound which was converted to the
corresponding HCl salt isolated as a yellow oil. 1H NMR (CD3OD)
d 2.41–2.54 (m, 2H), 2.66 (s, 3H), 2.84–2.89 (m, 1H) 3.11–3.16
(m, 1H), 3.62 (d, 1H, J = 16.5 Hz), 3.69 (d, 1H, J = 16.5 Hz), 7.29–
7.34 (m, 4H), 7.41 (d, 2H, J = 6.8 Hz), 7.51–7.56 (m, 1H), 7.90 (d,
1H, J = 7.7 Hz). 13C NMR (CD3OD) d 32.5, 37.0, 38.0, 44.1, 84.4,
124.5, 126.8 (2 C:s), 127.6, 128.0, 128.7 (2 C:s), 129.4, 133.9,
134.5, 137.6, 139.5, 164.9. Anal. Calcd for (C18H19Cl2NO2ꢂ0.5H2O):
C, 59.8; H, 5.6; N, 3.9. Found: C, 59.4; H, 5.4; N, 3.7.
5.6.15. 3-(2-Dimethylaminoethyl)-6,7-dimethyl-3-(2-
naphthyl)isochroman-1-one HCl (25)
2,4,5,N-Tetramethyl-benzamide (0.56 g, 3.2 mmol)and3-dimeth-
ylamino-1-(2-naphthyl)propan-1-one (0.55 g, 2.4 mmol) yielded
0.18 g (20%) of the title compound as a yellow oil, which was con-
verted to the corresponding HCl salt. 1H NMR (CD3OD) d 2.14 (s,
3H), 2.20 (s, 3H), 2.61–2.65 (m, 2H), 2.83 (s, 6H), 2.88–2.94 (m, 1H),
3.32–3.40 (m, 1H), 3.62 (d, 1H, J = 16.5 Hz), 3.73 (d, 1H, J = 16.5 Hz),
7.07 (s, 1H), 7.43–7.48 (m, 2H), 7.52 (dd, 1H, J = 1.8, 8.4 Hz), 7.65 (s,
1H), 7.77–7.79 (m, 2H), 7.83–7.85 (m, 2H). 13C NMR (CD3OD) d 17.9,
18.8, 36.5, 37.1, 42.3 (2 C:s), 53.0, 84.6, 122.1, 122.3, 124.5, 126.4,

F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
4853
5.7. General procedure for reduction of isochromanones to
isochromanes 8a–c
viscous oil was cooled (ꢁ15 °C) and stirred vigorously. Conc. sulfu-
ric acid (10 mL/g) was added slowly and the mixture was stirred
over night. Aqueous NaOH (1 M) was carefully added until pH
>12. Then EtOAc was added and the phases were separated. The
water phase was extracted twice with EtOAc. The combined organ-
ic phases were washed with water and brine and concentrated. The
residue was purified using flash chromatography (CH2Cl2/MeOH/
triethylamine; 94.9:5:0.1) to afford the pure tetrahydroisoquinoli-
none, which was converted to the corresponding HCl salt.
Sodium borohydride (4 equiv) was added to a solution of the iso-
chromanone (1 equiv) and boron trifluoride etherate (30 equiv) in
THF (3 mL) at 0 °C under nitrogen. The reaction mixture was stirred
for 6 h at rt., and then refluxed for 13 h. The reaction was carefully
quenched by addition of aqueous saturated NH4Cl (10 mL). Satu-
rated aqueous NaHCO3 was added and the mixture was extracted
twice with EtOAc. The combined organic phases were washed with
water and brine, dried over MgSO4, filtered and concentrated. The
residue was purified using flash chromatography (CH2Cl2/MeOH/
triethylamine; 94.9:5:0.1). The fractions containing product were
pooled and concentrated to afford the desired product, which was
converted to the corresponding HCl or oxalic acid salt.
5.8.1. 3-(4-Chlorophenyl)-3-(2-dimethylaminoethyl)-3,4-
dihydro-2-methyl-2H-isoquinolin-1-one HCl (9a)
2,N-Dimethyl-benzamide (1.0 g, 6.7 mmol) and 1-(4-chloro-
phenyl)-3-dimethylamino-propan-1-one
(0.70 g,
3.3 mmol)
yielded 0.57 g (50%) of the title compound, which was converted
to the corresponding HCl salt. Mp 179.0–179.9 °C. 1H NMR
(CD3OD) d 2.76–2.81 (m, 2H), 2.87 (s, 3H), 2.90 (s, 3H), 3.01–3.13
(m, 1H), 3.34–3.42 (m, 1H), 3.49 (s, 3H), 3.83 (d, 1H, J = 16.8 Hz),
3.94 (d, 1H, J = 16.8 Hz), 7.38 (d, 2H, J = 8.8 Hz), 7.44 (d, 2H,
J = 8.8 Hz), 7.48–7.55 (m, 2H), 7.73–7.77 (m, 1H), 8.01 (d, 1H,
J = 7.7 Hz). 13C NMR (CD3OD) d 29.0, 35.5, 36.4, 42.0, 42.4, 52.2,
89.2, 119.7, 126.8 (2 C:s), 127.5, 128.6, 129.2 (2 C:s), 129.4,
134.8, 136.4, 136.8, 136.9, 167.3. HRTofMS 342.1505 (C20H23ClN2O
requires 342.1499).
5.7.1. 3-(4-Chlorophenyl)-3-(2-dimethylaminoethyl)
isochromane HCl (8a)
Compound 1 (AC-7954) (0.28 g, 0.9 mmol), sodium borohydride
(0.13 g, 3.4 mmol) and boron trifluoride etherate (3.62 g,
25.5 mmol) yielded 78 mg (26%) of the title product as white crys-
tals. Mp 58–60 °C. 1H NMR d 2.26–2.50 (m, 2H), 2.51–2.81 (m, 7H),
2.91–3.26 (m, 3H), 4.69 (d, 1H, J = 16.0 Hz), 4.85 (d, 1H, J = 16.0 Hz),
6.90–7.40 (m, 8H). 13C NMR d 35.1, 38.4, 43.0, 53.8, 63.9, 75.5,
124.2, 126.7, 127.1 (3 C:s), 128.6, 129.1 (2 C:s), 131.3, 133.6,
133.7, 141.1. Anal. Calcd for (C19H23Cl2NOꢂ2/3H2O): C, 62.6; H,
6.7; N, 3.8. Found: C, 62.6; H, 6.7; N, 3.8.
5.8.2. 3-(4-Chlorophenyl)-3-(2-dimethylaminoethyl)-3,4-
dihydro-5-methoxy-2-methyl-2H-isoquinolin-1-one HCl (9b)
Benzamide 4c (0.50 g, 2.8 mmol) and 1-(4-chlorophenyl)-3-
dimethylamino-propan-1-one (0.29 g, 1.4 mmol) yielded 0.17 g
(29%) of the title compound, which was converted to the corre-
sponding HCl salt. Mp 136.5–137.7 °C. 1H NMR (CD3OD) d 2.77–
2.81 (m, 2H), 2.87 (s, 3H), 2.89 (s, 3H), 3.07–3.16 (m, 1H), 3.35–
3.41 (m, 1H), 3.47 (s, 3H), 3.53 (d, 1H, J = 17.2 Hz), 3.94 (s, 3H),
4.04 (d, 1H, J = 17.2 Hz), 7.38–7.42 (m, 5H), 7.44–7.47 (m, 1H), 7.57
(d, 1H, J = 7.7 Hz). 13C NMR (CD3OD) d 29.1, 29.9, 35.6, 42.0, 42.3,
52.2, 55.6, 89.0, 118.1, 118.6, 120.3, 125.1, 126.6, 129.2, 129.4,
134.8, 136.6, 156.7, 167.3. HRTofMS 372.1603 (C21H25ClN2O2 re-
quires 372.1605).
5.7.2. 3-(4-Chlorophenyl)-3-(2-dimethylaminoethyl)-6,7-
dimethyl-isochromane HCl (8b)
Compound 2 (0.55 g, 1.6 mmol), sodium borohydride (0.23 g,
6.1 mmol) and boron trifluoride etherate (6.0 g, 46.0 mmol) yielded
208 mg (36%) of the title product as a white hygroscopic solid. 1H
NMR (CD3OD) d 2.16 (s, 3H), 2.19 (s, 3H), 2.22–2.27 (m, 2H), 2.81
(s, 6H), 2.99–3.18 (m, 4H), 4.62 (d, 1H, J = 15.0 Hz), 4.79 (d, 1H,
J = 15.0 Hz), 6.73 (s, 1H), 6.94 (s, 1H), 7.32 (d, 2H, J = 8.8 Hz), 7.43
(d, 2H, J = 8.8 Hz). 13C NMR (CD3OD) d 18.0, 18.2, 35.9, 36.4, 42.3 (2
C:s), 53.8, 63.3, 76.2, 124.7, 127.5 (2 C:s), 128.4 (2 C:s), 128.9,
129.2, 131.0, 133.1, 134.5, 134.9, 141.3. Anal. (C21H27Cl2NOꢂH2O):
C, 63.3; H, 7.3; N, 3.5. Found: C, 63.7; H, 7.4; N, 3.2.
5.8.3. 3-(4-Chlorophenyl)-3-(2-dimethylaminoethyl)-3,4-
dihydro-2-isopropyl-2H-isoquinolin-1-one HCl (9c)
6.7.3. 3-(2-Dimethylaminoethyl)-6,7-dimethyl-3-(2-
N-Isopropyl-2-methyl-benzamide (0.50 g, 2.8 mmol) and 1-(4-
chlorophenyl)-3-dimethylamino-propan-1-one (0.29 g, 1.4 mmol)
yielded 0.35 g (68%) of the title compound, which was converted
to the corresponding HCl salt as a yellow oil. 1H NMR (CD3OD) d
1.53–1.56 (m, 6H), 2.85–2.90 (m, 2H), 2.88 (s, 3H), 2.90 (s, 3H),
3.08–3.16 (m, 1H), 3.32–3.37 (m, 2H), 3.88 (d, 1H, J = 16.8 Hz),
3.99 (d, 1H, J = 16.8 Hz), 7.38 (d, 2H, J = 8.8 Hz), 7.43 (d, 2H, J =
8.8 Hz), 7.48–7.52 (m, 1H), 7.56 (d, 1H, J = 7.3 Hz), 7.73–7.77 (m,
1H), 8.09 (d, 1H, J = 8.1 Hz). 13C NMR (CD3OD) d 20.4, 20.6, 35.6,
36.1, 42.1, 42.3, 47.3, 52.3, 89.3, 119.7, 127.0 (2 C:s), 128.1,
128.4, 129.2 (2 C:s), 129.3, 134.8, 136.4, 136.9, 137.2, 166.0.
HRTofMS 370.9266 (C22H27ClN2O requires 370.9263).
naphthyl)isochromane HCl (8c)
Compound 25 (0.16 g, 0.4 mmol), sodium borohydride (65 mg,
1.6 mmol) and boron trifluoride etherate (1.8 g, 12.9 mmol)
yielded 60 mg (35%) of the title product as a white gum. 1H NMR
(DMSO-d6) d 2.10 (s, 3H), 2.16 (s, 3H), 2.24–2.44 (m, 3H), 2.33 (s,
3H), 2.38 (s, 3H), 2.51–2.63 (m, 1H), 3.12 (d, 1H, J = 16.1 Hz), 3.23
(d, 1H, J = 16.1 Hz), 4.64 (d, 1H, J = 15.4 Hz), 4.84 (d, 1H,
J = 15.4 Hz), 6.74 (s, 1H), 6.98 (s, 1H), 7.47–7.50 (m, 2H), 7.63 (dd,
1H, J = 1.5, 8.8 Hz), 7.83–7.93 (m, 4H). 13C NMR (DMSO-d6) d
19.6, 19.7, 34.3, 37.4, 51.1, 51.9, 59.6, 62.9, 76.4, 124.4, 124.9,
125.3, 126.5, 126.7, 127.9, 128.6, 128.7, 129.7, 130.1, 131.4,
132.6, 133.2, 134.3, 134.7, 141.3. Anal. Calcd for (C25H30ClNO): C,
75.8; H, 7.6; N, 3.5. Found: C, 76.1; H, 7.3; N, 3.4.
6. Biological activity
6.1. R-SAT-testing
5.8. General procedure for the synthesis of tetrahydro-
isoquinolinones 9a–c
R-SAT™ assays for pharmacological testing were performed as
previously described,18 with the following modifications: NIH-
3T3 cells were grown to 80% confluence in Dulbecco’s modified Ea-
gle’s medium (DMEM) supplemented with 10% bovine calf serum
(Hyclone) and 1% penicillin/streptomycin/glutamine (Invitrogen).
Cells were transfected in cell factories (Nunc) with the human uro-
tensin II, somatostatin 1, and somatostatin 4 receptors and the b-
The benzamide was dissolved in THF (15 mL/g) and n-BuLi
(2.2 equiv) was added slowly at room temperature. The ketone
dissolved in THF (15 mL/g) was added dropwise and the solution
was stirred for 30 min. The reaction mixture was poured into sat-
urated aqueous ammonium chloride (twice the THF volume) and
extracted twice with EtOAc. The combined organic phases were
washed with water and brine and concentrated. The resulting

4854
F. Lehmann et al. / Bioorg. Med. Chem. 18 (2010) 4844–4854
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sinized, harvested, and frozen. Aliquots of frozen cell batches were
thawed and tested for response to control compound to perform
quality control before initiation of pharmacological testing, ensur-
ing the correct pharmacological response and sufficient sensitivity.
To initiate the pharmacological assay, cells were thawed rapidly
and prepared in DMEM media containing 0.4% calf serum (Hy-
clone), 30% UltraCulture (Biowhittaker), and 1% penicillin/strepto-
mycin/gluatmine (Invitrogen), and then added to half-area 96-well
microtiter plates containing either test compounds or reference li-
gands. After a five day incubation of drug with cells in 5% ambient
CO2, media was removed and reporter enzyme activity was mea-
sured at 420 nm. For control of the UII receptor selectivity all com-
pounds were tested against the m3 receptor as a negative control
(data not shown). For the selectivity test of 28 on somatostatin
receptors SST-14 was used as the reference compound.
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Acknowledgments
Financial support was obtained from The Knut and Alice Wal-
lenberg Foundation and The Swedish Research Council. We thank
Jenny Svallfors for skillful assistance in the laboratory.
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