Effects of substitution on 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2, 6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione, a dihydropyridine ATP-sensitive potassium channel opener

J. Med. Chem. 2006, 49, 6869-6887

6869

Effects of Substitution on 9-(3-Bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4-

azacyclopenta[b]naphthalene-1,8-dione, a Dihydropyridine ATP-Sensitive Potassium Channel

Opener

Robert J. Altenbach,* Michael E. Brune, Steven A. Buckner, Michael J. Coghlan,^†Anthony V. Daza, Adebola Fabiyi,^‡

Murali Gopalakrishnan, Rodger F. Henry, Albert Khilevich,^†Michael E. Kort, Ivan Milicic, Victoria E. Scott, Jamie C. Smith,^§

Kristi L. Whiteaker, and William A. Carroll

Neuroscience Research, Global Pharmaceutical Research and DeVelopment, Abbott Laboratories, 100 Abbott Park Road,

Abbott Park, Illinois 60064-6123

ReceiVed May 10, 2006

Structure-activity relationships were investigated on the tricyclic dihydropyridine (DHP) K_ATPopeners 9-(3-

bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (6) and 10-

(3-bromo-4-fluorophenyl)-9,10-dihydro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (65). Substitution off

the core of the DHP, absolute stereochemistry, and aromatic substitution were evaluated for K_ATPchannel

activity using Ltk- cells stably transfected with the Kir6.2/SUR2B exon 17- splice variant and in an

electrically stimulated pig bladder strip assay. A select group of compounds was evaluated for in vitro

inhibition of spontaneous bladder contractions. Several compounds were found to have the unique

characteristic of partial efficacy in both the cell-based and electrically stimulated bladder strip assays but

full efficacy in inhibiting spontaneous bladder strip contractions. For compound 23b, this profile was mirrored

in vivo where it was fully efficacious in inhibiting spontaneous myogenic bladder contractions but only

partially able to reduce neurogenically mediated reflex bladder contractions.

Introduction

Overactive bladder (OAB) is a symptomatic diagnosis and

is defined as the urgency to urinate with or without urge

incontinence. OAB is usually accompanied by frequency and

nocturia. The etiology of OAB has been linked to detrusor

overactivity, which is characterized by involuntary detrusor

contractions during the filling phase.¹OAB has been reported

to result from both myogenic and neurogenic origins.^2,3The

myogenic component is hypothesized to result from a reduction

in the activity of the efferent nerves of the bladder. This

reduction in efferent activity leads to alterations in the properties

of the detrusor, which include increases in detrusor excitability

and increases in the electrical coupling of the smooth muscle

cells throughout the bladder wall. Many detrusor strips from

unstable bladders show abnormal spontaneous mechanical

activity. The neurogenic component is believed to result from

damage to central inhibitory pathways or sensitization of peri-

pheral afferent nerves of the bladder, both of which can unmask

primitive voiding reflexes that trigger bladder overactivity.

ATP-sensitive potassium (K_ATP) channels⁴have been found

in many tissues including smooth muscle in the vasculature and

the bladder.⁵K_ATPchannel openers⁶relax smooth muscle by

increasing the permeability of the cell membrane to potassium

Figure 1.

ions, which results in hyperpolarization, decreased Ca²⁺influx,

(2) was shown to inhibit spontaneous contractions in vivo in

pigs without compromising normal voiding.⁸

and inhibition of contraction. K_ATPchannel openers may be

useful in the treatment of OAB because they have the potential

to eliminate undesired bladder contractions during the filling

phase by stabilizing the smooth muscle without affecting normal

micturition.⁷For example, the K_ATPchannel opener cromakalim

The K_ATPchannel openers ZD6169 (1)⁹and cromakalim (2)¹⁰

have been evaluated clinically for OAB (Figure 1). ZD6169

was further evaluated but subsequently withdrawn from phase

II trials perhaps because of an unfavorable side effect/efficacy

profile¹¹that may have included hypotensive effects. Recently,

other K_ATPchannel openers such as WAY-133537¹²(3) and

A-278637¹³(4) have been reported to have selectivity for

bladder versus cardiovascular effects in preclinical models.

We have recently published on a variety of tricyclic dihy-

dropyridine (DHP) K_ATPchannel openers,^14-17several of which

* To whom correspondence should be addressed. Phone: 847-935- 4194.

Fax: 847-937-9195. E-mail: Robert.j.altenbach@abbott.com.

^†Current address: Eli Lilly and Company, Lilly Corporate Center,

Indianapolis, IN 46285.

^‡Current address: John Radcliffe Hospital, Headley Way, Headington,

Oxford, Oxfordshire, OX3 9DU.

^§Current address: Cumbre Inc., 1502 Viceroy Drive, Dallas, TX 75235.

Published on Web 10/14/2006

6870 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23

Altenbach et al.

Table 1. Substitutions to Compound 6 and Activity at Kir6.2/Sur2B 17- K_ATPChannels^a

pEC₅₀( SEM

(% efficacy)

pEC₅₀( SEM

(% efficacy)

pEC₅₀( SEM

(% efficacy)

A

B

C

X, Y isomer^bracemate

(+)-enantiomer

(-)-enantiomer

H

Me

di-Me

Et

H

Me

F, Br

6

7

8

7.34 ( 0.05 (92)^c

6.30 ( 0.44 (81)

6.34 ( 0.04 (104)^c

7.62 ( 0.04 (86)^c

<5^c

6a^d

7a

8a

9a

10a

7.20 ( 0.00 (107)^c

6.76 ( 0.13 (17)^c

7.14 ( 0.00 (15)^c

7.57 ( 0.2 (104)

6.11 ( 0.12 (83)^c

6b

7b

8b

9b

10b

7.43 ( 0.17 (101)

6.29 ( 0.12 (94)^c

6.53 ( 0.12 (16)^c

5.55 (77)^e

Me

di-Me

Et

H

di-Me

H

cis

trans

9

cis

trans

cis

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

41

42

43

44

45

46

1

5.86 ( 0.07 (46)^c

5.99 ( 0.16 (97)^c

8.74 ( 0.33 (96)

6.99 ( 0.15 (73)

6.92 ( 0.13 (73)

7.74 ( 0.22 (90)^c

6.03 ( 0.14 (74)

8.26 ( 0.36 (100)^c

6.00 ( 0.02 (75)^c

7.57 ( 0.05 (77)^c

7.45 ( 0.01 (74)^c

7.02 ( 0.08 (40)

8.29 ( 0.05 (90)^c

6.81 ( 0.14 (36)

8.01 ( 0.05 (100)^c

7.64 ( 0.00 (103)^c

<5

trans

cis

trans

cis

17a

18a

9.04 ( 0.12 (105)

7.19 ( 0.10 (86)

17b^f

18b

7.29 ( 0.35 (89)

6.59 ( 0.07 (85)^c

trans

di-Me

Et

n-Pr

CH₂OMe F, Br

i-Pr

n-Bu

i-Bu

n-Pn

Ph

cis

trans

cis

trans

cis

trans

cis

trans

cis

trans

cis

trans

cis

trans

cis

trans

cis

trans

20a

21a^d

22a

23a

8.41 ( 0.18 (101)^c

5.14 ( 0.09 (54)

9.00. ( 0.06 (82)^c

5.49 ( 0.07 (75)^c

20b

21b

22b

23b

6.84 ( 0.08 (85)^c

6.77 ( 0.10 (46)

8.43 ( 0.07 (66)

7.56 ( 0.23 (45)

25a

6.32 ( 0.2 (95)^c

25b

7.64 ( 0.03(104)^c

H

F, Br

F, Cl

F, I

<5^c

7.53 (67)^e

5.66 (61)^e

29a

31a

5.29 ( 0.03 (62)

5.60 ( 0.10 (66)^c

29b

31b

6.07 ( 0.20 (68)^c

7.56 (83)^e

<5^c

@5 (59)^c

<5^c

H

6.59 ( 0.02 (68)^c

7.84 ( 0.12 (105)^c

6.55 ( 0.04 (70)^c

5.76 ( 0.10 (59)^c

5.46 ( 0.15 (48)^c

7.17 ( 0.16 (42)^d

7.12 ( 0.00 (105)^d

6.22 ( 0.10 (95)^d

6.76 ( 0.01 (120)^d

6.37 ( 0.02 (97)^d

6.48 ( 0.06 (119)^d

6.40 ( 0.03 (104)^d

5.87 ( 0.08 (100)

6.22 ( 0.02 (83)

5.63 ( 0.07 (71)

6.80 ( 0.08 (90)

7.28 ( 0.08 (101)

Et

36a

6.36 ( 0.13 (89)^c

36b

6.26 ( 0.26 (34)^c

di-Me Et

38a

39a

41a

42a

43a

44a

45a

46a

5.80 ( 0.03 (77)^c

5.47 ( 0.02 (74)^d

5.71 ( 0.02 (81)^d

5.88 ( 0.09 (87)^d

6.09 ( 0.08 (90)^d

5.98 ( 0.01 (121)^d

5.94 ( 0.04 (104)^d

5.46 ( 0.08 (81)^d

38b

39b

41b

42b

43b

44b

45b

46b

<5^c

H

n-Pr

7.04 ( 0.34 (39)^d

7.57 ( 0.02 (94)^d

5.70 ( 0.25 (62)^d

6.82 ( 0.08 (99)^d

6.36 ( 0.01 (92)^d

6.90 ( 0.05 108)^d

6.66 ( 0.08 (87)^d

n-Pr

Cl, Cl

Cl, Br

Br, Cl

Br, Br

H

Me, Br trans

ZD-6169

(-)-cromakalim

WAY-133537

A-278637

2

3

4

5

P1075

^aNumber of observations is g3, unless otherwise specified. Values are expressed as the average pEC₅₀( the standard error of the mean (SEM). The

efficacy (in parentheses) is the average maximum response of each compound expressed as % relative to 5. ^bRegiochemistry is reported as either cis or trans

and is based on compounds 7, 12, and 17, the structures of which were confirmed by X-ray. ^cn ) 2. ^dAbsolute stereochemistry confirmed by X-ray: 6a

is (R)-stereochemistry and 21a is (R)-stereochemistry at the benzylic position. ^en ) 1. ^fAbsolute stereochemistry of 3-fluoro-4-iodo analogue of compound

17b confirmed by X-ray to be (S)-stereochemistry.

were shown to have greater potency for inhibiting spontaneous

bladder contractions relative to their potencies to inhibit

contractions elicited by electrical stimulation. In vitro selectivity

for relaxing spontaneous bladder contractions over electrically

stimulated bladder contractions may be predictive of in vivo

selectivity for suppressing unstable bladder contractions versus

normal micturition and/or cardiovascular effects. We were

interested in exploring the effects of substitution on the DHP

core with the objective of finding compounds that were even

more selective for spontaneous versus electrically stimulated

contractions. The tricyclic DHP 6,¹⁷a potent K_ATPchannel

opener, was chosen as a scaffold. Compound 6 was attractive

from a synthetic point of view because derivatives of 6 with

substitutions at positions A, B, and C (see Table 1) could be

readily synthesized. Additionally, the symmetrical bis-pyran,

compound 65, was also amenable to substitution, and derivatives

of this compound were evaluated. We describe herein our

findings.

Chemistry

The Hantzsch reaction was used to synthesize the substituted

tricyclic DHPs described herein. An appropriate carbonyl-

containing substrate selected from c1-c12 (Figure 2) and an

enamine selected from e1-e17 (Figure 3) were reacted in EtOH

at 80 °C to provide a DHP (method A, Scheme 1). In the

Effects of Substitution on a Dione

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6871

conversion to the DHP (method B, Scheme 1). In the case where

both the enamine and the carbonyl were cyclic, a tricyclic DHP

was directly formed in the reaction. In the case where either

the enamine or the carbonyl was acyclic, an intermediate bicyclic

DHP ester was formed. These bicyclic esters were cyclized via

a bromo intermediate to the lactone or the lactam as shown in

Scheme 2. In the synthesis of thiopyrans 53 and 54, the sequence

in Scheme 2 was troublesome presumably because of bromi-

nation of the sulfur. Enamine e17 and carbonyl c9 were therefore

used to generate these thio analogues directly via Scheme 1.

The syntheses of pyrandione carbonyls c1-c6 and enamines

e1-e4 are shown in Scheme 3. By use of chemistry similar to

that described by Morgan et al.,¹⁸pyrandiones c1-c6, were

generated in three steps from appropriately substituted propargyl

alcohols. Pyrandiones c2-c6 were used in the Hantzsch reaction

to synthesize DHPs with substitutions at positions A and E in

Tables 1 and 3, respectively. The synthesis of DHPs with

substitution at position B in Table 1 or position F in Table 3

required the use of enamines e2-e4 in which the substituent is

locked into position. Enamines e2-e4 were generated from

pyrandiones c2-c4, respectively. As shown in Scheme 3,

treatment of a substituted pyrandione in EtOH with H₂SO₄

provided a mixture of vinyl ethers in approximately a 2:1 ratio

in which the minor isomer contains the substituent in the position

adjacent to the ethoxy group. This minor isomer was isolated

by chromatography and smoothly converted with ammonia in

ethanol to enamines e2-e4.

Figure 2. Carbonyl monomers: c1, R₁) H; c2, R₁) Me; c3, R₁)

di-Me; c4, R₁) Et; c5, R₁) di-Et; c6, R₁) -(CH₂)₄-.

Figure 3. Enamine monomers: e1, R₂) H; e2, R₂) Me; e3, R₂)

di-Me; e4, R₂) Et; e5, R₃) H; e6, R₃) Me; e7, R₃) di-Me; e8, R₃

) Et; e9, R₃) n-Pr; e10, R₃) CH₂OMe; e11, R₃) i-Pr; e12, R₃)

n-Bu; e13, R₃) CH₂CHMe₂; e14, R₃) n-Pn; e15, R₃) Ph.

Scheme 1^a

In Scheme 4, 3-ethoxy-2-cyclopenten-1-one was alkylated as

described by Curran.¹⁹Similar to Scheme 3, the resulting vinyl

ether was isomerized to a mixture of isomers. The desired minor

isomer, 3-ethoxy-4-ethyl-cyclopent-2-enone, was isolated by

chromatography and smoothly converted to enamine e16. In

Scheme 5, ethyl-substituted tetronic acid, generated in three steps

from diethyl malonate, was treated similarly to c2-c4 to provide

the vinyl ether that required relatively harsh conditions to

provide a moderate yield of enamine e17.²⁰

^aConditions: (i) EtOH, 80 °C, 16 h; (ii) 0.5 equiv of 1 M HCl in Et₂O,

80 °C, 45 min.

Scheme 2^a

The substituted tricyclic DHPs were obtained from Schemes

1 and 2 as a mixture of cis and trans isomers, which were

separated by crystallization and/or chromatography. In general,

the cis isomers were more crystalline and more polar on silica

gel than the corresponding trans isomers. Enantiomeric purifica-

tion of individual isomers was accomplished using chiral

chromatography. In the case of the compounds in Table 1, the

enantiomers of the cis isomers were more easily separated than

the trans. In particular, the enantiomers of the trans n-Pr

derivative, 23, were inseparable by chiral chromatography in

our hands whereas the enantiomers of the cis n-Pr derivative,

22, were easily separable. This problem was circumvented by

using the finding that cis isomers of lactone-containing DHPs

such as 22a could be isomerized to a mixture of cis and trans

isomers with retention of configuration of the carbon adjacent

to the aromatic ring. As can be seen in Scheme 6, heating a

solution of 22a in 2 M NH₃in EtOH resulted in the formation

of a mixture of 23a and 22a that were separated by chroma-

tography.

^aConditions: (i) pyridinium tribromide/pyridine, CHCl₃; (ii) NBS,

CHCl₃; (iii) 130 °C, 15 min; (iv) MeNH₂, EtOH, 80 °C, 16 h.

synthesis of compounds 70-78, an intermediate believed to be

a hemiaminal was observed in the reaction. Treatment of this

mixture with 0.5 equiv of 1 M HCl resulted in a smooth

Scheme 3^a

^aConditions: (i) NaH, THF; BrCH₂CO₂Me; (ii) Hg(OAc)₂, H₂O, H₂SO₄; (iii) KO-t-Bu, Et₂O, HO-t-Bu; (iv) catalytic H₂SO₄, EtOH; (v) chromatography;

(vi) NH₃, EtOH.

6872 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23

Altenbach et al.

omers 6a, 21a, 17b,²¹and 75b were found to possess (R)-, (R)-,

(S)-, and (S)-stereochemistry at the benzylic positions, respec-

tively. The assignment of cis vs trans for other derivatives was

based on similarity of NMR spectra and the relative polarity

on silica gel to the compounds whose structures were identified

by X-ray analysis. Absolute stereochemistry of compounds of

similar structure was assumed based on the order of elution from

the chiral columns and the signs of rotation.

Table 2. Modifications to Ring Systems of Substituted Compound 6

and Activity at Kir6.2/Sur2B 17- K_ATPChannels^a

Biological Evaluation

Fluorometric Imaging Plate Reader (FLIPR) Membrane

Potential Assay. Compounds were evaluated for potassium

channel opening activity using Ltk- cells stably transfected with

the Kir6.2/SUR2B exon 17- splice variant.²²Functional activity

at potassium channels was measured by evaluating changes in

membrane potential using DIBAC dye in a 96-well cell-based

kinetic assay system. Changes in fluorescence were measured

by comparison to the effect elicited by 5.²³The maximal

response of each compound is expressed as % relative to 5.

The observed effects were reversed by glyburide, confirming a

K_ATPmechanism. Inhibition of K_ATPchannel activity by

sulfonylurea K_ATPchannel blockers such as glyburide has been

used to define K_ATPchannels.²⁴The average reversal induced

by glyburide in the FLIPR assay for compounds described herein

was 65%. This is in line with what we have observed for

standard K_ATPchannel openers such as compounds 1, 2, 3, and

5, which have an average reversal induced by glyburide of 64%.

Field-Stimulated Landrace Pig Detrusor (FSLPD) Assay.²⁵

Compounds were evaluated for bladder K_ATPactivity using

tissue strips from Landrace pig bladders. Low-frequency

stimulation (0.05 Hz, 0.5 ms at 20 V) produced a stable twitch

response, the amplitude of which was reduced by increasing

concentrations of test agents. These field-stimulated contractions

have both cholinergic and noncholinergic components and are

partially sensitive to muscarinic blockers such as tolterodine.

Spontaneous Landrace Pig Detrusor (SLPD) Assay.²⁶

Spontaneously contracting bladder strips were obtained from

the area closer to the trigonal region of the bladder in Landrace

pigs. The reduction of the area under the curve (AUC) by

increasing concentrations of test agents was measured. These

spontaneous contractions are purely of myogenic origin, have

no cholinergic component, and thus are insensitive to the effects

of muscarinic blockers such as tolterodine. Concentration-

response curves were generated for each agent with the potency

expressed as the pEC₅₀. Confirmation of a K_ATPmechanism

was demonstrated for all compounds by reversal of the bladder

relaxant effect following addition of glyburide at the end of

each experiment. Because of the different sensitivities of FSLPD

and LPD to muscarinic antagonists, each may model bladder

overactivity of distinct etiology.

The DHPs described in this publication are structurally related

to 1,4-dihydropyridine L-type calcium channel ligands such as

nifedipine. Close analogues of the DHPs described in this

publication have been tested in radioligand binding and func-

tional studies and were shown to not interact with L-type

calcium channels.^13a,27

^aNumber of observations is g3, unless otherwise specified. Values are

expressed as the average pEC₅₀( the standard error of the mean (SEM).

The efficacy (in parentheses) is the average maximum response of each

compound expressed as % relative to 5. ^bRegiochemistry based on polarity

Results

Potassium Channel Opening Activity. Substitutions were

initially made at positions A, B, and C of the DHP core of

compound 6 (see Table 1). At position A, the cis and trans Me

analogues, 7 and 8, had reduced activity relative to 6 and were

equipotent with each other. Interestingly, the di-Me derivative,

9, picked up activity compared to the mono-Me analogues and

1

on silica gel and similarity of H NMR spectra to compounds in Table 1.

^cn ) 2.

The relative and absolute stereochemistry of select compounds

was confirmed by X-ray analysis. The racemates 7, 12, and 17

were all found to possess cis configuration. The single enanti-

Effects of Substitution on a Dione

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6873

Table 3. Substitutions to Compound 65 and Activity at Kir6.2/Sur2B 17- K_ATPChannels^a

pEC₅₀( SEM

(% efficacy)

pEC₅₀( SEM

(% efficacy)

pEC₅₀( SEM

(% efficacy)

E

F

X, Y

isomer^b,c

racemate

(+)-enantiomer

(-)-enantiomer

H

F, Br

F, Cl

F, I

Cl, Cl

Cl, Br

Br, Cl

Br, Br

Me, Br

65

66

67^b

68

69

70

71

72

73

74

75

76

77

78

7.56 ( 0.16 (87)

7.77 ( 0.13 (96)^d

5.41 ( 0.32 (61)^d

<5^d

di-Me

(CH₂)₄

di-Et

H

4.86 (42)^e

Et

cis

7.85 ( 0.10 (60)^d

6.73 ( 0.06 (30)

6.34 ( 0.01 (30)^d

4.92 ( 0.07 (47)^d

6.98 ( 0.12 (58)^d

5.79 ( 0.05 (70)^d

6.00 ( 0.05 (46)^d

6.87 ( 0.06 (76)^d

5.8 ( 00.16 (70)^d

70a

71a

72a

73a

74a

75a

76a

77a

78a

6.78 ( 0.10 (87)^d

6.77 ( 0.34 (40)

5.44 ( 0.10 (66)^d

5.89 ( 0.02 (69)^d

6.33 ( 0.25 (118)^d

6.12 ( 0.07 (89)^d

5.79 ( 0.23 (76)^d

6.51 ( 0.13(120)^d

6.14 ( 0.06 (94)^d

70b

71b

72b

73b

74b

75b^c

76b

77b

78b

7.70 ( 0.13 (94)^d

<5^d

trans

<5^d

5.53 ( 0.13 (53)^d

6.77 ( 0.18 (57)^d

5.26 ( 0.03 (54)^d

6.61 ( 0.31 (37)^d

6.37 ( 0.14(104)^d

5.25 ( 0.07 (56)^d

^aNumber of observations is g3, unless otherwise specified. Values are expressed as the average pEC₅₀( the standard error of the mean (SEM). The

efficacy (in parentheses) is the average maximum response of each compound expressed as % relative to 5. ^bG ) hydrogen for all compounds except

compound 67, where G ) di-Me. ^cRegiochemistry based on similarity to compound 75b that was confirmed by X-ray to be trans with absolute (S)-

stereochemistry at the benzylic position. ^dn ) 2. ^en ) 1.

Scheme 4^a

activity of the racemate. The cis and trans n-Pr derivatives, 22

and 23, had the same pattern of potency and efficacy as 20 and

21.

Further SAR was conducted at position C. The i-Pr derivatives

26 and 27 were inactive in the membrane potential assay. The

CH₂OMe derivatives, compounds 24 and 25, were similar in

potency relative to the Et and n-Pr derivatives but were fully

efficacious. Although the pEC₅₀values of the cis isomers of

n-Bu and i-Bu, compounds 28 and 30, remained >7, larger

groups were found to be less potent. Several acids and esters

were also examined, but these compounds all lost activity (pEC₅₀

< 6) (compounds not shown).

We also investigated the effects of simultaneous substitutions.

As was seen with derivatives 9 and 14, the analogues with A

) di-Me and C ) Et (compounds 35 and 36) were more potent

than the analogues with B ) di-Me and C ) Et (compounds

37 and 38). A slight increase in potency for compound 35 over

20 was observed. Although less potent than compound 21b,

compound 36b, with the same stereochemistry at position C,

also showed partial agonist activity.

^aConditions: (i) LDA, THF, -78 °C; EtI, HMPA, THF; (ii) catalytic

H₂SO₄, EtOH, 60 °C, 1 h; (iii) chromatography; (iv) concentrated aqueous

NH₄OH, EtOH, 85 °C, 16 h.

was even slightly more potent than compound 6. Evaluation of

the enantiomers of 9 revealed a 2 orders of magnitude difference

in potencies. This is in contrast to compounds 6-8 where there

was only less than a 10-fold difference in potencies between

their respective enantiomers. The mono-Et analogues, 10 and

11, were less potent.

Methyl substitution at position B revealed a large difference

in activity between the isomers, with the cis analogue 12 being

approximately 50-fold more potent than the trans 13. In contrast

to substitution at position A, the di-Me derivative at position

B, compound 14, lost activity compared with compound 6. The

Et analogues 15 and 16, although less potent than the corre-

sponding Me analogues, followed the trend of cis being more

potent than trans.

To better understand the structural features conferring partial

agonist activity to compounds such as 21b and 23b, we

evaluated a variety of aromatic modifications on derivatives

possessing trans n-Pr substitution at C (compounds 39-46).

Most derivatives lost potency relative to 23b. Somewhat

surprisingly, only the 4-F,3-Cl substitution retained partial

agonist activity (compound 39b).

Because of the relative ease of synthesis of enamines of

structures e5-e15, substitution at position C was explored most

thoroughly. Similar to what was observed in substitution at

position B, the cis Me derivative, 17, was over 2 orders of

magnitude more potent than the trans isomer, 18. Evaluation

of the enantiomers of 17 revealed that 17a was 50-fold more

potent than its antipode. The potency of dimethyl derivative 19

was between the potency of the cis and trans monomethyl

analogues. Evaluation of the Et analogues 20 and 21 revealed

that, as expected, the cis derivative 20 was more potent.

Interestingly, the trans isomer 21 possessed partial agonist

activity²⁸with only 40% efficacy relative to 5. The more potent

enantiomer of 21, compound 21b, retained the partial agonist

To further explore the SAR of the substituted tricyclic series,

different ring systems were explored (Table 2). As was seen in

Table 1, the cis isomers were approximately 10-fold more potent

than the trans isomers. Relative to compounds 20 and 21, the

corresponding cyclohexanone derivatives, compounds 47 and

48, lost potency and were fully efficacious. Replacement of the

pyran with the γ-lactone (compounds 49 and 50) resulted in a

slight boost in potency, whereas the δ-lactone derivatives, 51

and 52, lost potency by 10-fold. The cis thiopyran, 53, lost

potency relative to 20, but the trans analogue, 54, demonstrated

6874 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23

Altenbach et al.

Scheme 5^a

^aConditions: (i) Mg, EtOH, ∆; diethyl malonate, ∆; Et₂O, ∆; 0 °C, 2-bromobutyryl bromide; ∆; (ii) Et₃N, toluene; (iii) aqueous KOH, 2 h, then concentrated

HCl; (iv) catalyst H₂SO₄, MeOH; (v) NH₃/MeOH, 80 °C, 16 h.

Scheme 6^a

Table 4. Functional K_ATPActivity in Isolated Bladder Strips

pEC₅₀(% efficacy)^a

compd

FSLPD^b

SLPD^c

1

2

3

5

6a

6b

5.56 ( 0.13 (99)

6.59 ( 0.19 (99)

6.17 ( 0.13 (94)

7.07 ( 0.10 (99)

6.23 ( 0.14 (95)

6.67 ( 0.05 (88)

5.57 ( 0.18 (86)^d

6.05 ( 0.39 (95)^d

7.45 ( 0.31 (97)

6.31 ( 0.37 (88)^e

5.53 ( 0.03 (94)

6.55 ( 0.07 (77)

6.10 ( 0.10 (90)

6.29 ( 0.26 (34)

5.92 ( 0.02 (97)^d

5.78 ( 0.22 (51)

6.89 ( 0.38 (74)

6.99 ( 0.17 (35)^d

5.89 ( 0.24 (91)

6.89 ( 0.17 (66)

6.64 ( 0.35 (86)

6.05 ( 0.24 (100)^e

6.02 ( 0.11 (38)

6.90 ( 0.13 (97)

5.69 ( 0.19 (54)

5.64 ( 0.34 (41)^e

4.87 ( 0.16 (38)

6.53 ( 0.32 (100)

7.46 ( 0.20 (100)

6.99 ( 0.06 (100)

7.66 ( 0.16 (100)

9.17 ( 0.04 (100)^d

10a

10b

17a

21

21a

21b

23

23b

26

29b

30

31b

34

39b

41b

54

54b

65

71a

74b

76b

^aConditions: (i) 2 M NH₃in EtOH, ∆, 16 h.

a very low efficacy of 15%. The sulfone derivatives, compounds

55-58, all lost potency relative to the corresponding pyran

derivatives. Modifications to the lactone ring were also explored.

Replacement of the oxygen of the lactone with a N-Me led to

compounds with potencies similar to the potencies of 17 and

18 in the case where D ) Me (59 and 60) but were inactive in

the case of D ) Et (61 and 62). Replacement of the oxygen of

the lactone with the CH₂group led to over a 10-fold boost in

potency in the case of the cis isomer 63 compared to lactone

20.

7.72 ( 0.58 (96)^e

7.54 ( 0.10 (99)

6.48 ( 0.09 (100)^d

The symmetrical pyran DHP, compound 65, was also

amenable to substitution (see Table 3). Di-Me substitution at

position E, compound 66, led to retention of activity relative to

65, but larger groups (compounds 68 and 69) at E and di-Me

substitution at both E and G (compound 67) led to a significant

loss of activity. We investigated the effects of Et substitution

at position F of 65. Similar to the derivatives of compound 6 in

Table 1, the cis derivative, 70, was more potent than the trans,

71. Compound 71 was separated into its enantiomers, and

compound 71a, like the racemate 71, possessed reduced efficacy.

To investigate the significance of aromatic substitution on

the partial agonism of compound 71, derivatives of compound

71 were evaluated. Partial agonism was observed with the

4-Cl,3-Cl and 4-Br,3-Cl derivatives (compounds 74b and 76b,

respectively). Interestingly, compound 71a is an outlier in terms

of absolute stereochemistry, having opposite stereochemistry

((R)-stereochemistry at the benzylic position) from the other

compounds possessing partial agonist activity in FLIPR, namely,

21b, 36b, 23b, 39b, 74b, and 76b.

The impact of aromatic substitution on the partial agonism

of compound 71 diverged from that of compound 23, wherein

only the smaller F,Cl analogue retained partial agonistic activity.

This disparity, along with the lack of partial agonism in the

analogues described in Table 2, indicates that the structural

requirements for partial agonism by DHPs are specific and vary

between different DHP cores.

From the above SAR, substitution on the tricyclic DHP core

was most allowed at positions adjacent to the NH of the

molecule where longer chains up to n-Bu retained K_ATPchannel

opening activity. Increasing the steric bulk near the NH of the

molecule, for example, the i-Pr derivatives 26 and 27, as well

as the di-Me derivative 14, resulted in a loss of activity.

Dimethyl substitution next to the carbonyl maintained or slightly

6.89 ( 0.34 (98)

7.26 ( 0.65 (92)^d

6.61 ( 0.63 (97)^d

^apEC₅₀is expressed as a mean ( SEM, with % efficacy relative to 5 in

parentheses. n g 4 unless otherwise indincated. ^bField stimulated Landrace

pig detrusor strips. ^cSpontaneous Landrace pig detrusor strips. ^dn ) 2.^en

) 3.

increased activity, as in compounds 9, 35, and 66. Larger

substitutions next to the carbonyl resulted in a loss of activity.

FSLPD. To further investigate the potassium channel opening

activity of these substituted tricyclic DHPs, we examined several

for their ability to relax field-stimulated pig detrusor strips (see

Table 4). Compounds that were fully efficacious in FLIPR

(efficacy of >60%) were also fully efficacious in FSLPD.

Compounds that showed partial agonist activity in FLIPR

were also evaluated in FSLPD. Interestingly, racemic com-

pounds such as 21, 23, and 54 that were partial agonists in

FLIPR were full agonists in FSLPD. For example, the racemic

trans ethyl derivative, compound 21, which had only 40%

efficacy in FLIPR, was a full agonist in FSLPD (88%). The

more potent enantiomer of 21, compound 21b, did display a

reduced efficacy in FSLPD relative to 21 with 77% efficacy.

Single enantiomers, compounds 23b, 29b, 31b, 39b, 71a, 74b,

and 76b that had reduced activity in FLIPR (45%, 68%, 59%,

39%, 40%, 57%, and 37%) also had reduced efficacy in FSLPD

(30%, 51%, 35%, 66%, 54%, 41%, and 38%).

Plots were generated in order to evaluate if potency in FLIPR

predicts potency in FSLPD.²⁹As can be seen from Figure 4,

the predictive value was best for compounds that were full

agonists in FLIPR (plot B, r²) 0.84) and worst for partial

Effects of Substitution on a Dione

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6875

Figure 4. Comparison of potencies between FLIPR and FSLDP.

Table 5. Compound 23b in Neurogenic vs Myogenic Rat Models^a

neurogenic model

% ∆ AUC % ∆ MAP

myogenic model

concn

(µmol/kg)

% ∆ AUC

% ∆ MAP

0.03

0.1

0.3

1

-4.2 (14.3)^b

-19.1 (11.4)

-5.1 (1.2)^b

-9.6 (1.3)

-23.6 (2.7)

-40.7 (1.6)

-16 (7.7)^b

-31.9 (4.1) -43.8 (1.9)

-37.4 (4)^c-49.7 (2.4)^c

-22.6 (4.0)^b-46.7 (10.4)

-93.1 (6.1)

3

^aData expressed as % reduction in the area under the curve (AUC) of

bladder contractions. Standard error of the mean (SEM) is in parentheses.

Number of observations n is 7 unless otherwise indincated. ^bn ) 3. ^cn )

4.

Figure 5. Comparison of FSLPD with SLPD for 23b.

As can be seen in Figure 5, compound 23b was fully

efficacious in SLPD but only partially efficacious in FSLPD.

This agent has a unique pharmacological profile compared to

prototypical K_ATPchannel openers such as 1 and 3, which are

all fully efficacious in both SLPD and FSLPD. This agent is

also different from tolterodine, a muscarinic antagonist used

clinically to treat OAB that acts via neurogenic mechanisms.

Tolterodine is partially efficacious for relaxing FSLPD (pEC₅₀

) 7.1 ( 0.17 with 50% efficacy) but is inactive at relaxing

SLPD.²⁶Spontaneous contractions in detrusor tissue are believed

to be myogenic in origin.²We hypothesized that a compound

such as 23b might be more selective in vivo for relaxing

myogenic contractions over neurogenic contractions.

In Vivo. Compound 23b was evaluated in the partial outlet

obstructed rat and in the urethral ligated rat, using models of

spontaneous myogenic bladder contractions and volume-induced

reflex neurogenic bladder contractions, respectively.³⁰The

results are displayed in Figure 6 and Table 5. As can be seen

from the plots, compound 23b was completely effective at

eliminating myogenic bladder contractions, whereas it was only

agonists (plot C, r²) 0.27). Overall, compounds that were

weaker in FLIPR (pEC₅₀≈ 6) had similar potencies in FSLPD

whereas more potent compounds (pEC₅₀> 7) in FLIPR were

over an order of magnitude less potent in FSLPD.

SLPD. Several of the compounds were evaluated for their

K_ATPchannel opening activity in SLPD (see Table 4). As seen

with other K_ATPchannel openers,^16,17,26all of the compounds

displayed greater potency to relax spontaneous bladder contrac-

tions than to inhibit those elicited by electrical stimulation.

Interestingly, all of the compounds, including the ones that were

partial agonists in FSLPD, were fully efficacious in SLPD.

Functional selectivity can be achieved by increasing the

separation between the potencies for the desired and undesired

responses. Functional selectivity can also be achieved by

reducing or eliminating the efficacy of the undesired response.

The partial agonists described herein are more potent for relaxing

SLPD over FSLPD and have reduced efficacy in the FSLPD

model.

Figure 6. Compound 23b: myogenic vs neurogenic activity in vivo.

6876 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23

Altenbach et al.

partially efficacious against neurogenically mediated contrac-

tions at a dose 3-fold higher. At the doses tested, these effects

on myogenic and neurogenic contractile activity parallel what

was observed in vitro.

whereas (S)-stereochemistry at the benzylic position was, in

general, the more potent enantiomer in the trans isomers. Partial

agonist activity in FLIPR and FSLPD was observed with several

Et and Pr trans substituted compounds. These agents were potent

and full agonists at relaxing SLPD and thus were highly selective

for spontaneous (SLPD) versus field-stimulated (FSLPD) blad-

der strips. In vivo, compound 23b fully inhibited myogenic

contractions but only partially inhibited neurogenic contractions.

This unique pharmacological profile of selectively relaxing

myogenic contractions over neurogenic contractions may be

useful as an alternative treatment for OAB.

Blood pressure effects were monitored simultaneously in the

two models and were similar in both assays. Over the dose range

examined, compound 23b reduced MAP in parallel with effects

on inhibiting reflex neurogenic contractions. A maximum

reduction in MAP of 49.7% was observed at 3 mmol/kg iv.

Solubility limitations prevented the exploration of higher doses

to assess whether the MAP effects plateaued at this level.

Nonetheless, the magnitude of the MAP effects observed at the

approximate ED₅₀(0.3 mmol/kg) for inhibition of spontaneous

bladder contractions was similar to that seen with ZD6169 and

cromakalim.³⁰

Similar to compound 23b, other K_ATPchannel openers tested

in vivo also relaxed myogenic contractions more potently than

neurogenic contractions.³⁰But unlike the other K_ATPchannel

openers, the efficacy of compound 23b plateaus at about 40%

in the neurogenic model. The in vivo profile of compound 23b

parallels what was observed in the in vitro functional models.

Compound 23b fully relaxed SLPD but only partially relaxed

FSLPD. As previously reported, tolterodine in the above in vivo

models partially relaxed neurogenic contractions but had no

effect on myogenic contractions.³⁰Interestingly, the in vivo

results for tolterodine also parallel the in vitro results, wherein

tolterodine was 50% efficacious in relaxing FSLPD but was

essentially inactive in suppressing contraction in SLPD.²⁶

The in vivo myogenic and neurogenic models may represent

unstable nonvoiding bladder contractions of myogenic origin

and normal bladder function, respectively. The lack of activity

of a muscarinic antagonist such as tolterodine in the myogenic

models supports the hypothesis that these spontaneous bladder

contractions are of smooth muscle origin. Normal bladder

function is largely driven by parasympathetic neurons. The

efficacy seen with tolterodine in the neurogenic model indicates

that parasympathetic activity contributes in part to these reflex

contractions.

Achieving high selectivity for relaxing myogenic contractions

over neurogenic contractions in vivo may represent an approach

to inhibiting disease-related involuntary bladder contractions

without disrupting normal voiding function. Currently, OAB is

clinically treated with muscarinic antagonists such as tolterodine.

Muscarinic antagonists reduce the efferent activity to the

bladder, which is innervated mainly by parasympathetic neurons.

Because these agents reduce the overall efferent activity to the

bladder, they may inhibit to some extent the normal micturition

reflexes of the bladder at higher doses. K_ATPchannel openers

such as 23b, with reduced efficacy for neurogenically mediated

bladder contractions, represent a novel approach toward iden-

tifying agents with potential to more selectively inhibit disease-

related bladder contractions of myogenic origin. It remains to

be determined if further optimization of this pharmacological

profile can yield agents with acceptable selectivity versus

cardiovascular effects.

Experimental Section

Chemistry. General. Proton NMR spectra were obtained on a

General Electric QE 300 or QZ 300 MHz instrument with chemical

shifts (δ) reported relative to tetramethylsilane as internal standard.

Melting points were determined on a Thomas-Hoover capillary

melting point apparatus and are uncorrected. Tricyclic DHPs for

which melting points are not reported were isolated as amorphous

solids. Elemental analyses were performed by Robertson Microlit

Laboratories. Column chromatography was carried out on silica

gel 60 (230-400 mesh). Thin-layer chromatography (TLC) was

performed using 250 mm silica gel 60 glass-backed plates with

F254 as indicator. HPLC separations were done using a Gilson

system with a 215 liquid handler and a UV detector. Optical

rotations were measured with a Perkin-Elmer 541 polarimeter. X-ray

crystal structures were obtained on a Bruker SMART system. All

single enantiomers described herein were enantiomerically pure to

the level of detection of chiral HPLC.

Synthesis of Carbonyl Monomers: 2-Methyl-2H-pyran-3,5-

(4H,6H)-dione (c2). A mechanically stirred suspension of NaH

(60% dispersion in mineral oil, 10 g, 0.25 mol) in THF (160 mL)

at 0 °C under N₂was treated with a solution of 3-butyn-2-ol (21 g,

0.30 mol) in THF (35 mL) over 30 min, stirred for 35 min, treated

with a solution of methyl bromoacetate in THF (50 mL) over 10

min, stirred for 30 min at 0 °C, stirred at room temperature for 16

h, and treated with 2 M HCl (150 mL). The organic layer was

isolated, and the aqueous layer was extracted with EtOAc (2 ×

100 mL). The combined organic layers were washed with brine,

dried (MgSO₄), filtered, concentrated, and distilled under vacuum

(75-90 °C at 15 mmHg) to provide methyl [(1-methyl-2-propynyl)-

oxy]acetate (20 g). ¹H NMR (CDCl₃) δ 1.51 (d, 3H), 2.46 (d, 1H),

3.76 (s, 3H), 4.25 (AB q, 2H), 4.39 (dq, 1H). This product (20 g,

0.14 mol) in MeOH (700 mL) was treated with Hg(OAc)₂(4.6 g,

0.014 mol), treated with concentrated H₂SO₄(0.5 mL), heated to

reflux for 1 h, concentrated to approximately 100 mL total volume,

treated with 1 M HCl (100 mL), and extracted with CH₂Cl₂(3 ×

100 mL). The extractions were combined, dried (MgSO₄), filtered,

and concentrated to provide methyl (1-methyl-2-oxopropoxy)-

1

acetate. H NMR (CDCl₃) δ 1.37 (d, 3H), 2.31 (s, 3H), 3.76 (s,

3H), 3.96 (q, 1H), 4.15 (AB q, 2H). A mechanically stirred solution

of KO-t-Bu in t-BuOH (1 M, 203 mL) under N₂was treated with

anhydrous ether (125 mL), cooled to 0 °C, treated with the product

from above (15.5 g, 97 mmol) in ether (55 mL) over 2 min, stirred

for 10 min, and then treated with 2 M HCl (240 mL). The layers

were separated, and the aqueous layer was extracted with EtOAc

(2 × 200 mL). The combined organic layers were washed with

brine, dried (MgSO₄), filtered, and concentrated. The residue was

purified on silica gel, eluting with hexane/EtOAc/HCO₂H/H₂O (200:

200:1:1) to provide c2. ¹H NMR (CDCl₃) δ 1.48 (d, 3H), 3.43 (d,

1H), 3.92 (d, 1H), 3.97 (q, 1H), 4.04 (d, 1H), 4.44 (d, 1H).

2,2-Dimethyl-2H-pyran-3,5(4H,6H)-dione (c3). 2-Methyl-3-

butyn-2-ol was processed as described for compound c2 to provide

the crude product, which was treated with 10% CH₂Cl₂in hexane

(5 mL) and stored at 0 °C for 1 h. The resulting crystals were

collected by filtration, washed with a cold solution of 10% CH₂-

Conclusion

In conclusion, we have demonstrated that substitution is

allowed on the flanking rings of compounds 6 and 65. In general,

smaller groups such as Me in a cis fashion on the carbon

adjacent to the NH of the DHP provided a boost in potency in

FLIPR and FSLPD. Separation of enantiomers of derivatives

of compound 6 revealed that (R)-stereochemistry at the benzylic

position was the more potent enantiomer in the cis isomers,

1

Cl₂in hexane, and dried to provide the title compound. H NMR

(CDCl₃) δ 1.25 (s, 6H), 4.16 (s, 2H), 5.20 (s, 1H), 11.70 (s, 1H).

2-Ethylpyran-3,5-dione (c4). 1-Pentyn-3-ol was processed as

described for compound c2 to provide the title compound, which

Effects of Substitution on a Dione

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6877

1

was not chromatographed. H NMR (DMSO) δ 0.90 (t, J ) 7.46

provide the title compound. ¹H NMR (CDCl₃) δ 0.90 (t, J ) 6.78

Hz, 3H), 1.28-1.35 (m, 4H), 1.49-1.60 (m, 2H), 2.08-2.15 (m,

2H), 3.64 (s, 3H), 4.54 (s, 1H); MS (DCI/NH₃) m/z 172 (M + H)⁺.

3-Amino-6-methylhept-2-enoic Acid Methyl Ester (e13).

6-Methyl-3-oxoheptanoic acid methyl ester³³was treated as de-

Hz, 3 H), 1.56-1.84 (m, 2 H), 3.87-3.97 (m, 1 H), 4.14 (s, 2 H),

5.30 (s, 1 H).

2,2-Diethylpyran-3,5-dione (c5). 3-Ethyl-1-pentyn-3-ol was

processed as described for compound c2 to provide the title

compound, which was not chromatographed. ¹H NMR (DMSO) δ

0.80 (t, J ) 7.29 Hz, 6H), 1.54 (m, 2H), 1.74 (m, 2H), 4.16 (s,

2H), 5.25 (s, 1H).

6-Oxaspiro[4.5]decane-8,10-dione (c6). 1-Ethynylcyclopentanol

was processed as described for compound c2 to provide the title

compound, which was not chromatographed. H NMR (DMSO-

1

scribed for compound e6 to provide the title compound. H NMR

(CDCl₃) δ 0.91 (d, J ) 6.78 Hz, 6H), 1.38-1.49 (m, 2H), 1.52-

1.70 (m, 1H), 2.08-2.17 (m, 2H), 3.64 (s, 3H), 4.55 (s, 1H).

3-Aminonon-2-enoic Acid Methyl Ester (e14). 3-Oxononanoic

acid methyl ester³²was treated as described for compound e6 to

provide the title compound. ¹H NMR (CDCl₃) δ 0.88 (t, J ) 6.78

Hz, 3H), 1.23-1.39 (m, 6H), 1.46-1.61 (m, 2H), 2.09-2.15 (m,

2H), 3.64 (s, 3H), 4.54 (s, 1H); MS (DCI/NH₃) m/z 186 (M + H)⁺.

3-Amino-4-phenylbut-2-enoic Acid Ethyl Ester (e15). 3-Oxo-

4-phenylbutyric acid ethyl ester³⁴was treated as described for

1

d₆) δ 1.60-1.72 (m, 4H), 1.72-1.91 (m, 4H), 4.14 (s, 2H), 5.27

(s, 1H), 11.5 (bs, 1H).

Synthesis of Enamine Monomers: 5-Amino-6-methyl-2H-

pyran-3(6H)-one (e2). Compound c2 (3.0 g, 23 mmol) was

dissolved in EtOH (50 mL), treated with concentrated H₂SO₄(5

drops), heated to reflux for 3 h, and concentrated. The residue was

purified by chromatography, eluting with 10:1, 5:1, and then 2:1

hexane/EtOAc to provide 5-ethoxy-2-methyl-2H-pyran-3(6H)-one

(¹H NMR (DMSO-d₆) δ 1.38 (t, 3H), 1.40 (d, 3H), 3.89-4.06 (m,

3H), 4.29 (s, 2H), 5.41 (s, 1H)) as the faster moving isomer and

5-ethoxy-6-methyl-2H-pyran-3(6H)-one (¹H NMR (DMSO-d₆) δ

1.39 (t, 3H), 1.44 (d, 3H), 3.91-4.01 (m, 2H), 4.03 (dd, 1H), 4.21

(d, 1H), 4.37 (q, 1H), 5.41 (s, 1H)) as the slower moving isomer in

a 2:1 ratio. The slower moving 5-ethoxy-6-methyl-2H-pyran-3(6H)-

one was treated with NH₃saturated EtOH (60 mL), stirred at room

temperature for 16 h, and concentrated to provide the title compound

1

compound e6 to provide the title compound. H NMR (CDCl₃) δ

1.26 (t, J ) 7.12 Hz, 3H), 3.46 (s, 2H), 4.12 (q, J ) 7.12 Hz, 2H),

4.64 (s, 1H), 7.21-7.37 (m, 5H).

3-Amino-4-ethylcyclopent-2-enone (e16). A solution of diiso-

propylethylamine (7.5 mL, 54 mmol) in THF (30 mL) under N₂at

-78 °C was treated over 5 min with n-BuLi (2.5 M in hexanes, 21

mL, 52 mmol), stirred for 30 min, treated with a solution of

3-ethoxy-2-cyclopenten-1-one (5 g, 40 mmol) in THF (30 mL)

dropwise, stirred for 45 min, treated with a solution of EtI (4.8

mL, 60 mmol) and HMPA (14 mL, 80 mmol) in THF (30 mL),

and stirred at room temperature overnight. The mixture was diluted

with Et₂O (250 mL), washed with H₂O (125 mL), washed with

brine (30 mL), dried (MgSO₄), filtered, and concentrated. The crude

product was dissolved in EtOH (200 mL), treated with concentrated

H₂SO₄(1 mL), refluxed for 1 h, cooled, concentrated to 50 mL,

treated with NaHCO₃solution (100 mL), and extracted with Et₂O

(3 × 100 mL). The combined Et₂O layers were washed with brine,

dried (MgSO₄), filtered, and concentrated to provide 4 g of crude

product. The crude product was chromatographed via multiple

injections on a YMC column, eluting with 3% EtOH in hexane to

provide 1.09 g (18%) of 3-ethoxy-5-ethylcyclopent-2-enone (¹H

NMR (CDCl₃) δ 0.94 (t, J ) 7.46 Hz, 3H), 1.35-1.54 (m, 1H),

1.41 (t, J ) 7.12 Hz, 3H), 1.77-1.93 (m, 1H), 2.29 (ddd, J )

17.63, 2.71, 1.02 Hz, 1H), 2.37-2.47 (m, 1H), 2.74 (ddd, J ) 17.55,

7.21, 1.02 Hz, 1H), 4.04 (q, J ) 7.12 Hz, 2H), 5.24 (s, 1H)) as the

less polar isomer and 1.13 g (18%) of 3-ethoxy-4-ethylcyclopent-

2-enone (¹H NMR (CDCl₃) δ 0.92 (t, J ) 7.46 Hz, 3H), 1.33-

1.52 (m, 1H), 1.43 (t, J ) 7.12 Hz, 3H), 1.76-1.92 (m, 1H), 2.12

(dd, J ) 17.80, 2.54 Hz, 1H), 2.57 (dd, J ) 17.97, 7.12 Hz, 1H),

2.71-2.85 (m, 1H), 3.95-4.11 (m, 2H), 5.24 (s, 1H)) as the more

polar isomer. A solution of 3-ethoxy-4-ethylcyclopent-2-enone (1.13

g, 7.3 mmol) in EtOH (10 mL) was treated with 28% aqueous NH₄-

OH (5 mL), heated to 85 °C for 16 h, cooled, and concentrated to

1

(0.52 g). H NMR (DMSO-d₆) δ 1.38 (d, 3H), 3.77 (d, 1H), 3.91

(d, 1H), 4.32 (q, 1H), 4.96 (s, 1H), 6.84 (bs, 1H), 7.07 (bs, 1H).

5-Amino-6,6-dimethyl-6H-pyran-3-one (e3). Compound c3 was

treated as described for compound e2 to provide the title compound.

¹H NMR (DMSO-d₆) δ 1.38 (s, 6H), 3.86 (s, 2H), 4.90 (s, 1H),

6.92 (s, 2H).

5-Amino-6-ethyl-6H-pyran-3-one (e4). Compound c4 was

treated as described for compound e2 to provide the title compound.

¹H NMR (DMSO-d₆) δ 0.95 (t, J ) 7.29 Hz, 3H), 1.65-1.88 (m,

2H), 3.38-3.49 (m, 1H), 3.74 (d, J ) 15.94 Hz, 1H), 3.89 (d, J )

15.94 Hz, 1H), 4.10 (dd, J ) 8.99, 3.56 Hz, 1H), 4.97 (s, 1H),

6.97 (bs, 2H).

3-Aminopent-2-enoic Acid Methyl Ester (e6). A mixture of

methyl 3-oxopentanoate (10 g, 77 mmol) and 2 M NH₃in EtOH

(100 mL) was heated to 80 °C for 16 h in a sealed tube. After

cooling, the mixture was concentrated to dryness to provide the

title compound. H NMR (CDCl₃) δ 1.15 (t, J ) 7.63 Hz, 3H),

2.17 (q, J ) 7.46 Hz, 2H), 3.65 (s, 3H), 4.56 (s, 1H).

Ethyl (2E)-3-Amino-4-methyl-2-pentenoate (e7). Ethyl 4-meth-

yl-3-oxopentanoate was treated as described for compound e6 to

provide the title compound. ¹H NMR (CDCl₃) δ 1.16 (d, 6H), 1.26

(t, 3H), 2.32 (m, 1H), 4.11 (q, 2H), 4.57 (s, 1H)

1

dryness to provide 0.9 g (98%) of the title compound. H NMR

3-Aminohex-2-enoic Acid Methyl Ester (e8). Methyl butyryl

acetate was treated as described for compound e6 to provide the

title compound. H NMR (CDCl₃) δ 0.96 (t, J ) 7.29 Hz, 3H),

1.26 (t, J ) 7.12 Hz, 3H), 1.51-1.65 (m, 2H), 2.10 (t, J ) 7.80

Hz, 2H), 4.11 (q, J ) 7.12 Hz, 2H), 4.54 (s, 1H).

(DMSO-d₆) δ 0.82 (t, J ) 7.29 Hz, 3H), 1.25-1.42 (m, 1H), 1.69-

1.85 (m, 1H), 1.80 (dd, J ) 17.12, 2.54 Hz, 1H), 2.25 (dd, J )

17.29, 7.46 Hz, 1H), 2.57-2.67 (m, 1H), 4.74 (s, 1H), 6.98 (s,

1H), 7.29 (s, 1H); MS (ESI+) m/z 126 (M + H)⁺; MS (ESI-) m/z

124 (M - H)^-.

1

3-Aminohept-2-enoic Acid Ethyl Ester (e9). 3-Oxoenanthic

acid ethyl ester was treated as described for compound e6 to provide

the title compound. ¹H NMR (CDCl₃) δ 0.92 (t, J ) 7.29 Hz, 3H),

1.26 (t, J ) 7.12 Hz, 3H), 1.30-1.43 (m, 2H), 1.48-1.59 (m, 2H),

2.12 (t, J ) 7.80 Hz, 2H), 4.11 (q, J ) 7.12 Hz, 2H), 4.54 (s, 1H).

3-Amino-5-methoxypent-2-enoic Acid Methyl Ester (e10).

5-Methoxy-3-oxovaleric acid methyl ester was treated as described

for compound e6 to provide the title compound. ¹H NMR (CDCl₃)

δ 2.38 (t, J ) 5.76 Hz, 2H), 3.36 (s, 3H), 3.58 (t, J ) 5.42 Hz,

2H), 3.64 (s, 3H), 4.49 (s, 1H); MS (DCI/NH₃) m/z 160 (M + H)⁺.

3-Amino-5-methylhex-2-enoic Acid Methyl Ester (e11). 5-Meth-

yl-3-oxohexanoic acid methyl ester³¹was treated as described for

General Methods for Synthesizing Final Products. Method

A: Methyl 4-(3-Bromo-4-fluorophenyl)-2,6-dimethyl-5-oxo-

4,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxylate. Car-

bonyl c2 (1.3 g, 10 mmol), 3-bromo-4-fluorobenzaldehyde (2.4 g,

12 mmol), and methyl 3-aminocrotonate (e5) (1.2 g, 10 mmol) in

EtOH (10 mL) were heated at 80 °C in a sealed tube for 16 h.

After cooling to room temperature, the mixture was filtered and

the filtercake washed with EtOH and dried to provide the title

compound. The filtrate was concentrated and chromatographed on

silica gel, eluting with a gradient of 1%, 2%, and 5% MeOH in

CH₂Cl₂to provide additional quantities of the title compound: 1.03

g total (25% yield). MS (ESI+) m/z 410 (M + H)⁺; MS (ESI-)

m/z 408 (M - H)^-.

1

compound e6 to provide the title compound. H NMR (CDCl₃) δ

0.94 (s, 3H), 0.96 (s, 3H), 1.78-2.01 (m, 3H), 3.65 (s, 3H), 4.52

Method B: cis-10-(3-Bromo-4-fluorophenyl)-1-ethyl-9,10-

dihydro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (70) and

trans-10-(3-Bromo-4-fluorophenyl)-1-ethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (71). A mixture of enamine

(s, 1H).

3-Aminooct-2-enoic Acid Methyl Ester (e12). 3-Oxooctanoic

acid methyl ester³²was treated as described for compound e6 to

6878 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23

Altenbach et al.

e4 (1.3 g, 9.2 mmol), 4-bromo-3-fluorobenzaldehyde (2.4 g, 12

mmol), and pyran-3,5-dione³⁵c1 (1.3 g, 11 mmol) in EtOH (16

mL) was heated to 80 °C in a sealed tube for 20 h, cooled to room

temperature, treated with a 1 M solution of HCl in Et₂O (5 mL),

heated to 80 °C for 45 min, cooled to room temperature, and

concentrated to dryness. The residue, which contained a mixture

of cis and trans isomers, was purified by chromatography using a

gradient of 2%, 3%, and 4% EtOH in CH₂Cl₂to provide 71 (1.3 g,

33%, less polar; mp 244-245 °C; ¹H NMR (DMSO-d₆) δ 1.02 (t,

3H), 1.59-1.67 (m, 1H), 1.89-2.03 (m, 1H), 3.93 (d, 1H), 4.03

(s, 2H), 4.22 (d, 1H), 4.42 (dd, 1H), 4.51 (AB q, 2H), 4.92 (s, 1H),

7.18-7.30 (m, 2H), 7.41 (dd, 1H), 9.96 (s, 1H); MS (ESI+) m/z

422 (M + H)⁺; MS (ESI-) m/z 420 (M - H)^-; Anal. (C₁₉H₁₇-

NO₄FBr) C, H, N) and 70 (1.6 g, 41%, more polar; mp 221-226

Chiralcel OJ column, eluting with 3:1 hexane/EtOH to provide 7b

(less polar; mp 267-277 °C; Anal. (C₁₇H₁₃NO₄FBr) C, H, N; [R]²³

D

-232 (c 0.26, acetone)) and 7a (more polar; mp 261-274 °C; Anal.

(C₁₇H₁₃NO₄FBr) C, H, N; [R]²³+274 (c 0.28, acetone)).

D

(+)-trans-9-(3-Bromo-4-fluorophenyl)-7-methyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (8a)

and (-)-trans-9-(3-Bromo-4-fluorophenyl)-7-methyl-5,9-dihy-

dro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-di-

one (8b). The enantiomers of compound 8 (330 mg) were separated

using a (R,R)-Whelk-O1 column, eluting with 3:2:1 hexane/CH₃-

OH/CH₂Cl₂to provide 8b (less polar; Anal. (C₁₇H₁₃NO₄FBr) C,

H, N; [R]²³- 78 (c 0.27, acetone)) and 8a (more polar; Anal.

D

(C₁₇H₁₃NO₄FBr) C, H, N; [R]²³+88 (c 0.27, acetone)).

D

9-(3-Bromo-4-fluorophenyl)-7,7-dimethyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (9). Carbonyl

c3 (0.50 g, 3.5 mmol), 3-bromo-4-fluorobenzaldehyde (0.88 g, 4.2

mmol), and methyl 3-aminocrotonate (0.40 g, 3.5 mmol) via

methods A and C provided the title compound (0.31 g, 22%): mp

1

°C; H NMR (DMSO-d₆) δ 0.96 (t, J ) 7.29 Hz, 3H), 1.91-2.03

(m, 2H), 3.98-4.15 (m, 4H), 4.42-4.51 (m, 2H), 4.63 (d, J )

16.28 Hz, 1H), 4.96 (s, 1H), 7.17 (ddd, J ) 8.39, 5.00, 2.20 Hz,

1H), 7.27 (t, J ) 8.65 Hz, 1H), 7.37 (dd, J ) 6.78, 2.03 Hz, 1H),

9.54 (s, 1H); MS (ESI+) m/z 422 (M + H)⁺; MS (ESI-) m/z 420

(M - H)^-; Anal. (C₁₉H₁₇NO₄FBr) C, H, N).

1

>250 °C; H NMR (DMSO-d₆) δ 1.15 (s, 3H), 1.26 (s, 3H), 4.55

(s, 2H), 4.68 (s, 1H), 4.83 (dd, 1H), 4.98 (d, 1H), 7.26 (m, 2H),

7.46 (dd, 1H), 10.40 (s, 1H); MS (APCI+) m/z 408 (M + H)⁺;

Anal. (C₁₈H₁₅BrFNO₄‚0.1CHCl₃) C, H, N.

Method C: (cis)-9-(3-Bromo-4-fluorophenyl)-7-methyl-5,9-

dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-di-

one (7) and (trans)-9-(3-Bromo-4-fluorophenyl)-7-methyl-5,9-

dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-

dione (8). The product from method A (1.0 g, 2.5 mmol) was

dissolved in CHCl₃(15 mL) under N₂, cooled to 0 °C, treated with

pyridine (0.24 mL, 3.0 mmol) and pyridinium tribromide (0.97 g,

3.0 mmol), stirred at 0 °C for 20 min, diluted with CH₂Cl₂(100

mL), and treated with 1 M HCl (10 mL). The layers were separated,

and the aqueous layer was extracted with CH₂Cl₂(50 mL). The

combined organic layers were dried (MgSO₄), filtered, concentrated,

heated neat to 130 °C under N₂for 15 min, and cooled to room

temperature. The residue was purified by chromatography on silica

gel, eluting with 40:38:1:1 hexane/EtOAc/HCO₂H/H₂O to provide

the trans isomer (compound 8) as the faster moving isomer and

the cis isomer (compound 7) as the slower moving isomer. Both

isomers were crystallized from CH₂Cl₂. Compound 7: mp 234-

(+)-9-(3-Bromo-4-fluorophenyl)-7,7-dimethyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (9a)

and (-)-9-(3-Bromo-4-fluorophenyl)-7,7-dimethyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (9b).

The enantiomers of compound 9 (500 mg) were separated using a

Chiralpak AS column, eluting with 6:4 hexane/EtOH to provide

9a (less polar; mp 246-252 °C; Anal. (C₁₈H₁₅BrFNO₄) C, H, N;

[R]²³+199 (c 0.28, acetone)) and 9b (more polar; mp 242-250

D

°C; Anal. (C₁₈H₁₅BrFNO₄) C, H, N; [R]²³_D-235 (c 0.24, acetone)),

each of which were individually rechromatographed with 2% and

5% MeOH in CH₂Cl₂.

cis-9-(3-Bromo-4-fluorophenyl)-7-ethyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (10) and trans-

9-(3-Bromo-4-fluorophenyl)-7-ethyl-5,9-dihydro-3H,4H-2,6-dioxa-

4-azacyclopenta[b]naphthalene-1,8-dione (11). Carbonyl c4 (0.50

g, 3.5 mmol), 3-bromo-4-fluorobenzaldehyde (0.88 g, 4.2 mmol),

and methyl 3-aminocrotonate (0.40 g, 3.5 mmol) via method A

(42% yield) and method C provided 11 as the less polar product

(75 mg, 5%) and 10 as the more polar product (125 mg, 9%).

Compound 11: ¹H NMR (DMSO-d₆) δ 0.89 (t, J ) 7.46 Hz, 3H),

1.59-1.72 (m, 2H), 3.89 (t, J ) 7.12 Hz, 1H), 4.48 (d, J ) 16.27

Hz, 1H), 4.62 (d, J ) 15.93 Hz, 1H), 4.67 (s, 1H), 4.86 (dd, J )

16.27, 1.02 Hz, 1H), 4.99 (d, J ) 16.61 Hz, 1H), 7.26 (dd, J )

6.10, 1.02 Hz, 2H), 7.46-7.50 (m, 1H), 10.41 (s, 1H); mp 227-

233 °C; MS (ESI+) m/z 408 (M + H)⁺, 425 (M + NH₄)⁺; MS

(ESI-) m/z 406 (M - H)^-; Anal. (C₁₈H₁₅BrFNO₄) C, H, N.

Compound 10: ¹H NMR (DMSO-d₆) δ 0.76 (t, J ) 7.29 Hz, 3H),

1.45-1.60 (m, 1H), 1.69-1.81 (m, 1H), 3.95 (ddd, J ) 7.12, 3.73,

1.02 Hz, 1H), 4.49-4.64 (m, 2H), 4.76 (s, 1H), 4.86 (dd, J ) 16.27,

1.36 Hz, 1H), 5.01 (d, J ) 16.27 Hz, 1H), 7.25-7.30 (m, 2H),

7.42-7.47 (m, 1H), 10.45 (s, 1H); mp 227-229 °C; MS (ESI+)

m/z 408 (M + H)⁺, 425 (M + NH₄)⁺; MS (ESI-) m/z 406 (M -

H)^-; Anal. (C₁₈H₁₅BrFNO₄) C, H, N.

1

239 °C; H NMR (DMSO-d₆) δ 1.16 (d, 3H), 4.11 (q, 1H), 4.55

(s, 2H), 4.72 (s, 1H), 4.86 (dd, 1H), 5.01 (d, 1H), 7.22-7.32 (m,

2H), 7.46 (dd, 1H), 10.45 (bs, 1H); MS (ESI+) m/z 394 (M +

H)⁺, 411 (M + NH₄)⁺; MS (ESI-) m/z 392 (M - H)^-; Anal.

1

(C₁₇H₁₃NO₄FBr) C, H, N. Compound 8: mp >260 °C; H NMR

(DMSO-d₆) δ 1.22 (d, 3H), 4.12 (q, 1H), 4.48 (d, 1H), 4.65 (d,

1H), 4.68 (s, 1H), 4.86 (dd, 1H), 4.99 (d, 1H), 7.24-7.28 (m, 2H),

7.48 (dd, 1H), 10.42 (bs, 1H); MS (ESI+) m/z 394 (M + H)⁺, 411

(M + NH₄)⁺; MS (ESI-) m/z 392 (M - H)^-; Anal. (C₁₇H₁₃NO₄-

FBr‚0.2CH₂Cl₂) C, H, N.

4-(3-Bromo-4-fluorophenyl)-2-isopropyl-5-oxo-4,5,6,8-tetrahy-

dro-1H-pyrano[3,4-b]pyridine-3-carboxylic Acid Ethyl Ester.

Pyran-3,5-dione³⁵(c1) (0.30 g, 2.6 mmol), 3-bromo-4-fluoroben-

zaldehyde (0.70 g, 3.4 mmol), and enamine e7 (0.50 g, 3.2 mmol)

via method A (0.75 g, 53%) provided the title compound.

Method D: 9-(3-Bromo-4-fluorophenyl)-3,3-dimethyl-5,9-

dihydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-di-

one (19). The compound from above (4-(3-bromo-4-fluorophenyl)-

2-isopropyl-5-oxo-4,5,6,8-tetrahydro-1H-pyrano[3,4-b]pyridine-3-

carboxylic acid ethyl ester) (0.58 g, 1.3 mmol) was dissolved in

CHCl₃(20 mL), treated with NBS (0.29 g, 1.6 mmol), stirred at

RT for 30 min, refluxed for 1.5 h, concentrated to dryness, heated

neat to 130 °C for 15 min, cooled, chromatographed (2% and then

5% MeOH in CH₂Cl₂) and crystallized from EtOAc/hexane to

(+)-cis-9-(3-Bromo-4-fluorophenyl)-7-ethyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (10a) and

(-)-cis-9-(3-Bromo-4-fluorophenyl)-7-ethyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (10b). The

enantiomers of compound 10 (80 mg) were separated using a

Chiralpak AS column, eluting with 1:4 EtOH/hexane to provide

10a (less polar, 35 mg; Anal. (C₁₈H₁₅BrFNO₄‚0.25 acetone) C, H,

1

provide 19 (127 mg, 19%). mp 219-221 °C; H NMR (DMSO-

N; [R]²³+235 (c 0.27, acetone)) and 10b (more polar, 30 mg;

d₆) δ 1.49 (s, 3H), 1.50 (s, 3H), 4.06 (s, 2H), 4.57 (AB q, 2H),

4.73 (s, 1H), 7.22 (m, 1H), 7.29 (t, 1H), 7.47 (dd, 1H), 10.44 (bs,

1H); MS (ESI+) m/z 408 (M + H)⁺, 425 (M + NH₄)⁺; MS (ESI-)

m/z 406 (M - H)^-; Anal. (C₁₈H₁₅NO₄FBr) C, H, N.

D

Anal. (C₁₈H₁₅BrFNO₄) C, H, N; [R]²³-235 (c 0.18, acetone)).

D

(cis)-9-(3-Bromo-4-fluorophenyl)-5-methyl-5,9-dihydro-3H-

furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (12) and

(trans)-9-(3-Bromo-4-fluorophenyl)-5-methyl-5,9-dihydro-3H-

furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (13). Enamine

e2 (0.50 g, 3.9 mmol), 3-bromo-4-fluorobenzaldehyde (0.96 g, 4.7

mmol), and methyl acetoacetate (0.46 g, 3.9 mmol) via method A

(0.97 g, 61%), heating for 60 h instead of 16 h, and method C, but

(+)-cis-9-(3-Bromo-4-fluorophenyl)-7-methyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (7a)

and (-)-cis-9-(3-Bromo-4-fluorophenyl)-7-methyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (7b).

The enantiomers of compound 7 (430 mg) were separated using a

Effects of Substitution on a Dione

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6879

eluting with 40:38:1:1, 30:38:1:1, and then 20:38:1:1 hexanes/

enantiomers of compound 17 (470 mg) were separated using a

Chiralpak AS column, eluting with 1:1 EtOH/hexane to provide

17a (95 mg, less polar, rechromatographed with 2% MeOH in CH₂-

Cl₂; mp 230-233 °C; Anal. (C₁₇H₁₃NO₄FBr) C, H, N; [R]²³_D+204

(c 0.18, acetone)) and 17b (65 mg, more polar, crystallized from

EtOAc/hexane; mp 230-233 °C; Anal. (C₁₇H₁₃NO₄FBr) C, H, N;

EtOAc/HCO₂H/H₂O, provided 13 (55 mg, 4%) (less polar, crystal-

1

lized from EtOAc/hexanes; mp 240-243 °C; H NMR (DMSO-

d₆) δ 1.50 (d, 3H), 3.96 (d, 1H), 4.24 (d, 1H), 4.72-4.80 (m, 2H),

4.88 (d, 1H), 5.01 (d, 1H), 7.25-7.29 (m, 2H), 7.48 (dd, 1H), 10.32

(bs, 1H); MS (ESI+) m/z 394 (M + H)⁺, 411 (M + NH₄)⁺; MS

(ESI-) m/z 392 (M - H)^-; Anal. (C₁₇H₁₃NO₄FBr 0.25 H₂O) C,

H, N)) and 12 (140 mg, 9%) (more polar, crystallized from EtOAc/

[R]²³-169 (c 0.26, acetone)).

D

(+)-(trans)-9-(3-Bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-

3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (18a) and

(-)-(trans)-9-(3-Bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-

3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (18b). The

enantiomers of compound 18 (250 mg) were separated using a

Chiralpak AS column, eluting with 3:7 EtOH/hexane to provide

18a (less polar, crystallized from EtOAc/hexane, 25 mg; mp >260

°C; Anal. (C₁₇H₁₃NO₄FBr) C, H, N; [R]²³_D+282 (c 0.34, DMSO))

and 18b (more polar, crystallized from EtOAc/hexane, 25 mg; mp

1

hexane; mp 260-263 °C; H NMR (DMSO-d₆) δ 1.52 (d, 3H),

4.07 (s, 2H), 4.66 (q, 1H), 4.77 (s, 1H), 4.86 (dd, 1H), 5.02 (d,

1H), 7.20-7.26 (m, 1H), 7.29 (t, 1H), 7.46 (dd, 1H), 10.12 (bs,

1H); MS (ESI+) m/z 394 (M + H)⁺, 411 (M + NH₄)⁺; MS (ESI-)

m/z 392 (M - H)^-; Anal. (C₁₇H₁₃NO₄FBr) C, H, N)).

9-(3-Bromo-4-fluorophenyl)-5,5-dimethyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (14). Enam-

ine e3 (0.52 g, 3.7 mmol), 3-bromo-4-fluorobenzaldehyde (0.89 g,

4.4 mmol), methyl acetoacetate (0.43 g, 3.7 mmol) via method A,

heating for 60 h instead of 16 h (0.60 g, 38%), and method C, but

purified with 2% MeOH in CH₂Cl₂, provided 14 (recrystallized

>260 °C; Anal. (C₁₇H₁₃NO₄FBr) C, H, N; [R]²³-285 (c 0.21,

D

DMSO)).

(cis)-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,9-dihydro-3H-furo-

[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (20) and (trans)-

9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,9-dihydro-3H-furo[3,4-b]-

pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (21). Enamine e8 (0.083

g, 0.52 mmol), pyran-3,5-dione³⁵(0.050 g, 0.44 mmol), and

3-bromo-4-fluorobenzaldehyde (0.116 g, 0.57 mmol) via method

A (0.17 g, 90%) and method D provided after chromatography (40:

38:1:1, 30:38:1:1, and then 20:38:1:1 hexane/EtOAc/HCO₂H/H₂O)

21 as the less polar isomer (crystallized from CH₂Cl₂; mp 161-

1

from EtOAc/hexane, 125 mg, 8%). H NMR (DMSO-d₆) δ 1.51

(s, 3H), 1.54 (s, 3H), 3.98 (d, J ) 16.95 Hz, 1H), 4.24 (d, J )

16.61 Hz, 1H), 4.76 (s, 1H), 4.89 (dd, J ) 16.61, 1.36 Hz, 1H),

5.02 (d, J ) 16.61 Hz, 1H), 7.22 (ddd, J ) 8.48, 5.09, 2.03 Hz,

1H), 7.29 (t, J ) 8.65 Hz, 1H), 7.46 (dd, J ) 6.78, 2.03 Hz, 1H),

10.05 (s, 1H); mp >260 °C; MS (ESI+) m/z 408 (M + H)⁺; MS

(ESI-) m/z 406 (M - H)^-; Anal. (C₁₈H₁₅BrFNO₄) C, H, N.

(cis)-9-(3-Bromo-4-fluorophenyl)-5-ethyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (15) and

(trans)-9-(3-Bromo-4-fluorophenyl)-5-ethyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (16). Enam-

ine e4 (0.50 g, 3.5 mmol), 3-bromo-4-fluorobenzaldehyde (0.94 g,

4.6 mmol), and methyl acetoacetate (0.50 g, 4.3 mmol) via method

A (0.70 g, 47%) and method C provided 16 (less polar, 87 mg,

1

162 °C; H NMR (DMSO-d₆) δ 0.84 (t, 3H), 1.54-1.70 (m, 1H),

1.92-2.06 (m, 1H), 4.05 (s, 2H), 4.55 (AB q, 2H), 4.74 (s, 1H),

5.21 (dd, 1H), 7.27-7.31 (m, 2H), 7.49 (m, 1H), 10.42 (bs, 1H);

MS (ESI+) m/z 408 (M + H)⁺, 425 (M + NH₄)⁺; MS (ESI-) m/z

406 (M - H)^-; Anal. (C₁₈H₁₅NO₄FBr) C, H, N) and 20 as the

more polar isomer (crystallized from EtOAc/hexane; mp 246-248

°C; ¹H NMR (DMSO-d₆) δ 0.81 (t, 3H), 1.63-1.79 (m, 1H), 1.95-

2.09 (m, 1H), 4.05 (s, 2H), 4.55 (AB q, 2H), 4.74 (s, 1H), 5.12 (m,

1H), 7.23 (ddd, 1H), 7.29 (t, 1H), 7.45 (dd, 1H), 10.43 (bs, 1H);

MS (ESI+) m/z 408 (M + H)⁺, 425 (M + NH₄)⁺; MS (ESI-) m/z

406 (M - H)^-; Anal. (C₁₈H₁₅NO₄FBr) C, H, N).

1

15%; H NMR (DMSO-d₆) δ 1.02 (t, J ) 7.12 Hz, 3H), 1.63-

1.78 (m, 1H), 1.93-2.06 (m, 1H), 3.94 (d, J ) 16.95 Hz, 1H),

4.19 (d, J ) 16.62 Hz, 1H), 4.47 (dd, J ) 10.51, 2.71 Hz, 1H),

4.74 (s, 1H), 4.87 (d, J ) 16.28 Hz, 1H), 5.01 (d, J ) 16.62 Hz,

1H), 7.27 (d, J ) 7.12 Hz, 2H), 7.48 (d, J ) 6.78 Hz, 1H), 10.34

(s, 1H); MS (ESI+) m/z 408 (M + H)⁺; MS (ESI-) m/z 406 (M

- H)^-; Anal. (C₁₈H₁₅BrFNO₄‚0.5 acetone) C, H, N)) and compound

15 (more polar, 120 mg, rechromatographed using 2:1 hexane/

acetone; mp 236-240 °C (dec); ¹H NMR (DMSO-d₆) δ 0.98 (t, J

) 7.29 Hz, 3H), 1.89-2.00 (m, 2H), 4.08 (AB q, 2H), 4.54 (t, J )

5.09 Hz, 1H), 4.76 (s, 1H), 4.85 (dd, J ) 16.28, 1.02 Hz, 1H),

5.02 (d, J ) 16.28 Hz, 1H), 7.22 (ddd, J ) 8.48, 4.92, 2.20 Hz,

1H), 7.29 (t, J ) 8.65 Hz, 1H), 7.44 (dd, J ) 6.61, 2.20 Hz, 1H),

10.15 (s, 1H); MS (ESI+) m/z 408 (M + H)⁺; MS (ESI-) m/z

406 (M - H)^-; Anal. (C₁₈H₁₅BrFNO₄) C, H, N).

(+)-(cis)-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,9-dihydro-3H-

furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (20a) and

(-)-(cis)-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,9-dihydro-3H-

furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (20b). The

enantiomers of compound 20 (500 mg) were separated using a

(R,R)-Whelk-O1 column, eluting with 9:4:2 hexane/MeOH/CH₂-

Cl₂to provide 20b (less polar, crystallized from EtOH; mp 131-

136 °C (foams); Anal. (C₁₈H₁₅NO₄FBr EtOH) C, H, N; [R]²³_D-163

(c 1.1, acetone)) and 20a (more polar, crystallized from EtOH; mp

131-136 °C (foams); Anal. (C₁₈H₁₅NO₄FBr EtOH) C, H, N; [R]²³

+123 (c 0.61, acetone)).

D

(cis)-9-(3-Bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-3H-

furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (17) and

(trans)-9-(3-Bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-3H-

furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (18). 5-Amino-

6H-pyran-3-one³⁵(e1) (0.82 g, 7.3 mmol), 3-bromo-4-fluoroben-

zaldehyde (1.8 g, 8.7 mmol), and methyl 3-oxopentanoate (1.0 g,

7.3 mmol) via method A (0.53 g, 18%) and method C, eluting with

40:38:1:1, 30:38:1:1, and then 20:38:1:1 hexanes/EtOAc/HCO₂H/

H₂O, provided compound 18 (70 mg, 2%) (less polar; mp >260

°C; ¹H NMR (DMSO-d₆) δ 1.43 (d, 3H), 4.05 (s, 2H), 4.55 (AB q,

2H), 4.74 (s, 1H), 5.26 (q, 1H), 7.26-7.30 (m, 2H), 7.49 (d, 1H),

10.44 (bs, 1H); MS (ESI+) m/z 394 (M + H)⁺, 411 (M + NH₄)⁺;

MS (ESI-) m/z 392 (M - H)^-; Anal. (C₁₇H₁₃NO₄FBr) C, H, N))

(R)-(+)-(trans)-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,9-dihy-

dro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (21a)

and (S)-(-)-(trans)-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,9-di-

hydro-3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione

(21b). The enantiomers of compound 21 (500 mg) were separated

using a Chiralpak AS column, eluting with 1:9 EtOH/hexane to

provide 21a (less polar; mp 249-251 °C; Anal. (C₁₈H₁₅NO₄FBr)

C, H, N; [R]²³+229 (c 1.0, acetone)) and 21b (more polar,

D

crystallized from EtOH; mp 250-252 °C; Anal. (C₁₈H₁₅NO₄FBr)

C, H, N; [R]²³-229 (c 0.43, acetone)).

D

cis-9-(3-Bromo-4-fluorophenyl)-3-propyl-5,9-dihydro-3H-furo-

[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (22) and trans-

9-(3-Bromo-4-fluorophenyl)-3-propyl-5,9-dihydro-3H-furo[3,4-

b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (23). Enamine e9 (0.42

g, 2.6 mmol), 3-bromo-4-fluorobenzaldehyde (0.56 g, 2.9 mmol),

and pyran-3,5-dione³⁵c1 (0.25 g, 2.2 mmol) via method A (0.71

g, 71%) and method D provided, after chromatography using

hexane/EtOAc/HCO₂H/H₂O (40:38:1:1, 30:38:1:1, and then 20:38:

1:1), 23 (58 mg, 5%) (less polar, rechromatographed using 2%

MeOH in CH₂Cl₂, rechromatograhed using hexanes:acetone (3:1),

1

and compound 17 (77 mg, 3%) (more polar; mp 213-216 °C; H

NMR (DMSO-d₆) δ 1.45 (d, 3H), 4.05 (s, 2H), 4.55 (AB q, 2H),

4.75 (s, 1H), 5.15 (q, 1H), 7.19-7.25 (m, 1H), 7.29 (t, 1H), 7.47

(dd, 1H), 10.48 (bs, 1H); MS (ESI+) m/z 394 (M + H)⁺, 411 (M

+ NH₄)⁺; MS (ESI-) m/z 392 (M - H)^-; Anal. (C₁₇H₁₃NO₄FBr)

C, H, N).

(+)-(cis)-9-(3-Bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-

3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (17a) and

(-)-(cis)-9-(3-Bromo-4-fluorophenyl)-3-methyl-5,9-dihydro-3H-

furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (17b). The

1

recrystallized from acetone/hexanes; mp 206-208 °C; H NMR

6880 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23

Altenbach et al.

(DMSO-d₆) δ 0.92 (t, 3H), 1.28-1.42 (m, 2H), 1.47-1.61 (m, 1H),

1.86-1.98 (m, 1H), 4.05 (s, 2H), 4.54 (AB q, 2H), 4.73 (s, 1H),

5.23 (dd, 1H), 7.29 (m, 2H), 7.48 (dd, 1H), 10.42 (bs, 1H); MS

(ESI+) m/z 422 (M + H)⁺, 439 (M + NH₄)⁺; MS (ESI-) m/z 420

(M - H)^-; Anal. (C₁₉H₁₇NO₄FBr) C, H, N) and 22 (46 mg, 4%,

more polar, recrystallized from EtOAc/hexane; mp 219-220 °C;

¹H NMR (DMSO-d₆) δ 0.91 (t, 3H), 1.22-1.42 (m, 2H), 1.53-

1.69 (m, 1H), 1.88-2.02 (m, 1H), 4.05 (s, 2H), 4.55 (AB q, 2H),

4.74 (s, 1H), 5.13 (dd, 1H), 7.22 (ddd, 1H), 7.29 (t, 1H), 7.44 (dd,

1H), 10.44 (bs, 1H); MS (ESI+) m/z 422 (M + H)⁺, 439 (M +

NH₄)⁺; MS (ESI-) m/z 420 (M - H)^-; Anal. (C₁₉H₁₇NO₄FBr‚

0.25 C₆H₁₄) C, H, N).

cis-9-(3-Bromo-4-fluorophenyl)-3-isopropyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (26) and trans-

9-(3-Bromo-4-fluorophenyl)-3-isopropyl-5,9-dihydro-3H,4H-2,6-

dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (27). Enamine

e11 (0.99 g, 6.3 mmol), 3-bromo-4-fluorobenzaldehyde (1.4 g, 6.8

mmol), and pyran-3,5-dione³⁵c1 (0.60 g, 5.3 mmol) via method

A, chromatographing using 5:1, 3:1, and 2:1 hexane/acetone (1.7

g, 73%), and method C, chromatographing with 80:38:1:1, 40:38:

1:1, 27:38:1:1, and 20:38:1:1 hexane/EtOAc/HCO₂H/H₂O, provided

1

27 (0.65 g, 50%, less polar; mp 230-232 °C; H NMR (DMSO-

d₆) δ 0.65 (d, J ) 6.78 Hz, 3H), 1.08 (d, J ) 7.12 Hz, 3H), 2.15-

2.26 (m, 1H), 4.05 (s, 2H), 4.54 (ABq, 2H), 4.74 (s, 1H), 5.16 (d,

J ) 2.37 Hz, 1H), 7.25-7.33 (m, 2H), 7.46-7.51 (m, 1H), 10.35

(s, 1H); MS (ESI+) m/z 422 (M + H)⁺; MS (ESI-) m/z 420 (M

- H)^-; Anal. (C₁₉H₁₇BrFNO₄) C, H, N) and 26 (0.29 g, 22%, more

polar; mp 169-171 °C; ¹H NMR (DMSO-d₆) δ 0.66 (d, J ) 6.78

Hz, 3H), 1.06 (d, J ) 7.12 Hz, 3H), 2.20-2.33 (m, 1H), 4.05 (s,

2H), 4.50 (d, J ) 16.28 Hz, 1H), 4.60 (d, J ) 16.28 Hz, 1H), 4.73

(s, 1H), 5.01-5.05 (m, 1H), 7.23 (ddd, J ) 8.65, 5.26, 2.37 Hz,

1H), 7.29 (t, J ) 8.48 Hz, 1H), 7.44 (dd, J ) 6.61, 1.86 Hz, 1H),

10.37 (s, 1H); MS (ESI+) m/z 422 (M + H)⁺; MS (ESI-) m/z

420 (M - H)^-; Anal. (C₁₉H₁₇BrFNO₄‚0.4H₂O) C, H, N).

(+)-cis-9-(3-Bromo-4-fluorophenyl)-3-propyl-5,9-dihydro-3H-

furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (22a) (-)-cis-

9-(3-Bromo-4-fluorophenyl)-3-propyl-5,9-dihydro-3H-furo[3,4-

b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (22b). The enantiomers

of compound 22 (620 mg) were separated using a (R,R)-Whelk-

O1 column, eluting with 9:4:2 hexane/MeOH/CH₂Cl₂to provide

22b (less polar, recrystallized from EtOAc/hexane; mp 219-230

°C; Anal. (C₁₉H₁₇NO₄FBr‚0.3EtOAc‚0.1 hexane) C, H, N; [R]²³

D

-108 (c 0.15, acetone)) and 22a (more polar, recrystallized from

EtOAc/hexane; mp 215-217 °C; Anal. (C₁₉H₁₇NO₄FBr‚0.3EtOAc‚

0.3 hexane) C, H, N).

cis-(3-Bromo-4-fluorophenyl)-3-butyl-5,9-dihydro-3H,4H-2,6-

dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (28) and trans-

(3-Bromo-4-fluorophenyl)-3-butyl-5,9-dihydro-3H,4H-2,6-dioxa-

4-azacyclopenta[b]naphthalene-1,8-dione (29). Enamine e12 (0.54

g, 3.2 mmol), 3-bromo-4-fluorobenzaldehyde (0.70 g, 3.4 mmol),

and pyran-3,5-dione³⁵c1 (0.30 g, 2.6 mmol) via method A (0.92

g, 78%) and method C, eluting with 40:38:1:1 and 20:38:1:1 hexane/

EtOAc/HCO₂H/H₂O, provided 29 (0.27 g, 31%) (less polar,

recrystallized from EtOAc/hexane; mp 228-230 °C; ¹H NMR

(DMSO-d₆) δ 0.88 (t, J ) 7.12 Hz, 3H), 1.23-1.37 (m, 4H), 1.48-

1.60 (m, 1H), 1.89-2.02 (m, 1H), 4.05 (s, 2H), 4.54 (ABq, 2H),

4.73 (s, 1H), 5.21 (dd, J ) 8.14, 3.05 Hz, 1H), 7.25-7.33 (m,

2H), 7.46-7.51 (m, 1H), 10.40 (s, 1H); MS (ESI+) m/z 436 (M +

H)⁺; MS (ESI-) m/z 434 (M - H)^-; Anal. (C₂₀H₁₉BrFNO₄0.1

hexane) C, H, N) and 28 (more polar, recrystallized from EtOAc/

hexane; mp 192-194 °C; ¹H NMR (DMSO-d₆) δ 0.87 (t, J ) 6.78

Hz, 3H), 1.16-1.36 (m, 4H), 1.58-1.73 (m, 1H), 1.90-2.06 (m,

1H), 4.05 (s, 2H), 4.55 (ABq, 2H), 4.73 (s, 1H), 5.10-5.16 (m,

1H), 7.24 (ddd, J ) 8.31, 4.92, 1.70 Hz, 1H), 7.29 (t, J ) 8.48 Hz,

1H), 7.42 (dd, J ) 6.61, 1.86 Hz, 1H), 10.44 (s, 1H); MS (ESI+)

m/z 436 (M + H)⁺; MS (ESI-) m/z 434 (M - H)^-; Anal. (C₂₀H₁₉-

BrFNO₄) C, H, N).

(+)-trans-9-(3-Bromo-4-fluorophenyl)-3-propyl-5,9-dihydro-

3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (23a). Com-

pound 22a (0.30 g, 0.71 mmol) was taken up in a solution of NH₃

in MeOH (10 mL), heated to 90 °C overnight in a sealed tube,

cooled, concentrated, and chromatographed (2:1 hexane/acetone)

to provide 23a (80 mg, 27%) (less polar, recrystallized from

acetone/hexane; mp 215-217 °C; Anal. (C₁₉H₁₇NO₄FBr) C, H, N;

[R]²³+175 (c 0.03, acetone) and recovered 22a (more polar).

D

(-)-trans-9-(3-Bromo-4-fluorophenyl)-3-propyl-5,9-dihydro-

3H-furo[3,4-b]pyrano[4,3-e]pyridine-1,8(4H,7H)-dione (23b). Com-

pound 22b (0.44 g) was taken up in a solution of NH₃in MeOH

(20 mL), heated to 90 °C ON in a sealed tube, cooled, concentrated,

and chromatographed (2:1 hexane/acetone) to provide 23b (0.20

g, 45%) (less polar, recrystallized from EtOAc/hexane; mp 216-

217 °C; Anal. (C₁₉H₁₇NO₄FBr) C, H, N; [R]²³-196 (c 0.03,

D

acetone)) and recovered 22b (more polar).

cis-9-(3-Bromo-4-fluorophenyl)-3-methoxymethyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (24)

and trans-9-(3-Bromo-4-fluorophenyl)-3-methoxymethyl-5,9-di-

hydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-di-

one (25). Enamine e10 (0.57 g, 3.6 mmol), 3-bromo-4-fluoroben-

zaldehyde (0.79 g, 3.9 mmol), pyran-3,5-dione³⁵c1 (0.34 g, 3.0

mmol) via method A (0.75 g, 57%) and via method C, eluting with

2%, 4%, and 6% EtOH in CH₂Cl₂, provided 25 (0.12 g 9%) (less

polar, recrystallized from hexane/EtOAc; mp 213-215 °C; ¹H NMR

(DMSO-d₆) δ 3.28 (s, 3H), 3.65 (dd, J ) 11.53, 4.41 Hz, 1H),

3.78 (dd, J ) 11.53, 2.71 Hz, 1H), 4.06 (ABq, 2H), 4.54 (ABq,

2H), 4.73 (s, 1H), 5.36 (dd, J ) 4.24, 2.54 Hz, 1H), 7.25-7.32

(m, 2H), 7.47-7.51 (m, 1H), 10.44 (s, 1H); MS (ESI+) m/z 424

(M + H)⁺; MS (ESI-) m/z 422 (M - H)^-; Anal. (C₁₈H₁₅BrFNO₅)

C, H, N) and 24 (0.89 g, 70%) (more polar, recrystallized from

(+)-trans-(3-Bromo-4-fluorophenyl)-3-butyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (29a) (-)-

trans-(3-Bromo-4-fluorophenyl)-3-butyl-5,9-dihydro-3H,4H-2,6-

dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (29b). The enantio-

mers of compound 29 were separated using a Chiralpak AS column,

eluting with 1:4 EtOH:hexane to provide 29a (less polar, rechro-

matographed using 2:1 hexane/acetone; MS (ESI-) m/z 434 (M -

H)^-; Anal. (C₂₀H₁₉BrFNO₄) C, H, N; [R]²³_D+172 (c 0.56, acetone))

and 29b (more polar, rechromatographed using 2:1 hexane/acetone;

MS (ESI+) m/z 436 (M + H)⁺, 453 (M + NH₄)⁺; MS (ESI-) m/z

434 (M - H)^-; Anal. (C₂₀H₁₉BrFNO₄) C, H, N; [R]²³-159 (c

1

hexane/EtOAc; mp 234-236 °C; H NMR (DMSO-d₆) δ 3.35 (s,

D

0.43, acetone)).

3H), 3.76-3.86 (m, 2H), 4.05 (s, 2H), 4.52 (ABq, 2H), 4.77 (s,

1H), 5.26-5.30 (m, 1H), 7.24-7.35 (m, 2H), 7.46 (dd, J ) 6.78,

2.03 Hz, 1H), 10.50 (s, 1H); MS (ESI+) m/z 424 (M + H)⁺; MS

(ESI-) m/z 422 (M - H)^-; Anal. (C₁₈H₁₅BrFNO₅) C, H, N).

cis-9-(3-Bromo-4-fluorophenyl)-3-isobutyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (30) and trans-

9-(3-Bromo-4-fluorophenyl)-3-isobutyl-5,9-dihydro-3H,4H-2,6-

dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (31). Enamine

e13 (0.54 g, 3.2 mmol), 3-bromo-4-fluorobenzaldehyde (0.70 g,

3.4 mmol), and pyran-3,5-dione³⁵c1 (0.30 g, 2.6 mmol) via method

A (0.89 g, 76%) and method C provided 31 (less polar; mp 136-

(+)-trans-9-(3-Bromo-4-fluorophenyl)-3-methoxymethyl-5,9-

dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-di-

one (25a) (-)-trans-9-(3-Bromo-4-fluorophenyl)-3-methoxymethyl-

5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-

1,8-dione (25b). The enantiomers of compound 25 (490 mg) were

separated using a Chiralpak AS column, eluting with 1:4 EtOH/

hexane to provide 25a (less polar, recrystallized from EtOH; mp

224-225 °C; Anal. (C₁₈H₁₅BrFNO₅) C, H, N; [R]²³_D+183 (c 0.27,

acetone)) and 25b (more polar, recrystallized from EtOH; mp 224-

1

140 °C; H NMR (DMSO-d₆) δ 0.93 (d, J ) 6.44 Hz, 3H), 0.97

(d, J ) 6.10 Hz, 3H), 1.32-1.46 (m, 1H), 1.72-1.86 (m, 2H),

4.05 (s, 2H), 4.54 (ABq, 2H), 4.73 (s, 1H), 5.23-5.29 (m, 1H),

7.26-7.32 (m, 2H), 7.46-7.50 (m, 1H), 10.40 (s, 1H); MS (ESI+)

m/z 436 (M + H)⁺, 453 (M + NH₄)⁺; MS (ESI-) m/z 434 (M -

H)^-; Anal. (C₂₀H₁₉BrFNO₄) C, H, N) and 30 (more polar; mp 141-

153 °C; ¹H NMR (DMSO-d₆) δ 0.94 (d, J ) 6.10 Hz, 6H), 1.34-

225 °C; Anal. (C₁₈H₁₅BrFNO₅) C, H, N; [R]²³-181 (c 0.28,

D

acetone)).

Effects of Substitution on a Dione

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6881

1.50 (m, 1H), 1.72-1.88 (m, 2H), 4.06 (s, 2H), 4.55 (ABq, 2H),

4.74 (s, 1H), 5.13 (d, J ) 8.81 Hz, 1H), 7.21 (ddd, J ) 8.48, 4.92,

2.20 Hz, 1H), 7.29 (t, J ) 8.65 Hz, 1H), 7.45 (dd, J ) 6.61, 2.20

Hz, 1H), 10.44 (s, 1H); MS (ESI+) m/z 436 (M + H)⁺, 453 (M +

NH₄)⁺; MS (ESI-) m/z 434 (M - H)^-; Anal. (C₂₀H₁₉BrFNO₄‚

0.5H₂O) C, H, N).

(m, 2H), 7.46 (dd, 1H), 10.32 (s, 1H); MS (ESI+) m/z 436 (M +

H)⁺; MS (ESI-) m/z 434 (M - H)^-; Anal. (C₂₀H₁₉BrFNO₄) C, H,

N.

(+)-trans-9-(3-Bromo-4-fluorophenyl)-3-ethyl-7,7-dimethyl-

5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-

1,8-dione (36a) and (-)-trans-9-(3-Bromo-4-fluorophenyl)-3-

ethyl-7,7-dimethyl-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclo-

penta[b]naphthalene-1,8-dione (36b). The enantiomers of com-

pound 36 (560 mg) were separated using a Chiralpak AS column,

eluting with 14:86 EtOH/hexanes to provide 36a (less polar,

crystallized from EtOAc, 0.15 g; mp 257-259 °C; Anal. (C₂₀H₁₉-

(+)-trans-9-(3-Bromo-4-fluorophenyl)-3-isobutyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (31a)

(-)-trans-9-(3-Bromo-4-fluorophenyl)-3-isobutyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (31b).

The enantiomers of compound 31 were separated using a Chiralpak

AD column, eluting with 1:9 EtOH/hexane to provide 31a (less

polar; Anal. (C₂₀H₁₉BrFNO₄) C, H, N; [R]²³_D+191 (c 1.0, acetone)

BrFNO₄) C, H, N; [R]²³+243 (c 0.3, acetone)) and 36b (more

D

polar, crystallized from EtOAc, 0.16 g; mp 270-273 °C; Anal.

(C₂₀H₁₉BrFNO₄) C, H, N; [R]²³- 248 (c 0.4, acetone)).

and 31b (more polar; Anal. (C₂₀H₁₉BrFNO₄) C, H, N; [R]²³

180 (c 0.6, acetone)).

-

D

cis-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,5-dimethyl-5,9-di-

hydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-di-

one (37) and trans-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,5-

dimethyl-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta-

[b]naphthalene-1,8-dione (38). Enamine e3 (0.60 g, 4.3 mmol),

3-bromo-4-fluorobenzaldehyde (1.7 g, 8.5 mmol), and ethyl bu-

tyrylacetate (1.1 g, 6.8 mmol) via method A (0.64 g of intermediate

obtained after chromatography using 5:1 hexane/acetone) and

method C provided, after chromatography using 4:1 and 1:1 hexane/

acetone, compound 38 (0.19 g, 10%, less polar; ¹H NMR (DMSO-

d₆) δ 0.82 (t, J ) 7.29 Hz, 3H), 1.51 (s, 3H), 1.58 (s, 3H), 1.64-

1.75 (m, 1H), 2.03-2.13 (m, 1H), 3.98 (d, J ) 16.61 Hz, 1H),

4.23 (d, J ) 16.61 Hz, 1H), 4.75 (s, 1H), 5.19 (dd, J ) 6.78, 3.05

Hz, 1H), 7.21 (ddd, J ) 8.56, 5.00, 2.03 Hz, 1H), 7.29 (t, J ) 8.48

Hz, 1H), 7.46 (dd, J ) 6.61, 2.20 Hz, 1H), 9.76 (s, 1H); MS (ESI+)

m/z 436 (M + H)⁺; MS (ESI-) m/z 434 (M - H)^-; Anal. (C₂₀H₁₉-

BrFNO₄) C, H, N) and 37 (0.20 g, 11%) (more polar, crystallized

from EtOAc/hexane; mp 239-246 °C; ¹H NMR (DMSO-d₆) δ 0.85

(t, J ) 7.29 Hz, 3H), 1.15 (s, 3H), 1.25 (s, 3H), 1.56-1.68 (m,

1H), 1.95-2.04 (m, 1H), 4.57 (s, 2H), 4.67 (s, 1H), 5.16 (dd, J )

6.78, 3.39 Hz, 1H), 7.24-7.29 (m, 2H), 7.46 (dd, 1H), 10.32 (s,

1H); MS (ESI+) m/z 436 (M + H)⁺; MS (ESI-) m/z 434 (M -

H)^-; Anal. (C₂₀H₁₉BrFNO₄) C, H, N).

cis-9-(3-Bromo-4-fluorophenyl)-3-pentyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (32) and trans-

9-(3-Bromo-4-fluorophenyl)-3-pentyl-5,9-dihydro-3H,4H-2,6-

dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (33). Enamine

e14 (0.59 g, 3.2 mmol), 3-bromo-4-fluorobenzaldehyde (0.70 g,

3.4 mmol), and pyran-3,5-dione³⁵c1 (0.30 g, 2.6 mmol) via method

A (0.95 g, 78%) and method C, chromatographing with 40:38:1:1

and 20:38:1:1 hexane/EtOAc/HCOOH/H₂O, provided 33 (0.26 g,

30%) (less polar, recrystallized from EtOAc/hexane; mp 119-129

1

°C; H NMR (DMSO-d₆) δ 0.87 (t, J ) 6.44 Hz, 3H), 1.24-1.39

(m, 6H), 1.46-1.60 (m, 1H), 1.89-2.02 (m, 1H), 4.05 (s, 2H),

4.54 (ABq, 2H), 4.73 (s, 1H), 5.21 (dd, J ) 8.14, 3.05 Hz, 1H),

7.25-7.32 (m, 2H), 7.46-7.50 (m, 1H), 10.36-10.43 (m, 1H);

MS (ESI+) m/z 450 (M + H)⁺, 467 (M + NH₄)⁺; MS (ESI-) m/z

448 (M - H)^-; Anal. (C₂₁H₂₁BrFNO₄) C, H, N) and 32 (0.12 g,

14%, more polar, recrystallized from EtOAc/hexane; mp 220-223

1

°C; H NMR (DMSO-d₆) δ 0.84 (t, J ) 6.78 Hz, 3H), 1.20-1.31

(m, 6H), 1.58-1.71 (m, 1H), 1.91-2.04 (m, 1H), 4.05 (s, 2H),

4.55 (ABq, 2H), 4.73 (s, 1H), 5.11-5.16 (m, 1H), 7.20-7.26 (m,

1H), 7.28 (t, J ) 8.48 Hz, 1H), 7.42 (dd, J ) 6.78, 2.03 Hz, 1H),

10.43 (s, 1H); MS (ESI+) m/z 450 (M + H)⁺, 467 (M + NH₄)⁺;

MS (ESI-) m/z 448 (M - H)^-; Anal. (C₂₁H₂₁BrFNO₄) C, H, N).

(+)-trans-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,5-dimethyl-

5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-

1,8-dione (38a) and (-)-trans-9-(3-Bromo-4-fluorophenyl)-3-

ethyl-5,5-dimethyl-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclo-

penta[b]naphthalene-1,8-dione (38b). The enantiomers of com-

pound 38 (163 mg) were separated using a Chiralpak AS column,

eluting with 12:88 EtOH/hexanes to provide 38a (less polar,

rechromatographed 2:1 hexane/acetone, 70 mg; Anal. (C₂₀H₁₉-

cis-9-(3-Bromo-4-fluorophenyl)-3-phenyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (34). Enam-

ine e15 (0.87 g, 4.2 mmol), 3-bromo-4-fluorobenzaldehyde (0.93

g, 4.6 mmol), and pyran-3,5-dione³⁵c1 (0.40 g, 3.5 mmol) via

method A (1.15 g, 68%) and method C, chromatographing with

2% MeOH in CH₂Cl₂, recrystallizing with EtOAc/hexane, rechro-

matographing with 2:1 hexane/acetone, recrystallizing with EtOAc/

hexane, provided the title compound (75 mg, 5%; mp 167-170

°C; ¹H NMR (DMSO-d₆) δ 4.05 (s, 2H), 4.49 (ABq, 2H), 4.83 (s,

1H), 6.17 (d, J ) 1.02 Hz, 1H), 7.25-7.39 (m, 4H), 7.45-7.52

(m, 4H), 10.39 (s, 1H); MS (ESI+) m/z 456 (M + H)⁺, 473 (M +

NH₄)⁺; MS (ESI-) m/z 454 (M - H)^-; Anal. (C₂₂H₁₅BrFNO₄0.5

H₂O) C, H, N).

BrFNO₄) C, H, N; [R]²³+198 (c 0.2, acetone)) and 38b (more

D

polar, rechromatographed 2:1 hexane/acetone, 60 mg; Anal. (C₂₀H₁₉-

BrFNO₄) C, H, N; [R]²³-206 (c 0.4, acetone)).

D

trans-9-(3-Chloro-4-fluorophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (39). Enam-

ine e9 (1.1 g, 6.3 mmol), 3-chloro-4-fluorobenzaldehyde (1.1 g,

6.8 mmol), and pyran-3,5-dione³⁵c1 (0.60 g, 5.3 mmol) via method

A, chromatographing with 1:1 hexane/EtOAc (1.9 g, 88%), and

method C, chromatographing with 2% and 5% EtOH in CH₂Cl₂,

provided 39 (0.63 g, 31%) as the less polar isomer: mp 199-201

cis-9-(3-Bromo-4-fluorophenyl)-3-ethyl-7,7-dimethyl-5,9-di-

hydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-di-

one (35) and trans-9-(3-Bromo-4-fluorophenyl)-3-ethyl-7,7-

dimethyl-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta-

[b]naphthalene-1,8-dione (36). Enamine e8 (1 g, 6.4 mmol),

carbonyl c3 (1.4 g, 10 mmol), and 3-bromo-4-fluorobenzaldehyde

(1.7 g, 8.3 mmol) via method A (2.4 g, 81%) and method C

provided, after crystallization from acetone, compound 35 (0.15 g,

5%) (more polar isomer by TLC, recrystallized from EtOAc; mp

1

°C; H NMR (DMSO-d₆) δ 0.91 (t, J ) 7.12 Hz, 3H), 1.28-1.42

(m, 2H), 1.47-1.61 (m, 1H), 1.86-1.99 (m, 1H), 4.05 (s, 2H),

4.54 (ABq, 2H), 4.73 (s, 1H), 5.23 (dd, J ) 7.97, 3.22 Hz, 1H),

7.24 (ddd, J ) 8.56, 4.83, 2.20 Hz, 1H), 7.32 (t, J ) 8.81 Hz, 1H),

7.36 (dd, J ) 7.12, 2.37 Hz, 1H), 10.40 (s, 1H); MS (ESI+) m/z

378 (M + H)⁺, 395 (M + NH₄)⁺; MS (ESI-) m/z 376 (M - H)^-;

Anal. (C₁₉H₁₇ClFNO₄‚0.15CH₂Cl₂) C, H, N.

1

274-277 °C; H NMR (DMSO-d₆) δ 0.78 (t, J ) 7.29 Hz, 3H),

1.15 (s, 3H), 1.25 (s, 3H), 1.63-1.74 (m, 1H), 1.95-2.06 (m, 1H),

4.57 (AB q, 2H), 4.67 (s, 1H), 5.06-5.12 (m, 1H), 7.19-7.26 (m,

1H), 7.28 (t, J ) 8.48 Hz, 1H), 7.44 (dd, J ) 6.78, 2.03 Hz, 1H),

10.35 (s, 1H); MS (ESI+) m/z 436 (M + H)⁺; MS (ESI-) m/z

434 (M - H)^-; Anal. (C₂₀H₁₉BrFNO₄) C, H, N. The acetone filtrate

was concentrated and chromatographed to provide 36 (0.60 g,

21%): less polar isomer, crystallized from EtOAc; mp 239-242

(+)-trans-9-(3-Chloro-4-fluorophenyl)-3-propyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (39a)

and (-)-trans-9-(3-Chloro-4-fluorophenyl)-3-propyl-5,9-dihy-

dro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-di-

one (39b). The enantiomers of compound 39 were separated using

a Chiralpak AS column, eluting with 12:88 EtOH/hexane to provide

39a (less polar, recrystallized from EtOAc; mp 226-229 °C; Anal.

(C₁₉H₁₇ClFNO₄) C, H, N; [R]²³_D+221 (c 0.58, acetone)) and 39b

1

°C; H NMR (DMSO-d₆) δ 0.85 (t, J ) 7.29 Hz, 3H), 1.15 (s,

3H), 1.25 (s, 3H), 1.56-1.68 (m, 1H), 1.95-2.04 (m, 1H), 4.57

(s, 2H), 4.67 (s, 1H), 5.16 (dd, J ) 6.78, 3.39 Hz, 1H), 7.24-7.29

6882 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23

Altenbach et al.

(more polar, recrystallized from EtOAc; mp 226-229 °C; Anal.

C, H, N; [R]²³+198 (c 0.34, acetone)) and 42b (more polar,

D

(C₁₉H₁₇ClFNO₄) C, H, N; [R]²³- 219 (c 0.61, acetone)).

recrystallized from EtOAc; mp 253-255 °C; Anal. (C₁₉H₁₇Cl₂NO₄‚

D

0.25H₂O) C, H, N; [R]²³- 208 (c 0.38, acetone)).

cis-9-(4-Fluoro-3-iodophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (40) and trans-

9-(4-Fluoro-3-iodophenyl)-3-propyl-5,9-dihydro-3H,4H-2,6-dioxa-

4-azacyclopenta[b]naphthalene-1,8-dione (41). Enamine e9 (1.1

g, 6.3 mmol), 3-iodo-4-methylbenzaldehyde³⁶(1.7 g, 6.8 mmol),

and pyran-3,5-dione³⁵c1 (0.60 g, 5.3 mmol) via method A,

chromatographing with 4:1 and 2:1 hexane/acetone (2.0 g, 76%),

and method C, chromatographing with 2% and 5% EtOH in CH₂-

Cl₂, provided 41 (0.81 g, 43%, less polar, recrystallized from

EtOAc; mp 238-240 °C; ¹H NMR (DMSO-d₆) δ 0.91 (t, J ) 7.12

Hz, 3H), 1.27-1.41 (m, 2H), 1.47-1.61 (m, 1H), 1.86-1.99 (m,

1H), 4.05 (s, 2H), 4.54 (ABq, 2H), 4.70 (s, 1H), 5.23 (dd, J )

8.14, 3.05 Hz, 1H), 7.16 (t, J ) 8.31 Hz, 1H), 7.26 (ddd, J ) 8.56,

5.17, 2.20 Hz, 1H), 7.63 (dd, J ) 6.10, 2.03 Hz, 1H), 10.38 (s,

1H); MS (ESI+) m/z 470 (M + H)⁺, 487 (M + NH₄)⁺; MS (ESI-)

m/z 468 (M - H)^-; Anal. (C₁₉H₁₇FINO₄) C, H, N) and 40 (more

polar, recrystallized from EtOAc; mp 246-247 °C; ¹H NMR

(DMSO-d₆) δ 0.92 (t, J ) 7.46 Hz, 3H), 1.21-1.40 (m, 2H), 1.55-

1.70 (m, 1H), 1.88-2.01 (m, 1H), 4.05 (s, 2H), 4.54 (ABq, 2H),

4.70 (s, 1H), 5.11-5.16 (m, 1H), 7.16 (t, J ) 8.1 Hz, 1H), 7.22

(ddd, J ) 8.48, 5.26, 2.20 Hz, 1H), 7.58 (dd, J ) 6.10, 2.03 Hz,

1H), 10.42 (s, 1H); MS (ESI+) m/z 470 (M + H)⁺, 487 (M +

NH₄)⁺; MS (ESI-) m/z 468 (M - H)^-; Anal. (C₁₉H₁₇FINO₄‚

0.5EtOAc) C, H, N).

D

trans-9-(3-Bromo-4-chlorophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (43). Enam-

ine e9 (1.1 g, 6.3 mmol), 3-bromo-4-chlorobenzaldehyde³⁷(1.5 g,

6.8 mmol), and pyran-3,5-dione³⁵c1 (0.60 g, 5.3 mmol) via method

A, chromatographing with 1:1 hexane/EtOAc (1.9 g, 76%), and

method C, chromatographing with 2% and 5% EtOH in CH₂Cl₂,

provided 43 (0.68 g, 38%) as the less polar isomer, which was

1

recrystallized from EtOAc: mp 223-227 °C; H NMR (DMSO-

d₆) δ 0.91 (t, J ) 7.12 Hz, 3H), 1.27-1.42 (m, 2H), 1.47-1.62

(m, 1H), 1.85-1.98 (m, 1H), 4.05 (s, 2H), 4.54 (d, J ) 2.71 Hz,

2H), 4.73 (s, 1H), 5.23 (dd, J ) 7.97, 2.88 Hz, 1H), 7.26 (dd, J )

8.48, 2.03 Hz, 1H), 7.53 (d, J ) 8.48 Hz, 1H), 7.56 (d, J ) 2.03

Hz, 1H), 10.41 (s, 1H); MS (ESI+) m/z 438 (M + H)⁺, 455 (M +

NH₄)⁺; MS (ESI-) m/z 436 (M - H)^-; Anal. (C₁₉H₁₇BrClNO₄)

C, H, N.

(+)-trans-9-(3-Bromo-4-chlorophenyl)-3-propyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (43a)

and (-)-trans-9-(3-Bromo-4-chlorophenyl)-3-propyl-5,9-dihy-

dro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-di-

one (43b). The enantiomers of compound 43 were separated using

a Chiralpak AS column, eluting with 1:1 EtOH/hexane to provide

43a (less polar, recrystallized from EtOAc; mp 249-252 °C; Anal.

(C₁₉H₁₇BrClNO₄) C, H, N; [R]²³_D+191 (c 0.51, acetone)) and 43b

(more polar, recrystallized from EtOAc; mp 255-256 °C; Anal.

(+)-cis-9-(4-Fluoro-3-iodophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (40a) and

(-)-cis-9-(4-Fluoro-3-iodophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (40b). The

enantiomers of compound 40 were separated using a Chiralpak AS

column, eluting with 1:1 EtOH/hexane to provide 40a (less polar;

Anal. (C₁₉H₁₇FINO₄) C, H, N; [R]²³_D+168 (c 0.29, acetone)) and

(C₁₉H₁₇BrClNO₄) C, H, N; [R]²³- 196 (c 0.36, acetone)).

D

trans-9-(4-Bromo-3-chlorophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (44). Enam-

ine e9 (0.56 g, 3.3 mmol), 4-bromo-3-chlorobenzaldehyde³⁷(0.60

g, 2.7 mmol), and pyran-3,5-dione³⁵c1 (0.32 g, 2.7 mmol) via

method A, chromatographing with 4:1 and 2:1 hexane/acetone (0.84

g, 66%), and method C, chromatographing with 2% and 5% EtOH

in CH₂Cl₂, provided 44 (0.33 g, 44%) as the less polar isomer,

which was recrystallized from EtOAc: mp 243-245 °C; ¹H NMR

(DMSO-d₆) δ 0.91 (t, J ) 7.12 Hz, 3H), 1.28-1.41 (m, 2H), 1.47-

1.61 (m, 1H), 1.85-1.98 (m, 1H), 4.05 (s, 2H), 4.54 (ABq, 2H),

4.72 (s, 1H), 5.22 (dd, J ) 7.97, 2.88 Hz, 1H), 7.15 (dd, J ) 8.31,

2.20 Hz, 1H), 7.42 (d, J ) 2.37 Hz, 1H), 7.67 (d, J ) 8.48 Hz,

1H), 10.42 (s, 1H); MS (ESI+) m/z 438 (M + H)⁺, 455 (M +

NH₄)⁺; MS (ESI-) m/z 436 (M - H)^-; Anal. (C₁₉H₁₇BrClNO₄)

C, H, N).

40b (more polar; Anal. (C₁₉H₁₇FINO₄) C, H, N; [R]²³- 176 (c

D

0.33, acetone)).

(+)-trans-9-(4-Fluoro-3-iodophenyl)-3-propyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (41a).

Compound 40a (200 mg) was taken up in 2 M NH₃in EtOH (15

mL), heated to 80 °C ON, cooled, concentrated, and chromato-

graphed (2% and 5% EtOH in CH₂Cl₂) to provide 41a as the less

polar isomer (Anal. (C₁₉H₁₇FINO₄) C, H, N; [R]²³_D+165 (c 0.27,

acetone)) and recovered 40a as the more polar isomer.

(-)-trans-9-(4-Fluoro-3-iodophenyl)-3-propyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (41b).

Compound 40b (150 mg) was taken up in 2 M NH₃in EtOH (10

mL), heated to 80 °C ON, concentrated, and chromatographed (2%

and 5% EtOH in CH₂Cl₂) to provide 41b as the less polar isomer

(+)-trans-9-(4-Bromo-3-chlorophenyl)-3-propyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (44a)

and (-)-trans-9-(4-Bromo-3-chlorophenyl)-3-propyl-5,9-dihy-

dro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-di-

one (44b). The enantiomers of compound 44 were separated using

a Chiralpak AS column, eluting with 15:85 EtOH/hexane to provide

44a (less polar, recrystallized from EtOAc; mp 258-260 °C; Anal.

(C₁₉H₁₇BrClNO₄) C, H, N; [R]²³_D+190 (c 0.28, acetone)) and 44b

(more polar, recrystallized from EtOAc; mp 258-260 °C; Anal.

(Anal. (C₁₉H₁₇FINO₄) C, H, N; [R]²³- 184 (c 0.53, acetone))

D

and recovered 40b as the more polar isomer.

trans-9-(3,4-Dichlorophenyl)-3-propyl-5,9-dihydro-3H,4H-2,6-

dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (42). Enamine e9

(1.1 g, 6.3 mmol), 3,4-dichlorobenzaldehyde (1.2 g, 6.8 mmol),

and pyran-3,5-dione³⁵c1 (0.60 g, 5.3 mmol) via method A,

chromatographing with 4:1 and 2:1 hexane/acetone (1.6 g, 71%),

and method C, chromatographing with 2% and 5% EtOH in CH₂-

Cl₂, provided 42 (0.58 g, 39%) as the less polar isomer, which was

(C₁₉H₁₇BrClNO₄) C, H, N; [R]²³- 207 (c 0.26, acetone)).

D

trans-9-(3,4-Dibromophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (45). Enam-

ine e9 (1.1 g, 6.3 mmol), 3,4-dibromobenzaldehyde (1.8 g, 6.8

mmol), and pyran-3,5-dione³⁵c1 (0.60 g, 5.3 mmol) via method

A, chromatographing with 1:1 hexane/EtOAc (2.0 g, 74%), and

method C, chromatographing with 2% and 5% EtOH in CH₂Cl₂,

provided 45 (0.67 g, 36%) as the less polar isomer, which was

1

recrystallized from EtOAc: mp 227-230 °C; H NMR (DMSO-

d₆) δ 0.91 (t, J ) 7.12 Hz, 3H), 1.28-1.41 (m, 2H), 1.47-1.62

(m, 1H), 1.86-1.98 (m, 1H), 4.05 (s, 2H), 4.54 (d, J ) 2.71 Hz,

2H), 4.74 (s, 1H), 5.22 (dd, J ) 7.80, 3.05 Hz, 1H), 7.23 (dd, J )

8.48, 2.03 Hz, 1H), 7.43 (d, J ) 2.03 Hz, 1H), 7.54 (d, J ) 8.48

Hz, 1H), 10.42 (s, 1H); MS (ESI+) m/z 394 (M + H)⁺, 411 (M +

NH₄)⁺; MS (ESI-) m/z 392 (M - H)^-; Anal. (C₁₉H₁₇Cl₂NO₄) C,

H, N.

1

recrystallized from EtOAc: mp 240-244 °C; H NMR (DMSO-

d₆) δ 0.91 (t, J ) 7.12 Hz, 3H), 1.28-1.41 (m, 2H), 1.47-1.60

(m, 1H), 1.85-1.98 (m, 1H), 4.05 (s, 2H), 4.54 (ABq, 2H), 4.71

(s, 1H), 5.23 (dd, J ) 7.97, 2.88 Hz, 1H), 7.18 (dd, J ) 8.48, 2.03

Hz, 1H), 7.55 (d, J ) 2.37 Hz, 1H), 7.66 (d, J ) 8.14 Hz, 1H),

10.41 (s, 1H); MS (ESI+) m/z 482 (M + H)⁺, 499 (M + NH₄)⁺;

MS (ESI-) m/z 480 (M - H)^-; Anal. (C₁₉H₁₇Br₂NO₄) C, H, N.

(+)-trans-9-(3,4-Dibromophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (45a) and

(-)-trans-9-(3,4-Dibromophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (45b). The

(+)-trans-9-(3,4-Dichlorophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (42a) and

(-)-trans-9-(3,4-Dichlorophenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (42b). The

enantiomers of compound 42 were separated using a Chiralpak AS

column, eluting with 12:88 EtOH/hexane to provide 42a (less polar,

recrystallized from EtOAc; mp 253-255 °C; Anal. (C₁₉H₁₇Cl₂NO₄)

Effects of Substitution on a Dione

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6883

enantiomers of compound 45 were separated using a Chiralpak AS

column, eluting with 12:88 EtOH/hexane to provide 45a (less polar,

recrystallized from EtOAc; mp 257-260 °C; Anal. (C₁₉H₁₇Br₂NO₄)

7.36 (m, 2H), 7.53 (dd, J ) 6.78, 2.03 Hz, 1H), 10.80 (s, 1H); MS

(ESI+) m/z 394 (M + H)⁺, 411 (M + NH₄)⁺; MS (ESI-) m/z 392

(M - H)^-; Anal. (C₁₇H₁₃BrFNO₄) C, H, N).

C, H, N; [R]²³+175 (c 0.44, acetone)) and 45b (more polar,

D

cis-9-(3-Bromo-4-fluorophenyl)-3-ethyl-4,5,6,9-tetrahydro-

3H-2,7-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (51) and

trans-9-(3-Bromo-4-fluorophenyl)-3-ethyl-4,5,6,9-tetrahydro-3H-

2,7-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (52). Enam-

ine e17 (0.17 g, 1.4 mmol), 3-bromo-4-fluorobenzaldehyde (0.28

g, 1.4 mmol), and dihydro-2H-pyran-2,4(3H)-dione³⁹(c7) (0.12 g,

1.1 mmol) via method A, heated to 80 °C for 60 h, and

chromatographed with 2% and 5% EtOH in CH₂Cl₂provided 52

recrystallized from EtOAc; mp 257-260 °C; Anal. (C₁₉H₁₇Br₂NO₄)

C, H, N; [R]²³- 183 (c 0.42, acetone)).

D

trans-9-(3-Bromo-4-methylphenyl)-3-propyl-5,9-dihydro-3H,4H-

2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (46). Enam-

ine e9 (1.1 g, 6.3 mmol), 3-bromo-4-methylbenzaldehyde³⁸(1.4 g,

6.8 mmol), and pyran-3,5-dione³⁵c1 (0.60 g, 5.3 mmol) via method

A, chromatographing with 4:1 and 2:1 hexane/acetone (2.0 g, 84%),

and method C, chromatographing with 2% and 5% EtOH in CH₂-

Cl₂, provided 46 as the less polar isomer, which was recrystallized

1

(less polar, recrystallized from EtOH; mp 252-255 °C; H NMR

(DMSO-d₆) δ 0.85 (t, J ) 7.46 Hz, 3H), 1.56-1.71 (m, 1H), 1.95-

2.08 (m, 1H), 2.61 (dt, J ) 17.46, 3.6 Hz, 1H), 2.75-2.90 (m,

1H), 4.19-4.37 (m, 2H), 4.67 (s, 1H), 5.15 (dd, J ) 6.78, 3.39

Hz, 1H), 7.23-7.33 (m, 2H), 7.48-7.53 (m, 1H), 10.26 (s, 1H);

MS (ESI+) m/z 408 (M + H)⁺, 425 (M + NH₄)⁺; MS (ESI-) m/z

406 (M - H)^-; Anal. (C₁₈H₁₅BrFNO₄) C, H, N) and 51 (more polar,

recrystallized from EtOH; mp 226-229 °C; ¹H NMR (DMSO-d₆)

δ 0.80 (t, J ) 7.29 Hz, 3H), 1.61-1.77 (m, 1H), 1.94-2.08 (m,

1H), 2.63 (dt, J ) 17.29, 3.90 Hz, 1H), 2.74-2.87 (m, 1H), 4.21-

4.36 (m, 2H), 4.67 (s, 1H), 5.06-5.12 (m, 1H), 7.22-7.32 (m,

2H), 7.47 (dd, J ) 6.78, 1.70 Hz, 1H), 10.32 (s, 1H); MS (ESI+)

m/z 408 (M + H)⁺, 425 (M + NH₄)⁺; MS (ESI-) m/z 406 (M -

H)^-; Anal. (C₁₈H₁₅BrFNO₄‚0.25H₂O) C, H, N).

1

from EtOAc: mp 223-234 °C; H NMR (DMSO-d₆) δ 0.91 (t, J

) 7.12 Hz, 3H), 1.27-1.41 (m, 2H), 1.46-1.60 (m, 1H), 1.85-

1.98 (m, 1H), 2.27 (s, 3H), 4.04 (s, 2H), 4.54 (ABq, 2H), 4.67 (s,

1H), 5.23 (dd, J ) 8.14, 3.05 Hz, 1H), 7.13 (dd, J ) 7.80, 2.03

Hz, 1H), 7.24 (d, J ) 8.14 Hz, 1H), 7.37 (d, J ) 2.03 Hz, 1H),

10.35 (s, 1H); MS (ESI+) m/z 418 (M + H)⁺, 435 (M + NH₄)⁺;

MS (ESI-) m/z 416 (M - H)^-; Anal. (C₂₀H₂₀BrNO₄) C, H, N.

(+)-trans-9-(3-Bromo-4-methylphenyl)-3-propyl-5,9-dihydro-

3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (46a)

and (-)-trans-9-(3-Bromo-4-methylphenyl)-3-propyl-5,9-dihy-

dro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-di-

one (46b). The enantiomers of compound 46 were separated using

a Chiralpak AS column, eluting with 1:9 EtOH/hexane to provide

46a (less polar, recrystallized from EtOAc; mp 249-251 °C; Anal.

cis-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,9-dihydro-3H,4H-

2-oxa-6-thia-4-azacyclopenta[b]naphthalene-1,8-dione (53) and

trans-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,9-dihydro-3H,4H-2-

oxa-6-thia-4-azacyclopenta[b]naphthalene-1,8-dione (54). Enam-

ine e17 (0.19 g, 1.5 mmol), 3-bromo-4-fluorobenzaldehyde (0.40

g, 1.9 mmol), and thiopyran-3,5-dione⁴⁰(c9) (0.24 g, 1.8 mmol)

via method A, heated to 80 °C for 60 h, and chromatographed with

2% and 5% EtOH in CH₂Cl₂provided 54 (0.15 g, 24%) (less polar,

recrystallized from EtOH; mp 236-240 °C (dec); ¹H NMR

(DMSO-d₆) δ 0.84 (t, J ) 7.12 Hz, 3H), 1.53-1.69 (m, 1H), 1.95-

2.06 (m, 1H), 3.14 (dd, J ) 15.93, 1.70 Hz, 1H), 3.50 (dd, J )

7.46, 2.03 Hz, 1H), 3.55 (dd, J ) 8.31, 1.86 Hz, 1H), 3.87 (dd, J

) 16.95, 1.36 Hz, 1H), 4.73 (s, 1H), 5.15 (dd, J ) 6.95, 3.22 Hz,

1H), 7.23-7.32 (m, 2H), 7.44-7.48 (m, 1H), 10.30 (s, 1H); MS

(ESI+) m/z 441 (M + NH₄)⁺; MS (ESI-) m/z 422 (M - H)^-;

Anal. (C₁₈H₁₅BrFNO₃S‚0.2EtOH‚0.1CH₂Cl₂) C, H, N) and 53 (0.20

g, 31%) (more polar, recrystallized from EtOH; mp 251-254 °C

(C₂₀H₂₀BrNO₄) C, H, N; [R]²³+211 (c 0.35, acetone)) and 46b

D

(more polar, recrystallized from EtOAc; mp 252-254 °C; Anal.

(C₂₀H₂₀BrNO₄) C, H, N; [R]²³- 223 (c 0.54, acetone)).

D

cis-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,6,7,9-tetrahydro-

3H,4H-furo[3,4-b]quinoline-1,8-dione (47) and trans-9-(3-Bromo-

4-fluorophenyl)-3-ethyl-5,6,7,9-tetrahydro-3H,4H-furo[3,4-b]-

quinoline-1,8-dione (48). Enamine e8 (1.7 g, 11 mmol), 3-bromo-

4-fluorobenzaldehyde (2.4 g, 12 mmol), and 1,3-cyclohexanedione

(c8) (1.0 g, 8.9 mmol) via method A (3.6 g, 93%) and method C,

chromatographing with 13:38:1:1 hexane/EtOAc/HCO₂H/H₂O,

provided 48 (0.22 g, 7%) (less polar, recrystallized from EtOAc;

1

mp 230-232 °C; H NMR (DMSO-d₆) δ 0.84 (t, J ) 7.29 Hz,

3H), 1.54-1.72 (m, 1H), 1.79-2.09 (m, 3H), 2.20-2.30 (m, 2H),

2.55-2.64 (m, 2H), 4.67 (s, 1H), 5.12 (dd, J ) 6.78, 3.39 Hz,

1H), 7.19-7.29 (m, 2H), 7.41-7.47 (m, 1H), 10.11 (s, 1H); MS

(ESI+) m/z 406 (M + H)⁺, 423 (M + NH₄)⁺; MS (ESI-) m/z 404

(M - H)^-; Anal. (C₁₉H₁₇BrFNO₃) C, H, N) and 47 (0.66 g, 20%)

(more polar, recrystallized from EtOAc; mp 245-247 °C; ¹H NMR

(DMSO-d₆) δ 0.77 (t, J ) 7.29 Hz, 3H), 1.62-1.77 (m, 1H), 1.81-

2.09 (m, 3H), 2.21-2.31 (m, 2H), 2.53-2.69 (m, 2H), 4.66 (s,

1H), 5.03-5.10 (m, 1H), 7.18 (ddd, J ) 8.56, 5.00, 2.37 Hz, 1H),

7.24 (t, J ) 8.65 Hz, 1H), 7.41 (dd, J ) 6.78, 2.03 Hz, 1H), 10.13

(s, 1H); MS (ESI+) m/z 406 (M + H)⁺, 423 (M + NH₄)⁺; MS

(ESI-) m/z 404 (M - H)^-; Anal. (C₁₉H₁₇BrFNO₃) C, H, N).

1

(dec); H NMR (DMSO-d₆) δ 0.76 (t, J ) 7.29 Hz, 3H), 1.61-

1.76 (m, 1H), 1.95-2.06 (m, 1H), 3.16 (dd, J ) 15.94, 1.70 Hz,

1H), 3.48 (dd, J ) 15.94, 1.36 Hz, 1H), 3.58 (dd, J ) 16.95, 1.70

Hz, 1H), 3.82 (d, J ) 16.28 Hz, 1H), 4.72 (s, 1H), 5.08 (dd, J )

5.76, 3.73 Hz, 1H), 7.18-7.24 (m, 1H), 7.27 (t, J ) 8.48 Hz, 1H),

7.42 (dd, J ) 6.78, 2.03 Hz, 1H), 10.32 (s, 1H); MS (ESI+) m/z

441 (M + NH₄)⁺; MS (ESI-) m/z 422 (M - H)^-; Anal. (C₁₈H₁₅-

BrFNO₃S) C, H, N).

(-)-trans-9-(3-Bromo-4-fluorophenyl)-3-ethyl-5,9-dihydro-

3H,4H-2-oxa-6-thia-4-azacyclopenta[b]naphthalene-1,8-dione

(54b). The enantiomers of compound 54 were separated using a

Chiralpak AS column, eluting with 15:85 EtOH/hexane to provide

54b as the less polar enantiomer, which was recrystallized from

cis-8-(3-Bromo-4-fluorophenyl)-3-ethyl-5,8-dihydro-3H,4H-

2,6-dioxa-4-aza-s-indacene-1,7-dione (49) and trans-8-(3-Bromo-

4-fluorophenyl)-3-ethyl-5,8-dihydro-3H,4H-2,6-dioxa-4-aza-s-

indacene-1,7-dione (50). Methyl 3-aminocrotonate (e5) (6.3 g, 55

mmol), 3-bromo-4-fluorobenzaldehyde (14 g, 71 mmol), and ethyl

butyrylacetate (c12) (10.4 g, 65 mmol) via method A, chromato-

graphing with 2:1 hexane/EtOAc (9.6 g, 40%), and method D, using

2.1 equiv of NBS and chromatographing with 3% MeOH in CH₂-

Cl₂, provided 50 (0.49 g, 14%, less polar; ¹H NMR (DMSO-d₆) δ

0.88 (t, J ) 7.29 Hz, 3H), 1.58-1.72 (m, 1H), 1.92-2.05 (m, 1H),

4.69 (s, 1H), 4.94 (dd, J ) 16.28, 0.68 Hz, 1H), 5.04 (d, J ) 16.62

Hz, 1H), 5.21 (dd, J ) 6.61, 3.56 Hz, 1H), 7.29-7.35 (m, 2H),

7.54-7.58 (m, 1H), 10.74 (s, 1H); MS (ESI+) m/z 394 (M + H)⁺,

411 (M + NH₄)⁺; MS (ESI-) m/z 392 (M - H)^-; Anal. (C₁₇H₁₃-

BrFNO₄) C, H, N) and 49 (0.49 g, 14%, more polar; mp >250 °C;

¹H NMR (DMSO-d₆) δ 0.85 (t, J ) 7.29 Hz, 3H), 1.66-1.77 (m,

1H), 1.95-2.05 (m, 1H), 4.69 (s, 1H), 4.94 (dd, J ) 16.27, 0.68

Hz, 1H), 5.04 (d, J ) 16.27 Hz, 1H), 5.16-5.20 (m, 1H), 7.25-

EtOAc: mp >260 °C; Anal. (C₁₈H₁₅BrFNO₃S) C, H, N; [R]²³

-227 (c 0.43, DMSO).

D

cis-8-(3-Bromo-4-fluorophenyl)-5-methyl-1,1-dioxo-1,2,3,4,5,8-

hexahydro-6-oxa-1λ⁶-thia-4-aza-s-indacen-7-one (55) and trans-

8-(3-Bromo-4-fluorophenyl)-5-methyl-1,1-dioxo-1,2,3,4,5,8-hexahy-

dro-6-oxa-1λ⁶-thia-4-aza-s-indacen-7-one (56). Enamine c6 (1.6

g, 12 mmol), 3-bromo-4-fluorobenzaldehyde (2.6 g, 13 mmol), and

tetrahydrothiophene-3-oxo-1,1-dioxide⁴¹(c10) (1.3 g, 10 mmol) via

method A (2.3 g, 53%) and method C, chromatographing with 1:1

hexane/acetone and rechromatographing with 10:38:1:1 hexane/

EtOAc/HCO₂H/H₂O, provided 56 (0.16 g, 7%, less polar; mp >250

°C; ¹H NMR (DMSO-d₆) δ 1.43 (d, J ) 6.78 Hz, 3H), 2.82-2.97

(m, 1H), 3.00-3.14 (m, 1H), 3.35-3.46 (m, 2H), 4.81 (s, 1H),

5.20 (q, J ) 6.78 Hz, 1H), 7.26-7.38 (m, 2H), 7.55 (dd, J ) 6.78,

1.70 Hz, 1H), 10.39 (s, 1H); MS (ESI+) m/z 414 (M + H)⁺; MS

6884 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23

Altenbach et al.

(ESI-) m/z 412 (M - H)^-; Anal. (C₁₆H₁₃BrFNO₄S) C, H, N) and

cis-9-(3-Bromo-4-fluorophenyl)-3-ethyl-2,3,5,9-tetrahydro-

4H-6-oxa-4-azacyclopenta[b]naphthalene-1,8-dione (63) and trans-

9-(3-Bromo-4-fluorophenyl)-3-ethyl-2,3,5,9-tetrahydro-4H-6-

oxa-4-azacyclopenta[b]naphthalene-1,8-dione (64). Enamine e16

(0.50 g, 4.0 mmol), 3-bromo-4-fluorobenzaldehyde (1.1 g, 5.2

mmol), and pyran-3,5-dione³⁵c1 (0.55 g, 4.8 mmol) via method

A, chromatographing with 1:1 hexane/EtOAc (2.7 g, 65%), and

method C, chromatographing with 2%, 4%, 8%, and 10% EtOH in

CH₂Cl₂, provided 64 (0.47 g, 13%) (less polar; mp 251-253 °C;

¹H NMR (DMSO-d₆) δ 0.84 (t, J ) 7.29 Hz, 3H), 1.29-1.44 (m,

1H), 1.79-1.92 (m, 1H), 1.99 (dd, J ) 17.97, 2.03 Hz, 1H), 2.42-

2.50 (m, 1H), 2.91-3.01 (m, 1H), 4.03 (s, 2H), 4.55 (ABq, 2H),

4.69 (s, 1H), 7.17-7.28 (m, 2H), 7.43 (dd, J ) 6.78, 1.70 Hz,

1H), 10.17 (s, 1H); MS (ESI+) m/z 406 (M + H)⁺; MS (ESI-)

m/z 404 (M - H)^-; Anal. (C₁₉H₁₇BrFNO₃) C, H, N) and 63 (0. 57

1

55 (0.053 g, 2%, more polar; mp >250 °C; H NMR (DMSO-d₆)

δ 1.44 (d, J ) 6.78 Hz, 3H), 2.82-2.95 (m, 1H), 3.00-3.13 (m,

1H), 3.36-3.46 (m, 2H), 4.83 (s, 1H), 5.14 (q, J ) 6.89 Hz, 1H),

7.27-7.36 (m, 2H), 7.50-7.57 (m, 1H), 10.44 (s, 1H); MS (ESI+)

m/z 414 (M + H)⁺; MS (ESI-) m/z 412 (M - H)^-; Anal. (C₁₆H₁₃-

BrFNO₄S) C, H, N).

cis-9-(3-Bromo-4-fluorophenyl)-3-methyl-8,8-dioxo-4,5,6,7,8,9-

hexahydro-3H-2-oxa-8λ⁶-thia-4-azacyclopenta[b]naphthalen-

1-one (57) and trans-9-(3-Bromo-4-fluorophenyl)-3-methyl-8,8-

dioxo-4,5,6,7,8,9-hexahydro-3H-2-oxa-8λ⁶-thia-4-azacyclopenta-

[b]naphthalen-1-one (58). Enamine e17 (0.53 g, 4.0 mmol),

3-bromo-4-fluorobenzaldehyde (0.89 g, 4.4 mmol), and tetrahy-

drothiopyran-3-one 1,1-dioxide⁴¹(c11) (0.50 g, 3.4 mmol) via

method A (0.94 g, 62%) and method C, chromatographing with

1:1 hexane/acetone and rechromatographing with hexane/EtOAc/

HCO₂H/H₂O 10:38:1:1, provided 58 (0.035 g, 4%) (less polar,

1

g, 16%) (more polar; mp 218-226 °C; H NMR (DMSO-d₆) δ

0.82 (t, J ) 7.29 Hz, 3H), 1.39-1.53 (m, 1H), 1.80-1.90 (m, 1H),

2.02 (dd, J ) 17.97, 2.03 Hz, 1H), 2.40-2.49 (m, 1H), 2.86-2.94

(m, 1H), 4.03 (s, 2H), 4.54 (ABq, 2H), 4.70 (s, 1H), 7.17 (ddd, J

) 8.48, 4.92, 2.20 Hz, 1H), 7.25 (t, J ) 8.48 Hz, 1H), 7.39 (dd, J

) 6.78, 2.03 Hz, 1H), 10.23 (s, 1H); MS (ESI+) m/z 406 (M +

H)⁺; MS (ESI-) m/z 404 (M - H)^-; Anal. (C₁₉H₁₇BrFNO₃) C, H,

N).

1

recrystallized from EtOAc; mp 257-259 °C; H NMR (DMSO-

d₆) δ 1.41 (d, J ) 6.78 Hz, 3H), 2.16-2.28 (m, 2H), 2.52-2.69

(m, 2H), 3.17-3.26 (m, 2H), 4.85 (s, 1H), 5.16 (q, J ) 6.78 Hz,

1H), 7.26-7.33 (m, 2H), 7.45-7.50 (m, 1H), 10.01 (s, 1H); MS

(ESI+) m/z 428 (M + H)⁺; MS (ESI-) m/z 426 (M - H)^-;

Anal. (C₁₇H₁₅BrFNO₄S‚0.4H₂O) C, H, N) and 57 (0.034 g, 4%)

1

10-(3-Bromo-4-fluorophenyl)-3,3-dimethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (66). 5-Amino-6H-pyran-3-

one³⁵(e1) (1.6 g, 12 mmol), 3-bromo-4-fluorobenzaldehyde (2.6

g, 13 mmol), and carbonyl c3 (1 g, 8.8 mmol) via method A,

chromatographing with 5% MeOH in CH₂Cl₂and then recrystal-

lizing from MeOH, provided the title compound (0.22 g, 47%):

(more polar, recrystallized from EtOAc; mp >260 °C; H NMR

(DMSO-d₆) δ 1.40 (d, J ) 6.78 Hz, 3H), 2.15-2.28 (m, 2H), 2.52-

2.71 (m, 2H), 3.16-3.26 (m, 2H), 4.86 (s, 1H), 5.06 (q, J ) 6.67

Hz, 1H), 7.24 (ddd, J ) 8.48, 5.09, 2.37 Hz, 1H), 7.30 (t, J ) 8.65

Hz, 1H), 7.44 (dd, J ) 6.44, 2.03 Hz, 1H), 10.06 (s, 1H); MS

(ESI+) m/z 428 (M + H)⁺; MS (ESI-) m/z 426 (M - H)^-; Anal.

(C₁₇H₁₅BrFNO₄S‚0.25H₂O) C, H, N).

1

mp >250 °C; H NMR (DMSO-d₆) δ 1.17 (s, 3H), 1.25 (s, 3H),

4.04 (s, 2H), 4.50 (m, 4H), 4.89 (s, 1H), 7.24 (m, 2H), 7.40 (dd,

1H), 10.02 (s, 1H); MS (APCI+) m/z 422 (M + H)⁺; Anal. (C₁₉H₁₇-

NO₄BrF‚0.25H₂O) C, H, N.

cis-9-(3-Bromo-4-fluorophenyl)-2,3-dimethyl-2,3,5,9-tetrahy-

dro-4H-6-oxa-2,4-diazacyclopenta[b]naphthalene-1,8-dione (59)

and trans-9-(3-Bromo-4-fluorophenyl)-2,3-dimethyl-2,3,5,9-tet-

rahydro-4H-6-oxa-2,4-diazacyclopenta[b]naphthalene-1,8-di-

one (60). The product from method A of compounds 17 and 18

was brominated as described in method C but, after concentration,

was not heated. Instead, 0.90 g (1.8 mmol) of this brominated

intermediate was treated with 2 M NH₃in MeOH (20 mL), heated

to 80 °C for 2 h, cooled, concentrated, and chromatographed (2%,

4%, 5%, 6%, 7%, and 10% EtOH in CH₂Cl₂) to provide 60 (0.038

g, 5%) (less polar, recrystallized from EtOAc; mp 248-252 °C;

¹H NMR (DMSO-d₆) δ 1.29 (d, J ) 6.78 Hz, 3H), 2.75 (s, 3H),

4.02 (s, 2H), 4.23 (q, J ) 6.78 Hz, 1H), 4.52 (d, J ) 5.09 Hz, 2H),

4.75 (s, 1H), 7.21-7.30 (m, 2H), 7.43-7.48 (m, 1H), 10.05 (s,

1H); MS (ESI+) m/z 407 (M + H)⁺; MS (ESI-) m/z 405 (M -

H)^-; Anal. (C₁₈H₁₆BrFN₂O₃) C, H, N) and 59 (0.045 g, 6%) (more

polar, recrystallized from EtOAc; mp 242-244 °C; ¹H NMR

(DMSO-d₆) δ 1.33 (d, J ) 6.78 Hz, 3H), 2.75 (s, 3H), 4.03 (s,

2H), 4.11 (q, J ) 6.67 Hz, 1H), 4.51 (ABq, 2H), 4.75 (s, 1H), 7.18

(ddd, J ) 8.48, 5.09, 2.37 Hz, 1H), 7.26 (t, J ) 8.65 Hz, 1H), 7.43

(dd, J ) 6.78, 2.03 Hz, 1H), 10.08 (s, 1H); MS (ESI+) m/z 407

(M + H)⁺; MS (ESI-) m/z 405 (M - H)^-; Anal. (C₁₈H₁₆BrFN₂O₃)

C, H, N).

cis-9-(3-Bromo-4-fluorophenyl)-3-ethyl-2-methyl-2,3,5,9-tet-

rahydro-4H-6-oxa-2,4-diazacyclopenta[b]naphthalene-1,8-di-

one (61) and trans-9-(3-Bromo-4-fluorophenyl)-3-ethyl-2-methyl-

2,3,5,9-tetrahydro-4H-6-oxa-2,4-diazacyclopenta[b]naphthalene-

1,8-dione (62). The product from method A of compounds 20 and

21 was treated as described in the procedure for compounds 59

and 60 to provide 62 (less polar; ¹H NMR (DMSO-d₆) δ 0.51 (t, J

) 7.29 Hz, 3H), 1.78-2.00 (m, 2H), 2.73 (s, 3H), 4.03 (s, 2H),

4.32 (t, J ) 3.73 Hz, 1H), 4.52 (ABq, 2H), 4.76 (s, 1H), 7.22-

7.29 (m, 2H), 7.44-7.49 (m, 1H), 9.98 (s, 1H); MS (ESI+) m/z

421 (M + H)⁺; MS (ESI-) m/z 419 (M - H)^-. Anal. Calcd for

C₁₉H₁₈BrFN₂O₃: C, 54.17; H, 4.31; N, 6.65. Found: C, 53.75; H,

5.35; N, 7.28) and 61 (more polar; ¹H NMR (DMSO-d₆) δ 0.56 (t,

J ) 7.29 Hz, 3H), 1.84-1.98 (m, 2H), 2.72 (s, 3H), 4.02 (s, 2H),

4.20 (t, J ) 3.22 Hz, 1H), 4.52 (ABq, 2H), 4.73 (s, 1H), 7.17-

7.29 (m, 2H), 7.37-7.46 (m, 1H), 10.00 (s, 1H); MS (ESI+) m/z

421 (M + H)⁺; MS (ESI-) m/z 419 (M - H)^-; Anal. (C₁₉H₁₈-

BrFN₂O₃) C, H, N).

10-(3-Bromo-4-fluorophenyl)-3,3,6,6-tetramethyl-9,10-dihy-

dro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (67). Carbonyl

c3 was substituted for carbonyl c2 in the procedure for enamine

e2, and the resulting major isomer, 5-ethoxy-2,2-dimethyl-6H-

pyran-3-one, was treated with NH₃-saturated EtOH to provide

5-amino-2,2-dimethyl-6H-pyran-3-one: ¹H NMR (DMSO-d₆) δ

1.18 (s, 6H), 4.20 (s, 2H), 4.87 (s, 1H), 6.83 (bs, 2H). 5-Amino-

2,2-dimethyl-6H-pyran-3-one (0.20 g, 1.4 mmol), 3-bromo-4-

fluorobenzaldehyde (0.30 g, 1.4 mmol), and carbonyl c3 (0.20 g,

1.4 mmol) via method A provided the title compound (0.20 g,

32%): mp >250 °C; ¹H NMR (DMSO-d₆) δ 1.15 (s, 6H), 1.25 (s,

6H), 4.49 (s, 4H), 4.81 (s, 1H), 7.24 (m, 2H), 7.39 (m, 1H), 9.94

(s, 1H); MS (APCI+) m/z 450 (M + H)⁺; Anal. (C₂₁H₂₁BrFNO₄)

C, H, N.

Spiro[5-(3-bromo-4-fluorophenyl)-5,10-dihydro-1H,3H-dipyr-

ano[3,4-b:4,3-e]pyridine-4,6(7H,9H)-dione-3,1′-cyclopentane] (68).

5-Amino-6H-pyran-3-one³⁵(e1) (0.11 g, 1.0 mmol), 3-bromo-4-

fluorobenzaldehyde (0.25 g, 1.2 mmol), and carbonyl c6 (0.17 g,

1.0 mmol) via method A, chromatographing with 5% MeOH in

CH₂Cl₂and recrystallized from CH₂Cl₂, provided the title compound

(0.16 g, 36%): mp >260 °C; ¹H NMR (DMSO) δ 1.40-1.53 (m,

1H), 1.53-1.71 (m, 5H), 1.87-1.98 (m, 1H), 2.04-2.14 (m, 1H),

4.04 (s, 2H), 4.48 (AB q, 2H), 4.51 (s, 2H), 4.90 (s, 1H), 7.18-

7.24 (m, 1H), 7.27 (t, 1H), 7.41 (dd, 1H), 10.06 (bs, 1H); MS

(ESI+) m/z 448 (M + H)⁺, 465 (M + NH₄)⁺; MS (ESI-) m/z 446

(M - H)^-; Anal. (C₂₁H₁₉NO₄FBr‚0.1CH₂Cl₂) C, H, N.

10-(3-Bromo-4-fluorophenyl)-3,3-diethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (69). 5-Amino-6H-pyran-3-

one³⁵(e1) (0.11 g, 1.0 mmol), 3-bromo-4-fluorobenzaldehyde (0.25

g, 1.2 mmol), and carbonyl c5 (0.17 g, 1.0 mmol) via method A,

chromatographing with 5% MeOH in CH₂Cl₂and recrystallized

from CH₂Cl₂, provided the title compound (0.14 g, 31%): mp 260-

262 °C; ¹H NMR (DMSO) δ 0.54 (t, 3H), 0.81 (t, 3H), 1.39-1.54

(m, 2H), 1.60-1.84 (m, 2H), 4.04 (s, 2H), 4.44-4.56 (m, 4H),

4.94 (s, 1H), 7.18-7.24 (m, 1H), 7.25 (t, 1H), 7.41 (dd, 1H), 10.01

(bs, 1H); MS (ESI+) m/z 450 (M + H)⁺, 467 (M + NH₄)⁺; MS

(ESI-) m/z 448 (M - H)^-; Anal. (C₂₁H₂₁NO₄FBr‚0.5CH₂Cl₂) C,

H, N.

Effects of Substitution on a Dione

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23 6885

(+)-cis-10-(3-Bromo-4-fluorophenyl)-1-ethyl-9,10-dihydro-

1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (70a) and (-)-cis-

10-(3-Bromo-4-fluorophenyl)-1-ethyl-9,10-dihydro-1H,8H-2,7-

dioxa-9-azaanthracene-4,5-dione (70b). The enantiomers of

compound 70 (from method B) were separated using a Chiralcel

OD column, eluting with 15:85 EtOH/hexane to provide 70b (less

polar, rechromatographed with 4:1, 3:1, and 2:1 hexane/acetone;

Anal. (C₁₉H₁₇NO₄FBr) C, H, N; [R]²³_D-21 (c 0.33, acetone)) and

70a (more polar, rechromatographed with 4:1, 3:1, and 2:1 hexane/

1H); MS (ESI+) m/z 394 (M + H)⁺; MS (ESI-) m/z 392 (M -

H)^-; Anal. (C₁₉H₁₇Cl₂NO₄) C, H, N.

(+)-trans-10-(3,4-Dichlorophenyl)-1-ethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (74a) and (-)-trans-10-(3,4-

Dichlorophenyl)-1-ethyl-9,10-dihydro-1H,8H-2,7-dioxa-9-azaan-

thracene-4,5-dione (74b). The enantiomers of compound 74 were

separated using a Chiralpak AS column, eluting with 1:4 EtOH/

hexane to provide 74b (less polar, recrystallized from EtOAc; mp

243-245 °C; Anal. (C₁₉H₁₇Cl₂NO₄) C, H, N; [R]²³-52 (c 0.27,

D

acetone; Anal. (C₁₉H₁₇NO₄FBr) C, H, N; [R]²³+16 (c 0.45,

acetone)) and 74a (more polar, recrystallized from EtOAc; mp 245-

D

247 °C; Anal. (C₁₉H₁₇Cl₂NO₄) C, H, N; [R]²³+52 (c 0.34,

acetone)).

D

(+)-trans-10-(3-Bromo-4-fluorophenyl)-1-ethyl-9,10-dihydro-

1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (71a) and (-)-trans-

10-(3-Bromo-4-fluorophenyl)-1-ethyl-9,10-dihydro-1H,8H-2,7-

dioxa-9-azaanthracene-4,5-dione (71b). The enantiomers of

compound 71 (from method B) were separated using a Chiralpak

AS column, eluting with 3:7 EtOH/hexane to provide 71b (less

polar, rechromatographed with 2:1 hexane/acetone; Anal. (C₁₉H₁₇-

acetone)).

trans-10-(3-Bromo-4-chlorophenyl)-1-ethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (75). 3-Bromo-4-chloroben-

zaldehyde³⁷(1.2 g, 5.5 mmol) via method B provided 75 (0.72 g,

38%) as the less polar isomer: mp 246-249 °C; ¹H NMR (DMSO-

d₆) δ 1.01 (t, J ) 7.29 Hz, 3H), 1.59-1.75 (m, 1H), 1.90-2.04

(m, 1H), 3.93 (d, J ) 16.95 Hz, 1H), 4.04 (s, 2H), 4.21 (d, J )

16.95 Hz, 1H), 4.38-4.45 (m, 1H), 4.50 (ABq, 2H), 4.91 (s, 1H),

7.21 (dd, J ) 8.31, 2.20 Hz, 1H), 7.47-7.54 (m, 2H), 9.97 (s,

1H); MS (ESI+) m/z 438 (M + H)⁺; MS (ESI-) m/z 436 (M -

H)^-; Anal. (C₁₉H₁₇BrClNO₄) C, H, N.

NO₄FBr) C, H, N; [R]²³- 38 (c 0.25, acetone)) and 71a (more

D

polar, rechromatographed with 2:1 hexane/acetone; Anal. (C₁₉H₁₇-

NO₄FBr) C, H, N; [R]²³+50.6 (c 0.49, acetone)).

D

trans-10-(3-Chloro-4-fluorophenyl)-1-ethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (72). 3-Chloro-4-fluoroben-

zaldehyde (0.88 g, 5.5 mmol) via method B provided 72 (0.47 g,

29%) as the less polar isomer: ¹H NMR (DMSO-d₆) δ 1.01 (t, J

) 7.29 Hz, 3H), 1.59-1.74 (m, 1H), 1.91-2.04 (m, 1H), 3.93 (d,

J ) 16.61 Hz, 1H), 4.04 (s, 2H), 4.21 (d, J ) 16.61 Hz, 1H), 4.37-

4.46 (m, 1H), 4.50 (ABq, 2H), 4.93 (s, 1H), 7.18 (ddd, J ) 8.48,

4.75, 2.03 Hz, 1H), 7.25-7.33 (m, 2H), 9.96 (s, 1H); MS (ESI+)

m/z 378 (M + H)⁺; MS (ESI-) m/z 376 (M - H)^-; Anal. (C₁₉H₁₇-

ClFNO₄) C, H, N.

(R)-(+)-trans-10-(3-Bromo-4-chlorophenyl)-1-ethyl-9,10-dihy-

dro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (75a) and (S)-

(-)-trans-10-(3-Bromo-4-chlorophenyl)-1-ethyl-9,10-dihydro-

1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (75b). The enantiomers

of compound 75 were separated using a Chiralpak AS column,

eluting with 1:4 EtOH/hexane to provide 75b (less polar, recrystal-

lized from EtOAc; mp 249-250 °C; Anal. (C₁₉H₁₇BrClNO₄) C,

H, N; [R]²³-50 (c 0.45, acetone)) and 75a (more polar,

D

recrystallized from EtOAc; mp 255-256 °C; Anal. (C₁₉H₁₇-

(+)-trans-10-(3-Chloro-4-fluorophenyl)-1-ethyl-9,10-dihydro-

1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (72a) and (-)-trans-

10-(3-Chloro-4-fluorophenyl)-1-ethyl-9,10-dihydro-1H,8H-2,7-

dioxa-9-azaanthracene-4,5-dione (72b). The enantiomers of

compound 72 were separated using a Chiralpak AS column, eluting

with 1:4 EtOH/hexane to provide 72b (less polar, rechromato-

graphed with 2:1 hexane/acetone; Anal. (C₁₉H₁₇ClFNO₄) C, H, N;

BrClNO₄) C, H, N; [R]²³+50 (c 0.31, acetone)).

D

trans-10-(4-Bromo-3-chlorophenyl)-1-ethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (76). 4-Bromo-3-chloroben-

zaldehyde³⁷(0.60 g, 2.7 mmol) via method B provided 76 (0.36 g,

30%) as the less polar isomer, which was recrystallized from

1

EtOAc: mp 251-254 °C; H NMR (DMSO-d₆) δ 1.01 (t, J )

7.29 Hz, 3H), 1.61-1.74 (m, 1H), 1.90-2.04 (m, 1H), 3.93 (d, J

) 16.95 Hz, 1H), 4.04 (s, 2H), 4.21 (d, J ) 16.62 Hz, 1H), 4.41

(dd, J ) 10.68, 2.88 Hz, 1H), 4.50 (ABq, 2H), 4.91 (s, 1H), 7.10

(dd, J ) 8.14, 2.03 Hz, 1H), 7.35 (d, J ) 2.03 Hz, 1H), 7.65 (d, J

) 8.48 Hz, 1H), 9.97 (s, 1H); MS (ESI+) m/z 438 (M + H)⁺; MS

(ESI-) m/z 436 (M - H)^-; Anal. (C₁₉H₁₇BrClNO₄) C, H, N.

(+)-trans-10-(4-Bromo-3-chlorophenyl)-1-ethyl-9,10-dihydro-

1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (76a) and (-)-trans-

10-(4-Bromo-3-chlorophenyl)-1-ethyl-9,10-dihydro-1H,8H-2,7-

dioxa-9-azaanthracene-4,5-dione (76b). The enantiomers of

compound 76 were separated using a Chiralpak AS column, eluting

with 1:4 EtOH/hexane to provide 76b (less polar, recrystallized

from EtOAc; mp 251-253 °C; Anal. (C₁₉H₁₇BrClNO₄) C, H, N;

[R]²³- 54 (c 0.34, acetone)) and 72a (more polar, rechromato-

D

graphed with 2:1 hexane/acetone; Anal. (C₁₉H₁₇ClFNO₄) C, H, N;

[R]²³+54 (c 0.33, acetone)).

D

trans-1-Ethyl-10-(4-fluoro-3-iodophenyl)-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (73). 4-Fluoro-3-iodoben-

zaldehyde³⁶(1.4 g, 5.5 mmol) via method B provided 73 (0.70 g,

35%) as the less polar isomer, which was recrystallized from

1

EtOAc: mp 233-235 °C; H NMR (DMSO-d₆) δ 1.01 (t, J )

7.29 Hz, 3H), 1.61-1.72 (m, 1H), 1.90-2.05 (m, 1H), 3.93 (d, J

) 16.62 Hz, 1H), 4.03 (s, 2H), 4.20 (d, J ) 16.95 Hz, 1H), 4.37-

4.45 (m, 1H), 4.50 (ABq, 2H), 4.90 (s, 1H), 7.14 (t, J ) 8.31 Hz,

1H), 7.17-7.24 (m, 1H), 7.58 (dd, J ) 6.10, 2.03 Hz, 1H), 9.94

(s, 1H); MS (ESI+) m/z 470 (M + H)⁺; MS (ESI-) m/z 468 (M

- H)^-; Anal. (C₁₉H₁₇FINO₄) C, H, N.

[R]²³-49 (c 0.48, acetone)) and 76a (more polar, recrystallized

D

from EtOAc; mp 251-255 °C; Anal. (C₁₉H₁₇BrClNO₄) C, H, N;

[R]²³+49 (c 0.4, acetone)).

(+)-trans-1-Ethyl-10-(4-fluoro-3-iodophenyl)-9,10-dihydro-

1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (73a) and (-)-trans-

1-Ethyl-10-(4-fluoro-3-iodophenyl)-9,10-dihydro-1H,8H-2,7-dioxa-

9-azaanthracene-4,5-dione (73b). The enantiomers of compound

73 were separated using a Chiralpak AS column, eluting with 1:4

EtOH/hexane to provide 73b (less polar, recrystallized from EtOAc;

mp 212-216 °C; Anal. (C₁₉H₁₇FINO₄‚0.5EtOAc‚0.25H₂O) C, H,

N; [R]²³_D-40 (c 0.28, acetone)) and 73a (more polar, recrystallized

D

trans-10-(3,4-Dibromophenyl)-1-ethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (77). 3,4-Dibromobenzal-

dehyde (1.5 g, 5.5 mmol) via method B provided 77 (0.75 g, 36%)

as the less polar isomer, which was recrystallized from EtOAc:

1

mp 251-254 °C; H NMR (DMSO-d₆) δ 1.01 (t, J ) 7.29 Hz,

3H), 1.59-1.75 (m, 1H), 1.91-2.05 (m, 1H), 3.93 (d, J ) 16.61

Hz, 1H), 4.04 (s, 2H), 4.21 (d, J ) 16.95 Hz, 1H), 4.38-4.45 (m,

1H), 4.50 (ABq, 2H), 4.89 (s, 1H), 7.13 (dd, J ) 8.31, 2.20 Hz,

1H), 7.49 (d, J ) 2.03 Hz, 1H), 7.64 (d, J ) 8.48 Hz, 1H), 9.97 (s,

1H); MS (ESI+) m/z 482 (M + H)⁺; MS (ESI-) m/z 480 (M -

H)^-; Anal. (C₁₉H₁₇Br₂NO₄) C, H, N.

from EtOAc; mp 234-235 °C; Anal. (C₁₉H₁₇FINO₄) C, H, N; [R]²³

+46 (c 0.32, acetone)).

D

trans-10-(3,4-Dichlorophenyl)-1-ethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (74). 3,4-Dichlorobenzal-

dehyde (0.97 g, 5.5 mmol) via method B provided 74 (0.62 g, 37%)

as the less polar isomer, which was recrystallized from EtOAc:

(+)-trans-10-(3,4-Dibromophenyl)-1-ethyl-9,10-dihydro-1H,8H-

2,7-dioxa-9-azaanthracene-4,5-dione (77a) and (-)-trans-10-(3,4-

Dibromophenyl)-1-ethyl-9,10-dihydro-1H,8H-2,7-dioxa-9-azaan-

thracene-4,5-dione (77b). The enantiomers of compound 77 were

separated using a Chiralpak AS column, eluting with 1:4 EtOH/

hexane to provide 77b (less polar, recrystallized from EtOAc; mp

255-256 °C (dec); Anal. (C₁₉H₁₇Br₂NO₄) C, H, N; [R]²³_D-42 (c

1

mp 249-252 °C; H NMR (DMSO-d₆) δ 1.01 (t, J ) 7.29 Hz,

3H), 1.61-1.76 (m, 1H), 1.92-2.04 (m, 1H), 3.93 (d, J ) 16.61

Hz, 1H), 4.04 (s, 2H), 4.21 (d, J ) 16.61 Hz, 1H), 4.38-4.45 (m,

1H), 4.50 (ABq, 2H), 4.92 (s, 1H), 7.18 (dd, J ) 8.31, 2.20 Hz,

1H), 7.35 (d, J ) 2.03 Hz, 1H), 7.52 (d, J ) 8.14 Hz, 1H), 9.97 (s,

6886 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23

Altenbach et al.

hexahydrothieno(3,2-b)quinolin-8(4H)-one 1,1-dioxide (A-278637):

a novel ATP-sensitive potassium channel opener efficacious in

suppressing urinary bladder contractions. I. In vitro characterization.

J. Pharmacol. Exp. Ther. 2002, 303, 379-386. (b) Brune, M. E.;

Fey, T. A.; Brioni, J. D.; Sullivan, J. P.; Williams, M.; Carroll, W.

A.; Coghlan, M. J.; Gopalakrishnan, M. (-)-(9S)-9-(3-Bromo-4-

fluorophenyl)-2,3,5,6,7,9-hexahydrothieno(3,2-b)quinolin-8(4H)-

one 1,1-dioxide (A-278637): a novel ATP-sensitive potassium

channel opener efficacious in suppressing urinary bladder contrac-

tions. II. In vivo characterization. J. Pharmacol. Exp. Ther. 2002,

303, 387-394.

0.3, acetone)) and 77a (more polar, recrystallized from EtOAc; mp

256-258 °C (dec); Anal. (C₁₉H₁₇Br₂NO₄) C, H, N; [R]²³_D+44 (c

0.35, acetone)).

trans-10-(3-Bromo-4-methylphenyl)-1-ethyl-9,10-dihydro-

1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (78). 3-Bromo-4-

methylbenzaldehyde³⁸(1.1 g, 5.5 mmol) via method B provided

78 (0.69 g, 38%) as the less polar isomer, which was recrystallized

1

from EtOAc: mp 237-238 °C; H NMR (DMSO-d₆) δ 1.01 (t, J

) 7.12 Hz, 3H), 1.60-1.74 (m, 1H), 1.89-2.06 (m, 1H), 2.25 (s,

3H), 3.92 (d, J ) 16.95 Hz, 1H), 4.03 (s, 2H), 4.20 (d, J ) 16.61

Hz, 1H), 4.38-4.44 (m, 1H), 4.50 (ABq, 2H), 4.89 (s, 1H), 7.08

(dd, J ) 7.80, 1.70 Hz, 1H), 7.22 (d, J ) 7.80 Hz, 1H), 7.32 (d, J

) 1.70 Hz, 1H), 9.91 (s, 1H); MS (ESI+) m/z 418 (M + H)⁺; MS

(ESI-) m/z 416 (M - H)^-; Anal. (C₂₀H₂₀BrNO₄) C, H, N.

(14) Drizin, I.; Holladay, M. W.; Yi, L.; Zhang, H. Q.; Gopalakrishnan,

S.; Gopalakrishnan, M.; Whiteaker, K. L.; Buckner, S. A.; Sullivan

J. P.; Carroll, W. A. Structure-activity studies for a novel series of

tricyclic dihydropyrimidines as KATP channel openers (KCOs).

Bioorg. Med. Chem. Lett. 2002, 12, 1481-1484.

(15) Drizin, I.; Altenbach, R. J.; Buckner, S. A.; Whiteaker, K. L.; Scott,

V. E.; Darbyshire, J. F.; Jayanti, V.; Henry, R. F.; Coghlan, M. J.;

Gopalakrishnan, M.; Carroll, W. A. Structure-activity studies for a

novel series of tricyclic dihydropyridopyrazolones and dihydropy-

ridoisoxazolones as KATP channel openers. Bioorg. Med. Chem.

2004, 12, 1895-1904.

(16) Carroll, W. A.; Altenbach, R. J.; Bai, H.; Brioni, J. D.; Brune, M.

E.; Buckner, S. A.; Cassidy, C.; Chen, Y.; Coghlan, M. J.; Daza, A.

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Zhang, H.; Sullivan J. P. Synthesis and structure-activity relation-

ships of a novel series of 2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-

8(4H)-one 1,1-dioxide KATP channel openers: discovery of (-)-

(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-

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(+)-trans-10-(3-Bromo-4-methylphenyl)-1-ethyl-9,10-dihydro-

1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (78a) and (-)-trans-

10-(3-Bromo-4-methylphenyl)-1-ethyl-9,10-dihydro-1H,8H-2,7-

dioxa-9-azaanthracene-4,5-dione (78b). The enantiomers of

compound 78 were separated using a Chiralpak AS column, eluting

with 1:4 EtOH/hexane to provide 78b (less polar, recrystallized

from EtOAc; mp 248-250 °C (dec); Anal. (C₂₀H₂₀BrNO₄) C, H,

N; [R]²³_D-51 (c 0.3, acetone)) and 78a (more polar, recrystallized

from EtOAc; mp 250-251 °C (dec); Anal. (C₂₀H₂₀BrNO₄) C, H,

N; [R]²³+52 (c 0.4, acetone)).

D

Supporting Information Available: X-ray crystallographic data

on compounds 7, 12, 17, 21a, 75b, and the 3-fluoro-4-iodo

derivative of 17b; results from elemental analysis. This material is

available free of charge via the Internet at http://pubs.acs.org.

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Henry, R. F.; Kort, M. E.; Kym, P. R.; Milicic, I.; Smith, J. C.; Tang,

R.; Turner, S. C.; Whiteaker, K. L.; Zhang, H.; Sullivan, J. P.

Synthesis and structure-activity relationships of a novel series of

tricyclic dihydropyridine-based KATP openers that potently inhibit

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JM060549U

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Effects of substitution on 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2, 6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione, a dihydropyridine ATP-sensitive potassium channel opener

DOI: 10.1021/jm060549u

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