Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing α1A-adrenoceptor agonist

DOI: 10.1021/jm030551a

Source and publish data:

Journal of Medicinal Chemistry p. 3220 - 3235 (2004)

Update date:2022-08-17

Topics:

Authors:

Altenbach, Robert J.

Khilevich, Albert

Kolasa, Teodozyj

Rohde, Jeffrey J.

Bhatia, Pramila A.

Patel, Meena V.

Searle, Xenia B.

Yang, Fan

Bunnelle, William H.

Tietje, Karin

Bayburt, Erol K.

Carroll, William A.

Meyer, Michael D.

Henry, Rodger

Buckner, Steven A.

Kuk, Jane

Daza, Anthony V.

Milicic, Ivan V.

Cain, John C.

Kang, Chae H.

Ireland, Lynne M.

Carr, Tracy L.

Miller, Thomas R.

Hancock, Arthur A.

Nakane, Masaki

Esbenshade, Timothy A.

Brune, Michael E.

O'Neill, Alyssa B.

Gauvin, Donna M.

Katwala, Sweta P.

Holladay, Mark W.

Brioni, Jorge D.

Sullivan, James P.

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Article abstract of DOI:10.1021/jm030551a

Structure-activity studies were performed on the α _1A-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the α_1A, α_1b, α_1d, α_2a, and α_2B subtypes. Functional activity in tissues containing the α_1A (rabbit urethra), α_1B (rat spleen), α_1D (rat aorta), and α_2A (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the α_1A-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective α₁-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater α_1A selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the α_1A-AR subtype in the control of MAP.

Full text of DOI:10.1021/jm030551a

220

J . Med. Chem. 2004, 47, 3220-3235

Syn th esis a n d Str u ctu r e-Activity Stu d ies on

N-[5-(1H-Im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-1-n a p h th a len yl]m eth a n esu lfon a m id e,

a n Im id a zole-Con ta in in g r1A-Ad r en ocep tor Agon ist¹

†

Robert J . Altenbach,* Albert Khilevich, Teodozyj Kolasa, J effrey J . Rohde, Pramila A. Bhatia, Meena V. Patel,

Xenia B. Searle, Fan Yang, William H. Bunnelle, Karin Tietje, Erol K. Bayburt, William A. Carroll,

Michael D. Meyer, Rodger Henry, Steven A. Buckner, J ane Kuk, Anthony V. Daza, Ivan V. Milicic,

J ohn C. Cain, Chae H. Kang, Lynne M. Ireland, Tracy L. Carr, Thomas R. Miller, Arthur A. Hancock,

Masaki Nakane, Timothy A. Esbenshade, Michael E. Brune, Alyssa B. O’Neill, Donna M. Gauvin,

‡

Sweta P. Katwala, Mark W. Holladay, J orge D. Brioni, and J ames P. Sullivan

Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories,

00 Abbott Park Road, Abbott Park, Illinois 60064-6123

Received October 28, 2003

Structure-activity studies were performed on the R1A-adrenoceptor (AR) selective agonist N-[5-

1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were

(

evaluated for binding activity at the R1A, R1b, R1d, R2a, and R2B subtypes. Functional activity in

tissues containing the R1A (rabbit urethra), R1B (rat spleen), R1D (rat aorta), and R2A (rat prostatic

vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral

pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the

compounds. Many of the compounds that were highly selective in vitro for the R1A-AR subtype

were also more uroselective in vivo for increasing IUP over MAP than the nonselective R -

agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine),

supporting the hypothesis that greater R1A selectivity would reduce cardiovascular side effects.

However, the data also support a prominent role of the R1A-AR subtype in the control of MAP.

In tr od u ction

Ch a r t 1. Selective and Nonselective R -Agonists

Stress urinary incontinence (SUI) is due to the

inability of the urethra to restrict the leakage of urine

during stresses such as coughing or sneezing. In the

human, postsynaptic urethral tone is largely mediated

by activation of R-adrenoceptors (R-ARs). The nonselec-

tive R1-adrenergic agonists 1 and midodrine have been

found to be efficacious in clinical studies for the treat-

ment of SUI. Unfortunately, these agents suffer from

side effects that include increases in blood pressure

subtype in the control of blood pressure.¹¹The role of

the R1D-AR has not been fully elucidated, but this

subtype has been demonstrated to play a part in the

-5

(BP).

Three subtypes of the R1-AR have been identified (R1A,

2-14

pressor responses to sympathetic stimulation.

There-

R1B, and R1D), and there is strong evidence that the R1A-

AR is the primary subtype in the human urethra and

the receptor most likely to be responsible for constriction

fore, we were interested in finding R1A selective agonists

with the hope that these agents would constrict the

urethra with fewer hypertensive side effects than seen

with the nonselective R1 agonists.

of the urethra. Evidence has pointed toward a promi-

nent role of the R1B-AR in the control of BP. In vitro

radioligand binding selectivity of antagonists selective

for the R1A over the R1B subtype has been shown to

correspond to selectivity in vivo for blockade of agonist-

induced increases of intraurethral pressure (IUP) versus

arterial pressure.⁸Treatment with tamsulosin, an R1-

antagonist with affinity for the R1B-AR lower than that

of the R1A and R1D subtypes, is associated with fewer

vascular events, compared to classical nonselective R1-

AR antagonists.¹⁰In addition, a mouse knockout study

provided evidence for a prominent role of the R1B

In searching for novel structures based on the selec-

tive R1A-agonist A-61603 (3), we discovered imidazole

An in vivo dog model demonstrated that 4 was more

selective than 1-3 (see Chart 1) for increasing IUP over

mean arterial pressure (MAP). SAR studies were per-

formed on 4 in which modifications were made to the

sulfonamide, the aromatic ring, the tetralin, and the

imidazole. The results of these studies are presented.

Ch em istr y

The syntheses of the compounds are shown in Schemes

-3. Starting with a nitroketone of structure A (see

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

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

Scheme 1), the imidazole ring was introduced via a

Grignard reagent generated in situ from 4-iodo-1-(N,N-

dimethylsulfamoyl)-1H-imidazole 5 or 4-iodo-1-trityl-

1H-imidazole 6. The intermediate alcohol (not shown)

†

Present address: Pfizer, Skokie, IL 60077.

Present address: Novartis, Boston, MA.

Present address: Siddco Inc., Tucson, AZ 85747.

Present address: Pfizer, Ann Arbor, MI 48105.

‡

Published on Web 05/11/2004

Synthesis and SAR of a Methanesulfonamide

J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3221

Sch em e 1^a

Conditions: (i) EtMgBr, 5, CH2Cl2; (ii) EtMgBr, 6, CH2Cl2; (iii) aqueous HCl, ∆; (iv) Boc2O, CH3CN, ∆; (v) TFA; (vi) H2, Pd/C, EtOAc;

vii) R′Cl or R′2O, pyridine, CH2Cl2. Method A: conditions i, iii. Method B: conditions ii, iii. Method C: conditions i, v. Method D: condition

(

iv. Method E: condition vi. Method F: condition vii. Method G: condition v. Method H: condition iii.

Sch em e 2^a

Conditions: (i) NaH, DMF; MOMCl; (ii) NaH, DMF; Boc2O; (iii) R′′SO2Cl, pyridine, CH2Cl2; (iv) EtMgBr, 5, CH2Cl2; (v) aqueous HCl,

∆

; (vi) H2, Pd/C (0.1 wt equiv), MeOH; (vii) H2, Pd/C (1 wt equiv), MeOH. Method B: conditions iv, v. Method I: condition vii; Method J :

condition vi.

Sch em e 3^a

sulfonamide was obtained after the dehydration step.

Reduction of the double bond with concomitant removal

of the Bn group when PG′′ ) Bn provided the desired

products.

In cases where the benzylic position was unsubsti-

tuted (Scheme 3), nitroaldehydes of structure K were

treated with the Grignard reagent derived from 5. The

resulting intermediate alcohol was reduced by treat-

ment with triethylsilane in the presence of TFA to

provide intermediate L, which was sulfonated and

deprotected as described in Scheme 1.

Reagents and conditions: (i) EtMgBr, 5, CH2Cl2; (ii) Et3SiH,

TFA, ∆; (iii) H2, Pd/C, EtOAc; (iv) R′′SO2Cl, pyridine, CH2Cl2; (v)

aqueous HCl, ∆.

Syntheses of individual compounds such as the imi-

dazole modifications in Table 5 can be found in the

Experimental Section.

was dehydrated under acidic conditions with or without

deprotection of the imidazole to provide alkenes B or

D. Imidazole B was protected with a Boc group to

provide derivative C. Hydrogenation of C or D provided

the saturated aniline intermediate of structure E.

Formation of the sulfonamide, carbamate, or amide

followed by deprotection provided the desired products.

Enantiomeric separation for several examples was ac-

complished by chiral chromatography of the Boc-

protected intermediates of structure F .

Biologica l Eva lu a tion

Compounds were evaluated in radioligand binding

assays. The R1 binding assays (R1A, R1b, and R1d) were

performed (see Tables 1-5) essentially as described by

Knepper et al. The R2a and R2B binding assays (see

0,21

Table 6) were performed as described.

The binding

In certain cases, protected sulfonamidotetralones of

structure I were suitable intermediates for elaboration

to the final compounds (see Scheme 2). Intermediate I

was available via N-protection of sulfonamides G or by

sulfonation of benzylanilines H . Treatment of the

protected ketosulfonamides with the Grignard reagent

derived from 5 followed by acidic deprotection provided

the unsaturated imidazoles J . In the cases where the

protecting group (PG′′) was MOM or Boc, the NH

selectivities of the compounds for the R1A subtype versus

the other subtypes are shown.

The functional agonism of the test compounds to

constrict tissue containing the R1A (rabbit urethra), R1B

(rat spleen), and R1D (rat aorta) ARs was evaluated.²

Efficacy of less than 15% relative to phenylephrine (PE)

was considered inactive. The R1D functional data for the

test compounds were excluded from Tables 2-5 because

all of the compounds except for two were inactive in rat

222 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12

Altenbach et al.

Ta ble 1. In Vitro Profile of 1-3

binding, pK

(% efficacy)^b

functional, pD

rat spleen R1B

selectivity

1d/R1A rabbit urethra R1A

selectivity

compd

1b/R1A

rat aorta R1D

1B/R1A

1D/R1A

5.01 ( 0.20 5.02 ( 0.18 5.07 ( 0.19

5.70 ( 0.10 5.16 ( 0.05 5.78 ( 0.06

7.92 ( 0.10 5.53 ( 0.18 5.83 ( 0.05

200

0.8

100

3.63 ( 0.10 (68)

5.15 ( 0.07 (133) 4.07 ( 0.07 (68) 5.73 ( 0.14 (68)

8.03 ( 0.13 (88) 6.50 ( 0.10 (91) 5.59 ( 0.07 (100)

3.55 ( 0.14 (34) 4.12 ( 0.11 (91)

0.2

200

R1A, rat submaxillary gland; R1b, hamster clone; R1d, rat clone. Number of determinations, g3. The pKi (-log Ki) ( standard error of

the mean (SEM) are reported. R1-Agonist dose-response curves were determined against rabbit urethra (R1A), rat spleen (R1B), and rat

aorta (R1D). The pD2 (-log EC50) ( SEM of the dose that contracted the tissue 50% (EC50) and percent (%) efficacy (in parentheses)

relative to phenylephrine (PE) are reported. Number of determinations, g4.

Ta ble 2. Sulfonamide Modifications of 4

R1 binding, pKi

selectivity

R1b/R1A R1d/R1A rabbit urethra R1A

functional, pD2 (% efficacy)^a

compd

R1A

R1b

R1d

rat spleen R1B

N(H)SO2Me

6.71 ( 0.05

7.04 ( 0.06

5.94 ( 0.05

6.69 ( 0.01

7.33 ( 0.06

5.33 ( 0.12

5.70 ( 0.02

4.98 ( 0.02

5.80 ( 0.03

5.72 ( 0.03

5.77 ( 0.02

6.15 ( 0.08^b

>50

>80

>19

100

6.35 ( 0.06 (83)

6.45 ( 0.06 (84)

4.67 ( 0.08 (57)

6.16 ( 0.09 (79)

6.77 ( 0.11 (71)

5.73 ( 0.12 (52)

inactive

5.65 ( 0.09 (21)

inactive

(R)-(+)-N(H)SO2Me

(S)-(-)-N(H)SO2Me

N(Me)SO2Me

(+)-N(H)SO2Et

(+)-N(H)SO2CH2CF3 6.91 ( 0.01

N(H)SO2n-Pr

N(H)SO2i-Pr

N(H)SO2c-Pr

N(H)SO2(2-nap)

N(H)SO2NMe2

N(H)COMe

N(H)COCF3

N(H)COOMe

5.88 ( 0.01

5.97 ( 0.04

>80

<5_c

5.77 ( 0.06

5.94 ( 0.04

6.27 ( 0.05

6.16 ( 0.20

6.01 ( 0.01

6.28 ( 0.01

6.78 ( 0.04

6.83 ( 0.08

6.94 ( 0.02

6.86 ( 0.02

5.69 ( 0.03^b

5.57 ( 0.07

7.00^c

5.17 ( 0.08 (74)

0.4

5.25 ( 0.1 (51)

b,d

6.67

inactive

5.80

5.89 ( 0.05 (70)

6.28 ( 0.16(118)

4.84 ( 0.07 (35)

5.47 ( 0.15 (19)

5.48 ( 0.04

b,d

5.52^c

5.00

6.84

6.28

7.51

6.72^c

NH2

6.56 ( 0.14 (84)

6.01 ( 0.01 (35)

See Table 1 footnotes. NT ) not tested. ^bNumber of determinations is 2. ^cNumber of determinations is 1. ^dBovine clone. ^eCompound

1 is a chroman derivative.

aorta.²³Relaxation of field-stimulated rat prostatic vas

deferens was used to measure the R2A functional activity

and referenced against clonidine.²

Compound 4 bound to the R1A subtype with a pKi of

6.71 and was 20- and 8-fold selective for the R1A over

R₁_band R₁_dsubtypes, respectively (see Table 2). In

comparison to the compounds displayed in Table 1, 4

was between 3 and 2 in binding potency and selectivity

for the R1A subtype. Compound 4 had similar binding

potency for the R1A and the R2 subtypes (see Table 6).

Many of the compounds in this series bound with high

affinity to the R2 subtypes, and this will be addressed

later in this paper.

In vivo assessment of uroselectivity was performed

in a dog model similar to one used to evaluate R1

antagonists. Briefly, MAP and IUP were measured

simultaneously in isoflurane anesthetized female beagles

using a chronically implanted telemetry transducer/

transmitter and a urethral catheter, respectively. In-

creasing doses of the target agents were administered

via iv injection, and the maximal effect²⁵of each dose

was determined. The doses corresponding to a 5 mmHg

In functional studies, 4 contracted the rabbit urethra

(R1A) with a pD2 ) 6.35 and an efficacy of 83% relative

increase in IUP (IUP ED∆5) and a 20 mmHg increase

in MAP (MAP ED∆20)²⁷were calculated. For the pur-

poses of comparing compounds, the ratios of the MAP

ED∆20 over the IUP ED∆5 (MAP/IUP ratio) for selected

test compounds are shown in Table 7.

to PE. In contrast to the agents depicted in Table 1, 4

was inactive at both rat spleen (R1B) and rat aorta (R1D).

Separation of the enantiomers revealed that the (R)-

(

+)-enantiomer 7 possessed the activity and had an in

vitro profile similar to that of the racemate.

Small modifications to the sulfonamide of 4 were

allowed. Methylation of the sulfonamide NH produced

9, a compound with a binding potency similar to that

of 4 but over twice as selective for the R1A over the R1B

subtype. The (+)-ethylsulfonamide, 10, was more potent

and selective for the R1A subtype than 4 in the binding

assay and functional studies. The improved potency of

10 led us to incorporate the ethyl sulfonamide into many

In Vitr o Stu d ies

In vitro data for the R1-AR agonists 1-3 are displayed

in Table 1. Compounds 1 and 2 demonstrated no

selectivity for the R1A subtype in binding studies, and

only 2 showed any functional (R1A over R1B) selectivity.

Compound 3 was highly selective for the R1A-AR in

binding and functional studies.

Synthesis and SAR of a Methanesulfonamide

J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3223

Ta ble 3. Substitutions on the Aromatic Portion of 4

R1 binding, pKi

selectivity

functional, pD2 (% efficacy)^a

rabbit urethra R1A rat spleen R1B

compd

R1A

R1b

R1d

R1b/R1A

R1d/R1A

2-OH

2-OCH3

3-F

7.44 ( 0.06

6.30 ( 0.03

7.08 ( 0.10

7.34 ( 0.06

6.57 ( 0.00

6.15 ( 0.11

5.77 ( 0.05

6.41 ( 0.12

6.51 ( 0.07

6.35 ( 0.06

5.60 ( 0.01_b

5.77 ( 0.12

5.90 ( 0.09_b

6.32 ( 0.04

5.44 ( 0.22

6.44 ( 0.06

6.35 ( 0.02

>121

>217

>14

>26

>32

>20

7.77 ( 0.04 (104)

6.64 ( 0.13 (94)

inactive

4.74 ( 0.21 (26)

inactive

inactive^c

3-Cl

3-c-hexyl

4-OH

4-MeO

4-Me

4-F

6.05 ( 0.03

>14

4.61 ( 0.12 (34)

4.81 ( 0.10 (57)

4.40 ( 0.10 (35)

5.31 ( 0.11 (64)

4.35 ( 0.14 (41)

5.57 ( 0.03^b

5.52 ( 0.07^b

5.54 ( 0.04^b

4-Cl

See Table 1 footnotes. NT ) not tested. Number of determinations is 2. ^cAgonist dose-response curves determined against rat

epididymal vas deferens.

of the modifications of compound 4. The (+)-trifluoro-

ethyl analogue 11 had a similar binding affinity com-

pared to 4 for the R1A subtype but was less potent in

functional studies.

loss of activity. Reduction of the ring size from tetralin

to indane, 34, resulted in a compound that was ap-

proximately 8-fold more potent and more selective for

the R1A subtype in binding and functional studies.²⁹

Increasing the size of the tetralin to the benzocyclohep-

tane 35 resulted in a significant loss of in vitro potency.

The chroman 39 and thiochroman 40 displayed a 2- and

5-fold reduction in potency, respectively, compared to

4. The isobenzofuran 41 was over 40-fold less potent in

binding to the R1A subtype than the indane 34. This

reduction in potency may be a result of hydrogen

bonding between the imidazole and the oxygen of 41. A

similar hydrogen-bonding effect may be the cause for

the reduced potency for compound 28. The regioisomeric

derivative 42 essentially lost all activity for the R1A

subtype but was fairly potent at the R2 subtypes (see

Table 6). Removal of the aliphatic portion of the tetralin

provided 36 (ABT-866), an agent on which we have

Further increases in the size of the aliphatic group

on the sulfonamide (compounds 12-14) resulted in

decreased potency in binding and functional studies.

Aromatic sulfonamides were generated using parallel

synthesis techniques. In summary, aromatic substitu-

tions on the sulfonamide provided compounds that

either had no affinity for the R1A subtype or bound (i.e.,

5) but did not have any functional activity in rabbit

urethra.

Replacement of the sulfonamide with other groups

was examined. Compared with 4, the sulfonyl urea, 16,

and the acetamide, 17, provided slightly reduced po-

tency for the R1A subtype in binding studies. The

trifluoroacetamide 18 was equipotent with 4 for the R1A

subtype in binding and functional studies. The carbam-

ate 19 showed good potency and selectivity in binding

studies. The phenol and aniline, 20²and 21, bound

effectively with the R1A subtype but were less selective

against the R1B and R1D subtypes.

2a,30

previously published.

Compound 36 was found to

possess antagonistic activity for the R1B and R1D sub-

types. Compound 37 had a R1A binding potency similar

to that of 36 but with improved selectivity. A methyl

group at the benzylic position as in 38 was found to be

deleterious to R1A potency.

Substitutions were made on the aromatic portion of

the tetralin of 4 (Table 3). The 2-hydroxy analogue, 22,

is structurally similar to 3 and has a similar pharma-

Several modifications were made to the imidazole and

the benzylic portion of the molecule (see Table 5). None

of the modifications examined were favorable. Methyl

substitution of the imidazole (43-45) reduced activity.

cological profile as a full agonist at the R1B and R1D

subtypes. The 2-methoxy derivative 23 had reduced

activity and selectivity in binding studies and was

inactive in functional studies. Substitution at the 3

position with F or Cl provided compounds both potent

and highly selective for the R1A subtype vs R1B. Com-

pound 26, with a bulky cyclohexyl group at the 3

position, maintained good affinity for the R1A subtype,

but the selectivity was diminished. Substitution at the

Although 43 displayed binding potency (R₁_ApK ) 6.56)

similar to that of 4, 43 was very weak in constricting

the rabbit urethra (pD ) 5.26). Primary and secondary

amines (46, 47, 51, and 54) had moderate affinity for

the R₁_Asubtype (R₁_ApK ) 6.10, 5.86, 6.15, and 6.30,

respectively) but were found to be inactive in functional

studies. The 2-imidazoline, 48, was slightly weaker in

binding potency at the R₁_Asubtype but had an overall

position resulted in compounds (27-31) with reduced

potency in binding and functional studies.

in vitro profile similar to that of 4 (R₁_ApK ) 6.34, rabbit

Modifications were made to the aliphatic portion of

the tetralin ring of 4 (Table 4). Incorporation of a

hydroxyl group R to the imidazole (32) or oxidation of

the ring to the dihydronaphthalene (33) resulted in a

urethra (R1A) pD2 ) 6.19, inactive in rat spleen (R1B)).

The clonidine analogue 50 was very weak in binding

(pKi ) 5.35) to the R1A subtype and inactive in rabbit

urethra. Removal (compound 49) or replacement of the

224 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12

Altenbach et al.

Ta ble 4. Carbocyclic Modifications to 4

binding (pKi)

selectivity

R1 functional, pD2 (% efficacy)^a

compd

R1A

R1b

R1d

R1b/R1A

R1d/R1A

rabbit urethra R1A

rat spleen R1B

<5^b

>10

0.2

5.67 ( 0.05^b

6.01 ( 0.1 _b

5.60 ( 0.03

6.56 ( 0.06

6.00 ( 0.1

6.08 ( 0.04

7.65 ( 0.06

5.87 ( 0.02

6.87 ( 0.05

6.89 ( 0.13

6.08 ( 0.02

6.32 ( 0.04

4.54 ( 0.21 (23)

inactive

5.70 ( 0.07

7.18 ( 0.15 (87)

5.00

4.72 ( 0.14 (17)

6.05 ( 0.07

5.09 ( 0.09

6.22 ( 0.05 (80)

5.6 ( 0.09 (69)

5.38 ( 0.04 (92)

6.00 ( 0.26 (88)

inactive

6.16 ( 0.04

5.94 ( 0.07

5.09 ( 0.09 (17)

6.00

<5^c

6.03 ( 0.00

5.69 ( 0.02

b,d

6.47^c

5.87

See Table 1 footnotes. NT ) not tested. ^bNumber of determinations is 2. ^cNumber of determinations is 1. ^dBovine clone.

Ta ble 5. Modifications to Imidazole

binding (pKi)

selectivity

R1 functional, pD2 (% efficacy)^a

compd

T/P

R1A

R1b

R1d

R1b/R1A

R1d/R1A

rabbit urethra R1A

rat spleen R1B

6.56 ( 0.03

5.69 ( 0.05

5.98 ( 0.08

5.26 ( 0.15 (40)

inactive

<5^c

6.10

>10

inactive

6.19 ( 0.07 (87)

4.44 ( 0.09 (17)

inactive

6.10 ( 0.02

5.86 ( 0.04

6.34 ( 0.21

<5_b

5.13 ( 0.14

5.37 ( 0.3

6.45 ( 0.13^b

5.53 ( 0.02

6.15 ( 0.01

>10

<0.04

6.30 ( 0.02

<5_b

6.30 ( 0.08

6.00 ( 0.00

5.19 ( 0.19

>20

5.00

See Table 1 footnotes. NT ) not tested. ^bNumber of determinations is 2. ^cNumber of determinations is 1.

methylene with a sulfur or sulfoxide group (compounds

100-fold less potent in vivo but more uroselective than

3 with an MAP/IUP ratio of 4.8. The active enantiomer

7 had an in vivo profile similar to that of the racemate.

Small modifications to the sulfonamide of 4 were

allowed in vivo. Although the N-methylated sulfonamide

2 and 53) led to inactive compounds. Partial reduction

of the imidazole (compound 55) also resulted in complete

loss of activity.

In Vivo Stu d ies

had in vitro functional potency and selectivity similar

Many of the compounds were evaluated in vivo, and

the results are shown in Table 7. The in vitro nonselec-

tive R1 agonist 1 was found to have a MAP/IUP ratio of

to those of 4, its in vivo potency was reduced by over

3-fold and the in vivo selectivity was reduced. As

expected from their relative R1A functional potencies in

rabbit urethra, the (+)-ethylsulfonamide 10 was 2-fold

more potent than 7 in vivo for constricting the urethra,

and the (+)-trifluoroethyl analogue 11 was less potent.

No improvement with in vivo uroselectivity over 7 was

found with these analogues.

.4 in vivo. Compounds 2 and 3, both selective for the

R1A over the R1B subtype in functional studies, had

improved in vivo profiles relative to 1.

Compound 4, an R1A-agonist devoid of activity at

functional R1B and R1D subtypes, was approximately

Synthesis and SAR of a Methanesulfonamide

J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3225

Ta ble 6. R2 Binding and Functional Data^a

R2 binding (pKi)

selectivity

R2A functional, pD2 (% efficacy)^c

rat prostatic vas R2A selectivity R2A/R1A

compd

R2a

R2B

R2a/R1A

R2B/R1A

6.56 ( 0.13

5.84 ( 0.16

7.48 ( 0.11

6.98 ( 0.08

6.58 ( 0.04

5.73 ( 0.07

6.61 ( 0.21

6.17 ( 0.08

0.03

0.7

0.03

0.9

5.17 ( 0.09 (85)

8.23 ( 0.05 (20)

0.03

0.001

0.5

7.45 ( 0.44 (62)

8.05 ( 0.18 (29)

7.08 ( 0.13 (100)

5.95 ( 0.14 (66)

6.59 ( 0.1 (100)

6.64 ( 0.24 (100)

7.14 ( 0.11 (100)

0.08

0.03

0.12

0.14

0.2

7.07 ( 0.06

6.88 ( 0.06

6.02 ( 0.02

6.26 ( 0.05

6.51 ( 0.09

6.04

0.4

0.2

0.6

>80

5.77 ( 0.15

5.52

6.18

8.42

7.31

0.1

8.06

7.14

0.1

0.4

7.35 ( 0.05

7.01 ( 0.06

6.77 ( 0.11

7.32 ( 0.06

6.73 ( 0.16

6.01 ( 0.02

6.68 ( 0.51 (26)

5.45 ( 0.19 (34)

7.64

7.65

0.02

Complete R2 table available in Supporting Information. ^bR2a, human clone; R2B, rat neonatal lung. Number of determinations, g3.

The pKi (-log Ki) ( standard error of the mean (SEM) are reported. NT ) not tested. ^cR2A dose-response curves were determined by the

inhibition of the field-stimulated contraction of rat prostatic vas deferens. The pD2 (-log EC50) ( SEM, which resulted in 50% (EC50) of

the total relaxation, and percent (%) efficacy (in parentheses) relative to clonidine are reported. Number of determinations, g4. NT ) not

tested. Number of determinations is 2. Number of determinations is 1.

relative to 4 of 6.5.³⁰In vivo analysis revealed that 37

lost 3-fold potency for increasing IUP compared to 36

but had similar uroselectivity.

Although incorporation of a methyl group at the

benzylic position of 36 reduced in vitro and in vivo

potency, compound 38 had a MAP/IUP ratio similar to

that of compound 4.

The N-methylated imidazole 43 was inactive in vivo.

The imidazoline 48, similar to 4 in its in vitro profile,

was nonselective in vivo.

Ta ble 7. In Vivo Assessment of Agonist Uroselectivity

_I_U_P_E_D_∆₅a

_M_A_P_E_D_∆₂₀a

_M_A_P_/_I_U_P_r_a_t_i_ob

compd

1100 ( 400

205 ( 32

0.16 ( 0.02

25.5 ( 5.3

20.4 ( 4.6

inactive

91.9 ( 16.2

10.5 ( 1.6

156 ( 18

68.4 ( 10.5

188 ( 46

330 ( 80

0.40 ( 0.10

1.3 ( 0.2

1.7 ( 0.4

4.8 ( 1.2

4.4 ( 1.9

250 ( 20

0.27 ( 0.05

102.3 ( 23.9

48.7 ( 5.9

inactive

225.3 ( 34.6

34.0 ( 9.4

450 ( 103

220 ( 52

2.5 ( 0.1

3.3 ( 0.7

3.0 ( 0.8

3.1 ( 0.4

1.1 ( 0.0

1.1 ( 0.2

1.0 ( 0.1

2.5 ( 0.2

2.6 ( 1.2

1.0 ( 0.2

1.3 ( 0.3

6.5 ( 0.5

5.6 ( 2.7

3.4 ( 1.2

2.3 ( 0.3

216 ( 59

Discu ssion

33.0 ( 6.6

0.18 ( 0.03

19.1 ( 1.6

653 ( 148

844 ( 298

4.4 ( 0.6

35.1 ( 1.7

0.16 ( 0.03

47.7 ( 0.2

1850 ( 1140

632 ( 96

Our original hypothesis was that compounds selective

for the R1A subtype would have reduced cardiovascular

effects over nonselective R1 agonists. Indeed, a number

of compounds such as 4, 10, 36, and 37 have improved

MAP/IUP ratios compared with 1 and 2. Surprisingly,

these highly selective R1A agents still possessed signifi-

cant ability for increasing MAP. In addition, many of

the highly in vitro selective agents such as 34 and 48

were nonselective in vivo. Recent evidence indicates that

the R1A subtype is important in the vasoconstriction of

5.6 ( 1.0

12 ( 1

80 ( 10

41.1 ( 6.2

91.6 ( 19.1

67.1 ( 15.5

inactive

202 ( 67

234 ( 43

163.9 ( 57.7

inactive

11.9 ( 4.7

9.2 ( 3.8

1.1 ( 0.7

Data expressed as nmol/kg ( SEM. Number of determinations,

g4. ^bData expressed as the mean ( SEM of the calculated MAP/

human and other species. Although the R1B and R1D

IUP ratios for each determination. Number of determinations is

11-14

subtypes may play a role in the control of MAP,

the

Number of determinations is 3.

compounds of this series are generally inactive in

1b,33

Replacement of the sulfonamide with an acetate group

functional studies for these subtypes. The R2A

and

(compounds 17 and 18) led to lower in vivo potency and

R2B subtypes have also been implicated in the control

of BP. The R2B-AR subtype in particular has been shown

to be responsible for the transient hypertensive effects

of iv administered R2 agonists. The compounds in this

series do have affinity for the R2A and R2B subtypes and

many have functional activity in the rat prostatic vas

deferens (R2A) and this R2 activity could play a role in

their MAP effects.

selectivity relative to 4. Removal of the sulfonamide, as

in 21, provided an agent with in vivo potency similar

to that of 4 but with reduced uroselectivity. Substitu-

tions to the aromatic ring of 4 had no advantage in vivo

(22, 25, 28, and 30). The highly potent 2-hydroxy

analogue 22 was very similar to 3 in its overall

pharmacological profile.

Modifications to the tetralin ring of 4 were also

examined in vivo. The chroman 39 had in vitro potency

similar to that of 4 but was less potent in vivo. Indane

Correlation plots were generated in order to compare

the R1 and R2 in vitro activity of the compounds in this

series with in vivo increases in IUP and MAP (see

4 was 6-fold more potent than 4 at increasing IUP but

had a similar potency for increasing MAP. Compound

6 was found to possess antagonistic activity for the R1B

and R1D subtypes and had an improved MAP/IUP ratio

Tables 8 and 9). A moderate correlation existed for the

binding affinity for the R1A subtype vs MAP ED∆20 (r

) 0.46) and vs IUP ED∆5 (r ) 0.62). Similar correlations

were seen for R2a binding vs MAP ED∆20 (r ) 0.63) and

226 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12

Altenbach et al.

Ta ble 8. Correlation of R-AR Binding Affinity (pKi) with MAP

(p ED∆20) and IUP (p ED∆5)

MAP (p ED∆20)

IUP (p ED∆5)

r²

slope

r²

slope

R1A

R1b

R1d

R2a

R2B

0.46

0.05

0.01

0.63

0.38

0.47

0.09

0.04

0.35

0.62

0.11

0.08

0.56

0.21

0.55

0.13

0.12

0.34

0.26

F igu r e 2. Pressor effects of 36 in the presence of prazosin

and idazoxan.

Ta ble 9. Correlation of Functional Agonism (pD2) with MAP

p ED∆20) and IUP (p ED∆5)

(

To more directly ascertain the potential influence of

R2 activity of this series on MAP, the pressor effects of

an iv administered 100 nmol/kg dose of 36 were mea-

sured in a conscious dog model in the presence of 0.3

mg/kg of the R1 antagonist prazosin or 1 mg/kg of the

R2 antagonist idazoxan (see Figure 2). Prazosin signifi-

cantly attenuated the vasoconstrictive effects of 36

whereas idazoxan did not, thus providing further evi-

dence for the prominent role of the R1A subtype in the

control of MAP.

MAP (p ED∆20)

IUP (p ED∆5)

r²

slope

r²

slope

rabbit urethra (R1a)

rat vas deferens (R2A)

0.70

0.02

0.81

0.14

0.72

20 0.82

16 0.05

0.87

0.21

0.52

rat vas deferens (R2A), 0.57

0.26

00% efficacy

In summary, the SAR of a series of imidazoles based

on the R1A selective agonist 4 was described. Small

modifications to the sulfonamide portion of the molecule

were allowed, and the ethyl sulfonamide 10 was found

to be more potent in vivo. Modifications to the aromatic

portion of the molecule were allowed, and some in-

creases in potency were noted. Removal of the carbocylic

ring allowed for the discovery of compound 36, an R1A

selective agonist with antagonism at the R1B and R1D

subtypes.

F igu r e 1. MAP and IUP vs functional R1A (rabbit urethra).

_v_s_I_U_P_E_D_∆₅₍_r2 ) 0.56). However, the potency for

relaxation of the rat prostatic vas deferens (R2A) had no

correlation vs MAP (r ) 0.002) or IUP (r ) 0.03). There

was also no correlation seen between R1b or R1d binding

and MAP or IUP.

In vivo analysis demonstrated that many of the

compounds were more uroselective than the nonselec-

tive R1-agonists 1 and 2, supporting the hypothesis that

greater R1A selectivity would reduce cardiovascular side

effects. Surprisingly, some of the highly in vitro selective

R1A-agonists such as 34 and 48 were nonselective in

vivo. Although we cannot completely rule out the

influence of other factors that may contribute to car-

diovascular (CV) effects such as peripheral postsynaptic

R2-ARs, this data set supports an important role of the

R1A-AR in the control of R1-agonist mediated increases

in MAP. Our results suggest that absolute uroselectivity

may not be achievable with agents that act solely via

the R1A mechanism. However, a partial R1A-agonist has

recently been reported to have efficacy in the treatment

The best correlations were observed for functional R1A

activity (constriction of rabbit urethra) vs MAP (r )

.70) and IUP (r ) 0.82). As can be seen from Figure

, compound 1 appears to be an outlier, being more

potent in vivo than in vitro relative to the other

compounds. Recalculation of the plots in the absence of

_i_m_p_r_o_v_e_s_b_o_t_h_o_f_t_h_e_s_e_c_o_r_r_e_l_a_t_i_o_n_s₍_r2 for rabbit

urethra vs MAP and vs IUP ) 0.85 and 0.85, respec-

tively). These correlations provide evidence that both

the MAP and IUP effects of the compounds in this series

are due to stimulation of the R1A-AR.

of SUI with minimal CV effects.

The lack of correlation between the rat prostatic vas

Exp er im en ta l Section

deferens vs MAP and IUP in the dog may be due to the

species differences. In addition, no correlation (r

)

Ch em istr y. 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

an internal standard. Melting points were determined on a

Thomas-Hoover capillary melting point apparatus and are

uncorrected. Elemental analyses were performed by Robertson

Microlit Laboratories. Column chromatography was carried

out on silica gel 60 (230-400 mesh). Optical rotations were

measured with a Perkin-Elmer 541 polarimeter. Thin-layer

chromatography (TLC) was performed using 250 mm silica gel

.002) was observed between the R2A binding (human

clone) and the rat prostatic vas deferens (graph not

shown). The R2A subtype found in humans, dogs, and

rabbits is a species orthologue of the R2A subtype found

in rat, known as the R2D-AR.³⁶Differences in affinities

of antagonists for these two receptors have been re-

ported.³Therefore, the R2A binding data (human clone)

may be more predictive of the R2A activity in dogs than

the rat prostaic vas deferens. Interestingly, reevaluation

of the rat prostatic vas deferens using only compounds

that were fully efficacious (100%) revealed an improved

0 glass-backed plates with F254 as indicator. NMR, MS, and

rotational data on intermediates are available in the Support-

ing Information.

Meth od A. 4-(5-Nitr o-3,4-d ih yd r on a p h th a len -1-yl)-1H-

im id a zole (4B). In part 1, a solution of 5 (3.0 g, 10 mmol) in

anhydrous CH Cl (40 mL) under N was treated with EtMgBr

correlation with the R2A binding data (r ) 0.53, slope

)

0.77) as well as with the MAP (r ) 0.57) and IUP (r

0.26).

(3.0 M in Et O, 3.3 mL) over 5 min, stirred for 30 min, cooled

Synthesis and SAR of a Methanesulfonamide

J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3227

to 0 °C, treated with 5-nitro-1-tetralone³⁹(2.6 g, 11.8 mmol),

stirred at ambient temperature overnight, and concentrated.

In part 2, this intermediate alcohol was treated with 30 mL

of 2 M HCl, heated to reflux for 7 h, cooled, neutralized to pH

2.33 (m, 1 H), 2.72 (m, 2 H), 3.10 (q, J ) 7 Hz, 2 H), 4.03 (m,

1 H), 6.5 (s, 1 H), 6.75 (s, 1 H), 6.95 (s, 1 H), 7.53 (s, 1 H), 8.80

(s, 1 H); MS (APCI+) m/z 388 (M + H) ; MS (APCI-) m/z 386

(M - H) , 422 (M + Cl) . Anal. (C21

S‚0.375H O) C,

with solid Na

, and extracted with CH

(4 × 150 mL).

H, N.

The combined CH

layers were dried (MgSO

), filtered, and

Meth od I. N-[(5R)-5-(1H-Im id a zol-4-yl)-5,6,7,8-tetr a h y-

d r o-1-n a p h th a len yl]m eth a n esu lfon a m id e (4). Intermedi-

ate 4J (1.1 g, 2.9 mmol) was hydrogenated using 10% Pd/C

concentrated to provide 4B that was carried to the next step

without purification.

Meth od B. 4-(8-Meth oxy-5-n itr o-3,4-d ih yd r on a p h th a -

len -1-yl)-1H-im id a zole (28B). A solution of 6 (2.2 g, 5.1

(1.1 g) in MeOH (30 mL) overnight under H

(1 atm). After

the atmosphere was exchanged with N , the mixture was

mmol) in anhydrous CH

with EtMgBr (3 M in Et

stirred for 30 min, treated with 28A (0.94 g, 4.2 mmol) in

anhydrous CH Cl (5 mL), stirred for 2 h, treated with NH Cl

solution, and extracted with CH Cl

(2×). The combined CH

Cl layers were dried (MgSO ), filtered, concentrated, and

treated with EtOAc and hexane, at which time the product

was allowed to crystallize for 15 min. The crystals were

collected by filtration, washed with 5:1 hexanes/EtOAc, dried

under vacuum, treated with TFA (25 mL), heated to reflux

(20 mL) under N

was treated

diluted with MeOH (300 mL), filtered to remove the Pd/C,

concentrated, and chromatographed (5%, 10%, and then 20%

O, 1.7 mL, 5.1 mmol) over 2 min,

MeOH in NH

which was converted to the HCl salt: mp 113-114 °C; H NMR

(DMSO-d ) δ 1.75 (m, 2 H), 1.98 (m, 2 H), 2.82 (t, J ) 6.25 Hz,

3 2 2

-saturated CH Cl ) to provide 0.36 g (43%) of 4,

2 H), 3.03 (s, 3 H), 4.34 (t, J ) 6.43 Hz, 1 H), 6.82 (d, J ) 7.72

Hz, 1 H), 7.13 (t, J ) 7.72 Hz, 1 H), 7.23 (d, J ) 7.35 Hz, 1 H),

7.25 (s, 1 H), 9.03 (s, 1 H), 9.07 (s, 1 H), 14.34 (s, 1 H). Anal.

(C14

S‚HCl‚0.25H O) C, H, N.

Meth od J . N-[5-(1H-Im id a zol-4-yl)-4-m eth yl-5,6,7,8-tet-

r a h yd r on a p h th a len -1-yl]m eth a n esu lfon a m id e Ma lea te

(29). Compound 29J (0.069 g, 0.23 mmol) was hydrogenated

in MeOH using 0.1 weight equivalent of 10% Pd/C overnight

for 30 min, concentrated, treated with NaHCO

extracted with CH Cl

(2×). The combined CH

were dried (MgSO ), filtered, and concentrated to provide 28B.

solution, and

Cl extracts

Meth od C. 4-(8-Nitr o-2H-th ioch r om en -4-yl)im id a zole-

-su lfon ic Acid Dim eth yla m id e (40D). 8-Nitrothiochroman-

-one (40A) (0.48 g, 2.3 mmol) was reacted with 5 (0.79 g,

.6 mmol) as described in method A, part 1. The intermediate

alcohol was dehydrated by stirring in refluxing TFA (10 mL)

for 2 h. The mixture was cooled, concentrated, and neutralized

under H

and worked up as described in method I to provide

0.033 g (48%) of 29, which was converted to the maleic acid

salt: mp 192-195 °C; H NMR (DMSO-d ) δ 1.38 (m, 1H),

1.69-2.07 (m, 3H), 2.01 (s, 3H), 2.66 (m, 1H), 2.94 (m, 1H),

3.00 (s, 3H), 4.31 (m, 1H), 6.06 (s, 2H), 6.75 (s, 1H), 7.05 (d,

1H), 7.19 (d, 1H), 8.92 (s, 2H); MS (APCI+) m/z 306 (M + H) ;

with aqueous NaHCO

to provide 40D as a brown solid, 0.31

MS (APCI-) m/z 304 (M - H) , 340 (M + Cl) . Anal.

g (37%), which was isolated by filtration.

(C15

S‚C

‚0.5H O‚0.25EtOAc) C, H, N.

Meth od D. ter t-Bu tyl 4-(5-Nitr o-3,4-d ih yd r o-1-n a p h -

th a len yl)-1H-im id a zole-1-ca r boxyla te (4C). A mixture of

N-Ben zyl-N-[5-(1H-im id a zol-4-yl)-7,8-d ih yd r on a p h th a -

len -1-yl]m eth a n esu lfon a m id e (4J ). By use of method A,

N-benzyl-N-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)methane-

sulfonamide⁴¹(4I) (3.0 g, 9.1 mmol) provided 1.1 g (84%) of

4J .

compound 4B (6.9 g, 29 mmol) and Boc

was refluxed in CH CN (100 mL) for 15 min, cooled, concen-

trated, and chromatographed (3:2 hexane/EtOAc) to provide

O (12.5 g, 57 mmol)

.7 g (89%) of 4C.

Meth od E. ter t-Bu tyl 4-(5-Am in o-1,2,3,4-tetr a h yd r o-1-

(+)-N-[(5R)-5-(1H -Im id a zol-4-yl)-5,6,7,8-t et r a h yd r o-1-

n a p h th a len yl]m eth a n esu lfon a m id e (7). The enantiomers

of 4F were separated by chiral chromatography on a Chiralcel

OJ column (5.0 cm inner diameter, 50 cm length, 20 µm

packing) using 90:10 hexanes/EtOH at a flow rate of 200 mL/

min as the mobile phase. Four separate injections of 150 mg

n a p h th a len yl)-1H-im id a zole-1-ca r boxyla te (4E). A mix-

ture of 4C (3.45 g, 10.1 mmol) and 10% Pd/C (0.42 g) in EtOAc

(30 mL) was stirred under H (1 atm) for 16 h and filtered.

The filtrate was concentrated and chromatographed (2:1, 3:2,

and then 1:1 hexane/EtOAc) to provide 2.83 g (89%) of

intermediate 4E.

2 2

each in 95:5 EtOH/CH Cl (6 mL) provided 320 mg of (+)-7F

as the faster moving enantiomer and 340 mg of (-)-8F as the

slower moving enantiomer. A solution of (+)-7F (130 mg, 0.33

mmol) in MeOH (10 mL) was treated with 1 N HCI (5 mL),

stirred for 1.5 h, concentrated at 45 °C, and dried under

vacuum for 30 min. The residue was dissolved in MeOH,

filtered through cotton, concentrated, and dried under vacuum

Meth od F . ter t-Bu tyl 4-{5-[(Meth ylsu lfon yl)a m in o]-

,2,3,4-tetr a h yd r o-1-n a p h th a len yl}-1H-im id a zole-1-ca r -

boxyla te (4F ). A solution of 4E (0.15 g, 0.48 mmol) in CH Cl

3 mL) was treated with pyridine (0.12 mL, 1.4 mmol) and then

(

MsCl (0.060 mL, 0.72 mmol), stirred at ambient temperature

overnight, concentrated, and chromatographed (1% MeOH in

Meth od G. (+)-N-[5-(1H-Im id a zol-4-yl)-5,6,7,8-tetr a h y-

d r o-1-n a p h th a len yl]eth a n esu lfon a m id e, Ma lea te (10). A

solution of (+)-10F (0.26 g, 0.64 mmol) in CH Cl (4 mL) was

2 2

treated with TFA (5 mL), heated on a steam bath for 1 min,

and concentrated. Purification of the residue on silica gel using

for 3 h to provide 7 as the HCl salt: mp 118-123 °C; [R]

-saturated CH

) to provide 0.18 g (94%) of 4F .

+41.8° (c 1.0, MeOH); MS (DCI/NH

) m/z 292 (M + H) ; H

NMR (DMSO-d

) δ 1.70-1.82 (m, 2H), 1.92-2.04 (m, 2H), 2.83

t, 2H), 3.03 (s, 3H), 4.34 (t, 1H), 6.82 (d, 1H), 7.14 (t, 1H),

(

.23 (d, 1H), 7.26 (s, 1H), 9.03 (s, 1H), 9.07 (s, 1H), 14.36 (bs,

H). Anal. (C14 S‚HCl‚0.5H O‚0.5MeOH) C, H, N.

(-)-N-[(5S)-5-(1H -Im id a zol-4-yl)-5,6,7,8-t et r a h yd r o-1-

% and then 10% MeOH in NH

-saturated CH

provided

n a p h th a len yl]m eth a n esu lfon a m id e (8). A solution of (-)-

8F (95 mg, 0.24 mmol) in MeOH (10 mL) was treated as

described for compound (+)-7 in the above procedure to provide

the free base of 10 (0.19 g), which was converted to the maleic

acid salt: mp 129-130 °C; [R]

(free base) +55.2 (c 1.1, 1:1

); H NMR (DMSO-d ) δ 1.28 (t, 3H), 1.67-1.85

m, 2H), 1.87-2.06 (m, 2H), 2.83 (t, 2H), 3.13 (q, 2H), 4.30 (t,

MeOH/CHCl

(

8: mp 118-123 °C; [R]

-40.8° (c 1.0, MeOH); H NMR

(DMSO-d ) δ 1.70-1.82 (m, 2H), 1.92-2.04 (m, 2H), 2.83 (t,

2H), 3.03 (s, 3H), 4.34 (t, 1H), 6.82 (d, 1H), 7.14 (t, 1H), 7.23

H), 6.05 (s, 2H), 6.80 (d, 1H), 7.12 (t, 1H), 7.16-7.23 (m, 2H);

MS (DCI/NH

C, H, N.

) m/z 306 (M + H) . Anal. (C15

S‚C

)

(d, 1H), 7.26 (s, 1H), 9.03 (s, 1H), 9.07 (s, 1H), 14.36 (bs, 2H);

MS (DCI/NH

) m/z 292 (M + H) . Anal. (C14

S‚HCl‚

Meth od H. N-[3-Cycloh exyl-5-(1H-im idazol-4-yl)-5,6,7,8-

tetr ah ydr o-1-n aph th alen yl]eth an esu lfon am ide (26). Com-

pound 26F (670 mg, 1.36 mmol) and 1 N HCl (5 mL) in THF

0.5CH OH‚0.5H O) C, H, N.

N-[5-(1H-Im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-1-n a p h th a -

len yl]-N-m eth ylm eth a n esu lfon a m id e, Ma lea te (9). A so-

(10 mL) were refluxed for 2 h. The mixture was cooled to

lution of 4F (0.18 g, 0.45 mmol) in DMF (2 mL) under N was

ambient temperature, and the THF was removed under

reduced pressure. The mixture was neutralized with solid

treated with NaH (0.020 g, 0.50 mmol), stirred for 45 min,

treated with MeI (0.031 mL, 0.50 mmol), stirred for 90 min,

diluted with EtOAc (60 mL), washed with water (2 × 25 mL),

NaHCO

and the resulting solid was filtered, dried under

reduced pressure, and purified on a silica gel column (12:1 CH

washed with brine, dried (MgSO ), filtered, and concentrated.

/MeOH) to provide 26 (365 mg) (70%): mp 207-209 °C; H

The residue was deprotected using method G to provide 120

mg of 9, which was converted to the maleic acid salt: mp 142-

NMR (DMSO-d

) δ 1.26 (m, 8 H), 1.70 (m, 7 H), 1.93 (m, 2 H),

228 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12

Altenbach et al.

cyclopropylsulfonyl chloride⁴²provided 14, which was con-

(

44 °C; H NMR (DMSO-d

) δ 1.67-2.07 (m, 4H), 2.70-2.86

m, 1H), 2.87-3.01 (m, 1H), 3.08 and 3.09 (s and s, 3H), 3.12

verted to the maleic acid salt: mp 156-157 °C; H NMR

and 3.13 (s and s, 3H), 4.24-4.35 (m, 1H), 6.05 (s, 2H), 6.94

(DMSO-d ) δ 0.88 (m, 2H), 0.97 (m, 2H), 1.76 (m, 2H), 1.97

(

t, 1H), 7.13-7.24 (m, 2H), 7.37 (d, 1H), 8.85 (s, 1H); MS (DCI/

(m, 2H), 2.65 (m, 1H), 2.87 (t, 2H), 4.30 (t, 1H), 6.04 (s, 2H),

) m/z 306 (M + H) . Anal. (C15

S‚C

) C, H, N.

6.82 (d, 1H), 7.12 (t, 1H), 7.17 (s, 1H), 7.24 (d, 1H), 8.85 (s,

H), 9.07 (s, 1H); MS (DCI/NH

S‚C ) C, H, N.

Na p h t h a len e-2-su lfon ic Acid [5-(1H -Im id a zol-4-yl)-

) m/z 318 (M + H) . Anal.

(

+)-N-[5-(1H-Im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-1-n a p h -

th a len yl]eth a n esu lfon a m id e, Ma lea te (10). After substitu-

tion of EtSO Cl for MsCl, 4E (2.0 g, 6.4 mmol) was reacted

4 4 4

H O

via method F and provided 1.52 g (59%) of 10F . The enanti-

omers of 10F were separated as described for compound 7

using 95:5 hexanes/EtOH, providing (+)-10F as the faster

moving enantiomer. Via method G, (+)-10F provided 10.

5,6,7,8-tetr a h yd r on a p h th a len -1-yl]a m id e Tr iflu or oa ce-

ta te (15). As for 12, 2-naphthalenesulfonyl chloride provided,

after HPLC chromatography, the trifluoracetic acid salt of 15.

H NMR (CD

.22 (t, J ) 4.2 Hz, 1H), 6.76 (d, J ) 7.7, 1H), 6.87 (d, J ) 7.3

Hz, 1H), 7.00 (t, J ) 7.8 Hz, 1H), 7.08 (d, J ) 0.7 Hz, 1H),

.65 (ddd, J ) 1.1, 6.9, 8.0 Hz, 1H), 7.70 (ddd, J ) 1.1, 7.0, 8.1

Hz, 1H), 7.78 (dd, J ) 2.2, 8.7 Hz, 1H), 8.03 (d, J ) 8.1 Hz,

H), 8.12 (t, J ) 8.0 Hz, 2H), 8.03 (d, J ) 1.8 Hz, 1H), 8.91 (d,

J ) 1.1 Hz, 1H), 9.65 (s, 1H). Anal. Calcd (C23 S‚

TFA): C, 51.35; H, 3.67; N, 6.65. Found: C, 52.21; H, 3.24;

N, 6.22.

OD) δ 1.44 (m, 2H), 1.83 (m, 2H), 3.15 (m, 2H),

(

+)-N-[5,6,7,8-Tetr a h yd r o-5-(1H-im id a zol-4-yl)-1-n a p h -

th alen yl]-2,2,2-tr iflu or oeth an esu lfon am ide (11). After sub-

stitution of F CCH SO Cl for MsCl, 4E was reacted via method

F and provided 11F . The enantiomers of compound 11F were

separated by chiral chromatography on a Chiralpak AD

column (5.0 cm inner diameter, 26 cm length, 20 µDp) using

21 3 2

H N O

6:4 hexanes/EtOH at a flow rate of 117 mL/min as the mobile

phase to provide (+)-11F as the slower moving enantiomer.

Via method G, compound (+)-11F (0.20 g, 0.44 mmol) provided

N′-[5-(1H-Im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-1-n a p h th a -

len yl]-N,N-d im eth ylsu lfa m id e (16). As in 13, dimethylsulf-

amoyl chloride provided 0.078 g (40%) of 16: mp 208-210 °C;

+30.4° (c 0.97, AcOH); ¹H NMR

(

1: mp >260 °C; [R]

DMSO-d

m, 2H), 4.06 (t, 1H), 4.48 (q, 2H), 6.64 (s, 1H), 6.95 (d, 1H),

) δ 1.61-1.83 (m, 2H), 1.83-2.06 (m, 2H), 2.67-2.87

H NMR (DMSO-d ) δ 1.85(m, 4H), 2.75 (s, 6H), 2.81 (m, 2H),

.08 (t, 1H), 7.17 (d, 1H), 7.54 (s, 1H), 9.8 (bs, 1H), 11.5 (bs,

4.05 (t, J ) 9 Hz, 1H), 6.53 (s, 1H), 6.84 (d, J ) 9 Hz, 1H),

H); MS (DCI/NH

) m/z 360 (M + H) . Anal. (C15

)

7.03(t, J ) 9 Hz, 1H), 7.15 (d, J ) 9 Hz, 1H), 7.54 (s, 1H), 8.86

C, H, N.

(bs, 1H), 12.0 (bs, 1H); MS (DCI/NH

) m/z 321 (M + H) . Anal.

(

S‚0.094CH

N-[5,6,7,8-Tetr a h yd r o-5-(1H-im id a zol-4-yl)-1-n a p h th a -

len yl]a ceta m id e, Ma lea te (17). As in 13, Ac O (0.083 mL,

0.88 mmol) provided 0.20 g (100%) of 17, which was converted

2 2

Cl ) C, H, N.

Exa m p le of High -Th r ou gh p u t Syn th esis: N-[5-(1H-

Im id a zol-5-yl)-5,6,7,8-tetr a h yd r o-1-n a p h th a len yl]-1-p r o-

p a n esu lfon a m id e (12). To a solution of 1-propanesulfonyl

chloride (20.5 mg, 0.14 mmol) in CH

pyridine (78 mL, 0.96 mmol) followed by a solution of 4E (30

mg, 0.096 mmol) in CH Cl (1 mL). The CH Cl was removed

2 2

Cl (250 mL) was added

to the maleic acid salt: mp 159-160 °C; H NMR (DMSO-d )

δ 1.67-1.86 (m, 2H), 1.88-2.04 (m, 2H), 2.06 (s, 3H), 2.68 (t,

under vacuum, and the reaction mixture was gently shaken

at ambient temperature overnight. To the reaction mixture

2H), 4.30 (t, 1H), 6.05 (s, 2H), 6.73 (d, 1H), 7.19 (t, 1H), 7.21

(s, 1H), 7.30 (d, 1H), 8.86 (s, 1H), 9.22 (s, 1H); MS (DCI/NH )

was added 1.0 mL of CH

followed by 200 mg of polymer-

m/z 256 (M + H) . Anal. (C15

4 4 4

O‚C H O ) C, H, N.

supported trisamine (Argonaut Laboratories). The reaction

mixture was shaken at room temperature for 30 min and

2,2,2-Tr iflu or o-N-[5-(1H-im id a zol-4-yl)-5,6,7,8-tetr a h y-

d r o-1-n a p h th a len yl]a ceta m id e, Ma lea te (18). As in 13,

trifluoroacetic anhydride (0.12 mL, 0.88 mmol) provided 0.21

washed with CH

brought to 5 mL with CH

, and the volume of the filtrate was

Cl . The organic layer was extracted

g (86%) of 18, which was converted into the maleic acid salt:

with 10% aqueous citric acid (3 × 4 mL) and brine (2 × 4 mL)

and was filtered (Varian CE1000M), and the solvent was

removed under vacuum. The resulting oil was dissolved in 2

mp 181-182 °C; H NMR (DMSO-d

) δ 1.67-1.85 (m, 2H),

1.92-2.06 (m, 2H), 2.65 (t, 2H), 4.33 (t, 1H), 6.05 (s, 2H), 6.93

(dd, 1H), 7.16-7.23 (m, 3H), 8.83 (s, 1H), 10.92 (s, 1H); MS

mL of CH

reaction mixture was shaken at room temperature for 72 h

and filtered. The resin was washed with CH

CN (2 × 2 mL)

and MeOH (2 × 2 mL) and was suspended in 2 M methanolic

NH (2 mL) for 2 h. The resin was filtered, washed with 0.5

mL of MeOH, and then re-treated with 2 M methanolic NH

CN, and 0.5 g of Amberlyst resin was added. The

(DCI/NH

H, N.

) m/z 310 (M + H) . Anal. (C15

4 4 4

‚C H O ) C,

Meth yl 5-(1H-Im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-1-n a p h -

th a len ylca r ba m a te Tr iflu or oa ceta te (19). Polymer-sup-

ported diisopropylamine (2 equiv) was treated with CH Cl

(0.75 mL) and methyl chloroformate (25.3 mg, 0.27 mmol, 1

as described. The combined filtrates were concentated under

vacuum, and the crude material was purified using reverse-

phase preparative HPLC to provide 6.7 mg (21.9%) of 12. H

equiv), mixed well, treated with a solution of 4E in CH Cl (1

mL), shaken for 16 h, treated with polymer-bound tris(2-

aminoethyl)amine (5 equiv), and shaken for 2 h. The resin was

NMR (500 MHz, DMSO-d

) δ 0.99 (t, J ) 7.5 Hz, 3H), 1.67

removed by filtration and washed with CH Cl₂(2×, 1 mL).

(m, 1H), 1.74 (m, 3H), 1.88 (m, 1H), 2.02 (m, 1H), 2.74 (m,

The combined filtrates were concentrated under reduced

pressure to dryness, treated with 30% TFA in CH Cl (1.5 mL),

H), 2.79 (m, 1H), 3.06 (t, J ) 7.7 Hz, 2H), 4.00 and 4.12 (2 m,

.4:1, 1H), 6.44 and 6.54 (2 bs, 1:2.4, 1H), 6.75 and 6.91 (2 bd,

:2.4, J ) 7.7, 1H), 7.02 (m, 1H), 7.10 (m, 1H), 7.49 and 7.51

shaken for 16 h, and concentrated under reduced pressure.

The residue was purified using reverse-phase preparative

(2 bs, 1:2.4, 1H), 8.85 (bs, 1H), 11.70 and 11.84 (2 bs, 2.4:1,

HPLC to provide 47.4 mg (69%) of 19 as the TFA salt. H NMR

H); MS (APCI-) m/z 319 (M - H) . Anal. Calcd (C16

S): C, 60.16; H, 6.63; N, 13.16. Found: C, 58.10; H, 5.32;

N, 11.92.

(500 MHz, DMSO-d ) δ 1.75 (m, 2H), 1.97 (m, 2H), 2.69 (t, J

) 6.4 Hz, 2H), 3.65 (s, 3H), 4.31 (t, J ) 6.6 Hz, 1H), 6.71 (d, J

) 7.7 Hz, 1H), 7.10 (t, J ) 7.9 Hz, 1H), 7.27 (m, 2H), 8.79 (s,

N-[5,6,7,8-Tetr a h yd r o-5-(1H-im id a zol-4-yl)-1-n a p h th a -

len yl]-2-m eth yleth a n esu lfon a m id e, Ma lea te (13). After

substitution of isopropylsulfonyl chloride (0.099 mL, 0.88

mmol) for MsCl, 4E was reacted via method F and, without

purification, the resulting intermediate was reacted via method

1H), 8.97 (s, 1H), 14.20 (bs, 1H); MS (ESI+) m/z 272 (M +

H) . Anal. (C15

17 3 2

H N O ‚1.3TFA) C, H, N.

4-(1H-Im id a zol-4-yl)ch r om a n -8-yla m in e, Ma lea te (21).

Via method G, compound 39E (0.35 g, 1.1 mmol) provided 21

that was converted to 0.19 g (50%) of the maleic acid salt: mp

G to provide 0.09 g (35%) of 13, which was converted to the

145-147 °C; MS (APCI+) m/z 216 (M + H) ; H NMR (DMSO-

maleic acid salt: mp 124-125 °C; H NMR (DMSO-d

) δ 1.30

d ) δ 2.18 (m, 2H), 4.19 (m, 2H), 4.21 (t, 1H), 6.09 (m, 3H),

(

d, 6H), 1.69-1.83 (m, 2H), 1.89-2.02 (m, 2H), 2.83 (t, 2H),

6.55 (m, 2H), 7.33 (s, 1H), 8.95 (d, 1H). Anal. (C H N O‚

.25-3.36 (m, 1H), 4.28 (t, 1H), 6.04 (s, 2H), 6.79 (d, 1H), 7.10

4 4 4

1.5C H O ) C, H, N.

(

t, 1H), 7.16-7.23 (m, 2H), 8.82 (bs, 1H), 8.94 (s, 1H); MS (DCI/

N-[2-Hyd r oxy-5-(1H-im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-

) m/z 320 (M + H) . Anal. (C16

4 4 4

S‚C H O ) C, H, N.

-n aph th alen yl]m eth an esu lfon am ide, Hydr och lor ide (22).

N-[5,6,7,8-Tetr a h yd r o-(1H-im id a zol-4-yl)-1-n a p h th a le-

n yl]cyclop r op a n esu lfon a m id e, Ma lea te (14). As in 13,

A suspension of compound 23 (320 mg, 1.0 mmol) in CH

2 2

(100 mL) at 0 °C was treated with BBr (1.0 M in CH Cl , 4.0

Synthesis and SAR of a Methanesulfonamide

J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3229

mL) over 5 min, stirred at 0 °C for 2 h, cooled to -78 °C,

treated with MeOH (10 mL), warmed to ambient temperature,

and concentrated. Purification of the residue on silica gel with

1H), 7.27 (d, 1H), 7.63 (s, 1H); MS (APCI+) m/z 340 (M + H) ;

MS (APCI-) m/z 338 (M - H) . Anal. (C15

18ClN

S‚0.3H O‚

0.2EtOH) C, H, N.

0% EtOH in NH

3 2 2

-saturated CH Cl provided 0.22 g (72%) of

-{7-Cycloh exyl-5-[(et h ylsu lfon yl)a m in o]-1,2,3,4-t et -

2 that was converted to the hydrochloride salt: mp 135-137

r a h yd r o-1-n a p h th a len yl}-N,N-d im eth yl-1H-im id a zole-1-

C; H NMR (DMSO-d

) δ 1.61-1.74 (m, 2H), 1.88-2.00 (m,

su lfon a m id e (26F ). 7-Cyclohexyl-3,4-dihydro-1(2H)-naph-

H), 2.86 (t, 2H), 3.03 (s, 3H), 4.21 (t, 1H), 6.69 (d, 1H), 6.75

thalenone45 (3.8 g, 16.6 mmol) in concentrated H SO (35 mL)

(d, 1H), 7.18 (d, 1H), 8.58 (s, 1H), 9.05 (d, 1H), 9.85 (s, 1H),

at -5 °C was treated in portions with solid NaNO (1.7 g, 20

mmol). After being stirred at 0 °C for 2 h, the mixture was

poured into ice and extracted with EtOAc. The EtOAc layer

4.38 (bs, 2H); MS (DCI/NH

S‚HCl‚EtOH) C, H, N.

N-[5-(1H-Im id a zol-4-yl)-2-m eth oxy-5,6,7,8-tetr a h yd r o-

n a p h t h a len -1-yl]m et h a n esu lfon a m id e, H yd r och lor id e

) m/z 308 (M + H) . Anal.

14 17 3 3

(C H N O

was dried (MgSO ), filtered, and concentrated. The residue was

purified by column chromatography (silica gel, 3:1 hexane/

EtOAc) to provide 1.5 g of a mixture of 26A and starting

material (60:40 ratio) that was used without further purifica-

tion. This mixture was reacted sequentially by methods C, E,

(

23). 6-Methoxy-5-nitro-1-tetralone (0.50 g, 2.3 mmol) was

reacted via method A (80%) to 23B, method D (80%) to 23C,

and method E (90%) to 23E and as in 13 using MsCl to provide

3 that was converted to the HCl salt: mp 209-211 °C; H

and F (using EtSO Cl) to provide 26F .

NMR (DMSO-d

) δ 1.65-1.72 (m, 2H), 1.88-2.01 (m, 2H), 1.88

N-[5,6,7,8-Tetr a h yd r o-4-h yd r oxy-5-(1H-im id a zol-4-yl)-

1-n a p h th a len yl]m eth a n esu lfon a m id e, Ma lea te (27). Com-

pound 28F (0.32 g, 0.76 mmol) was treated with 1.0 M BBr₃/

CH Cl (3 mL) as described for compound 22 to provide 0.13 g

(t, 2H), 3.00 (s, 3H), 3.79 (s, 3H), 4.27 (t, 1H), 6.88 (q, 2H),

.20 (s, 1H), 8.66 (s, 1H), 9.03 (s, 1H), 14.33 (bs, 2H); MS (DCI/

19 3 3

NH ) m/z 322 (M + H) . Anal. (C15H N O S‚HCl) C, H, N.

N-[3-F lu or o-5-(1H-im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-1-

n a p h th a len yl]eth a n esu lfon a m id e (24). A solution of 7-flu-

(54%) of 27, which was converted to the maleic acid salt: mp

127-131 °C; H NMR (DMSO-d

1.85 (m, 1H), 1.96 (m, 1H), 2.62 (m, 1H), 2.91 (m, 1H), 2.95 (s,

H), 4.29 (d, 1H), 6.04 (s, 2H), 6.66 (d, 1H), 6.85 (s, 1H), 7.07

d, 1H), 8.75 (s, 1H), 8.85 (s, 1H); MS (DCI/NH ) m/z 308 (M

) δ 1.44 (m, 1H), 1.74 (m, 1H),

oro-3,4-dihydro-1(2H)-naphthalenone (2.45 g, 14.9 mmol) was

treated with NH OH‚HCl (3.13 g, 45 mmol) and NaOAc (3.7

(

g, 45 mmol) in water (3 mL), heated at reflux for 24 h, cooled

to ambient temperature, concentrated, and triturated with

water. The resulting solid was collected by filtration and dried

to provide 2.4 g (100%) of the corresponding oxime. To a 85

H) . Anal. (C14

N-[5-(1H-Im id a zol-4-yl)-4-m eth oxy-5,6,7,8-tetr a h yd r o-

n a p h th a len -1-yl]m eth a n esu lfon a m id e (28). A solution of

8-methoxy-1-tetralone⁴⁶(2.26 g, 13 mmol) in Ac

O (11.5 mL)

was cooled to 0 °C, treated with a mixture of fuming HNO

S‚C

4 4 4

H O ) C, H, N.

C solution of polyphosphoric acid (0.5 g) in toluene (5 mL)

was added the oxime (0.18 g, 1 mmol). After 30 min at reflux,

the mixture was allowed to cool to ambient temperature,

diluted with water, and extracted with EtOAc. The EtOAc

(0.90 mL) in AcOH (0.70 mL) dropwise over 1 h, stirred at 0

°C for 1.5 h, treated with water (150 mL), and extracted with

layer was dried (MgSO

), filtered, and concentrated to provide

mL), washed with NaHCO

dried (MgSO ), filtered, and concentrated. Purification of the

O (300 mL). The organic layer was washed with water (150

.16 g (89%) of 8-fluoro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one.

solution (3×), washed with brine,

NaH (60% dispersion) (0.72 g, 18 mmol) was washed with

hexane, suspended in THF (10 mL), cooled to 0 °C, and treated

dropwise with a solution of the azepinone (2.16 g, 12 mmol)

in THF (40 mL). After being stirred at 0 °C for 1.5 h, the

mixture was treated with EtSO Cl (1.93 g, 15 mmol). After

being stirred at ambient temperature for 2.5 h, the mixture

was treated with water (5 mL) and 1 M NaOH solution (24

residue on silica gel using a gradient of 2:1 and then 3:2 and

finally 1:1 hexanes/EtOAc provided 0.84 g (30%) of 28A as the

more polar isomer. Compound 28A was reacted sequentially

by methods B and D-F to provide 28F , which was reacted by

method G to provide 28, which was converted to the maleic

acid salt: mp 181-184 °C; H NMR (DMSO-d

) δ 1.43 (m, 1H),

mL) and washed with Et

with 1 M HCl (25 mL) and extracted with CH

Cl layer was dried (MgSO ), filtered, and concentrated to

provide 4-{2-[(ethylsulfonyl)amino]-4-fluorophenyl}butanoic

acid (2.9 g, 84%). This acid (2.47 g, 8.5 mmol) in CH Cl (25

mL) and DMF (0.025 mL) was treated with oxalyl chloride

2.16 g, 17 mmol) and stirred at ambient temperature for 24

h. This solution was added to a 0 °C suspension of AlCl (4.53

g, 34 mmol) in CH Cl (25 mL). The mixture was stirred at

ambient temperature for 60 h, treated with water (50 mL),

and extracted with CH Cl . The CH Cl layer was dried

MgSO ), filtered, and concentrated. The residue was purified

O. The aqueous layer was acidified

1.75 (m, 1H), 1.85 (m, 1H), 1.97 (m, 1H), 2.66 (m, 1H), 2.93

(m, 1H), 2.98 (s, 3H), 3.64 (s, 3H), 4.34 (d, 1H), 6.04 (s, 2H),

Cl . The CH

6.82 (s, 1H), 6.86 (d, 1H), 7.24 (d, 1H), 8.85 (s, 1H), 8.87 (s,

1H); MS (DCI/NH

) C, H, N.

N-[5-(1H-Im id a zol-4-yl)-4-m eth yl-7,8-d ih yd r on a p h th a -

) m/z 322 (M + H) . Anal. (C15

S‚

4 4 4

C H O

(

len -1-yl]m eth an esu lfon am ide (29J ). Via method F, 5-amino-

8-methyltetralone⁴⁷(0.25 g, 1.4 mmol) provided 0.25 g (69%)

of 29G. A solution of 29G (0.23 g, 0.90 mml) in DMF (10 mL)

under N was treated with NaH (40 mg of 60% dispersion, 0.99

mmol), stirred for 15 min, treated with MOMCl (0.072 mL,

0.95 mmol), stirred for 1 h, treated with water, and extracted

(

by chromatography on silica gel, eluting with 3:7 EtOAc/

hexane to provide 24G. Compound 24G (0.38 g, 1.4 mmol) in

with Et O (3 × 75 mL). The combined extractions were washed

with water, washed with brine, dried (MgSO ), filtered, and

(7 mL) was treated with Et

N (0.22 mL, 1.6 mmol),

concentrated to provide 0.25 g (92%) of 29I. Via method A,

29I (0.25 g, 0.83 mmol) provided 0.074 g (29%) of 29J .

DMAP (0.012 g, 0.1 mmol), and Boc

O (0.33 g, 1.5 mmol). After

being stirred for 1.5 h, the mixture was concentrated and the

residue was purified by filtration through a pad of silica gel,

N-[4-F lu or o-5-(1H-im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-1-

n a p h th a len yl]m eth a n esu lfon a m id e, Ma lea te (30). A solu-

tion of 8-fluoro-5-methoxytetralone (7.0 g, 36 mmol) in 1,2-

dichloroethane (150 mL) was treated with AlCl (21 g, 157

mmol), refluxed for 3.5 h, cooled to ambient temperature,

poured carefully into 4 M HCl (500 mL), stirred for 16 h,

eluting with CH

to provide 24I. Via methods A and J , 24I

was converted to 24J and 0.085 g (29%) of 24, respectively.

H NMR (CD OD) δ 1.36 (t, 3H), 1.74-1.82 (m, 1H), 1.84-

.93 (m, 1H), 2.00-2.06 (m, 2H), 2.72-2.81 (m, 2H), 3.16 (q,

H), 4.13 (t, 1H), 6.57 (dd, 1H), 6.63 (s, 1H), 7.04 (dd, 1H),

treated with CH

solid was removed by filtration through Celite. The CH

(400 mL), and thoroughly shaken. A black

.59 (s, 1H); MS (APCI+) m/z 324 (M + H) ; MS (APCI-) m/z

22 (M - H) . Anal. (C15

18FN

S‚0.25H O‚0.1EtOH) C, H,

layer was isolated, combined with the black solid, and ex-

tracted with a 5% NaOH solution (3 × 150 mL). The combined

NaOH extracts were acidified with 4 M HCl, and the resulting

solid was collected by filtration to provide 3.7 g (57%) of the

phenol as a brown solid. A solution of this phenol (1.0 g, 5.5

N-[3-Ch lor o-5-(1H-im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-1-

n a p h th a len yl]eth a n esu lfon a m id e (25). 7-Chloro-3,4-dihy-

dro-2H-naphthalen-1-one was processed as described for 24

except that the reaction time for method J was 2.5 h instead

mmol) in pyridine (3 mL) under N

dropwise with Tf O (1.0 mL, 6.2 mmol), stirred for 16 h at

ambient temperature, treated with 2 M HCl (25 mL), stirred

for 30 min, and extracted with EtOAc (3 × 70 mL). The

was cooled to 0 °C, treated

of 16 h to provide 25. H NMR (CD

OD) δ 1.37 (t, 3H), 1.73-

.83 (m, 1H), 1.83-1.93 (m, 1H), 1.98-2.08 (m, 2H), 2.75-

.85 (m, 2H), 3.16 (q, 2H), 4.13 (t, 1H), 6.64 (s, 1H), 6.85 (d,

230 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12

Altenbach et al.

combined EtOAc extracts were washed with brine and con-

centrated. Purification of the residue on silica gel with 40%

EtOAc/hexanes provided 1.2 g (67%) of the triflate: trifluo-

romethanesulfonic acid 4-fluoro-5-oxo-5,6,7,8-tetrahydronaph-

7.30 (dd, J ) 7.72, 1.84 Hz, 1 H), 7.67 (d, J ) 1.10 Hz, 1 H).

Anal. Calcd (C14

17 3 3

H N O S): C, 56.06; H, 5.96; N, 13.07.

Found: C, 54.98; H, 5.64; N, 11.07.

N-[5-(1H -Im id a zol-4-yl)-7,8-d ih yd r o-1-n a p h t h a len yl]-

thalen-1-yl ester. A mixture of Pd

under N in toluene (136 mL) was treated with (R)-(+)-BINAP

0.96 g, 1.5 mmol), treated with NaOtBu (0.98 g, 10 mmol),

treated with benzylamine (1.1 mL, 10 mmol), warmed to 85

C, treated dropwise over 45 min with a solution of the triflate

2.1 g, 6.8 mmol) in toluene (30 mL), stirred at 85 °C for 1 h,

(dba)

(0.36 g, 0.34 mmol)

m eth a n esu lfon a m id e, Ma lea te (33). 5-Methanesulfona-

mido-1-tetralone41 (1.0 g, 4.2 mmol) was reacted with MOMCl

(

as described for 29I to provide 0.87 g (73%) of N-methoxy-

methyl-N-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)meth-

anesulfonamide (33I) and then via method A (86%) to provide

33, which was converted to the maleic acid salt: mp 161-165

(

and treated with water (50 mL). The organic layer was

isolated, and the aqueous layer was extracted with EtOAc. The

°C; H NMR (DMSO-d ) δ 2.28-2.38 (m, 2H), 2.85 (t, 2H), 2.98

(s, 3H), 6.07 (s, 2H), 6.49 (t, 1H), 7.11 (dd, 1H), 7.19-7.29 (m,

2H), 7.61 (s, 1H), 8.78 (s, 1H), 9.21 (s, 1H); MS (DCI/NH ) m/z

290 (M + H) , 307 (M + NH ) . Anal. (C H N O S‚C H O )

C, H, N.

combined organic layers were washed with brine, dried (Na

SO ), and concentrated. Purification of the residue on silica

gel with 30% EtOAc/hexanes provided 0.40 g (22%) of 30H. A

solution of 30H (0.40 g, 1.5 mmol) in CH Cl (9 mL) was

treated with pyridine (0.36 mL, 4.4 mmol) and MsCl (0.13 mL,

.6 mmol), stirred for 4 h, treated with pyridine (0.2 mL, 2.5

14 15

N -[1-(1H -Im id a zol-4-yl)-2,3-d ih yd r o-1H -in d e n -4-yl]-

eth a n esu lfon a m id e, Ma lea te (34). 4-Nitroindanone (34A)

was reacted via method B (73%) to 34B, method D (66%) to

mmol) and MsCl (0.10 mL, 1.3 mmol), stirred for 16 h, refluxed

for 9 h, cooled to ambient temperature, treated with water (25

4C, and method E (91%) 34E , as for 13 with EtSO

Cl, to

provide (54%) the free base of 34 that was converted to the

mL), and extracted with CH

(3 × 20 mL). The combined

maleic acid salt: mp 148-149 °C; H NMR (CD

OD) δ 1.36 (t,

H), 2.16 (m, 1H), 2.64 (m, 1H), 2.96-3.24 (m, 2H), 3.14 (q,

H), 4.62 (t, 1H), 6.25 (s, 2H), 6.92 (d, 1H), 7.21 (t, 1H), 7.29

CH Cl extracts were washed with brine, dried (Na

SO ), and

concentrated. Purification of the residue on silica gel with 1:1

EtOAc/hexanes provided 0.29 g (57%) of 30I. Compound 30I

(

m, 2H), 8.76 (d, 1H); MS (DCI/NH

S‚C ) C, H, N.

N-[5-(1H-Im id a zol-4-yl)-6,7,8,9-tetr a h yd r o-5H-ben zo[a ]-

cycloh ep t en -1-yl]m et h a n esu lfon a m id e, Ma lea t e (35).

-Benzosuberone (18.5 g, 11.5 mmol) was mechanically stirred

SO (41 mL) over

min, stirred for 10 min, treated dropwise over 10 min with

) m/z 292 (M + H) . Anal.

(0.29 g, 0.83 mmol) was reacted via method A (45%) to 30J

4 4 4

H O

and via method I to provide 0.097 g (87%) of 30, which was

converted to the maleic acid salt: mp 182-186 °C; H NMR

(

DMSO-d ) δ 1.50 (m, 1H), 1.76 (m, 1H), 1.95 (m, 2H), 2.70

(m, 1H), 2.92 (m, 1H), 3.02 (s, 3H), 4.42 (m, 1H), 6.07 (s, 2H),

at -15 °C and treated with concentrated H

.99 (s, 1H), 7.05 (t, 1H), 7.30 (dd, 1H), 8.86 (s, 1H), 9.08 (s,

H); MS (APCI+) m/z 310 (M + H) ; MS (APCI-) m/z 308 (M

3 2 4

a mixture of fuming HNO (9 mL) and concentrated H SO

H) . Anal. (C14

4 4 4

SF‚C H O ) C, H, N.

(14 mL), stirred at -15 °C for 15 min, and poured carefully

N-[4-Ch lor o-5-(1H-im id a zol-4-yl)-5,6,7,8-tetr a h yd r o-1-

n a p h th a len yl]m eth a n esu lfon a m id e, Ma lea te (31). A solu-

onto a mixture of ice (200 g) and water (200 mL). The resulting

solid was collected by filtration, washed with water (2 × 100

mL), dried, and recrystallized from EtOH (200 mL). The

resulting solid was removed by filtration and the filtrate was

adsorbed on silica gel and purified by flash chromatography

on silica gel, eluting with EtOAc/hexanes 12:88 to provide 35A

(13%) as the less polar product. Via methods B, D, E, F (using

tion of 5-amino-1-tetralone (0.50 g, 3.1 mmol) in DMF (15

mL) was treated with N-chlorosuccinimide (0.49 g, 3.7 mmol),

stirred for 60 h, treated with water, and extracted with Et

4 × 30 mL). The combined Et O extracts were washed with

brine, dried (Na SO ), and concentrated. Purification of the

residue on silica gel with 1:1 EtOAc/hexanes provided 0.31 g

51%) of 5-amino-8-chloro-3,4-dihydro-1(2H)-naphthalenone.

(

EtSO Cl), and G, 35A provided the free base of 35, which was

(

converted to the maleic acid salt: mp 162-164 °C; H NMR

This aniline was treated as described in 29 for the conversion

of 5-amino-8-methyltetralone to 29J to provide 31J . A mixture

of 31J (0.16 g, 0.50 mmol) and 10% Pd/C in 5:1 THF/5 M HCl

(CD OD) δ 1.58 (m, 1H), 1.83 (m, 3H), 2.06 (m, 1H), 2.17 (m,

1H), 2.97 (s, 3H), 3.00 (m, 1H), 3.18 (m, 1H), 4.54 (dd, 1H),

6.25 (s, 2H), 7.69 (d, 1H), 7.14 (t, 1H), 7.26 (dd, 1H), 7.29 (s,

(

6 mL) was stirred under hydrogen (1 atm) for 1 h, filtered,

and concentrated. Purification of the residue on silica gel with

0% MeOH in NH -saturated CH Cl provided 0.040 g (24%)

of 31 that was converted to the maleic acid salt: mp 175-178

1H), 8.81 (d, 1H); MS (DCI/NH

) m/z 306 (M + H) . Anal.

(C15

S‚C ‚0.5EtOAc) C, H, N.

4 4 4

H O

N-[3-(1H -Im id a zol-4-ylm et h yl)p h en yl]et h a n esu lfon -

a m id e, Ma lea te (36). 3-Nitrobenzaldehyde (36K) (1.6 g, 10.6

mmol) was reacted with 5 (2.4 g, 7.9 mmol) as described in

method A, part 1. The reaction mixture was not concentrated

C; H NMR (DMSO-d

) δ 1.30-1.85 (m, 2H), 1.86-2.08 (m,

H), 2.60-3.00 (m, 2H), 3.06 (s, 3H), 4.44 (m, 1H), 6.05 (s, 2H),

.82 (s, 1H), 7.32 (s, 2H), 8.80 (s, 1H), 9.15 (s, 1H); MS (APCI+)

but treated with aqueous NH

2×). The combined extractions were dried (MgSO

and concentrated to provide the intermediate alcohol. This

alcohol, Et SiH (3 mL), and TFA (30 mL) were refluxed for 16

h and concentrated. The residue was triturated with hexane

and then partitioned between CH Cl and aqueous NaHCO

The CH Cl layer was dried (MgSO ), filtered, concentrated,

and chromatographed (CH Cl and then 2:1 CH Cl /EtOAc) to

Cl and extracted with CH

2 2

m/z 326 (M + H) ; MS (APCI-) m/z 324 (M - H) . Anal.

SCl‚C ) C, H, N.

(

), filtered,

(

4 4 4

H O

Eth a n esu lfon ic Acid [5-Hyd r oxy-5-(1H-im id a zol-4-yl)-

,6,7,8-tetr a h yd r on a p h th a len -1-yl]a m id e (32). 5-Nitro-1-

tetralone (1.0 g, 5.2 mmol) was reacted by method B to

provide after chromatography (5% EtOH in CH Cl ) 0.83 g

63%) of the intermediate alcohol. This alcohol (0.49 g, 0.80

mmol) was dissolved in EtOH (10 mL), treated with water (5

mL), NH Cl (0.046 g, 0.88 mmol), and iron powder (0.34 g, 7.6

mmol), heated to reflux, cooled, filtered through Celite,

concentrated, and chromatographed (2% EtOH in CH Cl ) to

provide 0.30 g (80%) of the corresponding aniline. Via method

F, this aniline (0.22 g, 0.46 mmol) and EtSO Cl (0.068 mL,

.72 mmol) provided 0.23 g (89%) of the sulfonamide. The trityl

(

provide 36L (0.81 g, 33%). Via method E, 36L (0.81 g, 2.6

mmol) in 3:1 THF/EtOAc provided the aniline (0.74 g, 100%).

Via method F with EtSO Cl and then method H, the aniline

(0.28 g, 0.89 mmol) provided compound 36 (0.24 g, 92%), which

was converted to the maleic acid salt: mp 107-109 °C; H

NMR (DMSO-d ) δ 1.18 (t, 3H), 3.08 (q, 2H), 3.99 (s, 2H), 6.05

(s, 2H), 6.96 (d, 1H), 7.08 (m, 2H), 7.28 (m, 1H), 7.37 (d, 1H),

group was then removed by hydrogenating this sulfonamide

intermediate (0.10 g, 0.18 mmol) in EtOH (20 mL) in the

8.80 (d, 1H), 9.77 (s, 1H); MS (DCI/NH

Anal. (C12 S‚C ) C, H, N.

) m/z 266 (M + H) .

4 4 4

H O

presence of 90 mg of 10% Pd/C under 4 atm of H

and the mixture was filtered. The filtrate was concentrated

and chromatographed (10:1:89 MeOH/NH OH/CH Cl ) to pro-

OD) δ 1.37 (t, J ) 7.54

Hz, 3 H), 1.74 (m, 1 H), 2.02 (m, 2 H), 2.38 (m, 1 H), 2.89 (m,

for 53 h,

N-[3-(1H-Im id a zol-4-ylm eth yl)-2-m eth ylp h en yl]m eth -

a n esu lfon a m id e, Ma lea te (37). 2-Methyl-3-nitrobenzyl al-

cohol⁵¹(2.95 g, 17.5 mmol) and oxalyl chloride (6.1 mL, 70

vide 0.015 g (26%) of 32. H NMR (CD

mmol) in CH

dropwise with DMSO (8.7 mL, 123 mmol), stirred for 10 min,

treated with Et N (25 mL, 175 mmol), stirred for 10 min,

warmed to room temperature, stirred for 16 h, treated with

(61 mL) at -78 °C under N

were treated

H), 3.15 (q, J ) 7.35 Hz, 2 H), 6.73 (d, J ) 1.47 Hz, 1 H),

.17 (d, J ) 7.72 Hz, 1 H), 7.24 (dd, J ) 7.72, 1.47 Hz, 1 H),

Synthesis and SAR of a Methanesulfonamide

J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3231

aqueous NH

combined Et

MgSO ), filtered, concentrated, and chromatographed (5:1 and

Cl solution, and extracted with Et

O layers were washed with water and brine, dried

O (2×). The

the majority of the water, dried (MgSO

trated, and chromatographed (12:1:1 EtOAc/H

(100 mL), transferred to a separatory funnel to remove

), filtered, concen-

O/HCO H) to

(

then 2:1 hexane/EtOAc) to provide 2.73 g (94%) of 37K, which

was treated as described for 36 to provide 37, which was

converted to the maleic acid salt: mp 146-147 °C; H NMR

provide 0.12 g (24%) of the 3-methyl-3H-imidazol-4-yl isomer

as the less polar isomer and 0.23 g (45%) of the 1-methyl-1H-

imidazol-4-yl isomer as the more polar isomer. The more polar

1-methyl-1H-imidazol-4-yl isomer from above (0.22 g) was

hydrogenated via method I to provide the free base of 43, which

(

DMSO-d

) δ 1.26 (t, 3H), 3.25 (s, 3H), 3.06 (q, 2H), 4.01 (s,

H), 6.05 (s, 2H), 7.02 (dd, 1H), 7.17 (m, 2H), 7.24 (d, 1H),

.80 (d, 1H), 9.07 (s, 1H); MS (DCI/NH

) m/z 280 (M + H) .

was converted to the HCl salt: mp 130-135 °C; H NMR

Anal. (C13

S‚C

) C, H, N.

(DMSO-d ) δ 1.68-1.79 (m, 2H), 1.93-2.03 (m, 2H), 2.88 (t,

N-{3-[1-(1H-Im idazol-4-yl)eth yl]ph en yl}m eth an esu lfon -

a m id e, Ma lea te (38). 3-Nitroacetophenone (38A) (0.67 g, 4.0

mmol) was reacted via methods A, D, and E to provide 0.59 g

2H), 3.03 (s, 3H), 3.79 (s, 3H), 4.33 (t, 1H), 6.87 (d, 1H), 7.15

(t, 1H), 7.20-7.26 (m, 2H), 9.01 (s, 1H), 9.06 (s, 1H), 14.57

(bs, 1H); MS (DCI/NH

HCl‚0.5H O) C, H, N.

) m/z 306 (M + H) . Anal. (C15

S‚

(60% for three steps) of 38E. Aniline 38E (0.31 g, 1.1 mmol)

was reacted as in 13 using MsCl to provide 0.25 g (89%) of

N-[5-(3-Met h yl-3H -im id a zol-4-yl)-5,6,7,8-t et r a h yd r o-

n a p h t h a len -1-yl]m et h a n esu lfon a m id e, H yd r och lor id e

(44). The 3-methyl-3H-imidazol-4-yl isomer (0.12 g) from the

above procedure was hydrogenated via method I to provide

the free base of 44, which was converted to the HCl salt. MS

the free base of 38, which was converted to the maleic acid

salt: mp 135-136 °C; H NMR (DMSO-d

) δ 1.55 (d, 3H), 2.98

(

s, 3H), 4.20 (q, 1H), 6.05 (s, 2H), 6.98 (d, 1H), 7.05 (s, 1H),

.08 (d, 1H), 7.30 (t, 1H), 7.47 (s, 1H), 8.84 (s, 1H), 9.75 (s,

H); MS (DCI/NH

) C, H, N.

) m/z 266 (M + H) . Anal. (C12

S‚

(DCI/NH ) m/z 306 (M + H) ; H NMR (DMSO-d ) δ 1.67-

1.91 (m, 3H), 1.94 (m, 1H), 2.71-2.94 (m, 2H), 3.03 (s, 3H),

3.83 (s, 3H), 4.45 (t, 1H), 6.85 (d, 1H), 7.03 (s, 1H), 7.14 (t,

1H), 7.24 (d, 1H), 9.05 (s, 1H), 9.07 (s, 1H), 14.32 (bs, 1H).

N-[4-(1H-Im id a zol-4-yl)ch r om a n -8-yl]m eth a n esu lfon -

a m id e (39). 8-Nitrochroman-4-one⁵²(39A) (3.3 g, 17 mmol)

was reacted via method B (83%) to 39B, method D (78%) to

Anal. (C15

S‚HCl‚EtOH‚0.25H O) C, H, N.

9C, and method E (86%) to 39E and as for 13 using MsCl to

Eth a n esu lfon ic Acid [5-(2-Meth yl-1H-im id a zol-4-yl)-

provide the free base of 39 (41%), which was converted to the

5,6,7,8-tetr a h yd r on a p h th a len -1-yl]a m id e, Ma lea te (45).

maleic acid salt: mp 172-174 °C; H NMR (DMSO-d

) δ 2.22

5-Nitro-1-tetralone (0.38 g, 2 mmol) and 4-iodo-2-methyl-1-

(m, 2H), 2.99 (s, 3H), 4.25 (m, 2H), 4.40 (t, 1H), 6.06 (s, 2H),

triphenylmethylimidazole54 (0.99 g, 2.2 mmol) were reacted via

.78 (dd, 1H), 6.83 (t, 1H), 7.16 (dd, 1H), 7.29 (s, 1H), 8.80 (s,

methods B and D to provide 0.63 g (89%) of 45C after

chromatography (10:1 and then 5:1 hexane/EtOAc). Via method

E, 45C (0.63 g, 1.8 mmol) provided 0.40 g (100%) of 45E. As

H), 8.88 (s, 1H); MS (APCI+) m/z 294 (M + H) . Anal.

4 4 4

S‚C H O ) C, H, N.

Eth an esu lfon ic Acid [4-(1H-im idazol-4-yl)th ioch r om an -

in 13 using EtSO

Cl, 45E (0.40 g, 1.8 mmol) provided 0.27 g

-yl]a m id e (40). 8-Nitrothiochroman-4-one⁴⁰(40A) (0.48 g, 2.3

(69%) of 45, which was converted to the maleic acid salt: mp

mmol) was reacted via method C (37%) to 40D, method E (91%)

to 40E, and methods F (using EtSO Cl) and H to provide 40

) δ 1.30 (t, 3H),

73-77 °C; H NMR (DMSO-d ) δ 1.28 (t, 3H), 1.66-1.86 (m,

2H), 1.86-2.06 (m, 2H), 2.83 (t, 2H), 3.12 (q, 2H), 4.24 (t, 1H),

(

47%): mp 248-251 °C; H NMR (DMSO-d

.01 (m, 1H), 2.44 (m, 1H), 2.90 (m, 2H), 3.11 (q, 2H), 4.16 (m,

6.02 (s, 2H), 6.82 (d, 1H), 7.08 (s, 1H), 7.12 (t, 1H), 7.19 (dd,

1H), 8.99 (s, 1H), 13.60 (bs, 1H). Anal. (C16

0.25H O) C, H, N.

4 4 4

S‚C H O ‚

H), 6.40 (s, 1H), 6.95 (m, 2H), 7.11 (m, 1H), 7.80 (s, 1H), 9.0

(

s, 1H), 11.81 (bs, 1H); MS (APCI+) m/z 324 (M + H) . Anal.

Eth a n esu lfon ic Acid (5-Am in om eth yl-5,6,7,8-tetr a h y-

d r on a p h th a len -1-yl)a m id e, Ma lea te (46). In step 1, follow-

ing the reported procedure¹⁵described for the conversion of

3,4-dihydro-6-methoxy-5-nitro-1(2H)-naphthalenone to N-(5-

cyano-5,6,7,8-tetrahydro-2-methoxy-1-naphthalenyl)methane-

S‚0.25H

E t h a n esu lfon ic Acid [1-(1H -Im id a zol-4-yl)-1,3-d ih y-

d r oisoben zofu r a n -4-yl]a m id e (41). 4-Nitro-2-benzofuran-

O) C, H, N.

(3H)-one (41A) (2.4 g, 13 mmol) was reacted via method A,

part 1, and the intermediate alcohol (3.2 g, 69%) was isolated

after chromatography (1:1 and then 2:1 EtOAc/hexane). This

sulfonamide and substitution of EtSO Cl in place of MsCl,

5-nitro-1-tetralone³⁹(5.0 g, 26 mmol) was converted to 5.3 g

(77%) of ethanesulfonic acid (5-cyano-5,6,7,8-tetrahydro-naph-

thalen-1-yl)-amide. In step 2, a solution of this intermediate

(1.0 g, 3.8 mmol) in THF (45 mL) was added dropwise to a

suspension of LAH (0.58 g, 15 mmol) in THF (15 mL) at room

temperature. The mixture was then heated to reflux for 2 h

and cooled and the reaction mixture was quenched with the

addition of acetone. After being stirred for 1 h, the mixture

was concentrated, acidified with 1 M HCl, and extracted with

EtOAc to remove impurities. The aqueous layer was basified

with NaHCO and extracted with EtOAc (4×) and with CH -

alcohol (0.50 g, 1.4 mmol) was reduced by stirring in Et

2.5 mL) and TFA (15 mL) for 1 h to provide, after concentra-

tion and chromatography (1:1 and then 2:1 EtOAc/hexane),

.25 g (52%) of N,N-dimethyl-4-(4-nitro-1,3-dihydro-2-benzo-

SiH

(

furan-1-yl)-1H-imidazole-1-sulfonamide. Reduction by method

E (100%) and sulfonation/deprotection by method F (with

EtSO

converted to the maleic acid salt: mp 95-98 °C; H NMR

DMSO-d ) δ 1.25 (t, 3H), 3.14 (q, 2H), 5.12 (d, 1H), 5.26 (dd,

H), 6.09 (s, 2H), 6.31 (s, 1H), 6.98 (dd, 1H), 7.25-7.36 (m,

H), 7.51 (bs, 1H), 8.67 (bs, 1H), 9.59 (s, 1H), 14.6 (bs, 1H);

Cl) and method H (96%) provided 41, which was

(

Cl (3×). The combined organic layers were dried (Na SO ),

MS (ESI+) m/z 294 (M + H) ; MS (ESI-) m/z 292 (M - H) .

Anal. (C13 S‚C ‚0.5EtOAc) C, H, N.

filtered, and concentrated to provide 0.50 g (49%) of 46 that

was converted to the maleic acid salt. MS (APCI+) m/z 269

4 4 4

H O

- 1

Eth a n esu lfon ic Acid [8-(1H-Im id a zol-4-yl)-5,6,7,8-tet-

r a h yd r on a p h th a len -2-yl]a m id e (42). The title compound

was prepared according to methods A and D-G, substituting

(M + H) , MS (APCI-) m/z 267 (M - H) ; H NMR (DMSO-

d ) δ 1.25 (t, 3H), 1.73 (m, 4H), 2.40-2.50 (m, 1H), 2.77-2.90

(m, 1H), 2.90-3.02 (m, 1H), 3.02-3.10 (m, 2H), 3.10 (q, 2H),

-nitro-1-tetralone for 5-nitro-1-tetralone and EtSO

Cl in place

) δ 1.25 (t, J )

Hz, 3H), 1.70 (m, 2H), 1.94 (m, 2H), 2.71 (m, 2H), 2.94 (q, J

7 Hz, 2H), 4.00 (t, 1H), 6.51 (s, 1H), 6.86 (s, 1H), 6.97 (dd,

6.01 (s, 2H), 7.16 (m, 3H), 7.80 (s, 3H), 8.91 (s, 1H). Anal.

of MsCl: mp 187-188 °C; H NMR (DMSO-d

(C13

4 4 4

S‚C H O ) C, H, N.

Eth a n esu lfon ic Acid (5-Meth yla m in om eth yl-5,6,7,8-

tetr a h yd r on a p h th a len -1-yl)a m id e, Hyd r och lor id e (47).

A solution of the free base of 46 (0.67 g, 2.5 mmol) and ethyl

formate (7.7 mL) in toluene (20 mL) was refluxed for 1.5 h,

cooled, and concentrated. The residue was taken up in THF

)

J ) 2, 8 Hz, 1H), 7.04 (d, J ) 8 Hz, 1H), 7.52 (s, 1H), 9.47 (s,

H), 11.78 (bs, 1H). Anal. (C15

S‚0.25H

O) C, H, N.

N-[5-(1-Meth yl-1H-im idazol-4-yl)-5,6,7,8-tetr ah ydr on aph -

t h a len -1-yl]m et h a n esu lfon a m id e, H yd r och lor id e (43).

Compound 4J (0.49 g, 1.3 mmol) in anhydrous DMF (5 mL)

under N was treated with NaH (62 mg of 60% dispersion, 1.5

mmol), stirred for 15 min, treated with MeI (0.096 mL, 1.5

mmol), stirred for 1 h, and quenched with water (75 mL). The

semisolid was collected by decantation/filtration, dissolved in

(20 mL), treated with BH ‚THF complex (7.5 mL of 1 M

solution THF), heated to reflux for 2 h, cooled, treated with

MeOH (20 mL), concentrated, treated with MeOH (20 mL) and

MeOH saturated with HCl (20 mL), refluxed for 1 h, cooled,

and concentrated. The residue was taken up in water, adjusted

to pH ∼8 with NaHCO , extracted with EtOAc (3×), and

232 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12

Altenbach et al.

extracted with THF (3×). The EtOAc extractions were dis-

Eth a n esu lfon ic Acid (3-P yr r olid in -2-ylm eth ylp h en yl)-

a m id e (51). In step 1, a mixture of 3-nitrobenzaldehyde (10

g, 66 mmol), methyl 4-nitrobutyrate (8.8 mL, 69 mmol), and

DBU (1.0 mL, 6.7 mmol) in THF (12 mL) was stirred for 1

day, treated with more methyl 4-nitrobutyrate (8.8 mL, 69

mmol), stirred an additional day, and partitioned between

carded, the combined THF extractions were concentrated, and

2 2 2 4

the residue was redissolved in CH Cl , dried (Na SO ), filtered,

and concentrated to provide 0.22 g (32%) of 47, which was

converted to the HCl salt: mp 195-198 °C; MS (APCI+) m/z

(

83 (M + H) ; MS (APCI-) m/z 281 (M - H) ; H NMR

DMSO-d ) δ 1.25 (t, 3H), 1.71 (m, 3H), 1.88 (m, 1H), 2.59 (t,

H), 2.69-2.70 (m, 1H), 2.82 (m, 1H), 3.00-3.19 (m, 2H), 3.08

Cl solution and EtOAc. The EtOAc layer was washed with

), filtered, concentrated, and chromato-

brine, dried (MgSO

q, 2H), 3.23 (m, 1H), 7.16 (m, 3H), 8.78-9.08 (s, 2H), 8.93 (s,

H). Anal. (C14 S‚HCl‚0.25H O) C, H, N.

N-[5-(4,5-Dih yd r o-1H-im id a zol-2-yl)-5,6,7,8-tetr a h yd r o-

graphed (20% EtOAc in hexane) to provide 16.6 g (79%) of

5-hydroxy-4-nitro-5-(3-nitrophenyl)pentanoic acid methyl es-

ter. In step 2, this intermediate (16.4 g, 55 mmol) and NaOAc

(

5.0 g, 61 mmol) in Ac

h, concentrated, and partitioned between NaHCO

and EtOAc. The EtOAc layer was washed with brine, dried

Na SO ), filtered, and concentrated to provide 15.0 g of 4-nitro-

-(3-nitrophenyl)pent-4-enoic acid methyl ester. In step 3, this

intermediate (15.0 g, 534 mmol) in 340 mL of EtOH was cooled

to 0 °C, treated with NaBH (2.0 g), stirred at ambient

temperature for 35 min, concentrated, treated with NH Cl

solution, and extracted with EtOAc (3×). The combined organic

layers were washed with brine, dried (MgSO ), filtered, and

O (140 mL) were heated to 50 °C for 4

n a p h t h a len -1-yl]m et h a n esu lfon a m id e (48). In step 1, a

solution of N-benzyl-N-(5-cyano-7,8-dihydronaphthalen-1-yl)-

solution

methanesulfonamide (10 g, 30 mmol) in EtOH (200 mL) was

treated with NaBH (10 g, 260 mmol), stirred for 6 h,

concentrated, treated with water (200 mL), and extracted with

O (2×) and EtOAc. The combined organics were washed

with brine, dried (Na SO ), filtered, concentrated, and chro-

(

matographed (1:1 hexane/EtOAc) to provide 8.0 g (77%) of N-

benzyl-N-(5-cyano-5,6,7,8-tetrahydronaphthalen-1-yl)methane-

sulfonamide. In step 2, a solution of this intermediate (2.0 g,

concentrated to provided 12.6 g (83%) of 4-nitro-5-(3-nitrophe-

nyl)pentanoic acid methyl ester as a yellow oil. In step 4, this

intermediate (6.3 g, 22 mmol) in MeOH (45 mL) and concen-

trated HCl (45 mL) was treated with a suspension of zinc (14.6

g, 22 mmol) in MeOH (25 mL), stirred at ambient temperature

for 1 h, treated carefully with 6 M NaOH (300 mL), stirred

for 1.5 h, neutralized to pH 7 with HCl, and extracted with

2 2

.9 mmol) in CH Cl (30 mL) and MeOH (5 mL) at 0 °C was

treated with a stream of HCl gas for 30 min, sealed, stirred

overnight at ambient temperature, concentrated to dryness,

treated with EtOH (25 mL), treated with ethylenediamine (3

mL), stirred under N

the addition of 1 M HCl, and extracted with Et

layer was basified to pH 11 with a mixture of NH

over the weekend, brought to pH 1 with

O. The aqueous

OH solution

aminobenzyl)pyrrolidin-2-one. In step 5, via method F using

EtSO Cl, this intermediate (1.49 g, 7.8 mmol) provided 1.14 g

52%) of ethanesulfonic acid [3-(5-oxo-pyrrolidin-2-ylmethyl)-

(3×). The combined CH

2 2 2

Cl layers were dried (Na -

and ice and extracted with CH

CH Cl layers were dried (Na

(3 × 200 mL). The combined

), filtered, and concentrated to provide 1.49 g (35%) of 5-(3-

), filtered, and concentrated

to provide 2.3 g of N-benzyl-N-[5-(4,5-dihydro-1H-imidazol-2-

yl)-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide. In

step 3, this intermediate (1.5 g, 3.9 mmol) was hydrogenated

in MeOH (250 mL) using wet 20% Pd/C (1.5 g) under 4 atm of

(

phenyl]amide. In step 6, the product from above (0.40 g, 1.4

mmol) in THF (8 mL) was added over 15 min to a 0 °C slurry

of LAH (0.16 g, 4.2 mmol) in THF (1 mL). After 4 h at ambient

temperature, the mixture was carefully treated with excess

acetone and stirred for 1 h. The resulting salts were removed

by filtration and washed with THF. The combined filtrates

H , filtered, and concentrated to provide 1.06 g (92%) of 48,

which was converted to the HCl salt. H NMR (DMSO-d

.68 (m, 1 H), 1.95 (m, 3 H), 2.80 (m, 2 H), 3.02 (s, 3 H), 3.84

s, 4 H), 4.25 (t, J ) 6.99 Hz, 1 H), 7.00 (d, J ) 7.35 Hz, 1 H),

) δ

(

.21 (t, J ) 7.72 Hz, 1 H), 7.28 (d, J ) 6.99 Hz, 1 H), 9.18 (s,

H), 10.29 (s, 2 H). Anal. (C14 S‚0.25H O) C, H, N.

Eth a n esu lfon ic Acid [3-(1H-im id a zol-4-yl)p h en yl]a m -

were concentrated and chromatographed (10% EtOH in NH

saturated CH Cl ) to provide 0.095 g (25%) of 51: mp 55-58

°C; H NMR (DMSO-d ) δ 1.18 (t, 3H), 1.25 (m, 1H), 1.50-

20ClN

id e (49). In step 1, a mixture of 3-aminophenylboronic acid

monohydrate (0.23 g, 1.5 mmol) and 6 (0.50 g, 1.1 mmol) in

1.75 (m, 3H), 2.52-2.73 (m, 3H), 2.85 (m, 1H), 3.05 (q, 2H),

3.08 (m, 1H), 6.92 (d, 1H), 7.00-7.09 (m, 2H), 7.20 (dd, 1H).

Anal. (C H N O S‚0.25H O) C, H, N.

EtOH (4 mL) and toluene (8 mL) was treated with 0.85 M Na

CO (4 mL) and Pd(PPh (0.095 g, 0.082 mmol), stirred at 60

C for 1 h, stirred at 100 °C for 7 h, cooled, concentrated, and

partitioned between EtOAc and water. The EtOAc layer was

dried (MgSO ), filtered, concentrated, and chromatographed

2.5-4% MeOH in CH Cl ) to provide 0.16 g (35%) of 3-(1-trityl-

H-imidazol-4-yl)-phenylamine. In step 2, via method F using

Cl, this intermediate (0.085 g, 0.21 mmol) provided 0.17

3 4

)

Eth a n esu lfon ic Acid [3-(1H-Im id a zol-4-ylsu lfa n yl)p h e-

n yl]a m id e (52). In step 1, a solution of 5 (2.0 g, 6.6 mmol) in

THF (50 mL) under N

3.0 M in Et O, 2.5 mL), stirred for 15 min, treated with a

solution of 3-nitrophenyl disulfide (2.1 g, 6.6 mmol) in THF (5

mL), warmed to 0 °C, stirred for 45 min, quenched with NH

Cl solution, and diluted with Et O. The organic layer was

isolated, washed with brine, dried (MgSO ), filtered, and

at -78 °C was treated with EtMgBr

(

EtSO

g of ethanesulfonic acid [3-(1-trityl-1H-imidazol-4-yl)phenyl]-

amide. In step 3, via method H, this intermediate (0.13 g, 0.26

concentrated to provide 1.1 g (48%) of 4-(3-nitrophenylsulfa-

nyl)imidazole-1-sulfonic acid dimethylamide. In step 2, a

mixture of this intermediate (1.0 g, 3.1 mmol), iron powder

mmol) provided 0.033 g (50%) of 49. H NMR (DMSO-d

) δ

.20 (t, J ) 7.35 Hz, 3 H), 3.08 (q, J ) 7.35 Hz, 2 H), 7.04 (dd,

J ) 8.09, 1.47 Hz, 1 H), 7.27 (t, J ) 7.91 Hz, 1 H), 7.47 (d, J

7.72 Hz, 1 H), 7.56 (s, 1 H), 7.69 (m, 2 H), 9.74 (s, 1 H),

2.19 (broad s, 1 H). Anal. Calcd (C11 S): C, 52.57; H,

(

1.2 g, 21 mmol), and NH

mL) and H O (15 mL) was refluxed for 16 h, cooled, and filtered

through Celite. The filtrate was diluted with EtOAc, washed

with brine, dried (MgSO ), filtered, and concentrated to provide

0.95 g of 4-(3-aminophenylsulfanyl)imidazole-1-sulfonic acid

dimethylamide. In step 3, via method F using EtSO Cl, this

Cl (0.18 g, 3.3 mmol) in EtOH (30

)

13 3 2

H N O

.21; N, 16.72. Found: C, 51.89; H, 5.20; N, 14.96.

Eth a n esu lfon ic Acid [3-(4,5-Dih yd r o-1H-im id a zol-2-

yla m in o)p h en yl]a m id e (50). In step 1, via method F using

EtSO Cl, 3-nitroaniline (4.0 g, 29 mmol) provided 5.4 g of

intermediate (0.90 g, 3.0 mmol) provided 0.95 g (81%) of 4-(3-

ethanesulfonylaminophenylsulfanyl)imidazole-1-sulfonic acid

ethanesulfonic acid (3-nitrophenyl)amide. In step 2, via method

E, this intermediate provided 4.8 g (83%) of ethanesulfonic acid

dimethylamide. In step 4, via method H, this intermediate (0.4

(3-aminophenyl)amide. In step 3, this intermediate (1.2 g, 6.0

g, 1.0 mmol) provided 0.12 g (41%) of 52. H NMR (DMSO-d

)

mmol) was refluxed with 2-methylthio-2-imidazoline hydro-

δ 1.15 (t, J ) 7.35 Hz, 3 H), 3.03 (q, J ) 7.35 Hz, 2 H), 6.76 (d,

J ) 7.72 Hz, 1 H), 6.94 (m, 2 H), 7.18 (t, J ) 7.91 Hz, 1 H),

7.54 (s, 1 H), 7.85 (s, 1 H), 9.80 (s, 1 H), 12.51 (s, 1 H). Anal.

chloride (1.6 g, 6.6 mmol) in pyridine (8 mL) for 4.5 h, cooled,

concentrated, chromatographed (10% MeOH in CH Cl ), and

rechromatographed (10% EtOH in NH -saturated CH Cl ) to

provide 0.37 g (23%) of 50: mp 98-101 °C; MS (APCI+) m/z

Calcd (C11

6.09; H, 3.78; N, 13.74.

Eth a n esu lfon ic Acid [3-(1H-Im id a zole-4-su lfon yl)p h e-

n yl]a m id e (53). A 0 °C solution of the product from step 3 of

52 (0.42, 1.1 mmol) in CH Cl (30 mL) was treated with

13 3 2 2

H N O S ): C, 46.62; H, 4.62; N, 14.83. Found: C,

69 (M + H) ; H NMR (DMSO-d

.31 (s, 4H), 6.68 (dd, 2H), 6.82 (s, 1H), 7.07 (dd, 1H). Anal.

S‚EtOH‚0.25H O) C, H, N.

) δ 1.17 (t, 3H), 3.04 (q, 2H),

Synthesis and SAR of a Methanesulfonamide

J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3233

peracetic acid (32 wt % solution in AcOH, 2.5 mL), stirred for

solution, treated with brine, and extracted with THF (5×). The

h at ambient temperature, washed with NaHCO

dried (MgSO ), filtered, concentrated, treated with 1 M HCl

10 mL), heated to reflux for 2 h, neutralized with 1 M NaOH,

treated with silica gel (5 g), concentrated to dryness, and

chromatographed (10% MeOH in CH Cl ) to provide 0.14 g

) δ 1.18 (t, J ) 7.46 Hz, 3 H),

.14 (q, J ) 7.46 Hz, 2 H), 7.45 (dt, J ) 7.12, 2.20 Hz, 1 H),

.55 (m, 2 H), 7.76 (m, 1 H), 7.87 (d, J ) 1.36 Hz, 1 H), 8.01

solution,

combined THF layers were concentrated and chromatographed

(10% MeOH in NH

for two steps) of 55: mp 80-83 °C; H NMR (DMSO-d ) δ 1.18

3 2 2

-saturated CH Cl ) to provide 10.2 mg (10%

(

(t, 3H), 2.56 (m, 1H), 2.72 (m, 1H), 3.07 (m, 3H), 3.37 (m, 1H),

3.91 (m, 1H), 6.95 (d, 1H), 6.98 (s, 1H), 7.04 (m, 1H), 7.06 (s,

(40%) of 53. H NMR (DMSO-d

1H), 7.22 (t, 1H); MS (APCI+) m/z 268 (M + H) . Anal.

(C H N O S) C, H, N.

(

d, J ) 1.36 Hz, 1 H), 10.22 (s, 1 H), 12.97 (s, 1 H). Anal.

) C, H, N.

Eth a n esu lfon ic Acid (3-P yr r olid in -3-ylp h en yl)a m id e

54). In step 1, 3-(3-nitrophenyl)acrylic acid methyl ester (6.0

Su p p or tin g In for m a tion Ava ila ble: Table 6 (R binding

11 13 3 4 2

(C H N O S

and functional data), X-ray crystallographic data for compound

8, and spectral data of intermediates. This material is available

free of charge via the Internet at http://pubs.acs.org.

(

g, 29 mmol) was treated with nitromethane (50 mL) and

,1,3,3-tetramethylguanidine (1 mL), heated to 80 °C for 30

min, concentrated, and chromatographed (2:1 and then 1:1

hexane/EtOAc) to provide 3.7 g (48%) of 4-nitro-3-(3-nitrophe-

nyl)butyric acid methyl ester. In step 2, this intermediate (3.7

g, 14 mmol) and RaNi 2800 (0.4 g) in MeOH (40 mL) were

Refer en ces

(

1) Altenbach, R. J .; Khilevich, A.; Kolasa, T. P.; Rohde, J . J .; Bhatia,

P.; Patel, M. V.; Searle, X. B.; Yang, F.; Bunnelle, W.; Tietje, K.;

Bayburt, E. K.; Carroll, W. A.; Meyer, M. D.; Buckner, S. A.;

Kuk, J .; Daza, A. V.; Milicic, I. V.; Cain, J . C.; Kang, C. H.;

Ireland, L. M.; Hancock, A. A.; Nakane, M.; Esbenshade, T. A.;

Brune, M.; O’Neill, A. B.; Gauvin, D. M.; Katwala, S.; Brioni,

J .; Holladay, M. W.; Sullivan, J . P. Synthesis and structure

activity studies on a series of imidazoles as R1A adrenoceptor

agonists. Abstr. Pap.sAm. Chem. Soc. 2000, MEDI-293.

stirred at 60 °C for 16 h under 4 atm of H

concentrated, and chromatographed (5% and then 10% MeOH

in NH -saturated CH Cl ) to provide 1.6 g (57%) of 4-(3-

aminophenyl)pyrrolidin-2-one. In step 3, via method F using

EtSO Cl, this intermediate (1.0 g, 5.7 mmol) provided 1.3 g

87%) of ethanesulfonic acid [3-(5-oxopyrrolidin-3-yl)phenyl]-

amide. In step 4, a solution of this intermediate (1.28 g, 4.8

mmol) in THF was treated with 1 M BH ‚THF in THF (24

mL), heated to reflux overnight, cooled, treated with 1 M HCl

30 mL), heated to reflux for 1 h, cooled, concentrated, and

chromatographed (10% and then 20% MeOH in NH -saturated

CH Cl ) to provide 0.49 g of recovered starting material and

.71 g (59%) of 54. H NMR (DMSO-d

, cooled, filtered,

(2) Andersson, K. E. Pharmacology of Lower Urinary Tract Smooth

Muscles and Penile Erectile Tissues. Pharmacol. Rev. 1993, 45,

(

53-308.

(3) Collste, L.; Lindskog, M. Phenylpropanolamine in treatment of

female stress urinary incontinence. Double-blind placebo con-

trolled study in 24 patients. Urology 1987, 30, 398-403.

(

4) (a) J onas, D. Treatment of Female Stress Incontinence with

Midodrine: Preliminary Report. J . Urol. 1977, 118, 980-982.

(b) Garofalo, F.; Lalanne, G. M.; Nanni, G. Midodrine for Female

) δ 1.19 (t, J ) 7.29 Hz,

Incontinence: A Preliminary Report. Clin. Ther. 1986, 9, 44-

46. (c) Nito, H. Clinical effect of midodrine hydrochloride on the

patients with urinary incontinence. Hinyokika Kiyo 1994, 40,

H), 1.88 (m, 1 H), 2.31 (m, 1 H), 2.98 (t, J ) 10.85 Hz, 1 H),

.09 (q, J ) 7.57 Hz, 2 H), 3.19 (m, 1 H), 3.36 (m, 2 H), 3.57

1-94. (d) Weil, E. H.; Eerdmans, P. H.; Dijkman, G. A.;

(dd, J ) 11.02, 7.97 Hz, 1 H), 7.11 (m, 3 H), 7.30 (t, J ) 7.97

Tamussino, K.; Feyereisl, J .; Vierhout, M. E.; Schmidbauer, C.;

Egarter, C.; Kolle, D.; Plasman, J . E.; Heidler, H.; Abbuhl, B.

E.; Wein, W. Randomized Double-Blind Placebo-Controlled

Multicenter Evaluation of Efficacy and Dose Finding of Mido-

drine Hydrochloride in Women with Mild to Moderate Stress

Urinary Incontinence: A Phase II Study. Int. Urogyn. J . 1998,

Hz, 1 H), 9.36 (broad s, 2 H); MS (DCI/NH

55. Anal. (C12 S‚0.5H O‚0.5CH Cl ) C, H, N.

Eth a n esu lfon ic Acid [3-(4,5-Dih yd r o-1H-im id a zol-4-

ylm eth yl)ph en yl]am ide (55). In step 1, a solution of 2-amino-

) m/z (M + H)

-(3-nitro-phenyl)propionic acid hydrochloride (2.1 g, 8.4

mmol) in EtOH (40 mL) was treated with 100 mL of 1 M HCl

in Et O. The Et O was removed under reduced pressure and

, 145-150. (e) Andersson, K. E.; Ekman, G.; Henriksson, L.;

Ulmsten, U. The effect of midodrine and its active metabolite

ST 1059 on the human urethra in vitro and in vivo. Scand. J .

Urol. Nephrol. 1983, 17, 261-265.

the remaining mixture was refluxed for 8 h, cooled, and

concentrated to provide 2-amino-3-(3-nitrophenyl)propionic

acid ethyl ester hydrochloride. In step 2, this intermediate was

(5) (a) McClellan, K. J .; Wiseman, L. R.; Wilde, M. I. Midodrine. A

Review of Its Therapeutic Use in the Management of Orthostatic

Hypotension. Drugs Aging 1998, 12, 76-86. (b) Andersson, K.

E. Drug therapy for urinary incontinence. Best Pract. Res. Clin.

Obstet. Gynaecol. 2000, 14, 291-313. (c) Rackley, R. Treatment

of Stress Urinary Incontinence. In Voiding Dysfunction: Diag-

nosis and Treatment; Appell, R. A., Ed.; Humana Press: Totowa,

NJ , 2000; pp 163-184.

taken up in NH -saturated MeOH (40 mL), stirred for 3 days

in a sealed vessel, and concentrated to provide 2.1 g (100%

for two steps) of 2-amino-3-(3-nitrophenyl)propionamide as the

HCl salt. In step 3, this intermediate (1.5 g, 6.1 mmol) was

dissolved in THF (75 mL), treated with 10 M BH

‚Me S

complex (15 mL), refluxed overnight, cooled, treated carefully

with 100 mL of 6 M HCl, refluxed overnight, cooled, concen-

trated, neutralized to pH 9, treated with brine, and extracted

with THF (5 × 200 mL). The combined THF layers were dried

(6) (a) Hieble, J . P.; Bylund, D. B.; Clarke, D. E.; Eikenburg, D. C.;

Langer, S. Z.; Lefkowitz, R. J .; Minneman, K. P.; Ruffolo, R. R.

International Union of Pharmacology. X. Recommendation for

Nomenclature of Alpha 1-Adrenoceptors: Consensus Update.

Pharmacol. Rev. 1995, 47, 267-270. (b) Bylund, D. B.; Eiken-

berg, D. C.; Hieble, J . P.; Langer, S. Z.; Lefkowitz, R. J .;

Minneman, K. P.; Molinoff, P. B.; Ruffolo, R. R.; Trendelenburg,

U. International Union of Pharmacology Nomenclature of Adreno-

ceptors. Pharmacol. Rev. 1994, 46, 121-136.

7) Nasu, K.; Moriyama, N.; Fukasawa, R.; Tsujimoto, G.; Tanaka,

T.; Yano, J .; Kawabe, K. Quantification and Distribution of

Alpha1-Adrenoceptor Subtype mRNAs in human proximal ure-

thra. Br. J . Pharmacol. 1998, 123, 1289-1293.

(

MeOH in NH

-(3-nitrophenyl)propane-1,2-diamine as the less polar product

2 4

SO ), filtered, concentrated, and chromatographed (10%

2 2

-saturated CH Cl ) to provide 0.27 g (23%) of

and 0.11 g (11%) of 3-(3-aminophenyl)propane-1,2-diamine as

the more polar product. In step 4, the 3-(3-nitrophenyl)pro-

pane-1,2-diamine (0.27 g, 1.4 mmol) in DMF (6 mL) was

treated with Boc O (0.68 g, 3.1 mmol) stirred for 2 h, diluted

with water, and stirred for 30 min. The resulting precipitate

was collected by filtration and dried to provide 0.16 g (29%) of

(

(8) Brune, M. E.; Katwala, S. P.; Milicic, I.; Buckner, S. A.; Ireland,

L. M.; Kerwin, J . F.; Hancock, A. A. Effects of Selective and

Nonselective Alpha-1-Adrenoceptor Antagonists on Intraurethral

and Arterial Pressures in Intact Conscious Dogs. Pharmacology

[2-tert-butoxycarbonylamino-3-(3-nitrophenyl)propyl]carbam-

ic acid tert-butyl ester. In step 5, via method E, this intermedi-

ate (0.16 g, 0.40 mmol) provided 0.14 g (94%) of [2-(3-

aminophenyl)-1-(tert-butoxycarbonylaminomethyl)ethyl]-

carbamic acid tert-butyl ester. In step 6, via steps F and G,

this aniline (0.13 g, 0.37 mmol) and EtSO Cl provided 0.13 g

of ethanesulfonic acid [3-(2,3-diaminopropyl)phenyl]amide. In

step 7, this intermediate in EtOH (1.4 mL) was treated with

formamidine acetate (0.048 g, 0.46 mmol) under N at ambient

temperature, stirred overnight, concentrated, dissolved in 1

M HCl, washed with EtOAc, basified to pH 9 with 25% NaOH

996, 53, 356-368.

(

9) Hancock, A. A.; Brune, M. E.; Witte, D. G.; Marsh, K. C.;

Katwala, S.; Milicic, I.; Ireland, L. M.; Crowell, D.; Meyer, M.

D.; Kerwin, J . F. Actions of A-131701, a Novel, Selective

Antagonist for Alpha-1A Compared with Alpha-1B Adrenocep-

tors on Intraurethral and Blood Pressure Responses in Conscious

Dogs and a Pharmacodynamic Assessment of in Vivo Prostatic

Selectivity. J . Pharmacol. Exp. Ther. 1998, 285, 628-642.

(

10) Hieble, J . P. Adrenoceptor subclassification: an approach to

improved cardiovascular therapeutics. Pharm. Acta Helv. 2000,

74, 163-171.

234 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12

Altenbach et al.

(

11) Cavalli, A.; Lattion, A. L.; Hummler, E.; Nenniger, M.; Pe-

drazzini, T.; Aubert, J . F.; Michel, M. C.; Yang, M.; Lembo, G.;

Vecchione, C.; Mostardini, M.; Schmidt, A.; Beermann, F.;

Cotecchia, S. Decreased Blood Pressure Response in Mice

Deficient of the Alpha1b-Adrenergic Receptor. Proc. Natl. Acad.

Sci. U.S.A. 1997, 94, 11589-11594.

model, the baseline pressure measurement is of the catheter

balloon pressure and was measured at approximately 400

mmHg. This is not physiologic but due to the elastic forces in

the inflated balloon. The IUP measurement was recorded as the

net change in pressure above this baseline pressure. From

profilometry experiments (data not shown), the measured

urethral pressure (the PUCP or proximal urethral closure

pressure) that corresponds to the location of the balloon catheter

in the in vivo dog model was 4-5 mmHg. Therefore, a 5 mmHg

increase in IUP is approximately a 100% increase over physi-

ological baseline urethral pressure.

(

12) (a) Castillo, E. F.; Lopez, R. M.; Rodriguez-Silverio, J .; Bobadilla,

R. A.; Castillo, C. Alpha 1D-Adrenoceptors Contribute to the

Neurogenic Vasopressor Response in Pithed Rats. Fundam. Clin.

Pharmacol. 1998, 12, 584-589. (b) Villalobos-Molina, R.; Ibarra,

M. Vascular Alpha(1D)-Adrenoceptors: Are They Related to

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(

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(

2 2

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J M030551A

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