Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2- dihydropyridono[5,6-g]quinolines

623

J . Med. Chem. 1998, 41, 623-639

Syn th esis a n d Biologica l Activity of a Novel Ser ies of Non ster oid a l,

P er ip h er a lly Selective An d r ogen Recep tor An ta gon ists Der ived fr om

1,2-Dih yd r op yr id on o[5,6-g]qu in olin es

Lawrence G. Hamann,*^,†Robert I. Higuchi,^†Lin Zhi,^†J ames P. Edwards,^†Xiao-Ning Wang,^‡

Keith B. Marschke,^§J ames W. Kong,^†Luc J . Farmer^†,|and Todd K. J ones^†

Departments of Medicinal Chemistry, Pharmacology, and New Leads Discovery, Ligand Pharmaceuticals, Inc.,

10275 Science Center Drive, San Diego, California 92121

Received October 16, 1997

A new nonsteroidal antiandrogenic pharmacophore has been discovered using cell-based

cotransfection assays with human androgen receptor (hAR). This series of AR antagonists is

structurally characterized by a linear tricyclic 1,2-dihydropyridono[5,6-g]quinoline core.

Analogues inhibit AR-mediated reporter gene expression and bind to AR as potently as or better

than any known AR antagonists. Several analogues also showed excellent in vivo activity in

classic rodent models of AR antagonism, inhibiting growth of rat ventral prostate and seminal

vesicles, without accompanying increases in serum gonadotropin and testosterone levels, as is

seen with other AR antagonists. Investigations of structure-activity relationships surrounding

this pharmacophore resulted in molecules with complete specificity for AR, antagonist activity

on an AR mutant commonly observed in prostate cancer patients, and improved in vivo efficacy.

Molecules based on this series of compounds have the potential to provide unique and effective

clinical opportunities for treatment of prostate cancer and other androgen-dependent diseases.

In tr od u ction

to block this transcriptional activation represent attrac-

tive clinical targets.⁵

Prostate cancer is currently the most commonly

diagnosed nondermatologic cancer among United States

males, with an estimated incidence of 984 000 cases in

the U.S. alone and 200 000 new cases diagnosed each

year.¹Approximately one in five males will be diag-

nosed with this life-threatening disease by the age of

60. While historically both surgical and pharmaceutical

methods have been utilized to address this disease,

recent powerful advances in the area of early detection

through monitoring of prostate-specific antigen (PSA)²

levels have created a shift in strategy for treatment of

prostate cancer toward drug therapy and away from

surgical measures.

The male sexual accessory organs, such as the pros-

tate and seminal vesicles, play important roles in

reproductive function.³These glands are stimulated to

grow and are maintained in size and secretory function

by the continued actions of testosterone (T) and dihy-

drotestosterone (DHT). Testosterone is the androgen

produced by the Leydig cells (testis) in the greatest

proportion (95%) under the control of pituitary-lutein-

izing hormone (LH) and follicle-stimulating hormone

(FSH) and is converted to the more active DHT within

the prostate by 5R-reductase. These endogenous hor-

mones exert their effects at the level of the androgen

receptor (AR) which, as a member of the intracellular

receptor (IR) superfamily, acts as a ligand-dependent

transcription factor.⁴Small molecules with the ability

Prostatic tumor cells also require T for their continued

growth. Although 20% of the total prostatic DHT in the

rat and about 40% in 65-year-old men is of adrenal

origin, adrenal DHT is not sufficient to maintain normal

prostate and seminal vesicle growth and function, and

castration without concomitant adrenalectomy leads to

almost complete involution of these glands.⁶In cas-

trated prostate cancer patients, however, there is emerg-

ing evidence that the adrenal glands produce steroid

precursors that are converted to T in the prostate,

thereby exacerbating the disease.⁷For this reason,

administration of AR antagonists either following cas-

tration or in combination with luteinizing hormone-

releasing hormone (LHRH) agonists has become the

standard in treatment of prostate cancer.

Over the past two decades, AR antagonists have been

demonstrated clinically to constitute effective therapy

for the treatment of prostate cancer, including cypro-

terone acetate (1),⁸flutamide (2a ),⁹and bicalutamide

(Casodex, 3).¹⁰These and other agents have been the

subject of extensive clinical investigations for use either

alone as single-agent therapy¹¹or in combination with

a LHRH agonist.¹²Additionally, there exists significant

clinical opportunity to address other androgen-depend-

ent conditions, such as benign prostatic hypertrophy

(BPH),¹³hirsutism in women,¹⁴alopecia (male pattern

baldness),¹⁵and acne¹⁶through receptor-mediated in-

hibition of androgen-regulated gene transcription.

* Address correspondence to this author. Phone: (619) 550-7618.

Fax: 619-550-7249. E-mail: lhamann@ligand.com.

^†Department of Medicinal Chemistry.

Of the AR antagonists currently marketed or under-

going clinical trials, none achieves effective therapeutic

results without suboptimal pharmacokinetic properties

or substantial efficacy-limiting side effects. These side

effects in part reflect central effects of increases in

^‡Department of Pharmacology.

^§Department of New Leads Discovery.

^|Present address: Vertex Pharmaceuticals Inc., Cambridge, MA

02139.

Published on Web 01/22/1998

624 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4

Hamann et al.

circulating concentrations of luteinizing hormone (LH),

follicle-stimulating hormone (FSH), testosterone (T),

and dihydrotestosterone (DHT) induced by these drugs.

Additionally, severe gynecomastia, nausea, diarrhea,

and liver toxicity¹⁷have been observed in many patients,

and the predominance of prostate cancer patients

undergoing antiandrogen therapy ultimately become

resistant to antiandrogen therapy.¹⁸It is postulated

that emergence of this resistance is linked to mutations

in the AR, which subsequently recognize most antago-

nists as agonists.¹⁹The specific mechanisms by which

these latter side effects are manifested are as yet

unclear. Novel agents which selectively interact with

the hAR to inhibit cell growth and differentiation

processes downstream in male sexual accessory tissues

may have the potential to provide the therapeutic

benefit of AR antagonism without these liabilities.

In connection with our long-standing interest in the

discovery of structurally novel modulators of sex-steroid

receptor activation²⁰using cotransfection assays,²¹in-

tensive screening efforts resulted in the discovery of a

novel antagonist pharmacophore for the hAR. A cross-

reactivity screening campaign in support of another

internal discovery program led to the observation of AR

antagonist activity in the linear tricyclic pyridonodihy-

droquinoline compound 5. Through further screening

efforts, it was discovered that 5 inhibited dihydrotes-

tosterone-stimulated reporter gene expression in an

hAR cotransfection assay with excellent potency (IC₅₀

) 43 nM) but showed poor selectivity for AR, exhibiting

nearly equivalent antagonist activity when screened

against hPR-B. Further investigation into analogues

of 5, possessing a linear tricyclic core resulted in

substantially more potent effects on AR, much greater

selectivity for AR over PR (many with 1000-fold or

greater selectivity), and good oral activity in standard

rodent models for AR antagonism. Compounds de-

scribed herein are based on an entirely novel pharma-

cophore for modulation of AR-mediated gene transcrip-

tion.

synthetic work in this area and involved execution of

the Skraup²³reaction (acetone, I₂) on aromatic amines.

The Skraup cyclizations carried out on these particular

substrates, such as carbostyril 124 (4, eq 1), suffered

from very low yields and extremely poor regioselectivi-

ties and usually required high temperatures and sealed

tube conditions. It was generally observed that the

undesired, biologically inactive angular tricyclic regioi-

somer such as 6 was produced in great excess to the

desired linear regioisomer such as 5, which was typically

isolated in very low yield as a minor product.

A more practicable synthetic strategy was developed

whereby each terminal ring was successively built up

around a central aryl core fragment through sequential

cyclization reactions. Installment of the 2-pyridone ring

in the final step using the Knorr²⁴reaction allowed for

completely regioselective cyclization of diamine sub-

strates 8 and a â-keto ester (Scheme 1), with the

favorable electronic donation of the dihydroquinoline

nitrogen facilitating the incipient C-C bond formation.

Under the standard conditions employed for the Knorr

cyclization (ethyl 4,4,4-trifluoroacetoacetate, ZnCl₂, EtOH,

reflux), ethoxypyridine isomers 10 were also obtained,

typically comprising 20-40% of the reaction mixture.

These byproducts were easily transformed (essentially

quantitatively) into the desired 2-pyridone products 9

by treatment with 57% HI.

The syntheses of diamines 8a -d and 8e-i as precur-

sors for the Knorr reaction are outlined in Schemes 2

and 3, respectively. The commercially available nitroa-

nilines 11 (R ) H or Me) were used as the starting

materials to access analogues with 4-methyl substitu-

tion and 3,4-unsaturation (Scheme 2). Protection of the

aniline nitrogen using di-tert-butyl dicarbonate and

4-(N,N-dimethylamino)pyridine (DMAP), followed by

catalytic hydrogenation of the nitro group, affords the

desired substrates for a completely regioselective Sk-

raup cyclization reaction of the BOC-differentiated

diamine 13. After optional saturation of the 3,4-olefin

by catalytic hydrogenation, deprotection of the N-BOC

group is accomplished using trifluoroacetic acid (TFA)

in CH₂Cl₂to yield diamines 8a -d . Diamines 8e-i were

synthesized in a conceptually similar fashion by copper

chloride-catalyzed cyclization²⁵of aniline with 1,1-

disubstituted propargyl acetates 15 to yield dihydro-

quinolines 17 (Scheme 3). Catalytic hydrogenation of

the 3,4-olefin, followed by nitration and subsequent

Ch em istr y

Quinolines and dihydroquinolines are well-studied

bicyclic systems in the area of heterocyclic chemistry,

with powerful synthetic tools for their construction.²²

Our initial synthetic efforts to access linear tricyclic

pyridonoquinolines such as 5 were adapted from early

Androgen Receptor Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 625

Sch em e 1^a

a

(a) Ethyl 4,4,4-trifluoroacetoacetate, ZnCl₂, EtOH, reflux, 5 h; (b) 57% aqueous HI, 60 °C, 3 h.

Sch em e 2^a

a

(a) BOC₂O, THF, DMAP, 0 °C to rt, 12 h; (b) H₂, 10% Pd/C, EtOH/EtOAc (1:1), 6 h; (c) I₂, acetone, MgSO₄, 4-t-Bu-catechol, reflux, 8

h; (d) H₂, 10% Pd/C, EtOH/EtOAc (1:1), 6 h; (e) CF₃CO₂H, CH₂Cl₂, 3 h.

Sch em e 3^a

a

(a) Aniline, CuCl, NEt₃, THF, reflux; (b) CuCl, THF, reflux; (c) H₂, 10% Pd/C, EtOH/EtOAc (1:1), 6 h; (d) HNO₃, H₂SO₄, 0 °C.

reduction of the nitro group, afforded diamine Knorr

precursors 8e-i.

(superior results were obtained using the corresponding

organocerium reagents),²⁷followed by benzylic alcohol

reduction employing TFA-catalyzed hydrogenation over

10% palladium on carbon afforded intermediates 25;

enolate alkylation of 23 gave 3-substituted ketones 24

prior to either alkyl-Grignard addition or reduction to

quinoline intermediates 26 or 27, respectively. Stan-

dard nitro reduction of 28 and Knorr reaction of the

corresponding diamines afforded 3- and/or 4-substituted

analogues 29a -f.

Tetracyclic analogues 33 and 34 were obtained through

the intermediacy of tricyclic amine 32, prepared in three

steps from aniline and chloro-substituted propargyl

acetate 30 in a manner similar to that used for synthesis

of 9e-i (Scheme 6).

Limitations in the synthetic routes used for the

preparation of analogues in this series included the

inability to efficiently access 3,4-unsaturated analogues

(such as 36, eq 2) other than those bearing the 2,2,4-

trimethyldihydroquinoline ring introduced through the

Skraup protocol. This was in part due to the failure of

attempts to nitrate dihydroquinoline 17 without prior

reduction of the 3,4-olefin, as well as the failure of the

Selective alkylation of either nitrogen of AR antago-

nist analogues 9 was accomplished in a straightforward

fashion by treatment with sodium hydride in THF,

followed by iodoalkane (9 N) to give alkyl amides 19a -

g, or by reductive amine alkylation using paraformal-

dehyde/HOAc/sodium cyanoborohydride²⁶(1 N) to give

20 (Scheme 4). Alternatively, tandem methylation of

amide/amines 9 was accomplished using excess KOH

with iodomethane in DMF to give 21a -c directly.

The more synthetically complex 3- and/or 4-alkyl-

substituted analogues 29a -f were prepared from a

common bicyclic intermediate (Scheme 5). Protection

of dihydroquinoline 17 with a BOC group provided

intermediate 22, which then underwent regioselective

hydroboration and subsequent benzylic oxidation with

activated manganese dioxide to give BOC-protected

4-oxotetrahydroquinoline 23. Nitroquinolines 28a -f

were obtained from standard nitration of intermediates

25, 26, and 27. These intermediates were prepared

from the common intermediate ketone 23 by one of two

methods: alkyl-Grignard additions to the 4-ketone

626 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4

Hamann et al.

Sch em e 4^a

a

(a) NaH, DMF, 0 °C, then R⁵I, rt, 8 h; (b) (CH₂O)_n, NaCNBH₃, HOAc, rt, 6 h; (c) KOH, DMF, MeI, rt, 16 h.

Sch em e 5^a

a

(a) 9-BBN, THF, reflux; then H₂O₂, NaOH, rt; (b) MnO₂, CH₂Cl₂, reflux; (c) NaH, DMF, 0 °C; then R²I, rt; (d) R¹MgX, CeCl₃, THF,

0 °C; (e) H₂, 10% Pd/C, EtOH, TFA; (f) BF₃‚OEt₂, Et₃SiH, CH₂Cl₂, 100 °C, sealed tube; (g) HNO₃, H₂SO₄, 0 °C; (h) H₂, 10% Pd/C, EtOAc/

EtOH (1:1) rt; (i) ethyl 4,4,4-trifluoroacetoacetate, ZnCl₂, EtOH, reflux.

Sch em e 6^a

a

(a) Aniline, CuCl, NEt₃, THF, reflux; (b) CuCl, THF, reflux; (c) H₂, 10% Pd/C, EtOH/EtOAc (1:1), 6 h; (d) HNO₃, H₂SO₄, 0 °C; (e) ethyl

4,4,4-trifluoroacetate, ZnCl₂, PhH, 4 Å molecular sieves, reflux, 8 h; (f) NaH, DMF, 0 °C, then MeI, rt, 12 h.

Knorr reaction with diamine 35 (eq 2), prepared through

a very low-yielding route using a CuCl-mediated cy-

clization of monoprotected diamine 13.

Access to these 3,4-unsaturated analogues was

achieved by installation of unsaturation at the 3,4-

positions after construction of the tricyclic core (Scheme

7). The 2-ethoxypyridine moiety present in 10e, the

further chemistry to functionalize the benzylic 4-posi-

tion. This 2-alkoxypyridine moiety could readily be

major byproduct of Knorr cyclization reaction to prepare

analogue 9e, served as an excellent protective group for

Androgen Receptor Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 627

Sch em e 7^a

a

(a) PCC, CH₂Cl₂, rt; (b) 57% aqueous HI, 60 °C, 3 h; (c) NaBH₄, MeOH, 0 °C; (d) p-TsOH, PhH, 65 °C.

Sch em e 8^a

a

(a) BH₃‚THF, THF, rt; then H₂O₂, NaOH; (b) PDC, CH₂Cl₂, rt; (c) MeMgBr, THF, 0 °C; (d) p-TsOH, PhH, rt; (e) 57% aqueous HI, 60

°C, 3 h; (f) Et₃SiH, TFA, 1,2-dichloroethane, reflux, 9 h.

installed by O-selective alkylation of pyridones 9 using

CsF and the appropriate alkyl halide.²⁸Protection of

the amine portion of 10e was accomplished using the

procedure previously used for preparation of bicyclic

intermediate 22, yielding carbamate 37. Benzylic oxi-

dation to the 4-oxo compound 38 was achieved using

PCC.²⁹Both protective groups were simultaneously

removed using 57% HI to afford ketoamide 39. The 3,4-

olefin was then introduced by a two-step procedure

involving sodium borohydride reduction followed by

p-TsOH-catalyzed dehydration to yield 36.

Synthesis of a 3,4-dimethyl analogue with 3,4-unsat-

uration also required functionalization after precon-

struction of the linear tricyclic core using intermediate

40, derived from protection of 10a (Scheme 8). Regi-

oselective hydroboration of 40 and subsequent oxidative

workup, followed by PCC oxidation of the resultant

diastereomeric mixture of alcohols, afforded 3-ketone 41.

Methyl Grignard addition, followed by acid-catalyzed

dehydration and hydrolysis of the ethoxypyridine moi-

ety, gave 3,4-dimethyl analogue 42, which was subjected

to TFA-catalyzed triethylsilane reduction of the 3,4-

olefin to give a diastereomeric mixture of 43 and 44,

separable only by preparative HPLC.

in antagonist cotransfection assays with human proges-

terone receptor (hPR-B) are also included. Compounds

in this series were found to posses no intrinsic AR

agonist activity. Activity on other IRs including human

glucocorticoid receptor (hGR), human mineralocorticoid

receptor (hMR), and human estrogen receptor (hER)

were also determined, and there was found to be no

agonist or antagonist response induced by the analogues

in this series.³⁰

Im m a tu r e Ca str a ted Ra t Assa y. The androgen-

induced growth of the ventral prostate (VP) of immature

male rats was measured as a quantitative end point for

AR antagonist effects, as this male sexual accessory

organ is among the tissues most sensitive to modulation

by androgens, this sensitivity to changes in androgen

concentrations being greatest before puberty. Weight

gain and loss in VP reflects changes in cell number

(DNA content) and cell mass (protein content) in

response to serum androgen concentrations.³¹There-

fore, measurement of organ wet weight reflects the

bioactivity of AR antagonists. Daily injections of 1 mg/

kg testosterone propionate (TP) to immature castrated

rats achieved a steady serum T level within physiologic

range, and caused dose-dependent increases in VP

weight. Compounds from the present series of AR

antagonists were tested for activity against exogenous

TP and compared to the known AR antagonists 1, 2a ,

and 3. Test compounds were administered daily simul-

taneously with 1 mg/kg of TP (the ED80) for 3 days.

Each compound significantly inhibited the TP-mediated

increases in VP weight (Figure 1); results for 1, 2a , and

3 are in agreement with published studies.

In Vitr o a n d in Vivo Biologica l Activity

Cotr a n sfection a n d Bin d in g Assa ys. The AR

modulatory activity of analogues in this series as well

as that of known AR antagonists was studied experi-

mentally in a cellular background both through ligand-

dependent inhibition of DHT-stimulated reporter gene

(luciferase) induction using the cotransfection assay and

a whole-cell receptor binding assay. These results are

summarized in Table 1. Cross-reactivity data obtained

Ma tu r e In ta ct Ra t Assa y. Because there is no

blunting of the effects of endogenous hormones, the

628 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4

Hamann et al.

Ta ble 1. hAR Antagonist and hPR-B Antagonist Activity in Cotransfected CV-1 Cells and Binding Affinities for hAR in

Transiently-Transfected COS-1 Cells^a

hAR

hPR-B

hAR binding

b

compound

IC₅₀(nM)

efficacy^c(%)

IC₅₀(nM)

efficacy (%)

K_i^b(nM)

1

26 ( 23

15 ( 2

48 ( 6

83 ( 1

78 ( 3

75 ( 2

89 ( 2

70 ( 3

65 ( 5

82 ( 2

78 ( 2

74 ( 2

66 ( 3

75 ( 2

65 ( 3

85 ( 2

89 ( 2

95 ( 2

81 ( 5

74 ( 8

70 ( 4

87 ( 3

85 ( 1

87 ( 2

86 ( 1

81 ( 3

62 ( 6

81 ( 2

83 ( 2

49 ( 7

66 ( 4

88 ( 2

74 ( 2

86 ( 6

85 ( 2

71 ( 2

84 ( 3

83 ( 2

20

>10000

12 ( 8

90 ( 2

88 ( 2

96 ( 1

83 ( 3

62 ( 5

86

88 ( 1

74 ( 4

80

91 ( 2

81

86

94

88 ( 3

55

98 ( 1

68

79

74

73

55

91 ( 2

85

92

89

82

74 ( 5

59

98 ( 1

93

11

14 ( 5

27 ( 8

2b^d

3

2013 ( 194

1819 ( 245

157 ( 35

5 ( 2

117 ( 35

22 ( 1

RU-486

5

9a

9b

9c

9d

9e

9f

9g

0.18 ( 0.02

36 ( 6

109 ( 24

49 ( 11

231^e

62 ( 18

115 ( 24

76 ( 1

82 ( 4

85 ( 32

26 ( 5

29 ( 13

102 ( 25

69 ( 10

9 ( 2

28 ( 4

26 ( 4

23 ( 3

3346 ( 879

3726 ( 371

330e

22 ( 4

27 ( 5

23 ( 3

543 ( 215

27 ( 5

2708^e

9h

9i

42 ( 7

1144^e

35 ( 6

1828^e

19a

19b

19c

19d

19e

19f

19g

20

21a

21b

21c

29a

29b

29c

29d

29e

29f

33

34 ( 6

233 ( 69

81 ( 17

670 ( 467

46 ( 10

874 ( 178

40 ( 12

56 ( 14

69 ( 28

695 ( 432

39 ( 23

17 ( 4

692 ( 32

73 ( 29

2413 ( 786

31 ( 10

36 ( 5

1763^e

585 ( 41

4395^e

2931^e

1239^e

48 ( 4

3277^e

156 ( 26

46 ( 11

19 ( 3

1678^e

136 ( 88

2200^e

24 ( 4

30 ( 5

46 ( 12

27 ( 7

1105^e

10 ( 3

348^e

73 ( 11

251 ( 45

54 ( 11

650 ( 264

189 ( 89

358 ( 86

169 ( 88

78 ( 13

86 ( 51

268 ( 110

456

2334^e

274 ( 122

159 ( 83

83 ( 19

57 ( 6

3162^e

876 ( 68

362^e

325 ( 68

27 ( 5

>10000^e

34

36

42

43

398^e

84

58 ( 22

68 ( 4

390 ( 138

393 ( 152

310^e

81 ( 7

65 ( 9

95

164 ( 62

7042

44

735^e

92

151 ( 35

a

b

Cotransfection assay experiment values represent at least triplicate determinations. Values represent mean ( SEM. IC₅₀values

represent the concentration of ligand required to give half-maximal inhibition in the presence of DHT at its EC₅₀.

^cEfficacies were

d

determined as a function of maximal inhibition. 2-Hydroxyflutamide (2b) was used for in vitro assays, as this is the active metabolite

of 2a in vivo. ^eAssayed once.

duction and secretion of pituitary LH and FSH, i.e., a

negative feedback control for gonadal androgen produc-

tion.³²Therefore, the hypothalamus, pituitary gland,

testis, and gonadal steroid-sensitive end organs form a

closed homeostatic loop. Each component of this repro-

ductive hormonal axis functions in a closely regulated

manner to maintain the appropriate concentrations of

circulating gonadal steroids required for normal male

sexual development and behavior.

When AR antagonists are administered to intact rats,

they act peripherally to modulate AR actions at the

target organs, but can also interact with AR in the brain

(hypothalamus and pituitary) to block the feedback

control system, leading to overproduction of LH and

FSH, which in turn stimulate Leydig cells to produce

significantly higher amounts of T. Compounds 2a , 3,

F igu r e 1. Effects of AR antagonists 1, 2a , 3, 9a ,d ,e, and 19a

9a , and 9e (20 or 40 mg/kg daily for 2 weeks) were

(30 mg/kg po, once a day for 3 days) on ventral prostate wet

studied for their capacity to antagonize endogenous

weight in castrated immature rats. CC ) castrated control;

androgens in this model, which allows the measurement

of multiple end-points including increases in VP and

seminal vesicle (SV) weights (Figure 2), and alterations

in regulatory feedback mechanisms as reflected by

changes in concentrations of LH and T (Figure 3).

TP ) testosterone propionate (1 mg/kg sc once a day for 3 days)

treated control.

normal intact male rat model provides a more stringent

test for AR antagonists compared to the immature

castrated rat model. In the central nervous system,

gonadal T acts to inhibit the pulsatile release of

hypothalamic LHRH, which results in decreased pro-

Although 2a completely blocked the accessory sex

organ growth induced by exogenous T in castrated rats,

Androgen Receptor Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 629

F igu r e 2. Effects of AR antagonists 2a , 3, and 9a ,e (20 mg/kg or 40 mg/kg po, once a day for 2 weeks) on ventral prostate (VP)

and seminal vesicle (SV) wet weight in intact mature rats. IC ) intact control values; CC ) castrated control values. The width

of the IC and CC lines represent the average standard errors for control animals.

F igu r e 3. Effects of AR antagonists 2a , 3, and 9a ,e (20 mg/kg or 40 mg/kg po, once a day for 2 weeks) on serum luteinizing

hormone (LH) and testosterone (T) levels in intact mature rats. IC ) intact control values. The width of the IC line represents

the average standard error for control animals.

it caused only a partial decrease in sex organ weights

in intact rats. Bicalutamide (3) was more potent than

2a in decreasing organ growth in intact animals, due

at least in part to its peripheral selectivity, exhibiting

only limited penetration of the blood-brain barrier,

resulting in at most 2-fold increases in serum LH and

T.³³

Oral administration of 9a or 9e caused significant

inhibition of VP and SV growth comparable to that

following 2a administration. Effects on organ weights

occurred without alteration of serum concentrations of

LH and T. 2a induced approximately 2-3-fold increases

in serum LH concentrations, accompanied by 5-8-fold

increases in serum T concentrations. These results are

consistent with data described for 2a in preclinical and

clinical studies.³⁴By contrast with 2a and 3, neither

9a nor 9e caused any statistically relevant change in

serum hormone concentrations.

reaction allowed installation of a trifluoromethyl group

at the 6-position in place of the methyl group in 5, which

greatly improved solubility and pharmacokinetic prop-

erties. Additionally, the increased electrophilicity im-

parted to the trifluoromethyl ketone carbonyl of this

â-keto ester enhanced the Knorr reaction efficiency with

this substrate, and analogues with a 6-trifluoromethyl

substituent were generally pursued. Saturation of the

3,4-double bond in these analogues, while not signifi-

cantly affecting in vitro activity, greatly improved in

vivo efficacy. It was generally observed that alkylations

in the “southern” region of these analogues (positions

1, 9, or 10) had a profound effect on biological activity.

In most cases, methylation of the pyridone nitrogen

(position 9, 19a -g) had little effect on receptor binding

or cotransfection assay activity with AR, although this

change tended to confer greater selectivity for AR over

PR. Analogues bearing a 10-methyl group (9c, 9d )

enhanced this selectivity, as well as conferring antago-

nist activity on several AR mutants, including that

found in the LNCaP cell line.³⁵However, these changes

offered no significant enhancement of in vivo activity,

and were typically characterized by reduced animal

exposure levels.³⁶Alkylation at the quinoline nitrogen

(position 1) curiously had an inconsistent effect. Alone

Discu ssion of Str u ctu r e-Activity Rela tion sh ip s

The initial lead molecule 5 suffered from extremely

poor solubility properties and also failed to achieve blood

levels in rodents sufficient to elicit a pharmacologic

response. The use of ethyl 4,4,4-trifluoroacetoacetate

as the â-keto ester component in the Knorr cyclization

630 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4

Hamann et al.

are given in hertz (Hz). Selected data are reported in the

following manner: chemical shift, multiplicity, coupling con-

stants, and assignment. Infrared (IR) spectra were recorded

on a Mattson Galaxy Series 3000 FT infrared spectrometer.

Liquid samples were measured as neat films on NaCl plates;

solid samples were measured as KBr pellets. The reported

frequencies are given in reciprocal centimeters (cm^-1) with the

following relative intensities: s (strong, 70-100%), m (me-

dium, 40-70%), w (weak, 20-40%), br (br). Elemental

analyses were performed by Oneida Research Services, Inc.,

Whitesboro, NY; Galbraith Laboratories, Inc., Knoxville, TN;

or Quantitative Technologies, Inc., Whitehouse, NJ . Melting

points were taken on an Electrothermal IA9100 digital ap-

paratus and are uncorrected. Boiling points are reported

uncorrected. Ku¨gelrohr distillations were performed using a

Bu¨chi GKR-51 apparatus and reported boiling points cor-

respond to uncorrected oven air bath temperatures. Flash

column chromatography refers to the method of Still³⁷using

Merck 230-400 mesh silica gel. Gradient elution refers to

applying the compound as a solution in hexanes to the

hexanes-equilibrated column and then eluting with progres-

sively more polar hexanes/EtOAc solutions. Analytical thin

layer chromatography (TLC) was performed using Merck 60-

F-254 0.25 mm precoated silica gel plates. Compounds were

visualized using ultraviolet light, iodine vapor, or cerium

molybdate/sulfuric acid/methanol. Preparative thin layer

chromatography (PTLC) was performed using Merck 60-F-254

0.50 or 1.00 mm precoated silica gel plates. High-performance

liquid chromatography (HPLC) was performed on a Beckman

System Gold 126 chromatograph. Column: 4.6 × 250 mm

Beckman Ultrasphere ODS. Preparative HPLC was per-

formed on a Waters Delta Prep 4000. The detector wavelength

was set to 254 nm. Ethyl ether (Et₂O) and tetrahydrofuran

(THF) were distilled directly prior to use from sodium/

benzophenone ketyl. Dichloromethane (CH₂Cl₂), benzene, and

toluene were dried and stored under nitrogen over 4 Å

molecular sieves. Organic amines were distilled from CaH₂

and stored over solid KOH pellets under nitrogen. “Brine”

refers to a saturated aqueous solution of NaCl. Unless

otherwise specified, solutions of common inorganic salts used

in workups are aqueous solutions. All moisture-sensitive

reactions were carried out using oven-dried or flame-dried

round-bottomed (rb) flasks and glassware under an atmo-

sphere of dry nitrogen.

(20, 33), this change caused the loss of an order of

magnitude in AR antagonist cotransfection assay activ-

ity, whereas in combination with 9-methylation (21a -

c), in vitro activity was fully restored. These nitrogens

and adjacent regions are likely to play a critical role in

terms of receptor interactions, through participation in

hydrogen bonding with residues in the hormone binding

domain of the hAR. The receptor was quite tolerant of

varying alkyl substitution at positions 2, 3, and 4,

although geminal substitution at C-2 was essential for

AR antagonist activity, and 4-position alkyls generally

resulted in diminished in vivo exposure levels. None

of the compounds in this series exhibited AR agonist

activity in vitro or in vivo.

Con clu sion

Through ongoing efforts characterizing the SAR within

this lead series, we have identified a series of analogues

which act as AR antagonists and represent attractive

pharmaceutical opportunities. Most analogues are eas-

ily synthesized (five or fewer steps from inexpensive

starting materials), novel non-steroids exhibiting an-

tagonist potencies of 10-30 nM in the presence of 5 nM

DHT in cell-based reporter assays with hAR, and

comparable whole-cell binding K_ivalues. These ana-

logues are also highly selective for AR and are up to

1000-fold more potent on AR than any other IR in

cotransfection assays and binding studies. Additionally,

some analogues (9c,d , 19a ,b, 20) have the ability to

inhibit transcriptional activation of a mutant AR com-

monly found in hormone-refractory prostate tumor cells

(LNCaP),³⁶which responds to some AR antagonists as

if they were agonists. Many of the active members in

this series (e.g., 9a -e) are orally active as inhibitors of

male accessory sex organ growth in both castrated and

intact rats, some with oral in vivo efficacy equivalent

to known agents. Furthermore, 9e exhibited in vivo

efficacy superior to flutamide (2a ) as an inhibitor of

intact male rat sexual accessory organ growth. This

oral in vivo efficacy occurs with complete peripheral

selectivity, causing no accompanying increase in serum

concentrations of LH or T, as compared with the 8-10-

fold increase seen with 2a administration and the 2-fold

increase reported to occur with bicalutamide (3) admin-

istration. This may reflect greater selectivity for pe-

ripheral as opposed to central ARs relative to known

AR antagonists, providing pharmacological profiles

distinct from those of existing agents. We believe this

series of compounds demonstrates significant potential

for the development of therapeutically useful AR an-

tagonists. Guided by these initial findings, further

studies are in progress, directed at the discovery of

analogues that possess superior pharmacological ef-

ficacy and pharmacokinetic properties, while maintain-

ing the desirable receptor and tissue selectivities ob-

served with this novel pharmacophore.

1,2-Dih yd r o-2,2,4,6-tetr a m eth yl-8-p yr id on o[5,6-f]qu in -

olin e (5). A solution of carbostyril 124 (4, 500 mg, 2.8 mmol)

and iodine (40 mg, 0.16 mmol, 6.0 mol %) in acetone (25 mL)

was heated in a 70-mL sealed tube at 120 °C for 16 h. The

mixture was then cooled to room temperature, and the solvent

was removed under reduced pressure. The residue was then

dissolved in 50 mL of EtOAc, and the organic solution was

washed with 30 mL water, dried (Na₂SO₄), and concentrated

under reduced pressure. Purification by flash column chro-

matography (silica gel, hexanes/EtOAc, 9:1) afforded 175 mg

(25%) of the desired tricyclic lactam as a pale yellow solid (mp

282-284 °C), along with the isomers 6 and 7, obtained in 27%

and 26% yield, respectively. Da ta for 1,2-d ih yd r o-2,2,4,6-

tetr am eth yl-8-pyr idon o[5,6-g]qu in olin e (5): ¹H NMR 11.50

(br s, CONH), 7.24 (s, 1H, 5-H), 6.34 (s, 1H, 7-H), 6.23 (s, 1H,

10-H), 5.37 (s, 1H, 3-H), 2.41 (s, 3H, 6-CH₃), 2.04 (s, 3H, 4-CH₃),

1.29 [s, 6H, 2-C(CH₃)₂]; ¹³C NMR 165.0, 149.8, 146.5, 140.3,

129.2, 127.6, 119.1, 118.5, 114.9, 112.5, 97.2, 52.4, 31.8, 19.3,

18.9; IR (KBr) 2966, 2918, 1658, 1641, 1425, 1257. Anal.

(C₁₆H₁₈N₂O) C, H, N. Da ta for 1,2-d ih yd r o-2,2,4,8-tetr a -

m eth yl-6-p yr id on o[6,5-e]qu in olin e (6): ¹H NMR (acetone-

d₆) 7.50 (d, 1H, J ) 8.1, 10-H), 7.33 (s, 1H, 7-H), 6.52 (d, 1H,

J ) 8.1, 9-H), 6.10 (s, 1H, 3-H), 6.09 (s, 1H, 1-H), 2.79 (s, 3H,

8-CH₃), 2.46 (s, 3H, 4-CH₃) 1.37 [s, 6H, 2-C(CH₃)₂]. Da ta for

1,2,3,4-tetr ah ydr o-2,2,8-tr im eth yl-4-m eth ylen e-6-pyr idon o-

Exp er im en ta l Section

Gen er a l Ch em ica l P r oced u r es. Proton nuclear magnetic

resonance (¹H NMR) and carbon-13 nuclear magnetic reso-

nance (¹³C NMR) spectra were recorded with CDCl₃as the

solvent at 400 and 100 MHz, respectively (Bru¨ker AC 400),

except where otherwise noted. Chemical shifts are given in

parts per million (ppm) downfield from internal reference

tetramethylsilane in δ-units, and coupling constants (J values)

1

[6,5-e]qu in olin e (7): H NMR (acetone-d₆) 7.35 (d, 1H, J )

8.9, 10-H), 6.47 (d, 1H, J ) 8.9, 9-H), 6.03 (s, 1H, 7-H), 5.49

and 5.33 (2s, 2 × 1H, 4-CH₂), 2.36 and 2.34 (AB q, 2H, J _AB

)

11.2, 3-H), 2.35 (s, 3H, 8-CH₃), 1.26 [s, 6H, 2-C(CH₃)₂].

1-(ter t-Bu tyloxyca r ba m oyl)-3-n itr oben zen e (12). To a

Androgen Receptor Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 631

flame-dried 500-mL rb flask containing 3-nitroaniline 11a

(20.0 g, 145 mmol) in 150 mL of THF was added di-tert-butyl

dicarbonate (31.6 g, 145 mmol, 1.00 equiv), and the mixture

was cooled to 0 °C. 4-(N,N-Dimethylamino)pyridine (19.5 g,

159 mmol, 1.10 equiv) was added portionwise, and the mixture

was allowed to warm to room temperature overnight. Ethyl

acetate (400 mL) was added, and the mixture was washed with

1 M NaHSO₄(2 × 200 mL) and brine (200 mL), dried (Na₂SO₄),

and concentrated under reduced pressure. Purification by

flash column chromatography (silica gel, hexanes/EtOAc, 9:1)

afforded 31.4 g (91%) of the desired carbamate as a white solid

(mp 96-97 °C): ¹H NMR 8.31 (dd, 1H, J ) 2.2, 2.2, 2-H), 7.88

(dd, 1H, J ) 7.9, 1.5, 4-H), 7.69 (br d, 1H, J ≈ 7.8, 6-H), 7.44

(dd, 1H, J ) 8.3, 8.1, 5-H), 6.74 (br s, 1H, NH), 1.54 [s, 9H,

(CH₃)₃CO)].

3-(ter t-Bu tyloxyca r ba m oyl)a n ilin e (13). Gen er a l P r o-

ced u r e for th e Red u ction of a n Ar om a tic Nitr o Gr ou p .

To an oven-dried 1-L rb flask containing protected aniline 12a

(20.0 g, 83.9 mmol) in 500 mL of 1:1 EtOAc/ethanol at room

temperature was added 10% Pd on C (90 mg, ca. 1 mol %),

and the mixture was stirred under an atmosphere of H₂gas

for 6 h. The reaction mixture was then filtered and concen-

trated under reduced pressure to give 17.4 g (quantitative) of

the desired aniline as a white solid: ¹H NMR 7.04 (dd, 1H, J

) 8.0, 8.0, 5-H), 6.98 (br s, 1H, NH), 6.53 (dd, 1H, J ) 7.9, 1.8,

4-H), 6.36 (m, 2H, 6,2-H), 3.66 (br s, 2H, NH₂), 1.51 [s, 9H,

(CH₃)₃CO)].

7-(ter t-Bu tyloxyca r ba m oyl)-1,2-d ih yd r o-2,2,4-tr im eth -

ylqu in olin e (14). To an oven-dried 1-L rb flask containing

aniline 13a (17.4 g, 83.5 mmol), MgSO₄(50 g, 5 equiv), and

4-tert-butylcatechol (420 mg, 3.0 mol %) in 120 mL of acetone

(ca. 0.75 M in the aniline) was added iodine (1.1 g, 5.0 mol %),

and the mixture was heated to reflux for 8 h. The crude

reaction mixture was then cooled to room temperature, filtered

through a bed of Celite on a fritted-glass funnel, rinsing with

EtOAc, dried (Na₂SO₄), and concentrated under reduced

pressure. Purification by flash column chromatography (silica

gel, hexanes/EtOAc, gradient elution) afforded 19.9 g (82%)

of the desired cyclization product as a white solid, which was

further purified by recrystallization from CH₃CN to give white

needles (mp 163-164 °C): ¹H NMR 6.93 (d, 1H, J ) 8.3, 5-H),

6.81 (br s, 1H, HNBOC), 6.34 (m, 2H, 6,8-H), 5.21 (d, 1H, J )

0.9, 3-H), 3.71 (br s, 1H, NH), 1.94 (d, 3H, J ) 1.0, 4-CH₃),

1.50 [s, 9H, (CH₃)₃CO)], 1.24 [s, 6H, 2-C(CH₃)₂]. Anal.

(C₁₇H₂₄N₂O₂) C, 70.80; H, 8.39; N, 9.71. Found: C, 70.91; H,

8.14; N, 9.84.

4,4,4-Tr iflu or oa cetoa ceta te. To an oven-dried 10-mL rb

flask containing 7-amino-1,2-dihydro-2,2,4-trimethylquinoline

(100 mg, 0.53 mmol) and ethyl 4,4,4-trifluoroacetoacetate (85.4

µL, 0.58 mmol, 1.10 equiv) in 2.5 mL of absolute ethanol was

added ZnCl₂(110 mg, 0.81 mmol, 1.5 equiv), and the mixture

was heated to reflux for 3 h. Upon being cooled to room

temperature, the reaction mixture was diluted with 40 mL of

EtOAc, and the organic solution was washed with saturated

NH₄Cl, dried (Na₂SO₄), and concentrated under reduced

pressure. Purification by flash column chromatography (silica

gel, hexanes/EtOAc, gradient elution) afforded 70 mg (40%)

of the ethyl imino ether (10a , R_f0.61, hexanes/EtOAc, 2:1) as

a

pale yellow crystalline solid and 72 mg (44%) of the

2-quinolone (9a , R_f0.14, hexanes/EtOAc, 2:1) as a bright

fluorescent-yellow solid, which was recrystallized from 95%

EtOH (mp 286-288 °C). Da t a for 1,2-d ih yd r o-2,2,4-t r i-

m et h yl-6-(t r iflu or om et h yl)-8-p yr id on o[5,6-g]q u in olin e

(9a ): ¹H NMR 11.45 (br s, 1H, CONH), 7.38 (s, 1H, 5-H), 6.66

(s, 1H, 7-H), 6.27 (s, 1H, 10-H), 5.42 (s, 1H, 3-H), 4.35 [br s,

1H, (CH₃)₂CNH], 2.03 (s, 3H, 4-CH₃), 1.33 [s, 6H, 2-(CH₃)₂];

¹³C NMR (acetone-d₆) 162.1, 148.5, 142.9, 138.8 (q), 130.6,

127.5, 125.5 (q), 119.8, 119.0, 114.4, 105.4, 96.6, 53.2, 32.0,

18.6; IR (KBr) 3345 (m, br), 2973 (m, br), 1659 (s), 1628 (s),

1476 (m), 1443 (m). Anal. (C₁₆H₁₅F₃N₂O) C, H, N. Da ta for

8-eth oxy-1,2-d ih yd r o-2,2,4-tr im eth yl-6-(tr iflu or om eth yl)-

1

p yr id in o[5,6-g]qu in olin e (10a ): H NMR 7.56 (d, 1H, J )

1.8, 5-H), 6.84 (s, 1H, 7-H), 6.74 (s, 1H, 10-H), 5.52 (s, 1H,

3-H), 4.47 (q, 2H, J ) 7.0, CH₃CH₂O), 4.12 [br s, 1H, (CH₃)₂-

CNH], 2.09 (d, 3H, J ) 1.3, 4-CH₃), 1.42 (t, 3H, J ) 7.0, CH₃-

CH₂O), 1.34 [s, 6H, 2-(CH₃)₂]; IR (neat) 3393 (m, br), 2969 (m,

br), 1611 (s), 1524 (m), 1495 (s). This product was readily

converted to the 2-quinolone isomer 9a virtually quantitatively

by heating neat with excess 57% HI at 60 °C for 3 h, followed

by neutralization with saturated NaHCO₃, extraction with

EtOAc, and recrystallization.

1,2,3,4-Tetr a h yd r o-2,2,4-tr im eth yl-6-(tr iflu or om eth yl)-

8-p yr id on o[5,6-g]qu in olin e (9b). This compound was pre-

pared from amine 14b (98 mg, 0.51 mmol) in the manner

previously described for 9a , affording 66 mg (42%) of the

desired 2-quinolone as a fluorescent-yellow solid (mp 299-300

°C dec): ¹H NMR 11.32 (br s, 1H, CONH), 7.50 (s, 1H, 5-H),

6.64 (s, 1H, 7-H), 6.41 (s, 1H, 10-H), 4.55 [br s, 1H, (CH₃)₂-

CNH], 2.91 (ddq, 1H, J ) 12.6, 12.4, 6.3, 4-H), 1.76 and 1.41

[d of AB q, 2H, J _AB) 12.8, J _A) 5.5 (3-H_eq), J _B) 12.4 (3-H_ax)],

1.37 (d, 3H, J ) 6.8, 4-CH₃), 1.22 and 1.18 [2s, 2 × 3H,

2-(CH₃)₂]; ¹³C NMR 163.8, 147.7, 140.0, 139.2, 124.0, 122.6,

112.6, 105.9, 96.7, 49.7, 43.6, 31.1, 28.6, 27.3, 19.6. Anal.

(C₁₆H₁₇F₃N₂O) C, H, N.

1,2-Dih yd r o-2,2,4,10-t et r a m et h yl-6-(t r iflu or om et h yl)-

8-p yr id on o[5,6-g]qu in olin e (9c). This compound was pre-

pared from amine 14c (100 mg, 0.49 mmol) in the manner

previously described for 9a , affording 75 mg (47%) of the

desired 2-quinolone as a fluorescent-yellow solid (mp 245-246

°C): ¹H NMR 9.23 (br s, 1H, CONH), 7.37 (s, 1H, 5-H), 6.67

(s, 1H, 7-H), 5.45 (s, 1H, 3-H), 4.14 [br s, 1H, (CH₃)₂CNH],

2.12 (s, 3H, 10-CH₃), 2.04 (d, 3H, J ) 1.1, 4-CH₃), 1.37 [s, 6H,

2-(CH₃)₂]; ¹³C NMR 162.6, 144.3, 139.4, 138.7, 127.5, 124.3,

120.5, 118.2, 117.8, 113.8, 106.0, 101.4, 52.8, 32.2, 18.6, 9.4.

Anal. (C₁₇H₁₇F₃N₂O) C, H, N.

7-Am in o-1,2-d ih yd r o-2,2,4-t r im et h ylq u in olin e (8a ).

Gen er a l P r oced u r e for R em ova l of BOC P r ot ect ive

Gr ou p . To an oven-dried 25-mL rb flask containing dihyd-

roquinoline 14a (400 mg, 1.38 mmol) in 2 mL of CH₂Cl₂at 0

°C was added TFA (1.1 mL, 10 equiv), and the mixture was

allowed to warm to room temperature. After 3 h at room

temperature, the reaction mixture was diluted with 50 mL of

CH₂Cl₂, transferring to a 125-mL Erlenmeyer flask, and cooled

to 0 °C before adjusting to pH 8 with saturated NaHCO₃. The

biphasic mixture was transferred to a separatory funnel, the

layers were separated, and the organic phase was dried (Na₂-

SO₄) and concentrated under reduced pressure to afford a light

reddish oil. The crude material thus obtained was of greater

1

than 98% purity by H NMR and was carried on to the next

1,2,3,4-Tet r a h yd r o-2,2,4,10-t et r a m et h yl-6-(t r iflu or o-

m eth yl)-8-p yr id on o[5,6-g]qu in olin e (9d ). This compound

was prepared from amine 14d (2.92 g, 14.3 mmol) in the

manner previously described for 9a , affording 2.04 g (44%) of

the desired 2-quinolone as a pale fluorescent-yellow solid (mp

239-240 °C): ¹H NMR 9.70 (br s, 1H, CONH), 7.50 (s, 1H,

5-H), 6.68 (s, 1H, 7-H), 4.13 [br s, 1H, (CH₃)₂CNH], 3.00 (ddq,

1H, J ) 12.9, 12.4, 6.3, 4-H), 2.15 (s, 3H, 10-CH₃), 1.83 and

step without further purification. While the 7-aminoquinolines

14 obtained began to decompose appreciably within a few

hours upon standing at room temperature, ethanolic solutions

could be stored at -20 °C for 2-3 days without substantial

adverse effect on the subsequent reaction outcome. Typically,

however, the material was stored in bulk as the crystalline

BOC-protected amine and deprotected as needed: ¹H NMR

6.86 (d, 1H, J ) 8.2, 5-H), 5.99 (dd, 1H, J ) 8.0, 2.3, 6-H),

5.79 (d, 1H, J ) 2.0, 8-H), 5.12 (d, 1H, J ) 1.4, 3-H), 3.53 (br

s, 3H, NH₂, NH), 1.93 (d, 3H, J ) 1.2, 4-CH₃), 1.24 [s, 6H,

2-(CH₃)₂].

1.46 [dd of AB q, 2H, J _AB) 13.0, J _A) 5.3, 1.6 (3-H_eq), J _B

)

12.9, 0 (3-H_ax)], 1.40 (d, 3H, J ) 6.6, 4-CH₃), 1.36 and 1.25

[2s, 2 × 3H, 2-(CH₃)₂]; ¹³C NMR 162.5, 144.9, 139.1, 137.1,

124.3, 122.7, 120.9, 113.8, 105.7, 101.6, 50.2, 43.5, 31.8, 28.9,

27.6, 20.1, 9.7. Anal. (C₁₇H₁₉F₃N₂O) C, H, N.

Kn or r Rea ction of 7-Am in o-1,2-d ih yd r o-2,2,4-tr im eth -

ylqu in olin e (8a ). Gen er a l P r oced u r e for th e Kn or r

Cycliza tion of 7-Am in o-1,2-d ih yd r oqu in olin es 8a -i w ith

(2-Meth yl-3-bu tyn -2-yl)p h en yla m in e (16e). In a 500-mL

rb flask, a solution of 2-methyl-3-butyn-2-ol (10.0 mL, 0.10 mol,

632 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4

Hamann et al.

1.30 equiv) in CH₂Cl₂(100 mL) was treated sequentially with

Et₃N (15.0 mL, 0.11 mol, 1.40 equiv), acetic anhydride (11.6

mL, 0.12 mol, 1.50 equiv), and DMAP (0.6 g, 5.0 mmol, 5.0

mol %). The reaction mixture was stirred at room temperature

for 2 h and poured into saturated NH₄Cl (60 mL). The layers

were separated, and the aqueous layer was extracted with

CH₂Cl₂(2 × 100 mL). The combined organic layers were

washed with 1 N HCl (2 × 100 mL), dried (MgSO₄), filtered

through a pad of Celite, and concentrated under reduced

pressure. The residue was dissolved in THF (100 mL), and

aniline (7.00 mL, 770 mmol) was added slowly via syringe,

followed by CuCl (0.76 g, 10 mol %). The reaction mixture

was heated to reflux for 3 h. The resulting red solution was

allowed to cool to room temperature, and concentrated under

reduced pressure. The residue was then diluted with EtOAc

(120 mL), and the solution was washed with saturated NH₄Cl

(2 × 100 mL) and brine (1 × 100 mL). The aqueous layers

were extracted with EtOAc (2 × 100 mL), and the combined

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

under reduced pressure. Purification by flash column chro-

matography (silica gel, hexanes/EtOAc, 16:1) afforded 10.5 g

(87%) of amine 16e as a pale yellow liquid: ¹H NMR 7.20 (t,

2H, J ) 7.7, 3,5-H), 6.95 (d, 2H, J ) 7.7, 2,6-H), 6.80 (t, 1H, J

) 7.7, 4-H), 3.65 [br s, 1H, (CH₃)₂CNH], 2.36 (s, 1H, CtCH),

1.61 [s, 6H, 2-(CH₃)₂].

2.66 (dd, 2H, J ) 6.7, 6.6, 4-H), 1.65 (dd, 2H, J ) 6.7, 6.6,

3-H), 1.18 [s, 6H, 2-(CH₃)₂].

1,2,3,4-Tetr a h yd r o-2,2-d im eth yl-6-(tr iflu or om eth yl)-8-

p yr id on o[5,6-g]qu in olin e (9e). This compound was pre-

pared from amine 8e (0.85 g, 5.08 mmol) in the manner

previously described for 9a , affording 0.74 g (52%) of quinolone

9e as a yellow powder, which was further purified by recrys-

tallization from 2-propanol to give yellow needles (mp 287-

289 °C), along with 0.54 g (35%) of ethoxypyridine 10e as a

1

yellow solid. Da ta for 9e: H NMR (DMSO-d₆) 11.70 (s, 1H,

CONH), 7.18 (s, 1H, 5-H), 6.85 (s, 1H, 7-H), 6.35 (s, 1H, 10-

H), 2.65 (dd, 2H, J ) 6.6, 6.6, 4-H), 1.61 (dd, 2H, J ) 6.6, 6.6,

3-H), 1.17 [s, 6H, 2-(CH₃)₂]; ¹³C NMR 163.6, 147.6, 140.0, 138.9

(q), 124.8, 122.9 (q), 118.4, 112.9, 105.9, 97.0, 49.4, 33.8, 29.4,

24.1; IR (KBr) 3302 (m, br), 2971 (m, br), 1662 (s), 1630 (s),

1439 (m). Anal. (C₁₅H₁₅F₃N₂O) C, H, N. Da ta for 8-eth oxy-

1,2,3,4-tetr a h yd r o-2,2-d im eth yl-6-(tr iflu or om eth yl)p yr i-

d in o[5,6-g]qu in olin e (10e): ¹H NMR 7.56 (d, 1H, J ) 1.4,

5-H), 6.84 (s, 1H, 7-H), 6.78 (s, 1H, 10-H), 4.46 (q, 2H, J )

7.1, OCH₂CH₃), 4.16 (s, 1H, NH), 2.96 (t, 2H, J ) 6.7, 4-H),

1.78 (t, 2H, J ) 6.7, 3-H), 1.41 (t, 3H, J ) 7.2, OCH₂CH₃),

1.27 [s, 6H, NC(CH₃)₂].

2-Eth yl-1,2,3,4-tetr ah ydr o-2-m eth yl-6-(tr iflu or om eth yl)-

8-p yr id on o[5,6-g]qu in olin e (9f). This compound was pre-

pared from amine 8f (0.26 g, 1.36 mmol) in the manner

previously described for 9a , affording 282 mg (67%) of 9f as a

yellow solid (R_f0.35, EtOAc/CH₂Cl₂, 3:2), a portion of which

was recrystallized from methanol to give yellow needles (mp

268 °C): ¹H NMR 12.6 (br s, 1H, CONH), 7.34 (s, 1H, 5-H),

6.62 (s, 1H, 7-H), 6.49 (s, 1H, 10-H), 4.65 [br s, 1H, (CH₃)₂-

CNH], 2.78 (br t, 2H, J ) 6.2, 4-H), 1.65-1.75 and 1.55-1.65

(2 m, 2 × 1H, 3-H), 1.46 (br q, 2H, J ) 7.3, CH₂CH₃), 1.10 [s,

6H, 2-(CH₃)₂], 0.87 (t, 3H, J ) 7.4, CH₂CH₃); ¹³C NMR 163.7,

148.0, 140.0, 138.9 (q, J ) 31), 124.7, 122.8 (q, J ) 275), 118.7,

112.5, 105.8, 97.0, 51.7, 34.0, 31.2, 26.2, 23.7, 7.8. Anal.

(C₁₆H₁₇F₃N₂O) C, H, N.

1,2,3,4-Tetr a h yd r o-2,2-d im eth ylqu in olin e (17e). In a

1-L rb flask, a solution of 16e (24.3 g, 152 mmol) in THF (200

mL) was treated with CuCl (1.7 g, 11 mol %) and heated at

reflux for 14 h. The reaction mixture was cooled to room

temperature, filtered, and concentrated under reduced pres-

sure. The residue was poured into saturated NH₄Cl (200 mL)

and extracted with EtOAc (3 × 250 mL). The combined

organics were washed with saturated NH₄Cl (1 × 200 mL) and

brine (1 × 200 mL), dried (MgSO₄), filtered through a pad of

Celite, and concentrated under reduced pressure to an orange

oil. Purification by flash column chromatography (silica gel,

hexanes/EtOAc, 40:1) afforded 18.0 g (74%) of 1,2-dihydro-2,2-

dimethylquinoline as a pale yellow oil: ¹H NMR 6.95 (t, 1H,

J ) 7.7, 7-H), 6.87 (d, 1H, J ) 7.3, 5-H), 6.57 (t, 1H, J ) 7.3,

6-H), 6.40 (d, 1H, J ) 7.7, 8-H), 6.25 (d, 1H, J ) 9.7, 4-H),

5.46 (d, 1H, J ) 9.7, 3-H), 3.63 [br s, 1H, (CH₃)₂CNH], 1.31 [s,

6H, 2-(CH₃)₂]. To a 1-L rb flask containing a solution of the

dihydroquinoline (16.2 g, 102 mmol) in 1:1 EtOH/EtOAc (300

mL) was added 10% Pd/C (1.05 g, 0.99 mol %), and the mixture

was stirred under an atmosphere of H₂for 4 h. The reaction

mixture was purged with N₂and filtered through a pad of

Celite, rinsing with EtOAc (200 mL). Concentration of the

filtrate afforded 16.2 g (99%) of the tetrahydroquinoline as a

pale yellow oil: ¹H NMR 6.98 (m, 2H, 7,5-H), 6.60 (t, 1H, J )

7.3, 6-H), 6.44 (d, 1H, J ) 8.0, 8-H), 2.77 (dd, 2H, J ) 6.7, 6.7,

4-H), 1.70 (dd, 2H, J ) 6.7, 6.7, 3-H), 1.21 [s, 6H, 2-(CH₃)₂].

1,2,3,4-Tetr a h yd r o-2,2-d im eth yl-7-n itr oqu in olin e (18e).

To a 250-mL rb flask containing 17e (6.06 g, 37.6 mmol) in

H₂SO₄(40 mL) at -5 °C was added 90% HNO₃(1.70 mL)

dropwise over a 15 min period. The reaction mixture was

stirred an additional 15 min and poured over ice (300 g), and

K₂CO₃(100 g) was added slowly with vigorous stirring. The

mixture was extracted with CH₂Cl₂(3 × 300 mL), and the

combined extracts were washed with H₂O (200 mL) and

saturated NaHCO₃(100 mL), dried (MgSO₄), filtered through

pad of Celite, and concentrated under reduced pressure.

Purification by flash column chromatography (silica gel, hex-

anes/EtOAc, 40:1 to 20:1 gradient) afforded 4.40 g (57%) of

the product as an orange solid: ¹H NMR 7.39 (dd, 1H, J )

7.9, 2.2, 6-H), 7.27 (d, 1H, J ) 2.2, 8-H), 7.04 (d, 1H, J ) 7.9,

5-H), 3.95 [br s, 1H, (CH₃)₂CNH], 2.81 (dd, 2H, J ) 6.7, 6.7,

4-H), 1.72 (dd, 2H, J ) 6.7, 6.7, 3-H), 1.21 [s, 6H, 2-(CH₃)₂].

2,2-Dieth yl-1,2,3,4-tetr a h yd r o-6-(tr iflu or om eth yl)-8-p y-

r id on o[5,6-g]qu in olin e (9g). This compound was prepared

from 8g (0.230 g, 1.13 mmol) in the manner previously

described for 9a , affording 0.103 g (28%) of 9g as a yellow solid

(R_f0.34, EtOAc/CH₂Cl₂, 3:2). An analytically pure sample was

obtained by recrystallization from methanol (mp 261-262

°C): ¹H NMR 12.5 (br s, 1H, CONH), 7.36 (s, 1H, 5-H), 6.66

(s, 1H, 7-H), 6.45 (s, 1H, 10-H), 4.52 [br s, 1H, (CH₃)₂CNH],

2.80 (t, 2H, J ) 6.6, 4-H), 1.71 (t, 2H, J ) 6.6, 3-H), 1.60-1.40

(m, 4H, CH₂CH₃), 0.87 (t, 6H, J ) 7.5, CH₂CH₃); ¹³C NMR

163.7, 147.9, 140.0, 138.9 (q, J ) 31), 124.8, 122.8 (q, J ) 276),

118.9, 112.9 (br), 105.9, 97.2, 54.2, 30.5, 29.0, 23.4, 7.5. Anal.

(C₁₇H₁₉F₃N₂O) C, H, N.

1,2,3,4-Tet r a h yd r o-2-m et h yl-2-p r op yl-6-(t r iflu or om e-

th yl)-8-p yr id on o[5,6-g]qu in olin e (9h ). This compound was

prepared from 8h (0.774 g, 3.79 mmol) in the manner previ-

ously described for 9a , affording 690 mg (56%) of 9h . Recrys-

tallization from MeOH/CH₂Cl₂afforded 383 mg (31%) of 9h

as a yellow solid (mp 254-256 °C): ¹H NMR 12.32 (br s, 1H,

CONH), 7.36 (s, 1H, 5-H), 6.65 (s, 1H, 7-H), 6.41 (s, 1H, 10-

H), 4.53 [br s, 1H, (CH₃)₂CNH], 2.81 (t, 2H, J ) 6.4, 4-H), 1.72-

1.82 (m, 1H, 3-H), 1.62-1.72 (m, 1H, 3-H), 1.25-1.50 (m, 4H,

CH₂CH₂CH₃), 1.16 (s, 3H, 2-CH₃), 0.91 (t, 3H, J ) 7.0,

CH₂CH₃); ¹³C NMR 163.8, 148.0, 140.1, 138.8 (q, J ) 31), 124.7,

122.7 (q, J ) 276), 118.6, 112.3 (br), 105.7, 96.9, 51.4, 43.9,

31.8, 26.8, 23.6, 16.7, 14.4. Anal. (C₁₇H₁₉F₃N₂O) C, H, N.

1,2,3,4-Tet r a h yd r o-2-sp ir ocycloh exyl-6-(t r iflu or om e-

th yl)-8-p yr id on o[5,6-g]qu in olin e (9i). This compound was

prepared in from 8i (0.126 g, 0.582 mmol) in the manner

previously described for 9a , affording 32 mg (16%) of 9i (R_f

0.17, hexanes/EtOAc, 5:2). An analytical sample was obtained

by recrystallization from MeOH (mp 285-305 °C dec): ¹H

NMR 11.4 (br s, 1H, CONH), 7.36 (s, 1H, 5-H), 6.67 (s, 1H,

7-H), 6.33 (s, 1H, 10-H), 4.68 [br s, 1H, (CH₃)₂CNH], 2.82 (t,

2H, J ) 6.6, 4-H), 1.77 (t, 2H, J ) 6.6, 3-H), 1.65-1.45 (m,

9H, cyclohexyl-H), 1.45-1.35 (m, 1H, cyclohexyl-H); ¹³C NMR

(DMSO-d₆) 160.8, 148.0, 140.3, 136.4 (q, J ) 30), 123.5, 122.9

7-Am in o-1,2,3,4-tetr a h yd r o-2,2-d im eth ylqu in olin e (8e).

This compound was prepared from 18e (1.00 g, 4.84 mmol) in

the manner previously described for aniline 13, affording 0.85

g (99%) of the crude aniline as a reddish oil: ¹H NMR 6.77 (d,

1H, J ) 7.9, 5-H), 6.00 (dd, 1H, J ) 7.9, 2.2, 6-H), 5.81 (d, 1H,

J ) 2.2, 8-H), 3.47 [br s, 1H, (CH₃)₂CNH], 3.40 (br s, 2H, NH₂),

Androgen Receptor Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 633

(q, J ) 276), 117.3, 112.9 (br), 103.1, 96.3, 50.5, 37.2, 30.4,

8-p yr id on o[5,6-g]qu in olin e (19f). This compound was pre-

pared from 9e (830 mg, 2.80 mmol) in the manner previously

described for 19a , affording 735 mg (85%) of 19f (R_f0.48, CH₂-

Cl₂/MeOH, 15:1) as a yellow solid (mp 217-218 °C): ¹H NMR

7.35 (s, 1H, 5-H), 6.56 (s, 1H, 7-H), 6.52 (s, 1H, 10-H), 6.10 [s,

1H, (CH₃)₂CNH], 3.53 (s, 3H, NCH₃), 2.87 (t, 2H, J ) 6.7, 4-H),

1.76 (t, 2H, J ) 6.7, 3-H), 1.29 [s, 6H, 2-(CH₃)₂]; ¹³C NMR 161.6,

25.5, 22.7, 21.2. Anal. (C₁₈H₁₉F₃N₂O) C, H, N.

1,2-Dih yd r o-2,2,4,9-tetr a m eth yl-6-(tr iflu or om eth yl)-8-

p yr id on o[5,6-g]qu in olin e (19a ). Gen er a l P r oced u r e for

N-Alk yla tion of 2-Qu in olon es a t N-9: To an oven-dried 50-

mL rb flask containing 1,2-dihydro-2,2,4-trimethyl-6-(trifluo-

romethyl)-8-pyridono[5,6-g]quinoline (500.0 mg, 1.62 mmol) in

5 mL of THF at 0 °C was added portionwise sodium hydride

(71.4 mg of a 60% dispersion in mineral oil, 1.78 mmol, 1.10

equiv). After 30 min, iodomethane (101 µL, 1.62 mmol, 1.00

equiv) was added, and the mixture was allowed to warm to

room temperature, and after 4 h, the reaction mixture was

cooled to 0 °C, and water (5 mL) was added. The reaction

mixture was then diluted with 100 mL of EtOAc, and the

organic solution was washed with 50 mL of brine, dried (Na₂-

SO₄), and concentrated under reduced pressure. Purification

by flash column chromatography (silica gel, hexanes/EtOAc,

gradient elution) afforded 497 mg (95%) of the desired N-

methylamide as a bright fluorescent yellow solid (mp 248-

250 °C): ¹H NMR 7.41 (d, 1H, J ) 1.7, 5-H), 6.73 (s, 1H, 7-H),

6.28 (s, 1H, 10-H), 5.42 (s, 1H, 3-H), 4.36 [br s, 1H, (CH₃)₂-

CNH], 3.62 (s, 3H, NCH₃), 2.04 (d, 3H, J ) 1.2, 4-CH₃), 1.33

[s, 6H, 2-(CH₃)₂]; ¹³C NMR 161.4, 146.7, 142.5, 137.0 (q), 129.2,

127.1, 121.5, 120.5, 117.8, 114.1, 106.4, 95.9, 52.9, 32.0, 29.8,

18.3. Anal. (C₁₇H₁₇F₃N₂O) C, H, N.

1,2-Dih ydr o-9-eth yl-2,2,4-tr im eth yl-6-(tr iflu or om eth yl)-

8-p yr id on o[5,6-g]qu in olin e (19b). This compound was

prepared from 9a (34.1 mg, 0.111 mmol) and iodoethane in

the manner previously described for 19a , affording 19.8 mg

(56%) of 19b as a yellow solid (mp 231-233 °C): ¹H NMR 7.42

(d, 1H, J ) 1.6, 5-H), 6.72 (s, 1H, 7-H), 6.32 (s, 1H, 10-H),

5.42 (s, 1H, 3-H), 4.46 [br s, 1H, (CH₃)₂CNH], 4.25 (q, 2H, J )

7.2, NCH₂CH₃), 2.04 (d, 3H, J ) 1.4, 4-CH₃), 1.36 [s, 6H,

2-(CH₃)₂], 1.33 (t, 3H, J ) 7.3, NCH₂CH₃); ¹³C NMR 161.0,

147.1, 141.5, 137.0 (q), 129.4, 126.9, 123.0 (q), 120.5, 117.8,

113.8 (q), 106.5, 95.6, 52.8, 37.7, 32.0, 30.9, 18.3. Anal.

(C₁₈H₁₉F₃N₂O) C, H, N.

1,2,3,4-Te t r a h yd r o-2,2,4,9-t e t r a m e t h yl-6-(t r iflu or o-

m eth yl)-8-p yr id on o[5,6-g]qu in olin e (19c). This compound

was prepared from 9b (45.0 mg, 0.145 mmol) in the manner

previously described for 19a , affording 36.7 mg (78%) of 19c

as a fluorescent-yellow solid (mp 235-236 °C): ¹H NMR 7.56

(br s, 1H, 5-H), 6.73 (s, 1H, 7-H), 6.31 (s, 1H, 10-H), 4.43 [br

s, 1H, (CH₃)₂CNH], 3.61 (s, 3H, NCH₃), 2.98 (ddq, 1H, J )

12.8, 12.4, 6.0, 4-H), 1.83 (ddd, 1H, J ) 13.0, 5.2, 1.7, 3-H_eq),

1.47 (dd, 1H, J ) 12.8, 12.8, 3-H_ax), 1.40 (d, 3H, J ) 6.7, 4-CH₃),

1.32 and 1.26 [2s, 2 × 3H, 2-(CH₃)₂]; ¹³C NMR 161.5, 147.2,

141.2, 136.7 (q), 124.0, 123.0 (q), 122.2, 114.0, 106.2, 96.7, 50.1,

43.8, 31.4, 29.6, 28.5, 27.1, 19.8. Anal. (C₁₇H₁₉F₃N₂O) C, H,

N.

1,2-Dih ydr o-2,2,4,9,10-pen tam eth yl-6-(tr iflu or om eth yl)-

8-p yr id on o[5,6-g]qu in olin e (19d ). This compound was

prepared from 9c (33.9 mg, 0.105 mmol) in the manner

previously described for 19a , affording 25.5 mg (72%) of 19d

as a fluorescent yellow solid (mp 204-7 °C dec): ¹H NMR 7.55

(s, 1H, 5-H), 6.87 (s, 1H, 7-H), 5.56 (s, 1H, 3-H), 4.78 [br s,

1H, (CH₃)₂CNH], 4.07 (s, 3H, NCH₃), 2.45 (s, 3H, 10-CH₃), 2.11

(d, 3H, J ) 1.2, 4-CH₃), 1.38 [s, 6H, 2-(CH₃)₂]; ¹³C NMR 164.3,

145.9, 144.4, 128.8, 127.3, 124.3, 118.1, 117.8, 114.4, 108.1,

104.2, 52.9, 39.9, 32.3, 29.7, 18.5, 16.2. Anal. (C₁₈H₁₉F₃N₂O)

C, H, N.

147.5, 141.4, 136.8 (q, J _C-F) 30.8), 126.1, 123.1 (q, J _C-F

)

275), 117.1, 114.1 (q, J _C-F) 5.8), 106.2, 97.0, 49.9, 34.1, 29.8,

29.6, 23.9. Anal. (C₁₆H₁₇F₃N₂O) C, H, F, N.

2-E t h yl-1,2,3,4-t et r a h yd r o-2,9-d im et h yl-6-(t r iflu or o-

m eth yl)-8-p yr id on o[5,6-g]qu in olin e (19g). This compound

was prepared from 9f (25 mg, 0.08 mmol) in the manner

previously described for 19a , affording 17 mg (65%) of 19g as

a yellow solid (R_f0.32, EtOAc/CH₂Cl₂, 9:1). A portion of this

material was recrystallized from methanol (mp 234 °C): ¹H

NMR 7.41 (s, ¹H, 5-H), 6.72 (s, ¹H, 7-H), 6.34 (s, ¹H, 10-H),

1

4.44 [br s, H, (CH₃)₂CNH], 3.61 (s, 3H, NCH₃), 2.84 (t, 2H, J

) 6.6, 4-H), 1.65-1.85 (m, 2H, 3-H), 1.57 (q, 2H, J ) 7.5, CH₂-

CH₃), 1.22 (s, 3H, 2-CH₃), 0.96 (t, 3H, J ) 7.5, CH₂CH₃). ¹³C

NMR 161.4, 147.4, 141.2, 136.6 (q, J ) 31), 125.9, 122.9 (q, J

) 275), 117.1, 113.9 (q, J ) 5.8), 106.0, 96.8, 52.1, 34.3, 31.4,

29.6, 26.2, 23.4, 7.9. Anal. (C₁₇H₁₉F₃N₂O) C, H, N.

1,2-Dih yd r o-1,2,2,4-t et r a m et h yl-6-t r iflu or om et h yl-8-

p yr id on o[5,6-g]qu in olin e (20). To an oven-dried 50-mL rb

flask containing 9a (202 mg, 0.66 mmol) in 5 mL of HOAC at

room temperature was added paraformaldehyde (200 mg) and

NaCNBH₃(450 mg, 6.60 mmol, 10.0 equiv), and the mixture

was allowed to stir overnight. The reaction mixture was then

added to 50 mL of saturated NaHCO₃and extracted with

EtOAc (2 × 50 mL). The organic layer was dried (Na₂SO₄)

and concentrated under reduced pressure. Purification by

flash column chromatography (silica gel, hexane/EtOAc, 4:1)

afforded 191 mg (90%) of the methylated product 20 as a yellow

solid (mp 300-302 °C): ¹H NMR 11.72 (br s, 1H, CONH), 7.33

(d, 1H, J ) 1.4, 5-H), 6.68 (s, 1H, 7-H), 6.28 (s, 1H, 10-H),

5.39 (s, 1H, 3-H), 2.93 (s, 3H, 1-CH₃), 2.02 (s, 3H, 4-CH₃), 1.38

[s, 6H, 2-(CH₃)₂]. ¹³C NMR 163.6, 148.1, 141.8, 138.8 (q), 130.8,

126.7, 122.9 (q), 120.5, 128.7, 113.3 (q), 105.4, 94.8, 57.3, 31.3,

28.5, 18.5. Anal. (C₁₇H₁₇F₃N₂O) C, H, N.

1,2-Dih yd r o-1,2,2,4,9-p en ta m eth yl-6-tr iflu or om eth yl-8-

p yr id on o[5,6-g]qu in olin e (21a ). To a 25-mL rb flask con-

taining 9a (125.8 mg, 0.41 mmol) in 5 mL DMF at room

temperature was added 200 mg (ca. 10 equiv) of solid KOH.

After 30 min, iodomethane (129 µL, 2.04 mmol, 5.00 equiv)

was then added, and the mixture was allowed to stir at room

temperature overnight. Ethyl acetate (50 mL) was then added,

the biphasic mixture was neutralized to pH 6 with saturated

NH₄Cl, and the layers were separated. The organic phase was

washed with brine, dried (Na₂SO₄), and concentrated under

reduced pressure. Purification by flash column chromatogra-

phy (silica gel, hexanes/EtOAc, gradient elution) afforded 111

mg (81%) of the desired di-N-methylated product as a bright

fluorescent-yellow solid, which could be further purified by

recrystallization from EtOAc to give yellow needles (mp 210-

212 °C): ¹H NMR 7.37 (s, 1H, 5-H), 6.74 (s, 1H, 7-H), 6.21 (s,

1H, 10-H), 5.38 (s, 1H, 3-H), 3.69 (s, 3H, CONCH₃), 2.94 [s,

3H, (CH₃)₂CNCH₃], 2.03 (s, 3H, 4-CH₃), 1.40 [s, 6H, 2-(CH₃)₂];

¹³C NMR 161.4, 148.0, 142.8, 136.6 (q), 130.4, 126.5, 122.9 (q),

119.6, 119.2, 113.8, 105.3, 93.9, 57.6, 31.2, 29.8, 28.6, 18.4.

Anal. (C₁₈H₁₉F₃N₂O) C, H, N.

1,2,3,4-Te t r a h yd r o-1,2,2,9-t e t r a m e t h yl-6-t r iflu or o-

m eth yl-8-p yr id on o[5,6-g]qu in olin e (21b). This compound

was prepared from 19f (24.0 mg, 0.08 mmol) in the manner

previously described for 20, affording 24 mg (96%) of 21b (R_f

0.27, hexane/EtOAc, 1:1) as yellow needles (mp 193-194 °C).

¹H NMR 7.35 (s, 1H, 5-H), 6.72 (s, 1H, 7-H), 6.28 (s, 1H, 10-

H), 3.67 [s, 3H, CONCH₃], 2.96 [s, 3H, (CH₃)₂CNCH3], 2.83

(t, 2H, J ) 6.7, 4-H), 1.85 (t, 2H, J ) 6.7, 3-H), 1.32 [s, 6H,

2-(CH₃)₂]; ¹³C NMR 161.7, 149.2, 141.9, 136.6 (q, J _C-F) 31.0),

124.4, 123.2 (q, J _C-F) 275), 120.2, 113.8 (q, J _C-F) 5.7), 105.1,

94.8, 55.2, 36.7, 31.9, 29.9, 27.0, 24.5. Anal. (C₁₇H₁₉F₃N₂O)

C, H, N.

1,2,3,4-Tet r a h yd r o-2,2,4,9,10-p en t a m et h yl-6-(t r iflu o-

r om eth yl)-8-p yr id on o[5,6-g]qu in olin e (19e). This com-

pound was prepared from 9d (50.0 mg, 0.154 mmol) in the

manner previously described for 19a , affording 38.8 mg (75%)

of 19e as a fluorescent-yellow solid (mp 189-193 °C dec): ¹H

NMR 7.48 (s, 1H, 5-H), 6.73 (s, 1H, 7-H), 4.13 [s, 1H, (CH₃)₂-

CNH], 3.65 (s, 3H, NCH₃), 3.00 (m, 1H, 4-H), 2.24 (s, 3H, 10-

CH₃), 1.84 (dd, 1H, J ) 13.6, 4.9, 3-H_eq), 1.45 (dd, 1H, J )

12.8, 12.8, 3-H_ax), 1.40 (d, 3H, J ) 6.7, 4-CH₃), 1.37 and 1.27

[2s, 2 × 3H, 2-(CH₃)₂]; ¹³C NMR 164.3, 146.2, 142.9, 122.3,

121.4, 120.9, 114.2, 107.8, 105.0, 50.2, 43.5, 40.0, 31.8, 29.7,

29.0, 27.5, 20.0, 16.5. Anal. (C₁₈H₂₁F₃N₂O) C, H, N.

1,2,3,4-Tetr a h yd r o-2,2,9-tr im eth yl-6-(tr iflu or om eth yl)-

2-Eth yl-1,2,3,4-tetr a h yd r o-1,2,9-tr im eth yl-6-tr iflu or o-

634 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4

Hamann et al.

m eth yl-8-p yr id on o[5,6-g]qu in olin e (21c). This compound

was prepared from 19g (18.1 mg, 0.06 mmol) in the manner

previously described for 20, affording 10 mg (51%) of a yellow

solid (R_f0.32, EtOAc/CH₂Cl₂, 9:1). A portion of this material

was recrystallized from EtOAc/hexanes (mp 170-171 °C): ¹H

NMR 7.35 (s, 1H, 5-H), 6.74 (s, 1H, 7-H), 6.31 (s, 1H, 10-H),

3.69 (s, 3H, CONCH₃), 2.95 (s, 3H, CNCH₃), 2.72-2.90 (m, 2H,

4-H), 1.98 (ddd, 1H, J ) 13.9, 8.3, 5.6, 3-H), 1.60-1.82 (m,

3H, 3-H, CH₂CH₃), 1.29 (s, 3H, 2-CH₃), 0.85 (t, 3H, J ) 7.4,

CH₂CH₃); ¹³C NMR 161.6, 149.6, 141.7, 136.4 (q, J ) 31), 124.1,

122.9 (q, J ) 276), 120.2, 113.5 (q, J ) 5.7), 104.9, 94.6, 57.8,

31.9, 31.8, 31.6, 29.7, 25.0, 24.0, 8.2. Anal. (C₁₈H₂₁F₃N₂O) C,

H, N.

dimethylated material. The crude material thus obtained was

carried on to the next step without further purification. In a

25-mL sealed tube, a solution of 24a (75 mg, 0.40 mmol) in

CH₂Cl₂(4 mL) was treated with Et₃SiH (1.0 mL) and BF₃‚

OEt₂(0.3 mL) at 100 °C for 18 h. The reaction mixture was

quenched with 10% KOH (10 mL), extracted with EtOAc (2 ×

20 mL), dried (Na₂SO₄), and concentrated under reduced

pressure. Flash column chromatography (silica gel, 2-20%

EtOAc/hexanes, gradient) afforded 60 mg (86%) of 27a as a

colorless oil: ¹H NMR 7.00-6.91 (m, 2H, 5,6-H), 6.60 (t, 1H,

J ) 7.3, 7-H), 6.45 (d, 1H, J ) 7.3, 8-H), 3.61 (br s, NH), 2.74

(dd, 1H, J ) 16.6, 5.3, 4-H_eq), 2.47 (dd, 1H, J ) 16.6, 10.3,

4-H_ax), 1.82 (m, 1H, 3-H), 1.20 and 1.05 [2s, 2 × 3H, 2-C(CH₃)₂],

0.97 (d, 3H, J ) 7.2, 3-CH₃).

1-(ter t-Bu tyloxycar bon yl)-1,2-dih ydr o-2,2-dim eth ylqu in -

olin e (22). To a flame-dried 500-mL rb flask containing 1,2-

dihydro-2,2-dimethylquinoline (5.00 g, 31.4 mmol) in 80 mL

anhydrous Et₂O at -78 °C was slowly added n-butyllithium

(16.3 mL of a 2.5 M solution in hexanes, 40.8 mmol, 1.30

equiv), keeping the temperature below -65 °C. After 10 min,

di-tert-butyl dicarbonate (8.91 g, 40.8 mmol, 1.30 equiv) was

added dropwise as a solution in 20 mL of Et₂O. The mixture

was then allowed to warm to room temperature and stirred

for an additional 2 h before the reaction was quenched with

100 mL of 1.0 M NaHSO₄. The biphasic mixture was then

extracted with EtOAc (2 × 100 mL) and washed with brine

(150 mL). The organic solution was dried (Na₂SO₄) and

concentrated under reduced pressure. The resultant oil was

purified by flash column chromatography (silica gel, hexanes/

EtOAc, 9:1) to give 6.93 g (85%) of the desired BOC-protected

quinoline 22 as a colorless, low-melting solid: ¹H NMR 7.19

(d, 1H, J ) 9.2, 8-H), 7.09 (ddd, 1H, J ) 8.6, 6.9, 1.8, 6-H),

6.97 (dd, 1H, J ) 7.5, 1.8, 5-H), 6.92 (ddd, J ) 8.2, 7.2, 0.9,

7-H), 6.29 (d, 1H, J ) 9.7, 4-H), 5.60 (d, 1H, J ) 9.7, 3-H),

1.54 [s, 6H, NC(CH₃)₂], 1.53 [s, 9H, COC(CH₃)₃].

1-(ter t-Bu tyloxyca r bon yl)-1,2,3,4-tetr a h yd r o-4-oxo-2,2-

d im eth ylqu in olin e (23). To a 100-mL rb flask containing a

solution of protected quinoline 22 (1.3 g, 5.0 mmol) in 10 mL

of THF was added BH₃‚THF (10 mL of a 1.0 M solution in

THF, 10 mmol, 2.0 equiv), and the mixture was stirred at room

temperature for 5 h before the reaction was quenched with

10% KOH (0.5 mL). Hydrogen peroxide (1.0 mL of a 30%

solution in water) was added, and the mixture was stirred for

60 min. Water (10 mL) was added, and the mixture was

extracted with EtOAc (2 × 50 mL), washed with brine (10 mL),

and concentrated under reduced pressure. Purification by

flash column chromatography (silica gel, hexanes/EtOAc, 10:1

to 7:3 gradient elution) afforded a mixture of two regioisomers.

The 3-hydroxy isomer (260 mg, 20%), was removed by washing

with hexane (2 × 10 mL), giving 0.95 g (68%) of the 4-hydroxy

product as a white solid. This material was carried on to the

next step without further purification. In a 100-mL rb flask,

the 4-hydroxy intermediate (0.95 g, 3.4 mmol) was oxidized

with PCC (1.0 g, 4.6 mmol) in CH₂Cl₂(5 mL) at room

temperature for 3 h. Removal of solvent and purification by

flash column chromatography (silica gel, hexanes/EtOAc, 4:1)

afforded ketone 23 as a white solid (0.83 g, 88%): ¹H NMR

7.93 (dd, 1H, J ) 7.9, 1.7, 8-H), 7.43 (ddd, 1H, J ) 8.6, 6.8,

1.8, 6-H), 7.31 (d, 1H, J ) 8.4, 5-H), 7.02 (ddd, J ) 8.8, 7.8,

1.1, 7-H), 2.73 (s, 2H, 3-H), 1.56 [s, 9H, COC(CH₃)3], 1.50 [s,

6H, 2-C(CH₃)₂].

1,2,3,4-Tetr a h yd r o-2,2,3-tr im eth yl-6-tr iflu or om eth yl-8-

p yr id on o[5,6-g]qu in olin e (29a ). Quinoline 27a (60 mg, 0.34

mmol) was subjected to the general three-step nitration-

hydrogenation-Knorr sequence described previously for the

synthesis of 9e, affording 37 mg (35% overall) of the desired

29a as a yellow solid (mp 273-275 °C): IR (KBr) 3437 (m),

2970 (m), 1570 (s), 1529 (s), 1158 (m); ¹H NMR 11.46 (br s,

1H, CONH), 7.35 (s, 1H, 5-H), 6.66 (s, 1H, 7-H), 6.31 (s, 1H,

10-H), 4.40 [br s, 1H, (CH₃)₂CNH], 2.83 (dd, 1H, J ) 16.6, 4.8,

4-H_eq), 2.57 (dd, 1H, J ) 16.6, 10.3, 4-H_ax), 1.83 (m, 1H, 3-H),

1.25 and 1.10 [2s, 2 × 3H, 2-C(CH₃)₂], 0.99 (d, 3H, J ) 6.9,

3-CH₃); ¹³C NMR (acetone-d₆) 161.8, 148.8, 141.4, 125.1, 123.0

(q, J ) 274), 118.2, 114.2, 105.0, 97.1, 53.0, 36.7, 33.0, 23.4,

16.0. Anal. (C₁₆H₁₇F₃N₂O) C, H, N.

3-Eth yl-1,2,3,4-tetr a h yd r o-2,2-d im eth ylqu in olin e (27b).

Ketone 23 (0.10 g, 0.36 mmol) was subjected to the general

alkylation-reduction procedure previously described for 27a

using iodoethane, affording 20 mg (71%) of 27b as a colorless

oil: ¹H NMR 6.98 (d, 1H, J ) 7.5, 5-H), 6.96 (t, 1H, J ) 7.5,

6-H), 6.61 (t, 1H, J ) 7.5, 7-H), 6.44 (d, 1H, J ) 7.5, 8-H), 3.60

(s, 1H, NH), 2.90 (dd, 1H, J ) 16.7, 5.2, 4-H_eq), 2.41 (dd, 1H,

J

) 16.7, 10.7, 4-H_ax), 1.68 (m, 1H, 3-H), 1.52 (m, 2H,

3-CH₂CH₃), 1.23 (m, 3H, CH₂CH₃), 1.22 and 1.05 [2s, 2 × 3H,

2-C(CH₃)₂].

3-E t h yl-1,2,3,4-t e t r a h yd r o-2,2-d im e t h yl-6-t r iflu or o-

m eth yl-8-p yr id on o[5,6-g]qu in olin e (29b). Quinoline 27b

(18.5 mg, 0.10 mmol) was subjected to the general three-step

nitration-hydrogenation-Knorr sequence previously de-

scribed for the synthesis of 9e, affording 2.0 mg (6% overall)

of 29b as a yellow solid (252-254 °C): ¹H NMR (acetone-d₆)

10.65 (s, 1H, CONH), 7.31 (s, 5-H), 6.47 (s, 1H, 7-H), 6.41 (s,

1H, 10-H), 6.06 [s, 1H, (CH₃)₂CNH], 3.01 (dd, 1H, J ) 16.6,

4.8, 4-H_eq), 2.53 (dd, 1H, J ) 16.6, 11.0, 4-H_ax), 1.72 (m, 3-H),

1.53 (m, 1H, 3-CHHCH₃), 1.30 and 1.12 [2s, 2 × 3H, 2-C(CH₃)₂],

1.10 (m, 1H, 3-CHHCH₃), 1.05 (t, 3H, J ) 7.2, 3-CH₂CH₃); ¹³

C

NMR (acetone-d₆) 162.1, 148.9, 141.6, 125.2, 124.2 (q, J ) 270),

118.4, 114.2 (q, J ) 6.0), 105.3, 97.1, 53.3, 44.1, 29.4, 23.9,

23.4, 12.7. Anal. (C₁₇H₁₉F₃N₂O) C, H, N.

4-Eth yl-1,2,3,4-tetr a h yd r o-2,2-d im eth ylqu in olin e (25c).

A 50-mL two-necked rb flask containing cerium(III) chloride

heptahydrate under evacuation (0.5 Torr) was immersed in

an oil bath and heated gradually with stirring to 140 °C over

3-4 h. Nitrogen gas was then introduced, the flask was then

cooled in an ice bath and subsequently charged with THF (5

mL), and finally the flask was allowed to warm to room

temperature overnight. The reaction flask was then cooled

in an ice bath, and ethyl magnesium bromide (3.0 M in Et₂O,

1.46 mL, 4.38 mmol) was slowly added. After 1.5 h of stirring

at 0 °C, ketone 23 (802 mg, 2.92 mmol) in 3 mL of THF was

added dropwise, and stirring was continued for 45 min. The

reaction mixture was then quenched with 10% HOAc (5 mL),

stirring for 10 min. The biphasic mixture was then extracted

with EtOAc (3 × 15 mL) and washed with saturated NaHCO₃

(10 mL) and brine (10 mL). The organic solution was dried

(Na₂SO₄) and concentrated under reduced pressure. The

resultant oil was purified by flash column chromatography

(silica gel, hexanes/EtOAc, 2:1) to give 702 mg of an alcohol

as a colorless oil, which was carried on to the next step. To a

flame-dried 10-mL rb flask containing the alcohol product

dissolved in 1:1 EtOAc/EtOH solution (8 mL) was added 10%

1,2,3,4-Tetr a h yd r o-2,2,3-tr im eth ylqu in olin e (27a ). To

a solution of ketone 23 (0.14 g, 0.50 mmol) and iodomethane

(0.25 mL, 4.0 mmol) in DMF (5 mL) was added NaH (60 % in

mineral oil, 25 mg, 0.60 mmol), and the resulting mixture was

stirred at room temperature for 2 h. The reaction was

quenched with water (5 mL), and the mixture was extracted

with EtOAc (2 × 15 mL) and concentrated under reduced

pressure. The crude reaction mixture was then treated with

TFA (1 mL) in 1 mL CH₂Cl₂at room temperature for 60 min,

and then the reaction was quenched with 10% NaOH (10 mL).

Extraction with EtOAc (2 × 20 mL) and flash column chro-

matography of the crude residue (silica gel, hexanes/EtOAc,

gradient elution) afforded 24a (75 mg, 0.40 mmol, 80%) as a

colorless oil, which was contaminated with 10% of the 3,3-

Androgen Receptor Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 635

Pd on C (ca. 1 mol %) and TFA (20 µL). After flushing and

evacuation of the vessel three times with N₂, the mixture was

stirred at room temperature under an atmosphere of H₂

overnight. The mixture was then filtered through a pad of

Celite, and the eluent was concentrated under reduced pres-

sure to yield a yellow oil which was purified by flash column

chromatography (silica gel, hexanes/EtOAc, 3:1) to give the

BOC-protected tetrahydroquinoline product as a white solid.

The BOC-protected tetrahydroquinoline product was then

treated with TFA (1 mL) in 2 mL of CH₂Cl₂at room temper-

ature for 12 h, and the reaction was quenched with anhydrous

K₂CO₃(1 g) and H₂O (10 mL). The biphasic mixture was then

extracted with CH₂Cl₂(3 × 10 mL) and washed with H₂O (5

mL) and saturated NaHCO₃(5 mL). The organic solution was

dried (Na₂SO₄), and concentrated under reduced pressure

afforded 428 mg (78%) of tetrahydroquinoline 25c as a colorless

oil which required no purification before taken on to the next

step: ¹H NMR 7.17 (d, 1H, J ) 7.6, 5-H), 6.96 (t, 1H, J ) 7.6,

6-H), 6.65 (dt, 1H, J ) 7.6, 1.1, 7-H), 6.45 (dd, 1H, J ) 7.9,

1.0, 8-H), 3.53 (br s, 1H, NH), 2.76 (m, 1H, 4-H), 2.03 (m, 1H,

allowed to stir at room temperature for 30 min. The reaction

was then quenched with saturated NH₄Cl (5 mL), and the

mixture was diluted with EtOAc (5 mL). The layers were

separated, and the aqueous phase was extracted with EtOAc

(3 × 5 mL). The combined organic layers were washed with

brine (5 mL), dried (Na₂SO₄), and concentrated under reduced

pressure to yield a yellow oil. Purification by flash column

chromatography (silica gel, hexanes/EtOAc, 4:1) afforded 289

mg (87%) of the desired ketone as a white solid: ¹H NMR 7.95

(dd, 1H, J ) 7.9, 1.7, 5-H), 7.41 (ddd, 1H, J ) 8.7, 7.3, 1.8,

7-H), 7.18 (d, 1H, J ) 8.5, 8-H), 7.05 (t, 1H, J ) 7.8, 6-H), 1.51

[s, 9H, (CH₃)₃CO], 1.44 [s, 6H, 2-(CH₃)₂], 1.21 (s, 6H, 3-(CH₃)₂).

1,2,3,4-Te t r a h yd r o-2,2,3,3-t e t r a m e t h yl-6-t r iflu or o-

m eth yl-8-p yr id on o[5,6-g]qu in olin e (29e). The tetrameth-

ylated ketone 24e (153 mg, 0.50 mmol) was subjected to the

two-step reduction-deprotection sequence as previously de-

scribed for 27a , affording 66 mg (70% overall) of 27e as a

colorless oil. Quinoline 27e (66 mg, 0.35 mmol) was then

subjected to the general three-step nitration-hydrogenation-

Knorr sequence previously described for the synthesis of 9e,

affording 40 mg (35% overall) of 29e as a yellow solid (mp 308-

310 °C): ¹H NMR (acetone-d₆) 11.20 (br s, 1H, CONH), 7.30

(s, 1H, 5-H), 6.52 (s, 1H, H), 6.46 (s, 1H, 10-H), 6.10 [br s, 1H,

(CH₃)₂CNH], 2.68 (s, 2H, 4-H), 1.22 [s, 6H, 2-(CH₃)₂], 1.00 [s,

6H, 3-(CH₃)₂]; ¹³C NMR (acetone-d₆) 162.0, 148.5, 141.4, 125.6,

124 (q, J ) 274), 118.1, 114.3, 105.0, 97.1, 55.6, 40.1, 34.0,

25.1, 24.2; IR (KBr) 3342 (m), 3310 (m), 1664 (s), 1628 (s), 1435

(m), 1165 (s), 1134 (s). Anal. (C₁₇H₁₉F₃N₂O) C, H, N.

2,2,3,3,4-P en tam eth yl-1,2,3,4-tetr ah ydr oqu in olin e (26f).

To a flame-dried 10-mL rb flask containing methyllithium (1.0

mL of a 1.4 M solution in Et₂O, 1.4 mmol, 1.5 equiv) diluted

with Et₂O (2 mL) at -78 °C, a solution of ketone 24e (289 mg,

0.96 mmol) in Et₂O (2 mL) was added dropwise over 10 min.

The mixture was allowed to stir at -78 °C for 30 min and then

at 0 °C for 1.5 h. To the reaction mixture was then added

saturated NH₄Cl (1 mL) and Et₂O (5 mL). The layers were

separated, and aqueous layer was extracted with Et₂O (3 × 3

mL). The combined organic layers were washed with brine

(5 mL), dried (Na₂SO₄), and concentrated under reduced

pressure to yield a pale yellow oil. Purification by flash column

chromatography (silica gel, hexanes/EtOAc, 4:1) afforded 215

mg (71%) of 1-(tert-butyloxycarbamoyl)-1,2,3,4-tetrahydro-4-

hydroxy-2,2,3,3,4-pentamethylquinoline as a white solid: ¹H

NMR 7.47 (dd, 1H, J ) 7.7, 1.4, 5-H), 7.11 (m, 3H, 6,7,8-H),

1.63 (s, 3H, 4-CH₃), 1.55 [s, 9H, COC(CH₃)₃], 1.44, 1.37, 0.97,

and 0.95 [4s, 4 × 3H, 2,3-(CH₃)₃]. The tertiary alcohol thus

obtained was then subjected to the catalytic hydrogenation

procedure as previously described for the preparation of 25b,

affording 112 mg (82%) of pentamethyl compound 26f as a pale

yellow oil: ¹H NMR 7.17 (d, 1H, 5-H), 6.98 (t, 1H, J ) 7.5,

7-H), 6.67 (t, 1H, J ) 7.1, 6-H), 6.46, dd, 1H, J ) 7.9, 0.9, 8-H),

3.54 (br s, 1H, CONH), 2.79 (q, 1H, J ) 6.9, 4-H), 1.29 (d, 3H,

J ) 7.1, 4-CH₃), 1.21, 1.13, 0.99, and 0.76 [4s, 4 × 3H, 2,3-

(CH₃)₂].

1,2,3,4-Tet r a h yd r o-2,2,3,3,4-p en t a m et h yl-6-t r iflu or o-

m eth yl-8-p yr id on o[5,6-g]qu in olin e (29f). Quinoline 26f

(112 mg, 0.560 mmol) was subjected to the general three-step

nitration-hydrogenation-Knorr sequence described previ-

ously for the synthesis of 9e, affording 28 mg (14% overall) of

29f as a yellow solid (mp 300-301 °C dec): ¹H NMR 11.92 (br

s, 1H, CONH), 7.52 (s, 1H, 5-H), 6.66 (s, 1H, 7-H), 6.33 (s, 1H,

10-H), 4.43 [br s, 1H, (CH₃)₂CNH], 2.88 (q, 1H, J ) 6.4, 4-H),

1.24 (d, 3H, J ) 6.8, 4-CH₃), 1.24, 1.18, 1.03, and 0.71 [4s, 4 ×

3H, 2,3-(CH₃)₂]; ¹³C NMR 163.8, 147.1, 139.1 (q, J ) 31.0),

123.5, 122.9 (q, J ) 275.4), 112.6 (d, J ) 5.2), 106.0, 96.2, 77.2,

55.8, 36.7, 36.0, 26.1, 25.1, 22.5, 16.5, 13.1. Anal. (C₁₈H₂₁F₃N₂O)

C, H, N.

4-CHHCH₃), 1.78 and 1.43 [d of AB q, 2H, J _AB) 12.9, J _A

)

6.0, (3-H_eq), J _B) 12.3, (3-H_ax)], 1.59 (m, 1H, 4-CHHCH₃), 1.25

and 1.16 [2s, 2 × 3H, 2-(CH₃)₂], 0.95 (t, 3H, J ) 7.5, 4-CH₂CH₃).

4-E t h yl-1,2,3,4-t e t r a h yd r o-2,2-d im e t h yl-6-t r iflu or o-

m eth yl-8-p yr id on o[5,6-g]qu in olin e (29c). Quinoline 25c

(428 mg, 2.78 mmol) was subjected to the general three-step

nitration-hydrogenation-Knorr sequence previously de-

scribed for the synthesis of 9e, affording 249 mg (34% overall)

of 29c as a yellow solid (mp 276-278 °C): ¹H NMR (CD₃OD)

7.49 (d, 1H, J ) 1.4, 5-H), 6.48 (s, 1H, 7-H), 6.39 (s, 1H, 10-

H), 2.84 (m, 1H, 4-H), 2.06 (m, 1H, 4-CHHCH₃), 1.86 and 1.39

[d of AB q, 2H, J _AB) 12.9, J _A) 5.3, (3-H_eq), J _B) 12.7, (3-

H_ax)], 1.65 (m, 1H, 4-CHHCH₃), 1.30 and 1.21 [2s, 2 × 3H,

2-(CH₃)₂], 0.99 (t, 3H, J ) 7.5, 4-CH₂CH₃); ¹³C NMR 164.2,

150.6, 141.3, 140.2, 124.8, 123.6, 123.5, 112.8, 106.4, 97.8, 50.4,

40.8, 34.6, 31.3, 28.5, 27.3, 10.6. Anal. (C₁₇H₁₉F₃N₂O) C, H,

N.

4-Isop r op yl-1,2,3,4-tetr a h yd r o-2,2-d im eth ylqu in olin e

(25d ). Ketone 23 (800 mg, 2.92 mmol) was subjected to the

organocerium addition with in situ generation of the Grignard

reagent using 2-bromopropene (400 µL, 4.67 mmol) and

magnesium (1.13 g, 46.7 mmol), reduction-hydrogenation, and

deprotection previously described for the synthesis of 25c,

affording 284 mg (34% overall) of 29c as a colorless oil: ¹H

NMR 7.16 (d, 1H, J ) 7.7, 5-H), 6.95 (t, 1H, J ) 7.5, 6-H),

6.66 (t, 1H, J ) 7.1, 7-H), 6.45 (d, 1H, J ) 7.9, 8-H), 3.51 (br

s, 1H, NH), 2.84 (m, 1H, 4-H), 2.53 (m, 1H, isopropyl-CH), 1.60

and 1.47 [d of AB q, 2H, J _AB) 12.8, J _A) 6.1, (3-H_eq), J _B

)

12.6, (3-H_ax)], 1.26 and 1.14 [2s, 2 × 3H, 2-(CH₃)₂], 1.06 and

0.71 [2d, 2 × 3H, J ) 6.9, 6.9, isopropyl-C(CH₃)₂].

1,2,3,4-Tetr a h yd r o-4-isop r op yl-2,2-d im eth yl-6-tr iflu o-

r om eth yl-8-pyr idon o[5,6-g]qu in olin e (29d). Quinoline 25d

(284 mg, 1.41 mmol) was subjected to the general three-step

nitration-hydrogenation-Knorr sequence previously de-

scribed for the synthesis of 9e, affording 13 mg (3% overall) of

29d as a yellow solid (mp 278-279 °C dec): ¹H NMR (acetone-

d₆) 10.90 (br s, 1H, CONH), 7.49 (s, 1H, 5-H), 6.49 9s, 1H, 7-H),

6.45 (s, 1H, 10-H), 6.03 [br s, 1H, (CH₃)₂CNH], 2.92 (m, 1H,

4-H), 2.60 (m, 1H, isopropyl-CH), 1.76 and 1.45 [d of AB q,

2H, J _AB) 12.9, J _A) 5.3, (3-H_eq), J _B) 12.8, (3-H_ax)], 1.33 and

1.22 [2s, 2 × 3H, 2-(CH₃)₂], 1.12 and 0.77 [2d, 2 × 3H, J ) 7.0,

7.0, isopropyl-C(CH₃)₂]; ¹³C NMR (acetone-d₆) 162.0, 150.1,

141.2, 138.5, 124.2, 123.3, 121.2, 114.6, 114.5, 105.3, 97.9, 50.1,

38.3, 34.4, 31.4, 28.0, 21.0, 15.7. Anal. (C₁₈H₂₁F₃N₂O) C, H,

N.

1-(ter t-Bu tyloxyca r ba m oyl)-1,2,3,4-tetr a h yd r o-2,2,3,3-

tetr a m eth ylqu in olin -4-on e (24e). In a flame-dried 10-mL

rb flask, KH (131 mg, 3.27 mmol) was washed with pentane

(3 × 2 mL) and then suspended in THF (5 mL) at 0 °C. To

this suspension was added dropwise a solution of ketoquinoline

23 (300 mg, 1.09 mmol) in 2 mL of THF over 10 min. The

mixture was allowed to stir for 30 min at 0 °C and then for 30

min at room temperature. Iodomethane (2.04 mL, 32.7 mmol,

10.0 equiv) was added in one portion, and the mixture was

3-Acetoxy-6-ch lor o-3-m eth ylh ex-1-yn e (30). In a 1-L,

3-neck rb flask with an addition funnel, a solution of 5-chloro-

2-pentanone (33.1 g, 274 mmol) in THF (140 mL) was treated

with ethynylmagnesium bromide (564 mL of a 0.5 M solution

in THF, 282 mmol, 1.03 equiv) over 0.5 h at -78 °C. The

internal temperature rose to -30 °C during the addition. The

mixture was allowed to warm to 0 °C, stirred for 1 h, and then

636 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4

Hamann et al.

poured into a cold mixture of Et₂O (400 mL) and 1 N NaHSO₄

(400 mL). The aqueous layer was extracted with Et₂O (2 ×

200 mL), and the combined organic layers were washed with

brine, dried (MgSO₄), filtered, and concentrated under reduced

pressure to 42 g of a brown oil. This material was transferred

to a 250-mL rb flask, whereupon pyridine (27 mL) and acetic

anhydride (36.4 g, 356 mmol, 1.30 equiv) were added, and then

the flask was cooled to 0 °C. DMAP (1.67 g, 13.7 mmol, 5%)

was added, and the solution was stirred for 2 d and then

treated with MeOH (10 mL). After 1 h, the solution was

poured into a cold mixture of Et₂O (250 mL) and 2 N NaHSO₄

(250 mL). The aqueous layer was extracted with Et₂O (250

mL), and the combined organic layers were washed with brine

(250 mL), dried (MgSO₄), filtered, and concentrated under

reduced pressure to a brown oil. Distillation afforded 30.5 g

(59%) of 30 as a colorless oil (bp 79-80 °C at 10 mm Hg): ¹H

NMR 3.52-3.65 (m, 2H, 6-H), 2.57 (s, 1H, CtCH), 1.85-2.15

(m, 4H, 4,5-H), 2.04 (s, 3H, COCH₃), 1.71 (s, 3H, 3-CH₃).

2.96 g (82%) of the protected dihydroquinoline 37 as pale

yellow needles after recrystallization from methanol: ¹H NMR

7.57 (s, 1H, 5-H), 6.85 (s, 1H, 7-H), 5.91 (s, 1H, 10-H), 4.51 (q,

2H, J ) 7.1, OCH₂CH₃), 2.94 (t, 2H, J ) 6.8, 4-H), 1.77 (t, 2H,

J ) 6.8, 3-H), 1.65 [s, 9H, C(CH₃)₃], 1.41 (t, 3H, J ) 7.0,

OCH₂CH₃), 1.29 [s, 6H, NC(CH₃)₂].

1-(ter t-Bu tyloxyca r bon yl)-8-eth oxy-1,2,3,4-tetr a h yd r o-

2,2-dim eth yl-4-oxo-6-(tr iflu or om eth yl)pyr idin o[5,6-g]qu in -

olin e (38). To an oven-dried 200-mL rb flask containing 37

(3.02 g, 7.11 mmol) in 70 mL of benzene were added Celite

(10 g) and PCC (15.3 g, 71.1 mmol, 10.0 equiv), and the mixture

was heated to reflux for 4 h. Upon being cooled to room

temperature, the mixture was filtered through a short column

of Florisil, washing with CH₂Cl₂. The mixture was concen-

trated under reduced pressure, and the residue was purified

by flash column chromatography (silica gel, hexane/EtOAc,

gradient elution), affording 0.94 g (30%) of ketone 38 as an

off-white solid: ¹H NMR 8.61 (d, 1H, J ) 1.8, 5-H), 7.74 (s,

1H, 7-H), 7.08 (s, 1H, 10-H), 4.55 (q, 2H, J ) 7.0, OCH₂CH₃),

2.82 (s, 2H, 3-H), 1.62 [s, 9H, C(CH₃)₃], 1.55 and 1.54 [2s, 2 ×

3H, NC(CH₃)₂], 1.45 (t, 3H, J ) 7.0, OCH₂CH₃).

1,2,3,4-Tetr ah ydr o-2,2-dim eth yl-4-oxo-6-tr iflu or om eth yl-

8-p yr id on o[5,6-g]qu in olin e (39). To a 10-mL rb flask

containing protected ketone 38 (16.0 mg, 0.04 mmol) was

added 0.3 mL of TFA, and the mixture was warmed to 60 °C

for 5 min. Upon being cooled to room temperature, the

mixture was added to 10 mL of saturated NaHCO₃and

extracted with 20 mL of EtOAc. The organic layer was

concentrated under reduced pressure, and the residue was

heated to 80 °C with 1 mL of 57% HI in a 25-mL rb flask for

90 min. Upon being cooled to room temperature, the mixture

was added to 10 mL of saturated NaHCO₃and extracted with

20 mL of EtOAc. The organic layer was dried (Na₂SO₄) and

concentrated under reduced pressure. Purification by flash

column chromatography (silica gel, hexane/EtOAc, gradient

elution) afforded 10.4 mg (92%) of ketone 39 as a pale yellow

solid: ¹H NMR 11.38 (br s, 1H, CONH), 8.33 (s, 1H, 5-H), 6.75

(s, 1H, 7-H), 6.52 (s, 1H, 10-H), 4.70 [br s, 1H, (CH₃)₂CNH],

2.66 (s, 2H, 3-H), 1.36 [s, 6H, 2-(CH₃)₂].

1,2-Dih ydr o-2,2-dim eth yl-6-tr iflu or om eth yl-8-pyr idon o-

[5,6-g]qu in olin e (36). To a 5-mL rb flask containing ketone

39 (8.5 mg, 0.03 mmol) in 0.5 mL of MeOH at room temper-

ature was added NaBH₄(mg, mmol, equiv), and the mixture

was stirred for 1 h before the reaction was quenched with the

addition of 1 mL of water. The MeOH was removed under

reduced pressure, and the residue was extracted with EtOAc

(10 mL), washed with brine, dried (Na₂SO₄), and concentrated

under reduced pressure. The 4-hydroxy compound thus

obtained was homogeneous by TLC and was used without

further purification. A portion of the 4-hydroxy compound (5

mg) was treated with 2 mg of p-TsOH in 1 mL of benzene at

70 °C for 6 h. Upon being cooled to room temperature, the

mixture was added to 5 mL of saturated NaHCO₃and

extracted with 10 mL of EtOAc. The organic layer was dried

(Na₂SO₄) and concentrated under reduced pressure. Purifica-

tion by preparative TLC (silica gel, 250 µm plate, 2% EtOH in

EtOAc) afforded 3.9 mg (82%) of olefin 36 as a yellow solid:

¹H NMR 11.42 (br s, 1H, CONH), 7.23 (d, 1H, J ) 0.5, 5-H),

6.66 (s, 1H, 7-H), 6.32 (d, 1H, J ) 10.0, 4-H), 6.30 (s, 1H, 10-

H), 5.57 (dd, 1H, J ) 9.8, 1.9, 3-H), 4.33 [br s, 1H, (CH₃)₂-

CNH], 1.36 [s, 6H, 2-(CH₃)₂]. Anal. (C₁₅H₁₃F₃N₂O) C, H, N.

1-(ter t-Bu tyloxyca r bon yl)-8-eth oxy-1,2-d ih yd r o-2,2,4-

tr im eth yl-6-(tr iflu or om eth yl)pyr idin o[5,6-g]qu in olin e (40).

This compound was prepared from 10a (13.0 g, 38.7 mmol) in

the manner previously described for 22, affording 12.9 g (76%)

of 40 as a colorless, low-melting solid: ¹H NMR 7.56 (d, 1H, J

) 1.8, 5-H), 6.84 (s, 1H, 7-H), 6.74 (s, 1H, 10-H), 5.52 (s, 1H,

3-H), 4.47 (q, 2H, J ) 7.0, CH₃CH₂O), 4.12 [br s, 1H, (CH₃)₂-

CNH], 2.09 (d, 3H, J ) 1.3, 4-CH₃), 1.59 [s, 9H, C(CH₃)₃], 1.42

(t, 3H, J ) 7.0, CH₃CH₂O), 1.34 [s, 6H, 2-(CH₃)₂].

2-Eth yn yl-2-m eth yl-1-ph en ylpyr r olidin e (31). This com-

pound was prepared from 30 (10.2 g, 54.3 mmol) in a manner

similar to that described for 16, affording 6.35 g (63%) of 31

as a light golden oil (R_f0.32, hexanes/EtOAc, 19:1): ¹H NMR

7.20-7.28 (m, 2H, 3′-H), 6.95 (d, 2H, J ) 8.1, 2′-H), 6.72 (t,

1H, J ) 7.2, 4′-H), 3.43-3.52 (m, 1H, NCHH), 3.35-3.43 (m,

1H, NCHH), 2.40-2.50 (m, ¹H), 2.40 (s, 1H, CtCH), 2.05-

1

2.17 (m, 2H), 1.92-2.02 (m, H), 1.62 (s, 3H, CH₃).

5,6,6a ,10-Tetr a h yd r o-6a -m eth ylp yr r olid in o[1,2-a ]qu in -

olin e (32). This compound was prepared from 31 (1.85 g, 10.0

mmol) by cyclization in the manner previously described for

dihydroquinolines 17, followed by catalytic hydrogenation as

previously described for the synthesis of 18, affording 1.36 g

(99%) of 32, as a colorless oil, which was used without further

purification: ¹H NMR 7.07 (t, J ) 7.7, 1 H, 2-H), 7.03 (d, J )

7.4, 1H, 4-H), 6.55 (td, J ) 7.3, 0.9, 1H, 3-H), 6.41 (d, J ) 8.0,

1H, 1-H), 3.46 (td, J ) 9.1, 2.1, 1H, NCH), 3.19 (q, J ) 9.1,

1H, NCH), 2.86-2.96 (m, 1H, 4-H), 2.72 (ddd, J ) 16.5, 5.1,

1

1.9, 4-H), 2.05-2.20 (m, H), 1.88-2.08 (m, 3H), 1.60 (td, J )

12.0, 7.8, ¹H), 1.42 (td, J ) 13.2, 5.1, ¹H), 1.04 (s, 3H, CH₃).

6,7,7a ,11-Tet r a h yd r o-7a -m et h yl-4-t r iflu or om et h yl-2-

pyr idon o[5,6-g]pyr r olidin o[1,2-a ]qu in olin e (33). This com-

pound was prepared from 32 (1.21 g, 6.47 mmol) in three steps

by the general nitration-hydrogenation-Knorr procedure

previously described for the synthesis of 9e, affording 130 mg

(16% overall) of 33 (R_f0.15 EtOAc/CH₂Cl₂/hexanes, 1:1:1) as

a yellow solid, a portion of which was recrystallized from

methanol (mp 289-310 °C dec): ¹H NMR (acetone-d₆) 10.54

(s, 1H, CONH), 7.34 (s, 1H, 5-H), 6.42 (s, 1H, 3-H), 6.36 (s,

1H, 12-H), 3.52 (t, 1H, J ) 9.7, NCHH), 3.28 (q, 1H, J ) 9.6,

NCHH), 2.92-3.05 (m, 1H, 4-H), 2.80-2.90 (m, 1H, 4-H),

1

2.18-2.30 (m, H), 2.00-2.20 (m, 3H), 1.68 (td, 1H, J ) 12.1,

7.9), 1.46 (td, 1H, J ) 13.3, 5.1), 1.14 (s, 3H, CCH₃); ¹³C NMR

(DMSO-d₆) 160.6, 146.2, 140.9, 136.4 (q, J ) 30.0), 123.0 (q, J

) 276), 122.9, 118.0, 113.0 (q, J ) 6.0), 102.6, 94.0, 59.3, 46.5,

32.2, 24.0, 23.4, 21.4; HRMS calcd for C₁₇H₁₇F₃N₂O (M⁺): m/z

322.1293, found 322.1277. Anal. (C₁₇H₁₇F₃N₂O) C, H, N.

6,7,7a ,11-Tetr a h yd r o-1,7a -d im eth yl-4-tr iflu or om eth yl-

2-p yr id on o[5,6-g]p yr r olid in o[1,2-a ]qu in olin e (34). This

compound was prepared from 33 (73 mg, 0.23 mmol) in a

manner similar to that described for 19a , affording 31 mg

(41%) of 34 as a yellow solid (R_f0.52, CH₂Cl₂/EtOAc/hexanes,

2:1:1), a portion of which was recrystallized from methanol

(mp 170-171 °C): ¹H NMR 7.44 (s, 1H, 5-H), 6.71 (s, 1H, 3-H),

6.12 (s, 1H, 12-H), 3.67 (s, 3H, NCH₃), 3.56 (t, 1H, J ) 9.0,

NCHH), 3.30 (q, 1H, J ) 9.2, NCHH), 2.95-3.05 (m, 1H, 4-H),

2.80-2.90 (m, 1H, 4-H), 2.20-2.32 (m, ¹H), 2.08-2.20 (m, 2H),

2.03 (dd, 1H, J ) 11.9, 6.8), 1.68 (td, 1H, J ) 12.2, 7.9), 1.48

(td, 1H, J ) 13.3, 5.1), 1.13 (s, 3H, CCH₃); ¹³C NMR 161.6,

146.6, 141.7, 136.5 (q, J ) 31.0), 125.0 (br), 123.0 (q, J ) 276),

113 (q, J ) 5.8), 104.6, 93.8, 59.8, 46.9, 40.2, 32.9, 29.7, 24.4,

23.6, 22.0, 21.9. Anal. (C₁₈H₁₉F₃N₂O) C, H, N.

1-(ter t-Bu tyloxyca r bon yl)-8-eth oxy-1,2,3,4-tetr a h yd r o-

2,2-d im et h yl-6-(t r iflu or om et h yl)p yr id in o[5,6-g]q u in o-

lin e (37). This compound was prepared from 10e (2.76 g, 8.51

mmol) in the manner previously described for 23, affording

1-(ter t-Bu tyloxyca r bon yl-8-eth oxy-1,2,3,4-tetr a h yd r o-

2,2,4-tr im eth yl-3-oxo-6-(tr iflu or om eth yl)p yr id in o[5,6-g]-

qu in olin e (41). This compound was prepared from hydro-

boration-oxidation of 40 (9.69 g, 22.2 mmol) in the manner

Androgen Receptor Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4 637

previously described for 23, followed by oxidation of the

3-hydroxy compound (5.47 g, 12.0 mmol) with PDC (5.43 g,

14.4 mmol, 1.20 equiv) in 40 mL of CH₂Cl₂at room tempera-

ture for 8 h. Filtration through a short plug of Florisil,

followed by purification by flash column chromatography (silica

gel, hexane/EtOAc, gradient elution), afforded 3.31 g (61%) of

41 as a pale yellow solid: ¹H NMR 7.81 (s, 1H, 5-H), 7.69 (br

d, 1H, J ) 1.5, 7-H), 7.16 (s, 1H, 10-H), 4.53 (m, 2H, CH₃CH₂O),

4.03 (q, 1H, J ) 5.0, 4-H), 1.80 and 1.46 [2s, 2 × 3H, 2-(CH₃)₂],

1.59 (d, 3H, J ) 6.6, 4-CH₃), 1.57 [s, 9H, C(CH₃)₃], 1.45 (t, 3H,

J ) 7.2, CH₃CH₂O).

1,2-Dih yd r o-2,2,3,4-t et r a m et h yl-6-t r iflu or om et h yl-8-

p yr id on o[5,6-g]qu in olin e (42): This compound was pre-

pared from ketone 41 (331 mg, 0.73 mmol) by a three-step

addition-elimination-deprotection sequence similar to that

previously described for preparation of 25 and 36, affording

122 mg (52% overall, three steps) of 41 as a yellow solid. ¹H

NMR 11.66 (br s, 1H, CONH), 7.42 (s, 1H, 5-H), 6.69 (s, 1H,

7-H), 6.35 (s, 1H, 10-H), 4.30 [br s, 1H, (CH₃)₂CNH], 2.02 (s,

3H, 4-CH₃), 1.86 (s, 3H, 3-CH₃), 1.33 [s, 6H, 2-(CH₃)₂]; ¹³C NMR

(acetone-d₆) 161.9, 148.4, 142.9, 138.8 (q), 130.7, 127.2, 125.4

(q), 119.8, 119.0, 114.4, 104.7, 96.6, 53.2, 50.6, 32.3, 18.4. Anal.

(C₁₇H₁₇F₃N₂O) C, H, N.

Gal), was included as an internal control for evaluation of

transfection efficiency and compound toxicity. After transfec-

tion, media were removed and the cells were washed with

phosphate-buffered saline (PBS). Media containing reference

compounds (i.e., DHT and 2-hydroxyflutamide) or test com-

pounds in concentrations ranging from 10^-12to 10^-5M were

added to the cells. Three to four replicates were used for each

sample. After incubation, the cells were washed with PBS,

lysed with a Triton X-100 buffer and assayed for LUC and

â-Gal activities using a luminometer or spectrophotometer,

respectively. Data evaluation was performed using the Oracle

relational database management system with analysis reports

and programs designed at Ligand. For each replicate, the

normalized response (NR) was calculated as: LUC response/

â-Gal rate where â-Gal rate ) â-Gal × 1 × 10^-5/â-Gal

incubation time. The mean and standard error of the mean

(SEM) of the NR were calculated. Data were plotted as the

response of the compound compared to the reference com-

pounds over the range of the concentration-response curve.

For agonist experiments, the effective concentration that

produced 50% of the maximum response (EC₅₀) was quantified.

Agonist efficacy (%) was a function of LUC expression relative

to the maximum LUC production by the reference agonist,

DHT. Antagonist activity was determined by testing the

amount of LUC expression in the presence of DHT at its EC₅₀

concentration. The concentration of test compound that

inhibited 50% of LUC expression induced by progesterone was

quantified (IC₅₀). In addition, efficacy of antagonists was

determined as a function (%) of maximal inhibition (control

without DHT). Cotransfection studies with hPR-B with the

MMTV-LUC reporter were carried out as described above to

determine cross-reactivity of test compounds.

Recep tor Bin d in g Assa y. Receptor binding assays for

hAR were determined in a whole-cell format using COS-1 cells

in 96-well microtiter plates containing DMEM-10% FBS. Cells

were transfected as described above with pRShAR (2 ng/well),

pRS-â-Gal (50 ng/well), and pGEM (48 ng/well). Six hours

after transfection, medium was removed, the cells were washed

with PBS, and fresh medium was added. The next day, the

media were changed to DMEM-serum free to remove any

endogenous ligand complexed with hAR in the cells. After 24

h in serum-free media, either a saturation analysis to deter-

mine the K_dfor [³H]DHT on hAR or a competitive binding

assay to evaluate the ability of test compounds to compete with

[³H]DHT for hAR was performed. For the saturation analysis,

media (DMEM-0.2% CA-FBS) containing [³H]DHT (12-0.24

nM) in the absence (total binding) or presence (nonspecific

binding) of a 100-fold molar excess of unlabeled DHT were

added to the cells. For the competitive binding assay, media

containing 1 nM [³H]DHT and test compounds in concentra-

tions ranging from 10^-10to 10^-6M were added to the cells.

Three replicates were used for each sample. After 3 h at 37

°C, an aliquot of the total binding media at each concentration

of [³H]DHT was removed to estimate the amount of free [³H]-

DHT. The remaining media was removed, the cells were

washed three times with PBS to remove unbound ligand, and

cells were lysed with a Triton X-100-based buffer. The lysates

were assayed for bound [³H]DHT and â-Gal activity using a

scintillation counter or spectrophotometer, respectively. For

the saturation analyses, the difference between the total

binding and the nonspecific binding, normalized by the â-Gal

rate, was defined as specific binding, which was evaluated by

Scatchard analysis to determine the K_dfor [³H]DHT. For the

competition studies, the data was plotted as the amount of

[³H]DHT (% of control in the absence of test compound)

remaining over the range of the dose-response curve for a given

compound. The concentration of test compound that inhibited

50% of the amount of [³H]DHT bound in the absence of

competing ligand was quantified (IC₅₀) after log-logit trans-

formation. The K_ivalues were determined by application of

the Cheng-Prussof equation to the IC₅₀values, where

cis- a n d tr a n s-1,2,3,4-Tetr a h yd r o-2,2,3,4-tetr a m eth yl-

6-tr iflu or om eth yl-8-pyr idon o[5,6-g]qu in olin e (43 an d 44).

To an oven-dried 10-mL rb flask containing olefin 42 (11.2 mg,

0.035 mmol) in 1 mL of 1,2-dichloroethane was added 0.5 mL

of TFA and 0.5 mL of triethylsilane, and the mixture was

heated to reflux for 8 h. Upon being cooled to room temper-

ature, the mixture was added to 5 mL of saturated NaHCO₃

and extracted with 10 mL of EtOAc. The organic layer was

dried (Na₂SO₄) and concentrated under reduced pressure.

Purification by semipreparative HPLC (10 mm ODS, MeOH/

H₂O, 8:2, 3.0 mL/min) afforded 4.9 mg (43%) of the cis isomer

43 with a retention time of 5.34 min, followed by 4.3 mg (38%)

of the trans isomer 44 with a retention time of 6.01 min. The

relative stereochemical identity of the respective isomers was

confirmed by resynthesis of the cis isomer 43 through an

alternate route analogous to that used for 29a -f, where the

relative stereochemistry at C₃and C₄was set through catalytic

hydrogenation. Da ta for cis-1,2,3,4-tetr a h yd r o-2,2,3,4-tet-

r a m eth yl-6-tr iflu or om eth yl-8-p yr id on o[5,6-g]qu in olin e

(43): ¹H NMR 11.06 (br s, 1H, CONH), 7.55 (s, 1H, 5-H), 6.67

(s, 1H, 7-H), 6.28 (s, 1H, 10-H), 4.35 [br s, 1H, (CH₃)₂CNH],

2.54 (m, 1H, 4-H), 1.47 (s, 1H, 3-H), 1.38 (d, 3H, J ) 6.6,

4-CH₃), 1.06 [s, 6H, 2-(CH₃)₂], 1.05 (d, 3H, J ) 6.9, 3-CH₃);

¹³C NMR 163.2, 146.6, 140.3, 139.1 (q), 124.0, 122.7, 119.8,

112.8, 105.8, 95.9, 49.7, 43.3, 29.9, 28.1, 27.6, 21.1, 18.4. Anal.

(C₁₇H₁₉F₃N₂O) C, H, N. Da ta for tr a n s-1,2,3,4-tetr a h yd r o-

2,2,3,4-tetr a m eth yl-6-tr iflu or om eth yl-8-p yr id on o[5,6-g]-

qu in olin e (44): ¹H NMR 11.22 (br s, 1H, CONH), 7.48 (s,

1H, 5-H), 6.68 (s, 1H, 7-H), 6.31 (s, 1H, 10-H), 4.32 [br s, 1H,

(CH₃)₂CNH], 2.44 (m, 1H, 4-H), 1.57 (m, 1H, 3-H), 1.49 (d, 3H,

J ) 6.7, 4-CH₃), 1.11 (d, 3H, J ) 6.8, 3-CH₃), 1.02 [s, 6H,

2-(CH₃)₂]; ¹³C NMR 163.0, 146.6, 140.2, 138.8 (q), 124.5, 122.4,

120.0, 112.7, 105.6, 95.7, 49.7, 43.2, 31.5, 28.4, 27.6, 22.0, 18.6.

Anal. (C₁₇H₁₉F₃N₂O) C, H, N.

Cotr a n sfection Assa ys. Cotransfection assays using hAR

and hPR-B were performed in CV-1 cells as described in the

literature.²¹CV-1 cells (African green monkey kidney fibro-

blasts) were cultured in the presence of Dulbecco’s Modified

Eagle Medium (DMEM) supplemented with 10% charcoal

resin-stripped fetal bovine serum then transferred to 96-well

microtiter plates one day prior to transfection. Cells were

transiently transfected by the calcium phosphate coprecipita-

tion procedure with the following plasmids: pRShAR, MMTV-

LUC reporter, pRS-â-Gal, and filler DNA (pRS-CAT). The

receptor plasmid, pRShAR, contained the hAR under constitu-

tive control of the Rous Sarcoma Virus promoter. The reporter

plasmid, MMTV-LUC, contained the cDNA for firefly luciferase

(LUC) under control of the mouse mammary tumor virus

(MMTV) long terminal repeat, a conditional promoter contain-

ing an androgen response element. pRS-â-Gal, coding for

constitutive expression of Escherichia coli â-galactosidase (â-

IC₅₀

K_i)

(1 + {[³H]DHT})/K_dfor [³H]DHT

638 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 4

Hamann et al.

of the Prostate and Bladder; Alan R. Liss, Inc.: New York, 1988;

pp 63-75. (b) Neumann, F. The Antiandrogen Cyproterone

Acetate: Discovery, Chemistry, Basic Pharmacology, Clinical

Use and Tool in Basic Research. Exp. Clin. Endocrinol. 1994,

102, 1-32.

In Vivo Meth od s; Ca str a ted Ra t Mod el. Male immature

rats (60-70 g, 23-25-day-old, Sprague-Dawley, Harlan, five

animals/group) were castrated under metofane anesthesia.

Five days after castration, animals were divided into groups

and dosed for 3 days with one of the following: (1) control

vehicle (10% dimethylacetamide (DMA) in 0.2% Tween-80 and

0.25% carboxymethylcellulose) (3 mL/kg/day, orally); (2) TP

(1 mg/kg/day, subcutaneous injection in 0.2 mL of sesame oil);

(3) TP plus an AR antagonist 1, 2a , 3, 9a ,d ,e, or 19a (30 mg/

kg/day). At the end of treatment, animals were sacrificed, and

VPs were collected and weighed. To compare data from

different experiments, organ weights were first standardized

as mg/100 g of body weight; the increase in organ weight

induced by TP (1 mg/kg/day) was taken as the maximum

response (100%). One-factor ANOVA followed by the Fisher

protected least significant differences test was used for sta-

tistical analysis.

Ma tu r e In ta ct Ra t Mod el. Male mature rats (200-250

g, Sprague-Dawley, Harlan; four or five animals/group)

received one of the following treatments for 2 weeks. (1) Intact

control: oral dosing with vehicle (10% DMA in 0.2% Tween-

80 and 0.25% carboxymethylcellulose). (2) Castrated control:

oral dosing with vehicle only (surgery done at the time of the

first treatment). (3) 2a , 3, 9a , or 9e to intact rats: oral dosing

(20 or 40 mg/kg/day). At the end of treatment, animals were

sacrificed and the following occurred: (1) blood was collected

by cardiac puncture; serum was separated and stored at -20

°C. T was measured by RIA using SPA technique (Amer-

sham); LH was measured by RIA with kits supplied by

Amersham using NIH standards (NIADDK-rat-LH-RP2). (2)

Organ wet weights were determined for VP and SV and

calculated as before.

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J M970699S

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Synthesis and biological activity of a novel series of nonsteroidal, peripherally selective androgen receptor antagonists derived from 1,2- dihydropyridono[5,6-g]quinolines

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