New nonsteroidal steroid 5α-reductase inhibitors. Syntheses and structure-activity studies on carboxamide phenylalkyl-substituted pyridones and piperidones

Article abstract of DOI:10.1002/(SICI)1521-4184(20005)333:5<145::AID-ARDP145>3.0.CO;2-Q

In the search for nonsteroidal inhibitors of 5α-reductase for the treatment of benign prostatic hyperplasia (BPH), we synthesized diisopropyl (1a-8a) and tert-butyl (1b-8b) benzamides, as well as ethyl benzoates (1c, 3c), which were substituted in 4 posit

Full text of DOI:10.1002/(SICI)1521-4184(20005)333:5<145::AID-ARDP145>3.0.CO;2-Q

Nonsteroidal Steroid 5α-Reductase Inhibitors
145
New Nonsteroidal Steroid 5α-Reductase Inhibitors. Syntheses and
Structure-Activity Studies on Carboxamide Phenylalkyl-Substituted
Pyridones and Piperidones ✩
Rolf W. Hartmann* and Martin Reichert
Pharmazeutische und Medizinische Chemie, Universität des Saarlandes, P.O. Box 15 11 50, D-66041 Saarbrücken, Germany
Key Words: Rat and human steroid 5α-reductase; nonsteroidal inhibitors; 3- and 5-substituted 1-methyl-2-pyridones;
3- and 5-substituted 1-methyl-2-piperidones
membrane bound and no X-ray structure is available to date.
Summary
Nevertheless, efforts have been undertaken to develop ster-
[6–10]
oidal inhibitors of 5α-R
. One compound, finasteride
[11,12]
In the search for nonsteroidal inhibitors of 5α-reductase for the
treatment of benign prostatic hyperplasia (BPH), we synthesized
diisopropyl (1a–8a) and tert-butyl (1b–8b) benzamides, as well as
ethyl benzoates (1c, 3c), which were substituted in 4 position via
variable alkyl spacer (n = 0: 1–4, n = 1: 5, 7 and n = 3: 6, 8) with
a 1-methyl-2-pyridone (1, 2, 5, 6) or a 1-methyl-2-piperidone (3,
4, 7, 8) moiety mimicking steroidal ring A. The directly connected
benzamides (1a–4a, 1b–4b) and benzoates (1c, 3c) were obtained
by palladium-catalysed coupling reaction of diethyl(3-pyridyl)-
borane with 4-bromobenzoic acid derivatives, followed byα-oxid-
ation of the 1-methyl-pyridinium salt and subsequent separation of
the regioisomers. Catalytic hydrogenation of the pyridones (1, 2)
led to the piperidones (3, 4). The preparation of the benzamides
with a methylene (5, 7) and a propylene spacer (6, 8), respectively,
started with the reduction of the keto group of 5-benzoyl-1,2-di-
hydro-1-methyl-2(1H)-pyridone and catalytic hydrogenation of
the alkene obtained by Wittig reaction of 5-formyl-1,2-dihydro-1-
methyl-2(1H)-pyridone with (2-phenylethyl)triphenylphos-
phonium bromide, respectively. The phenyl ring was
functionalized by Friedel-Crafts reaction, haloform cleavage to
give the acid, formation of the acid chloride, and subsequent
treatment with the appropriate amines. Again, catalytichydrogena-
tion of the pyridones (5, 6) led to the piperidones (7, 8). The
5α-reductase inhibitory properties were determined using rat ven-
tral prostate, as well as human BPH tissue as enzyme source,
1β-2β-[3H]testosterone as substrate and a HPLC procedure for the
separation of dihydrotestosterone (DHT). Testedataconcentration
of 100 µM, the inhibition values of 1–8 ranged from 0–79%.
Significant differences were observed between rat and human
enzyme. The most active compound was ethyl 4-(1-methyl-2-
oxopiperid-5-yl)benzoate 3c (68%) for the human enzyme and
N,N-bis(1-methylethyl)-4-[3-(1,2-dihydro-1-methyl-2-oxopyrid-
5-yl)propyl]benzamide 6a (79%) for the rat enzyme.
(Chart 1) has recently come onto the market
. Long term
pharmacotherapy with finasteride has generally been well
[13]
tolerated
side effects related to sexual function
development of steroidal compounds, we and other groups
. Its activity, however, is limited and it shows
[14]
. In parallel to the
[15–24]
focused on nonsteroidal compounds
. One of those is
LY 191704 which shows some specificity towards iso-
[18,19]
zyme 1
. Recently we found potent inhibitors of 5α-R
isozymes 1 and 2 in the class of N-alkyl and N-arylalkyl
[22]
substituted 4-(5-indolyl)benzoic acids
as well as 6-(N-al-
[23]
kyl-carbamoylphenyl) substituted 1H-quinolin-2-ones
.
Potent inhibitors of the type 2 enzyme showing in vivo
activity in the rat have been discovered in the class of N-sub-
[24]
stituted piperidine-4-(benzylidene-4-carboxylic acids)
.
Some time ago we studied the effect of 1-methyl-2-pyridones
and 1-methyl-2-piperidones linked with a C-C or C-N spacer
in 5-position and a N-alkyl carbamoyl-phenyl moiety on 5α-R
[20]
isozyme 2
. The most active compound of this series was
. In this paper these studies are continued by
[20]
A (Chart 1)
including 3-substituted 1-methyl-2-pyridones and -piperi-
dones as well as by examining the effect of varying the spacer
length between the rings.
Introduction
For the therapy of benign prostatic hyperplasia (BHP),
4
steroid 5α-reductase (5α-R, NADPH: ∆ -3-oxosteroid-5α-
[1,2]
oxido-reductase has recently become a promising target
.
There are two isozymes of 5α-R expressed in men, isozyme 1
[3,4]
mainly in the skin and isozyme 2 in the prostate
. 5α-R
4
catalyses the stereospecific hydrogenation of the ∆ double
bond of the testicular androgen testosterone resulting in dihy-
drotestosterone, which shows enhanced androgenic potency
[5]
Chart 1. Inhibitors of 5α reductase and title compounds.
due to its higher affinity for the androgen receptor. 5α-R is
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0365-6233/00/0505/0145 $17.50 +.50/0

146
Hartmann and Reichert
Chemistry
4-(1,2-Dihydro-1-methyl-2-oxopyrid-5-yl and -3-yl) and
4-(1-methyl-2-oxopiperid-5-yl and -3-yl) substituted benz-
amides 1–4 were synthesized as outlined in Scheme 1.
3-Lithiopyridine, synthesized from 3-bromopyridine 9 and
n-butyllithium, was reacted with triethylborane yielding a
borate, which on treatment with iodine gave the diethyl-
[25]
(3-pyridyl)borane 10
. 4-Bromobenzoic acid 11 was con-
verted into the acid chloride by treatmentwith SOCl . Amida-
2
tion with the appropriate amine yielded the 4-bromobenz-
amides 12a and b (Method A, Scheme 1). The ethyl 4-bromo-
benzoate 12c was commercially available. The palladium
[26]
catalyzed coupling reaction of 10 with the 4-arylbromides
12 yielded the 3-arylpyridines 13 (method B). N-Methylation
of 13 and oxidation of the resulting N-methylpyridinium salts
(Method C) led to a mixture of isomers, consisting of the 5-
and 3-aryl substituted 1-methyl- 2-pyridones 1 and 2, respec-
tively, which were separated by column chromatography.
The corresponding 5- and 3-aryl substituted 1-methyl-2-
piperidones 3 and 4 were obtained by catalytic hydrogenation
of 1 and 2 (Method D).
Scheme 2 shows the route leading to the 4-[(1,2-dihydro-1-
methyl-2-oxopyrid-5-yl)alkyl] and 4-[(1-methyl-2-oxo-
piperid-5-yl)alkyl] substituted benzamides 5–8. Friedel-
Crafts acylation of benzene with the acid chloride of 1,2-di-
hydro-1-methyl-2-oxopyridine-5-carboxylic acid 14, ob-
[27]
tained by treatment with SOCl , yielded the ketone 15
2
(Scheme 2). Compound 15 was reduced in two steps using
NaBH in an appropriate solvent. Thus, the alcohol 16 was
4
[28]
obtained and subsequently the methylene compound 20
.
The corresponding propylene compound 21 was obtained by
catalytic hydrogenation of the E/Z mixture 19. Compound 19
was synthesized in a Wittig reaction of the aldehyde 17 with
the triphenylphosphonium salt 18. Friedel-Crafts acetylation
(Method E, Scheme 2), yielding 22 and 23, followed by a
haloform reaction with bromine in an alkaline solution, re-
sulted in the 4-substituted benzoic acids 24 and 25
(Method F). Treatment with SOCl and subsequent amida-
2
tion with tert-butyl- or diisopropyl amine (Method G) pro-
vided the benzamides 5 and 6, respectively. The benzamides
7 and 8 were obtained by catalytic hydrogenation
(Method H).
Biological Results
Scheme 1
Table 1 shows the inhibition values of the test compounds
at a concentration of 100 µM towards 5α-R from human BPH
tissue and rat ventral prostate. We recently described the
[20]
assays in detail
.
compounds b). Interestingly, the esters (compounds c) are the
most potent substituents for inhibition of the human enzyme.
The insertion of a methylene spacer (n = 1) between the two
rings (compounds 5 and 7) decreases inhibitory activity in the
rat and human enzyme. A propylene spacer (n = 3) increases
inhibition (compounds 6 and 8) only in the rat enzyme.
Beyond these findings the same structure activity relation-
ships are found as observed with the compounds lacking a
spacer. Thus, compounds 6a and 8a are the most potent
inhibitors of the rat enzyme, while the esters 1c and 3c exhibit
The compounds which are directly connected (1–4), i.e.
those without a spacer (n = 0) and thus mimicking LY
191704, show varying inhibitory activity. While the 5-substi-
tued pyridones and piperidones 1 and 3 are active, the corre-
sponding 3-substituted compounds 3 and 4 are inactive at the
concentration tested. It is striking that the inhibitory potency
of the pyridones 1 and 2 is almost identical to that of the
corresponding piperidones 3 and 4. However, enzyme inhi-
bition depends on the substituent at the benzene nucleus. In
general diisopropylamide is more potent thantert-butylamide
in the rat and human enzyme (compounds a compared to maximum inhibition of the human enzyme.
Arch. Pharm. Pharm. Med. Chem. 333, 145–153 (2000)

Nonsteroidal Steroid 5α-Reductase Inhibitors
147
Scheme 2
Discussion
Experimental Section
Comparing the compounds of the study (spacer length: 0,
1, and 3) with the corresponding ethylene-bridged derivatives
described earlier , it is striking that the new compounds are
Chemistry
[20]
Melting points were determined on a Kofler hot-stage apparatus (Reichert,
Wien) and are uncorrected. 1H-NMR spectra were measured on a Bruker
AW-80 (80 MHz), on a Bruker AM-400 (400 MHz) and on a Bruker DRX
500 (500 MHz) spectrometer using Me4Si as internal standard. IR spectra
were recorded as KBr pellets or as liquid films on a Perkin-Elmer Infrared
Spectrometer 398, the values are expressed in cm–1. Analytical TLC was
carried out on 0.25 mm layer silica gel plates (Macherey-Nagel, Alugram Sil
G/UV254, silica gel 60) containing a fluorescent indicator; spots were
detected under UV light (254 nm). The purification by flash column chro-
matography was performed on Macherey-Nagel silica gel 60 (0.04–
0.063 mm/230–400 mesh).
less active. Compound A (Chart 1) had shown an IC50 of
13 µM and had exhibited an inhibition exceeding 90 percent
[20]
at 100 µM
. Obviously, the ethylene-bridged compounds
mimic the steroidal substrate in a better way than compounds
with a shorter or longer spacer. Thus, it has to be assumed that
the steroidal A and D rings are mimicked by the heterocycle
and the benzene ring, respectively, whereas the ethylene
spacer imitates steroidal C atoms 8 and 9. Surprisingly,
compounds without spacer were found to be more active than
those with a methylene bridge. The reason for this might be
that the directly connected compounds are closer to the struc-
ture of LY 191704 (Chart 1) than the methylene-bridged
compounds.
3-Bromopyridine 9
Compound 9was obtained commerciallyfrom JanssenChimica, Germany.
Diethyl(3-pyridyl)borane 10
Acknowledgement
1H-NMR (400 MHz, CDCl3): δ = 0.47 (t, 6H, 3J = 7.5 Hz; 2 -CH3), 0.67
3
(m, 4H; 2 -CH2-), 7.24 (dd, 1H, J = 7 Hz, 3J = 6 Hz; C5-H), 7.57 (s, 1H;
Thanks are due to the Deutsche Forschungsgemeinschaft and to the Ver-
band der Chemischen Industrie, Fonds der Chemischen Industrie, for finan-
cial support. We wish to thank Dr. S. Göhring and Mrs. T. Kany for carrying
out the biochemical tests.
C2-H) 7.72 (ddd, 1H, 3J = 7 Hz, 4J = 1.5 Hz, 4J = 1.5 Hz; C4-H), 8.01 (d, 1H,
3J = 6 Hz; C6-H).– IR (KBr): ν = 3015, 2930, 2900, 2860, 2810, 1600, 1475,
1405, 1260, 1195, 1085, 1045, 1025, 900, 875, 800, 710.
Arch. Pharm. Pharm. Med. Chem. 333, 145–153 (2000)

148
Hartmann and Reichert
Table 1. Physical, chemical, and biological data of 4-substituted benzamides 1–8.
—————————————————————————————————————————————————————————————–
No.
Unsat-
uration
R
Formulaa
MW
Mp
[°C]
Eluentb Yield
(%)
BPHc
% inhib. % inhib.
RVPc
—————————————————————————————————————————————————————————————–
1 a
1 b
1 c
2 a
2 b
3 a
3 b
3 c
4 a
4 b
5 a
5 b
6 a
6 b
7 a
7 b
8 a
8 b
3-4, 5-6 N(CH(CH3)2)2
3-4, 5-6 NHC(CH3)3
3-4, 5-6 OCH2CH3
3-4, 5-6 N(CH(CH3)2)2
3-4, 5-6 NHC(CH3)3
N(CH(CH3)2)2
C19H24N2O2
C17H20N2O2
C15H15NO3
C19H24N2O2
C17H20N2O2
C19H28N2O2
C17H24N2O2
C15H19NO3
C19H28N2O2
C17H24N2O2
C20H26N2O2
C18H22N2O2
C22H30N2O2
C20H26N2O2
C20H30N2O2
C18H26N2O2
C22H34N2O2
C20H30N2O2
312.41
284.36
257.29
312.41
284.36
316.45
288.39
261.32
316.45
288.39
326.44
298.39
354.49
326.44
330.47
302.42
358.53
330.47
176–178
247–248
144–145
140–141
oil
A
A
B
A
B
A
A
A
C
C
B
Df
E
39
41
33
19
19
81
73
93
87
85
83
89
81
55
72
95
89
94
34
45
22
38
7
22
61
n. i.d
n. i.
37
9
126–128
180–182.5
57.5–60
138–141
160–163
154–157
178.5–179.5
oil
41
22
26
6
NHC(CH3)3
22
OCH2CH3
68
N(CH(CH3)2)2
n. i.
n. i.
n. i.
n. i.
27
NHC(CH3)3
5
e
3-4, 5-6 N(CH(CH3)2)2
3-4, 5-6 NHC(CH3)3
3-4, 5-6 N(CH(CH3)2)2
3-4, 5-6 NHC(CH3)3
N(CH(CH3)2)2
34
21
79
62
39
16
73
53
125.5–128
120–123
118.5–120.5
oil
E
12.
17
g
C
C
C
C
NHC(CH3)3
n. i.
35
N(CH(CH3)2)2
NHC(CH3)3
97–100
12
—————————————————————————————————————————————————————————————–
a C, H and N analyses were within ±0.4% of the theoretical values, except where noted; b eluent used for flash chromatography on silica gel column, A: ethyl
acetate, B: petroleum ether/acetone (3:2), C: petroleum ether/acetone (1:1) D: acetone, E: petroleum ether/acetone (1:3); c BPH: benign prostatic hyperplasia,
RVP: rat ventral prostate; concentration of inhibitor: 100 µM; mean value of at least two determinations. Each determination was run in duplicate (the
inhibition valueswere within ±5%); d n. i.: no inhibition (inhibition < 5%); e calc.: C: 73.59, H: 8.03, N: 8.58; found: C: 74.11, H: 7.96, N:8.16;frecrystallization
solvent; g calc.: C: 72.69, H: 9.15, N: 8.48; found: C: 73.15, H: 9.01, 8.34
4-Bromobenzoic Acid 11
N-1,1-Dimethylethyl-4-bromobenzamide 12 b
1H-NMR (80 MHz, CDCl3): δ = 1.45 (s, 9H; -C(CH3)3), 5.90 (s (broad),
1H; -NH-), 7.54 (s, 4H; 1,4-disubst. arom. H).– IR (KBr): ν = 3350, 3050,
3010, 2980, 2960, 2920, 1635, 1590, 1555, 1535, 1480, 1450, 1360, 1315,
1220, 1075, 1010, 875, 845, 760.
Compound 11 was obtained commercially from Janssen Chimica, Ger-
many.
Method A. General Procedure for the Preparation of 4-Bromobenzamides
12a and 12b
4-Bromobenzoic acid 11 (15 mmol, 3.0 g) was heated under reflux with
10 ml SOCl2 for 2 h. Excess SOCl2 was distilled off and the remaining
residue was distilled in vacuo to give the acid chloride. A solution of the
amine (30 mmol) in CH2Cl2 (20 ml) was added dropwise to a solution of the
acid chloride in CH2Cl2 (10 ml) during 0.5 h with stirring. After completion,
the mixture was stirred for further 15 min, before H2O (25 ml) was added
and stirring was continued for further 15 min. The layers were separated, the
organic layer was dried (anhydrous Na2SO4) and the solvent removed. The
residue was purified by flash column chromatography.
Ethyl 4-bromobenzoate 12c
Compound 12c was obtained commercially (Janssen Chimica, Germany).
Method B. General Procedure for the Preparation of 4-(3-Pyridyl)benz-
amides 13
A stirred mixture of 10 (8.2 mmol, 1.2 g), 4-bromobenzoic acid derivative
12 (10 mmol), KOH (25 mmol, 1.4 g), tetrabutylammoniumbromide
(8.2 mmol, 1.4 g) and tetrakis(triphenyl-phosphine)palladium (0.4 mmol,
0.5 g) in dry THF (40 ml) was heated under reflux for 20 h. The mixture was
diluted with ethyl acetate (50 ml), washed with brine and dried (anhydrous
Na2SO4). After removal of the solvent, the residue was purified by flash
column chromatography.
N,N-Bis(1-methylethyl)-4-bromobenzamide 12a
1H-NMR (80 MHz, CDCl3): δ = 1.31 (d, 12H, 3J = 7 Hz; 2 -CH(CH3)2),
3.64 (sept, 2H, 3J = 7 Hz; 2 -CH(CH3)2), 7.17 and 7.51 (AA′BB′, 4H, 3J =
9 Hz; 1,4-disubst. arom.. H).– IR (KBr): ν = 2960, 2920, 2860, 1630, 1590,
1435, 1375, 1365, 1345, 1210, 1035, 1010, 845, 825, 570.
Arch. Pharm. Pharm. Med. Chem. 333, 145–153 (2000)

Nonsteroidal Steroid 5α-Reductase Inhibitors
149
C5-H), 7.66 and 8.16 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H), 8.68
(dd, 1H, 3J = 5 Hz, 4J =2 Hz; C6-H), 8.92 (d, 1H, 4J = 2 Hz; C2-H).– IR (film):
ν = 3030, 2960, 2930, 2870, 1710, 1610, 1460, 1425, 1390, 1365, 1275, 1190,
1180, 1105, 1025, 1005, 860, 810, 765, 705.
Table 2. Physical and chemical data of compounds 10 and 12–25.
——————————————————————————————
No.
Formula
MW
Mp [°C]
Eluenta Yield
(%)
——————————————————————————————
Method C. General Procedure for the Preparation of 4-Substituted Benz-
amides 1 and 2
10
C9H14BN
147.03
284.20
256.14
282.39
254.33
227.26
153.14
137.14
213.24
215.25
447.35
225.29
199.25
227.31
241.29
269.34
243.26
271.32
160–161.5
61–63.5
135–135.5
82–85
A
B
47
75
95
78
67
27
62
87
64
95
~99
75
28
81
61
85
81
73
Dimethyl sulfate (2 mmol, 0.25 g) was slowly dropped to the 4-bromoben-
zoic acid derivative 13 (2 mmol) and heated at 80 °C for 0.5 h with stirring.
K3[Fe(CN)6] (5 mmol, 1.65 g) in H2O (5 ml) was added and subsequently
KOH (16 mmol, 0.9 g) in such a way as to keep the temperature between
0 and 5 °C. After completion CH2Cl2 (5 ml) was added, and the mixture
stirred for 1.5 h before once again K3[Fe(CN)6] (2.5 mmol, 0.82 g) in H2O
(2.5 ml) and KOH (8 mmol, 0.45 g) were added. The mixture was stirred for
12 h. After addition of H2O (20 ml) and CH2Cl2 (20 ml), the layers were
separated. The organic layer was washed with H2O, dried (anhydrous
Na2SO4) and the solvent was evaporated. The residue was purified by flash
column chromatography.
12 a
12 b
13 a
13 b
13 c
14
C13H18BrNO
C11H14BrNO
C18H22N2O
C16H18N2O
C14H13NO2
C7H7NO3
B
C
151–153
oil
D
E
240.5–241.5
119–120
182–184
143–145
F
15
C7H7NO2
Db
Db
Db
–
16
C13H11NO2
C13H13NO2
C26H24BrP
C15H15NO
C13H13NO
C15H17NO
C15H15NO2
C17H19NO2
C14H13NO3
C16H17NO3
N,N-Bis(1-methylethyl)-4-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl)benz-
amide 1a
17
c
18
–
1H-NMR (400 MHz, CDCl3): δ = 0.89–1.82 (m, 12H; 2 -CH(CH3)2),
3.33-4.00 (m, 2H; 2 -CH(CH3)2), 3.63 (s, 3H; -N(CH3)-), 6.67 (d, 1H, 3J =
9 Hz; C3-H), 7.36 and 7.42 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H),
7.54 (d, 1H, 4J = 2.5 Hz; C6-H), 7.63 (dd, 1H, 3J = 9 Hz, 4J = 2.5 Hz; C4-H).–
IR (KBr): ν = 3060, 3030, 2960, 2930, 2860, 1670, 1620, 1450, 1370, 1345,
1300, 1160, 850, 825, 765.
19d
175–180e
–
20
oil
G
G
H
I
21
oil
22
oil
23
oil
N-1,1-Dimethylethyl-4-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl)benzamide
1b
24
193–194
160–163
Db
Db
25
1H-NMR (400 MHz, CDCl3): δ = 1.49 (s, 9H; -C(CH3)3), 3.64 (s, 3H;
-N(CH3)-), 5.98 (s, 1H; -NH-), 6.70 (d, 1H, 3J = 9 Hz; C3-H), 7.45 and 7.77
——————————————————————————————
4
(AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H), 7.56 (d, 1H, J = 2.5 Hz;
a Eluent used for flash chromatography on silica gel column, A: petroleum
ether, B: petroleum ether/acetone (7:1), C: petroleum ether/acetone (3:1), D:
ethyl acetate, E: petroleum ether/acetone (4:1), F: H2O G: petroleum
ether/acetone (1:1), H: acetone, I: petroleum ether/acetone (1:2); b recrystal-
lization solvent; c compound 18 was obtained as a glass, which was pulver-
ized; d mixture of (E)- and (Z)-isomer (ratio = 2:5), an analytical sample was
separated into the stereoisomers by column chromatography (see Experimen-
3
C6-H), 7.61 (dd, 1H, J = 9 Hz, 4J = 2.5 Hz; C4-H).– IR (KBr): ν = 3360,
3050, 3030, 2970, 2920, 1665, 1655, 1600, 1535, 1505, 1440, 1425, 1305,
1220, 1160, 860, 835, 775.
Ethyl 4-(1,2-Dihydro-1-methyl-2-oxopyrid-5-yl)benzoate 1c
1H-NMR (400 MHz, CDCl3): δ = 1.41 (t, 3H, 3J = 7 Hz; -CH3), 3.65 (s,
3
3H; -N(CH3)-), 4.40 (quart, 2H, J = 7 Hz; -CH2-), 6.71 (d, 1H, 3J = 9Hz;
tal protocols); e bp(0.1 Torr)
.
C3-H), 7.47 and 8.09 (AA′BB′, 4H, 3J = 8.5 Hz; 1,4-disubst. arom. H), 7.59
(d, 1H, 4J = 2.5 Hz; C6-H), 7.67 (dd, 1H, 3J = 9 Hz, 4J = 2.5 Hz; C4-H).– IR
(KBr): ν = 3050, 2980, 2940, 2900, 1710, 1665, 1610, 1600, 1445, 1405,
1295, 1280, 1190, 1160, 1130, 1125, 1110, 830, 770.
N,N-Bis(1-methylethyl)-4-(3-pyridyl)benzamide 13a
1H-NMR (500 MHz, CDCl3): δ = 0.93–1.86 (m, 12H; 2 -CH(CH3)2),
3.36-4.12 (m, 2H; 2 -CH(CH3)2), 7.36 (dd, 1H, 3J = 5 Hz, 3J = 8 Hz; C5-H),
7.43 and 7.59 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H), 7.87 (ddd, 1H,
3J = 8 Hz, 4J = 1.5 Hz, 4J = 1.5 Hz; C4-H), 8.59 (d, 1H, 3J = 5 Hz; C6-H),
8.85 (d, 1H, 4J = 1.5 Hz; C2-H).– IR (KBr): ν = 3020, 2960, 2930, 2860,
1640, 1435, 1365, 1335, 1210, 1185, 1155, 1150, 1040, 1000, 850, 805, 760,
710.
N,N-Bis(1-methylethyl)-4-(1,2-dihydro-1-methyl-2-oxopyrid-3-yl)benz-
amide 2a
1H-NMR (400 MHz, CDCl3): δ = 0.97–1.73 (m, 12H; 2 -CH(CH3)2),
3.41-4.12 (m, 2H; 2 -CH(CH3)2), 3.62 (s, 3H; -N(CH3)-), 6.27 (dd, 1H, 3J =
7 Hz, 3J = 7 Hz; C5-H), 7.33 (dd, 1H, 3J = 7 Hz, 4J = 2 Hz; C4-H or C6-H),
7.34 and 7.71 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H), 7.50 (dd, 1H,
3J = 7 Hz, 4J = 2 Hz; C6-H or C4-H).– IR (KBr): ν = 3060, 3040, 2990, 2960,
2930, 1660, 1615, 1595, 1555, 1445, 1370, 1345, 1210, 1040, 825, 750.
N-1,1-Dimethylethyl-4-(3-pyridyl)benzamide 13b
1H-NMR (400 MHz, CDCl3): δ = 1.45 (s, 9H; -C(CH3)3), 6.06 (s, 1H;
-NH-), 7.39 (dd, 1H, 3J = 8 Hz, 3J = 5 Hz; C5-H), 7.62 and 7.84 (AA′BB′,
4H, 3J = 8 Hz; 1,4-disubst. arom. H), 7.89 (ddd, 1H, 3J = 8 Hz, 4J = 2 Hz, 4J
= 2 Hz; C4-H), 8.61 (dd, 1H, 3J = 5 Hz, 4J = 2 Hz; C6-H), 8.84 (d, 1H, 4J =
2 Hz; C2-H).– IR (KBr): ν = 3280, 3050, 2990, 2970, 2920, 1640, 1620, 1540,
1385, 1360, 1315, 1225, 1000, 860, 805, 770, 710.
N-1,1-Dimethylethyl-4-(1,2-dihydro-1-methyl-2-oxopyrid-3-yl)benzamide
2b
1H-NMR (400 MHz, CDCl3): δ = 1.47 (s, 9H; -C(CH3)3), 3.61 (s, 3H;
-N(CH3)-), 6.05 (s, 1H; -NH-), 6.26 (dd, 3J = 7 Hz, 3J = 7 Hz; C5-H), 7.34
(dd, 1H, 3J = 7 Hz, 4J = 2 Hz; C4-H or C6-H), 7.51 (dd, 1H, 3J = 7 Hz, 4J =
2 Hz; C6-H or C4-H), 7.72 (s, 4H, 1,4-disubst. arom. H).– IR (KBr): ν = 3330,
3050, 2960, 2920, 1645, 1595, 1580, 1550, 1535, 1500, 1450, 1435, 1360,
1300, 1215, 1120, 760, 725, 695, 540.
Ethyl 4-(3-Pyridyl)benzoate 13c
1H-NMR (400 MHz, CDCl3): δ = 1.42 (t, 3H, 3J = 7 Hz; -CH3), 4.42 (quart,
3
5
2H, 3J = 7 Hz; -CH2-), 7.46 (ddd, 1H, 3J = 8 Hz, J = 5 Hz, J = 0.5 Hz;
Arch. Pharm. Pharm. Med. Chem. 333, 145–153 (2000)

150
Hartmann and Reichert
Ethyl 4-(1,2-dihydro-1-methyl-2-oxopyrid-3-yl)benzamide 2c
5-Benzoyl-1,2-dihydro-1-methyl-2(1H)-pyridone 15
1H-NMR (400 MHz, CDCl3): δ = 1.40 (t, 3H; -3J = 7 Hz; -CH3), 4.39
(quart, 2H; 3J = 7 Hz;-CH2-), 6.28 (dd, 1 H, 3J = 7 Hz, 3J = 7 Hz; C5-H), 7.35
(dd, 1H, 3J = 7 Hz, 4J = 2 Hz; C4-H or C6-H), 7.55 (dd, 1H, 3J = 7 Hz, 4J =
2 Hz; C4-H or C6-H), 7.79 and 8.06 (AA′BB′, 4H, 3J = 8.5 Hz; 1,4-disubst.
arom. H).– IR (KBr): ν = 3060, 3030, 2970, 2920, 2870, 1710, 1645, 1605,
1595, 1550, 1365, 1310, 1280, 1105, 1020, 765, 700.
1H-NMR (80 MHz, CDCl3): δ = 3.58 (s, 3H; -N(CH3)-), 6.54 (d, 1H, 3J =
9.5 Hz; C3-H), 7.32–8.05 (m, 7H; C4-H, C6-H and monosubst. arom. H).–
IR (KBr): ν = 3045, 2920, 1720, 1670, 1650, 1595, 1570, 1540, 1440, 1425,
1320, 1310, 1285, 1135, 1120, 950, 750, 710.
1,2-Dihydro-1-methyl-5-(hydroxyphenylmethyl)-2(1H)-pyridone 16
To a stirred solution of 15 (30 mmol, 6.4 g) in ethanol (150 ml) was added
NaBH4 (32 mmol, 1.22 g) in small portions during 10 min. Stirring was
continued for 1 h at room temperature. Most of the solvent was evaporated
and H2O (100 ml) was added to the residue. The mixture was extracted
several times with diethyl ether. The organic layers were combined, washed
with brine, and dried (anhydrous Na2SO4). After evaporation of the solvent,
the residue was recrystallized from ethyl acetate.– 1H-NMR (80 MHz,
CDCl3): δ = 3.40 (s, 3H; -N(CH3)-), 4.05 (m, 1H; -CH(OH)-), 5.55 (m,1H;
-CH(OH)-), 6.36 (d, 1H, 3J = 8 Hz; C3-H), 7.11–7.40 (m, 7H; C4-H, C6-H
and monosubst. arom. H).– IR (KBr): ν = 3260, 3040, 1665, 1580, 1440,
1250, 1150, 1030, 1020, 835, 735, 700, 650.
Method D. General Procedure for the Preparation of 4-Substituted Benz-
amides 3 and 4
To an solution of 1 mmol of the 4-substituted benzamides 1 and 2 in ethanol
(30 ml), palladium on charcoal (5%, 150 mg) was added as a catalyst. The
mixture was hydrogenated for 48 h at room temperature at a pressure of
40 bar. After filtration, the solvent was evaporated to dryness and the residue
was purified by flash column chromatography.
N,N-Bis(1-methylethyl)-4-(1-methyl-2-oxopiperid-5-yl)benzamide 3a
1H-NMR (400 MHz, CDCl3): δ = 0.96–1.78 (m, 12 H; 2 -CH(CH3)2),
1.98–2.17 (m, 2H; -CO-CH2-CH2-), 2.44-2.65 (m, 2H; -CO-CH2-), 2.98 (s,
3H; -N(CH3)-), 3.07-3.18 (m, 1H; C5-H), 3.34–3.47 (m, 2H; -N(CH3)-CH2-),
(2-Phenylethyl)triphenylphosphonium Bromide 18
3
3.37–4.03 (m, 2H; 2 -CH(CH3)2), 7.25 and 7.29 (AA′BB′, 4H, J = 8 Hz;
2-Phenylethylbromide (50 mmol, 9.25 g) and triphenylphosphine
(50 mmol, 13.11 g) were melted together at 100 °C for 2 h. After cooling,
the glass-like residue was pulverized.– 1H-NMR (80 MHz, CDCl3): δ =
2.82–3.27 (m, 2H; -CH2-Ph), 3.84–4.28 (m, 2H; +PPh3-CH2-), 7.06–7.37 (m,
5H; monosubst. arom. H), 7.53–8.08 (m, 15H; +PPh3).– IR (KBr): ν = 3040,
3020, 2980, 2850, 1585, 1480, 1435, 1110, 990, 745, 720, 690, 520, 505.
1,4-disubst. arom. H).– IR (KBr): ν = 3060, 2960, 2930, 2870, 1640, 1630,
1615, 1500, 1450, 1375, 1350, 1210, 1160, 1135, 1035, 1020, 855, 835, 590,
525, 515.
N-1,1-Dimethylethyl-4-(1-methyl-2-oxopiperid-5-yl)benzamide 3b
1H-NMR (400 MHz, CDCl3): δ = 1.47 (s, 9H; -C(CH3)3), 1.98–2.21 (m,
2H; -CO-CH2-CH2-), 2.44–2.66 (m, 2H; -CO-CH2-), 2.99 (s, 3H; -N(CH3)-),
3.08–3.23 (m, 1H; C5-H), 3.32–3.48 (m, 2H; -N(CH3)-CH2-), 5.93 (s, 1H,
-NH-), 7.29 and 7.70 (AA′BB′, 4H, J = 8 Hz; 1,4-disubst. arom. H).– IR
(KBr): ν = 3300, 3060, 3000, 2970, 2950, 2920, 1660, 1640, 1610, 1535,
(E)- and (Z)-1,2-Dihydro-1-methyl-5-(3-phenyl-1-propenyl)-2(1H)-
pyridone 19
3
Butyllithium (45 mmol, 2.88 g) was added to a suspension of triphenyl-
phosphonium bromide 18 (45 mmol, 20.13 g) in dry THF (100 ml) and the
mixture was stirred for 0.5 h at room temperature. The aldehyde 17
(45 mmol, 6.17 g), dissolved in dry THF (150 ml), was added dropwise to
the mixture during 0.5 h and stirring was continued for 3 h. The solvent was
evaporated and the residue was distilled yielding a light-yellow oil (bp(0.1
Torr): 175–180 °C). The oil consisted of 28% (E)- and 72% (Z)-isomer; an
analytical sample of the isomers was separated by flash column chromatog-
raphy using ethyl acetate as eluent.
1505, 1460, 1360, 1315, 1215, 850, 775, 630.
Ethyl 4-(1-Methyl-2-oxopiperid-5-yl)benzoate 3c
1H-NMR (400 MHz, CDCl3): δ = 1.39 (t, 3H, 3J = 7 Hz; -CH3), 2.01–2.16
(m, 2H; -CO-CH2-CH2-), 2.44–2.67 (m, 1H; -CO-CH2-), 2.98 (s, 3H; -
N(CH3)-), 3.12–3.23 (m, 1H; C5-H), 3.35–3.48 (m, 2H; -N(CH3)-CH2-), 4.38
(quart, 2H, 3J = 7 Hz; -CH2-CH3), 7.31 and 8.02 (AA′BB′, 4H, 3J = 8 Hz;
1,4-disubst. arom. H).– IR (KBr): ν = 2980, 2930, 2860, 1715, 1640, 1630,
1610, 1500, 1370, 1280, 1125, 1110, 1020, 855, 770, 745, 705.
Isomer A: 1H-NMR (400 MHz, CDCl3): δ = 3.27 (d, 2H, 3J = 6.5 Hz;
-CH2-), 3.52 (s, 3H; -N(CH3)-), 6.23 (dt, 1H, 3J = 15.5 Hz, 3J = 6.5 Hz;
-CH=CH-CH2-), 6.44 (d, 1H, 3J = 15.5 Hz; -CH=CH-CH2-), 6.55 (d, 1H, 3J
= 9 Hz; C3-H), 7.09 (d, 1H, 4J = 2.5 Hz; C6-H), 7.18–7.39 (m, 6H; C4-H,
monosubst. arom. H).– IR (film): ν = 3050, 3020, 2910, 1665, 1610, 1605,
1595, 1585, 1535, 1440, 1325, 1260, 1145, 970, 830, 755, 740, 720, 695.
Isomer B: 1H-NMR (400 MHz, CDCl3): δ = 3.50 (d, 2H, 3J = 5.5 Hz;
-CH2-), 3.52 (s, 3H; -N(CH3)-), 6.03–6.14 (m, 2H, 3J = not detectable;
-CH=CH-) 6.56 (d, 1H, 3J = 9 Hz; C3-H), 7.16 (d, 1H, C6-H, 4J = 2.5 Hz;
C6-H), 7.17–7.36 (m, 6H; C4-H, monosubst. arom. H).– IR (film): ν = 3050,
3020, 2910, 1665, 1605, 1585, 1540, 1440, 1330, 1260, 1155, 1120, 835, 750,
725, 705, 540.
N,N-Bis(1-methylethyl)-4-(1-methyl-2-oxopiperid-3-yl)benzamide 4a
1H-NMR (400 MHz, CDCl3): δ = 0.93–1.71 (m, 12 H; 2 -CH(CH3)2),
1.75–2.00 and 2.10–2.23 (m, 4H; -N(CH3)-CH2-CH2-CH2-), 3.32–4.03 (m,
4H; -N(CH3)-CH2-, 2 -CH(CH3)2), 3.70 (t, 1H, 3J = 6.5 Hz; C5-H), 7.19 and
7.25 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H).– IR (KBr): ν = 2970,
2930, 2860, 1640, 1620, 1465, 1445, 1380, 1365, 1340, 1240, 1210, 1200,
1145, 1035, 835, 760.
N-1,1-Dimethylethyl-4-(1-methyl-2-oxopiperid-3-yl)benzamide 4b
1,2-Dihydro-1-methyl-5-phenylmethyl-2(1H)-pyridone 20
1H-NMR (400 MHz, CDCl3): δ = 1.46 (s, 9H; -C(CH3)3), 1.77–2.04 and
2.13–2.23 (m, 4H; -N(CH3)-CH2-CH2-CH2-), 3.03 (s, 3H; -N(CH3)-), 3.32–
3.50 (m, 2H; -N(CH3)-CH2-), 3.67–3.74 (t, 1H, 3J = 6.5 Hz; C5-H), 5.89 (s,
1H; -NH-), 7.23 and 7.65 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H).–
IR (KBr): ν = 3300, 3030, 2950, 2930, 2860, 1650, 1620, 1525, 1495, 1435,
1360, 1310, 1200, 1120, 845, 725, 535.
The alcohol 16 (26 mmol, 5.6 g) was added in small portions over 15 min
to a suspension of NaBH4 (55 mmol, 2.0 g) and trifluoroacetic acid (100 ml)
at room temperature under a nitrogen atmosphere. The mixture was stirred
for 40 h at room temperature. Water (100 ml) was then added and the mixture
rendered alkaline with NaOH pellets before being extracted several times
with diethyl ether. The organic layers were combined, washed with water
and brine, and dried (anhydrous Na2SO4). The solvent was evaporated and
the light yellow oil purified by flash column chromatography using petro-
leum ether/acetone (1:1) as an eluent.– 1H-NMR (80 MHz, CDCl3): δ = 3.47
(s, 3H; -N(CH3)-), 3.68 (s, 2H; -CH2-), 6.49 (d, 1H, 3J = 9.5 Hz; C3-H),
6.97–7.40 (m, 7H; C4-H, C6-H and monosubst. arom. H).– IR (film): ν =
3050, 3020, 2960, 2910, 1665, 1595, 1535, 1440, 1325, 1140, 830, 735, 700,
615.
5-Formyl-1,2-dihydro-1-methyl-2(1H)-pyridone 17
1H-NMR (80 MHz, CDCl3): δ = 3.63 (s, 3H; -N(CH3)-), 6.60 (d, 1H, 3J =
9 Hz; C3-H), 7.82 (dd, 1H, 3J = 9 Hz, 4J = 2.5 Hz; C4-H), 7.94 (d, 1H, 4J =
2.5 Hz; C6-H), 9.62 (s, 1H, -CHO).– IR (KBr): 3070, 3040, 2830, 1665, 1615,
1545, 1450, 1395, 1330, 1260, 1150, 935, 830, 640, 455.
Arch. Pharm. Pharm. Med. Chem. 333, 145–153 (2000)

Nonsteroidal Steroid 5α-Reductase Inhibitors
151
1,2-Dihydro-1-methyl-5-(3-phenylpropyl)-2(1H)-pyridone 21
2700–3200, 2920, 2850, 2610, 2480, 1710, 1660, 1610, 1570, 1540, 1245,
1170, 1160, 860, 835, 760, 625, 510.
The mixture of (E)- and (Z)-isomers (2:5) of 19 (30 mmol, 6.76 g) was
dissolved in ethanol (50 ml), mixed with palladium on charcoal (5%, 0.5 g)
as a catalyst, and hydrogenated for 6 h at room temperature and atmospheric
pressure. After filtration, the solvent was evaporated to dryness and the
residue was purified by flash column chromatography using petroleum
ether/acetone (1:1) as eluent.– 1H-NMR (400 MHz, CDCl3): δ = 1.86 (quint,
2H, 3J = 7.5 Hz; -CH2-CH2-CH2-), 2.37 (t, 2H, 3J = 7.5 Hz; -CH2-CH2-CH2-
Ph), 2.63 (t, 2H, 3J = 7.5 Hz; -CH2-Ph), 3.50 (s, 3H; -N(CH3)-), 6.53 (d, 1H,
3J = 9 Hz; C3-H), 7.01 (d, 1H, 4J = 2 Hz; C6-H), 7.12–7.34 (m, 6H; C4-H,
monosubst. arom. H).– IR (film): ν = 3050, 3020, 2930, 2850, 1665, 1605,
1595, 1535, 1450, 1435, 1325, 1150, 830, 745, 700.
Method G. General Procedure for the Preparation of 4-Substituted Benz-
amides 5 and 6
A 5 mmol portion of the 4-substituted benzoic acid 24 or 25 was stirred
withSOCl2 (3 ml) for 0.5 h at 0 °C for 15 min at room temperature and finally
for 10 min at 50 °C. Excess SOCl2 was removed in vacuo. The residue was
dissolved in CH2Cl2 (20 ml) and the amine (2 ml) was added. The mixture
was stirred for 1 h, before H2O (20 ml) was added. The layers were separated
and the organic layer was dried (anhydrous Na2SO4). The solvent was
evaporated to dryness and the residue was purified by flash column chroma-
tography.
Method E. General Procedure for the Preparation of 5-(4-Acetylphenyl-
alkyl)-1,2-dihydro-1-methyl-2(1H)-pyridones 22 and 23
N,N-Bis(1-methylethyl)-4-[(1,2-dihydro-1-methyl-2-oxopyrid-5-yl)methyl]-
benzamide 5a
AlCl3 (37.5 mmol, 5.0 g) was suspended in 1,2-dichloroethane (100 ml)
and mixed with acetic acid chloride (30 mmol, 2.36 g). A solution of com-
pound 20 or 21 (15 mmol) in 1,2-dichloroethane (20 ml) was added with
stirring. Stirring was continued for 2 h at room temperature. The mixture was
poured on ice-water; the layers were separated, and the organic layer was
dried (anhydrous Na2SO4). The solvent was evaporated and the oily residue
was purified by flash column chromatography.
1H-NMR (400 MHz, CDCl3): δ = 0.98–1.73 (m, 12H; 2 -CH(CH3)2),
3.39–4.02(m, 2H;2-CH(CH3)2), 3.52 (s, 3H; -N(CH3)-), 3.72 (s, 2H; -CH2-),
6.56 (d, 1H, 3J = 9 Hz; C3-H), 7.05 (d, 1H, 4J = 2 Hz; C6-H), 7.17 and 7.27
(AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H), 7.20 (dd, 1H, 3J = 9 Hz, 4J
= 2 Hz; C4-H).– IR (KBr): ν = 3030, 2960, 2920, 1665, 1620, 1605, 1530,
1440, 1375, 1365, 1340, 1150, 1035, 830.
5-(4-Acetylphenylmethyl)-1,2-dihydro-1-methyl-2(1H)-pyridone 22
1H-NMR (400 MHz, CDCl3): δ = 2.59 (s, 3H; -CO-CH3-), 3.52 (s, 3H;
-N(CH3)-), 3.77 (s, 2H, -CH2-), 6.54 (d, 1H, 3J = 9 Hz; C3-H), 7.08 (d, 1H,
4J = 2 Hz; C6-H), 7.16 (dd, 1H, 3J = 9 Hz, 4J = 2 Hz; C4-H), 7.27 and 7.92
(AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H).– IR (film): ν = 3020, 2990,
2960, 2910, 1710, 1665, 1610, 1600, 1595, 1545, 1440, 1410, 1355, 1220,
825, 605.
N-1,1-Dimethylethyl-4-[(1,2-dihydro-1-methyl-2-oxopyrid-5-yl)methyl]-
benzamide 5b
1H-NMR (400 MHz, CDCl3): δ = 1.47 (s, 9H; -C(CH3)3), 3.51 (s, 3H;
-N(CH3)-), 3.74 (s, 2H; -CH2-), 5.91 (s, 1H, -NH-), 6.55 (d, 1H, 3J = 9 Hz;
4
3
C3-H), 7.02 (d, 1H, J = 2 Hz; C6-H), 7.15 (dd, 1H, J = 9 Hz, 4J = 2 Hz;
C4-H, ), 7.21 and 7.69 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H).– IR
(KBr): ν = 3280, 3050, 3020, 2970, 2910, 1665, 1645, 1605, 1555, 1545,
1440, 1320, 1225, 1150, 835, 750.
5-(3-(4-Acetylphenyl)propyl)-1,2-dihydro-1-methyl-2(1H)-pyridone 23
1H-NMR (400 MHz, CDCl3): δ = 1.88 (quint, 2H, 3J = 7.5 Hz; -CH2-CH2-
CH2-), 2.39 (t, 2H, 3J = 7.5 Hz; -CH2-CH2-CH2-Ph-), 2.59 (s, 3H; -CO-CH3),
2.70 (t, 2H, 3J = 7.5 Hz; -CH2-Ph-), 3.52 (s, 3H; -N(CH3)-), 6.55 (d, 1H, 3J
= 9 Hz; C3-H), 7.04 (d, 1H, 4J = 2.5 Hz; C6-H), 7.22 (dd, 1H, 3J = 9 Hz, 4J
= 2.5 Hz; C4-H), 7.26 and 7.90 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom.
H).– IR (film): ν = 3050, 3020, 3000, 2930, 2860, 1680, 1665, 1605, 1595,
1590, 1580, 1540, 1440, 1410, 1355, 1270, 830, 590.
N,N-Bis(1-methylethyl)-4-[3-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl)-
propyl]benzamide 6a
1H-NMR (400 MHz, CDCl3): δ = 0.93–1.73 (m, 12H; 2 -CH(CH3)2), 1.86
3
3
(quint, 2H, J = 7.5 Hz; -CH2-CH2-CH2-), 2.37 (t, 2H, J = 7.5 Hz; -CH2-
CH2-CH2-Ph-), 2.64 (t, 2H, 3J = 7.5 Hz; -CH2-Ph-), 3.32–4.01 (m, 2H; 2
-CH(CH3)2), 3.52 (s, 3H; -N(CH3)-), 6.56 (d, 1H, 3J = 9 Hz; C3-H), 7.03 (d,
1H, 4J = 2 Hz; C6-H, ), 7.17 and 7.24 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst.
arom. H, ), 7.22 (dd, 1H, 3J = 9 Hz, 4J = 2 Hz; C4-H).– IR (KBr): ν = 3060,
3030, 2960, 2920, 1665, 1625, 1610, 1535, 1440, 1370, 1335, 1210, 1155,
1035, 830.
Method F. General Procedure for the Preparation of 4-Substituted Benzoic
Acids 24 and 25
To a cooled solution of NaOH (80 mmol, 3.2 g) in H2O (20 ml), bromine
was added dropwise (35 mmol, 4.0 g) in such a way as to keep the tempera-
ture below 10 °C. After completion, the solution was cooled to 0 °C. At this
temperature a solution of 8 mmol of compound 22 or 23 in dioxane (5 ml)
was added, and the mixture was stirred for 1.5 h at room temperature. The
formed CHBr3 was removed and Na2S2O5 (4 mmol, 0.8 g) dissolved in H2O
(10 ml) was added. After addition of concentrated HCl, the precipitated acid
was filtered off and recrystallized from ethyl acetate.
N-1,1-Dimethylethyl-4-[3-(1,2-dihydro-1-methyl-2-oxopyrid-5-yl)propyl]-
benzamide 6b
1H-NMR (400 MHz, CDCl3): δ = 1.86 (quint, 2H, 3J = 7.5 Hz; -CH2-CH2-
CH2-), 2.37(t, 2H, 3J = 7.5 Hz; -CH2-CH2-CH2-Ph-), 2.67 (t, 2H, 3J = 7.5 Hz;
-CH2-Ph-), 3.52 (s, 3H; -N(CH3)-), 5.92 (s, 1H, -NH-), 6.60 (d, 1H, 3J = 9 Hz;
C3-H), 7.02 (d, 1H, 4J = 2 Hz; C6-H), 7.20 and 7.65 (AA′BB′, 4H, 3J = 8 Hz;
1,4-disubst. arom. H), 7.25 (dd, 1H, 3J = 9 Hz, 4J = 2 Hz; C4-H).– IR (KBr):
ν = 3320, 3080, 3050, 3020, 2960, 2920, 2850, 1665, 1640, 1610, 1600, 1535,
1325, 1315, 1220, 1155, 850, 830, 765.
4-[(1,2-Dihydro-1-methyl-2-oxopyrid-5-yl)methyl)benzoic Acid 24
1H-NMR (400 MHz, DMSO): δ = 3.42 (s, 3H; -N(CH3)-), 3.76 (s, 2H;
-CH2-), 6.36 (d, 1H, 3J = 9 Hz; C3-H), 7.27 (dd, 1H, 3J = 9 Hz, 4J = 2 Hz;
C4-H), 7.36 and 7.90 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H), 7.65
(d, 1H, 4J = 2 Hz; C6-H), 12.88 (s (broad), 1H; -COOH).– IR (KBr): ν =
2700–3200, 2600, 2490, 1715, 1660, 1575, 1545, 1440, 1415, 1260, 1170,
1115, 750.
Method H. General Procedure for the Preparation of 4-Substituted Benz-
amides 7 and 8
4-[3-(1,2-Dihydro-1-methyl-2-oxopyrid-5-yl)propyl]benzoic Acid 25
A 2 mmol protion of the 4-substituted benzamide 6 or 7 was dissolved in
ethanol (30 ml), mixed with palladium on charcoal (10%, 100 mg) as a
catalyst and hydrogenated for 24 h at room temperature under atmospheric
pressure. After filtration, the solvent was evaporated to dryness and the
residue was purified by flash column chromatography using petroleum
ether/acetone (1:1) as eluent.
1H-NMR (400 MHz, DMSO): δ = 1.82 (quint, 2H, 3J = 7.5 Hz; -CH2-CH2-
CH2-), 2.35(t, 2H, 3J = 7.5 Hz; -CH2-CH2-CH2-Ph-), 2.66 (t, 2H, 3J = 7.5 Hz;
-CH2-Ph-), 3.40 (s, 3H; -N(CH3)-), 6.37 (d, 1H, 3J = 9 Hz; C3-H), 7.33 and
7.88 (AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H), 7.36 (dd, 1H, 3J = 9 Hz,
4J = 2.5 Hz; C4-H), 7.51 (d, 1H, 4J = 2.5 Hz; C6-H).– IR (KBr): ν =
Arch. Pharm. Pharm. Med. Chem. 333, 145–153 (2000)

152
Hartmann and Reichert
N,N-Bis(1-methylethyl)-4-[(1-methyl-2-oxopiperid-5-yl)methyl]benzamide
Incubation Procedure
7a
The assay was performed as described[29] with modifications[20]. All
values were run in duplicate. The incubation was carried out for 30 min at
37 °C in a total volume of 250 µl. In the case of rat enzyme preparation
phosphate buffer (40 mM, pH 6.6) and in the case of human enzyme prepa-
ration citrate buffer (40 mM, pH 5.5) was used. The incubation mixture
contained approximately 250 µg rat protein (125 µg human protein), 200 µM
NADPH (human enzyme:100 µM NADPH), 0.21 µM T including 45 nCi
[1,2-3H]-T, and 2% DMSO with or without test compound (100 µM). The
reaction was started by adding the prostatic enzyme preparation and stopped
by addition of 50 µl NaOH (10 M). The steroids were extracted using 500 µl
of diethyl ether. The mixture was shaken for 10 min and centrifuged 10 min
at 4000 rpm. The water layer was frozen and the ether layer was decanted in
fresh tubes and evaporated to dryness.
1H-NMR (400 MHz, CDCl3): δ = 0.95–1.72 (m, 13H; 2 -CH(CH3)2,
C5-H), 1.85–1.94 and 2.07–2.22 (2m, 2H; -CO-CH2-CH2-), 2.33 and 2.48
(ddd, 1H, 2J = 18 Hz, 3J = 11.5 Hz, 3J = 6.5 Hz and ddd, 1H, 2J = 18 Hz, 3J
= 5.5 Hz, 3J = 3.5 Hz; -CO-CH2-), 2.62 and 2.67 (dd, 1H, 2J 14 Hz, 3J 7 Hz
and dd, 1H, 2J 14 Hz, 3J 7 Hz; -Ph-CH2-), 2.90 (s, 3H, -N(CH3)-), 3.01 and
3.18 (dd, 1H, 2J = 12 Hz, 3J = 10 Hz and ddd, 1H, 2J = 12 Hz, 3J = 5 Hz, 4J
= 1.5 Hz; -N(CH3)-CH2-), 3.38–4.03 (m, 2H; 2 -CH(CH3)2), 7.16 and 7.27
(AA′BB′, 4H, 3J = 8 Hz; 1,4-disubst. arom. H).– IR (KBr): ν = 2970, 2930,
2860, 1640, 1630, 1500, 1465, 1435, 1370, 1340, 1035, 1020, 840, 610.
N-1,1-Dimethylethyl-4-[(1-methyl-2-oxopiperid-5-yl)methyl]benzamide 7b
1H-NMR (400 MHz, CDCl3): δ = 1.41–1.58 (m, 10H; -C(CH3)3, C5-H),
1.81–1.92 and 2.07–2.19 (2m, 2H; -CO-CH2-CH2-), 2.31 and 2.47 (ddd, 1H,
2J = 18 Hz, 3J = 11.5 Hz, 3J = 6.5 Hz and ddd, 1H, 2J = 18 Hz, 3J = 6 Hz, 3J
= 3.5 Hz; -CO-CH2-), 2.65 and 2.69 (dd, 1H, 2J 13 Hz, 3J 7 Hz and dd, 1H,
2J 13 Hz, 3J 7 Hz; -Ph-CH2-), 2.89 (s, 3H; -N(CH3)-), 3.00 and 3.15 (dd,
1H, 2J = 12 Hz, 3J = 10 Hz and ddd, 1H, 2J = 12 Hz, 3J = 5 Hz, 4J = 1.5 Hz;
-N(CH3)-CH2-), 5.93 (s, 1H, -NH-), 7.20 and 7.67 (AA′BB′, 4H, 3J = 8 Hz;
1,4-disubst. arom. H).– IR (KBr): ν = 3290, 3050, 2960, 2920, 1665, 1620,
1540, 1500, 1450, 1405, 1340, 1310, 1235, 1220, 880, 840, 760, 540.
HPLC Procedure
The procedure was carried out[20] similar to the method of Cook et al.[30]
.
The steroids were dissolved in 50 µl methanol and 25 µl injected into the
computer-controlled HPLC system, which was checked before usinglabelled
reference controls. Radioactivity was measured using a Berthold LB 506C
monitor. Using methanol/water (55:45, w/w) for T and DHT, with a flow of
0.4 ml/min and an additive flow of 1.0 ml for scintillator, base-line-separa-
tion of T and DHT was achieved within 20 min.
N,N-Bis(1-methylethyl)-4-[3-(1-methyl-2-oxopiperid-5-yl)propyl]benz-
amide 8a
Calculation Procedure
1H-NMR (400 MHz, CDCl3): δ = 0.97–1.62 (m, 15H; 2 -CH(CH3)2,
-CH2-CH2-CH2-Ph-, C5-H), 1.66 (m, 2H; -CH2-CH2-Ph-), 1.77–1.94 (m, 2H;
-CO-CH2-CH2-), 2.32–2.46 (ddd, 1H, 2J = 17.5 Hz, 3J = 11.5 Hz, 3J = 6 Hz
and ddd, 1H, 2J = 17.5 Hz, 3J = 5.5 Hz, 3J = 3 Hz; -CO-CH2-), 2.63 (t, 2H,
3J = 7.5 Hz; -CH2-Ph-), 2.92 (s, 3H; -N(CH3)-), 2.94 and 3.25 (dd, 1H, 2J =
12 Hz, 3J = 10 Hz and ddd, 1H, 2J =12 Hz, 3J = 5 Hz, 4J = 2 Hz; -N(CH3)-
The amount of DHT formed was calculated (% DHT). The zero value was
subtracted from the control (cv) and inhibition (iv) value (cvcorr and ivcorr).
Inhibition (I) was calculated using the following equation:
% I = (1 – ivcorr/cvcorr)100.
3
CH2-), 7.17 and 7.24 (AA′BB′, 4H, J = 8 Hz; 1,4-disubst. arom. H).– IR
(KBr): ν = 3040, 2960, 2920, 2850, 1640, 1630, 1500, 1440, 1400, 1365,
References
✩
Dedicated to Professor Dr. Dr. W. Schunack on the occasion of his 65th
1335, 1210, 1160, 1035, 1020, 830, 760.
birthday.
N-1,1-Dimethylethyl-4-[3-(1-methyl-2-oxopiperid-5-yl)propyl]benzamide
8b
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Received: December 28, 1999 [FP448]
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