Novel High Energy Intermediate Analogues with Triazasterol-related Structures as Inhibitors of the Ergosterol Biosynthesis V [1]. Synthesis of Hexahydro-5H-imidazo[1′,2′:1,2]pyrimido-[4,3-a]isoquinolines and 1-Alkyl Analogues Representing New 8,13,15-Triazasteroids

Article abstract of DOI:10.1007/s00706-003-0038-9

The synthesis of 1,2,6,10b,11,12-hexahydro-5H-imidazo[1′,2′:1, 2]pyrimido[4,3-a]isoquinolines representing new types of 8,13,15-triazasteroids is described. The tetracyclic title compounds were prepared from 4-(2-hydroxyalkylamino)tetrahydro-2H-pyrimidoisoquinolines, which furnish after conversion to the corresponding bromoalkylamino compounds and base-catalyzed intramolecular nucleophilic displacement cyclization of the latter the desired 1-substituted 8,13,15-triazasteroids with aromatic ring A. The structures of the compounds were proved and assigned on the basis of homo- and heteronuclear correlated 1D and 2D NMR experiments. The title compounds represent triaza-analogues of selected high energy intermediates (HEI) of steroidal substrates formed during the enzymatic transformation of squalene into ergosterol and are designed to act as inhibitory mimicries of HEIs and potential antimycotics.

Full text of DOI:10.1007/s00706-003-0038-9

Monatshefte f €u r Chemie 134, 1271–1282 (2003)
DOI 10.1007/s00706-003-0038-9
Novel High Energy Intermediate Analogues
with Triazasterol-related Structures
as Inhibitors of the Ergosterol
Biosynthesis V [1]. Synthesis of Hexahydro-
5
H-imidazo[19,29:1,2]pyrimido-
4,3-a]isoquinolines and 1-Alkyl Analogues
[
Representing New 8,13,15-Triazasteroids
ꢀ
Edith G o¨ ßnitzer and Asbj o¨ rn Punkenhofer
Institute of Pharmaceutical Chemistry and Pharmaceutical Technology,
Karl-Franzens-University Graz, A-8010 Graz, Austria
Received March 4, 2003; accepted March 7, 2003
Published online June 23, 2003 # Springer-Verlag 2003
0
0
Summary. The synthesis of 1,2,6,10b,11,12-hexahydro-5H-imidazo[1 ,2 :1,2]pyrimido[4,3-a]isoquino-
lines representing new types of 8,13,15-triazasteroids is described. The tetracyclic title compounds
were prepared from 4-(2-hydroxyalkylamino)tetrahydro-2H-pyrimidoisoquinolines, which furnish
after conversion to the corresponding bromoalkylamino compounds and base-catalyzed intramolecular
nucleophilic displacement cyclization of the latter the desired 1-substituted 8,13,15-triazasteroids with
aromatic ring A. The structures of the compounds were proved and assigned on the basis of homo- and
heteronuclear correlated 1D and 2D NMR experiments. The title compounds represent triaza-ana-
logues of selected high energy intermediates (HEI) of steroidal substrates formed during the enzymatic
transformation of squalene into ergosterol and are designed to act as inhibitory mimicries of HEIs and
potential antimycotics.
0
0
Keywords. Hexahydro-5H-imidazo[1 ,2 :1,2]pyrimido[4,3-a]isoquinolines; High energy intermedi-
ate analogues; Structure elucidation; Fungicides.
Introduction
Due to the increasing clinical importance of opportunistic fungal infections there is
a continuing demand for improved antifungal agents [2–4]. Most of the antifungal
drugs presently used belong to the ergosterol biosynthesis inhibitors, which have in
ꢀ Corresponding author. E-mail: edith.goessnitzer@uni-graz.at

1
272
E. G €o ßnitzer and A. Punkenhofer
Fig. 1. Carbocationic HEIs and general formulae of corresponding HEIAs of type 1 and 2a–2cꢁHCl
common the ability to block specific enzymes with the result of fatal malfunctions
of the fungal cell membrane [5].
In the course of our efforts to develop new antimicrobial agents we have
4
4
synthesized among others a series of N -alkyl- and N -alkenyltetrahydro-2H-py-
rimido[4,3-a]isoquinolin-4-amine salts 1 [6] (Fig. 1). The design of this new type of
triazasteroids was based on the knowledge, whereupon in the course of the enzy-
matic transformation of squalene into ergosterol the steroidal substrates are trans-
formed into carbocationic transition state intermediates, so called high energy
intermediates (HEI), and that HEI analogues (HEIAs) with positive charge are able
to act as inhibitors of specific fungal enzymes [5, 7, 8]. The 8,13,15-triazaseco-
steroids 1 with integrated guanidinium moiety and hence very stable positive charge
have been designed and prepared as HEIAs to mimic the HEI I–III (Fig. 1) [1, 6, 9].
Screening tests have shown recently, that HEIAs 1 indeed display significant anti-
mycotic effects on fungal organisms, in some cases comparable with the activity
observed for the potent azole derivative itraconazole [6].
In this contribution we report on the synthesis of hexahydro-5H-imi-
0
0
dazo[1 ,2 :1,2]pyrimido[4,3-a]isoquinolines representing new 8,13,15-triazasteroids
of HEIA-type 2 with complete tetracyclic skeleton and close structural resem-
blance to the native HEIs I–III generated by oxidosqualene lanosterol cyclase,
14
8
7
D -reductase, and D -D -isomerase, respectively (Fig. 1). Further structural ele-
ments considered as important for antifungal activity of the 8,13,15-triazasteroid
analogues 2a–2cꢁHCl are the stable positive charge and appropriate 1-alkyl sub-
stituents, i.e. hexyl and 1,5-dimethylhexyl residues, at C-17 (steroid numbering).
The positive charge in the guanidinium moiety of HEIAs 2 is delocalized and
spread over N-8, N-13, N-15, and C-14, that means the charge can appear at the
same ring positions as in native HEIs I–III.

New 8,13,15-Triazasteroids
1273
Results and Discussion
0
0
For the preparation of hexahydro-5H-imidazo[1 ,2 :1,2]pyrimido[4,3-a]isoquino-
lines 2a–2cꢁHCl we used the route illustrated in Scheme 1. In this approach the
two types of requisite precursors, the tricyclic methylthio compound 3ꢁHI and
aminoalkanols 6a–6c (Scheme 2) are built up first separately, and then coupled to
yield the 4-(2-hydroxyalkylamino)pyrimidoisoquinolines 4a–4cꢁHI. The conver-
sion of these salts into the corresponding bromoalkylamino compounds 5a–5cꢁHI
and intramolecular cyclization of the latter furnishes the desired tetracyclic com-
pounds 2a–2cꢁHCl with appropriate side chains at position 1.
The synthesis of the racemic 4-methylthio-1,6,7,11b-tetrahydro-2H-pyrimido-
[
4,3-a]isoquinoline hydroiodide (3ꢁHI) has been described previously [9].
Accordingly, ꢀ-phenylethylamine was transformed in two steps into N-phenethyl-
-phthalimidopropionamide, which is subsequently cyclized, saponified, and re-
3
duced to yield 1-(aminoethyl)tetrahydroisoquinoline. Condensation of the latter with
Scheme 1
Scheme 2

1
274
E. G €o ßnitzer and A. Punkenhofer
carbon disulfide and S-methylation of the generated pyrimidoisoquinolinethione
gives the angularly fused isothiuronium salt 3ꢁHI containing the rings A–C of the
steroid nucleus.
The l-amino-2-octanols 6b and 6c as second building block for the target
compounds 2b and 2c were synthesized in two steps as outlined in Scheme 2.
First, the cyanohydrins 9b and 9d were prepared from the corresponding commer-
cially available heptanal (8b) and ( ꢂ )-2,6-dimethyl-5-heptenal (8d) through addi-
tion of hydrogen cyanide. The reaction proceeded readily in methanolic solution
with potassium cyanide in the presence of glacial acetic acid [10] and was
complete within 30 min affording yields of 94% or higher. Cyanohydrin 9b was
subsequently reduced with lithium aluminum hydride in diethyl ether to the ( ꢂ )-
1-amino-2-octanol (6b). In order to reduce the cyano group and the double bond
simultaneously, the hydrogenation of dimethyloctenenitrile 9d was carried out with
palladium on charcoal as catalyst. After distillation a mixture of diastereomeric
saturated 3,7-dimethylaminooctanols 6c was isolated in 62% yield.
In initial efforts we tried to prepare bromoethylaminopyrimidoisoquinoline
aꢁHI in one step by direct reaction of methylthio compound 3ꢁHI with commer-
5
cially available 2-bromoethylamine (7) under various conditions (Scheme 1), but
the respective experiments were not successful.
Thus, we used the pathway via 4-(2-hydroxyalkylamino)pyrimidoisoquinolines
4
ꢀ
a–4cꢁHI, which were synthesized from 3ꢁHI and 2-aminoethanol (6a), as well as
-aminooctanols 6b and 6c (Scheme 1). Among various solvents examined for this
reaction (methanol, butanol, tert-butanol, THF, acetonitrile) the highest efficiency
was attained with acetonitrile. In the other solvents no (THF), or only little trans-
formation (methanol), or the production of great amounts of unidentified side
products (butanol, tert-butanol) were observed.
Next, the conversion of the alkanols 4a–4cꢁHI into corresponding bromoalkyl
compounds 5a–5cꢁHI was performed through a mild and very efficient general
method of bromination [11] by treatment of 4a–4cꢁHI with a slight excess of
ꢄ
phosphorus tribromide in dichloromethane at ꢃ 10 C. The yields of isolated pro-
ducts 5a–5cꢁHI were excellent. In contrast, treatment of hydroxy compounds
4
a–4cꢁHI with 48% hydrogen bromide in a two phase system (CH Cl =H O) under
2
2
2
reflux resulted in only poor yields of the desired bromo compounds 5a–5cꢁHI
mixed with unseparable impurities.
Finally, the imidazole ring D of the triazasteroids 2a–2c was closed by a base-
4
catalyzed nucleophilic displacement of bromine in the N -alkyl side chain by the
ring nitrogen N-3 of the pyrimidoisoquinolines 5a–5c. The reaction was performed
by treating a tetrahydrofuran solution of the salts 5a–5cꢁHI with pure NaH at low
temperatures under anhydrous conditions (Scheme 1). Thus, racemic hexahydro-
0
0
imidazo[1 ,2 :1,2]pyrimido[4,3-a]isoquinoline hydochloride (2aꢁHCl) and the dia-
stereomeric 1-hexyl analogue 2bꢁHCl could be synthesized in yields of 70% and
60%, respectively. Purification, in particular of the diastereomeric 1-(1,5-dimethyl-
hexyl) compound 2cꢁHCl proved to be tedious, hence it was obtained in only 30%
yield after chromatography.
In analogy to the above reaction sequence, the synthesis of the racemic D-homo
derivative 12ꢁHCl was accomplished, via the 4-hydroxypropylamino and 4-bro-
mopropylamino intermediates 10ꢁHI and 11ꢁHI, in 54% yield (Scheme 3).

New 8,13,15-Triazasteroids
1275
Scheme 3
The structures and complete signal assignments of the 4-substituted pyrimido-
isoquinolines of type 4ꢁHI and 5ꢁHI, of the imidazopyrimidoisoquinolines 2a–
2
cꢁHCl, and of the pyrimido-fused tetracyclus 12ꢁHCl were established by means
1
13
of NMR spectroscopic studies based on H and C NMR, HH-COSY, NOESY,
gs-HSQC, gs-HMBC, and 1D NOE difference experiments as well as by increment
calculations [12, 13].
Compounds 4aꢁHI, 5aꢁHI, 10–12ꢁHCl, and 2aꢁHCl with only one chiral center at C-11b and C-10b
0
are each racemates. Compounds 4bꢁHI, 5bꢁHI, and 2bꢁHCl possess a second chiral center at C-2 in the
1
-(2-substituted octylamino) side chains and in the 1-position. The C resonances of the chiral carbons
3
4
0
0
C-11b and C-2 of 4bꢁHI and 5bꢁHI, as well as of C-10b and C-1 of 2bꢁHCl are duplicated. Hence, these
1
products are mixtures of two diastereomeric racemates each. The H NMR spectra of the three salts in
different solvents (DMSO-d and CDCl ) and at various temperatures (293, 298, 305 K) exhibit for
6
3
1
nearly all hydrogen atoms only one signal each. Solely the H NMR of tetracyclus 2bꢁHCl shows two
separated doublets of triplets for H-10b and two singlets for NH-3.
The salts 4cꢁHI, 5cꢁHI, and 2cꢁHCl possess three chiral centers and could thus be mixtures of up to
1
four diastereomeric racemates each. However, the C NMR spectra of the three compounds exhibit
3
0
again only for some of the chiral carbons (C-2 of 4cꢁHI, C-11b of 4cꢁHI and 5cꢁHI, C-1 and C-10b of
2
cꢁHI) duplicated resonances. This finding points towards the existence of only two diastereomers in
1
each product, but does not prove it. Also the H NMR spectra are not sufficiently different, duplicated
0
signals were only observed for H-2 and OH in case of 4cꢁHI and H-11b of 5cꢁHI.
The chemical shifts and signal patterns of the proton resonances for the tetra-
hydropyrimidoisoquinoline moieties of all angularly fused compounds of type 2, 4,
and 5 as well as the NOE experiments reveal the existence of a half-chair conforma-
tion of the tetrahydropyridine ring with axially oriented methine protons H-10b (2a–
2
cꢁHCl) and H-11b (4a–4cꢁHI, 5a–5cꢁHI). Due to the planar guanidinium moiety the
fused tetrahydropyrimidine ring exhibited a sofa conformation as recently described
[
9]. As a consequence, the diastereomers of the tetracycles 2bꢁHCl and 2cꢁHCl differ
0
mainly with respect to the relative configuration at C-1 and (in case of 2cꢁHCl) C-1
of the side chain. Efforts to determine the relative configuration at the chiral centers
C-10b and C-1 of the two diastereomers to 2bꢁHCl, as well as at C-10b, C-1, and C-10
in the diastereomers of 2cꢁHCl by means of NOE experiments were not successful so
far. A detailed NMR study on the problem is in progress.
However, in case of the 1-(1,5-dimethyl)hexyl compound 2cꢁHCl the signal for
the methine proton H-1 appears as a triplet-doublet with J ¼ 10.4 and 3.2 Hz, which
is indicative for its axial location and a consequent equatorial orientation of the
0
side chain, and an approximate trans position of H-1 at the nucleus and H-1 of the
side chain. Figure 2 shows exemplarily the stereoformulae of the tetracyclic ring
systems of the (1R,10bS)- and (1S,10bS)-enantiomers of 2bꢁHCl and 2cꢁHCl.

1
276
E. G €o ßnitzer and A. Punkenhofer
Fig. 2. The diastereomers of 2bꢁHCl and 2cꢁHCl
For practical purposes, the tricyclic alkanols 4bꢁHI and 4cꢁHI as well as the
bromoalkyl compounds 5bꢁHI and 5cꢁHI were carried through the reaction
sequences as mixtures of diastereomers. The separation of the components of
the target compounds 2a–2cꢁHCl by proper methods such as fractional crystal-
lization, chromatography, and resolution is currently under investigation. The anti-
microbial screening of the HEIA-type imidazopyrimidoisoquinolines 2a–cꢁHCl is
carried out presently with the racemates and racemic diasteroisomers.
Experimental
All reactions were carried out under Ar atmosphere. Melting points were determined on a Kofler melting
point apparatus and are uncorrected. Thin-layer chromatograms (TLC) were run on TLC plastic sheets
silica gel 60 F254 (E. Merck, Darmstadt). The spots were detected by visual examination under UV light
(254 and 366 nm), and visualized with chlorine vapour or by spraying with an ethanolic solution of 0.5%
vanillin and 80% H SO and successive heating. Column chromatography (CC) was performed using
2
4
silica gel 60 (0.063–0.200 mm, Merck). Infrared spectra were recorded with a 2000 FTIR spectro-
photometer (s¼ strong, m ¼ medium, w ¼ weak). NMR spectra were aquired on a Varian 400 MHz
Unity Inova NMR spectrometer equipped with a Sun Sparc 5 computer system and operating at an
1
13
observation frequency of 399.98 MHz for H and 100.59 MHz for C. 1D and 2D NMR experiments
were performed using a pulsed magnetic field gradient unit and a 5 mm inverse broadband probehead.
The HH-COSY, gs-HSQC, gs-HMBC, NOESY, and 1D NOE difference experiments were performed
using the pulse programs supplied by the manufacturer. The gs-HMBC experiments were optimized for
n
, 8 and 10 Hz J giving delays of 125.0, 62.5, and 50.0ms. All NOEs were measured in degassed
4
CH
3
samples. Amounts of 15–25 mg of the substances were dissolved in 0.5cm of deuterated solvents and
measured at 298 K. All chemical shifts are reported with TMS as internal standard. For a convenient
reading correlating spin systems are reported coherently, assignments marked with an asterisk are
interchangeable. Elemental analyses (C, H, N, halogen) were performed by J. Theiner, Microanalytical
Laboratory at the University of Vienna, Institute of Physical Chemistry; they were found to agree
favourably with the calculated values.
(2RS)-2-Hydroxyoctanenitrile (9b)
The reported procedure was modified according to Ref. [10]. Heptanal (8b) (7.00 g, 50 mmol) in
1
3
0cm of MeOH was added slowly to an ice-cooled solution of 4.90 g of KCN (75 mmol) in
3
00 cm of MeOH. After stirring the mixture for 15 min, 6.00g of glacial acetic acid (100 mmol)
1
ꢄ
was added dropwise and stirred at 0 C for additional 15min. Then the mixture was poured into

New 8,13,15-Triazasteroids
1277
3
3
3
00 cm of H O and extracted with 3ꢅ60 cm of CH Cl . The combined organic layers were washed
2
2
2
with H O, dried over Na SO , and concentrated under reduced pressure to give 6.61 g (94%) of 2-
2
2
4
hydroxyoctanenitrile (9b) as yellowish liquid. TLC (light petroleum:Et O ¼ 1:1): R ¼ 0.42, visualiza-
2
f
tion with vanillin-H SO ; IR (neat): ꢁꢀ ¼ 3445(s), 2956(s), 2930(s), 2860(s), 2247(w), 1761(w),
2
4
ꢃ 1
466(m), 1125(w), 1070(m) cm ; H NMR (CDCl ): see Ref. [14]. C NMR (CDCl ): 13.9 (C-8),
3 3
1
13
1
2
2.4 (C-7), 24.4 (C-4), 28.5 (C-6), 31.4 (C-5), 35.0 (C-3), 61.1 (C-2), 120.2 (C-1) ppm.
(2RS)-1-Amino-2-octanol (6b)
3
Cyanohydrin 9b (6.40 g, 45.3 mmol) in 25 cm of dry Et O was added dropwise to the solution of 3.44g
2
3
of LiAlH (90.6 mmol) in 100 cm of anhydrous Et O at 0 C. After warming to room temperature the
ꢄ
4
2
3
mixture was stirred for 16h. The reaction was cautiously quenched by successive addition of 3.5 cm of
3
H O, 3.5 cm of 3 N NaOH, and 10 cm of H O, and the formed white slurry was filtered through a pad of
3
2
2
silica gel, which was washed twice with Et O. The combined organic phases were dried over Na SO and
2
2
4
the solvent was evaporated to give after distillation invacuo 4.05g (62%) of 6b as a colourless liquid. Bp
ꢄ
ꢄ
8
2 C=5 mbar (Ref. [15] 130–132 C=26 torr), TLC (basic Al O , ethyl acetate:MeOH¼ 1:1): R ¼ 0.24,
2
3
f
visualization with vanillin-H SO ; IR (neat): ꢁꢀ ¼ 3357(m), 2927(s), 1595(w), 1466(m), 1378(w),
2
4
ꢃ 1
1
13
1
062(w), 964(w) cm ; H NMR (CDCl ): see Ref. [16]. C NMR (CDCl ): ꢂ ¼ 13.9 (C-8), 22.5
3
3
(
C-7), 25.6 (C-4), 29.3 (C-5), 31.7 (C-6), 34.8 (C-3), 47.5 (C-1), 72.0 (C-2) ppm.
(
2RS,3RS)-2-Hydroxy-3,7-dimethyl-6-octenenitrile (9d, C H NO)
0 17
1
Following the procedure described for 9b, the reaction of 7.00g of dimethylheptenal 8d (50 mmol),
3
4
.90g of KCN (75 mmol), and 6.01 g of glacial acetic acid (100 mmol) in 100 cm of MeOH afforded
.35g of pure yellowish liquid 9d in quantitative yield. TLC (light petroleum:Et O ¼ 1:1): R ¼ 0.47,
8
2
f
visualization with vanillin-H SO ; IR (neat): ꢁꢀ ¼ 3445(s), 2968(s), 2920(s), 2859(s), 2246(w),
2
4
ꢃ 1
1
1
673(m), 1647(w), 1453(s), 1379(s), 1060(s) cm ; H NMR (CDCl ): ꢂ ¼ 1.04 (d, J ¼ 6.8 Hz,
3
CH -3), 1.27 and 1.67 (m, H -4, and m, partly overlapped, H -4), 1.58 (s, H -8), 1.66 (s, H -7),
3
3
a
b
3
1
.85 and 2.01 (m, H -5, and m, 1H, H -5), 1.97 (m, H-3), 3.43 (bs, OH), 4.33 (t, J ¼ 5.6 Hz, H-2),
a
b
13
.06 (t, J ¼ 6.8Hz, H-6) ppm; C NMR (CDCl ): ꢂ ¼ 14.7 (CH at C-3), 17.6 (C-8), 25.0 (C-5), 25.6
5
3
3
(CH at C-7), 31.5 (C-3), 37.2 (C-4), 65.7=66.0 (C-2), 119.2=119.6 (C-1), 123.4 (C-6), 132.3 (C-7) ppm.
3
(
2RS,3RS)-1-Amino-3,7-dimethyl-2-octanol (6c, C H NO)
1
0 23
3
Octenol 9d (7.25 g, 42.3mmol) dissolved in 75cm of ethyl acetate was hydrogenated at 2.75bar and
room temperature in the presence of 0.60 g of 10% Pd=C. After the uptake of H was complete (3h),
2
the catalyst was filtered off and the solvent was evaporated to yield after distillation in vacuo 4.57g
ꢄ
(
62%) of 6c as colourless oil. Bp 125 C=20mbar, TLC (basic Al O , ethyl acetate:MeOH¼ 1:1):
2
3
R ¼ 0.31, visualization with vanillin-H SO ; IR (neat): ꢁꢀ ¼ 3361(m), 2955(s), 2928(s), 1593(m),
f
2
4
ꢃ 1
1
1
467(m), 1383(m), 1366(m) cm
;
H NMR (CDCl ): ꢂ ¼ 0.82 (d, J ¼ 6.4 Hz, H -8), 0.84 (d,
3
3
J ¼ 6.4 Hz, H -7), 0.86 (d, J ¼ 6.8 Hz, H -3), 1.08–1.12 (overlapping multiplets, H -6, H -5), 1.34
3
3
2
2
(
m, H -4), 1.42 (m, partly overlapped, 1H, H-7), 1.48 (m, partly overlapped, H-3), 1.90 (b, OH, NH ),
2 2
1
3
2
.57 and 2.78 (m, H -1, and m, H -1), 3.25=3.33 (m, H-2) ppm; C NMR (CDCl ): ꢂ ¼ 14.5 (CH at
a
b
3
3
ꢀ
4.4=45.1 (C-1), 75.6=75.9 (C-2) ppm.
ꢀ
C-3), 22.5 (C-8 ), 22.7 (CH at C-7 ), 24.8 (C-5), 27.9 (C-6), 32.7 (C-4), 36.7 (C-7), 39.2 (C-3),
3
4
General Procedure for the Synthesis of 4-(2- and 3-Hydroxyalkylamino)tetrahydro-
2
H-pyrimido[4,3-a]isoquinoline hydroiodides 4a–4cꢁHI and 10ꢁHI
2
-Methylthiopyrimidoisoquinoline salt 3ꢁHI (10mmol) and 12mmol of the respective aminoalcohols
3
a–6c were dissolved in 50cm of anhydrous acetonitrile and refluxed under TLC monitoring for
6

1
278
E. G €o ßnitzer and A. Punkenhofer
1
4–16 h. The CH SH liberated during this time was discharged successively into 20% aqueous KMnO
3
4
and 6 N NaOH solutions. After cooling, dry N was passed through to remove remaining CH SH. Then
2
3
the solvent was evaporated under reduced pressure. The obtained solid was triturated three times with 2 N
aqueous HI and twice with H O, and filtered. After drying, the crude product was triturated successively
2
twice with Et O and once with n-hexane, filtered, and dried in vacuo to yield the yellowish crystalline,
2
slightly hygroscopic compounds.
(11bRS)-4-(2-Hydroxyethylamino)-1,6,7,11b-tetrahydro-2H-pyrimido[4,3-a]isoquinoline
hydroiodide (4aꢁHI, C H IN O)
1
4
20
3
ꢄ
Yield: 2.65g (71%), mp 45 C, TLC (CH Cl :MeOH¼ 4:1): R ¼ 0.60, visualization with Cl ; IR (KBr):
2
2
f
2
ꢁ
ꢀ ¼ 3260(s), 2928(m), 2876(m), 1612(s), 1492(m), 1451(m), 1392(m), 1346(m), 1152(m), 1041(m)
ꢃ 1 1
cm ; H NMR (DMSO-d ): ꢂ ¼ 1.84 (m, H -1), 2.64 (dm, J ¼ 13.6Hz, H -1), 2.86 (m, H -7), 3.00 (m,
6
a
b
a
0
0
H -7), 3.24 (m, H -1 ), 3.36 (m, H -2, H -6), 3.53 (t, J ¼ 5.6 Hz, H -2 ), 3.92 (dt, J ¼ 12.8, 4.8 Hz, H -6),
b
2
2
a
2
b
4
7
4
.77 (dd, J ¼ 10.0, 4.0 Hz, H-11b), 5.09 (bs, OH), 7.25 (m, H-8, H-9, H-10), 7.33 (d, J ¼ 6.8 Hz, H-11),
13
.51 (bs, H-4), 8.00 (bs, H-3); C NMR (DMSO-d ): ꢂ ¼ 27.7 (C-1), 28.0 (C-7), 37.1 (C-2), 43.4 (C-6),
6
0
0
ꢀ
ꢀ
4.0 (C-1 ), 53.7 (C-11b), 59.4 (C-2 ), 125.4 (C-11), 126.4 (C-10 ), 127.0 (C-9 ), 128.5 (C-8), 134.2
(
C-7a), 135.5 (C-11a), 152.6 (C-4) ppm.
(11bRS)-4-[(2RS)-2-Hydroxyoctylamino]-1,6,7,11b-tetrahydro-2H-pyrimido[4,3-a]isoquinoline
hydroiodide (4bꢁHI, C H IN O)
2
0
32
3
ꢄ
Yield: 3.97g (87%), mp 60 C, TLC (CH Cl :MeOH ¼ 6:1): R ¼ 0.88, visualization with Cl ; IR
2
2
f
2
ꢃ 1
1
(
KBr): ꢁꢀ ¼ 3258(s), 2927(s), 2855(s), 1613(s), 1454(m), 1306(m), 1244(m), 1068(m) cm ; H
0
0
0
0
0
NMR (DMSO-d ): ꢂ ¼ 0.85 (t, J ¼ 6.8 Hz, H -8 ), 1.25 (m, H -4 , H -5 , H -6 , H -7 ), 1.38 (m, H -
6
3
2
2
2
2
2
0
3
), 1.83 and 2.61 (m, H-1 , and dm, J ¼ 12.8 Hz, H-1 ), 2.84 and 2.98 (dm, J ¼ 15.6 Hz, H-7 and
ax
eq
eq
0
m, H-7 ), 3.21 (m, H -1 ), 3.36 and 3.98 (m, partly overlapped, H-6 , and dt, J ¼ 12.8, 5.6 Hz, H-6 ),
ax
2
ax
eq
0
3
.34 (m, partly overlapped, H -2) 3.60 (m, H-2 ), 4.76 (dd, J ¼ 10.4, 4.8 Hz, H-11b), 5.13 (d,
2
J ¼ 3.6 Hz, OH), 7.25 (m, H-8, H-9, H-10), 7.33 (d, J ¼ 6.8 Hz, H-11), 7.57 (t, J ¼ 5.2 Hz, H-4),
1
3
0
0
0
8
2
1
.14 (bs, H-3) ppm; C NMR (DMSO-d ): ꢂ ¼ 13.9 (C-8 ), 22.0 (C-7 ), 24.9 (C-5 ), 27.8 (C-1),
6
0
0
0
0
8.7 (C-7), 31.2 (C-6 ), 31.3 (C-4 ), 34.1 (C-3 ), 37.1 (C-2), 43.4 (C-6), 47.9 (C-1 ), 54.0=54.1 (C-
0
ꢀ
ꢀ
1b), 68.5=68.7 (C-2 ), 125.1 (C-11), 126.6 (C-10 ), 127.1 (C-9 ), 128.4 (C-8), 134.4 (C-7a), 135.7
(
C-11a), 152.8 (C-4) ppm.
(11bRS)-4-[(2RS, 3RS)-2-Hydroxy-3,7-dimethyloctylamino]-1,6,7,11b-tetrahydro-
2
H-pyrimido[4,3-a]isoquinoline hydroiodide (4cꢁHI, C H IN O)
2
2
36
3
ꢄ
Yield: 4.22g (87%), mp 48 C, TLC (CH Cl :MeOH ¼ 6:1): R ¼ 0.76, visualization with Cl ; IR
2
2
f
2
ꢃ 1
1
(
(
KBr): ꢁꢀ ¼ 3274(s), 2927(s), 1614(s), 1458(m), 1364(m), 1244(m), 1041(m) cm
;
H NMR
0
0
DMSO-d ): ꢂ ¼ 0.80 (d, J ¼ 7.2 Hz, CH -3), 0.85 (d, J ¼ 6.8 Hz, H -8 , CH -7), 1.11 (m, H -6 ,
6
3
3
3
2
0
0
0
0
H -5 ), 1.37 (m, H -4 ), 1.50 (m, H-3 , H-7 ), 1.83 and 2.63 (m, H -1, and m, H -1), 2.85 and 2.96
2
2
a
b
0
(
dm, J ¼ 14.8Hz, H-7 , and m, H-7 ), 3.20 (m, H -1 ), 3.28 and 3.92 (m, partly overlapped, H-6 ,
eq
ax
2
ax
0
and dt, J ¼ 14.8, 6.0Hz, H-6 ), 3.37 (m, partly overlapped, H -2), 3.47=3.55 (m=m, H-2 ), 4.77 (dd,
eq
2
J ¼ 10.8Hz, 4.4 Hz, H-11b), 5.02=5.10 (d=d, J ¼ 5.2 Hz, OH), 7.16 (m, H-8, H-9, H-10), 7.32 (d,
1
3
J ¼ 7.4 Hz, H-11), 7.40 (t, J ¼ 5.6Hz, H-4), 8.04 (bs, H-3) ppm; C NMR (DMSO-d ): ꢂ ¼ 19.3
6
0
0ꢀ
C-7), 29.8 (C-7 ), 35.3 (C-3 ), 37.2 (C-2), 38.7 (C-6 ), 39.6 (C-1 ), 43.5 (C-6), 54.0=54.2 (C-11b),
0ꢀ
0
0
0
(
CH at C-3 ), 22.5 (C-8 ), 22.7 (CH at C-7 ), 24.4 (C-5 ), 26.7 (C-1), 27.4 (C-4 ), 27.9
3
3
0
0
0
(
0
ꢀ
ꢀ
7
2.3=72.9 (C-2 ), 125.2 (C-11), 126.7 (C-10 ), 127.2 (C-9 ), 128.4 (C-8), 134.5 (C-7a), 135.8 (C-11a),
1
52.1 (C-4) ppm.

New 8,13,15-Triazasteroids
1279
(11bRS)-4-(3-Hydroxypropylamino)-1,6,7,11b-tetrahydro-2H-pyrimido[4,3-a]isoquinoline
hydroiodide (10ꢁHI, C H IN O)
1
5
22
3
ꢄ
Yield: 2.54g (66%), mp 72 C, TLC (CH Cl :MeOH ¼ 6:1): R ¼ 0.53, visualization with Cl ; IR
2
2
f
2
ꢃ 1
1
(
KBr): ꢁꢀ ¼ 3256(s), 2929(m), 2876(m), 1610(s), 1492(m), 1345(m), 1243(m), 1060(m) cm ; H
0
NMR (DMSO-d ): ꢂ ¼ 1.69 (quin, J ¼ 6.4 Hz, H -2 ), 1.84 (m, H -1), 2.63 (dd, J ¼ 13.2, 4.0Hz, H -1),
6
2
a
b
0
2
.84 (dt, J ¼ 16.4, 4.4 Hz, H -7), 2.98 (m, H -7), 3.20 (m, H -1 ), 3.36 (m, H -2, H -6), 3.47 (q,
a
b
2
2
a
0
J ¼ 4.8 Hz, H -3 ), 3.88 (dt, J ¼ 13.2, 4.8 Hz, H -6), 4.63 (t, J ¼ 4.4 Hz, OH), 4.76 (dd, J ¼ 10.4,
2
b
4
.8 Hz, H-11b), 7.25 (m, H-8, H-9, H-10), 7.33 (d, J ¼ 6.4 Hz, H-11), 7.44 (t, J ¼ 5.2 Hz, H-4), 8.04
13
0
0
(
s, H-3) ppm; C NMR (DMSO-d ): ꢂ ¼ 27.5 (C-1), 28.0 (C-7), 31.3 (C-2 ), 37.1 (C-2), 38.5 (C-1 ),
6
0
ꢀ
ꢀ
4
3.3 (C-6), 53.5 (C-11b), 57.9 (C-3 ), 125.2 (C-11), 126.1 (C-10 ), 126.9 (C-9 ), 128.7 (C-8), 134.2
(
C-7a), 135.1 (C-11a), 152.3 (C-4) ppm.
General Procedure for the Synthesis of 4-(2- and 3-Bromoalkylamino)tetrahydro-
H-pyrimido[4,3-a]isoquinoline hydroiodides 5a–5cꢁHI and 11ꢁHI
Phosphorus tribromide (9.60 mmol) was added dropwise to a cold solution of the respective hydro-
2
3
xyalkylaminopyrimidoisoquinoline (8mmol) 4a–4cꢁHI and 10ꢁHI in 50cm of dry CH Cl main-
2
2
ꢄ
taining the reaction temperature at ꢃ 10 C and stirring for 1 h. After warming to room temperature the
3
reaction mixture was stirred for 15h and then quenched cautiously with 2 cm of H O. After that, the
2
reaction mixture was dried (Na SO ) and the solvent evaporated under reduced pressure. The obtained
4
2
solid was treated successively twice with 2 N aqueous HI and Et O, filtered, and dried at room
2
temperature (1mbar). Trituration of the crystalline product with hexane gave the yellow compounds.
(11bRS)-4-(2-Bromoethylamino)-1,6,7,11b-tetrahydro-2H-pyrimido[4,3-a]isoquinoline
hydroiodide (5aꢁHI, C H BrIN )
1
4
19
3
ꢄ
Yield: 2.23 g (64%), mp 147 C, TLC (CH Cl :MeOH¼ 6:1): R ¼ 0.55, visualization with Cl ; IR
2
2
f
2
ꢃ 1
1
(
KBr): ꢁꢀ ¼ 3423(m), 3169(m), 2928(m), 1603(s), 1493(m), 1301(m), 1244(m), 1189(m) cm ; H
NMR (DMSO-d ): ꢂ ¼ 1.84 and 2.61 (m, H-1 , and dm, J ¼ 13.6Hz, H-1 ), 2.84 and 3.01 (dt,
6
ax
eq
0
J ¼ 16.0, 4.0 Hz, H-7 , and m, H-7 ), 3.23 (t, J ¼ 6.8 Hz, H -1 ), 3.30 (m, H -2), 3.51 (t, J ¼ 6.8 Hz,
eq
ax
2
2
0
H -2 ), 3.66 and 3.92 (m, H-6 , and dt, J ¼ 13.2, 5.6 Hz, H-6 ), 4.75 (dd, J ¼ 10.0, 4.8Hz, H-11b),
2
ax
eq
7
.25 (m, H-8, H-9, H-10), 7.33 (d, J ¼ 6.0 Hz, H-11), 7.79 (q, J ¼ 5.6 Hz, H-4), 8.27 (bs, H-3) ppm;
1
3
0
C NMR (DMSO-d ): ꢂ ¼ 27.7 (C-1), 27.8 (C-7), 37.2 (C-2), 44.1 (C-1 ), 43.4 (C-6), 54.1 (C-11b),
6
0
ꢀ
ꢀ
5
9.4 (C-2 ), 125.2 (C-11), 126.7 (C-10 ), 127.2 (C-9 ), 128.4 (C-8), 134.5 (C-7a), 135.7 (C-11a),
52.8 (C-4) ppm.
1
(11bRS)-4-[(2RS)-2-Bromooctylamino]-1,6,7,11b-tetrahydro-2H-pyrimido[4,3-a]isoquinoline
hydroiodide (5bꢁHI, C H BrIN )
2
0
31
3
ꢄ
Yield: 4.16 g (100%), mp 68 C, TLC (CH Cl :MeOH¼ 6:1): R ¼ 0.67, visualization with Cl ; IR
2
2
f
2
ꢃ 1
1
(
KBr): ꢁꢀ ¼ 3175(m), 2927(s), 2856(s), 1613(s), 1454(m), 1307(w), 1242(m), 1003(m) cm ; H
0
0
0
0
0
NMR (DMSO-d ): ꢂ ¼ 0.85 (t, J ¼ 6.8 Hz, H -8 ), 1.26 (m, H -4 , H -5 , H -6 , H -7 ), 1.53 and
6
3
2
2
2
2
0
0
1
.71 (m, H -3 , and m, H -3 ), 1.86 and 2.64 (m, H -1, and m, H -1), 2.87 and 3.01 (dm, J ¼ 16.8Hz,
a
b
a
b
H-7 , and m, H-7 ), 3.35 (m, H -2), 3.49 and 3.98 (m, partly overlapped, H-6 , and dt, J ¼ 13.2,
eq
ax
2
ax
0
0
5
.2 Hz, H-6 ), 3.54 (m, H -1 ), 4.31 (m, H-2 ), 4.80 (dd, J ¼ 10.0, 4.4 Hz, H-11b), 7.25 (m, H-8, H-9,
13
eq
2
H-10), 7.33 (d, J ¼ 5.6 Hz, H-11), 7.81 (m, H-4), 8.29 (bs, H-3) ppm; C NMR (DMSO-d ): ꢂ ¼ 13.9
6
0
0ꢀ
), 43.8 (C-6), 47.9 (C-1 ), 54.1=54.3 (C-11b), 68.6=68.8 (C-2 ), 125.1 (C-11), 126.7 (C-10 ), 127.2
0ꢀ
0
0
0
(
C-8 ), 22.0 (C-7 ), 22.2 (C-5 ), 27.8 (C-1), 28.4 (C-7), 31.0 (C-6 ), 31.3 (C-4 ), 35.1 (C-3 ), 37.1 (C-
0
0
ꢀ
2
ꢀ
(
C-9 ), 128.4 (C-8), 134.4 (C-7a), 135.6 (C-11a), 152.3 (C-4) ppm.

1
280
E. G €o ßnitzer and A. Punkenhofer
(11bRS)-4-[(2RS, 3RS)-2-Bromo-3,7-dimethyloctylamino]-1,6,7,11b-tetrahydro-
2
H-pyrimido[4,3-a]isoquinoline hydroiodide (5cꢁHI, C H BrIN )
2
2
35
3
ꢄ
Yield: 4.34g (99%), mp 70 C, TLC (CH Cl :MeOH ¼ 6:1): R ¼ 0.68, visualization with Cl ; IR
2
2
f
2
(
KBr): ꢁꢀ ¼ 3234(m), 2952(s), 2867(m), 1613(s), 1457(m), 1365(w), 1242(w), 1126(w), 1010(m)
ꢃ 1 1
0
0
0
cm
;
H NMR (DMSO-d ): ꢂ ¼ 0.84 (d, J ¼ 6.8 Hz, H -3 ), 0.86 (t, J ¼ 6.4 Hz, H -8 , H -7 ),
6
3
3
3
0 0 0 0
.09–1.25 (overlapping multiplets, H -5 , H -6 ), 1.45 (m, H -4 ), 1.50 (m, partly overlapped, H-7 ),
2 2 2
1
1
2
3
0
0
0
.68 (m, partly overlapped, H-3 ) 1.76 and 2.19 (m, partly overlapped, H -1 , and m, H -1 ), 1.83 and
a
b
.64 (m, partly overlapped, H -1, and m, H -1), 2.85 and 2.99 (dm, J ¼ 15.2Hz, H-7 , and m, H-7 ),
a
b
eq
ax
.34 and 3.95 (m, partly overlapped, H-6 , and dt, J ¼ 13.2, 4.0 Hz, H-6 ), 3.36 (m, H -2), 3.55 (m,
ax
eq
2
0
H-2 ), 4.75=4.78 (dd=dd, J ¼ 10.0, 4.4 Hz, H-11b), 7.25 (m, H-8, H-9, H-10), 7.33 (d, J ¼ 6.0 Hz, H-
13
0
ꢀ
C-7 ), 24.3 (C-5 ), 27.0 (C-4 ), 27.3 (C-1), 27.7 (C-7), 28.0 (C-7 ), 33.0 (C-3 ), 36.7 (C-6 ), 38.6 (C-
1
1), 8.14 (m, H-3, H-4) ppm; C NMR (DMSO-d ): ꢂ ¼ 18.5 (CH at C-3 ), 22.4 (C-8 ), 22.6 (CH at
6
3
3
0
ꢀ
), 39.8 (C-2), 43.3 (C-6), 53.7=54.0 (C-11b), 67.0=67.4 (C-2 ), 125.3 (C-11), 126.4 (C-10 ), 127.1
0
0
0
0
0
0
0
ꢀ
1
ꢀ
(C-9 ), 128.3 (C-8), 134.4 (C-7a), 135.4 (C-11a), 152.8 (C-4) ppm.
(11bRS)-4-(3-Bromopropylamino)-1,6,7,11b-tetrahydro-2H-pyrimido[4,3-a]isoquinoline
hydroiodide (11ꢁHI, C H BrIN )
1
5
21
3
ꢄ
Yield: 2.70 g (75%), mp 106 C, TLC (CH Cl :MeOH¼ 6:1): R ¼ 0.57, visualization with Cl ; IR
2
2
f
2
ꢃ 1
1
(
KBr): ꢁꢀ ¼ 3169(m), 2929(m), 1604(s), 1493(m), 1395(m), 1242(m), 1125(w), 1041(w) cm ; H
NMR (DMSO-d ): ꢂ ¼ 1.85 and 2.64 (m, H-1 , and dq, J ¼ 13.6, 4.4 Hz, H-1 ), 2.08 (quin,
6
ax
eq
0
J ¼ 6.8 Hz, H -2 ), 2.84 and 2.99 (dt, J ¼ 16.4, 4.0 Hz, H-7 , and m, H-7 ), 3.28 (t, J ¼ 6.8 Hz, H -
2
eq
ax
2
0
1
), 3.34 (m, partly overlapped, H -2), 3.37 and 3.89 (m, H-6 , and dt, J ¼ 12.8, 4.8Hz, H-6 ), 3.58 (t,
2
ax
eq
0
J ¼ 6.8 Hz, H -3 ), 4.76 (dd, J ¼ 10.0, 4.4 Hz, H-11b), 7.25 (m, H-8, H-9, H-10), 7.33 (d, J ¼ 6.0 Hz, H-
2
13
1
3
1
1), 7.52 (t, J ¼ 5.6 Hz, H-4), 8.11 (bs, H-3) ppm; C NMR (DMSO-d ): ꢂ ¼ 27.5 (C-1), 27.8 (C-7),
6
0
0
0
ꢀ
1.4 (C-2 ), 31.8 (C-3 ), 37.2 (C-2), 39.7 (C-1 ), 43.4 (C-6), 54.0 (C-11b), 125.1 (C-11), 126.7 (C-10 ),
ꢀ
27.1 (C-9 ), 128.3 (C-8), 134.4 (C-7a), 135.6 (C-11a), 152.3 (C-4) ppm.
0
0
General Procedure for the Synthesis of Hexahydro-5H-imidazo[1 ,2 :1,2]pyrimido[4,3-a]-
isoquinoline hydrochlorides 2a–2cꢁHCl and of the Pyrimido-fused Derivative 12ꢁHCl
Sodium hydride 60% oil suspension (1.20 g) was washed three times with n-hexane and filtered under
3
Ar. The pure NaH (0.72 g, 30 mmol) was immediately dissolved in dry 80cm of THF, cooled to
ꢄ
ꢃ 10 C, and the respective 4-bromoalkylaminopyrimidoisoquinoline 5a–5cꢁHI, 11ꢁHI (5mmol) was
ꢄ
added in portions over 10 min. Stirring was continued for 1 h at ꢃ 10 C and then, after warming to
3
room temperature, for additional 20 h. Then, 2 cm of EtOH were added dropwise to destroy excessive
3
NaH. The reaction mixture was diluted with ethyl acetate (50 cm ) and filtered over a bed of Celite
3
45, which was washed twice with ethyl acetate. To the filtrate 10 cm of EtOH and 5 cm of 6 N
3
5
ethanolic HCl were added and it was evaporated to dryness. The residue was triturated with hexane
(
2aꢁHCl, 2cꢁHCl) or light petroleum (2bꢁHCl), filtered, and dried under reduced pressure. Next, the
3
solid was dissolved in 10cm of acetone, and Et O (100 cm ) was added slowly to precipitate the crude
3
2
product, which was purified by column chromatography (CC).
0
0
(
10bRS)-1,2,6,10b,11,12-Hexahydro-5H-imidazo[1 ,2 :1,2]pyrimido[4,3-a]isoquinoline
hydrochloride (2aꢁHCl, C H ClN )
1
4
18
3
ꢄ
CC (CH Cl :MeOH ¼ 6:1), yield 1.24 g (70%), beige powder, mp 74 C; TLC (CH Cl :MeOH¼ 6:1):
2
2
2
2
R ¼ 0.46, visualization with Cl ; IR (KBr): ꢁꢀ ¼ 3151(m), 2930(m), 1650(s), 1572(s), 1452(m),
f
2
ꢃ 1
1
1
368(m), 1299(s), 1145(w), 1084(w), 1040(w) cm ; H NMR (DMSO-d ): ꢂ ¼ 1.88 and 2.67 (m,
6
H-11 , and dq, J ¼ 13.6, 4.0Hz, H-11 ), 2.83 and 2.96 (dt, J ¼ 16.4, 3.2 Hz, H-6 , and m, H-6 ),
ax
eq
eq
ax

New 8,13,15-Triazasteroids
1281
3
.34 and 3.44 (m, partly overlapped, H-12 , and td, J ¼ 13.6, 4.0 Hz, H-12 ), 3.38 and 3.85 (m, partly
ax
eq
overlapped, H-5 , and dt, J ¼ 12.8, 3.2 Hz, H-5 ), 3.60 and 3.64 (t, J ¼ 9.2 Hz, H -2, and m, partly
ax
eq
a
overlapped, H -2), 3.66 and 3.70 (m, partly overlapped, H -1, and t, J ¼ 9.2 Hz, H -1), 4.77 (dd,
b
a
b
J ¼ 10.8, 3.2Hz, H-10b), 7.23 (m, H-7, H-8, H-9), 7.37 (d, J ¼ 7.6 Hz, H-10), 8.45 (s, NH) ppm;
1
3
C NMR (DMSO-d ): ꢂ ¼ 27.8 (C-11), 28.1 (C-6), 40.7 (C-12), 43.3 (C-5), 43.0 (C-2), 48.7 (C-1),
6
ꢀ
ꢀ
5
4.0 (C-10b), 125.6 (C-10), 126.4 (C-9 ), 127.0 (C-8 ), 128.6 (C-7), 133.8 (C-6a), 134.5 (C-10a),
55.3 (C-3a) ppm.
1
0
0
(
1RS, 10bRS)-1-Hexyl-1,2,6,10b,11,12-hexahydro-5H-imidazo[1 ,2 :1,2]pyrimido-
[
4,3-a]isoquinoline hydrochloride (2bꢁHCl, C H ClN )
2
0
30
3
ꢄ
Yield 1.05 g (60%), yellowish, hygroscopic crystals, mp 42 C; TLC (CH Cl :MeOH ¼ 6:1): R ¼ 0.76,
2
2
f
visualization with Cl ; IR (KBr): ꢁꢀ ¼ 3424(m), 3147(m), 2927(s), 2855(m), 1649(s), 1569(s),
2
ꢃ 1
1
0
1
456(m), 1306(m), 1039(m) cm ; H NMR (DMSO-d ): ꢂ ¼ 0.85 (t, J ¼ 6.8 Hz, H -6 ), 1.28 (m,
6
3
0
0
0
0
0
0
H -2 , H -3 , H -4 , H -5 ), 1.53 and 1.90 (m, H -1 , and m, H -1 ), 1.74 and 2.62 (m, H-11 , and dm,
ax
2
2
2
2
a
b
J ¼ 13.6Hz, H-11 ), 2.84 and 2.94 (dm, J ¼ 16.0Hz, H-6 , and m, H-6 ), 3.25 and 3.76 (t,
eq
eq
ax
J ¼ 14.0Hz, H -2, and dd, J ¼ 14.0, 9.2 Hz, H -2), 3.30 (m, partly overlapped, H -12), 3.46 and
a
b
2
3
.85 (m, partly overlapped, H-5 , and dm, J ¼ 12.4 Hz, H-5 ), 3.94 (m, H-1), 4.76=4.79 (dd=dd,
ax
eq
J ¼ 10.4, 3.2 Hz, H-10b), 7.23 (m, H-7, H-8, H-9), 7.37 (d, J ¼ 8.0Hz, H-10), 8.41=8.53 (s=s, H-3)
1
3
0
0
0
ppm; C NMR (DMSO-d ): ꢂ ¼ 13.9 (C-6 ), 21.9 (C-5 ), 23.5 (C-3 ), 27.6 (C-6), 28.0 (C-11), 28.6 (C-
6
0
0
0
2
1
), 30.1 (C-1 ), 31.0 (C-4 ), 38.4 (C-12), 43.2 (C-5), 45.8 (C-2), 52.6=52.9 (C-10b), 59.6=60.3 (C-1),
ꢀ
ꢀ
25.4 (C-10), 126.7 (C-9 ), 127.0 (C-8 ), 128.6 (C-7), 133.6 (C-6a), 134.5 (C-10a), 155.4 (C-3a) ppm.
0
0
(
1RS, 10bRS)-1-[(1RS)-1,5-Dimethylhexyl]-1,2,6,10b,11,12-hexahydro-5H-imidazo[1 ,2 :1,2]-
pyrimido [4,3-a]isoquinoline hydrochloride (2cꢁHCl, C H ClN )
2
2
34
3
ꢄ
CC (CH Cl :MeOH¼ 15:1), yield 0.56 g (30%), yellow crystals, mp 65 C; TLC (CH Cl :
2
2
2
2
MeOH ¼ 15:1): R ¼ 0.46, visualization with Cl ; IR (KBr): ꢁꢀ ¼ 3421(m), 3178(m), 2953(s),
f
2
ꢃ 1
1
928(s), 2868(m), 1651(s), 1606(s), 1456(m), 1364(w), 1124(w), 1040(w) cm ; H NMR (DMSO-
2
0
0
0
d ): ꢂ ¼ 0.85 (m, H -6 , H -5 ), 0.87 (d, J ¼ 6.8 Hz, CH at C-1 ), 1.07–1.27 (overlapping multiplets,
6
3
3
3
0
0
0
0
0
H -4 , H -3 , H -2 ), 1.37 (m, H-5 ), 1.51 (m, H-1 ), 1.96 and 2.62 (m, H -11, and m, H -11), 2.84 and
2
2
2
a
b
2
.96 (dm, J ¼ 16.0Hz, H-6 , and m, H-6 ), 3.32 and 3.60 (m, partly overlapped, H -2, and t,
eq
ax
a
J ¼ 10.4Hz, H -2), 3.38 (m, H -12), 3.45 and 3.84 (m, H-5 , and td, J ¼ 13.2, 4.0 Hz, H-5 ), 4.03
b
2
ax
eq
(
td, J ¼ 10.4, 3.2Hz, H-1), 4.79 (m, H-10b), 7.23 (m, H-7, H-8, H-9), 7.36 (d, J ¼ 6.8 Hz, H-10),
1
3
0
0
8
.40=8.51 (s=s, H-3) ppm; C NMR (DMSO-d ): ꢂ ¼ 22.4 (C-6 ), 22.5 (CH at C-5 ), 22.6 (CH at
6
3
3
0
0
0
0
0
C-1 ), 27.3 (C-11), 27.6 (C-6), 27.9 (C-5 ), 30.8 (C-1 ), 32.0 (C-3 ), 37.2 (C-12), 38.5 (C-4 ), 40.9 (C-2),
ꢀ
ꢀ
4
7.2 (C-5), 52.6=53.0 (C-10b), 62.9=63.9 (C-1), 125.8 (C-10), 126.7 (C-9 ), 127.1 (C-8 ), 128.6
C-7), 133.7 (C-6a), 134.5 (C-10a), 154.7 (C-3a) ppm.
(
0 0
11bRS)-2,3,7,11b,12,13-Hexahydro-1H,6H-pyrimido[1 ,2 :1,2]pyrimido[4,3-a]isoquinoline
(
hydrochloride (12ꢁHCl, C H ClN )
1
5
20
3
3
Workup: Under cooling the reaction mixture was made alkaline with 2 N NaOH solution (40 cm ) and
3
3
then extracted with 2ꢅ20 cm of Et O and 1ꢅ20 cm of ethyl acetate. The combined extracts were
2
washed with H O, dried over Na SO , filtered, and the solvent was evaporated to dryness in vacuo. The
2
3
residue was mixed with 6 N ethanolic HCl (2cm ) and it was evaporated to an oily residue, which was
2
4
next triturated successively twice with ethyl acetate and Et O to yield 0.75g (54%) of 12ꢁHCl as beige,
2
very hygroscopic powder (no melting point determination possible). TLC (CH Cl :MeOH¼ 9:1):
2
2
R ¼ 0.23, visualization with Cl ; IR (KBr): ꢁꢀ ¼ 3406(s), 3210(s), 2935(s), 1605(s), 1595(s),
f
2
ꢃ 1
1
1
442(m), 1323(s), 1210(m), 1042(m) cm ; H NMR (DMSO-d ): ꢂ ¼ 1.89 (m, H -2), 1.94 and 2.59
6
2

1
282
E. G €o ßnitzer and A. Punkenhofer: New 8,13,15-Triazasteroids
(
m, partly overlapped, H-12 , dm, J ¼ 10.4Hz, H-12 ), 2.81 and 2.97 (dm, J ¼ 16.4Hz, H-7 , and m,
ax
eq
eq
H-7 ), 3.22 (m, partly overlapped, H -13), 3.29 and 3.98 (m, H-6 , and dm, J ¼ 13.6Hz, H-6 ), 3.32
ax
2
ax
eq
and 3.51 (m, partly overlapped, H-3 , and tm, J ¼ 11.2 Hz, H-3 ), 3.38 (m, partly overlapped, H -1),
eq
ax
2
4
1
.70 (dm, J ¼ 7.6Hz, H-11b), 7.22 (m, H-8, H-9, H-10), 7.32 (d, J ¼ 6.4 Hz, H-11), 8.39 (s, H-4) ppm;
3
C NMR (DMSO-d ): ꢂ ¼ 20.1 (C-2), 27.7 (C-12), 27.9 (C-7), 38.1 (C-13), 43.1 (C-6), 45.9 (C-3),
6
ꢀ
ꢀ
4
7.3 (C-1), 53.5 (C-11b), 125.1 (C-11), 126.6 (C-10 ), 127.0 (C-9 ), 128.3 (C-8), 134.3 (C-7a), 135.6
(
C-11a), 150.5 (C-4a) ppm.
Acknowledgment
Financial support from the Austrian Fonds zur F €o rderung der wissenschaftlichen Forschung (P14758-
CHE) is gratefully acknowledged. The authors also thank Prof. W. Wendelin, University of Graz, for
helpful discussions.
References
[
[
[
[
[
[
[
[
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1
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[
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