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Pyridazines LXXIIOn the Synthesis of Azinium and Diazinium Compounds Structurally Related to Pyridazomycin.

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307
Azinium and Diazinium Compounds
Pyridazines, LXXII'):
On the Synthesis of Azinium and Diazinium Compounds Structurally
Related to Pyridazomycin +)
Johnny Easmona), Gottfried Heinischa)*, Wolfgang Holzerb),and Barbara Matuszczaka)
a)
Institute of Pharmaceutical Chemistry, University of hnsbruck. Innrah 52a. A-6020 Innsbruck, Austria
b,
Institute of Pharmaceutical Chemistry, University of Vienna, Pharmaziezentrum, Althanstr. 14, A-1090 Vienna, Austria
Received August 9,1994
Pyridazine, 7 2 Mitt.'):
Zur Synthese von Azinium und Diazinium Verbdungen n i t struktureller Verwnudtwhaf't zu Pyridazomyan
R e p a t i o n of&= ofpyridine-, pyridazine-,and pyrazine-derived &xamides bearing at the ring N-atom an alkyl side-chain with a terminal
carboxylicgroup (7-11) or with a terminal acetylaminomalonic ester moiety
(13-17,1943) is described. Two desaza-pyridazomycinderivatives(24,26)
and homologs thereof (25, 27) were synthesised. The novel compounds
which are structurallyrelated tothe antifungalantibioticpyridazomycinwere
screenedfor antifungal activity: preliminaryin vifrotests showed no activity.
In 1988, the first example of a natural product containing the aromatic
was isolated from the culture filtrate
pyridazine nucleus, pyridazomycin 0).
of Srreptomyces violaceoniger sp. griseofuscus (strain Tii 2557)2). The
antifungal activity and the antagonistic behaviour against basic amino acids
(degradation at pH > 7.5) now
together with the only limited stability of 12)
prompted us to start a program directed to modifications of this interesting
1.2-diazinium derivative. Furthermore we intended to find out those structural features &tical for antimicrobial activity.
Scheme 1
Es wird iiber die Darstellmg von Pyridazomycin-Analoga (Derivate von
Pyridin-, Pyridazin- und Pyrazinchxamiden mit c&arboxyalkylseitenkette am Ringstickstoff (7-11) bzw. mit terminaler Acetylaminomalonester
Teilstruktur(1>17,1%23)und zweier Desaza-PyridazomycinDerivate(24,
26) sowie deren Homologen (25.27) berichtet. Die neuen Verbindungen
wurden in Hinblick auf antimykotische Wirkung untersucht. Erste in vitro
Tests zeigten keine Wikung.
cessible by treatment of 7a and 8s with Amberlite IRA4 10khloride-form. According to NMR-investigations (NOE
difference experiments) the compound resulting from the
reaction of pyrazinecarboxamide(6)with 2 turned out to have
the N-alkyl chain and the carboxamide function in 1,3-position (product g4)>.
Thus. upon irradiation of the N-CHzresonance of 9, a marked NOE on the
pyrazine 2-H and 6-H signals was ohserved (Figure 1). These findings tule
out attack of the alkylating agent at the nitrogen atom adjacent to the
carboxamidegroup. Moreover, the observed NOES provide the unequivocal
assignmentof the signals due to pyrazine 5-H and pyrazine 6-H in compound
9. Similar NOES on the signals of hetecoaromatic protons adjacent to the
quaternary N-atom were observed with the pyridinium compounds7a and 8a
(hadiation of the N-CHz- resonance resulted in NOES on the pyridine 2-H
and 6-H signals).
Pyridazomycin(I)
In this communication we report on the preparation and
preliminary antifungal evaluation of selected pyridazomycin
congeners characterised a) by the lack of the amino function
in the side-chain, b) by replacement of the glycine substructure by a diethyl N-acetylaminomalonate moiety, c) by homologation of the aliphatic side-chain, d) by replacement of
the pyridazinecarboxamide substructure by a pyridine- or
pyrazinecarboxamide system.
b
Results and Discussion
In order to synthesise the des-amino pyridazomycin-congeners 7-9, the N-heteroaromaticcarboxamides3.4, and 6 were
alkylated by refluxing them in dry acetonitril with 540dovaleric acid (21, prepared according to ref35. Thus, the
azinium iodides 7a, 8a, and 9 were obtained in high yields
(70-80%). The corresponding chlorides 7b, 8b become ac-
I
I
I
I
I
10
8
6
4
2
1
PPm
+) Dedicated with best personal wishes 10 Prof Dr. F. Saufer, Technical
University of Vienna. on the occasion of his 65th birthday.
Arch. P
h (Weinhain)Z& M7-312(1!@5)
Figure 1: a) 'H-NMR spectrum of compound 9 (in [D6]DMSO).b) NOEdifference spectrum of 9 resulting from irradiation of the N-CHz resonance.
@VCHVdagsgeseUschaftmbH, -51
Weinhek 1995
0365-6233195/0404-03O7$5.00 + .2510
308
Easmon, Heinisch, Holzer, and Matwzczak
By contrast, alkylation of 4-pyridazinecarboxamide (5f)
with 2 yielded a 1:1 mixture of desamino-pyridazomycin 10
and the corresponding N-2substitution product 11, as indicated by !he 'H-NMR spectrum. Attempts to separate these
two regioisomersby crystallisationor chromatographyso far
failed owing to their extremely polar nature and the low
stability. As shown by preliminary tests for antimicrobial
activity against microorganisms sensitive to pyridazomycin
(Exper.Part) the replacement of the a-amino group by hydrogen results in loss of activity.
2
/
J
0+
0
c-f-
0
X@
&!--
+
I* X.1
8b X=CI
10
11
Scheme 2
n=l I 6
21
2.n
n.1
16
2.n
22
n.1 tr
n=2 23
COOEt
n.1 IZ
n=2 18
nil 13
n=2 19
0
Scheme 3
II
6NHCI
4
n=2 26
Arch P h a m (Weinhein) 328,307-312 (1995)
309
Azinium and Diazinium Compounds
Compounds of type 13-17, characterised by a terminal acetamidomalonate with amolein led to ethyl 2-acetamide2-ethoxycardiethyl N-acetylaminomalonate moiety in the sidechain, ap- bonyl-5-hydroxyvalerate'), which was transformed into ethyl 2-acetamido2-ethoxycarbonyl-5-bromovalerateby treatment with PBr3l0). Ethyl
peared of interest as potential precursors for the synthesis of 2-acetamido-2-ethoxycarbonyl-bbromoca~oate
was synthesised from dirac. pyridazomycin, its regioisomer with the amino acid ethyl acetamidomalonateand 1.5-dibromopentane lo). 4-F'y~idazinecarboxside-chain attached to N-2 and of congeners in which the amide (5) was prepared from 4-pyridazinecarboxylic acid by esterification
pyridazine ring is replaced by a pyridine or pyrazine system. and subsequenttreatment of the resulting ethyl ester with anhydrous ammoAlso these compounds could be obtained in satisfactory nia'). 4-Pyridazinecarboxylic acid was available from 3.6-dichloro-4methylpyridazine") by oxidation (K2Crm) and subsequent catalytic
yields simply by reacting the appropriate pyridazine-, dehalogenation
of the thus obtained 3,6-dichlorpyridazine-4-carboxylic
pyrazine-, or pyridine-derived carboxamides with the alky- acidI2).
lating agent 12, which was conveniently accessible from its
bromo congener by a Finkelstein-typereaction. Analogously General Methodfor fhePreparation of Conpounds 7% 8e, and 9-11
compounds 19-23 (employing the hitherto not described
To a solution of the appropriate carboxamide 3,4,5, or 6 (3 mmol) in 20
iodide 18 as the alkylating agent) were prepared, which were ml of dry acetonitrile were added 2 equivalents of 2 (1.39 g, 6 mmol). and
expected to provide access to homologs of pyridazomycin the mixture was heated at 80 "C. The reaction was monitored by TLC
and its above mentioned congeners. In accordance with the (dichloromethane/ethylacetatdmethanol35:l). Reaction times varied beobservations made in the reactions of pyrazinecarboxamide tween 18 and 24 h and the solutions obtained were treated as follows:
(6) and 4-pyridazinecarboxamide (9,respectively, with the
iodide 2, we again obtained a single product upon alkylation 3-(Amnocarbonyl)-I44-carboxybutyl)py~niumiadide (7a)
of 6 with 12 or 18 (attack at N-4 of amide 6)6), whereas in the
The product precipitated from the hot solution as the reaction proceeded.
pyridazine c e a mixture of the regioisomers 16/17 and 22/23 Finally, the reaction mixture was cooled. the crystals were filtered off and
was formed+f
.
washed with cooled acetonitrile. Yield 0.73 g (70%) of pale yellow crystals
(ethanol), mp. 168-172 OC.- IR:3298; 3138; 3045; 1689; 1645; 1587; 1406
Although the in-vitro tests so far performed with com- cm-'.'H-NMR 6 (ppm) = 1.37-1.66 (m.2H, COCHz-CHz). 1.78-2.07 (m,
pounds 13, 14, 16. 17, 19,20, 22, and 23 did not reveal any 2H, NCHZ-CHZ),
2.28 (t, J = 7.1 Hz, 2H. CHKOOH), 4.67 (t, J = 7.1 H z
activity'), in-vivo studies of the diethyl N-acetylaminomalon- 2H, NCHz), 8.13 (s, lH, DzOexchange. CONH), 8.26(m, 1H.pyridine-5-H).
ates (as possible prodrugs) are envisaged, provided that our 8.53 (s, lH, DzO exchange. CONH), 8.93 d, J 8.3 Hz, lH, pyridine-4-H ,
target a-amino acid derivatives should exhibit antifungal 9.21 (d. J = 5.9 Hz, lH, pyridine-6-H) I", 9.; (s. lH, pyridine-2-H) 131
11.75-12.35 (broads, lH, DzOexchange. COOH).-CIIHISN~~~I
(350.16).
activity.
Calcd. C 37.7 H 4.32 N 8.0 Found C 37.9 H 4.22 N 7.8.
After transforming the iodides 13, 14, 19, and 20 into the
corresponding chlorides by ion-exchange chromatography, 4-(Aminocarbonyl)-l-(4-carboqbutyl)pyridi~~idinium
iadide (8s)
removal of the protecting groups smoothly proceeds upon
solution was cooled overnight and the precipitate formed was filtered
refluxing in 6N HCl to give the pyridine-derived target a- andThewashed
with cooled acetonitrile. Yield 0.79 g (76%) of light yellow
amino acid derivatives 24-27. Although pure educts were crystals (ethanol), mp. 224-227 OC.- IR: 3356 3177; 3111; 1712; 1672;
used in this deprotection step, we so far failed in obtaining 1618; 1570; 1400 cm-'.- 'H-NMR 6 (ppm) = 1.38-1.64 (m.2H. COCH2our target compounds in a degree of purity sufficient for CH2), 1.78-2.06 (m, 2H, NCHFCHZ),2.27 (t, J = 7.1 Hz, 2H, CHKOOH),
acceptable elemental analyses or for biological evaluation. 4.66 2, J = 7.1 Hz, 2H, NCH2). 8.23 (s, lH, DzO exchange, CONH), 8.43
However, there can not be any doubt about the assigned ('d', J = 6.6 Hz, 2H. pyridine-3-WS-H), 8.75 (s, 1H DzO exchange.
9.26 ('d', 3J = 6.6Hz. 2H, pyridine-2-W6-H) 14).- CiiH15Nz031
structures considering the H-NMR and Electrospray-MS CONH),
(350.16) Calcd. C 37.7 H 4.32 N 8.0Found C 37.8 H 4.18 N 7.9.
data.
.
3-(Aminocarbonyl)-l~4-car~~butyl)pyra.?.inium
iodide (9) 4,
Experimental Part
Chemisfry
General remarks: IR spectra: Mattson Galaxy Series FTIR 3000 spectrophotometer, KBr pellets.- Mass spectra: API-Electrospray technique,
Hewlett-Packard HP 5989. The samples were dissolved in watedmethanoVacetic acid (49/49/2) and introduced by infusion into the ElectrosprayMS system. 'H and I3C NMR spectra: [&]DMSO solutiom, Bmker AC 80
('H: 80.13 MHz, I 3 C 20.15 MHz) speclrometer: Varian Unityplus 300
spectrometer CH: 299.95 MHz I3C: 75.43 MHz). The center of the DMSO
multiplet was used as internal standard which was related to TMS with 6
(ppm)2.49 for 'H and 6 @pm) 39.50 for %. Assignments are based on
chemical shift considerations, on homonuclear and heteronuclear shift-correlations (COSY, HETCOR, HBMC). on coupling information ('H-coupled
%-NMR spectra, multiplicity selection by the APT-technique) and on
NOE-difference experiments.- Melting points: Reichert-Thennovar hotstage microscope, uncorrected.- Elemental analyses: 'Miboanalytisches
Laboratorium', Institute of Physical Chemistry, University of Vienna, Austria.- TLC.Polygram SIL G l w z v (Macherey-Nagel)plastic-backedplates
(0.25 mm), detection: W 254 nm or 12 vap0ur.- Column chromatography:
Kieselgel60 (0.040-0.063 nun, Merck).
Starting materials: 5-iodovaleric acid (2) was obtained by heating commercially available 5-chlorovaleric acid with NaI in dry acetonitrile 3).
Raney-Nickel reduction ofthe product obcained from the reaction of diethyl-
The precipitate obtained upon cooling was filtered off and washed with
cooled acetonitrile. Recrystallization from methanol gave yellow crystals.
Yield 0.58 g (55%), mp. 205-208 "C.- I R 3441; 3348; 3107; 3036; 3011;
2986; 1724; 1707; 1691; 1599; 1402cm-'.- 'H-NMR: 6 @pm) = 1.38-1.63
(m2H, COCH2-CHz), 1.81-2.06 (m. 2H, NCHz-CHz), 2.28 (t, J = 7.1 H z
ZH,CHKOOH),4.74(t, J=7.1 Hz2H.NCHz). 8.31 (s, lH,DzOexchange,
CONH), 8.65 (s, lH, DzO exchange, CONH), 9.40 (A-part of an AB-system,
3Jws3.6 Hz, 1H, pyrazine-GH),9.55 (B-part of an AB-system,3Jwa=3.6 H z
lH, pyrazine-5-H). 9.74 (s, lH, pyrazine-2-H), 11.51-12.25 (broad s, lH,
DzO exchange, COOH).- I3C-NMR: 6 (ppm) = 20.8 (COCHrCH2), 29.8
(NCHFCH~),32.8 (CH2COOH), 61.5 (NCHz), 137.1 (pyrazine-C-2), 138.8
(pyrazine-C-6), 149.2 (pyrazine-C-5), 150.9 (pyrazine-C-3). 162.2
(CONHz), 174.0 (COOH).- CioH~N3031(351.14) Calcd. C 34.2 H 4.02
Found C 34.3 H 3.84.
4-(Aminocarbaryl)-l~4carboxybutyl)py~inium
iodide (10) and
5-(Aminocarbonyl)-l~4-carboxybutyl)py~inium
iodide (11) (mixture)
The resulting mixture was evaporated in yacuo, the oily residue solidified
upon addition of dichloromethane. After storing overnight in a refrigerator,
the product was filtered off, washed with cooled ethanol, and recrystallized
from ethanol to afford a mixture of compounds 10 and 11 (ratio 1 : 1.25
according to 'H-NMR data I"). Yield 0.79 g (75%) of orange crystals, mp.
15CL153 'C and 161-165 "C.-IR 3367; 3317; 3180 3065; 2% 1726
1693; 1672; 1630 1413 cm-'.
310
Isomer 10 'H-NMR 6 @pm) = 1.441.71 (m2H, COCHz--2).
1.872.15
ZH, NCH~-CHZ),2.29 (t, J = 7.0 Hz, 2H, CHZCOOH), 4.87 (t, J =
7.0 Hz. 2H. NCHz), 8.43 (s, lH, D20 exchange, CONH), 8.80 (s, lH, D S
exchange, C?NH), 8.95 (m, 1H. pyridazine-5-H), 9.83 (s, lH, pyridazine-3H), 10.12 (d. J y 6 = 6.1 Hz, lH, pyridazine-6-H).
Isomer 11: 'H-NMR: 6 (ppm) = 1.44-1.71 (m2H, COCHz-CHz), 1.872.15 (m2H. NCH2-CH2). 2.29 (t, J = 7.0 Hz, ZH, CHzCOOH), 4.87 (t, J =
7.0 Hz. ZH, NCHz), 8.43 (s. lH, DzO exchange, CONH), 8.80 (s, lH, DzO
exchange, CONH), 8.90 (m, lH, pyridazine-4-H), 9.79 (d. 3Jw4= 6.OHz, 1H.
pyridazine-3-H), 10.28 (s, 1H. pyridazinebH).- C10H14N3@I (351.14)
Calcd. C 34.2 H 4.02 N 12.0 Found C 34.4 H 4.01 N 11.8.
Tmfoormation ofthe Iodides 78 Sa to rhe Chlorides 7b. 8b
'Ihe iodide 7a (0.5 g. 1.43 mmol) or Sa (0.5 g, 1.43 mmol) in 2 ml of
methand-water (3:l) was passed through a column of Amberlite IRA-410
ion-exchangeresin (25 g), which had been successively washed with a 0.5
N HCI solution, water, a 5% solutionof sodiumchloride,and water. Fractions
containing the product after elution with methanol-water (3:l) were e v a p
rated, the residue was then dried at 60 "C in vacuo and recrystallizedfrom
ethanol.
3-(Aminoca&myl)-l-(4-carboxybutyl~yridiidiniumchloride (7b)
Yield 0.32 g (87%) of colourless crystals, mp. 217-220 "C.- I R 3275;
3132; 3032; 1726; 1695: 1645 cm-'.- 'H-NMR: 6 (ppm) = 1.39-1.65 (m,
2H, COCHz-CH2). 1.81-2.08 (m, 2H, NCHz-CHz), 2.27 (t, J = 7.1 Hz. 2H,
CHKOOH), 4.69 (t. J = 7.1 Hz 2H, NCHz), 8.15 (s, lH, DzO exchange,
CONH), 8.24 (m, lH, pyridined-H), 8.99 (s, lH, D20 exchange, CONH),
9.01 (m lH, pyridine-4-H), 9.28 (d, 'J.5.6 = 6.1 Hz pyridine-6-H) 13), 9.75
(s, 1H. ~yridine-2-H)'~).-I3C-NMR S (ppm) = 20.9 (COCHz-CHz), 29.9
(NCHZ-CHZ),32.9 (CHKOOH). 60.7 (NCH2). 127.7 (pyridim-C-5), 133.7
@yridine-C-3), 143.6 (pyridine-C-4),144.8(pyridine-C-6).146.3 (pyridineC-2), 162.7 (CONHZ), 173.9 (COOH).- C11H15N2@Cl (258.74) Calcd. C
51.1H5.84N 10.8FoundC51.4H5.60N 10.6.
4-(Aminaca~onyl)-l-(4~arbo~butylbyridinium
chloride (sb)
Yield 0.35 g (94%) of colourless crystals, mp. 234-238 "C.- IR: 3352;
3173; 3057; 2966; 1711; 1674; 1620; 1570; 1404cm-'.-'H-NMR S(ppm)
= 1.36-1.63 (m, 2H. COCHz-CHz), 1.77-2.03 (m+2H. NCHz-CHz), 2.27 (t,
J = 7.1 Hz, 2H, CHzCOOH), 4.69 (t, I = 7.1 Hz 2H. NCHz), 8.25 (s, lH,
DzO exchange, CONH), 8.53 ('d', 3J = 6.6 Hz 2H. pyridine-3-H,5-H), 8.96
(s, 1H. DzO exchange, CONH), 9.32 ('a,3J = 6.6 Hz. 2H. pyridine-2-H,
6-Hj3'.- I3C-NMR: 6 @pm) = 20.8 (COCH2-CHz). 30.0 (NCHz-CH2),32.9
(CH2COOH). 60.4 (NCHz), 125.9 @yridine-C-3;C-5),145.6 byridine-C2;C-6), 148.1 (pyridine-C-4), 163.2 (CONHz), 173.8 (COOH).C I I H I ~ N Z ~(258.74)
~ C I Calcd. C 51.1 H 5.84 N 10.8 Found C 51.4 H 5.51
N 10.6.
Easmon, Heinisch. Holm, and Matuszczak
Ethyl 2-aceramido-2-ethaxycarbonyl-6-iodocapro
(18)
The yellow oil was subjected to cc with ethyl acetatdcyclohexane(75:25)
to furnish colourless needles. Yield 13 g (76%). mp. 74-75 OC.- I R 3256;
2982; 2937; 1743; 1641; 1523 cm-'.- 'H-NMR: S @pm) = 0.99-1.23 (m
2H, CHz), 1.15 (t. I= 7.1 H z 6H, CH2CH3), 1.62-1.79 (m.2H, CHz), 1.90
(s, 3H. COCH3). 1.99-2.19 (m, 2H, CHz), 3.24 (t, J = 6.6 H z 2H, I-CHz),
4.13 (q, J = 7.3 Hz, 4H, CHKH3), 8.24 6 , lH, NH).-CI~HZZNO~I
(399.22)
Calcd. C 39.1 H 5.55 N 3.5 Found C 39.4 H 5.67 N 3.4.
General Procedurefor rhe Preparation of Compounds 13-17 and 19-23
At 80 OC, to the appropriatecarboxamide 3.4,5, oc 6 (4 mmol) in 20 ml
of dry acetonitrilewere added 2 equiv. of 12 (3.08 g, 8 mmol) or 18(3.19 g,
8 mmol) with stirring which was continued at this temp. until TLC (eluent:
acetonitrile)indicated no further conversion (reaction times varied between
20 and 48 h). The solutions thus obtained were treated as describedbelow.
3-(Aminocarbonyl)-l-[4-(aceiantido)~,4-bis(erharycarbonyl)bu~l]pyriahium iodide (13)
'Ihe reaction mixture was evaporated in vacuo, the residue was dissolved
in hot ethyl acetate and refrigeratedovernight. The precipitate was collected
by filtration and recrystallized from methanollethyl acetate: light brown
crystals. Yield 1.85 g (91 %), mp. 117-121 "C.-IR 3435; 3339; 3171; 3045;
2982; 1766,1734 1689; 1637 cm-'.- 'H-NMR 6 (ppm) = 1.11 (t, J = 7.1
Hz, 6H, CHKH3). 1.60-2.17 (m4H, CCHzCHz-C), 1.88 (s, 3H, COCH3),
4.11(q,J=7.1H~,4H,CH2CH3),4.66(t.J=6.6Hz2H,NCHz),8.16-8.37
(broad s,2H, DzO exchange,NHCOCH:, and CONH), 8.23 m, 1H, pyridine5-H). 8.52 (broad s, lH, DzO exchange, CONH), 8.94 (d, J = 8.1 Hz, lH,
pyridine-4-H), 9.22 (d, J = 6.2 Hz, lH, pyridine-dH), 9.50 (s, lH, pyridine2-H).- Ci8H2aN3061(507.33) Calcd. C 42.6 H 5.17 N 8.3 Found C 42.7 H
5.13 N 8.3.
6
4-(Antinocarbmyl)-l-[4-(ace~'~~-4,4-bi~ethaxycarbonyl)bu~l]pyri~
nium iodide (14)
'Ihe reactionmixture was cooled. the precipitatewas collected and recrystallized from acetonitrile to give yellow crystals. Yield 1.66 g (81%), mp.
89-93 OC.- IR: 3414 3275; 3045; 3013; 1759; 1726, 1666; 1612; 1518
cm-'.- 'H-NMR 6 (ppm) = 1.11 (t. J = 7.1 Hz, 6H, CHzCH3). 1.60-2.30 (m,
4H, C-CHKHZ-C), 1.89 (s, 3H, COCH3). 4.1 1(q, J = 7.1 Hz,4H, CHKH,),
4.66 (t, J = 6.6 H z 2H, NCHz). 8.25 (s, DzO exchange, lH, NH). 8.45 ('d',
3J = 6.6 H z 2H, yridine-3-H;5-H) 8.50-8.90 (broad s, DZO exchange, 2H,
?
NH), 9.26 ('d', J = 6.6 H z pyridine-2-H; 6-H).- CisH2aN3061 (507.33)
Calcd.C42.6H5.17N8.3FoundC42.6N5.18N8.3.
34AAminocarbmyl)-l-[4-(acetamido)4,4-bis(etharycarbonyl)butyl]pyrazinium iodide (IS)@
General Merhodfor r rhe Preparation of Compounds 12 and 18
After removing the solvent in vacuo the residue was subjected to cc
(acetonitrile). 'Ihe reddish-brown gum obtained after evaporation in vacuo
To a solution of ethyl 2-acetamido-2-ethoxy~~nyl-5-bromovalerate
lo)
(15 g, 44.35 mmol) or ethyl 2-acetamido-2-ethoxyca~nyl-6-bromo-turned to an oil in air. Yield 0.72 g (35%).- I R 3423 (head): 2984; 1738;
caproate lo) (15.61 g, 44.35 mmol) in 100 ml of dry acetone were added 2
1701; 1662; 1510 cm-'.- 'H-NMR: 6 (ppn) = 1.14 (t. J = 7.1 Hz, 6H.
equiv. of NaI (13.30 g, 88.70 -1)
and the mixture was refluxed for 16h.
After cooling to room temperature the solids were filtered off and the
remaining solution was evaporated in vacuo. The yellow oily residue was
diluted with 100ml of water and was then extracted with 3 x 100ml of ether.
The ether phases were washed with 0.1 N NaS20., (2 x 50 ml) and then with
50ml ofsatd. NaCl solution. After drying over anhydrousNazS04thesolvent
was removed under reduced pressure to obtain a light yellow oil.
Ethyl 2-aceramido-2-erhaxycarbo~l-S-iodovalera
(12)
CH2CH3). 1.70-2.40 (m4H, CCHzCH2-C), 1.91 (s. 3H, COCb), 4.14 (q,
J = 7.1 Hz, 4H, CH2CH3), 4.73 (t, J = 7.1 Hz, 2H, NCHz), 8.25 (s, lH, Dfl
exchange, NHCOCH3), 8.33 (s, lH, DzO exchange, CONH), 8.67 (s. 1H.
Dzo exchange, CONH), 9.40 (A-part of an AB-system, 3J5,3.4 H z lH,
pyrazine-6-H), 9.57 @-part of an --system, 3 J 9 ~ 3 . 4Hz,1H. pyrazine-5H). 9.76 (s. lH, pyrazine-2-H).
4-(Aminocarbonyl)-l-[4~ace~'do)4,4-bis(e~haxycarbonyl)bu~l]pyriakinium iodide (16) and SfAAminocarbonyl)-l-~4~acetamido)4 , 4 - b P ( e t ~ ~ c a ~ n y l ) b u t y li ]d~d ~e (17)
~um
(mirture)
The light yellow oil solidified on standing in a vacuum desiccator, recrystalliultion from ethyl acetateflight petroleum afforded colourless needles.
The resulting solution was evaporated to dryness and the residue was
Yield 15 g (91 %), mp. 70-72 "C.- IR: 3256; 2982; 2950; 1741; 1641; 1523 purified by prep. TLC (Kieselgel 60 F z Y + ~2, mm, Merck; dichle
cm-'.-'H-NMR 6 (ppm) = 1.14 (t, J = 7.1 Hz, 6H. CHZCH~),
l.49-l776(m,
romethanelethyl acetatelmethand (3:5:1)) Yield 1.92 g (94% of a mixture
2H,CH2), 3.24(t, J=6.6Hz,
2H,CHa), 1.89(~,3H,COCH3).2.09-2.29(m
of isomers 16and 17(ratio 1:1.2 according to'H-NMRdata 14)), darkbrown
2H,ICH2),4.13 (q, J=7.1 Hz, 4H,cH~CH3),8.27(~.
~H,NH).-CIZH~NO~I~rystalsof
111-115 "C.- I R 3406 (broad); 2982; 2939; 1739; 1657;
(385.ZO)Calcd. C37.4H 5.23 N 3.6FoundC 37.5 H5.27N3.6.
1574; 15u); 1420 mi'.
Arch Phann (Weinheim)328,307-312 (1995)
31 1
Azinium and Diazinium Compounds
1 6 'H-NMR 6 (ppm) = 1.12 (t. J = 7.1 Hz, 6H, CH2CH3). 1.67-2.41 (m.
4H. C-CHZCH~C),
1.89 (s, 3H, COCH3), 4.1 1 (q, J = 7.1 Hz, 4H, CHzCH3).
4.85 (t. J = 6.5 Hz, 2H, NCHz). 8.30 (s, lH, NHCOCH3), 8.43 (broads, lH,
CONH), 8.80 (broad S, lH, CONH), 8.90 (ID,lH, pyridazine-5-H) 9.78 (s,
1H. pyridazine-3-H), 10.04 (d, 3J = 6.2 Hz, 1H. pyridazine-6-H).
1 7 'H-NMR: S (ppm) = 1.12 (t. J = 7.1 Hz, 6H. CH2CH3). 1.67-2.41 (m,
4H, C-CHZCHZ-C),1.89 (s, 3H, COCHs), 4.1 1 (4. J = 7.1 Hz. 4H. CH2CH3),
4.85 (t, J =6.5 Hz. 2H. NCHz), 8.30 (s* lH, NHCOCH3). 8.43 (broads, lH,
CONH), 8.80 (broads, lH, CONH). 8.81 (d, lH, pyridazine-4-H),9.75 (d,
3J = 6.0 Hz, 1H. pyridazine-3-H), 10.21 (s. lH, pyridazine-6-H).Ci7HzN40aI (508.83) Calcd. C 40.2 H 4.% N 11.0 Found C 40.3 H 4.92 N
11.1.
3-(Aminocarbonyl)-l-[(54cetamido)-5,
5-bis(et~~carbo]pyiidnium iodide (19)
The solid obtained after evaporation of the reaction mixture was dissolved
in hot ethyl acetate and the solution was cooled overnight. The precipitated
pale yellow crystals were collected by filtration, dried in a desiccator and
recrystallizedfrom methanollethylacetate. Yield 2.05 g (95%), mp.153-157
'C.-IR 3612; 3420; 3259; 3022; 1757; 1739; 1687; 1664; 1637; 1616 1518
cm-1 .- 1H-NMR 6 @pm) = 1.0-1.50 (m. 2H, NCHKHz-CH2), 1.12 (t, J =
7.1 Hz, 6H, CHZCH~),
1.89 (s, 3H, COCH3). 1.80-2.35 (m, 4H. COC-CHz
and NCHZ-CHZ).4.12 (q, J = 7.1 Hz,4H, CHzCH3). 4.62 (t, J = 7.5 Hz, 2H,
NCHz), 8.16 (broad s. lH, DzO exchange, CONH), 8.24 (m, lH, pyridine5-H). 8.27 (s, lH, D?o exchange, NHCOCH3), 8.54 (broad s, lH, DzO
exchange, CONH), 8.93 (d, J = 8.1 Hz, 1H. pyridine-4-H), 9.19 (d, J = 6.0
Hz, lH, pyridine-bH), 9.49 (s, lH, pyridine-2-H).- CigH2sN306I (521.13)
Calcd. C 43.8 H 5.41 N 8.1 Found C 43.9 H 5.31 N 8.0.
I-(Aminocarbonyl)-l-[(5acetamido)-5,5-bir(efhoxycarbos?vIhpencyllpyridiniurn iodide (20)
Isomer 2 2 'H-NMR: 6 @pm) = 1.0-1.40 (m,2H, NCHzCHz-CHz), 1.13
(t, J = 7.1 Hz, 6H, CHKH3). 1.89 (s. 3H, COCH3), 1.90-2.30 (m,4H,
COC-CHZand NCHFCHZ). 4.27 (q, J = 7.1 Hz.4H, CHZCH~),
4.93 (t, J =
6.5 Hz,2H, NCHz), 8.23 (s, 1H. exchanges slowly with DzO, NHCOCH3).
8.45 (broads, lH, DzO exchange,CONH), 8.74 (broad s. lH, DzO exchange,
CONH), 8.97 (m, J = 1.2 Hz, lH, pyridazine-5-H), 9.82 (d, J = 1.2 Hz, 1H.
pyridazine-3-H), 10.11 (d, J = 6.1 Hz, lH, pyridazine-6-H).
Isomer U:'H-NMR: 6 @pm)= 1.00-1.40 (m, 2H, NCHKHz-CHz), 1.13
(t, J = 7.1 Hz, 6H, CHZCH~),1.89 (s, 3H, COCH3), 1.90-2.30 (m.4H,
CO-C-CHZand NCHZ-CHZ),4.27 (q, J = 7.1 Hz,4H, CHZCH~),
4.93 (1. J =
6.5 Hz,2H, NCHz). 8.23 (s. lH, exchanges slowly with DzO, NHCOCH3),
8.45 (broads. lH, DzO exchange,CONH), 8.74 (broad s, 1H, DzO exchange,
CONH),8.85('d', J=5.2Hz, lH,pyridazine-4H),9.8O('d', J=5.2Hz, 1H.
pyridazine-3-H),10.28 (s, lH, pyridazine-6-H).
Mixture 22K4: %NMR 6 (ppm) = 14.5 (CHZCH~),20.6 (NCHKHzCHZ),22.8 (COCH3). 29.9 (NCHZ-CHZ),32.7 (CO-C-CHZ). 63.0 (OCHZ),
65.4 and 65.6 (NCHz), 66.8 (N-C-CO), 134.3 and 134.5 (pyridazine-C-5of
22 and pyridazine-C-4 of 23). 139.5 and 140.7 (pyridazine-C-4 of 22 and
pyridazine-C-5of 23), 149.1, 150.9. 153.1, and 155.6 (pyridazine-C-3and
pyridazine-C-6), 162.3 and 163.0 (CONHz), 168.4 (CO). 171.1 and 171.3
(CO).-CisHz7N40aI (522.34) Calcd.C 41.4 H 5.21 N 10.7 Found C 41.4 H
5.20 N 10.6.
Hydrolysis of Compounds 13, 14,19, and 20
The iodides 13 (0.5 g, 0.98 mmol), 14 (0.5g, 0.98 mmol),19 (0.5 g, 0.96
mmol), or 20 (0.5 g. 0.96 mmol) were dissolved in methanol-water (3:l) and
passed through a column of Amberlite IRA-410 ion-exchange resin which
had been conditioned as described for compounds 7b and 8b. Fractions
containing the product were evaporated to dryness and the residues were
refluxedin lSml6NHClfor 12h.Theproductsthenobtainedbyevaporation
to dryness were recrystallized from ethanoVdiethyl ether. Acceptable elemental analysescould not be obtained forthe compoundsresulting from these
hydro1yses.
The solution was cooled overnight at -20 'C. The separated yellow solid
was collected and recrystallized from methanol. Yield 2.06 g (96%). mp.
178-182 OC.- I R 3531; 3252; 3165; 3011; 1757; 1695; 1639; 1570; 1406 (RS)-4-(Aminocarbonyl)-l-(4~mjno4-carboqbutyl)pyridinium
chloride
cm-'.- 'H-NMR 6 (ppm) = 0.95-1.40 (m, 2H, NCHzCHz-CHz). 1.13 (t,
Hydrochloride(24)
J = 7.1 Hz, 6H, CHzCH3). 1.75-2.25 (m, 4H. CO-C-CHI and NCHz-CHz),
Yield 0.25 g (82%) of a grey powder, mp. 205-208 "C.- I R 3435; 3053;
~.~O(S,~H,COCH~),~.~~(~,J=~.~HZ,~H,CHZCHJ),~.~~(~,
J=7.3Hz
2H, NCHz), 8.26 (s, 2H, DZO exchange, NHCOCH3 and CONH). 8.44 ('d', 2987; 2926; 2606,2467; 1724; 1639; 1576 cm-'.- 'H-NMR ([DslDMSO +
3J = 6.6 Hz, 2H, p);ridine-J-H;SH), 8.67 (broad s, lH, DzO exchange, DzO): S (ppm) = 1.96-2.1 1 (m 4H, CHzCHz), 3.88-3.91 (m 1H. CH). 4.79
CONH). 9.23 ('a, J = 6.6 Hz 2H, pyridine-2-H;6-H).- CigH2sN3061 (t, J = 6.4 Hz, 2H. NCHz), 8.46 ('d', J = 6.5 Hz, 2H, pyridine-3-HSH) 8.68
(broad s, 3H, exchanges slowly with DzO. NH3+), 9.36 ('d', J = 6.5 Hz. 2H,
(521.13)Calcd.C43.8H5.41 N8.1FoundC44.0H5.34N8.0.
pyridine-2-H;6-H).- %-NMR ([DaJDMSO): 6 (Em) = 26.3 (C-CH2-C),
26.6(C-CHz-C). sl.O(CHNHz), 59.9 (NCHz), 127.3 (pyridine-C-3;5).145.6
3-(Aminocarbonyl)-l-[(5-acetamido)-5,5-bis(ethoxycarba?yl~e~l](pyridine C-4), 146.3 (pyridine C-2;6). 163.4 (CONHz), 170.4 (COOH).pyminium iodide (21) @
MS (Flectraspray): mlz = 239 (M+H+)*,261 (M+Na+)+.
The reaction mixture was subjected to cc (acetonitrile)to give dark brown
crystals. Yield 0.8 g (52%), mp. 127-132 "C.-IR 3445 (broad); 3261; 2984;
(RS)-4-(Aminocar~nyl)-l-(5~~no-5-car~~pentyl)~~nium
chloride
1738; 1701; 1662; 1512 cm-'.- 'H-NMR 6 (ppm) = 1.W1.50 (m.2H,
Hydrochloride(25)
NCHzCHz-CHz). 1.14 (t, J = 7.1 Hz, 6H, CHzCH3). 1.80-2.40 (m.4H,
Yield 0.28 g (90%) of light yellow needles, mp. 218-222 "C.- I R 3421;
COC-CHZand NCHFCHZ), 1.90 (s, 3H, COCH3), 4.13 (q,J = 7.1 Hz, 4H,
CHzCH3), 4.72 (t. J = 7.4 Hz, 2H. NCHz), 8.24 (s, 1H. DzO exchange, 3124-2756 (broad); 2623; 1743; 1730; 1645; 1599; 1575; 1502 cm-'.NHCOCH3). 8.31 (broads, 1H. Dz0 exchange, CONH), 8.66 (broad s, 1H.
'H-NMR([Da]DMSO+ DzO):S@pm)=1.20-1.75(m2H,CHz),
1.75-2.40
DzO exchange, CONH), 9.38 (A-part of an AB-system, 3J = 3.5 Hz, lH,
(m4H, CHzCHz), 3.65415 (m lH, CH), 4.76 (t, J = 6.3 Hz 2H. NCHz).
pyrazine-6-H), 9.56 (B-partof an AB-system, 3J =3.5 Hz, 1H pyrazine-5-H) 8.46 ('d', J = 6.4 Hz, pyridine-3-H;5-H),8.63 (broads, 3H. exchan es slowly
with DiO, NHf). 9.38 ('d', J = 6.4 Hz, 2H, pyridine-2-H;fSH).- C-NMR:
9.74 (s, lH, pyrazine-2-H).- I3C-NMR S @pm) = 13.8 (CHZCH~),20.0
(NCHKH~CHZ),22.2 (COCH3). 30.4 (NCHZ-CHZ),32.0 (CO-C-CHZ), (PalDMSO) S (ppm) = 20.8 (NCHzCHzCHz), 29.0 (NCHzCHz), 30.0
61.4 (NCHz), 61.6 (OCHz), 66.0 (N-C-CO), 137.3 (pyrazine-c-;?), 138.8 (CH(NHz)CHz),51.5 (CHNHz), 60.4(NCHz), 127.2 (pyridine-C-3;5). 145.4
(pyrazine-C-6), 149.1 @yrazine-C-5). 151.0 (pyrazine-C-3). 162.1
(pyridine-C-4), 146.3 (pyridine-C-26). 163.4 (CONHz), 170.6 (COOH).(CONHz), 167.5 (CO). 169.1 (CO).
MS (Electrospray): positive: mlz = 253 (M+H+)+.negative: mlz = 251
w
(M- P)-.
4-(AminocarbOnyl)-l -[(54ceramido)-5, s-bis(erhoxycarbar?vl~e~lpyrihziniurn iodide (22) and S-(Anrinocarbonyl)-I-[(5~ce~'~~
5,5-~ethaxycnrbonyl)pentylpyridr4inium
iodide (23)(mixture)
(RS)-3-(Aminocarbonyl)-l-(4-a~04~arboxybutyl)pydinium
chloride
Hydrochloride(26)
The residue obtained after evaporation was dissolved in hot dichloromethane. ethyl acetate was added and the mixture was cooledovernight. The
precipitate was collected and recrystallized from methanoUethyl acetate to
givereddish-browncrysta~of22and23(1:1accordingto'H-NMRdata'4)).
Yield 1.52g(73%). mp. 127-13O"Cand 134-139°C.-IR:3393;3250;3182;
2980; 1757: 1739; 1697: 1670; 1643; 1520 cm-'.
Yield 0.28 g (90%) of colourless crystals, mp. 22&223 "(2.- IR: 34433376 (broad); 3096-3303 (broad); 1731; 1637m-'.-'H-NMR ([DalDMSO
+Dz0):6@pm)=1.75-2.26(m.4H,CH2CH2).3.93(t,J=5.7Hz 1H.CH).
4.74 (t, J = 6.5 Hz,2H, NCHz). 8.24 (dd,J5.6 = 6.1 Hz, J45 = 8.0 Hz, lH,
pyridine-5-H), 8.93 (d, J4.5 = 8.0 Hz, lH, pyridine+H), 9.30 (d. Js,a = 6.1
Hz, lH, pyridine-6-H),9.52 (s, lH, pyridine-2-H).- I3C-NMR ([DaIDMSO):
312
6 (ppm) = 26.5 (C-CHz-C), 26.9 (C-CHz-C), 51.4 (CHNHz), 60.5 (NCHz),
128.8 (pyridine-C-5). 131.5 (pyridine-C-3). 145.8 (pyridine-C-4). 146.3
@yridine-C-6),148.0(pyridineC-2). 163.2 (CONHz), 170.6 (COOH).- MS
(Electrospray): positive: m/z = 239 (M+H+)+,261 (M+Na+)+.negative: d z
= 237 (M-H+)-.
(RS)-3-(Ami'nocarbonyl)-I
-(5-antino-S-carboxypentyl)pyn~niumchloride
Hydrochloride (27)
Easmon, Heinisch, Holzer, and Matuszczak
References and Notes
1 Part LXXI G. Heinisch, B. Matuszczak,K. Mereiter,Heierocycles 1994,
38,2081-2089.
2 R. Grote, Y. Chen, A. Zeeck. Z Chen, H. Zihner, P. Mischnick-Lobbecke. W.A. Konig, J. Antibiotics 1988,41,595-601.
3 F. L. Pattison. J. B. Stothers, R. G. Woolford. J. A m Chem SOC.1956,
78.2255-2259.
4 Otherthan withcompounds7ab,8ab, 10,andllwesofardidnotsucceed
in preparing a sampleof compound9 sufficientlypure to give satisfactory
analytical values for nitrogen (N Calc 12.0 Found 9.9).
Yield 0.30 g (%%) of colourless crystals, mp. 220-223 "C.- IR: 3512;
32162875 (broad): 2562; 2465; 1726 1710 1635; 1578 cm-'.- 'H-NMR
5
([D6]DMSO+ DzO): 6 @pm) = 1.24-1.55 (m2H, CHz). 1.60-2.08 (m, 4H,
CHKHz). 3.84 (t, J = 6.0 Hz, 1H. CH), 4.68 (t, J = 7.1 Hz, 2H, NCHz), 8.20
(dd, Js.6 = 6.1 Hz,J4.5 = 8.0 Hz. lH, pyridine-5-H), 8.91 (d, J4.5 = 8.0 Hz.
6
1H. pyidine-4-A), 9.23 (d, J5.a = 6.1 Hz, 1H. pyridine-dH), 9.46 (s, lH,
pyridine-2-H).- "C-NMR ([DalDMSO): 6 (ppm) = 21.4 (NCHZCH~CH~),
29.5 (NCHzCHz),30.4 (CH(NHz)CHz), 51.9 (CHNHz). 61.3 (NCHz), 128.9
(pyridiine-C-5). 131.6 @yridine-C-3),145.8 (py~idine-C-4),146.3 (pyridine7
C-6). 148.0 (pyridine-C-2), 163.4 (CONHz), 171.0 (COOH).- MS (Electrospray): pitive: m/z = 253 (M+H*)+.275 (M+Na+)*,negative: m/z= 251
8
(M-H+)-.
W. H. Leanza, H. J. Becker. E. F. Rogers, J. A m Chem SOC.1953, 75.
40864087.
Compounds 15 and 21 are extremely unstable. Accordingly, we so far
failed to prepare samples giving satisfactory elemental analyses. However, there cannot be any doubt about the structures of these compounds
duetotheclosesimilarity oftheirspectroscopicdata(1H-and13C-NhfR)
to those of the unambiguouslyassigned congener 9.
So far no attempts were made to separate the 1 M 7 and W23 mixtures.
Details regarding these biological investigations will be presented in a
forthcoming paper.
9 0. A. Moe, D. T. Warner, J. A m Chem Soc. 1948, 70,2763-2765.
B. Aniimikrobial Testing
The antimicrobial activity of the compounds was determined against the
following organisms: Bacillus subtilis, Escherichia coli, Mucor hiemalis,
Mucor miehei, Paecilomyces varioiii. Yarrowia lipolyiica, and Streptomyces
viridochmmogenes using the disk diffusion assay at concentrations of 1
mg/ml, 0.32 mg/ml, and 0.1 mg/m18).
This project has been generously supported by the Austrian 'Fonds ZUT
Fijrderungder WissenschaftlichenForschung', project No. P8529-CHE. The
authors gratefully acknowledge screening of selected compounds for antifungal activity by Prof. Ix.H. Z(ihner, University of Tubingen, Germany.
Moreover, we want to thank Dr. B. L Chenard, Pfizer Central Research,
Connecticut, USA, for providing a sample of ethyl 2-acetamido-2-ethoxycarbonyl-5-hydroxyvalerateand Dr.H.-P. Kdhlig, Universityof Vienna, for
recording a inverse H,C-shift correlation of compound 9. We are also very
grateful to Dr. L Jirmefz, University of Vienna, and to Dr. V. Ravedino,
Hewlett-Packard,Meyrin, Switzerland for the Electrospray mass spectra.
10 B. L. Chenard, C. A. Lipinski, B. W. Dominy. E. E. Mena, R. T. Ronau,
G. C. Butterfield,L. C. Marinovic. M. Pagnozzi. T. W. Butler, T. Tsang,
J. Med Chem 1990.33.1077-1083.
11 G. Heinisch, Momish Chem 1973,104.953-962.
12 R. H. Mizzoni, P. E. Spoerri, J. Am. Chem SOC.1954,76,2201-2203.
13 Assignments based on chemical shift considerations were confiied by
NOE-differenceexperiments as irradiation of the NCHz resonance resulted in a marked enhancement of the signals due to pyridine-2-H and
pyridine-6-H.
14 Discrimination of the isomers 10 and 11was achieved by comparison
with the 'H chemical shifts of 1.4- and 1,5-dimethylpyridadniumiodide
given in ref. Is).
15 M. S. Bate, A. B. Simmonds. W. F. Trager, J. Chem Soc. B 1966,
867-870.
[Ph 2821
Arch Pharm (Weinheim) 328, 307-312 (1995)
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synthesis, compounds, structurale, pyridazine, pyridazomycin, related, lxxiion, azinium, diazinium
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