Chapter 24
Electrophilic Addition to "AminoNONOate" (R R NN(O)NO ) Ions 1
2
-
1
1
2
Joseph E. Saavedra , Tambra M. Dunams , Judith L. Flippen-Anderson , and Larry Κ. Keefer 1
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1
Laboratory of Comparative Carcinogenesis, Frederick Cancer Research and Development Center, National Cancer Institute, Frederick, MD 21702 Naval Research Laboratory, Washington, DC 20375 2
Nitric oxide (·NO) has long been known to be an important air pollutant, a harmful constituent of cigarette smoke and a nitrosamine precursor. In spite of these deleterious effects, this simple diatomic molecule is produced by numerous tissues of the body and is involved in many key bioregulatory processes (1). Several complex ions of structures R N[N O ] 1 and RNH[N O ] 2 have been prepared by reacting nitric oxide with secondary and primary amines, respectively (2). These adducts are of current interest as pharmacological probes by virtue of their ability to regenerate nitric oxide under physiological conditions (3). The decomposition to ·NO is a spontaneous, first order reaction where protonation of the anion is a key step. We have been interested in blocking the anionic oxygen with an alkyl group in order to provide stable, covalently bonded adducts, Et N[N O ]R' 3. Compounds of this type might serve as prodrugs which cannot release nitric oxide until they are metabolically reconverted t0o 1a (1 in which R=Et) by enzymes specific to the desired target cell type. -
2
2
-
2
2
\ +
E t 2
E t
/ " = \ OOR'
\ /
*
2
2
2
E t
¥
a
2
RON:
+
NO
IR'X E
t
* \
RX
>=!-
Et N
OR'
2
Ο)
V ο
ο
NO
ία JBrCH CH Br 2
E
2
(g)
t,N N
O-
=
* , Ν
χ
+
N = N
N N
OCH CH Br 2
2
O"
+
O C H C H N^ 2
2
{^J
This chapter not subject to U.S. copyright Published 1994 American Chemical Society
Loeppky and Michejda; Nitrosamines and Related N-Nitroso Compounds ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
24.
ElectrophUic Addition to "AminoNONOate" Ions
SAAVEDRA ET AL.
305
Anions of structure là proved reactive toward a variety of electrophiles (4-6), such as alkyl halides, sulfate esters and epoxides, Table I. Alkylation had been reported (4) to occur at the interior oxygen of la to form N-nitroso derivatives of structure R NN(OR')NO as the major product. However, we discovered that alkylation of l a gives a product where the electrophile attaches to the exterior oxygen. This was established by comparing our product of ethylation to Et2NN(0)=NOEt, a compound derived from the regiospecific trapping of ethoxynitrene by diethylnitrosamine, as described by Artsybasheva and Ioffe (7).
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2
A species involving electrophilic attack on the interior oxygen was never observed in the alkylation of la. The structure was unequivocally confirmed by single crystal X-ray analysis of £. This product was obtained from the reaction of lâ and the bifunctional electrophile, 1,2-dibromoethane, to give 4 followed by addition to pyridine. Intermediate 4 proved to be a useful alkylating agent towards a variety of nucleophiles. The reaction of 4 with pyridine gave §, the crystalline product used for structure confirmation. The NONOate salt la reacted with 4 to give the bis-adduct Et N(N 0 )CH CH (0 N2)NEt . Moreover, 4 was reacted with methylamine to give 2â β in which R ' ^ C H ^ N H M e ] , was hydrolyzed to the corresponding alcohol, and was dehydrobrominated to the vinyl derivative. These further reactions of 4 have been useful in providing us with structurally diverse prodrug candidates. 2
2
2
2
2
2
2
TABLE I. Alkylation products 2 by reacting la with electrophiles R'
solvent
electrophile
Et n-Pr CH —CHCH MeCHOHCH HOCH CH MeOCH 2
2
2
2
2
2
2
MeOH DMF DMF THF THF THF
Et S0 n-Prl allyl bromide propylene oxide BrCH CH OH MeOCH Cl 4
2
2
2
yield(%) 33 33 36 6 33 41
Conclusion. A wide variety of potential prodrugs are now available by O-derivatization of the anionic functional group in secondary amine-nitric oxide complexes. The products of alkylation have the oxo-triazene structure, R NN(0)=NOR\ These agents are remarkably resistant to hydrolysis, and are thermally stable. Preliminary data with a few of these O-functionalized derivatives indicate that they can be used to lower blood pressure in rats and rabbits. 2
References. 1. Moncada, S.; Palmer, R. M . J.; Higgs, E. A. Pharmacol. Rev. 1991, 43, 109142. 2. Drago, R. S.; Karstetter, B. R. J. Am. Chem. Soc. 1961, 83, 1819-1822.
Loeppky and Michejda; Nitrosamines and Related N-Nitroso Compounds ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
NTFROSAMINES AND RELATED ΛΓ-NITROSO COMPOUNDS
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3. Maragos, C. M.; Morley, D.; Wink, D. Α.; Dunams, T. M.; Saavedra, J. E.; Hoffman, Α.; Bove, Α. Α.; Isaac, L.; Hrabie, J. Α.; Keefer L. K. J. Med. Chem. 1991, 34, 3242-3247. 4. Reilly, E. L. U.S. Patent No. 3,153,094, Oct. 13, 1964 (cf. Chem. Abstr. 1965, 62, 5192h). 5. Longhi, R.; Drago, R. S. Inorg. Chem. 1963, 2, 85-88. 6. Saavedra, J. E.; Dunams, T. M.; Flippen-Anderson, J. L.; Keefer L. K. J. Org. Chem. 1992, 57, 6134-6138. 7. Artsybasheva, Y. P.; Ioffe, Β. V. J. Org. Chem. USSR (Engl. Transl.) 1987, 23, 1056-1060.
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RECEIVED January 26, 1994
Loeppky and Michejda; Nitrosamines and Related N-Nitroso Compounds ACS Symposium Series; American Chemical Society: Washington, DC, 1994.
