100437

1188 Journal of Medicinal Chemittry, 1991, Vol. 34, No. 3

Scheme I

Cristolli et al.

CN	HjSCHCjH, 3
CNKN,	1 + CM OH	unijCi
COOEt	CH,

0

1

Ito-C

NH.OH

0

II

H₂N -C H₂N

2

3

N«N0, / NCI /

N*NO,

O    0    0

	"■':u	EtO-C X?
A	i	A
♦	6	4
	A	***/ j IMM,
-CMC,M„ 1 CH OH 1	TT	HOHjC N
CH,	A 9	A a

o

MlN-C. _N

s,	Sal	' A
Cp	R,
5	H	H
!•	M	CH
Sb	H	CM
Se	H	"CM
Sd	H	OvCHQH
Se	M	tWHjCMtOMKK
sr	H	1»JC*CCH|0M|CM.
99	H	<C,H
9h	H	CHAH
Si		CH

no.	X	Y	Z	K,.M
la*	N	N	N	0.7 X 10 •
lb*	CH	N	N	1.6 x 10-^T
lc«	N	CH	N	1.0 x 10 *
ld*	N	N	CH	4.0 X 10 ^4
le*	CH	CH	N	7.1 X 10*^s
lf	CH	N	N	6.6 x 1C^T
la	N	CH	N	3.6 x 10 *
lh	N	N	CH	not active
U	CH	CH	N	U x 10*
11	CH	N	CH	not active

* Mialurc of two isomers: 2'S.VR and 2'R&S.

of EHNA itself, and 1-deaza-EHNA (lb), though less po-tent, is a good inhibitor. On the contrary, substitution of a raethine group for the nitrogen atom in the 7*position of the purine moiety of EHNA produces a dramatic drop in the inhibitory activity (ld). Also the contemporary substitution of pyrimidine nitrogens by carbons brings about a conaiderable reduction of activity (le). In order to introduce additional simplifications to the EHNA Chemical atructure, a series of er>Ł/iro-l-(2-hydroxy-3-nonyl)imidazole derivatives have been synthesized.

Chemlstry

Condenaation of ethył 2-amino-2-cyanoacetate^: with eo'fńro-3-amino-2-nonanol^# in the preaence of triethyl orthoformate gave ethył eryf/iro5-amino*l-(2-hydroxy-3-nonyl)imidazule-4-carboxylate (2) (Scheme I). Ammo-nolysis of 2 in a sealed tubę at 110 °C for 3 days afforded eryfhro-5-amino-l-(2-hydroxy-3-nonyl)imidazole-4-carboxamide (3).

(7)    Lagemann, F. I.; Shaw. G. B. Chem. Ind. {London) 1980, Ml.

(8)    Shaeffer. H. J.. Schwender. C. F. J. Med. Chem. 1974. 17.6.

Table I. tnhibition Con&tanU of Calf Intestinal Adenoeine Deaminase⁵

CHC«H„	HOCH,
CHOW 1	- lę
CH,	HO
ia-a	1«-l

Treatment of the same compound (2) with sodium ni-trite at -20 °C in the preaence of 50% hypophosphorous acid gave ethył enfbro-l-(2-hydroxy-3*nonyl)imidazole-4-carboxylate (4), which was converted by methanolic ammonia at 110 °C to eryfhro-l-(2-hydroxy-3-nonyl)-iraidazole-4-carboxainide (5). Treatment of ethył ester 4 with the appropriate aminę provided N-substituted amides 5a-ł. Nitrosation of compound 2 at --25 °C in the presence of 6 N hydrochloric acid and cuprous chloride afforded ethył er>(/jro-5-chloro-l-(2-hydroxy-3*nonyl)imidazole-4-carboxylate (6) which was comerted by 30% ammonium hydroxide at 110 °C to erythro-5-chloro-l-(2-hydroxy-3-nonyl)imidazo)e-4-carboxamide (7). Reduction of 4 with LiAłH₄ in THF provided eryt/iro-l-(2-hydroxy-3-nonyl)-4-(hydroxymethyl)imidazole (8).

Basic hydrołysis of the same ester 4 gave erythro-l-(2-hydroxy-3-nonyl)imidazole-4-carboxylic acid (9) in 66% yield. Condenaation of aminomalonitriłe with erythro-3-amino-2-nonanol⁵ in the presence of triethyl orthoformate gave eryfhro-5-amino-l-(2-hydroxy-3-nonyl)imidazołe-4-carbonitrile (10). Compound 10 was diazotized with iso-pentyl nitrite in tetrahydrofuran (THF) at reflux to give 50% erythro- l-(2-hvdroxv-3-nonyl)imidazole-4-carbonitrile (13).

Amidine 12 was prepared from 10 in two steps: treatment of nitrile 10 with dry hydrogen chloride in methanoł at 0 °C provided 83% methyl eryf/iro-5-araino-l-(2* hydroxy-3-nonyl)imidazole-4-carboximidate hydrochloride (11) (Scheme II). The latter compound was further con-verted into eryf/tro-5-amino-l-(2-hydroxy-3-nonyl)-imidazole-4-carboxamidine hydrochloride (12) when treated with methanolic ammonia at 80 °C for 4 h. The same reactions did not work well in the case of nitrile 13. The alternative route includcs synthesis of amidoxime 14 by treatment of 13 with hydroxylamine, followed by reduction with hydrogen and Raney Ni catalyst at 45 psi for 6 h to give eryf/jro-l-(2-hydroxy-3-nonyl)imidazole-4-carboxamidine hydrochloride (15). Treatment of 13 with hydrogen sulfide in dry pyridir.e and triethylamine at room temperatura gave eryt/iro-l-(2-hydroxy-3-nonyl)-imidazole-4-thiocarboxamide (16). Hydrogenation ofthe same carbonitrile 13 in the presence of 5% Pd/C tri-