Process for preparing N6-substituted adenosine derivatives

Details Process for preparing N6-substituted adenosine derivatives Process for preparing N6-substituted adenosine derivatives

2000-01-21

2002-08-06

Geist, Gary (Department: 1627)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C544S264000, C536S027110, C536S027200, C536S027230

Reexamination Certificate

active

06429315

ABSTRACT:

TECHNICAL FIELD
This invention is directed to a process for preparing N6-substituted adenosine derivatives, to intermediates useful therefor and to methods of preparing these intermediates.
BACKGROUND OF THE INVENTION
N6-substituted adenosine derivatives, as exempliified by [1S-[1a,2b,3b,4a(S*)]]-4-[7-[[1-(3-chloro-2-thienyl)methyl]propyl]amino]-3 H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxycyclopentanecarboxamide, are useful as a cardiovascular agents, more particularly as antihypertenisive and anti-ischemic agents, as cardioprotective agents which ameliorate ischemic injury or myocardial infarct size consequent to myocardial ischemia, and as antilipolytic agents which reduce plasma lipid levels, serum triglyceride levels, and plasma cholesterol levels. See U.S. Pat. Nos. 5,364,862 and 5,561,134 and International Patent Application No. PCT/US97/11320.
Methods of preparing these compounds and intermediates thereto are disclosed in U.S. Pat. Nos. 5,364,862 and 5,561,134 and Internationial Patent Application Nos. PCT/US97/11320, PCT/US97/15729 and PCT/US97/21439.
SUMMARY OF THE INVENTION
This invention is directed to a process for preparing an N-protected N6-substituted adenosine compound of formula
wherein
P is a nitrogenl protecting group;
Q is CH
2
or O;
T is
 or R
3
O—CH
2
;
X is a straight or branched chain alkylene, cycloakylyene or cycloalkenylene group;
Y is NR
4
, O or S;
a=0 or 1;
Z is of the formula
Z
1
is N, CR
5
, (CH)
m
-CR
5
or (CH)
m
-N, m being 1 or 2;
Z
2
is N, NR
6
, O or S;
n is 0 or 1;
R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are independently H, alkyl, aryl or heterocyclyl;
R
7
and R
8
are independently H, alkyl, aralkyl, carbamoyl, alkyl carbamoyl, dialkylcarbamoyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, or aryloxycarbonyl; or R
7
and R
8
together may form
 where R
c
is hydrogen or alkyl,
 where R
d
and R
e
are independently hydrogen, or alkyl, or R
d
and R
e
together with the carbon atom to which they are attached may form a 1,1-cycloalkyl group; and
R
a
and R
b
are independently H, OH, alkyl, hydroxyalkyl, alkyl mercaptyl, thioalkyl, alkoxy, alkyoxyalkyl, amino, alkyl amino, carboxyl, acyl, halogen, carbamoyl, alkyl carbamoyl, aryl or heterocyclyl, this process comprising reacting a 4-N-protected-2,3,4-triaminopyridine compound of formula
with a formic acid derivative.
The process of the present invention offers improved yields, purity, ease of preparation and/or isolation of intermediates and final product, and more industrially useful reaction conditions and workability over previously disclosed methods of preparation.
DETAILED DESCRIPTION OF THE INVENTION
Definitions of Terms
As used above and throughout the description of the invention, the following terms, unless otherwise indicated, have the following meanings:
“Acyl” means a straight or branched alkyl-C═O group. “Thioacyl” means a straight or branched alkyl-C═S group. Preferred acyl and thioacyl groups are lower alkanoyl and lower thioalkanloyl having from 1 to about 6 carbon atoms in the alkyl group.
“Alkyl” means a saturated aliphatic hydrocarbon group which may be straight or branched and has 1 to about 20 carbon atoms in the chain. Preferred alky groups may be straight or branched and has 1 to about 10 carbon atoms in the chain. Branched means that a lower alkyl group such as methyl, ethyl or propyl is attached to a linear alkyl chain.
“Lower alkyl” means an alkyl group having 1 to about 6 carbons.
“Cycloalkyl” means an aliphatic ring having 3 to about 10 carbon atoms in the ring. Preferred cycloalkyl groups have 4 to about 7 carbon atoms in the ring.
“Carbamoyl” means an
group. Alkylcarbamoyl and dialkylcarbamoyl means that the nitrogen of the carbamoyl is substituted by one or two alkyl groups, respectively.
“Carboxyl” means a COOH group.
“Alkoxy” means an alkyl-O, group in which “alkyl” is as previously described. Lower alkoxy groups are preferred. Exemplary groups include methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.
“Alkoxyalkyl” means an alkyl group, as previously described, substituted by an alkoxy group, as previously described.
“Alkoxycarbonyl means an alkoxy-C═O group.
“Aralkyl” means an alkyl group substituted by an aryl radical, wherein “aryl” means a phenyl or naphthyl. “Substituted aralkyl” and “substituted aryl” means that the aryl group, or the aryl group of the aralkyl group is substituted with one or more substituents which include alkyl, alkoxy, amino, nitro, carboxy, carboalkoxy, cyano, alkyl amino, halo, hydroxy, hydroxyalkyl, mercaptyl, alkylmercaptyl, trihaloalkyl, carboxyalkyl or carbamoyl.
“Aralkoxycarbonyl” means an aralkyl-O-C═O group.
“Aryloxycarbonyl” means an aryl-O-C═O group.
“Carbalkoxy” means a carboxyl substituent esterified with an alcohol of the formula C
n
H
2n+1
OH, wherein n is from 1 to about 6.
“Halogen” (or “halo”) means chlorine (chloro), fluorine (fluoro), bromine (bromo) or iodine (iodo).
“Heterocyclyl” means about a 4 to about a 10 membered ring structure in which one or more of the atoms in the ring is an element other than carbon, e.g., N, O or S. Heterocyclyl may be aromatic or non-aromatic, i.e., may be saturated, partially or fully unsaturated. Preferred heterocyclyl groups include pyridyl, pyridazinyl, pyrimidinyl, isoquinolinyl, quinoliniyl, quinazolinyl. imidazolyl, pyrrolyl, furanyl, thienyl, thiazolyl, benzothiazolyl, piperidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and morphonlinyl groups.
“Substituted heterocyclyl” means that the heterocyclyl group is substituted by one or more substituents wherein the substituents include alkoxy, alkylainino, aryl, carbalkoxy, carbamoyl, cyano, halo, heterocyclyl, trihalomethyl, hydroxy, mercaptyl, alkylmercaptyl or nitro.
“Hydroxyalkyl” means an alkyl group substituted by a hydroxy group. Hydroxy lower alkyl groups are preferred. Exemplary preferred groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl and 3-hydroxypropyl.
“Nitrogen protecting group” means an easily removable group which is known in the art to protect an amino (group against undesirable reaction during synthetic procedures and to be selectively removable. The use of N-protecting groups is well known in the art for protecting groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, CF, for example, T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991), incorporated herein by reference. Representative N-protecting groups include sulfonainides such as methanesufonyl (Ms), trifluoromethanesulfonyl (Tf), benzenesulfonyl (or pheniylsuilfonvyl), p-toluenesulfonyl (Ts), p-methoxybenzenesulfonyl, phenacylsulfonyl, and the like; carbamates such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl (Troc), 2-trimethylsilylethyloxycarbonyl (Teoc), tert-butoxycarbonyl (Boc), and the like; amides such as formyl, acetyl, benzoyl, trifluoroacetyl, and the like; N-alkyl derivatives such as benzyl; and N-phosphinyl derivatives such as diphenylphosphinoyl.
In a specific embodiment, the term “about” or “approximately” means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.
Preferred Embodiments
The preparation of N6-substituted adenosine derivatives of formula (1) wherein X
1
, X
2
, X, Y, a, Z, P, Q, T, R
7
and R
8
, are defined above is outlined in Scheme 1.
As shown in the foregoing Scheme 1, reaction of the 2,4-dihalo-3-nitropyridine compound (II) and the N-protected amine (III) provides the 2-halo-3-nitro-4-N-protected aminopyridine compound (IV). The reaction is carried out in the presence of an alkoxide such as potassium tert-butoxide or potassium tert-amylate, and the like; an inorganic carbonate base such as potassium carbonate; a metal hydride base such as sodium or potassium hydride; an alkyllithium base such as butyllithium; or a fluoride base such as potassium fluoride. When weaker bases such as pot

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