Methods for the synthesis of unsymmetrical cycloalkyl substituted xanthines
View Patent ↗The present invention provides processes for making pyridyl-linked-xanthines of formula VII, from 5,6-diamino-1H-pyrimidine-2,4-diones of formula II and acylating agents of formula VI. The xanthines are expected to be are selective antagonists of A 2B adenosine receptors (ARs).
1. A process for preparing a compound of formula VII:
the process, comprising:
(a) contacting a 5,6-diamino-1H-pyrimidine-2,4-dione of formula II:
with an acylating agent of formula VI:
in an aprotic solvent to produce a 1H-pryimidine-2,4-dione of formula IV:
(b) contacting the 1H-pryimidine-2,4-dione of formula IV with a base to produce a xanthine of formula VII;
wherein:
X′ and X″ are each independently selected from the group consisting of Cl, Br, and I;
R 1 is (C 3-8 )cycloalkyl; and,
R 2 is hydrogen, or is selected from the group consisting of substituted or unsubstituted (C 1-8 )alkyl, halo(C 1-8 )alkyl-, (C 3-8 )alkenyl, (C 3-8 )alkenyl(C 1-8 )alkyl-, (C 3-8 )alkynyl, (C 3-8 )alkynyl(C 1-8 )alkyl-, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 4-10 )hererocyclyl, (C 4-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )aryloxy, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl, and (C 5-10 )heteroaryl(C 1-8 )alkyl-.
2. The process of claim 1 , wherein the acylating agent is further selected from the group consisting of:
and the resulting xanthine products formed are selected from the group consisting of VIIa-VIIe;
3. The process of claim 1 , wherein a compound of the formulae VII and VIIa-VIIe is further contacted with an amine of the formula R′—NH 2 to produce a compound of the formula VIII-VIIIe;
which is further contacted with a compound of the formula Z 1 C(O)—W to form a compound of the formula IX-IXe:
wherein:
W is a leaving group;
R′ is selected from the group consisting of amino, (C 1-4 )alkyl, halo(C 1-4 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 1-4 )alkoxy(C 1-4 )alkyl-, R 4 R 5 N(C 1-4 )alkyl-, R 4 R 5 NC(O)(C 1-4 )alkyl-, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl(C 1-4 )alkyl-, (C 4-10 )heterocyclyl(C 1-4 )alkyl-, (C 6-10 )aryl(C 1-4 )alkyl-, and (C 5-10 )heteroaryl(C 1-8 )alkyl-, each substituted or unsubstituted;
R 1 is (C 3-8 )cycloalkyl;
R 2 is hydrogen, or is selected from the group consisting of substituted or unsubstituted (C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkenyl(C 1-8 )alkyl-, (C 3-8 )alkynyl, (C 3-8 )alkynyl(C 1-8 )alkyl-, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 4-10 )heterocyclyl, (C 4-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )aryloxy, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl, and (C 5-10 )heteroaryl(C 1-8 )alkyl-;
Z 1 is a 5-14 member substituted or unsubstituted monocyclic aryl, polycyclic aryl, or heteroaryl ring; and,
R 4 and R 5 each are independently hydrogen or are selected from the group consisting of (C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 6-18 )polycycloalkyl, (C 6-18 )polycycloalkyl(C 1-8 )alkyl-, (C 3-10 )heterocyclyl, (C 3-10 )heterocyclyl(C 1-8 )alkyl-, ((C 1-8 )alkyl) 2 N—(C 6-10 )aryl-, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl, (C 5-10 )heteroaryl(C 1-8 )alkyl-, (C 1-8 )alkyl)C(O)—, (C 1-8 )alkyCO 2 —, —C(O)N((C 1-8 )alkyl) 2 , —S(O)(C 1-8 )alkyl, —S(O)N((C 1-8 )alkyl) 2 , —S(O) 2 (C 1-8 )alkyl, and —S(O) 2 N((C 1-8 )alkyl) 2 .
4. The process of claim 2 , wherein a compound of formula VII-VIIe is further contacted with an amine of the formula R′—NHC(O)Z 1 at an elevated temperature to produce a compound of the formula IX-IXe:
wherein:
R′ is selected from the group consisting of amino, (C 1-4 )alkyl, halo(C 1-4 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 1-4 )alkoxy(C 1-4)alkyl-, R 4 R 5 N(C 1-4 )alkyl-, R 4 R 5 NC(O)(C 1-4 )alkyl-, (C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl(C 1-4 )alkyl-, (C 4-10 )heterocyclyl(C 1-4 )alkyl-, (C 6-10 )aryl(C 1-4 )alkyl- and (C 5-10 )heteroaryl(C 1-8 )alkyl-, each substituted or unsubstituted;
Z 1 is a 5-14 member substituted or unsubstituted monocyclic aryl, polycyclic aryl, or heteroaryl ring; and
R 4 and R 5 each are independently selected from the group consisting of hydrogen, (C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 6-18 )polycycloalkyl, (C 6-8 )polycycloalkyl(C 1-8 )alkyl-, (C 3-10 )heterocyclyl, (C 3-10 )heterocyclyl(C 1-8 )alkyl-, ((C 1-8 )alkyl) 2 N—(C 6-10 )aryl-, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl, (C 5-10 )heteroaryl(C 1-8 )alkyl-, (C 1-8 )alkylC(O)—, (C 1-8 )alkylCO 2 —,—C(O)N((C 1-8 )alkyl) 2 , —S(O)(C 1-8 )alkyl, —S(O)N((C 1-8 )alkyl) 2 , —S(O) 2 (C 1-8 )alkyl, and —S(O) 2 N((C 1-8 )alkyl) 2 .
5. The process of claim 1 , wherein the elevated temperature is between about 75 and about 185° C.
6. The process of claim 1 , wherein the aprotic solvent is an amine.
7. The process of claim 1 , wherein the aprotic solvent is a mixture of dichloromethane and pyridine.
8. The process of claim 1 , wherein the base is a metal hydroxide selected from the group consisting of lithium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, and mixtures thereof.
9. The process of claim 8 , wherein the base is sodium hydroxide.
10. The process of claim 1 , wherein the 1H-pyrimidine-2,4-dione of formula IV is prepared and is converted to the xanthine of the formula V without further purification.