Process for preparing substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines   

This application is a Divisional application of U.S. patent application Ser. No. 11/788,682, filed Apr. 20, 2007, which application is incorporated herein in its entirety by reference as if fully set forth, and which application in turn is a continuing application based on and claiming the priority of U.S. patent application Ser. No. 10/973,631, filed Oct. 26, 2004, which application in turn is based on and claims the priority of U.S. Provisional Application Ser. No. 60/515,051, filed Oct. 28, 2003, the disclosure of each of which applications are also incorporated herein by reference in their entirety as if fully set forth.

FIELD OF THE INVENTION

The present invention relates to a process for preparing substituted 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine compounds having an aminoalkyl substituent at the 7-position.

Substituted 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine compounds disclosed in WO 01/92264 are useful as A2a, receptor antagonists in the treatment of central nervous system diseases, in particular Parkinson\'s disease.

WO 01/92264 discloses processes for preparing 5-amino-2-substituted-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines comprising dehydrative rearrangement of hydrazines. Baraldi et al, J. Med. Chem., 41, (1998), p. 2126-2133 disclose formation of a 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine having a phenylalkyl substituent at the 7-position, wherein the reaction comprises reacting a phenylalkyl-substituted hydrazide with (ethoxymethylene)malonitrile to form a substituted pyrazole. Baraldi et al, J. Med. Chem., 39, (1996), p. 1164-1171 disclose formation of a 7-substituted 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine by reaction of an alkylated pyrazole with (ethoxymethylene)malonitrile. Both Baraldi et al process use NH2CN to accomplish the final ring closure.

SUMMARY

The present invention relates to a process for preparing compounds having the structural formula I

or a pharmaceutically acceptable salt or solvate thereof, wherein

R is R1-furanyl, R1-thienyl, R1-pyridyl, R1-pyridyl N-oxide, R1-oxazolyl, R10-phenyl, R1-pyrrolyl or cycloalkenyl;

X is C2-C6 alkylene;

Y is —N(R2)CH2CH2N(R3)—, —OCH2CH2N(R2)—, —(CH2)2—NH—, or

and

Z is R5-phenyl, R5-phenylalkyl, R5-heteroaryl, diphenylmethyl, R6—C(O)—

R6—SO2—,

or phenyl-CH(OH)—; or when Q is

Z is also phenylamino or pyridylamino; or

Z and Y together are

R1 is 1 to 3 substituents independently selected from hydrogen, alkyl, —CF3, halogen, —NO2, —NR12R13, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl;

R2 and R3 are independently selected from the group consisting of hydrogen and alkyl;

m and n are independently 2-3;

Q is

R4 is 1-2 substituents independently selected from the group consisting of hydrogen and alkyl, or two R4 substituents on the same carbon can form ═O;

R5 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN, dialkyl-amino, —CF3, —OCF3, acetyl, —NO2, hydroxyalkoxy, alkoxyalkoxy, dialkoxy-alkoxy, alkoxy-alkoxy-alkoxy, carboxy-alkoxy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-amino-alkoxy, morpholinyl, alkyl-SO2—, alkyl-SO2-alkoxy, tetrahydropyranyloxy, alkylcarbonyl-alkoxy, alkoxycarbonyl, alkylcarbonyloxy-alkoxy, —SO2NH2, or phenoxy; or adjacent R5 substituents together are —O—CH2—O—, —O—CH2CH2—O—, —O—CF2—O— or —O—CF2CF2—O— and form a ring with the carbon atoms to which they are attached;

R6 is alkyl, R5-phenyl, R5-phenylalkyl, thienyl, pyridyl, cycloalkyl, alkyl-OC(O)—NH—(C1-C6)alkyl-, dialkyl-aminomethyl, or

R9 is 1-2 groups independently selected from hydrogen, alkyl, hydroxy, alkoxy, halogen, —CF3 and alkoxy-alkoxy;

R10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN, —NH2, alkylamino, dialkylamino, —CF3, —OCF3 and —S(O)0-2 alkyl;

R12 is H or alkyl; and

R13 is alkyl-C(O)— or alkyl-SO2—; comprising a) reacting the hydroxyl group of a pyrazole of formula II

with an activating agent in the presence of a base to obtain a compound of formula III

wherein L is a leaving group, and coupling the compound of formula III with a compound of formula IV

Z-Y—H  IV in the presence of a base to obtain a compound of formula V

b) treating the compound of formula V with trialkyl orthoformate in the presence of a catalytic amount of acid to obtain a compound of formula VI

wherein R7 is alkyl; c) condensing the compound of formula VI with a hydrazide of formula VII

H2NHN—C(O)—R  VII in the presence of an acid to obtain a compound of formula VIII

and hydrolyzing the compound of formula VIII to obtain a compound of formula IX

d) cyclizing the compound of formula IX with a cyanating agent selected from the group consisting of cyanates and cyanogen halides in the presence of a base to obtain a compound of formula I.

In particular, the invention relates to cyclizing a compound of formula IX with a cyanating agent to obtain a compound of formula I.

DETAILED DESCRIPTION

Preferred compounds of formula I prepared by the claimed process are those wherein R is R1-furanyl, R1-thienyl, R1-pyrrolyl or R10-phenyl, more preferably R1-furanyl. R1 is preferably hydrogen or halogen.

Another group of preferred compounds is that wherein X is ethylene.

Y is preferably

wherein Q is

with Q preferably being nitrogen. Preferably, m and n are each 2, and R4 is H.

A preferred definition for Z is R5-phenyl, R5-heteroaryl, R6—C(O)— or R6—SO2—. R5 is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxy. R6 is preferably R5-phenyl. Especially preferred are compounds wherein Z is R5-phenyl and R5 is one substituent selected from the group consisting of alkoxy and alkoxyalkoxy. A preferred alkoxy group is methoxy, with alkoxyalkoxy being more preferred, e.g., methoxyethoxy and ethoxyethoxy; methoxyethoxy is most preferred.

In step a, preferred embodiments of the process use a compound of formula IV-A:

In step b, the preferred trialkyl orthoformate is triethyl orthoformate.

Preferred embodiments of the process use 2-furoic hydrazide in step c (formula VII), thus preparing compounds of formula I wherein R is 2-furyl.

Preferred reagents for the cyclization in step f are cyanates.

In a preferred aspect, the process of the invention comprises the preparation of compounds of the formulas I-A to I-C:

In a most preferred aspect, the process of the invention comprises the preparation of a compound of formula I-A comprising: a) reacting the hydroxyl group of a pyrazole of formula II

with methanesulfonyl chloride in the presence of a base to obtain a compound of formula IIIa

and coupling the compound of formula IIIa with a compound of formula IVa

in the presence of a base to obtain a compound of formula Va

b) treating the compound of formula Va with trimethyl orthoformate in the presence of a catalytic amount of an acid to obtain a compound of formula VIa

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