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

1. A process for preparing compounds having the structural formula I

or a pharmaceutically acceptable salt thereof, wherein

R is R 1 -furanyl, R 1 -thienyl, R 1 -pyridyl, R 1 -pyridyl N-oxide, R 1 -oxazolyl, R 10 -phenyl, R 1 -pyrrolyl or cycloalkenyl;

X is C 2 –C 6 alkylene;

Y is —N(R 2 )CH 2 CH 2 N(R 3 )—, —OCH 2 CH 2 N(R 2 )—, —(CH 2 ) 2 —NH—, or

and

Z is R 5 -phenyl, R 5 -phenylalkyl, R 5 -heteroaryl, diphenylmethyl, R 6 —C(O)—, R 6 —SO 2 —,

or phenyl-CH(OH)—; or when Q is

Z is also phenylamino or pyridylamino;

or

Z and Y together are

R 1 is 1 to 3 substituents independently selected from hydrogen, alkyl, —CF 3 , halogen, —NO 2 , —NR 12 R 13 , alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl;

R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl;

m and n are independently 2–3;

Q is

R 4 is 1–2 substituents independently selected from the group consisting of hydrogen and alkyl, or two R 4 substituents on the same carbon can form ═O;

R 5 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN, dialkyl-amino, —CF 3 , —OCF 3 , acetyl, —NO 2 , hydroxyalkoxy, alkoxyalkoxy, dialkoxy-alkoxy, alkoxy-alkoxy-alkoxy, carboxy-alkoxy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-amino-alkoxy, morpholinyl, alkyl-SO 2 —, alkyl-SO 2 -alkoxy, tetrahydropyranyloxy, alkylcarbonyl-alkoxy, alkoxycarbonyl, alkylcarbonyloxy-alkoxy, —SO 2 NH 2 , or phenoxy; or adjacent R 5 substituents together are —O—CH 2 —O—, —O—CH 2 CH 2 —O—, —O—CF 2 —O— or —O—CF 2 CF 2 —O— and form a ring with the carbon atoms to which they are attached;

R 6 is alkyl, R 5 -phenyl, R 5 -phenylalkyl, thienyl, pyridyl, cycloalkyl, alkyl-OC(O)—NH—(C 1 –C 6 )alkyl-, dialkyl-aminomethyl, or

R 9 is 1–2 groups independently selected from hydrogen, alkyl, hydroxy, alkoxy, halogen, —CF 3 and alkoxy-alkoxy;

R 10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN, —NH 2 , alkylamino, dialkylamino, —CF 3 , —OCF 3 and —S(O) 0-2 alkyl;

R 12 is H or alkyl; and

R 13 is alkyl-C(O)— or alkyl-SO 2 —;

comprising

a) reacting the hydroxyl group of a pryazole 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 an acid to obtain a compound of formula VI

wherein R 7 is alkyl;

c) condensing the compound of formula VI with a hydrazide of formula VII

H 2 NHN—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.

2. The process of claim 1 for preparing compounds of formula I wherein: R is R 1 -furanyl, R 1 -thienyl, R 1 -pyrrolyl or R 10 -phenyl; R 1 is hydrogen or halogen; X is ethylene; Y is

wherein Q is

Z is R 5 -phenyl, R 5 -heteroaryl, R 6 —C(O)— or R 6 —SO 2 —; and R 6 is R 5 -phenyl.

3. The process of claim 2 wherein R is R 1 -furanyl; R 1 is hydrogen or halogen; Q is

m and n are each 2; R 4 is H; Z is R 5 -phenyl; and R 5 is one substituent selected from the group consisting of alkoxy and alkoxyalkoxy.

4. The process of claim 2 wherein L is an optionally substituted alkylsulfonyl- or arylsulfonyl-group.

5. The process of claim 4 wherein L is a alkylsulfonyl- or arylsulfonyl-group, selected from the group consisting of methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, p-bromobenzenesulfonyl and m-nitrobenzenesulfonyl.

6. The process of claim 5 wherein L is methanesulfonyl.

7. The process of claim 1 , step b, wherein the trialkyl orthoformate is trimethyl orthoformate.

8. The process of claim 1 wherein the cyanating agent in step d is a cyanate.

9. The process of claim 8 wherein the cyanate is selected from the group consisting of 2-methoxyphenyl cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl cyanate and bisphenol A cyanate.

10. The process of claim 9 wherein the cyanate is 2-methoxyphenyl cyanate.

11. The process of claim 1 for preparing 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

c) condensing the compound of formula VIa with a hydrazide of formula VIIa

in the presence of an acid to obtain a compound of formula VIIa

and hydrolyzing the compound of formula VIIIa to obtain a compound of formula IXa

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

12. The process of claim 11 wherein the cyanating agent is a cyanate selected from the group consisting of 2-methoxyphenyl cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl cyanate and bisphenol A cyanate.

13. A process for preparing a compound of formula I

or a pharmaceutically acceptable salt or thereof, wherein

R is R 1 -furanyl, R 1 -thienyl, R 1 -pyridyl, R 1 -pyridyl N-oxide, R 1 -oxazolyl, R 10 -phenyl, R 1 -pyrrolyl or cycloalkenyl;

X is C 2 –C 6 alkylene;

Y is —N(R 2 )CH 2 CH 2 N(R 3 )—, —OCH 2 CH 2 N(R 2 )—, —(CH 2 ) 2 —NH—, or

and

Z is R 5 -phenyl, R 5 -phenylalkyl, R 5 -heteroaryl, diphenylmethyl, R 6 —C(O)—, R 6 —SO 2 —,

or phenyl-CH(OH)—; or when Q is

Z is also phenylamino or pyridylamino;

or

Z and Y together are

R 1 is 1 to 3 substituents independently selected from hydrogen, alkyl, —CF 3 , halogen, —NO 2 , —NR 12 R 13 , alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl;

R 2 and R 3 are independently selected from the group consisting of hydrogen and alkyl;

m and n are independently 2–3;

Q is

R 4 is 1–2 substituents independently selected from the group consisting of hydrogen and alkyl, or two R 4 substituents on the same carbon can form ═O;

R 5 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN, dialkyl-amino, —CF 3 , —OCF 3 , acetyl, —NO 2 , hydroxyalkoxy, alkoxyalkoxy, dialkoxy-alkoxy, alkoxy-alkoxy-alkoxy, carboxy-alkoxy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-amino-alkoxy, morpholinyl, alkyl-SO 2 —, alkyl-SO 2 -alkoxy, tetrahydropyranyloxy, alkylcarbonyl-alkoxy, alkoxycarbonyl, alkylcarbonyloxy-alkoxy, —SO 2 NH 2 , or phenoxy; or adjacent R 5 substituents together are —O—CH 2 —O—, —O—CH 2 CH 2 —O—, —O—CF 2 —O— or —O—CF 2 CF 2 —O— and form a ring with the carbon atoms to which they are attached;

R 6 is alkyl, R 5 -phenyl, R 5 -phenylalkyl, thienyl, pyridyl, cycloalkyl, alkyl-OC(O)—NH—(C 1 –C 6 )alkyl-, dialkyl-aminomethyl, or

R 9 is 1–2 groups independently selected from hydrogen, alkyl, hydroxy, alkoxy, halogen, —CF 3 and alkoxy-alkoxy;

R 10 is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, —CN, —NH 2 , alkylamino, dialkylamino, —CF 3 , —OCF 3 and —S(O) 0-2 alkyl;

R 12 is H or alkyl; and

R 13 is alkyl-C(O)— or alkyl-SO 2 —;

comprising cyclizing a compound of formula IX

with a cyanating agent selected from the group consisting of cyanates and cyanogen halides in the presence of a base.

14. The process of claim 13 wherein the cyanating agent is a cyanate selected from the group consisting of 2-methoxyphenyl cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl cyanate and bisphenol A cyanate.

15. The process of claim 13 for preparing compounds of formula I wherein R is R 1 -furanyl, R 1 -thienyl, R 1 -pyrrolyl or R 10 -phenyl; R 1 is hydrogen or halogen; X is ethylene; Y is

wherein Q is

Z is R 5 -phenyl, R 5 -heteroaryl, R 6 —C(O)— or R 6 —SO 2 —; and R 6 is R 5 -phenyl.

16. The process of claim 15 wherein R is R 1 -furanyl; R 1 is hydrogen or halogen; Q is

m and n are each 2; R 4 is H; Z is R 5 -phenyl; and R 5 is one substituent selected from the group consisting of alkoxy and alkoxyalkoxy.