2-furyl-oxazolo[5,4-d]-pyrimidines

• US 5,300,509 A
• Filed: 11/20/1992
• Issued: 04/05/1994
• Est. Priority Date: 11/25/1991
• Status: Expired due to Term

• Current Assignee: Imperial Chemical Industries PLC (IMPERIAL CHEMICAL INDUSTRIES)
• Original Assignee: Imperial Chemical Industries PLC (IMPERIAL CHEMICAL INDUSTRIES)
• Inventors: Block, Michael H., Hargreaves, Rodney B., Harrison, Alison
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): GUPTA, YOGENDRA N
• Application Number:
  US07/979,019
• Time in Patent Office: 501 Days
• Field of Search: 544/250, 544/252, 544/255, 514/258, 514/267, 514/275, 540/362
• US Class Current: 514/259.2
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 473/16 two nitrogen atoms
• CPC Class Codes: C07D 473/24 one nitrogen and one sulfur atom
• CPC Class Codes: C07D 473/34 attached in position 6, e.g. adenine
• CPC Class Codes: C07D 475/06 with a nitrogen atom directly attached in position 4
• CPC Class Codes: C07D 475/08 with a nitrogen atom directly attached in position 2

Abstract

Compounds of formula I, and pharmaceutically acceptable salts thereof, ##STR1## in which R1 is hydrogen (1-6C)alkyl or (1-4C)alkanoyl;

A is --N═CQ--O--, N═CQ--NR⁸ --, --N═CQ--CH═N--

or --N═CH--CQ═N--;

Q is 2-furyl;

R⁸ is hydrogen or C1-4C)alkyl;

and R² has any of the meanings given in the specification, processes for preparing the compounds and pharmaceutical compositions containing them. The compounds are useful as adenosine antagonists.

Claims

1. A compound of the formula I wherein:

R¹ is hydrogen, (1-6C)alkyl, or (1-4C)alkanoyl;

R² is hydrogen, cyano or a group of formula R³ X;

R³ (when not as hereinbelow defined together with X) is (3-12C)cycloalkyl, (3-6C)alkenyl, phenyl(3-6C)alkenyl, 5- or 6-membered heteroaryl, optionally substituted (1-6C)alkyl or optionally substituted phenyl,

said optionally substituted alkyl being unsubstituted or substituted by one of (3-6C)cycloalkyl, optionally substituted 5-or 6-membered heteroaryl, optionally substituted phenyl and a group of formula R⁴ (CO)_n X_a (CO)_m in which R⁴ is (1-6C)alkyl, (3-6C)cycloalkyl, optionally substituted phenyl or optionally substituted phenyl(1-4C)alkyl, n and m are each 0 or 1, provided that n+m is 0 or 1, and that when m is 0, X and X_a are separated by at least two carbon atoms, X_a is oxy, thio, sulphinyl, sulphonyl or an imino group of formula --NRb in which Rb is hydrogen, (1-6C)alkyl or together with R⁴ and the adjacent nitrogen atom forms a 4 to 6-membered saturated heterocyclic ring,

said optionally substituted 5- or 6-membered heteroaryl being unsubstituted or substituted by 1 or 2 of (1-4C)alkyl, (1-4C)alkoxy and halogeno,

and any of said optionally substituted phenyl being unsubstituted or substituted by (1-4C)alkylenedioxy or by 1, 2 or 3 of halogeno, cyano, trifluoromethyl, (1-4C)alkoxycarbonyl, hydroxy, hydroxymethyl, amino, (1-4C)alkanoylamino, (1-4C)alkoxymethyl, (1-4C)alkanoyloxy, benzyloxy, halogenobenzyloxy, (1-4C)alkylsulphonylamino, (1-4C)haloalkylsulphonylamino, nitro, and (1-4C)alkyl or alkoxy optionally bearing a group of formula R⁵ CO in which R⁵ is (1-4C)alkoxy, (3-6C)alkylamino, (3-6C)cycloalkylamino or (N-(1-4C)alkyl) (N-(1-4C)dialkylamino(1-4C)alkyl)amino, and sulphamoyl of formula --SO₂.NR⁶ R⁷ in which R⁶ and R⁷ are independently hydrogen or (1-4C)alkyl, or R⁶ is hydrogen and R⁷ is ((2-5C)alkoxycarbonyl)(CH₂)q-, carbamoyl(CH₂)q or (N-(1-4C)alkylcarbamoyl)(CH₂)q, in which q is 0 or an integer from 1 to 4, or R⁶ is (1-4C)alkyl and R⁷ is di(1-4C)alkylamino(1-4C)alkyl; and

X is a direct bond or oxy, thio, sulphinyl, sulphonyl or an imino group of formula --NRa-- in which Ra is hydrogen, (1-6C)alkyl or together with R³ and the adjacent nitrogen atom forms a 4 to 6-membered saturated heterocyclic ring;

A is --N═

CQ--O--;

Q is 2-furyl;

or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1, in which R¹ is hydrogen.

3. A compound as claimed in claim 1, in which said 5- or 6-membered heteroaryl represented by R³ is selected from pyridyl, isoxazolyl and thiadiazolyl, and the 5- or 6-membered heteroaryl in said optionally substituted 5- or 6-membered heteroaryl is selected from furyl, pyridyl and thienyl.

4. A compound as claimed in claim 1 or claim 2, in which R² is hydrogen, cyano or R³ X in which R³ is (1-4C)alkyl, (3-6C)alkenyl, pyridyl(1-4C)alkyl or phenyl(1-4C)alkyl optionally substituted on the phenyl moiety by 1 or 2 of halogen, hydroxy, (1-4C)alkanoyloxy, (1-4C)alkyl and (1-4C)alkoxy;

and X is a direct bond, oxy, thio or NH.

5. A compound as claimed in claim 4, in which R² is 4-chlorobenzyl, 2-phenylethyl, 2-phenylethylamino, 2-(4-hydroxyphenyl)ethylamino, 2-(4-methylphenyl)ethylamino, 2-(4-methoxyphenyl)ethylamino or 2-(3,4-dimethoxyphenyl)ethylamino.

6. A compound as claimed in claim 1, in which

R¹ is hydrogen;

R² is R³ X

R³ is (1-4C)alkyl, (3-6C)alkenyl, pyridyl(1-4C)alkyl or phenyl(1-4C)alkyl optionally substituted on the phenyl moiety by 1 or 2 of halogen, hydroxy, (1-4C)alkanoyloxy, (1-4C)alkyl and (1-4C)alkoxy;

X is a direct bond, oxy, thio or NH;

A is --N═

CQ--O--;

Q is 2-furyl.

7. A pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof as defined in claim 1, in a mixture or together with a pharmaceutically acceptable diluent or carrier.

8. A method of antagonising one or more of the actions of adenosine in a warm-blooded animal requiring such treatment by administering an effective amount of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof.