WO1990012013A1 - NEW 1,2,3-TRIAZOLO-PYRIDO[2,1-b]QUINAZOLINES, THEIR PREPARATION AND DRUGS CONTAINING THEM - Google Patents

Abstract

The invention concerns compounds of the formula (I) which is defined in the description. The compounds can be prepared by the usual methods and used for therapeutic purposes.

Description

 New 1, 2, 3-triazolo-pyridü [2,1-b] quinazolines, their preparation and medicaments containing them

 The invention relates to new 1,2,3-triazolo-pyrido

 [2,1-b] quinazolines, which are known per se

Processes can be produced and which can be used as active ingredients in medicinal products.

The new compounds correspond to the formula

worin die Gruppe -N=N-NH- (bzw. die tautomere Gruppe

where the group -N = N-NH- (or the tautomeric group

-NH-N = N-), is bonded to two adjacent C atoms of the pyridine ring and

R ₁ for H, R, HCO, R-CO, RNH-CO, RO-CO or R-SO ₂ ,

R _{2 stands} for H, R or R-CO and the entire group

R ₁ R ₂ N also for a 3 to 7-membered, saturated or unsaturated ring which can be substituted by one or two oxo groups and optionally one or two hydroxyl groups or can be condensed with a benzene ring, and R for an optionally hydroxyl and / or carboxy-substituted aliphatic radical with up to 12 C-atoms, a cycloaliphatic radical with 3 to 7 C-atoms, an aryl- or aryloxy-substituted aliphatic radical with a total of up to 12 C-atoms,

and can exist as free compounds or as salts.

 The aliphatic radicals can be straight-chain or

branched, saturated or - if sufficient

Chain length - also be mono- or polyunsaturated and possibly also contain a triple bond. R ₂ preferably represents H or an aliphatic radical having up to 8 carbon atoms. As far as the radicals R hydroxy and / or

 are carboxy-substituted, it can be, for example, groups derived from glycolic, succinic, lactic, citric, tartaric or maleic acid. In the case of unsaturated aliphatic substituents on nitrogen, the double bond is in the

 generally not on the C atom linked to the N atom. Aliphatic residues of this type are e.g. Allyl, propargyl. Contains R aromatic systems, e.g. a benzene ring, these can also be substituted one or more times, in particular by halogen,

C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, CF ₃ , CN, nitro,

 Hydroxy.

A preferred basic structure within the formula I is represented by Ia:

worin R₁ und R₂ die obigen Bedeutungen haben. R₁ steht vor allem für die Gruppen R-CO und R-NH-CO, wobei R einen geradkettigen oder verzweigten aliphatischen Rest mit bis zu 8 C-Atomen, der auch phenylsubstituiert sein kann, einen Phenylrest oder einen

wherein R ₁ and R _{2 have} the above meanings. R ₁ stands primarily for the groups R-CO and R-NH-CO, where R is a straight-chain or branched aliphatic radical with up to 8 C atoms, which can also be phenyl-substituted, a phenyl radical or a

C ₃ -C ₇ cycloalkyl radical.

The group R ₁ R ₂ N means one

oxo group-substituted residue, so it can

for example a derivative of a dicarboxylic acid

represent, about

Die Herstellung der neuen Verbindungen gelingt mit Hilfe von chemischen Analogieverfahren, insbesondere wie folgt :

The new compounds can be produced using chemical analogy processes, in particular as follows:

1. Triazolo-pyridyl-anthranilic acids of the formula

worin R₁ und R₂ die obige Bedeutung haben,

where R ₁ and R _{2 have} the meaning given above,

 are ring closed in the presence of inorganic or organic acids

 subject.

 Instead of compound II, its precursors can also be used as starting materials by

 Antranilic acids of formula III with

 Triazolo-2-halopyridines of the formula IV for

Response:

 The reaction can take place in the melt at 120-200 ° C, preferably 160-175 ° C, or in

alcoholic solution (for example in ethanol) in the presence of acid, for example hydrochloric acid under reflux, the reaction temperatures being 20 to 120 hours. 2. To prepare compounds of the formula I in which R ₁ and R _{2 are not} hydrogen, the amino compounds of the formula

by alkylation (or introduction of a

aliphatic radical), acylation or reaction with insocyanates converted into those compounds of the formula I in which at least one of the radicals R ₁ and R _{2 has} a meaning other than

 Has hydrogen.

The starting materials IV for process 1 can e.g. be constructed as follows:

The starting materials of formula V (for process 2) are, for example, from the corresponding Nitro compounds prepared by process 1 or by nitration and reduction from the compounds of the formula VI:

The new compounds of formula I are as

 Drugs and as intermediates for the

 Manufacture of drugs usable. Their property of lowering uric acid levels should be emphasized. This results in applicability in conditions in which the uric acid level is increased, for example in the primary or in the secondary gout which occurs after chemotherapy or radiotherapy. Further areas of application of the new compounds are

 Therapy of ischemia, e.g. cardiac, cerebral, gastrointestinal, renal, pulmonary ischemia and in diseases such as Crohn's disease, ulcerative colitis, arthritis, pancreatitis or Lesch-Nyphan syndrome. The new compounds are also anti-allergic.

The therapeutic dose depends on the

 Nature and seriousness of the

 Disease state and the mode of administration. The dose for adults is between 0.1 and 100 mg for oral administration and 0.01-10 mg for intravenous administration. It is used in the form of conventional pharmaceutical preparations such as capsules, tablets,

Dragees, solutions, suspensions, powders. These preparations contain the active compounds according to the invention in addition to those for such preparations

 known auxiliaries and / or carriers and

 if desired, additional known active ingredients.

The high effectiveness of

 Compounds of formula I based on the inhibition of

 Show xanthine oxidase. The inhibitory values (K. values) of the new compounds are approximately three orders of magnitude lower than for the gout agent allopurinol, as can be seen from the table below

 Compounds of formula I were listed:

I: R _χ = (CH ₃ ) ₂ CH-CO

II: R _χ = (CH ₃ ) ₃ C-NH-CO

III: R _χ = nC ₆ H ₁₃ -CO

Die Verfahren zur Herstellung der neuen Verbindungen sind in den nachstehenden Beispielen näher erläutert,

The processes for the preparation of the new compounds are explained in more detail in the examples below,

example 1

7-acetamido-5-oxo-5H-triazolo [5,4-e] pyrido [2,1-b] quinazoline

3.56 g of N- (4-azabenztriazol-5-yl) -5-acetamido-anthranilic acid disodium are dissolved in 50 ml of water and 50 ml of dimethylformamide at 40-50 ° C., then acidified with 10 ml of glacial acetic acid, the precipitate is suctioned off and washed well with water.

Analysis: C ₁₄ H ₁₀ N ₆ O ₂ X 1 CH ₃ COOH

C% H% N%

calc: 54.24 3.95 23.72

found: 55.01 4.59 23.87

Example 2

9- (2-Methyl-propionylamido) -11-oxo-3H-1,2,3-triazolo [4 ', 5': 5,6] pyrido- [2,1-b] quinazoline

1.4 g of 9-amino-11-oxo-3H-1,2,3-triazolo [4 ', 5': 5.6] pyrido [2,1-b] quinazoline, 2.25 ml of triethylamine and 2, 55 ml of isobutyric anhydride are heated in 90 ml of dimethylformamide at 90 ° C for 2 hours.

 The mixture is then cooled to 20 ° C. and mixed with 50 ml of 2.5% ammonia water, stirred for 10 minutes and acidified with 7.5 ml of glacial acetic acid. The precipitated crystals are filtered off and washed well with water.

 The raw material obtained is recrystallized from 40 times the amount of dimethylformamide.

Analysis: C ₁₆ H ₁₄ N ₆ O ₂

C% H% N%

calcd: 59.62 4.38 26.08

found: 59.73 4.45 26.15 Example 3

9- (N-tert-Butyl-ureido) -11-oxo-3H-1,2,3-triazolo [4 ', 5': 5,6] pyrido- [2,1-b] quinazoline

1.4 g of 9-amino-11-oxo-3H-1,2,3-triazolo [4 ', 5': 5,6] pyrido [2,1-b] quinazoline, 1.3 ml of triethylamine and 5 ml tert. -Butyl isocyanate are heated to 70 ° C for 6 hours in 50 ml of dimethylformamide.

The mixture is then cooled to 20 ° C., acidified with 7 ml of glacial acetic acid and diluted with 100 ml of water. The precipitate is filtered off and recrystallized twice from dimethylformamide.

Analysis: C ₁₇ H ₁₇ N ₇ O ₂ x 1.5 H ₂ O

C% H% N%

calc: 53.96 5.33 25.91

found: 54.01 5.30 26.14

The compounds of Table I can be prepared analogously to the examples above:

 General formula

Claims

 Claims Compounds of the formula

wherein the group -N = N-NH- or -KH-N = N- is bonded to two adjacent C atoms of the pyridine ring and R ₁ for H, R, HCO, R-CO, RNH-CO, RO-CO or R-SO ₂ , R _{2 stands} for H, R or R-CO and the entire group NR ₁ R ₂ also for a 3-bis  7-membered, saturated or unsaturated ring with one or two oxo groups and optionally one or two hydroxyl groups  substituted or condensed with a benzene ring, R for a possibly hydroxy and or  carboxy-substituted aliphatic radical with up to 12 carbon atoms, a cycloaliphatic radical with 3 to 7 carbon atoms, an aryl- or aryloxy-substituted aliphatic radical with a total of up to 12 carbon atoms, as free compounds or as salts. Compounds according to claim I having the formula

in which R ₁ and R _{2 have} the above meaning. 3. Compounds of formula la, wherein R _{1 is} R-CO or R-NH-CO, where R is a straight-chain or branched aliphatic radical having up to 8 C atoms and R _{2 is} H or C ₁ -C ₄ alkyl. 4th Medicaments, characterized in that they contain a compound according to claims 1 to 3 in addition to conventional auxiliaries and / or carriers. 5. Use of compounds according to claim 1 to 3 for or in the treatment of diseases. 6. A process for the preparation of compounds according to claims 1 to 3 in a manner known per se, characterized in that a) triazolopyridylanthranilic acids of the formula

wherein R ₁ and R _{2 have} the above meaning  have in the heat in the presence of an inorganic or organic acid ring closure or that b) into a compound of formula

introducing a radical R ₁ and / or R ₂ by alkylation, acylation or reaction with isocyanates, where R ₁ and / or R _{2 have} a meaning other than hydrogen, and that the salts obtained according to a) or b) are converted into free compounds or initially Free compounds obtained converted into salts. 7. modification of the method according to claim 6a),  characterized in that the compound II in situ by reacting an anthranilic acid of the formula

 with a triazolo-2-halopyridine of the formula

 in the melt or in solution at elevated  Produces temperature and wins the compounds of formula I without intermediate insulation.