IE49624B1 - Intermediates for the preparation of xanthine derivatives for use in the treatment of chronic obstructive airway disease and cardiac disease - Google Patents

Description

The present invention relates to a novel group of compounds which are valuable intermediates in the preparation of compounds which have a relaxing effect on the bronchial smooth muscle and are useful in treating chronic obstructive airway disease (COAD) or cardiac disease. This application is a divisional of Irish Patent Application 1988/79 which describes and claims pharmaceutical compositions containing the final compounds.

The present invention relates to compounds useful 1o in the preparation of compounds of the formula and therapeutically acceptable salts thereof, wherein R is the group -ch2ch2ch3 or -ch2ch2ch2ch3 15 Formula I includes the compound of the formula T Y> D 4028 6h, CH2CH3 - 2This compound is disclosed in the Bull. Chem. Soc. Jap. 1973, 46 (2), pages 506-9, where a method for its preparation is described.

Formula 1 includes also the compound of the formula 4031 This compound is disclosed in the Bull Chem. Soc. Jap. 1973, 46 (2), pages 506-9, where a method for its preparation is described.

Thus the present application provides compounds of formula NH - 3wherein R^ is n-propyl or n-butyl. These compounds are valuable starting materials for the preparation of the compounds D 4028 and D 4031, respectively. A description of their preparation can be found in the following Examples.

EXAMPLE 1. Preparation of 3,7-dihydro-3-propyl-1H-purine-2,6-dione VI a/ Preparation of 6-amino-1-propyl-2,4-(IH,3H)-pyrimidinedione II To a solution of 47 g (0.55 mol) cyanoacetic acid and 100 ml of acetic anhydride was added 50 g (0.49 mol) of n-propylurea. The solution was stirred at 60-70°C for 1 hour. After cooling white crystals were filtered off and washed with ethanol. Yield 56.2 g (66%) (I). This was stirred in 100 ml of hot water and 60 ml of 2 N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5 N HCL. After cooling, white crystals were filtered off. Yield 34.3 g (61%) (XI) NMR. b/ Preparation of 6-amino-5-nitroso-1-propyl-2,4-(1H,3H)-pyrimidinedrone III To 34.3g(0.20 mol) of 6-amino-propyl-2,4-(1H,3H)-pyrimidinedione (111), dissolved in 900 ml hot water, was added 45 ml ot 5 N HC1 and 15g of NaNC^ (0.22 mol) whicn was dissolved in water. After cooling the red crystals were - 4 9 6 2 4. - 4filtered off and washed with water. Yield 33.3 g (83%) (III) NMR. c/ Preparation of 5,6-diamino-1-propyl-2,4-(1H,3H)-pyrimidinedione IV of the present invention. 33.3 g of 6-amino-5-nitroso-1-propyl-2,4-(1H,3H)-pyrimidinedione (III) was catalytically hydrogenated in 800 ml of DMF and in the presence of 0.1 g PtO2 for 3 hours and at room temperature and at a pressure of 200 kPa. The catalyst and the crystals were filtered off and washed with ethanol. Yield 29 g (93%) (IV). d/ Conversion of the compound of the present invention produced in paragraph c/ above to 3,7-dihydro-3propyl-lH-purine-2,6-dione VI A solution of 29 g of 5,6-diamino-1-propyl-2,4-(1H,3H)-pyrimidine-dione (IV) in 100 ml of formic acid was refluxed for 2 hours. The hot solution was filtered and 50 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 30.9 g (V).

The amide (V) was refluxed in 90 ml of 2 N NaOH for 2 hours and then neutralized with 5 N HCI. The crystals were filtered off and recrystallized from 1.9 1 ethanol. Yield 21.2 g (68%) (VI) NMR. ncch2cooh o II HN CH.

NH2CONHCH 2CH2CH3 Ex 1 a C . C = N O NH I CH2CH2CH3 NaOH -> Ex 1 a II c HN''' ^C-H O HN C-NO Ex 1 c NaOH Ex 1 d /C-NH, Ο N I CH2CH2CH3 Ex 1 b C C-NH, Ο | CH2CH2CH3 II III KN I . C C-NHC-NH. s' N I CH2CH2CH3 IV HCOOH Ex 1 d 0 H II H HN-C-c/\ CH C\ CH2CH2CH3 HN O it o C 11 ^C-NHC-H I CH2CH2CH3 VI - 6 EXAMPLE 2. Preparation of 3-butyl-3,7-dihydro-1H-purine-2,6-dione (XII) a/ Preparation of 6-amino-l-butyl-2,4-(1H,3H)-pyrimidinedione (VIII) To a solution of 46 g (0.55 mol) cyanoacetic acid and 100 ml of acetic anhydride was added 58 g (0.5 mol) of n-butylurea. The solution was stirred at 70°C for 2 hours. After cooling white crystals were filtered off and washed with ethanol.

Yield 68 g (74%) (VIX). This was stirred in 500 ml of water and 20 ml of 5 N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5 N HCI. After cooling, white crystals were filtered off. Yield 50.6 g (75%) (VIII), NMR. b/ Preparation of 6-amino-1-butyl-5-nitroso-2,4-(1H,3H)-pyrimidinedione (IX) To 50.6 g (0.276 mol) of 6-amino-1-butyl-2,4-(1H,3H)-pyrimidinedione (VIII) dissolved in 1.8 1 of water at 80°C was added 60 ml of 5 N HCI and 20 g (0.29 mol) of NaNO2 which was dissolved in water. After cooling the red crystals were filtered off and washed with water. Yield 52.8 g (97%) (IX), NMR. -Ίο/ Preparation of 1-butyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (X) of the present invention. 52.8 g (0.27 mol) of 6-amino-1-butyl-5-nitroso-2,4-(1H,3H)pyrimidinedione (IX) was dissolved in 1 1 of DMF at 90°C and catalytically hydrogenated in the presence of 0.1 g PtO2 for 18 hours and at room temperature and at a pressure of 200 KPa The catalyst and the crystals were filtered off and washed with ethanol. Yield 36.6 g (67%) (X), NMR. d/ Conversion of the compound of the present invention produced in paragraph c/ above to 3-butyl-3,7- dihydro-IH-purine-2,6-dione (XII) A solution of 36.6 g of 1-butyl-5,6-diamino-2,4-(1H,3H)-pyrimidinedione (X) in 100 ml of formic acid was refluxed for 2 hours. The hot solution was filtered and 30 ml of chloroform was added and ether was then added slowly. The received crystals were filtered off. Yield 42.9 g (not dried). (XI). The amide (XI) was refluxed in 100 ml of N NaOH for 2 hours and then neutralized with 5 N HCI. The crystals were filtered off and washed with ethanol. Yield 28.4 g (74¾) (XII), NMR.

NH2CONHCH2CH2CH2-CH3 NCCHjCOOH Ex 2 a N C ey'' V I CH2CH2CH2-CH3 VII NaOH O U / C\ HN C-H HN NO Ex 2 a Ex 2 b HN Ex 2 c NaOH Ex 2 d CH2CH2CH2-CH3 CH2CH2CH2-CH3 VIII HCOOH ^C\^xC-NH2 Ex 2 d CH2CH2CH2-CH3 O II HN / \ R CH Hx CH2CH2CH2-CH3 IX £ 0 HNX ^C-NHC-H XC-NH O N z I CH2CH2CH2-CH3 XI XII

Claims (4)

1. WE CLAIM

1. A compound of the formula HN C-NH, J !. X'S NH, wherein R 1 is n-propyl and n-butyl.

2. A process for the preparation of a compound 1U according to claim 1 substantially as hereinbefore described with reference to Example 1(c) or Example 2(c).

3. A process for the preparation of a compound according to claim 1 substantially as hereinbefore described witn reference to Examples 1(a), 1(b) and 1(c) or Examples 2(a), 15 2(b) and 2(c).

4. A compound as defined in claim 1 obtained by a process according to claim 2 or 3.