DE1140194B - Process for the preparation of descendants of 7-beta-oxypropyltheophylline. - Google Patents

Description

GERMAN

PATENT OFFICE

N19287IVd / 12p

REGISTRATION DATE: DECEMBER 7, 1960

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EDITORIAL: NOVEMBER 29, 1962

The invention relates to a process for the production of descendants of 7 - /? - oxypropyl theophylline the general formula

Th-CH ₂ -CH-CH ₂ -N

"Ri

(I)

in Th the theophyllinyl (7) radical, Z a hydroxyl or acyloxy radical and R and Ri alkyl radicals with each 4 carbon atoms, as well as their salts.

These new compounds are used as remedies, e.g. B. as diuretic and cardiovascular agents, usable. The free bases obtained according to the process and their salts are water-soluble and can be found application in the form of injection solutions.

The process products are produced by reacting 7 - (/ S, y-epoxypropyl) -theophylline with an amine of the general formula

HN

(Π)

Ri

and, if appropriate, subsequent acylation of the hydroxyl group in a manner known per se and / or Conversion of a compound of the general formula I obtained into its salts.

When carrying out the process, the 7 - (/ ?, y-epoxypropyl) -theophylline with the amine is the general formula II heated directly or in a solvent. The corresponding acylating agent is used Acid chloride or acid anhydride applied.

The following examples serve to illustrate the process.

example 1

A mixture of 24 g of diisobutylamine and 44 g of 7 - (/ S, γ-epoxypropyl) -theophylline in 120 ml of ethanol is heated to a temperature of 90 to 92 ° C for about 3 hours. Then the solution cooled and the obtained crystals are subjected to purification. The 7- (γ-diisobutylamino-β-hydroxypropyl) -theophylline obtained has a melting point of 150 to 150.5 ° C. and is obtained in a yield of 80%.

Analysis data for C18H31O3N5:

Calculated C 59.15, H 8.55, N 19.16%;

found C 58.83, H 8.73, N 19.30%.

Process for the production of

Descendants of the
7-ß-oxypropyl theophylline

Applicant:
Nippon Shinyaku Co., Ltd., Kyoto (Japan)

Representative: Dipl.-Ing. A. Kuhn, patent attorney,
Berlin 33, Wildpfad 3

Claimed priority:
Japan December 18, 1959 (No. 39 841)

Niro Yoshida and Hiroichi Fukuda, Kyoto (Japan), have been named as inventors

2
Example 2

The reaction of the product obtained according to Example 1 with acetyl chloride leads to 7- (γ-diisobutylamino- / 3-acetoxypropyl) -theophylline with a melting point of 117.degree.
Analysis data for C20H33O4N5:

Calculated C 58.94, H 8.16, N 17.19%;

found C 59.30, H 8.17, N 17.53%.

Example 3

The reaction of the product obtained according to Example 1 with benzoyl chloride leads to 7- ( γ-diisobutylamine-β- benzoyloxypropyl) -theophylline with a melting point of 99.5 ° C.
Analysis data for C25H35O4N5 .:

Calculated C 63.94, H 7.51, N 14.92%;

found C 63.84, H 7.43, N 14.77%.

The 7-theophylline derivatives given in the following list are produced in an analogous manner manufactured:

45 R Ri Z Fp. ( ⁰ C) n-butyl
n-butyl n-butyl
n-butyl Hydroxyl
Acetoxy 116
60 to 62

7 - [(9-Hydroxy-y- (methoxyethylamino) propyl] -theophylhn-nicotinate is used for the comparative pharmacological investigation used. These

209 709/339

3 4

Compound and its own pharmacological formula

in the magazine »Münchener medizi- π

niche Wochenschrift «, vol. 100, 1958, p. 2036 to /

2038. In the following, _T *, /-.u __ _rxx __ pu vr / _T \

J L 4. £ C Λ ΛΤ 1. "Ii · J ΛΛΤ- 1 J * ^Π V'-fS <-ü CH.2 JN (1)

the relevant ratios of the degree of efficiency, 5 ι \

namely the ratio of the increase in the quantity 2 Ri

of the corona blood flow indicated:

7 - [^ Hydroxy- _r (methoxyethylamino) -propyll- j? the Th of the theophymnyl (7) radical Z is a hy-

Lophylline nicotinate 0.16 droxyl or acyloxy radical and R and Ri alkyl

η j 1 * u t> ■ '· 1 1' τ αϊ 10 residues with 4 carbon atoms each, as well as

Product according to Example 1 1.31 _{whose s} ^ _{is characterized in that} 7. ^.

Product according to Example 3 1.74 Epoxypropyl) theophylline with an amine of

The toxicities of both the above compound and the general formula

the new connections also amount to "

more than 2000 mg / kg as measured by oral administration i ₅ /

enriching mice. This means that the toxici- HN (II)

would be extremely small and practically this \

Compounds are to be addressed as non-toxic. Ri

It thus follows that the process products

an approximately 9 to 12 times greater effectiveness than the 20 is implemented and, if necessary, subsequently

7 - [/ S-Hydroxy-y- (methoxyethylamino) propyl] -theo- the hydroxyl group in a manner known per se

phylline nicotinate. is acylated and / or a compound obtained

These novel compounds show an influence on the respiration at a dose of. __ ^ __
10 mg / kg in the dog and do not result in a 25
Change in the electrocardiogram. Considered publications:

"'. "Bulletin de la Societe Chimique de France", 1955,

Claims (1)

PATENT CLAIM: p.946ff .; Process for the production of descendants H ο ü en — Weyl, »Methods of organic des 7-0-Oxypropyltheophyllins der Allgemeine 30 Chemie ", Vol. 11/1, 1957, p. 314ff. A priority document was displayed when the registration was announced. θ 209 709/339 11.62