DE1795828A1 - ADENOSINE DERIVATIVES - Google Patents

Description

BOEHRINGER MANNHEIM GMBH

1479-11. '

Elimination from and addition to the registration file number P 16 f0 175.0-44

Adenosine derivatives and processes for their preparation

The main application file number P 16 70 175-0-44 relates to adenosine derivatives of the general formula I.

B _v / AXB

Ci).

-OHOE

_. in which

, Y. Halogen or a hydroxyl group. ^v .R hydrogen or a lower alkyl group,

; 'A is a saturated, gerädkettigen oder.yer - "- ,. · -; - branched Älkylenrest.mit 1-4 carbon' ■ '■■■' atoms, which may optionally be substituted by a \ Bydroxylgruppe '. an allyl radical or a cyclopropyl r.:^-;i ": rest, 1 · ..-;: ^ Χ;"'^;<;-;: · - ■ .'.- · - · ■ ^v ''ν .λ · ". : '' ■ '^ ".

ORIGINAL INSPECTED

X is a valence stroke or an oxygen f or. Sulfur torn and

B is hydrogen or a phenyl or naphthyl radical, which optionally by halogen, hydroxy or methoxy groups is substituted,.

bode ^1. "ten,

Process for the production of the same, as well as drugs with P Cardiovascular action, consisting of one of the mentioned

Connections and carriers ». '' .. · .. ■

It has now been found that compounds of the formula I, in which B denotes a phenyl radical substituted by 1-2 methyl groups, interesting cardiovascular effects exhibit.

The present application therefore relates to adenosine derivatives of the general formula I ¹¹ . . ■ ■ -

AXB ¹

ι-.

50 9 848./08.84.

ORIGINAL. INSPECTED

in which *

Y halogen or a hydroxy group, "

R is hydrogen or a lower alkyl group,

A is a saturated, straight-chain or branched alkylene radical with 1-4 carbon atoms, which can optionally be substituted by a hydroxyl group, an allyl radical or an = '. - "■ '·" ■: Cyclöpropylrest,. "· ™

"X is a valence stroke or an oxygen or sulfur atom and

. B 'is a phenyl radical substituted by 1 - "2 methyl groups

mean. Process for producing the same, as well as pharmaceuticals with cardiovascular effects, consisting of one of the named compounds and carriers *

The new compounds I ¹ 'are prepared according to the in

methods detailed in the main application. i

The invention is explained in more detail in the following examples.

(The symbols "L" and "D" are intended in the context of this application - ■ * denote the left-handed or right-handed isomer, without to make a statement about the absolute configuration).

./. ORIGINAL INSPECTED

509848/0884 -

example 1

N (6) - (3-m-cresoxy-2-hydroxypropyl) -2-chloro-adenosine

4.5 g of triacetyl-2,6-dichloro-9- (ß-D-ribofuranosyl) -purine, 2.7 g of 3-m-cresoxy-2-hydroxypropylamine and 2.02 g of triethylamine are dissolved in 50 ml of isopropanol Boiled under reflux for 2 hours, then concentrated in vacuo, the residue taken up with ether and water and the ether phase washed twice with water, dried and concentrated. 40 ml of ammonia-saturated methanol are added to the residue. After standing overnight at room temperature, the solution is treated with activated charcoal and concentrated in vacuo. The crude product is purified by preparative thin layer chromatography. The silica gel eluate is concentrated in vacuo and the solid, foam-like residue is triturated with ligroin. Yield: 21. g (45 % of theory), melting point 84-86 ° C. . .

example

N (6) - (2-methylbenzyl) -2-chloro-adenosine

4.5. ε triacetyl-2,6-dichloro-9- (β-D-ribofuranosyl) -purine, 1.8 g 2-methylbenzylamine and 2.02 g of triethylamine are as in the example 1 implemented and worked up. The crude product is through purified preparative thin layer chromatography. Bas silica gel eluate is concentrated in vacuo and the residue is triturated with ligroin. Yield: 2.1 g (52 # of theory), melting point 103-105 °.

509848/0884

■. ■ - 5 - ■ ■

Example 3

N (6) "[D..L- 1- (m-cresoxy) -oropyl-2] -2-chloro-adenosine

Jj 5 S triacetyl-2 _> 6-aichlor-9-fß-D-ribofuranosyl) -purine, 2.5 g of 1- (m-cresoxy) -2-aminopropane and 2.02 g of triethyjarain are reacted as in Example 1 and worked up. The crude product is purified by preparative thin layer chromatography. The silica gel eluate is concentrated in vacuo. The solid, foamy residue is triturated with ligroin, filtered off with suction and dried. Yield: 1.6 g (35 % of theory), melting point 102-105 °. . |

Example 4

N (β) - (2-methylbenzyl) -2-hydroxy-adenosine

3.9 g of 2-hydroxy-6-benzyl: nercapto-9- (β-D-ribofuranosyl) -purine Tind 1.8 g of 2-methylbenzylamine are refluxed in 50 ml of isopropanol for 2 hours. It is then concentrated in vacuo and the residue is recrystallized from isopropanol with the addition of activated charcoal. Yield: 1.5 g (33 # of theory), melting point 180-182 ° (decomp.). .. "-.- ..:, ·. -..-., - ·;.. '". -

N (6) -C2-H7 / hydroxy-3-m-cresoxy-propyl) -2-hydroxy-adenosine

3 * 9 ß 2-hydroxy-6-benzylniercapto-9- (ß-D-ribofuranosyl) -purine and 2.7 g of 2-hydroxy-3-m-cresoxypropylamine are refluxed in 50 ml of isopropanol for 3 hours. The precipitate which separates out on cooling is filtered off with suction and recrystallized twice from isopropanol. Yield: 1.8 g (40 # of theory), m.p.

S 0 9 8 4 Β / 0 884

Example 6 *

N (6) - (2 , 5-methylbenzyl) -2-chloro-adenosine

6.8 g of triacetyl-2,6-dichloro-9- (β-D-ri'bofuranosyl) -purine, 3.2 g of 2 _f 5 -methylbenzylamine and 3> 0 g of triethylamine are refluxed in 50 ml of isopropanol for 2 hours cooked. It is then concentrated in vacuo, the residue is taken up in ether and water and the ether phase is washed twice with water, dried and concentrated. 40 ml of ammonia-saturated methanol are added to each residue. After standing overnight at room temperature, the solution is treated with activated charcoal and concentrated in vacuo. The residue is recrystallized from methanol. N (6) - (2,5-dimethylbenzyl) -2-chloro-adenosine is obtained in a yield of 4.9 g (77.6% of theory); Mp. 112-115 ⁰ C.

The following compounds are obtained in an analogous manner:

a) H (6) -r2- (2-HethylT> henyl) -ethyl1-2-chloro-adenosine

: from triacetyl-2,6-dichloro-9- (ß-D-ribofuranosyl) -purine and 2- (2-kethyl-; • phenyl) -ethylamine. Yield: 48 1 ° of theory, melting point 93-100 C.

from triacetyl-2-bromo-6-chloro-9- (ß-D-ritofuranosyl) -purine and 2- (2-methylphenyl) -ethylamine. Yield: 71 > of theory, m.p. 90-95 Q. ^

c) ir (6) - (2,5-diethylbenzyl) -2-hydro-y-adenosine from 2-hydroxy-6-benzylmercapto-9- (β-D-ribofuranosyl) -purine and 2,5-dimechylbenzylanine. Yield: 20 fa of theory, m.p. 195-198 C.

SO 9-8487 08.84 · 'OBiginal inspected

The triacetyi-2-bron) -6-chloro-9- (ß-D-ribofuranosyl) -purine used as the starting product is made as follows:

4 »4 g of nitrosyl bromide (20 μl of a solution of 22 g of ITitrosyl bromide in 100 nl methylenebronide) added in portions. The temperature of the contents of the flask rises to approx. 50 ° C. After another 5 minutes 40 nan πί 5 sweep ITatriua3ulfitlösung are added and stirred the reaction rate Λ mixed intensively. The aqueous phase is then separated off and the ethylene bromide solution is washed with bicarbonate solution and water. Kach drying over sodium sulfate the solvent is distilled off Vakuun. The residue is recrystallized from 40 nl acetonitrile / l-ethanol (1: 1). Yield: 10.9 g (63 ° of theory), m.p. 158-160 ° G.

S09848- / 0884

- 3 -

m -

To demonstrate the superior effect * of the new compounds, the following comparative tests were carried out with those listed below Substances carried out;

Example no *

2 = N (6) - (2-methylbenzyl) -2-chloro-adenosine

3 = N (6) - / D, L-1- (m-kresdxy) -propyl-2-7-2-chloro-adenosine

4 = N (6) - (2-methylbenzyl) -2-hydroxy-adenosine

. N (6) - (2-Hydroxy-3-m-cresoxy-propyl) -2-hydroxy-adenosine

6 = N (6) - (2,5-dimethylbenzyl) -2-chloro-adenosine

a) = N (6) - / 2- (2-methylphenyl) -ethyl_ / - 2-chloro-adenosine

b) = N (6) - / 2- (2-methylphenyl) -ethyl_7-2-bromo-adenosine

N (6) - (2,5-dimethylbenzyl) -2-hydroxy-adenosine

Comparative substance:. - .. '■ · ■ ·· ■ _.;. . ^!

A = 2 _# 6-Bls- ^ bis- (ß-hydroxyethyl) -amino _? - 4 _r 8-dipiperidino- ^ pyrimido / 5 _f 4-d_7pyrimidine C = dipyridamole - persantine)

.B β N (6} -Benzyl-adenosine "" ■■ - '. ■■''[.Vr.'

. U.S. Patent No. 2,881,164 ^ 7 '.. V'

■ S098i8 / 0884

Adenosine performs during intravenous administration in mammals and people to a vasodilator. Especially on the coronary vascular system This vasodilation leads to a strong increase in blood flow (BERNE, BLACKMON and GARDNER, J.-Elin-. Invest. , 36, 1101 [1957]). Due to the quick desamination of adenosine, this effect is extremely volatile. N -substituted derivatives of adenosine are also strong Coronary vasodilators with high specificity, but in contrast to adenosine with a long duration of action.

An increased blood flow to the coronary system leads - provided that no significant changes in the myocardial oxygen consumption occur - to a reciprocal reduction in the coronary arteriovenous oxygen difference. This reduction in oxygen extraction means an increased supply of oxygen, i.e. an improvement in the oxygen supply to the myocardium, which is ultimately a declared therapeutic goal of all coronary dilators. '■' _- ': "'

For a clear assessment of the test results, the respective reduction in the coronary arteriovenous oxygen difference in volume% compared to the initial value was given in Table I, namely at the time of maximum effect. The larger this value, the stronger. . the coronary oxygen supply was improved. ■ ■ "- .. ■ _ · . ·

When assessing the effect, the dosage must also be taken into account. Because of the very, very different The steepness of the dose-response curve for adenosine derivatives is the absolute measured value of the reduction in the AV difference in of the table is less decisive than its relationship to the consistently lower dosage of the company's own process products irisparticularly compared to the comparison compound B (dipyridamole).

,; .-., -:, - ■ ;. _ ■ 50984-8 / 0884. = / ·: _0R1Q , _NA ^ _1NS P _E CTED

The tests were carried out on 28 conscious dogs weighing between 12 and 16 kg. Based on the method of RAYFORD, HUVOS and GREGG, Proc. Soc. exp. Biol. Med. 113 , 876 (1963) 'catheters have been surgically implanted in the coronary sinus, the aorta and the vena cava . This made it possible to photometrically by blood sampling the coro- nare arteriovenous saturation difference (after BRINKMAN, Arch.Chir.Neer. 1> ¹⁷⁷ [1949]) to determine and P ... convert considering the current hemoglobin values in% by volume of . The connections were made with the respective. intravenously .. 400 dissolved in 5.5% aqueous glucose time amount by weight in 1 ml of a 5% solution of liquid Polyäthylenoxi-d, mol. wt. approx. ·

509.8.48 / 0884. _Ofi , _GlNAL

substance ■ 6th dose Reduction of the coronary (Example no.) a) (mgAg IV) O ₂ exhaustion in% by volume b) compared to the controls c) irax »effect 2 A. 0.2 5.6 3 B. 0.2 1.0. 4th 0.4 6.0. 5 0.4 1.7 Π7Γ. ... "■ ·. ' 0.4 3.2 - 0.4 . 9.6 0.4 _ • 5.4- 0.2 ; ■ "" ■■ ■> "" 6.9 .. ' 0.5 ■ L..; ■. 5.6 0.4 ^ 2.5 . \. ■

The "therapeutic index" was also determined for the substances mentioned above. For this purpose, the toxic dose LD ₅₀ on the mouse and the "therapeutic DQsis" on the dog were determined in the usual way; in the latter case it is the dosage that leads to a reduction in the

coronary O ₃ exhaustion of 6% compared to the controls ^ is required at maximum effect. These values and the “therapeutic index” calculated therefrom and the ratio of the therapeutic indices are compiled in Table II below. . . "

SUN 9.8.4 8/08 84

- 12 -

U C) O) X ".

»Ϋ υ to cj

• Η 4-

.IJ CJ H

rj

V) Pi O)

u · η «

O) 'Ö .Q

H W

GJ

ü W • rj 4 * ti C)

CJ O

iv r \ »-ν H O .cj O'Ö} -:

ti H>

W VD

CJ D

• »J M -f

IO

to • rl

C)

S * ι »

OO tr »

■ · Λ

W • Η W O ö

ω υ W • Η

G) P

HO

fii VD J-I I OO Λ W

Λ · υ η

SÄ

O) Ή CU

to

• Η

(N

<Ο

ΓΟ »* ·

r ^ ιη ή ιη O ro Γ-ί cm

OO

in

T-t

cn

in co ro

in in vo

in

OO

OfM j

jn co j

r- \ CM

OO

O rH

VO CO

O

CO

vo

CO CTj

O γη

CO ri

-1

O ro

CM

t
ι

■■■■: ■! ·· S

a [

in

ns

5-η Q ft A ft / Λ fl ft /.

ORIGINAL INSPECTED

As can be seen from the tables, the new Connections * a much better coronary dilator Effect as the commercial product A. and the * comparative compound B.

In addition, there is a clear superiority over A and B when determining the so-called therapeutic index.

50 984 8/0884

Claims (3)

Claims 1. Adenosine derivatives of the general formula I '' in which γ halogen or a hydroxyl group . R is hydrogen or a lower alkyl- ■ '. group, - ■ _>'·.',.''. 'A a saturated, straight-chain or branched alkylene radical with 1-4 carbon atoms, which optionally 'substituted by a hydroxyl group can be an allyl radical or a _t . '· ■'. Cyclopropyl radical, "X is a valence stroke or an oxygen or sulfur atom and.. ^{; B} * a sub- .-V '. ·, ...--. substituted phenyl radical '- ·· ■■■' mean, 9848/0884 2. Process for the preparation of adenosine derivatives of the general formula I ¹ '- in which .. - - . - ■ ··:. ··. Y is halogen or a hydroxy group, . "·... R is hydrogen or a lower alkyl group, ; '·.' ■. A is a saturated, straight-chain or branched alkylene radical with 1-4 carbon . .; ' lens toffatomen, which optionally .- ■. ■ - ■; ":."': · "■ substituted by a hydroxyl group I .-. · ■ '.".'_: can be an allyl radical or Cyclopropyl radical, '. . ^:: '. - X is a valence stroke or a. Oxygen f -.... or sulfur atom and '; B * one sub- by 1 - 2 methyl groups. . substituted phenyl radical .. .. mean, -. - 5σ: 9: 8 ^ -87 "0 S8'4:. .. ^ / ORlGiNAl; JNSPECtED f. characterized in that in a known manner Purine ribosides of the general formula II '' (II ¹ - · .. · ■ '■. · ■ OH OH' in which ' ' Y has the meaning given above and ■ '. Z is a Kalogenatoia or a reactive Kercaptov grouping,. ·. · with amines of the general formula III ¹ ' B.
I. HN-A-X-B - -;. in which R »-Af X and B ^{1 have} the meaning given above . . · ... . - - "· ■ .- timsetzt, if necessary, the hydroxyl groups of the ribose Eestes Internally, easily split off after condensation has taken place -Groups blocked. -. .- ■ - 3. Medicament consisting of a compound according to claim and usual carriers. SO 9 8 A 8/0 8 8 4. . '/ ORiGlNA ₁ INSPECTED