DE3125291A1 - Use of 5-alkylpyrimidine nucleosides as virostatics and pharmaceuticals with virostatic action - Google Patents

Abstract

Use of 5-alkylpyrimidine nucleosides of the general formula I: <IMAGE> in which R is alkyl with 2-10 C atoms; X is H or OH; <IMAGE> where R<1> is straight-chain or branched C1-C6-alkyl, especially ethyl, isopropyl or isobutyl; <IMAGE> <IMAGE> where R<2> = -NH2, -COOH, n = 1 to 4, <IMAGE> where n = 1 to 4, <IMAGE> where Hal = F or Cl, <IMAGE> where n = 1 to 4 and A is a pyrimidine nucleoside of the formula: <IMAGE> in which R and X have the abovementioned meanings, it being possible for the radicals Y to be esterified if required with the OH group in the 3' position in place of the 5'-OH group; as virostatic. The invention also relates to a pharmaceutical with virostatic action containing at least one of the said compounds.

Description

PROF. DR. DR. J. REIT.§YÖTTEF3 ^: "bft.:W;ER>JER KINZEBACH

DR. ING. WÖLFRAM ΒϋΝΤΕ '« _ββ β-ϊ _β7 β)

HEIT3KÖTTER. KINZEBACH ft PARTNER POST BOX 78Ο, D-βΟΟΟ MUNICH 43

PATENT LAWYERS APPROVED REPRESENTATIVES AT THE EUROPEAN PATENT OFFICE EUROPEAN PATENT ATTORNEYS

TELEPHONE: (Ο89) 2 7t 83 83 TELEX: OS21S2O8 ISAR D BAUERSTRASSE 22, D-SOOO MUNICH

Munich, June 26, 1981

OUR FILES:

OUR REP:

M / 22

REFERENCE: RE

ROBUGEN GMBH. Pharmaceutical Factory P.O. Box 266

7300 Essiingen

Use of 5-alkyl pyrimidine nucleosides as antivirals and medicinal products with antiviral effects

Addition to P 30 10 397.0

POSTAL ADDRESS; D-SOOO MUNICH 41. POST BOX 78Ο

M / 22 148

The invention relates to the use of 5-alkyl-pyrimidine-j nucleosides as antivirals, as well as a drug with a virostar tic effect.

To combat diseases caused by herpes viruses 5-ethyl-2'-deoxyuridine has proven to be valuable

(E proved to be a full drug. This compound has been on the market as aeduride for many years as a topical virostatic against herpes diseases of the eye.

It was now increasingly sought after means that the cheap have virostatic properties of 5-ethyl-2'-deoxyuridine, but at the same time can also be given topically on the skin and systemically.

It has now surprisingly been found that certain 5-alkylpyrimidine nucleosides have a virostatic activity which is comparable to that of 5-ethyl-2'-deoxyuridine, but which at the same time are better lipoid-accessible and after oral Long-term administration results in higher blood levels.

M / 22 148

The invention thus relates to the use of 5-alkyl-pyrimidine nucleosides of the general formula I:

Y-O-C

(D

OH

wherein:

R = alkyl with 2-10 carbon atoms;

X = H or OH;

Y = - C - R ¹ ,

- C - CH_ - O - C - R

-C-CH-O-C-O-R, CH.,

M / 22 148

where R =

straight-chain or branched Cj-Cg-alkyl, in particular ethyl, Isopropyl or isobutyl;

R ² , where R ² = -NH ₂ , -COOH,

(CH ₂ ) _n - CN,

Shark

C <- shark, Shark

η = 1 to 4,

where η = 1 to 4 where Hai = F or Cl,

(CH ₂ ) _n - CA,

where η = 1 to 4 and

A for a pyrimidine nucleoside of the formula:

² I .0

HO X

stands in which R and X the

have the meanings given above,

. w4- ^ 31-15.29J

M / 22 148 - Y ~

where the radicals Y with the S'-OH group are twisted for 1 s the OH group can be esterified in the 3 'position;

as an antiviral agent.

The S-alkyl-pyrimidine used in a form suitable for systemic, \ especially for application tntraperitonealen Formu>-regulation: According to a preferred embodiment of the invention. According to another preferred embodiment; » In the form of the invention, the 5-alkyl-pyrimidine nucleosides are used in a formulation suitable for topical application. The topical form of application is particularly suitable

i for the skin.

The invention also relates to a medicament with a virostatic Effect, which is characterized by a content of '' at least one 5-alkyl-pyrimidine nucleoside of the above ι

ι

ι general formula I as active ingredient. The drug can ' also contain other active ingredients. |

In a preferred embodiment, the virostatic drug is with a pharmaceutically acceptable carrier and / or formulated diluents.

The alkyl radicals R of the compound of the general formula I are for example ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl and, Decyl. The residues can be straight-chain or branched. j

Examples of radicals R in the general formula I, embodying the Bedeutungsiflögiichkeit C.-Cg-alkyl are methyl 'ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl tert-butyl _s j pentyl or Hexyl. Particularly preferred radicals are ethyl, isopropyl and isobutyl.

The use of the indungspmgge includes the </ - and ß-anomeric numbers of the fh-alkyl'pyrimidine nucleques of the general formula I "Bä§t expressed by the undulating connecting line between dim Iuek§rre§t and the pyrimidine nitrogen. Similarly Wei§g the radical A in the compound of the general · my formula I (Y = CQ = (CHg) _n -C = QA) in "- and there are beta-anomeric i, in all cases, the mixtures can der 'Verliggen';

Big connections described here can be analogous to the procedure! der DOl 2B Q7 §88 can be prepared by adding a nucleoside of the general formula Ils

II

wherein R di§ has the meanings already mentioned and

R for H or a customary protecting group, in particular

stands for the acetyl or the propionyl radical, with a functional carbonyl derivative which is derived from one of the radicals of the formula Y defined above, in particular §in§m haloarbonyl derivative of the formula Y-Cl, in a basic medium between about -10 and +100 ⁰ C. Appropriate

M / 22 148

one works at a temperature between about O ⁰ C and room temperature.

I ^:

ι As a functional carbonyl derivative can also be a common, easily ! transesterifiable esters can be used.

The base is appropriately pyridine, triethylamine or dimethyl, formamide used.

I The starting compounds of the general formula II can according to]

: DOS 16 20 185 can be obtained. ■■

I ■

I The test results are described below Compared to the known 5-ethyl-2'-deoxyuridine with regard to

; antiviral effectiveness and blood levels were obtained. It can be seen that the use according to the invention is essential ^;

j to achieve better blood level values with comparable effectiveness permitted.

TABLE- I

HSV-1
(Kos) Minimal inhibitory concentration (pg / .ml) HSV-1
(F) HSV-1
(Mclntyre) HSV-2
(Lyons) HSV-2
(G) HSV-2
(196) 0.1 0.2 0.2 0.4 0.1 0.1 5 ¹ -isobutyryl-5-ethyl-
2'-deoxyuridine 0.7 0.4 0.7 0.7 0.2 0.2 5'-furanoyl-5-ethyl-2 ¹ -
deoxyuridine 0.4 0.2 0.07 0.4 0.2 0.2 5'-n-butyryl-5-ethyl-2'-
deoxyuridine 0.4 1 2 0.7 0.2 0.4 5'-pivaloyl-5-ethy1-2'-
deoxyuridine 2 2 2 0.4 0.2 0.7 5'-adamantanoyl-5-ethyl-
2'-deoxyuridine 0.2 0.4 0.4 0.2 0.4 0.2 State of the art:
5-ethyl-2'-deoxyuridine 0.1 0.2 0.2 0.1 0.7 0.2 5-iodo-2'-deoxyuri din

TABLE II

Antiviral effectiveness, determined according to the appearance of herpetic
Skin lesions and mortality in nude mice exposed intracutaneously
had been infected with HSV-1 (Kos). The compounds were administered intraperitoneally, once daily from day 0 to day 11 of infection

number of
Mice Number of mice with skin lesion /
Total number of surviving mice at
4 5 6 7 8 9 0/10 0/10 0/6 0/5 Day:
10 11 12 13 14th Living
Mice on
Days 15 control 10 0/10 0/10 0/10 0/10 0/10 0/10 2/5 1/4 1/3 0/1 1/1 0 B'-Adamantanoyl-
5-ethyl-2'-deoxy-
uridine (5 mg per
Mouse) 10 0/10 0/10 0/10 1/9 0/10 1/10 2/10 3/10 3/10 10 5'-pivaloyl-5-
ethyl-2'-deoxy-
uridine (1 mg per
Mouse) 10 0/10 0/10 3/10 3/8 4/7 4/6 5 5-ethyl-2'-deoxy-
uridine (5 mg per
Mouse) 10 0/10 5/9 3/6 3/6 5

JNJ CD

M / 22 148

J}

yi -

The results of the antiviral testing show that the 5'-derivatives of 5-ethyl-2'-deoxyuridine tested in cell culture have a similar virostatic effect as 5-ethyl-2'-deoxyuridine or that also used as a reference 5-iodo-2'-deoxyuridine.

When administered intraperitoneally, the compounds tested show significant advantages over 5-ethyl-2'-deoxy

uridine. Thus showed 5'-pivaloyl-5-ethyl-2'-deoxyuridine mg in the dosage of 1 per mouse the same protection effect as 5 mg 5-ethyl-2 ¹ deoxyuridine per mouse. With the same dosage, 5-Ädamantanoyl-5-ethyl-2'-deoxyuridine protects all mice from death from herpes infection.

To determine the blood level, mice were given a dose of 1500 mg 5'-pivaloyl-5-ethyl-2'-deoxyuridine or 5-ethyl-2'-deoxyuridine per kg and the active substance in the plasma determined after 1, 2, 4, 6 hours by means of HPLC.

Time after
application
in hours Concentration in
Plasma in pg / ml 5-ethyl-2'-
deoxyuridine 5 ¹ -pivaloyl-5-ethyl-
2 ¹ -deoxyuridine 1
2
4th
6th 2.7
2.5
below 0.5
below 0.5 250
21.5
5.2
under 1

M / 22 148

From the results, it can be seen that 5'-pivaloyl-5-ethyl-2 'deoxyuridine after oral administration, it delivers significantly higher blood levels than 5-ethyl-2'-deoxyuridine and therefore for an oral dose systemic application is more appropriate.

Her s te Tl υ η gs example

5- Eth y1-Z'-deoxyuridine - S'-0-pivaloate

A solution of 25.8 g (0.1 mol) of 5-ethyl-2'-deoxyuridine in 150 ml of dry pyridine is slowly stirred and cooled in an ice bath to a solution of 12 g (0.1 mol) of pivaloyl chloride in 80 ml of pyridine added dropwise. The reaction solution is stirred at room temperature for 4 hours, then the mixture is concentrated in vacuo and the residue is taken up in methylene chloride. This solution is extracted first with 1% strength aqueous sulfuric acid and then with 5% strength aqueous sodium bicarbonate solution. The methylene chloride solution is dried over sodium sulfate and then concentrated. The residue is purified on a silica gel column using chloroform / methanol = 98/2 ι. Thin-layer homogeneous fractions are collected and _; constricted. The desired product is obtained in pure form. Yield 19.5g. Melting point: 181 ⁰ C (after temporary melting). j

In the same manner there is obtained from 5-n-hexyl-2 '.- desoxyur idin the 5-n-hexyl-2'-deoxyuridine-5 ^-0-1 pivaloate of melting point 143 ⁰ C in 65% yield.

In an analogous manner, the other can be compared according to the invention Make the turned connections. i

Claims (1)

M / 22 148 Claims Use of 5-alkyl-pyrimidine nucleosides of the general Formula I: γ -o- wherein:
ι - = Alkyl with R t 2-10 Carbon atoms; R = = H or OH; CH ₂ ! ^{χ =} 0
π CH -
ι Y = • ο
Il
-C- CH_ - 0 - 0
Il Λ
-CR ¹ 0
Il ό - 0
Il Λ
COR ¹ , (D M / 22 148 where R straight-chain or branched C.-C ^ -alkyl, especially ethyl, Isopropyl or isobutyl; _ΐΓ / (CH) - CN, Hal C <- Hal, Hal R ² , where R ² = -NH ₃ , -COOH, η = 1 to 4, where η = 1 to 4 where Hai = F or Cl, -C-A, where η = 1 to 4 and A for a pyrimidine nucleoside of the formula: HO X stands in which R and X the have the meanings given above, M / 22 148 - 3 - where the radicals Y instead of the 5'-OH group desired- j ¹ ι if esterified with the OH group in the 3'-position; ¹ j. I. ! as an antiviral agent. ! ¹ 2. Use of the 5-alkyl-pyrimidine nucleosides according to claim 1 · i in a formulation suitable for systemic, in particular intraperitoneal, administration. j ι j 3. Use of the 5-alkyl-pyrimidine nucleosides according to claim 1> ! in a formulation suitable for topical application. ' ! j ι 4. Medicines with antiviral effects, thus identified ^] ! indicates that there is at least one 5-alkyl ¹ pyrimidine nucleoside according to claim 1 contains. '' 5. Medicament according to claim 4, characterized in that da3
it with a pharmaceutically acceptable carrier and / or
Diluent is formulated.