AU6830490A

AU6830490A - 2-formylbenzylphosphonic acid derivatives, their preparation and their use for the treatment of diseases caused by viruses

Info

Publication number: AU6830490A
Application number: AU68304/90A
Authority: AU
Inventors: Matthias Helsberg; Christoph Meichsner; Anuschirwan Peyman; Eugen Uhlmann; Irvin Winkler
Original assignee: Aventis Pharma Deutschland GmbH
Current assignee: Sanofi Aventis Deutschland GmbH
Priority date: 1989-12-21
Filing date: 1990-12-20
Publication date: 1991-06-27
Anticipated expiration: 2010-12-20
Also published as: NO179614C; ZA9010269B; KR910011874A; IL96730A; FI102280B; NO179614B; RU2039063C1; DE3942318A1; AU640723B2; NO905521L; DE59008715D1; CA2032772A1; EP0433928A1; JP2997552B2; HU208144B; PT96287B; PT96287A; PL288361A1; FI906268L; FI102280B1

Abstract

The compound of the formula I <IMAGE> in which R represents an aldehyde group or a group which can be converted into an aldehyde, R<1> and R<2> represent alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, hydrogen, sodium, potassium, calcium, magnesium, aluminium, lithium, ammonium or triethylammonium or R<1> and R<2> together form a cyclic diester, R<3> and R<4> represent alkyl, alkenyl, alkynyl, cycloalkyl, hydrogen, alkoxy or halogen, R<5> and R<8> represent alkyl, alkenyl, alkynyl, aralkyl, cycloalkyl, alkoxy, phenyl, cyanide, hydroxyl or hydrogen, X, Y or Z represent oxygen or sulphur, or prodrug forms of the compound of the formula I can be used for treatment of diseases caused by viruses. The preparation of these compounds and pharmaceutical preparations which contain them and also their use are described.

Description

COMMONWEALTH OF AUSTRALIA Patents Act 1952 DECLARATION IN SUPPORT OF A CONVENTION APPLICATION UNDER PART XVI., FOR A PATENT

In support of the Convention application made under Part XVI. of the Patents Act 1952 by HOECHST AKTIENGESELLSCHAFT D-6230 Frankfurt am Main 80, Federal Republic of Germany

for a patent for an invention entitled: 2-Formylbenzylphosphonic acid derivatives, their preparation and their use for the treatment of diseases caused by viruses I/We, Kurt Euler, RiedmuhlstraGe 39, D-6367 Karben Fed.Rep.of Germany Adalbert Otto, BienerstraGe 26, D-6238 Hofheim am Taunus Fed.Rep.of Germany

do solemnly and sincerely declare as follows: We are authorized by HOECHST AKTIENGESELLSCHAFT the applicant/s for the patent to make this declaration on its/their behalf. 2. The basic application/s as defined by Section 141 of the Act was/were made by HOECHST AKTIENGESELLSCHAFT Federal Republic of Germany P 39 42 318.2 of December 21, 1989

1) Anuschirwan PEYMAN, In den Bleichwiesen 9, D-6233 Kelkheim (Taunus) 2) Eugen UHLMANN, Zum Talblick 31, D-6246 GlashUtten/Taunus 3) Irvin WINKLER, In den Eichen 40, D-6237 Liederbach 4) Matthias HELSBERG, MUnsterer StraBe 14, D-6233 Kelkheim (Taunus) Christoph MEICHSNER, BienerstraBe 30, D-6238 Hofheim am Taunus S Fed.Rep.of Germany

is/are the actual inventor/s of the invention and the facts upon which HOECHST AKTIENGESELLSCHAFT is/are entitled to make the application are as follows: The said HOECHST AKTIENGESELLSCHAFT is/are the assignee/s of the said inventor/s

4. The basic application/s referred to in paragraph 2 of this Declaration was/were the the first application/s made in a Convention country in respect of the invention the subject of the application.

Dated Frankfurt am Main, Fed.Rep.of Germany, October 2, 1990

HOECHST AKTIE GESELLSCHAFT

ppa. Euler i.V. Otto

To the Commissioner of Patents

(12) PATENT ABSTRACT (11) Document No. AU-A-68304/90 (19) AUSTRALIAN PATENT OFFICE

(54) Title 2-FORMYLBENZYLPHOSPHONIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE FOR THE TREATMENT OF DISEASES CAUSED BY VIRUSES

International Patent Classification(s) (51 C07F 009/40 A61K 031/66 C07F 009/6564 (21) Application No. 68304/90 (22) Application Date 20.12.90 Priority Data 31) Number (32) Date (33) Country 3942318 21.12.89 DE FEDERAL REPUBLIC OF GERMANY (43) Publication Date 27.06.91 171) Applicant(s) HOECHST AKTIENGESELLSCHAFT

(72) Inventor(s) ANUSCHIRWAN PEYMAN; EUGEN UHLMANN; IRVIN WINKLER; MATTHIAS HELSBERG; CHRISTOPH MEICHSNER

(74) Attorney or Agent WATERMARK PATENT TRADEMARK ATTORNEYS, Locked Bag 5, HAWTHORN VIC 3122

(57) Claim

1. A compound of the formula (I)

x R II C(R 3 R )-P-YR 1 4

ZR 2 R5 R7, RB

in which R is an aldehyde group or a group which can be converted into an aldehyde, R' and R2 which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-.chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or 1 2 triethylammonium or R and R together form a cyclic diester having 2 to 6 carbon atoms in the ring, R3 and R4 which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkynyl or

i Z.

(11)68304/90 -2- alkenyl group having 2 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine, R5 R6 R7 and R8 which may be identical or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula Ia 0 It C-0-RI 9 Ia

R19 is a straight--chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and X, Y and Z, which may be identical or different, are oxygen or sulfur or a prodrug form of the compound of the formula I.

The process for the preparation of the compound of the formula I as claimed in claim 3, which comprises reacting the compound of the formula I in which R is an aldehyde group with the compound of the formula IVa, IVb and/or

I

Sealor b Com pany and 'y Signatures of its Officers as D. B. Mischlewski prescribed by its Articles of e 3"Pa e. .egis Association.

To: THE COMMISSIONER OF PATENTS.

WATERMARK PATENT TRADEMARK ATTORNEYS

-3 (11) 68304/90 IVc, IVd or IVe

OH HO-(CH 2 )-CH2 R 1 0 -0H R 1 1 -OH

IVa IVb IVc

15 1 4 R R

R161 R1 3 M-NH 2 12 HV R -NH

]Vd IV.e

in which R10 and R1 are a straight-chain or branched alkyl group having 1 to 10 carbon atoms, R"2 to R16 which may be identicalor different, are a straight-chain or branched alkyl group having 1 to carbon atoms or an aryl group having 6, 10 or 14 carbon atoms, V is oxygen or sulfur, M is a hydroxyl group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an aryl group having 6, or 14 carbon atoms or a radical of the formula Ie or If

V 0 17 -0-C-R1 -NH- C-R

I.

in which R 17 is a straight-chain or branched alkyl group having 1 to 10 carbon atoms, or an amino, pyridine, or an aryl group having 6, 10 or 14 carbon atoms and R 18 is an amino group, a pyridine group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or an aralkyl group having 7 to 20 carbon atoms.

11. The use of the compound of the formula I as claimed in claim 1 for the production of a pharmaceutical for the treatment of diseases which are caused by RNA or DNA viruses.

uaeo Frankfurt am Main, Fed.Rep.of Germany, October 2, 1990

HOECHST AKITE GESELLSCHAFT

ppa. Euler i.V. Otto

To the Commissioner of Patents I

Form COMMONWEALTH OF AUSTRALIA

PATENTS ACT 1952-69

COMPLETE SPECIFICATION (ORIGINAL)

Class Int. Class

Application Number: Lodged:

Complete Specification Lodged: Accepted: Published:

Priority

Related Art

Name of Applicant HOECHST AKTIENGESELLSCHAFT

Address of Applicant 50 Bruningstrasse, D-6230 Frankfurt/Main 80, Federal Republic of Germany

Actual Inventor ANUSCHIRWAN PEYMAN, EUGEN UHLMANN, IRVIN WINKLER, MATTHIAS HELSBERG and CHRISTOPH MEICHSNER

Address for Service WATERMARK PATENT TRADEMARK ATTORNEYS. LOCKED BAG NO. 5, HAWTHORN, VICTORIA 3122, AUSTRALIA

Complete Specification for the invention entitled:

2-FORMYLBENZYLPHOSPHONIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE FOR THE TREATMENT OF DISEASES CAUSED BY VIRUSES

The following statement is a full description of this invention, including the best method of performing it known to

HOECHST AKTIENGESELLSCHAFT HOE 89/F 398 Dr. WN

Description

2-Formylbenzylphosphonic acid derivatives, their prepar- ation and their use for the treatment of diseases caused by viruses

The invention relates to novel 2-formylbenzylphosphonic acid derivatives, to processes for the preparation of these compounds, to pharmaceutical agents which contain the active compounds according to the invention and to their use as medicaments, in particular for the treatment of diseases caused by viruses.

In order to treat diseases caused by viruses, various preparations have hitherto been employed, such as, for example, nucleoside analogs, amantadine, pyrophosphate analogs or immunomodulators Wood, A.M. Geddes, The Lancet, 1987, 1189). Some phosphonic acid derivatives are known which exhibit antiviral activity. These include compounds such as phosphonoformic acid (PFA), phosphono- acetic acid (PAA), methylenediphosphonic acid (MDP) and tetrazolephosphonic acids Roberts, NATO ASI Ser., Ser. A 143, 1988, 37; D.W. Hutchinson, M. Naylor, Nucleic Acids Res., 13, 1985, 8519). PFA has a wide antiviral spectrum, but causes some toxic side effects, which have hitherto prevented development to the antiviral medi- cament Wood, A.M. Geddes, The Lancet, 1987, 1189). It is known of ortho-phosphonyloxy-acetophenone deriv- atives that they are especially active against picorna- viruses (EP 21,000).

Diana et al. Med. Chem. 27, 1984, 691; DOS 2,922,054) report on a class of compound of the type in which A is an aromatic ring and C is a phosphonate or a p-ketophosphonate in which A and C are separated from one another by means of a bridge of 3-8 methylene groups From this class of compound, arylalkylphos- phonic acids having methylene bridges of more than carbon atoms showed antiviral activity against herpes- viruses. However, arylalkylphosphonic acids having methylene bridges of less than 5 carbon atoms do not show antiviral activity. The substitution of the aromatic radical of these compounds is carried out, in Diana et al., essentially by means of a 2-chloro-, 4-methoxy- or 4-carbethoxyphenoxy group.

Benzylphosphonic acids have hitherto not been described as active antiviral compounds Mao et al., Anti- microb. Agents Chemother. 27, 1985, 197).

Surprisingly, it has now been found that 2-formylbenzyl- phosphonic acid derivatives have antiviral activity.

The invention therefore relates to a compound of the formula I X R 3 4 II 1 C(R R )-P-YR ZR 2 6 RS,R ,RT,RB

in which R is an aldehyde group or a group which can be converted into an aldehyde, R 1 and R 2 which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or andR1 R2 together form a cyclic diester having 2 to 6 carbon atoms in the ring,

R 3 and R 4which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkynyl or alkenyl group having 2 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine, R R 6 R 7 and R 8 which may be identical or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula Ia 0

C-O-R 1 9 la R 19 is a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and X, Y and Z, which may be identical or different, are oxygen or sulfur or a prodrug form of the compound of the formula I.

A compound of the formula I in which R1 and R 2 are an alkyl group having 1 to 10 carbon atoms, an alkenyl or alkynyl group having 2 to 10 carbon atoms, hydrogen or an aralkyl group having 7 to 16 carbon atoms, R3 and R1 are an alkyl group having 1 to 4 carbon atoms, an alkenyl or alkynyl group having 2 to 4 carbon atoms or hydrogen, R5 R6 R 7 and R 8 are chlorine, bromine, methoxy or hydrogen and

X, Y and Z are oxygen, is preferred.

By the term "prodrug form of the compound of the formula compounds are meant which are converted into a compound of the formula I in which R is an aldehyde group, en route to the site of action. In the article by H. Bundgaard (Design of Prodrugs, 1985, pp. 1 92, Elsevier-Verlag), the term "Prodrug form" is defined and illustrated by examples.

The notation alkyl group having 1 to 10 carbon atoms is to be understood as meaning, for example, the following radicals: methyl, ethyl, propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, 2,2-dimethyl-l-propyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. By the notation alkenyl group having 2 to 10 carbon atoms, the following compounds, for example, are meant: ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl. By the notation alkynyl group having 2 to 10 carbon atoms, the following compounds are meant, for example: ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, nonynyl, octynyl or decynyl. An aralkyl group having 7 to 16 carbon atoms is understood as meaning the following radicals, for example: phenyl- methyl, phenylethyl, phenylbutyl, phenylpropyl, phenyl- pentyl, phenylhexyl, phenylheptyl, phenyloctyl, phenyl- nonyl or phenyldecyl. A cycloalkyl group having 3 to 8 carbon atoms is understood as meaning radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo- heptyl or cyclooctyl. Alkoxy groups having 1 to 4 carbon atoms are radicals such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec.-butoxy or tert.-butoxy.

The invention furthermore relates to a process fcr the preparation of the compound of the formula I in which R is an aldehyde group, which comprises reacting the compound of the formula II

0 H C R3

\R4 R ,R 6 ,R 7 ,R 8 5

in which R 3 and which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkynyl or alkenyl group having 2 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine, R5 R6, R 7 and R 8 which may be identical or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula la 0 II C-0-R 19 Ia R 19 is a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and T is chlorine, bromine, iodine, methylsulfonate, phenylsulfonate or tosylsulfonate, with the compound of the formula III

9 X-R P-Y-R1 111 Z-R2

in which, R and R 2 which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or R 1 and R 2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, R 9 is a straight-chain or branched alkyl group having 1 to 4 carbon atoms and X, Y and Z, which may be identical or different, are oxygen or sulfur.

The invention furthermore relates to a process for the preparation of the compound of the formula I in which R is a group which can be converted into an aldehyde, which comprises reacting the compound of the formula I in which R is an aldehyde in such a way that a group which can be converted into an aldehyde is formed.

The term "group which can be converted into an aldehyde" is understood as meaning radicals which are converted into an aldehyde en route to the site of action Bundgaard, Design of Prodrugs, 1985, pp. 1 92, Elsevier-Verlag).

In particular, the aldehyde group can be derivatized in such a way that the compound of the formula I is formed in which R is a group, which can be converted into an aldehyde, of the formula Ib, Ic or Id

R14

I N CH CH

lb Ic Id in which R10 and R1 which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 carbon atoms or R 10 and R1 together form a cyclic acetal having 2 or 3 carbon atoms in the ring, R 12 to R 16 which may be identical or different, are a straight-chain or branched alkyl group having 1 to carbon atoms or an aryl group having 6, 10 or 14 carbon atoms, V is oxygen or sulfur, M is a hydroxyl group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an aryl group having 6, or 14 carbon atoms or a radical of the formula Ie or If

V 0 -NH-C-R 1 7 -0-C-R 1I

i

in which R 17 is a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an amino, pyridine, or an aryl group having 6, 10 or 14 carbon atoms and R"8 is an amino group, a pyridine group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or an aralkyl group having 7 to 20 carbon atoms.

The synthesis of the compound of the formula I in which R is an aldehyde group is carried out by reacting the compound of the formula II with the compound of the formula III, expediently at temperatures between 100 and 250 0 C, preferably between 120 and 180 0 C (US 4,299,615; Houben-Weyl, Methoden der Org. Chemie (Methods of Organic Chemistry), Vol. XII/1, page 423, Thieme-Verlag, Stuttgart; Houben-Weyl, Methoden der Org. Chemie (Methods

'A of Organic Chemistry), Vol. E2, page 300). The reaction can be carried out in a suitable solvent, such as hexa- methylphosphoramide (HMPA), dimethylylformamide (DMF), dimethyl sulfoxide (DMSO), N,N'-dimethyl-N,N'-propylene- urea (DMPU) or N,N'-dimethyl-N,N'-ethyleneurea (DMEU). The reaction can also be carried out without solvent. Purification is carried out by generally customary methods, preferably by chromatography on silica gel using suitable eluents, by distillation or by recrystallization from suitable solvents.

The compounds of the formula II and III can be prepared in a manner known per se. The conversion of the phos- phonic acid diesters into their monoesters, and also into the corresponding free rjids or their salts is carried out, for example, by boiling with dilute hydrochloric acid (Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Vol. XII/1, 1963), or by reaction with trimethylbromosilane McKenna, J. Schmidhauser, J.C.S. Chem. Commun., 1979, 739). Purification is carried out by recrystallization in suitable solvents or by chromatographic methods, prefer- ably by ion exchange chromatography using suitable eluents. The desired salt forms can also be obtained by ion exchange chromatography.

The synthesis of a prodrug form of the compound of the formula I can be carried out, for example, by derivatiz- ing the aldehyde group in the compound of the formula I in such a way that compounds such as oximes, thiosemi- carbazones, carboxylic acid hydrazones, Schiff's bases, oxazolidines, thiazolidines or acetals are formed. For this purpose, the compound of the formula I in which R is an aldehyde group can be reacted with the compound of the formula IVa, IVb and/or IVc, IVd or IVe

OH HO-(CH 2 )-CH 2 R 1 0 -OH R 1I-OH

S]Va ]Vb IVc

1 5 14 SR R

R 16 R13 M-NH 2

HV R 1 2 -NH

IVd IVe

1 to R 16 in which R" M and V have the meaning mentioned and n is 1 or 2.

Other prodrug forms are formed in an analogous manner by the methods described in Bundgaard. The compounds of the formula I derivatized on the aldehyde group can be converted in vitro and in vivo into the active, anti- virally active form (aldehyde form) Bundgaard, Design of Prodrugs, 185, 1 92, Elsevier-Verlag). The conver- sion into the active form can be carried out, for ex- ample, by hydrolysis in aqueous solution or by enzymatic catalysis in or en route to the site of action.

A test for activity of chemotherapeutics for HIV infec- tions in man causes difficulties, since no infection model in laboratory animals yet exists. Infection with other retroviruses therefore has to be resorted to for testing chemotherapeutics. In this case, the infection of the mouse with the Friend leukemia virus has been chosen. For this purpose, normal NMRI laboratory mice (NMRI Naval Medical Research Institute) were infected by intravenous injection with mouse serum containing Friend leukemia virus. In the untreated control animals, a distinct enlargement of the spleen and liver developed as a symptom of the infection in the course of 2 weeks. Treatment was carried out over 10 days, starting 48 hours after the infection. On the 14th day of the experiment, the animals were sacrificed and dissected. The spleen was removed and weighed. As a measurement parameter of the therapeutic activity, the weight of the spleen of the treated animals was related to that of the untreated infection control.

In the case of uninfected adult laboratory mice (20 -24 g body weight), the spleen weighed about 1 of the body weight or less, while in the case of infected animals, the spleen attained about 10 of the body weight at the end of the experiment.

The compound of the formula I in which R is an aldehyde group possesses useful pharmacological properties, in particular an antiviral action and in particular against diseases caused both by DNA and RNA viruses, particularly against diseases which are caused by Herpes simplex virus (HSV myxoviruses, Friend leukemia virus (FLV) or human immunodeficiency virus (HIV). The compounds according to the invention are therefore suitable for combating various diseases caused by viruses, such as respiratory tract disease, diseases of the skin, the eyes, the central nervous system, AIDS and AIDS-related conditions, such as AIDS-related complex (ARC), genera- lized lymphadenopathy AIDS-related neuralgic conditions (such as mental deficiency or trophic para- peresis), anti-HIVantibody-positive conditions, Kaposi sarcoma or thrombopenic purpura.

The compound of the formula I and/or its prodrug form can either be used as a pharmaceutical alone or mixed with physiologically tolerable auxiliaries or excipients in effective amounts. It can be administered, for example, orally in a dose of 1 to 500 mg/kg/day, preferably 5 to mg/kg/day. The -dministration for parenteral, rectal or topical use or as an aerosol is carried out, for example in an amount of 0.5 to 500 mg/kg/day, preferably of 2 to 100 mg/kg/day. The compound of the formula I and/or its prodrug form are expediently administered in dosage units which contain at least the effective amount having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or R 1 and R 2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, R 3 and R4 which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkynyl or

11

of the compounds according to the invention, preferably to 6000 mg, particularly preferably 100 to 1000 mg. These values relate to an adult human having a weight of kg. These dosage units can also be administered several times per day. The dosage can also be increased in severe cases. In many cases, however, lower amounts are also sufficient. For combating diseases which are caused by RNA or DNA viruses, the following are suitable in particular diethyl 2-formylbenzylphosphonate, 2-formylbenzylphosphonic acid di(triethylammonium) salt, monoethyl 2-formylbenzylphosphonate triethylammonium salt, diethyl 2-formylbenzylphosphonate thiosemicarbazone, diethyl 2-formylbenzylphosphonate nicotinic acid hydrazone or diethyl 2-(3,4-dimethyl-5-phenyloxazolidin-2-yl)benzyl- phosphonate.

The compound of the formula I according to the invention and/or its prodrug form can also be administered in combination with other substances, in particular anti- viral agents and immunostimulators, such as interferons. The compound of the formula I and/or its prodrug form are referred to as the active compound in the following.

The invention furthermore includes the use of the active compound in the preparation of pharmaceuticals which are employed for the treatment and prophylaxis of the above- mentioned diseases. The invention furthermore relates to pharmaceuticals which contain one or more active compounds.

The pharmaceuticals are prepared by processes which are known per se and familiar to those skilled in the art. As a pharmaceutical, the active compound is either employed as such or preferably in combination with suitable pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the content of active compound being up to about 95 advantageously between 10 and 75

In addition to solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound carriers, suitable auxiliaries or excipients for the desired pharmaceutical formulation are also, for example, antioxidants, dispersants, emulsifiers, defoaming agents, flavor modifiers, preservatives, solubilizers or colorants.

The active compound can be administered orally, parenter- ally, intravenously or rectally, intranasal administra- tion as an aerosol being preferred in particular in addition to oral administration.

For a form for oral use, the active compound is mixed with the additives suitable for this purpose such as excipients, stabilizers or inert diluents and brought into a suitable form for administration, such as tablets, coated tablets, hard gelatin capsules, and aqueous or oily solutions by the customary methods. Inert excipientp which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular cornstarch. In this case, preparation can be carried out both as dry and as moist granules. Oily excipients or solvents which are suitable are, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compound is brought into solution, suspension or emulsion with the substances suitable for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Suitable solvents are, for example, physiological saline solution, alcohols, for example ethanol, propanol, glycerol, sugar solutions such as glucose or monnitol solutions or a mixture of solvents.

aryl group having 6, 10 or 14 carbon atoms or an aralkyl group having 7 to 20 carbon atoms.

13

The following examples serve to illustrate the invention further.

Example 1 Preparation of diethyl 2-formylbenzylphosphonate (A)

47.9 g (0.31 mol) of 2-chloromethylbenzaldehyde were heated 160 to 0C together with 51.5 g (0.31 mol) of triethyl phosphite. Ethyl chloride distilled off during the course of this. The product was purified by fraction- al distillation. Yield: 64.5 g (81 130°C/0.3 mm; 1H-NMR (270 MHz, CDCl 3 /TMS): 6 1.23 6H, P-O-CH2 CH 3 3.78 2H, CH2 Jp. 24 Hz, 4.04 (dq,4H, P-0-CH2 -CH 3 7.19 7.97 (m,4H,Ar-H)

Example 2 Preparation of 2-formylbenzylphosphonic acid di(triethyl- ammonium) salt and monoethyl 2-formylbenzylphosphonate triethylammonium salt (C)

100 ml of 6 M HC1 were added to 5.0 g (20 mmol) of diethyl 2-formylbenzylphosphonate and the mixture was boiled under reflux for 6 h. Water and HC1 were distilled off in vacuo, and the residue was co-evaporated three times with toluene. The remaining brown material was chromatographed on silica gel (CH2Cl 2 /methanol/triethyl- amine: 75/24/1). Compounds B and C were obtained as oily products. It was possible to separate them by chromato- graphy on diethylaminoethyl *Sephadex A25 (Et3NH form, Pharmacia, Freiburg, West Germany). They differ in their elution behavior (Rf value). Elution was carried out with a triethylammonium bicarbonate gradient of from 0.3 M. Rf 0.1; yield: 2.4 g (30 m.p.: 1H-NMR (270 MHz, DMSO/TMS): 6 1.07 (t,18H,N-CH2 -CH 3 2.86 (q,12H,N-CH 2 -CH3 3.23 (d,2H,CH2 Jp-1 23 Hz,

In t±AilvINT OF DISEASES CAUSED BY VIRUSES----' mI -L

The following statement is a full description of this invention, including the best method of performing it known to us

1.

14

7.24 7.78 (m,4H,Ar-H), 10.31 (s,1H,CHO). Rf 0.3; yield: 1.4 g (21 1H-NMR (270 MHz, DMSO/TMS): 6 1.01 1.17 (m,12H, N-CH 2-CH3 P-0-CH 2-CH3 2.88 (q,6H,N-CH2-C 3 3.27 (d,2H,CH2 Jp.H 23 Hz, 3.68 ((dq,2H, P-O-CH 2-CH3 7.18 7.78 (m,4H,Ar-H), 10.31 (s,1H,CHO).

Example 3 Preparation of 2-formylbenzylphosphonic acid di(triethyl- ammonium) salt (B)

3.2 g (21 mmol) of trimethylsilyl bromide were added dropwise to 2.0 g (8 mmol) of the compound A in 10 ml of absolute dioxane, and the reaction mixture was heated to and stirred at this temperature for 6 h. The mixture was evaporated, water was added several times and the solution was lyophilized. The crude product was purified by chromatography as in Example 2. Yield: 1.98 g (62

Example 4 Diethyl 2-formylbenzylphosphonate thiosemicarbazone (D)

2.0 g (8 mmol) of the compound A and 0.73 g of thiosemi- carbazide were dissolved or suspended in 200 ml of absolute ethanol. 2 Pl, of acetic acid were added and the mixture was boiled under reflux for 3 h. In the course of the slow cooling, the product D precipitated in crystal- 25 line form. Yield: 1.8 g (68 195 to 197 0 C; 1H-NMR (270 MHz, CDCl 3/TMS): 6 1.16 (t,6H,CH2-CH3 3.38 (d,2H,CH2 Jp.H 23 Hz), 3.94 (dq,4H, CH2 -CH3 7.23 7.39 (m,3H,Ar-H), 8.40 (s,IH,Ar-H), 11.37 (s,lH,Ar-CH=N).

A C B

Eicample Diethyl 2-formylbenzylphosphonate nicotinic acid hydrazone (E)

g (8 nimol) of the compound A and 1.07 g (8 nimol) of nicotinic acid hydrazide were dissolved in 30 ml of absolute ethanol. After adding 1 ml of acetic acid, the mixture was boiled under reflux for 8 h. The solvent was removed by rotary evaporation and the residue was chrom- atographed on silica gel (eluent CH2 C1 2 /EtOH 9.5/0.5; Rf 0.45). The product E was obtained in crystalline form. Yield: 2.2 g (73 136 to 140 0 C; 'H-NMR 270 MHz, CDCl 3 /TMS): 6 =1.14 1.37 (xn,6H,CH.), 3.61 3.79 (d,2H,CH2 -P)I JP_ 24 Hz, 3.87 4.16 (m,4H,CH2 -CH3 7.11 7.49 (m,4H,Ar-H), 7.70 9.23 (m,5H,Py-H), 10.17 11.25 (each s, ratio 1 3, 1H,NI).

Example 6 Diethyl 2- (3,4-di'ethyl-5-phenyloxazolidin-2-yl)benzyl- phosphonate (F)

g (8 nimol) of the compound A and 1.32 g (8 nimol) of n0 (-)-ephedrine were dissolved in 100 ml of benzene and heated under ref lux in a water separator for 24 h. The solvent was then removed by rotary evaporation and the residue was chromatographed on silica gel (eluent o CH 2 Cl 2 /ethanol 9.5/0.5; Rf 0.55). The product F was obtained as an oil. Yield: 2.4 g (75 'H-NMR (270 MHz, CDC1 3 /TMS); 6 0.80, (d,3H,CH-CH3 1.25 (m,6H,O-CH 2 ,-CH 3 2.27 (s,3H,N-CH3 3.18 (dq,1H,CH-CH3 3.20 3.28 (dd,1H,Ph-CH-CH), 3.59 3.76 (m,2H,CH.-P); 4.01 (m,4H,O-CH2-CH 3 5.19 7.16 7.45 (m,8H,Ar-H), 7.89 7.98 (m,1H,Ar-H).

Example 7

Pathogen-free N1ARI mice having a weight of about 15 g were infected intraperitoneally with Herpes simplex

I C&L-.LUL L '-j.LUc.LJ%.yL V.LJU LL.P

having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or R1 and R2 together form a cyclic diester having 2 to 6 carbon atoms in the ring,

16

Type 1 and then treated intraperitoneally, orally or subcutaneously with the compounds mentioned in Table 1. The treatment was carried out twice daily over the course of 2.5 days, starting after infection. The result of treatment was determined on the basis of the course of the disease and the survival rate compared to the un- treated infection controls. The controls received a water-soluble methylhydroxyethylcellulose (viscosity 300 Pa.s, administered in 2 strength solution) instead of the compounds to be tested. The experiments were carried out using groups of 5 mice each per preparation.

The chemotherapeutic action of the compound A can be seen from Table 1.

Table 1 Herpes simplex 1 Preparation Dosage Surviving Average survival (mg/kg) animals time (days) Control sc 0 1 6.7 A sc 2.5 2 A sc 25 0 7.2 A sc 250 0 8.4 Control po 0 1 A po 2.5 4 A po 25 5 A po 2 50 4 Control sc 0 1 8.3 C sc 3 1 C sc 10 3 C sc 30 4 10.0 Control po 0 1 7.8 C po 3 4 C po 10 3 C po 30 1 8.3 Control sc 0 1 8.3 B sc 3 2 7.8 B sc 10 3 B sc 30 3 an alkenyl or alkynyl group having 2 to 4 carbon atoms or hydrogen, R5 R R7 and R8 are chlorine, bromine, methoxy or hydrogen and

17

Table 1, continuation Herpes simplex 1 Preparation Dosage Surviving Average animals survival (mg/kg) time (days)

Control po 0 1 7.8 B po 3 3 B po 10 2 8.3 B po 30 3 Control ip 0 1 8.3 A ip 3 0 A ip 10 4 A ip 30 3

po orally sc subcutaneously ip intraperitoneally

Example 8 Cell cultures of Hela and Vero cells were inoculated into microtitre plates and infected with myxoviruses (influenza A2). 2 Hours after infection, the compounds B and C were added to the infected cell cultures in various dilutions. 48 to 72 hours after infection, the result of treatment was determined microscopically and photometric- ally by neutral red absorption (color test according to Finter) (Finter, N.B. Interferons, 1966) on the basis of the cytopathogenic effect. The minimum concentration at which about half the infected cells do not show a cyto- pathogenic effect is regarded as the minimum inhibitory concentration (MIC). The results are summarized in Table 2.

The invention furthermore relates to a process for the preparation of the compound of the formula I in which R is an aldehyde group, which comprises reacting the compound of the formula II

18

Table 2 Influenza A2 Substance MIC (pg/ml) MTD (pg/ml)

C 44.4 400 B 4.94 400

MIC minimum inhibitory concentration MTD maximum tolerated dose

Example 9

Pathogen-free NMRI mice having a weight of about 16 g were infected intranasally with influenza A2 and then treated subcutaneously and orally with the compounds mentioned in Table 3. The compounds, were administered to the animals under slight ether anesthesia using one drop of virus suspension in each of the nostrils. The treat- ment was carried out twice daily over the course of days, starting after infection. Amantadine was always used as the comparison. The success of the treatment was determined on the basis of the course of the disease and the survival rate compared to the untreated infection controls. The controls received a water-soluble methyl- hydroxyethylcellulose (viscosity 300 Pa.s, administered in 2 strength solution) instead of the compounds to be tested. The experiments were carried out using groups of 5 mice each per preparation.

The chemotherapeutic action is shown in Table 3.

with the compound of the formula III

19

3Influenza Table A2

Preparation Dosage Number of Average survival (mg/kg) surviving time (days) H animals 57. Control po 0 27. Amantadine p0 80 5 A po 2.5 4 A po 3 4 A po 10 4 A po 25 2 6.3 A po 30 2 7.3 Control sc 0 0 6.6 Axantadine sc 80 5 A sc 2.5 2 6.7 A sc 25 3 Control sc 0 2 6.7 Amantadine sc 80 5 B sc 1.5 1 B sc 15 4 Control po 0 1 Arnantadine pc 80 4 B pa 1.5 3 B po 15 5 B po 150 3 Control sc 0 0 6.8 C sc 0.25 5 C sc 2.5 5 C sc 25 3 Control po 0 0 7.2 C pa 0.25 5 C po 2.5 2 25 5 C Po Control pa 0 0 6.6 D p0 0.25 4 D pa 2.5 1 D po 25 2 7.3

Table 3, continuation Influenza A2 Preparation Dosage Number of Average (mg/kg) Surviving time animals (days) Control po 0 0 6.6 E po 0.25 4 E po 2.5 3 6.7 E po 25 3 Control po 0 1 F po 0.25 3 F po 2.5 3 F po 25 2

sc subcutaneously po orally

Example

Laboratory mice (NMRI, female, weight 20 24 g) were infected intravenously with Friend leukemia virus (FLV)- containing mouse serum. The treatment was started 48 h after infection. The mice were treated over the course of days with the substances indicated in Table 4. The substances indicated were administered orally or intra- peritoneally once a day. 14 days after infection, the animals were sacrificed by dislocation and the spleens were removed. The weight of the spleens was determined. As a measurement parameter of the therapeutic activity, the weight of the spleen of the animals which had been treated with compounds A and D was related to that of the '0 untreated infection control.

Suramin and azidothymidine (AZT) were used as standard substances. The action of the preparations is shown in Table 4.

formula III, expeaLently at Temper~Li-ut=? =6=.iwii 0C (US 4,299,615; 250 0 C, preferably between 120 and 180 Houben-Weyl, Methoden der Org. Chemie (Methods of Organic Chemistry), Vol. XII/1, page 423, Thieme-Verlag, Stuttgart; Houben-Weyl, Methoden der Org. Chemie (Methods

21

Table 4 Friend leukemia virus Preparation Dosage Survival Relative weight rate of the spleen of body weight Control po 0 100 12.36 AZT po 15.5 100 3.26 A po 17.5 100 7.74 A po 81 100 5.67 Control ip 0 100 10.64 AZT ip 50.0 100 7.60 D ip 50.0 100 7.60 Control ip 0 100 12.36 Suramin ip 50 70 6.06 A ip 25 90 6.27 A ip 50 100 6.52

ip intraperitoneally po orally

Claims

HOE 89/F 398 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: PaeMntex0iMadsx

1. A compound of the formula (I)

X R 3 4 II C(R R )-P-YR' 0 ZR 2

R 5 ,R 6 ,R 7 ,TR

in which R is an aldehyde group or a group which can be converted into an aldehyde, R1 and R2 which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or R1 and R 2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, R 3 and R 4 which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkynyl or alkenyl group having 2 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine, R 5 R 6 R 7 and R 8 which may be identical or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula Ia

0

C-0-R 1 9 Ia

R 19 is a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an &ralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and X, Y and Z, which may be identical or different, are oxygen or sulfur or a prodrug form of the compound of the formula I.

2. A compound of the formula I as claimed in claim 1, in which R1 and R 2 are an alkyl group having 1 to 10 carbon atoms, an alkenyl or alkynyl group having 2 to 10 carbon atoms, hydrogen or an aralkyl group having 7 to 16 carbon atoms, R 3 and R 4 are an alkyl group having 1 to 4 carbon atoms, an alkenyl or alkynyl group having 2 to 4 carbon atoms or hydrogen, R5 R6 R7 and R8 are chlorine, bromine, methoxy or hydrogen and X, Y and Z are oxygen.

3. A compound as claimed in claim 1, in which R is a group, which can be converted into an aldehyde, of the formula Ib, Ic or Id 1 R1 R1 RIO R R13 R16 M 0 0 R1 N CH C CH

lb Ic Id in which R 10 and R1 which may be identical or different, are a straight-chain or branched alkyl group having 1 to carbon atoms or R10 and R1 together form a cyclic acetal having 2 or 3 carbon atoms in the ring, a pharmaceutical, the active compound is either employed as such or preferably in combination with suitable pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories,

24

R1 to R 16 which may be identical or different, are a straight-chain or branched alkyl group having 1 to carbon atoms or an aryl group having 6, 10 or 14 carbon atoms, V is oxygen or sulfur, M is a hydroxyl group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an aryl group having 6, or 14 carbon atoms or a radical of the formula Ie or If

V 0 11 1 II 1 -NH-C-R 7~ -0-C-R1 B

IQ If

in which R 17 is a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an amino, pyridine, or aryl group having 6, 10 or 14 carbon atoms and R 1 is an amino group, a pyridine group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or an aralkyl group having 7 to 20 carbon atoms.

4. Diethyl 2-formylbenzylphosphonate.

2-Formylbenzylphosphonic acid di(triethylammonium) salt.

6. Monoethyl 2-formylbenzylphosphonate triethylammonium salt.

7. Diethyl 2-formylbenzylphosphonate thiosemicarbazone.

8. A process for the preparation of the compound of the formula I as claimed in claim 1, in which R is an aldehyde group, which comprises reacting the compound of the formula II

0 H C R3 C-T \R4 B R5,R6,R7,R in which R 3 and R 4 which may be the same or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkynyl or alkenyl group having 2 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine, R R 6 R 7 and R 8 which n.ay be identical or different, are a straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula Ia 0 II -C-O-R 1 9 Ia R 19 is a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and T is chlorine, bromine, iodine, methylsulfonate, phenylsulfonate or tosylsulfonate, with the compound of the formula III 9 X-R 1 P-Y-R 2 Z-_R

in which, R and R2 which may be the same or different, are a i.U M.

Rf 0.1; yield: 2.4 g (30 m.p.: 1H-NMR (270 MHz, DMSO/TMS): 6 1.07 (t,18H,N-CHz-CH3 2.86 (q,12H,N-CH2-CH 3 3.23 (d,2H,CH2 Jp. 23 Hz,

26

straight-chain or branched alkyl group having 1 to carbon atoms, a straight-chain or branched alkenyl or alkynyl group having 2 to 20 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or R1 and R2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, R9 is a straight-chain or branched alkyl group having 1 to 4 carbon atoms and X, Y and Z, which may be identical or different, are oxygen or sulfur.

9. The process for the preparation of the compound of the formula I as claimed in claim 1, in which R is a group which can be converted into an aldehyde, which comprises reacting the compound of the formula I in which R is an aldehyde in such a way that a group which can be con- verted into an aldehyde is formed.

The process for the preparation of the compound of the formula I as claimed in claim 3, which comprises reacting the compound of the formula I in which R is an aldehyde group with the compound of the formula IVa, IVb and/or IVc, IVd or IVe

OH 1 HO-(CH 2 )-CH 2 R 1 0 -OH R1 -OH n

IVa IVb IVc

1 5 1 4 R R 1 6 1 3 R R M-NH 2 1 HV R 2-NH

IVd IV.

in which R i0 and R 11 are a straight-chain or branched alkyl group having 1 to 10 carbon atoms, R 12 to R 16 which may be identical or different, are a straight-chain or branched alkyl group having 1 to carbon atoms or an aryl group having 6, 10 or 14 carbon atoms, V is oxygen or sulfur, M is a hydroxyl group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an aryl group having 6, or 14 carbon atoms or a radical of the formula Ie or If

V 0 17 18 -NH-C-R -O-C-R

e if

in which R 17 is a straight-chain or branched alkyl group having 1 to 10 carbon atoms, or an amino, pyridine, or an aryl group having 6, 10 or 14 carbon atoms and R 18 is an amino group, a pyridine group, a straight-chain or branched alkyl group having 1 to 10 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or an aralkyl group having 7 to 20 carbon atoms.

11. The use of the compound of the formula I as claimed in claim 1 for the production of a pharmaceutical for the treatment of diseases which are caused by RNA or DNA viruses.

12. The use of the compound of the formula I as claimed in claim 2 for the production of a pharmaceutical for the treatment of diseases which are caused by RNA or DNA viruses.

13. The use of the compound of the formula I as claimed in claim 3 for the production of a pharmaceutical for the treatment of diseases which are caused by RNA or DNA viruses.

14. A pharmaceutical preparation containing an effective amount of the compound as claimed in claim 1.

A method for the production of a pharmaceutical, wherein an effective amount of a compound as claimed in claim 1 is converted into a suitable form for administration.

DATED this 19th day of December 1990.

HOECHST AKTIENGESELLSCHAFT

WATERMARK PATENT TRADEMARK ATTORNEYS "THE ATRIUM" 290 BURWOOD ROAD HAWTHORN. VIC. 3122.