NZ236554A

NZ236554A - 2-formylbenzyl phosphonic acid derivatives and pharmacetical compositions

Info

Publication number: NZ236554A
Application number: NZ236554A
Authority: NZ
Inventors: Anuschirwan Peyman; Eugen Uhlmann; Irvin Winkler; Matthias Helsberg; Christoph Meichsner
Original assignee: Hoechst Ag
Priority date: 1989-12-21
Filing date: 1990-12-19
Publication date: 1992-12-23
Also published as: PT96287A; KR100191087B1; FI102280B; EP0433928B1; NO905521D0; JPH0616685A; IE904625A1; NO905521L; ATE119908T1; NO179614C; IE67439B1; KR910011874A; PL288361A1; FI102280B1; FI906268A0; JP2997552B2; IL96730A0; AU640723B2; ZA9010269B; DE3942318A1

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

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £36554 236 55 Henry Hughes Ltd Patents Form 5 |cvjz."ft o 5 C: 66"5<?> 6Sf' 'hS-k<" 1 I 2 3 DEC 1992 j j.'.,"'. P.V.TrtT QFFiCE _ 13 DEC 1SSQ • N.Z. No. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION 2-F0RMYLBENZYLPH0SPH0NIC ACID DERIVATIVES. THEIR PREPARATION AND THEIR USE FOR THE TREATMENT OF DISEASES CAUSED BY VIRUSES We, HOECHST AKTIENGESELLSHAFT, a Corporation organized under the laws of the Federal Republic of Germany, of D-6230 Frankfurt am Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (Followed by 1A) 23655 Dcocription - 1A - 2-Fonnylbenzylphosphonic acid derivatives, their preparation and their use for the treatment of diseases caused 5 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 10 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 15 analogs or immunomodulators (M.J. 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 20 tetra2olephosphonic acids (S.M. 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-25 cament (M.J. Wood, A.M. Geddes, The Lancet, 1987, 1189). It is known of ortho-phosphonyloxy-acetophenone derivatives that they are especially active against picorna-viruses (EP 21,000). Diana et al. (J. Med. Chem. 27, 1984, 691? DOS 2,922,054) 30 report on a class of compound of the type A C B - 2 - 23655 in which A is an aromatic ring and C is a phosphonate or a /S-ketophosphonate in which A and C are separated from one another by means of a bridge of 3-8 methylene groups (B). From this class of compound, arylalkylphos-5 phonic acids having methylene bridges of more than 5 carbon atoms showed antiviral activity against herpesviruses. However, arylalkylphosphonic acids having methylene bridges of less than 5 carbon atoms do not show antiviral activity. The substitution of the aromatic 10 radical of these compounds is carried out, in Diana et al.f essentially by means of a 2-chloro-, 4-methoxy-or 4-carbethoxyphenoxy group. Benzylphosphonic acids have hitherto not been described as active antiviral compounds (J.C.H. Mao et al., Anti-15 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 - - II -c(r3r4)-p-yr1 Irh 1 r5,r6,r7,rb 20 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 20 25 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 30 triethylammonium or R1 and R2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, - 3 - 236554 R3 and RA, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkynyl or alkenyl group having 2 to 20 carbon atoms, a cycloalkyl 5 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 20 10 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, 15 iodine, a cyanide, hydroxyl or phenyl group or the radical of the formula la 0 C-O-R*9 la R1S 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 20 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 25 oxygen or sulfur or a prodrug form of the compound of the formula I. A compound of the formula I in which R1 and R2 are an alkyl group having 1 to 10 carbon atoms, an alkenyl or alkynyl group having 2 to 10 carbon atoms, 30 hydrogen or an aralkyl group having 7 to 16 carbon atoms, R3 and R4 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 35 hydrogen and 236 - 4 - X, Y and Z are oxygen, is preferred. By the term "prodrug form of the compound of the formula I", compounds are meant which are converted into 5 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. 10 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-dimethy 1-1-propyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. By the 15 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, 20 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-25 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 30 atoms are radicals such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec.-butoxy or tert.-butoxy. 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 35 compound of the formula II - 5 - 236 D 5 10 15 J 20 h I^^T" r3 / c-t nr4 I I r5,r6,r7,rb in which R3 and R*, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 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, R7 and Re, which may be identical or different, are 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, 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-O-R19 la 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 T is chlorine, bromine, iodine, metliylsulfonate, phenylsulfonate or tosylsulfonate, with the compound of the formula III 2365 X-R9 Y-R1 1 3 ! 2~R2 in which, R1 and R2, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 carbon atoms, a straight-chain or branched alkenyl or 5 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 10 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. 15 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 20 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 (H. Bundgaard, Design of Prodrugs, 1985, pp. 1-92, 25 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 lb, Ic or Id - 7 - 236 5 5 R14 R15 R10 R11 R13-^ V-R1& \ " i~X ^2-J \ n 0. 0 p 1 2-m V ^ 'Of" CH 1 1 ch i lb Ic Id in which R10 and R11, which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 carbon atoms or R10 and R11 together form a cyclic acetal having 2 or 3 carbon atoms in the ring, 5 R12 to R16, which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 carbon atoms or an aryl group having 6, 10 or 14 carbon atoms, V is oxygen or sulfur, 10 Mis 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, 10 or 14 carbon atoms or a radical of the formula Ie or If -nh-c-r17 1. 0 :0-c-r1b If in which R17 is a straight-chain or branched alkyl group 15 having 1 to 10 carbon atoms, an amino, pyridine, or an aryl group having 6, 10 or 14 carbon atoms and R18 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 20 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 25 250°C, preferably between 120 and 180°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 - 8 - 236 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 acids 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 (C.E. McKenna, J. Schmidhauser, J.C.S. Chem. Commun., 1979, 739). Purification is carried out by recrystallization in suitable solvents or by chromatographic methods, preferably 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, carboxylie 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 l h0-(ch2)-ch2 ] vc - 9 - r1°-oh ] Vb 236554 r1 1-oh 1 vc r15 R1 6 R14 r13 hv r12-nh m-nh; 1 vd ] v. in which R10 to R16, M and V have the meaning mentioned and n is 1 or 2. 10 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) (H. Bundgaard, Design of Prodrugs, 1985, 1-92, Elsevier-Verlag). The conversion into the active form can be carried out, for example, 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 infections in man causes difficulties, since no infection model in laboratory animals yet exists. Infection with 15 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 20 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 25 after the infection. On the 14th day of the experiment, the animals were sacrificed and dissected. The spleen was - 10 - 236554 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. 5 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. 10 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 15 virus (HSV I), 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 20 eyes, the central nervous system, AIDS and AIDS-related conditions, such as AIDS-related complex (ARC), generalized lymphadenopathy (GL), AIDS-related neuralgic conditions (such as mental deficiency or trophic para-peresis), anti-HIVantibody-positive conditions, Kaposi 25 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, 30 orally in a dose of 1 to 500 mg/kg/day, preferably 5 to 50 mg/kg/day. The administration 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 35 and/or its prodrug form are expediently administered in dosage units which contain at least the effective amount - 11 - 236554 of the compounds according to the invention, preferably 25 to 6000 mg, particularly preferably 100 to 1000 mg. These values relate to an adult human having a weight of 75 kg. These dosage units can also be administered 5 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 10 diethyl 2-formylbenzylphosphonate, 2-formylbenzylphosphonic acid di(triethylammonium) salt, monoethyl 2-formylbenzylphosphonate triethylammonium salt, diethyl 2-formylbenzylphosphonate thiosemicarbazone, 15 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 20 and/or its prodrug form can also be administered in combination with other substances, in particular antiviral 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. 25 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 30 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 35 pharmaceutical auxiliaries or excipients in the form of tablets, coated tablets, capsules, suppositories. - 12 - 236554 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 ^ 5 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 % 10 colorants. The active compound can be administered orally, parenter-ally, intravenously or rectally, intranasal administration as an aerosol being preferred in particular in addition to oral administration. 15 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 20 oily solutions by the customary methods. Inert excipients 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 25 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 30 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 mannitol 35 solutions or a mixture of solvents. - 13 - 236554 The following examples serve to illustrate the invention further. Example 1 -n Preparation of diethyl 2-formylbenzylphosphonate (A) 5 47.9 g (0.31 mol) of 2-chloromethylbenzaldehyde were heated to 160°C 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. 10 Yield: 64.5 g (81 %); b.p.: 130°C/0.3 mm; 1H-NMR (270 MHz, CDC13/TMS) : S = 1.23 (t, 6H, P-0-CH2-CH3), 3.78 (d, 2H, CH2-P) Jp.h = 24 Hz, 4.04 (dq,4H, P-0-CH2-CH3), 7.19 - 7.97 (m,4H,Ar-H) Example 2 15 Preparation of 2-formylbenzylphosphonic acid di(triethyl-aninionium) salt (B) and monoethyl 2-formylbenzylphosphonate triethylammonium salt (C) 100 ml of 6 M HCl were added to 5.0 g (20 mmol) of 20 diethyl 2-formylbenzylphosphonate and the mixture was ^ boiled under reflux for 6 h. Water and HCl were distilled off in vacuo, and the residue was co-evaporated three times with toluene. The remaining brown material was chromatographed on silica gel (CH2Cl2/methanol/triethyl-25 amine: 75/24/1). Compounds B and C were obtained as oily products. It was possible to separate them by chromatography on diethylaminoethyl *Sephadex A25 (Et3NH+ form, Pharmacia, Freiburg, West Germany). They differ in their elution behavior (Rf value). Elution was carried out with 30 a triethylammonium bicarbonate gradient of from 0.3 -1.0 M. (B): Rf = 0.1; yield: 2.4 g (30 %); m.p.s 1H-NMR (270 MHz, DMSO/TMS): 5 = 1.07 (t, 18H,N-CH2-CH3), 2.86 (q,l2H,N-CH2-CH3), 3.23 (d,2H,CH2-P) JP.H = 23 Hz, r - 14 - 236554 7.24 - 7.78 (m,4H,Ar-H), 10.31 (s,lH,CHO). (C): Rf = 0.3? yield: 1.4 g (21 %)? 1H-NMR (270 MHz, DMSO/TMS): 6 = 1.01 - 1.17 (m/12H/ N-CH2-CH3 & P-0~CH2-CH3) / 2.88 (q, 6H,N-CH2-CH3), 3.27 5 (d,2H,CH2-P) JP.H = 23 Hz, 3.68 ((dq,2H, P-0-CH2-CH3), 7.18 - 7.78 (m,4H,Ar-H), 10.31 (s,lHrCHO). Example 3 Preparation of 2-formylbenzylphosphonic acid di(triethylammonium) salt (B) 10 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 50cC and stirred at this temperature for 6 h. The mixture was evaporated, water was added several times and the 15 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) 20 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 ml 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 %)? m.p.: 195 to 197°C; ^-NMR (270 MHz, CDC13/TMS) : S = 1.16 (t,6H,CH2-CH3) , 3.38 (d,2H,CH2-P, JP_H = 23 Hz), 3.94 (dq,4H, CH2-CH3), 7.23 - 7.39 (m,3H,Ar-H), 8.40 (s,lH,Ar-H), 11.37 30 (s,lH,Ar-CH=N). r - 15 - 23 6 5 5 -' Example 5 Diethyl 2-formylbenzylphosphonate nicotinic acid hydrazone (E) 2.0 g (8 mmol) of the compound A and 1.07 g (8 mmol) of 5 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 CH2Cl2/EtOH 9.5/0.5? Rf 10 =0.45). The product E was obtained in crystalline form. Yield: 2.2 g (73 %); m.p.: 136 to 140"C; ^-NMR 270 MHz, CDC13/TMS): S = 1.14 - 1.37 (m,6H,CH3), 3.61 - 3.79 (d,2H,CH2-P), Jp.H = 24 Hz, 3.87 - 4.16 (m,4H,CH2-CH3), 7.11 - 7.49 (m, 4H,Ar-H), 7.70 - 9.23 15 (m,5H,Py-H), 10.17 & 11.25 (each s, ratio 1 : 3, 1H,NH). Example 6 Diethyl 2-(3,4-dimethyl-5-phenyloxazolidin-2-yl)benzyl-pho sphonate (F) 2.0 g (8 mmol) of the compound A and 1.32 g (8 mmol) of 20 (-)-ephedrine were dissolved in 100 ml of benzene and heated under reflux in a water separator for 24 h. The solvent was then removed by rotary evaporation and the residue was chroraatographed on silica gel (eluent CH2Cl2/ethanol 9.5/0.5; Rf =0.55). The product F was 25 obtained as an oil. Yield: 2.4 g (75 %); ^-NMR (270 MHz, CDC13/TMS); 6 = 0.80, (d,3H,CH-CH3), 1.25 (m,6H,0-CH2-CH3), 2.27 (s,3H,N-CH3), 3.18 (dq, 1H,CH-CH3), 3.20 & 3.28 (dd,lH,Ph-CH-CH), 3.59 - 3.76 (m,2H,CHz-P); 30 4.01 (m, 4H,0-CH2-CH3), 5.19 (s,lH,Ar-CH(0-)(N-), 7.16 -7.45 (m,8H,Ar-H), 7.89 - 7.98 (m,lH,Ar-H). Example 7 Pathogen-free NMRI mice having a weight of about 15 g were infected intraperitoneally with Herpes simplex - 16 - 23655* 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 5 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 methylhydroxyethylcellulose (viscosity 300 Pa.s, administered in 2 % strength solution) instead 10 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 15 Preparation Dosage Surviving Average survival (mg/kg) animals time (days) Control sc 0 1 6.7 A sc 2.5 2 9.0 20 A sc 25 0 7.2 A sc 250 0 8.4 Control po 0 1 8.0 A po 2.5 4 8.0 A po 25 5 25 A po 250 4 8.0 Control sc 0 1 8.3 C sc 3 1 8.5 C sc 10 3 8.0 C sc 30 4 10.0 30 Control po 0 1 7.8 C po 3 4 9.0 C po 10 3 00 o C po 30 1 8.3 Control sc 0 1 8.3 35 B sc 3 2 7.8 B sc 10 3 7.0 B sc 30 3 6.5 10 15 - 17 - Table lf continuation Herpes simplex 1 Preparation Dosage (mg/kg) Control B B B Control A A A po po 0 3 po 10 po 30 IP ip 0 3 ip 10 ip 30 po = orally sc = subcutaneously ip = intraperitoneally Surviving animals 1 3 2 3 1 0 4 3 236554 Ave rage survival time (days) 7.8 7.0 8.3 6.0 8.3 8.0 9.0 8.5 Example 8 Cell cultures of Hela and Vero cells were inoculated into 20 microti tre 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-25 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 cytopathogenic effect is regarded as the minimum inhibitory 30 concentration (MIC). The results are summarized in Table 2. - 18 - 23 6 5 5 Table 2 Influenza A2 Substance MIC (/*g/ml) MTD (pg/ml) C 44.4 > 400 B 4.94 > 400 MIC = minimum inhibitory concentration MTD = maximum tolerated dose Example 9 10 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 15 of virus suspension in each of the nostrils. The treatment was carried out twice daily over the course of 2.5 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 20 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 25 5 mice each per preparation. The chemotherapeutic action is shown in Table 3. y Table 3 Preparation Dosage (mg/kg) - 19 - Influenza A2 Number of surviving animals 23 6 5 5/ Average survival time (days) Control po 0 2 7.5 Amantadine po 80 5 — A po 2.5 4 9.0 A po 3 4 8.0 10 A po 10 4 7.0 A po 25 2 6.3 A po 30 2 7.3 Control sc 0 0 6.6 Amantadine sc 80 5 — 15 A sc 2.5 2 6.7 A sc 25 3 7.0 Control sc 0 2 6.7 Amantadine sc 80 5 — B sc 1.5 1 8.5 20 B sc 15 4 8.0 Control po 0 1 6.5 Amantadine po 80 4 CO • o B po 1.5 3 8.5 B po 15 5 — 25 B po 150 3 7.0 Control sc 0 0 6.8 C sc 0.25 5 — C sc 2.5 5 — C sc 25 3 7.5 30 Control po 0 0 7.2 C po 0.25 5 — C po 2.5 2 6.0 C po 25 5 — Control po 0 0 6.6 35 D po 0.25 4 8.0 D po 2.5 1 7.0 D po 25 2 7.3 10 15 - 20 - Table 3, continuation Preparation Control E E E Control F F F Influenza A2 Dosage Number of (mg/kg) Surviving animals po po po po po po po po 0 0.25 2.5 25 0 0.25 2.5 25 0 4 3 3 1 3 3 2 sc = subcutaneously po = orally 236554 Average time (days) 6.6 8.0 6.7 6.0 7.0 6.5 6.5 7.0 Example 10 Laboratory mice (NMRI, female, weight 20 - 24 g) were infected intravenously with Friend leukemia virus (FLV)-20 containing mouse serum. The treatment was started 48 h after infection. The mice were treated over the course of 10 days with the substances indicated in Table 4. The substances indicated were administered orally or intraperitoneally once a day. 14 days after infection, the 25 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 30 untreated infection control. Suramin and azidothymidine (AZT) were used as standard substances. The action of the preparations is shown in Table 4. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 21 - 23 6 5 5 Table 4 Friend leukemia virus Preparation Dosage Survival rate % Relative weight 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 i-P 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 D 3 236 22 - WHAT WE CLAIM IS:

1. A compound of the formula (I) r x C(R3R4)-P-YR1 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 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 or R1 and R2 together form a cyclic diester having 2 to 6 carbon atoms in the ring, R3 and R*, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 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, R7 and R8, which may be identical or different, are 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, 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 - 23 - 236554 0 II C-O-R19 la 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. A compound of the formula I as claimed in claim 1, in which R1 and Rz 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 R* 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 Re are chlorine, bromine, methoxy or hydrogen and X, Y and Z are oxygen. A compound as claimed in claim 1, in which R is a group, which can be converted into an aldehyde, of the formula lb, Ic or Id p 14 p 1 5 ?10 I*" RlS-H-V*16 \ 0 0 R12-M v ^ \ ^ ri_r ch ch v im I 1 lb ]c ]d in which R10 and Rn, which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 carbon atoms or R10 and R11 together form a cyclic acetal having 2 or 3 carbon atoms in the ring, - 24 - 2 R12 to R16, which may be identical or different, are a straight-chain or branched alkyl group having l to 10 carbon atoms or an aryl group having 6, 10 or 14 carbon atoms, V is oxygen or sulfur, M is a hydroxy 1 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, 10 or 14 carbon atoms or a radical of the formula Ie or If V 0 II 1 II i Q -nh-c-r17 -0-c-r1b !• If in which R17 is a straight-chain or branchejdl alkyl group having 1 to 10 carbon atoms, an amino, ^arigfine, or aryl group having 6, 10 or 14 c^rjbon atoms and R18 is an amino group, a ^ricL.no 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. Diethyl 2-formylbenzylphosphonate.

2-Formylbenzylphosphonic acid di (triethylammonium) salt. Monoethyl 2-formylbenzylphosphonate triethylammonium salt. Diethyl 2-formylbenzylphosphonate thiosemicarbazone. r Q A process for the preparation ofcompound of the formula I as claimed in claim 1, in which R is an aldehyde group, which comprises reacting fefce compound of the formula II •7„ T" ! o •"w ( - 25 - ^{>554 j ] 3 > ^R5,R6,R7,RB in which R3 and R4, which may be the same or different, are a straight-chain or branched alkyl group having 1 to 20 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, R7 and Rs, which may be identical or different, are 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 2 0 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 -C-O-RlS la R1S 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 111 x-r9 p-y-r1 ^Z-R2 in which, R1 and R2, which may be the same or different, are •'13HGVm2\ - 26 - I 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 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. r ^ 9. The process for the preparation of Ifehe 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 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. 10. The process for the preparation offthe compound of the formula I as claimed in claim 3, which comprises reacting Pthe 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 I ho-(ch2)"ch2 IVc O-OH 1 Vb r11-oh IVc r1s r = 1 6 , 1 A -r1 3 hv r12-nh IVd m-nh2 IV. s; '."i i C) * ' in which R10 and Rn are a straight-chain or branched alkyl < ; tjiiovrr>2 . ' -27- (l o I) {/ {) ■ / " •' group having 1 to 10 carbon atoms, R12 to R16, which may be identical or different, are a straight-chain or branched alkyl group having 1 to 10 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 alley 1 group having 1 to 10 carbon atoms, an aralkyl group having 7 to 20 carbon atoms, an aryl group having 6, 10 or 14 carbon atoms or a radical of the formula Ie or If v 0 I I 4 " 1 Q -nh-c-r17 -o-c-r1b ]. If in which R17 is a straight-chain or branched alkyl group having 1 to 10 carbon atoms, or an amino, pyridyi , or an aryl group having 6, 10 or 14 carbon atoms and R18 is an amino group, a pyridyl 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. r-C\ ^ 11. The use of |£he 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 Ifcfee compound of the formula I as claimed in i claim 2 for the production of a pharmaceutical for the treatment of diseases which are caused by RNA or DNA viruses. r-° 13. The use of jfehe 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 1 effective _ , r* 1 I . ,3 W Lj-fir "tKe. <ft'seas2£ cauy^ by vi/u&es a ^ j «i::i - ; ' amount o-f tho compound as claimed in claim 1. 15. A method for the production of a pharmaceutical, wherein ^GiAA?4tft _ f -foc-tWo-f^arf^eyd o£ di^ea^ caufcfd. by Viru&ed, . an\effective I amount of a compound as claimed m claim 1 is converted into a suitable form for administration. 16. A compound according to claim 1 substantially as herein described or exemplified. 17. A process according to claim 8 substantially as herein described or exemplified. 18. A pharmaceutical preparation according to claim 14 substantially as herein described or exemplified. 19. A method according to claim 15 substantially as herein described or exemplified. -2CL Any ■ novel. feature or novel combination of foatur-oo disclosed herein. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LIMITED </div>