NL8720745A - NEW ANTIVIRALS. - Google Patents

Description

N.0. 35,242 Λ Λ * 87 2 0 7 4 5-

New antivirals.

«

Field of the invention

The invention relates to nucleotide analogues and to their preparation and use. More particularly, the invention relates to phosphonic acid analogues of natural and synthetic nucleoside phosphates and to their preparation and use as antiviral agents.

Background of the invention

There is a recognized need for antivirals. Currently, between 50 and 150 million Americans are infected by Herpes virus hominus alone. Some of the antivirals currently considered to be most effective against herpes are among the nucleoside analogues. These substances include iodo-deoxyuridine, 2-hydroxyethoxymethylguanine, 2'-fluoro-5-iodo-1-arabinofuranosylcytosine and 5-E-bromovinyldeoxyuridine. These substances are believed to act through conversion by viral thymidine kinase (but not host thymidine kinase) into the nucleotide which is then converted to the triphosphate and incorporated into viral DNA. The incorporation of these analogs into the viral DNA prevents their propagation and is therefore lethal to the virus. However, two drawbacks of this antiviral mechanism are recognized. First, thy-midine kinase-negative herpes mutants (TK-) have been identified which, by their nature, cannot phosphorylate these analogues and thus cannot build them into the viral DNA. In addition, H. Field et al., J. Infect. Dis. 143, 281 (1981) have been observed in murine mutants resistant to 2-hydroxyethoxymethylguanine. TfC1 mutants resistant to iododoxyuridine have been described by A. Hirano et al.

30 (Acta Virol. 23, 226 (1979)) has been observed in humans. These recently discovered resistant viral strains may not undergo the monophosphorylation or triphosphate formation required for incorporation into the DNA.

Publications on these known antivirals and their use include Am. J. Med. 73, (IA), July 20, 1982, "Proceedings of a Symposium on Acyclovir"; Biochem · Biophys. Acta, 32.

295-6, (1959); Antimicrob. Agents Cheraother. 578-584 (1965); Science, 145, 585-6 (1964); Science, 255, 468-80 (1975); J. Med. Chem. 19, 495-8 (1976); Proc. Natl. Acad. Sci. 76, 4415-18 (1979) and J. Med. Chem. 22, 40 21-24 (1979).

* 8720745 f 2%

The invention provides antiviral agents that can be lethally incorporated into DNA without dependence on enzyme-driven phosphorylation. The substances according to the invention are phosphonate analogues of the mono-, di- and triphosphates of the deoxynucleotide analogues. An article by Robert Engel in Chem. Reviews, 11, (3) 349-367 (1977) describes phosphonate analogues of nucleotides and the like. Others also partly in the article in Chem. Reviews mentioned in this field are German Offenlegungsschrift 2,350,608 (1974) by Syntex (inventors Jones and Moffatt), German Offenlegungsschrift 2,009,834 (1970) also by Syntex with Jones and Moffatt as inventors, British patent 1,243,214 to Syntex and U.S. Patent 3,560,478 to Myers.

Explanation of the invention A group of new substances has been found. These substances are, generally speaking, phosphonate analogues of mono-, di- and triphosphates of antiviral nucleoside analogues. These analogues differ from non-lethal natural nucleosides by abnormalities in the ribose sugar group and / or abnormalities in the nucleoside base groups. These substances are structurally represented as 0 X r3 25 Z20 ^ || | |

P-C- (CH2) n-CHB

ZiO | 1 / ° \ 1

Y CH CH

I I

R 2 R 1 wherein and Z 2 are the same or different and are selected from 35 are hydrogen, alkyl groups of 1 to 6 carbon atoms, phenyl and benzyl, X is equal to H, OH, or, together with Y, = 0, Y is equal to H or , together with X, = 0, n is an integer 0, 2 or 4, R ^ and R2 together complete a β-pentofuranose whether R ^ is H and R2 is H or CH2 OH, R3 is H or OH and B is a purine or pyrimidine-40 base.

T8720745 3 i

The invention also relates to the preparation of these substances, to their processing into antiviral pharmaceutical preparations and to the use of these preparations for the treatment of viral infections, in particular herpes infections.

5

Detailed description of the invention The compounds

The compounds according to the invention are phosphonates with the structure given above in the explanation of the invention. The unit »3!

15 -CH B

I |

CH CH

i r r2 Hl 20 represents an antiviral nucleoside.

As already indicated, in this structure R1 and R2 together can complete a g-pentafuranose. Here, they preferably form an unsubstituted or substituted g-ribofuranose or g-arabinofuranose such as such as ribose, 2-deoxyribose, 2,3-dideoxyribose, 3-deoxyribose, 2-fluoro-2-deoxyrihose, arabinose or the like.

In this structure, Zj and Z2 preferably represent hydrogen and / or an alkyl group of 1-4 carbon atoms. With particular preference, Zi and Z2 are both hydrogen. Furthermore, in this structure, the number n has significance for determining whether the compound corresponds in size to a nucleoside monophosphate, diphosphate, or triphosphate.

Preferred bases include guanine, adenine, 5-iodo-uracil, 5-trifluorothymine, 5-iodo-cytosine, E-5- (2-bromovinyl) uracil, 5-propyluracil and 5-ethyluracil.

Preferred nucleoside analogues of the formula below. 8720745 '4' R3

5 -CH B

'/ ° \'

CH CH

I I

R2 Ri 10 include 5-iodo-2'-deoxyuridine, 9-BD-arabinofuranosyladenine, 5-trifluorothymidine, E-5- (2-bromovinyl) -2'-deoxyuridine, 1- (21-deoxy-2'- fluoro-BD-arabinofuranosyl) -5-iodo-cytosine, 5-ethyl-2'-deoxyuridine, 15 5-propyl-2'-deoxyuridine, 9- (2-hydroxyethoxymethyl) guanine, 9- (ethoxy-methyl) guanine, 9- (2-hydroxyethoxymethyl) adenine and 9- (ethoxymethyl) adenine.

These nucleoside analogues lead to phosphonate analogs (corresponding to mono-, di- or triphosphates) with general formulas below.

0 X R3 Z20 II I I

P-C-CH B

ZX0 I I ^ 0 I.

Y CH CH

I I

r2 r1 30 O X R3

Z20 || I I

35 P-C- (CH2) 2-CH B

ZiO 1 1 / ° \ 1 "and

Y CH CH

I I

r2 r1 40 .8720745 5 OX R3

Z20 | j I I

5 P-C- (CH2) 4-CH B

ΖχΟ I I I

Y CH CH

I I

R2 Rx 10 in which X, Y, Ζχ, Z2, B, Rx, R2 and R3 have the aforementioned meanings. Preferably X is hydrogen or hydroxyl and Y is hydrogen. Typical compounds can therefore have the structures listed in Table I.

8720745

Table I

Structure Structure number 6

Representative structures <Y% 22 ° \? 1? -Ch2- (ch,). -Ch2 I * ^

Zl ° 'I / ° \ ir «* j 2 c" 1 o </ ir VJs ---- 2 P-CH-tCHjJ.-CHj zl "Ov r · - · 7 V · v' 'C“ 2 C ~ 2

O

O 1? -C- (CH 1) n -CH 2! Sun / I “I.

I Ί / ° \ 3 o ch2 ch2: 8720745

Structure Structure number 7

Table I (continued) 0 Sr yl rT -— r! ! 0 yL Y 4 22 ~ i | 0 s

«« ^ O I

- f b I i

OH

C r c ^ c ^ -

N

J i, „? r / \ / -2 '\! .-w .., -v_ „2 i ZZ ^ i i» 1, "Ö l"

OH

O z = r

Jl rxz - r 'hx ^ N / ^ N:

! : 6 22-J

? -C— (CH2) a-CH2 | T Λ / I ^ «7 w} * Λ i J b

OH

87 2 07 45 8

Table I (continued)

Structure Structure number HN ^ N / CH2l: '2' CH3

0 J

ο2ο ^ ||

cs2- (iH2) n-CH2 I

z, 0 ^ J 7 w

OK

O

Z2CvJ

2 0 ^? “CH2“ iCH2) a “CH2 ï 8 Ö

OH

0

II r * TT

ΗΝ ^ Λγ '"3

ZjOvJl, "/ p-CH2- <CK2> n-CH2 9

£] O

YOU

I I

OH

. 872 0745

Structure Structure number

Table I (continued) 9 f2 „10 Z2 ° \ l

2, c ^ P-CH2- [CH2 ^ n-CH2 I

O

OH

N'H-I "ΛΤ ^ ϊ 2 ·» · ->. > 1 V- Λ .. I \ -1 11. - ""> »* · *» "v% ·. *«, N - Ν ~ Π -5 i * ^ - i%: 'ίι

CF

N'H-

i A

= \ j ί Z2 = \: l 12, \

-1 "CL

i / Mu c ** 2 '- • o, 8720745 10

Table I (continued)

Structure Structure number CO ”z2 ° 1 P-CK - (CS2! N-C“ j

21'OHO

ch2 ch2 O 3r -20 - 14 Z10 - '"· 2" v "' - 2) rrv — 2 | 0« 0 / 2r 0 Λ Jv. / Z20 H 0 Z, 0 -? "X: j" < I 15

Cri: „o v: o oh 1 • 87 2 0745

Table I (continued) 11

Structure number

Structure - Q Sr O ^ 16

ζ, ο. II

2 G ^? 'S f \ -j OH "η, Α ^ - c" J \ / ~ π C N ..

^ 2 ^ \ »N 17

rM

H

II

* '"1 I

I I

32o u 0 <^ N,: r Σ, Ο - ^^ - ίΖΚ ^ -ΟΗ. 18 / ° \

Γ HO

W.

OH

. 87 2 07 45

Table I (continued)

Structure Structure number 12

^ 2 T

I I 19 z2o ^ l |

Z10 - CH2 - (CH2) n -CH2

* O

0 HH '0 // 0 \!' ! 20 3.rf- _ / \ ~ · <i · ’* - ... 2 ** '-y

siB

Τ'2 ~ "2 • * ^ 'r * fc · V * * o w o

II

N * H

0 \ i I

Z2 ° ^ 21 - (CH2) n-cn2 Z η 0 OH | n 1 ° x ch2 xch2 hoh2c ♦ 87 2 07 45 5 13

Table I (continued)

Structure Structure number

Np /

o <T JL

z -> o U

10 * -? - C - (CH 3) n -CH 2 I.

Z-: lï | o I

O Cr. 2 ur. 2

KCK2C

15

Table II

Representative Compounds Monophosphate Analogs 20

Connection nr Structure nr Z] _ Z2 n la 1 Η H 0

lb 1 CH3 CH3 O

25 lc 1 H CH3 0 ld 1 H C2H5 0 2a 2 Η H 0 2b 2 CH3 CH3 0 30 2c 2 H CH3 0 2d 2 H C2H5 0 3a 3 H R 0 3b 3 CH3 CH3 0

35 3c 3 H CH 3 O

3d 3 H C2H5 0 2èa 22 Η H 0 22b 22 CH3 CH3 0

22c 22 H CH 3 O

40 22d 22 H C2H5 0.8720745 v Table II (continued) 14

Representative Compounds Monophosphate Analogs 5

Connection nr Structure nr Z \ Z2 n le 1 Η H 2

If 1 'CH3 CH3 2 10 lg 1 H CH3 2 lh 1 H C2H5 2 2e 2 Η H 2 2f 2 CH3 CH3 2 15 2g 2 H CH3 2 2h 2 H C2H5 2 22e 22 Η H 2 22f 22 CH3 CH3 2 22g 22 H CH3 2 20 22h 22 H C2H5 2

Table II (continued)

Representative Compounds Triphosphate Analogs

Compound nr Structure nr Ζγ Z2 n 1 1 Η H 4 30 1 1 CH3 CH3 4 1 1 H CH3 4 1 1 H CH3 4 22 22 Η H 4 22 22 CH3 CH3 4 35 22 22 H CH3 4 22 22 H C2H5 4

The above-mentioned compounds are only representative compounds and it will be apparent to those skilled in the art that other combinations of substituents and bases can be used equally well.

.8720745 15

Preparation

The compounds of the invention can be prepared by the following general methods. The substances that do not contain 6-pentofuranose such as the substances with structures JL, 2, 12, 13, 20, 21 and 22 in Table I can be prepared according to scheme I below.

0 »1 (R0) 3P + BrCH2 (CH2) nCH2Br _ (RO) 2PCH2 (CH2) nCH2Br Δ

1. NaOAc / DMF

2. HVEtOH 15

Hf o o

II II

(R0) 2PCH2 (CH2) nCH20CH2Cl ζ CH2 ° __ (RO) 2PCH2 (CH2) nCH2OH

HCl.

20 tris (trimethyΙέ ilvl) guanine 0 Gu 0 Gu 25

II I II I

(R0) 2PCH2 (CH2) nCH20CH2 BrSiMe3 or ^ (HO) 2PCH2 (CH2) nCH2OCH2 1. NaOCH2C6H5

2. PD-H

30

Schedule I 35

According to this scheme, a tri (C2, C4 or Cg) alkylphosphite reacts in an Arbuzov reaction with a dibromoalkane to form the bromoalkylphosphonate (see J. Am. Chem. Soc., B7 (2) 253 (1965)) . 40 (All references cited are hereby inserted).

78720745 * 16

Replacement of the bromide with sodium acetate in DMF followed by hydrolysis of the acetic acid ester gives diethyl 3-hydroxypropyl phosphonate (in scheme I, R C2 H5, n = 1). This material is chloromethylated to the chloromethyl ether and then with an appropriately protected base such as tris-trimethylsilylguanine, according to the method of Kelley et al., J. Med. Chem., 2k> 1528, (1981). This directly supplies the phosphonoproduct, for example 9- (3-phosphonopropoxy-methyl) guanine. Phosphonate esters are easily converted to the phosphonic acid with bromotrimethylsilane by the method of McKenna, et al. 10 Tetrah. Letts, 155, (1977).

The preparation of a representative deoxyriboside is shown in Scheme II.

Oxidation of 2'-O-isopropylidene-S-propyluridine (1) by the method Moffatt (Pfitzner and Moffatt J. Am. Chem. Soc. R5, 3027 (1963)) yields the 5'-aldehyde (2) . Reaction of (2) with the Wittig reagent (3) prepared according to Scheme II above gives the unsaturated "extended chain nucleotide" (4). Hydrogenation and cleavage of acetone from the nucleotide (4) gives the partially demasked nucleotide (5).

The conversion of the riboside (5) to the deoxyriboside (7) is performed according to a method described by Lessor and Leonard, J. Org. Chem. Jto, 4300 (1981), which is based on the selective partial deacylation of fully acylated nucleosides as described by Ishido et al, J. Chem. Soc. Perkin I, 563 (1980). Thus, benzoylation of (5) to the 2 ', 3'-di-O-benzoate followed by treatment with hydroxylaminium acetate in dry pyridine gives the 3'-benzoate (6). Thiobenzoylation of (6) followed by treatment with tributyltin and debenzoylation with sodium benzyloxide leads to conversion of the 2'-hydroxyl group to H, deacylation of the 3'-0-benzoate and substitution of the phenyl phosphate ester by the Jones and Moffatt benzyl phosphonate esters , J. Am. Chem. Soc. jiO, 5337 (1968). The benzyl group is removed by hydrogenolysis and the desired phosphonic acid is formed (7).

Alternatively, compounds in the 2-deoxyribose series can be prepared from the 2'-deoxynucleoside according to the reactions given in scheme III. According to that scheme, selective tritylation followed by mesylation of 5-propyl-2'-deoxyuridine (1) gives the derivative (8) containing sodium benzoate in DMF (Yung and Fox, J. Am. Chem. Soc. 83_, 3060 (1961). )) is converted to the 2,3'-cyclonucleoside (9). Oxidation to the aldehyde (10) followed by Wittig condensation gives the unsaturated phosphonate (11). Hydrogenation and ring-opening (Yung and Fox) gives the phosphonate ester (7) identified in the US patent. 87 2 07 45 17 3 * 524,846 and J »Am. Chem. Soc90, 5337 (1968) in the free phosphonic acid t can be converted. Hydroboration of (11) followed by ring opening gives a mixture of 5'-hydroxy and 6'-hydroxy isomers.

An oxygen function at the o-position relative to the phosphonate 5 can be introduced via the reactions of scheme IV. The necessary propynylphosphonic acid (13) can be prepared according to the method of Chattha and Aquiar, J. Org. Chem. 36, 2719-20 (1971) are prepared from tetrahydropyranyl propargylether (12). Selective hydrogenation to the vinyl phosphonate followed by the steps shown in Scheme IV results in phosphonate analogs with one or two hydroxyl groups in the phosphonate chain.

8720745 18 ° C. CHa) -1Sr. fl - * OlOJ-P'CH ^^ ar - '»(RO), r-c * h5" s: - 0 ,,

II

(ro),? (C5,) -: h *? 23 π o \ o

HNx ^ N ^ 'C3'i ·' y /> S \ S

XJ "XJ

* o! SCCHj η OCH o CRO'PCHa 'CH-CH,

O IQ O

° w ° v J ~ *? 1 I? ; ^ _ 0 ~ o | = ^ s> '

0 -, c T

(ROaP <CHa): HaCHa _0 ^ <RCV. = Ka; - CH-CHa! 0 o

1 I I

0Bi OH OH ÓH

1 5 0

; XJ

O

II

(R'0) a? Ccaa) Chacaa, O1

OH

7 n-0.2,;

R-CeHs. H

Schedule II

.8720745 19? 0 0 0 HS ^ s ^ CaH 'N' ^ Sr01 ^ jji Yy Yy _ * r cr OH 1 OKs 9

1 o 6 I. H * O

νΑ ^ = οΗ, - * W Χ, = Λ jy * 0> v

ο η h r * 1 111 .........? I

: I I f (itm '~ 9 * Γν- \ mmC - »i ^ CS» -

% λ ·· 't + - - •• s / V ». w k t I

0 o 1 I i 1.>: '1. hydr = b = reriny:. SaOS: 0 «F 0 '. SaC3i. zyj., A. «ΛΤ · 8’ * you now ^ ** ·. 9 w r; rarsP'KaiaCHïCHï a f? .C) ;? '3,) "" -: - CX 0

Ö 'Q

CH OH

^? .mCiHs ΐΐ R “C; H«

”R» r! R “H

* 8720745

Schedule III

20 1 luL 'fi HC = CrCHa) nCHa0R' Q-► (R0) a? C5C (CHa) nCHa0R '12 2. (RO) a? CI 13 [H] Lindiar kataiysaire ▼ 0 o II Η (X0) a ? CH-CH (CHa) „CHaBr« ------------- (R0) aPCH-CH rCHa) “CHa0R * R” «tecrahydropvranvl

X'-H

1. e3P R’-Ks 2. OH * hydrsborecing ♦

O ▼ O

II II

(R0) j? Ra-CHfc: -: 2; n »c-r (ai3 (RC) a? CHOia.'CHa) rc-: acMs

OH

h “2. Li3r« iing Reaction p (RC) aP <pCHarCHa>, CKa3r

OH

0 ^ 11 (XC) a? CH-CH (CKa) -HCHCCH n 3ase

I.Q

II. (RO) a? CHCHa (CH5} CH3 PiC: a OH 1 n

OH

Hydrsbcreriny 1. Wittig reaction ♦ 2. Hydrïg.T-ringf 0 o * CXO) aPCHCHa (CHa) nCH — CH Q Sase {RCIa? CHaa (CHs> B3> .arHa c Base

OH \. OH VnnJ

w w1

OH OH

R-alvl R-alkvl

R-H R-H

T87 2 07 45

Schedule IV

5 21

Carbonyl analogues can be prepared according to the reactions shown in scheme V. This scheme includes an Arbuzov reaction of triethylphosphite with g-acetoxypropionyl chloride (14) according to the method of Yamashita et al. Bull. Chem. Soc. Japan, 53 (6), 1625 (1980).

5 10 P. 00

II tl II

(E: d) 3P + ClCCaiCHaCAc - - ► (SiO) a? -CCHaCHi3Ac 14 15 1. S «0E £. 2. 03? -3r3 ♦ 0 0 0 0 II tl 1 lill (EïO) 3P-CCHaCH- «3 * 1 - 2. OH-- (EïO) s? -CCKjC: -: iBr 1? 15 5 - it ii

EWE - «I

. iO

I 4 «M * Ψ - 20 o o

Ai I I! o \ / 0 0 Cr, 0 0 tl It | 1. ^ (E £ 0) aP-CCHiCK »CK 2. '.IZlz' z>? (R0)? -CCO'.s) .IICA - 3. SrSi.Mea OH *

. 1B

- 19 R- ££. bi

R * b, n »X

30

Schedule V

This gives the o-carbonyl phosphonate ester (15). Conversion of 15 to the bromoethyl derivative 16, followed by reaction thereof with triphenyl-35 phosphine gives the Wittig reagent (17). Condensation of IJ with the appropriate aldehyde (e.g. 10) provides the unsaturated compound 18, which after hydrogenation and deblocking to the desired product 19, provides a nucleoside diphosphonate analog. The nucleoside triphosphonate analog 19 (wherein n * 3) can be prepared from 5-acetoxyvaleryl-40 chloride.

.8720745 22

The nucleoside monophosphate analog (20) can be prepared according to scheme VI.

0 0 ojj xi 0j? "CHj f OCH o * CHj-CH 0 kTj o 10 '

Hydraboration I

0 I 0 IJ II π

o 0 CT

15 CICCHJ o * 4 ·· Sl £? ^. Fri - r5g HOCHjChJ - i> \ 2 · ίιΛ- ^ rV ° \ (EtO) j?

20 * M

/ 0 Or O 0 h 0 0, II II 1 'ttc * ï / Tj'rF II il

(Et °) aP ^ raJ.o 4: ltsX "» IHOaP-CCHa ^ o B

25 KL / fO

1 rio

Schedule VI

30 Salts

Physiologically acceptable salts of compounds of the invention are prepared by known methods. Those salts include ammonium salts and salts of physiologically acceptable metals, in particular Li +, K +, Na ",", Ca "^ and Mg" * - and these salts are new compounds to which the invention also relates.

Metal salts can be prepared by reacting a metal hydroxide with a compound of the invention. Examples of metal salts which can thus be prepared are salts containing Li +, Na + and KT * -. A less soluble metal salt can be precipitated from a solution 40 of a more soluble salt by adding a suitable metal compound. Acid addition salts can be prepared by reacting a compound of the invention with an acid such as HCl, HBr, H2SO4 or an organic sulfonic acid.

5 Pharmaceutical preparations

The compounds of the invention (including their physiologically acceptable salts) have antiviral activity. They are effective against Herpes Simplex viruses and related viruses, for example Herpes Simplex virus I, Herpes Simplex virus II, Epstein-Barr-10 virus, Varicella Zoster virus and cytomegalo virus. The compounds can therefore be processed into pharmaceutical preparations. Such formulations consist of one or more of the compounds combined with a pharmaceutically acceptable carrier. In the book Remington's Pharmaceutical Sciences, 15th edition by E.W. Martin (Mark Publ. Co., 1975), which is incorporated herein by reference, describes representative carriers and methods of preparation.

The compound can be administered topically, orally, parenterally (eg intravenously by injection into the muscle tissue or by intraperitoneal injection) or the like, depending on the viral infection to be treated.

For internal infections, the compounds are administered orally or parenterally in dosages of about 0.1-300 mg / kg, preferably 1.0-30 mg / kg, of mammalian body weight; in humans, the compounds may be administered in unit doses of 1-250 mg per unit dose administered one to four times daily. For oral administration, fine powders or granules may contain diluents, dispersants and / or surfactants and may be presented in water or in a syrup, in capsules or sachets in a dry state or in a non-aqueous solution or suspension in which suspending agents 30 may be present, in tablets, which may contain binders and lubricants, or in a suspension in water or a syrup. If desired or necessary, flavors, preservatives, suspending agents, thickeners or emulsifying agents may be present. Tablets and granules are preferred oral administration forms and may be coated.

For parenteral administration or for administration in the form of drops, for example for eye infections, the compounds may be presented in aqueous solution at a concentration of about 0.1 to 10%, preferably about 0.1 to 7%. The solution can contain antioxidants, buffers, etc.

.8720745 24

Instead, for infections of the eyes or other external tissues, for example, mouth and skin, the compounds may be applied topically as an ointment, cream, aerosol or powder, preferably as an ointment or cream, preferably on the infected part of the body. fitted. The compounds can be presented in an ointment, for example, with a water-soluble ointment base, or in a cream, for example, with an oil-in-water cream base in a concentration of about 0.01 to 10%, preferably 0.1 to 7 %, most preferably about 0.5% (m / v). In addition, viral infections of the eyes, such as herpes keratitis, can be treated using a sustained release drug delivery system as described in the art.

The precise rules for the administration of the compounds and compositions disclosed herein obviously depend on the needs of the treated patient, the type of treatment and, of course, the judgment of the treating physician. The invention is further illustrated by the non-limiting examples below.

Example I

20 0 0 0 I I 1 25 (C2H50) 2P (CH2) 3Br - »(C2H50) jP (CH2) 30CCH3 0

30 (C2H50) 2P (CH2) 3OH

Diethyl 3-hydroxypropyl phosphonate

Diethyl 3-bromophosphonate (12.0 g, 46 mmol, prepared according to the method of Anatol Eberhard and FH Westheimer, JACS. 87_, 253-260 (1965)) was stirred with 12.0 g NaOAc.3H20 in 125 ml DMF. , heated on a boiling water bath. The reaction mixture was evaporated to dryness under reduced pressure for 2 hours and partitioned between water and EtOAc, extracting the aqueous layer 8720745 five times. The ethyl acetate extract was washed once with brine, dried with Na 2 SO 4, filtered and evaporated under reduced pressure to give 9.8 g of a light yellow oil (89%). * H NMR (CDCl 3) 1.3 (tr, 6H), 1.5-2.0 (m, 4H), 2.03 (s, 3H>, 4.1 (asym quintet, 6H); thin layer chromatography on SiGF developed with 2: 1 EtOAc: CH 2 Cl 2 gave an Rf of 0.30 The isolated diethyl 3-acetoxypropylphosphonate (9.8 g, 41 mmol) was dissolved in 200 ml abs.

EtOH stirred with 30 ml Dowex 50 (ff * -) which was rinsed three times with H2O and EtOH. After 4.5 days at room temperature, an additional 10 ml of the similarly prepared resin was added. Six hours later, the reaction mixture was filtered and evaporated under reduced pressure. The entire yield of yellow oil was purified by dry column chromatography on 400 g of silica in a nylon tube with a flat diameter of 70 mm. The column was eluted with 1: 9 Me0H: Et0Ac 15 and the good fractions were cut and suspended with 1: 1

MeOH: EtOAc. After filtration and evaporation under reduced pressure, 5.33 g (66%) of a pale yellow oil was obtained. NMR (CDGI3, D2O): δ 1.30 (tr, 6H), 1.60-2.08 (m, 4H), 3.67 (tr, 2H), 4.13 (quintet, 4H); thin layer chromatography on SiGF developed with 1: 9 MeOH: EtOAc gave an Rf of 0.57.

9- (3-Phosphonopropoxymethyl) guanine

9.40 mmol of silylated guanine (James L. Kelley, Mark P. Krochmal and Howard J. Sheaffer, J. Med. Chem., 24_, 1528-1531, (1981)) in 9 ml of dry toluene was added to 7.60 mmole of diethyl 3-chloromethoxypropylphosphonate prepared from diethyl 3-hydroxypropylphosphonate according to the method of Kelley et al., followed by 2.2 ml triethylamine. The reaction mixture was refluxed for 24 hours and then evaporated to dryness under reduced pressure. The residue was treated with 70 ml EtOH 30 and the bulky yellow-brown solid was isolated by suction filtration. The solid was dissolved in water, made basic with concentrated ammonia and treated with an excess of aqueous lead diacetate. The lead salt was isolated by centrifugation and dissolved in 50% acetic acid, after which it was treated with H 2 S for 20 min.

The black lead sulfide was removed by filtration under suction through Celite. The filtrate was evaporated under reduced pressure and the residue thereof was crushed in EtOH and filtered. The residue was further crushed in DMF and filtered to give 320 mg of a whitish solid. This solid was dissolved in the minimum amount of water and acidified with 1 M HCl. Then with 1 M NaOH

8720745 26 neutralized and lyophilized. The solid residue was triturated in a mixture of DMF, H 2 O and EtOH and filtered to give 276 mg of 9- (3-phosphonopropoxymethyl) guanine as a white solid (8.3%). Analysis (CgHj ^^ C ^ P ^ Na.S ^ O) C, Η, N; 5 m ^ max (£)! pH 1: 255 (14 * 70 °); PH 7: 251 (15,600); pH 11: 257 (12,800), 267 (12,800); mass spectrum (TMS derivative) m / z 591 (M * of TMS4 derivative); * Η NMR (D20): ί 1.25-1.90 (m, 4H), 3.42 (tr, 2H), 5.50 (s, 2H), 7.92 (s, 1H). Thin layer chromatography on SiGF developed with 7: 3 CH 3 CN: 0.1 N NH 4 Cl gave an Rf of 0.20.

10

Example II 15

Cl

\ J J <C2H50) 2P (CH2> 30H

H 2 20

"I

• Cl

O

// (I 51. "25 \ I + ^ ^ 2K5 °) CH2) 3OCH2CI -> I NSi (ch3) 3

Si (CH3) 3 30

Cl o <Ίίί C2S5 °> Uh2-ch2 ν · η2 35 C2HS ° I 0 * ^ \ l CH, c «2 - · 2 •. 8720745 40 5 27 6-Chloro-9- (3-diethylphosphonopropoxymethyl) guanine

To 0.5 g (2.95 mmol) of 2-amino-6-chloropurine, which had been silylated and treated with Hg (CN> 2 by the method of Robins and Hatfield (Morris J. Robins and Peter W. Hatfield, Can. J. Chem. 60, 547-553 (1982), in 40 ml of benzene, a solution of 2.68 mmol of diethyl-3-chloromethoxypropylphosphonate prepared from 0.525 g of diethyl-3-hydroxypropylphosphonate according to the method of Kelley et al. , (James L. Kelley,

Mark P. Krochmal and Howard J. Sheaffer, J. Med. Chem. j £ 4.1528-1531 (1981)). The reaction mixture was refluxed for 2 hours, cooled and 400 ml of CHCl 3 was added. The organic phase was washed successively with 80 ml of saturated aqueous NaHCO 3 and 1 M KI in water each time. The organic solution was dried over Na2SO4, filtered and evaporated to a yellow resin of 790 mg. Part of this crude material was used to carry out hydrolysis tests. The rest of the material was chromatographed on a silica column. A solution of 574 mg of the crude reaction product was placed on a column with 20 g of silica using 5: 3 EtOACrnPrOH. Elution with the same solvent mixture gave 16 fractions of 10-20 ml each. Fractions 7-12 were combined and 1-20 required 258 mg of colorless oil which crystallized spontaneously. Trituration in CH 2 Cl 2 * Et 2 O provided two aliquots of white solid (207 mg), mp 109-110 ° C (28%). A yield of 46% was obtained from a reaction carried out on 45.2 mmol of the starting purine. Analysis (C13H2iClN504P) C, N, N; UV λ ^ (£): pH 1: 246 (£ 6600), 310 (7200); pH 7: 247 (6800), 308 (7400); pH 11: 247 (6600), 308 (7100); mass spectrum: m / z 377 (M +); NMR (CDCl3): <5 1.3 (tr, 6H), 1.52-2.18 (m, 4H), 3.58 (tr, 2H), 4.09 (qu, 4H), 548 (s , with broad base, 4H), 7.89 (s, 1H). Thin layer chromatography with 5: 3 EtOAc: nPr0H gave an Rj of 0.40.

30- 9- (3-Ethyphosphonopropoxymy 1) guanine 6-Chloro-9- (3-diethylphosphonopropoxymethyl) guanine (75 mg; 0.2 mmol) was combined with 5 ml 1 N aqueous NaOH and 1 hour refluxed. After cooling, the reaction mixture was neutralized with Dowex 50X8 (pyridinium form) and filtered with rinsing with plenty of water. The solution was partially evaporated to remove pyridine and then lyophilized. The orange residue (74 mg) was redissolved in water and centrifuged to remove insoluble material. The decanted solution-40 (2 ml) was chromatographed on a 0.9 x 46 cm column • 8720745, 28

Whatman DE-52 cellulose, -HCO3 form, with a linear 1 liter gradient of both H2O and 0.2 M NH4HCO3 after initial elution with Η20. Fractions 43-47 (7 ml each) yielded 25 mg (36%) of a fluffy white solid after freeze-drying three times. The electron impact 5 mass spectrum (TMS derivative) showed m / 1 547 (M * of TMS derivative); the mass spectrum of chemical ionization (TMS derivative) showed m / 1 548 (M + + H of TMS3 derivative); * Η NMR (D20): i 1.19 (tr, 3H), 1.4-1.9 (m, 4H), 3.59 (tr, 2H), 3.90 (quintet, 2H), 5, 47 (s, 2H), 8.2 (br.s, 1H). Thin layer chromatography on SiGF: Rf 0.40 when developed with 7ï CH 3 CN-0.1N NH 4 Cl in water. The substance had a formula CClH18N505P.H 2 O) Calculated: 0: 37.82%, H: 5.77%, N: 20.0%.

Found: 0: 38.27%, H: 5.84%, N: 19.65%. UV spectrum: λ (£): max pH 1: 256 (10,400), 278 (shoulder); pH 7: 252 (11,300), 271 (shoulder); pH 11: 256-258 (9600), 267 (shoulder). The product was again lyophilized.

Example III

Cl N ^ 0 // r N 11 20 \ I I (c2h5o) 2? (Ch2) 7o: -: \ T N ^ «u

H

* y 25 C1 0 / l! * vil + (c2h5o) 2p (ch2) 7och, c: -> * ^ N ^ NSi (CH3) 3

Si (CH3) 2 30

Cl

/ vS

.P (CH2) eCH, ί Λ 'id2

C 2 H 5 ° 10 O J

ch2 ch2 40 • 8720745 29 6-Chloro-9- (7-diethylphosphonoheptyloxymethyl) guanine »

Diethyl 7- (chloromethoxy) heptylphosphonate was prepared from 1,7-dibromo-heptane and triethylphosphite by the method of preparing diethyl-3-chloronethoxypropylphosphonate (Example I). The product was reacted with silylated 2-amino-6-chloropurine. and mercury (II) cyanine as described for the preparation of 6-chloro-9- (3-diethylphosphonopropoxymethyl) guanine (Example II) to yield 32% of a product in the form of a colorless resin. UV λ: pH 1: 246 nm max (6,220), 310 nm (6,380); pH 7: 247 nm (£ 5910), 310 nm (£ 6410); pH 10 11: 246 nm (£ 5950), 309 nm (£ 6380); mass spectrum; * H NMR (GDCI3) é 1.1-1.9 (m, 18H), 3.48 (t, 2H), 4.10 (q, 4H), 5.47 (s, 2H), 5.88 (s, 2H), 7.93 (s, 1H). Thin layer chromatography on silica gel GF gave an Rf of 0.15 with ethyl acetate: ethanol (100: 1).

15

Cl OCa - 20 = 2H5av4, C 2 S ° 10 I o i

L '' L

Ch2 Cr. 2 25 C2K5 <V, 30 10 αΰ> ^ η * 2 o ch {nch2 35 9- (7-Ethylphosphonoheptyloxymethyl) guanine 6-Chloro-9- (7-diethylphosphonoheptyloxymethyl) guanine was hydrolyzed by boiling with 1 N sodium hydroxide in water for 4 hours to a 30% yield as described for the preparation of 9- (3-40 ethylphosphonopropoxymethyl) guanine (Example II). The product had a .8720745

Rf of 0.5 on silica gel GF with acetonitrile / 0.1 N aqueous ammonium chloride (7: 3). XH NMR (D 2 O) 1 1.1-1.5 (m, 15H), 3.5 (t, 2H), 3.90 (q, 2H), 5.45 (s, 2H); UV.

5 Organic tests

The compounds of Examples I and II were tested in vitro as antivirals against herpes virus.

The strain of virus used was Strain McCrae of type 1 herpes (thymidin kinase positive virus), prepared and seeded in MA-104 cells and frozen at -90 ° C until use.

Continuously treated monkey kidney cells (MA-104) were used with a growth medium consisting of Minimum Essential Medium (MEM) to which was added 0.1% NaHCO 2 and 9% fetal calf serum. The test medium consisted of MEM to which was added 2% fetal bovine serum, 0.18% NaHCO 3 and 50 µl gentamicin.

The latter compounds were added for testing the medium at a concentration of 2000 µg / ml and served as a positive control.

20 Antiviral Test Method

0.1 ml with varying concentrations (half log ^ g) of test compound was added to a 96-well microtiter plate with a 24-hour mono-layer cells whose medium had been decanted and incubated on the cells for 15 min, after which 0.1 ml virus in a concentration of 320 cell culture 50% infectious doses (CCID50) / 0.1 ml was added. The plate was covered with a plastic cover and incubated at 37 ° C. Testing included toxicity controls (any concentration of compound + test medium in place of virus), virus control (virus + test medium in place of compound) and cell controls (test-30 medium in place of compound and virus). The cells were examined microscopically after 72 hours for evidence of cytotoxicity and for viral cytopathic effects (CPE) · Vidarabine was finished in parallel at the same site.

The antiviral activity was determined by observation of the inhibition of viral CPE. This activity was expressed in the minimum inhibitory concentration (MIC), defined as the dose compound that causes 50% inhibition of CPE. Also a virus classification (VR) was determined, a numerical expression of the antiviral activity corrected for any observed cytotoxicity. A VR of 0.1-0.4 usually indicates a low antiviral effect, 0.5-0.9 a moderate .8720745 31 antiviral effect and 1.0 or more a strong anti-viral effect.

The results of these tests are summarized in Tables A and B. The test compound had a strong activity against the thymidine kinase positive type I herpes virus. The activity was considered equivalent to that of vidarabine.

TABLE A

Effect of compound of example I and vidarabine on herpes virus infections of thymidine kinase positive type 1 in MA-104 cells.

Connection of verb. I Vidarabine___ 15 CPEa CPEa

Conc. Remra. Conc. Remm.

(yg / ml) (%) (y / ml) (%) 1000 100 1000 100 20 320 94 320 100 100 79 100 87 32 62 32 87 10 49 10 69 3.2 28 3.2 28 25 1.0 31 1.0 56 0 0 VRb 1.4 1.3 MICC 10 10 30 a Cytopathogenic effect,% change or breakdown of cells.

b Virus classification, numerical expression of antiviral activity (Sidwell et al., Appl. Microbiol., 22: 797, (1971), 35 0.1-0.4 = low activity, 0.5-0.9 = moderate activity, £ 1.0 = high activity.

c Minimum inhibition concentration: dose at which 50% inhibition of CPE is observed, yg / ml. 8720745 32 *

TABLE B

Effect of compound of example II and vidarabine 5 on thymidine kinase positive type 1 herpesvirus in MA-104 cells (two experiments)

Connection of connection. II Vidarabine (Control) 10 Trial 1 Trial 2 Trial 1 Trial 2 CPEa CPEa CPEa CPEa

Conc. Remm. Remm. Conc. Remm. Remm.

(Vg / ml) (%) (%) (Vg / ml) (%) (%) 15 1000 100 76 1000 100 100 320 82 67 320 100 100 100 47 57 100 96 85 32 6 57 32 96 57 10 38 48 10 60 39 20 3.2 96 52 3.2 2 0 1.2 69 48 1.0 0 0 0 0 VRb> 2.0> 1.4 VRb 0.8 07 MICc <1.0 <1.0 MICc 10 10 25 MTDd 320> 1000 10 10 a Cytopathogenic effect,% change or breakdown of cells.

30 b Virus classification, numerical expression of antiviral activity (Sidwell et al., Appl. Microbiol., 22: 797, (1971), 0.1-0.4 = low activity, 0.5-0.9 = moderate activity, > 1.0 high activity.

35 c Minimum inhibition concentration: dose at which 50% inhibition of CPE is observed, yg / ml d Maximum tolerated dose, yg / ml

. 87 2 07 4 U

33 ft

The compound of Example II was further investigated in the above described in vitro test method against cytomegalovirus. The connection was very active with a VR of 2.1-2.3.

The compound of Example II was tested in vivo in guinea pigs as an agent against thymidine kinase positive herpes virus. The animals were infected with the virus. Eighteen hours later, the substance of Example II (0.4% aqueous solution or 1-2% solution), a 5% acyclovir solution or a 1.4% polyvinyl alcohol solution was administered and five days later the diameters of blisters measured at point 10 of the infestation. Accompanying damages were also measured.

The results of these tests are shown in Table C and demonstrate that the compound has superior activity against TicC virus.

15

TABLE C

Effect of the compound of Example II in vivo against herpes virus 20

Placebo, 1.4% Acyclovir, Verb. II Verb. II

Virus polyvinyl alcohol 5% l-2% * 0.4% 25 TK * 1.7 ** 1.0 0.9 2.1 'accompanying damage 9 4 6 11 30 * saturated solution ** average number of damage 35 Preparations

The following preparations based on the compounds of the invention and their preparation are representative.

A formulation suitable for intramuscular or intraperitoneal injection is prepared by combining the first four of the following 40 substances • 8720745 3.

34 compound according to the invention 1 g polyethylene glycol 50 g propylene glycol 50 g 5 Tween 80 suspending agent 1.5 g injectable saline 200 ml and adding the latter component thereto. The whole forms a clear solution which is filtered and sealed in sterile containers.

A simple preparation for intravenous injection is obtained by dissolving 1 g of an active compound of the invention in 250 ml of injectable saline which is packed in sterile bottles after filtration.

A topical application cream is formulated by stirring 10 g of the active compound of the invention with 20 g of mineral oil, 40 g of gelatin, 0.3 g of mixed methyl / propyl paraben and 5 g of nonionic surfactant at 50 ° C. Then, 150 ml of water is stirred at 50 ° C at high speed in the mixture to form a cream and the mixture is cooled and packed in cap tubes.

An oral dosage form is prepared from 10 g of the compound of the invention, 100 g of lactose and 1 g of starch, the ingredients of which are mixed with 0.1 g of magnesium stearate and granulated with methanol. The methanol is removed by gentle heating with stirring. A portion of this material is used as a granular powder for oral use and the remainder is hand-processed into 250 mg tablets in a hand-held tablet.

The above examples and preparations are described to illustrate the invention and are not to be construed to limit the scope of the invention; the scope is determined by the following claims.

• 8720745

Claims (15)

1. Compound of formula 0 B-CH2-O-CH (CH2) nCHP (OH) 2 (U R1 R2 10) in which B is a purine base connected via the 9 position to the rest of the structure, R1 is selected from H, methyl, hydroxymethyl and the lower alkyl esters thereof, halomethyl, azidomethyl and cyano; R2 is selected from H, methyl, hydroxymethyl and the lower alkyl esters thereof, halomethyl, azidomethyl, cyano and OH and the lower alkyl testers thereof; or R2 and the H bonded to the same carbon atom together are = 0; and n is an integer from 0-5, 20 and the pharmaceutically acceptable acid addition salts, mono- and di-basic salts and mono- and diesters thereof, or wherein when n is 0 or 1 and R 1 is CH 2 OH, the compound of formula 1 satisfies the formula B-CH2-OCH- (CH2) nCHR2-P-0H (1a) -CH2-O2 wherein B and R2 have the meanings defined above, and the pharmaceutically acceptable acid addition salts, monobasic salts and monoesters thereof. * »87-20745 £ (.) 39 1. Compound of formula 0 S B-CH2-O-CH (CH2) nCHP (OH> 2>> R1 R2) in which B is a substituted or unsubstituted purine base linked via the 9-position to the rest of the structure is, 2. A compound according to claim 1, characterized in that B is selected from guanine, 8-halo-guanine, adenine, 8-haloadenine, 2-hydroxy-6-halo-purine and 2-amino-6-halo-purine (6 haloguanine), 2-aminopurine and 2,6-diaminopurine. A compound according to claim 1, characterized in that the phosphonic acid ester or diester is the C 1 -C 6 alkyl ester or diester. A compound according to claim 3, characterized in that it is selected from the free phosphonic acid, the phosphonic acid monoethyl ester and the phosphonic acid diethyl ester. B-CH2-OCH- (CH2) nCHR2-P-0H (1a) CH2-O 2 and the pharmaceutically acceptable acid addition salts, monobasic salts and monoesters thereof. A compound according to claim 1, characterized in that R 1 is selected from H, CH 3 and 0Η20Η, and R 2 is H or OH. A compound according to claim 1, characterized in that n equals .8720745 * (Ο ύ equals 1 or 2). A compound according to claim 1, satisfying the formula 0 A compound according to claim 6, characterized in that B is guanine or 6-halo guanine. A compound according to claim 1, characterized in that B is guanine, R1 and R2 are H and η is 1, in the form of the phosphonic acid or the monoethyl ester, diethyl ester or the monoethyl ester / monosodium salt thereof. 9. A compound according to claim 1, characterized in that B is guanine, R1 and R2 are H and η is 1, in the form of the phosphonic acid or the monoethyl ester, diethyl ester or the monoethyl ester / monosodium salt thereof. A compound according to claim 1, characterized in that B is guanine, R1 and R2 are H and n is 5, in the form of the phosphonic acid or the monoethyl ester, diethyl ester or the monoethyl ester / monosodium salt thereof. 10 [Conclusion 11 deleted] .8720745 (·) Η0 [Conclusion 11 deleted (continued)] A compound according to claim 1, characterized in that B is guanine, R1 and R2 are H and n is 5, in the form of the phosphonic acid or the monoethyl ester, diethyl ester or the monoethyl ester / monosodium salt thereof. R 1 is selected from H, methyl, hydroxymethyl and the lower alkyl esters thereof, halomethyl, azidomethyl and cyano; R2 is selected from H, methyl, hydroxymethyl and the lower alkyl esters thereof, halomethyl, azidomethyl, cyano and OH and the lower alkyl esters thereof; or R2 and the H15 bonded to the same carbon atom together are = 0; and n is an integer from 0-5, and the pharmaceutically acceptable acid addition salts, mono- and di-basic salts and mono- and diesters thereof, or wherein, when n is 0 or 1 and R 1 is CH 0 0H , the compound of formula 1 satisfies the formula 0 B-CH 2 -OCH- (CH 2) n CHR 2 -P-0H (1a) -'ch 2 -O / 25 wherein B and R 2 have the meanings defined above, and the pharmaceutically acceptable acid addition salts, monobasic salts and monoesters thereof. A compound according to claim 4, characterized in that it is selected from the following group: 6-chloro-9- (3'-diethylphosphonopropyloxymethyl) guanine; 9- (3'-diethylphosphonopropyloxymethyl) guanine; 9- (3'-ethylphosphonopropyloxymethyl) guani; 9- (3'-Phosphonopropyloxymethyl] guanine; 9- (31-ethylphosphonopropyloxymethyl) guani-monosodium salt; 6-chloro-9- (7'-diethylphonoheptyloxymethyl! 9- (31-ethylphosphono-1'-hydroxymethylpropyloxymethyl!) Guani; 30 6-chloro-9- (3'-diethylphosphono-1'-acetoxymethyl 1 propyloxymethyl) guanine; 9- (3'-phosphono-11 -hydroxy methyl propyloxymethyl) guani; 9- (31-ethylphosphono-1'-methyl propyloxymethyl) guani; 9- (3'-phosphono-1'-hydroxymethylpropyloxymethyl) guanine, cyclic ester; 9- (3'-ethylphosphono- 3'-Hydroxypropyloxymethyl) guanin; 35 6-Chloro-9- (3'-diethylphosphono-3'-hydroxypropy 1oxymethyl) guanine; 8-Bromo-9- (3'-ethylphosphonopropyloxymethyl) guanine; and 2-ami no- 9- (3'-ethylphosphonopropyloxymethyl) adenine. Pharmaceutical composition for the treatment of herpes virus infection, characterized in that it contains an effective amount of the compound according to claim 1 mixed with a suitable pharmaceutically acceptable carrier. Pharmaceutical preparation for the treatment of herpes virus infection, characterized in that it contains an effective amount of the compound according to claim 1 mixed with a suitable pharmaceutically acceptable .8720745 (*) η · acceptable carrier. A method for the treatment of herpes infection in an infected body, characterized in that an effective amount of the compound of the formula 1 or pharmaceutical preparations thereof is administered to the body. 13. Method for the treatment of herpes infection in an infected body, characterized in that an effective amount of the compound of the formula 1 or pharmaceutical preparations thereof is administered to the body. Pharmaceutical composition for the treatment of an RNA retroviral infection, characterized in that it contains an effective amount of the compound according to claim 1 mixed with a suitable pharmaceutically acceptable carrier. Pharmaceutical composition for the treatment of an RNA retroviral infection, characterized in that it contains an effective amount of the compound according to claim 1 mixed with a suitable pharmaceutically acceptable carrier. Method for the treatment of an RNA retrovirus infection in an infected body, characterized in that an effective amount of the compound of the formula 1 or pharmaceutical preparations thereof is administered to the body. +++++++ .8720745 * ιΟ Μ Amended conclusions [received by the International Bureau on 11 July 1988, original claim 11 has been deleted, claim 1 has been amended, new claims 16-53 have been added] 15. Method for the treatment of an RNA retrovirus infection in an infected body, characterized in that an effective amount of the compound of the formula 1 or pharmaceutical preparations thereof is administered to the body. 872 0745 /, Ml 16. (New claim) A compound according to claim 4, characterized in that it is selected from the following group: 2-amino-6-chloro-9- {3'-diethylphonopropyloxymethyl) purine; 9- (3'-diethylphosphonopropyloxymethyl) guanine; 9- (3 "-ethylphosphonopropyloxymethyl) guanine; 9- (3'-ethylphosphonopropyloxymethyl) guanin-mononatrium sodium; 2-amino-6-chloro-9- (7'-diethylphosphonoheptyloxymethyl) purine; 9- (3'-ethylphosphonoheptyloxymethyl 1) guanine; 9- (3'-ethylphosphono-1 '-hydroxy methyl propyl oxymethyl) guanine; 2-amino-6-chloro-9- {3'-diethylphosphono-1'-acetoxymethylpropyloxymethyl) purine; 9- (3'-phosphono-1'-hydroxymethyl propyloxymethyl) guanine; 9- (3'-ethylphosphono-11-methylpropyl oxymethyl) guanine; 9- (31-ethylphosphono-3'-hydroxypropyloxymethyl) guanine; 2-amino-6-chloro-9- (3 * -diethylphosphono-31-hydroxypropyloxymethyl) purine; 8-bromo-9- (31-ethylphosphonopropyloxymethyl) guanene; and 2-amino-9- (3'-ethylphosphonopropyloxymethylladenine. 17. (New claim) A compound according to claim 1 of formula (1), wherein R 1 is H and either R 2 is H or R 2 together with the same carbon atom bound H-O, and the pharmaceutically acceptable acid addition salts, monobasic salts and monoesters thereof 18. (New claim) Phosphonic acid monoester of the compound of claim 1, wherein the ester is C 1 -C 6 alkyl, phenyl or benzyl. optionally substituted with one or more halogen atoms, hydroxy groups or alkoxy groups 19. A new claim Phosphonic acid monoester of the compound according to claim 7, wherein the ester is C 1 -C 6 alkyl, phenyl or benzyl, optionally with one or more halogen atoms, hydroxy groups or alkoxy groups is substituted 20. (New Claim) Phosphonic acid monoester of the compound according to claim 17, wherein the ester is C 1 -C 8 alkyl, phenyl or benzyl, optionally with one or more halogen atoms, hydroxy groups or alkoxy groups substituted. 21. (New Claim) Phosphonic acid monoester of the compound of claim 18, wherein the ester is Cx-C8 alkyl optionally substituted with one or two halogen, hydroxy or alkoxy groups. (New Claim) Phosphonic acid monoester of a compound 40 according to Claim 19, wherein the ester is C 1 -C 6 alkyl, optionally substituted with one or two halogen, hydroxy or alkoxy groups with "8720745 * (*). 23. (New claim) Phosphonic acid monoester of a compound according to claim 20, wherein the ester is C 1 -C 6 alkyl, optionally substituted with one or two halogen, hydroxy or alkoxy groups. 24. (New claim) Phosphonic acid according to claim 7. 25. (New claim) Compound according to claim 1, characterized in that it is selected from the group 9- (3'-phosphonopropyloxymethyl) guanine, 9- (3 -ethylphosphonopropyloxymethyl) guanine monosodium salt, 9- (3'-ethylphosphonopropy 1 oxymethyl 1) guanin ammonium salt, 9- (3'-ethylphosphono-1'-hydroxymethylpropyloxymethyl) guanine and 9- (1 ', 3'- phospho-no-1'-hydroxymethylpropyloxymethyl] guanine, cyclic ester. 26. (New claim) Compound according to claim 1, characterized in that it is 9- (3'-phosphonopropyloxymethyl) guanine. (New claim) A compound according to claim 1, characterized in. that it is 9- (3'-ethylphosphonopropyloxymethyliguanine-mononatrium salt). 28. (New claim) Compound according to claim 1, characterized in that it is 9- (3'-ethylphosphono-1'-hydroxymethylpropyloxymethyl) -guanine. 29. (New claim) Compound according to claim 1, characterized in that it is 9- (1 ', 3'-phosphono-1'-hydroxymethylpropyloxymethyl) guanine, cyclic ester 30. (New claim) Compound according to claim 1, characterized in that it is 9- (3'-methylphosphonopropyloxymethyl) guanine 31. (New claim) Compound according to claim 1, characterized in that it is 9- (3'-butylphosphonopropyloxymethyl) guanine. 32. (New claim) Compound according to claim 1, characterized in that it is 9- (3'-benzylphosphonopropyloxymethyl) guanine 33. (New claim) Compound according to claim 1, characterized in that it is 9- (3 Phenylphosphonopropyloxymethyl) guanine 34. (New claim) Compound according to claim 1, characterized in that it contains 9- [3 '- (p-met hoxyphenylphosphono) propyloxymethyl] guanine 35. (New claim) A compound according to claim 1, characterized in that it is 9- (3'-ethylphosphono-3'-hydroxypropyloxymethyl) guanine. 36. (New claim) Compound according to claim 1, characterized in that it conforms to the structure -872074 $ 33 9> 33 EtOPCCH 2 CH * 0 1 1 'v'. HO CKi CHl 10 where n equals 0, 2, 3, 4 or 5. 37. (New claim) Compound according to claim 36, characterized in that it is 9- (2'-ethylphosphonoethyloxymethyl] guanine. 38. (New claim) Compound according to claim 36, characterized in that it is 9 "(4, - 39. (New claim) Compound according to claim 36, characterized in that it is 9- (5'-ethylphosphonopentyloxymethylJguanine. 40. (New claim) Compound according to claim 36, characterized in that it is 9- (6 41- (New claim) Compound according to claim 36, characterized in that it is 9- (7'-ethylphosphonoheptyloxymethyl-guuan). 42. (New claim) Pharmaceutical preparation for the treatment of herpes virus infection, characterized in that it contains an effective amount of the compound according to claim 7. 43. (New claim) Method for the treatment of herpes infection in an infected body, characterized in that an active agent is administered to the body administering amount of the compound according to claim 7 or pharmaceutical preparations thereof. 44. (New claim) Pharmaceutical composition for the treatment of an RNA retrovirus, characterized in that it contains an effective amount of the compound according to claim 7. 45. (New claim) Method for the treatment of an RNA retrovirus infection in an infected body, characterized in that an effective amount of the compound according to claim 7 or pharmaceutical preparations thereof is administered to the body. 46. (New claim) Pharmaceutical composition according to claim 44, characterized in that the RNA retrovirus is HIV. (New claim) Method according to claim 45, characterized in that the RNA retrovirus is HIV. 40 48. (New claim) Pharmaceutical preparation for the treatment of herpes virus infection, 8720745 *, characterized in that it contains an effective amount of a compound according to claim 17. 49. (New claim) Method for the treatment of herpes infection in an infected body, characterized in that an effective amount of the compound according to claim 17 or pharmaceutical preparations thereof is administered to said body 50. (New claim) Pharmaceutical preparation for the treatment of an RNA retrovirus infection, characterized in that it contains an effective amount of the compound according to claim 17. 51. (New claim) Method for the treatment of an RNA retroviral infection in an infected body, characterized in that an active agent is administered to that body amount of the compound according to claim 17 or pharmaceutical preparations thereof 52. (New claim) Pharmaceutical preparation according to con clusion 50, characterized in that the RNA retrovirus is HIV. 53. (New claim) Method according to claim 51, characterized in that. that the RNA retrovirus is HIV. +++++++. 8720745