WO1996030342A1 - Pyridone compounds as inhibitors of retroviruses - Google Patents

Abstract

Pyridone compounds of formula (I) wherein R?1, R2, R3, R3', R3', R4, R4' and R4'¿ are as defined are disclosed as are processes for their preparation. These and related pyridone compounds disclosed herein find use as inhibitors of retroviruses.

Description

Pyridone compounds as inhibitors of retroviruses

The present invention relates to pyridone compounds, processes for their preparation, their use in the inhibition of retroviruses and pharmaceuticals containing them.

It is generally accepted that the cause of the acquired immunodeficiency syndrome (AIDS) is the human immunodeficiency virus (HIV), a retrovirus. One of the first generation anti-AIDS drugs approved for use was the nucleoside analog azidothymidine (AZT) which produces its desired effect by inhibiting reverse transcriptase (RT), an enzyme which catalyzes the conversion of the viral genomic DNA into a double-stranded DNA copy and which is therefore necessary for HIV replication. A problem with AZT, however, is that it has toxic side effects with long-term use which in many cases has necessitated the withdrawal of therapy. A further problem is the rapid development of drug resistant strains of the virus. Alternative nucleoside-based inhibitors of RT developed since AZT which have been used as anti-AIDS agents include 2', 3'- dideoxyinosine (ddl) and 2' , 3'-dideoxycytidine (ddC) . However, these agents also produce serious side effects and furthermore resistant strains of the virus have appeared against them.

The discovery of the first nonnucleoside RT inhibitors, the tetrahydro- imidazo[4, 5, 1 -jk][ 1 ,4]-benzodiazepin-2(1 H)-one and -thione (TIBO) derivatives, stimulated research in a new field. As a consequence, a number of chemically very diverse classes of heterocyclics have been developed which are reported to selectively inhibit the human immunodeficiency virus type 1 ( HIV-1 ) RT. Examples of some of these classes of RT inhibitors are: dipyridodiazepinones, 1 -[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymines (HEPTs), bis (heteroaryl)piperazines (BHAPs) and [2' ,5'-bis-0-(tert-butyldimethylsilyl)-3'-spiro- 5"-(4"-amino- 1 ",2"-oxathiole-2",2"-dioxide)]-pyrimidines (TSAOs), and α- anilinophenylacetamides ( α-APAs) .

Certain pyridone compounds as inhibitors of HIV-RT are disclosed in EP 462 800 and J. Med. Chem. 1 992, 35, 3784-3791 .

An alternative approach to combat the HIV has been directed at the HIV protease enzyme. This enzyme, a member of the aspartic protease family of enzymes, processes HIV polyproteins to produce structural and functional proteins and is essential for viral life-cycle and replication. Current inhibitors of HIV-protease fall into two structural classes: "Peptide-based" and "Non-peptide- based" (see S. S. Abdel-Meguid, Med. Res. Rev. 1 3 (1 993) 731 ) . The peptide- based inhibitors generally have low oral bioavailability and rapid biliary excretion, however, which has limited their utility as potential therapeutic agents. Non-peptide-based inhibitors, such as cyclic urea derivatives as described, for example, in P.Y.S. Lam et al., Science 263 ( 1 994) 380 and 4-hydroxy pyrone derivatives as described, for example, in S. Thaisrivongs et al., J. Med. Chem. 37 (1 994) 3200, are more orally bioavailable but resistance can develop against these compounds as well.

To date there is no agent which is both safe and fully effective against the HIV. This, together with the problem that the HIV has developed rapid resistance to existing anti-HIV agents, means that alternative, improved agents are still needed.

It has now surprisingly been found that certain pyridone compounds are effective in inhibiting HIV replication. The present invention accordingly is a compound of the formula (I) :

wherein

> 1 is -H, or -R⁵;

R² is (a) -H,

(b) -(C_rC₂₀)alkyl,

(c) -(C₂-C₂₀)alkenyl,

(d) -(C₂-C₂₀)alkynyl,

(e) -(C₇-C₂₀)arylalkyl,

(f) -(C₆-C₂₀)aryl,

(g) -(C₃-C₈)cycloalkyl, or wherein the groups (b) to (g) are optionally substituted by one or more identical or different R⁷ groups, and wherein one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from, for example: O, S and N;

R³ , R^3", R⁴, R⁴ and R^4", independently of one another, are

(a) -(C_rC₂₀)alkyl,

(b) -(C₂-C₂₀)alkenyl,

(c) -(C₂-C₂₀)alkynyl,

(d) -(C₇-C₂₀)arylalkyl,

(e) -(C₆-C₂₀)aryl,

(f) -(C₃-C₈)cycloalkyl, or

(g) -R⁶ wherein the groups (a) to (f) are optionally substituted by one, two or three identical or different R⁶ and/or R⁷ groups, and wherein one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from, for example: O, S and N, and wherein in addition to the above

R³ and R⁴, independently of one another, may be H;

R⁵ is (a) -(C_rC₂₀)alkyl,

(b) -(C₂-C₂₀)alkenyl,

(c) -(C₂-C₂₀)alkynyl,

(d) -(C₇-C₂₀)arylalkyl,

(e) -(C₆-C₂₀)aryl,

(f) -(C₃-C₈)cycloalkyl,

(g) -R⁶-[(C_rC₆)-alkyl]-,or (h) -R⁶; wherein the groups (a) to (g) are optionally substituted by one or more identical or different R⁷ groups, and wherein one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from, for example: O, S and N;

R⁶ is an isocyclic and/or heterocyclic saturated, unsaturated or partly saturated 3-35 membered ring system which has 3-9 membered rings, wherein two or more rings as components of such a system are fused, spirolinked and/or connected together by a side chain selected from: (C_r C₂₀)alkyl, (C₂-C₂₀)alkenyl and (C₂-C₂₀)alkynyl, which side chain may have one or more C atoms replaced with heteroatoms selected from, for example: O, S and N, and wherein the ring system is substituted by one or more identical or different R⁷ groups;

is -R⁸, -OR⁸, -NR⁹R^{1 0}, oxo,

-C(O)OR⁸,

-C(O)NR⁹R^{1 0},

-CN,

-Halo,

-NO₂,

-CH₂NR⁹R^{1 0},

(C₂-C₆)-alkoxyalkyl,

-S(O)_mR⁸,

-(C_rC₆)-alkyl-S(O)_mR⁸,

-NHC( = NH)NHR⁸,

-C( = NH) NHR⁸,

-NR⁹C( = O)R⁸,

= NOR⁸,

-NR⁹C( = O)OR^{1 0},

-OC( = O)NR⁹R¹⁰, or

-NR⁹C( = O)NR⁹R^{1 0}, where m is the number 0, 1 or 2, preferably the number 1 or 2;

R⁸ is (a) -H,

(b) -{C_rC_{1 8})-alkyl,

(c) -(C₂-C_{1 8})-alkenyl,

(d) -(C₂-C_{1 8})-alkynyl,

(e) -(C₆-C_{1 2})-aryl, or

(f) -(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl, wherein the groups (b) to (f) are optionally substituted by one or more of the radicals selected from: -OH, (C_rC₄)-alkoxy and Halo;

R⁹ and R^{1 0}, independently of one another, are (a) -H,

(b) -(C_rC_{1 8})-alkyl,

(c) -(C₂-C_{1 8})-alkenyl,

(d) -(C₂-C_{1 8})-alkynyl,

(e) -(C₆-C_{1 2})-aryl, or

(f) -(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl, wherein the groups (b) to (f) are optionally substituted by one or more of the radicals selected from: . -Oh!, (C-, -C₄)-alkoxy and Halo, or R⁹ and R^{1 0} together with N form a 4-7 membered ring;

or an equivalent physiologically acceptable salt thereof .

Conveniently, a prodrug group is present at the 1 and/or 4 position of the pyridone ring of the compound of the formula (I) which is converted to OR¹ and/ or OR², respectively, under physiological conditions. Such prodrug groups are well known to the skilled man and are described, for example, in H. Bundgaard, Design of Prodrugs, Elsevier Science Publishers B.V., Amsterdam 1 985.

The compounds of the formula (I) are preferred in which the radicals R¹ , R², R⁵, R⁶, R⁷ and R⁸ have the following meanings:

R¹ is H.

R² is H.

R⁵ is (C_rC₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -R⁶, or -R⁶-[(C_rC₃)-alkyl]-. More preferably R⁵ is methyl or benzyl.

R⁶ is (C₆-C_{1 2})-aryl, (C₃-C-_{| 2})-cycloalkyl or a heterocyclic ring system of 3 to 1 0 members which are either unsubstituted or substituted by 1 to 3 identical or different -R⁷ groups. More preferably R⁶ is -(C₆-C_{1 2})aryl, which is unsubstituted or monosubstituted with -R⁷.

R⁷ is -R⁸, -OR⁸, -NR⁹R^{1 0}, -CN, Halo, or -CH²NR⁹R^{1 0}. More preferably R⁷ is -R⁸, -OR⁸ or Halo. Most preferably R⁷ is -R⁸.

R⁸ is

-H,

-{C-_j -C₆)alkyl, which is unsubstituted or substituted by 1 to 3 identical or different groups selected from: -OH. (C_rC₄)alkoxy and Halo,

-(C₆-C_{1 2})aryl, or

-(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl.

More preferably R⁸ is

-H, or

-(C-, -C₆)-alkyl, which is unsubstituted or substituted by 1 to 3 -OH groups.

Most preferably, R⁸ is

-H, or

-(C-_| -C₃)-alkyl, which is unsubstituted or monosubstituted by -OH.

As used herein, the following terms are used as defined below unless otherwise indicated.

Alkyl represents straight and branched carbon chains containing no unsaturation and the specified number of carbon atoms. The same applies to radicals derived therefrom, such as alkoxy and arylalkyl. Examples of alkyl include: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, iso-propyl, iso- butyl, decyl, dodecyl, tert-butyl and iso-pentyl. Examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, iso- propoxy, iso-butoxy, decoxy, dodecoxy, tert-butoxy and iso-pentoxy. A cycloalkyl represents as alkyl where the carbon atoms are arranged in a closed ring structure. Examples of cycloalkyl include: cyclo-propyl, cyclo-butyl, cyclo- pentyl, cyclo-hexyl and cyclo-heptyl.

Isocyclic ring systems have ring members of C-atoms and heterocyclic ring systems differ from the isocyclic ring systems in that they have one or more C atom ring members replaced with an O, N and/or S atom. Both types of ring systems can optionally contain one or more double bonds. They are substituted by one or more identical or different R⁷ groups and where more than one -R⁷ group is present these can be in either the cis- or the trans¬ position relative to one another.

Examples of isocyclic ring systems include: phenyl, naphthyl, pyrenyl, anthracenyl, phenanthryl, biphenyl, binaphthyl, tetracenyl, pentacenyl, hexacenyl, triphenylenyl, chrysenyl, benzopyrenyl; cyclo-propyl, cyclo-butyl, cyclo-pentyl, cyclohexyl, cyclo-pentenyl, cyclo-hexenyl, norbornyl, camphoryl, camphanyl, caranyl, cyclo-hexadienyl, epibornyl, iso-bornyl and norpinanyl.

Examples of heterocyclic ring systems include: chromanyl, chromenylium- 1 -yl, furanyl, isochromenyl, isoquinolyl, piperazinyl, quinolinyl, pyridinyl, pyrrolidinyl, imidazyl, tetrahydrofuranyl, aziranyl, oxiranyl, thiophenyl, pyrimidinyl, thielanyl, thiazolyl, azepinyl, pyrrolyl, tetrahydropyrrolyl, benzofuranyl, indolyl, isoindolyl, istainyl, dioxindolyl, indoxylyl, coumarinyl, coumaronyl, carbazolyl, pyrazolyl, pyrrollyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, 1 ,2,4-triazoyl, 1 ,2, 3-triazoyl, tetrazolyl, pentazolyl, piperidinyl, pyradizinyl, phenazinyl, phenoxazinyl, phenothizinyl, morpholinyl, thiazinyl, benzodiazepinyl, purinyl, xanthinyl, hypoxanthinyl, theophyllinyl, theobrominyl, coffeinyl, pteridinyl, pterinyl, pteridinyl, alloxazinyl and nortropinyl.

Alkenyl represents straight and branched carbon chains having at least one carbon to carbon double bond containing the specified number of carbon atoms. Examples of alkenyl include: ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, nonenyl and decenyl.

Alkynyl represents straight and branched carbon chains having at least one carbon to carbon triple bond containing the specified number of carbon atoms. Examples of alkynyl include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, nonynyl, octynyl and decynyl.

Aryl represents an aromatic hydrocarbon containing the specified number of carbon atoms. Examples of aryl include: phenyl, 1 -naphthyl and 2-naphthyl. Examples of arylalkyl include: benzyl, 2-naphthylmethyl, 1 -naphthylmethyl, phenylethyl, 1 -phenylpropyl, 2-naphthylethyl, 2-naphthylpropyl, 1 -naphthylethyl and 1 -naphthylpropyl.

Halo is a halogen selected from: -F, -Cl, and -Br.

When a compound of the present invention contains a chiral center or some other form of an isomeric center, all forms of such isomer(s) are considered to be an aspect of the present invention, for example racemic mixtures and enantiomers.

The present invention also relates to a process for the preparation of compounds of the formula (I) which comprises reacting a compound of formula (II) below:

wherein R², R³, R³ , R^3", R⁴, R⁴ and R^4" are as defined above with an appropriate amino compound and, optionally, converting ths compound thus obtained into its physiologically acceptable salt.

Suitably, the amino compound is OR¹ -NH₂, where R¹ is as defined in formula (I), or salts thereof. Preferably the amino compound is hydroxylamine. A suitable process for the production of 1 -hydroxy 2-pydridone is described in DE 2214608 in which a 2-pyrone is reacted with hydroxylamine or its salts in the presence of the optionally substituted amines imidazole or 2-aminopyridine at room temperature to 1 50°C. A preferred process for the production of 1 -hydroxy 2-pyridone is described in DE 362621 0 in which 2-pyrone is reacted with a hydroxylammonium salt in the presence of basic alkali metal carbonates and/or hydrogen carbonates. Compounds of formula (I) wherein R¹ is H are converted to such compounds wherein R¹ is R⁵ and R⁵ is a salt by reaction with, for example, a suitable base as is well known to the skilled man.

The pyrones used as starting products are easily accessible by known processes. For example, in the publications J . Med. Chem. 1 994, 37, 3200; K.-H. Boltze et al. , Ber. Deutsch. Ges. 92 (1 959) 982 and T. M. Harris et al., Tetrahedron 24 ( 1 968) 6897 are described the synthesis of 3 and 6 substituted 4-OH pyrones.

The preliminary and subsequent operations required for the preparation of compounds of the formula (I), such as the introduction and splitting off of protective groups, are known from the literature and are described, for example, in Greene, Wilts, "Protective groups in organic synthesis", (J . Wiley, New York 1 991 ) . For example, oxo groups may be protected in the form of ketones such as acetone and ethylene ketone (see, for example, N. Takeuchi et al., Chem. Pharm. Bull. 37 (1 989) 201 2) and acids may be protected as esters, such as t-butylester. Salts of the compounds of the formula (I) having salt-forming groups are prepared in a manner which is known per se, for example by reacting a compound of the formula (I) having a basic group with a stoichiometric amount of a suitable acid or compounds of the formula (I) having an acid group with a stoichiometric amount of a suitable base.

The invention furthermore relates to the use of the compounds of the formula (III) below:

wherein R^{1 1} is -H, or -R⁵;

> 1 2 is (a) -H,

(b) -XH,

(c) -X_n(C_rC₂₀)alkyl,

(d) -X_n(C₂-C₂₀)alkenyl,

(e) -X_n(C₂-C₂₀)alkynyl,

(f) -X_n(C₇-C₂₀)arylalkyl,

(g) -X_π(C₆-C₂₀)aryl, or (h) -X_n(C₃-C₈)cycloalkyl, wherein X is O or S, preferably O, and n is the number 0 or 1 , the groups (b) to (h) are optionally substituted by one or more identical or different R⁷ groups, and one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from, for example: O, S and N;

R ³ and R¹⁴, independently of one another, are

(a) -(C C₂₀)alkyl,

(b) -(C₂-C₂₀)alkenyl,

(c) -(C₂-C₂₀)alkynyl,

(d) -(C₇-C₂₀)arylalkyl,

(e) -(C₆-C₂₀)aryl,

(f) -(C₃-C₈)cycloalkyl, or

(g) -R⁶; wherein the groups (a) to (f) are optionally substituted by one, two or three, preferably one or two, identical or different R⁶ and/or R⁷ groups and one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from, for example: O, S and N, or

R⁵ is (a) -(C_rC₂₀)alkyl,

(b) -(C_rC₂₀)alkenyl,

(c) -(C₂-C₂₀)alkynyl,

(d) -(C₂-C₂₀)arylalkyl,

(e) -(C₆-C₂₀)aryl,

(f) -(C₃-C₈)cycloalkyl,

(g) -R⁶-[(C C₆)-alkyl]-, or (h) -R⁶; wherein the groups (a) to (g) are optionally substituted by one or more identical or different R⁷ groups and wherein one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from, for example: O, S and N, or

R⁶ is an isocyclic and/or heterocyclic saturated, unsaturated or partly saturated 3-35 membered ring system which has 3-9 membered rings, wherein two or more rings as components of such a system are fused, spirolinked and/or are connected together by a side chain selected from: (C₁ -C₂₀)alkyl, (C₂-C₂₀)alkenyl and (C₂-C₂₀)alkynyl, which side chain may have one or more C atoms replaced with heteroatoms selected from, for example: O, S and N, and where the ring system is substituted by one or more identical or different R⁷ groups;

R⁷ is -R⁸, -OR⁸, -NR⁹R^{1 0},

0X0,

-C(O)OR⁸, -C(O)NR⁹R^{1 0}, -CN, -Halo, -NO₂,

-CH₂NR⁹R^{1 0}, -(C₂-C₆)-alkoxyalkyl, -S(O)_mR⁸,

-(C_rC₆)-alkyl-S(O)_mR⁸, -NHC( = NH)NHR⁸, -C( = NH)NHR⁸, -NR⁹C( = O)R⁸, = NOR⁸,

-NR⁹C( = O)OR¹⁰, -OC( = O)NR⁹R^{1 0}, or -NR⁹C( = O)NR⁹R^{1 0}, where m is the number 0, 1 or 2, preferably the number 1 or 2;

R⁸ is (a) -H,

(b) -(C_rC_{1 8})-alkyl,

(c) -(C₂-C_{1 8})-alkenyl, (d) -(C₂-C_{1 8})-alkynyl,

(e) -(C₆-C_{1 2})-aryl,

(f) -(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl, wherein the groups (b) to (f) are optionally substituted by one or more of the radicals selected from: -OH, (C₁ -C₄)-alkoxy and Halo;

R⁹ and R^{1 0}, independently of one another, are

(a) -H,

(b) -(C_rC_{1 8})-alkyl,

(c) -(C₂-C_{1 8})-alkenyl,

(d) -(C₂-C_{1 8})-alkynyl,

(e) -(C₆-C_{1 2})-aryl, or

(f) -(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl, wherein the aforesaid groups (b) to (f) are optionally substituted by one or more of the radicals selected from: OH, (C_rC₄)-alkoxy and Halo, or R⁹ and R^{1 0} together with N form a 4-7 membered ring;

or a physiologically acceptable salt thereof, for the manufacture of a medicament. Preferably, the medicament is for the inhibition of retroviruses, more preferably for the treatment of acquired immunodeficiency syndrome.

The use of those compounds of the formula (III) is preferred in which the radicals R^{1 2}, R⁵, R⁶, R⁷ and R⁸ have the following meanings:

R^{1 2} is -OH;

R⁵ is (C, -C₆)alkyl, -(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, -R⁶ or -R⁶-[(C_rC₃)-alkyl]-. More preferably R⁵ is methyl or benzyl; R⁶ is -(C₆-C_{1 2})-aryl, (C₃-C_{1 2})-cycloalkyl, or a heterocyclic ring system of 3 to 1 0 atoms which are unsubstituted or substituted by 1 , 2 or 3 identical or different R⁷ groups. More preferably R⁶ is -(C₆-C_{1 2})-aryl which is unsubstituted or monosubstituted with R⁷;

R⁷ is -R⁸, -OR⁸, -NR⁹R^{1 0}, -CN, -Halo or -CH²NR⁹R^{1 0}. More preferably R⁷ is R⁸, -OR⁸ or Halo. Most preferably R⁷ is -R⁸;

R⁸ is -H,

-(C_rC₆)-alkyl, which is unsubstituted or substituted by 1 , 2 or 3 identical or different groups selected from: -OH, (C_rC₄)-alkoxy and Halo,

-(C₆-C_{1 2})-aryl, or

-(C₆-C_{1 2})-aryl-(C C₆)-alkyl.

More preferably R⁸ is -H, or

-(C-, -C₆)-alkyl, which is unsubstituted or substituted by 1 , 2, or 3 -OH groups.

Most preferably R⁸ is -H, or

-(C- -C₃)alkyl, which is unsubstituted or monosubstituted by an -OH group.

Salts of compounds of the formula (I) or (III) are to be understood as meaning, in particular, pharmaceutically usable or non-toxic salts. In the case where the group -OR⁵ is attached to the N atom in the formula (I) or (III), R⁵ may be as defined or an equivalent physiologically acceptable salt.

Inorganic and organic salts of the compounds of the formula (I) or (III) may be formed as described in Remington's Pharmaceutical Sciences [1 7th edition, page 141 8 ( 1 985)]. Salts are formed, for example, from compounds of the formula (I) or (III) which contain acid groups, such as carboxyl, and alkali metals or alkaline earth metals, such as Na, K, Mg and Ca, and physiologically acceptable organic amines, such as triethylamine, tris-(2-hydroxyethyl)-amine, ethanolamine and ammonium. Compounds of formula (I) or (III) which contain basic groups, for example an amino group or a guanidino group, form salts with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, and with organic carboxylic or sulfonic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.

The group at the 1 and/or 4 position of the pyridone ring of the compound of the formula (III) is conveniently a prodrug group which is converted to OR^{1 1} and/or R^{1 2}, respectively, under physiological conditions.

Pharmaceutical preparations according to the present invention contain an effective amount of one or more of the active compounds of the formula together with an inorganic or organic pharmaceutically acceptable carrier

The pharmaceutical preparations of the present invention are prepared by dissolving, mixing, granulating or coating processes which are known per se.

For an oral use form, the active compounds are mixed with the additives customary for this, such as excipients, stabilizers or inert diluents, and the mixture is brought by customary methods into suitable adminstration forms, such as tablets, coated tablets, two-piece capsules and aqueous, alcoholic or oily suspensions or solutions. Inert excipierts which can be used are, for example, gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, in particular corn starch. The formulation here can be in the form of dry granules or moist granules. Suitable oily excipients or solvents are, for example, vegetable or animal oils, such as sunflower oil and fish-liver oil.

For subcutaneous or intravenous administration, the active compounds or physiologically acceptable salts thereof are dissolved, suspended or emulsified, if desired using the substances customary for this purpose, such as solubilizing agents, emulsifiers or other auxiliaries. Suitable solvents are, for example, water, physiological saline solution or alcohols, for example ethanol, propanediol or glycerol, and in addition also sugar solutions such as glucose solutions or mannitol solutions, or alternatively a mixture of the various solvents mentioned.

Also possible is the use of injectable sustained release formulations. Pharmaceutical forms which can be used are, for example, oily crystal suspensions, microcapsules, rods or implants, it being possible for the latter to be made of tissue-compatible polymers, in particular biodegradable polymers, such as, for example, those based on polylactic acid-polyglycolic acid copolymers of human albumin.

The pharmaceutical preparations of the present invention are particularly useful in the treatment of HIV type 1 . They can be administered orally, intravenously, subcutaneously, intramuscularily, rectally or by inhalation. The dosage of the active compound may lie between 0.05 to 1 00 mg/kg of body weight. Typically each dosage contains 50 to 1 000 mg and is administered one to ten times a day for acute or chronic infections. The required dosage is well known to the skilled man and depends on the age, body weight and condition of the patient as well as the mode of administration.

The compound of the formula (III) according to the present invention is advantageously administered with other active compounds, in particular antiviral agents. Suitable combined therapy formulations are described, for example, in EP-A-337714.

The following Examples are provided for illustrative proposes only and are not to be construed as limiting the present invention. Reference Example 1

Preparation of 6-(1 -benzylpropyl)-4-hydroxy-3-( 1 -phenylpropyl)-2-pyridone (Diastereomer mixture)

36.3 g (0.1 mol) of 6-( 1 -benzylpropyl)-1 ,4-dihydroxy-3-( 1 -phenylpropyl)-2- pyrone is added dropwise, under cooling at a temperature of below 20°C, to a 1 4 % aqueous ammonia solution. The resultant mixture is stirred for 90 minutes at room temperature. The mixture is then partioned between ethyl acetate/ 1 N hydrochloric acid, the organic phase is neutralized and the solvent is distilled off .

Physical characteristics are as follows: MS(ES ⁺ ) : m/e = 362 (M + H ⁺ )

Example 2

Preparation of 6-(1 -benzylpropyl)-1 ,4-dihydroxy-3-(-1 -phenylpropyl)-2-pyridone (Ethanolamine salt of diastereomer mixture)

36.3 g (0.1 mol) of 6-(1 -benzylpropyl)-1 ,4-dihydroxy-3-(1 -phenyl propyl)-2- pyrone, 23.1 g (0.14 mol) hydroxylammonium sulphate (99 % purity) and 1 5.1 g (0.14 mol) sodium carbonate (99 % purity) are combined and then suspended in heptane and water. The mixture is warmed to 95°C for 1 5 hours with stirring, extracted with water and the solvent is distilled off in vacuum. The resultant residue is dissolved in ethyl acetate and mixed with ethanolamine at around 50°C. The product starts to crystalize upon cooling. The crystals are removed by suction, washed with a small amount of cold ethyl acetate and then dried.

Physical characteristics are as follows: MS (ES ⁺ ) : m/e = 378 (M + H ⁺ ) Example 3

4-hyd^roxy-6-methyl-3-(1 -phenylpropyl)-2-pyrone (racemic mixture)

50.4 g (0.4 mol) of 4-hydroxy-6-methyl-2-pyrone and 2 g of toluolsulfonacid are heated with azeotropic removal of water. Thereto is added dropwise a solution of 81 .6 g (0.6 mol) 1 -phenyl-1 -propanol and 5 g toluolsulfonacid within a period of up to 1 6 hours. After the removal of 14 ml water the reaction mixture is reduced and the residue is subjected to flash chromatography with ethyl acetate/n-heptane, 2: 1 , on silicon gel. The main fraction provides, after recrystalization from ethyl acetate/n-heptane, 1 : 1 , 23. 1 g (24%) colourless crystals having a melting point of 1 58 °C. MS (El ⁺ ) : m/e = 244.3 (M ⁺ )

Example 4

1 ,4-dihydroxy-6-methyl-3-( 1 -phenylpropyl)-2-pyridone (racemic mixture)

2.3 g (9.6 mmol) 4-hydroxy-6-methyl-3-(1 -phenylpropyl)-2-pyrone (racemate) are placed in 25 ml n-heptane, 2.3 g ( 14 mmol) hydroxylaminehydrochloride, 1 .5 g ( 14 mmol) soda and 0.3 ml water are added and 0.14 ml trifluorethyl acetic acid is added dropwise thereto. The mixture is stirred for 1 1 hours at 95 °C, cooled, 50 ml water and 0.4 ml concentrated sulfuric acid are added, and is then extracted with acetic acid. The organic phases are washed with 50 ml salt solution, dried and reduced. From the concentrated solution arise 250 mg ( 1 0%) of colourless crystals which after washing with ether have a melting point of 21 2°C. MS (El ⁺ ) : m/e = 259.3 (M ⁺ )

Example 5

4-hydroxy-6-methyl-3-(1 -benzyl-benzyl)-2-pyrone (racemic mixture)

50.4 g (0.4 mol) of 4-hydroxy-6-methyl-2-pyrone and 2 g of toluolsulfonacid are heated with azeotropic removal of water. Thereto is added dropwise a solution of 1 1 9 g (0.6 mo!) 1 ,2-diphenylethanol and 5 g toluolsulfonacid within a period of up to 1 6 hours. After the removal of 14 ml water the reaction mixture is reduced and the residue is subjected to flash chromatography with ethyl acetate/n-heptane, 2: 1 , on silicon gel. The main fraction provides, after recrystalization from ethyl acetate/n-heptane, 1 : 1 , 1 7.1 g ( 14%) colourless crystals having a melting point of 242°C. MS (El ⁺ ) : m/e = 306.4 (M ⁺ )

Example 6

1 ,4-dihydroxy-6-methyl-3-(1 -benzyl-benzyl)-2-pyridone (racemic mixture)

2.9 g (9.6 mmol) 4-hydroxy-6-methyl-3-(1 -benzyl-benzyl)-2-pyrone (racemate) are placed in 25 ml n-heptane, 2.3 g (14 mmol) hydroxylaminehydrochloride, 1 .5 g (14 mmol) soda and 0.3 ml water are added and 0.14 ml trifluorethyl acetic acid is added dropwise thereto. The mixture is stirred for 1 1 hours at 95°C, cooled, 50 ml water and 0.4 ml concentrated sulfuric acid are added, and is then extracted with acetic acid. The organic phases are washed with 50 ml salt solution, dried and reduced. From the concentrated solution arise 925 mg (30%) of colourless crystals which after washing with ether have a melting point of 224°C; MS (El ⁺ ) : m/e = 322.4 (M ⁺ )

Example 7

6-( 1 -ethylphenethyl)-4-hydroxy-3-( 1 -phenylpropyl)-2-pyrone (racemic mixture of

Diastereomers)

a) 4-hydroxy-6-phenethyl-3-(1 -phenylpropyl)-2-pyrone

8.8 g (88 mmol) diisopropylamine are placed in 50 ml dry tetrahydrofuran (THF) in the presence of protective gas and deprotonized at -30°C with 55 ml 1 .6 M (88 mmol) N-butyllithium/hexane. After thawing at 0°C and further cooling to 30° C, the solution is mixed with 9.3 g (38 mmol) 4-hydroxy-6-methyl-3-( 1 - phenylpropyl)-2-pyroπe in 200 ml absolute THF within 30 minutes and then additionally mixed for 30 minutes. Over a further period of 30 minutes benzylbromide in 50 ml absolute THF is added dropwise thereto, the mixture is stirred for 30 minutes and allowed to thaw for up to 1 6 hours. The reaction mixture is poured onto 400 ml 2N HCI, extracted several times with ethyl acetate, the organic phases washed with salt solution and dried. Flash chromatography with ethyl acetate/n-heptane, 1 : 1 , on silicon gel results in a main fraction of 7.6 g (60%) colourless crystals with a melting point of 145- 146°C. Unpolarized subsidiary components found are 2.0 g ( 1 2%) 6-( 1 - benzylphenethyl)-4-hydroxy-3-( 1 -phenylpropyl)-2-pyrone as colourless crystals with a melting point of 1 64-1 65°C.

b) 6-(1 -ethylphenethyl)-4-hydroxy-3-(1 -phenylpropyl)-2-pyrone

2.7 g (26 mmol) diisopropylamine are exposed to protective gas in 90 ml dry THF and deprotonized at -30°C with 1 6.5 ml 1 .6 M (26 mmol) N-butyllithium/hexane. After thawing at 0°C and cooling again at -30° C, the solution is mixed with 4.0 g ( 1 2 mmol) 4-hydroxy-6-phenethyl-3-( 1 - phenylpropyl)-2-pyrone in 90 ml absolute THF and stirred 30 minutes. 4.1 g (26 mmol) iodethane in 35 ml abs. THF is added dropwise thereto, stirred for 30 minutes and thawed within 1 6 hours at room temperature. The reaction mixture is shaken in 1 80 ml 2 N HCI, extracted several times with ethyl acetate, the organic phases are washed with salt solution and dried. Flash chromatography with ethyl acetate/n-heptane, 1 :2, on silicon gel results in 3.5 g (80%) colourless crystals with a melting point of 1 23-1 25 °C. MS (El ⁺ ) : m/e = 362.5 (M ⁺ ) Example 8

6-( 1 -ethylphenethyl)-1 ,4-dihydroxy-3-(1 -phenylpropyl)-2-pyridone (racemic mixture of diastereomers)

3.48 g (9.6 mmol) 6-( 1 -ethylphenethyl)-1 -hydroxy-3-( 1 -phenylpropyl)-2-pyrone (racemate) are placed in 25 ml n-heptane, 2.3 g ( 14 mmol) hydroxylaminehydrochloride, 1 .5 g ( 14 mmol) soda and 0.3 ml water are added and 0.1 4 ml trifluorethyl acetic acid is added dropwise thereto. The mixture is stirred for 1 1 hours at 95 ° C, cooled, 50 ml water and 0.4 ml concentrated sulfuric acid are added, and is then extracted with acetic acid. The organic phases are washed with 50 ml salt solution, dried and reduced. From the concentrated solution arise 435 mg (30%) of a colourless oil. MS (El ⁺ ) : m/e = 377.5 (M ⁺ )

Example 9

4-hydroxy-3-(1 -benzyl-benzyl)-6-phenethyl-2-pyrone (racemic mixture)

8.8 g (88 mmol) diisopropylamine are placed in 50 ml dry tetrahydrofuran (THF) in the presence of protective gas and deprotonized at -30°C with 55 ml 1 .6 M (88 mmol) N-butyllithium/hexane. After thawing at 0° C and further cooling to 30°C, the solution is mixed with 1 1 .6 g (38 mmol) 4-hydroxy-6-methyl-3-( 1 - benzyl-benzyl)-2-pyrone in 200 ml absolute THF within 30 minutes and then additionally mixed for 30 minutes. Over a further period of 30 minutes benzylbromide in 50 ml absolute THF is added dropwise thereto, the mixture is stirred for 30 minutes and allowed to thaw for up to 1 6 hours. The reaction mixture is poured onto 400 ml 2N HCI, extracted several times with ethyl acetate, the organic phases washed with salt solution and dried. Flash chromatography with ethyl acetate/n-heptane, 1 : 1 , on silicon gel results in a main fraction of 1 1 .1 g (74%) colourless crystals with a melting point of 1 55 °C; MS (FAB) : m/e = 397.5 (M + H ⁺ ) . Example 10

1 ,4-dιhydroxy-3-(1 -benzyl-benzyl)-6-phenethyl-2-pyrιdone (racemic mixture)

3.8 g (9.6 mmol)4-hydroxy-3-(1-benzyl-benzyl)-6-phenethyl-2-pyrone (racemate) are placed in 25 ml n-heptane, 2.3 g (14 mmol) hydroxylaminehydrochloride, 1.5 g (14 mmol) soda and 0.3 ml water are added and 0.14 ml trifluorethyl acetic acid is added dropwise thereto. The mixture is stirred for 11 hours at 95°C, cooled, 50 ml water and 0.4 ml concentrated sulfuric acid are added, and is then extracted with acetic acid. The organic phases are washed with 50 ml salt solution, dried and reduced. From the concentrated solution arise 990 mg (25%) of colourless crystals which after washing with ether have a melting point of 217°C. MS (El ⁺ ) : m/e = 412.5 (M ⁺ )

Example 11

6-(1-benzylphenethyl)-4-hydroxy-3-(1-phenylpropyl)-2-pyrone (racemic mixture of dtastereomers)

Unpolaπzed subsidiary components found in Example 9 are 2.0 g (12%) 6-(1- benzylphenethyl)-4-hydroxy-3-(1-phenylpropyl)-2-pyrone as colourless crystals with a melting point of 164-165°C; MS (El ⁺ ) : m/e = 424.5 (M + H ⁺ )

Example 12

6-(1 -benzylphenethyD-1 ,4-dιhydroxy-3-(1 -phenylpropyl)-2-pyrιdone (racemic mixture)

4.1 g (9.6 mmol) 6-(1-benzylphenethyl)-4-hydroxy-3-(1-phenylpropyl)-2-pyrone (racemate) are placed in 25 ml n-heptane, 2.3 g (14 mmol) hydroxylaminehydrochloride, 1.5 g (14 mmol) soda and 0.3 ml water are added and 0.14 ml trifluorethyl acetic acid is added dropwise thereto. The mixture is stirred for 1 1 hours at 95°C, cooled, 50 ml water and 0.4 ml concentrated sulfuric acid are added, and is then extracted with acetic acid. The organic phases are washed with 50 ml salt solution, dried and reduced. Flash chromatography with ethyl acetate/n-heptane on silicon gel results in 800 mg (1 9 %) of a colourless oil. MS (FAB) : m/e = 440.6 (M + H ⁺ )

Example 1 3 a.) 1 -benzyloxy-4-hydroxy-6-methyl-3-(1 -phenylpropyl)-2-pyridone (racemic mixture) b.) 1 ,4-dibenzyloxy-6-methyl-3-( 1 -phenylpropyl)-2-pyridone (racemic mixture)

0.52 g (2.0 mmol) 1 ,4-dihydroxy-6-methyl-3-(1 -phenylpropyl)-2-pyridone

(racemic mixture) are placed in 25 ml dry tetrahydrofuran (THF) and 32 mg (4.0 mmol) lithium hydroxide are added. The solution is mixed with 0.43 g (2.5 mmol) benzyl bromide and then additionally mixed for 24 hours. The reaction mixture is poured onto 50 ml 2N HCI, extracted several times with ethyl acetate, the organic phases washed with salt solution and dried. Flash chromatography with ethyl acetate/n-heptane, 1 :2, on silicon gel results in a main fraction of 0.39 g (56%) colourless crystals with a melting point of

200°C.

MS (ES ⁺ ) : m/e = 350 (M + H ⁺ ) .

Unpolarized subsidiary components found are 0.1 8 g (21 %) 1 ,4-dibenzyloxy-6- methyl-3-(1 -phenylpropyl)-2-pyridone (racemic mixture) as colourless oil.

MS (ES ⁺ ) : m/e = 440 (M + H ⁺ ) .

Activity Tests

Protease Assay

The HIV protease-inhibitory action of the compounds of formula (III) of the present invention was determined according to the test described in EP-A-428849.

Reverse Transcriptase Assay

The activity of reverse transcriptase (RT) was determined with the aid of a scintillation proximity assay (SPA) .

The reagent kit for the RT-SPA was obtained from Amersham/Buchler

(Braunschweig) . The enzyme RT (from HIV cloned in E. coli) originated from

HT-Biotechnology Ltd, Cambridge, UK.

Mixture

The assay was carried out using the manufacturer's (Amersham) protocol manual, with the following modifications:

bovine serum albumin was added to the assay buffer to give an end concentration of 0.5 mg/ml

the assay was carried out in Eppendorf reaction vessels, using 1 00 μl volume per batch

the manufacturer's RT concentrate (5000 U/ml) was diluted in Tris-HCI buffer 20 mM; pH 7.2; 30% of glycerol, to an activity of 1 5 U per ml

the incubation time for the mixtures was 60 minutes (37°C)

after stopping the reaction and "developing" with the bead suspension, 1 30 JI of mixture were transferred to 4.5 ml of Tris-HCI buffer, 1 0 mM; pH 7.4; 0.1 5 M NaCl, and the tritium activity was measured by means of a "-counter. Assay

For a pre-assay for inhibitory activity, the substances were dissolved in DMSO

(stock solution c = 1 mg/ml), and tested as a 1 0^{" 1} , 1 0^"2, 1 0^~3, etc. , dilution in

DMSO.

To determine IC₅₀ values, the inhibitor stock solutions were diluted further in Tris-HCI buffer, 50 mM, pH 8, and tested in suitable concentrations.

The concentration corresponding to a 50% enzyme inhibition was determined from a plot of RT activity versus log C_jnh.

Test of preparations against HIV in cell culture

Description of method

Medium:

RMPI pH 6.8

Complete medium additionally contains 20% fetal calf serum and 40 lU/ml recombinant interleukin 2.

Cells:

Lymphocytes which have been isolated from fresh donor blood by means of Ficoll" gradient centrifugation are cultured for 36 hours in complete medium with an addition of 2 /yg/ml phytohemagglutinin (Wellcome) at 37°C under 5% of CO₂. After 1 0% of DMSO has been added, the cells are frozen at a density of 5 ■ 10⁶ and stored in liquid nitrogen. For the test, the cells are defrosted, washed in RPMI medium and cultured for 3 - 4 days in the complete medium.

Mixture:

The test preparations were dissolved in DMSO at a concentration of

1 6.7 mg/ml and diluted in complete medium to 1 mg/ml. 0.4 ml of medium was introduced into 24-multiwell dishes. 0.1 ml of the dissolved preparation was added to the upper row of the dish, and, by transferring 0.1 ml portions, a geometric dilution series was established. Controls without preparation always contained 0.4 ml of complete medium containing 0.5% of DMSO. Lymphocyte cultures with a cell density of 5 ■ 10⁵ cells/ml were infected by adding 1 /50 volume supernatant from HIV-infected lymphocyte cultures. The titer of these culture supernatants was determined by end-point titration as 1 - 5 ■ 10⁶ infectious units/ml. After 30 minutes' incuba¬ tion at 37°C, the infected lymphocytes were removed by centrifugation and taken up in an equal volume of medium. From this cell suspension, 0.6 ml aliquots were transferred into all wells of the test plate. The mixtures were incubated for 3 days at 37°C.

Evaluation:

The infected cell cultures were examined under the microscope for the presence of giant cells, which indicate active virus multiplication in the culture. The lowest concentration of preparation where no giant cells were observed was determined as inhibitory concentration against HIV. As a control, the supernatants from the culture plates were tested for the presence of HIV antigen with the aid of an HIV antigen test following the manufacturer's instructions (Organon) . Table: Summary of Results

Example Molecular Molecular MIC MTC SI No. Formula Mass

3 C"I 5^H16⁰3 224.29 > 1 00 100 1

4 C_{1 5}H_{1 7}NO₃ 259.31 > 0.8 > 20 25

5 ^20^18^3 306.36 > 20 < 20 1

6 C₂₀H_{1 9}NO₃ 321 .38 < 0.8 > 0.8 < 1

7 ^24^26^3 362.47 > 4 > 4 1 8 C₂₄H₂₇NO₃ 377.49 >20 >100 5

9 C₂₇H₂₄O₃ 396.49 >4 >4 1

10 C₂₇H₂₅NO₃ 411.51 >0.8 >0.8 1

11 ^29^28^3 424.54 >4 >4 1

12 C.29H29NO.3 439.56 >20 >20 1

13a C₂₂H₂₃NO₃ 349.43 >100 <100 <1

13b C₂₉H₂₉NO₃ 439.56 >20 <20 <1

MIC = Minimum Inhibitory Concentration in /g/ml MTC = Maximum Tolerated Concentration in /yg/ml SI = Selectively Index calculated as MTC/MIC

Our preliminary investigations show that the pyridone compounds of the present invention have improved antiviral and pharmacological characteristics in comparison with the corresponding pyrones.

Claims

CLAIMS:

1 . A compound of the formula (I) below:

wherein ι 1 is -H, or -R⁵;

is (a) -H,

(b) -(C_rC₂₀)alkyl,

(c) -(C₂-C₂₀)alkenyl,

(d) -(C₂-C₂₀)alkynyl,

(e) -(C₇-C₂₀)arylalkyl,

(f) -(C₆-C₂₀)aryl, or

(g) -(C₃-C₈)cycloalkyl, wherein the groups (b) to (g) are optionally substituted by one or more identical or different R⁷ groups, and one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from: O, S and N;

R³, R³ , R^3", R⁴, R⁴ and R^{4 '}, independently of one another, are (a) -(C_rC₂₀)alkyl, (b) -(C₂-C₂₀)alkenyl,

(c) -(C₂-C₂₀)alkynyl,

(d) -(C₇-C₂₀)arylalkyl,

(e) -(C₆-C₂₀)aryl,

(f) -(C₃-C₈)cycloalkyl, or

(g) -R⁶, wherein the groups (a) to (f) are optionally substituted by one, two or three identical or different R⁶ and/or R⁷ groups and one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from: O, S and N, and wherein, in addition,

R³ and R⁴, independently of one another, may be H;

R⁵ is (a) -(C_rC₂₀)alkyl,

(b) -(C₂-C₂₀)alkenyl,

(c) -(C₂-C₂₀)alkynyl,

(d) -(C₇-C₂₀)arylalkyl,

(e) -(C₆-C₂₀)aryl,

(f) -(C₃-C₈)cycloalkyl,

(g) -R⁶-[(C_rC₆)-alkyl]-, or (h) -R⁶; wherein the groups (a) to (g) are optionally substituted by one or more identical or different R⁷ groups and wherein one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from: O, S and N;

R⁶ is an isocyclic and/or heterocyclic saturated, unsaturated or partly saturated 3-35 membered ring system which has 3-9 membered rings where two or more rings as components of such a system are fused or spirolinked and/or are connected together by a side chain selected from: (C_rC₂₀)alkyl,

and (C₂-C₂₀)alkynyl, which side chain may have one or more C atoms replaced with heteroatoms selected from: O, S and N, and where the system is substituted by one or more identical or different R⁷ groups;

R⁷ is -R⁸,

-OR⁸,

-NR⁹R^{1 0}, oxo,

-C(O)OR⁸,

-C(O)NR⁹R^{1 0},

-CN,

-Halo,

-NO₂,

-CH₂NR⁹R^{1 0},

-(C₂-C₆)-alkoxyalkyl,

-S(O)_mR⁸,

-(C_rC₆)-alkyl-S(O)_mR⁸,

-NHC( = NH)NHR⁸,

-C( = NH)NHR⁸,

-NR⁹C( = O)R⁸,

= NOR⁸,

-NR⁹C( = O)OR^{1 0},

-OC( = O)NR⁹R^{1 0}, or

-NR⁹C( = O)NR⁹R^{1 0}, where m is the number 0, 1 or 2;

R⁸ is (a) -H,

(b) -(C_rC_{1 8})-alkyl,

(c) -(C₂-C_{1 8})-alkenyl,

(d) -(C₂-C_{1 8})-alkynyl, (e) -(C₆-C_{1 2})-aryl, or

(f) -(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl, wherein the groups (b) to (f) are optionally substituted by one or more of the radicals selected from: -OH, (C_rC₄)-alkoxy and Halo;

R⁹ and R^{1 0}, independently of one another, are

(a) -H,

(b) -(C_rC_{1 8})-alkyl,

(c) -(C₂-C_{1 8})-alkenyl,

(d) -(C₂-C_{1 8})-alkynyl,

(e) -(C₆-C_{1 2})-aryl, or

(f) -(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl, wherein the groups (b) to (f) are optionally substituted by one or more of the radicals selected from: -OH, (C C₄)-alkoxy and Halo, or R⁹ and R^{1 0} together with N form a 4-7 membered ring;

or an equivalent physiologically acceptable salt thereof.

2. A compound of the formula I as claimed in claim 1 , wherein R¹ is -H;

R² is -H;

R⁵ is -(C_rC₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -R⁶, or -R⁶-[(C_rC₃)-alkyl]- R⁶ is -(C₆-C_{1 2})-aryl,

(C₃-C-_{| 2})-cycloalkyl, or a heterocyclic ring system of 3 to 1 0 atoms,

wherein the aforesaid R⁶ groups are unsubstituted or substituted by 1 , 2 or 3 identical or different R⁷ groups;

R⁷ is -R⁸, -OR⁸, -NR⁹R^{1 0}, -CN,

-Halo, or -CH²NR⁹R^{1 0}; and

R⁸ is -H,

-{C C₆)-a\ky\, which is unsubstituted or substituted by 1 , 2 or 3 identical or different groups selected from:

OH, (C_rC₄)-alkoxy, F, Cl and Br,

-(C₆-C_{1 2})-aryl, or

-(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl;

or an equivalent physiologically acceptable salt thereof.

3. A compound of the formula I as claimed is claim 1 or claim 2, wherein R⁵ is methyl or benzyl;

R⁶ is (C₆-C_{1 2})-aryl, which is unsubstituted or monosubstituted with R⁷;

R⁷ is -R⁸,

-OR⁸, or -Halo; and

R⁸ is -H, or

-(C- Cgl-alkyl, which is unsubstituted or substituted by 1 , 2 or 3 OH groups.

4. A compound of the formula (I) as claimed in any one of the preceding claims, wherein

R⁷ is -R⁸; and

R⁸ is -H, or

-(C C₃)alkyl, which is unsubstituted or monosubstituted by -OH.

5. A process for the preparation of a compound of the formula (I) as claimed in any one of claims 1 to 3 which comprises reacting a compound of formula (II) below:

wherein R², R³, R³ , R^3", R⁴, R⁴ and R⁴ are as defined in claim 1 or claim 2, with an appropriate amino compound and, optionally, converting the compound thus obtained into its physiologically acceptable salt.

The use of a compound of the formula (III) below:

wherein

R 1 1 is -H, or -R⁵;

R^{1 2} is (a) -H,

(b) -XH,

(c) -X_n(C_rC₂₀)alkyl,

(d) -X_n(C₂-C₂₀)alkenyl,

(e) -X_n(C₂-C₂₀)alkynyl,

(f) -X_n(C₇-C₂₀)arylalkyl,

(g) -X_n(C₆-C₂₀)aryl, or (h) -X_n(C₃-C₈)cycloalkyl, wherein X is O or S and n is the number 0 or 1 , the groups (b) to (h) are optionally substituted by one or more identical or different R⁷ groups, and one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from: O, S and N;

I^{1 3} and R^{1 4}, independently of one another, are

(a) -(C_rC₂₀)alkyl,

(b) -{C₂-C₂₀)alkenyl,

(c) -(C₂-C₂₀)alkynyl,

(d) -(C₇-C₂₀)arylalkyl,

(e) -(C₆-C₂₀)aryl, (f) -(C₃-C₈)cycloalkyl, or

(g) -R⁶; wherein the groups (a) to (f) are optionally substituted by one, two or three identical or different R⁶ and/or R⁷ groups and one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from: 0, S and N;

R⁵ is (a) -(C_rC₂₀)alkyl,

(b) -(C₂-C₂₀)alkenyl,

(c) -(C₂-C₂₀)alkynyl,

(d) -(C₇-C₂₀)arylalkyl,

(e) -(C₆-C₂₀)aryl,

(f) -(C₃-C₈)cycloalkyl,

(g) -R⁶-[(C_rC₆)-alkyl]-, or (h) -R⁶; wherein the groups (a) to (g) are optionally substituted by one or more identical or different R⁷ groups and one or more carbon atoms of the aforesaid groups are optionally replaced with heteroatoms selected from: O, S and N;

R⁶ is an isocyclic and/or heterocyclic saturated, unsaturated or partly saturated 3-35 membered ring system which has 3-9 membered rings where two or more rings as components of such a system are fused, spirolinked and/or connected together via a ring atom or a side chain selected from: (C_rC₂₀)alkyl, (C₂-C₂₀)alkenyl and (C₂-C₂₀)alkynyl, which side chains may have one or more C atoms replaced with heteroatoms selected from: O, S and N, and where the ring system is substituted by one or more identical or different R⁷ groups;

is -R⁸, -OR⁸, -NR⁹R¹⁰, oxo,

-C(O)OR⁸, -C(O)NR⁹R¹⁰, -CN, -Halo, -NO₂,

-CH₂NR⁹R¹⁰, -(C₂-C₆)-alkoxyalkyl, -S(O)_mR⁸,

-(C_rC₆)-alkyl-S(O)_mR⁸, -NHC( = NH)NHR⁸, -C( = NH)NHR⁸, -NR⁹C( = O)R⁸, = NOR⁸,

-NR⁹C( = O)OR¹⁰, -OC( = O)NR⁹R¹⁰, or -NR⁹C( = O)NR⁹R¹⁰, where m is the number 0, 1 or 2;

R⁸ is (a) -H,

(b) -(C_rC₁₈)-alkyl,

(c) -(C₂-C₁₈)-alkenyl,

(d) -(C₂-C₁₈)-alkynyl,

(e) -(C₆-C₁₂)-aryl, or

(f) -(C₆-C₁₂)-aryl-(C_rC₆)-alkyl, wherein the aforesaid groups (b) to (f) are optionally substituted by one or more of the radicals selected from: -OH, (C_rC₄)-alkoxy and Halo; R⁹ and R^{1 0}, independently of one another, are

(a) -H,

(b) -(C_rC_{1 8})-alkyl,

(c) -(C₂-C_{1 8})-alkenyl,

(d) -(C₂-C_{1 8})-alkynyl,

(e) -(C₆-C_{1 2})-aryl, or

(f) -(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl, wherein the aforesaid groups (b) to (f) are optionally substituted by one or more of the radicals selected from: OH, (C_rC₄)-alkoxy and Halo, or R⁹ and R^{1 0} together with N form a 4-7 membered ring;

or a physiologically acceptable salt thereof, for the manufacture of a medicament.

The use as claimed in claim 6, wherein in formula (III)

R^{1 2} is -OH;

R⁵ is (C_rC₆)alkyl, -(C₂-C₆)alkenyl, -(C₂-C₆)alkynyl, -R⁶, or -R⁶-[(C_rC₃)-alkyl];

R⁶ is -(C₆-C_{1 2})-aryl,

-(C₃-C_{1 2})-cycloalkyl, or a heterocyclic ring system of 3 to 1 0 atoms, wherein the aforesaid R⁶ groups are unsubstituted or substituted by 1 , 2 or 3 identical or different R⁷ groups; R⁷ is -R⁸, -OR⁸, -NR⁹R^{1 0}, -CN,

-Halo, or -CH²NR⁹R^{1 0}; and

R⁸ is -H,

-(C_rC₆)-alkyl which is unsubstituted or substituted by 1 , 2 or 3 identical or different groups selected from: -OH, (C_rC₄)-alkoxy and Halo,

-(C₆-C_{1 2})-aryl, or -(C₆-C_{1 2})-aryl-(C_rC₆)-alkyl.

8. The use as claimed in claim 6 or claim 7, wherein R⁵ is methyl or benzyl;

R⁶ is -(C₆-C_{1 2})-aryl which is unsubstituted or monosubstituted with R⁷;

R⁷ is -R⁸,

-OR⁸, or -Halo; and

R⁸ is -H, or

-(C_| -C₆)-alkyl which is unsubstituted or substituted by 1 , 2 or 3 OH groups.

9. The use as claimed in any one of claims 6 to 8, wherein R⁷ is -R⁸; and R⁸ is -H, or

-(C-_| -C₃)alkyl, which is unsubstituted or monosubstituted by -OH.

10. The use of a compound of the formula (III) as claimed in any one of claims 6 to 9, or a physiologically acceptable salt thereof, for the manufacture of a medicament for the inhibition of retroviruses.

1 1 . The use of a compound of the formula (III) as claimed in any one of claims 6 to 9, or a physiologically acceptable salt thereof, for the manufacture of a medicament for the treatment of acquired immunodeficiency syndrome.

12. A pharmaceutical composition comprising a compound of the formula as claimed in any one of claims 6 to 9, or a physiologically acceptable salt thereof, and a pharmaceutically acceptable carrier.