AU752714B2

AU752714B2 - Combined preparation of anti-infectiously active compounds which inhibit the 2-C-methylerythrose-4 metabolic pathway, and inhibitors of lipid metabolism

Info

Publication number: AU752714B2
Application number: AU46155/99A
Authority: AU
Inventors: Hassan Jomaa
Original assignee: Jomaa Pharmaka GmbH
Current assignee: Bioagency AG
Priority date: 1998-06-24
Filing date: 1999-06-23
Publication date: 2002-09-26
Anticipated expiration: 2019-06-23
Also published as: CA2334645A1; AU4615599A; TR200003783T2; PL345513A1; WO1999066875A2; EP1100510A2; JP2002518418A; SK19612000A3; IL139965A0; CN1348374A; WO1999066875A3

Description

Combined preparation of anti-infectiously active compounds which inhibit the 2-Cmethylerythrose-4 metabolic pathway, and inhibitors of lipid metabolism The invention relates to combined preparations of anti-infectiously active compounds which inhibit the 2-C-methylerythrose-4 metabolic pathway as well as their salts and esters and of inhibitors of lipid metabolism and their simultaneous, separate or successive use in prophylactics and therapy of infectious processes in plants, humans, and animals as well as their use as herbicides. The lipid metabolism inhibitors according to the present invention suit in particular for the therapeutic and prophylactic treatment of infections by unicellular or multicellular parasites, fungi, bacteria or viruses as well as as herbicides.

The suitability of different organophosphoric compounds as well as of some of their esters and salts as pharmaceutical compositions is already known.

For example the antimicrobial efficacy ofaminohydrocarbyl phosphonic acid derivatives against bacteria in humans and animals and against fungi in plants has been described (DE 27 33 658 Al, US 4,143,135, US 4,182,758 and US 4,206,156, US 4,994,447, US 4,888,330, US 4,210,635, US 3,955,958, US 4,196,193, US 4,268,503, US 4,330,529, US 5,189,030, US 3,764,677, US 3,764,676). Further substances of these groups have been described as herbicides (US 4,693,742, US 5,002,602, US 4,131,448, US 3,977,860, US 4,062,669), as algicides (US 3,887,353), as plant growth regulators (US 4,127,401, US 4,120,688, US 3,961,934, US 4,431,438, US 3,853,530, US 4,205,977, US 4,025,332, US 3,894,861) and as reagents in the production of pigments (US 4,051,175).

The application for example of aminohydrocarbyl phosphonic acid derivatives in the control of bacterial infections proved to be very difficult. Many bacteria which are responsible for ambulant infections and for infections which have been caught during a clinical stay are not sensitive to therapy by this group. Bacteria of the genus Staphylococcus belong to them, in particular the species Staphylococcus aureus. This germ of skin is a danger for the patient who stay in a clinic. Further studies including a phase Ia study of the applicant of the patent application DE 27 33 658 show a very quick built-up of resistance of the originally sensitive germs. Therefore these derivatives have not established in clinical application.

Further, also the use ofbisphosphonic acids and some of their derivatives in pharmaceutical compositions is already known. Up to now, the microbiostatic efficacy ofbisphosphonic acids (DE 3 611 522), their efficacy in the treatment of disorders in the calcium and phosphate metabolic pathway (DE 2 534 390, DE 2 534 391, DE 3 334 211, DE 3 434 667, DE 2 745 k \083), the cytostatic efficacy (DE 3 425 812), their lipid lowering efficacy (Arzneimittelforschung 46, 759-62) and their capacity for stimulating immuncompetent cells (WO 97/38 696) is known.

The antimicrobial efficacy of fosfonochlorine against bacteria and an effect of foscarnet against viruses have been described. Further, the suitability of fosamine ammonium and N,Ndimethyl-(hydroxy-2-oxo-2-methoxyethyl) phosphonoamide as herbicides have been reported.

The use of inhibitors of the lipid metabolism is a for a longer time past accepted and widespread principle of treatment. These inhibitors are used for reducing the risk of heart and vascular diseases caused by hyperlipidaemia. The pharmacotherapy of said hyperlipidaemia in general is based on regulating the intake and controlling the synthesis of fats or in particular of cholesterol. Generally the synthesis of cholesterol is controlled by enzyme P-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase). In general the self synthesis of cholesterol is higher than the intake by food. (Berthold ofBergmann Dtsch. Med. Wochenschr. 121, S.729 (1996); Richter Fortschr. med. 114, S. 177, 193) Anion exchangers and p-sitosterol are known for controlling the intake of fats from the digestive tract. The ion exchangers contain cholestyr amine and colestipol. They resorb bile acids and thereby interrupt the entero hepatic return transportation and thereby cause a significant increase of sterolene in faeces. P-Sitosterol is a phytogenic sterol structurally related to cholesterol. It inhibits the resorption of food cholesterol at the intestinmucosa.

Further, nicotinic acids and their derivatives, clofibrate and their derivatives and probucol have been used for controlling the lipid metabolism or the prevention of subsequent diseases of hyperlipidaemia. Nicotinic acids and nicotinic acid derivatives lead to a lowering of fatty acids, triglyceride and cholesterol. Up to now the mechanism is not known. The ethyl ester of clofibrin acid, clofibrate and derivatives as well as analogues lead to a lowering of cholesterol, the mechanism of action is also not known. Also the mechanism of action of probucol is not clarified.

For controlling the synthesis HMG-CoA synthetase inhibitors (US 50 64 856, US 47 51 237), HMG-CoA reductase inhibitors (US 38 18 080, US 39 83 140, US 40 49 495, US 41 37 322, US 42 55 444, US 41 98 425, US 42 62 013, US 42 31 938, US 43 75 475, US 43 46 227,US 44 106 29, US 44 447 84, US 44 50 171, US 45 54 359, US 49 201 09, EP 0065835A1, EP 0142146A2, GB 15 86 152, US 33 75 475, GB 21 62 179A, EP 164698A, WO 8402903, WO 8401231, WO 8603488A US 46 81 893, US 46 45 858, US 52 36 946, US 55 06 262, US 017, US 48 47 271, US 46 22 338, US 49 04 646, US 48 73 345, US 55 93 971, US 52 305, US 52 02 327, US 49 40 727, US 52 72 166, US 53 85 932, US 54 61 039, US 55 56 -7 T^ -3- 990, US 55 61 143, US 55 63 128), inhibitors of squalene synthetase, in particular pyrophosphates, pyrophosphate derivatives, bisphosphonic acid derivatives, phosphinylmethylphosphonic acid derivatives, phosphinylformyl derivatives, phosphonocarboxyl derivatives, phosphonosulfonic acid derivatives, phosphinylmethylphosphonic acid derivatives, which partly are known as pharmaceutical and cosmetic preparations for controlling the calcium and phosphate metabolism (DE 25 34 390, DE 25 34 391, DE 33 34 211, DE 34 34 667, DE 27 083, US 53 12 814, US 52 54 544, US 54 70 845, US 50 25 003, US 55 34 532, US 48 71 721, WO 92 15 579, US 51 35 935, WO 92 12 160, WO 92 12 159, WO 92 12 158, WO 92 12 157, WO 92 12 156, US 52 73 969, US 53 95 846, US 54 41 946, US 54 51 596, US 54 260, US 55 63 128, US 52 02 327, US 49 04 646), and other inhibitors of the synthesis of cholesterol (US 56 61 145, US 57 44 467) are used which assignment is not clarified. HMG- CoA reductase inhibitors competitively inhibit the rate of controlling enzyme of the synthesis of cholesterol, HMG-CoA reductase. Their enzyme affinity is up to 20000-times higher than that of substrate HMG-CoA. The HMG-CoA reductase results in transformation of HMG- CoA to mevalonate, from which besides cholesterol inter alia isopentenyl adenine as well as farnesyl pyrophosphate, the preliminary stage ofdolichol and ubiquinone, originate. In bacteria, fungi and parasites which have a HMG-CoA reductase isopentenyl diphosphates are generated upon the acetate/mevalonate pathway, which is inhibited by HMG-CoA reductase inhibitors.

The first discovered inhibitors have been isolated from a penicillium (mevastatin) and an aspergillus fungi (lovastatin). The modification of the side chain led to simvastatin, the advancement of mevastatin to pravastatin. Meanwhile also a completely synthetic enzyme inhibitor (fluvastatin) is available representing a mevalonic lactone derivative of a fluorophenyl substituted indole ring.

In the past attempts for use of these substances in the control of infectious diseases have been made. In particular attempts have been made to inhibit the growth of plants, fungi, parasites, bacteria and viruses by the use of HMG-CoA inhibitors. The HMG-CoA synthetase and HMG-CoA reductase inhibitors inhibit the acetate/mevalonate pathway in some bacteria, fungi (US 50 26 554, US 50 64 856, US 49 20 111, US 49 20 113) and parasites. However many bacteria, for example Escherichia coli, do not show inhibition by HMG-CoA reductase inhibitors. Probably the reason is that these bacteria have an alternative metabolic pathway. In Escherichia coli indeed the absence of the acetate/mevalonate metabolic pathway and the presence of another metabolic pathway has been proved (Rohmer M. et al., Biochem.J. 295, S.517( 1993); Lois E.M. et al., Proc. Natl. Acad. Sci. USA 95, S.2105 (1998)).

For parasites up to now no alternative metabolic pathway has been known. The applicant of the present invention succeeded in proving an alternative metabolic pathway, the so-called 1- 4 or 2-C-methylerythrose-4-phosphate pathway for parasites.

Studies of HMG-CoA-reductase inhibitors in parasites resulted in different results in dependence on the parasites. For example, pathogens of schistosomiasis are not killed by high doses of lovastatin, while pathogens of malaria are killed in vitro, but not in vivo.

Also, the pathogens of sleeping sickness are not fully inhibited by inhibitors of HMG- CoA-reductase. Similar attempts in inhibiting the increase of viruses show that cells infected by viruses loose the inhibiting influence of the HMG-CoA-reductase inhibitors.

Also, squalene synthetase inhibitors, such as the aminobisphosphonate, have been examined without success as inhibitors of the amoebic dysentery. A low efficiency of killing has been shown. Similar experiments with toxoplasm also show no satisfying results. Further also, inhibitors of squalene monooxygenase have been developed as fungicides (US 4,782,059).

It is therefore an object of the present invention to provide agents which may be used against infectious processes in humans, animals and plants and as herbicides and against which the built-up resistance in plants, viruses, fungi, parasites and bacteria is significantly reduced.

Surprisingly, it has been found that the combination of anti-infectiously active compounds which inhibit the 2-C-methylerythrose-4 metabolic pathway, and inhibitors of the lipid synthesis, in particular the synthesis of cholesterol, in particular inhibitors of HMG-CoA-reductase, and the squalene synthetase increase the scope and the effectiveness of therapy and prophylaxis of infections. Surprisingly, the combination kills microorganisms which are killed neither by the first nor the second group. Surprisingly, the combinations show a significant reduction of build-up of resistance against the used compounds, which is generally the major problem in handling the compound group of 25 lipid metabolism inhibitors.

According to a first embodiment of the invention there is provided a composition comprising as active ingredients at least one anti-infectiously active compound which inhibits the 2-C-methylerythrose-4 metabolic pathway, and at least one inhibitor of the lipid metabolism, wherein the inhibitor of the lipid metabolism and the anti-infectiously 30 active compound are not identical.

Lipid metabolism inhibitors of anti-infectiously active compounds which inhibit the 2-C-methylerythrose-4 metabolic pathway, and inhibitors of the lipid metabolism are suited for the therapeutic and prophylactic treatment of infections in plants, in particular in humans and animals, in particular of infections which are caused by parasites, bacteria, fungi and viruses, and as herbicides in plants.

Accordingly, in a second embodiment of the invention there is provided the use of a composition according to the first embodiment of the invention for the therapeutic and [R:\LIBH]01456.doc:UG 4a prophylactic treatment of infectious processes in humans, animals and plants and as herbicides in plants.

According to a third embodiment of the invention there is provided a method for the treatment and prophylaxis of infectious processes in humans, animals and plants, comprising administering to said human, animal or plant a composition according to the first embodiment of the invention.

According to a fourth embodiment of the invention there is provided a composition according to the first embodiment of the invention, when used for the treatment or prophylaxis of infectious processes in humans, animals or plants.

Lipid metabolism inhibitors according to the invention contain at least one antiinfectiously active compound which inhibits the 2-C-methylerythrose-4 metabolic pathway and/or their esters and/or their salts. Generally, pharmaceutically acceptable salts, esters, salts of esters or compounds which upon application provide compounds according to the invention as metabolic products or decomposition products, also called "prodrugs", are included.

In the following some groups of substances are described by example which show excellent

,I

*g *go• oooo *oo [R:\LIBH]01 456.doc:LJG success in therapy and prophylactic treatment of infections in combination with lipid metabolism inhibitors.

The groups of anti-infectiously active substances may be determined by a method, in which the proteins being part of the 2-C-methylerythrose-4 metabolic pathway or their derivatives are contacted with the active agents to be examined, and the active agents inhibiting the proteins or derivatives are selected. The method is known by a person skilled in the art.

I. Combined preparations of lipid metabolism inhibitors and aminohydrocarbyl phosphonic acid derivatives The aminohydrocarbyl phosphonic acid derivatives as well as their preparation have been described in DE-A1-2733658 and the PCT/EP99/02462 in detail.

The aminohydrocarbyl phosphonic acid derivatives correspond to the general formula RI, 0

II

N-AI-P-RI

3 (I)

I

RI2 RI4 in which Rn and R2 may be the same or different and are selected from the group which consists of H, OH, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, and substituted and unsubstituted heterocyclic radicals, Ru and R 4 are selected from the group which consists of substituted and unsubstituted alkyl with 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl with 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl with 1 to 26 carbon atoms, substituted and unsubstituted alkynyl with 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radicals, halogen, XL and X 14

X

3 and XI 4 may be the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl with 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl with 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl with 1 to 26 carbon atoms, substituted and unsubstituted alkynyl with 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which dive from ethylene diamine or amino acids, and A is an alkylene radical, alkenylene radical or hydroxy alkylene radical or corresponds to the following formula (IA):

B

11 BI3 B 15

B

1 7 BI9 -CI1-CI2-CI3-CI4-CI5- (IA) I I I I I

BI

2

BI

4

BI

6

BI

8

BI

10 wherein one or more carbon atoms, selected from the group Cu, CI4, CIS, together with their substituents may also be absent, and at least one present substitute of B to Bio is a C3- 8 cycloalkyl-(Co-9)-alkyl group, wherein the C 3 .8-cycloalkyl group as well as the Co.

9 -alkyl group may comprise one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein the cycloalkyl group as well as the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups with branched or straight Ci.9-alkyl groups and C 2 -9-alkenyl groups, wherein the Ci-9-alkyl groups and C 2 -9-alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, and the remaining present substituents Bn to Bno are selected from the group which consists of hydrogen, hydroxy, halogen, amino groups, C-.

26 -alkyl radicals, Ci- 26 -alkoxy radicals, C 1 26 -alkoxy-Ci.

26 -alkyl radicals or both substituents of one C-atom together form an oxo group, wherein each C.- 26 -alkyl radical and each Ci- 26 -alkoxy radical may be branched or straight and saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups.

According to the invention the inhibitor of lipid metabolism is not an aminohydrocarbyl phosphonic acid derivative of the formula if an aminohydrocarbyl phosphonic acid derivative is used as the anti-infectiously compound.

The invention also comprises the pharmaceutically acceptable salts, esters and salts of esters.

Preferably Rn is OXu, RI is OX3, and RI4 is OX 1 4 wherein Xn is selected from the group which consists of hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclic radical and R 12 Xu, X 14 and A contain the same meaning as in formula Preferably the carbon chain of Ai consists of three carbon atoms.

Compounds in which the carbon chain of Ai of formula (IA) consists of four carbon atoms

CI

1 CI2, C3, CI 4 and B 1 7 or Big or both are hydroxy groups are also preferred. In this case methylene groups are also preferred for Ru and R 4 Preferably Bn and BI2 together form furthermore an oxo group. In this case the carbon chain in AI consists of the four carbon atoms Cn, CI, CU, CI 4 Preferably, B 17 and Bg 8 together form furthermore an oxo group. In this case the carbon chain in A also consists of four carbon atoms Cn, Cn, Cu, C 14 The carbon chain preferably consists of 5 carbon atoms Cn, Cu, Cu, C 1 4, C 1 5 wherein Bn 1 and

BI

2 together form an oxo group and at least one substituent of Bs or Bno is a hydroxy group or BI 9 and B 1 o together also form an oxo group.

Also substances are suitable, in which a phosphonic acid or phosphinic acid or phosphinoyl group is replaced by a sulfonic group or sulfonyl group: 0

S-RI

3 (IB) 0 Po *0 *9 **oo This page has been left blank intentionally S S S S

S

S.

S S

S

S S S S 5S S S 55

S

*SSS

S

[]:\DAYLIB\LIBHIO I 456.doc:aei 1I. Combined preparations of lipid metabolism inhibitor with organophosphorus compounds comprising a keto group These compounds are described in detail in the German Patent specification DE-A-198 31 637.2.

These compounds according to the invention correspond to the general formula (III): 0 0 II

II

RIIIi-AIII 1 -C-AI I 2

-P-RIII

4

(III)

RIII3 in which RIun is selected from the group which consists of H, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radicals, halogen and OXml, wherein Xmi is selected from the group which consists of hydrogen, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, a silyl, substituted and unsubstituted heterocyclic radicals, a cation of an organic and 9 20 an inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds,

R

14 and RII3 may be the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsub- *i 25 stituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen and OXm4 and OX3m, wherein XmI4 and Xim are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, 30 substituted and unsubstituted cycloalkyl, a silyl, substituted and unsubstituted heterocyclic radical, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylene diamine or amino acids, and Ann and AIII 2 of which one or both may be absent are the same or different and represent an alkylene radical, alkenylene radical, an oxo radical, a hydroxy radical or oxo hydroxyalkylene radical, wherein Ann2 is preferably absent.

The invention comprises as well the pharmaceutically acceptable salts, amides, esters and salts of esters.

The phosphonic acid derivatives of the present invention prove to be especially suited. In this case RU 14 is OXIII4 and RII3 is OXn 1 I3, wherein Rmi, XIII4, X 11 I3, Ai 1 and AII2 contain the same meaning as in formula (I1).

Particularly preferred phosphonic acid derivatives are chloroacetyl phosphonic acid (fosfonochlorin), phosphonoformic acid (foscarnet), phosphonoacetic acid, N,N-dimethyl-(1-hydroxy- 2-oxo-2-methoxy-ethyl)-phosphonamide and 2-hydroxy-2-hydroxymethyl-3-oxobutylphosphonic acid (phosphonothrixine) and ammonium-ethylcarbamoyl phosphonate (fosamine ammonium).

IV. Combined preparations of lipid metabolism inhibitor and organophosphorus compounds which contain at least one ether group or one keto group These compounds according to the invention correspond to the general formula (IV): Rjvj 0

II

N-Bjv- P-RIV3

RIV

2 RIV4

(IV)

in which Rivi and RIv2 being the same or different are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXIvl and OXIv2, wherein Xvi and XIv2 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radicals, 7 -11- Biv is selected from the group which consists of ether group (IVA)

Y

Aiv O Aiv2 C (IVA),

Z

wherein Avi and AIv 2 of which AIV 2 also may be absent are the same or different and are selected from the group which consists of alkylene radical, alkenylene radical and hydroxyalkylene radical, keto group (IVB) 0

II

AIv 3 C Aiv 4

(IVB)

wherein AIv 3 and AIV 4 of which one or also both may be absent, are the same or different, are selected from the group which consists ofalkylene radical, Alkenylene radical and hydroxyalkylene radical, and 5 and 6 membered cyclic, in particular heterocyclic compounds, which contain additionally to carbon at least one heteroatom as a ring member, wherein the heteroatom is selected from the group which consists of oxygen and nitrogen, Riv 3 and RIV4 being the same or different are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OXv 3 or OXV 4 wherein Xv3 or Xv4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radicals, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylene diamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts of esters.

In particular compounds are preferred which correspond to the formula (IVC) iS -12- HO HO I II N-Axvi-O-C-P-OXIv 3

(IVC)

II

R

I

V

2 H OXiv 4 wherein Riv 2 is selected from the group which consists ofacetyl and formyl, AIvI is selected from the group which consists of methylene, ethylene, ethenylene, hydroxyethylene, 2-hydroxypropylene, and

XIV

3 and XIV4 are the same or different and are selected from the group which consists of sodium, potassium, methyl, ethyl.

Preferably the chain -Aivi-O-C(ZY)- consists of one oxygen atom and two or three carbon atoms (substituents are not taken into consideration), particularly preferred two carbon atoms.

Out of the ether compounds the compounds are particularly preferred which are selected from the group which consists of ((N-formyl-N-hydroxyamino)-methoxy)-methylphosphonic acid disodium salt, ((N-acetyl-N-hydroxyamino)-methoxy)-methylphosphonic acid disodium salt, (2-(N-formyl-N-hydroxyamino)-ethenoxy)-methylphosphonic acid disodium salt, acetyl-N-hydroxyamino)-ethenoxy)-methyl-phosphonic acid disodium salt, (3-(N-formyl-Nhydroxyamino)-2-hydroxypropoxy)-methylphosphonic acid disodium salt, (3-(N-acetyl-Nhydroxyamino)-2-hydroxypropoxy)-methylphosphonic acid disodium salt.

Further those compounds are preferred, which correspond to the formula (IVD) HO 0 0 II II N-Aiv3-C-AIV4-P-OXIV3 (IVD)

R

I

V

2 OXIv4 wherein Riv 2 is selected from the group which consists ofacetyl and formyl, Aiv 3 is selected from the group which consists of methylene, ethylene, ethenylene, hydroxymethylene, hydroxyethylene and 2-hydroxypropylene, Aiv 4 is absent or is methylene, and Xiv 3 and XIV4 are the same or different and are selected from the group which consists of a metal of the first, second or third main group of the periodic system, in particular sodium, potassium, and methyl, ethyl.

Preferably the chain -Avi-CO-AIv 2 consists of two to four carbon atoms (substituents are not taken into consideration), particularly preferred of three carbon atoms.

v Ls'I 13 Out of these compounds 2-(N-formyl-N-hydroxyamino)-1-oxoethylphosphonic acid disodium salt, 2-(N-acetyl-N-hydroxyamino)-l1-oxoethylphosphonic acid disodium salt, 3-(N-formyl-Nhydroxy amino)-1I-oxopropylphosphonic acid disodium salt, 3-(N-acetyl-N-hydroxy amino)- 1 -oxopropyiphosphonic acid disodium salt, 3-(N-formyl-N-hydroxyamino)-l1-oxo-2propenyl-phosphonic acid disodium salt, 3-(N-acetyl-N-hydroxyamino)-l1-oxo-2propenyiphosphonic acid disodium salt, 4-(N-formyl-N-hydroxyamino)-l1-oxo-3hydroxybutyiphosphonic acid disodium salt, 4-(N-acetyl-N-hydroxyamino)- 1 -oxo-3 hydroxybutyl-phosphonic acid disodium salt, 3-(N-formyl-N-hydroxyamino)-2-oxopropylphosphonic acid disodium salt, 3 -(N-acetyl-N-hydroxyamino)-2-oxoproylphosphonic acid disodium salt, 4 -(N-formyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-methylbutylphosphonic acid disodium salt, 4 -(N-acetyl-N-hydroxyamino)-3-oxo-2-hydroxy-2-methylpropylphosphonic acid disodium salt, 4-(N-formyl-N-hydroxyanlino)-3-oxo-2-hydroxy-2- (hydroxymethyl)-butyl-phosphonic acid disodium salt, 4-(N-acetyl-N-hydroxyamino)-3-oxo- 2 -hydroxy-2-(hydroxymethyl)-propylphosphonic acid disodium salt are particularly preferred.

In the cyclic compounds the amino group and the phosphorus atom may be bound to any Catoms of the ring. However, compounds are preferred, in which they are bound to two Catoms, which are separated only by one additional atom. In the heterocyclic compounds both carbon atoms preferably are separated by one heteroatom.

The following compounds are particularly preferred: Rjvj 0 NP-0XIV 3

(IVE)

Rjvj 0 N PIOI3(IVF) RiV 2

XV

Rjvj 0 N -P-OXIV 3

(IVG)

/j2UAV 14 Additionally, substances are suitable in which the phosphonic acid or phophinic acid or phosphinoyl group is replaced by a sulfonic group or sulfonyl group: 0 I I 0

(VIIE)

RALIBH]O 456.doc: UG This page has been left blank intentionally C. C C C CCC C 3? [R:\LIBH]01456.doc:LJG This page has been left blank intentionally

S

S.

S

5555

*SSS

[R:\LIBH]01I 456.doc: UG -17- VI. Combined preparation of lipid metabolism inhibitor and organophosphorus or organosulfur compounds containing an amine or imine group The organophosphorus compounds according to the invention correspond to the general formula (VI): 0 BvI-P-Rvi3

(VI)

1 RvI4 wherein RvI 3 and RvI4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radicals, halogen, OXvu or OXI4, wherein Xv 3 or XVI4 are the same or different and are selected from the group which consists is of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylene diamine or amino acids, and Bvi is selected from the group which consists of the group (VIA) •0 0 -18- RvI 1 N-Avi- (VIA) Ry 2 and the group (VIB) RvII-N=Avi- (VIB) wherein Avi is selected from the group which consists of an alkyleneamine radical, an alkenyleneamine radical, a hydroxyalkyleneamine radical, an alkyleneimine radical, an alkenylene imine radical and a hydroxyalkyleneimine radical, wherein the nitrogen atom is a member of the chain which connects the phosphorus atom with the nitrogen atom of the group Rvii N- or the group Rvn-N= and Rvi2 in which Rvii and RvI 2 in group (VIA) are the same or different and Rvn and Rvl2 in group (VIA) and Rvii in group (VIB) are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXvl and OXv2, wherein Xvii and Xv2 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, and their pharmaceutically acceptable salts, esters and amides and salts of esters.

Preferably, Avi is an amino group, in which the nitrogen atom is not in the end position. Preferably, Avi connects the nitrogen and the phosphorus atom by three atoms (without substituents).

In particular those compounds are preferred, which correspond to the formula (VI) 0 v -19- Rvil 0

II

N-Avi-P-RvI3 (VI) RvI2 OXI 4 wherein RvII, RVI 2 RvI 3 and XVI4 are defined the same as in formula and Avi is selected from the group which consists of C-N-C, C=N-C, C-N=C, wherein the carbon atoms may be substituted with a hydroxy or alkyl group having up to 7 carbon atoms.

Particularly preferably Rvn is a hydroxy group, RvI2 is selected from the group which consists of acetyl and formyl, Rv3 is selected from the group which consists of hydrogen, methyl, ethyl, hexadecyl, octadecyl and OXv3, and Xv13 and XVI4 selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl, hexadecyl and octadecyl, and may be, as far both are present, the same or different.

Further compounds are preferred which correspond to the formula (VID) 0 I RviN=Avi- P-Rv 3

(VID)

OXvi4 wherein RvII, Rvi2, RV13 and Xvi 4 are defined the same as in formula and A is selected from the group which consists of C-N-C, C=N-C, C-N=C, wherein the carbon atoms may be substituted with a hydroxy or alkyl group having up to 7 carbon atom.

Particularly preferably Rvii is selected from the group which consists ofacetyl and formyl, and Rvi 3 is selected from the group which consists of hydrogen, methyl, ethyl, hexadecyl, octadecyl and OXVI3, and Xvu and Xvi 4 are selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl, hexadecyl and octadecyl, and may be the same or different as far both are present.

VII. Combined preparation of lipid metabolism inhibitor with organophosphorus compounds, which contain a nitrogen heterocycle The organophosphorus compounds used according to the invention correspond to the general 0

I

Rv 11 -Avi 1 n-P-Rv 3

(VII)

RvII4 in which Avii is selected from the group which consists of (Ci.

9 )-alkylene radical, which may comprise one or more double bonds and may be substituted with hydroxy, halogen, amino, oxo groups with branched or straight C 1 9 -alkyl groups and C2-9-alkenyl groups, wherein the Ci.

9 -alkyl groups and C2- 9 -alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, and wherein the carbon atoms of-C-O-C- and C-N-C- may be substituted with an alkyl having up to 7 carbon atoms or hydroxy groups, or in which Avi corresponds to the following formula (VIIA): BvIII BvII3 BvIIS BvII7 BvII9 -CvIICV II2- 1 CvII3-CvII4 -CvII5- (VIIA) I I I I I BVII2 BviI4 BvII6 BVII8 wherein one or more of the carbon atoms selected from the group Cv3, CVI 4 Cvn 5 may also be absent together with their substituents, and at least one present substitute of Bvm 1 to Bvno is a C3.s-cycloalkyl-(Co.9)-alkyl group, wherein the C3.-cycloalkyl group as well as the Co- 9 alkyl group may contain one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein the cycloalkyl group as well as the alkyl group may by substituted with hydroxy, halogen, amino, oxo groups, with branched or straight Ci.

9 -alkyl groups and with C2 9 -alkenyl groups, wherein the Cl.9-alkyl groups and C 2 -9-alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, and the remaining present substituents Bvm to Bvmo are selected from the group which consists of hydrogen, hydroxy, halogen, amino groups, Ci- 26 -alkyl radicals, Ci- 26 -alkoxy radicals, CI- 26 -alkoxy-Ci.

26 -alkyl radicals or both substituents of one Catom together form an oxo group, wherein each Ci- 26 -alkyl radical and each C.i 26 -alkoxy radical may be branched or straight and saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups, in which Rvi 1 is selected from the group which consists of 5 and 6 membered heterocycles with one or two nitrogen, oxygen or sulfur atoms in the ring, wherein the heterocycle may be saturated or unsaturated with one or more double or triple bonds and may be substituted with hydroxy, halogen, amino, oxo groups and by branched or straight Ci.9-alkyl groups and by C2- 9-alke-nyl groups, wherein the Ci.9-alkyl groups and C2-9-alkenyl groups may be saturated or unsaturated with one or more double or triple bonds and may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, II I -21 in which Rvm and RvH4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted Ci- 26 -alkyl, hydroxy-C 1 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C.i 26 -alkenyl, substituted and unsubstituted Ci.

26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OXVI3 and OXVII 4 wherein Xvu3 and XviI4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted Ci.

26 -alkyl, substituted and unsubstituted hydroxy-C- 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C- 26 -alkenyl, substituted and unsubstituted Ci- 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylene diamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts of esters.

If two heteroatoms are present in the heterocycle Rvni, of course they also may be present in mixed form, for example an oxygen atom and a nitrogen atom.

Preferably RvIIi is a heterocycle containing nitrogen atoms, wherein substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrrole and substituted or unsubstituted pyrazole are particularly preferred and or -N are especially particularly preferred.

Preferably the organophosphorus compound corresponds to the formula (VIIC) 0 I RvI I-AvII-P-RvII3 (VI IC) OXvi14 wherein RvI preferably is hydrogen, methyl, ethyl or an amide radical and XVI4 is selected from the group which consists of hydrogen, sodium, potassium, methyl, ethyl, S-and particularly preferably correspond to the formula (VIID) -22- 0 11 RvI1-AvII-P-OXv 1 3 (VIID)

I

UXv 1 14 Additionally, substances are suitable in which the phosphonic acid or phosphinic acid or phosphinoyl group is replaced by sulfonic group or sulfonyl group: 0 11

S-R

1 1 3

(VIIE)

0 VIII. Combined preparation of lipid metabolism inhibitor and phosphonoformic acid derivatives The compounds are described in WO 98/16537.

The organophosphorus compounds used according to the present invention correspond to the general formula (VIII): 0O 0 Rv 1115 O RvIII11

(CHR

11 4 )n ORvIII 1 Rv 1 1 1 3

RV

111 2 wherein the wavy line represents a bond which has either a- or 3-configutiration, n is 0 or 1, wherein Rvii 11 is selected from the group which consists of substituted and unsubstituted Cl- 26 -alkyl, hydroxy-C 1 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted Cl- 26 -alkenyl, substituted and unsubstituted Ci-2 6 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radicals, halogen and OXvmiI, wherein Xvn 11 I is selected from the group which consists of hydrogen, substituted and unsubstituted Cl- 26 -alkyl, substituted and unsubstituted hydroxy-C- 2 6-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted CI- 26 -alkenyl, -23substituted and unsubstituted Ci- 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylene diamine or amino acids, RvIII 1 is selected from the group which consists of C1i24-alkyl radicals,

C

2 24 -alkenyl radicals, C2.2 4 -alkapolyenyl radicals, which contain 2 to 6 double bonds, C2- 24 alkynyl radicals, C3.s-cycloalkyl radicals, C3-8-cycloalkyl-Cl-2 4 -alkyl radicals and C -12alkoxy-C.-1 2 -alkyl radicals, RvnII 2

RVII

3 and RVII 4 each are selected independently from the group which consists of hydrogen, halogen, amino, acetylamino, azido and XRvIl6-groups, wherein X is O or S and Rvni 6 is selected from the group which consists of a hydrogen radical, branched or straight Cl-4-alkyl radicals and C2-4-alkenyl radicals, wherein the C1-4-alkyl radicals as well as the C2-4-alkenyl radicals optionally may be substituted with hydrogen, amino, halogen or oxo groups, or

RVIII

2 RVII3 and RVIII 4 together with the respective geminal hydrogen group represent an oxo group, RviII 5 is selected from the group which consists of hydrogen, CI- 24 -alkyl groups, C 3 8 cycloalkyl radicals, ar(Ci- 24 -alkyl) groups, aryl groups, acyl groups, heterocyclic radicals, halogen, wherein all radicals may be branched or straight and optionally may be substituted with hydroxy, amino, halogen or oxo groups and may contain 2-6 double and triple bonds or Rviis 5 is a phenyl radical of the formula VIIIA or XIIIB,

(VIIIA)

RRvv 11

CH

2 Q

(VIIIB)

RvR 11 8 RvIII7 wherein Rvm 17 and Rv 1 18 are the same or different and are bound to any two positions of the -7 phenyl ring and are selected independently from the group which consists of hydrogen, haloci

I!

-24gen, C 14 -alkyl radicals, C 14 -alkoxy radicals, formyl, acetyl, propionyl, butyryl radicals, formyl, acetyl, propionyl, butyryloxy radicals, C2.s-alkoxycarbonyl radicals, which all may be branched or straight, or R 7 and Rviii may form together a straight saturated alkylene chain having 3 to 4 carbon atoms bound to adjacent positions, for example the 2,3-position or 3,4position of the phenyl ring, or R 7 and Rs together form a methylenedioxy radical, a 1,1ethylidenedioxy radical or a 1,2-ethylenedioxy radical, which are bound to the 2,3- or 3,4positions of the phenyl ring, or is selected from the group which consists of Rvm9COOCHRvmio- and 1 1 wherein Rvii9 is selected from the group which consists of Ci.-alkyl radicals, C2-6-alkenyl radicals, C2-6-alkynyl radicals, C3.

8 -cycloalkyl radicals, C3 8 -cycloalkyl-Ci.

6 -alkyl radicals and Ci.-alkoxy-Ci-6-alkyl radicals, wherein all radicals may be branched or straight and optionally may be substituted with hydroxy, amino, halogen or oxo groups, and RIO is a branched or straight C-4-alkyl radical, and wherein the configurations of the substituents Rvm, Rvn3, RV 4 and 2 in (VIII) are selected independently from D-gluco, L-gluco, Dgalacto, L-galacto, D-manno, L-manno, D-talo, L-talo, D-allo, L-allo, D-altro, L-altro, Dgulo, L-gulo, D-ido or L-ido, if n is 1 or the configurations of the substituents R 2

R

3 and RsOOCPO(OH)OCH 2 in I are independent D-ribo, L-ribo, D-arabino, L-arabino, D-xylo, Lxylo, D-lyxo or L-lyxo, if n is 0.

According to the invention the configuration of the glycosidic bond of the compounds is preferably a.

Preferred compounds of formula (VIII) are those, wherein Rvmi is selected from the group which consists of C 9 -2 4 -alkyl radicals, C9- 24 -alkenyl radicals, C9.24-alkapolyenyl radicals, which contain 2 to 6 double bonds, C9-24-alkynyl radicals, C 3 -8-cycloalkyl-C6- 24 -alkyl radicals and Cl.

1 2-alkoxy-C8- 1 2 -alkyl radicals, which each may optionally be branched or straight and may be substituted with hydrogen, amino, halogen or oxo radicals.

In particular the use of any compound is preferred, in which Rvin is selected from the group which consists of a n-tetradecyl radical, n-octadecyl-1-yl radical, a trans-9-octadecenyl radical and a cis-9-octadecen-1- radical. Preferably RvnM, Rvm3, RVII4 each are hydroxy groups.

Preferably Rvmi5 is a hydrogen, a formyl group or a acetyl group. Furthermore n is preferably 1 and the configuration of the substituents Rvi 2 Rvm3, RVII 4 and RvIimOOCPO(OH)OCH2is D-gluco.

Preferably RvIim represents OXviiII with Xvnn hydrogen.

L/ .1'7 O i" IX. Combined preparation of lipid metabolism inhibitor and heterocyclic phosphonoformic acid derivatives The organophosphorus compounds according to the invention are described in W098/16537 and correspond to the formula (IX) 0 0 SRIX11 0 (IX) Rjxj RIX2 wherein RIxI is selected from the group which consists of substituted and unsubstituted C1- 26 alkyl, hydroxy-Ci-2 6 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C1-2 6 -alkenyl, substituted and unsubstituted Cl.-2 6 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen and OXjx 11 wherein Xxj I is selected from the group which consists of hydrogen, substituted and unsubstituted Cl-2 6 -alkyl, substituted and unsubstituted hydroxy-Cl- 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Ci-2 6 s-alkenyl, substituted and unsubstituted Ci-.

26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylene diamine or amino acids, wherein Rix and RI each are selected independently from the group which consists of C 1 24 alkyl radicals, C3.s-cycloalkyl radicals, C3.s-cycloalkyl-C- 2 4 -alkyl radicals, C.z- 24 -alkoxy radicals, C1-24-alkylthio radicals, C1.-24-alkoxy-Cl- 24 -alkyl radicals and CI- 24 -aikylthio-Ci-2 4 -alkyl radicals, acyl radicals, aryl radicals, aralkyl radicals, heterocyclic radicals, halogen and hydrogen, and each CI.

24 -alkyl radical and Cl.-2 4 -alkoxy radical may be branched or straight and may be saturated or unsaturated with 2 to 6 double bonds and optionally may be substituted with hydroxy, amino, mercapto, halogen, oxo groups or CI- 24 -alkoxy radicals, CI- 2 4 alkylcarbonyl-oxy radicals, C1-24-alkoxycarbonyloxy radicals, Ci- 24 -alkylthio radicals, C 1 2 4 alkylcarbonyl-thio radicals, Cl-24-alkylamino radicals, di-(C1-2 4 -alkyl)amino radicals, C1-24alkylcabonyl-amino radicals, C1-24-alkyl-(CI-24-alkylcarbonyl)amino radicals, C 1 -24alkoxycarbonylamino radicalsorC-.

24 -alkyl-(CI-24-alkoxycarbonyl)amino radicals, wherein each aralkyl radical, heterocyclic radical, C1-24-alkyl radical and Ci.- 24 -alkoxy radical may be -26branched or straight and may be saturated or unsaturated with 2 to 6 double bonds or triple bonds, or wherein RIxi-CH-CH-Rax 2 form part of a C4-8s-carbon ring, which optionally may be substituted with hydroxy, mercapto, amino, halogen, oxo groups or with CI- 24 -alkyl radicals, C 1 2 4 alkoxy radicals, CI.-2 4 -alkylthio radicals, CI.-24-alylamino radicals, di-(C 1 .2 4 -alkyl)aminoradicals, CI-24-alkylcabonyl radicals, C1-24-alkylcarbonyloxy radicals, C1.24-alkoxycarbonyl radicals, C1-24-alkylcarbonylthio radicals or Cl-2 4 -alkylcarbonylamino radicals, C 1 2 -alkyl-(C 1 24-alkylcarbonyl)-amino radicals, all Cl- 24 -alkyl radical may be branched or straight and saturated or unsaturated with 1 to 6 double bonds, or wherein Rxjo is a branched or straight C1-4-alkyl radical, and wherein RIx-CH-CH-H-Rx2 form a part of the furanose or pyranose ring of a sugar, for example D-ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, Dtalose, D-allose, D-altrose, D-gulose, D-idose or the corresponding L-isomers, wherein the hydroxy groups each may be optionally substituted with hydrogen, amino, azido, oxo, mercapto radicals or Cl-2 4 -alkoxy radicals, Cl-2 4 -alkylthio radicals, Cl-24-alkylamino radicals, di- (Cl-24-alkyl)amino radicals, C-1.24-alkylcabonyloxy radicals, Cl-2 4 -alkylcarbonylthio radicals, C1-24-alkylcarbonylamino radicals, C1-24-alkyl-(C1-2 4 -alkylcarbonyl)amino radicals, wherein each CI.-2 4 -alkyl radical may be branched or straight and saturated or unsaturated with 1 to 6 double bonds, and their pharmaceutically acceptable salts, esters and amides and salts of esters as well as their optical isomers.

In particular Rux and Rx2 each may be selected independently from the group which consists of carboxyl radicals, carboxamido radicals, aryl radicals, aryloxycarbonyl radicals, aryl-CI- 24 alkyl radicals, C-1.24-alkoxycarbonyloxy radicals, C1-24-alkCylaminocarbonyl radicals, di-(CI- 24 alkyl)-aminocarbonyl radicals, aryl-C1-24-alkoxycarbonyl radicals, aryl-C 1 24 -alkylamino- carbonyl radicals, Cl-24-alkylcabonyloxy-(Cl-4)-alkylmethoxycarbonyl radicals, CI- 24 -alkoxycarbonyloxymethoxycarbonyl radicals, CI-24-alkoxycarbonyl-oxy-(C-4-alkyl)methoxycarbonyl, wherein each Ci- 2 4 -alkyl radical may be branched or straight and saturated or unsaturated with 2 to 6 double bonds, and each Cl-4-alkyl radical and C 1 24 -alCkoxy radical may be branched or straight and saturated or unsaturated, and each aryl radical corresponds to the formula IXA

(IXA)

RIx 4 RIx3 wherein RDO and Rx 4 are the same or different and each are selected from the group which -27consists of hydrogen, halogen, C-4-alkyl radicals, Ci-4-alkoxy radicals, formyl, acetyl, propionyl, butyryl radicals, formyl, acetyl, propionyl, butyryloxy radicals, Ci.4-alkoxy carbonyl radicals, which all may be branched or straight, or Roo and RIx 4 together form a straight saturated alkylene chain with 3 to 4 carbon atoms, which is bound to adjacent positions of the phenyl ring, or RDx3 and Rix 4 together form a methylene dioxy radical, a 1,1-ethylidenedioxy radical or a 1,2-ethylenedioxy radical which is bound to adjacent positions of the phenyl ring.

The use of compounds is preferred, in which Rixl and RDQ each are independently selected from the group which consists of hydrogen, hydroxy groups, formyl, acetyl and methyl, wherein the methyl radical optionally may be substituted with a hydroxy group or mercapto group or with Ci-2 4 -alkoxy radicals, C1-24-alkylcarbonyloxy radicals, C 1 -2 4 -alkylthio radicals or C1-24-alkylcarbonylthio radicals, wherein the C1-2 4 -alkyl groups and the Ci- 24 -alkoxy groups may be branched or straight and saturated or unsaturated with 1 to 6 double bonds.

Rix 1 is particularly preferred a methyl radical, which optionally may be substituted with a hydroxy group or mercapto group or by Cl-2 4 -alkoxy radicals, Ci-2 4 -alkylcarbonyloxy radicals,

C

1 -2 4 -alkylthio radicals or C-12 4 -alkylcarbonylthio radicals, wherein the CI- 24 -alkyl groups and the Ci- 24 -alkoxy groups may be branched or straight and saturated or unsaturated with 1 to 6 double bonds, and Rix 2 a hydrogen radical.

Especially good results are achieved by compounds, wherein Rixi and RIx2 each is independently selected from the group which consists of hydrogen and a n-octadecylmethyl radical, wherein Rixi is preferably a n-octadecylmethyl radical and R 2 is a hydrogen radical. Special advantages are achieved, if the compound is of configuration Preferably RIxi represents OXIxi with Xixii hydrogen.

X. Combined preparation of lipid metabolism inhibitor and hydroxy aminooxocarbyl derivatives The hydroxy aminooxocarbyl derivative used according to the present invention correspond to the general formula HO 0

II

N-C-Rx 2 (X) Rxl wherein Rxl is selected from the group which consists of hydrogen, substituted and unsubstituted Ci_9-alkyl, substituted and unsubstituted hydroxy-Ci-9-alkyl, substituted and unsubstituted Ci.

9 -alkenyl, substituted and unsubstituted CI.9-alkynyl, substituted and unsubstituted IK ~>l 28 aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen and OXxi, wherein Xxi is selected from the group which consists of hydrogen, substituted and unsubstituted CI.

9 -alkyl, substituted and unsubstituted hydroxy-Ci.9-alkyl, substituted and unsubstituted C 1 -9-alkenyl, substituted and unsubstituted Ci.9-alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, wherein R 2 is selected from the group which consists of C1- 26 -alkyl radicals, C.- 26 -alkoxy radicals, Ci.

26 -alkoxy-Ci- 26 -alkyl- radicals, C 3 cycloalkyl-(Co.

26 )-alkyl radicals, wherein one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, each C 3 26 -alkyl radical and each C3- 26 -alkoxy radical being branched or straight and each C3.8-cycloalkyl radical, each C 2 26 -alkyl radical and each C2- 26 -alkoxy radical may be saturated or unsaturated with one or more double bonds and each C3.s-cycloalkyl radical, each

C

1 26 -alkyl radical and each Ci- 26 -alkoxy radical may be substituted with hydroxy, amino, halogen and oxo groups or with the carbyl group CORx 3 wherein Rx 3 is selected from the group which consists of substituted and unsubstituted C1- 26 alkyl, hydroxy-C.- 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted Ci- 26 -alkenyl, substituted and unsubstituted Ci- 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen and OXx 3 wherein Xx 3 is selected from the group which consists of hydrogen, substituted and unsubstituted Cl.

26 -alkyl, substituted and unsubstituted hydroxy-Ci- 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Ci- 2 6 -alkenyl, substituted and unsubstituted Ci.

26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylene diamine or amino acids,.

Preferably Rx 2 represents the carboxylic acid group -COOH, wherein Rxi is a branched or straight Ci-4-alkyl group, particularly preferred an isopropyl group, as well as their pharmaceutically acceptable salts, esters and amides.

The salts of the carboxylic acid group are preferred, in which H is replaced by a metal of the first, second or third main group of the periodic system, ammonium or substituted ammonium, or ammonium compounds, which derive from ethylene diamine or amino acids. I.e. the salt compounds of hydroxy aminooxocarbylcarbonic acid derivatives and organic or inorganic bases (for example sodium salt, potassium salt, calcium salt, aluminium salt, ammonium salt, -29magnesium salt, triethyl amine salt, ethanol amine salt, dicyclohexyl amine salt, ethylene diamine salt, N,N'-dibenzylethylene diamine salt etc.) as well as salts of amino acids (for example arginine salt, asparagine acid salt, glutamine acid salt etc.) and the like are formed.

Preferably additionally esters of the carboxylic acid group may be formed. Suitable examples of such esters are suitable mono and diesters, and preferred examples of such esters include alkylester (for example hexadecanylester, octadecanylester etc.).

XI. Combined preparation of lipid metabolism inhibitor and organophosphorus compounds, which either contain two oxyphosphorus groups or one oxyphosphorus group and one oxysulfur group The organophosphorus compounds used according to the present invention correspond to the general formula (XI): 0 0 II II RxII-ZxI-AxI-P-RXI 3

(XI)

I I Rxi2 Rx i 4 wherein Zxj is a phosphorus atom or a sulfur atom, wherein Axi is a straight C 2 9 -alkylene chain having substituents which are the same or different and are selected from the group which consists of hydrogen, hydroxy, halogen, amino and oxo groups, Ci- 26 -alkyl radicals, C 1 2 6 -alkoxy radicals, Ci.

26 -alkoxy-C 1 26 -alkyl radicalsorC 3 -scycloalkyl-(Co_9)-alkyl radicals, wherein each Ci- 26 -alkyl radical and each Ci- 26 -alkoxy radical may be branched or straight and saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups and the C 3 s-cycloalkyl group as well as the Co-9-alkyl group of the C 3 cycloalkyl-(Co.-)-alkyl group may contain one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein the cycloalkyl group as well as the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups with branched or straight Ci.

9 -alkyl groups and C 2 -9-alkenyl groups, wherein the Ci-9-alkyl groups and C2- 9 alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, wherein Rxii and RxI2 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C.-9-alkyl, substituted and unsubstituted hydroxy-C-.

9 -alkyl, substituted and unsubstituted Ci.

9 -alkenyl, substituted and unsubstituted C1.9-alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXx 1 and OXx1, wherein Xxia and Xx2 are the same or different and are selected from the group which consists of hydrogen, substituted and unsub- S II stituted Ci-9-alkyl, substituted and unsubstituted hydroxy-Ci- 9 -alkyl, substituted and unsubstituted Ci-9-alkenyl, substituted and unsubstituted CI-9-alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, wherein Rxi 3 and RXI 4 are the same or different and are selected from the group which consists of substituted and unsubstituted Ci- 26 -alkyl, hydroxy-C1- 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted Ci- 26 -alkenyl, substituted and unsubstituted Ci-2 6 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OXx 3 and OXXI 4 wherein Xxis and Xx 4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C 1 2 6 -alkyl, substituted and unsubstituted hydroxy-C.- 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Ci- 26 -alkenyl, substituted and unsubstituted C 1 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, silyl, cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylene diamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts of esters.

Preferably Axi is a C 3 .5-alkyl chain.

Particularly preferred are compounds, in which Rxi2 represents a methyl group and Zxi, Rxn, RxI, RXI 4 are defined the same as above, wherein Rxii is preferably substituted with a hydroxy group at the C-atom adjacent to the heteroatom, and compounds, in which RxI represents a hydroxy group wherein Zxi, RxuI, RxiU, RxI 4 is defined the same as above, wherein Rxn is preferably an acyl group, particularly preferably is a formyl, acetyl, propionyl or butyryl group.

Also compounds having the following structures are preferred: 00 0 H II II RxI1- ZxI-C-C-C-C-P-RxI3 (XIA) OH Rx 4 O OH O II I II Rxi 1 -ZxI--C-C-C-C-P-RxI3 (XIB) Rx 1 2 Rx 14 I cw' -31 0 0 0 Rx 1 i- ZX -C-C-C-C-P-Rx 13

(XIC),

Rx 12

OH

O HOO0 Rxj Zxi-C-C_-C-C- P-RxI 3

(XID),

0 0 0 0 Rx 1 1 -Zx C-C-CC-PRx 1 3

(XIE),

OH OH O OH HOO0 Rxjj-Zxj-C_-C-C-C_-C-P-Rx 13

(XIF),

HX

12 Rx 14 O OH 0 0 Rxji-Zxi-C_-C-C-C-C-P-RxI 3 (X IG) and Rx 12 OH7 O 0 HOO0 Rx 1 ZXI- C -C -C -C -C -P -RxI 3

(XIH)

XII. Combined preparation of lipid metabolism inhibitor with 3-isoxazolidinones and hydroxy amine acids These compounds are described in US patent document 4 405 357.

The compounds according to the invention contained in the pharmaceutical compositions correspond to the general formula 0 R X 1 14 Ax 11 C N-0-Rx11 3

(XII)

wherein Aa 1 is selected from the group which consists of hydrogen, substituted and unsubstituted CI.

28 -alkyl radicals, substituted and unsubstituted alkoxy-(CO.

28 )-alkyl radicals, substituted and unsubstituted cycloalkyl-(CO- 2 8)-alkyl radicals, substituted and unsubstituted. cycloalkoxy-(Co.

28 )-alkyl radicals, substituted and unsubstituted amino-(CO.

28 )-alkyl radicals and substituted, unsubstituted. thio-(Co.

28 )-alkyl radicals and substituted or unsubstituted. acyl-(Co.

28 )-alkyl radicals and halogen, wherein each alkyl radical, each alkoxy radical and each acyl -32radical may be branched or straight and each alkyl radical, each alkoxy radical each acyl radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, Rx 3 is selected from the group which consists of hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy-(Co.

26 )-alkyl radicals, substituted and unsubstituted C3-14-cycloalkyl-(Co 26 )-alkyl radicals, substituted and unsubstituted Cycloalkoxy- (Co- 2 6 )-alkyl radicals, substituted and unsubstituted amino-(Co- 26 )-alkyl radicals, substituted and unsubstituted silyl-(Co.2 6 )-alkyl radicals and substituted and unsubstituted thio-(Co-2 6 alkyl groups, wherein each alkyl radical and each alkoxy radical may be branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, or a carbon chain made of two C-atoms in Axn forms a ring together with Rxm, such that an isoxazolidone ring is formed, and

RX

14 is selected from the group which consists of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted acyl radicals and substituted and unsubstituted cycloalkyl-(Co.

26 )-alkyl radicals, wherein each alkyl radical and each acyl radical may be branched or straight and each alkyl radical, each acyl radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms.

Preferably Axn corresponds to the formula (XIIA)

RXII

5 RxII 1 I I Rx 11 6 C C I I Rx 117 Rx 112

(II)

wherein Rxiil and RxI 1 2 are the same or different and are selected from the group which consists of hydrogen, hydroxy, halogen, substituted and unsubstituted amino radicals, substituted and unsubstituted alkyl radicals, substituted and unsubstituted alkoxy radicals and substituted and unsubstituted cycloalkyl-(Co-2 6 )-alkyl radicals, wherein each alkyl radical and each alkoxy radical are branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group are saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, Rxis, Rxu 6 and Rxu? are the same or different and are selected from the group which consists of hydrogen, hydroxy, halogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl-(Co-26)-alkyl radicals, substituted and unsubstituted cycloalkoxy-(Co.

26 )-alkyl radicals, substituted and unsubstituted alkoxy-(Co.26)-alkyl radicals, substituted and i i -33unsubstituted amino groups and substituted, unsubstituted thio-(Co- 26 )-alkyl radicals and substituted or unsubstituted acyl radicals, wherein each alkyl radical, each alkoxy radical and each acyl radical is branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group is saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, wherein Rxiis may alternatively form a ring with Rxim, and RX13 and RxIi 7 may comprise a carbon-oxygen-simple bond such that a ring structure is present.

The invention also includes the pharmaceutically acceptable salts, esters and salts of esters.

Preferably Rxmn and RxI2 are the same or different and selected from the group which consists of substituted and unsubstituted alkyl group, preferably CI-C 4 -alkyl groups.

Preferably Rxm is selected from the group which consists of hydrogen, substituted and unsubstituted alkyl group, preferably Ci-C 4 -alkyl groups, substituted and unsubstituted aromatic C 7 C1 4 -cycloalkyl radicals, a pyranyl group and a t-butyldimethylsilyl group and 0

II

RxI8e wherein RxIi is selected from the group which consists of substituted and unsubstituted, preferably with halogen substituted alkyl groups, substituted and unsubstituted cyloalkyl(CO-26)alkyl radicals, substituted and unsubstituted amino groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted phenoxy groups, substituted and unsubstituted alkylthio groups, substituted and unsubstituted, preferably unsubstituted or with halogen, methyl, methoxy, nitro, amino or CF 3 -groups substituted aromatic cycloalkylthio groups.

RXII

4 is preferably selected from the group which consists of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted phenyl radicals and ZxII

-CH

2 CH2 (YxII)n wherein Zxui is selected from the group which consists of hydrogen, halogen, Ci- 4 -alkyl radicals and phenyl radicals and Yxi is selected from the group which consists of hydrogen, halo- I I io 34 gen, C 14 -alkyl radicals, nitro radicals, methoxy radicals, methylenedioxy groups, wherein n is o or 1.

Rx117 is preferably selected from the group which consists of hydrogen and halogen, or RXui 3 and RX11 7 comprise a carbon-oxygen-simple bond, such that a ring structure is present.

Compounds are particularly preferred, in which Rxiii and RxI 1 2 independently are selected fr~om the group which consists of methyl and ethyl, Rx14 is

ZXII

-CH

2 -a (YXII)n and Rxi[[ and Ru 1 6 are independently selected fr~om the group which consists of hydrogen, chlorine, bromine and methoxy groups.

In particular compounds are preferred in which R 14 is

ZXII

(YXII)n wherein Z is selected from the group which consists of 2-chloro, 2-bromo, 2-fluoro, and Y is selected from the group which consists of 4-chioro, 4-bromo, 4-fluoro, 5-fluoro and methylenedioxy groups, wherein n is 0 or 1.

Compounds are particularly especially preferred, in which RxIII and RX11 2 are methyl groups and Rx11 3 and Ra 1 7 are hydrogen or contain a carbon-oxygen-bond forming a ring structure.

Examples of preferred compounds are 3 -chloro-N-(2-chlorophenyl)methyl-Nhydroxy-2,2.

dimethylpropanamide,

N-(

2 -chlorophenyl)methyl-Nhydroxy-.2,2dimethylpropanamide, 3chloro-NhydroxyNphenyl..22dimethylpropanaride, N-(2-bromophenyl)-methyl-3-chloro- N-hydroxy-2,2-dimethylpropanamide, 3 -chloro-N-hydroxy-2,2dimethyl-N(2-methyl.

phenyl)methylpropanamide, 3 -chloro-N-hydroxy-2,2-N..trimethylpropanaAde, 3 -chloro-Nhydroxy-2,2dimethylN(phenylmethyl)propnaide, 3-chloro-N-(2,4-dichlorophenylmethyl)-N-hydroxy2,2dimethylpropanamide, 3 -chloro-N-(2-chlorophenyl)methyl-N- 35 methoxy-2,2-dimethylpropanamide, 3 3 -dichloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2 'dimethyipropanamide, 3 -chloro-N-(2-fluoropheny)methyNhydro-,2-dimethylpropanamide, 3 -bromo-N-(2-chlorophenymethy1Nhydroxy22dimethypropanmide,

N-

benzoyloxy- 3 -chloro-N-(2-chlorophenyl)methy-22-dimethylpropanamide, N-acetoxy-3chloro-N-( 2 -chlorophenyl)methyl-2,2-dimethylpropanamide, N-(chloroacetoxy)-3 -chloro-N- (2-chlorophenyl)methyl-2,2-dimethylpropanamide, 2 2 -chloropheny1)methy1-4,4-dimethy13 isoxazolidinone, 4 4 -dimethyl-2-phenyl-3-isoxazolidinone, 2-(2-bromopheny)methy.4,4dimethyl-3-isoxazolidinone, 4 4 -dimethy1-2-(2-methyl-pheny)methyl-3-isoxazolidinone, 2,4trimethyl-3 -isoxazolidinone, 4,4-dimethyl-2-phenylmethyl-3 -isoxazolidinone, 2-(2,4dichlorophenyl)methyl..4,4-dimethyl3isoxazolidinone, 5-chloro-2-(2-chlorophenyl)methyl.

4 ,4-dimethyl-3-isoxazolidinone, 2 -(2-chlorophenyl)methyl-5-methoxy44dimethy.3.

isoxazolidinone, 2-(2-fluorophenyl)methyl-4,4-dimethyl-3 -isoxazolidinone, N-[2chlorophenyl)methyl]-N,3 -dihydroxy-2,2-dimethylpropanamide, 3-chloro-N+[2chlorophenyl)methy1]-2,2-dimethy-N(methylamino-cabonyloxy)propanamide, 3 -chloro-N- [(-hoohnlmty]N[2ttayrprnloy-,-iehlpoaaie 3 -chioro- 2 -chloropheny)methy1]-2,2-dimethy1-N-[dinethyl(l 1, -dimethyl-ethyl)silyloxy propanamide, 3 -acetoxy-N-[(2-chlorophenoxy)-methy]Nhydroxy-2,2-dimethylpropan amide, 2, [(2-chloro-4-fluorophenyl)methyl].4,4-dimethyl-3 -isoxazolidinone, 2-[(2-chloro-5 fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone, 5-trichlorophenyl)methyl]-4,4dimethyl-3-isoxazolidinone, 2 -[(2-chloro-6-fluorophenyl)methylpi4,4-dimethyl.3 isoxazolidinone, 2 -[(2-chlorophenyl)methyl]-5-ethoxyA,4-.dimethyl-3-isoxazolidinone, 2-112chlorophenyl)methyl]4,4-dimethy-5-phenylamino-3-isxazoidilone, 2+[2chlorophenyl)methy]-5-hydroxyA,4-dimethy..3-.isoxazolidinone, 3 -choro-N-[(2choohnlmty]22dmty--(hnlmn~abnlx]poaaie 3-chioro- 2 -chloropheny)methy]-2,2.dimethy..N.([(2..chlorophenyl)methyl]y2,2dimethy..N phenoxycarbonyl-oxy)propanamide, 3-chloro-N-[(2-chlorophenyl)methyl]-N-ethoxy.

carbonyloxy-2,2-dimethylpropanamide, N-benzoyloxy-3,3-dichloro-N-[(2chlorophenyl)methyl]-2,2-dimethylpropanamide, N-(2-bromophenyl)methyl-3 ,3 -dichloro-Nhydroxy-2,2-dimethyl)propanamide, 3-chloro-N-[(2-chlorophenyl)methyl]-N-(4nitrobenzoyloxy)-2,2-dimethylpropanamide, 3-chloro-N-[2-chlorophenyl'methyl)]-2,2dimethyl-N-[(2-methylphenyl)carbonyloxcy]propanamide, 3-chloro-N-dichloroacetoxy-N-[(2chlorophenyl)methyl]-2,2-dimethylpropanamide, 3-chloro-N-[2-chlorophenyl)methyl]-2,2.

dimethyl-N-[(4-methylphenyl)sulfonyloxy]propanamide, 3 -chloro-N-[2-chlorophenyl)methyl]-2,2-dimethyl-N-[( 1,1-dimethylethyl)carbonyl-oxy]propanamide, 3 -chloro-N- 2 -chlorophenyl)-methy1]-2,2-dimethy1N-(ethylthiocarbonyloxy)propanamide, 3-chloro-N- 2 2 2 -trichloroethoxy)carbonyoxy)-N-[(2-chlorophenyl)methyl]-2,3-dimethyipropanamide, 3 -chloro-N-[(2-chlorophenyl)aminocarbonyl-oxyN.[(2-clorophenyl)methyl].2,2dimethyipropanamide, 3 -chloro-N-[(4-chloropheny1)aminocarbonyloxfrN-(2.

c:,hlorophenyl)methyl]-2,2-dimethyl-propanamide, 3 -chloro-N-[2-chlorophenyl)methyl]-2,2- -36dimethyl-N-(phenylmethoxy)-propanamide, 3-chloro-N-[(2,4-dichlorophenyoxy)acetoxy)-N- [(2-chlorophenyl)methyl]-2,2-dimethyl-propanamide, 3-chloro-N-[2-chlorophenyl)methyl]- 2,2-dimethyl-N-[(3-trifluoromethyl)benzoyloxypropanamide, 3-chloro-N-[2-chlorophenyl)methyl]-2,2-dimethyl-N-[(4-methylphenyl)aminocarbonyl-oxy)-propananiide, 3chloro-N-[2-chlorophenyl)methyl]-N-[(3 ,4-chlorophenyl)aminocarbonyloxy]-2,2dimethyipropanamide, 3-chloro-N-(3 -chloro-2,2-diniethyl-lI-oxo-propoxy)-N-[(2chlorophenyl)-methyl]-2,2-dimethylpropanamide, 3-bromo-N-[(2-bromophenyl)-methyl]-Nhydroxy-2,2-dimethylpropanamide, 3 -chloro-N-[(2-chlorophenyl)-methyl]-N-[(2fluorophenyl)aminocarbonyloxy]-2,2-dimethylpropanamide, 3 -chloro-N-[(2chlorophenyl)methyl]-N-[(4-methoxyphenyl)aminocarbonyloxy]-2,2-dimethylpropanamide, 3-chloro-N-[(2-chlorophenyl)methyl]-N-[(3-trifluormnethylphenyl)-aminocarbonyloxy]-2,2dimethyipropanamide, 3-bromo-N-[(2-chlorophenyl)methyl]-N-(methylaminocarbonyloxy)- 2,2-dimethyl-propanamide, 3-bromo-N-(2-chloroacetoxy)-N-[(2-chlorophenyl)-methyl]-2,2dimethyipropanamide, 3 -chloro-N-[2,5-dichloro-(formylamino)-benzoyl]oxy-N-[(2-chlorophenyl)methyl]-2,2-dimethylpropanamide, 3-bromo-N-[(2-bromophenyl)methyl]-Nchloroacetoxy-2,2-dimethylpropanamide, 3 -bromo-N-[(2-bromophenyl)-methyl]-N-(methylcarbonyloxy)-2,2-dimethylpropanamide, 3 -bromo-N-[(2-bromophenyl)methyl]-N-[(2chlorophenyl)aminocarbonyloxy]-2,2-dimethylpropanamide, 2-[(2-chlorophenyl)methyl]-Nhydroxy-2,2-dimethyl-3 -methylthio-propanamide, 3-phenylcarbonyloxy)-N-[(2chlorophenyl)-methyl]-N-hydroxy-2,2-dimethylpropanamide, 2-[(4-chlorophenyl)methyl]- 4,4-dimethyl-3 -isoxazolidinone, 2-[(3,4-dichlorophenyl)methyl]-4,4-dimethyl-3 isoxazolidinone, 2-[(chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone-5-ylacetate, 2- [(chlorophenyl)methylll-4,4-dimethyl-3 -isoxazolidinone-5-ylbenzoate, 2- I(chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone-5-yldichloroacetate, 2- [(chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone-5-ylphenylcarbamate, 2- [(chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone-5-ylmethyl-carbamate, 2-[(2-chloro- 4-cyanophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chloro-5-methoxyphenyl) methyl]-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chloro-4-methoxyphenyl)-methyl]-4,4dimethyl-3 -isoxazolidinone, 2-[(2,4-difluorophenyl)methyll-4,4-dimethyl-3-isoxazolidinone, 2-[(4-bromo-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone, 2-[(2-bromo-4fluorphenyl)methyl]-4,4-dimethyl-3 -isoxazolidinone, 2-[(6-chloro- 1,3-benzdioxol-5yl)methyl]-4,4-dimethyl-3-isoxazolidinone, 2-Ij(2-chlorophenyl)methyl]-4,4-dimethyl-5phenoxy-3-isoxazolidinone, 2-[(2-chlorophenyl)methyl]-4,4-dimethyl-5-(1 -methylethoxy)-3isoxazolidinone, 2-[(2-chlorophenyl)methyl]-4,4-dimethyl-5-(phenylmethoxy)-3isoxazolidinone, 2-[(2-bromophenyl)methyl]-5-chloro-4,4-dimethyl-3 -isoxazolidinone, 2- [(2,5-dichlorophenyl)methyl]-4,4-dimethyl--3-isoxazolidinone, 2+[2-chlorophenyl)methyl]- 4,4-dimethyl-5-propoxy-3-isoxazolidinone, 2-[(2-chlorophenyl)methyl]-4,4-dimethyl-5-(2propenyloxy)-3-isoxazolidinone, 2-[(2-chlorophenyl)methyl]-4,4-dimethyl-5-(2-propilyloxy)-3-isoxazolidinone, 2-[(2-chlorophenyl)methyll-4,4-dimethyl-5-(2-methoxyethoxy)-3- -37isoxazolidinone, 2-[(4-fluoro-2-iodophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone, chlorophenyl)methyl]-5-cyclopentoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl)methyl]-4,4-dimethyl-5-(4-nitophenoxy)-3-isoxazolidinone, 2-[(2-chlorophenyl)methyl]-5cyclopropyl-methoxy-4,4-dimethyl-3 -isoxazolidinone, 2-[(2-bromophenyl-(methyl)]-4,4dimethyl-5-(2-propinoxy)-3-isoxazolidinone, 2-[(2-chlorophenyl)methyl]-5-(3 -butinoxy)-4,4dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl)methyl]-5-(2-butinoxy)-4,4-dimethyl-3isoxazolidinone, 2-[(2-chlorophenyl)methyl]-5-(3-butenoxy)-4,4-dimethyl-3 -isoxazolidinone, 2-[(2-chlorophenyl)-methyl]-5-pentoxy-4,4-dimethyl-3-isoxazolidinone, 2-[2-chlorophenyl)methyl]-5-hexoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl)methyl]-5-( 1methylpropoxy)-4,4-dimethyl-3 -isoxazolidinone, 2-[(2-chlorophenyl)methyl]-5-(3 -methyl-3 butenoxy)-4,4-dimethyl-3 -isoxazolidinone, 2-[(2-chlorophenyl)-methyl]-5-butoxy-4,4dimethyl-3 -isoxazolidinone, 2-[(2-chloro-phenyl)methyl]-4,4-dimethyl-3 -isoxazolidinone.

XIH. Combined preparation of lipid metabolism inhibitor with thiadiazole derivatives The thiadiazole derivatives used according to the present invention correspond to the general formula (XIII): R 1112 Rx 11 1 3 Rxx 11 i S (XIII) N S RXII 5 X111 6 wherein n is an integer from 0 to 4, and wherein Rm 111 RX1 11 2, RXMu, RM 0 114

R,

15 and RXM6 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted alkoxy radicals, substituted and unsubstituted acyl radicals, substituted or unsubstituted cycloalkyl-(CO- 26 )-alkyl radicals, substituted and unsubstituted cycloalkyl-(CO- 26 )-alkoxy radicals and halogen, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each acyl radical, each alkoxy radical and each cyclO-(CO..

26 )-alkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfuir atoms.

Preferably Rxiiii represents COOC 2

H

5 -38- Furthermore compounds are preferred, in which RxnM to Rxm6 are selected from the group which consists of hydrogen and halogen, in particular chlorine,.

Preferably n furthermore represents 1 or 2.

XIV. Combined preparation of lipid metabolism inhibitor and a nitrogen-oxygenheterocycle The compounds according to the invention contained in the pharmaceutical compositions correspond to the general formula (XIV): RxIV 13 Rxiv 1 4 Y IV N-BxIv-Zxiv

(XIV)

RxIv7 O RxIve wherein Yxv is a Ci- 3 -alkenylene group, which is substituted with the substituents Rxrv and Rxwv2 and optionally with the substituents Rxv3 to Rxiv6, wherein Rxrvi to Rxrs are the same or different and are selected from the group which consists of hydrogen, hydroxy, halogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl-(Co-2 6 )-alkyl radicals, substituted and unsubstituted cycloalkoxy-(Co- 26)-alkyl radicals, substituted and unsubstituted alkoxy-(Co.

26 )-alkyl radicals, substituted and unsubstituted amino groups and substituted, unsubstituted thio-(Co- 26 )-alkyl radicals, substituted and unsubstituted sulfonyl-(Co- 2 6)-alkyl radicals, substituted and unsubstituted sulfinyl- (Co- 26 )-alkyl radicals and substituted or unsubstituted acyl radicals, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms and Rxrvl3 and Rxvl4 are defined the same as Rxivi to Rxvs or together form an oxo group, wherein Zxiv represents the organophosphorus group 0 -P-RxIvs

I

RxIv l o wherein RxIv9 and RXIVIO are the same or different and are selected from the group which con- S

'C

-39sists of hydrogen, substituted and unsubstituted (Ct.26)-alkyl groups, substituted and unsubstituted hydroxy-(Ci.

26 )-alkyl radicals, substituted and unsubstituted cycloalkyl-(Co.

26 )-alkyl radicals, substituted and unsubstituted acyl, halogen, OXxIv 9 or OXxivlo, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, wherein Xxv9 or Xxivio are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted (Ci.

26 )-alkyl groups, substituted and unsubstituted hydroxy-(C 1 26 )-alkyl radicals, substituted and unsubstituted cycloalkyl-(Co- 26 )-alkyl radicals, substituted and unsubstituted acyl, a silyl, a cation of an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylene diamine or amino acids, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, or wherein Zxiv represents the amino group -N-RxIvll

I

RXIV12 wherein Rvi 1 and Rxv 12 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl-(Co.

26 )-alkyl radicals, substituted and unsubstituted cycloalkoxy-(Co.

26 )-alkyl radicals, substituted and unsubstituted alkoxy-(Co.

26 )-alkyl radicals and substituted or unsubstituted acyl radicals, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, wherein Bxiv is selected from the group which consists of substituted and unsubstituted C1- 26 alkenylene groups, wherein a C-atom may be replaced by an oxygen atom and a C-atom may be replaced by a sulfur atom or two C-atoms may be replaced by an S-hetrocycle and wherein each alkenylene radical may be branched or straight and saturated or unsaturated with one or more double or triple bonds and may be substituted with one or more hydroxy groups, halogen groups or oxo groups.

Preferably Riv 13 and RXIV4 together form an oxo group in a-position regarding the nitrogen atom.

7 Preferably Yxr represents a methylene group, which is particularly preferably substituted with two methyl groups.

Furthermore compounds are advantageous, in which Bxv represents the ether group (XIVA) Axvl O Axv 2

(XIVA)

wherein Axivi is absent or a (Ci.

9 )-alkylene radical, and Axiv 2 is absent or selected from the group which consists of(Ci.

9 )-alkylene radicals, a sulfur atom and a (C3.-)-heterocycle, which comprises at least one sulfur atom. Particularly preferably Axivi and AxIv 2 each represent a methylene group.

Also compounds are advantageous, in which Bxav represents the keto group (XIVB) 0

II

AxIv3 C AxIV 4

(XIVB)

wherein AxIv3 and AX

I

V

4 out of which one or both may be absent, are the same or different and are selected from the group which consists of (C.-9)-alkylene radicals, wherein all (CI-9)-alkylene radicals may be branched or straight, may contain one or more double bonds or may be substituted with a hydroxy group or a halogen group. Particularly preferred Axiv 3 is absent and AxIv 4 represents a methylene or an ethylene group.

Preferably Bxiv is further a 2-hydroxypropylene group.

Rxiv9 and Rxivio preferably represent OXxiv9 and OXxivio, wherein XxIv9 and Xxivio are the same or different and are selected from the group which consists of a metal of the first, second or third main group of the periodic system, in particular sodium and potassium, and methyl, ethyl.

Special features of the above definitions and suitable examples thereof are given below: ,,Acyl" is a substituent which originates from an acid such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioacid or imidic acid corresponding to the individually present acids, or from an organic sulfonic acid, wherein in each case these acids comprise aliphatic, aromatic and/or heterocyclic groups in the molecule as well as carbamoyl or carbamimidoyl.

Suitable examples of these acyl groups were given below:.

I! [y' -41- Acyl radicals originating from aliphatic acid are designated as aliphatic acyl groups and include: Alkanoyl formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl etc.); alkenoyl acryloyl, methacryloyl, crotonoyl etc.); alkylthioalkanoyl (for example methylthioacetyl, ethylthioacetyl etc.) alkane sulfonyl (for example mesyl, ethane sulfonyl, propane sulfonyl etc.); alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl etc.); alkylcarbamoyl (for example methylcarbamoyl etc.); (N-alkyl)-thiocarbamoyl for example (N-methyl)-thiocarbamoyl etc.); alkylcarbamimidoyl (for example methylcarbamimidoyl etc.); oxalo; alkoxalyl (for example methoxalyl, ethoxalyl, propoxalyl etc.).

In the above examples of aliphatic acyl groups the aliphatic hydrocarbon part, in particular the alkyl group and the alkane radical may optionally contain one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (for example methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (for example benzyloxycarbonylamino etc.), acyloxy (for example acetoxy, benzoyloxy etc.) and the like. Preferred aliphatic acyl radicals with such substituents are for example alkanoyls substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.

Acyl radicals originating from an acid with substituted or unsubstituted aryl groups, wherein the aryl group may comprise phenyl, toluyl, xylyl, naphthyl and the like are designated as aromatic acyl radicals. Suitable examples are given below: Aroyl (for example benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl etc.); Aralkanoyl (for example phenylacetyl etc.); Aralkenoyl (for example cinnamoyl etc.); Aryloxyalkanoyl (for example phenoxyacetyl etc.); Arylthioalkanoyl (for example phenylthioacetyl etc.); Arylaminoalkanoyl (for example N-phenylglycyl, etc.); Arene sulfonyl (for example benzene sulfonyl, tosyl bzw. toluene sulfonyl, naphthalene sulfonyl etc. Aryloxycarbonyl (for example phenoxycarbonyl, naphthyl-oxycarbonyl etc.); Aralkoxycarbonyl (for example benzyloxycarbonyl etc.); Arylcarbamoyl (for example phenylcarbamoyl, naphthylcarbamoyl etc.); Arylglyoxyloyl (for example phenylglyoxyloyl etc.).

A -42- In the present examples of aromatic acyl radicals the aromatic hydrocarbon part (in particular the aryl radical) and/or the aliphatic hydrocarbon part (in particular the alkane radical) may optionally contain one or more suitable substituents, such as those which were already mentioned as suitable substituents of the alkyl group and the alkane radical. In particular and as an example for preferred aromatic acyl radicals with particular substituents, aroyl substituted with halogen and hydroxy or by halogen and acyloxy and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino are mentioned as well as arylthiocarbamoyl (for example phenylthiocarbamoyl etc.); arylcarbamimidoyl (for example phenylcarbamimidoyl etc.).

A heterocyclic acyl radical is understood to be an acyl radical which originates from an acid with heterocyclic group. These include: heterocyclic carbonyl in which the heterocyclic radical is an aromatic or aliphatic 5 to 6 membered heterocycle and has at least one heteroatom from the group nitrogen, oxygen and sulfur (for example thiophenyl, furoyl, pyrrolcarbonyl, nicotinoyl etc.); heterocyclic alkanoyl, in which the heterocyclic radical is 5 to 6 membered and has at least one heteroatom from the group nitrogen, oxygen and sulfur (for example thiophenyl-acetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2-(2-amino-4-thiazolyl)-2methoxyiminoacetyl etc.) and the like.

In the above examples of heterocyclic acyl radicals the heterocycles and/or the aliphatic hydrocarbon part may optionally contain one or more suitable substituents, such as the same as those which were mentioned as suitable for alkyl and alkane groups.

,,Alkyl" is a straight- or branched-chain alkyl radical having up to 9 carbon atoms, unless defined otherwise, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and the like.

,,Alkenyl" includes straight- or branched-chain alkenyl groups with up to 9 carbon atoms, unless defined otherwise, for example vinyl, propenyl (for example 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexenyl.

,,Alkynyl" includes straight- or branched-chain alkynyl radicals having up to 9 carbon atoms, unless defined otherwise.

Cycloalkyl preferably represents an optionally substituted C 3 to C7 cycloalkyl. alkyl, alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), f, -43nitro and the like are inter alia suitable as possible substituents.

Aryl is an aromatic hydrocarbon radical such as phenyl, naphthyl etc., which may optionally contain one or more suitable substituents such as alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitro and the like.

,,Aralkyl" includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, wherein the aromatic part may optionally contain one or more suitable substituents such as alkoxy (for example methoxy, ethoxy etc.), halogen (for example fluorine, chlorine, bromine etc.), nitro and the like.

,,Alkylene" includes straight- or branched-chain alkylene groups, which contain up to 9 carbon atoms and may be represented by the formula -(CnH 2 in which n is an integer from 1 to 9, such as methylene, ethylene, trimethylene, methylethylene, tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2methyltetramethylene, isopropylethylene, hexamethylene, and the like. Preferred alkylene radicals contain up to 4 carbon atoms and radicals with 3 carbon atoms, such as for example trimethylene are particularly preferred.

,,Alkenylene" includes straight- or branched-chain alkenylene groups with up to 9 carbon atoms which may be reproduced by the formula: -(CnH2n-2)in which n is an integer from 2 to 9, for example vinylene, propenylene (for example 1propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene, 2ethylpropenylene, pentenylene, hexenylene and the like. The alkenylene radical may particularly preferably contain up to 5 carbon atoms and in particular 3 carbon atoms, for example 1propenylene.

,,Hydroxyalkylene" may include straight- or branched-chain alkylene radicals which contain up to 9 carbon atoms, wherein one or more selected carbon atoms are substituted with a hydroxy group. These radicals may be represented by the formula: -(CnH 2 n-z)(OH)zin which n is an integer from 1 to 9 and z is an integer, to which z n applies. Suitable examples of such hydroxyalkylene groups include hydroxymethylene, hydroxyethylene (for example 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (for example 1hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (for example 2-hydroxytetramethylene), 2-hydroxy-2-methyltrimethylene, hydroxypentamethylene (for example 2-hydroxypentamethylene), hydroxyhexamethylene (for example 2-hydroxyhexamethylene) and the like. A lower hydroxyalkylene with up to 4 car- -44bon atoms is particularly preferred and in particular one with 3 carbon atoms for example 2hydroxytrimethylen.

,,Alkyleneamine" includes straight- or branched-chain alkylene amine groups, which contain up to 9 carbon atoms and may be represented by the formula: -(CnH 2 n)-N-(CmH 2 m)in which n and m may be the same or different and be an integer from 0 to 9, to which 1 n m 9 applies, such as methyleneamine, ethyleneamine, dimethylene amine, trimethylene amine, methylene ethyleneamine, tetramethylene amine, 1-methyltrimethylene amine, 2ethylethylene amine, ethylenemethylene amine, pentamethylene amine, 2methyltetramethylene amine, isopropylethylene amine, hexamethylene amine, and the like.

Preferred alkylene amine radicals contain 2 carbon atoms, which are end positioned. Dimethylene amine is particularly preferred. The hydrogen atoms may be replaced by substituents, for example halogen radicals.

,,Alkyleneimine" includes straight- or branched-chain alkyleneimine groups, which contain up to 9 carbon atoms and may be represented by the formula -(CnH 2 n.l)=N-(CmH 2 m)-Or the formula -(CnH 2 n)-N=(CmH 2 in which n and m may be the same or different and are an integer from 0 to 9, to which 1 n m 9 applies, such as methyleneimine, ethyleneimine, dimethyleneimine, trimethyleneimine, methylenethyleneimine, tetramethyleneimine, 1-methyltrimethyleneimine, 2ethylethyleneimine, ethylenemethyleneimine, pentamethyleneimine, 2methyltetramethyleneimine, isopropylethyleneimine, hexamethyleneimine, and the like. Preferred alkylene imine radicals contain 2 carbon atoms, which are end positioned. Dimethyleneimine is particularly preferred. The hydrogen atoms may also be replaced by substituents, for example by halogen radicals.

,,Alkenyleneamine" includes straight- or branched-chain alkenylene amine groups having up to 9 carbon atoms, which may be represented by the formula -(CnH2n-2)-N-(CH2m-2)-; -(CoH2o)-N-(CnH2n-2)-; -(CnH2n-2)-N-(CoH2o)in which n and m are the same or different and are an integer from 2 to 9, to which m n 9 applies, and o is a number between 0 and 7, to which o n 9 applies, for example vinyleneamine, methylenevinyleneamine, divinyleneamine, propenyleneamine (for example 1propenyleneamine, 2-propenyleneamine), methylenpropenyleneamine, 1methylpropenyleneamine, 2-methylpropenyleneamine, butenyleneamine, 2-ethylenepropenyleneamine, pentenyleneamine, hexenyleneamine, vinylmethyleneamine and the like. The hydrogen atoms may also be replaced by substituents, for example by halogen radicals.

T C ,,Alkenyleneimine" includes straight- or branched-chain alkenylene imine groups having up to 9 carbon atoms, which may be represented by the formula -(CnH 2 n.

3

)=N-(CH

2 m.- 2 -(CoH 2 o.I)=N-(CJI 2 -(CnH2.

3

)=N-(CH

2 o)- -(CnH 2 n- 2 )N-(CmH 2 m 3 -CoH 2 o)-N=(CmH 2 m- 3 -(CnH 2 2 )-N=(CoH 2 o-1)in which n and m are the same or different and are an integer from 2 to 9, to which m n 9 applies, and o is a number from 0 to 7, to which o n 9 applies, for example vinyleneimine, methylenevinyleneimine, ethylenevinyleneimine, propenyleneimine (for example 1propenylene imine, 2-propenylene imine), methylenepropenyleneimine, 1methylpropenyleneimine, 2-methylpropenyleneimine, butenyleneimine, 2-ethylenepropenyleneimine, pentenyleneimine, hexenyleneimine, vinylemethyleneimine and the like. The hydrogen atoms may also be replaced by substituents, for example by halogen radicals.

,,Hydroxyalkyleneamine" may be straight- or branched-chain alkylene radicals which contain up to 9 carbon atoms, wherein at least one selected carbon atom is substituted with a hydroxy group; these radicals being represented by the formula -(CHn-(OH-(CnH 2 (CmH 2 m-y)(OH)y in which n and m are the same or different and are an integer from 0 to 9, to which 1 n m 9 applies, and z and y are the same or different and are an integer, to which 0 z n and 0 y m and y z 1 applies. Suitable examples of such hydroxyalkyleneamine groups include hydroxymethyleneamine, hydroxyethyleneamine (for example 1-hydroxyethylenamine and 2-hydroxyethyleneamine), hydroxytrimethyleneamine (for example 1-hydroxytrimethylene, 2-hydroxytrimethylenamine and 3-hydroxytrimethyleneamine), hydroxytetramethylene amine (for example 2-hydroxytetramethyleneamine), 2-hydroxy-2-methyltrimethyleneamine, hydroxypentamethyleneamine (for example 2-hydroxypentamethyleneamine), hydroxyhexamethyleneamine (for example 2-hydroxyhexamethyleneamine), methylenehydroxymethyleneamine, methylenehydroxyethyleneamine and the like. A lower hydroxyalkylene amine with 2 carbon atoms and one nitrogen atom is particularly preferred wherein both carbon atoms are end positioned. The hydrogen atoms may also be replaced by substituents, for example by halogen radicals.

,,Hydroxyalkyleneimine" includes straight- or branched-chain alkylene radicals, which contain up to 9 carbon atoms, wherein at least one selected carbon atom is substituted with a hydroxy group. These radicals may be represented by the formula

-(C.H

2 n-z.

1 )(OH)z =N-(CmH 2 m-y)(OH)y; -(CnH 2 n-z-i)(OH)z -N=(CmH 2 my)(OH)y in which n and m are the same or different and are an integer from 0 to 9, to which 1 n m 9 applies, and z and y are the same or different and an integer, to which 0 z n-I and 0 y 5 m- 1 and y z 1 applies. Suitable examples of such hydroxyalkyleneimine groups include hydroxymethyleneimine, hydroxyethyleneimine (for example 1-hydroxyethyleneimine and 2-hydroxyethyleneimine), hydroxytrimethyleneimine (for example 1-hydroxytrian -yrxehlnemn) yrxtietyeemn frexml -yrxti -46methyleneimine, 2-hydroxytrimethyleneimine and 3-hydroxytrimethyleneimine), hydroxytetramethyleneimine (for example 2-hydroxy-tetramethyleneimine), 2-hydroxy-2-methyltrimethylene imine, hydroxypentamethyleneimine (for example 2-hydroxypentamethyleneimine), hydroxyhexamethyleneimine (for example 2-hydroxyhexamethyleneimine), methylenehydroxymethyleneimine, methylenehydroxyethyleneimine and the like. A lower hydroxyalkyleneimine with 2 carbon atoms and a nitrogen atom, wherein the two carbon atoms are end positioned, is particularly preferred. The hydrogen atoms may also be replaced by substituents, for example by halogen radicals.

The 5 and 6 membered cyclic compounds, which are represented by Biv may be aromatic or aliphatic and may be substituted for example by alkyl groups with up to 7 carbon atoms and hydroxy groups.

The 5 and 6 membered heterocyclic compounds, which may be represented by Rvini and RvIII 2 as well as Rxl and RX2, and which contain beside carbon one or two nitrogen, oxygen or sulfur atoms as a ring member, may be saturated or unsaturated.

,,Alkoxy radical" is, unless defined otherwise, a straight- or branched-chain alkoxy radical having up to 26 carbon atoms, such as a methoxy, ethoxy radicals, etc.. It may be substituted for example by hydroxy, amino, halogen, oxo groups and alkoxy radicals, such as methoxy-, ethoxy radicals.

,,Alkoxy-(CO- 2 6 )-alkyl radicals" are alkoxy radicals, which may also be bound to the basic structure upon an alkyl radical. The alkyl- and alkoxy groups are defined the same as above.

,,Cycloalkyl-(Co- 26 )-alkyl radicals" are cyclic compounds having 3 to 8 carbon atoms, unless defined otherwise, which are bound to the basic structure directly or upon an alkylene radical.

The alkylene radical may be branched, straight and saturated or unsaturated with double bonds. Possible substituents of the cycloalkyl radicals are inter alia alkoxy radicals, alkyl radicals, hydroxy radicals, halogen radicals, amino radicals, oxo radicals. Providing a respective number of double bonds, the cycloalkyl radicals may also be aromatic, i.e. may be aryl- (Co-2 6 )-alkyl radicals (for example phenyl, pyridyl, naphthyl etc.). In particular the aromatic cyclic compounds may further contain substituents, such as nitro groups and CF 3 and phenyl radicals.

,,Cycloalkoxy-(Co- 26 )-alkyl radicals" are cyclic compounds with 3 to 8 carbon atoms, which are bound to the basic structure directly at an oxygen or upon an alkylene radical. The alkylene radical may be branched, straight and may be saturated or unsaturated with double bonds. Possible substituents of the cycloalkyl radicals are inter alia radicals (also alkylenedi- -47oxy radicals, such as methylenedioxy), alkyl radicals, hydroxy radicals, halogen radicals, amino radicals, oxo radicals. Providing the respective number of double bonds the cycloalkyl radicals may also be multicycles and aromatic (for example phenoxy, pyridoxy, naphthoxy etc.). In particular the aromatic cyclic compounds further may contain substituents, such as nitro groups, CF 3 -groups and phenyl radicals.

For example the ,,amino radicals" may be substituted for example with the with the above defined alkyl radicals or cycloalkyl-(Co- 26 )-alkyl radicals.

,,Amino-(Co- 26 )-alkyl radicals" are amino radicals, which also may be bound to the basic structure upon an alkyl radical. The alkyl and amino groups are defined the same as above.

,,Silyl radicals" may be substituted for example with the above defined alkyl radicals or cycloalkyl-(Co.

2 6 )-alkyl radicals.

,,Silyl"-(CO- 26 )-alkyl radicals" are silyl radicals, which also may be bound to the basic structure upon an alkyl radical. The alkyl and silyl groups are defined the same as above.

,,Thio-(Co- 26 )-alkyl radicals" may be substituted for example with the above defined alkyl radicals or cycloalkyl-(CO- 26 )-alkyl radicals. The (Co- 26 )-alkyl groups are straight- or branchedchain alkylene radicals such as methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert.-butylene, pentylene, hexylene and the like. They may contain double or triple bonds and be substituted for example with hydroxy, amino, halogen (for example fluorine, bromine, chlorine), oxo radicals and alkoxy radicals, such as methoxy, ethoxy radicals.

Preferably, the radicals Xu to Xvi3 and X4 to Xvn4 as well as Rvms, RIxII, Xxi3 and Xxi4, X 1 and X 1

I

2 may be selected such, that esters form on the phosphono group or the sulfonyl group.

Suitable examples of esters of the compounds used according to the present invention are suitable mono and diesters, and preferred examples of such esters includes alkylester (for example methylester, ethylester, propylester, isopropylester, butylester, isobutylester, hexylester etc.); aralkyl ester (benzyl ester, phenethyl ester, benzohydryl ester, trityl ester etc.); aryl ester (for example phenyl ester, toluyl ester, naphthyl ester etc.); aroylalkyl ester (for example phenacyl ester etc.); and silylester (for example oftrialkylhalogensilyl, dialkyldihalogensilyl, alkyltrihalogensilyl, dialkylarylhalogensilyl, trialkoxyhalogensilyl, dialkylaralkylhalogensilyl, dialkoxydihalogensilyl, trialkoxyhalogensilyl etc.) and the like.

With the above esters the alkane and/or arene part may optionally contain at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.

-48- Xu to XvI and XI4 to XVM4 as well as Xxu and Xxi4, Xni and Xi2 are preferably a metal from the first, second or third main group of the periodic system, ammonium, substituted ammonium, or ammonium compounds, which derive from ethylene diamine or amino acids. In other words the salt compounds of the ammonium phosphonic acid derivatives with organic or inorganic bases (for example sodium salt, potassium salt, calcium salt, aluminium salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N,N'-dibenzylethylenedi amine salt etc.) as well as salts with amino acids (for example arginine salt, aspartic acid salt, glutamic acid salt etc.) and the like.

The compounds according to the invention in accordance with the formulae to (XIV) permit for example the emergence of spatial isomers for groups containing double bonds or chiral groups R or A or B or Y or Z or X. The use of the compounds according to the invention includes all spatial isomers both as pure substances and in form of their mixtures.

Pharmaceutically acceptable salts of the aminohydrophosphonic acid derivative include salts, which form the compounds according to the invention in their protonised form as an ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfur acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluene sulfonic acid.

Salts which are formed by suitable selection of X 3 (XI3 to Xv 3 and X4 (XI 4 to Xv 4 as well as Xm and X2 are especially suited, such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.

The lipid metabolism inhibitors according to the invention contain one or more inhibitors of lipid metabolism. Inhibitors may be used which control the intake of fats as well as inhibitors, which control the synthesis of fats. The inhibitors include anion exchangers, preferably cholestyr amine and colestipol, 3-sitosterol, nicotinic acids and their derivatives, such as nicotinyl alcohol, clofibrate and their derivatives, such as clofibrin acid ethylester, as well as their analogues, such as bezafibrate, fenofibrate and gemfibrozil, and probucol.

The inhibitors, which control the synthesis of fats, include HMG-CoA synthetase inhibitors, HMG-CoA reductase inhibitors, preferably lovastatin, mevastatin, simvastatin, fluvastatin, atorvastatin, pravastatin and cerivastatin, inhibitors the squalene synthetase, preferably pyrophosphate, pyrophosphate derivatives, bisphosphonic acid derivatives, phosphinylmethylphosphonic acid derivatives, phosphinylformyl derivatives, phosphonocarboxyl derivatives, phosphonosulfonic acid derivatives, phosphinylmethylphosphonic acid derivatives, inhibitors of the squalene monooxygenase and other inhibitors of the synthesis of cholesterol.

U V* -49- Inhibitors of the HMG-CoA-reductase and inhibitors of the squalene synthetase are especially preferred.

Out of the bisphosphonates clodronate, etidronate, pamidronate, ibandronate, alendronate, zoledronate, risedronate, tiludronate and cimadronate are especially preferred.

Upon simultaneous, separate or successive administration together with inhibitors of lipid metabolism synthesis the infectiously active compounds and their esters as well as their salts show a strong cytotoxic efficacy against unicellular and multicellular parasites, fungi, bacteria and cells infected by viruses. The compounds according to the invention are usable in the treatment of infectious diseases which are caused by parasites, fungi, bacteria or viruses in humans and animals. The compounds are also suitable for the use for preventing these diseases.

The lipid metabolism inhibitors are effective against unicellular parasites (protozoa), in particular against pathogens of malaria and the sleeping sickness as well as the Chagas' disease, the toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiasis, sarcocystosis, acanthamebiasis, naegleriasis, coccidiosis, giardiasis and lambliosis.

Therefore, they are particularly suitable as malaria prophylactics and as prophylactics of sleeping sickness as well as the Chagas' disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiasis, cryptosporidiasis, sarcocystosis, acanthamebiasis, naegleriasis, coccidiosis, giardiasis and lambliosis.

"1 The lipid metabolism inhibitors according to the invention may in particular be used against the following bacteria: Bacteria of the family Propionibacteriaceae, in particular the genus Propionibacterium, in particular the species Propionibacterium acnes; bacteria of the family Actinomycetaceae, in particular the genus Actinomyces; bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis; bacteria of the family Mycobacteriaceae, the genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium; bacteria of the family Chlamydiaceae, in particular the species Chlamydia trachomatis and Chlamydia psittaci; bacteria of the genus Listeria, in particular the species Listeria monocytogenes; bacteria of the species Erysipelthrix rhusiopathiae; bacteria of the genus Clostridium; bacteria of the genus Yersinia, the species Yersinia pestis, Yersinia pseudotuberculosis, Yersinia enterocolitica and Yersinia ruckeri; bacteria of the family Mycoplasmataceae, the genus Mycoplasma and Ureaplasma, in particular the species Mycoplasma pneumoniae; bacteria of the genus Brucella; bacteria of the genus Bordetella; bacteria of the family Neiseriaceae, in particular the genuses Neisseria and Moraxella, in particular the species Neisseria meningitides, Neisseria gonorrhoeae and Moraxella bovis; bacteria of the family Vibrionaceae, in particular the genuses Vibrio, Aeromonas, Plesiomonas and Photobacterium, in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmonicidas; bacteria of the genus Campylobacter, in particular the species Campylobacter jejuni, Campylobacter coli and Campylobacter fetus; bacteria of the genus Helicobacter, in particular the species Helicobacter pylori; bacteria of the families Spirochaetaceae and the Leptospiraceae, in particular the genus Treponema, Borrelia and Leptospira, in particular Borrelia burgdorferi; bacteria of the genus Actinobacillus; bacteria of the family Legionellaceae, the genus Legionella; bacteria of the family Rickettsiaceae and family Bartonellaceae; bacteria of the genus Nocardia and Rhodococcus; bacteria of the genus Dermatophilus; bacteria of the family Pseudomonadaceae, in particular the genuses Pseudomonas and Xanthomonas; bacteria of the family Enterobacteriaceae, in particular the genuses Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Serratia and Shigella; bacteria of the family Pasteurellaceae, in particular the genus Haemophilus; bacteria of the family Micrococcaceae, in particular the genus Micrococcus and Staphylococcus; bacteria of the family Streptococcaceae, in particular the genus Streptococcus and Enterococcus and bacteria of the family Bacillaceae, in particular the genus bacillus and clostridium.

Accordingly, the lipid metabolism inhibitors according to the invention are suitable for treatment of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas gangrene in humans and in animals, diseases in humans and animals caused by clostridium septicum, tuberculosis in humans and animals, leprosy, and further mycobacteriosis in humans and animals, paratuberculosis in animals, pestis, mesenterial lymphadenitis and pseudotuberkulosis in humans and animals, cholera, legionnaires disease, borrelioses in humans and animals, leptospiroses in humans and animals, syphilis, campylobacter enteritides in humans and animals, moraxella keratoconjunctivitis and serositis in animals, brucelloses in animals and in humans, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichosis, psittakosis/ornithosis in animals, and Q-fever and ehrlichiosis.

Further the use is advantageous in helicobacter eradication therapy of ulcera of the gastroenteric tract.

Further combinations with an additional antibiotic may also be used for treatment of the above mentioned diseases. As lipid metabolism inhibitors with other antiinfective agents in .particular isoniazide, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and 'o -51 dapson are suitable for the treatment of tuberculosis.

The lipid metabolism inhibitors according to the invention may furthermore be used in particular in infections with following viruses: Parvoviridae: parvo viruses, dependo viruses, Denso viruses; Adenoviridae: adeno viruses, mastadeno viruses, aviadeno viruses; Papovaviridae: papova viruses, in particular papilloma viruses (so called wart viruses), Polyoma viruses, in particular JC virus, BK virus, and miopapova viruses; herpes viruses: all herpes viruses, in particular herpes simplex viruses, the varizella-zoster viruses, human cytomegalo virus, Epstein-Barr viruses, all human herpes viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8; Poxviridae: pox viruses, orthopox, parapox, molluscum contagiosum virus, avipox viruses, capripox viruses, leporipox viruses; all primary hepatotropic viruses, Hepatitis viruses: hepatitis A viruses, hepatitis B viruses, hepatitis C viruses, hepatitis D viruses, hepatitis E viruses, hepatitis F viruses, hepatitis G viruses; Hepadna viruses: all hepatitis viruses, hepatitis B virus, hepatitis D viruses; Picornaviridae: picorna viruses, all entero viruses, all polio viruses, all coxsackie viruses, all echo viruses, all rhino viruses, hepatitis A virus, aphtho viruses; Calciviridae: hepatitis E viruses; Reoviridae: reo viruses, orbi viruses, rota viruses; Togaviridae: toga viruses, alpha viruses, rubi viruses, pesti viruses, rubella virus; Flaviviridae: flavi viruses, ESME virus, hepatitis-C-Virus; Orthomyxoviridae: all influenza viruses; Paramyxoviridae: paramyxo viruses, morbilli virus, pneumo virus, measles virus, mumps virus; Rhabdoviridae: rhabdo viruses, rabies virus, lyssa virus, viscula stomatitis virus; Corona viridae: corona viruses; Bunyaviridae: bunya viruses, nairo virus, phlebo virus, uuku virus, hanta virus; Arenaviridae: arena viruses, lymphocytic choriomeningitis-virus; Retroviridae: retro viruses, all HTL viruses, human T-cell leukaemia virus, oncorna viruses, spuma viruses, lenti viruses, all HIviruses; Filoviridae: Marburg and Ebola virus; Slow-virus-infections, prions; Onco viruses, leukemia viruses.

The preparations used according to the invention are therefore suitable for fighting the following viral infections: Eradication of papilloma viruses to prevent tumors, in particular tumors in the sexual organs caused by papilloma viruses in humans, eradication of JC viruses and BK viruses, eradication of herpes viruses, eradication of human herpes viruses 8 for the treatment of Kaposi's sarcoma, eradication of cytomegalo viruses before transplants, eradication of Eppstein-Barr viruses before transplants and to prevent tumors associated with Eppstein-Barr viruses, eradication of hepatitis viruses for the treatment of chronic liver diseases and for the prevention of tumors of the liver and cirrhosis of the liver, eradication of coxsackie viruses patients with cardiomyopathy, eradication of coxsackie viruses in diabetes mellitus patients, eradication of immune system debilitating viruses in humans and animals, treatment of secondary infections in AIDS-patients, treatment of inflammations of viral origin of the respiratory tract (larynx 1, -52papillomas, hyberplasias, rhinitis, pharyngitis, bronchitis, pneumonias), of the sensory organs (Keratoconjunctivitis), of the nervous system (poliomyelitis, meningoenzephalitis, encephalitis, subacute sklerosing panencephalitis SSPE, progressive multifocal leukoencephalopathie, lymphocytic choriomeningitis), of the gastro-intestinal tract (stomatitis, gingivostomatitis, oesophagitis, gastritis, gastroenteritis, diarrhoea-causing diseases), the liver and the gall bladder system (hepatitis, cholangitis, hepatocellular carcinoma), of the lymphatic tissue (mononucleosis, lymphadenitis), of the haematopoetic system, of the sexual organs (mumpsorchitis), of the skin (warts, dermatitis, herpes labialis, heat rush, herpes zoster, shingles), of the mucous membranes (papillomas, conjunctiva papillomas, hyperplasias, dysplasias), of the heart/blood vessel system (arteriitis, myocarditis, endocarditis, pericarditis), the kidney/urinary tract systems, of the sexual organs (anogenital lesions, warts, genital warts, acute condylomas, displasias, papillomas, cervix dysplasias, condylomata acuminata, epidermodysplasia verruci formis), of the organs of motion (myositis, myalgien), treatment of foot and mouth diseases in cloven-hoofed animals, of Colorado tick fever, of Dengue-syndrome, of haemorrhagic fever, of early summer meningoencephalitis (FSME) and of yellow fever.

The agents are suited for combination with other agents with antiviral characteristics.

The compounds used according to the invention which generally include pharmaceutically acceptable salts, esters, a salt of such an esters or else compounds which upon application provide the compounds use according to the invention metabolic products or decomposition products, also called "prodrugs" may all be prepared for administration like known antiinfectious agents in any suitable manner (mixed with non-toxic pharmaceutically acceptable carriers).

The combined preparation used according to the invention may be administered together with non-toxic, inert pharmaceutically suitable carriers. These are understood to mean solid, semisolid or liquid diluents, fillers and formulation auxiliary agents of all kinds.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays are mentioned as pharmaceutical preparations. Tablets, dragees, capsules, pills and granules may contain in addition to the conventional excipients the active ingredient, such as fillers and diluents, for example starches, lactose, cane sugar, glucose, mannitol and silicic acid, binders, for example carboxymethylcellulosis, alginate, gelatine, polyvinylpyrrolidone, moisture-retaining agents, for example glycerol, dispersing agents, for example agar-agar, calcium carbonate and sodium carbonate, solution retarders, for example paraffin and resorption accelerators, for example quaternary ammonium compounds, wetting agents, for example cetyl alcohol, glycerol monostearate, adsorption agents, e.g. kaolin and betonite and lubricants, for S. -53example talcum, calcium and magnesium stearate and solid polyethylene glycol or mixtures of the substances listed under to The inventive compounds may furthermore be incorporated into other carrier materials for example plastics, (plastics chains for topical therapy), collagen or bone cement.

The tablets, dragees, capsules, pills and granules may be provided with the conventional coatings and casings optionally comprising opaquing agents and may also be put together so that they release the active ingredient or active ingredients only or preferably in a specific part of the intestinal optionally with sustain release, wherein polymer substances and waxes for example may be used as embedding compounds.

The active ingredients may optionally also be present in microencapsulated form with one or more of the above mentioned excipients.

In addition to the active ingredients suppositories may also contain the conventional water soluble or water insoluble excipients, for example polyethylene glycols, fats, for example cacoa fat and higher esters (for example C 14 alcohol with C 16 -fatty acid) or mixtures of these substances.

In addition to the active ingredients ointments, pastes, creams and gels may contain the conventional excipients, for example animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivative, polyethylene glycols, silicones, bentonites, silicic acid, Talc and zink oxide or mixtures of these substances.

In addition to the active ingredients powders and sprays may contain the conventional excipients, for example lactose, talcum, silicic acid, aluminium hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain the conventional blowing agents, for example chlorofluorohydrocarbons.

In addition to the active ingredients solutions and emulsions may contain the conventional excipients such as solvents, solubilisers and emulgators, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular cotton seed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, glycerol formal, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances.

The solutions and emulsions may also be present in sterile and blood isotonic form for parenteral application.

v-V 3 /O -54- In addition to the active ingredients suspensions may contain conventional excipients such as liquid diluents, for example water, ethyl alcohol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.

The active ingredient or the active ingredients of the formulae to (XIV) shall be present in the above mentioned pharmaceutical preparations, preferably in a concentration of approximately 0.1 to 99,5 weight preferably of approximately 0.5 to 95 weight of the total mixture. The ratio of the substances to be individually combined is dependent on the individual active ingredient. Therefore, active agents are present, which are administered in a general dose of 0.1 mg/kg body weight per day (ibandronate and alendronate), 0.5 mg/kg body weight per day (mevastatin, simvastatin, pravastatin, fluvastatin), 10 mg/kg body weight per day (pamidronate).

In addition to the compounds of the formulae to (XIV) and the inhibitors of lipid metabolism the above mentioned pharmaceutical preparations may also contain further pharmaceutical active ingredients, such as antiviral, antiparasitic, antimycotic or antibacterial active agents.

The lipid metabolism inhibitors used according to the invention further may contain sulfonamide, sulfadoxin, artemisinin, atovaquon, chinin, chloroquine, hydroxychloroquin, mefloquin, halofantrin, pyrimethamine, armesin, tetracycline, doxycyclin, proguanil, metronidazol, praziquantil, niclosamide, mebendazol, pyrantel, tiabendazole, diethylcarbazin, piperazin, pyrivinum, metrifonate, oxamniquin, bithionol or suramin or several of these substances.

Preferably lovastatin, atorvastatin, simvastatin, mevastatin, pravastatin and fluvastatin are administered orally, wherein pravastatin and fluvastatin are administered in active form.

In general it has proved advantageous both in human and veterinary medicine to administer the active ingredient or ingredients of formulae and in total quantities of approximately to approximately 600, preferably 1 to 200 mg/kg body weight per 24 hours, optionally in the form of several individual doses in order to achieve the desired results. An individual dose contains the active ingredient or ingredients preferably in quantities of approximately 0.5 to approximately 200, in particular 1 to 60 mg/kg body weight. It may, however, be necessary to deviate from the above-mentioned dosages and this is dependent on the nature and the body weight of the patient to be treated, the nature and the severity of the disease, the nature and the method and the application of the pharmaceutical compositions as well as the time scale or interval within the administration takes place.

S

V

It has proved advantageous to administer the inhibitors of the lipid metabolism in the known range of dosage, which are known from the treatment of disorders of the lipid metabolism and the calcium and phosphate metabolism. These are total quantities of approximately 0.005 to approximately 200, preferably 0.01 to 100 mg/kg body weight per 24 hours, are optionally administered in the form of several individual doses in order to achieve the desired results. An individual dose contains the active ingredient or ingredients (inhibitors of the lipid metabolism) preferably in quantities of approximately 0.002 to approximately 50, in particular 0.01 to 10 mg/kg body weight. It may however be necessary to deviate from the above-mentioned dosages and this is dependent on the nature and the body weight of the patient to be treated, the nature and the severity of the disease, the nature and the method and the application of the pharmaceutical compositions as well as the time scale or interval within the administration takes place. With amino bisphosphonates it has to be considered that their resorbility is very low. This characteristic is advantageous in the case of an attack in the intestinal tract (for example in the case of amoebic dysentery). Here doses of up to 10 mg/kg body weight pamidronate are administered orally. For injection in general doses up to 2 mg/kg body weight are sufficient.

Thus in some cases it may be sufficient to get by with less than the above mentioned quantity of active ingredient, whilst in other cases the above-stated quantity of active ingredient must be exceeded. The person skilled in the art may determine the optimum dosage and method of application of the active ingredient in each case by virtue of his expert experience.

The lipid metabolism inhibitors according to the invention may be administered in animals in the conventional concentrations and preparations together with the feed or feed preparations or the drinking water.

The lipid metabolism inhibitors may be administered simultaneously, separately or successively.

Example Preparation anti-infectiously active agents Preparation for injection The necessary quantity of the sterile anti-infectiously active agents, 500 mg 3-(Nacetyl-N-hydroxy amino)-propyl-phosphonic acid monosodium salt and 90 mg 3-amino-lhydroxy-propyliden-1, 1-bisphosphonic acid disodium salt are distributed on flasks or ampules. The flasks are sealed hermetically for excluding bacteria. For injection it is taken in 500 ml physiologic solution of sodium chloride respectively and administered.

-56- In principle in the same manner as describe above under further injectable preparations of the anti-infectiously active agents are prepared: 250 mg 3-(N-formyl-N-hydroxy amino)-propylphosphonic acid -monosodium salt and 1 mg 3-methylpentylamino-1-hydroxypropyliden-1,1-bisphosphonic acid disodium salt are used for injections.

250 mg 3-(N-formyl-N-hydroxy amino)-trans-l-propenylphosphonic acid monosodium salt and 90 mg 3-amino-l-hydroxypropyliden-l,l-bisphosphonic acid disodium salt are used as an active ingredient for injection.

Preparation of tablets: A suitable tablet formulation is formed by the following mixture: 3-(N-formyl-N-hydroxy amino)propylphosphonic acid -monosodium salt 200 mg lovastatin 10 mg mannitol 400 mg starch 50 mg magnesium stearate 10 mg Preparation of capsules 3-(N-formyl-N-hydroxy amino)propylphosphonic acid monopotassium salt 300 mg simvastatin 10 mg magnesium stearate 15 mg The present ingredients are mixed and then filled into a hard gelatine capsule in usual manner.

Claims

1. A composition comprising as active ingredients at least one anti-infectiously active compound which inhibits the 2-C-methylerythrose-4 metabolic pathway, and at least one inhibitor of the lipid metabolism, wherein the inhibitor of the lipid metabolism and the anti-infectiously active compound are not identical.

2. The composition according to claim 1, wherein the inhibitors of lipid metabolism are selected from the group which consists of cholestyramine, p-sitosterol, colestipol, probucol, nicotinic acid, nicotinyl alcohol, clofibrin acid derivative and 0o analogues of the clofibrin acid derivative, HMG-CoA-synthetase-inhibitors, HMG-CoA- reductase-inhibitors, squalene synthetase inhibitors and squalene monooxygenase inhibitors.

3. The composition according to claim 2, wherein the inhibitors of lipid metabolism are inhibitors of squalene synthetase.

4. The composition according to claim 3, wherein the inhibitor of squalene synthetase is selected from pyrophosphates, pyrophosphate derivatives, bisphosphonic acid derivatives, phosphinylmethyl phosphonic acid derivatives, phosphinylformyl derivatives, phosphonocarboxyl derivatives, phosphonosulfonic acid derivatives, and phosphinylmethylphosphonic acid derivatives.

5. The composition according to claim 2, wherein the inhibitors of lipid metabolism are inhibitors of HMG-CoA-reductase.

6. The composition according to claim 5, wherein the inhibitor of HMG-CoA reductase is selected from lovastatin, atorvastatin, mevastatin, simvastatin, fluvastatin, pravastatin and cerivastatin. 25 7. The composition according to claim 2, wherein the inhibitors of lipid metabolism are clofibrin acid derivatives and their analogues.

8. The composition according to claim 7, wherein the clofibrin acid derivatives and their analogues are selected from gemfibrozil, fenofibrate, bezafibrate, clofibrate, ciprofibrate and clinofibrate. 30 9. The composition according to claim 2, wherein the inhibitors of the lipid metabolism are bisphosphonic acid derivatives. The composition according to claim 9, wherein the bisphosphonic acid derivatives are selected from clodron acid derivatives, etidron acid derivatives, pamidron acid derivatives, ibandron acid derivatives, alendron acid derivatives, zoledron acid 35 derivatives, risedron acid derivatives, tiludron acid derivatives and cimadron acid derivatives.

11. The composition according to claim 10, wherein the pamidron acid derivative S is pamidronate. [R:\LIBH]01456.doc:UG 58

12. The composition according to claim 10, wherein the ibandron acid derivative is ibandronate.

13. The composition according to claim 10, wherein the alendron acid derivative is alendronate.

14. The composition according to claim 10, wherein the zoledron acid derivative is zoledronate, The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one aminohydrocarbyl phosphonic acid derivative of the general formula (I) O RIN\ I| N-AI-P-RI 3 R R4 (I) wherein R 1 and RI2 are the same or different and are selected from the group which consists of H, OH, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, and substituted and unsubstituted heterocyclic radical, R 1 3 and RI4 are selected from the group which consists of substituted and unsubstituted alkyl with 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl with 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl with 1 to 26 carbon atoms, substituted and unsubstituted alkynyl with 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, X 13 and X 14 wherein X 13 and X 1 4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted *i alkyl with 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl with 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyi, 25 substituted and unsubstituted alkenyl with 1 to 26 carbon atoms, substituted and unsubstituted alkynyl with 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, and A represents an alkylene radical, alkenylene radical or hydroxyalkylene radical or corresponds to the following formula (IA): B 1 B 1 3 B 1 5 BI 7 B 19 1 I I I4 -CI -G 2 -C 3 -C 1 4 -C 5 1 BI 2 BI 4 A 1 6 8 110 (IA) wherein one or more of the carbon atoms, selected from the group C3, C 14 C 15 together with their substituents also may be absent, and at least one present substituent out [R:\LIBH]01456.doc:LG 59 of B 1 to Blo is a C3. 8 -cycloalkyl-(Co-9)-alkyl group, wherein the C 3 8 -cycloalkyl group as well as the Co-9-alkyl group may comprise one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein the cycloalkyl group as well as the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups, with branched or straight Cl-9-alkyl groups and C2-9-alkenyl groups, wherein the Cl-9-alkyl groups and C 2 9 -alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, and the remaining present substituents B 1 1 to B 1 lo are selected from the group which consists of hydrogen, hydroxy-, halogen-, amino groups, C 1 26 -alkyl radicals, C 1 26 -alkoxy radicals, C1- 26 alkoxy-C 1 i 26 -alkyl radicals or both substituents of one C-atom together form an oxo group, wherein each Ci- 26 -alkyl radical and each Cl- 26 -alkoxy radical may be branched or straight and saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups.

16. The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one compound of the general formula (III): o 0 II II RIII 1 -AIII-C-AIII 2 -P-R 1 11 4 II1 (III) wherein R 1 n 1 is selected from the group which consists of H, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted ohydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen and OXn 11 wherein Xn 1 1 is selected from the group which consists of hydrogen, 25 substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, a silyl, substituted and unsubstituted heterocyclic radical, a cation of an organic and inorganic base, 30 R 14 and R 1 113 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen and OXII 1 4 and OXI 13 wherein XmI4 and X 1 1 1 3 are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted [R:\LIBH]01456.doc:JG and unsubstituted cycloalkyl, a silyl, substituted and unsubstituted heterocyclic radical, a cation of an organic and inorganic base, and Aml and A 111 2 out of which one or both may be absent, are the same or different and represent an alkylene radical, alkenylene radical, an oxo radical, a hydroxy radical or oxo hydroxyalkylene radical.

17. The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one compound of the general formula (IV): Rlvl 0 II N -BI-P-Riv3 RIV o R~i RIV 4 (IV) in which Rrvl and Riv2 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXIvi and OXIV 2 wherein XIvi and XIV2 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, B[v selected from the group which consists of the ether group (IVA) Y -AIvi-- -AIV2-C- Z (IVA) wherein AIvl and AIV 2 out of which AIV 2 also may be absent, are the same or different and are selected from the group which consists of alkylene radical, alkenylene radical and hydroxyalkylene radical, the keto group (IVB) 0 II -AI3-C-AIv 4 (IVB) wherein AIV3 and AIV4, out of which one or both also may be absent, are the same or different, and are selected from the group which consists of alkylene radical, alkenylene S R radical and hydroxyalkylene radical, and 5 and 6 membered cyclic radical, [R:\LIBH]01456.doc:JG 61 RIV 3 and RIV 4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OXIv3 or OXIV 4 wherein Xiv 3 or XIV4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, and their pharmaceutically acceptable salts, esters and amides and salts of esters.

18. The composition according to claim 17, wherein said 5 and 6 membered cyclic radical include heterocyclic compounds which contain beside carbon at least one heteroatom as a ring member, wherein the heteroatom is selected from the group which consists of oxygen and nitrogen.

19. The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one compound of the general formula (VI): o oo *o I i: i 0 II RV 14 (VI) 25 wherein Rv 13 and RV I4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having up to 26 carbon atoms, 30 substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OXV13 or OXV14, wherein Xvi3 or XV14 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and Sunsubstituted alkenyl having up to 26 carbon atoms, substituted and unsubstituted alkynyl -o0 S/fc *i [R:\LIBH]01456.doc:UG 62 having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, and Bvl is selected from the group which consists of the group (VIA) RvjI N-AvI- RI2 (VIA) and the group (VIB) RVI 1-N=AvI- (VIB) wherein Avi is selected from the group which consists of an alkyleneamine radical, an alkenyleneamine radical, a hydroxyalkyleneamine radical, an alkyleneimine radical, an alkenyleneimine radical and a hydroxyalkyleneimine radical, wherein the nitrogen atom is a member of the chain, which connects the phosphorus atom with the nitrogen atom of the group RvII N- or the group and RVI2 wherein Rvn and RvI2 in group (VIA) are the same or different and Rvii and RvI2 in group (VIA) and Rvn in group (VIB) are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted 20 cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXvn and OXvl2, wherein XviI and Xv 12 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, S. substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, or their pharmaceutically acceptable salts, esters and amides and salts of esters. The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one compound of the general formula (VII): o I I 0 I RVII1-Av ll RVII3 RV114 (VII) [R:\LIBH]01456.doc:UG 63 in which AvI is selected from the group which consists of a (C 1 -9)-alkylene radical, which may contain one or more double bonds and may be substituted with hydroxy, halogen, amino, oxo groups, with branched or straight C 1 -9-alkyl groups and C2-9-alkenyl- groups, wherein the Cl-9-alkyl groups and C 2 9 -alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, and wherein the carbon atoms of and may be substituted with an alkyl having up to 7 carbon atoms or hydroxy groups, or in which AvuI corresponds to the following formula (VIIA): I I I I I -CVII I-CV 1 1 2 -CvI 1 3 -CV 1 I 4 -CV II S I I I I I (VIIA) r r wherein one or more carbon atoms, selected from the group Cvll 3 CV 14 Cvll 5 together with their substituents may be absent, and at least one present substituent of BvIl to Bvuilo is a C3-8-cycloalkyl-(Co-9)-alkyl group, wherein the C 3 cycloalkyl group as well as the Co-9-alkyl group may comprise one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein the cycloalkyl group as well as the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups with branched or straight Cl-9-alkyl groups and C2- 9 -alkenyl groups, wherein the C 1 -9-alkyl groups and C 2 -9-alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, and the remaining present substituents Bvml to Bvmlo are selected from the group which consists of hydrogen, hydroxy, halogen, amino groups, Cl- 26 -alkyl radicals, Cl-2 6 -alkoxy radicals, C1-2 6 -alkoxy- C 1 -2 6 -alkyl radicals or both substituents of one C-atom together form an oxo group, wherein each Cl- 26 -alkyl radical and each Cl- 26 -alkoxy radical is branched or straight and saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups, wherein Rvml is selected from the group which consists of 5 and 6 membered heterocycles with one or two nitrogen, oxygen or sulfur atoms in the ring, wherein the heterocycle may be saturated or unsaturated with one or more double or triple bonds and may be substituted with hydroxy, halogen, amino, oxo groups and with branched or straight Cl-9-alkyl groups and C2- 9 -alkenyl groups, wherein the Cl-9-alkyl groups and C2- 9 alkenyl groups may be saturated or unsaturated with one or more double or triple bonds and may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, wherein Rvu 1 3 and RVII4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C 1 26 -alkyl, hydroxy-C 1 26 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted Ci- 2 6 -alkenyl, substituted and A- Li'! \2o JJQ [R:\LIBH]01456.doc:LG 64 unsubstituted C 1 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OXV113 and OXVII 4 wherein Xvl3 and Xv114 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C 1 26 -alkyl, substituted and unsubstituted hydroxy-C 1 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Ci-2 6 -alkenyl, substituted and unsubstituted Cl- 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, and their pharmaceutically acceptable salts, esters and amides and salts of esters.

21. The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one compound of the general formula (VIII): O 0 RvIIIO Rv ilI I (CHRVI 14)n ORvIIII RvI 11 3 Rv 11 12 (VIII) wherein the wavy line represents a bond, which either has a- or P-configuration, n is 0 or 1, wherein RvIIII is selected from the group which consists of substituted and unsubstituted Ci- 26 -alkyl, hydroxy-Cl-2 6 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C-1 26 -alkenyl, substituted and unsubstituted Ci- 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen and OXviII 1 wherein XvlIIl is selected from the group which consists of hydrogen, substituted and unsubstituted C 1 26 -alkyl, substituted and unsubstituted hydroxy-Ci- 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and S 25 unsubstituted C.- 26 -alkenyl, substituted and unsubstituted C.- 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, RvIII 1 is selected from the group which consists of C- 24 -alkyl radicals, C2-2 4 -alkenyl radicals, C2-24-alkapolyenyl radicals containing 2 to 6 double bonds, C 2 24 -alkynyl radicals, C3-8-cycloalkyl radicals, C3-8-cycloalkyl-C 1 .2 4 -alkyl radicals and C 1 1 2 -alkoxy-C-. 12 -alkyl radicals, RvII 1 2 RvII 3 and RV 11 14 each are selected independently from the group which ,consists of hydrogen, halogen, amino, acetylamino, azido and XRVII1 6 -groups, wherein X [R:\LIBH]01456.doc:JG I I I I is O or S and RvII 16 is selected from the group which consists of a hydrogen radical, branched or straight Ci-4-alkyl radicals and C2- 4 -alkenyl radicals, wherein the C 1 -4-alkyl radicals as well as the C 2 4 -alkenyl radicals may be optionally substituted with hydrogen, amino, halogen or oxo groups, or RvII 1 2 Rvi 13 and Rv 1 14 together with the respective geminal hydrogen group represent an oxo group, Rv 11 5 is selected from the group which consists of hydrogen, Ci- 24 -alkyl groups, C 3 8-cycloalkyl radicals, Ar(CI- 2 4 -alkyl) groups, aryl groups, acyl groups, heterocyclic radicals, halogen, wherein all radicals may be branched or straight and may be optionally to substituted with hydroxy, amino, halogen or oxo group and may contain 2 to 6 double and triple bonds or Rv 1 11 5 is a phenyl radical of the formula VIIIA or XIIIB, RVIII RVI 1 7 (VIIIA) -CH 2 RV1118 RV 1 117 (VIIIB) wherein RVII 17 and RvIs 8 are the same or different and are bound to any two positions of the phenyl ring and each are selected independently from the group which consists of hydrogen, halogen, C 1 4 -alkyl radicals, C 1 4 -alkoxy radicals, formyl, acetyl, propionyl, butyryl radicals, formyl, acetyl, propionyl, butyryloxy radicals, C2- 5 20 alkoxycarbonyl radicals, which all may be branched or straight, or R 7 and RvIn 1 may form S.together a straight saturated alkylene chain with 3 to 4 carbon atoms, which are bound to adjacent positions, including the 2,3-positions and the 3,4-positions of the phenyl ring, or R 7 and R 8 together form a methylenedioxy radical, a 1,1-ethylidenedioxy radical or a 1,2- ethylenedioxy radical, which is bound to the 2,3- or 3,4-positions of the phenyl ring, or 25 RvII 15 is selected from the group which consists of RvIII9COOCHRvIII 1 o- and RvI 1 i 9 0COOCHRvIIlo-, wherein RvnI9 is selected from the group which consists of Ci-6-alkyl radicals, C2- 6 alkenyl radicals, C2- 6 -alkynyl radicals, C3_-cycloalkyl radicals, C3-8-cycloalkyl-C 1 _6-alkyl radicals and Cl. 6 -alkoxy-C 1 6 -alkyl radicals, wherein all radicals may be branched or 30 straight and may be optionally substituted with hydroxy, amino, halogen or oxo groups, and RIO is a branched or straight Ci-4-alkyl radical, and wherein the configurations of the substituents RvII2, Rv 1 13 RVII 4 and RVIs50OCPO(OH)OCH 2 in (VIII) is independently selected from D-gluco, L-gluco, D- [R:\LIBH]01456.doc:LG 66 galacto, L-galacto, D-manno, L-manno, D-talo, L-talo, D-allo, L-allo, D-altro, L-altro, D- gulo, L-gulo, D-ido or L-ido are, if n is 1 or the configurations of the substituents R 2 R 3 and R 5 00CPO(OH)OCH 2 in I are independently D-ribo, L-ribo, D-arabino, L-arabino, D-xylo, L-Xylo, D-lyxo or L-lyxo, if n is 0.

22. The composition according any one of claims 1 to 14, comprising as an active ingredient at least one compound the general formula (IX) RIl RIX 2 (IX) wherein RjxII is selected from the group which consists of substituted and unsubstituted C 1 26 -alkyl, hydroxy-C 1 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted Cl-2 6 -alkenyl, substituted and unsubstituted Cl-2 6 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen and OXIXI l, wherein Xjx1I is selected from the group which consists of hydrogen, substituted and unsubstituted C 1 26 -alkyl, substituted and unsubstituted hydroxy-C 1 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Cl- 26 -alkenyl, substituted and unsubstituted Cl-26-alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a 20 cation of an organic and inorganic base, wherein Rixj and RIX 2 each are selected independently from the group which consists of Cl-2 4 -alkyl radicals, C 3 8 -cycloalkyl radicals, C 3 8 -cycloalkyl-C 1 24 -alkyl radicals, Cl-2 4 -alkoxy radicals, C 1 24 -alkylthio- radicals, C- 1 24 -alkoxy-C 1 24 -alkyl radicals and C 1 2 4 -alkylthio-C 1 24 -alkyl radicals, acyl radicals, aryl radicals, aralkyl radicals, 25 heterocyclic radicals, halogen and hydrogen, and each Cl-2 4 -alkyl radical and Cl- 24 -alkoxy radical may be branched or straight and saturated or unsaturated with 2 to 6 double bonds and optionally may be substituted with hydroxy, amino, mercapto, halogen, oxo groups or Cl-2 4 -alkoxy radicals, C 1 -24-alkylcarbonyloxy radicals, C 1 -2 4 -alkoxycarbonyloxy radicals, C 1 24 -alkylthio radicals, C 1 24 -alkylcarbonylthio radicals, Cl- 2 4 -alkylamino radicals, di- (C 1 24 -alkyl)amino radicals, C 1 24 -alkylcarbonylamino radicals, C 1 24 -alkyl-(C 1 -24- alkylcarbonyl)amino radicals, C 1 24 -alkoxycarbonylamino radicals or Cl- 24 -alkyl-(C 1 -24- alkoxycarbonyl)amino radicals, wherein each aralkyl radical, heterocyclic radical, C 1 -24- alkyl radical and C 1 24 -alkoxy radical may be branched or straight and saturated or unsaturated with 2 to 6 double bonds or triple bonds, or wherein RIxI-CH-CH-RIX 2 form a

35. part of a C 4 -8-carbon ring, which optionally may be substituted with hydroxy, mercapto, ,I [R:\LIBH]01 I 456.doc:UG 67 amino, halogen, oxo groups or with Cl- 2 4 -alkyl radicals, Cl- 24 -alkoxy radicals, C 1 24 alkylthio radicals, Cl- 24 -alkylamino radicals, di-(C 1 24 -alkyl)amino- radicals, C 1 24 alkylcarbonyl radicals, C 1 24 -alkylcarbonyloxy radicals, C 1 24 -alkoxycarbonyl radicals, C 1 24 -alkylcarbonylthio radicals or C 1 -2 4 -alkylcarbonylamino radicals, C 1 24 -alkyl-(CI-24- alkylcarbonyl)-amino radicals, wherein each Cl-2 4 -alkyl radical may be branched or straight and saturated or unsaturated with 1 to 6 double bonds, or wherein RIx o is a branched or straight C 1 -4-alkyl radical, and wherein RIx-CH-CH- RIX 2 form a part of the furanose or pyranose ring of a sugar, wherein the hydroxy groups each optionally may be substituted with hydrogen, amino, azido, oxo, mercapto radicals or CI. 24 -alkoxy radicals, Cl- 24 -alkylthio radicals, C 1 2 4 alkylamino radicals, di-(C 1 24 -alkyl)amino radicals, C1-2 4 -alkylcarbonyloxy radicals, C 1 2 4 alkylcarbonylthio radicals, C 1 -24-alkylcarbonylamino radicals, Cl- 2 4 -alkyl-(C -24- alkylcarbonyl)amino radicals, wherein each C 1 24 -alkyl radical may be branched or straight and saturated or unsaturated with 1 to 6 double bonds, and their pharmaceutically is acceptable salts, esters and amides and salts of esters as well as their optical isomers, R I x, and RIX2 may be selected independently from the group which consists of carboxyl radicals, carboxamido radicals, aryl radicals, aryloxycarbonyl radicals, aryl- C 1 24 -alkyl radicals, C 1 -24-alkoxycarbonyloxy radicals, C -24-alkylaminocarbonyl radicals, di-(C- 1 24-alkyl)-aminocarbonyl radicals, aryl-C1 -2 4 -alkoxycarbonyl radicals, aryl-C 1 -24- alkylaminocarbonyl radicals, C- 1 24 -alkylcarbonyloxy-(C- 4)alkylmethoxycarbonyl radicals, C 1 -24-alkoxycarbonyloxymethoxycarbonyl radicals, C 1 -24-alkoxycarbonyl-oxy- (C 1 -4-alkyl)-methoxycarbonyl, wherein each CI- 24 -alkyl radical may be branched or straight and saturated or unsaturated with 2 to 6 double bonds, and each C14-alkyl radical and Cl- 24 -alkoxy radical may be branched or straight and saturated or unsaturated, and each aryl radical of the formula IXA 00*0 I RIx 3 (IXA) wherein RIX 3 and RIX 4 are the same or different and each are selected from the group which consists of hydrogen, halogen, C00-alkyl radicals, C 1 4 -alkoxy radicals, S 30 formyl, acetyl, propionyl, butyryl radicals, formyl, acetyl, propionyl, butyryloxy radicals, CI-4-alkoxycarbonyl radicals, which all may be branched or straight, or RIX 3 and RIX4 .0 together form a straight saturated alkylene chain with 3 to 4 carbon atoms, which are bound to adjacent positions of the phenyl ring or RIX 3 and RIX 4 together form a methylenedioxy radical, a 1,1-ethylidendioxy radical or a 1,2-ethylenedioxy radical, which is bound to adjacent positions of the phenyl ring. [R:\LIBH]01456.doc:UG 68 23. The composition according to claim 22, wherein the furanose or pyranose ring of a sugar is selected from. D-ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D- galactose, D-mannose, D-talose, D-allose, D-altrose, D-gulose, D-idose and the respective L-isomers. 24. The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one compound of the general formula O HO\ I N-C-Rx2 Rxi (X) wherein Rx is selected from the group which consists of hydrogen, substituted and unsubstituted Cl-9-alkyl, substituted and unsubstituted hydroxy-Cl-9-alkyl, substituted and unsubstituted Ci-9-alkenyl, substituted and unsubstituted C 1 -9-alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen and OXxl, wherein Xxl is selected from the group which consists of hydrogen, substituted and unsubstituted Ci-9-alkyl, substituted and unsubstituted hydroxy-C._ 9 -alkyl, substituted and unsubstituted Cl-9-alkenyl, substituted and unsubstituted Cl-9-alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, wherein Rx 2 is selected from the group which consists of C_- 26 -alkyl radicals, C1- 26 alkoxy radicals, C 1 26 -alkoxy-C 1 26 -alkyl- radicals, C 3 -8-cycloalkyl-(CO- 26 )-alkyl radicals, wherein one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, 25 oxygen or sulfur atoms, each C 3 26 -alkyl radical and each C 3 26 -alkoxy radical branched or straight and each C3-8-cycloalkyl radical, each C 2 26 -alkyl radical and each C2- 26 -alkoxy radical may be saturated or unsaturated with one or more double bonds and each C 3 8 i cycloalkyl- radical, each C 1 26 -alkyl radical and each C 1 -2 6 -alkoxy radical may be substituted with hydroxy, amino, halogen and oxo groups or by the carbyl group CORx 3 30 wherein Rx 3 is selected from the group which consists of substituted and unsubstituted C 26 -alkyl, hydroxy-C 26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C 1 26 -alkenyl, substituted and unsubstituted C 1 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen and OXx 3 wherein Xx3 is selected from the group which consists of hydrogen, substituted and ",un substituted CI- 26 -alkyl, substituted and unsubstituted hydroxy-CI- 26 -alkyl, substituted L, i 1 [R:\LIBH]01456.doc:UG 69 and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Ci- 26 -alkenyl, substituted and unsubstituted Cl-2 6 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base. 25. The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one compound of the general formula (XI): 0 0 II II RxII- Zx-IAx-P-RxI3 I Ri4 RXI 2 RXI 4 (XI) wherein Zx is a phosphorus atom or a sulfur atom, in which Axi is a straight C 2 9 -alkylene chain with substituents which are the same or different and are selected from the group which consists of hydrogen, hydroxy, halogen, amino and oxo groups, C-1 26 -alkyl radicals, Cl. 26 -alkoxy radicals, C 1 -2 6 -alkoxy- C 1 26 -alkyl radicals orC 3 .8-cycloalkyl-(Co-9)-alkyl radicals, wherein each C 1 26 -alkyl radical and each Cl- 26 -alkoxy radical may be branched or straight and saturated or unsaturated with one or more double bonds and may be substituted with hydroxy, amino, halogen and oxo groups and the C3.s-cycloalkyl group as well as the Co-9-alkyl group of the C3-8-cycloalkyl-(Co-9)-alkyl group may contain one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and wherein the cycloalkyl group as well as the alkyl group may be substituted with hydroxy, halogen, amino, oxo groups, with branched or straight Ci-9-alkyl groups and C2-9-alkenyl groups wherein the C-1 9 -alkyl groups and C 2 9 -alkenyl groups may be substituted with hydrogen, hydroxy, amino, halogen and oxo groups, in which Rxll and Rx 2 are the same or different and are selected from the group which consists of hydrogen, 25 substituted and unsubstituted Cl-9-alkyl, substituted and unsubstituted hydroxy-Cl-9-alkyl, substituted and unsubstituted Cl-9-alkenyl, substituted and unsubstituted Cl-9-alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXxll and OXXI2, wherein Xxli and X X12 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted Cl-9-alkyl, substituted and unsubstituted hydroxy-Cl-9-alkyl, substituted and unsubstituted Cl-9-alkenyl, substituted and unsubstituted Ci- 9 -alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, Rx 13 and RX 1 4 are the same or different and are selected from the group which consists of substi [R:\LIBH]01456.doc:UG tuted and unsubstituted C 1 26 -alkyl, hydroxy-Ci-2 6 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted Cl-2 6 -alkenyl, substituted and unsubstituted Cl-26- alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, halogen, OXXI3 and OXXI 4 wherein XX13 and Xxi4 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted C 26 -alkyl, substituted and unsubstituted hydroxy-C 1 -26-alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted Cl-2 6 -alkenyl, substituted and unsubstituted Ci-2 6 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, a silyl, a cation of an organic and inorganic base, and their pharmaceutically acceptable salts, esters and amides and salts of esters. 26. The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one compound the general formula (XII): o RX 114 II I AXII-C-NO -RX 1 13 (XII) wherein Axii is selected from the group which consists of hydrogen, substituted and unsubstituted Cl- 28 -alkyl radicals, substituted and unsubstituted alkoxy-(Co- 28 )-alkyl radicals, substituted and unsubstituted cycloalkyl-(Co- 28 )-alkyl radicals, substituted and unsubstituted cycloalkoxy-(CO- 28 )-alkyl radicals, substituted and unsubstituted amino- (Co- 28 )-alkyl radicals, substituted and unsubstituted thio-(Co- 28 )-alkyl radicals and substituted or unsubstituted acyl-(Co-2 8 )-alkyl radicals and halogen, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each alkoxy radical, each acyl radical and each cycloalkyl group may be 25 saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, Rx 113 is selected from the group which consists of hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy-(Co-2 6 )-alkyl radicals, substituted and unsubstituted C3-14-cycloalkyl-(CO- 26 )-alkyl radicals, substituted and unsubstituted cycloalkoxy-(Co- 26 )-alkyl radicals, substituted and unsubstituted amino- (Co-2 6 )-alkyl radicals, substituted and unsubstituted silyl-(Co-2 6 )-alkyl radicals, and substituted and unsubstituted thio-(Co-2 6 )-alkyl-groups, wherein each alkyl radical and each alkoxy radical may be branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more 35 double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, or a carbon chain of two C-atoms in Axii forms a ring together with RXII 3 such that 1_ an isoxazolidone ring is formed, and C/vT <C [R:\LIBH]01456.doc:LG 71 RxII 4 is selected from the group which consists of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted acyl radicals and substituted and unsubstituted cycloalkyl-(CO- 26 )-alkyl radicals, wherein each alkyl radical and each acyl radical may be branched or straight and each alkyl radical, each acyl radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms. 27. The composition according to any one of claims 1 to 14, comprising as an active ingredient at least one compound of the general formula (XIII): RXII12 RX 1 11 3 RXII S n S RxII5 RXII6 N (XIII) wherein n is an integer from 0 to 4, and wherein Rxi 1 lI, RxIII 2 RxIII 3 RXII 14 Rxi 15 and RxIl 1 6 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted alkoxy radicals, substituted and unsubstituted acyl radicals, substituted or unsubstituted cycloalkyl-(CO- 2 6 )-alkyl radicals, substituted and unsubstituted cycloalkyl-(Co- 26 )-alkoxy radicals and halogen, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each acyl radical, each alkoxy radical and each cyclo-(Co- 26 )-alkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms. .28. The composition according to any one of claims 1 to 14, comprising as an i. active ingredient at least one compound of the general formula (XIV): Rxlv13 RXIV14 YxIv N-BxIv-ZxIv I7 RxV8 (XIV) wherein Yxiv is a C.-3-alkenylene group, which is optionally substituted with the substituents Rxwiv and RxIV2 and optionally substituted with the substituents RXIV 3 to 30 RxIV 6 wherein Rxivi to Rxivs are the same or different and are selected from the group ^i which consists of hydrogen, hydroxy, halogen, substituted and unsubstituted alkyl groups, [R:\LIBH]01456.doc:LJG 72 substituted and unsubstituted cycloalkyl-(CO- 26 )-alkyl radicals, substituted and unsubstituted cycloalkoxy-(CO- 26 )-alkyl radicals, substituted and unsubstituted alkoxy- (CO- 26 )-alkyl radicals, substituted and unsubstituted amino groups, substituted and unsubstituted thio-(CO- 26 )-alkyl radicals, substituted and unsubstituted sulfonyl-(Co- 26 alkyl radicals, substituted and unsubstituted sulfinyl-(Co-2 6 )-alkyl radicals and substituted or unsubstituted acyl radicals, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, and RxIvl 3 and RX I VI 4 are defined the same as Rxivl to RxwIV or together form an oxo group, wherein Zxjv represents the organophosphorus group O -P-Rxlv9 I wherein Rxlv 9 and Rxivio are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted (C 1 -2 6 )-alkyl groups, substituted and unsubstituted hydroxy-(C 1 -2 6 )-alkyl radicals, substituted and unsubstituted cycloalkyl- (Co-2 6 )-alkyl radicals, substituted and unsubstituted acyl, halogen, OXxIv9 or OXxrvio, wherein each alkyl radical, each alkoxy radical and each acyl radical may by branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, wherein XXIV9 or Xxivio are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted (Cl. 26 )-alkyl groups, substituted and unsubstituted hydroxy-(Cl- 26 )-alkyl radicals, substituted and unsubstituted cycloalkyl-(Co- 26 )-alkyl radicals, substituted and unsubstituted acyl, a silyl, a cation of an organic and inorganic base, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, or wherein Zxiv represents the amino group .00. :00:* T [R:\LIBH]01456.doc:UG R x iv II 73 wherein RxIIvI and Rxiv1 2 are the same or different and are selected from the group which consists of hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl-(Co- 26 )-alkyl radicals, substituted and unsubstituted cycloalkoxy- (CO- 26 )-alkyl radicals, substituted and unsubstituted alkoxy-(Co-2 6 )-alkyl radicals and s substituted or unsubstituted acyl radicals, wherein each alkyl radical, each alkoxy radical and each acyl radical may be branched or straight and each alkyl radical, each alkoxy radical and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl radicals may be replaced by nitrogen, oxygen or sulfur atoms, wherein Bxiv is selected from the group which consists of substituted and unsubstituted Ci- 26 -alkenylene groups, wherein one C-atom may be replaced by one oxygen atom and one C-atom by one sulfur atom or two C-atoms may be replaced by a S-heterocycle and wherein each alkenylene radical may be branched or straight and saturated or unsaturated with one or more double or triple bonds and may be substituted with one or more hydroxy groups, halogen groups or oxo groups. 29. The composition according to any one of claims 15 to 25 or 28, wherein said base is selected from a metal of the first, second or third main group of the periodic system, ammonium, substituted ammonium and ammonium compounds which derive from ethylenediamine or amino acids. A composition as defined in claim 1, substantially as hereinbefore described with reference to the Example. 31. Use of a composition according to any one of claims 1 to 30 for the therapeutic and prophylactic treatment of infectious processes in humans, animals and plants and as herbicides in plants. 32. Use according to claim 31, wherein the infectious processes are caused by unicellular or multicellular parasites, fungi, bacteria or viruses. 33. Use according to claim 31 or 32, wherein the processes are infectious processes in humans or animals. 34. A method for the treatment of prophylaxis of infectious processes in humans, animals and plants, comprising administering to said human, animal or plant a 30 composition according to any one of claims 1 to 35. The method according to claim 34, wherein the infectious processes are caused by unicellular or multicellular parasites, fungi, bacteria or viruses.

36. The method according to claim 34 or 35, wherein the processes are infectious processes in humans or animals.

37. A composition according to any one of claims 1 to 30, when used for the treatment or prophylaxis of infectious processes in humans, animals or plants.

38. The composition when used according to claim 37, wherein the infectious processes are caused by unicellular or multicellular parasites, fungi, bacteria or viruses. S [R:\LIBH]01456.doc:UG 74

39. The composition when used according to claim 37 or 38, wherein the processes are infectious processes in humans or animals. Dated 4 July, 2002 Jomaa Pharmaka GmbH Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0**S S *S5* S S S S SSS* )1456.doc:UG