DE19828097A1 - Identifying antiparasitic agents used to treat or prevent parasitic infections, especially malaria, sleeping sickness and leishmaniosis - Google Patents

Abstract

Identification of agents (A) suitable for treatment of infections caused by mono- or poly-cellular parasites comprises (i) treating a test compound with a protein (I) that is involved in the 1-deoxy-D-xylulose-5-phosphate (dDXP) metabolic pathway (or its derivatives with equivalent activity) and (ii) selecting compounds that inhibit (I) or its derivatives. Independent claims are also included for the following: (a) proteins (II) encoded by approximately 3.8 kb (1b) or 3.7 kb (2b) sequences or by sequences that hybridize to (1b) or (2b), or their fragments that encode the mature protein; (b) proteins (III) encoded by approximately 1.5 kb (1a) or 1.5 kb (2a) sequences or by sequences that hybridize to (1a) or (2a) or their fragments that encode the mature protein; (c) (II), (III) and other proteins (IV) involved in the dDXP metabolic pathway isolated from parasite culture media or lysate by chromatography and electrophoresis; (d) (1a), (1b), (2a) and (2b) and sequences that hybridize with them or that would do so but for the degeneracy of the genetic code; (e) recombinant expression vector containing DNA (V) that encodes (II)-(IV) and expresses them in a transformed microorganism or eukaryotic cell, animal or plant; (f) host cells transformed with (V) and able to express (II)-(IV); (g) antibodies (Ab) raised against (II)-(IV); and (h) (A), or herbicides, identified using (I).

Description

The invention relates to combination preparations of Aminohydro carbylphosphonic acid derivatives and their salts and esters and of inhibitors of lipid metabolism and their simultaneous, ge separate or staggered use for prophylaxis and Therapy of infectious processes, especially in humans and Animal. The combination preparations of the present invention are particularly suitable for therapeutic and prophylactic purposes treatment of infections by unicellular or multicellular Parasites, fungi, bacteria or viruses.

The suitability of aminohydrocarbylphosphonic acid derivatives as well some of their esters and salts are already being used as medicinal products knows. However, so far it is exclusively their antimicrobial le effectiveness against bacteria in humans and animals and against Fungi has been described in plants (DE 27 33 658 A1, 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, U.S. 4,330,529, U.S. 5,189,030, U.S. 3,764,677, U.S. 3,764,676). In Commonly assigned DE-A-198 16 196 as this invention becomes the use of aminohydrocarbylphosphonic acid derivatives to treat parasitic infections caused by infections Viruses and infections caused by fungi are described. Are further Substances of this group as herbicides (US Pat. No. 4,693,742, US Pat. No. 5,002,602, US 4,131,448, US 3,977,860, US 4,062,669), as algaecides (US 3,887,353) as plant growth regulating agents (US 4,127,401, US 4,120,688, US 3,961,934, US 4,431,438, U.S. 3,853,530, U.S. 4,205,977, U.S. 4,025,332, U.S. 3,894,861) and as Reagents for dye production (US 4,051,175) been.

The application of aminohydrocarbylphosphonic acid derivatives in the fight against bacterial infections turned out to be very good difficult. Lots of bacteria responsible for ambulatory infections and are responsible for infections that occur during a clinic are acquired over a The rapie with this group not sensitive. This includes Bak teries of the genus Staphylococcus, in particular the species Sta phylococcus aureus. This skin germ poses a risk to Patients who are in clinics. Further studi en, including a phase IIa of the applicant for the patent DE 27 33 658, showed a very rapid development of resistance originally sensitive germs. These derivatives were therefore not established in clinical use.

The use of inhibitors of fat metabolism is one Be recognized and widespread for a long time principle of action. These inhibitors are used to prevent the Risk of cardiovascular disease due to hyperlipi lower demia. The pharmacotherapy of these hyperlipidemias is usually based on a regulation of the intake and re regulation of the synthesis of fats or, in particular, of choles sterol. As a rule, the synthesis of cholesterol is carried out the enzyme β-hydroxymethylglutaryl-CoA reductase (HMG-CoA-Re ductase) controlled. The self-synthesis of cholesterol is in usually greater than dietary intake. (Berthold H. K., from Bergmann K., Dtsch. Med. Wochenschr. 121, p. 729 (1996); Judge W. O., Fortschr. med. 114, pp. 177, 193).

To regulate the absorption of fats from the digestive system Anion exchangers and β-sitosterol are known in the tract. To the Ion exchangers include cholestyramine and colestipol. she absorb bile acids and thereby interrupt the entero hepatic return transport and thus cause a significant Increase in stool sterols. β-sitosterol is a herbal one Sterol, structurally related to cholesterol. It inhibits them Resorption of food cholesterol in the intestinal mucosa.

Next have nicotinic acids and their derivatives, clofibrates and their derivatives and probucol use in the regulation of the Fat metabolism or the prevention of secondary diseases of hyperlipidemias found. Nicotinic acids and nicotinic acid derivatives lead to a reduction in fatty acids, the triglyces ride and cholesterol. The mechanism so far is not known. The ethyl ester of clofibric acid, clofibrate and De derivatives, as well as analogues, lead to a lowering of cholesterol, the mechanism of action is also unknown. Also the Mechanism of action of probucol is not clear.

To regulate 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 50 25 017, US 48 47 271, US 46 22 338, US 49 04 646, US 48 73 345, US 55 93 971, US 52 60 305, US 52 02 327, US 49 40 727, US 52 72 166, US 53 85 932, US 54 61 039, US 55 56 990, US 55 61 143, US 55 63 128), Squalene synthetase inhibitors, especially pyro phosphates, pyrophosphate derivatives, bisphosphonic acid derivatives, Phosphinylmethylphosphonic acid derivatives, phosphinylformylderiva te, phosphonocarboxyl derivatives, phosphonosulfonic acid derivatives, Phosphinylmethylphosphonic acid derivatives, some of which are also called pharmaceutical and cosmetic products in the regulation of the Calcium and phosphate metabolism are known (DE 2534 390, DE 25 34 391, DE 33 34 211, DE 34 34 667, DE 27 45 083, 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 55 260, US 55 63 128, US 52 02 327, US 49 04 646), and others Inhibitors of cholesterol synthesis (US 56 61 145, US 57 44 467), whose assignment has not been clarified, is used. HMG-CoA- Reductase inhibitors competitively inhibit the speed Determining enzyme of cholesterol synthesis, HMG-CoA reductase. They have an affinity for the enzyme that is up to 20,000 times higher than the substrate HMG-CoA. The HMG-CoA reductase leads to Um Conversion of HMG-CoA to mevalonate, from which in addition to cholesterol i.a. Isopentenyladenine and farnesyl pyrophosphate, the preliminary stage fe from dolichol and ubiquinone. In bacteria, pil zen and parasites that have an HMG-CoA reductase, the isopentenyl diphosphates are created via the acetate / mevalo nat pathway that is inhibited by HMG-CoA reductase inhibitors will.

The first inhibitors discovered were from a penicilli um- (Mevastatin) and an Aspergillus mushroom (Lovastatin) iso lates. The modification of the side chain resulted in simvastatin, the further development of mevastatin to pravastatin. Meanwhile schen is also a fully synthetic enzyme inhibitor (Fluvasta tin), which is a mevalonlactone derivative of a fluorophe represents nyl-substituted indole ring.

Approaches to the use of these substances in the fight against Infectious diseases have been targeted in the past. In particular, attempts have been made through the use of HMG-CoA inhibitors the growth of fungi, parasites, To inhibit bacteria and viruses. The HMG-CoA synthetase and HMG-CoA reductase inhibitors inhibit the acetate mevalonate Way in some bacteria, fungi (US 50 26 554, US 50 64 856, US 49 20 111, US 49 20 113) and parasites. However, show many bacteria, such as Escherichia coli, have no In hibition by HMG-CoA reductase inhibitors. This is ver presumably because this bacteria is an alternative substance own changeable way. For Escherichia coli was actually made the absence of the acetate-mevalonate metabolic pathway and that Evidence of the existence of another metabolic pathway (Rohmer M. et al., Biochem. J. 295, p. 517 (1993); Lois E. M. et al., Proc. Natl. Acad. Sci. USA 95, p. 2105 (1998)).

Studies with HMG-CoA reductase inhibitors on parasites have shown different results depending on the parasite. For example, high doses of lovastatin do not kill pathogens of schistosomiasis, while in malaria pathogens egg ne killing is achieved in vitro, but not in vivo. Even the pathogens of sleeping sickness cannot be completely removed inhibit by inhibiting HMG-CoA reductase. Similar Versu che to inhibit virus replication show that virus-infecting the inhibitory influence of the HMG-CoA reductase Lose inhibitors.

Also squalene synthetase inhibitors, such as the aminobisphospho Nates have been dormant as inhibitors of amoeba without success checks. A low killing efficiency was found. Similar experiments with toxoplasmas do not show any there either satisfactory results. Squalene Epoxidase inhibitors developed as fungicides (US 47 82 059).

It has surprisingly been found that the combination of Aminohydrocarbylphosphonic acid derivatives with inhibitors of the Fat synthesis, especially cholesterol synthesis, in particular others of inhibitors of HMG-CoA reductase and squalene Synthetase the breadth and effectiveness of therapy and increase the prophylaxis of infections. This is surprising because lipid lowering agents only partially stimulate the growth of Para sites, the fungi, the bacteria inhibit. The combination leads to a killing of microorganisms that are neither by let one of them be killed by the second group. Even the combinations show a strong reduction in education of resistance to aminohydrocarbylphosphonic acid derivatives, which is usually the biggest problem in handling this Represents connection group.

The combination preparations of Aminohydrocarbylphosphonsäurede Derivatives and inhibitors of lipid metabolism are essential for thera therapeutic and prophylactic treatment of infections, ins particularly suitable for humans and animals, especially by In infections caused by parasites, bacteria, fungi and viruses caused.

The combination preparations according to the invention contain at least at least one aminohydrocarbylphosphonic acid derivative and / or their Esters and / or their salts. This generally includes pharmaceutically acceptable salts, esters, a salt of a sol Chen esters, or compounds that, when applied, the compounds according to the invention as metabolic products or Provide degradation products, also called "prodrugs".

The aminohydrocarbylphosphonic acid derivatives according to the invention correspond to the general formula (I):

R ₁ and R ₂ can be the same or different and are selected from the group consisting of H, OH, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted aryl, a substituted and unsubstituted cycloalkyl, contains a substituted and unsubstituted aralkyl, and a substituted and unsubstituted heterocyclic radical,
R ₄ and R ₅ can be the same or different and are selected from the group consisting of hydrogen, a substituted and unsubstituted alkyl, a substituted and unsubstituted aryl, a substituted and unsubstituted aralkyl, a substituted and unsubstituted cycloalkyl, a silyl , substituted and unsubstituted heterocyclic radical, a cation of an organic and inorganic base, in particular a metal from the first, second and third main groups of the periodic table, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids, and
A stands for an alkylene radical, alkenylene radical or hydroxyalkylene radical.

According to the invention, the inhibitor of lipid metabolism is not Aminohydrocarbylphosphonic acid derivative of the formula (I).

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

Aminohydrocarbylphosphonic acid derivatives which have the formula (II) are particularly suitable

correspond, where
R ₃ is selected from the group consisting 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;
R ₂ , R ₄ , R ₅ and A have the same meaning as in formula (I).

Special features of the above definitions and suitable examples are given below:
"Acyl" is a substituent derived from an acid, such as from an organic carboxylic acid, carbonic acid, carbamic acid or the thioic acid or imidic acid corresponding to the individual acids above, or from an organic sulfonic acid, these acids being aliphatic, aromatic and / or heterocyclic groups in the molecule include as well as carbamoyl or carbamimidoyl.

Suitable examples of these acyl groups are given below specified.

Aliphatic acyl groups are acyl radicals derived from an aliphatic acid, which include the following:
Alkanoyl (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.);
Alkenoyl (e.g. acryloyl, methacryloyl, crotonoyl, etc.);
Alkylthioalkanoyl (e.g. methylthioacetyl, ethylthioacetyl, etc.);
Alkanesulfonyl (e.g. mesyl, ethanesulfonyl, propanesulfonyl, etc.);
Alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.);
Alkylcarbamoyl (e.g. methylcarbamoyl, etc.);
(N-alkyl) -thiocarbamoyl (e.g. (N-methyl) -thiocarbamoyl, etc.);
Alkylcarbamimidoyl (e.g., methylcarbamimidoyl, etc.);
Oxalo;
Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).

In the above examples of aliphatic acyl groups, the aliphatic hydrocarbon part, especially the Al alkyl group or the alkane radical, optionally one or more suitable have te substituents, such as amino, halogen (e.g. fluorine, Chlorine, bromine etc.), hydroxy, hydroxyimino, carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy, etc.), alkoxycarbonyl, acylami no (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, Benzoyloxy, etc.) and the like; as preferred aliphatic Acyl radicals with such substituents are, for. B. with Amino, Car boxy, amino and carboxy, halogen, acylamino, or the like to name substituted alkanoyles.

Aromatic acyl radicals are those acyl radicals which originate from an acid with a substituted or unsubstituted aryl group, it being possible for the aryl group to include phenyl, tolyl, xylyl, naphthyl and the like; suitable examples are given below:
Aroyl (e.g. benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.);
Aralkanoyl (e.g. phenylacetyl, etc.);
Aralkenoyl (e.g. cinnamoyl, etc.);
Aryloxyalkanoyl (e.g. phenoxyacetyl, etc.);
Arylthioalkanoyl (e.g. phenylthioacetyl, etc.);
Arylaminoalkanoyl (e.g., N-phenylglycyl, etc.);
Arenesulfonyl (for example benzenesulfonyl, tosyl or toluenesulfonyl, naphthalenesulfonyl, etc.);
Aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc.);
Aralkoxycarbonyl (e.g. benzyloxycarbonyl, etc.);
Arylcarbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl, etc.);
Arylglyoxyloyl (e.g. phenylglyoxyloyl, etc.).

In the above examples of aromatic acyl radicals, the aromatic hydrocarbon moiety (in particular the aryl moiety) and / or the aliphatic hydrocarbon moiety (in particular the alkane moiety) can optionally have one or more suitable substituents, such as those that are suitable as substituents for the alkyl group or . The alkane residue has already been specified. In particular and as an example of preferred aromatic acyl radicals with particular substituents, aroyl substituted with halogen and hydroxy or halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihaloalkanoyloxyimino are given and
Arylthiocarbamoyl (e.g. phenylthiocarbamoyl, etc.);
Arylcarbamimidoyl (e.g. phenylcarbamimidoyl, etc.).

A heterocyclic acyl radical is understood to be an acyl radical which originates from an acid with a heterocyclic group; this includes:
Heterocyclic carbonyl, in which the heterocyclic radical is an aromatic or aliphatic 5- to 6-membered heterocycle with at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophenyl, fluoryl, pyrrole carbonyl, nicotinoyl, etc.);
Heterocycle-alkanoyl, in which the heterocyclic radical is 5- to 6-membered and has at least one heteroatom from the group nitrogen, oxygen and sulfur (e.g. thiophenylacetyl, furylacetyl, imidazolylpropionyl, tetrazolylacetyl, 2- (2- Amino-4-thiazolyl) -2-methoxyiminoacetyl etc.) and the like.

In the above examples of heterocyclic acyl radicals, the heterocycle and / or the aliphatic hydrocarbon partly, if necessary, one or more suitable substituents sen, like the same ones as suitable for alkyl and alkane groups were specified.

"Alkyl" is a straight or branched chain alkyl radical with up to 9 carbon atoms, such as methyl, ethyl, propyl, isopro pyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like chen.

Cycloalkyl preferably represents an optionally substituted C3- C7 cycloalkyl; possible substituents include: Alkyl, Al koxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, Bromine etc.), nitro and the like are suitable.

Aryl is an aromatic hydrocarbon radical like phenyl Naphthyl, etc., the optionally one or more suitable substituents such as alkoxy (e.g. methoxy, ethoxy etc.), Halogen (e.g. fluorine, chlorine, bromine, etc.), nitro and the like.

"Aralkyl" includes mono-, di-, triphenylalkyls such as benzyl, Phenethyl, benzhydryl, trityl and the like, the aro matic part optionally one or more suitable substituents may have such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine, etc.), nitro and the like.

"Alkylene" includes straight or branched chain alkylene groups which have up to 9 carbon atoms and are represented by the formula

- (C _n H _2n ) -

can be reproduced in which n is an integer from 1 to 9, such as methylene, ethylene, trimethylene, methylethylene, Tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentame ethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the same; preferred alkylene radicals have up to 4 Koh lenstoffatome and radicals with 3 Koh are particularly preferred fuel atoms such as B. trimethylene.

"Alkenylene" includes straight or branched chain alkenylene groups with up to 9 carbon atoms represented by the formula

- (C _n H _2n-2 ) -

can be reproduced in which n is an integer of 2 to 9, such as B. vinylene, propenylene (e.g. 1-propenylene, 2- Propenylene), 1-methylpropenylene, 2-methylpropenylene, buteny len, 2-ethylpropenylene, pentenylene, hexenylene and the like; the alkenylene radical can particularly preferably contain up to 5 carbons have substance atoms and in particular 3 carbon atoms such as z. B. 1-propenylene.

"Hydroxyalkylene" can include straight or branched chain alkylene radicals which have up to 9 carbon atoms, where one or more selected carbon atoms is substituted with a hydroxy group; these residues can be represented by the formula

- (C _n H _2n-z ) (OH) ₂ -

in which n is an integer from 1 to 9 and z is an integer for which z ≦ n holds. To suitable Examples of such hydroxyalkylene groups include hydroxyme ethylene, hydroxyethylene (e.g. 1-hydroxyethylene and 2- Hydroxyethylene), hydroxytrimethylene (e.g. 1- Hydroxytrimethylene, 2-hydroxytrimethylene and 3- Hydroxytrimethylene), hydroxytetramethylene (e.g. 2- Hydroxytetramethylene), 2-hydroxy-2-methyltrimethylene, hydroxy pentamethylene (e.g. 2-hydroxypentamethylene), hydroxyhexamethylene len (e.g. 2-hydroxyhexamethylene) and the like. Particularly a lower hydroxyalkylene with up to 4 Koh lenstoffatomen and especially one with 3 carbon fatomen such as B. 2-hydroxytrimethylene.

The radicals R ₄ and R ₅ can preferably be chosen so that esters are formed on the phosphono group. Suitable examples of esters on the phosphono group of the compounds according to the invention according to the formulas (I) and (II) include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (e.g. methyl esters, ethyl esters, propyl esters , Isopropyl ester, butyl ester, isobutyl ester, hexyl ester, etc.);
Aralkyl esters (benzyl esters, phenethyl esters, benzhydryl esters, trityl esters, etc.);
Aryl esters (e.g. phenyl esters, tolyl esters, naphthyl esters, etc.); Aroyl alkyl esters (e.g. phenacyl esters, etc.); and silyl esters (e.g. of trialkylhalosilyl, dialkyldihalosilyl, alkyl trihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.) and the like.

In the above esters, the alkane and / or arene moiety can be chosen wise have at least one suitable substituent such as Halogen, alkoxy, hydroxy, nitro, or the like.

_{R 4} and R ₅ are preferably a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium, or ammonium compounds which are derived from ethylenediamine or amino acids. I. E. The salt compounds of the ammonium phosphonic acid derivatives with organic or inorganic bases (e.g. sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, dicyclohexylamine salt, ethylenediamine salt, N, N'-dibenzylethylenediamine salt, etc.) and Salts with amino acids (e.g. arginine salt, aspartic acid salt, glutamine acid salt, etc.) and the like are formed.

The compounds according to the invention according to the formula (I) can in their protonated form as the ammonium salt of organic or inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, lactic acid, maleic acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid , etc. are available. The compounds of the formula (I) according to the invention allow, for example, for double bond-containing or chiral groups R ₁ , R ₂ , R ₃ , R ₄ , R ₅ or A, the occurrence of spatial isomers. The use according to the invention of the compounds includes all spatial isomers both as pure substances and in the form of their mixtures.

To pharmaceutically acceptable salts of aminohydrophosphon acid derivatives include salts that make up the compound of the invention formulas (I) and (II) in their protonated form as Ammonium salt of inorganic or organic acids, such as salt acid, sulfuric acid, citric acid, maleic acid, fumaric acid, Form tartaric acid, p-toluenesulfonic acid.

Also particularly pharmaceutically suitable are the salts which are formed by suitable selection of R ₄ and R ₅ , such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexylamine salt and salts of an amino acid such as arginine salt, aspartic acid salt, glutamic acid salt.

The combination preparations according to the invention contain one or several inhibitors of lipid metabolism. It can do both Inhibitors are used that re the absorption of fats regulate, as well as inhibitors, which re the synthesis of fats gulate. The inhibitors include anion exchangers, be preferably cholestyramine and colestipol, β-sitosterol, nicotinic acid ren and their derivatives, such as nicotinyl alcohol, clofibrates and their derivatives, such as ethyl clofibric acid, and their analogs ga such as bezafibrate, fenofibrate and gemfibrozil, and probucol.

Among the inhibitors that regulate the synthesis of fats, include HMG-CoA synthetase inhibitors, HMG-CoA reductase Inhibitors, preferably lovastatin, mevastatin, simvastatin, Fluvastatin, atorvastatin and pravastatin, inhibitors of the Squalene synthetase, preferably pyrophosphates, pyrophosphate derivatives vate, bisphosphonic acid derivatives, phosphinylmethylphosphonic acid derivatives, phosphinylformyl derivatives, phosphonocarboxyl derivatives, Phosphonosulfonic acid derivatives, Phosphinylmethylphosphonsäurede derivatives, inhibitors of squalene epoxidase and other inhibito the synthesis of cholesterol.

Inhibitors of HMG-CoA reductase and Inhibito are preferred ren of squalene synthetase.

Of the bisphosphonates, in particular clodronate and etidro are nat, pamidronate, ibandronate, alendronate, zoledronate, risedro nat, tiludronate and cimadronate preferred.

The aminohydrocarbylphosphonic acid derivatives according to formula (I) and the hydroxylaminohydrocarbylphosphonic acid derivatives according to formula (II) and esters thereof on the phosphono group and salts same show with simultaneous, separate or graded ter administration with inhibitors of lipid metabolism synthesis ei ne strong cytotoxic effectiveness against single and multiple ligen parasites, fungi, bacteria and virus-infected cells len, especially against the pathogens causing malaria, the Sleeping sickness, schistosomiasis and tuberculosis. The he inventive compounds are for the treatment of In infectious diseases caused by parasites, fungi, Bacteria or viruses in humans and animals. The compounds are also for use in the prevention suitable for these diseases.

The aminohydrocarbylphosphonic acid derivatives according to the invention and Hydroxylaminohydrocarbylphosphonsäurederivate, ge generally hear pharmaceutically acceptable salts, esters, a salt of such an ester, or compounds that with Application of the compounds according to the invention as metabolism provide selproducts or degradation products, also "prodrugs" called, may be suitable for administration in any th way analogous to known anti-infectious agents (mixed with a non-toxic pharmaceutically acceptable Carrier).

The inhibitors of lipid metabolism used are ent speaking of the known instructions for preparing Mit to regulate the cholesterol level and other disturbances gene of lipid metabolism and calcium and phosphate substances alternately prepared.

The anti-infectious combined medicament according to the invention tel can be in the form of pharmaceutical preparations in Thu sizing units are prepared. This means that the Preparation in the form of individual parts, e.g. B. tablets, coated tablets, Capsules, pills, suppositories and ampoules are available, their Active ingredient content a fraction or a multiple of one Single dose. The dosage units can be, for. B. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a one dose included. A single dose preferably contains the Amount of active ingredient that is administered in one application and usually a whole, a half or a third tel or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically acceptable carriers substances are solid, semi-solid or liquid diluents tel, fillers and formulation auxiliaries of all kinds stand.

Preferred pharmaceutical preparations are tablets, Dragees, capsules, pills, granules, suppositories, solutions, Suspensions and emulsions, pastes, ointments, gels, creams, lo ions, powders and sprays. Tablets, coated tablets, capsules, Pills and granules can contain the active ingredients in addition to the usual ones Contain carriers, such as (a) fillers and extenders, e.g. B. Starches, milk sugar, cane sugar, glucose, mannitol and pebbles acid, (b) binders, e.g. B. carboxymethyl cellulose, Algina te, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. B. Glycerin, (d) disintegrant, e.g. B. agar-agar, calcium carbonate nat and sodium carbonate, (e) dissolution retarders, e.g. B. paraffin and (f) absorption accelerators, e.g. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, glycerine mo nostearate, (h) adsorbent, e.g. B. kaolin and bentonite and (i) lubricants, e.g. B. talc, calcium and magnesium stea rat and solid polyethylene glycols or mixtures of the under (a) to (i) listed substances.

The tablets, coated tablets, capsules, pills and granules can with the usual, optionally opaque agents contained tend to be provided with covers and sheaths and also together be set that they the active ingredients only or preferentially in a certain part of the intestinal tract, if applicable release delayed, with such. B. Polymer substances and waxes can be used.

The active ingredients can optionally with one or more of the above-mentioned carriers also in microencapsulated Form.

In addition to the active ingredients, suppositories can do the usual things contain water-soluble or water-insoluble carriers, e.g. B. Polyethylene glycols, fats, e.g. B. Cocoa fat and higher esters (e.g. C14 alcohol with C16 fatty acid) or mixtures of these Fabrics.

Ointments, pastes, creams and gels can be used alongside the or the Active ingredients contain the usual carriers, e.g. B. tieri cal and vegetable fats, waxes, paraffins, starch, tra gant, cellulose derivatives, polyethylene glycols, silicones, bento nite, silica, talc and zinc oxide or mixtures of these Fabrics.

Powders and sprays can, in addition to the active ingredient or ingredients, the usual union carriers contain, z. B. lactose, talc, kie acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also be used union propellants, e.g. B. chlorofluorocarbons, ent keep.

Solutions and emulsions can, in addition to the active ingredients, the usual Chen carriers such as solvents, solubilizers and Emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, Ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Pro pylene glycol, 1,3-butylene glycol, dimethylformamide, oils, esp special cottonseed oil, peanut oil, corn oil, olive oil, Castor oil and sesame oil, glycerin, glycerin formal, tetrahydro furfuryl alcohol, polyethylene glycols and fatty acid esters des Contain sorbitans or mixtures of these substances.

The solutions and Emulsio They are also available in sterile and blood isotonic form.

Suspensions can add the usual carriers to the active ingredients such as liquid diluents, e.g. B. water, ethyl alcohol, Propylene glycol, suspending agents, e.g. B. ethoxylated isosteas ryl alcohols, polyoxyethylene sorbitol and sorbitan esters, micro crystalline cellulose, aluminum metahydroxide, bentonite, agar Contain agar and tragacanth or mixtures of these substances.

The mentioned formulation forms can also colorants, Preservatives as well as smell and taste improved Additives, e.g. B. peppermint oil and eucalyptus oil and sweeteners, z. B. saccharin.

The active ingredient (s) of the formulas (I) and (II) should be included in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5% by weight, preferably present from about 0.5 to 95 percent by weight of the total mixture be. The relationship between each to be combined Substances depend on the individual active ingredient. So are Active substances represented, which have a standard dose of 0.1 mg / kg body weight per weight per day (ibandronate and alendronate), 0.5 mg / kg body weight per weight per day (Mevastatin, Simvastatin, Pravastatin, Flu vastatin), 10 mg / kg body weight per day (pamidronate) will.

The pharmaceutical preparations listed above can apart from the compounds of the formulas (I) and (II) and the inhibitors the lipid metabolism also other active pharmaceutical ingredients, such as antiviral, antiparasitic, antimycotic or antibacterial rially effective agents.

The combination preparations according to the invention can also Sulfonamide, sulfadoxine, artemisinin, atovaquone, quinine, chlo roquin, hydroxychloroquine, mefloquine, halofantrine, pyrimetha min.armesin, tetracycline, doxycycline, proguanil, metronida zol, praziquantil, niclosamide, mebendazole, pyrantel, tiabenda zol, diethylcarbazine, piperazine, pyrivinum, metrifonate, oxam niquin, bithionol or suramin or more of these substances contain.

The manufacture of the pharmaceutical accessories listed above riding takes place in the usual way according to known methods, z. B. by mixing the active ingredient or ingredients with the one or more Carriers.

The preparations mentioned can entwe in humans and animals the oral, rectal, parenteral (intravenous, intramuscular, sub cutaneous), intracisternal, intravaginal, intraperitoneal, local (Powder, ointment, drops) and for the treatment of infections in Cavities, body cavities are applied. As suitable to Preparations come injection solutions, solutions and suspensio nen for oral therapy, gels, infusion formulations, emul sions, ointments or drops in question. For local therapy can ophthalmological and dermatological formulations, Silver and other salts, ear drops, eye ointments, powder or solutions can be used.

Lovastatin, atorvastatin, simvastatin, Meva are preferred statin, pravastatin and fluvastatin administered orally, being Pravastatin and fluvastatin are administered in active form the.

In animals, the intake can also be through the food or drink water in suitable formulations. Furthermore can Gels, powder, powder, tablets, retard tablets, premixes, Concentrates, granules, pellets, tablets, boluses, capsules, Ae rosole, sprays, inhalants in humans and animals who used the. Furthermore, the compounds according to the invention can be used in other More carrier materials such as plastics, (art fabric chains for local therapy), collagen or bone cement be incorporated.

In general, it has been found in both human and veterinary medicine proven beneficial to the or the Active ingredients of the formula (I) and (II) in total amounts of about 0.5 to about 600, preferably 1 to 200 mg / kg of body weight every 24 hours, if necessary in the form of several individual doses, to be administered to achieve the desired results. One Single dose contains the active ingredient (s) preferably in Amounts from about 0.5 to about 200, especially 1 to 60 mg / kg Body weight. However, it may be necessary to use the ge The stated dosages vary, depending on the type and body weight of the patient to be treated, the type and severity of the disease, the type of preparation direction and the application of the drug as well as the period or the interval within which the administration takes place.

It has proven advantageous to use the inhibitors of the Lipid metabolism in the known dosage ranges to ge ben involved in treating disorders of lipid metabolism sels and the calcium and phosphate balance are known. It these are total amounts from about 0.005 to about 200, preferably 0.01 to 100 mg / kg of body weight per 24 hours the, if necessary in the form of several individual gifts, for education administration of the desired results. A single administration contains the active ingredient (s) (inhibitors of Fat metabolism) preferably in amounts of about 0.002 to about 50, in particular 0.01 to 10 mg / kg of body weight. It can however, it may be necessary to deviate from the stated dosages give way, depending on the type and body weight of the patient to be treated, the type and severity the disease, the type of preparation and the application of the drug and the period or interval within to which the administration takes place. This is the case with aminobisphospho It is important to note that their absorbability is very low. This property is important when the intestine is infested (for example in Case of amoebic dysentery). Here are doses of up to 10 mg / kg body weight pamidronate given orally. For injection as a rule, doses of up to 2 mg / kg body weight are sufficient.

So in some cases it can be sufficient with less than get along with the above amount of active ingredient while in an the cases of which exceeded the amount of active ingredient listed above must become. The determination of the required optima in each case len dosage and type of application of the active ingredients can by be done by the specialist on the basis of his specialist knowledge.

The combination preparations according to the invention can be used for animals in the usual concentrations and preparations together with with the feed or with feed preparations or with the drinking water should be given.

The combination preparations can be used simultaneously, separately or be administered in staggered intervals.

example Manufacture of anti-infectious agents Preparation for injection

(1) The required amount of sterile anti-infectious we kenden agent, 500 mg 3- (N-acetyl-N-hydroxylamino) -propyl phosphonic acid monosodium salt and 90 mg 3-amino-1-hydroxy Propylidene-1,1-bisphosphonic acid disodium salt are supplied in bottles small or ampoules. The vials become the end hermetically sealed against bacteria. For injections is made up in 500 ml of physiological saline solution taken and administered.

Essentially in the same way as above under (1) has been described, other injectable preparations of the manufactured anti-infectious agents:

(2) 250 mg of 3- (N-formyl-N-hydroxylamino) propylphosphonic acid monosodium salt and 1 mg 3-methylpentylamino-1- hydroxypropylidene-1,1-bisphosphonic acid disodium salt who used as the active ingredient for the injections.

(3) 250 mg 3- (N-Formyl-N-hydroxylamino) -trans-1- propenylphosphonic acid monosodium salt and 90 mg 3-amino 1-hydroxypropylidene-1,1-bisphosphonic acid disodium salt are used as the active ingredient for the injections.

Manufacture of tablets

A suitable tablet formulation is made up of the following mixture:

3- (N-Formyl-N-hydroxylamino) -propyl-phosphonic acid monosodium salt 200 mg Lovastatin 10 mg Mannitol 400 mg strength 50 mg Magnesium stearate 10 mg

Manufacture of capsules

3- (N-Formyl-N-hydroxylamino) propyl-phosphonic acid monopotassium salt 300 mg Simvastatin 10 mg Magnesium stearate 15 mg

The above ingredients were mixed and then placed in egg ne hard gelatin capsule introduced in a conventional manner.

Claims (45)

1. Combination preparation containing as active ingredients at least one inhibitor of lipid metabolism and at least one aminohydrocarbylphosphonic acid derivative of the general formula (I)
in which R ₁ and R _{2 can be the} same or different and are selected from the group consisting of hydrogen, hydroxyl group, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical and substituted and unsubstituted acyl, and
A is selected from the group consisting of alkylene radical, alkylene radical and hydroxyalkylene radical, and
R ₄ and R _{5 are} identical or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, a silyl, substituted and unsubstituted heterocyclic Remainder, a cation of an organic and inorganic base, in particular a metal from the first, second and third main groups of the periodic table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids,
and their pharmaceutically acceptable salts, esters and salts of the esters or else compounds which, when administered, provide the compounds to be used according to the invention as metabolic products or degradation products,
for simultaneous, separate or staggered use, the fat metabolism inhibitor not being an aminohydrocarbylphosphonic acid derivative of the formula (I). 2. Combination preparation according to claim 1, characterized in that the inhibitors of lipid metabolism selected from the group are derived from Cholestyramine, β-Sitosterol, Colestipol, Pro bucol, nicotinic acid, nicotinyl alcohol, clofibric acid deri derivatives and analogues of clofibric acid derivatives, HMG-CoA- Synthetase inhibitors, HMG-CoA reductase inhibitors, Squalene Synthetase Inhibitors and Squalene Epoxidase Inhibitors. 3. Combination preparation according to claim 2, characterized in that the lipid metabolism inhibitors are inhibitors of the Squalene synthetase acts. 4. Combination preparation according to claim 3, characterized in that the squalene synthetase inhibitors selected from the group are made from pyrophosphates, pyrophosphate derivatives, Bisphosphonic acid derivatives, phosphinylmethylphosphonic acid derivatives, phosphinylformyl derivatives, phosphonocarboxyl derivatives vaten, phosphonosulfonic acid derivatives, phosphinylmethylphos Phonic acid derivatives. 5. Combination preparation according to claim 2, characterized in that the lipid metabolism inhibitors are inhibitors of the HMG-CoA reductase. 6. Combination preparation according to claim 5, characterized in that the inhibitors of HMG-CoA reductase selected from the group are derived from lovastatin, atorvastatin, mevastatin, simva statin, fluvastatin, and pravastatin. 7. Combination preparation according to claim 2, characterized in that the lipid metabolism inhibitors are clofibrin acid derivatives and their analogues. 8. Combination preparation according to claim 7, characterized in that the clofibric acid derivatives and their analogs from the group are selected from gemfibrozil, fenofibrate, bezafi brat, clofibrate, ciprofibrate and clinofibrate. 9. Combination preparation according to claim 2, characterized in that the fat metabolism inhibitors are bisphos Phonic acid derivatives. 10. Combination preparation according to claim 9, characterized in that the bisphosphonic acid derivatives selected from the group are derived from clodronic acid derivatives, etidronic acid derivatives, Pamidronic acid derivatives, especially pamidronate, ibandron acid derivatives, especially ibandronate, alendronic acid derivatives vaten, especially alendronate, zoledronic acid derivatives, in particular zoledronate, risedronic acid derivatives, tiludron acid derivatives and cimadronic acid derivatives. 11. Combination preparation according to one of claims 1 to 10, characterized in that the aminohydrocarbylphosphonic acid derivatives of the formula (II)
correspond,
where R ₂ , A, R ₄ and R _{5 have} the meaning given in claim 1 and R ₃ is selected from the group consisting 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. 12. Combination preparation according to claim 11, characterized in that in formula (II) R ₂ = acyl, R ₃ = H and A = alkylene, alkenylene or hydroxyalkylene. 13. Combination preparation according to claim 12, characterized in that at least one of R ₄ and R ₅ is selected from the group consisting of hydrogen, ammonium and metals from the first and second main groups of the periodic table, preferably sodium, potassium, calcium or magnesium . 14. Combination preparation according to claim 13, characterized in that at least one of R ₄ and R ₅ is selected from the group consisting of ammonium compounds derived from ethylenediamine or amino acids, preferably ethanolamine, ethylenediamine, N, N-dibenzylethylenediamine and arginine , consists. 15. Combination preparation according to claim 13, characterized in that A is an alkylene radical having 1 to 6 carbon atoms. 16. Combination preparation according to claim 12, characterized in that in formula (II) R _{2 is} an alkanoyl radical and A is an alkylene radical, where R _{2 is} preferably formed by formyl or acetyl and A is preferably formed by trimethylene. 17. Combination preparation according to claim 16, characterized in that the aminohydrocarbylphosphonic acid derivative 3- (N-formyl-N- hydroxylamino) propylphosphonic acid or one of its salts is. 18. Combination preparation according to one of claims 16 or 17, characterized in that at least one of R ₄ and R ₅ is selected from the group consisting of ammonium, sodium, potassium, calcium, magnesium and ammonium residues, which are derived from ethanolamine, ethylenedia min Derive N, N'-dibenzylethylenediamine or arginine, exist. 19. Combination preparation according to claim 18, characterized in that the aminohydrocarbylphosphonic acid derivative 3- (N-acetyl-N- hydroxylamino) propylphosphonic acid or one of its salts is. 20. Combination preparation according to claim 19, characterized in that at least one of R ₄ and R _{5 is} sodium. 21. Combination preparation according to claim 13, characterized in that A is formed by an alkenylene radical and R ₂ by an alkanoyl radical having 1 to 6 carbon atoms and A in particular are propenylene and R ₂ in particular are formyl or acetyl. 22. Combination preparation according to claim 21, characterized in that at least one of R ₄ and R ₅ is selected from the group consisting of sodium and potassium. 23. Combination preparation according to claim 22, characterized in that R _{2 is} acetyl and at least one of R ₄ and R _{5 is} sodium. 24. Combination preparation according to one of claims 21, 22 or 23, characterized in that the aminohydrocarbylphosphonic acid derivative 3- (N-formyl-N- hydroxylamino) -1-propenylphosphonic acid or 3- (N-acetyl-N- hydroxylamino) -1-propenylphosphonic acid or one of its Salts is. 25. Combination preparation according to claim 24, characterized in that the aminohydrocarbylphosphonic acid derivative the cis- or the trans isomers of 3- (N-formyl-N-hydroxylamino) -1-propenyl phosphonic acid or of 3- (N-acetyl-N-hydroxylamino) -1- is propenylphosphonic acid. 26. Combination preparation according to claim 13, characterized in that A is a hydroxyalkylene _{radical, preferably a Hydroxytrimethy len and R 2 is} an alkanoyl radical, preferably a formyl or acetyl radical, and preferably at least one of R ₄ or R ₅ is selected from the group which consists of sodium and potassium. 27. Combination preparation according to one of claims 21, 22 or 23, characterized in that the aminohydrocarbylphosphonic acid derivative 3- (N-formyl-N- hydroxylamino) -2-hydroxypropyl-phosphonic acid or 3- (N- Acetyl-N-hydroxylamino) -2-hydroxypropyl-phosphonic acid or is one of their salts. 28. Combination preparation according to claim 11, characterized in that R ₂ = H, R ₄ = H and R ₅ = H. 29. Combination preparation according to claim 28, characterized in that R _{3 is} hydrogen. 30. Combination preparation according to one of claims 28 or 29, characterized in that A is an alkylene radical. 31. Combination preparation according to claim 29, characterized in that the aminohydrocarbylphosphonic acid derivative (N-hydroxylamino) - alkylphosphonic acid, preferably (N-hydroxylamino) - propylphosphonic acid and especially 3- (N-hydroxylamino) - is propylphosphonic acid. 32. Combination preparation according to one of claims 28 or 29, characterized in that A is a linear or branched alkenylene radical with 2 to 6 Is carbon atoms. 33. Combination preparation according to claim 32, characterized in that the aminohydrocarbylphosphonic acid derivative (N-hydroxylamino) - alkenylenephosphonic acid, preferably (N-hydroxylamino) - propenylphosphonic acid and especially 3- (N-hydroxylamino) - Is 1-propenylphosphonic acid. 34. Combination preparation according to claim 33, characterized in that the aminohydrocarbylphosphonic acid derivative is a cis or a trans isomer of (N-hydroxylamino) alkenylenephosphone acid, preferably of (N-hydroxylamino) propenylphosphonic acid and especially of 3- (N-hydroxylamino) -1-propenyl phosphonic acid). 35. Combination preparation according to claim 28 or 29, characterized in that A is a hydroxyalkylene radical having 1 to 4 carbon atoms. 36. Combination preparation according to claim 35, characterized in that the aminohydrocarbylphosphonic acid derivative (N-hydroxylamino) - hydroxyalkylphosphonic acid, preferably (N-hydroxylamino) - hydroxypropylphosphonic acid and especially 2-hydroxy-3- (N- hydroxylamino) propyl phosphonic acid. 37. Combination preparation according to one of claims 1 to 11, characterized in that R ₄ and R _{5 are} identical or different and are selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl , substituted or unsubstituted cycloalkyl and silyl. 38. Combination preparation according to claim 37, characterized in that at least one of R ₄ and R ₅ is selected from the group consisting of alkyl, aralkyl, aryl and residues of Silylver compounds, each of which may have substituents, be. 39. Combination preparation according to claim 38, characterized in that R _{2 is} an alkanoyl radical and A is an alkylene radical, an alkenylene radical or a hydroxyalkylene radical and R _{2 is} preferably formed by formyl or acetyl and A is preferably formed from trimethylene, propenylene or hydroxytrimethylene. 40. Combination preparation according to one of the preceding claims che, characterized in that the combination preparation is a pharmaceutically acceptable one Has carrier. 41. Combination preparation according to one of the preceding claims che, characterized in that the combination preparation also has one or more Be components of the group consisting of antiviral, antipa Rasitic, mycotic and antibacterial agents be stands. 42. Combination preparation according to claim 41, characterized in that the combination preparation also has one or more Be having constituents of the group consisting of sulfonamide, sulfa doxin, artemisinin, atovaquone, quinine, chloroquine, hydroxy chloroquine, mefloquine, halofantrine, pyrimethamine, armesine, Tetracyclines, Doxycycline, Proguanil, Metronidazole, Prazi quantil, niclosamide, mebendazole, pyrantel, tiabendazole, Diethylcarbazine, Piperazine, Pyrivinum, Metrifonat, Oxamni quin, bithion oil and suramin. 43. Use of combination preparations according to one of the before related claims for therapeutic and prophylactic treatment of infectious processes. 44. Use according to claim 43, characterized in that the infectious processes through single or multicellular Para sites, fungi, bacteria or viruses. 45. Use according to claim 43 or claim 44, characterized in that it is an infectious process in humans or animals delt.