Classifications

• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
  • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/44—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from protozoa
  • C07K14/445—Plasmodium
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
  • C12N15/09—Recombinant DNA-technology
  • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
  • C12N15/52—Genes encoding for enzymes or proenzymes
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
  • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
  • C12N9/88—Lyases (4.)
• • C—CHEMISTRY; METALLURGY
  • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
  • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
  • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
  • C12Q1/527—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving lyase

Definitions

• the invention relates to combination preparations of compounds having an anti-infectious effect, which inhibit the 2-C-Memylerythrose-4-metabolic pathway, as well as their salts and esters and of inhibitors of the fat metabolism and their simultaneous, separate or graded use for the prophylaxis and therapy of infectious processes in plants , Humans and animals and their use as herbicides.
• the combination preparations of the present invention are particularly suitable for the therapeutic and prophylactic treatment of infections by single or multi-cell parasites, fungi, bacteria or viruses, but also as herbicides.
• fat metabolism inhibitors have long been a recognized and widespread treatment principle. These inhibitors are used to reduce the risk of heart and vascular diseases due to hyperlipidemia.
• the pharmacotherapy of these hyperlipidemias is usually based on regulating the uptake and regulating the synthesis of fats or cholesterol in particular.
• the synthesis of cholesterol is controlled by the enzyme ⁇ -hydroxy-methylglutaryl-CoA reductase (HMG-CoA reductase).
• HMG-CoA reductase ⁇ -hydroxy-methylglutaryl-CoA reductase
• the intrinsic synthesis of cholesterol is usually greater than the food intake.
• Anion exchangers and ⁇ -sitosterol are known for regulating the absorption of fats from the digestive tract.
• the ion exchangers include cholestyramine and colestipol. They absorb bile acids and thereby interrupt the enterohepatic return transport and thus cause a significant increase in sterols in the stool.
• ⁇ -sitosterol is a plant sterol, structurally related to cholesterol. It inhibits the absorption of food cholesterol on the intestinal mucosa.
• Nicotinic acids and their derivatives, clofibrates and their derivatives and probucol have also been used in regulating fat metabolism or in preventing secondary diseases of hyperlipidemia. Nicotinic acids and nicotinic acid derivatives reduce fatty acids, triglycerides and cholesterol. The mechanism is not yet known. The ethyl ester of clofibric acid, clofibrate and derivatives as well as analogues lead to a lowering of cholesterol, the mechanism of action is also unknown. The mechanism of action of Probucol is also not clear.
• 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 4049 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 46227, US 44 10629, US 44447 84, US 44 50 171, US 45 54359, US 49201 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 4645 858, US 52 36946, US 55 06 262, US 50 25 017, US 4847271, US 46 22 338, US 49 04 646, US 48 73 345, US 55 93 971,
• HMG-CoA reductase inhibitors competitively inhibit the rate-limiting enzyme in cholesterol synthesis, HMG-CoA reductase. They have an affinity for the enzyme up to 20,000 times higher than the substrate HMG-CoA.
• the HMG-CoA reductase leads to the conversion of HMG-CoA to mevalonate, from which, in addition to cholesterol, inter alia, isopentenyladenine and farnesyl pyrophosphate, the precursor of dolichol and ubiquinone arise.
• the isopentenyl diphosphates are formed via the acetate / mevalonate pathway, which is inhibited by HMG-CoA reductase inhibitors.
• the first discovered inhibitors were isolated from a Penicillium (Mevastatin) and an Aspergillus mushroom (Lovastatin). The modification of the side chain led to simvastatin, the further development from mevastatin to pravastatin.
• a fully synthetic enzyme inhibitor (fluvastatin) is now also available, which is a mevalonlactone derivative of a fluorophenyl-substituted indole ring.
• HMG-CoA inhibitors have been used to inhibit the growth of plants, fungi, parasites, bacteria and viruses.
• the HMG-CoA synthetase and HMG-CoA reductase inhibitors inhibit the acetate-mevalonate pathway in some bacteria, fungi (US 50 26 554, US 5064 856, US 49 20 111, US 49 20 113) and parasites.
• fungi US 50 26 554, US 5064 856, US 49 20 111, US 49 20 113
• parasites are used to inhibit the acetate-mevalonate pathway in some bacteria, fungi (US 50 26 554, US 5064 856, US 49 20 111, US 49 20 113) and parasites.
• many bacteria, such as Escherichia coli show no inhibition by HMG-CoA reductase inhibitors. This is probably due to the fact that these bacteria have an alternative metabolism own it.
• Squalene synthetase inhibitors such as the aminobisphosphonates, were also unsuccessfully tested as inhibitors of amoebic dysentery. The kill efficiency was low. Similar experiments with toxoplasma show no satisfactory results there either. Squalene epoxidase inhibitors have also been developed as fungicides (US Pat. No. 4,782,059).
• the object of the present invention is therefore to provide an agent which can be used against infectious processes in humans, animals and plants and as a herbicide and for which the formation of resistance in plants, viruses, fungi, parasites and bacteria can be considerably reduced.
• the combination of anti-infectious compounds that inhibit the 2-C-Me ⁇ ylerythrose-4 pathway, with inhibitors of fat synthesis, especially cholesterol synthesis, especially inhibitors of HMG-CoA reductase and squalene synthetase Increase breadth and effectiveness of therapy and prophylaxis of infections.
• the combination leads to the killing of microorganisms that cannot be killed by either one or the second group.
• the combinations show a strong reduction in the formation of resistance to the compounds used, which generally represents the greatest problem when handling the connecting group of the fat metabolism inhibitors.
• the combination of anti-infectious compounds that inhibit the 2-C-Memyle ⁇ ythrose-4-pathway and inhibitors of fat metabolism are for the therapeutic and prophylactic treatment of infections in plants, in particular Particularly suitable for humans and animals, in particular infections caused by parasites, bacteria, fungi and viruses and as a herbicide in plants.
• the combination preparations according to the invention contain at least one anti-infectious compound which inhibits the 2-C-MemylerytJ ⁇ rose-4 metabolic pathway and / or its esters and / or salts.
• These generally include pharmaceutically acceptable salts, esters, a salt of such an ester, or else compounds which, when applied, provide the compounds according to the invention as metabolites or degradation products, also called “prodrugs”.
• the anti-infectious substance groups can be determined by a method in which proteins that are involved in the 2-C-Memylerythrose-4 metabolic pathway or their derivatives are brought into contact with the active substances to be investigated and the active substances that the proteins or Inhibit derivatives are selected.
• the method is known to the person skilled in the art.
• aminohydrocarbylphosphonic acid derivatives and their preparation are described in detail in DE-Al-2733658 and PCT / EP99 / 02462.
• aminohydrocarbylphosphonic acid derivatives correspond to the general formula (I):
• Rn and Rn 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, a substituted and unsubstituted Aralkyl, and contains a substituted and unsubstituted heterocyclic radical,
• RB and R ⁇ are selected from the group consisting of substituted and unsubstituted alkyl of 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of 1 up 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 Rest, halogen, XB and X ⁇ , XB and X ⁇ may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl having 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having 1 to 26 carbon atoms,
• Ai stands for an alkylene radical, alkenylene radical or hydroxyalkylene radical or corresponds to the following formula (LA):
• Cycloalkyl group as well as the Co- 9 alkyl group can have one or more double bonds and one or two carbon atoms of the cycloalkyl group can be replaced by nitrogen, oxygen or sulfur atoms, and both the cycloalkyl group and the alkyl group with hydroxy, halogen -, Amino, oxo groups with branched or unbranched C 9 alkyl groups and C 2 .
• the fat metabolism inhibitor is not an aminohydrocarbylphosphonic acid derivative of the formula (I) if an aminohydrocarbylphosphonic acid derivative is used as the anti-infectious compound.
• the invention also includes the pharmaceutically acceptable salts, esters and salts of the esters.
• Rn is preferably OXn
• R is OXB and R ⁇ is OX ⁇
• Xu 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 and R 12 , X, X I and Ai have the same meaning as in formula (I).
• the carbon chain of Ai preferably consists of three carbon atoms.
• Bn and B 12 together form an oxo group.
• the carbon chain in Ai consists of the four carbon atoms Cn, C12, C, 4 .
• the carbon chain in A also consists of the four carbon atoms Cn, C _, C B , C M.
• the carbon chain preferably consists of 5 carbon atoms Cn, C12, CB, 4 , 5, where Bn and B 12 together form an oxo group and at least one substituent of B »or Bno is a hydroxyl group or B 19 and Bn 0 together likewise form an oxo group.
• Substances are also suitable in which, instead of phosphonic acid or phosphonic acid or
• Phosphinoyl group is the sulfone group or sulfonyl group:
• Xin, X112, X113, X114 which may be the same or different, are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical , Metals of the 1st, 2nd and 3rd main group of the periodic system, such as Na, K, Ca, Mg, Al as well as substituted and unsubstituted ammonium and ammonium compounds derived from ethylenediamine or amino acids,
• AH which can also be omitted, is selected from the group consisting of alkylene, alkenylene and hydroxyalkylene,
• Rm, R 112 which may be the same or different, are selected from the group consisting of H, OH, -NH 2 , substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical and -SR I B, Cl and -NR 113 R 11 4, wherein
• R11 3 , R1 1 4, which may be the same or different, are selected from the group consisting of H, OH, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl and substituted and unsubstituted heterocyclic radical, and their pharmaceutically acceptable salts, esters and salts of the esters or compounds which, when administered, form the compounds to be administered as metabolic or degradation products.
• Bisphosphonic acid derivatives of the formula II are particularly preferred in which Xm, X ⁇ , X ⁇ 3, X 114 , which may be the same or different, are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl , substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical the metals of the 1st, 2nd or 3rd main group of the periodic system, such as Na, K, substituted and unsubstituted ammonium and ammonium compounds derived from emylenedia or amino acids. 3rd exists
• An which can also be omitted, is selected from the group consisting of alkyl, (CH 2 ) o- 6 , in particular (CH2) ⁇ -5 and amidino,
• R ⁇ i is selected from the group consisting of H, OH, NH 2 , -CH 3 , and
• Ri ⁇ is selected from the group consisting of -NH 2 , -N,
• the bisphosphonates selected from the group consisting of amino-hydroxy-methylidene-bisphosphonic acid, 2-amino-1-hydroxyethylidene-1,1-bisphosphonic acid are particularly preferred.
• the fat metabolism inhibitor is not a bisphosphonic acid derivative.
• Run is selected from the group consisting of H, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted hydroxyalkyl, a substituted and unsubstituted alkenyl, a substituted and unsubstituted alkynyl, a substituted and unsubstituted aryl, a substituted ized and unsubstituted cycloalkyl, a substituted and unsubstituted aralkyl, a substituted and unsubstituted heterocyclic radical, halogen and OXmi, where Xmi is selected from the group consisting of hydrogen, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted hydroxyalkyl, a substituted and unsubstituted alkenyl, a substituted and unsubsti
• RUM and R ⁇ may be the same or different and are selected from the group consisting of hydrogen, a substituted and unsubstituted acyl, a substituted and unsubstituted alkyl, a substituted and unsubstituted hydroxyalkyl, a substituted and unsubstituted alkenyl, a substituted and unsubstituted alkynyl, one substituted and unsubstituted aryl, a substituted and unsubstituted cycloalkyl, a substituted and unsubstituted aralkyl, a substituted and unsubstituted heterocyclic radical, halogen and OX ⁇ M and OX ⁇ B, where XHM and X ⁇ are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycl
• Ami and AUE are the same or different and represent an alkylene radical, alkenylene radical, an oxo radical, a hydroxyl radical or oxo-hydroxyalkylene radical, with Ann preferably being omitted
• the invention also includes the pharmaceutically acceptable salts, amides, esters and salts of the esters.
• R UM OX ⁇ M and RUB OX ⁇ B, where R ⁇ n, X ⁇ i4, X ⁇ i3, Ami and A ⁇ 2 have the same meaning as in formula (III).
• Particularly preferred phosphonic acid derivatives are chloroacetylphosphonic acid (Fosfonochlorin), phosphonoformic acid (Foscarnet), phosphonoacetic acid, N, N-dimethyl (1-hydroxy-2-oxo-2-methoxy-ethyl) -phosphonamide and 2-hydroxy-2-hydroxy -methyl-3-oxo- l ⁇ butylphosphonic acid (phosphonothrixin) and Ammomum-ethylcarbamoylphosphonate (Fosamin-ammonium).
• Rivi and Rrv2 are identical or different and are selected from the group consisting 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, OXrvi and OX ⁇ v2, where Xivi and X ⁇ v 2 may be the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubsti
• Aivi and A ⁇ v 2 are the same or different and are selected from the group consisting of alkylene radical, alkenylene radical and hydroxyalkylene radical, the keto group (IVB)
• a ⁇ v 3 and A ⁇ v 4 are the same or different, are selected from the group consisting of alkylene radical, alkenylene radical and There is hydroxyalkylene, and 5- and 6-membered cyclic, especially heterocyclic, compounds which contain, apart from carbon, at least one heteroatom as a ring member, the heteroatom being selected from the group consisting of oxygen and nitrogen, R ⁇ v3 and R ⁇ v 4 being the same or different and are selected from the group consisting 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 with up to 26 carbon
• Rrv 2 is selected from the group consisting of acetyl and formyl
• Arvi is selected from the group consisting of methylene, ethylene, ethenylene, hydroxyethylene, 2-hydroxypropylene, and
• X ⁇ v 3 and Xrv 4 are the same or different and are selected from the group consisting of sodium, potassium, methyl, ethyl.
• the chain -A ⁇ v ⁇ -OC (ZY) - preferably consists of one oxygen atom and two or three Carbon atoms (not including substituents), particularly preferably two carbon atoms.
• the compounds are selected from the group consisting of ((N-formyl-N-hydroxyla ⁇ rüno) -memoxy) -memylphosphonic acid di-sodium salt, ((N-acetyl-N-hydroxylam o) -me ⁇ oxy) -meftylphosphon ⁇ hydroxylan ⁇ mo) -emenoxy) -memylphosphor ⁇ klaredi-narriumsaLz, (2- (N-acetyl-N-hydroxyl-a ⁇ mo) -e enoxy) -methyl-phosphonic acid disodium salt, (3- (N-formyl-N-hydroxylamino) -2-hydroxypropoxy) -methylphosphon acid disodium salt, (3- (N-acetyl-N-hydroxylamino) -2-hydroxypropoxy) methylphosphonic acid disodium salt, is particularly preferred.
• R ⁇ v 2 is selected from the group. which consists of acetyl and formyl
• Arv3 is selected from the group consisting of methylene.
• Arv 4 is eliminated or methylene
• Xrv 3 and X ⁇ v4 are the same or different and are selected from the group consisting of a metal from the first, second or third main group of the periodic table, in particular sodium. Potassium, and methyl, ethyl.
• the chain -A ⁇ v ⁇ -CO-A ⁇ v2- preferably consists of two to four carbon atoms (not including substituents), particularly preferably of three carbon atoms.
• the amino group and the phosphorus atom can be bonded to any C atoms of the ring. However, preference is given to compounds in which they are bonded to two carbon atoms which are only separated by another atom. In the heterocyclic compounds, the two carbon atoms are preferably separated from one another by a heteroatom.
• Avi and Av 2 can be the same or different and are selected from the group containing an alkylene radical, an alkenylene radical and a hydroxyalkylene radical, and preferably the carbon chain -Avi-CHOH-
• Av2 consists of 2 to 5 carbon atoms, particularly preferably consists of 3-4 carbon atoms,
• Bv is selected from the group consisting of a radical of the formula (VA)
• Rvi is selected from the group consisting of hydrogen, OH, 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 halogen consists of a radical of the formula (VB)
• Rv 2 , Rv 3 and Rv 4 are the same or different and are selected from the group consisting 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, I L and a radical of the formula (VC)
• Rv6 Rv7 is selected, wherein Rvs, RV O and Rv7 are the same or different and are selected from the group consisting of hydrogen, OH, 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, where Xv 3 or Xv 4 may be the same or different and are selected from the group consisting of hydrogen , substituted and unsubstituted alkyl, substituted and unsubstituted hydroxylalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralky
• Rvi in formula (VA) is preferably a methyl group.
• Rv 2 and Rv 4 are preferably hydrogen and Rv3 are a methyl group.
• Rvs are preferably a methyl group
• Ry 6 is selected from the group consisting of H, OH and methyl
• Rw is a hydroxy group.
• Av2 is an unbranched hydroxyalkylene having 1 to 3 carbon atoms and Xv3 and Xv 4 are identical or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the periodic table, in particular sodium, potassium and methyl, Ethyl exists.
• 3,4-dihydroxy-5-oxo-hexylphosphonic acid disodium salt, l, 2,3,4-tetrahydroxy-5-oxo-hexylphosphonic acid disodium salt, 2,3,4-trihydroxy-5-oxo-hexylphosphonic acid disodium salt, l , 2,3-trihydroxy-4-oxopentylphosphonic acid disodium salt and 2,3-dihydroxy-4-oxopentylphosphonic acid disodium salt are particularly preferred.
• Av 2 is an unbranched hydroxyalkylene with 1 to 3 carbon atoms and Xv 3 and Xv 4 are the same or different and are selected from the group consisting of hydrogen, a metal of the first, second or third main group of the periodic table, in particular sodium, potassium, methyl and there is ethyl.
• a ⁇ 2 is an unbranched hydroxyalkylene or an unbranched alkylene and consists of 1 to 3 carbon atoms and
• Xv 3 and Xv 4 are the same or different and are selected from the group consisting of water ⁇ ⁇ serstoff, a metal of the first, second or third main group of the periodic table, in particular sodium, potassium, and methyl, ethyl.
• organophosphorus compounds according to the invention correspond to the general formula (VI):
• RVB and RVM are the same or different and are selected from the group consisting 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 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, OXVB or OXVM, where XVB or XVM are the same or different can and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to
• Avi is selected from the group consisting of an alkylene amine group, an alkenylene amine group, a hydroxyalkylene amine group, an alkylene imine group, an AJkenylene imine group and a hydroxyalkylene imine group, the nitrogen atom being in the chain which connects the phosphorus atom to the nitrogen atom of the group
• Rvn and Rvn in group (VIA) are the same or different and Rvn and Rvn for group (VIA) and Rvn for group (VIB) are selected from the group consisting 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 aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic radical, halogen, OXvn and Xxn and Xxn and Xxnn or may be different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted
• Avi is preferably an amino group in which the nitrogen atom is not terminal. Avi preferably connects the nitrogen and the phosphorus atom with three atoms (without substituents). 2o
• Rvn is particularly preferably a hydroxyl group
• Rvn is selected from the group consisting of acetyl and formyl
• R VB is selected from the group consisting of hydrogen, methyl, ethyl, hexadecanyl, octadecanyl and OX V B
• X V B and Xv ⁇ 4 selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecanyl and octadecanyl, and, if they are both present, may be the same or different.
• Rvn is selected from the group consisting of acetyl and formyl
• R V B is selected from the group consisting of hydrogen, methyl, ethyl, hexadecanyl, octadecanyl and OX V B
• X are V and XVM selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecanyl and octadecanyl, and, if both are present, may be the same or different.
• organophosphorus compounds used according to the invention correspond to the general formula (VII):
• I is selected in the Avn from the group consisting of a (C 1 - 9) - alkylene group which may have one or more double bonds and with hydroxy, halogen, amino, oxo groups with branched or unbranched alkyl groups, and C ⁇ -9 C 2-9 alkenyl groups may be substituted, wherein the alkyl groups and C Cug - 9 alkenyl groups with hydrogen, hydroxy, amino, halogen and oxo groups may be substituted, -COC- and -CNC- consists, where the carbon atoms of -COC- and -CNC- can be substituted with an alkyl having up to 7 carbon atoms or hydroxyl groups, or in which Avn corresponds to the following formula (VIIA):
• each C 1-26 - alkyl radical and each C ⁇ . 26 -alkoxy radical may be branched or unbranched and saturated or unsaturated with one or more double bonds and may be substituted by hydroxyl, amino, halogen and oxo groups,
• Rvm is selected from the group consisting of 5- and 6-membered heterocycles with one or two nitrogen, oxygen or sulfur atoms in the ring, the heterocycle being saturated or unsaturated with one or more double or triple bonds can and with hydroxyl, halogen, amino, oxo groups and with branched or un- 27.
• Branched C ⁇ .9 alkyl groups and C 2 -9-alkenyl groups can be substituted, the. 9 - alkyl groups and C -9-alkenyl groups can be saturated or unsaturated with one or more double or triple bonds and can be substituted with hydrogen, hydroxyl, amino, halogen and oxo groups,
• RVIB and RV I M are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 26 alkyl, hydroxy-C ⁇ ⁇ 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, OX VI B and OXv ⁇ 4 ,
• XVIB and X V I M are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted .2 6 - alkyl, substituted and unsubstituted hydroxy -CC. 26 alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C 1 - 20 - alkenyl, substituted and unsubstituted C 1 - 26 - alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, a silyl, a cation an organic and inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts of the esters.
• heterocycle Rvm If there are two heteroatoms in the heterocycle Rvm, they can of course also be mixed, e.g. an oxygen atom and a nitrogen atom.
• Rvm is preferably a heterocycle with nitrogen atoms, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrrole and substituted or unsubstituted pyrazole being particularly preferred and very particularly preferred
• the organophosphorus compound preferably corresponds to the formula (VIIC)
• RV IB is preferably hydrogen, methyl, ethyl or an amide residue and Xv ⁇ 4 is selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl,
• organophosphorus compounds used according to the invention correspond to the general formula (VIII):
• n is 0 or 1
• Rv ⁇ ni is selected from the group consisting of substituted and unsubstituted C ⁇ .2 6 - 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.
• Xvm 11 is selected from the group consisting of hydrogen, substituted and unsubstituted C ⁇ -2 6 - alkyl, substituted and unsubstituted hydroxy-C ⁇ - 26 alkyl , substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C ⁇ -2 6 - 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, in particular a metal of the first, second or third main group of the periodic table, ammonium, substituted am
• Rv ⁇ i2, RVIIB and RVHM are each independently selected from the group consisting of hydrogen, halogen, amino, acetylamino, azido and XRvm ⁇ groups, where X is O or S and Rvni ⁇ is selected from the group consisting of consists of a hydrogen radical, branched or unbranched C 4 alkyl radicals and C 2 - 4 alkenyl radicals, where both the C alkyl radicals and the C 2 -4 alkenyl radicals can optionally be substituted with hydrogen, amino, halogen or oxo groups, or
• Rvii ß , R VIIB and R VH M together with the respective geminal hydrogen group represent an oxo group
• Rv ⁇ i 5 is selected from the group consisting of hydrogen, C ⁇ . 24 -alkyl groups, C 3 - 8 - cycloalkyl groups, Ar (C ⁇ . 24 -alkyl) groups, aryl groups, acyl groups, heterocyclic radicals, halogen, where all radicals can be branched or unbranched and optionally with hydroxy, amino. Halogen or oxo groups can be substituted and can contain 2-6 double and triple bonds or Rvms is a phenyl radical of the formula VI LA or XIIIB,
• Rvii ⁇ and Rvins are the same or different and are bonded to the phenyl ring at any two positions and are each independently selected from the group consisting of hydrogen, halogen, C ⁇ - 4 alkyl radicals, Formyl, acetyl, propionyl, Butyrylresten, formyl, acetyl, propionyl, Butyryloxyresten, C 2 - 5 consists -Alkoxycarbonylresten all may be branched or unbranched, or R 7 and RVMs together may form an unbranched saturated alkylene chain with 3 form up to 4 carbon atoms which are bonded to adjacent positions, for example the 2,3-positions or the 3,4-positions of the phenyl ring, or R 7 and Rs together form a methylenedioxy radical, a 1,1-ethylidenedioxy radical or a 1 , 2-ethylenedioxy which are attached to the 2,3- or 3,4-positions of the phenyl ring, or
• Rv ⁇ i5 is selected from the group consisting of RvnreCOOCHRvmio- and Rv ⁇ i9 ⁇ COOCHRv ⁇ iQ- where Rvn »is selected from the group consisting of C 1-6 alkyl residues, C2- 6 alkenyl residues, C 2 . 6 - alkynyl, C 3-8 cycloalkyl, Cs-s-cycloalkyl-Ci ⁇ alkyl and Ci. 6 alkoxy Ci.
• R 6 - alkyl radicals where all radicals can be branched or unbranched and can optionally be substituted with hydroxyl, amino, halogen or oxo groups
• R 10 is a branched or unbranched C alkyl radical
• Preferred compounds of formula (VIII) are those in which rvim is selected from the group consisting of C 9-24 alkyl radicals, C. 9 24 alkenyl radicals, C 9 . 24 -Alkapolyenyl residues containing 2 to 6 double bonds, C 9 . 24 alkynyl radicals, C 3 . 8- cycloalkyl-C6-24-alkyl radicals and CM2- there is either branched or unbranched can and can be substituted with hydrogen, amino, halogen or oxo radicals.
• Rv ⁇ n is selected from the group consisting of a “tetradecyl radical, rc-octadecyl-l-yl radical, a trans-9-octadecenyl radical and a cz ' s-9-octadecen-l radical consists.
• Rv ⁇ n, Rv ⁇ i 3 , Rv ⁇ i 4 are preferably each a hydroxyl group.
• Rvms is preferably a hydrogen, a formyl group or an acetyl group.
• n is preferably 1 and the configuration of the substituents Rvnn, RVIIB, RVHM and Rv ⁇ 5 OOCPO (OH) OCH 2 - D-gluco.
• organophosphorus compounds according to the invention are described in WO98 / 16537 and correspond to the formula (LX)
• R ⁇ is selected from the group consisting 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 ⁇ - 26 - alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic residue, halogen and OXixi i, where Xixn is selected from the group consisting of hydrogen, substituted and unsubstituted C ⁇ .
• 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.
• RD CI and R ⁇ 2 are each independently selected from the group consisting of C ⁇ - 24 - alkyl radicals, C 3 -8-cycloalkyl radicals, C3-8-cycloalkyl-Ci.2 4 -alkyl radicals, C ⁇ - 24 alkoxy radicals, Ci.
• 24-alkylthio radicals Ci.24-alkoxy-C ⁇ .24-alkyl radicals and C ⁇ .24-alkylthio-C ⁇ _ 24 -alkyl radicals, acyl radicals, aryl radicals, aralkyl radicals, heterocyclic radicals, halogen and hydrogen and each C ⁇ -24- Alkyl radical and C ⁇ .24-alkoxy radical may be branched or unbranched and saturated or unsaturated with 2 to 6 double bonds and optionally with hydroxyl, amino, mercapto, halogen, oxo groups or C ⁇ .24-alkoxy radicals, C ⁇ .
• Ci- 24- alkylthio radicals Ci- 24- alkylthio radicals, ⁇ -Allcylamino radicals, di- (C ⁇ . 24 -alkyl) amino radicals, Ci. 24 -Alkylcabonylreste, C ⁇ . 24 -alkylcarbonyloxy radicals, C ⁇ . 24 alkoxycarbonyl radicals, C 1 . 24 - alkylcarbonylthio radicals or Ci. 2 4-alkylcarbonylamino radicals, C ⁇ . 24 alkyl (C 1, 2 - alkylcarbonyl) amino radicals can be substituted, each C ⁇ .
• R f ⁇ -CH-CH-R ⁇ 2 is part of furanose or form pyranose rings of a sugar, for example D-ribose, D-arabinose, D-xylose, D-lyxose, D-glucose, D-galactose, D-mannose, D-talose, D-allose, D-altrose, D-gulose , D-idose or the corresponding L-isomers, the hydroxyl groups each optionally by hydrogen, amino, azido, oxo, mercapto or C ⁇ .
• R ⁇ and R ⁇ 2 can in particular each be independently selected from the group consisting of carboxyl residues, carboxamido residues, aryl residues, aryloxycarbonyl residues, aryl-C ⁇ .24- alkyl residues, C ⁇ .
• R D G and R ⁇ 4 are the same or different and are each selected from the group consisting of hydrogen, halogen, Formyl, acetyl, propionyl, butyryl, formyl, acetyl, propionyl, butyryloxy, C ⁇ - alkoxycarbonyl, which can all be branched or unbranched, or Rp ⁇ and R ⁇ together form an unbranched saturated alkylene chain with 3 to 4 carbon atoms , which is bonded to adjacent positions of the phenyl ring, or R DO and R ⁇ together form a methylenedioxy radical, a 1,1-ethylidendioxy radical or a 1,2-ethylenedioxy radical which are bonded to adjacent positions of the phenyl ring.
• R ⁇ and Rc ⁇ are each independently selected from the group consisting of hydrogen, hydroxyl groups, formyl, acetyl and methyl, the methyl radical optionally having a hydroxyl group or mercapto group or with Ci 24 - Alkoxy residues, C ⁇ . 24 -alkylcarbonyloxy radicals, C ⁇ . 24 -alkylthio or C ⁇ . 24 -Alkylcarbonylthioresten can be substituted, wherein the C ⁇ - 24 alkyl groups and the C ⁇ - 24 alkoxy groups can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds.
• R ⁇ ⁇ is particularly preferably a methyl radical, optionally with a hydroxyl group or mercapto group or with Ci. 24 alkoxy radicals, C 1 . 2 4-alkylcarbonyloxy radicals, C 1 - 24 - alkylthio radicals or C ⁇ . 24 -Alkylcarbonylthioresten can be substituted, the Ci.24- alkyl groups and the C ⁇ . 24 alkoxy groups can be branched or unbranched and saturated or unsaturated with 1 to 6 double bonds, and RQQ. a hydrogen residue
• R ⁇ and Ro ⁇ are each independently selected from the group consisting of hydrogen and an n-octadecylmethyl radical, where Rc ⁇ is preferably a / j-octadecylmethyl radical and R2 is a hydrogen radical.
• Rc ⁇ is preferably a / j-octadecylmethyl radical
• R2 is a hydrogen radical.
• hydroxy inooxocarbyl derivatives used according to the invention correspond to the general formula (X):
• R ⁇ is selected from the group consisting of hydrogen, substituted and unsubstituted Ci. 9 -alkyl, substituted and unsubstituted hydroxy-Ci.g-alkyl, substituted and unsubstituted C].
• R ⁇ 2 is selected from the group, from C ⁇ . 26 -alkyl radicals, d ⁇ ⁇ -alkoxy radicals, d- 26 - alkoxy-C ⁇ - 26 -alkyl radicals, C 3 .
• R ⁇ 2 preferably represents the carboxylic acid group -COOH, where R ⁇ is a branched or unbranched C 1 -4- alkyl group, particularly preferably an isopropyl group, and its pharmaceutically acceptable salts, esters and amides.
• organic or inorganic bases for example sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triemyl
• Esters can preferably also be formed on the carboxylic acid group. Suitable examples of such esters include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (e.g. hexadecanyl ester, octadecanyl ester, etc.);
• organophosphorus compounds used according to the invention correspond to the general formula (XI):
• Z ⁇ is a phosphorus atom or a sulfur atom
• a ⁇ is an unbranched C2-9 alkylene chain with substituents that are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, amino and oxo groups, C ⁇ -26 alkoxy radicals, C1.26-alkoxy-C 1 . 26 - alkyl radicals or C3.8-cycloalkyl- (Co-9) alkyl groups, each C ⁇ .
• each C ⁇ - 26 alkoxy radical and each C ⁇ - 26 alkoxy radical may be branched or unbranched and saturated or unsaturated with one or more double bonds and may be substituted with hydroxyl, amino, halogen and oxo groups and both the C 3 - 8 cycloalkyl group and the C 0-9 - alkyl 8 cycloalkyl (co- 9) may have one or more double bonds and one or two carbon atoms of the cycloalkyl group by nitrogen, oxygen or sulfur atoms may be substituted, and wherein each of - alkyl group of the C 3 the cycloalkyl group and the alkyl group with hydroxyl, halogen, amino, oxo groups with branched or unbranched C ⁇ .9 alkyl groups and C 2 - 9 alkenyl groups can be substituted, the C ⁇ - 9 alkyl groups and C 2 .
• 9 alkenyl groups can be substituted with hydrogen, hydroxyl, amino, halogen and oxo groups in which Rxn and Rxn are identical or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1 .
• 26 -alkyl substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C 1 .2 6 -alkenyl, substituted and unsubstituted C ⁇ - 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical , halogen, OXX and OXX, wherein XX and X ⁇ i 4 are identical or different and are selected from the group consisting of hydrogen, substituted and unsubstituted C 1 - 26 - alkyl, substituted and unsubstituted hy- droxy-C ⁇ .
• 26 -alkyl substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C 1 .2 6 -alkenyl, substituted and unsubstituted C ⁇ - 26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic radical, one silyl, one Cation of an organic and 3Z inorganic base, in particular a metal of the first, second or third main group of the periodic table, ammomum, substituted ammonium and ammomum compounds derived from ethylene amine or amino acids, and their pharmaceutically acceptable salts, esters and amides and salts of the esters.
• a ⁇ is preferably a C 3 . 5 -Alkylke.te.
• Rxn represents a methyl group and Z ⁇ , Rxn, RXD, R ⁇ i4 are as defined above, where Rxn is preferably substituted on the C atom adjacent to the heteroatom with a hydroxy group, and compounds in which Rx represents a
• the hydroxyl group is where Z M , Rxn, RXB, RXM are as defined above, where Rxn is preferably an acyl group, particularly preferably a formyl, acetyl, propionyl or butyryl group.
• Axn is selected from the group consisting of hydrogen, substituted and unsubstituted C ⁇ . 28 -alkyl radicals, substituted and unsubstituted alkoxy (C 0. 28 ) alkyl groups, substituted and unsubstituted cycloalkyl (Co- 28 ) alkyl groups, substituted and unsubstituted cycloalkoxy (Co. 28 ) alkyl groups, substituted and unsubstituted amino ( Co. 28) alkyl groups and substituted, unsubstituted thio- (C 0.
• alkyl and substituted or unsubstituted acyl (co- alkyl is 28), and halogen wherein each alkyl radical, each alkoxy radical and each acyl group is branched or unbranched and each Alkyl radical, any alkoxy radical, any acyl radical and any cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl groups may be replaced by nitrogen, oxygen or sulfur atoms,
• Rxi B is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkoxy- (C 0 - 26) - alkyl groups alkyl groups, substituted and unsubstituted C 3 .i 4 -cycloalkyl- (C 26 ö) , substituted and unsubstituted cycloalkoxy (Co- 26 ) alkyl groups, substituted and unsubstituted amino (Co-26) alkyl groups, substituted and unsubstituted silyl (Co- 26 ) alkyl groups and substituted and unsubstituted thio- (Co- 26 ) -alkyl groups, where each alkyl radical and each alkoxy radical is branched or unbranched and each alkyl radical, each alkoxy radical and each cycloalkyl group can be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycl
• R ⁇ H4 is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted acyl radicals and substituted and unsubstituted cycloalkyl (Co-26) alkyl groups, each alkyl radical and each acyl radical being branched or unbranched and each alkyl radical, each acyl radical and each cycloalkyl group can be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl groups can be replaced by nitrogen, oxygen or sulfur atoms.
• Axn preferably corresponds to the formula (XILA)
• R ⁇ n and R ⁇ n are the same or different and are selected from the group consisting of hydrogen, hydroxyl, halogen, substituted and unsubstituted amino radicals, substituted and unsubstituted alkyl radicals, substituted and unsubstituted alkoxy radicals and substituted and unsubstituted cycloalkyl (Co.
• each alkyl radical and each alkoxy radical may be branched or unbranched 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 groups by nitrogen, oxygen or sulfur atoms may be replaced
• R ⁇ i 5 , R ⁇ i6 and R ⁇ n 7 are the same or different and are selected from the group consisting of hydrogen, hydroxy, halogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl (Co-2 6 ) alkyl groups , substituted and unsubst ituated cycloalkoxy- (Co- 2 6) -alkyl groups, substituted and unsubstituted alkoxy- (C 0 .
• the invention also includes the pharmaceutically acceptable salts, esters and salts of the esters.
• Rxm and R »n are preferably identical or different and selected from the group consisting of substituted and unsubstituted alkyl groups, preferably C 1 -C 4 alkyl groups.
• R ⁇ n 3 is preferably selected from the group consisting of hydrogen, substituted and unsubstituted alkyl groups, preferably C 1 -C4 alkyl groups, substituted and unsubstituted aromatic C -Ci4 cycloalkyl groups, a pyranyl group and a t-
• Rxns is selected from the group consisting of substituted and unsubstituted, preferably halogen-substituted alkyl groups, substituted and unsubstituted cycloalkyl (Co- 26 ) alkyl groups, substituted and unsubstituted amino groups, substituted and unsubstituted alkoxy groups, substituted and unsubstituted phenoxy groups, substituted and unsubstituted alkylthio groups, substituted and unsubstituted, preferably an unsubstituted or substituted with halogen, methyl, methoxy, nitro, amino or CF 3 groups, aromatic cycloalkylthio groups.
• Rxi M is preferably selected from the group consisting of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted phenyl radicals and
• Z ⁇ is selected from the group consisting of hydrogen, halogen, C ⁇ - alkyl and phenyl and Yx ⁇ is selected from the group consisting of hydrogen, halogen, C-alkyl, nitro, methoxy, methylenedioxy, where n 0 or 1.
• R ⁇ 7 is preferably selected from the group consisting of hydrogen and halogen, or R XI and R ⁇ n 7 have a carbon-oxygen single bond, so that there is a ring structure.
• Rx and R ⁇ n are independently selected from the group consisting of methyl and ethyl, R ⁇ i4 z XII
• R ⁇ i5 and R ⁇ n6 are independently selected from the group consisting of hydrogen, chlorine, bromine and methoxy groups.
• Z is selected from the group consisting of 2-chloro, 2-bromo, 2-fluorine and Y is selected from the group consisting of 4-chloro, 4-bromo, 4-fluoro , 5-fluorine and 4,5-methylenedioxy groups, where n is 0 or 1.
• Rxm and R ⁇ are methyl groups
• RXIB and R ⁇ are hydrogen or contain a carbon-oxygen bond which form a ring structure.
• Examples of preferred compounds are 3-CMor-N- (2-C ⁇ orphenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, N- (2-CWorphenyl) memyl-N-hyoxyoxy-2,2-dimethylpropanamide, 3 - CMor-N-hy (koxy-N-phenyl-2,2-dimethylpropanamide, N- (2-bromophenyl) methyl-3-chloro-N-hydroxy-2,2-dimethylpropanamide, 3-CMor-N-hyo !
• n is an integer from 0 to 4, and in which R ⁇ m ⁇ , R ⁇ m, Rxim, R ⁇ i4, RXIIIS and R ⁇ ni6 are identical or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl radicals, substituted and unsubstituted alkoxy radicals groups, substituted and unsubstituted acyl radicals, substituted or unsubstituted cycloalkyl- (Co-26) -alkyl radicals, substituted and unsubstituted cycloalkyl- (Co-26) alkoxy, and halogen wherein each alkyl radical, each alkoxy radical and each acyl group is branched or unbranched and each alkyl radical, each The acyl radical, any alkoxy radical and any cyclo (Co- 2 6) alkyl group can be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl groups can be
• R ⁇ m is preferably COOC 2 H 5 .
• Rx ⁇ n to R ⁇ n ⁇ 6 are selected from the group consisting of hydrogen and halogen, especially chlorine
• N is also preferably 1 or 2.
• Yxrv is a C ⁇ .3-alkenylene group which is substituted by the substituents R ⁇ rvi and R ⁇ rv 2 and optionally by the substituents R ⁇ rv 3 to R ⁇ rv 6 , where Rj ⁇ vi to R MVS are the same or different and are selected from the group consisting of hydrogen , Hydroxy, halogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl (Co- 26 ) alkyl groups, substituted and unsubstituted cycloalkoxy (Co-26) alkyl groups, substituted and unsubstituted alkoxy (C 0 - 26 ) - alkyl groups, substituted and unsubstituted amino groups and substituted, unsubstituted thio- (Co-26) alkyl groups, substituted and unsubstituted sulfonyl- (co- 26) - alkyl groups, substituted and unsubsti
• R ⁇ rv9 and Rxivio are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted (C 1. 26 ) - alkyl groups, substituted and unsubstituted hydroxy (C ⁇ - 26 ) alkyl groups, substituted and unsubstituted cycloalkyl - (Co- 2 6) alkyl groups, substituted and unsubstituted acyl, halogen, OX ⁇ r 9 or OX ⁇ rv ⁇ o where each alkyl radical, each alkoxy radical and each acyl radical is branched or unbranched and each alkyl radical, each alkoxy radical and each cycloalkyl group saturated or with one or more doubles - or triple bonds can be unsaturated and one or two carbon atoms of the cycloalkyl groups can be replaced by nitrogen, oxygen or sulfur atoms, where X ⁇ rv9 or X ⁇ v ⁇ o can be the same or different and are selected from the group consisting of hydrogen
• Rxrvi 1 and R ⁇ rvi2 are the same or different and are selected from the group consisting of hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl (Co-26) alkyl groups, substituted and unsubstituted cycloal- koxy- (Co- 26 ) alkyl groups, substituted and unsubstituted alkoxy- (Co- 26 ) alkyl groups and substituted or unsubstituted acyl radicals, where each alkyl radical, each alkoxy radical and each acyl radical is branched or unbranched and each alkyl radical, each alkoxy radical and each cycloalkyl group is saturated or can be unsaturated with one or more double or triple bonds and one or two carbon atoms of the cycloalkyl groups can be replaced by nitrogen, oxygen or sulfur atoms, B ⁇ v being selected from the group consisting of substituted and un
• each alkenylene radical is branched or unbranched and saturated or with one or several double or triple bonds can be unsaturated and can be substituted with one or more hydroxyl groups, halogen groups or oxo groups.
• R ⁇ rvi 3 and R ⁇ rvi4 preferably together form an oxo group in the ⁇ position to the nitrogen atom.
• Yxrv preferably represents a methylene group which is particularly preferably substituted by two methyl groups.
• B ⁇ v for the ether group (XIV A) - Axrvi - O -Ax - (XTVA) * stands, where A ⁇ v ⁇ is omitted or is a (C 1.9) alkylene radical, and A ⁇ r 2 is omitted or is selected from the group consisting of (C ⁇ . 9 ) alkylene radicals, a sulfur atom and a (C3-8) heterocycle has at least one sulfur atom.
• a ⁇ rv ⁇ and A ⁇ rv2 each particularly preferably represent a methylene group.
• a ⁇ rv3 is particularly preferably eliminated and A ⁇ rv 4 stands for a methylene or an ethylene group.
• B ⁇ v is also preferably a 2-hydroxypropylene group.
• R ⁇ rv9 and Rxivio are preferably OX rv9 and OX ⁇ v ⁇ o, where X ⁇ rv9 and X ⁇ rv ⁇ o are the same or different and are selected from the group consisting of a metal from the first, second or third main group of the periodic table, in particular sodium and potassium, and methyl, ethyl .
• 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 in each case aliphatic, aromatic and / or heterocyclic groups include in the molecule as well as carbamoyl or carbamimidoyl.
• 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.
• Alkyl carbamoyl e.g. methyl carbamoyl etc.
• N-alkyl thiocarbamoyl e.g. (N-methyl) thiocarbamoyl etc.
• Alkylcarbarmmidoyl e.g. memylcarbamimidoyl etc.
• Oxalo Alkoxalyl (e.g. methoxalyl, ethoxalyl, propoxalyl etc.).
• the aliphatic hydrocarbon part in particular the alkyl group or the alkane radical, can optionally have one or more suitable substituents, such as amino, halogen (for example fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, Carboxy, alkoxy (e.g. methoxy, ethoxy, propoxy etc.), alkoxycarbonyl, acylamino (e.g. benzyloxycarbonylamino etc.), acyloxy (e.g. acetoxy, benzoyloxy etc.) and the like; as preferred aliphatic acyl radicals with such substituents are e.g. alkanoyl substituted with amino, carboxy, amino and carboxy, halogen, acylamino or the like.
• suitable substituents such as amino, halogen (for example fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, Carboxy, alkoxy (e.g. methoxy,
• Aromatic acyl radicals are those acyl radicals which originate from an acid having a substituted or unsubstituted aryl group, where the aryl group can 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 e.g. 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.
• aromatic hydrocarbon part in particular the aryl radical
• aliphatic hydrocarbon part in particular the alkane radical
• suitable substituents such as those which are suitable substituents for the alkyl group or the alkane radical already indicated were.
• aromatic acyl radicals with special substituents aroyl substituted with halogen and hydroxy or with halogen and acyloxy and aralkanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimmo and arylthiocarbamoyl (for example phenylthiocarbamoyl etc.); Arylcarbamimidoyl (e.g. phenylcarbamimidoyl etc.).
• a heterocyclic acyl radical is understood to mean an acyl radical which comes 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. thiophene-yl, furoyl, pyrrole carbonyl, nicotinoyl etc.);
• Heterocycle aikanoyl in which the heterocyclic radical is 5- to 6-membered and ⁇ has at least one heteroatom from the group consisting of nitrogen, oxygen and sulfur (e.g. thiophenyl-acetyl, furylacetyl, irnidazolylpropionyl, tetrazolylacetyl, 2- (2-amino -4-thiazolyl) -2-methoxyiminoacetyl etc.) and the like.
• nitrogen, oxygen and sulfur e.g. thiophenyl-acetyl, furylacetyl, irnidazolylpropionyl, tetrazolylacetyl, 2- (2-amino -4-thiazolyl) -2-methoxyiminoacetyl etc.
• heterocyclic acyl groups the heterocycle and / or the aliphatic hydrocarbon portion may optionally have one or more suitable substituents, such as the same ones that have been stated to be suitable for alkyl and alkane groups.
• Alkyl is a straight or branched chain alkyl radical having up to 9 carbon atoms, unless otherwise defined, 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 otherwise defined, such as vinyl, propenyl (e.g. 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2 -Ethylpropenyl, pentenyl, hexenyl.
• Alkynyl includes straight or branched chain alkynyl groups with up to 9 carbon atoms, unless defined otherwise.
• Cycloalkyl preferably represents an optionally substituted C3-C 7 -cycloalkyl.
• alkyl, alkoxy (eg methoxy, ethoxy etc.), halogen (eg fluorine, chlorine, bromine etc.), nitro and the like are suitable as possible substituents. 4r
• Aryl is an aromatic hydrocarbon residue such as phenyl naphthyl, etc., which may optionally have one or more suitable substituents such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. fluorine, chlorine, bromine etc.), nitro and the like.
• alkoxy e.g. methoxy, ethoxy etc.
• halogen e.g. fluorine, chlorine, bromine etc.
• Alkyl includes mono-, di-, triphenylalkyls such as benzyl, phenethyl, benzhydryl, trityl and the like, where the aromatic part may have one or more suitable substituents such as alkoxy (e.g. methoxy, ethoxy etc.), halogen (e.g. Fluorine, chlorine, bromine, etc.), nitro and the like.
• alkoxy e.g. methoxy, ethoxy etc.
• halogen e.g. Fluorine, chlorine, bromine, etc.
• Alkylene includes straight or branched chain alkylene groups which have up to 9 carbon atoms and can be represented by the formula - (C n H2 n ) -, in which n is an integer from 1 to 9, such as methylene, ethylene, Trimethylene, methylethylene, tetramethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, isopropylethylene, hexamethylene, and the like; preferred alkylene radicals have up to 4 carbon atoms and radicals with 3 carbon atoms such as trimethylene are particularly preferred.
• Alkenylene includes straight or branched chain alkenylene groups with up to 9 carbon atoms, which are represented by the formula:
• n is an integer from 2 to 9, such as vinylene, propenylene (e.g. 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene , 2-ethylpropenylene, pentenylene, hexenylene and the like;
• the alkenylene radical can particularly preferably have up to 5 carbon atoms and in particular 3 carbon atoms such as, for example, 1-propenylene.
• Haldroxyalkylene can include straight or branched chain alkylene radicals which have up to 9 carbon atoms, one or more selected carbon atoms being substituted by a hydroxyl group; these radicals can be represented by the formula:
• hydroxyalkylene groups include hydroxymethylene, hydroxyethylene (eg 1-hydroxyethylene and 2-hydroxyethylene), hydroxytrimethylene (eg 1-hydroxytrimethylene, 2-hydroxytrimethylene and 3-hydroxytrimethylene), hydroxytetramethylene (eg 2-hydroxytetramethylene), 2 -Hydroxy-2-methyltrimethylene, hydroxypentamethylene (eg 2-hydroxypenta-methylene), hydroxyhexamethylene (eg 2-hydroxyhexamethylene) and the like.
• a lower hydroxyalkylene with up to 4 carbon atoms and in particular one with 3 carbon atoms such as 2-hydroxytrimethylene is particularly preferred. 4t
• Alkylenamine includes straight-chain or branched-chain alkyleneamine groups which have up to 9 carbon atoms and can be represented by the formula: - (C n H 2n ) -N- (C m H 2m ) -, in which n and m are equal to and can be different and are an integer from 0 to 9 for which l ⁇ n + m ⁇ 9 applies, such as methylene amine, ethylene amine, dimethylene amine, tir ernylene amine, methylene ethylene amine, tetramethylene amine, 1-methyltrimethylene amine, 2-ethylethylene amine, ethylene methylene amine, Pentamethylene amine, 2-methyl tetramethylene amine, isopropyl ethylene amine, hexamethylene amine, and the like, preferred alkylene amine residues have 2 carbon atoms which are present at the ends, particularly preferred is dimethylene amine, and the hydrogen atoms can also be replaced by substitu
• Alkenylene amine includes straight or branched chain alkenylene amine groups with up to 9 carbon atoms, which are represented by the formulas - (C n H2 ".2) -N- (C m H2 m .2) -; - (C 0 H2o) -N - (C n H2n-2) -; - (C n H 2 bother.2) -N- (C 0 H2o) - in which n and m are the same or different and an integer from 2 to 9 are for which m + n ⁇ 9 applies, and o is a number between 0 and 7 and o + n ⁇ 9 applies, such as, for example, vinylene amine, methylene ylene vinyl amine, divinylene amine, propenylene amine (e.g.
• the hydrogen atoms can also be replaced by substituents such as halogen radicals.
• Alkenyleneimine includes straight or branched chain alkenyleneimine groups with up to 9 carbon atoms, which are represented by the formulas
• n and m are identical or different and are an integer from 2 to 9, for which m + n ⁇ 9 applies, and o is a number between 0 and 7 and o + n ⁇ 9 applies, such as e.g. vinyleneimine, memylenvmylenimine, ethylenevmylenimine, propenyleneimine (e.g. 1-propenyleneimine, 2-propenyleneimine), methylene propenyleneimine, 1-methylpropenylene imine, 2-methylpropenylene imine, butenylene imine, 2-ethylene propenylene imine, pentenylene imine, hexenylene imine, vinyl methylene imine and the like.
• the hydrogen atoms can also be replaced by substituents, such as halogen radicals.
• “Hydroxyalkylene amine” can include straight or branched chain alkylene radicals which have up to 9 carbon atoms, at least one selected carbon atom being substituted by a hydroxyl group. These radicals can be represented by the formula - (C “H 2 " - z ) (OH) z -N- (C m H 2m - y ) (OH) y are reproduced, in which n and m are identical or different and are an integer from 0 to 9, for 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.
• hydroxyalkylene amine groups include hydroxymethylene amine, hydroxyemylene amine (eg 1-hydroxyethylene amine and 2-hydroxyethylene amine), hydroxytrimethylene amine (e.g. 1-hydroxy trimethylene, 2-hydroxytrimethylene amine and 3-hydroxy trimethylene amine), hydroxytetramethylene amine (e.g. 2-hydroxy tetramethylene amine), 2-hydroxy-2-methyltrimethylene amine, hydroxypentamethylene amine (eg 2-hydroxypenta-methylenamine), hydroxy- h examethyleneamine (e.g. 2-hydroxyhexa-methylene amine), methylene hyoxy oxymethylene amine, methylene hyoxy oxyethylene amine and the like.
• a lower hydroxyalkylene amine with 2 carbon atoms and one nitrogen atom is particularly preferred, the two carbon atoms being terminal.
• the hydrogen atoms can also be replaced by substituents, such as halogen radicals.
• hydroxyalkyleneimine groups include hydroxymethyleneimine, hydroxyemylerimine (e.g. 1-hydroxyethylemmine and 2-hydroxyethyleneimine), hydroxytrimethyleneimine (e.g.
• a lower hydroxyalkyleneimine with 2 carbon atoms and one nitrogen atom is particularly preferred, the two carbon atoms being terminal.
• the hydrogen atoms can also be replaced by substituents, such as halogen radicals.
• the 5- and 6-membered cyclic compounds which Biv can represent can be aromatic or aliphatic and substituted, for example by alkyl groups having up to 7 carbon atoms and hydroxyl groups.
• the 5- and 6-membered heterocyclic compounds for which Rvim and Rv ⁇ u as well as R ⁇ and R ⁇ 2 can stand, and which contain one or two nitrogen, oxygen or sulfur atoms as a ring member in addition to carbon, can be saturated or unsaturated.
• alkoxy radical is a straight-chain or branched-chain alkoxy radical having up to 26 carbon atoms, such as a methoxy, ethoxy radicals, etc. It can, for example, contain hydroxyl, amino, halogen, oxo groups and alkoxy radicals, such as methoxy -, Ethoxy radicals, may be substituted.
• Alkoxy (Co- 26 ) alkyl groups are alkoxy radicals which can also be bonded to the basic structure via an alkyl radical.
• the alkyl and alkoxy groups are as defined above.
• Cycloalkyl- (Cö-26) alkyl radicals are cyclic compounds with 3 to 8 carbon atoms, unless otherwise defined, which are bonded to the basic structure directly or via an alkylene radical.
• the alkylene radical can be branched, unbranched and saturated or with double bonds Possible substituents of the cycloalkyl radical include alkoxy radicals, alkyl radicals, hydroxy radicals, halogen radicals, amino radicals, oxo radicals.
• the cycloalkyl groups can also be aromatic with the corresponding number of double bonds, ie aryl (Co- 26 ) alkyl radicals (eg phenyl, pyridyl -, naphthyl, etc.)
• the aromatic cyclic compounds can also contain substituents such as nitro groups and CF 3 and phenyl radicals.
• Cycloalkoxy (Co- 26 ) alkyl groups are cyclic compounds having 3 to 8 carbon atoms which are bonded to the basic structure via an oxygen directly or via an alkylene radical.
• the alkylene radical can be branched, unbranched and saturated or unsaturated with double bonds.
• Possible Substituents of the cycloalkyl radical include alkoxy radicals (also alkylenedioxy radicals such as methylenedioxy), alkyl radicals, hydroxyl radicals, halogen radicals, amino radicals, oxo radicals. With the corresponding number of double bonds, the cycloalkyl groups can also be multiple cycles and aromatic (eg phenoxy, pyridoxy, naphthoxy, etc.
• the aromatic cyclic compounds in particular can furthermore have substituents, such as nitro groups, CF 3 groups and phenyl radicals.
• R amino radicals can be substituted, for example, with the alkyl radicals or cycloalkyl (Co- 26 ) alkyl radicals as defined above.
• Mino (Co- 26 ) alkyl groups are amino radicals which can also be bonded to the basic structure via an alkyl radical.
• the alkyl and amino groups are as defined above.
• silica radicals can be substituted, for example, with the alkyl radicals or cycloalkyl (Co- 26 ) alkyl radicals as defined above.
• silyl - (Co -26 ) alkyl groups are silyl radicals which can also be bonded to the basic structure via an alkyl radical.
• the alkyl and silyl groups are as defined above.
• “Thio (C 0 .26) alkyl groups” can for example be substituted with the alkyl radicals or cycloalkyl (C 0. 26 ) alkyl radicals as defined above.
• the (C 0-26 ) alkyl groups are straight or branched chain alkylene radicals such as methylene, ethylene, propylene, isopropylene, butylene, isobutylene, tert-butylene, pentylene, hexylene, etc. They can contain double or triple bonds and, for example, with hydroxy, amino, halogen (for example fluorine, bromine, chlorine) , Oxo residues and alkoxy residues, such as methoxy, ethoxy residues, may be substituted.
• halogen for example fluorine, bromine, chlorine
• esters of the compounds used in the present invention include suitable mono- and diesters, and preferred examples of such esters include alkyl esters (e.g. methyl ester, ethyl ester, propyl ester, 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.
• silyl esters e.g. from trialkylhalosilyl, dialkyldihalosilyl, alkyltrihalosilyl, dialkylarylhalosilyl, trialkoxyhalosilyl, dialkylaralkylhalosilyl, dialkoxydihalosilyl, trialkoxyhalosilyl, etc.
• the alkane and / or arene part can optionally have at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or the like.
• X 13 to Xvm and X w to XVIM and XXB and X XM , X ⁇ I and X112 are preferably a metal of •
• the salt compounds of the ammonium phosphonic acid derivatives with organic or inorganic bases for example sodium salt, potassium salt, calcium salt, Aumium salt, ammonium salt, magnesium salt, triethylamine salt, emanolamine salt, dicyclohexylamine salt, ethylenediarnine salt, KN'-dibenzylethylenediamine salt etc.
• organic or inorganic bases for example sodium salt, potassium salt, calcium salt, Aumium salt, ammonium salt, magnesium salt, triethylamine salt, emanolamine salt, dicyclohexylamine salt, ethylenediarnine salt, KN'-dibenzylethylenediamine salt etc.
• saline salt salt
• arginine salt aspartic acid salt, glutamic acid salt etc.
• the compounds of the formulas (I) to (XTV) according to the invention allow, for example for double-containing or chiral groups of the substituents R or A or B or Y or Z or X, the occurrence of spatial isomers.
• the use of the compounds according to the invention includes all spatial isomers both as pure substances and in the form of their mixtures.
• salts of the aminohydrophosphonic acid derivatives include salts which form the compounds according to the invention in their protonated form as the ammonium salt of inorganic or organic acids, such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid.
• salts which are formed by suitable selection of X 3 (X B to Xv3) and 4 (X to Xv 4 ) and Xm and Xm, such as sodium salt, potassium salt, calcium salt, ammonium salt, ethanolamine salt, triethylamine salt, dicyclohexyla min salt and salts of an amino acid such as argim salt, aspartic acid salt, glutamic acid salt.
• the combination preparations according to the invention contain one or more inhibitors of fat metabolism. Both inhibitors that regulate the absorption of fats and inhibitors that regulate the synthesis of the fats can be used.
• the inhibitors include anion exchangers, preferably cholestyramine and colestipol, ⁇ -sitosterol, nicotinic acids and their derivatives, such as nicotinyl alcohol, clofibrates and their derivatives, such as ethyl clofibrinate, and their analogs, such as bezafibrate, fenofibrate and gemfibrozil, and probucol.
• Inhibitors which regulate the synthesis of fats include HMG-CoA synthetase inhibitors, HMG-CoA reductase inhibitors, preferably lovastatin, mevastatin, simvastatin, fluvastatin, atorvastatin, pravastatin and cerivastatin, inhibitors of squalene synthetase , preferably pyrophosphates, pyrophosphate derivatives, biphosphonic acid derivatives, phosphinylmethylphosphonic acid derivatives, phosphinylformyl derivatives, phosphonocarboxyl derivatives, phosphonosulfonic acid derivatives, phosphinylmethylphosphonic acid derivatives, inhibitors of squalene epoxidase and other inhibitors of cholesterol synthesis.
• HMG-CoA synthetase inhibitors preferably lovastatin, mevastatin, simvastatin, fluvastatin, atorvastatin, pravastatin and
• Inhibitors of HMG-CoA reductase and inhibitors of squalene synthetase are preferred.
• clodronate etidronate, pamidronate, ibandronate, alendronate, zoledronate, risedronate, tiludronate and cimadronate are particularly preferred.
• infectious compounds and esters thereof and salts thereof show simultaneous, separate or graded administration with inhibitors of fat metabolism a strong cytotoxic activity against single and multicellular parasites, fungi, bacteria and virus-infected cells.
• the compounds according to the invention are useful for the treatment of infectious diseases caused by parasites, fungi, bacteria or viruses in humans and animals.
• the compounds are also suitable for use in the prevention of these diseases.
• the combination preparations are effective against unicellular parasites (protozoa), in particular against pathogens of malaria and sleeping sickness as well as Chagas disease, toxoplasmosis, amoebic dysentery, leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis and sarcozystosis , the Akanthamöbose. nailerosis, coccidiosis, giardiosis and lambliosis.
• malaria prophylaxis and as prophylaxis of sleeping sickness and Chagas disease, toxoplasmosis, amoebic dysentery, Leishmaniasis, trichomoniasis, pneumocystosis, balantidiosis, cryptosporidiosis, sarcolocystosis, acanthamoebosis, cocoonosis, naeglerosis Giardiosis and Lambliosis.
• the combination preparations according to the invention can be used in particular against the following bacteria:
• Bacteria of the Propionibacteriaceae family in particular of the Propionibacterium genus, in particular the Propionibacterium acnes species; Bacteria of the Actinomycetaceae family, in particular of the Actinomyces genus; Bacteria of the genus Corynebacterium, in particular the species Corynebacterium diphteriae and Corynebacterium pseudotuberculosis; Bacteria of the family Mycobacteriaceae, of the genus Mycobacterium, in particular the species Mycobacterium leprae, Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium avium; Bacteria of the Chlamydiaceae family, in particular the species Chlamydia trachomatis and Chlamydia psittaci; Bacteria of the genus Listeria, especially the species Listeria mo- nocytogenes; Bacteria of the species Erysipelth
• Vibrio, Aeromonas, Plesiomonas and Photobacterium in particular the species Vibrio cholerae, Vibrio anguillarum and Aeromonas salmomci- das; 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 Spirochaetaceae and Leptospiraceae families, in particular the Treponema, Borrelia and Leptospira genera, in particular Borrelia burgdorferi; Bacteria of the genus Actinobacillus; Bacteria of the family Legionellaceae, of the genus Legionella; Bacteria of the Rickettsiaceae family and Bartonellaceae family; Bacteria of the genera Nocardia and Rh
• the combination preparations according to the invention are thus suitable for the treatment of diphtheria, acne vulgaris, listeriosis, erysipelas in animals, gas burns in humans and animals, para-noise burns in humans and animals, tuberculosis in humans and animals, leprosy and other mycobacteriosis in humans and animals, paratuberculosis in animals, plague, mesenteric lymphadenitis and pseudotuberculosis in humans and animals, cholera, legionnaires' disease Lyme disease in humans and animals, leptospirosis in humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella keratoconjunc- animal tivitis and serositis, animal and human brucellosis, anthrax in humans and animals, actinomycosis in humans and animals, streptotrichoses, psittacosis / ornithosis in animals, and Q fever and Ehrlichio
• the use is also useful in Helicobacter eradication therapy for ulcers of the gastrointestinal tract.
• Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, protionamide and dapsone are particularly suitable for the treatment of tuberculosis for combination preparations with other anti-infectives.
• the combination preparations according to the invention can also be used in particular for infections with the following viruses:
• Parvoviridae Parvoviruses, Dependoviruses, Densoviruses
• Adenoviridae adenoviruses, mastade noviruses, aviadenoviruses
• Papovaviridae papovaviruses, in particular papillomaviruses (so-called wart viruses), polyomaviruses, in particular JC virus, BK virus, and miopapovavirus
• He ⁇ esviridae all He ⁇ esviruses, in particular He ⁇ es-Simplex virus, the varicella / zoster virus, human cytomegalovirus, Epstein-Barr virus, all human He ⁇ esviruses, human He ⁇ esvirus 6, human He ⁇ esvirus 7, human He ⁇ esvirus 8
• Poxviridae smallpox virus, Orthopox, Parapox, Molluscum Contagiosum virus, aviviruses, capriviruses, leporipox
• compositions according to the invention are therefore suitable for combating the following viral infections:
• the agents are suitable for combination with other agents with antiviral properties.
• the compounds according to the invention generally include pharmaceutically acceptable salts, esters, a salt of such an ester, or compounds which, when applied, provide the compounds according to the invention as metabolites or degradation products, also called “prodrugs", can be administered in any suitable manner analogous to known anti-infectious agents (mixed with a non-toxic pharmaceutically acceptable carrier).
• the combination preparation according to the invention can be administered in conjunction with non-toxic, inert pharmaceutically suitable excipients.
• non-toxic, inert pharmaceutically suitable excipients includes solid, semi-solid or liquid diluents, fillers and formulation aids of all kinds.
• Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as pharmaceutical preparations.
• Tablets, coated tablets, capsules, pills and granules can contain the active substances in addition to the usual carriers, such as (a) fillers and extenders, for. B. starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. B. carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) humectants, e.g. B.
• glycerin (d) disintegrant, e.g. B. Agar, calcium carbonate and sodium carbonate (s) Solution delay, e.g. B. paraffin and (f) Reso ⁇ tions accelerator, z. B. quaternary ammonium compounds, (g) wetting agents, e.g. B. cetyl alcohol, glycerol monostearate (h) Adso ⁇ ti- onsstoff, z. B. kaolin and bentonite and (i) lubricants, e.g. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
• the compounds according to the invention can be incorporated into other carrier materials such as plastics, (plastic chains for local therapy), collagen or bone cement.
• the tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings, optionally containing opacifying agents, and can also be composed such that they release the active substances only, or preferably in a certain part of the intestinal tract, with a delay, where appropriate, as embedding compounds, e.g. . B. polymer substances and waxes can be used.
• the active compounds can also be present in microencapsulated form with one or more of the above-mentioned carriers.
• Suppositories can contain the usual water-soluble or water-insoluble carriers in addition to the active ingredients, e.g. B. polyethylene glycols, fats, e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C16 fatty acid) or mixtures of these substances.
• B. polyethylene glycols e.g. B. polyethylene glycols
• fats e.g. B. cocoa fat and higher esters (z. B. C 14 alcohol with C16 fatty acid) or mixtures of these substances.
• Ointments, pastes, creams and gels can contain the usual excipients in addition to the active ingredient (s), e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
• active ingredient e.g. B. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and zinc oxide or mixtures of these substances.
• Powder and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. B. milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.
• Sprays can also use the usual blowing agents, e.g. B. chlorofluorocarbons.
• solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerol formal, Contain tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
• solvents e.g. B. water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
• solutions and emulsions can also be in sterile and blood-isotonic form.
• Suspensions can contain the usual excipients such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum dimethyl hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
• liquid diluents e.g. Water, ethyl alcohol, propylene glycol
• suspending agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum dimethyl hydroxide, bentonite, agar and tragacanth or mixtures of these substances.
• the active ingredient or formulas (I) to (XTV) should be present in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5% by weight, preferably of about 0.5 to 95% by weight. % of the total mixture.
• the ratio between the individual substances to be combined depends on the individual active substance. Active substances are represented with a standard 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) and 10 mg / kg body weight per day (pamidronate).
• the pharmaceutical preparations listed above can also contain other pharmaceutical active ingredients, such as antiviral, antiparasitic, antimycotic or antibacterial agents.
• the combination preparations according to the invention can also sulfonamide, sulfadoxin, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, Armes ⁇ n, tetracycline, doxycycline, proguanil, metronidazole, praziquantantel, tiazolazole, tiazolazine, niclosamidine, niclosolizine, niclosamidine, niclosamidine, niclosamidine, niclosolizine, niclosamide, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclosamidine, niclos
• Lovastatin, atorvastatin, simvastatin, mevastatin, pravastatin and fluvastatin are preferably administered orally, with pravastatin and fluvastatin being administered in active form.
• the active ingredient (s) of formula (I) and (V) in total amounts of about 0.5 to about 600, preferably 1 to 200 mg / kg body weight per 24th Hours, if necessary in the form of several single doses, to achieve the desired results.
• a single dose contains the active ingredient (s) preferably in amounts of about 0.5 to about 200, in particular 1 to 60 mg / kg body weight.
• a single dose 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 body weight.
• the combination preparations according to the invention can be given to animals in the usual concentrations and preparations together with the feed or with feed preparations or with the drinking water.
• the combination preparations can be administered simultaneously, separately or at different times.
• the required amount of the sterile anti-infectious agent 500 mg of 3- (N-acetyl-N-hydroxylamino) propylphosphonic acid monosodium salt and 90 mg of 3-amino-1-hydroxypropylidene-l, l-bisphosphonic acid disodium salt in vials or ampoules distributed
• the vials are hermetically sealed to exclude bacteria.
• 500 ml of physiological saline solution is taken up and administered
• a suitable tablet formulation is formed by the following mixture: 3 - (N-formyl-N-hydroxylamino) propylphosphonic acid monosodium salt 200 mg

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Genetics & Genomics (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Molecular Biology (AREA)
• Zoology (AREA)
• Wood Science & Technology (AREA)
• Biomedical Technology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biotechnology (AREA)
• Biochemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Microbiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Veterinary Medicine (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Public Health (AREA)
• Immunology (AREA)
• Oncology (AREA)
• Physics & Mathematics (AREA)
• Biophysics (AREA)
• Communicable Diseases (AREA)
• Analytical Chemistry (AREA)
• Urology & Nephrology (AREA)
• Hematology (AREA)
• Cell Biology (AREA)
• Tropical Medicine & Parasitology (AREA)
• Plant Pathology (AREA)
• Gastroenterology & Hepatology (AREA)
• Toxicology (AREA)
• Virology (AREA)
• Food Science & Technology (AREA)

Applications Claiming Priority (5)

Publications (1)

Family

ID=26047010

Family Applications (1)

Country Status (10)

Families Citing this family (2)

Family Cites Families (5)

• 1999
  • 1999-06-23 IL IL13996599A patent/IL139965A0/xx unknown
  • 1999-06-23 EP EP99929309A patent/EP1100510A2/de not_active Withdrawn
  • 1999-06-23 TR TR2000/03783T patent/TR200003783T2/xx unknown
  • 1999-06-23 SK SK1961-2000A patent/SK19612000A3/sk unknown
  • 1999-06-23 CN CN99809991A patent/CN1348374A/zh active Pending
  • 1999-06-23 PL PL99345513A patent/PL345513A1/xx unknown
  • 1999-06-23 AU AU46155/99A patent/AU752714B2/en not_active Ceased
  • 1999-06-23 CA CA002334645A patent/CA2334645A1/en not_active Abandoned
  • 1999-06-23 WO PCT/EP1999/004360 patent/WO1999066875A2/de not_active Application Discontinuation
  • 1999-06-23 JP JP2000555562A patent/JP2002518418A/ja active Pending

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events