JP2002518418A - Composite preparation of an anti-infective compound inhibiting the metabolic pathway of 2-C-methylerythrose-4 and an inhibitor of lipid metabolism - Google Patents

Abstract

  (57) [Summary] A complex preparation comprising at least one anti-infective active compound that inhibits 2-C-methylerythrose-4-metabolism pathway and at least one lipid metabolism inhibitor as an active ingredient. This complex preparation is used in particular for infectious processes in humans and animals and as a fungicide in plants. The accumulation of resistance to the composite preparation according to the invention is significantly reduced compared to the resistance accumulation of the individual compounds.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to anti-infective compounds which inhibit the 2-C-methylerythrose-4 metabolic pathway and complex preparations of salts and esters thereof with inhibitors of lipid metabolism, and furthermore on plants, humans and It relates to the simultaneous, discontinuous or sequential use of said composite preparation in the prevention and treatment of the infectious process in animals, as well as to the use of said composite preparation as a fungicide. The lipid metabolism inhibitors according to the invention are suitable for the treatment and prophylaxis of infections by single or multicellular parasites, fungi, bacteria or viruses, and as fungicides.

[0002]

[Prior art]

The suitability of certain organic phosphonic acid compounds, certain of their esters and salts, as pharmaceutical compositions is known.

For example, the antimicrobial efficacy of aminohydrocarbylphosphonic acid derivatives against bacteria in humans and animals and against fungi in plants has been disclosed (DE 27 33 685 A1, US 4,143,135, US 4,182,758 and US 4,206,156, U
S 4,994,447, US 4,888,330, US 4,210,635, US 3,955,958, US 4,196,193, US
4,268,503, US 4,330,529, US 5,189,030, US 3,764,676). In addition, these groups of substances are used as fungicides (US 4,693,742, US 5,002,602, US 4,131,448, US 3,9
77,860, US 4,062,669), as algicide (US 3,887,353), and as a plant growth regulator (US 4,127,401, US 4,120,688, US 3,961,934, US 4,431,438,
US 3,853,530, US 4,205,977, US 4,025,332, US 3,894,861) and as reactants in pigment production (US 4,051,175).

For example, the application of aminohydrocarbylphosphonic acid derivatives for controlling bacterial infection has proven to be extremely difficult. Many bacteria responsible for pedestrian infections and infections during the clinical stay are not sensitive to treatment with this taxon. Staphylococcus bacteria, especially Staphylococcus aureus species belong to these. This type of pathogen on the skin is dangerous for patients in clinical practice. Patent application DE
Further work, including the Phase IIa study by Applicant No. 27 33 658,
It shows that the resistance of the initially sensitive pathogen rapidly builds up. Therefore, these derivatives have not been clinically applied.

In addition, it is known to use certain bisphosphonic acids and their derivatives as pharmaceutical compositions. To date, the microbiostatic efficacy of bisphosphonic acids (DE 3 611 522), their efficacy in disorders of calcium and phosphorus metabolic pathways
(DE 2 534 390, DE 2 534 391, DE 3 334 211, DE 3 434 667, DE 2 745 083)
, Bacteriostatic efficacy (DE 3 425 812), their lipid-lowering efficacy (Arzneimittelfo
rschung 46, 759-62) and their ability to stimulate immune competent cells (WO 97/38
696) is known.

[0006] The antimicrobial efficacy of phosphonochlorin on bacteria and the efficacy of foscarnet on viruses have been disclosed. In addition, the suitability of phosamine ammonium and N, N-dimethyl- (hydroxy-2-oxo-2-methoxyethyl) phosphonoamide as fungicides has been reported. The use of inhibitors of lipid metabolism has been accepted and widespread as the basis of therapy for a long time. These inhibitors are used to reduce the risk of cardiac and vascular disorders due to cardiac disorders and hyperlipidemia. Pharmacological treatment of hyperlipidemia is generally based on regulating fat intake and controlling fat, especially cholesterol synthesis. Cholesterol synthesis is generally controlled by β-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase). Cholesterol self-synthesis is generally higher than food intake (Berthold HK, of Bergmann K., Dtsch
Med. Wochenschr. 121, S.729 (1996); Richter WO, Fortscher. Med. 114,
S.177, 193).

[0007] Anion exchangers and β-sitosterol are known to control fat intake from the digestive tract. The ion exchanger contains cholestyramine and colestipol. They absorb bile acids, thereby inhibiting enterohepatic return transport and significantly increasing fecal sterolene. β-sitosterol is a plant sterol structurally related to cholesterol. It inhibits the absorption of dietary cholesterol in the intestinal mucosa.

In addition, nicotinic acid and its derivatives, clofibrate and their derivatives and probucol have been used for controlling lipid metabolism or preventing disorders from hyperlipidemia. Nicotinic acid and nicotinic acid derivatives reduce fatty acids, triglycerides and cholesterol. To date, the mechanism is unknown. Either clofibric acid ethyl ester, clofibrate and their derivatives and analogs reduce cholesterol, but the mechanism is unknown. The active mechanism of probucol is not clear.

To control this synthesis, HMG-CoA synthetase inhibitors (US 50 64 856, US 475
1237), HMG-CoA reductase inhibitor (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 9
38, US 43 75 475, US 43 46 227, US 44 106 29, US 44 447 84, US 44 50 17
1, 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 860
3488A, 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 9397
1, 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 pyrophosphate, pyrophosphate derivatives, bisphosphonic acid derivatives, phosphunylmethylphosphonic acid derivatives, phosphinylformyl derivatives , Phosphonocarboxy derivatives, phosphonosulfonic acid derivatives, phosphinylmethylphosphonic acid derivatives, some of which are known as pharmaceutical and cosmetic preparations for controlling calcium and phosphorus metabolism (DE 25 34 390, DE 25 34 391, DE 33 34 211, DE
34 34 667, DE 27 45 083, US 53 12 814, 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 96
9, 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 other inhibitors of cholesterol synthesis (US 5
6 61 145, US 57 44 467) are used, but their role is unclear. HMG-Co
A reductase inhibitors reduce the rate at which the cholesterol synthase HMG-CoA reductase is regulated. These enzyme affinities are less than 20000-fold higher than those of the substrate HMG-CoA. This HMG-CoA reductase converts HMG-CoA to mevalonate, which gives rise to the primary steps of dolochol and ubiquinone in addition to cholesterol, in particular isopentenyladenine and huanesylpyrophosphate. In bacteria, fungi and parasites that have HMG-CoA reductase,
Isopentenyl diphosphate is formed during the acetate / mevalonate pathway and is suppressed by HMG-CoA reductase inhibitors.

[0010] The first inhibitors found were penicillium (mevastatin) and aspergillus
fungi (lovastatin). Modification of this side chain leads to simvastatin, an advance of mevastatin to pravastatin. On the other hand, a complete synthase inhibitor (fluvastatin) is also commercially available, which is a mevalonate lactone derivative having a fluorophenyl-substituted indole ring.

In the past, attempts have been made to use these substances for the control of infectious disorders. In particular, attempts have been made to inhibit the growth of plants, fungi, parasites, bacteria and viruses by using HMG-CoA inhibitors. HMG-CoA synthetase and H
MG-Co reductase inhibitors are useful for certain bacteria and fungi (US 50 26 554, US 50 64 8
56, US 49 20 111, US 49 2-113) and the acetate / mevalonate pathway in parasites. However, many bacteria such as Escherichia coli are HMG-CoA
Does not show inhibition by reductase inhibitors. The reason is that these bacteria probably have separate metabolic pathways. In fact, in Escherichia coli, acetate /
The lack of mevalonate metabolic pathway and the existence of other metabolic pathways have been demonstrated (Rohm
er M. et al., Biochem. J. 295, S. 517 (1993); Lois EM et al., Proc.
Acad. Sci. USA 95, S.2105 (1998)).

[0012]

[Problems to be solved by the invention]

In the case of parasites, no separate route is known to date. The applicant of the present invention has reported that so-called 1-deoxyxylulose, a separate metabolic pathway in the case of parasites.
ylulose) or the 2-C-methylerythrose-4 phosphate pathway has been successfully demonstrated. Studies of HMG-CoA reductase inhibitors in parasites have produced different results depending on the parasite. For example, schistosomiasis pathogens cannot be killed by high doses of lovastamine, whereas malaria pathogens can be killed in vitro but not in vivo. Sleep pathogens cannot be completely inhibited by HMG-CoA reductase inhibitors.
In a similar attempt to inhibit viral multiplication, virus-infected cells
This shows that the inhibitory effect of the oA reductase inhibitor is weakened.

[0013] Similarly, squalene synthetase inhibitors, such as aminobisphosphonates, have been successfully tested as inhibitors of amoebic dysentery. Low insecticidal effect was observed. Similar experiments with toxoplasma have also not shown satisfactory results. In addition, squalene monooxygenase inhibitors have also been developed as fungicides.

[0014]

[Means for Solving the Problems]

Accordingly, it is an object of the present invention to provide a drug that can be used to prevent infectious processes in humans, animals and plants, and to provide a drug as a bactericide, and
It is an object of the present invention to provide a drug that significantly reduces the accumulation of drug resistance in plants, viruses, fungi, parasites and bacteria.

Unexpectedly, the combination of an anti-infective compound inhibiting the metabolic pathway of 2-C-methylerythrose-4 with a lipogenesis inhibitor, in particular a cholesterol synthesis inhibitor, in particular an HMG-CoA reductase inhibitor, and Squalene synthetase was found to enhance the efficacy and effectiveness of infection prevention and treatment. Surprisingly, the combination kills microorganisms that cannot be killed by either the first group or the second group. Surprisingly, it has been shown that this combination can significantly reduce the accumulation of resistance to the compounds used, a concern when dealing with lipid metabolism inhibitor compounds.

Lipid metabolism inhibitors consisting of anti-infective active compounds that inhibit the 2-C-methylerythrose-4 metabolic pathway, and inhibitors of lipid metabolism, are useful for infection of plants, especially humans and animals, especially parasites, bacteria Suitable for the prevention and treatment of infections caused by fungi and viruses and as fungicides in plants.

The lipid metabolism inhibitor according to the present invention contains at least one anti-infective active compound that inhibits the 2-C-methylerythrose-4 metabolic pathway and / or salts thereof. Generally, pharmaceutically acceptable salts, esters, ester salts, or compounds that upon application provide the compounds according to the invention as metabolites or degradation products (these are also referred to as "prodrugs"). contains.

The following are some classes of substances that have shown excellent success in preventing and treating infections in combination with lipid metabolism inhibitors.

The group of anti-infective active substances can be measured and determined by the following method: contacting a protein or a derivative thereof which is part of the 2-C-methylerythrose-4 metabolic pathway with an active agent to be tested, Active agents that inhibit the protein or derivative are selected. This method is known to the parties.

I. Complex preparation of lipid metabolism inhibitors and aminohydrocarbylphosphonic acid derivatives Aminohydrocarbylphosphonic acid derivatives and their preparation are described in DE-Al-27336
A detailed description can be found in No. 58 and PCT / EP99 / 02462. Aminohydrocarbylphosphonic acid derivatives corresponding to general formula (I):

Embedded image Wherein R ₁₁ and R ₁₂ are the same or different and are H, OH, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted R ₁₃ and R ₁₄ are selected from the group consisting of aralkyl, and substituted and unsubstituted heterocyclic groups, wherein R ₁₃ and R ₁₄ are substituted and unsubstituted alkyl of 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of 1 to 26 carbon atoms, substituted And unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, 1 to 26 carbon atoms
A substituted and unsubstituted alkenyl of 1 to 26 carbon atoms, a substituted and unsubstituted cycloalkyl, a substituted and unsubstituted heterocyclic group, a halogen,
Selected from the group consisting of X ₁₃ and X ₁₄ , wherein X ₁₃ and X ₁₄ are the same or different and are hydrogen, substituted and unsubstituted alkyl having 1 to 26 carbon atoms, substituted with 1 to 26 carbon atoms and Unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl of 1 to 26 carbon atoms, substituted and unsubstituted alkynyl of 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkyl An unsubstituted heterocyclic group, silyl, a cation of an organic or inorganic base, particularly a metal cation of the first, second or third group of the periodic table, ammonium, a substituted ammonium, and an ethylenediamine or an ammonium compound derived from an amino acid; and, A ₁ is an alkylene group, an alkenylene group or hydroxyalkyl Corresponding to the emissions group or the following formula:

Embedded image Wherein the group C together with the substituents₁₃, C₁₄, C_FifteenOne or more selected from
The carbon atom above may be deleted and B₁ From B_TenAt least one of
The substituent is C_3-8 -Cycloalkyl- (C_0-9 ) -Alkyl groups, wherein C_3-8 
-Cycloalkyl group and C_0-9 -An alkyl group is one or more double bonds
And one or two carbon atoms of the cycloalkyl group may be
May be substituted with a nitrogen, oxygen or sulfur atom, and
And alkyl groups are hydroxy, halogen, amino, oxo, branched or
Straight chain C_1-9 -Alkyl group and C_2-9 -May be substituted with an alkenyl group
, Where C_1-9 -Alkyl group and C_2-9 An alkenyl group is hydrogen, hydroxy,
May be substituted with amino, halogen, and oxo groups;
Existing substitution B₁₁From B₁₁₀ Is hydrogen, hydroxy, halogen, amino, C _1-26 -Alkyl group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26-Al
Selected from the group consisting of a kill group, or both substituents on one carbon atom are
To form an oxo group,_1-26Alkyl groups and each C_1-26An alkoxy group is
Branched or linear, and saturated or one or more double bonds
Which is substituted with a hydroxy, amino, halogen and oxo group
It may be.

According to the invention, when the aminohydrocarbylphosphonic acid derivative is used as an anti-infective compound, the inhibitor of lipid metabolism is not an aminohydrocarbylphosphonic acid derivative of formula (I).

The present invention also includes pharmaceutically acceptable salts, esters and ester salts.

Preferably R₁₁Is OX₁₁, R₁₃Is OX₁₃And R₁₄ Is OX₁₄And where
X₁₁Is hydrogen, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and
Unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl
And R is selected from the group consisting of substituted and unsubstituted heterocyclic groups;₁₂, X₁₃, X ₁₄ And A₁ Has the same meaning as in formula (I). Preferably A₁ Carbon chain
Consists of three carbon atoms.

The carbon chain A ₁ of formula (IA) consists of four carbon atoms C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ ;
Compounds in which B ₁₇ or B ₁₈ or both are hydroxy groups are also preferred. Here, a methylene group is also preferable for R ₁₃ and R ₁₄ .

Preferably B₁₁And B₁₂Together form further oxo groups. In this case, A ₁ Has four carbon atoms C₁₁, C₁₂, C₁₃, C₁₄Consists of Preferably
Is B₁₇And B₁₈Further form together an oxo group. Where the charcoal in A
The strand has four carbon atoms C₁₁, C₁₂, C₁₃, C₁₄Consists of

The carbon chain preferably consists of five carbon atoms C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , wherein B ₁₁ and B ₁₂ together form an oxo group, and One substituent B ₁₉ or B ₁₁₀ is a hydroxy group, or B ₁₉ and B ₁₁₀ also form an oxo group.

Substances in which the phosphonic or phosphinic acid or phosphinoyl group is replaced by a sulphone or sulphonyl group are also suitable:

Embedded image

II. Complex Preparations of Lipid Metabolism Inhibitors and Bisphosphonic Acid Derivatives Bisphosphonic acids and their derivatives are described in detail in parallel international patent applications filed simultaneously by the same applicant. Bisphosphonic acids, such as general formula (II), and derivatives thereof, and pharmaceutically acceptable salts, esters and ester salts thereof, or compounds capable of providing the compound to be administered upon application as a metabolite or degradation product used:

Embedded image _Wherein X _II1 , X _II2 , X _II3 , and X _II4 are the same or different, and represent hydrogen,
Substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, Na,
K, Ca, Mg, Periodic Table 1 such as Al, second or third group metal is selected from substituted and unsubstituted ammonium and the group consisting of ammonium compounds from Echinjiamin or amino, A ₁₁ is deleted Also selected from the group consisting of alkylene, alkenylene and hydroxyalkylene, wherein R _II1 and R _II2 are the same or different and are H, OH, —NH ₂ , substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, a substituted and unsubstituted heterocyclic group and -SR _II3 Cl, and the group consisting of -NR _II3 R _II4, wherein R _II3, R _II4 is a same or different, H, OH, substituted and unsubstituted acyl, substituted and unsubstituted Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, selected from the group consisting of substituted and unsubstituted cycloalkyl and substituted and unsubstituted heterocyclic group.

Bisphosphonic acid derivatives of the formula II are particularly preferred, wherein X _II1 , X _{II 2} , X _II3 , X _II4 are the same or different and are H, substituted and unsubstituted alkyl, substituted and unsubstituted Aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, metals of Group 1, 2 or 3 of the periodic table such as Na, K, substituted and unsubstituted ammonium, and A is selected from the group consisting of ethylenediamine or ammonium compounds derived from amino acids, A _II may be deleted and is selected from the group consisting of alkyl, (CH ₂ ) _0-6, especially (CH ₂ ) _1-5 and amidino; _II1 is selected H, OH, NH _2, from the group consisting of -CH _3, R _II2 is -NH _2,

Embedded image Selected from the group consisting of:

Bisphosphonates are particularly preferred, these being aminohydroxy-methylidene-
Bisphosphonic acid, 2-amino-1-hydroxyethylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid,
-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid, 6-amino-
1-hydroxyhexylidene-1,1-bisphosphonic acid, aminomethylenebisphosphonic acid, 3-methylpentylamino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2- (3-pyridinyl) -1-hydroxyethylidene- Bisphosphonic acid, 1-hydroxy-2- (imidazol-1-yl) -ethylidene-1,
It is selected from the group consisting of 1-bisphosphonic acid, cyclopentylaminomethylene diphosphonic acid, 4-chlorophenyl-1-thiomethylene-1,1-bisphosphonic acid and derivatives thereof. When the anti-infective active compound is a bisphosphonic acid derivative, the lipid metabolism inhibitor is not a bisphosphonic acid derivative.

III. Complex preparations of organophosphorus compounds containing a keto group with inhibitors of lipid metabolism These compounds are described in detail in DE-A-198 31 637.2. These compounds according to the invention correspond to the general formula (III):

Embedded image Where R_III1Is H, substituted and unsubstituted acyl, substituted and unsubstituted alkyl,
Substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted
And unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloal
Alkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen and
And OX_III1Selected from the group consisting of_III1Is hydrogen, substituted and unsubstituted
Sil, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted
And unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted ant
, Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, silyl
, Substituted and unsubstituted heterocyclic groups, cations of organic and inorganic bases, especially
Cations of group 2 or 3 metals, ammonium, substituted ammonium and
R is selected from the group consisting of ammonium compounds_III4, R_III3Are the same or different and include hydrogen, substituted and unsubstituted acyl,
Substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted
Unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl,
Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted
Substituted heterocyclic group, halogen and OX_III4And OX_III3Selected from the group consisting of
, Where X_III4, X_III3Is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted
Substituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl,
Silyl, substituted and unsubstituted heterocyclic groups, cations of organic and inorganic bases, especially periodicity
Cation, ammonium, substituted ammonium of metals of group 1, 2 or 3
, And an ammonium compound derived from ethylenediamine or an amino acid
Selected from the group; and A_III1And A_III2One or both may be deleted,_III1And A _III2 Are the same or different, alkylene group, alkenylene group, oxo group,
Represents a hydroxy group or an oxohydroxyalkylene group. A_III2Is preferably not present. This invention relates to a pharmaceutically acceptable salt,
, Esters and ester salts are also included.

[0032] phosphonic acid derivatives according to the invention was found to be particularly suitable, in this case, R _III4 the OX _III4 and R _III3 are _{OX III3, R III1, X III4} , X III3,
A _III1 and A _III2 includes same meaning as in formula (III).

Particularly preferred phosphonic acid derivatives are chloroacetylphosphonic acid (phosphonochlorin), phosphonoformic acid (foscarnet), phosphonoacetic acid, N, N-
Dimethyl- (1-hydroxy-2-oxo-2-methoxy-ethyl) -phosphonoamide and 2-hydroxy-2-hydroxymethyl-3-oxo-butylphosphonic acid (phosphonotricin) and ammonium-ethylcarbamoylphosphonic acid (phos Amine ammonium).

IV. Lipid metabolism inhibitors and organic compounds containing at least one ether or keto group
Complex Preparations with Phosphorus Compounds These compounds according to the invention are compounds corresponding to the following general formula (IV) and their pharmaceutically acceptable salts, esters and amides and ester salts:

Embedded image Wherein R _IVI and R _IV2 are the same or different and are 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,
Selected from the group consisting of substituted and unsubstituted heterocyclic groups, halogen, OX _IVI and OX _IV2 , wherein X _IVI and X _IV2 are the same or different and are hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxy. From the group consisting of alkyl, 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 groups B _IV is selected from the group consisting of the following ether groups (IVA):

Embedded image Wherein, A _IV2 in A _IV1 and A _IV2 are possible deletions, and A _IV1 and A _IV2 is a same or different, consist of an alkylene group, alkenylene group and hydroxy alkylene, keto group (IVB) Selected from group:

Embedded image Where A_IV3 And A_IV4 One or both of the two can be deleted and _IV3 And A_IV4 Are the same or different, and include an alkylene group, an alkenylene group,
And hydroxyalkylene groups, and especially at least one heterocyclic atom in the ring
5- and 6-membered rings containing other than carbon atoms, especially selected from the group consisting of heterocyclic compounds
Wherein the heterocyclic ring atoms are selected from the group consisting of oxygen and nitrogen;_IV3 And R_IV4 Are the same or different, and have the same meaning as hydrogen,
Substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl having less than 26 carbon atoms
Killed, substituted and unsubstituted aryl groups, substituted and unsubstituted acyl, substituted and unsubstituted
Substituted aralkyl, substituted and unsubstituted alkenyl having less than 26 carbon atoms,
Less than substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl,
And unsubstituted heterocyclic groups, halogen, OX_IV3 Or OX_IV4 Selected from the group consisting of
Where X_IV3 Or X_IV4 Are the same or different, and represent hydrogen, carbon atom 2
Substituted and unsubstituted alkyl of less than 6, substituted and unsubstituted hydrid of less than 26 carbon atoms
Loxyalkyl, substituted and unsubstituted aryl groups, substituted and unsubstituted aralkyl,
Substituted and unsubstituted alkenyl with less than 26 carbon atoms, substituted and unsubstituted with less than 26 carbon atoms
And unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted hetero
Cations of cyclic groups, silyls, organic and inorganic bases, especially the first, second or
Group 3 metal cations, ammonium, substituted ammonium, and ethylenedia
It is selected from the group consisting of min or ammonium compounds derived from amino acids.

In particular, compounds corresponding to formula (IVC) are preferred:

Embedded image Wherein R _IV2 is selected from the group consisting of acetyl and formyl, A _IV1 is selected from the group consisting of methylene, ethylene, ethynylene, hydroxyethylene, 2-hydroxypropylene, and X _IV3 and X _IV4 are the same. Or, they are different and are selected from the group consisting of sodium, potassium, methyl, and ethyl. The preferred chain -A _IV1 -OC (ZY)-consists of one oxygen atom and two or three carbon atoms (without regard for substituents), two carbon atoms being particularly preferred.

Among the ether compounds, compounds selected from the following group are particularly preferred: ((N
-Formyl-N-hydroxyamino) -methoxy) -methylphosphonic acid disodium salt, ((N-acetyl-N-hydroxyamino) -methoxy) -methylphosphonic acid disodium salt, ((N-formyl-N-hydroxy Amino) -ethenoxy) -methylphosphonic acid disodium salt, (2- (N-acetyl-N-hydroxyamino) -ethenoxy) -methyl-phosphonic acid disodium salt, (3
-(N-formyl-N-hydroxyamino) -2-hydroxypropoxy) -methylphosphonic acid disodium salt, (3- (N-acetyl-N-hydroxyamino) -2-hydroxypropoxy) -methylphosphonic acid disodium salt salt.

Further, compounds corresponding to the following formula (IVD) are preferred:

Embedded image Wherein R _IV2 is selected from the group consisting of acetyl and formyl, A _IV3 is selected from the group consisting of methylene, ethylene, ethenylene, hydroxymethylene, hydroxyelene and 2-hydroxypropylene, and A _IV4 is deletion or methylene. _Yes , X _IV3 and _IV4 are the same or different and are selected from the group consisting of metals of the first, second or third groups of the periodic table, especially sodium, potassium and methyl, ethyl.

Preferred chains —A _IV1 —CO—A _IV2- — are preferably chains of 2 to 4 carbon atoms (substituents not taken into account), especially 3 carbon atoms.

Among these, the following compounds are particularly preferred: 2- (N-formyl-N-hydroxyamino) -1-oxoethylphosphonic acid · 2
Sodium salt, 2- (N-acetyl-N-hydroxyamino) -1-oxoethylphosphonic acid disodium salt, 3- (N-formyl-N-hydroxyamino)
-1-oxopropylphosphonic acid disodium salt, 3- (N-acetyl-N-
Hydroxyamino) 1-oxopropylphosphonic acid disodium salt, 3- (
N-formyl-N-hydroxyamino) -1-oxo-2-propenyl-phosphonic acid disodium salt, 3- (N-acetyl-N-hydroxyamino) -1-oxo-2-propenyl phosphonic acid disodium salt Salt, 4- (N-formyl-N-
(Hydroxyamino) -1-oxo-3-hydroxybutylphosphonic acid disodium salt, 4- (N-acetyl-N-hydroxyamino) -1-oxo-3-hydroxybutylphosphonic acid disodium salt, 3 -(N-formyl-N-hydroxyamino) -2-oxopropylphosphonic acid disodium salt, 3- (N-
Acetyl-N-hydroxyamino) -2-oxopropylphosphonic acid disodium salt, 4- (N-formyl-N-hydroxyamino) -3-oxo-2-hydroxy-2-methylbutylphosphonic acid disodium salt , 4- (N-acetyl-
N-hydroxyamino) -3-oxo-2-hydroxy-2-methylpyrropylphosphonic acid disodium salt, 4- (N-formyl-N-hydroxyamino) 3-
Disodium oxo-2-hydroxy-2- (hydroxymethyl) -butylphosphonate, 4- (N-acetyl-N-hydroxyamino) -3-oxo-2-hydroxy-2- (hydroxymethyl) -propiphosphone Acid disodium salt.

In cyclic compounds, amino acid groups and phosphorus atoms can be attached to any ring carbon atom. However, compounds where the bond is to two carbon atoms separated by only one additional atom are preferred. In heterocyclic compounds, it is preferred if both carbon atoms are separated by one heteroatom.

The following compounds are particularly preferred:

Embedded image

In addition, substances in which the phosphonic or phosphinic acid or phosphinoyl group has been replaced by the following sulphone or sulphonyl group are suitable:

Embedded image

V. A lipid metabolism inhibitor, an organic phosphorus compound containing at least one hydroxy group,
Complex preparations of the phosphonic acid derivatives according to the invention are derivatives corresponding to the formula (V) and their salts, esters, amides and ester salts:

Embedded image Wherein one or both of A _V1 and A _V2 can be deleted, and A _V1 and A _V2 are the same or different and are selected from the group consisting of an alkylene group, an alkenylene group and a hydroxyalkylene group. They are a carbon chain -A _V1 -CHOH-A _V2 -
Preferably consists of 2 to 5, especially 3 to 4 carbon atoms, and B _V is selected from the group consisting of groups of formula (VA):

Embedded image Wherein R _V1 is hydrogen, OH, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl,
Selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups and halogen, and the following groups (VB):

Embedded image Wherein R _V2 , R _V3 and R _V4 are the same or different and are hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Selected from the group consisting of aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, and the following group (VC):

Embedded image Wherein R _V5 , R _V6 and R _V7 are the same or different and are hydrogen, OH, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted substituted and unsubstituted Selected from the group consisting of alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen, wherein X _V3 and X _V4 are the same or different. Wherein hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkyl, Heterocyclic groups, silyl, cations of organic and inorganic bases, especially The first table, second or third group of metal cations, ammonium, is selected from the group consisting of substituted ammonium, and ethylene diamine or ammonium compounds derived from amino acids. Preferred R _V1 in formula (VA) is a methyl group. In formula (VB), preferred R _V2 and R _V4 are hydrogen and R _V3 is a methyl group
In formula (VC), preferred R _V5 is a methyl group, R _V6 is selected from the group consisting of H, OH and methyl, and R _V7 is a hydroxy group.

Particularly preferred compounds are those of the formula (VD):

Embedded image In the formula, A _V2 is a straight-chain hydroxyalkylene having 1 to 3 carbon atoms, and X _V3 and X _V4 are the same or different and include hydrogen, a metal of Group 1, 2 or 3 of the Periodic Table. Particularly selected from the group consisting of sodium, potassium and methyl, ethyl.

Among these compounds, 3,4-dihydroxy-5-oxo-hexylphosphonic acid disodium salt, 1,2,3,4-tetrahydroxy-5-oxo-hexylphosphonic acid disodium salt, , 3,4-Trihydroxy-5-oxo-
Hexylphosphonic acid disodium salt, 1,2,3-trihydroxy-4-oxo-pentylphosphonic acid disodium salt, and 2,3-dihydroxy-4-
Oxopentyl phosphonic acid disodium salt is particularly preferred.

Furthermore, compounds corresponding to formula (VE) are particularly preferred:

Embedded image _Wherein A _V2 is a straight-chain hydroxyalkylene having 1 to 3 carbon atoms, X _V3 and X _V4 are the same or different and include hydrogen, a metal of Group 1, 2 or 3 of the Periodic Table, especially sodium. , Potassium, methyl and ethyl.

Among these compounds, 3,4,5-trihydroxy-4-methyl-pentylphosphonic acid disodium salt, 2,3,4,5-tetrahydroxy-4-methyl-pentylphosphonic acid · 2 Sodium salt, 1,3,4,5-tetra-4-methylpentylphosphonic acid disodium salt, and 1,2,3,4,5-pentahydroxy-4-methyl-pentylphosphonic acid disodium salt are particularly preferred. preferable.

In particular, compounds corresponding to formula (VF) are also preferred:

Embedded image _Wherein A _V2 is a straight-chain hydroxyalkylene having 1 to 3 carbon atoms, and X _V3 and X _V4 are the same or different and include hydrogen, a metal of Group 1, 2 or 3 of the Periodic Table, especially It is selected from the group consisting of sodium, potassium, methyl and ethyl.

Among these compounds, 3,4-dihydroxy-4-methyl-5-oxo-
Pentylphosphonic acid disodium salt, 2,3,4,5-trihydroxy-4-
Methyl-5-oxo-pentylphosphonic acid disodium salt, 1,2,3-trihydroxy-4-methyl-5-oxo-pentylphosphonic acid disodium salt,
2-monohydroxy-3-methyl-4-oxo-butylphosphonic acid disodium salt, 1,2-dihydroxy-3-methyl-4-oxo-butylphosphonic acid / 2
Sodium salts are particularly preferred.

VI. Lipid metabolism inhibitors and organophosphorus or organosulphurization containing amine or imine groups
Complex preparations with the compounds The organic compounds according to the invention are compounds corresponding to the following general formula (VI) and their pharmaceutically acceptable salts, esters and amides and ester salts:

Embedded image _Wherein R _VI3 and R _VI4 are the same or different and are hydrogen, substituted and unsubstituted alkyl having less than 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having less than 26 carbon atoms, substituted and unsubstituted aryl groups, substituted and unsubstituted Substituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl of less than 26 carbon atoms, substituted and unsubstituted alkynyl of less than 26 carbon atoms, substituted and unsubstituted cycloalkyl,
Selected from the group consisting of substituted and unsubstituted heterocyclic groups, halogen, OX _Vi3 or OX _Vi4 , wherein X _VI3 or X _VI4 are the same or different and include hydrogen, substituted and unsubstituted alkyl having less than 26 carbon atoms, Substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl groups, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, less than 26 carbon atoms, substituted and unsubstituted alkynyl, substituted and unsubstituted, less than 26 atoms Cycloalkyls, substituted and unsubstituted heterocyclic groups, silyls, cations of organic and inorganic bases, especially cations of metals of groups 1, 2 or 3 of the periodic table, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids Selected from the group consisting of
And _BVI is the following group (VIA):

Embedded image And selected from the group consisting of the following groups (VIB):

Embedded image In the formula, A _VI is selected from the group consisting of an alkyleneamine group, an alkenyleneamine group, a hydroxyalkyleneamine group, an alkyleneimine group, an alkenyleneimine group and a hydroxyalkylenimine group, wherein the nitrogen atom is represented by the following group: Is a member of the chain connecting the nitrogen and phosphorus atoms:

Embedded imageOr group R_VII-N =. Wherein R in group (VIA)_VI1 And R_VI2 Are the same or different,
R in the group (IVA)_VI1 And R_VI2 And R in group (VIB)_VI1 Is
Hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted
And unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted ant
, Substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and
Unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, OX_VI1 And OX _VI2 Selected from the group consisting of_VI1 And X_VI2 Are the same or different
Hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl
, Substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted
Substituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted
Selected from the group consisting of substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups
You. Preferably A_VIIs an amino group, wherein the nitrogen atom is not located at the end. Good
Preferably A_VISeparates the nitrogen and phosphorus atoms by three atoms (without considering substituents)
Join.

Particularly preferred these compounds correspond to formula (VI):

Embedded image _{Wherein, R VI1, R VI2, R} VI3 and X _VI4 are the same as defined in the case of formula (VI), and, A _VI is C-N-C, C = N-C, C-N = C Wherein the carbon atoms can be replaced by hydroxy groups or alkyl groups having less than 7 carbon atoms.

Particularly preferred R _VI1 is a hydroxy group, R _VI2 is selected from the group consisting of acetyl, formyl, R _VI3 is selected from the group consisting of hydrogen, methyl, ethyl, hexadecyl, octadecyl and OX _VI3 , and X _VI3 and X _VI4 are selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecyl and octadecyl, and when both are present, X _VI3 and X _VI4 are the same or different.

Furthermore, compounds corresponding to formula (VID) are preferred:

Embedded image _{Wherein, R VI1, R VI2, R} VI3 and X _VI4 are as defined in formula (I) selected, A is C-N-C, C = N-C, from the group consisting of C-N = C Wherein the carbon atom may be replaced by a hydroxy group or by less than 7 carbon atoms.

Particularly preferred R _VI1 is selected from the group consisting of acetyl and formyl, R _{VI 3} is selected from the group consisting of hydrogen, methyl, ethyl, hexadecyl, octadecyl and OX _VI3 and X _VI3 and X _VI4 are hydrogen, sodium , Potassium, methyl, ethyl, hexadecyl and octadecyl, wherein X _VI3 and X _VI4 are the same or different as long as both are present.

VII. Complex preparation of lipid metabolism inhibitor and organophosphorus compound having nitrogen heterocycle

The organophosphorus compounds used according to the invention are compounds corresponding to the following general formula (VII) and their pharmaceutically acceptable salts, esters and amides and ester salts:

Embedded image _Wherein A _VII is selected from the group consisting of a (C _1-9 ) -alkylene group, which may contain one or more double bonds, and hydroxy, halogen,
Amino, oxo, branched or linear C _1-9 -alkyl and C _2-9 -alkenyl may be substituted, wherein C _1-9 -alkyl and C _2-9 -alkenyl are It may be substituted by hydrogen, hydroxy, amino, halogen and oxo groups, -C-OC- and -C-N-C-, wherein -C-O-C- and -C-N
The -C- carbon atom may be substituted with an alkyl or hydroxy group having less than 7 carbon atoms, or A _VII corresponds to formula (VIIA):

Embedded image Wherein, together with their substituents, C_VII3, C_VII4, C_VII5One selected from
Or two or more carbon atoms may be deleted and B_VII1From B_VII10 Less of
One of the substituents is C_3-8 -Cycloalkyl- (C_0-9 ) -Alkyl groups;
Where C_3-8 A cycloalkyl group and (C_0-9 ) -Alkyl group is one or two
May contain one or more double bonds and one or two of the cycloalkyl groups
May be replaced by a nitrogen, oxygen or sulfur atom, wherein cyclo
Alkyl groups and alkyl groups are hydroxy, halogen, amino, oxo group, branched
Or linear C_1-9 An alkyl group, and C_2-9 -May be substituted with an alkenyl group
And here C_1-9 -Alkyl group and C_2-9 An alkenyl group is hydrogen, amino, ha;
Or an oxo group, and the remaining substituent B_VII1From
B_VII10 Is hydrogen, hydroxy, halogen, amino group, C_1-26-Alkyl group, C_{1- 26} -Alkoxy group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26−Aki
Or both substituents of one carbon atom are taken together
To form an oxo group, where each C_1-26Alkyl groups and each C_1-26-Alkoxy
The group may be branched or straight-chain and saturated or one or more double
Unsaturated type having a bond, substituted with hydrogen, amino, halogen and oxo groups
Where R_VII1Has one or two nitrogen, oxygen or sulfur atoms in the ring
Selected from the group consisting of 5- and 6-membered heterocycles, wherein the heterocycle is saturated or monocyclic.
An unsaturated type having one or more double bonds or triple bonds, and
By hydrogen, halogen, amino, oxo group and branched or straight-chain C_1-9 −
Alkyl group and C_2-9 -Alkenyl group, wherein C _1-9 -Alkyl group and C_2-9 The alkenyl group is saturated or one or two
Unsaturated hydrogen having the above double bond or triple bond, hydrogen, hydroxy, amino,
Optionally substituted by halogen and oxo groups;_VII3And R_VII4Are the same or different and include hydrogen, substituted and unsubstituted C_{1- 26} -Alkyl, hydroxy-C_1-26-Alkyl, substituted and unsubstituted aryl,
Substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26 Alkenyl, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cyclo
Alkyl, substituted and unsubstituted heterocyclic group, halogen, OX_VII3And OX_VII4From
Selected from the group_VII3And X_VII4Are the same or different and are hydrogen, substituted and unsubstituted
Exchange C_1-26-Alkyl, substituted and unsubstituted hydroxy-C_1-26-Alkyl, substituted or
And unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26−
Alkenyl, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cycloalkyl
Alkyl, substituted and unsubstituted heterocyclic groups, silyl, organic and inorganic base cations
The cation, ammonium, and substituted anion of a metal of Group 1, 2, or 3 of the periodic table
Monium and ammonium compounds derived from ethylenediamine or amino acids
Selected from the group consisting of: If heterocycle R_VII1If there are two heteroatoms in it,
Can also be present, for example, in a mixed form of oxygen and nitrogen atoms.

Preferred R _VII1 is a heterocycle containing a nitrogen atom, wherein substituted and unsubstituted pyridine, substituted and unsubstituted pyrimidine, substituted and unsubstituted pyrrole and substituted and unsubstituted pyrazole moieties are particularly preferred,

Embedded image Is particularly preferred.

The organophosphorus compound preferably corresponds to the formula (VIIC):

Embedded image Wherein, R _VII3 is hydrogen, methyl, preferably an ethyl or an amide group, and X _VII4 is selected from hydrogen, sodium, potassium, methyl, from the group consisting of ethyl. Particularly preferably, it corresponds to the formula (VIID):

Embedded image

In addition, preference is given to substances in which the phosphonic or phosphinic acid or phosphinoyl group has been replaced by a sulphone or sulphonyl group (VIIE):

Embedded image

VIII. Complex preparation of lipid metabolism inhibitor and phosphonoformic acid derivative This compound is described in WO 9/16537. The organophosphorus compounds used according to the invention correspond to the following general formula (VIII):

Embedded image _Wherein the wavy line represents a bond having an α- or β-configuration, n is 0 or 1, R _III11 is substituted and unsubstituted C _1-26 -alkyl, hydroxy-C _1-26 -alkyl, substituted and unsubstituted Aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C _1-26 -alkenyl, substituted and unsubstituted C _1-26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic group _Wherein X _VIII11 is hydrogen, substituted and unsubstituted C _1-26 -alkyl, substituted and unsubstituted hydroxy-C _1-26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclic aralkyl, substituted and unsubstituted C _1-26 - alkenyl, substituted and unsubstituted C _1-26 - alkynyl, substituted and unsubstituted cycloalkyl, Contact substituted And unsubstituted heterocyclic groups, silyls, cations of organic and inorganic bases, especially cations of metals of Groups 1, 2 or 3 of the Periodic Table, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids. is selected, R _VIII1 is C _1-24 - alkyl group, C _2-24 - alkapolyenyl group, C _2-24 - - alkenyl, C _2-24 having six double bonds 2 alkynyl group, C _3-8 - cycloalkyl group, C _3-8 - cycloalkyl -C _1-24 - alkyl and C _1-12 - alkoxy -C _1-12 - is selected from the group consisting of alkyl groups, each R _VIII2, R _VIII3 and R _VIII4 are selected from the group consisting of hydrogen, halogen, amino, acetylamino, azide and XR _VIII6 groups, wherein X is O or S
_Wherein R _VIII6 is selected from the group consisting of hydrogen, branched or straight chain C _1-4 -alkyl and C _2-4 -alkenyl, wherein C _1-4 -alkyl and C _2-4-
The alkenyl group is optionally substituted with hydrogen, amino, halogen or oxo group, or R _VIII2 , R _VIII3 and R _VIII4 together with the respective gem-hydrogen group represent an oxo group, R _VIII5 is hydrogen, C _{VIII 1-24} - alkyl group, C _3-8 - cycloalkyl group, Ar (C _1-24 - alkyl) group, an aryl group, an acyl group, a heterocyclic group, selected from the group consisting of halogen, where all groups Is branched or linear and may be optionally substituted by a hydroxy, amino, halogen or oxo group and may contain from 2 to 6 double and triple bonds, or R _VIII5 has the formula VIIIA or XIIIB is a phenyl group:

Embedded image _Wherein R _VIII7 and R _VIII8 are the same or different, are attached to any two positions of the phenyl ring, and R _VIII7 and R _VIII8 are hydrogen, halogen,
C _1-4 - alkyl group, C _1-4 - is independently selected from alkoxy group consisting of a carbonyl group - alkoxy, formyl, acetyl, propionyl, butyryl, formyl, acetyl, propionyl, butyryloxy, C _{2-5 May be} all branched or linear, or R ₇ and R _VIII8 may be taken together at adjacent positions, such as the 2,3-position or 3-position of the phenyl ring.
Can form a linear saturated alkylene group with 3 to 4 carbon atoms attached at the, 4-position, or R ₇ and R ₈ together form the 2,3- or 3,4-
A methylenedioxy group, 1,1-ethylidenedioxy group or 1,
To form a 2-ethylenedioxy group, or R _VIII5 is R _III9 COOCHR _VIII10 - it is selected from the group consisting of, R _Viii9 is, C _1-6 - - and R _III9 OCOOCHR _VIII10 alkyl group, C _2-6 - alkenyl Group, C _2-6 -alkynyl group, C _3-8 -cycloalkyl group, C _3-8 -cycloalkyl-C _1-6 -alkyl group and C _1-6 -alkoxy-C _1-6 -alkyl group Wherein all groups are branched or straight-chain and can be optionally substituted with hydroxy, amino, halogen or oxo groups;
R ₁₀ is branched or linear C _1-4 alkyl, wherein, if n = 1, substituents R _VIII2 in formula _{(VIII), R VIII3, R} VI II4 and R _III5 OOCPO (OH) OCH ₂ -configuration is D-gluco, L-gluc
o, D-galacto, L-galacto, D-manno, L-manno, D-talo, L-ta
lo, D-allo, L-allo, D-altro b, L-altro b, D-gulo, L-gulo,
When independently selected from D-ido or L-ido, and n = 0, the relative configurations of the substituents R ₂ , R ₃ and R ₅ OOCPO (OH) OCH ₂ — in formula (I) are independently D-ribo, L-ribo, D-arabino, L-arabino, D-xylo, L-xylo, D
-Lyxo or L-lyxo. According to the invention, the configuration of the glycosidic bond of the compound is preferably α.

[0061] Preferred compounds of formula (VIII), R _VIII1 is C _9-24 - alkyl groups, C _9-24 - alkenyl group, the double bond 2 to 6 C _9-24 - alkapolyenyl groups, C _9-24 −
An alkynyl group, a _C3-8 -cycloalkyl _C6-24 -alkyl group and a _C1-12 -alkoxy _C8-12 -alkyl group, each of which is optionally branched or straight-chain; It can be substituted by hydrogen, amino, halogen or oxo group.

In particular, R_VIII1 Is an n-tetradecyl group, an n-octadecyl-1-yl group,
The group consisting of cis-9-octadecenyl and cis-9-octadecene-1- groups
The use of any compound selected from is preferred. Preferably R_VIII2 , R _III3 , R_III4This is the case where each is a hydroxy group. Preferred R_III5Is hydrogen, e
It is a rumyl group or an acetyl group. Further, n is preferably 1, and the substituent R_VIII2 
, R_III3, R_III4And R_III5OOCPO (OH) OCH_Two The arrangement of-is D-gluc
o is preferred. X_VIII11= H_VIII11Is preferably OX_VIII11Represents

IX. Complex preparation of a lipid metabolism inhibitor and a heterocyclic phosphonoformic acid derivative The organophosphorus compound according to the present invention is described in WO 98/16535, and has the following formula (I)
Compounds corresponding to X) and their pharmaceutically acceptable salts, esters and amines, ester salts and their optical isomers:

Embedded image Where R_IX11Is a substituted and unsubstituted C_1-26-Alkyl, hydroxy-C_1-26−
Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted
Substituted aralkyl, substituted and unsubstituted C_1-26-Alkenyl, substituted and unsubstituted -C _1-26 Alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups
, Halogen and OX_IX11Selected from the group consisting of_IX11Is hydrogen, substituted and unsubstituted C_1-26-Alkyl, hydroxy-C_{1- 26} -Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted
And unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26Alkynyl, substituted and
And unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, organic and inorganic
Cations of bases, especially cations of metals of the first, second or third groups of the periodic table;
, Substituted ammonium, and ethylenediamine or amino acid-derived
R is selected from the group consisting of ammonium compounds_IX1 And R_IX2 Each of C_1-24-Alkyl group, C_3-8 -Cycloalkyl
Group, C_3-8 -Cycloalkyl-C_1-24-Alkyl group, C_1-24-Alkoxy group, C _1-24 -Alkylthio group, C_1-24-Alkoxy-C_1-24Alkyl group and C_1-24−
Alkylthio-C_1-24-Alkyl group, acyl group, aryl group, aralkyl group,
Independently selected from the group consisting of a ring group, halogen and hydrogen;_1-24-Al
Kill group and C_1-24Each of the alkoxy groups may be branched or linear;
Saturated or unsaturated from 2 to 6 double bonds, and hydrogen, amino
, Mercapto, halogen, oxo group, or C_1-24-Alkoxy group, C_1-24-A
Alkylcarbonyl-oxy group, C_1-24-Alkoxycarbonyloxy group, C_1-24 -Alkylthio group, C_1-24-Alkylcarbonylthio group, C_1-24-Alkylami
No group, di- (C_1-24) Amino group, C_1-24-Alkylcarbonylamino group, C_1-24 -Alkyl- (C_1-24-Alkylcarbonyl) amino group, C_1-24-Alkoxyka
Rubonylamino group or C_1-24Alkyl- (C_1-24-Alkoxycarbonyl) a
Optionally substituted with a mino group, wherein an aralkyl group, a heterocyclic group,_1-24 Alkyl group and C_1-24Each alkoxy group is branched or straight-chain and
It may be a sum or an unsaturated type having 2 to 6 double bonds or triple bonds.
Or R_IX1 -CH-CH-R_IX2 Is C_4-8 Forms part of a carbocycle, which ring is
Si, mercapto, amino, halogen, may be optionally substituted with an oxo group,
Is C_1-24-Alkyl group, C_1-24-Alkoxy group, C_1-24-Alkylthio group, C_{1- twenty four} -Alkylamino group, di- (C_1-24-Alkyl) amino group, C_1-24-Alkyl
Carbonyl group, C_1-24-Alkyl carbonyloxy group, C_1-24-Alkoxycarboni
Group, C_1-24-Alkylcarbonylthio group, or C_1-24-Alkylcarbonyl
Amino group, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) amino group
Where C is_1-24Each alkyl group is branched or linear
May be a saturated or unsaturated type having 1 to 6 double bonds,
Or R_IX1 Is a branched or linear C_1-4 -An alkyl group, and R_IX1 -CH-CH-R_IV1 Is, for example, D-ribose, D-arabinose, D-ki
Sylose, D-lyxose, D-glucose, D-galactose, D
-Mannose, D-talose, D-allose, D-artose, D-glucose
Furanose or pyranose of saccharides such as D-idose or the corresponding L-isomer
Form part of a ring, wherein each of the hydroxy groups is hydrogen, amino, azide,
Oxo, mercapto group or C_1-24-Alkoxy group, C_1-24An alkylthio group,
C_1-24-Alkylamino group, di- (C_1-24) Amino group, C_1-24-Alkyl carbo
Nyloxy group, C_1-24-Alkylcarbonylthio group, C_1-24-Alkyl carboni
Ruamino group, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) amino group
Where each C is_1-24Alkyl groups are branched or linear and
May be an unsaturated type having 1 to 6 double bonds or double bonds,

In particular, R_IX1 And R_IX2 Each represents a carboxyl group or a carboxamide group
, Aryl group, aryloxycarbonyl group, aryl-C_1-24Alkyl group, C _1-24 -Alkoxycarbonyloxy group, C_1-24An alkylaminocarbonyl group,
Di- (C_1-24-Alkyl) -aminocarbonyl group, aryl-C_1-14Alkoxy
Carbonyl group, aryl-C_1-24-Alkylaminocarbonyl group, C_1-24-Al
Kill carbonyloxy- (C_1-4 ) -Alkylmethoxycarbonyl group, C_1-24−
Alkoxy-carbonyloxymethoxycarbonyl group, C_1-24-Alkoxycal
Bonyl-oxy- (C_1-24Alkyl) -methoxycarbonyl group
Selected, where each C_1-24The alkyl group is branched or straight-chain, saturated or
It may be an unsaturated type having 2 to 6 heavy bonds, and_1-4 -Alkyl group and C _1-24 The alkoxy group may be branched or linear, saturated or unsaturated,
And each aryl group corresponds to formula (IXA):

Embedded image _Wherein R _IX3 and R _IV4 are the same or different and are each hydrogen, halogen, C _1-24 -alkyl, C _1-24 -alkoxy, formyl, acetyl, propionyl, butyryl, formyl, acetyl, Selected from the group consisting of propionyl, butyryloxy, C _1-4 -alkoxycarbonyl, all of which may be branched or straight-chain, or R _IX3 and R _IV4 are taken together at adjacent positions on the phenyl ring. Forming a linear saturated alkylene chain of 3 to 4 carbon atoms attached,
Or R _IX3 and R _IV4 together form a methylenedioxy, 1,1-ethylidenedioxy or 1,2-ethylenedioxy group bonded at an adjacent position on the phenyl ring.

It is preferred to use a compound wherein each of R _IX1 and R _IX2 is independently selected from the group consisting of hydrogen, hydroxy, formyl, acetyl and methyl, wherein the methyl group is optionally a hydroxy or mercapto group. , or C _1-24 - alkoxy, C _1-24 - alkyl carbonyloxy group, C _1-24 - alkylthio group or a C _1-24 - may be substituted with an alkyl carbonyl thio group, the C _1-24 - The alkyl group and the C _1-24 -alkoxyl group may be branched or straight-chain, and may be saturated or unsaturated with 1 to 6 double bonds.

[0066] R _IX1 preferably a methyl group, this group is a hydroxyl group or a mercapto group, or a C _1-24 - alkoxy, C _1-24 - alkyl carbonyloxy group, C _1-24 - alkylthio or C ₁ The C _1-24 -alkyl group and the C _1-24 -alkoxyl group may be optionally substituted with a _-24- alkylcarbonylthio group. It may be unsaturated and R _IX2 may be a hydrogen group.

Particularly good results are obtained with compounds where R _IX1 and R _IX2 are each independently selected from the group consisting of hydrogen, n-octadecylmethyl, wherein R _IX1
Is preferably an n-octadecylmethyl group, and R ₂ is a halogen group. It is particularly advantageous if the compounds are in the relative configuration (R). When X _IX11 = halogen,
A preferred R _iX11 is OX _IX11 .

X. Complex preparation of a lipid metabolism inhibitor and a hydroxyaminooxocarbyl derivative The hydroxyaminooxocarbyl derivative used according to the invention corresponds to the following general formula (X):

Embedded image Wherein R _X1 is hydrogen, substituted and unsubstituted C _1-9 -alkyl, substituted and unsubstituted hydroxy C _1-9 -alkyl, substituted and unsubstituted C _1-9 -alkenyl, substituted and unsubstituted C ₁ -alkyl. ₉ -alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic group ₁ , halogen and OX _X1 , _Wherein X _X1 is hydrogen, substituted and unsubstituted C _1-9 -alkyl, substituted and unsubstituted hydroxy C _1-9 -alkyl, substituted and unsubstituted C _1-9 -alkenyl, substituted and unsubstituted C _1-9 -alkyl. Selected from the group consisting of alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups Wherein R _X2 represents a C _1-26 -alkyl, C _1-26 -alkoxy group, C _1-26 -alkoxy-C _1-26 -alkyl group, C _3-8 -cycloalkyl- (C _{0- 26} ) -alkyl groups, wherein one or more carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and each _-C3-26 alkyl group And each C- _3-26 alkoxy group is branched or linear, and each -C _3-8 cycloalkyl group, C _2-26 -alkyl group and each C _2-26 -alkoxy group are saturated or Alternatively, it may be an unsaturated type having two or more double bonds, wherein each C _3-8 -cycloalkyl group, each C _1-26 -alkyl group and each C _1-26 -alkoxy group are hydroxy, amino , Halogen and oxo, or with the carbyl group COR _X3 , R _{X 3} is substituted and unsubstituted C _1-26 alkyl, hydroxy-C _1-26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C _1-26 -alkenyl Substituted and unsubstituted C _1-26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen, O
_XX3 is selected from the group consisting of _XX3 , wherein _XX3 is hydrogen, substituted and unsubstituted _C1-26 -alkyl, hydroxy- _C1-26-
Alkyl, substituted and unsubstituted aryl, 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 group , Silyl, cations of organic and inorganic bases, especially cations of metals of groups 1, 2 or 3 of the periodic table, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids.

Preferred R _X2 is a carboxylic acid group —COOH, wherein R _X1 is a branched or straight-chain C _1-4 alkyl group, particularly preferably an isopropylyl group and their pharmaceutically acceptable salts, esters, amides. is there.

As the salt of the carboxylic acid group, a salt in which H is substituted by a metal of the first, second or third group of the periodic table, ammonium or substituted ammonium, or ethylenediamine or an ammonium compound derived from an amino acid is preferable. . That is, a hydroxyaminooxocarbylcarboxylic acid derivative and an organic or inorganic base (eg, sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, ethylenediamine salt, N, N′- Dibenzylethylenediamine salts and the like, as well as amino acid salts (eg, alginate, aspartate, glutamate) and other salt compounds are formed.

In addition, esters of carboxylic acid groups may be formed. Preferred examples of such esters are suitable mono- and diesters, and preferred examples of such esters include alkyl esters (eg, hexadecanyl esters, octadecanyl esters, etc.).

XI. Either two oxyline groups or one oxyline group, and one
Complex Preparation of a Lipid Metabolism Inhibitor and an Organophosphorus Compound Containing an Oxysulfur Group of the Invention: The organophosphorus compounds according to the invention are compounds corresponding to the general formula (XI) and their pharmaceutically acceptable salts, esters Amide and ester salts are:

Embedded image Wherein Z _XI is a phosphorus or sulfur atom, wherein A _XI is hydrogen, hydroxy, halogen, amino and oxo, and
A C _1-26 -alkyl group, a C _1-26 -alkoxy group, a C _1-26 -alkoxy-C _1-26 -alkyl group or a C _3-8 -cycloalkyl- (C _0-9 ) -alkyl group. A linear _2-9 alkylene chain having the same or different substituents selected from the group,
Here, each C _1-26 -alkyl group and each C _1-26 -alkoxy group are branched or linear and saturated or unsaturated with one or more double bonds, and include hydroxy, amino, may be substituted by halogen and oxo groups, and C _3-8 - cycloalkyl - (C _0-9) - C alkyl group _3-8 - Shikurorukiru groups and C _0-9
The alkyl group may contain one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, wherein cycloalkyl The groups and alkyl groups may be substituted with hydroxy, halogen, amino, oxo, branched or straight chain C _1-9 -alkyl and C _2-9 -alkenyl groups, wherein C _1-9 alkyl and The C _2-9 -alkenyl group may be substituted by hydrogen, hydroxy, amino, halogen and oxo groups, and R _XI1 and R _XI2 are the same or different and are hydrogen, substituted and unsubstituted C _1-9
Alkyl, substituted and unsubstituted hydroxy- _1-9 -alkyl, substituted and unsubstituted _C1-9 -alkenyl, substituted and unsubstituted _C1-9 -alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic group, a halogen, selected from the group consisting of OX _Xi1 and OX _XI2, wherein X _Xi1 and X _XI2 is a same or different hydrogen, Substituted and unsubstituted C _1-9 -alkyl, substituted and unsubstituted hydroxy-C _1-9 alkyl, substituted and unsubstituted C _1-9 -alkenyl, substituted and unsubstituted C _1-9 -alkynyl, substituted and unsubstituted aryl , Substituted and unsubstituted acyl,
R _XI3 and R _XI4 are the same or different and are substituted and unsubstituted C _1-26 -alkyl. Hydroxy-C _1-26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C _1-26 -alkenyl, substituted and unsubstituted C _1-26 -alkynyl, _Selected from the group consisting of substituted and unsubstituted cycloalkyl, substituted and unsubstituted bicyclic groups, halogen, _OXxI3 and _OXXI4 , wherein _XXI3 and _XXI4 are the same or different and are hydrogen, substituted and unsubstituted C _1-26 - alkyl, substituted and unsubstituted hydroxy -C _1-26 - alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, location And unsubstituted C _1-26 - alkenyl, substituted and unsubstituted C _1-26 - alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted double ring group, a silyl, a cation particular cycle of organic and inorganic bases Table first , A cation of a Group 2 or 3 metal, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids. Preferred _AXI is a _C3-5 -alkyl chain.

R_XI2 Represents a methyl group, and Z_XI, R_XI1 , R_XI3, R_XI4 Is as defined above
The same, R_XI1 Is substituted by a hydroxy group at a carbon atom adjacent to a hetero atom
And R and_XI2 Represents a hydroxy group, Z_XI, R_XI1 , R _XI3 , R_XI4 Is the same as defined above,_XI1 Is preferably an acyl group, particularly preferably
Or a compound having a formyl, acetyl, propionyl or butyl group.
Preferred. Compounds having at the same time the following structures are preferred:

Embedded image XII. Lipid metabolism inhibitor, 3-isoxazolidinone and hydroxyamic acid
Lipid metabolism inhibitors these compounds A is described in US patent 4 405 357. The compound according to the invention contained in a pharmaceutical composition corresponds to general formula (XII):

Embedded image _Wherein A _XII is hydrogen, substituted and unsubstituted C _1-28 -alkyl, substituted and unsubstituted alkoxy- (C _0-28 ) -alkyl, substituted and unsubstituted cycloalkyl-
(C _0-28 ) -alkyl, substituted and unsubstituted cycloalkoxy- (C _0-28 ) -alkyl, substituted and unsubstituted amino- (C _0-28 ) -alkyl, substituted and unsubstituted thio- ( C _0-28 ) -alkyl groups, and substituted and unsubstituted acyl- (C _0-28 )
-Selected from the group consisting of alkyl groups and halogens, each alkyl group, each alkoxy group and each acyl group may be branched or linear, and each alkyl group, each alkoxy group, each acyl group and each cyclo group. The alkyl group may be saturated or unsaturated with one or more double or triple bonds and one or two carbon atoms, and the cycloalkyl group may be substituted by nitrogen, oxygen or sulfur. R _XII3 may be a hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy-
(C _0-26 ) alkyl groups, substituted and unsubstituted C _3-14 -cycloalkyl- ( _0-26 )-
Alkyl groups, substituted and unsubstituted cycloalkoxy- (C _0-26 ) -alkyl groups, substituted and unsubstituted amino- (C _0-26 ) -alkyl groups, substituted and unsubstituted silyl- (
Selected from the group consisting of C _0-26 ) -alkyl groups and substituted and unsubstituted thio- (C _0-26 ) -alkyl groups, wherein each alkyl group and each alkoxy group may be branched or straight chain; Each alkyl group, each alkoxy group and each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds, and may further comprise one or two cycloalkyl groups. carbon atoms is nitrogen, it can be replaced by oxygen or sulfur atom, or two carbon chains of carbon atoms in a _XII forms Isokisazoridon ring together with R _XII3, and R _XII4 is hydrogen, substituted and unsubstituted alkyl , Substituted and unsubstituted acyl, and substituted and unsubstituted cycloalkyl- (C _0-26 ) -alkyl groups, wherein each alkyl group and each acyl group are branched. Alternatively, each alkyl group, each acyl group and each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds. One or two carbon atoms of the group can be replaced by nitrogen, oxygen or sulfur.

A _XII preferably corresponds to formula (XIIA):

Embedded image Where R_XII1And R_XII2Are the same or different and include hydrogen, hydroxy, ha
Halogen, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkyl groups,
Unsubstituted alkoxy groups, substituted and unsubstituted cycloalkyl- (C_0-26) -Alkyl
Selected from the group consisting of groups, each alkyl group, each alkoxy group is branched or linear
Each alkyl group, each alkoxy group and each cycloalkyl group are saturated or
One or more double or triple bonds and one or more carbons
Is an unsaturated type having one or more atoms, wherein one or two carbon atoms of the cycloalkyl group are
Can be replaced by nitrogen, oxygen or sulfur;_XII5, R_XII6And R_XII7Are the same or different and include hydrogen, hydroxy, ha
Logen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 ) -Alkyl groups, substituted and unsubstituted cycloalkoxy- (C_0-26)-Archi
Group, substituted and unsubstituted alkoxy- (C_0-26) -Alkyl groups, substituted and unsubstituted
Substituted amino groups and substituted and unsubstituted thio- (C_0-26) -Alkyl groups and substituents
And unsubstituted acyl groups, each alkyl group, each alkoxy group and
And each acyl group is branched or linear, each alkyl group, each alkoxy group and
Each cycloalkyl group is saturated or has one or more double or triple bonds
Unsaturated with one or two carbon atoms and a cycloalkyl group
One or two carbon atoms of can be replaced by nitrogen, oxygen or sulfur;_XII5Is R_XII1And can form a ring with_XII3And R_XII7Forms a carbon-nitrogen single bond in such a way that a ring structure is present
it can. The invention also relates to pharmaceutically acceptable salts, esters and ester salts thereof.
Is also included. Preferred R_XII1And R_XII2Are the same or different and are substituted and unsubstituted
Lucil, preferably C₁ -C_Four -Selected from the group consisting of alkyl groups. Preferred R_XII3Is hydrogen, a substituted and unsubstituted alkyl group, preferably C₁ -C_Four 
Alkyl groups, substituted and unsubstituted C₇ -C₁₄-Cycloalkyl, pyranyl and
And a t-butyldimethylsilyl group and

Embedded image _Wherein R _XII8 is preferably a substituted or unsubstituted alkyl group substituted with halogen, a substituted or unsubstituted cycloalkyl- (C _0-26 ) -alkyl, a substituted or unsubstituted amino group, a substituted or unsubstituted alkoxy group , substituted and unsubstituted Fuenokishiki, substituted and unsubstituted alkylthio groups, substituted and unsubstituted preferably unsubstituted or halogen-substituted methyl, methoxy, nitro, amino or CF ₃ - is selected from the group consisting of substituted aromatic cycloalkylthio groups ] Is selected from the group consisting of:

R _XII4 represents hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group and

Embedded image[Where Z is_XII Is hydrogen, C_1-4 -Selected from the group consisting of alkyl groups and phenyl groups.
Selected, Y_XII Is hydrogen, halogen, C_1-4 -Alkyl, nitro, methoxy
, Methylenedioxy group, and n is 0 or 1.]. R_XII7Is selected from the group consisting of hydrogen and halogen;_XII3And R _XII7 Forms a carbon-oxygen single bond in such a manner that a ring structure is present.

[0076] These compounds are particularly preferred if R _XII1 and R _XII2 are independently selected from methyl and ethyl, R _XII4 is

Embedded image And R _XII5 and R _XII6 are independently selected from the group consisting of hydrogen, chlorine, bromine and methoxy groups.

In particular, these compounds have R _XII4

Embedded image [Z is selected from the group consisting of 2-chloro, 2-bromo-, 2-fluoro-
And Y are selected from the group consisting of 4-chloro, -4-bromo-, 4-fluoro, 5-fluoro and 4,5-methylenedioxy groups, and n is 0 or 1.
Is preferred. These compounds, R _XII1 and R _XII2 are methyl groups, R _XII3 and R _{XI I7} carbon to form a one, or cyclic hydrogen - where oxygen bond is particularly preferred.

Preferred examples of these compounds include 3-chloro-N- (2-chlorophenyl) methyl-N-hydroxy-2,2-dimethylpyropenamide, N- (2-chlorophenyl9methyl-N-hydroxy-
2,2-dimethylpropanamide, 3-chloro-N-hydroxy group-N-funyl-2,2-dimethylpropanamide, N- (2-bromophenyl) -methyl-3
-Chloro-N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N
-Hydroxy-2,2-dimethyl-N- (2-methylphenyl) methylpropanamide, 3-chloro-N-hydroxy-2,2-N-trimethylpyropenamide, 3-chloro-N-hydroxy-2,2 -Dimethyl-N- (phenylmethyl)-
Propanamide, 3-chloro-N- (2,4-dichlorophenylmethyl) -N-
Hydroxy-2,2-methylpropanamide, 3-chloro-N- (2-chlorophenyl) methyl-N-methoxy-2,2-dimethylpropanamide, 3,3-dichloro- (2-chlorophenyl) methyl-N- Hydroxy-2,2-dimethylpropanamide, 3-chloro-N- (2-fluorophenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, 3-bromo-N- (2-chlorophenylmethyl- N-hydroxy-2,2-dimethylpropanamide, N-benzoyloxy-3-chloro-N- (2-chlorofunyl) methyl-2,2-dimethylpropanamide, N-acetoxy-3-chloro-N- (2 -Chlorophenyl) methyl-2,2-dimethyllopanamide, N- (chloroacetoxy) -3-chloro-N
-(2-chlorophenyl) methyl-2,2-dimethylpropanamide, 2- (2
-Chlorophenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 4,
4-dimethyl-2-phenyl-3-isoxazolidinone, 2- (2-bromophenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 4,4-dimethyl-2- (2-methyl- Phenyl) methyl-3-isoxazolidinone, 2,4-trimethyl-3-isoxazolidinone, 4,4-dimethyl-2-
Phenylmethyl-3-isoxazolidinone, 4,4-dimethyl-2-phenylmethyl-3-isoxazolidinone, 2- (2,4-dichlorophenyl) methyl-4
, 4-Dimethyl-3-isoxazolidinone, 5-chloro-2- (2-chlorophenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 2- (2-chlorophenyl) methyl-5-methoxy -4,4-dimethyl-3-isoxazolidinone, 2- (2-fluorophenyl) methyl-4,4-dimethyl-3-isoxazolidinone, N-[(2-chlorophenyl) methyl] -N , 3-dihydroxy-2,
2-dimethylpropanamide, 3-chloro-N-[(2-chlorophenyl) methyl] -2,2-dimethyl-N- (methylamino-carbonyloxy) propanamide, 3-chloro-N-[(2-chlorophenyl ) Methyl] -N-[(2-tetrahydropyranyl) oxy-2,2-dimethyl-propanamide, 3-chloro-
N-[(2-chlorophenyl) methyl-2,2-dimethyl-N- [dimethyl (1
, 1-Dimethyl-ethyl) silyloxypropanamide, 3-acetoxy-N-
[(2-chlorophenoxy) -methyl] -N-hydroxy-2,2-dimethylpropanamide, 2-[(2-chloro-4-fluorophenyl) methyl
-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chloro-5-fluorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2- [
(2,4,5-trichlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(2-chloro-6-fluorophenyl) methyl] -4,4
-Dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl]
-5-ethoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5-phenylamino-3-isoxazolidinone, 2-[( 2-chlorophenyl) methyl] -5-hydroxy-4,
4-dimethyl-3-isoxazolidinone, 3-chloro-N-[(2-chlorophenyl) methyl] -2,2-dimethyl-N-[(phenylamino) carbonyloxy] -propanamide, 3-chloro-N -[(2-chlorophenyl) methyl]-
2,2-dimethyl-N-([(2-chlorophenyl) methyl] -2,2-dimethyl-N-phenoxycarbonyl-oxy) propanamide, 3-chloro-N- [
(2-chlorophenyl) methyl] -N-ethoxy-carbonyloxy-2,2-
Dimethylpropanamide, N-benzoyloxy-3,3-dichloro-N-[(
2-chlorophenyl) methyl] -2,2-dimethylpropanamide, N- (2-
Bromophenyl) methyl-3,3-dichloro-N-hydroxy-2,2-dimethyl) propanamide, 3-chloro-N-[(2-chlorophenyl) methyl] -N
-(4-Nitrobenzoyloxy) -2,2-dimethylpropanamide, 3-chloro-N- [2-chlorophenylmethyl)]-2,2-dimethyl-one-[(2-
Methylphenyl) carbonyloxy] propanamide, 3-chloro-N-dichloroacetooxy-N-[(2-chlorophenylomethyl [-2,2-dimethylpropanamide, 3-chloro-N- [2-chlorophenyl) methyl ] -2,2-dimethyl-N-[(4-methylphenyl) sulfonyloxy] propanamide, 3
-Chloro-N- [2-chloro-phenyl) methyl] -2,2-dimethyl-N- [
(1,1-dimethylethyl) carbonyl-oxy] propanamide, 3-chloro-N- [2-chlorophenyl) methyl] -2,2-dimethyl-N- (ethylthiocarbanoyloxy) propanamide, 3-chloro -N-[(2,2,2-trichloroethoxy) carbonyloxy) -N-[(2-chlorophenyl) methyl]
-2,3-dimethylpropanamide, 3-chloro-N-[(2-chlorophenyl) aminocarbonyloxy-N-[(2-chlorophenyl) methyl] -2,2-
Dimethylpropanamide, 3-chloro-N-[(4-chlorophenyl) aminocarbonyloxy-N-[(2-chlorophenyl) methyl] -2,2-dimethyl-
Propanamide, 3-chloro-N- [2-chlorophenyl) methyl] -2,2-
Dimethyl-N- (phenylmethoxy) -propanamide, 3-chloro-N-[(
2,4-dichlorophenoxy) acetoxy) -N-[(2-chlorophenyl) methyl] -2,2-dimethyl-propanamide, 3-chloro-N- [2-chlorophenyl) methyl] -2,2- Dimethyl-N- [3-trifluoromethyl) zenzoyloxypropanamide, 3-chloro-N- [2-chlorophenyl) methyl]
-2,2-dimethyl-N-[(4-methylphenyl) aminocarbonyl-oxy) -propanamide, 3-chloro-N- [2-chlorophenyl) methyl] -N-
[(3,4-chlorophenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 3-chloro-N- (3-chloro-2,2-dimethyl-1-oxo-propoxy) -N-[(2 -Chlorophenyl) methyl-]-2,2-dimethylpyropenamide, 3-bro-N-[(2-bromophenyl) -methyl] -N-hydroxy-2,2-dimethylpyropenamide, 3-chloro-N -[(2-chlorophenyl) methyl] -N-[(2-fluorophenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 3-chloro-N-[(2-chlorophenyl) methyl] -N- [(4-methoxyphenyl) aminocarbonyloxy] -2
, 2-Dimethylpropanamide, 3-chloro-N-[(2-chlorophenyl) methyl] -N-[(3-trifluoromethylphenyl) aminocarbonyloxy]
-2,2-dimethylpropanamide, 3-bromo-N-[(2-chlorophenyl) methyl] -N- (methylaminocarbonyloxy) -2,2-dimethyl-propanamide, 3-bromo-N-[( 2-chloroacetoxy) -N-[(2-chlorophenyl) methyl] -2,2-dimethylpropanamide, 3-chloro-N- [
2,5-dichloro- (formylamino) -benzoyl] oxy-N-[(2-chlorophenyl) methyl] -2,2-dimethyllopanamide, 3-bromo-N- [
(2-Bromophenyl) methyl] -N- (methylcarbonyloxy) -2,2-
Dimethylpropanamide, 3-bromo-N-[(2-bromophenyl) methyl]
-N-[(2-chlorophenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 2-[(2-chlorophenyl) methyl] -N-hydroxy-2
, 2-Dimethyl-3-methylthio-propanamide, 3-phenylcarbyloxy) -N-[(2-chlorophenyl) methyl] -N-hydroxy-2,2dimethylpropanamide, 2-[(4-chlorophenyl ) Methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(3,4-dichlorophenyl) methyl] -4
, 4-Dimethyl-3-isoxazolidinone, 2-[(chlorophenyl) methyl]
-4,4-dimethyl-3-isoxazolidinone-5-yl acetate, 2-[(
Chlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone-5
Ylbenzoate, 2-[(chlorophenyl) methyl] -4,4-dimethyl-3
-Isoxazolidinone-5-yldichloroacetate, 2-[(chlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone-5-ylphenylcarbamate, 2-[(2-chloro-4- Cyanophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone-2-[(2-chloro-5-methoxyphenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2- [(Chloro-4
-Methoxyphenyl) -methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(2,4-difluorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(4-bromo-2-chlorophenyl) methyl] -4,
4-dimethyl-3-isoxazolidinone, 2-[(2-bromo-4-fluorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(6-
Chloro-1,3-benzodioxol-5-yl) methyl] -4,4-dimethyl-
3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5-phenoxy-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4- Dimethyl-5- (1-methylethoxy) -3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5-
(Phenylmethoxy) -3-isoxazolidinone, 2-[(2-bromophenyl) methyl] -5-chloro-4,4-dimethyl-3-isoxazolidinone, 2- [
(2,5-dichlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(2-dichlorophenyl) methyl] -4,4-dimethyl-5-propoxy-3- Isoxazolidinone, 2-[(2-chlorophenyl) methyl]-
4,4-dimethyl-5- (2-propenyloxy) -3-isoxazolidinone,
2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5- (2-propynyloxy) -3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl- 5- (2-methoxyethoxy) -3-isoxazolidinone, 2-[(4-fluoro-2-iodophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(2- Chlorophenyl) methyl] -5-cyclopentoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5- (4-nitrophenoxy) -3
-Isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5-chloropropyl-methoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-
Bromophenyl- (methyl)]-4,4-dimethyl-5- (2-pyropinoxy)
-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5- (3
-Butynoxy) -4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5- (2-butynoxy) -4,4-dimethyl-3-isoxazolidinone, -[(2-chlorophenyl) methyl] -5- (3-butenoxy) -4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5-pentoxy-4,4- Dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5-hexoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5- (1
-Methylpropoxy) -4,4-dimethyl-3-isoxazolidinone, 2-[(
2-chlorophenyl) methyl] -5- (3-methyl-3-butenoxy) -4,4
-Dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl]
-5-4,4-dimethyl-3-isoxazolidinone and 2-[(2-chloro-phenyl) methyl] -4,4-dimethyl-3-isoxazolidinone.

XIII. Complex preparation of lipid metabolism inhibitors and thiadiazoles The thiadiazole derivatives used according to the invention correspond to the following general formula (XIII):

Embedded image Wherein, n is an integer from 0 to 4, and _{R XIII1, R XIII2, R XIII3} , X XIII4, X XIII5 and X _III6 are identical or different, hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted Selected from the group consisting of substituted alkoxy groups, substituted and unsubstituted acyl groups, substituted and unsubstituted cycloalkyl- ( _C0-26 ) alkyl groups, substituted and unsubstituted cycloalkyl- ( _C0-26 ) -alkoxy groups, and halogens. Wherein each alkyl group, each alkoxy group and each acyl group are branched or linear, and each alkyl group, each acyl group, each alkoxy group and each _cyclo- (C _0-26 ) -alkyl group are saturated or monocyclic. It is unsaturated with one or more double or triple bonds, and one or two carbon atoms of the cycloalkyl group can be replaced by nitrogen, oxygen or sulfur. Preferred R _XIII1 is COOC ₂ H ₅ . Further, in these compounds, R _{XIII 2} to R _XIII6 are preferably selected from the group consisting of hydrogen and halogen, especially chlorine, and n is preferably 1 or 2.

XIV. The compound according to the invention contained in a complex preparation pharmaceutical composition of a lipid metabolism inhibitor and a nitrogen-oxygen heterocycle corresponds to the general formula (XIV):

Embedded image Where Y_XIV Is C_1-3 -Alkylene group, wherein the alkylene group is a substituent R_{XI V1} And R_XIV2 And optionally R_XIV3 To R_XIV6 Replace with
Where R_XIV1To R_XIV8Are the same or different and include hydrogen, hydroxy, ha
Logen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 ) -Alkyl groups, substituted and unsubstituted cycloalkyl- (C_0-26) -Alkyl
Group, substituted and unsubstituted alkoxy- (C_0-26) -Alkyl groups, substituted and unsubstituted
Amino groups and substituted and unsubstituted thio- (C_0-26) -Alkyl groups, substituted and unsubstituted
Substituted sulfonyl- (C_0-26) -Alkyl groups, substituted and unsubstituted sulfinyl- (
C_0-26-) Selected from the group consisting of alkyl groups and substituted and unsubstituted acyl groups
, Each alkyl group, each alkoxy group and each acyl group are branched or linear,
Each alkyl group, each alkoxy group, each cycloalkyl group may be saturated or one or more
May be an unsaturated type having two or more double bonds or triple bonds, and
Replace one or more carbon atoms of a cycloalkyl group with nitrogen, oxygen or sulfur
Can and R_XIV13 And R_XIV14 Is R_XIV1To R_XIV8Is the same as or
To form an oxo group, and Z_XIV Represents the following organic phosphorus groups:

Embedded image In the formula, R _XIV9 and R _XIV10 are the same or different, and each represents a hydrogen, a substituted or unsubstituted (C _1-26 ) -alkyl group, a substituted or unsubstituted hydroxy- (C _1-26 ) -alkyl group, _Selected from the group consisting of substituted cycloalkyl- (C _0-26 ) -alkyl groups, substituted and unsubstituted acyl, halogen, OX _XIV9 or OX _XIV10 , wherein each alkyl group, each alkoxy group and each acyl group is branched or linear. And each alkyl group, each alkoxy group, and each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds. One or two carbon atoms may be replaced by nitrogen, oxygen or sulfur, wherein a X _XIV9 or X _XIV10 the same or different, hydrogen, substituted and unsubstituted (C _1-26) - alkyl group, location And unsubstituted hydroxy - (C _1-26) - alkyl group substituted, unsubstituted cycloalkyl - (C _0-26) - alkyl groups, substituted and unsubstituted acyl, silyl, a cation especially the Periodic Table of the organic and inorganic bases Selected from the group consisting of cations of Group 1, 2 or 3 metals, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids, wherein each alkyl group, each alkoxy group, and each acyl group is a branched or linear type. Wherein each alkyl group, each alkoxy group, and each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds, and one of the cycloalkyl groups Or two or more carbon atoms can be replaced by nitrogen, oxygen or sulfur, or Z _XIV represents the following amino group:

Embedded image _Wherein R _XIV11 and R _XIV12 are the same or different and are hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 ) -alkyl groups, substituted and unsubstituted cycloalkoxy- ( Selected from the group consisting of C _0-26 ) -alkyl groups, substituted and unsubstituted alkoxy- (C _0-26 ) -alkyl groups, substituted and unsubstituted acyl groups, wherein each alkyl group, each alkoxy group and each acyl group is branched. Or a linear type, each alkyl group, each alkoxy group, each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds, and a cycloalkyl one or more carbon atoms of the group may be replaced by nitrogen, oxygen or sulfur, B _XIV is substituted and unsubstituted C _1-26 - is selected from the group consisting of-out alkenylene, wherein By one carbon atom one oxygen atom, and either one carbon atom is replaced by one sulfur atom, or two carbon atoms may be replaced with S- heterocycle,
Each alkylene group is branched or linear and saturated or unsaturated with one or more double or triple bonds and can be substituted with one or more hydroxy, halogen or oxo groups. R _XIV13 and R _XIV14 together form an oxo group at the α-position with respect to the nitrogen atom.
Preferred Y _XIV represents a methylene group, particularly preferably substituted by two methyl groups.

Furthermore, these compounds are advantageous when B _XIV represents an ether group (XIVA): —A _XIV1 —O—A _XIV2 — (XIVA) where A _XIV1 is deleted or (C _1-9 ) -alkylene group and A _XIV2 is deleted or selected from the group consisting of (C _1-9 ) -alkylene group, sulfur atom and (C _3-8 ) -heterocycle; The heterocycle contains at least one sulfur atom. Particularly preferred A _XIV1 and A _XIV2 each represent methylene.

These compounds are also advantageous when B _XIV represents a keto group (XIVB):

Embedded image _Wherein A _XIV3 and A _XIV4 may be deleted in one or both of the same or different species and are selected from the group consisting of (C _1-9 ) -alkylene groups;
Here, all (C _1-9 ) -alkylene groups are branched or straight-chain, contain one or more double bonds, or may be substituted by hydroxy groups or halogen groups. Particularly preferred is the case where A _XIV3 is deleted and A _IV4 is a methylene or ethylene group. Further, a preferred _BXIV is a 2-hydroxypropylene group.

R _XIV9 and R _XIV10 preferably represent OX _XIV9 and OX _XIV10 , wherein X _XIV9 and X _XIV10 are the same or different and are metals of the first, second or third main group of the periodic table Particularly selected from the group consisting of sodium and potassium, and methyl, ethyl.

The following are particular features of the above definitions and suitable examples thereof: “Acyl” is derived from an organic carboxylic acid, carbonic acid, carbamic acid or a thioacid or imidic acid corresponding to an individually present acid. Or a substituent derived from an acid such as an organic sulfonic acid, which in each case contains an aliphatic, aromatic and / or heterocyclic group and a carbamoyl or carbamidoyl group in the molecule.

Preferred examples of these acyl groups are as follows: An acyl group derived from an aliphatic acid is defined as an aliphatic acyl group and includes: alkanoyl (eg, formyl, acetyl, propionyl, butyl, isobutyl, valeryl) Alkenoyl (eg, acryloyl, methacryloyl, crotonoyl, etc.); alkylthioalkanoyl (eg, methylthioacetyl, ethylthioacetyl, etc.); alkanesulfonyl (eg, mesyl, ethanesulfonyl, propanesulfonyl, etc.); alkoxycarbonyl (eg, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.); alkylcarbamoyl (eg, methylcarbamo) (N-alkyl) -thiocarbamoyl (eg, (N-methyl) -thiocarbamoyl, etc.); alkylcabamidoyl (eg, methylcarbamidoyl, etc.); oxalo; Propoxalyl, etc.).

In the above examples of aliphatic acyl groups, aliphatic hydrocarbon moieties, especially alkyl and alkane groups, are amino, halogen (eg, fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, carboxy, alkoxy (eg, methoxy, One or more suitable substituents such as ethoxy, propoxy, etc., alkoxycarbonyl, acylamino (eg, benzyloxycarbonylamino, etc.), acyloxy (eg, acetooxy, benzoyloxy, etc.) can be optionally included. Examples of preferred aliphatic acyl groups having such substituents are alkanoyl substituted with amino, carboxy, amino and carboxy, halogen, acylamino or others.

When the aryl group comprises phenyl, tolyl, xylyl, naphthyl and the like, acyl groups derived from acids having a substituted and unsubstituted aryl group are referred to as aromatic acyl groups and suitable examples are as follows: aroyl (Eg, benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.); aralcanoyl (eg, phenylacetyl, etc.); aralkenoyl (eg, cinnamoyl, etc.); aryloxyalkanoyl (eg, phenoxyacetyl, etc.); Arylaminoalkanoyl (eg, N-phenylglycyl); alensulfonyl (eg, benzenesulfonyl, tosyl bzw. toluenesulfonyl, naphthalenesulfonyl, etc.); aryloxycarbonyl (eg, phenyl) Oxycarbonyl, naphthyloxycarbonyl, etc.); aralkoxycarbonyl carboxylic yl (e.g. benzyloxycarbonyl group); arylcarbamoyl (e.g. phenylene carbamoyl, naphthyridone carbamoyl, etc.); aryl glyoxyloyl yl (e.g. phenylalanine glyoxyloyl yl, etc.).

In the examples of the aromatic acyl group in the present invention, an aromatic hydrocarbon moiety (particularly an aryl group) and / or an aliphatic hydrocarbon moiety (particularly an alkane group) is, for example, a suitable substituent for an alkyl group and an alkane group. It may optionally contain one or more substituents as already mentioned. Examples of particularly preferred aromatic acyl groups having specific substituents include aroyl substituted with halogen and hydroxy, or aroyl substituted with halogen and acyloxy, and aralcanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino. And arylthiocarbamoyl (eg, phenylthiocarbamoyl); and arylcarbamimidyl (eg, phenylcarbamimidyl).

A heterocyclic acyl group is understood to be an acyl group derived from an acid having a heterocyclic group, examples of which include: a heterocyclic carbonyl; It is an aromatic or aliphatic 5- to 6-membered heterocycle and has at least one heteroatom from a nitrogen, oxygen and sulfur (eg, thiophenyl, furoyl, pyrrolecarbonyl, nicotinoyl, etc.) group. Heterocyclic alkanoyl; wherein the heterocyclic group is a 5- to 6-membered ring having nitrogen, oxygen and sulfur (eg, thiophenyl-acetyl, furylacetyl, imidazoylpropionyl, tetrazoylacetyl, 2- (2-amino-4-thiazoyl) ) -2-methoxyiminoacetyl, etc.).

In the above examples of heterocyclic acyl groups, the heterocyclic ring and / or the aliphatic hydrocarbon moiety thereof may be substituted with one or more than It may optionally include suitable substituents.

The term “alkyl”, unless stated otherwise, is a branched or straight-chain alkyl group of less than 9 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and the like. . The term "alkenyl", unless otherwise specified, includes carbon atoms such as, for example, vinyl, propenyl (eg, 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexyl, and the like. Less than 9 branched or straight-chain alkenyl groups. The term "alkynyl", unless otherwise specified, is a branched or straight-chain alkynyl group having less than 9 carbon atoms. Cycloalkyl, C ₇ C ₃ to an optionally substituted - cycloalkyl.
Alkyl, alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, fluorine, chlorine, bromine, etc.), nitro, and the like are particularly suitable as possible substituents.

Aryl is an aromatic hydrocarbon group such as phenyl and naphthyl, and alkoxy (
One or more suitable substituents, such as methoxy, ethoxy, etc.), halogens (eg, fluorine, chlorine, bromine, etc.), nitro, etc., can optionally be included.

The term “aralkyl” includes benzyl, phenethyl, benzhydryl, trityl, and other mono-, di-, and triphenylalkyl, where the aromatic moiety is one or more suitable substituted Groups such as alkoxy (eg methoxy,
Ethoxy, etc.), halogens (eg, fluorine, chlorine, bromine, etc.), nitro, and the like.

The term “alkylene” includes 9 carbon atoms of the formula — (C _n H _2n ) —
Less than branched or linear alkylene groups, where n is methylene, ethylene, trimethylene, methylethylene, tettamethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, i It is an integer in the case of 1 to 9 carbon atoms such as soropyrethylene, hexamethylene and the like. Preferred alkylene groups include groups with less than 4 carbon atoms and 3 carbon atoms, with trimethylene being particularly preferred.

The term “alkenylene” includes straight-chain or branched alkenylene groups having less than 9 carbon atoms represented by the formula: — (C _n H _2n-2 ) —, wherein n is from 2 to An integer of 9, for example, vinylene, propylene (eg, 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene, 2-ethylpropenylene, pentenylene, hexenylene and other cases It is. This alkenylene group is particularly preferably less than 5 carbon atoms, especially 3 carbon atoms, for example 1-propenylene.

The term “hydroxyalkylene” includes straight or branched alkylene groups having less than 9 carbon atoms, wherein one or more selected carbon atoms are replaced by a hydroxy group. These groups represented by the following _{formula: - (C n H 2n-} z) (OH) z - wherein, n is an integer from 1 to 9, z is a z ≦ n an integer. Among suitable examples of such preferred hydroxyalkylene groups are 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-hydroxypentamethylene), hydroxyhexamethylene (eg, 2-hydroxyhexamethylene) and the like. You. Particularly preferred are lower hydroxyalkylenes having less than 4 carbon atoms, particularly those having 3 carbon atoms such as 2-hydroxytrimethylene.

The term “alkyleneamine” includes straight-chain or branched alkylenamine groups having less than 9 carbon atoms represented by the formula: — (C _n H _2n ) —N— ( C _m H _2m )-wherein n and m are the same or different and are integers from 0 to 9, and 1 ≦ n + m
≦ 9, methyleneamine, ethyleneamine, dimethyleneamine, trimethyleneamine, methyleneethyleneamine, tetramethyleneamine, 1-methyltrimethyleneamine, 2-ethylethyleneamine, ethylenemethyleneamine, pentamethyleneamine, 2- Methyltetramethyleneamine, isopropylethyleneamine, heisamethyleneamine and others. Preferred alkyleneamine groups are
Contains two terminal carbon atoms. Dimethyleneamine is particularly preferred. This hydrogen atom may be substituted, for example, by a halogen group.

The term “alkyleneimine” includes straight or branched alkylenimines having less than 9 carbon atoms represented by the formula: — (C _n H _2n-1 ) = N— (C _m H _2m) - or _{- (C n H 2n) -N} = (C m H 2m-1) - , wherein, n and m are integers from the same or different 0 9, 1 ≦ n + m ≦
9, methyleneimine, ethyleneimine, dimethyleneimine, trimethyleneimine, methyleneethyleneimine, tetramethyleneimine, 1-methyltrimethyleneimine, 2-ethylethyleneimine, ethylenemethyleneimine, pentamethyleneimine, 2-methyl Tetramethylene imine, isopropyl ethylene imine,
Corresponds to hexamethylene imine and other cases. Preferred alkylene imine groups contain two terminal carbon atoms. Dimethylene imine is particularly preferred. This hydrogen atom may be substituted, for example, by a halogen group.

The term “alkenyleneamine” includes straight-chain or branched alkenyleneamines having less than 9 carbon atoms represented by the formula: — (C _n H _2n-2 ) —N— (C _{m H 2m-2) -; -} (C 0 H 2o) -N- (C n H 2n -2) ;-( C n H 2n-2) -N- (C 0 H 2o) - wherein, n and m is the same or a different integer from 0 to 9, m + n ≦ 9, _o is a number from 0 to 7, _o + n ≦ 9, for example, vinyleneamine, methylenevinyleneamine, divinyleneamine, propene Nyleneamine (eg, 1-propenyleneamine, 2-propenyleneamine), methylenepropenyleneamine,
This corresponds to 1-methylpropenyleneamine, 2-methylpropenyleneamine, butenyleneamine, 2-ethylenepropenyleneamine, pentenyleneamine, hexenyleneamine, vinylmethyleneamine and other cases. This hydrogen atom may be substituted, for example, by a halogen group.

The term “alkenylene imine” includes straight-chain or branched alkenylene amines having less than 9 carbon atoms represented by the formula:-(C _n H _2n-3 ) = N- (C _m H _{2m-2) - ;-( C o} H 2o-1) = N- (C m H 2m-2) -;
_{- (C n H 2n-3} ) = N- (C o H 2o) -;
_{- (C n H 2n-2} ) = N- (C m H 2m-3) - ;-( C o H 2o) = N- (C m H 2m-3) -; - (C n H 2n-2 ) = N- (C _o H _2o-1 ) _-wherein n and m are the same or different and are integers from 2 to 9, m + n ≦ 9, _o is a number from 0 to 7, and _o + n ≦ 9. For example, vinylene imine, methylene vinylene imine, ethylene vinylene imine,
Propenyleneimine (eg, 1-propenyleneimine), methylenepropenyleneimine, 1-methylpropenyleneimine, 2-methylpropenyleneimine, butenyleneimine, 2-ethylenepropenyleneimine, pentenenyleneimine , Hexenylene imine, vinylene methylene imine and the like. This hydrogen atom may be substituted, for example, by a halogen group.

“Hydroxyalkyleneamine” is a straight or branched alkylene group having less than 9 carbon atoms, wherein at least one selected carbon atom is replaced by a hydroxy group; these groups are represented by the formula: _{- (C n H 2n-z} ) (OH) z -N- (C m H 2m-y) (OH) _y in formula, n and m are integers from 0 in the same or different 9, 1 ≦ n + m ≦ 9 , And z and y are the same or different and are integers, 0 ≦ z ≦ n and 0 ≦ y ≦ m and y +
z ≧ 1. Preferred examples of this type of hydroxyalkyleneamine include hydroxy group methyleneamine, hydroxyethyleneamine (eg, 1-hydroxyethyleneamine and 2-hydroxyethyleneamine), hydroxytrimethyleneamine (eg, 1-hydroxytrimethylene, 2 -Hydroxytrimethyleneamine and 3-hydroxytrimethyleneamine), hydroxytetramethyleneamine (e.g., 2-
Hydroxytetramethyleneamine), 2-hydroxy-2-methyltrimethyleneamine, hydroxypentamethyleneamine (e.g., 2-hydroxypentamethyleneamine), hydroxyhexamethyleneamine (e.g., 2-hydroxyhexamethyleneamine), methylenehydroxymethyleneamine, Methylene hydroxyethylene amine and others are included. Particularly preferred are lower hydroxyalkyleneamines having two carbon atoms and one nitrogen atom, wherein both carbon atoms are terminal. This hydrogen atom may be substituted, for example, by a halogen group.

[0102] Examples of "hydroxyalkylenimines" include straight or branched alkylene groups with less than 9 carbon atoms, wherein at least one selected carbon atom is replaced with a hydroxy group. These groups represented by the following _{formula: - (C n H 2n-} z-1) (OH) z = N- (C m H 2m-y) (OH) y; - (C n H 2n-z _{-1) (OH) z -N =} (C m H 2m-y) (OH) _y in formula, n and m are integers from 0 in the same or different 9, 1 ≦ n + m ≦ 9, and z and y The same or different integers, 0 ≦ z ≦ n−1 and 0 ≦ y ≦ m−1 and y + z ≧ 1. Among preferred examples of this type of hydroxyalkylenimine are hydroxymethyleneimine, hydroxyethyleneimine (e.g. 1-hydroxyethyleneimine and 2-hydroxyethyleneimine), hydroxytrimethyleneimine (e.g.
-Hydroxytrimethylene, 2-hydroxytrimethyleneimine and 3-hydroxytrimethyleneimine), hydroxytetramethyleneimine (e.g., 2-hydroxytetramethyleneimine), 2-hydroxy-2-methyltrimethyleneimine, hydroxypentamethyleneimine ( For example, 2-hydroxypentamethyleneimine), hydroxyhexamethyleneimine (eg, 2-hydroxyhexamethyleneimine), methylenehydroxymethyleneimine, methylenehydroxyethyleneimine and the like are included. Particularly preferred are lower hydroxyalkylenimines having two carbon atoms and one nitrogen atom, wherein both carbon atoms are terminal. This hydrogen atom may be substituted, for example, by a halogen group.

The 5- and 6-membered ring compounds represented by B _IV are of the aromatic or aliphatic type and can be substituted with alkyl groups having less than 7 carbon atoms and a hydroxy group.

The 5- and 6-membered heterocyclic compounds represented by R _VIII1 and R _VIII2 and R _X1 and R _X2 , which contain one or more nitrogen, oxygen or sulfur other than carbon atoms as ring members, are saturated. Or it may be unsaturated.

An “alkoxy group” is a straight or branched alkoxy group having less than 26 carbon atoms, such as methoxy and ethoxy, unless otherwise specified. These can be substituted, for example, with hydroxy, amino, halogen, oxo groups and with alkoxy groups such as methoxy-, ethoxy groups and the like.

An “alkoxy- (C _0-26 ) -alkyl group” is an alkoxy group, which may be bonded to the basic structure on the alkyl group.

A “cycloalkyl- (C _0-26 ) -alkyl group” is a cyclic compound having 3 to 8 carbon atoms and is bonded to a basic structure directly or on an alkylene group unless otherwise specified. This alkylene group may be linear or branched having a double bond. Possible substituents of a cycloalkyl group are, in particular, alkoxy groups, alkyl groups, hydroxy groups, halogen groups, amino groups, oxo groups. When comprising a double bond in the respective number, the cycloalkyl group of the aromatic That aryl (C _0-26) - alkyl group (e.g. phenyl, pyridyl, naphthyl, etc.) may also. In particular, the aromatic cyclic compound may further comprise nitro groups and substituents such as CF ₃ and phenyl groups.

A “cycloalkoxy- (C _0-26 ) -alkyl group” is a cyclic compound having 3 to 8 carbon atoms, which is directly bonded to the basic structure by an oxygen atom or bonded to the basic structure on an alkylene group. ing. The alkylene group is a saturated type or an unsaturated type having a double bond, and may be a linear or branched type. Possible substituents of a cycloalkyl group are, in particular, groups (also alkylenedioxy groups such as methylenedioxy), alkyl groups, hydroxy groups, halogen groups, amino groups, oxo groups. With each number of double bonds, the cycloalkyl group can be polycyclic and aromatic (eg, phenoxy, pyridoxy, naphthoxy, etc.). In particular, the aromatic cyclic compound may further comprise nitro groups and substituents such as CF ₃ and phenyl groups.

[0109] For example, "amino group" in the above definition alkyl group or a cycloalkyl - (C _{0- 26)} - may be substituted with an alkyl group.

An “amino- (C _0-26 ) -alkyl group” is an amino group, which may be bonded to the basic structure on the alkyl group.

A “silyl group” may be substituted by an alkyl group or a cycloalkyl- (C 0 _-26 ) -alkyl group as defined above.

A “thio- (C _0-26 ) -alkyl group” may be attached to a basic structure on an alkyl group. The alkyl and silyl groups are as defined above.

The “thio- (C _0-26 ) -alkyl group” may be substituted by an alkyl group or a cycloalkyl- (C _0-26 ) -alkyl group as defined above. The (C _0-26 ) -alkyl group is a linear or branched alkylene group, for example, methylene, ethylene,
Propylene, isopropylene, butylene, isobutylene, tert.-butylene, pentylene, hexylene and the like. These may contain double or triple bonds, for example hydroxy, amino, halogen (eg fluorine, bromine, chlorine),
It may be substituted with an oxo group and an alkoxy group such as a methoxy and ethoxy group.

The radicals X _I3 to X _VI13 , and X _I4 to X _VI14 and R _VII15 , R _IX11 , X _XI3
And X _XI4 X _II1 and X _II2 are selected in such a way that an ester is formed on the phosphono or sulfonyl group. Illustrative of the preferred esters of the compounds used according to the invention are the mono- and diesters, and in preferred examples of such esters are the alkyl esters (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl) Aralkyl esters (benzyl esters, phenethyl esters, benzohydryl esters, trityl esters, etc.); aryl esters (eg, phenyl esters, toluyl esters, naphthyl esters, etc.); aroyl alkyl esters (eg, phenacyl esters). And silyl esters (eg, trialkylsilyl ester, dialkyldihalogensilyl, alkyltrihalogensilyl, dialkylarylhalogensilyl, tria Job halogenated silyl, dialkyl aralkyl halogen silyl, dialkoxy halogen silyl ium, trialkoxy halogen silyl, etc.); others.

For the above esters, the alkane and / or allene moieties can optionally include at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or other.

[0116] X from X _I3 from X _VII3 and X _{I4 VII4} and X _XI3 and X _XI4, X _II1 and X _II2 are periodic table 1, second or third metals, ammonium, substituted ammonium or, It is preferably an ethylene compound or an ammonium compound derived from an amino acid. In other words, organic or inorganic bases (e.g., sodium, potassium, calcium, aluminum, ammonium, magnesium, triethylamine, ethanolamine, dicyclohexylamine, ethylenediaminethio, N, N'-dibenzylethylene) Salt salts of ammonium phosphonic acid derivatives having an amine salt or the like and an amino acid (eg, arginine salt, aspartate, glutamate, etc.) and the like.

The compounds according to the invention according to the formulas (I) to (XIV) may, for example in the case of a double bond or a group comprising a chiral group R or A or B or Y or Z or X, give rise to stereoisomers Make it possible. The use of the compounds according to the invention includes all stereoisomers, both pure and in the form of mixtures thereof.

Examples of pharmaceutically acceptable aminohydrophosphonic acid derivative salts include ammonium salts of inorganic or organic acids such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid and the like. And salts which form the compounds according to the invention in their protonated form.

[0119] X ₃ (X _I3 from X _V3) and X ₄ (from X _I4 X _V4) and X _I11 and X _I1 properly at preferably salts formed by selecting _2, for example, sodium, potassium, calcium, Ammonium, ethanolamine, triethylamine, dicyclohexylamine salts, and amino acid salts such as alginate, aspartate, and glutamate.

[0120] The lipid metabolism inhibitors according to the present invention comprise one or more lipid metabolism inhibitors. Inhibitors can be used as inhibitors to control fat intake and regulate fat synthesis. Examples of these inhibitors include anion exchangers, preferably cholestyramine and colestipol, β-sitosterol, nicotinic acid and their derivatives such as nicotinyl alcohol, clofibrate and their derivatives such as clofibric acid ethyl ester and Analogues of e.g. bezafibrate,
Includes fenofibrate and gemfibrozil and probucol.

Examples of inhibitors that regulate fat synthesis include HMG-CoA synthetase inhibitors, HM
G-CoA reductases, preferably lovastatin, mevastatin, simvastatin, fluvastatin, atorvastatin, pravastatin and cerivastatin, and squalene synthetase inhibitors preferably pyrophosphate, pyrophosphate derivatives, biphosphonic acid derivatives, phosphinylmethylphosphonic acid derivatives, phosphine Inylformyl derivatives, phosphonocarboxyl derivatives, phosphonosulfonic acid derivatives, phosphinylmethylphosphonic acid derivatives, squalene monooxygenase inhibitors and cholesterol synthesis inhibitors are included. HMG-CoA-reductase inhibitors and squalene synthesis inhibitors are particularly preferred.

Among the bisphosphonates, clodronate, etidronate, pamidronate, ibandronate, alendronate, zoledronate, risedronate (
risedronate), tiludronate and simadronate are particularly preferred.

When the above-mentioned infectious active compound and its ester and its salt are simultaneously, intermittently or continuously administered with a lipid metabolism synthesis inhibitor, they show strong cytotoxicity against single-cell and multicellular parasites, fungi, bacteria and virus-infected cells. . The compounds according to the invention are useful for treating infectious disorders caused by parasites, fungi, bacteria or viruses in humans and animals. The compounds are also useful for preventing these diseases.

This lipid metabolism inhibitor is particularly effective against unicellular parasites (protozoa) against malaria and sleep sickness as well as chagas disease, toxoplasmosis, dysentery amoeba, leishmaniasis, trilomonosis, neumocysteosis, balantidiasis, Cryptosporidiosis, sporosporosis, acanthamoebiasis, negreliasis, coccidiosis,
It is effective against pathogens of giardiasis and giardiasis.

Thus, these are antimalarial agents and sleep sickness and chagas disease, toxoplasmosis, dysentery amoeba, leishmaniasis, trilomonosis, neumocystis, barantidiasis, cryptosporidiosis, sporosporosis, It is particularly suitable as a prophylactic agent for acanthamoebiasis, negleriosis, coccidiosis, giardia flagellosis, lambru flagellosis.

The lipid metabolism inhibitors according to the invention are used in particular against the following bacteria: Propionibacteriaceae family bacteria, especially Propionibacterium, especially Propionibacte
rium acnes; Actinomycetaceae bacteria, especially Actinomyces; Corynebacter
bacteria, especially Corynebacterium diphteriae species and Corynebacterium pse
bacterium of the species udotuberculosis; Mycobacteriaceae family bacteria, genus Mycobacterium, especially M
ycobacerium leprae, Mycobacterium tuberculosis, Ycobacterium bovis and Mycobacterium avium; Chlamydiaceae bacteria, especially Chlamydiatis and Chlamydia psittaci species; Listeria bacteria, especially Listeria monocytogene
s species; Erysipelthrix rhusiopathiae bacteria; Clostridium bacteria; Yetsinia bacteria, Yersinia pestis species, Yersinia pseudotuberculosis, Yer sinia entero
colitia and Yersinia ruckeri; Mycoplasmatacea family bacteria, Mycoplasma and Ureaplasma spp., especially Mycoplasma pneumoniae species; Brucella spp .; Bordetel
La bacteria; Neisseroaceae family bacteria, especially Neisseria and moraxella species, especially Neisseria meningitides species, Neisseria gonorrhoeae and Moraxella bo
vis; vibrionaceae family bacteria, especially Vibrio family, Aeromonas, Plesiomonas and Photoobacterium, especially Vibrio cholerae, Vubrio angillarum and Aeromo
nas salmonicidas; Campylibacter bacteria, especially Campylibacter jejuni, Campy
genus libacter coli and Campylibacter fetus; genus Helicobacter, especially Helicobacter
bacteria of the species pylori; spirochaetaceae and genus Leptospiraceae, especially Treponem
a, genus Borrelia and Leptospira, especially Borrelia burgdorferi; Actinob
bacteria of the genus acillus; bacteria of the genus Legionellaceae, genus of Legiononella; bacteria of the genus Rickettsiaceae and Bartonellaceae; bacteria of the genus Nocardia and Rhodococcus; Dermatophi
genus lus; Pseudomonadaceae family bacteria, especially Pseudomonas and Xanthomonas
Enterobacteriaceae bacteria, especially Escherichia, Klebsiella, Proteu
genus s, Providencia, Salmonella, Serratia and Shigella; Pasteurellace
ae bacteria, especially Haemophilus; Micrococcaceae bacteria, especially Micrococcus
And Staphylococcus; Streptococcaceae bacteria, especially Streptococcus
And Enterococcus and Bcillaceae bacteria, especially bacillus and c
genus lostridium.

Accordingly, lipid metabolism inhibitors according to the present invention include diphtheria, acne vulgaris,
Listeriosis, erysipelas in animals, gangrene in humans and animals, disease in humans and animals due to Clostridium septicum, tuberculosis in humans and animals, leprosy in humans and animals, further mycobacteriosis, paratuberculosis in animals, plague Mesenteric lymphitis and pseudotuberculosis in humans and animals, cholera, regenerosis, borreliosis in humans and animals, leptospirosis in humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella keratoconjunctivitis and serosa in animals Inflammation, brucellosis in humans and animals, anthrax in humans and animals, actinomycosis in humans and animals, streptotrix, animal parrot / ornithosis, and Q fever and Ehrlichiosis Suitable for treatment.

Furthermore, the use described above is advantageous for Helicobacter radiation treatment of gastrointestinal tract tumors.

Furthermore, combinations with additional antibiotics are used for the treatment of the above diseases.
Lipid metabolism inhibitors, especially isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, prothionamide, and dapsone in combination with other anti-infective agents are suitable for the treatment of tuberculosis.

The lipid metabolism inhibitors according to the invention can furthermore be used in particular for the following viral infections: Parvoviridae: Parvovirus, Dependovirus, Densovirus; Adenoviridae: Adenovirus, Mastadenovirus, Bird Adenoviruses, viruses; Papovaviridae: Papovaviruses, especially papillomaviruses (so-called wart viruses), polioviruses, especially JC virus, BK virus, and myopapaviruses; Herpes viruses: all herpes viruses, especially herpes simplex virus, v blister Virus, human cytomegalovirus, EB virus, all human herpes viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8; Poxviridae: poxvirus, orthopox, Lapox, infectious molluscum virus, avian pox virus, capripox virus, repolipox virus; all primary hepatotropic viruses, hepatitis viruses: hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, hepatitis E virus, hepatitis F virus, hepatitis G virus; Hepadna virus: all hepatitis viruses, hepatitis B virus, hepatitis D virus; picornaviridae; picornavirus, all enterelivirus, all poliovirus ,
All coxsackieviruses, all ECHO viruses, all rhinoviruses, hepatitis A virus, aphthavirus; Caliciviridae: Hepatitis E virus, reoviridae: reovirus, orbivirus, rotavirus; Togaviridae:
Togavirus, alhavirus, rubivirus, pestivirus, rubella virus; flavivirus genus; flaviviridae: ESME virus, hepatitis C virus;
Orthomyxoviridae: All influenza viruses; Paramyxoviridae: Paramyxovirus, Morbillivirus, Pneumonia virus, Measles virus,
Mumps virus; rhabdoviridae: rhabdovirus, rabies virus,
Rabies virus (lyssa), viscula stomatitis virus; Coronary virus; Bunyaviridae: Bunyavirus, Nyrovirus, Phlebovirus, uuku virus, Hantavirus; Arenaviridae: Arenavirus, lymphocytic choriomeningitis virus; retrovirus Family: retroviruses, all HTL viruses, human T-cell leukemia virus, oncovirus, spimavirus, lentivirus, all
HI-virus; genus Filovirus: Marburg-Ebola virus; delayed viral infection, prion; oncovirus, leukemia virus.

The preparations used according to the invention are therefore suitable for combating the following viral infections: Eradication of papillomaviruses to prevent tumors caused by papillomaviruses in humans, especially those of the reproductive organs, JC Virus and BK virus eradication, herpes virus eradication, human herpes virus 8 eradication in case of Kaposi's sarcoma treatment, cytomegalovirus eradication, EB virus eradication prior to transplantation and EB virus tumor prevention, chronic liver Eradication of hepatitis virus for the treatment of disease and prevention of liver tumors and cirrhosis, eradication of patients with cardiomyopathy Cocksackie virus,
Eradication of the diabetic Cocksackie virus, eradication of the immune system wasting virus in humans and animals, treatment of secondary infections in AIDS patients, treatment of respiratory viral inflammation (
Laryngeal papilloma, hyberplasias, acute rhinitis, laryngitis, bronchitis, pneumonia, treatment of viral inflammation of sensory organs (keratoconjunctivitis), nervous system (polio, meningitis, encephalitis, subacute sclerosing panencephalitis SSPE, progression) Polyfocal leukoencephalopathy, choriomeningitis, gastrointestinal tract (stomatitis, gingival stomatitis, colon infection, gastritis, gastroenteritis, diarrheal disease, liver and gallbladder system (hepatitis, cholangitis, hepatocellular carcinoma) Treatment of viral inflammation, treatment of lymphoid tissue (mononucleosis, lymphitis), treatment of viral inflammation, treatment of hematopoietic viral inflammation, treatment of viral inflammation of the reproductive organs (mumpsorchitis), skin (warts, skin) Inflammation, shingles, shingles help), treatment of viral inflammation of mucous membranes (papilloma, conjunctival papilloma, hyperplasia, dysplasia), heart / vasculature (arteritis, myocarditis,
Endocarditis, epicarditis), treatment of viral inflammation of the renal / urinary tract, reproductive organs (anogenital lesions, warts, genital warts, acute condyloma acuminatum, displasias, papilloma, cervical dysplasia, cuspoid Treatment of viral inflammation of condyloma, epidermal dysplasia wart), treatment of motor organ (myositis, myalgia) viral inflammation, treatment of foot-and-mouth disease in double-footed animals, treatment of viral inflammation of tick fever, dengue fever Treatment of viral inflammation of syndrome, treatment of viral inflammation of hemorrhagic fever, Early summer meningoencephalomyelitis (FSME)
For the treatment of viral inflammation, as well as for the treatment of viral inflammation of yellow fever.

This agent is suitable for use in combination with other antiviral agents.

Compounds according to the invention, generally including pharmaceutically acceptable salts, esters, salts of such esters, or other compounds which upon application provide the above compounds according to the invention as metabolites or degradation products Compounds, so-called "prodrugs", as well as known anti-infective agents, can be prepared for administration in any suitable manner.

The composite preparations used according to the invention can be administered as non-toxic, inert medicaments together with a suitable carrier. These carriers are understood to mean 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 are mentioned as pharmaceutical preparations. Tablets, dragees, capsules, pills, and granules can be used in addition to conventional excipients, (a) fillers and diluents, such as starch, lactose, sucrose, glucose, mannitol, and silicates; Alginate, gelatin, polyvinylpyrrolidone, (c) humectants such as glycerol, d) dispersants such as agar, calcium carbonate and sodium carbonate, (e)
Solution inhibitors such as paraffin and (f) absorption enhancers such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol, glycerol monostearate, (h) adsorbents such as kaolin and bentonite and (i) lubricants such as It can contain active ingredients such as talc, calcium and magnesium stearate, and solid polyethylene glycols or mixtures of the substances described in (a) to (i). Furthermore, the compounds according to the invention can be incorporated into other carrier materials such as, for example, plastics (plastic topical therapeutic chain), collagen or bone cement.

Tablets, dragees, capsules, pills, granules may be provided with a conventional coating and mantle, optionally containing an opacifying agent, and furthermore, only at certain sites in the intestine, or preferably at certain sites. The active ingredient or active ingredients can be packaged in such a manner that the active ingredient or the active ingredients are released in a sustained manner, in which case polymeric substances and waxes can be used as embedding agents.

The active ingredients can optionally be provided in microencapsulated form together with one or more excipients.

In addition to the above active ingredients, suppositories may include, for example, polyethylene glycols, oils such as cocoa fat, and higher esters (eg, C ₁₄ -alcohols with C ₁₆ fatty acids).
Alternatively, a mixture thereof can be contained.

In addition to the active ingredient, ointments, pastes, creams and gels contain conventional excipients such as animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and It may contain zinc oxide or a mixture of these substances.

In addition to the active ingredient, the powders and sprays may contain conventional vehicles such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders or mixtures thereof. Sprays may contain, in addition to these, conventional blowing agents such as chlorofluorohydrocarbons.

In addition to the active ingredients, solutions and emulsions may contain solvents, stabilizers and emulsifiers (em
ulgators) For example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, fats and oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castors It may contain sesame and sesame oil, glycerol, glycerol methylal, tetrahydrofurryl alcohol, polyethylene glycol and sorbitan fatty acid esters or mixtures of these substances. Solutions and displacement and emulsions can also be provided for parenteral use in the form of sterile solutions and isotonic blood solutions. In addition to the active ingredient, suspensions include liquid diluents such as water, ethyl alcohol, propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite. , Agar and gum tragacanth or mixtures thereof.

The active ingredient or the active ingredients of the formulas (I) to (XIV) may be present in the pharmaceutical preparation in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight ( (Based on the total mixture). The proportion of the substances combined individually depends on the individual components. Thus, the administered active agent generally has a weight of 1 body weight per day.
Provided at a dose of 0.1 mg per kg (ibandronate and alendronate), a 0.5 mg dose per kg body weight per day (mevastatin, simvastatin, pravastatin, fluvastatin), and a 10 mg dose per kg body weight per day (pamidronate) You.

In addition to the compounds of the formulas (I) to (XIV) and the lipid metabolism inhibitors, the pharmaceutical preparations further comprise a pharmaceutically active ingredient such as an antiviral, antiparasitic, antifungal or antibacterial agent. Is also good.

The lipid metabolism inhibitors used according to the present invention further include sulfonamides, sulfadoxins, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, almesin, tetracycline, doxycycline, proguanil, metronidazole, It may further contain praziquantel, niclosamide, mebendazole, pyrantel, thiabendazole, diethylcarbazine, piperazine, pyribinum, metrifonate, oxamnikin, bitionol or suramin or several of these substances. Lovastatin, atorvastatin, simvastatin, mevastatin, pravastatin and fluvastatin are administered orally, while pravastatin and fluvastatin are administered in active form.

In the case of both human and vertebrate medicines, the active ingredients or active ingredients of the formulas (I) and (V) will generally be present in a total amount of 24 hours, in order to achieve the desired result. It has proven advantageous to administer about 0.5 to about 600, preferably 1 to 200 mg / kg of body weight, optionally in various individual dose forms. Individual doses may range from about 0.5 to about 200 / kg, especially from 1 to 6 / kg body weight.
Preferably, the active ingredient or ingredients are contained in an amount of 0 mg. However, there may be a need to diverge from the above doses, which need depends on the condition and weight of the patient to be treated, the nature and severity of the disease, the nature and method of the pharmaceutical composition and the package and the time scale or interval of administration. I do.

The lipid metabolism inhibitors have proven to be advantageous to administer in the known dose ranges known from the treatment of disorders of lipid metabolism and of calcium and phosphorus metabolism. To achieve the desired result, a total amount of about 0.005 to about 200, preferably 0.01 to 10 mg / kg of body weight per 24 hours, optionally administered in various individual dosage forms. In individual doses, preferably about 0.000 / kg body weight
It contains from 2 to about 50, in particular from 0.01 to 10 mg, of active ingredient or ingredients (lipid metabolism inhibitors). However, there may be a need to deviate from the above dosages, which may include the condition and weight of the patient to be treated, the nature and severity of the disease, the nature and method of the pharmaceutical composition and the application and the timescale or interval of administration. Depends on. When using aminobisphosphonates, it should be taken into account that these absorptions are very low. This property is advantageous in the case of an intestinal attack (eg in the case of amoebic dysentery). In this case, pamidronate at a dose of less than 10 mg per kg of body weight is orally administered. In the case of injection, a dose of less than 2 mg per kg of body weight is generally sufficient.

In some cases, less than the above amount of active ingredient is sufficient, while in other cases it is necessary to exceed the above amount of active ingredient. The person skilled in the art should be able to determine the optimal dose and the application of the active ingredient in each case based on experience.

The lipid metabolism inhibitors according to the present invention can be administered to animals with feed or feed preparations or drinking water in conventional concentrations and preparations. The lipid metabolism inhibitor can be administered simultaneously, intermittently or continuously.

[0149]

EXAMPLES Preparation of Anti-infective Active Agent Preparation of Injectable Preparation (1) 500 mg of 3- (N-acetyl-N
-Hydroxyamino) -propyl-phosphonic acid monosodium salt and 90 mg
Disperse the 3-amino-1-hydroxy-propylidene-1,1-bisphosphonic acid disodium salt in a flask or ampoule. Seal flask to eliminate bacteria. In the case of injection, this is taken up and administered in 500 ml each of sodium chloride physiological solution. A further injectable preparation of the anti-infective active agent is prepared in principle in the same manner as described above (1):

(2) 250 mg of 3- (N-formyl-N-hydroxyamino) -propylphosphonic acid monosodium salt and 1 mg of 3-methylpentylamino-1-hydroxypropylidene-1,1-bisphosphonic acid Disodium salt is used for injection.

(3) 250 mg of 3- (N-formyl-N-hydroxyamino) -trans-1-propenylphosphonic acid ・ an atrium salt and 90 mg of 3-amino-
1-Hydroxypropylidene-1,1-bisphosphonic acid disodium salt is used as the active ingredient for injection.

Tablet Preparation: The following mixture forms a suitable tablet preparation: 3- (N-formyl-N-hydroxyamino) -propylphosphonic acid monosodium salt 200 mg lovastatin 10 mg mannitol 400 mg starch 50 mg stearic acid Preparation of capsule 10 mg of magnesium: 3- (N-formyl-N-hydroxyamino) -propylphosphonic acid monopotassium salt 300 mg Sumivastatin 10 mg Magnesium stearate 15 mg These components are mixed, and then filled into hard gelatin by a conventional method. .

[Procedure amendment]

[Submission date] March 30, 2001 (2001.3.30)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Full text

[Correction method] Change

[Correction contents]

Title: Complex preparation of an anti-infective compound inhibiting the metabolic pathway of 2-C-methylerythrose-4 and an inhibitor of lipid metabolism

[Claims]

Embedded image Wherein R ₁₁ and R ₁₂ are the same or different and are H, OH, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted R ₁₃ and R ₁₄ are selected from the group consisting of aralkyl, and substituted and unsubstituted heterocyclic groups, wherein R ₁₃ and R ₁₄ are substituted and unsubstituted alkyl of 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of 1 to 26 carbon atoms, substituted And unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, 1 to 26 carbon atoms
Selected from the group consisting of substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl of 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen, X ₁₃ and X ₁₄ , wherein , X ₁₃ and X ₁₄ are the same or different and include hydrogen, substituted and unsubstituted alkyl having 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aryl. Substituted aralkyl, substituted and unsubstituted alkenyl of 1 to 26 carbon atoms, substituted and unsubstituted alkynyl of 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, cations of organic and inorganic bases In particular, metal cations of Group 1, 2, or 3 of the periodic table, ammonium,
Selected from the group consisting of substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and A ₁ corresponds to an alkylene, alkenylene or hydroxyalkylene group or a formula:

Embedded image Wherein the group C together with the substituents₁₃, C₁₄, C_FifteenOne or more carbon sources selected from
The offspring may be deleted and B₁ From B_TenIs at least one substituent of C_{3- 8} -Cycloalkyl- (C_0-9 ) -Alkyl groups, wherein C_3-8 -Cycloa
Alkyl group and C_0-9 An alkyl group contains one or more double bonds
And one or two carbon atoms of the cycloalkyl group may be nitrogen, oxygen
Or may be substituted with a sulfur atom, and wherein a cycloalkyl group and
Alkyl groups are hydroxy, halogen, amino, oxo, branched or straight chain C_1-9
-Alkyl group and C_2-9 -Alkenyl group, wherein C_{1- 9} -Alkyl group and C_2-9 An alkenyl group is hydrogen, hydroxy, amino, halo
And oxo groups, and any other substituted B ₁₁ From B₁₁₀ Is hydrogen, hydroxy, halogen, amino, C_1-26-Archi
Group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26-From an alkyl group
Or both substituents of one carbon atom are taken together to form an oxo group
To form each C_1-26Alkyl groups and each C_1-26An alkoxy group is branched or
Linear and saturated or unsaturated with one or more double bonds
And may be substituted with hydroxy, amino, halogen and oxo groups.

Embedded image _Wherein X _II1 , X _II2 , X _II3 , and X _II4 are the same or different and are hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl,
Substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, Na, K, Ca
, Mg, Periodic Table 1 such as Al, second or third group metal, selected substituted and unsubstituted ammonium, and from the group consisting of ammonium compounds from Echinjiamin or amino, A ₁₁ is deleted also possible Wherein R _II1 , R _II2 are the same or different and are 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 groups and -SR _II3 , Cl, and -NR _II3 R _II4 , wherein R _II3 , R _II4 is a same or different, H, OH, substituted and unsubstituted acyl, substituted and unsubstituted alkyl , Substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, selected from the group consisting of substituted and unsubstituted cycloalkyl and substituted and unsubstituted heterocyclic group.

Embedded image Where R_III1Is H, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted
And unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted
Alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted
Substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen and OX_{II I1} Selected from the group consisting of_III1Is hydrogen, substituted and unsubstituted acyl,
Substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted
Substituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted
Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, silyl, substituted and unsubstituted
And unsubstituted heterocyclic groups, cations of organic and inorganic bases, especially Periodic Tables 1 and 2
Or cations of group 3 metals, such as ammonium, substituted ammonium and ammonium.
R compound selected from the group consisting of_III4, R_III3Are the same or different and include hydrogen, substituted and unsubstituted acyl,
Substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted
Unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl,
Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted
Substituted heterocyclic group, halogen and OX_III4And OX_III3Selected from the group consisting of
, Where X_III4, X_III3Is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted
Substituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl,
Silyl, substituted and unsubstituted heterocyclic groups, cations of organic and inorganic bases, especially periodicity
Cation, ammonium, substituted ammonium of metals of group 1, 2 or 3
, And an ammonium compound derived from ethylenediamine or an amino acid
Selected from the group; and A_III1And A_III2One or both may be deleted,_III1And A _III2 Are the same or different, alkylene group, alkenylene group, oxo group,
Represents a hydroxy group or an oxohydroxyalkylene group.

Embedded image Wherein R _IVI and R _IV2 are the same or different and are 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 groups, halogen, OX _IVI and OX _IV2 , wherein X _IVI and X _IV2 are the same or Heterologous, 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,
B _IV is selected from the group consisting of substituted and unsubstituted heterocyclic groups; B _IV is selected from the group consisting of the following ether groups (IVA):

Embedded image Wherein, A _IV2 in A _IV1 and A _IV2 are possible deletions, and A _IV1 and A _IV2 is a same or different, consist of an alkylene group, alkenylene group and hydroxy alkylene, keto group (IVB) Selected from group:

Embedded image Wherein one or both in the A _IV3 and A _IV4 are possible deletions, and A _IV3 and A _IV4 are same or different, alkylene, alkenylene and hydroxyalkylene groups, and in particular in the ring It is selected from 5 and 6-membered ring group, especially consisting of heterocyclic compounds containing at least one heteroatom as a ring member in addition to carbon atoms, wherein the hetero atoms are selected from the group consisting of oxygen and nitrogen, R _IV3 and R _IV4 is the same or different and includes 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 of up to 26 carbon atoms, 26 carbon atoms
Selected from the group consisting of the following substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen, OX _IV3 or OX _IV4 , wherein X _IV3 or X _IV4 is the same or different. And hydrogen, carbon atom 2
Up to 6 substituted and unsubstituted alkyl, up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl groups, substituted and unsubstituted aralkyl,
Substituted and unsubstituted alkenyl of up to 26 carbon atoms, substituted and unsubstituted alkynyl of up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, cations of organic and inorganic bases, especially It is selected from the group consisting of cations of Group 1, 2 or 3 metals, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids.

Embedded image Wherein one or both of A _V1 and A _V2 can be deleted, and A _V1 and A _V2 are the same or different and are selected from the group consisting of an alkylene group, an alkenylene group and a hydroxyalkylene group. Wherein the carbon chain -A _V1 -CHOH-A _V2 -comprises 2 to 5, especially 3 to 4 carbon atoms, and B _V is selected from the group consisting of groups of formula (VA):

Embedded image Wherein R _V1 is 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 acyl. Substituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups and halogen, selected from the group consisting of groups of formula (VB):

Embedded image Wherein R _V2 , R _V3 and R _V4 are the same or different and are hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl,
Consisting of substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, and the following group (VC) Selected from the group:

Embedded image Wherein R _V5 , R _V6 and R _V7 are the same or different and are 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,
Wherein X _V3 and X _V4 are the same or different and are hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted Aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, cations of organic and inorganic bases, especially Periodic Table 1, It is selected from the group consisting of Group 2 or Group 3 metal cations, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids.

Embedded image _Wherein R _VI3 and R _VI4 are the same or different and are hydrogen, substituted or 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. Substituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl of up to 26 carbon atoms, substituted and unsubstituted alkynyl of up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen, OX _VI3 or it is selected from the group consisting of OX _VI4, wherein X _VI3 or X _VI4 is same or different, hydrogen, a substituted carbon atoms 26 or less and unsubstituted alkyl, carbon atoms 26 following substituted and unsubstituted hydroxyalkyl, substituted And unsubstituted aryl groups, substituted and unsubstituted aralkyl, substituted and unsubstituted And unsubstituted alkenyl, substituted and unsubstituted alkynyl having up to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, cations of organic and inorganic bases, especially the first, second or third cations of the Periodic Table Selected from the group consisting of Group 3 metal cations, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids, and B _VI is the following group (VIA):

Embedded image And selected from the group consisting of the following groups (VIB):

Embedded image In the formula, A _VI is selected from the group consisting of an alkyleneamine group, an alkenyleneamine group, a hydroxyalkyleneamine group, an alkyleneimine group, an alkenyleneimine group and a hydroxyalkyleneimine group, wherein the nitrogen atom is represented by the following group: Is a member of the chain connecting the nitrogen and phosphorus atoms:

Embedded image Or the group R _VII -N =. Wherein R _VI1 and R _VI2 in the group (VIA) are the same or different, and
R _VI1 and R _VI2 and R _VI1 in group (VIB) in IVA) is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Selected from the group consisting of substituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, _OXVI1 and _OXVI2 , where _XVI1 and X _VI2 is the same or different,
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 It is selected from the group consisting of aralkyl, substituted and unsubstituted heterocyclic groups.

Embedded image _Wherein A _VII is selected from the group consisting of a (C _1-9 ) -alkylene group, which group may contain one or more double bonds, and hydroxy, halogen, amino,
An oxo group, a branched or straight-chain C _1-9 -alkyl group and a C _2-9 -alkenyl group may be substituted, wherein the C _1-9 -alkyl group and the C _2-9 -alkenyl group are hydrogen, Hydroxy, amino, halogen and oxo groups, -COC- and -C
May be substituted with -NC-, wherein the carbon atoms of -CO-C- and -C-NC- may be substituted with an alkyl group or hydroxy group having 7 or less carbon atoms. Or A _VII corresponds to formula (VIIA):

Embedded image Wherein the group C together with their substituents_VII3, C_VII4, C_VII5One or two selected from
One or more carbon atoms may be deleted and B_VII1From B_VII10 At least
Also one substituent is C_3-8 -Cycloalkyl- (C_0-9 ) -Alkyl group,
Here C_3-8 A cycloalkyl group and (C_0-9 )-One or two alkyl groups
It may contain the above double bond, and one or two of the cycloalkyl groups
Carbon atoms may be replaced by nitrogen, oxygen or sulfur atoms, where
Alkyl and alkyl groups include hydroxy, halogen, amino, oxo,
Or straight chain C_1-9 An alkyl group, and C_2-9 -May be substituted with an alkenyl group
, Where C_1-9 -Alkyl group and C_2-9 An alkenyl group is hydrogen, amino, halo
Or an oxo group, and the remaining substituent B_VII1From B _VII10 Is hydrogen, hydroxy, halogen, amino group, C_1-26-Alkyl group, C_1-26 -Alkoxy group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26-Achill
Selected from the group consisting of the groups or both substituents of one carbon atom are taken together
Forming an oxo group, where each C_1-26Alkyl groups and each C_1-26-Alkoxy group
Is branched or straight-chain and is saturated or one or more double-bonded
Unsaturated, substituted with hydrogen, amino, halogen and oxo groups
May be R_VII1Represents 5 having one or two nitrogen, oxygen or sulfur atoms in the ring and
Selected from the group consisting of 6-membered heterocycles, wherein the heterocycle is saturated or one or more
An unsaturated compound having two or more double bonds or triple bonds, and
By halogen, amino, oxo group and branched or straight-chain C_1-9 -Al
Kill group and C_2-9 -Alkenyl group, wherein C_1-9 
-Alkyl group and C_2-9 The alkenyl group is saturated or one or more
Hydrogen, hydroxy, amino, halo in unsaturated form having a double or triple bond
And phenyl or oxo._VII3And R_VII4Are the same or different and include hydrogen, substituted and unsubstituted C_{1- 26} -Alkyl, hydroxy-C_1-26-Alkyl, substituted and unsubstituted aryl,
Substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26 Alkenyl, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cyclo
Alkyl, substituted and unsubstituted heterocyclic group, halogen, OX_VII3And OX_VII4From
Selected from the group_VII3And X_VII4Are the same or different and are hydrogen, substituted and unsubstituted
Exchange C_1-26-Alkyl, substituted and unsubstituted hydroxy-C_1-26-Alkyl, substituted or
And unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26−
Alkenyl, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cycloalkyl
Alkyl, substituted and unsubstituted heterocyclic groups, silyl, organic and inorganic base cations
The cation, ammonium, and substituted anion of a metal of Group 1, 2, or 3 of the periodic table
Monium and ammonium compounds derived from ethylenediamine or amino acids
Selected from the group consisting of:

Embedded image _Wherein the wavy line represents a bond having an α- or β-configuration, n is 0 or 1, R _VIII11 is substituted and unsubstituted C _1-26 -alkyl, hydroxy-C _1-26 -alkyl, substituted and unsubstituted Aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C _1-26 -alkenyl, substituted and unsubstituted C _1-26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic group _Wherein X _VIII11 is hydrogen, substituted and unsubstituted C _1-26 -alkyl, substituted and unsubstituted hydroxy-C _1-26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclic aralkyl, substituted and unsubstituted C _1-26 - alkenyl, substituted and unsubstituted C _1-26 - alkynyl, substituted and unsubstituted cycloalkyl, substituted And unsubstituted heterocyclic groups, silyls, cations of organic and inorganic bases, especially cations of metals of Groups 1, 2 or 3 of the Periodic Table, ammonium, substituted ammonium, and ethylenediamine or ammonium compounds derived from amino acids. is selected, R _VIII1 is C _1-24 - alkyl groups, C _2-24 - alkapolyenyl groups, C _2-24 - - alkenyl groups, C _2-24 having 6 from double bonds 2 alkynyl groups, C _3-8 - cycloalkyl group, C _3-8 - cycloalkyl -C _1-24 - alkyl and C _1-12 - alkoxy -C _1-12 - is selected from the group consisting of alkyl groups, each R _VIII2, R _VIII3 and _RVIII4 are selected from the group consisting of hydrogen, halogen, amino, acetylamino, azide and _XRVIII6 groups, wherein X is O or S
_Wherein R _VIII6 is selected from the group consisting of hydrogen, branched or straight chain C _1-4 -alkyl and C _2-4 -alkenyl, wherein C _1-4 -alkyl and C _2-4-
The alkenyl group is optionally substituted with hydrogen, amino, halogen or oxo group, or R _VIII2 , R _VIII3 and R _VIII4 together with the respective gem-hydrogen group represent an oxo group, R _VIII5 is hydrogen, C _{VIII 1-24} - alkyl group, C _3-8 - cycloalkyl group, Ar (C _1-24 - alkyl) group, an aryl group, an acyl group, a heterocyclic group, selected from the group consisting of halogen, where all groups Is branched or linear and may be optionally substituted by a hydroxy, amino, halogen or oxo group and may contain from 2 to 6 double and triple bonds, or R _VIII5 has the formula VIIIA or XIIIB is a phenyl group:

Embedded image

Embedded image Wherein, R _VIII7 and R _VIII8 is a same or different, it is bonded to any two positions of the phenyl ring, and R _VIII7 and R _VIII8 hydrogen, halogen, C _1-4 -
Alkyl group, C _1-4 -alkoxy group, formyl, acetyl, propionyl, butyryl group, formyl, acetyl, propionyl, butyryloxy group, C _2-5 -alkoxycarbonyl group, all independently selected from the group consisting of R ₇ and R _VIII8 may be taken together at adjacent positions, such as the 2,3-position or 3-position of the phenyl ring.
Can form a linear saturated alkylene chain with 3 to 4 carbon atoms attached at the, 4-position, or R ₇ and R ₈ together form the 2,3- or 3,4-
A methylenedioxy group, 1,1-ethylidenedioxy group or 1,
R _VIII5 forms a 2-ethylenedioxy group, or R _VIII9 COOCHR _VIII10 -and R _VIII9 OCOOCHHR _VIII10-
It is selected from the group consisting of, R _Viii9 is, C _1-6 - alkyl group, C _2-6 - alkenyl group, C _2-6 - alkynyl group, C _3-8 - cycloalkyl group, C _3-8 - cycloalkyl alkyl -C _1-6 - alkyl and C _1-6 - alkoxy -C _1-6 - is selected from the group consisting of an alkyl group, wherein all groups is a branched or straight chain hydroxy, amino, halogen Or optionally substituted with an oxo group, and R ₁₀ is a branched or straight-chain C _1-4 alkyl, where n = 1, if the substituent R _VIII2 in formula (VIII), R _VIII3, R _{VI II4} and _{R III5 OOCPO (OH) OCH 2} - arrangement of D-gluco, L-gluc
o, D-galacto, L-galacto, D-manno, L-manno, D-talo, L-ta
lo, D-allo, L-allo, D-altro, L-altro, D-gulo, L-gulo, D-
ido or L-ido, and if n = 0, the substituent R _{2 in} formula I
, R ₃ and R ₅ OOCPO (OH) OCH ₂ — are independently D-ribo, L-
ribo, D-arabino, L-arabino, D-xylo, L-Xxylo, D-lyxo or L
-Lyxo.

Embedded image Where R_IX11Is a substituted and unsubstituted C_1-26-Alkyl, hydroxy-C_1-26-Alkyl
Substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aryl
Alkyl, substituted and unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26-Al
Quinyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen
And OX_IX11Selected from the group consisting of_IX11Is hydrogen, substituted and unsubstituted C_1-26-Alkyl, substituted and unsubstituted
Hydroxy-C_1-26-Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted
Aralkyl, substituted and unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26−
Alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups,
Lil, cations of organic and inorganic bases, especially gold of the first, second or third groups of the periodic table
Genus cations, ammonium, substituted ammonium, and ethylenediamine
R is selected from the group consisting of ammonium compounds derived from amino acids;_IX1 And R_IX2 Each of C_1-24-Alkyl group, C_3-8 -Cycloalkyl
Group, C_3-8 -Cycloalkyl-C_1-24-Alkyl group, C_1-24-Alkoxy group, C _1-24 -Alkylthio group, C_1-24-Alkoxy-C_1-24Alkyl group and C_1-24−
Alkylthio-C_1-24-Alkyl group, acyl group, aryl group, aralkyl group,
Independently selected from the group consisting of a ring group, halogen and hydrogen;_1-24-Al
Kill group and C_1-24Each alkoxy group may be branched or linear
, Saturated or unsaturated from 2 to 6 double bonds, and hydrogen, amino,
Mercapto, halogen, oxo group, or C_1-24-Alkoxy group, C_1-24-Al
Killcarbonyl-oxy group, C_1-24-Alkoxycarbonyloxy group, C_1-24−
Alkylthio group, C_1-24-Alkylcarbonylthio group, C_1-24-Alkylamino
Group, di- (C_1-24-Alkyl) -amino group, C_1-24-Alkylcarbonylamino
Group, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) -amino group, C_1-24−
Alkoxycarbonylamino group or C_1-24-Alkyl- (C_1-24-Alkoxy
Carbonyl) amino group which may be arbitrarily substituted.
Ring group, C_1-24-Alkyl group and C_1-24Each of the alkoxy groups is branched or
Straight-chain, saturated or unsaturated having 2 to 6 double or triple bonds
May be a sum, or R_IX1 -CH-CH-R_IX2 Is C_4-8 Forms part of a carbocycle, which ring is
Si, mercapto, amino, halogen, may be optionally substituted with an oxo group,
Is C_1-24-Alkyl group, C_1-24-Alkoxy group, C_1-24-Alkylthio group, C_{1- twenty four} -Alkylamino group, di- (C_1-24-Alkyl) amino group, C_1-24-Alkyl
Carbonyl group, C_1-24-Alkyl carbonyloxy group, C_1-24-Alkoxycarboni
Group, C_1-24-Alkylcarbonylthio group or C_1-24-Alkylcarbonyla
Mino group, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) amino group optionally
May be substituted, where C_1-24-Each alkyl group is branched or linear
Or a saturated or unsaturated form having 1 to 6 double bonds, or R_IX10Is a branched or linear C_1-4 -An alkyl group, and R_IX1 -CH-CH-R_IX2Is, for example, D-ribose, D-arabinose, D-ki
Sylose, D-lyxose, D-glucose, D-galactose, D-mannoh
, D-talose, D-allose, D-altrose, D-glucose, D-y
Of the furanose or pyranose ring of sugars such as doose or the respective L-isomer
Form a part, where each of the hydroxy groups is hydrogen, amino, azido, oxo
, A mercapto group or C_1-24-Alkoxy group, C_1-24-Alkylthio group, C_1-24 -Alkylamino group, di- (C_1-24-Alkyl) amino group, C_1-24-Alkylka
Rubonyloxy group, C_1-24-Alkylcarbonylthio group, C_1-24-Alkylcal
Bonylamino group, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) amino group
May be optionally substituted, wherein each C_1-24-The alkyl group is branched or linear
May be a saturated type or an unsaturated type having 1 to 6 double bonds._IX1 And R_IX2 Each represents a carboxyl group or a carboxamide group
, Aryl group, aryloxycarbonyl group, aryl-C_1-24Alkyl group, C _1-24 -Alkoxycarbonyloxy group, C_1-24An alkylaminocarbonyl group,
Di- (C_1-24-Alkyl) aminocarbonyl group, aryl-C_1-24-Alkoxy
Carbonyl group, aryl-C_1-24-Alkylaminocarbonyl group, C_1-24-Al
Kill carbonyloxy- (C_1-4 ) -Alkylmethoxycarbonyl group, C_1-24−
Alkoxy-carbonyloxymethoxycarbonyl group, C_1-24-Alkoxycal
Bonyl-oxy- (C_1-24Alkyl) -methoxycarbonyl group
Selected, where each C_1-24The alkyl group is branched or straight-chain, saturated or
It may be an unsaturated type having 2 to 6 heavy bonds, and_1-4 -Alkyl group and C _1-24 The alkoxy group may be branched or linear, saturated or unsaturated,
And each aryl group is of the formula (IXA):

Embedded image Where R_IX3 And R_IV4 Are the same or different and are each hydrogen, halogen, C _1-4 -Alkyl group, C_1-4An alkoxy group, formyl, acetyl, propionyl,
Butyryl group, formyl, acetyl, propionyl, butyryloxy group, C_1-4−
Selected from the group consisting of alkoxycarbonyl groups, all of which are branched or linear
May be of type R_IX3 And R_IX4Are together positioned adjacent to the phenyl ring
Forms a linear saturated alkylene chain of 3 to 4 carbon atoms bonded to_IX3 
And R_IX4Is a methylenedioxy group bonded to the adjacent position of the phenyl ring together,
, 1-ethylidenedioxy or 1,2-ethylenedioxy groups.

Embedded image Where R_X1Is hydrogen, substituted and unsubstituted C_1-9 Alkyl, substituted and unsubstituted hydroxy
C_1-9 -Alkyl, substituted and unsubstituted C_1-9 Alkenyl, substituted and unsubstituted C_{1- 9} -Alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted
And unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted
Ring group, halogen and OX_X1Selected from the group consisting of_X1Is hydrogen, substituted and unsubstituted C_1-9 -Alkyl, substituted and unsubstituted
Droxy C_1-9 -Alkyl, substituted and unsubstituted C_1-9 Alkenyl, substituted and
Unsubstituted C_1-9 -Alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl
, Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and
Selected from the group consisting of unsubstituted heterocyclic groups, where R_X2Is C_1-26-Alkyl, C_1-26-Alkoxy group, C_1-26-Alkoxy
-C_1-26-Alkyl group, C_3-8 Cycloalkyl- (C_0-26) Consisting of an alkyl group
Selected from the group wherein one or two carbon atoms of the cycloalkyl group are nitrogen,
Each C may be replaced by an oxygen or sulfur atom._3-26Alkyl groups and each C _3-26 -Alkoxy groups are branched or straight-chain,_3-8 -Cycloalkyl group,
Each C_2-26Alkyl groups and each C_2-26The alkoxy group is saturated or one or two
It may be an unsaturated type having one or more double bonds, and each C_3-8 -Cycloalkyl
Group, each C_1-26Alkyl groups and each C_1-26-Alkoxy groups are hydroxy, amino
, Halogen and oxo, or the carbyl group COR_X3May be replaced by
R_X3Is a substituted and unsubstituted C_1-26-Alkyl, hydroxy-C_1-26-Alkyl,
Substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted arals
Kill, substituted and unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26-Archi
Nil, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen
, OX_X3Selected from the group consisting of_X3Is hydrogen, substituted and unsubstituted C_1-26-Alkyl, substituted and unsubstituted hydr
Roxy-C_1-26Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted arals
Kill, substituted and unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26-Archi
Nil, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl,
Cations of organic and inorganic bases, especially those of metals of groups 1, 2 or 3 of the periodic table
Thione, ammonium, substituted ammonium, and ethylenediamine or
It is selected from the group consisting of amino compounds derived from amino acids.

Embedded image Where Z_XIIs a phosphorus atom or a sulfur atom, wherein A_XIIs hydrogen, hydroxy, halogen, amino and oxo groups, and C _1-26 -Alkyl group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26-Al
Kill group or C_3-8 -Cycloalkyl- (C_0-9 ) -Alkyl groups
Straight chain with selected same or different substituents_2-9 An alkylene chain,
Here each C_1-26Alkyl groups and each C_1-26The alkoxy group is branched or linear
Saturated or unsaturated having one or more double bonds and hydroxy
, Amino, halogen and oxo groups;_3-8 -Shiku
Lower alkyl- (C_0-9 ) -Alkyl group C_3-8 Cycloalkyl group and C_0-9 The alkyl group may contain one or more double bonds, and may be a cycloalkyl.
One or two carbon atoms of the radical is replaced by a nitrogen, oxygen or sulfur atom
Wherein the cycloalkyl group and the alkyl group are hydroxy, halogen,
, Amino, oxo group, branched or linear C_1-9 -Alkyl group and C_2-9 −Arche
And may be substituted with a phenyl group._1-9 -Alkyl group and C_2-9 -A
Lucenyl groups are substituted by hydrogen, hydroxy, amino, halogen and oxo groups
May be, R_XI1 And R_XI2 Are the same or different and are hydrogen, substituted and unsubstituted C_1-9
Alkyl, substituted and unsubstituted hydroxy-C_1-9 -Alkyl, substituted and unsubstituted
C_1-9 Alkenyl, substituted and unsubstituted C_1-9 Alkynyl, substituted and unsubstituted
Reel, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted
And unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, OX_Xi1 And O
X_XI2 Selected from the group consisting of_Xi1 And X_XI2 Is the same or different
Wherein hydrogen, substituted and unsubstituted C_1-9 -Alkyl, substituted and unsubstituted hydroxy
Sea C_1-9 Alkyl, substituted and unsubstituted C_1-9 -Alkenyl, substituted and unsubstituted
C_1-9 Alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted
And unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted
R is selected from the group consisting of heterocyclic groups;_XI3 And R_XI4 Are the same or different and are substituted and unsubstituted C_1-26Al
Kill, hydroxy-C_1-26-Alkyl, substituted and unsubstituted aryl, substituted and
Unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26−Arche
Nil, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cycloalkyl
, Substituted and unsubstituted bicyclic groups, halogen, OX_xI3 And OX_XI4 From the group consisting of
Selected, where X_XI3 And X_XI4 Is the same or different and is hydrogen, substituted or unsubstituted
C_1-26-Alkyl, substituted and unsubstituted hydroxy-C_1-26-Alkyl, substituted and
And unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26-A
Lucenyl, substituted and unsubstituted C_1-26Alkynyl, substituted and unsubstituted cycloal
Cations of killed, substituted and unsubstituted bicyclic groups, silyl, organic and inorganic bases, especially
Cation, ammonium, substituted ammonium of metals of Group 1, 2 or 3 of the Periodic Table
And ammonium compounds derived from ethylenediamine or amino acids
Selected from the group consisting of:

Embedded image Where A_XII Is hydrogen, substituted and unsubstituted C_1-28-Alkyl groups, substituted and unsubstituted al
Coxy (C_0-28) -Alkyl groups, substituted and unsubstituted cycloalkyl- (C_0-28 ) Alkyl groups, substituted and unsubstituted cycloalkoxy- (C_0-28) -Alkyl groups,
Substituted and unsubstituted amino- (C_0-28) Alkyl groups, substituted and unsubstituted thio- (C _0-28 ) -Alkyl groups, and substituted and unsubstituted acyl- (C_0-28) -Alkyl group
And each alkyl group, each alkoxy group and
Each acyl group may be branched or linear, and each alkyl group, each alkoxy group
Si, each acyl and each cycloalkyl are saturated or one or more
May be an unsaturated type having a double bond or a triple bond, a cycloalkyl group
One or two carbon atoms may be replaced by nitrogen, oxygen or sulfur;_{XI I3} Is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy- (C _0-26 ) -Alkyl groups, substituted and unsubstituted C_3-14-Cycloalkyl- (C_0-26)-
Alkyl groups, substituted and unsubstituted cycloalkoxy- (C_0-26) -Alkyl group, position
Substituted and unsubstituted amino- (C_0-26) -Alkyl groups, substituted and unsubstituted silyl- (
C_0-26) -Alkyl groups and substituted and unsubstituted thio- (C_0-26) -Alkyl group
Selected from the group consisting of: each alkyl group and each alkoxy group are branched or linear
Each alkyl group, each alkoxy group and each cycloalkyl group may be saturated.
Sum type or unsaturated type having one or more double bonds or triple bonds
And one or two carbon atoms of the cycloalkyl group may be nitrogen, acid
A or A_XII The carbon chain consisting of two carbon atoms is R_XII3With isoxazoli
Form a don ring, and R_XII4Is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted acyl, and
Substituted and unsubstituted cycloalkyl- (C_0-26)-Selected from the group consisting of alkyl groups
Each alkyl group and each acyl group may be branched or straight-chain,
Alkyl group, each acyl group and each cycloalkyl group are saturated or one or two
Unsaturated type having the above double bond or triple bond, and cycloalkyl
One or two carbon atoms of the radical can be replaced by nitrogen, oxygen or sulfur.

Embedded image Wherein, n is an integer from 0 to 4, and _{R XIII1, R XIII2, R XIII3} , X XIII4, X XIII5 and X _III6 are identical or different, hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted From the group consisting of substituted alkoxy, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl- ( _C0-26 ) -alkyl, substituted and unsubstituted cycloalkyl- ( _C0-26 ) -alkoxy and halogen Selected, each alkyl group, each alkoxy group and each acyl group are branched or straight-chain, and each alkyl group, each acyl group, each alkoxy group and each _cyclo- (C _0-26 ) -alkyl group are saturated or Unsaturated with one or more double or triple bonds, and one or two carbon atoms of the cycloalkyl group can be replaced by nitrogen, oxygen or sulfur

Embedded image Wherein, Y _XIV is C _1-3 - alkenylene group, optionally substituted by a substituent R _XIV1 and R _XIV2, and substituted from R _XIV3 arbitrarily by R _XIV6, wherein the R _XIV1 R _XIV8 allogeneic Or heterologous, hydrogen, hydroxy, halogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 ) -alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 )- Alkyl, substituted and unsubstituted alkoxy- (C _0-26 ) -alkyl, substituted and unsubstituted amino and substituted and unsubstituted thio- (C _0-26 ) -alkyl, substituted and unsubstituted sulfonyl- (C _0-26 ) -alkyl groups, selected from the group consisting of substituted and unsubstituted sulfinyl- (C _0-26 ) -alkyl groups and substituted and unsubstituted acyl groups, wherein each alkyl group, each alkoxy group and each The acyl group is branched or linear, and each alkyl group,
Each alkoxy group and each cycloalkyl group may be saturated or unsaturated having one or more double bonds or triple bonds, and one or more carbon atoms of the cycloalkyl group Can be replaced by nitrogen, oxygen or sulfur, and R _XIV13 and R _XIV14 are the same as or together with R _XIV1 to R _XIV8 , forming an oxo group, and Z _XIV represents the following organophosphorus group :

Embedded image _Wherein R _XIV9 and R _XIV10 are the same or different and are hydrogen, substituted or unsubstituted (
C _1-26 ) -alkyl group, substituted and unsubstituted hydroxy- (C _1-26 ) -alkyl group substituted, unsubstituted cycloalkyl- (C _0-26 ) -alkyl group, substituted and unsubstituted acyl, halogen, OX _Selected from the group consisting of _XIV9 or OX _XIV10 , each alkyl group, each alkoxy group and each acyl group are branched or straight-chain, each alkyl group, each alkoxy group, each cycloalkyl group is saturated or one or It may be unsaturated, having two or more double or triple bonds, and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur, wherein X _{XI V9} or X _XIV10 is a same or different, hydrogen, substituted and unsubstituted (C _{1- 26)} - alkyl groups, substituted and unsubstituted hydroxy - (C _1-26) - alkyl group, a substituted, unsubstituted cycloalkyl - (C _0-26) - alkyl groups, substituted and unsubstituted acyl, silyl, a cation especially the Periodic Table first organic and inorganic bases, second or third group of metal cations, ammonium, substituted ammonium, and ethylene diamine Alternatively, each alkyl group, each alkoxy group and each acyl group are branched or linear, and each alkyl group, each alkoxy group, and each cycloalkyl group are saturated or monovalent. It may be unsaturated with one or more double or triple bonds, and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur, or
Z _XIV represents the following amino group:

Embedded image _Wherein R _XIV11 and R _XIV12 are the same or different and are hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 ) -alkyl groups, substituted and unsubstituted cycloalkoxy- ( C _0-26) - alkyl groups, substituted and unsubstituted alkoxy - (C _0-26) alkyl group, is selected from the group consisting of substituted and unsubstituted acyl, each alkyl group, each alkoxy group and the acyl group branched or Linear, each alkyl group, each alkoxy group, each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds, and a cycloalkyl group one or two carbon atoms may be replaced by nitrogen, oxygen or sulfur, B _XIV is selected from the group consisting of substituted and unsubstituted C _1-26 alkenylene group, wherein one of the charcoal The atoms can be replaced by one oxygen atom and one carbon atom by one sulfur atom, or two carbon atoms can be replaced by an S-heterocycle, and each alkenylene group is branched or linear. It can be saturated or unsaturated with one or more double or triple bonds and substituted with one or more hydroxy, halogen or oxo groups.

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an anti-infective compound which inhibits the metabolic pathway of 2-C-methylerythrose-4, and a complex preparation of salts and esters thereof and an inhibitor of lipid metabolism. And further relates to the simultaneous, discontinuous or sequential use of said composite preparation in the prevention and treatment of infectious processes in plants, humans and animals, as well as to the use of said composite preparation as a fungicide. The lipid metabolism inhibitors according to the invention are suitable for the treatment and prevention of infections by single or multicellular parasites, fungi, bacteria or viruses, and as herbicides.

[0002]

BACKGROUND OF THE INVENTION The suitability of certain organic phosphonic acid compounds, their esters and salts, as certain pharmaceutical compositions is known.

For example, the antimicrobial efficacy of aminohydrocarbylphosphonic acid derivatives against bacteria in humans and animals and against fungi in plants has been disclosed (DE 27 33 685 A1, US 4,143,135, US 4,182,758 and US 4,206,156, U
S 4,994,447, US 4,888,330, US 4,210,635, US 3,955,958, US 4,196,193, US
4,268,503, US 4,330,529, US 5,189,030, US 3,764,676). In addition, these groups of substances are used as fungicides (US 4,693,742, US 5,002,602, US 4,131,448, US 3,9
77,860, US 4,062,669), as algicide (US 3,887,353), and as a plant growth regulator (US 4,127,401, US 4,120,688, US 3,961,934, US 4,431,438,
US 3,853,530, US 4,205,977, US 4,025,332, US 3,894,861) and as reactants in pigment production (US 4,051,175).

For example, the application of aminohydrocarbylphosphonic acid derivatives for controlling bacterial infection has proven to be extremely difficult. Many bacteria responsible for pedestrian infections and infections during the clinical stay are not sensitive to treatment with this taxon. Staphylococcus bacteria, especially Staphylococcus aureus species belong to these. This type of pathogen on the skin is dangerous for patients in clinical practice. Patent application DE
Further work, including the Phase IIa study by Applicant No. 27 33 658,
It shows that the resistance of the initially sensitive pathogen rapidly builds up. Therefore, these derivatives have not been clinically applied.

In addition, it is known to use certain bisphosphonic acids and their derivatives as pharmaceutical compositions. To date, the microbiostatic efficacy of bisphosphonic acids (DE 3 611 522), their efficacy in disorders of calcium and phosphorus metabolic pathways
(DE 2 534 390, DE 2 534 391, DE 3 334 211, DE 3 434 667, DE 2 745 083)
, Bacteriostatic efficacy (DE 3 425 812), their lipid-lowering efficacy (Arzneimittelfo
rschung 46, 759-62) and their ability to stimulate immune competent cells (WO 97/38
696) is known.

[0006] The antimicrobial efficacy of phosphonochlorin on bacteria and the efficacy of foscarnet on viruses have been disclosed. In addition, the suitability of phosamine ammonium and N, N-dimethyl- (hydroxy-2-oxo-2-methoxyethyl) phosphonoamide as fungicides has been reported. The use of inhibitors of lipid metabolism has been accepted and widespread as the basis of therapy for a long time. These inhibitors are used to reduce the risk of cardiac and vascular disorders due to cardiac disorders and hyperlipidemia. Pharmacological treatment of hyperlipidemia is generally based on regulating fat intake and controlling fat, especially cholesterol synthesis. Cholesterol synthesis is generally controlled by β-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase). Cholesterol self-synthesis is generally higher than food intake (Berthold HK, of Bergmann K., Dtsch
Med. Wochenschr. 121, S.729 (1996); Richter WO, Fortscher. Med. 114,
S.177, 193).

[0007] Anion exchangers and β-sitosterol are known to control fat intake from the digestive tract. The ion exchanger contains cholestyramine and colestipol. They absorb bile acids, thereby inhibiting enterohepatic return transport and significantly increasing fecal sterolene. β-sitosterol is a plant sterol structurally related to cholesterol. It inhibits the absorption of dietary cholesterol in the intestinal mucosa.

In addition, nicotinic acid and its derivatives, clofibrate and their derivatives and probucol have been used for controlling lipid metabolism or preventing disorders from hyperlipidemia. Nicotinic acid and nicotinic acid derivatives reduce fatty acids, triglycerides and cholesterol. To date, the mechanism is unknown. Either clofibric acid ethyl ester, clofibrate and their derivatives and analogs reduce cholesterol, but the mechanism is unknown. The active mechanism of probucol is not clear.

To control this synthesis, HMG-CoA synthetase inhibitors (US 50 64 856, US 475
1237), HMG-CoA reductase inhibitor (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 9
38, US 43 75 475, US 43 46 227, US 44 106 29, US 44 447 84, US 44 50 17
1, 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 860
3488A, 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 9397
1, 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 pyrophosphate, pyrophosphate derivatives, bisphosphonic acid derivatives, phosphunylmethylphosphonic acid derivatives, phosphinylformyl derivatives , Phosphonocarboxy derivatives, phosphonosulfonic acid derivatives, phosphinylmethylphosphonic acid derivatives, some of which are known as pharmaceutical and cosmetic preparations for controlling calcium and phosphorus metabolism (DE 25 34 390, DE 25 34 391, DE 33 34 211, DE
34 34 667, DE 27 45 083, US 53 12 814, 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 96
9, 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 other inhibitors of cholesterol synthesis (US 5
6 61 145, US 57 44 467) are used, but their role is unclear. HMG-Co
A reductase inhibitors reduce the rate at which the cholesterol synthase HMG-CoA reductase is regulated. These enzyme affinities are less than 20000-fold higher than those of the substrate HMG-CoA. This HMG-CoA reductase converts HMG-CoA to mevalonate, which gives rise to the primary steps of dolochol and ubiquinone in addition to cholesterol, in particular isopentenyladenine and huanesylpyrophosphate. In bacteria, fungi and parasites that have HMG-CoA reductase,
Isopentenyl diphosphate is formed during the acetate / mevalonate pathway and is suppressed by HMG-CoA reductase inhibitors.

[0010] The first inhibitors found were penicillium (mevastatin) and aspergillus
fungi (lovastatin). Modification of this side chain leads to simvastatin, an advance of mevastatin to pravastatin. On the other hand, a complete synthase inhibitor (fluvastatin) is also commercially available, which is a mevalonate lactone derivative having a fluorophenyl-substituted indole ring.

In the past, attempts have been made to use these substances for the control of infectious disorders. In particular, attempts have been made to inhibit the growth of plants, fungi, parasites, bacteria and viruses by using HMG-CoA inhibitors. HMG-CoA synthetase and H
MG-Co reductase inhibitors are useful for certain bacteria and fungi (US 50 26 554, US 50 64 8
56, US 49 20 111, US 49 2-113) and the acetate / mevalonate pathway in parasites. However, many bacteria such as Escherichia coli are HMG-CoA
Does not show inhibition by reductase inhibitors. The reason is that these bacteria probably have separate metabolic pathways. In fact, in Escherichia coli, acetate /
The lack of mevalonate metabolic pathway and the existence of other metabolic pathways have been demonstrated (Rohm
er M. et al., Biochem. J. 295, S. 517 (1993); Lois EM et al., Proc.
Acad. Sci. USA 95, S.2105 (1998)).

[0012]

[0005] In the case of parasites, no separate route is known to date. The applicant of the present invention has reported that so-called 1-deoxyxylulose, a separate metabolic pathway in the case of parasites.
ylulose) or the 2-C-methylerythrose-4 phosphate pathway has been successfully demonstrated. Studies of HMG-CoA reductase inhibitors in parasites have produced different results depending on the parasite. For example, schistosomiasis pathogens cannot be killed by high doses of lovastamine, whereas malaria pathogens can be killed in vitro but not in vivo. Sleep pathogens cannot be completely inhibited by HMG-CoA reductase inhibitors.
In a similar attempt to inhibit viral multiplication, virus-infected cells
This shows that the inhibitory effect of the oA reductase inhibitor is weakened.

[0013] Similarly, squalene synthetase inhibitors, such as aminobisphosphonates, have been successfully tested as inhibitors of amoebic dysentery. Low insecticidal effect was observed. Similar experiments with toxoplasma have also not shown satisfactory results. In addition, squalene monooxygenase inhibitors have also been developed as fungicides.

[0014]

Accordingly, it is an object of the present invention to provide a medicament which can be used to prevent infectious processes in humans, animals and plants, and a medicament as a fungicide, and
It is an object of the present invention to provide a drug that significantly reduces the accumulation of drug resistance in plants, viruses, fungi, parasites and bacteria.

Unexpectedly, the combination of an anti-infective compound inhibiting the metabolic pathway of 2-C-methylerythrose-4 with a lipogenesis inhibitor, in particular a cholesterol synthesis inhibitor, in particular an HMG-CoA reductase inhibitor, and Squalene synthetase was found to enhance the efficacy and effectiveness of infection prevention and treatment. Surprisingly, the combination kills microorganisms that cannot be killed by either the first group or the second group. Surprisingly, it has been shown that this combination can significantly reduce the accumulation of resistance to the compounds used, a concern when dealing with lipid metabolism inhibitor compounds.

Lipid metabolism inhibitors consisting of anti-infective active compounds that inhibit the 2-C-methylerythrose-4 metabolic pathway, and inhibitors of lipid metabolism, are useful for infection of plants, especially humans and animals, especially parasites, bacteria Suitable for the prevention and treatment of infections caused by fungi and viruses and as fungicides in plants.

The lipid metabolism inhibitor according to the present invention contains at least one anti-infective active compound that inhibits the 2-C-methylerythrose-4 metabolic pathway and / or salts thereof. Generally, pharmaceutically acceptable salts, esters, ester salts, or compounds that upon application provide the compounds according to the invention as metabolites or degradation products (these are also referred to as "prodrugs"). contains.

The following are some classes of substances that have shown excellent success in preventing and treating infections in combination with lipid metabolism inhibitors.

The group of anti-infective active substances can be measured and determined by the following method: contacting a protein or a derivative thereof which is part of the 2-C-methylerythrose-4 metabolic pathway with an active agent to be tested, Active agents that inhibit the protein or derivative are selected. This method is known to the parties.

I. Complex preparation of lipid metabolism inhibitors and aminohydrocarbylphosphonic acid derivatives Aminohydrocarbylphosphonic acid derivatives and their preparation are described in DE-Al-27336
A detailed description can be found in No. 58 and PCT / EP99 / 02462. Aminohydrocarbylphosphonic acid derivatives corresponding to general formula (I):

Embedded image Wherein R ₁₁ and R ₁₂ are the same or different and are H, OH, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted R ₁₃ and R ₁₄ are selected from the group consisting of aralkyl, and substituted and unsubstituted heterocyclic groups, wherein R ₁₃ and R ₁₄ are substituted and unsubstituted alkyl of 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl of 1 to 26 carbon atoms, substituted And unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, 1 to 26 carbon atoms
Selected from the group consisting of substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl of 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen, X ₁₃ and X ₁₄ , wherein , X ₁₃ and X ₁₄ are the same or different and include hydrogen, substituted and unsubstituted alkyl having 1 to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having 1 to 26 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted aryl. Substituted aralkyl, substituted and unsubstituted alkenyl of 1 to 26 carbon atoms, substituted and unsubstituted alkynyl of 1 to 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, cations of organic and inorganic bases In particular, metal cations of Group 1, 2, or 3 of the periodic table, ammonium,
Selected from the group consisting of substituted ammonium and ammonium compounds derived from ethylenediamine or amino acids, and A ₁ corresponds to an alkylene, alkenylene or hydroxyalkylene group or a formula:

Embedded image Wherein the group C together with the substituents₁₃, C₁₄, C_FifteenOne or more selected from
The carbon atom above may be deleted and B₁ From B_TenAt least one of
The substituent is C_3-8 -Cycloalkyl- (C_0-9 ) -Alkyl groups, wherein C_3-8 
-Cycloalkyl group and C_0-9 -An alkyl group is one or more double bonds
And one or two carbon atoms of the cycloalkyl group may be
May be substituted with a nitrogen, oxygen or sulfur atom, and
And alkyl groups are hydroxy, halogen, amino, oxo, branched or
Straight chain C_1-9 -Alkyl group and C_2-9 -May be substituted with an alkenyl group
, Where C_1-9 -Alkyl group and C_2-9 An alkenyl group is hydrogen, hydroxy,
May be substituted with amino, halogen, and oxo groups;
Existing substitution B₁₁From B₁₁₀ Is hydrogen, hydroxy, halogen, amino, C _1-26 -Alkyl group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26-Al
Selected from the group consisting of a kill group, or both substituents on one carbon atom are
To form an oxo group,_1-26Alkyl groups and each C_1-26An alkoxy group is
Branched or linear, and saturated or one or more double bonds
Which is substituted with a hydroxy, amino, halogen and oxo group
It may be.

According to the invention, when the aminohydrocarbylphosphonic acid derivative is used as an anti-infective compound, the inhibitor of lipid metabolism is not an aminohydrocarbylphosphonic acid derivative of formula (I).

The present invention also includes pharmaceutically acceptable salts, esters and ester salts.

Preferably R₁₁Is OX₁₁, R₁₃Is OX₁₃And R₁₄ Is OX₁₄And where
X₁₁Is hydrogen, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and
Unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl
And R is selected from the group consisting of substituted and unsubstituted heterocyclic groups;₁₂, X₁₃, X ₁₄ And A₁ Has the same meaning as in formula (I). Preferably A₁ Carbon chain
Consists of three carbon atoms.

The carbon chain A ₁ of formula (IA) consists of four carbon atoms C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ ;
Compounds in which B ₁₇ or B ₁₈ or both are hydroxy groups are also preferred. Here, a methylene group is also preferable for R ₁₃ and R ₁₄ .

Preferably B₁₁And B₁₂Together form further oxo groups. In this case, A ₁ Has four carbon atoms C₁₁, C₁₂, C₁₃, C₁₄Consists of Preferably
Is B₁₇And B₁₈Further form together an oxo group. Where the charcoal in A
The strand has four carbon atoms C₁₁, C₁₂, C₁₃, C₁₄Consists of

The carbon chain preferably consists of five carbon atoms C ₁₁ , C ₁₂ , C ₁₃ , C ₁₄ , C ₁₅ , wherein B ₁₁ and B ₁₂ together form an oxo group, and One substituent B ₁₉ or B ₁₁₀ is a hydroxy group, or B ₁₉ and B ₁₁₀ also form an oxo group.

Substances in which the phosphonic or phosphinic acid or phosphinoyl group is replaced by a sulphone or sulphonyl group are also suitable:

Embedded image

II. Complex Preparations of Lipid Metabolism Inhibitors and Bisphosphonic Acid Derivatives Bisphosphonic acids and their derivatives are described in detail in parallel international patent applications filed simultaneously by the same applicant. Bisphosphonic acids, such as general formula (II), and derivatives thereof, and pharmaceutically acceptable salts, esters and ester salts thereof, or compounds capable of providing the compound to be administered upon application as a metabolite or degradation product used:

Embedded image _Wherein X _II1 , X _II2 , X _II3 , and X _II4 are the same or different, and represent hydrogen,
Substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, Na,
K, Ca, Mg, Periodic Table 1 such as Al, second or third group metal is selected from substituted and unsubstituted ammonium and the group consisting of ammonium compounds from Echinjiamin or amino, A ₁₁ is deleted Also selected from the group consisting of alkylene, alkenylene and hydroxyalkylene, wherein R _II1 and R _II2 are the same or different and are H, OH, —NH ₂ , substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, a substituted and unsubstituted heterocyclic group and -SR _II3 Cl, and the group consisting of -NR _II3 R _II4, wherein R _II3, R _II4 is a same or different, H, OH, substituted and unsubstituted acyl, substituted and unsubstituted Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, selected from the group consisting of substituted and unsubstituted cycloalkyl and substituted and unsubstituted heterocyclic group.

Bisphosphonic acid derivatives of the formula II are particularly preferred, wherein X _II1 , X _{II 2} , X _II3 , X _II4 are the same or different and are H, substituted and unsubstituted alkyl, substituted and unsubstituted Aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, metals of Group 1, 2 or 3 of the periodic table such as Na, K, substituted and unsubstituted ammonium, and A is selected from the group consisting of ethylenediamine or ammonium compounds derived from amino acids, A _II may be deleted and is selected from the group consisting of alkyl, (CH ₂ ) _0-6, especially (CH ₂ ) _1-5 and amidino; _II1 is selected H, OH, NH _2, from the group consisting of -CH _3, R _II2 is -NH _2,

Embedded image Selected from the group consisting of:

Bisphosphonates are particularly preferred, these being aminohydroxy-methylidene-
Bisphosphonic acid, 2-amino-1-hydroxyethylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid,
-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid, 6-amino-
1-hydroxyhexylidene-1,1-bisphosphonic acid, aminomethylenebisphosphonic acid, 3-methylpentylamino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2- (3-pyridinyl) -1-hydroxyethylidene- Bisphosphonic acid, 1-hydroxy-2- (imidazol-1-yl) -ethylidene-1,
It is selected from the group consisting of 1-bisphosphonic acid, cyclopentylaminomethylene diphosphonic acid, 4-chlorophenyl-1-thiomethylene-1,1-bisphosphonic acid and derivatives thereof. When the anti-infective active compound is a bisphosphonic acid derivative, the lipid metabolism inhibitor is not a bisphosphonic acid derivative.

III. Complex preparations of organophosphorus compounds containing a keto group with inhibitors of lipid metabolism These compounds are described in detail in DE-A-198 31 637.2. These compounds according to the invention correspond to the general formula (III):

Embedded image Where R_III1Is H, substituted and unsubstituted acyl, substituted and unsubstituted alkyl,
Substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted
And unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloal
Alkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen and
And OX_III1Selected from the group consisting of_III1Is hydrogen, substituted and unsubstituted
Sil, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted
And unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted ant
, Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, silyl
, Substituted and unsubstituted heterocyclic groups, cations of organic and inorganic bases, especially
Cations of group 2 or 3 metals, ammonium, substituted ammonium and
R is selected from the group consisting of ammonium compounds_III4, R_III3Are the same or different and include hydrogen, substituted and unsubstituted acyl,
Substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted
Unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl,
Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted
Substituted heterocyclic group, halogen and OX_III4And OX_III3Selected from the group consisting of
, Where X_III4, X_III3Is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted
Substituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl,
Silyl, substituted and unsubstituted heterocyclic groups, cations of organic and inorganic bases, especially periodicity
Cation, ammonium, substituted ammonium of metals of group 1, 2 or 3
, And an ammonium compound derived from ethylenediamine or an amino acid
Selected from the group; and A_III1And A_III2One or both may be deleted,_III1And A _III2 Are the same or different, alkylene group, alkenylene group, oxo group,
Represents a hydroxy group or an oxohydroxyalkylene group. A_III2Is preferably not present. This invention relates to a pharmaceutically acceptable salt,
, Esters and ester salts are also included.

[0032] phosphonic acid derivatives according to the invention was found to be particularly suitable, in this case, R _III4 the OX _III4 and R _III3 are _{OX III3, R III1, X III4} , X III3,
A _III1 and A _III2 includes same meaning as in formula (III).

Particularly preferred phosphonic acid derivatives are chloroacetylphosphonic acid (phosphonochlorin), phosphonoformic acid (foscarnet), phosphonoacetic acid, N, N-
Dimethyl- (1-hydroxy-2-oxo-2-methoxy-ethyl) -phosphonoamide and 2-hydroxy-2-hydroxymethyl-3-oxo-butylphosphonic acid (phosphonotricin) and ammonium-ethylcarbamoylphosphonic acid (phos Amine ammonium).

IV. Lipid metabolism inhibitors and organic compounds containing at least one ether or keto group
Complex Preparations with Phosphorus Compounds These compounds according to the invention are compounds corresponding to the following general formula (IV) and their pharmaceutically acceptable salts, esters and amides and ester salts:

Embedded image Wherein R _IVI and R _IV2 are the same or different and are 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,
Selected from the group consisting of substituted and unsubstituted heterocyclic groups, halogen, OX _IVI and OX _IV2 , wherein X _IVI and X _IV2 are the same or different and are hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxy. From the group consisting of alkyl, 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 groups B _IV is selected from the group consisting of the following ether groups (IVA):

Embedded image Wherein, A _IV2 in A _IV1 and A _IV2 are possible deletions, and A _IV1 and A _IV2 is a same or different, consist of an alkylene group, alkenylene group and hydroxy alkylene, keto group (IVB) Selected from group:

Embedded image Where A_IV3 And A_IV4 One or both of the two can be deleted and _IV3 And A_IV4 Are the same or different, and include an alkylene group, an alkenylene group,
And hydroxyalkylene groups, and in particular at least one heteroatom in the ring
Consists of 5- and 6-membered rings containing not only carbon atoms but also ring members, especially heterocyclic compounds
A heteroatom is selected from the group consisting of oxygen and nitrogen;
R_IV3 And R_IV4 Are the same or different, and include hydrogen,
Substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms
Killed, substituted and unsubstituted aryl groups, substituted and unsubstituted acyl, substituted and unsubstituted
Substituted aralkyl, substituted and unsubstituted alkenyl of up to 26 carbon atoms,
The following substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl,
And unsubstituted heterocyclic groups, halogen, OX_IV3 Or OX_IV4 Selected from the group consisting of
Where X_IV3 Or X_IV4 Are the same or different, and represent hydrogen, carbon atom 2
Up to 6 substituted and unsubstituted alkyl, up to 26 substituted and unsubstituted carbon atoms
Loxyalkyl, substituted and unsubstituted aryl groups, substituted and unsubstituted aralkyl,
Substituted and unsubstituted alkenyl of up to 26 carbon atoms, substituted and unsubstituted of up to 26 carbon atoms,
And unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted hetero
Cations of cyclic groups, silyls, organic and inorganic bases, especially the first, second or
Group 3 metal cations, ammonium, substituted ammonium, and ethylenedia
It is selected from the group consisting of min or ammonium compounds derived from amino acids.

In particular, compounds corresponding to formula (IVC) are preferred:

Embedded image Wherein R _IV2 is selected from the group consisting of acetyl and formyl, A _IV1 is selected from the group consisting of methylene, ethylene, ethynylene, hydroxyethylene, 2-hydroxypropylene, and X _IV3 and X _IV4 are the same. Or, they are different and are selected from the group consisting of sodium, potassium, methyl, and ethyl. The preferred chain -A _IV1 -OC (ZY)-consists of one oxygen atom and two or three carbon atoms (without regard for substituents), two carbon atoms being particularly preferred.

Among the ether compounds, compounds selected from the following group are particularly preferred: ((N
-Formyl-N-hydroxyamino) -methoxy) -methylphosphonic acid disodium salt, ((N-acetyl-N-hydroxyamino) -methoxy) -methylphosphonic acid disodium salt, ((N-formyl-N-hydroxy Amino) -ethenoxy) -methylphosphonic acid disodium salt, (2- (N-acetyl-N-hydroxyamino) -ethenoxy) -methyl-phosphonic acid disodium salt, (3
-(N-formyl-N-hydroxyamino) -2-hydroxypropoxy) -methylphosphonic acid disodium salt, (3- (N-acetyl-N-hydroxyamino) -2-hydroxypropoxy) -methylphosphonic acid disodium salt salt.

Further, compounds corresponding to the following formula (IVD) are preferred:

Embedded image Wherein R _IV2 is selected from the group consisting of acetyl and formyl, A _IV3 is selected from the group consisting of methylene, ethylene, ethenylene, hydroxymethylene, hydroxyelene and 2-hydroxypropylene, and A _IV4 is deletion or methylene. _Yes , X _IV3 and _IV4 are the same or different and are selected from the group consisting of metals of the first, second or third groups of the periodic table, especially sodium, potassium and methyl, ethyl.

Preferred chains —A _IV1 —CO—A _IV2- — are preferably chains of 2 to 4 carbon atoms (substituents not taken into account), especially 3 carbon atoms.

Among these, the following compounds are particularly preferred: 2- (N-formyl-N-hydroxyamino) -1-oxoethylphosphonic acid · 2
Sodium salt, 2- (N-acetyl-N-hydroxyamino) -1-oxoethylphosphonic acid disodium salt, 3- (N-formyl-N-hydroxyamino)
-1-oxopropylphosphonic acid disodium salt, 3- (N-acetyl-N-
Hydroxyamino) 1-oxopropylphosphonic acid disodium salt, 3- (
N-formyl-N-hydroxyamino) -1-oxo-2-propenyl-phosphonic acid disodium salt, 3- (N-acetyl-N-hydroxyamino) -1-oxo-2-propenyl phosphonic acid disodium salt Salt, 4- (N-formyl-N-
(Hydroxyamino) -1-oxo-3-hydroxybutylphosphonic acid disodium salt, 4- (N-acetyl-N-hydroxyamino) -1-oxo-3-hydroxybutylphosphonic acid disodium salt, 3 -(N-formyl-N-hydroxyamino) -2-oxopropylphosphonic acid disodium salt, 3- (N-
Acetyl-N-hydroxyamino) -2-oxopropylphosphonic acid disodium salt, 4- (N-formyl-N-hydroxyamino) -3-oxo-2-hydroxy-2-methylbutylphosphonic acid disodium salt , 4- (N-acetyl-
N-hydroxyamino) -3-oxo-2-hydroxy-2-methylpyrropylphosphonic acid disodium salt, 4- (N-formyl-N-hydroxyamino) 3-
Disodium oxo-2-hydroxy-2- (hydroxymethyl) -butylphosphonate, 4- (N-acetyl-N-hydroxyamino) -3-oxo-2-hydroxy-2- (hydroxymethyl) -propiphosphone Acid disodium salt.

In cyclic compounds, amino acid groups and phosphorus atoms can be attached to any ring carbon atom. However, compounds where the bond is to two carbon atoms separated by only one additional atom are preferred. In heterocyclic compounds, it is preferred if both carbon atoms are separated by one heteroatom.

The following compounds are particularly preferred:

Embedded image

In addition, substances in which the phosphonic or phosphinic acid or phosphinoyl group has been replaced by the following sulphone or sulphonyl group are suitable:

Embedded image

V. A lipid metabolism inhibitor, an organic phosphorus compound containing at least one hydroxy group,
Complex preparations of the phosphonic acid derivatives according to the invention are derivatives corresponding to the formula (V) and their salts, esters, amides and ester salts:

Embedded image Wherein one or both of A _V1 and A _V2 can be deleted, and A _V1 and A _V2 are the same or different and are selected from the group consisting of an alkylene group, an alkenylene group and a hydroxyalkylene group. They are a carbon chain -A _V1 -CHOH-A _V2 -
Preferably consists of 2 to 5, especially 3 to 4 carbon atoms, and B _V is selected from the group consisting of groups of formula (VA):

Embedded image Wherein R _V1 is hydrogen, OH, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl,
Selected from the group consisting of substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups and halogen, and the following groups (VB):

Embedded image Wherein R _V2 , R _V3 and R _V4 are the same or different and are hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Selected from the group consisting of aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, and the following group (VC):

Embedded image Wherein R _V5 , R _V6 and R _V7 are the same or different and are hydrogen, OH, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and Selected from the group consisting of unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, wherein X _V3 and X _V4 are the same or different Wherein hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, Substituted and unsubstituted heterocyclic groups, silyl, organic and inorganic bases On particular periodic table 1, second or third group of metal cations, ammonium, is selected from the group consisting of substituted ammonium, and ethylene diamine or ammonium compounds derived from amino acids. Preferred R _V1 in formula (VA) is a methyl group. In formula (VB), preferred R _V2 and R _V4 are hydrogen and R _V3 is a methyl group
In formula (VC), preferred R _V5 is a methyl group, R _V6 is selected from the group consisting of H, OH and methyl, and R _V7 is a hydroxy group.

Particularly preferred compounds are those of the formula (VD):

Embedded image In the formula, A _V2 is a straight-chain hydroxyalkylene having 1 to 3 carbon atoms, and X _V3 and X _V4 are the same or different and include hydrogen, a metal of Group 1, 2 or 3 of the Periodic Table. Particularly selected from the group consisting of sodium, potassium and methyl, ethyl.

Among these compounds, 3,4-dihydroxy-5-oxo-hexylphosphonic acid disodium salt, 1,2,3,4-tetrahydroxy-5-oxo-hexylphosphonic acid disodium salt, , 3,4-Trihydroxy-5-oxo-
Hexylphosphonic acid disodium salt, 1,2,3-trihydroxy-4-oxo-pentylphosphonic acid disodium salt, and 2,3-dihydroxy-4-
Oxopentyl phosphonic acid disodium salt is particularly preferred.

Furthermore, compounds corresponding to formula (VE) are particularly preferred:

Embedded image _Wherein A _V2 is a straight-chain hydroxyalkylene having 1 to 3 carbon atoms, X _V3 and X _V4 are the same or different and include hydrogen, a metal of Group 1, 2 or 3 of the Periodic Table, especially sodium. , Potassium, methyl and ethyl.

Among these compounds, 3,4,5-trihydroxy-4-methyl-pentylphosphonic acid disodium salt, 2,3,4,5-tetrahydroxy-4-methyl-pentylphosphonic acid · 2 Sodium salt, 1,3,4,5-tetra-4-methylpentylphosphonic acid disodium salt, and 1,2,3,4,5-pentahydroxy-4-methyl-pentylphosphonic acid disodium salt are particularly preferred. preferable.

In particular, compounds corresponding to formula (VF) are also preferred:

Embedded image _Wherein A _V2 is a straight-chain hydroxyalkylene having 1 to 3 carbon atoms, and X _V3 and X _V4 are the same or different and include hydrogen, a metal of Group 1, 2 or 3 of the Periodic Table, especially It is selected from the group consisting of sodium, potassium, methyl and ethyl.

Among these compounds, 3,4-dihydroxy-4-methyl-5-oxo-
Pentylphosphonic acid disodium salt, 2,3,4,5-trihydroxy-4-
Methyl-5-oxo-pentylphosphonic acid disodium salt, 1,2,3-trihydroxy-4-methyl-5-oxo-pentylphosphonic acid disodium salt,
2-monohydroxy-3-methyl-4-oxo-butylphosphonic acid disodium salt, 1,2-dihydroxy-3-methyl-4-oxo-butylphosphonic acid / 2
Sodium salts are particularly preferred.

VI. Lipid metabolism inhibitors and organophosphorus or organosulphurization containing amine or imine groups
Complex preparations with the compounds The organic compounds according to the invention are compounds corresponding to the following general formula (VI) and their pharmaceutically acceptable salts, esters and amides and ester salts:

Embedded image _Wherein R _VI3 and R _VI4 are the same or different and are hydrogen, substituted or unsubstituted alkyl having up to 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having up to 26 carbon atoms, substituted and unsubstituted aryl groups, substituted and unsubstituted. Substituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl of up to 26 carbon atoms, substituted and unsubstituted alkynyl of up to 26 carbon atoms, substituted and unsubstituted cycloalkyl,
Selected from the group consisting of substituted and unsubstituted heterocyclic groups, halogen, OX _Vi3 or OX _Vi4 , wherein X _VI3 or X _VI4 is the same or different and is hydrogen, substituted or unsubstituted alkyl having up to 26 carbon atoms, Substituted and unsubstituted hydroxyalkyl of up to 26 atoms, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl of up to 26 carbon atoms, substituted and unsubstituted alkynyl of up to 26 atoms, substituted and unsubstituted Cycloalkyls, substituted and unsubstituted heterocyclic groups, silyls, cations of organic and inorganic bases, especially cations of metals of groups 1, 2 or 3 of the periodic table, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids Selected from the group consisting of
And _BVI is the following group (VIA):

Embedded image And selected from the group consisting of the following groups (VIB):

Embedded image In the formula, A _VI is selected from the group consisting of an alkyleneamine group, an alkenyleneamine group, a hydroxyalkyleneamine group, an alkyleneimine group, an alkenyleneimine group and a hydroxyalkylenimine group, wherein the nitrogen atom is represented by the following group: Is a member of the chain connecting the nitrogen and phosphorus atoms:

Embedded imageOr group R_VII-N =. Wherein R in group (VIA)_VI1 And R_VI2 Are the same or different,
R in the group (IVA)_VI1 And R_VI2 And R in group (VIB)_VI1 Is
Hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted
And unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted ant
, Substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and
Unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, OX_VI1 And OX _VI2 Selected from the group consisting of_VI1 And X_VI2 Are the same or different
Hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl
, Substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted
Substituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted
Selected from the group consisting of substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups
You. Preferably A_VIIs an amino group, wherein the nitrogen atom is not located at the end. Good
Preferably A_VISeparates the nitrogen and phosphorus atoms by three atoms (without considering substituents)
Join.

Particularly preferred these compounds correspond to formula (VI):

Embedded image _{Wherein, R VI1, R VI2, R} VI3 and X _VI4 are the same as defined in the case of formula (VI), and, A _VI is C-N-C, C = N-C, C-N = C Wherein the carbon atoms can be replaced by hydroxy groups or alkyl groups having less than 7 carbon atoms.

Particularly preferred R _VI1 is a hydroxy group, R _VI2 is selected from the group consisting of acetyl, formyl, R _VI3 is selected from the group consisting of hydrogen, methyl, ethyl, hexadecyl, octadecyl and OX _VI3 , and X _VI3 and X _VI4 are selected from the group consisting of hydrogen, sodium, potassium, methyl, ethyl, hexadecyl and octadecyl, and when both are present, X _VI3 and X _VI4 are the same or different.

Furthermore, compounds corresponding to formula (VID) are preferred:

Embedded image _{Wherein, R VI1, R VI2, R} VI3 and X _VI4 are as defined in formula (I) selected, A is C-N-C, C = N-C, from the group consisting of C-N = C Wherein the carbon atom may be replaced by a hydroxy group or by less than 7 carbon atoms.

Particularly preferred R _VI1 is selected from the group consisting of acetyl and formyl, R _{VI 3} is selected from the group consisting of hydrogen, methyl, ethyl, hexadecyl, octadecyl and OX _VI3 and X _VI3 and X _VI4 are hydrogen, sodium , Potassium, methyl, ethyl, hexadecyl and octadecyl, wherein X _VI3 and X _VI4 are the same or different as long as both are present.

VII. Complex preparation of lipid metabolism inhibitor and organophosphorus compound having nitrogen heterocycle

The organophosphorus compounds used according to the invention are compounds corresponding to the following general formula (VII) and their pharmaceutically acceptable salts, esters and amides and ester salts:

Embedded image _Wherein A _VII is selected from the group consisting of a (C _1-9 ) -alkylene group, which may contain one or more double bonds, and hydroxy, halogen,
Amino, oxo, branched or linear C _1-9 -alkyl and C _2-9 -alkenyl may be substituted, wherein C _1-9 -alkyl and C _2-9 -alkenyl are It may be substituted by hydrogen, hydroxy, amino, halogen and oxo groups, -C-OC- and -C-N-C-, wherein -C-O-C- and -C-N
The -C- carbon atom may be substituted with an alkyl or hydroxy group of 7 carbon atoms or less, or A _VII corresponds to formula (VIIA):

Embedded image Wherein, together with their substituents, C_VII3, C_VII4, C_VII5One selected from
Or two or more carbon atoms may be deleted and B_VII1From B_VII10 Less of
One of the substituents is C_3-8 -Cycloalkyl- (C_0-9 ) -Alkyl groups;
Where C_3-8 A cycloalkyl group and (C_0-9 ) -Alkyl group is one or two
May contain one or more double bonds and one or two of the cycloalkyl groups
May be replaced by a nitrogen, oxygen or sulfur atom, wherein cyclo
Alkyl groups and alkyl groups are hydroxy, halogen, amino, oxo group, branched
Or linear C_1-9 An alkyl group, and C_2-9 -May be substituted with an alkenyl group
And here C_1-9 -Alkyl group and C_2-9 An alkenyl group is hydrogen, amino, ha;
Or an oxo group, and the remaining substituent B_VII1From
B_VII10 Is hydrogen, hydroxy, halogen, amino group, C_1-26-Alkyl group, C_{1- 26} -Alkoxy group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26−Aki
Or both substituents of one carbon atom are taken together
To form an oxo group, where each C_1-26Alkyl groups and each C_1-26-Alkoxy
The group may be branched or straight-chain and saturated or one or more double
Unsaturated type having a bond, substituted with hydrogen, amino, halogen and oxo groups
Where R_VII1Has one or two nitrogen, oxygen or sulfur atoms in the ring
Selected from the group consisting of 5- and 6-membered heterocycles, wherein the heterocycle is saturated or monocyclic.
An unsaturated type having one or more double bonds or triple bonds, and
By hydroxy, halogen, amino, oxo group and branched or linear C _1-9 -Alkyl group and C_2-9 -May be substituted by an alkenyl group;
Here C_1-9 -Alkyl group and C_2-9 The alkenyl group is saturated or one or more
Is an unsaturated type having two or more double bonds or triple bonds, and is hydrogen, hydroxy, a
May be substituted with a mino, halogen and oxo group;_VII3And R_VII4Are the same or different and include hydrogen, substituted and unsubstituted C_{1- 26} -Alkyl, hydroxy-C_1-26-Alkyl, substituted and unsubstituted aryl,
Substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26 Alkenyl, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cyclo
Alkyl, substituted and unsubstituted heterocyclic group, halogen, OX_VII3And OX_VII4From
Selected from the group_VII3And X_VII4Are the same or different and are hydrogen, substituted and unsubstituted
Exchange C_1-26-Alkyl, substituted and unsubstituted hydroxy-C_1-26-Alkyl, substituted or
And unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26−
Alkenyl, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cycloalkyl
Alkyl, substituted and unsubstituted heterocyclic groups, silyl, organic and inorganic base cations
The cation, ammonium, and substituted anion of a metal of Group 1, 2, or 3 of the periodic table
Monium and ammonium compounds derived from ethylenediamine or amino acids
Selected from the group consisting of: If heterocycle R_VII1If there are two heteroatoms in it,
Can also be present, for example, in a mixed form of oxygen and nitrogen atoms.

Preferred R _VII1 is a heterocycle containing a nitrogen atom, wherein substituted and unsubstituted pyridine, substituted and unsubstituted pyrimidine, substituted and unsubstituted pyrrole and substituted and unsubstituted pyrazole moieties are particularly preferred,

Embedded image Is particularly preferred.

The organophosphorus compound preferably corresponds to the formula (VIIC):

Embedded image Wherein, R _VII3 is hydrogen, methyl, preferably an ethyl or an amide group, and X _VII4 is selected from hydrogen, sodium, potassium, methyl, from the group consisting of ethyl. Particularly preferably, it corresponds to the formula (VIID):

Embedded image

In addition, preference is given to substances in which the phosphonic or phosphinic acid or phosphinoyl group has been replaced by a sulphone or sulphonyl group (VIIE):

Embedded image

VIII. Complex preparation of lipid metabolism inhibitor and phosphonoformic acid derivative This compound is described in WO 9/16537. The organophosphorus compounds used according to the invention correspond to the following general formula (VIII):

Embedded image _Wherein the wavy line represents a bond having an α- or β-configuration, n is 0 or 1, R _III11 is substituted and unsubstituted C _1-26 -alkyl, hydroxy-C _1-26 -alkyl, substituted and unsubstituted Aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C _1-26 -alkenyl, substituted and unsubstituted C _1-26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic group _Wherein X _VIII11 is hydrogen, substituted and unsubstituted C _1-26 -alkyl, substituted and unsubstituted hydroxy-C _1-26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted heterocyclic aralkyl, substituted and unsubstituted C _1-26 - alkenyl, substituted and unsubstituted C _1-26 - alkynyl, substituted and unsubstituted cycloalkyl, Contact substituted And unsubstituted heterocyclic groups, silyls, cations of organic and inorganic bases, especially cations of metals of Groups 1, 2 or 3 of the Periodic Table, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids. is selected, R _VIII1 is C _1-24 - alkyl group, C _2-24 - alkapolyenyl group, C _2-24 - - alkenyl, C _2-24 having six double bonds 2 alkynyl group, C _3-8 - cycloalkyl group, C _3-8 - cycloalkyl -C _1-24 - alkyl and C _1-12 - alkoxy -C _1-12 - is selected from the group consisting of alkyl groups, each R _VIII2, R _VIII3 and R _VIII4 are selected from the group consisting of hydrogen, halogen, amino, acetylamino, azide and XR _VIII6 groups, wherein X is O or S
_Wherein R _VIII6 is selected from the group consisting of hydrogen, branched or straight chain C _1-4 -alkyl and C _2-4 -alkenyl, wherein C _1-4 -alkyl and C _2-4-
The alkenyl group is optionally substituted with hydrogen, amino, halogen or oxo group, or R _VIII2 , R _VIII3 and R _VIII4 together with the respective gem-hydrogen group represent an oxo group, R _VIII5 is hydrogen, C _{VIII 1-24} - alkyl group, C _3-8 - cycloalkyl group, Ar (C _1-24 - alkyl) group, an aryl group, an acyl group, a heterocyclic group, selected from the group consisting of halogen, where all groups Is branched or linear and may be optionally substituted by a hydroxy, amino, halogen or oxo group and may contain from 2 to 6 double and triple bonds, or R _VIII5 has the formula VIIIA or XIIIB is a phenyl group:

Embedded image _Wherein R _VIII7 and R _VIII8 are the same or different, are attached to any two positions of the phenyl ring, and R _VIII7 and R _VIII8 are hydrogen, halogen,
C _1-4 - alkyl group, C _1-4 - is independently selected from alkoxy group consisting of a carbonyl group - alkoxy, formyl, acetyl, propionyl, butyryl, formyl, acetyl, propionyl, butyryloxy, C _{2-5 May be} all branched or linear, or R ₇ and R _VIII8 may be taken together at adjacent positions, such as the 2,3-position or 3-position of the phenyl ring.
Can form a linear saturated alkylene group with 3 to 4 carbon atoms attached at the, 4-position, or R ₇ and R ₈ together form the 2,3- or 3,4-
A methylenedioxy group, 1,1-ethylidenedioxy group or 1,
To form a 2-ethylenedioxy group, or R _VIII5 is R _III9 COOCHR _VIII10 - it is selected from the group consisting of, R _Viii9 is, C _1-6 - - and R _III9 OCOOCHR _VIII10 alkyl group, C _2-6 - alkenyl Group, C _2-6 -alkynyl group, C _3-8 -cycloalkyl group, C _3-8 -cycloalkyl-C _1-6 -alkyl group and C _1-6 -alkoxy-C _1-6 -alkyl group Wherein all groups are branched or straight-chain and can be optionally substituted with hydroxy, amino, halogen or oxo groups, and R ₁₀ is a branched or straight-chain C _1-4. alkyl, wherein, if n = 1, the substituents in the formula _{(VIII) R VIII2, R VIII3} , R VI II4 and _{R III5 OOCPO (OH) OCH 2} - arrangement of D-gluco, L- gluc
o, D-galacto, L-galacto, D-manno, L-manno, D-talo, L-ta
lo, D-allo, L-allo, D-altro b, L-altro b, D-gulo, L-gulo,
When independently selected from D-ido or L-ido, and n = 0, the relative configurations of the substituents R ₂ , R ₃ and R ₅ OOCPO (OH) OCH ₂ — in formula (I) are independently D-ribo, L-ribo, D-arabino, L-arabino, D-xylo, L-xylo, D
-Lyxo or L-lyxo. According to the invention, the configuration of the glycosidic bond of the compound is preferably α.

[0061] Preferred compounds of formula (VIII), R _VIII1 is C _9-24 - alkyl groups, C _9-24 - alkenyl group, the double bond 2 to 6 C _9-24 - alkapolyenyl groups, C _9-24 −
An alkynyl group, a _C3-8 -cycloalkyl _C6-24 -alkyl group and a _C1-12 -alkoxy _C8-12 -alkyl group, each of which is optionally branched or straight-chain; It can be substituted by hydrogen, amino, halogen or oxo group.

In particular, R_VIII1 Is an n-tetradecyl group, an n-octadecyl-1-yl group,
The group consisting of cis-9-octadecenyl and cis-9-octadecene-1- groups
The use of any compound selected from is preferred. Preferably R_VIII2 , R _III3 , R_III4This is the case where each is a hydroxy group. Preferred R_III5Is hydrogen, e
It is a rumyl group or an acetyl group. Further, n is preferably 1, and the substituent R_VIII2 
, R_III3, R_III4And R_III5OOCPO (OH) OCH_Two The arrangement of-is D-gluc
o is preferred. X_VIII11= H_VIII11Is preferably OX_VIII11Represents

IX. Complex preparation of a lipid metabolism inhibitor and a heterocyclic phosphonoformic acid derivative The organophosphorus compound according to the present invention is described in WO 98/16535, and has the following formula (I)
Compounds corresponding to X) and their pharmaceutically acceptable salts, esters and amines, ester salts and their optical isomers:

Embedded image Where R_IX11Is a substituted and unsubstituted C_1-26-Alkyl, hydroxy-C_1-26−
Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted
Substituted aralkyl, substituted and unsubstituted C_1-26-Alkenyl, substituted and unsubstituted -C _1-26 Alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups
, Halogen and OX_IX11Selected from the group consisting of_IX11Is hydrogen, substituted and unsubstituted C_1-26-Alkyl, substituted and unsubstituted
Hydroxy-C_1-26-Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted
Aralkyl, substituted and unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26Al
Quinyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl
Cations of organic and inorganic bases, in particular of metals of group 1, 2 or 3 of the periodic table
Cation, ammonium, substituted ammonium, and ethylenediamine or
R is selected from the group consisting of ammonium compounds derived from amino acids;_IX1 And R_IX2 Each of C_1-24-Alkyl group, C_3-8 -Cycloalkyl
Group, C_3-8 -Cycloalkyl-C_1-24-Alkyl group, C_1-24-Alkoxy group, C _1-24 -Alkylthio group, C_1-24-Alkoxy-C_1-24Alkyl group and C_1-24−
Alkylthio-C_1-24-Alkyl group, acyl group, aryl group, aralkyl group,
Independently selected from the group consisting of a ring group, halogen and hydrogen;_1-24-Al
Kill group and C_1-24Each alkoxy group may be branched or linear
, Saturated or unsaturated from 2 to 6 double bonds, and hydrogen, amino,
Mercapto, halogen, oxo group, or C_1-24-Alkoxy group, C_1-24-Al
Killcarbonyl-oxy group, C_1-24-Alkoxycarbonyloxy group, C_1-24−
Alkylthio group, C_1-24-Alkylcarbonylthio group, C_1-24-Alkylamino
Group, di- (C_1-24-Alkyl) amino group, C_1-24-Alkylcarbonylamino group
, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) amino group, C_1-24-Al
Coxycarbonylamino group or C_1-24Alkyl- (C_1-24-Alkoxycarbo
Nil) optionally substituted with an amino group, wherein an aralkyl group, a heterocyclic group
, C_1-24Alkyl group and C_1-24Each of the alkoxy groups is branched or linear
And is saturated or unsaturated having 2 to 6 double bonds or triple bonds.
Or R_IX1 -CH-CH-R_IX2 Is C_4-8 Forms part of a carbocycle, which ring is
Si, mercapto, amino, halogen, may be optionally substituted with an oxo group,
Is C_1-24-Alkyl group, C_1-24-Alkoxy group, C_1-24-Alkylthio group, C_{1- twenty four} -Alkylamino group, di- (C_1-24-Alkyl) amino group, C_1-24-Alkyl
Carbonyl group, C_1-24-Alkyl carbonyloxy group, C_1-24-Alkoxycarboni
Group, C_1-24-Alkylcarbonylthio group, or C_1-24-Alkylcarbonyl
Amino group, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) amino group
Where C is_1-24Each alkyl group is branched or linear
May be a saturated or unsaturated type having 1 to 6 double bonds,
Or R_IX10Is a branched or linear C_1-4 -An alkyl group, and R_IX1 -CH-CH-R_IX2Is, for example, D-ribose, D-arabinose, D-ki
Sylose, D-lyxose, D-glucose, D-galactose, D-mannoh
, D-talose, D-allose, D-artose, D-glucose, D-id
Part of the furanose or pyranose ring of saccharides such as glucose or the corresponding L-isomer
Where each of the hydroxy groups is hydrogen, amino, azide, oxo,
Lcapto group or C_1-24-Alkoxy group, C_1-24-Alkylthio group, C_1-24-A
Alkylamino group, di- (C_1-24-Alkyl) amino group, C_1-24-Alkyl carbo
Nyloxy group, C_1-24-Alkylcarbonylthio group, C_1-24-Alkyl carboni
Ruamino group, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) amino group
Where each C is_1-24Alkyl groups are branched or linear and
May be an unsaturated type having 1 to 6 double bonds or double bonds,

In particular, R_IX1 And R_IX2 Each represents a carboxyl group or a carboxamide group
, Aryl group, aryloxycarbonyl group, aryl-C_1-24Alkyl group, C _1-24 -Alkoxycarbonyloxy group, C_1-24An alkylaminocarbonyl group,
Di- (C_1-24-Alkyl) -aminocarbonyl group, aryl-C_1-24Alkoxy
Carbonyl group, aryl-C_1-24-Alkylaminocarbonyl group, C_1-24-Al
Kill carbonyloxy- (C_1-4 ) -Alkylmethoxycarbonyl group, C_1-24−
Alkoxy-carbonyloxymethoxycarbonyl group, C_1-24-Alkoxycal
Bonyl-oxy- (C_1-24Alkyl) -methoxycarbonyl group
Selected, where each C_1-24The alkyl group is branched or straight-chain, saturated or
It may be an unsaturated type having 2 to 6 heavy bonds, and_1-4 -Alkyl group and C _1-24 The alkoxy group may be branched or linear, saturated or unsaturated,
And each aryl group corresponds to formula (IXA):

Embedded image _Wherein R _IX3 and R _IV4 are the same or different and are each hydrogen, halogen, C _1-4 -alkyl, C _1-4 -alkoxy, formyl, acetyl, propionyl, butyryl, formyl, acetyl, Propionyl, butyryloxy group,
R _IX3 and R _IX4 are selected from the group consisting of C _1-4 -alkoxycarbonyl groups, all of which may be branched or straight chain, or R _IX3 and R _IX4 are three carbon atoms bonded together at adjacent positions on the phenyl ring. Or R _IX3 and R _IV4 together form a methylenedioxy group, a 1,1-ethylidenedioxy group, or 1,2-ethylene bonded to a phenyl ring at an adjacent position. Form a dioxy group.

It is preferred to use a compound wherein each of R _IX1 and R _IX2 is independently selected from the group consisting of hydrogen, hydroxy, formyl, acetyl and methyl, wherein the methyl group is optionally a hydroxy or mercapto group. , or C _1-24 - alkoxy, C _1-24 - alkyl carbonyloxy group, C _1-24 - alkylthio group or a C _1-24 - may be substituted with an alkyl carbonyl thio group, the C _1-24 - The alkyl group and the C _1-24 -alkoxyl group may be branched or straight-chain, and may be saturated or unsaturated with 1 to 6 double bonds.

[0066] R _IX1 preferably a methyl group, this group is a hydroxyl group or a mercapto group, or a C _1-24 - alkoxy, C _1-24 - alkyl carbonyloxy group, C _1-24 - alkylthio or C ₁ The C _1-24 -alkyl group and the C _1-24 -alkoxyl group may be optionally substituted with a _-24- alkylcarbonylthio group. It may be unsaturated and R _IX2 may be a hydrogen group.

Particularly good results are obtained with compounds where R _IX1 and R _IX2 are each independently selected from the group consisting of hydrogen, n-octadecylmethyl, wherein R _IX1
Is preferably an n-octadecylmethyl group, and R ₂ is a halogen group. It is particularly advantageous if the compounds are in the relative configuration (R). When X _IX11 = halogen,
A preferred R _iX11 is OX _IX11 .

X. Complex preparation of a lipid metabolism inhibitor and a hydroxyaminooxocarbyl derivative The hydroxyaminooxocarbyl derivative used according to the invention corresponds to the following general formula (X):

Embedded image Wherein R _X1 is hydrogen, substituted and unsubstituted C _1-9 -alkyl, substituted and unsubstituted hydroxy C _1-9 -alkyl, substituted and unsubstituted C _1-9 -alkenyl, substituted and unsubstituted C ₁ -alkyl. ₉ -alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic group ₁ , halogen and OX _X1 , _Wherein X _X1 is hydrogen, substituted and unsubstituted C _1-9 -alkyl, substituted and unsubstituted hydroxy C _1-9 -alkyl, substituted and unsubstituted C _1-9 -alkenyl, substituted and unsubstituted C _1-9 -alkyl. Selected from the group consisting of alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups Wherein R _X2 represents a C _1-26 -alkyl, C _1-26 -alkoxy group, C _1-26 -alkoxy-C _1-26 -alkyl group, C _3-8 -cycloalkyl- (C _{0- 26} ) -alkyl groups, wherein one or more carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, and each _-C3-26 alkyl group And each C- _3-26 alkoxy group is branched or linear, and each -C _3-8 cycloalkyl group, C _2-26 -alkyl group and each C _2-26 -alkoxy group are saturated or Alternatively, it may be an unsaturated type having two or more double bonds, wherein each C _3-8 -cycloalkyl group, each C _1-26 -alkyl group and each C _1-26 -alkoxy group are hydroxy, amino , Halogen and oxo, or with the carbyl group COR _X3 , R _{X 3} is substituted and unsubstituted C _1-26 alkyl, hydroxy-C _1-26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C _1-26 -alkenyl Substituted and unsubstituted C _1-26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen,
Selected from the group consisting of OX _X3 , wherein X _X3 is hydrogen, substituted and unsubstituted C _1-26 -alkyl, substituted and unsubstituted hydroxy-C _1-26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted Aralkyl, substituted and unsubstituted C _1-26 -alkenyl, substituted and unsubstituted C _1-26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, cations of organic and inorganic bases, especially periodicity Table 1 is selected from the group consisting of cations of metals of Group 1, 2 or 3; ammonium; substituted ammonium; and ammonium compounds derived from ethylenediamine or amino acids.

Preferred R _X2 is a carboxylic acid group —COOH, wherein R _X1 is a branched or straight-chain C _1-4 alkyl group, particularly preferably an isopropylyl group and their pharmaceutically acceptable salts, esters, amides. is there.

As the salt of the carboxylic acid group, a salt in which H is substituted by a metal of the first, second or third group of the periodic table, ammonium or substituted ammonium, or ethylenediamine or an ammonium compound derived from an amino acid is preferable. . That is, a hydroxyaminooxocarbylcarboxylic acid derivative and an organic or inorganic base (eg, sodium salt, potassium salt, calcium salt, aluminum salt, ammonium salt, magnesium salt, triethylamine salt, ethanolamine salt, ethylenediamine salt, N, N′- Dibenzylethylenediamine salts and the like, as well as amino acid salts (eg, alginate, aspartate, glutamate) and other salt compounds are formed.

In addition, esters of carboxylic acid groups may be formed. Preferred examples of such esters are suitable mono- and diesters, and preferred examples of such esters include alkyl esters (eg, hexadecanyl esters, octadecanyl esters, etc.).

XI. Either two oxyline groups or one oxyline group, and one
Complex Preparation of a Lipid Metabolism Inhibitor and an Organophosphorus Compound Containing an Oxysulfur Group of the Invention: The organophosphorus compounds according to the invention are compounds corresponding to the general formula (XI) and their pharmaceutically acceptable salts, esters Amide and ester salts are:

Embedded image Wherein Z _XI is a phosphorus or sulfur atom, wherein A _XI is hydrogen, hydroxy, halogen, amino and oxo, and
A C _1-26 -alkyl group, a C _1-26 -alkoxy group, a C _1-26 -alkoxy-C _1-26 -alkyl group or a C _3-8 -cycloalkyl- (C _0-9 ) -alkyl group. A linear _2-9 alkylene chain having the same or different substituents selected from the group,
Here, each C _1-26 -alkyl group and each C _1-26 -alkoxy group are branched or linear and saturated or unsaturated with one or more double bonds, and include hydroxy, amino, may be substituted by halogen and oxo groups, and C _3-8 - cycloalkyl - (C _0-9) - C alkyl group _3-8 - Shikurorukiru groups and C _0-9
The alkyl group may contain one or more double bonds and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur atoms, wherein cycloalkyl The groups and alkyl groups may be substituted with hydroxy, halogen, amino, oxo, branched or straight chain C _1-9 -alkyl and C _2-9 -alkenyl groups, wherein C _1-9 alkyl and The C _2-9 -alkenyl group may be substituted by hydrogen, hydroxy, amino, halogen and oxo groups, and R _XI1 and R _XI2 are the same or different and are hydrogen, substituted and unsubstituted C _1-9
Alkyl, substituted and unsubstituted hydroxy- _1-9 -alkyl, substituted and unsubstituted _C1-9 -alkenyl, substituted and unsubstituted _C1-9 -alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic group, a halogen, selected from the group consisting of OX _Xi1 and OX _XI2, wherein X _Xi1 and X _XI2 is a same or different hydrogen, Substituted and unsubstituted C _1-9 -alkyl, substituted and unsubstituted hydroxy-C _1-9 alkyl, substituted and unsubstituted C _1-9 -alkenyl, substituted and unsubstituted C _1-9 -alkynyl, substituted and unsubstituted aryl , Substituted and unsubstituted acyl,
R _XI3 and R _XI4 are the same or different and are substituted and unsubstituted C _1-26 -alkyl. Hydroxy-C _1-26 -alkyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C _1-26 -alkenyl, substituted and unsubstituted C _1-26 -alkynyl, _Selected from the group consisting of substituted and unsubstituted cycloalkyl, substituted and unsubstituted bicyclic groups, halogen, _OXxI3 and _OXXI4 , wherein _XXI3 and _XXI4 are the same or different and are hydrogen, substituted and unsubstituted C _1-26 - alkyl, substituted and unsubstituted hydroxy -C _1-26 - alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, location And unsubstituted C _1-26 - alkenyl, substituted and unsubstituted C _1-26 - alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted double ring group, a silyl, a cation particular cycle of organic and inorganic bases Table first , A cation of a Group 2 or 3 metal, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids. Preferred _AXI is a _C3-5 -alkyl chain.

R_XI2 Represents a methyl group, and Z_XI, R_XI1 , R_XI3, R_XI4 Is as defined above
The same, R_XI1 Is substituted by a hydroxy group at a carbon atom adjacent to a hetero atom
And R and_XI2 Represents a hydroxy group, Z_XI, R_XI1 , R _XI3 , R_XI4 Is the same as defined above,_XI1 Is preferably an acyl group, particularly preferably
Or a compound having a formyl, acetyl, propionyl or butyl group.
Preferred. Compounds having at the same time the following structures are preferred:

Embedded image XII. Lipid metabolism inhibitor, 3-isoxazolidinone and hydroxyamic acid
Lipid metabolism inhibitors these compounds A is described in US patent 4 405 357. The compound according to the invention contained in a pharmaceutical composition corresponds to general formula (XII):

Embedded image _Wherein A _XII is hydrogen, substituted and unsubstituted C _1-28 -alkyl, substituted and unsubstituted alkoxy- (C _0-28 ) -alkyl, substituted and unsubstituted cycloalkyl-
(C _0-28 ) -alkyl, substituted and unsubstituted cycloalkoxy- (C _0-28 ) -alkyl, substituted and unsubstituted amino- (C _0-28 ) -alkyl, substituted and unsubstituted thio- ( C _0-28 ) -alkyl groups, and substituted and unsubstituted acyl- (C _0-28 )
-Selected from the group consisting of alkyl groups and halogens, each alkyl group, each alkoxy group and each acyl group may be branched or linear, and each alkyl group, each alkoxy group, each acyl group and each cyclo group. The alkyl group may be saturated or unsaturated with one or more double or triple bonds, wherein one or two carbon atoms of the cycloalkyl group are replaced by nitrogen, oxygen or sulfur. R _XII3 may be a hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy-
(C _0-26 ) alkyl groups, substituted and unsubstituted C _3-14 -cycloalkyl- (C _0-26 )
An alkyl group, a substituted and unsubstituted cycloalkoxy- (C _0-26 ) -alkyl group,
Substituted and unsubstituted amino- (C _0-26 ) -alkyl groups, substituted and unsubstituted silyl-
Selected from the group consisting of (C _0-26 ) -alkyl groups and substituted and unsubstituted thio- (C _0-26 ) -alkyl groups, wherein each alkyl group and each alkoxy group may be branched or linear. , Each alkyl group, each alkoxy group and each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds. One carbon atom is nitrogen,
Can be replaced by an oxygen or sulfur atom, or two carbon chains of carbon atoms in A _XII forms Isokisazoridon ring together with R _XII3, and R _XII4 is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted Acyl, and selected from the group consisting of substituted and unsubstituted cycloalkyl- (C _0-26 ) -alkyl groups, wherein each alkyl group and each acyl group may be branched or straight chain; The acyl group and each cycloalkyl group may be saturated or unsaturated having one or more double bonds or triple bonds, and one or two carbon atoms of the cycloalkyl group may be nitrogen, oxygen or sulfur. Can be replaced by

A _XII preferably corresponds to formula (XIIA):

Embedded image Where R_XII1And R_XII2Are the same or different and include hydrogen, hydroxy, ha
Halogen, substituted and unsubstituted amino groups, substituted and unsubstituted alkyl groups, substituted and unsubstituted alkyl groups,
Unsubstituted alkoxy groups, substituted and unsubstituted cycloalkyl- (C_0-26) -Alkyl
Selected from the group consisting of groups, each alkyl group, each alkoxy group is branched or linear
Each alkyl group, each alkoxy group and each cycloalkyl group are saturated or
One or more double or triple bonds and one or more carbons
Is an unsaturated type having one or more atoms, wherein one or two carbon atoms of the cycloalkyl group are
Can be replaced by nitrogen, oxygen or sulfur;_XII5, R_XII6And R_XII7Are the same or different and include hydrogen, hydroxy, ha
Logen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 ) -Alkyl groups, substituted and unsubstituted cycloalkoxy- (C_0-26)-Archi
Group, substituted and unsubstituted alkoxy- (C_0-26) -Alkyl groups, substituted and unsubstituted
Substituted amino groups and substituted and unsubstituted thio- (C_0-26) -Alkyl groups and substituents
And unsubstituted acyl groups, each alkyl group, each alkoxy group and
And each acyl group is branched or linear, each alkyl group, each alkoxy group and
Each cycloalkyl group is saturated or has one or more double or triple bonds
Unsaturated with one or two carbon atoms and a cycloalkyl group
One or two carbon atoms of can be replaced by nitrogen, oxygen or sulfur;_XII5Is R_XII1And can form a ring with_XII3And R_XII7Forms a carbon-nitrogen single bond in such a way that a ring structure is present
it can. The invention also relates to pharmaceutically acceptable salts, esters and ester salts thereof.
Is also included. Preferred R_XII1And R_XII2Are the same or different and are substituted and unsubstituted
Lucil, preferably C₁ -C_Four -Selected from the group consisting of alkyl groups. Preferred R_XII3Is hydrogen, a substituted and unsubstituted alkyl group, preferably C₁ -C_Four 
Alkyl groups, substituted and unsubstituted C₇ -C₁₄-Cycloalkyl, pyranyl and
And a t-butyldimethylsilyl group and

Embedded image _Wherein R _XII8 is preferably a substituted or unsubstituted alkyl group substituted with halogen, a substituted or unsubstituted cycloalkyl- (C _0-26 ) -alkyl, a substituted or unsubstituted amino group, a substituted or unsubstituted alkoxy group , substituted and unsubstituted Fuenokishiki, substituted and unsubstituted alkylthio groups, substituted and unsubstituted preferably unsubstituted or halogen-substituted methyl, methoxy, nitro, amino or CF ₃ - is selected from the group consisting of substituted aromatic cycloalkylthio groups ] Is selected from the group consisting of:

R _XII4 represents hydrogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group and

Embedded image[Where Z is_XII Is hydrogen, C_1-4 -Selected from the group consisting of alkyl groups and phenyl groups.
Selected, Y_XII Is hydrogen, halogen, C_1-4 -Alkyl, nitro, methoxy
, Methylenedioxy group, and n is 0 or 1.]. R_XII7Is selected from the group consisting of hydrogen and halogen;_XII3And R _XII7 Forms a carbon-oxygen single bond in such a manner that a ring structure is present.

[0076] These compounds are particularly preferred if R _XII1 and R _XII2 are independently selected from methyl and ethyl, R _XII4 is

Embedded image And R _XII5 and R _XII6 are independently selected from the group consisting of hydrogen, chlorine, bromine and methoxy groups.

In particular, these compounds have R _XII4

Embedded image [Z is selected from the group consisting of 2-chloro, 2-bromo-, 2-fluoro-
And Y are selected from the group consisting of 4-chloro, -4-bromo-, 4-fluoro, 5-fluoro and 4,5-methylenedioxy groups, and n is 0 or 1.
Is preferred. These compounds, R _XII1 and R _XII2 are methyl groups, R _XII3 and R _{XI I7} carbon to form a one, or cyclic hydrogen - where oxygen bond is particularly preferred.

Preferred examples of these compounds include 3-chloro-N- (2-chlorophenyl) methyl-N-hydroxy-2,2-dimethylpyropenamide, N- (2-chlorophenyl9methyl-N-hydroxy-
2,2-dimethylpropanamide, 3-chloro-N-hydroxy group-N-funyl-2,2-dimethylpropanamide, N- (2-bromophenyl) -methyl-3
-Chloro-N-hydroxy-2,2-dimethylpropanamide, 3-chloro-N
-Hydroxy-2,2-dimethyl-N- (2-methylphenyl) methylpropanamide, 3-chloro-N-hydroxy-2,2-N-trimethylpyropenamide, 3-chloro-N-hydroxy-2,2 -Dimethyl-N- (phenylmethyl)-
Propanamide, 3-chloro-N- (2,4-dichlorophenylmethyl) -N-
Hydroxy-2,2-methylpropanamide, 3-chloro-N- (2-chlorophenyl) methyl-N-methoxy-2,2-dimethylpropanamide, 3,3-dichloro- (2-chlorophenyl) methyl-N- Hydroxy-2,2-dimethylpropanamide, 3-chloro-N- (2-fluorophenyl) methyl-N-hydroxy-2,2-dimethylpropanamide, 3-bromo-N- (2-chlorophenylmethyl- N-hydroxy-2,2-dimethylpropanamide, N-benzoyloxy-3-chloro-N- (2-chlorofunyl) methyl-2,2-dimethylpropanamide, N-acetoxy-3-chloro-N- (2 -Chlorophenyl) methyl-2,2-dimethyllopanamide, N- (chloroacetoxy) -3-chloro-N
-(2-chlorophenyl) methyl-2,2-dimethylpropanamide, 2- (2
-Chlorophenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 4,
4-dimethyl-2-phenyl-3-isoxazolidinone, 2- (2-bromophenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 4,4-dimethyl-2- (2-methyl- Phenyl) methyl-3-isoxazolidinone, 2,4-trimethyl-3-isoxazolidinone, 4,4-dimethyl-2-
Phenylmethyl-3-isoxazolidinone, 4,4-dimethyl-2-phenylmethyl-3-isoxazolidinone, 2- (2,4-dichlorophenyl) methyl-4
, 4-Dimethyl-3-isoxazolidinone, 5-chloro-2- (2-chlorophenyl) methyl-4,4-dimethyl-3-isoxazolidinone, 2- (2-chlorophenyl) methyl-5-methoxy -4,4-dimethyl-3-isoxazolidinone, 2- (2-fluorophenyl) methyl-4,4-dimethyl-3-isoxazolidinone, N-[(2-chlorophenyl) methyl] -N , 3-dihydroxy-2,
2-dimethylpropanamide, 3-chloro-N-[(2-chlorophenyl) methyl] -2,2-dimethyl-N- (methylamino-carbonyloxy) propanamide, 3-chloro-N-[(2-chlorophenyl ) Methyl] -N-[(2-tetrahydropyranyl) oxy-2,2-dimethyl-propanamide, 3-chloro-
N-[(2-chlorophenyl) methyl-2,2-dimethyl-N- [dimethyl (1
, 1-Dimethyl-ethyl) silyloxypropanamide, 3-acetoxy-N-
[(2-chlorophenoxy) -methyl] -N-hydroxy-2,2-dimethylpropanamide, 2-[(2-chloro-4-fluorophenyl) methyl
-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chloro-5-fluorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2- [
(2,4,5-trichlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(2-chloro-6-fluorophenyl) methyl] -4,4
-Dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl]
-5-ethoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5-phenylamino-3-isoxazolidinone, 2-[( 2-chlorophenyl) methyl] -5-hydroxy-4,
4-dimethyl-3-isoxazolidinone, 3-chloro-N-[(2-chlorophenyl) methyl] -2,2-dimethyl-N-[(phenylamino) carbonyloxy] -propanamide, 3-chloro-N -[(2-chlorophenyl) methyl]-
2,2-dimethyl-N-([(2-chlorophenyl) methyl] -2,2-dimethyl-N-phenoxycarbonyl-oxy) propanamide, 3-chloro-N- [
(2-chlorophenyl) methyl] -N-ethoxy-carbonyloxy-2,2-
Dimethylpropanamide, N-benzoyloxy-3,3-dichloro-N-[(
2-chlorophenyl) methyl] -2,2-dimethylpropanamide, N- (2-
Bromophenyl) methyl-3,3-dichloro-N-hydroxy-2,2-dimethyl) propanamide, 3-chloro-N-[(2-chlorophenyl) methyl] -N
-(4-Nitrobenzoyloxy) -2,2-dimethylpropanamide, 3-chloro-N- [2-chlorophenylmethyl)]-2,2-dimethyl-one-[(2-
Methylphenyl) carbonyloxy] propanamide, 3-chloro-N-dichloroacetooxy-N-[(2-chlorophenylomethyl [-2,2-dimethylpropanamide, 3-chloro-N- [2-chlorophenyl) methyl ] -2,2-dimethyl-N-[(4-methylphenyl) sulfonyloxy] propanamide, 3
-Chloro-N- [2-chloro-phenyl) methyl] -2,2-dimethyl-N- [
(1,1-dimethylethyl) carbonyl-oxy] propanamide, 3-chloro-N- [2-chlorophenyl) methyl] -2,2-dimethyl-N- (ethylthiocarbanoyloxy) propanamide, 3-chloro -N-[(2,2,2-trichloroethoxy) carbonyloxy) -N-[(2-chlorophenyl) methyl]
-2,3-dimethylpropanamide, 3-chloro-N-[(2-chlorophenyl) aminocarbonyloxy-N-[(2-chlorophenyl) methyl] -2,2-
Dimethylpropanamide, 3-chloro-N-[(4-chlorophenyl) aminocarbonyloxy-N-[(2-chlorophenyl) methyl] -2,2-dimethyl-
Propanamide, 3-chloro-N- [2-chlorophenyl) methyl] -2,2-
Dimethyl-N- (phenylmethoxy) -propanamide, 3-chloro-N-[(
2,4-dichlorophenoxy) acetoxy) -N-[(2-chlorophenyl) methyl] -2,2-dimethyl-propanamide, 3-chloro-N- [2-chlorophenyl) methyl] -2,2- Dimethyl-N- [3-trifluoromethyl) zenzoyloxypropanamide, 3-chloro-N- [2-chlorophenyl) methyl]
-2,2-dimethyl-N-[(4-methylphenyl) aminocarbonyl-oxy) -propanamide, 3-chloro-N- [2-chlorophenyl) methyl] -N-
[(3,4-chlorophenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 3-chloro-N- (3-chloro-2,2-dimethyl-1-oxo-propoxy) -N-[(2 -Chlorophenyl) methyl-]-2,2-dimethylpyropenamide, 3-bro-N-[(2-bromophenyl) -methyl] -N-hydroxy-2,2-dimethylpyropenamide, 3-chloro-N -[(2-chlorophenyl) methyl] -N-[(2-fluorophenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 3-chloro-N-[(2-chlorophenyl) methyl] -N- [(4-methoxyphenyl) aminocarbonyloxy] -2
, 2-Dimethylpropanamide, 3-chloro-N-[(2-chlorophenyl) methyl] -N-[(3-trifluoromethylphenyl) aminocarbonyloxy]
-2,2-dimethylpropanamide, 3-bromo-N-[(2-chlorophenyl) methyl] -N- (methylaminocarbonyloxy) -2,2-dimethyl-propanamide, 3-bromo-N-[( 2-chloroacetoxy) -N-[(2-chlorophenyl) methyl] -2,2-dimethylpropanamide, 3-chloro-N- [
2,5-dichloro- (formylamino) -benzoyl] oxy-N-[(2-chlorophenyl) methyl] -2,2-dimethyllopanamide, 3-bromo-N- [
(2-Bromophenyl) methyl] -N- (methylcarbonyloxy) -2,2-
Dimethylpropanamide, 3-bromo-N-[(2-bromophenyl) methyl]
-N-[(2-chlorophenyl) aminocarbonyloxy] -2,2-dimethylpropanamide, 2-[(2-chlorophenyl) methyl] -N-hydroxy-2
, 2-Dimethyl-3-methylthio-propanamide, 3-phenylcarbyloxy) -N-[(2-chlorophenyl) methyl] -N-hydroxy-2,2dimethylpropanamide, 2-[(4-chlorophenyl ) Methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(3,4-dichlorophenyl) methyl] -4
, 4-Dimethyl-3-isoxazolidinone, 2-[(chlorophenyl) methyl]
-4,4-dimethyl-3-isoxazolidinone-5-yl acetate, 2-[(
Chlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone-5
Ylbenzoate, 2-[(chlorophenyl) methyl] -4,4-dimethyl-3
-Isoxazolidinone-5-yldichloroacetate, 2-[(chlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone-5-ylphenylcarbamate, 2-[(2-chloro-4- Cyanophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone-2-[(2-chloro-5-methoxyphenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2- [(Chloro-4
-Methoxyphenyl) -methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(2,4-difluorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(4-bromo-2-chlorophenyl) methyl] -4,
4-dimethyl-3-isoxazolidinone, 2-[(2-bromo-4-fluorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(6-
Chloro-1,3-benzodioxol-5-yl) methyl] -4,4-dimethyl-
3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5-phenoxy-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4- Dimethyl-5- (1-methylethoxy) -3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5-
(Phenylmethoxy) -3-isoxazolidinone, 2-[(2-bromophenyl) methyl] -5-chloro-4,4-dimethyl-3-isoxazolidinone, 2- [
(2,5-dichlorophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(2-dichlorophenyl) methyl] -4,4-dimethyl-5-propoxy-3- Isoxazolidinone, 2-[(2-chlorophenyl) methyl]-
4,4-dimethyl-5- (2-propenyloxy) -3-isoxazolidinone,
2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5- (2-propynyloxy) -3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl- 5- (2-methoxyethoxy) -3-isoxazolidinone, 2-[(4-fluoro-2-iodophenyl) methyl] -4,4-dimethyl-3-isoxazolidinone, 2-[(2- Chlorophenyl) methyl] -5-cyclopentoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -4,4-dimethyl-5- (4-nitrophenoxy) -3
-Isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5-chloropropyl-methoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-
Bromophenyl- (methyl)]-4,4-dimethyl-5- (2-pyropinoxy)
-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5- (3
-Butynoxy) -4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5- (2-butynoxy) -4,4-dimethyl-3-isoxazolidinone, -[(2-chlorophenyl) methyl] -5- (3-butenoxy) -4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5-pentoxy-4,4- Dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5-hexoxy-4,4-dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl] -5- (1
-Methylpropoxy) -4,4-dimethyl-3-isoxazolidinone, 2-[(
2-chlorophenyl) methyl] -5- (3-methyl-3-butenoxy) -4,4
-Dimethyl-3-isoxazolidinone, 2-[(2-chlorophenyl) methyl]
-5-4,4-dimethyl-3-isoxazolidinone and 2-[(2-chloro-phenyl) methyl] -4,4-dimethyl-3-isoxazolidinone.

XIII. Complex preparation of lipid metabolism inhibitors and thiadiazoles The thiadiazole derivatives used according to the invention correspond to the following general formula (XIII):

Embedded image Wherein, n is an integer from 0 to 4, and _{R XIII1, R XIII2, R XIII3} , X XIII4, X XIII5 and X _III6 are identical or different, hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted Selected from the group consisting of substituted alkoxy groups, substituted and unsubstituted acyl groups, substituted and unsubstituted cycloalkyl- ( _C0-26 ) alkyl groups, substituted and unsubstituted cycloalkyl- ( _C0-26 ) -alkoxy groups, and halogens. Wherein each alkyl group, each alkoxy group and each acyl group are branched or linear, and each alkyl group, each acyl group, each alkoxy group and each _cyclo- (C _0-26 ) -alkyl group are saturated or monocyclic. It is unsaturated with one or more double or triple bonds, and one or two carbon atoms of the cycloalkyl group can be replaced by nitrogen, oxygen or sulfur. Preferred R _XIII1 is COOC ₂ H ₅ . Further, in these compounds, R _{XIII 2} to R _XIII6 are preferably selected from the group consisting of hydrogen and halogen, especially chlorine, and n is preferably 1 or 2.

XIV. The compound according to the invention contained in a complex preparation pharmaceutical composition of a lipid metabolism inhibitor and a nitrogen-oxygen heterocycle corresponds to the general formula (XIV):

Embedded image Where Y_XIV Is C_1-3 An alkenylene group, and the substituent R_XIV1And R_XIV2 
And optionally R_XIV3 To R_XIV6 Where R is_XIV1To R_XIV8Are the same or different and include hydrogen, hydroxy, ha
Logen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 ) -Alkyl groups, substituted and unsubstituted cycloalkyl- (C_0-26) -Alkyl
Group, substituted and unsubstituted alkoxy- (C_0-26) -Alkyl groups, substituted and unsubstituted
Amino groups and substituted and unsubstituted thio- (C_0-26) -Alkyl groups, substituted and unsubstituted
Substituted sulfonyl- (C_0-26) -Alkyl groups, substituted and unsubstituted sulfinyl- (
C_0-26-) Selected from the group consisting of alkyl groups and substituted and unsubstituted acyl groups
, Each alkyl group, each alkoxy group and each acyl group are branched or linear,
Each alkyl group, each alkoxy group, each cycloalkyl group may be saturated or one or more
May be an unsaturated type having two or more double bonds or triple bonds, and
Replace one or more carbon atoms of a cycloalkyl group with nitrogen, oxygen or sulfur
Can and R_XIV13 And R_XIV14 Is R_XIV1To R_XIV8Is the same as or
To form an oxo group, and Z_XIV Represents the following organic phosphorus groups:

Embedded image In the formula, R _XIV9 and R _XIV10 are the same or different, and each represents a hydrogen, a substituted or unsubstituted (C _1-26 ) -alkyl group, a substituted or unsubstituted hydroxy- (C _1-26 ) -alkyl group, _Selected from the group consisting of substituted cycloalkyl- (C _0-26 ) -alkyl groups, substituted and unsubstituted acyl, halogen, OX _XIV9 or OX _XIV10 , wherein each alkyl group, each alkoxy group and each acyl group is branched or linear. And each alkyl group, each alkoxy group, and each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds. One or two carbon atoms may be replaced by nitrogen, oxygen or sulfur, wherein a X _XIV9 or X _XIV10 the same or different, hydrogen, substituted and unsubstituted (C _1-26) - alkyl group, location And unsubstituted hydroxy - (C _1-26) - alkyl group substituted, unsubstituted cycloalkyl - (C _0-26) - alkyl groups, substituted and unsubstituted acyl, silyl, a cation especially the Periodic Table of the organic and inorganic bases Selected from the group consisting of cations of Group 1, 2 or 3 metals, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids, wherein each alkyl group, each alkoxy group, and each acyl group is a branched or linear type. Wherein each alkyl group, each alkoxy group, and each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds, and one of the cycloalkyl groups Or two or more carbon atoms can be replaced by nitrogen, oxygen or sulfur, or Z _XIV represents the following amino group:

Embedded image _Wherein R _XIV11 and R _XIV12 are the same or different and are hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 ) -alkyl groups, substituted and unsubstituted cycloalkoxy- ( Selected from the group consisting of C _0-26 ) -alkyl groups, substituted and unsubstituted alkoxy- (C _0-26 ) -alkyl groups, substituted and unsubstituted acyl groups, wherein each alkyl group, each alkoxy group and each acyl group is branched. Or a linear type, each alkyl group, each alkoxy group, each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds, and a cycloalkyl one or more carbon atoms of the group may be replaced by nitrogen, oxygen or sulfur, B _XIV is substituted and unsubstituted C _1-26 - is selected from the group consisting of an alkenylene group, wherein By one carbon atom one oxygen atom, and either one carbon atom is replaced by one sulfur atom, or two carbon atoms may be replaced with S- heterocycle,
Each alkenylene group is branched or linear and saturated or unsaturated with one or more double or triple bonds and can be substituted with one or more hydroxy, halogen or oxo groups. R _XIV13 and R _XIV14 together form an oxo group at the α-position with respect to the nitrogen atom.
Preferred Y _XIV represents a methylene group, particularly preferably substituted by two methyl groups.

Furthermore, these compounds are advantageous when B _XIV represents an ether group (XIVA): —A _XIV1 —O—A _XIV2 — (XIVA) where A _XIV1 is deleted or (C _1-9 ) -alkylene group and A _XIV2 is deleted or selected from the group consisting of (C _1-9 ) -alkylene group, sulfur atom and (C _3-8 ) -heterocycle; The heterocycle contains at least one sulfur atom. Particularly preferred A _XIV1 and A _XIV2 each represent methylene.

These compounds are also advantageous when B _XIV represents a keto group (XIVB):

Embedded image _Wherein A _XIV3 and A _XIV4 may be deleted in one or both of the same or different species and are selected from the group consisting of (C _1-9 ) -alkylene groups;
Here, all (C _1-9 ) -alkylene groups are branched or straight-chain, contain one or more double bonds, or may be substituted by hydroxy groups or halogen groups. Particularly preferred is the case where A _XIV3 is deleted and A _IV4 is a methylene or ethylene group. Further, a preferred _BXIV is a 2-hydroxypropylene group.

R _XIV9 and R _XIV10 preferably represent OX _XIV9 and OX _XIV10 , wherein X _XIV9 and X _XIV10 are the same or different and are metals of the first, second or third main group of the periodic table Particularly selected from the group consisting of sodium and potassium, and methyl, ethyl.

The following are particular features of the above definitions and suitable examples thereof: “Acyl” is derived from an organic carboxylic acid, carbonic acid, carbamic acid or a thioacid or imidic acid corresponding to an individually present acid. Or a substituent derived from an acid such as an organic sulfonic acid, which in each case contains an aliphatic, aromatic and / or heterocyclic group and a carbamoyl or carbamidoyl group in the molecule.

Preferred examples of these acyl groups are as follows: An acyl group derived from an aliphatic acid is defined as an aliphatic acyl group and includes: alkanoyl (eg, formyl, acetyl, propionyl, butyl, isobutyl, valeryl) Alkenoyl (eg, acryloyl, methacryloyl, crotonoyl, etc.); alkylthioalkanoyl (eg, methylthioacetyl, ethylthioacetyl, etc.); alkanesulfonyl (eg, mesyl, ethanesulfonyl, propanesulfonyl, etc.); alkoxycarbonyl (eg, Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, etc.); alkylcarbamoyl (eg, methylcarbamo) (N-alkyl) -thiocarbamoyl (eg, (N-methyl) -thiocarbamoyl, etc.); alkylcabamidoyl (eg, methylcarbamidoyl, etc.); oxalo; Propoxalyl, etc.).

In the above examples of aliphatic acyl groups, aliphatic hydrocarbon moieties, especially alkyl and alkane groups, are amino, halogen (eg, fluorine, chlorine, bromine, etc.), hydroxy, hydroxyimino, carboxy, alkoxy (eg, methoxy, One or more suitable substituents such as ethoxy, propoxy, etc., alkoxycarbonyl, acylamino (eg, benzyloxycarbonylamino, etc.), acyloxy (eg, acetooxy, benzoyloxy, etc.) can be optionally included. Examples of preferred aliphatic acyl groups having such substituents are alkanoyl substituted with amino, carboxy, amino and carboxy, halogen, acylamino or others.

When the aryl group comprises phenyl, tolyl, xylyl, naphthyl and the like, acyl groups derived from acids having a substituted and unsubstituted aryl group are referred to as aromatic acyl groups and suitable examples are as follows: aroyl (Eg, benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.); aralcanoyl (eg, phenylacetyl, etc.); aralkenoyl (eg, cinnamoyl, etc.); aryloxyalkanoyl (eg, phenoxyacetyl, etc.); Arylaminoalkanoyl (eg, N-phenylglycyl); alensulfonyl (eg, benzenesulfonyl, tosyl bzw. toluenesulfonyl, naphthalenesulfonyl, etc.); aryloxycarbonyl (eg, phenyl) Oxycarbonyl, naphthyloxycarbonyl, etc.); aralkoxycarbonyl carboxylic yl (e.g. benzyloxycarbonyl group); arylcarbamoyl (e.g. phenylene carbamoyl, naphthyridone carbamoyl, etc.); aryl glyoxyloyl yl (e.g. phenylalanine glyoxyloyl yl, etc.).

In the examples of the aromatic acyl group in the present invention, an aromatic hydrocarbon moiety (particularly an aryl group) and / or an aliphatic hydrocarbon moiety (particularly an alkane group) is, for example, a suitable substituent for an alkyl group and an alkane group. It may optionally contain one or more substituents as already mentioned. Examples of particularly preferred aromatic acyl groups having specific substituents include aroyl substituted with halogen and hydroxy, or aroyl substituted with halogen and acyloxy, and aralcanoyl substituted with hydroxy, hydroxyimino, dihalogenalkanoyloxyimino. And arylthiocarbamoyl (eg, phenylthiocarbamoyl); and arylcarbamimidyl (eg, phenylcarbamimidyl).

A heterocyclic acyl group is understood to be an acyl group derived from an acid having a heterocyclic group, examples of which include: a heterocyclic carbonyl; It is an aromatic or aliphatic 5- to 6-membered heterocycle and has at least one heteroatom from a nitrogen, oxygen and sulfur (eg, thiophenyl, furoyl, pyrrolecarbonyl, nicotinoyl, etc.) group. Heterocyclic alkanoyl; wherein the heterocyclic group is a 5- to 6-membered ring having nitrogen, oxygen and sulfur (eg, thiophenyl-acetyl, furylacetyl, imidazoylpropionyl, tetrazoylacetyl, 2- (2-amino-4-thiazoyl) ) -2-methoxyiminoacetyl, etc.).

In the above examples of heterocyclic acyl groups, the heterocyclic ring and / or the aliphatic hydrocarbon moiety thereof may be substituted with one or more than It may optionally include suitable substituents.

The term “alkyl”, unless stated otherwise, is a branched or straight-chain alkyl group of less than 9 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, hexyl and the like. . The term "alkenyl", unless otherwise specified, includes carbon atoms such as, for example, vinyl, propenyl (eg, 1-propenyl, 2-propenyl), 1-methylpropenyl, 2-methylpropenyl, butenyl, 2-ethylpropenyl, pentenyl, hexyl, and the like. Less than 9 branched or straight-chain alkenyl groups. The term "alkynyl", unless otherwise specified, is a branched or straight-chain alkynyl group having less than 9 carbon atoms. Cycloalkyl, C ₇ C ₃ to an optionally substituted - cycloalkyl.
Alkyl, alkoxy (eg, methoxy, ethoxy, etc.), halogen (eg, fluorine, chlorine, bromine, etc.), nitro, and the like are particularly suitable as possible substituents.

Aryl is an aromatic hydrocarbon group such as phenyl and naphthyl, and alkoxy (
One or more suitable substituents, such as methoxy, ethoxy, etc.), halogens (eg, fluorine, chlorine, bromine, etc.), nitro, etc., can optionally be included.

The term “aralkyl” includes benzyl, phenethyl, benzhydryl, trityl, and other mono-, di-, and triphenylalkyl, where the aromatic moiety is one or more suitable substituted Groups such as alkoxy (eg methoxy,
Ethoxy, etc.), halogens (eg, fluorine, chlorine, bromine, etc.), nitro, and the like.

The term “alkylene” includes 9 carbon atoms of the formula — (C _n H _2n ) —
Less than branched or linear alkylene groups, where n is methylene, ethylene, trimethylene, methylethylene, tettamethylene, 1-methyltrimethylene, 2-ethylethylene, pentamethylene, 2-methyltetramethylene, i It is an integer in the case of 1 to 9 carbon atoms such as soropyrethylene, hexamethylene and the like. Preferred alkylene groups include groups with less than 4 carbon atoms and 3 carbon atoms, with trimethylene being particularly preferred.

The term “alkenylene” includes straight-chain or branched alkenylene groups having less than 9 carbon atoms represented by the formula: — (C _n H _2n-2 ) —, wherein n is from 2 to An integer of 9, for example, vinylene, propylene (eg, 1-propenylene, 2-propenylene), 1-methylpropenylene, 2-methylpropenylene, butenylene, 2-ethylpropenylene, pentenylene, hexenylene and other cases It is. This alkenylene group is particularly preferably less than 5 carbon atoms, especially 3 carbon atoms, for example 1-propenylene.

The term “hydroxyalkylene” includes straight or branched alkylene groups having less than 9 carbon atoms, wherein one or more selected carbon atoms are replaced by a hydroxy group. These groups represented by the following _{formula: - (C n H 2n-} z) (OH) z - wherein, n is an integer from 1 to 9, z is a z ≦ n an integer. Among suitable examples of such preferred hydroxyalkylene groups are 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-hydroxypentamethylene), hydroxyhexamethylene (eg, 2-hydroxyhexamethylene) and the like. You. Particularly preferred are lower hydroxyalkylenes having less than 4 carbon atoms, particularly those having 3 carbon atoms such as 2-hydroxytrimethylene.

The term “alkyleneamine” includes straight-chain or branched alkylenamine groups having less than 9 carbon atoms represented by the formula: — (C _n H _2n ) —N— ( C _m H _2m )-wherein n and m are the same or different and are integers from 0 to 9, and 1 ≦ n + m
≦ 9, methyleneamine, ethyleneamine, dimethyleneamine, trimethyleneamine, methyleneethyleneamine, tetramethyleneamine, 1-methyltrimethyleneamine, 2-ethylethyleneamine, ethylenemethyleneamine, pentamethyleneamine, 2- Methyltetramethyleneamine, isopropylethyleneamine, heisamethyleneamine and others. Preferred alkyleneamine groups are
Contains two terminal carbon atoms. Dimethyleneamine is particularly preferred. This hydrogen atom may be substituted, for example, by a halogen group.

The term “alkyleneimine” includes straight or branched alkylenimines having less than 9 carbon atoms represented by the formula: — (C _n H _2n-1 ) = N— (C _m H _2m) - or _{- (C n H 2n) -N} = (C m H 2m-1) - , wherein, n and m are integers from the same or different 0 9, 1 ≦ n + m ≦
9, methyleneimine, ethyleneimine, dimethyleneimine, trimethyleneimine, methyleneethyleneimine, tetramethyleneimine, 1-methyltrimethyleneimine, 2-ethylethyleneimine, ethylenemethyleneimine, pentamethyleneimine, 2-methyl Tetramethylene imine, isopropyl ethylene imine,
Corresponds to hexamethylene imine and other cases. Preferred alkylene imine groups contain two terminal carbon atoms. Dimethylene imine is particularly preferred. This hydrogen atom may be substituted, for example, by a halogen group.

The term “alkenyleneamine” includes straight-chain or branched alkenyleneamines having less than 9 carbon atoms represented by the formula: — (C _n H _2n-2 ) —N— (C _{m H 2m-2) -; -} (C 0 H 2o) -N- (C n H 2n -2) ;-( C n H 2n-2) -N- (C 0 H 2o) - wherein, n and m is the same or a different integer from 0 to 9, m + n ≦ 9, _o is a number from 0 to 7, _o + n ≦ 9, for example, vinyleneamine, methylenevinyleneamine, divinyleneamine, propene Nyleneamine (eg, 1-propenyleneamine, 2-propenyleneamine), methylenepropenyleneamine,
This corresponds to 1-methylpropenyleneamine, 2-methylpropenyleneamine, butenyleneamine, 2-ethylenepropenyleneamine, pentenyleneamine, hexenyleneamine, vinylmethyleneamine and other cases. This hydrogen atom may be substituted, for example, by a halogen group.

The term “alkenylene imine” includes straight-chain or branched alkenylene amines having less than 9 carbon atoms represented by the formula:-(C _n H _2n-3 ) = N- (C _m H _{2m-2) - ;-( C o} H 2o-1) = N- (C m H 2m-2) -;
_{- (C n H 2n-3} ) = N- (C o H 2o) -;
_{- (C n H 2n-2} ) = N- (C m H 2m-3) - ;-( C o H 2o) = N- (C m H 2m-3) -; - (C n H 2n-2 ) = N- (C _o H _2o-1 ) _-wherein n and m are the same or different and are integers from 2 to 9, m + n ≦ 9, _o is a number from 0 to 7, and _o + n ≦ 9. For example, vinylene imine, methylene vinylene imine, ethylene vinylene imine,
Propenyleneimine (eg, 1-propenyleneimine), methylenepropenyleneimine, 1-methylpropenyleneimine, 2-methylpropenyleneimine, butenyleneimine, 2-ethylenepropenyleneimine, pentenenyleneimine , Hexenylene imine, vinylene methylene imine and the like. This hydrogen atom may be substituted, for example, by a halogen group.

“Hydroxyalkyleneamine” is a straight or branched alkylene group having less than 9 carbon atoms, wherein at least one selected carbon atom is replaced by a hydroxy group; these groups are represented by the formula: _{- (C n H 2n-z} ) (OH) z -N- (C m H 2m-y) (OH) _y in formula, n and m are integers from 0 in the same or different 9, 1 ≦ n + m ≦ 9 , And z and y are the same or different and are integers, 0 ≦ z ≦ n and 0 ≦ y ≦ m and y +
z ≧ 1. Preferred examples of this type of hydroxyalkyleneamine include hydroxy group methyleneamine, hydroxyethyleneamine (eg, 1-hydroxyethyleneamine and 2-hydroxyethyleneamine), hydroxytrimethyleneamine (eg, 1-hydroxytrimethylene, 2 -Hydroxytrimethyleneamine and 3-hydroxytrimethyleneamine), hydroxytetramethyleneamine (e.g., 2-
Hydroxytetramethyleneamine), 2-hydroxy-2-methyltrimethyleneamine, hydroxypentamethyleneamine (e.g., 2-hydroxypentamethyleneamine), hydroxyhexamethyleneamine (e.g., 2-hydroxyhexamethyleneamine), methylenehydroxymethyleneamine, Methylene hydroxyethylene amine and others are included. Particularly preferred are lower hydroxyalkyleneamines having two carbon atoms and one nitrogen atom, wherein both carbon atoms are terminal. This hydrogen atom may be substituted, for example, by a halogen group.

[0102] Examples of "hydroxyalkylenimines" include straight or branched alkylene groups with less than 9 carbon atoms, wherein at least one selected carbon atom is replaced with a hydroxy group. These groups represented by the following _{formula: - (C n H 2n-} z-1) (OH) z = N- (C m H 2m-y) (OH) y; - (C n H 2n-z _{-1) (OH) z -N =} (C m H 2m-y) (OH) _y in formula, n and m are integers from 0 in the same or different 9, 1 ≦ n + m ≦ 9, and z and y The same or different integers, 0 ≦ z ≦ n−1 and 0 ≦ y ≦ m−1 and y + z ≧ 1. Among preferred examples of this type of hydroxyalkylenimine are hydroxymethyleneimine, hydroxyethyleneimine (e.g. 1-hydroxyethyleneimine and 2-hydroxyethyleneimine), hydroxytrimethyleneimine (e.g.
-Hydroxytrimethylene, 2-hydroxytrimethyleneimine and 3-hydroxytrimethyleneimine), hydroxytetramethyleneimine (e.g., 2-hydroxytetramethyleneimine), 2-hydroxy-2-methyltrimethyleneimine, hydroxypentamethyleneimine ( For example, 2-hydroxypentamethyleneimine), hydroxyhexamethyleneimine (eg, 2-hydroxyhexamethyleneimine), methylenehydroxymethyleneimine, methylenehydroxyethyleneimine and the like are included. Particularly preferred are lower hydroxyalkylenimines having two carbon atoms and one nitrogen atom, wherein both carbon atoms are terminal. This hydrogen atom may be substituted, for example, by a halogen group.

The 5- and 6-membered ring compounds represented by B _IV are of the aromatic or aliphatic type and can be substituted with alkyl groups having less than 7 carbon atoms and a hydroxy group.

The 5- and 6-membered heterocyclic compounds represented by R _VIII1 and R _VIII2 and R _X1 and R _X2 , which contain one or more nitrogen, oxygen or sulfur other than carbon atoms as ring members, are saturated. Or it may be unsaturated.

An “alkoxy group” is a straight or branched alkoxy group having less than 26 carbon atoms, such as methoxy and ethoxy, unless otherwise specified. These can be substituted, for example, with hydroxy, amino, halogen, oxo groups and with alkoxy groups such as methoxy-, ethoxy groups and the like.

An “alkoxy- (C _0-26 ) -alkyl group” is an alkoxy group, which may be bonded to the basic structure on the alkyl group.

A “cycloalkyl- (C _0-26 ) -alkyl group” is a cyclic compound having 3 to 8 carbon atoms and is bonded to a basic structure directly or on an alkylene group unless otherwise specified. This alkylene group may be linear or branched having a double bond. Possible substituents of a cycloalkyl group are, in particular, alkoxy groups, alkyl groups, hydroxy groups, halogen groups, amino groups, oxo groups. When comprising a double bond in the respective number, the cycloalkyl group of the aromatic That aryl (C _0-26) - alkyl group (e.g. phenyl, pyridyl, naphthyl, etc.) may also. In particular, the aromatic cyclic compound may further comprise nitro groups and substituents such as CF ₃ and phenyl groups.

A “cycloalkoxy- (C _0-26 ) -alkyl group” is a cyclic compound having 3 to 8 carbon atoms, which is directly bonded to the basic structure by an oxygen atom or bonded to the basic structure on an alkylene group. ing. The alkylene group is a saturated type or an unsaturated type having a double bond, and may be a linear or branched type. Possible substituents of a cycloalkyl group are, in particular, groups (also alkylenedioxy groups such as methylenedioxy), alkyl groups, hydroxy groups, halogen groups, amino groups, oxo groups. With each number of double bonds, the cycloalkyl group can be polycyclic and aromatic (eg, phenoxy, pyridoxy, naphthoxy, etc.). In particular, the aromatic cyclic compound may further comprise nitro groups and substituents such as CF ₃ and phenyl groups.

[0109] For example, "amino group" in the above definition alkyl group or a cycloalkyl - (C _{0- 26)} - may be substituted with an alkyl group.

An “amino- (C _0-26 ) -alkyl group” is an amino group, which may be bonded to the basic structure on the alkyl group.

A “silyl group” may be substituted by an alkyl group or a cycloalkyl- (C 0 _-26 ) -alkyl group as defined above.

A “thio- (C _0-26 ) -alkyl group” may be attached to a basic structure on an alkyl group. The alkyl and silyl groups are as defined above.

The “thio- (C _0-26 ) -alkyl group” may be substituted by an alkyl group or a cycloalkyl- (C _0-26 ) -alkyl group as defined above. The (C _0-26 ) -alkyl group is a linear or branched alkylene group, for example, methylene, ethylene,
Propylene, isopropylene, butylene, isobutylene, tert.-butylene, pentylene, hexylene and the like. These may contain double or triple bonds, for example hydroxy, amino, halogen (eg fluorine, bromine, chlorine),
It may be substituted with an oxo group and an alkoxy group such as a methoxy and ethoxy group.

The radicals X _I3 to X _VI13 , and X _I4 to X _VI14 and R _VII15 , R _IX11 , X _XI3
And X _XI4 X _II1 and X _II2 are selected in such a way that an ester is formed on the phosphono or sulfonyl group. Illustrative of the preferred esters of the compounds used according to the invention are the mono- and diesters, and in preferred examples of such esters are the alkyl esters (eg methyl, ethyl, propyl, isopropyl, butyl, isobutyl) Aralkyl esters (benzyl esters, phenethyl esters, benzohydryl esters, trityl esters, etc.); aryl esters (eg, phenyl esters, toluyl esters, naphthyl esters, etc.); aroyl alkyl esters (eg, phenacyl esters). And silyl esters (eg, trialkylsilyl ester, dialkyldihalogensilyl, alkyltrihalogensilyl, dialkylarylhalogensilyl, tria Job halogenated silyl, dialkyl aralkyl halogen silyl, dialkoxy halogen silyl ium, trialkoxy halogen silyl, etc.); others.

For the above esters, the alkane and / or allene moieties can optionally include at least one suitable substituent such as halogen, alkoxy, hydroxy, nitro or other.

[0116] X from X _I3 from X _VII3 and X _{I4 VII4} and X _XI3 and X _XI4, X _II1 and X _II2 are periodic table 1, second or third metals, ammonium, substituted ammonium or, It is preferably an ethylene compound or an ammonium compound derived from an amino acid. In other words, organic or inorganic bases (e.g., sodium, potassium, calcium, aluminum, ammonium, magnesium, triethylamine, ethanolamine, dicyclohexylamine, ethylenediaminethio, N, N'-dibenzylethylene) Salt salts of ammonium phosphonic acid derivatives having an amine salt or the like and an amino acid (eg, arginine salt, aspartate, glutamate, etc.) and the like.

The compounds according to the invention according to the formulas (I) to (XIV) may, for example in the case of a double bond or a group comprising a chiral group R or A or B or Y or Z or X, give rise to stereoisomers Make it possible. The use of the compounds according to the invention includes all stereoisomers, both pure and in the form of mixtures thereof.

Examples of pharmaceutically acceptable aminohydrophosphonic acid derivative salts include ammonium salts of inorganic or organic acids such as hydrochloric acid, sulfuric acid, citric acid, maleic acid, fumaric acid, tartaric acid, p-toluenesulfonic acid and the like. And salts which form the compounds according to the invention in their protonated form.

[0119] X ₃ (X _I3 from X _V3) and X ₄ (from X _I4 X _V4) and X _I11 and X _I1 properly at preferably salts formed by selecting _2, for example, sodium, potassium, calcium, Ammonium, ethanolamine, triethylamine, dicyclohexylamine salts, and amino acid salts such as alginate, aspartate, and glutamate.

[0120] The lipid metabolism inhibitors according to the present invention comprise one or more lipid metabolism inhibitors. Inhibitors can be used as inhibitors to control fat intake and regulate fat synthesis. Examples of these inhibitors include anion exchangers, preferably cholestyramine and colestipol, β-sitosterol, nicotinic acid and their derivatives such as nicotinyl alcohol, clofibrate and their derivatives such as clofibric acid ethyl ester and Analogues of e.g. bezafibrate,
Includes fenofibrate and gemfibrozil and probucol.

Examples of inhibitors that regulate fat synthesis include HMG-CoA synthetase inhibitors, HM
G-CoA reductases, preferably lovastatin, mevastatin, simvastatin, fluvastatin, atorvastatin, pravastatin and cerivastatin, and squalene synthetase inhibitors preferably pyrophosphate, pyrophosphate derivatives, biphosphonic acid derivatives, phosphinylmethylphosphonic acid derivatives, phosphine Inylformyl derivatives, phosphonocarboxyl derivatives, phosphonosulfonic acid derivatives, phosphinylmethylphosphonic acid derivatives, squalene monooxygenase inhibitors and cholesterol synthesis inhibitors are included. HMG-CoA-reductase inhibitors and squalene synthesis inhibitors are particularly preferred.

Among the bisphosphonates, clodronate, etidronate, pamidronate, ibandronate, alendronate, zoledronate, risedronate (
risedronate), tiludronate and simadronate are particularly preferred.

When the above-mentioned infectious active compound and its ester and its salt are simultaneously, intermittently or continuously administered with a lipid metabolism synthesis inhibitor, they show strong cytotoxicity against single-cell and multicellular parasites, fungi, bacteria and virus-infected cells. . The compounds according to the invention are useful for treating infectious disorders caused by parasites, fungi, bacteria or viruses in humans and animals. The compounds are also useful for preventing these diseases.

This lipid metabolism inhibitor is particularly effective against unicellular parasites (protozoa) against malaria and sleep sickness as well as chagas disease, toxoplasmosis, dysentery amoeba, leishmaniasis, trilomonosis, neumocysteosis, balantidiasis, Cryptosporidiosis, sporosporosis, acanthamoebiasis, negreliasis, coccidiosis,
It is effective against pathogens of giardiasis and giardiasis.

Thus, these are antimalarial agents and sleep sickness and chagas disease, toxoplasmosis, dysentery amoeba, leishmaniasis, trilomonosis, neumocystis, barantidiasis, cryptosporidiosis, sporosporosis, It is particularly suitable as a prophylactic agent for acanthamoebiasis, negleriosis, coccidiosis, giardia flagellosis, lambru flagellosis.

The lipid metabolism inhibitors according to the invention are used in particular against the following bacteria: Propionibacteriaceae family bacteria, especially Propionibacterium, especially Propionibacte
rium acnes; Actinomycetaceae bacteria, especially Actinomyces; Corynebacter
bacteria, especially Corynebacterium diphteriae species and Corynebacterium pse
bacterium of the species udotuberculosis; Mycobacteriaceae family bacteria, genus Mycobacterium, especially M
ycobacerium leprae, Mycobacterium tuberculosis, Ycobacterium bovis and Mycobacterium avium; Chlamydiaceae bacteria, especially Chlamydiatis and Chlamydia psittaci species; Listeria bacteria, especially Listeria monocytogene
s species; Erysipelthrix rhusiopathiae bacteria; Clostridium bacteria; Yetsinia bacteria, Yersinia pestis species, Yersinia pseudotuberculosis, Yer sinia entero
colitia and Yersinia ruckeri; Mycoplasmatacea family bacteria, Mycoplasma and Ureaplasma spp., especially Mycoplasma pneumoniae species; Brucella spp .; Bordetel
La bacteria; Neisseroaceae family bacteria, especially Neisseria and moraxella species, especially Neisseria meningitides species, Neisseria gonorrhoeae and Moraxella bo
vis; vibrionaceae family bacteria, especially Vibrio family, Aeromonas, Plesiomonas and Photoobacterium, especially Vibrio cholerae, Vubrio angillarum and Aeromo
nas salmonicidas; Campylibacter bacteria, especially Campylibacter jejuni, Campy
genus libacter coli and Campylibacter fetus; genus Helicobacter, especially Helicobacter
bacteria of the species pylori; spirochaetaceae and genus Leptospiraceae, especially Treponem
a, genus Borrelia and Leptospira, especially Borrelia burgdorferi; Actinob
bacteria of the genus acillus; bacteria of the genus Legionellaceae, genus of Legiononella; bacteria of the genus Rickettsiaceae and Bartonellaceae; bacteria of the genus Nocardia and Rhodococcus; Dermatophi
genus lus; Pseudomonadaceae family bacteria, especially Pseudomonas and Xanthomonas
Enterobacteriaceae bacteria, especially Escherichia, Klebsiella, Proteu
genus s, Providencia, Salmonella, Serratia and Shigella; Pasteurellace
ae bacteria, especially Haemophilus; Micrococcaceae bacteria, especially Micrococcus
And Staphylococcus; Streptococcaceae bacteria, especially Streptococcus
And Enterococcus and Bcillaceae bacteria, especially bacillus and c
genus lostridium.

Accordingly, lipid metabolism inhibitors according to the present invention include diphtheria, acne vulgaris,
Listeriosis, erysipelas in animals, gangrene in humans and animals, disease in humans and animals due to Clostridium septicum, tuberculosis in humans and animals, leprosy in humans and animals, further mycobacteriosis, paratuberculosis in animals, plague Mesenteric lymphitis and pseudotuberculosis in humans and animals, cholera, regenerosis, borreliosis in humans and animals, leptospirosis in humans and animals, syphilis, Campylobacter enteritis in humans and animals, Moraxella keratoconjunctivitis and serosa in animals Inflammation, brucellosis in humans and animals, anthrax in humans and animals, actinomycosis in humans and animals, streptotrix, animal parrot / ornithosis, and Q fever and Ehrlichiosis Suitable for treatment.

In addition, the above uses are advantageous for Helicobacter radiotherapy for gastrointestinal tract tumors.

Furthermore, combinations with additional antibiotics are used for the treatment of the above diseases.
Lipid metabolism inhibitors, especially isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin, prothionamide, and dapsone in combination with other anti-infective agents are suitable for the treatment of tuberculosis.

The lipid metabolism inhibitors according to the invention can furthermore be used in particular for the following viral infections: Parvoviridae: Parvovirus, Dependovirus, Densovirus; Adenoviridae: Adenovirus, Mastadenovirus, Bird Adenoviruses, viruses; Papovaviridae: Papovaviruses, especially papillomaviruses (so-called wart viruses), polioviruses, especially JC virus, BK virus, and myopapaviruses; Herpes viruses: all herpes viruses, especially herpes simplex virus, v blister Virus, human cytomegalovirus, EB virus, all human herpes viruses, human herpes virus 6, human herpes virus 7, human herpes virus 8; Poxviridae: poxvirus, orthopox, Lapox, infectious molluscum virus, avian pox virus, capripox virus, repolipox virus; all primary hepatotropic viruses, hepatitis viruses: hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, hepatitis E virus, hepatitis F virus, hepatitis G virus; Hepadna virus: all hepatitis viruses, hepatitis B virus, hepatitis D virus; picornaviridae; picornavirus, all enterelivirus, all poliovirus ,
All coxsackieviruses, all ECHO viruses, all rhinoviruses, hepatitis A virus, aphthavirus; Caliciviridae: Hepatitis E virus, reoviridae: reovirus, orbivirus, rotavirus; Togaviridae:
Togavirus, alhavirus, rubivirus, pestivirus, rubella virus; flavivirus genus; flaviviridae: ESME virus, hepatitis C virus;
Orthomyxoviridae: All influenza viruses; Paramyxoviridae: Paramyxovirus, Morbillivirus, Pneumonia virus, Measles virus,
Mumps virus; rhabdoviridae: rhabdovirus, rabies virus,
Rabies virus (lyssa), viscula stomatitis virus; Coronary virus; Bunyaviridae: Bunyavirus, Nyrovirus, Phlebovirus, uuku virus, Hantavirus; Arenaviridae: Arenavirus, lymphocytic choriomeningitis virus; retrovirus Family: retroviruses, all HTL viruses, human T-cell leukemia virus, oncovirus, spimavirus, lentivirus, all
HI-virus; genus Filovirus: Marburg-Ebola virus; delayed viral infection, prion; oncovirus, leukemia virus.

The preparations used according to the invention are therefore suitable for combating the following viral infections: Eradication of papillomaviruses to prevent tumors caused by papillomaviruses in humans, especially those of the reproductive organs, JC Virus and BK virus eradication, herpes virus eradication, human herpes virus 8 eradication in case of Kaposi's sarcoma treatment, cytomegalovirus eradication, EB virus eradication prior to transplantation and EB virus tumor prevention, chronic liver Eradication of hepatitis virus for the treatment of disease and prevention of liver tumors and cirrhosis, eradication of patients with cardiomyopathy Cocksackie virus,
Eradication of the diabetic Cocksackie virus, eradication of the immune system wasting virus in humans and animals, treatment of secondary infections in AIDS patients, treatment of respiratory viral inflammation (
Laryngeal papilloma, hyberplasias, acute rhinitis, laryngitis, bronchitis, pneumonia, treatment of viral inflammation of sensory organs (keratoconjunctivitis), nervous system (polio, meningitis, encephalitis, subacute sclerosing panencephalitis SSPE, progression) Polyfocal leukoencephalopathy, choriomeningitis, gastrointestinal tract (stomatitis, gingival stomatitis, colon infection, gastritis, gastroenteritis, diarrheal disease, liver and gallbladder system (hepatitis, cholangitis, hepatocellular carcinoma) Treatment of viral inflammation, treatment of lymphoid tissue (mononucleosis, lymphitis), treatment of viral inflammation, treatment of hematopoietic viral inflammation, treatment of viral inflammation of the reproductive organs (mumpsorchitis), skin (warts, skin) Inflammation, shingles, shingles help), treatment of viral inflammation of mucous membranes (papilloma, conjunctival papilloma, hyperplasia, dysplasia), heart / vasculature (arteritis, myocarditis,
Endocarditis, epicarditis), treatment of viral inflammation of the renal / urinary tract, reproductive organs (anogenital lesions, warts, genital warts, acute condyloma acuminatum, displasias, papilloma, cervical dysplasia, cuspoid Treatment of viral inflammation of condyloma, epidermal dysplasia wart), treatment of motor organ (myositis, myalgia) viral inflammation, treatment of foot-and-mouth disease in double-footed animals, treatment of viral inflammation of tick fever, dengue fever Treatment of viral inflammation of syndrome, treatment of viral inflammation of hemorrhagic fever, Early summer meningoencephalomyelitis (FSME)
For the treatment of viral inflammation, as well as for the treatment of viral inflammation of yellow fever.

This agent is suitable for use in combination with other antiviral agents.

Compounds according to the invention, generally including pharmaceutically acceptable salts, esters, salts of such esters, or other compounds which upon application provide the above compounds according to the invention as metabolites or degradation products Compounds, so-called "prodrugs", as well as known anti-infective agents, can be prepared for administration in any suitable manner.

The composite preparations used according to the invention can be administered as non-toxic, inert medicaments together with a suitable carrier. These carriers are understood to mean 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 are mentioned as pharmaceutical preparations. Tablets, dragees, capsules, pills, and granules can be used in addition to conventional excipients, (a) fillers and diluents, such as starch, lactose, sucrose, glucose, mannitol, and silicates; Alginate, gelatin, polyvinylpyrrolidone, (c) humectants such as glycerol, d) dispersants such as agar, calcium carbonate and sodium carbonate, (e)
Solution inhibitors such as paraffin and (f) absorption enhancers such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol, glycerol monostearate, (h) adsorbents such as kaolin and bentonite and (i) lubricants such as It can contain active ingredients such as talc, calcium and magnesium stearate, and solid polyethylene glycols or mixtures of the substances described in (a) to (i). Furthermore, the compounds according to the invention can be incorporated into other carrier materials such as, for example, plastics (plastic topical therapeutic chain), collagen or bone cement.

Tablets, dragees, capsules, pills, granules may be provided with a conventional coating and mantle, optionally containing an opacifying agent, and furthermore, only at certain sites in the intestine, or preferably at certain sites. The active ingredient or active ingredients can be packaged in such a manner that the active ingredient or the active ingredients are released in a sustained manner, in which case polymeric substances and waxes can be used as embedding agents.

The active ingredients can optionally be provided in microencapsulated form together with one or more excipients.

In addition to the above active ingredients, suppositories may include, for example, polyethylene glycols, oils such as cocoa fat, and higher esters (eg, C ₁₄ -alcohols with C ₁₆ fatty acids).
Alternatively, a mixture thereof can be contained.

In addition to the active ingredient, ointments, pastes, creams and gels contain conventional excipients such as animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and It may contain zinc oxide or a mixture of these substances.

In addition to the active ingredient, the powders and sprays may contain conventional vehicles such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders or mixtures thereof. Sprays may contain, in addition to these, conventional blowing agents such as chlorofluorohydrocarbons.

In addition to the active ingredients, solutions and emulsions may contain solvents, stabilizers and emulsifiers (em
ulgators) For example, water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, fats and oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castors It may contain sesame and sesame oil, glycerol, glycerol methylal, tetrahydrofurryl alcohol, polyethylene glycol and sorbitan fatty acid esters or mixtures of these substances. Solutions and displacement and emulsions can also be provided for parenteral use in the form of sterile solutions and isotonic blood solutions. In addition to the active ingredient, suspensions include liquid diluents such as water, ethyl alcohol, propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite. , Agar and gum tragacanth or mixtures thereof.

The active ingredient or the active ingredients of the formulas (I) to (XIV) may be present in the pharmaceutical preparation in a concentration of about 0.1 to 99.5% by weight, preferably about 0.5 to 95% by weight ( (Based on the total mixture). The proportion of the substances combined individually depends on the individual components. Thus, the administered active agent generally has a weight of 1 body weight per day.
Provided at a dose of 0.1 mg per kg (ibandronate and alendronate), a 0.5 mg dose per kg body weight per day (mevastatin, simvastatin, pravastatin, fluvastatin), and a 10 mg dose per kg body weight per day (pamidronate) You.

In addition to the compounds of the formulas (I) to (XIV) and the lipid metabolism inhibitors, the pharmaceutical preparations further comprise a pharmaceutically active ingredient such as an antiviral, antiparasitic, antifungal or antibacterial agent. Is also good.

The lipid metabolism inhibitors used according to the present invention further include sulfonamides, sulfadoxins, artemisinin, atovaquone, quinine, chloroquine, hydroxychloroquine, mefloquine, halofantrine, pyrimethamine, almesin, tetracycline, doxycycline, proguanil, metronidazole, It may further contain praziquantel, niclosamide, mebendazole, pyrantel, thiabendazole, diethylcarbazine, piperazine, pyribinum, metrifonate, oxamnikin, bitionol or suramin or several of these substances. Lovastatin, atorvastatin, simvastatin, mevastatin, pravastatin and fluvastatin are administered orally, while pravastatin and fluvastatin are administered in active form.

In the case of both human and vertebrate medicines, the active ingredients or active ingredients of the formulas (I) and (V) will generally be present in a total amount of 24 hours, in order to achieve the desired result. It has proven advantageous to administer about 0.5 to about 600, preferably 1 to 200 mg / kg of body weight, optionally in various individual dose forms. Individual doses may range from about 0.5 to about 200 / kg, especially from 1 to 6 / kg body weight.
Preferably, the active ingredient or ingredients are contained in an amount of 0 mg. However, there may be a need to diverge from the above doses, which need depends on the condition and weight of the patient to be treated, the nature and severity of the disease, the nature and method of the pharmaceutical composition and the package and the time scale or interval of administration. I do.

The lipid metabolism inhibitors have proven to be advantageous to administer in the known dose ranges known from the treatment of disorders of lipid metabolism and of calcium and phosphorus metabolism. To achieve the desired result, a total amount of about 0.005 to about 200, preferably 0.01 to 10 mg / kg of body weight per 24 hours, optionally administered in various individual dosage forms. In individual doses, preferably about 0.000 / kg body weight
It contains from 2 to about 50, in particular from 0.01 to 10 mg, of active ingredient or ingredients (lipid metabolism inhibitors). However, there may be a need to deviate from the above dosages, which may include the condition and weight of the patient to be treated, the nature and severity of the disease, the nature and method of the pharmaceutical composition and the application and the timescale or interval of administration. Depends on. When using aminobisphosphonates, it should be taken into account that these absorptions are very low. This property is advantageous in the case of an intestinal attack (eg in the case of amoebic dysentery). In this case, pamidronate at a dose of less than 10 mg per kg of body weight is orally administered. In the case of injection, a dose of less than 2 mg per kg of body weight is generally sufficient.

In some cases, less than the above amount of active ingredient is sufficient, while in other cases it is necessary to exceed the above amount of active ingredient. The person skilled in the art should be able to determine the optimal dose and the application of the active ingredient in each case based on experience.

The lipid metabolism inhibitors according to the present invention can be administered to animals with feed or feed preparations or drinking water in conventional concentrations and preparations. The lipid metabolism inhibitor can be administered simultaneously, intermittently or continuously.

[0149]

EXAMPLES Preparation of Anti-infective Active Agent Preparation of Injectable Preparation (1) 500 mg of 3- (N-acetyl-N
-Hydroxyamino) -propyl-phosphonic acid monosodium salt and 90 mg
Disperse the 3-amino-1-hydroxy-propylidene-1,1-bisphosphonic acid disodium salt in a flask or ampoule. Seal flask to eliminate bacteria. In the case of injection, this is taken up and administered in 500 ml each of sodium chloride physiological solution. A further injectable preparation of the anti-infective active agent is prepared in principle in the same manner as described above (1):

(2) 250 mg of 3- (N-formyl-N-hydroxyamino) -propylphosphonic acid monosodium salt and 1 mg of 3-methylpentylamino-1-hydroxypropylidene-1,1-bisphosphonic acid Disodium salt is used for injection.

(3) 250 mg of 3- (N-formyl-N-hydroxyamino) -trans-1-propenylphosphonic acid ・ an atrium salt and 90 mg of 3-amino-
1-Hydroxypropylidene-1,1-bisphosphonic acid disodium salt is used as the active ingredient for injection.

Tablet Preparation: The following mixture forms a suitable tablet preparation: 3- (N-formyl-N-hydroxyamino) -propylphosphonic acid monosodium salt 200 mg lovastatin 10 mg mannitol 400 mg starch 50 mg stearic acid Preparation of capsule 10 mg of magnesium: 3- (N-formyl-N-hydroxyamino) -propylphosphonic acid monopotassium salt 300 mg Sumivastatin 10 mg Magnesium stearate 15 mg These components are mixed, and then filled into hard gelatin by a conventional method. .

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 43/00 A61P 43/00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DK, EE, ES, FI, GB, G E, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK , MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZW F term (reference) 4C084 AA20 MA02 NA05 NA14 ZB321 ZB331 ZB351 ZC022 ZC332 ZC751 4C086 AA01 AA02 BA17 DA34 DA37 MA02 MA04 NA05 NA14 ZB32 ZB33 ZB35 ZC02 ZC33 ZC75

Claims (23)

[Claims] 1. A composite preparation comprising as active ingredients at least one anti-infective compound inhibiting the metabolic pathway of 2-C-methylerythrose-4 and at least one inhibitor of lipid metabolism, comprising: Preparation in which the inhibitor of the compound and the anti-infective active compound are not identical. 2. The inhibitor of lipid metabolism is cholestyramine, β-sitosterol, colestipol, probucol, nicotinic acid, nicotinyl alcohol, clofibric acid derivative and clofibric acid derivative analogue, HMG-CoA-synthetase-inhibitor. The composite preparation according to claim 1, characterized in that it is selected from the group consisting of an agent, an HMG-CoA-reductase inhibitor, a squalene synthetase inhibitor and a squalene monooxygenase inhibitor. 3. The method of claim 1, wherein the inhibitor of lipid metabolism is an inhibitor of squalene synthetase, in particular a pyrophosphate,
3. A pyrophosphate derivative, a bisphosphonic acid derivative, a phosphinylmethylphosphonic acid derivative, a phosphinylformyl derivative, a phosphonocarboxyl derivative, a phosphonosulfonic acid derivative, and a phosphinylmethylphosphonic acid derivative. A composite preparation according to claim 1. 4. The method according to claim 2, wherein the inhibitor of lipid metabolism is an inhibitor of HMG-CoA-reductase, in particular, a commercially available lovastatin, atorvastatin, mevastatin, simvastatin, fluvastatin, pravastatin and cerivastatin. A composite preparation as described. 5. The inhibitor of lipid metabolism is characterized in that it is a clofibric acid derivative and an analogue thereof, in particular, gemfibrozil, fenofibrate, benzafibrate, clofibrate, ciprofibrate and clinofibrate. The composite preparation according to claim 2, wherein 6. The lipid metabolism inhibitor is a bisphosphonic acid derivative, in particular, a clodronic acid derivative, an etidronic acid derivative, a pamidronic acid derivative, especially pamidronate, an ibandronic acid derivative, especially ibandronate, an alendronic acid derivative, especially alendronate, zoledronic acid. Composite preparation according to claim 2, characterized in that they are derivatives, in particular zoledronate, risedronic acid derivatives, tailedronic acid derivatives and simadronic acid derivatives. 7. At least one aminohydrocarbylphosphonic acid derivative represented by the general formula (I)
The composite preparation according to any one of claims 1 to 6, comprising a conductor as an active ingredient.
: Where R₁₁And R₁₂Are the same or different and are H, OH, substituted and unsubstituted
Sil, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted
Substituted cycloalkyl, substituted and unsubstituted aralkyl, and substituted and unsubstituted hetero
R is selected from the group consisting of:₁₃And R₁₄Is a substituted and unsubstituted alkyl of 1 to 26 carbon atoms, carbon atom
1 to 26 substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl
Substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, 1 to 26 carbon atoms
Substituted and unsubstituted alkenyl of 1 to 26 carbon atoms
, Substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen,
X₁₃And X₁₄Selected from the group consisting of₁₃And X₁₄Is like
Is heterologous, hydrogen, substituted and unsubstituted alkyl of 1 to 26 carbon atoms, carbon
Substituted and unsubstituted hydroxyalkyl of 1 to 26 atoms, substituted and unsubstituted ants
, Substituted and unsubstituted aralkyl, substituted and unsubstituted aralkyl of 1 to 26 carbon atoms
Lucenyl, substituted and unsubstituted aquinyl, substituted and unsubstituted from 1 to 26 carbon atoms
Cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, organic and inorganic bases
Thiones, especially metal cations of groups 1, 2 or 3 of the periodic table, ammonium, substitution
Ammonium compounds derived from ammonium and ethylenediamine or amino acids
Selected from the group consisting of:₁ Is an alkylene group, alkenylene group or hydroxyalkylene group or
Corresponds to the formula: Wherein the group C together with the substituents₁₃, C₁₄, C_FifteenOne or more carbon sources selected from
The offspring may be deleted and B₁ From B_TenIs at least one substituent of C_{3- 8} -Cycloalkyl- (C_0-9 ) -Alkyl groups, wherein C_3-8 -Cycloa
Alkyl group and C_0-9 An alkyl group contains one or more double bonds
And one or two carbon atoms of the cycloalkyl group may be nitrogen, oxygen
Or may be substituted with a sulfur atom, and wherein a cycloalkyl group and
Alkyl groups are hydroxy, halogen, amino, oxo, branched or straight chain C_1-9
-Alkyl group and C_2-9 -Alkenyl group, wherein C_{1- 9} -Alkyl group and C_2-9 An alkenyl group is hydrogen, hydroxy, amino, halo
And oxo groups, and any other substituted B ₁₁ From B₁₁₀ Is hydrogen, hydroxy, halogen, amino, C_1-26-Archi
Group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26-From an alkyl group
Or both substituents of one carbon atom are taken together to form an oxo group
To form each C_1-26Alkyl groups and each C_1-26An alkoxy group is branched or
Linear and saturated or unsaturated with one or more double bonds
And may be substituted with hydroxy, amino, halogen and oxo groups. 8. At least one bisphosphonic acid according to general formula (II), or a pharmaceutically acceptable salt, ester and ester salt thereof, or a compound to be administered, may be provided on application as a metabolite or degradation product. 7. A complex preparation according to any one of claims 1 to 6, comprising a compound as an active ingredient: _Wherein X _II1 , X _II2 , X _II3 , and X _II4 are the same or different and are hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl,
Substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, Na, K, Ca
, Mg, Periodic Table 1 such as Al, second or third group metal, selected substituted and unsubstituted ammonium, and from the group consisting of ammonium compounds from Echinjiamin or amino, A ₁₁ is deleted also possible Wherein R _II1 and R _II2 are the same or different and are 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 groups and -SR _II3 Cl, and -NR _II3 R _II4 , wherein R _II3 , R _II4 is a same or different, H, OH, substituted and unsubstituted acyl, substituted and unsubstituted alkyl Substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, selected from the group consisting of substituted and unsubstituted cycloalkyl and substituted and unsubstituted heterocyclic group. 9. An active ingredient comprising at least one compound corresponding to the general formula (III):
A composite preparation according to any one of claims 1 to 6: Where R_III1Is H, substituted and unsubstituted acyl, substituted and unsubstituted alkyl, substituted and unsubstituted
And unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted
Alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted cycloalkyl, substituted
Substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen and OX_{II I1} Selected from the group consisting of_III1Is hydrogen, substituted and unsubstituted acyl,
Substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted
Substituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted
Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, silyl, substituted and unsubstituted
And unsubstituted heterocyclic groups, cations of organic and inorganic bases, especially Periodic Tables 1 and 2
Or cations of group 3 metals, such as ammonium, substituted ammonium and ammonium.
R compound selected from the group consisting of_III4, R_III3Are the same or different and include hydrogen, substituted and unsubstituted acyl,
Substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted
Unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl,
Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted
Substituted heterocyclic group, halogen and OX_III4And OX_III3Selected from the group consisting of
, Where X_III4, X_III3Is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted
Substituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted cycloalkyl,
Silyl, substituted and unsubstituted heterocyclic groups, cations of organic and inorganic bases, especially periodicity
Cation, ammonium, substituted ammonium of metals of group 1, 2 or 3
, And an ammonium compound derived from ethylenediamine or an amino acid
Selected from the group; and A_III1And A_III2One or both may be deleted,_III1And A _III2 Are the same or different, alkylene group, alkenylene group, oxo group,
Represents a hydroxy group or an oxohydroxyalkylene group. 10. The composition according to claim 1, which comprises at least one compound corresponding to the following general formula (IV) and pharmaceutically acceptable salts, esters and amides and ester salts thereof as active ingredients. A composite preparation according to any one of the preceding claims: Wherein R _IVI and R _IV2 are the same or different and are 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 groups, halogen, OX _IVI and OX _IV2 , wherein X _IVI and X _IV2 are the same or Heterologous, 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,
B _IV is selected from the group consisting of substituted and unsubstituted heterocyclic groups, and B _IV is selected from the group consisting of the following ether groups (IVA): Wherein, A _IV2 in A _IV1 and A _IV2 are possible deletions, and A _IV1 and A _IV2 is a same or different, consist of an alkylene group, alkenylene group and hydroxy alkylene, keto group (IVB) Selected from the group: Wherein one or both in the A _IV3 and A _IV4 are possible deletions, and A _IV3 and A _IV4 are same or different, alkylene, alkenylene and hydroxyalkylene groups, and in particular in the ring is selected from at least one heterocyclic atom a group consisting of 5 and 6-membered rings, especially heterocyclic compound containing in addition to carbon atoms, wherein the heterocyclic atom is selected from the group consisting of oxygen and nitrogen, R _IV3 and R _IV4 is the same or different and includes hydrogen, substituted and unsubstituted alkyl having less than 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having less than 26 carbon atoms, substituted and unsubstituted aryl groups, substituted and unsubstituted acyl, substituted and unsubstituted acyl. Substituted aralkyl, substituted and unsubstituted alkenyl having less than 26 carbon atoms, 26 carbon atoms
Less than one or more substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen, OX _IV3 or OX _IV4 , wherein X _IV3 or X _IV4 is the same or different. And hydrogen, carbon atom 2
Less than 6 substituted and unsubstituted alkyl, less than 26 carbon atoms substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl groups, substituted and unsubstituted aralkyl,
Substituted and unsubstituted alkenyl of less than 26 carbon atoms, substituted and unsubstituted alkynyl of less than 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, cations of organic and inorganic bases, especially The cation is selected from the group consisting of cations of Group 1, 2 or 3 metals, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids. 11. The composition according to claim 1, comprising at least one phosphonic acid derivative corresponding to the following formula (V) and salts, esters, amides and ester salts thereof as active ingredients:
A composite preparation according to any one of the preceding clauses: Wherein one or both of A _V1 and A _V2 can be deleted, and A _V1 and A _V2 are the same or different and are selected from the group consisting of an alkylene group, an alkenylene group and a hydroxyalkylene group. Wherein the carbon chain -A _V1 -CHOH-A _V2 -preferably consists of 2 to 5, especially 3 to 4 carbon atoms, and B _V is selected from the group consisting of groups of formula (VA): 9] Wherein R _V1 is 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 Substituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups and halogen, selected from the group consisting of groups of formula (VB): Wherein R _V2 , R _V3 and R _V4 are the same or different and are hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl,
Consisting of substituted and unsubstituted alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, and the following group (VC) Selected from the group: Wherein R _V5 , R _V6 and R _V7 are the same or different and are hydrogen, OH, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted substituted and unsubstituted Selected from the group consisting of alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen, wherein X _V3 and X _V4 are the same or different. Wherein hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkyl, Heterocyclic groups, silyl, cations of organic and inorganic bases, especially The first table, second or third group of metal cations, ammonium, is selected from the group consisting of substituted ammonium, and ethylene diamine or ammonium compounds derived from amino acids. 12. The compound according to claim 1, comprising at least one compound corresponding to the general formula (VI) or a pharmaceutically acceptable salt, ester and amide thereof, and an ester salt as an active ingredient. Complex preparation described in: _Wherein R _VI3 and R _VI4 are the same or different and are hydrogen, substituted or unsubstituted alkyl having less than 26 carbon atoms, substituted and unsubstituted hydroxyalkyl having less than 26 carbon atoms, substituted and unsubstituted aryl groups, substituted and unsubstituted aryl groups. Substituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl having less than 26 carbon atoms, substituted and unsubstituted alkynyl having less than 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen, OX _VI3 or it is selected from the group consisting of OX _VI4, wherein X _VI3 or X _VI4 is same or different, hydrogen, substituted and unsubstituted alkyl of less than carbon atoms 26, substituted and unsubstituted hydroxyalkyl fewer carbon atoms 26, substituted And unsubstituted aryl groups, substituted and unsubstituted aralkyl, substituted and unsubstituted aralkyl groups having less than 26 carbon atoms. And unsubstituted alkenyl, substituted and unsubstituted alkynyl having less than 26 carbon atoms, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, cations of organic and inorganic bases, in particular the first, second or third periodic table _BVI is selected from the group consisting of Group 3 metal cations, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids, and _BVI is the following group (VIA): And selected from the group consisting of the following groups (VIB): In the formula, A _VI is selected from the group consisting of an alkyleneamine group, an alkenyleneamine group, a hydroxyalkyleneamine group, an alkyleneimine group, an alkenyleneimine group and a hydroxyalkyleneimine group, wherein the nitrogen atom is represented by the following group: Is a member of the chain that connects the nitrogen atom and the phosphorus atom: Or the group R _VII -N =. Wherein R _VI1 and R _VI2 in the group (VIA) are the same or different, and
R _VI1 and R _VI2 and R _VI1 in group (VIB) in IVA) is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted hydroxyalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted Selected from the group consisting of substituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, _OXVI1 and _OXVI2 , where _XVI1 and X _VI2 is the same or different,
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 It is selected from the group consisting of aralkyl, substituted and unsubstituted heterocyclic groups. 13. At least one compound corresponding to the general formula (VII) and pharmaceutically acceptable
Salts, esters and amides thereof and ester salts as active ingredients
7. A composite preparation according to any one of the preceding claims, comprising: Where A_VII Is (C_1-9 ) -Alkylene group;
Or two or more double bonds, and may contain hydroxy, halogen, amino,
Oxo group, branched or linear C_1-9 -Alkyl group and C_2-9 -With an alkenyl group
May be substituted, where C_1-9 -Alkyl group and C_2-9 An alkenyl group is water
Hydrogen, hydroxy, amino, halogen and oxo groups, -CO-C- and -C
-NC-, where -CO-C- and -C-NC- can be substituted.
Carbon atoms may be substituted with alkyl or hydroxy groups having less than 7 carbon atoms.
Or A_VII Corresponds to the following formula (VIIA): Wherein the group C together with their substituents_VII3, C_VII4, C_VII5One or two selected from
One or more carbon atoms may be deleted and B_VII1From B_VII10 At least
Also one substituent is C_3-8 -Cycloalkyl- (C_0-9 ) -Alkyl group,
Here C_3-8 A cycloalkyl group and (C_0-9 )-One or two alkyl groups
It may contain the above double bond, and one or two of the cycloalkyl groups
Carbon atoms may be replaced by nitrogen, oxygen or sulfur atoms, where
Alkyl and alkyl groups include hydroxy, halogen, amino, oxo,
Or straight chain C_1-9 An alkyl group, and C_2-9 -May be substituted with an alkenyl group
, Where C_1-9 -Alkyl group and C_2-9 An alkenyl group is hydrogen, amino, halo
Or an oxo group, and the remaining substituent B_VII1From B _VII10 Is hydrogen, hydroxy, halogen, amino group, C_1-26-Alkyl group, C_1-26 -Alkoxy group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26-Achill
Selected from the group consisting of the groups or both substituents of one carbon atom are taken together
Forming an oxo group, where each C_1-26Alkyl groups and each C_1-26-Alkoxy group
Is branched or straight-chain and is saturated or one or more double-bonded
Unsaturated, substituted with hydrogen, amino, halogen and oxo groups
May be R_VII1Are those having one or two nitrogen, oxygen or sulfur atoms in the ring.
And 6 membered heterocycles, wherein the heterocycle is saturated or one or more
Is an unsaturated type having two or more double bonds or triple bonds, and is hydrogen, ha
By a logen, amino, oxo group and branched or linear C_1-9 -Alkyl
Group and C_2-9 -Alkenyl group, wherein C_1-9 -A
Alkyl group and C_2-9 An alkenyl group is saturated or one or more
Unsaturated hydrogen, hydroxy, amino, halogen having a heavy or triple bond
And an oxo group._VII3And R_VII4Are the same or different and include hydrogen, substituted and unsubstituted C_{1- 26} -Alkyl, hydroxy-C_1-26-Alkyl, substituted and unsubstituted aryl,
Substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26 Alkenyl, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cyclo
Alkyl, substituted and unsubstituted heterocyclic group, halogen, OX_VII3And OX_VII4From
Selected from the group_VII3And X_VII4Are the same or different and are hydrogen, substituted and unsubstituted
Exchange C_1-26-Alkyl, substituted and unsubstituted hydroxy-C_1-26-Alkyl, substituted or
And unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26−
Alkenyl, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cycloalkyl
Alkyl, substituted and unsubstituted heterocyclic groups, silyl, organic and inorganic base cations
The cation, ammonium, and substituted anion of a metal of Group 1, 2, or 3 of the periodic table
Monium and ammonium compounds derived from ethylenediamine or amino acids
Selected from the group consisting of: 14. The complex preparation according to claim 1, comprising at least one compound corresponding to the general formula (VIII) as an active ingredient. _Wherein the wavy line represents a bond having an α- or β-configuration, n is 0 or 1, R _III11 is substituted and unsubstituted C _1-26 -alkyl, hydroxy-C _1-26 -alkyl, substituted and unsubstituted Aryl, substituted and unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C _1-26 -alkenyl, substituted and unsubstituted C _1-26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups _Wherein X _VIII11 is hydrogen, substituted and unsubstituted C _1-26 -alkyl, substituted and unsubstituted hydroxy-C _1-26 -alkyl, substituted and unsubstituted aryl, substituted And unsubstituted heterocyclic groups aralkyl, substituted and unsubstituted C _1-26 -alkenyl, substituted and unsubstituted C _1-26 -alkynyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted cycloalkyl, And cations of unsubstituted heterocyclic groups, silyls, organic and inorganic bases, especially cations of metals of Groups 1, 2 or 3 of the periodic table, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids. is selected, R _VIII1 is C _1-24 - alkyl groups, C _2-24 - alkapolyenyl groups, C _2-24 - - alkenyl groups, C _2-24 having 6 from double bonds 2 alkynyl groups, C _3-8 - cycloalkyl group, C _3-8 - cycloalkyl -C _1-24 - alkyl and C _1-12 - alkoxy -C _1-12 - is selected from the group consisting of alkyl groups, each R _VIII2, R _VIII3 and _RVIII4 are selected from the group consisting of hydrogen, halogen, amino, acetylamino, azide and _XRVIII6 groups, wherein X is O or S
_Wherein R _VIII6 is selected from the group consisting of hydrogen, branched or straight chain C _1-4 -alkyl and C _2-4 -alkenyl, wherein C _1-4 -alkyl and C _2-4-
The alkenyl group is optionally substituted with hydrogen, amino, halogen or oxo group, or R _VIII2 , R _VIII3 and R _VIII4 together with the respective gem-hydrogen group represent an oxo group; R _VIII5 is hydrogen, C _{VIII 1-24} - alkyl group, C _3-8 - cycloalkyl group, Ar (C _1-24 - alkyl) group, an aryl group, an acyl group, a heterocyclic group, selected from the group consisting of halogen, where all groups Is branched or linear and may be optionally substituted by a hydroxy, amino, halogen or oxo group and may contain 2 to 6 double and triple bonds, or R _VIII5 has the formula VIIIA or XIIIB is a phenyl group: Embedded image Wherein, R _VIII7 and R _VIII8 is a same or different, it is bonded to any two positions of the phenyl ring, and R _VIII7 and R _VIII8 hydrogen, halogen, C _1-4 -
Alkyl group, C _1-4 -alkoxy group, formyl, acetyl, propionyl, butyryl group, formyl, acetyl, propionyl, butyryloxy group, C _2-5 -alkoxycarbonyl group, all independently selected from the group consisting of R ₇ and R _VIII8 may be taken together at adjacent positions, such as the 2,3-position or 3-position of the phenyl ring.
Can form a linear saturated alkylene group with 3 to 4 carbon atoms attached at the, 4-position, or R ₇ and R ₈ together form the 2,3- or 3,4-
A methylenedioxy group, 1,1-ethylidenedioxy group or 1,
To form a 2-ethylenedioxy group, or R _VIII5 is R _III9 COOCHR _VIII10 - it is selected from the group consisting of, R _Viii9 is, C _1-6 - - and R _III9 OCOOCHR _VIII10 alkyl group, C _2-6 - alkenyl Group, C _2-6 -alkynyl group, C _3-8 -cycloalkyl group, C _3-8 -cycloalkyl-C _1-6 -alkyl group and C _1-6 -alkoxy-C _1-6 -alkyl group Wherein all groups are branched or straight-chain and can be optionally substituted with hydroxy, amino, halogen or oxo groups, and further wherein R ₁₀ is a branched or straight-chain C _1-4. alkyl, wherein, if n = 1, the substituents in the formula _{(VIII) R VIII2, R VIII3} , R VI II4 and _{R III5 OOCPO (OH) OCH 2} - arrangement of D-gluco, L- gluc
o, D-galacto, L-galacto, D-manno, L-manno, D-talo, L-ta
lo, D-allo, L-allo, D-altro b, L-altro, D-gulo, L-gulo, D
-Ido or L-ido, and if n = 0, the relative configuration of the substituents R ₂ , R ₃ and R ₅ OOCPO (OH) OCH ₂ — in formula (I) is independently D
-Ribo, L-ribo, D-arabino, L-arabino, D-xylo, L-Xxylo, D-
lyxo or L-lyxo. 15. At least one compound corresponding to formula (IX): and pharmaceutically acceptable
Salts, esters and amides thereof, ester salts, and optical isomers thereof.
A complex preparation according to any one of claims 1 to 6, comprising the body as an active ingredient: Where R_IX11Is a substituted and unsubstituted C_1-26-Alkyl, hydroxy-C_1-26-Alkyl
Substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted aryl
Alkyl, substituted and unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26-Al
Quinyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen
And OX_IX11Selected from the group consisting of_IX11Is hydrogen, substituted and unsubstituted C_1-26-Alkyl, hydroxy-C_{1- 26} -Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted
And unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26Alkynyl, substituted
And unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, organic and
Cations of inorganic bases, particularly cations of metals of Groups 1, 2 or 3 of the Periodic Table;
From ammonium, substituted ammonium, and ethylenediamine or amino acids
R is selected from the group consisting of:_IX1 And R_IX2 Each of C_1-24-Alkyl group, C_3-8 -Cycloalkyl
Group, C_3-8 -Cycloalkyl-C_1-24-Alkyl group, C_1-24-Alkoxy group, C _1-24 -Alkylthio group, C_1-24-Alkoxy-C_1-24Alkyl group and C_1-24−
Alkylthio-C_1-24-Alkyl group, acyl group, aryl group, aralkyl group,
Independently selected from the group consisting of a ring group, halogen and hydrogen;_1-24-Al
Kill group and C_1-24Each of the alkoxy groups may be branched or linear;
Saturated or unsaturated from 2 to 6 double bonds, and hydrogen, amino
, Mercapto, halogen, oxo group, or C_1-24-Alkoxy group, C_1-24-A
Alkylcarbonyl-oxy group, C_1-24-Alkoxycarbonyloxy group, C_1-24 -Alkylthio group, C_1-24-Alkylcarbonylthio group, C_1-24-Alkylami
No group, di- (C_1-24) -Amino group, C_1-24-Alkylcarbonylamino group, C_{1- twenty four} -Alkyl- (C_1-24-Alkylcarbonyl) -amino group, C_1-24-Alkoki
Cicarbonylamino group or C_1-24-Alkyl- (C_1-24-Alkoxycarboni
Ru) optionally substituted with an amino group, wherein an aralkyl group, a heterocyclic group,
C_1-24An alkyl group and C_1-24Each of the alkoxy groups is branched or linear.
Saturated or unsaturated with 2 to 6 double or triple bonds.
Or R_IX1 -CH-CH-R_IX2 Is C_4-8 Forms part of a carbocycle, which ring is
Si, mercapto, amino, halogen, may be optionally substituted with an oxo group,
Is C_1-24-Alkyl group, C_1-24-Alkoxy group, C_1-24-Alkylthio group, C_{1- twenty four} -Alkylamino group, di- (C_1-24-Alkyl) amino group, C_1-24-Alkyl
Carbonyl group, C_1-24-Alkyl carbonyloxy group, C_1-24-Alkoxycarboni
Group, C_1-24-Alkylcarbonylthio group or C_1-24-Alkylcarbonyla
Mino group, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) amino group optionally
May be substituted, where C_1-24-Each alkyl group is branched or linear
Or a saturated or unsaturated form having 1 to 6 double bonds, or R_IX1 Is a branched or linear C_1-4 -An alkyl group, and R_IX1 -CH-CH-R_IV1 Is, for example, D-ribose, D-arabinose, D-ki
Sylose, D-lyxose, D-glucose, D-galactose, D
-Mannose, D-talose, D-allose, D-artose, D-glucose
Furanose or pyranose of saccharides such as D-idose or the corresponding L-isomer
Form part of a ring, wherein each of the hydroxy groups is hydrogen, amino, azide,
Oxo, mercapto group or C_1-24-Alkoxy group, C_1-24An alkylthio group,
C_1-24-Alkylamino group, di- (C_1-24) Amino group, C_1-24-Alkyl carbo
Nyloxy group, C_1-24-Alkylcarbonylthio group, C_1-24-Alkyl carboni
Ruamino group, C_1-24-Alkyl- (C_1-24-Alkylcarbonyl) amino group
Where each C is_1-24The alkyl group is branched or straight-chain;
It may be a saturated or unsaturated type having 1 to 6 double bonds._IX1 And R_IX2 Each represents a carboxyl group or a carboxamide group
, Aryl group, aryloxycarbonyl group, aryl-C_1-24Alkyl group, C _1-24 -Alkoxycarbonyloxy group, C_1-24An alkylaminocarbonyl group,
Di- (C_1-24-Alkyl) aminocarbonyl group, aryl-C_1-14-Alkoxy
Carbonyl group, aryl-C_1-24-Alkylaminocarbonyl group, C_1-24-Al
Kill carbonyloxy- (C_1-4 ) -Alkylmethoxycarbonyl group, C_1-24−
Alkoxy-carbonyloxymethoxycarbonyl group, C_1-24-Alkoxycal
Bonyl-oxy- (C_1-24Alkyl) -methoxycarbonyl group
Selected, where each C_1-24The alkyl group is branched or straight-chain, saturated or
It may be an unsaturated type having 2 to 6 heavy bonds, and_1-4 -Alkyl group and C _1-24 The alkoxy group may be branched or linear, saturated or unsaturated,
And each aryl group is of the formula (IXA): Where R_IX3 And R_IV4 Are the same or different and are each hydrogen, halogen, C _1-24 -Alkyl group, C_1-24-Alkoxy groups, formyl, acetyl, propionyl
, Butyryl group, formyl, acetyl, propionyl, butyryloxy group, C_1-4
-Alkoxycarbonyl groups, all of which are branched or straight-chain.
May be in chain form, or_IX3 And R_IV4 Are together adjacent to the phenyl ring
Form a linear saturated alkylene chain of 3 to 4 carbon atoms attached to the_{IX Three} And R_IV4 Is a methylenedioxy group bonded to the adjacent position of the phenyl ring together,
Form a 1,1-ethylidenedioxy group or a 1,2-ethylenedioxy group. 16. An active ingredient comprising at least one compound corresponding to the following general formula (X):
A composite preparation according to any one of claims 1 to 6: Where R_X1Is hydrogen, substituted and unsubstituted C_1-9 Alkyl, substituted and unsubstituted hydroxy
C_1-9 -Alkyl, substituted and unsubstituted C_1-9 Alkenyl, substituted and unsubstituted C_{1- 9} -Alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted
And unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted
Ring group₁ , Halogen and OX_X1Selected from the group consisting of_X1Is hydrogen, substituted and unsubstituted C_1-9 -Alkyl, substituted and unsubstituted
Droxy C_1-9 -Alkyl, substituted and unsubstituted C_1-9 Alkenyl, substituted and
Unsubstituted C_1-9 -Alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl
, Substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and
Selected from the group consisting of unsubstituted heterocyclic groups, where R_X2Is C_1-26-Alkyl, C_1-26-Alkoxy group, C_1-26-Alkoxy
-C_1-26-Alkyl group, C_3-8 Cycloalkyl- (C_0-26) Consisting of an alkyl group
Selected from the group wherein one or two carbon atoms of the cycloalkyl group are nitrogen,
Each C may be replaced by an oxygen or sulfur atom._3-26Alkyl groups and each C _3-26 -Alkoxy groups are branched or straight-chain,_3-8 -Cycloalkyl group,
Each C_2-26Alkyl groups and each C_2-26The alkoxy group is saturated or one or two
It may be an unsaturated type having one or more double bonds, and each C_3-8 -Cycloalkyl
Group, each C_1-26Alkyl groups and each C_1-26-Alkoxy groups are hydroxy, amino
, Halogen and oxo, or the carbyl group COR_X3May be replaced by
R_X3Is a substituted and unsubstituted C_1-26-Alkyl, hydroxy-C_1-26-Alkyl,
Substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted and unsubstituted arals
Kill, substituted and unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26-Alkini
, Substituted and unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, halogen,
OX_X3Selected from the group consisting of_X3Is hydrogen, substituted and unsubstituted C_1-26-Alkyl, hydroxy-C_1-26A
Alkyl, substituted and unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and
Unsubstituted C_1-26Alkenyl, substituted and unsubstituted C_1-26Alkynyl, substituted and
Unsubstituted cycloalkyl, substituted and unsubstituted heterocyclic groups, silyl, organic and inorganic salts
Cations of groups, especially cations of metals of the first, second or third group of the periodic table, ammonium
Ammonium, substituted ammonium, and ethylenediamine or amino acids derived from amino acids.
It is selected from the group consisting of monium compounds. 17. At least one compound corresponding to the following general formula (XI):
Contains recognized salts, esters, amides and ester salts as active ingredients
A composite preparation as claimed in any one of claims 1 to 6: Where Z_XIIs a phosphorus atom or a sulfur atom, wherein A_XIIs hydrogen, hydroxy, halogen, amino and oxo groups, and C _1-26 -Alkyl group, C_1-26-Alkoxy group, C_1-26-Alkoxy-C_1-26-Al
Kill group or C_3-8 -Cycloalkyl- (C_0-9 ) -Alkyl groups
Straight chain with selected same or different substituents_2-9 An alkylene chain,
Here each C_1-26Alkyl groups and each C_1-26The alkoxy group is branched or linear
Saturated or unsaturated having one or more double bonds and hydroxy
, Amino, halogen and oxo groups;_3-8 -Shiku
Lower alkyl- (C_0-9 ) -Alkyl group C_3-8 Cycloalkyl group and C_0-9 The alkyl group may contain one or more double bonds, and may be a cycloalkyl.
One or two carbon atoms of the radical is replaced by a nitrogen, oxygen or sulfur atom
Wherein the cycloalkyl group and the alkyl group are hydroxy, halogen,
, Amino, oxo, branched or straight chain C_1-9 -Alkyl group and C_2-9 -Alkene
Which may be substituted by_1-9 -Alkyl group and C_2-9 -Al
Kenyl groups are substituted by hydrogen, hydroxy, amino, halogen and oxo groups.
May be R_XI1 And R_XI2 Are the same or different and are hydrogen, substituted and unsubstituted C_1-9
Alkyl, substituted and unsubstituted hydroxy-C_1-9 -Alkyl, substituted and unsubstituted
C_1-9 Alkenyl, substituted and unsubstituted C_1-9 Alkynyl, substituted and unsubstituted
Reel, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted
And unsubstituted aralkyl, substituted and unsubstituted heterocyclic groups, halogen, OX_Xi1 And O
X_XI2 Selected from the group consisting of_Xi1 And X_XI2 Is the same or different
Wherein hydrogen, substituted and unsubstituted C_1-9 -Alkyl, substituted and unsubstituted hydroxy
Sea C_1-9 Alkyl, substituted and unsubstituted C_1-9 -Alkenyl, substituted and unsubstituted
C_1-9 Alkynyl, substituted and unsubstituted aryl, substituted and unsubstituted acyl, substituted
And unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted
R is selected from the group consisting of heterocyclic groups;_XI3 And R_XI4 Are the same or different and are substituted and unsubstituted C_1-26Al
Kill, hydroxy-C_1-26-Alkyl, substituted and unsubstituted aryl, substituted and
Unsubstituted acyl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26−Arche
Nil, substituted and unsubstituted C_1-26-Alkynyl, substituted and unsubstituted cycloalkyl
, Substituted and unsubstituted bicyclic groups, halogen, OX_xI3 And OX_XI4 From the group consisting of
Selected, where X_XI3 And X_XI4 Is the same or different and is hydrogen, substituted or unsubstituted
C_1-26-Alkyl, substituted and unsubstituted hydroxy-C_1-26-Alkyl, substituted and
And unsubstituted aryl, substituted and unsubstituted aralkyl, substituted and unsubstituted C_1-26-A
Lucenyl, substituted and unsubstituted C_1-26Alkynyl, substituted and unsubstituted cycloal
Cations of killed, substituted and unsubstituted bicyclic groups, silyl, organic and inorganic bases, especially
Cation, ammonium, substituted ammonium of metals of Group 1, 2 or 3 of the Periodic Table
And ammonium compounds derived from ethylenediamine or amino acids
Selected from the group consisting of: 18. An active ingredient comprising at least one compound corresponding to the general formula (XII):
A composite preparation according to any one of claims 1 to 6: Where A_XII Is hydrogen, substituted and unsubstituted C_1-28-Alkyl groups, substituted and unsubstituted al
Coxy (C_0-28) -Alkyl groups, substituted and unsubstituted cycloalkyl- (C_0-28 ) Alkyl groups, substituted and unsubstituted cycloalkoxy- (C_0-28) -Alkyl groups,
Substituted and unsubstituted amino- (C_0-28) Alkyl groups, substituted and unsubstituted thio- (C _0-28 ) -Alkyl groups, and substituted and unsubstituted acyl- (C_0-28) -Alkyl group
And each alkyl group, each alkoxy group and
Each acyl group may be branched or linear, and each alkyl group, each alkoxy group
Si, each acyl and each cycloalkyl are saturated or one or more
With unsaturated double or triple bonds and one or two carbon atoms
A cycloalkyl group may be substituted with nitrogen, oxygen or sulfur;
R_XII3Is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkoxy-
(C_0-26) -Alkyl groups, substituted and unsubstituted C_3-14-Cycloalkyl- (_0-26)
-Alkyl group, substituted and unsubstituted cycloalkoxy- (C_0-26) -Alkyl groups,
Substituted and unsubstituted amino- (C_0-26) -Alkyl groups, substituted and unsubstituted silyl-
(C_0-26) -Alkyl groups and substituted and unsubstituted thio- (C_0-26) -Alkyl group
Wherein each alkyl group and each alkoxy group are branched or linear
Each alkyl group, each alkoxy group and each cycloalkyl group may be
Saturated type or unsaturated type having one or more double bonds or triple bonds
And one or two carbon atoms of the cycloalkyl group may be nitrogen,
Can be replaced by an oxygen or sulfur atom, or A_XII The carbon chain consisting of two carbon atoms is R_XII3With isoxazoli
Form a don ring, and R_XII4Is hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted acyl, and
Substituted and unsubstituted cycloalkyl- (C_0-26)-Selected from the group consisting of alkyl groups
Each alkyl group and each acyl group may be branched or straight-chain,
Alkyl group, each acyl group and each cycloalkyl group are saturated or one or two
Unsaturated type having the above double bond or triple bond, and cycloalkyl
One or two carbon atoms of the radical can be replaced by nitrogen, oxygen or sulfur. 19. The complex preparation according to claim 1, which comprises at least one compound corresponding to the following general formula (XIII) as an active ingredient: Wherein, n is an integer from 0 to 4, and _{R XIII1, R XIII2, R XIII3} , X XIII4, X XIII5 and X _III6 are identical or different, hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted From the group consisting of substituted alkoxy, substituted and unsubstituted acyl, substituted and unsubstituted cycloalkyl- ( _C0-26 ) -alkyl, substituted and unsubstituted cycloalkyl- ( _C0-26 ) -alkoxy and halogen Selected, each alkyl group, each alkoxy group and each acyl group are branched or straight-chain, and each alkyl group, each acyl group, each alkoxy group and each _cyclo- (C _0-26 ) -alkyl group are saturated or Unsaturated with one or more double or triple bonds, and one or two carbon atoms of the cycloalkyl group can be replaced by nitrogen, oxygen or sulfur 20. The complex preparation according to claim 1, comprising at least one compound corresponding to the general formula (XIV) as an active ingredient: _Wherein Y _XIV is a C _1-3 -alkylene group, which alkylene group is optionally substituted by substituents R _XIV1 and R _XIV2 , and optionally substituted by R _XIV3 to R _XIV6 , wherein R _XIV1 R _XIV8 is the same or different and includes hydrogen, hydroxy,
Halogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (
_C0-26 ) -alkyl, substituted and unsubstituted cycloalkyl- ( _C0-26 ) -alkyl, substituted and unsubstituted alkoxy- ( _C0-26 ) -alkyl, substituted and unsubstituted amino and substituted And unsubstituted thio- (C _0-26 ) -alkyl groups, substituted and unsubstituted sulfonyl- (C _0-26 ) -alkyl groups, substituted and unsubstituted sulfinyl-
Selected from the group consisting of (C _0-26 ) -alkyl groups and substituted and unsubstituted acyl groups, wherein each alkyl group, each alkoxy group and each acyl group are branched or linear, and each alkyl group and each alkoxy group Each cycloalkyl group may be saturated or unsaturated with one or more double or triple bonds, and one or more carbon atoms of the cycloalkyl group may be nitrogen, R _XIV13 and R _XIV14 can be substituted with oxygen or sulfur and R _{XIV1 to} R _XIV8 are the same as or defined together with R _XIV1 to R _XIV8 , and Z _XIV represents the following organophosphorus group: 28] _Wherein R _XIV9 and R _XIV10 are the same or different and are hydrogen, substituted or unsubstituted (
C _1-26 ) -alkyl group, substituted and unsubstituted hydroxy- (C _1-26 ) -alkyl group, substituted and unsubstituted cycloalkyl- (C _0-26 ) -alkyl group, substituted and unsubstituted acyl, halogen, OX _Selected from the group consisting of _XIV9 or OX _XIV10 , each alkyl group, each alkoxy group and each acyl group is branched or linear, each alkyl group, each alkoxy group, each cycloalkyl group is saturated or one or It may be unsaturated, having two or more double or triple bonds, and one or two carbon atoms of the cycloalkyl group may be replaced by nitrogen, oxygen or sulfur, wherein X _{XI V9} or X _XIV10 is a same or different, hydrogen, substituted and unsubstituted (C _{1- 26)} - alkyl groups, substituted and unsubstituted hydroxy - (C _1-26) - alkyl group substituted, unsubstituted cycloalkyl (C _0-26) - alkyl groups, substituted and unsubstituted acyl,
Selected from the group consisting of silyl, cations of organic and inorganic bases, especially cations of metals of Groups 1, 2 or 3 of the Periodic Table, ammonium, substituted ammonium, and ammonium compounds derived from ethylenediamine or amino acids; Each alkoxy group and each acyl group are branched or linear, and each alkyl group, each alkoxy group, each cycloalkyl group is a saturated type or an unsaturated type having one or more double bonds or triple bonds. And one or two carbon atoms of the cycloalkyl group can be replaced by nitrogen, oxygen or sulfur, or Z _XIV represents the following amino group: _Wherein R _XIV11 and R _XIV12 are the same or different and are hydrogen, substituted and unsubstituted alkyl groups, substituted and unsubstituted cycloalkyl- (C _0-26 ) -alkyl groups, substituted and unsubstituted cycloalkoxy- ( C _0-26) - alkyl groups, substituted and unsubstituted alkoxy - (C _0-26) alkyl group, is selected from the group consisting of substituted and unsubstituted acyl, each alkyl group, each alkoxy group and the acyl group branched or Linear, each alkyl group, each alkoxy group, each cycloalkyl group may be a saturated type or an unsaturated type having one or more double bonds or triple bonds, and a cycloalkyl group one or two carbon atoms may be replaced by nitrogen, oxygen or sulfur, B _XIV is selected from the group consisting of-out substituted and unsubstituted C _1-26 alkenylene, wherein one of the charcoal The atoms can be replaced by one oxygen atom and one carbon atom by one sulfur atom, or two carbon atoms can be replaced by an S-heterocycle, each alkylene group being branched or straight-chain. It is saturated or unsaturated with one or more double or triple bonds and can be substituted by one or more hydroxy, halogen or oxo groups. 21. Use of a lipid metabolism inhibitor according to any one of claims 1 to 20 for the treatment and prevention of infectious processes in humans, animals and plants and for plant fungicides. 22. The use according to claim 21, wherein the infectious process is caused by a single or multicellular parasite, fungus, bacterium or virus. 23. Use according to claim 21 or 22, wherein the process is an infectious process in a human or animal.