EP1372646A2

EP1372646A2 - Use of sugar phosphates, sugar phosphate analogues, amino acids, amino acid analoges for modulating transaminases and/or the association of p36/malate dehydrogenase

Info

Publication number: EP1372646A2
Application number: EP02750522A
Authority: EP
Inventors: Erich Eigenbrodt; Sybille Mazurek; Stefan Müllner
Original assignee: ScheBo Biotech AG
Current assignee: ScheBo Biotech AG
Priority date: 2001-03-13
Filing date: 2002-03-12
Publication date: 2004-01-02
Also published as: WO2002072078A2; US20050054584A1; WO2002072078A9; CA2458451A1; WO2002072078A3; DE10112925A1; AU2002308368A1

Abstract

The invention relates to the use of a substance selected from the group consisting of sugar phosphates, sugar phosphate analogues, amino acids, amino acid analogues and mixtures of said substances, for producing a pharmaceutical composition for reducing weight and/or preventing delayed damage caused by diabetes mellitus by modulating the association p36/malate dehydrogenase and/or transaminases.

Description

Use of sugar phosphates, sugar phosphate analogs,

■ Amino acids, amino acid analogs for modulating transaminases and / or the association p36 / malate dehydrogenase.

Field of the Invention.

The invention relates to the use of substances for producing a pharmaceutical composition for modulating transaminases or the p36 / malate dehydrogenase complex.

Background of the Invention.

A problem that is widespread in affluent societies is that many people are overweight due to malnutrition. Obesity leads to serious health problems, starting with cardiovascular problems and ending with orthopedic findings. There are various approaches to fight overweight or to reduce the weight of overweight people. Practically all approaches have a purely dietary element in common. This means that the person consumes a reduced amount of calories within a monitored period of time and, if necessary supported by exercise therapies, breaks down stored fat. All of these approaches have in common that after the end of the monitored period, the people usually return to the wrong eating and other lifestyle habits with the consequence of one subsequent weight gain. One speaks of a yo-yo effect.

A major health problem in diabetes rαellitus patients is that late damage in the form of vascular damage occurs in the course of the disease. These are irreversible. The cause of the vascular damage is an increased production of peroxides due to illness as part of the metabolism via the malate-aspartate shuttle.

State of the art.

For example, from Eigenbrodt, E. et al., Biochemical and Molecular Aspects of selected Cancers, 2: 311ff. (1996), various cell metabolic mechanisms are known through which glycolytic hydrogen is transported from the cytosol into the mitochondria. These are the Glycerol 3-phosphate shuttle, the malate-aspartate shuttle and the citrate shuttle. All three shuttles are active in differentiated tissues. The Glycerol 3-Phosphate .Shuttle is very strongly stimulated by thyroxine. This leads to a sharp increase in energy turnover in hyperthyroidism. The glycerol 3-phosphate shuttle is always switched off for tumor cells. Accordingly, hydrogen generated within the glycolysis in the glyceraldehyde 3-phosphate dehydrogenase reaction can be transported either via the glycerol 3-phosphate shuttle or the malate-aspartate shuttle into the mitochondria, where it is burned. When transported via glycerol 3-phosphate shuttle produces 2 moles of ATP per mole of hydrogen. When transported via the malate-aspartate shuttle, 3 moles of ATP are generated per mole of hydrogen. The latter shuttle works with a higher energy yield. It is also known that the malate dehydrogenase and transaminases are components of the malate-aspartate shuttle.

From the Mazurek, S. et al. , J. Cell. Physiol. 167: 238-250 (1996) it is known that malate dehydrogenase exists in a cell in three forms, a mitochondral form comprising the mature mitochondral isoenzyme and its precursor, a cytosolic form and a form associated with the p36 protein (Phosphoprotein 36). The latter form is the precursor of the mitochondral isoenzyme, which is held in the cytosol by association with p36. The association promotes hydrogen transport via the malate aspartate shuttle.

The above findings have regularly been obtained in the prior art in connection with transformation-related peculiarities of cell metabolism in tumor tissue. Other disease-related relationships are not addressed.

Technical problem of the invention.

The present invention is based on the technical problem of specifying active substances which are able to control the metabolism of foods in such a way that that obesity is prevented or reduced and late damage in diabetes ellitus avoided.

5 principles of the invention.

To solve this technical problem, the invention teaches the use of a substance selected from the group consisting of "sugar phosphates, sugar phosphates.

! phatanaloge, amino acids, amino acid analogs, and mixtures of such substances "for the manufacture of a pharmaceutical composition for weight loss and / or for the prevention of late damage in diabetes mellitus by modulating the association p36 / malate

15 dehydrogenase and / or transaminases.

The invention is based on the one hand on the knowledge that the substances mentioned dissolve the association p36 / malate dehydrogenase in the cytosol with the result that the isoenzyme migrates into the mitochondria, where it is withdrawn from the cytosolic part of the malate-aspartate shuttle. The result is that the metabolism of food is driven towards the glycerol 3-phosphate shuttle, which is lower in energy ^• 5 on the one hand and on the other hand leads to fewer peroxides. As a result, a given amount of food consumed is metabolized less efficiently. The treated person therefore loses weight with unchanged food intake or keeps a reduced weight. In addition, damage caused by diabetes mellitus - overweight people are also a group with an increased risk of illness - is avoided. The invention is further based on Recognition that the substances mentioned can simultaneously inhibit transaminases, ie that there is a synergistic effect in the shift to the glycerol 3-phosphate shuttle.

The term analogs refers to compounds that can be structurally derived from natural amino acids or sugars, i.e. are different from these, which, however, bring about the same or an even greater modulation of the p36 / malate dehydrogenase association and / or transaminase inhibition than the underlying natural substance. An analog can in particular represent a derivative, i.e. a naturally occurring functional group or an H atom can be replaced by another, non-naturally occurring group. This affects both side chains and the core structure; the carboxyl group of an amino acid can in particular be replaced by a nitrile group. In the case of sugar phosphate analogs, a phosphate group can be replaced by a -CN group. It is also possible to replace several phosphate groups with one -CN group.

Preferred embodiments of the invention.

Various, non-limiting embodiments are possible within the scope of the invention. Thus, a pharmaceutical composition according to the invention can contain several different compounds used according to the invention. Furthermore, a pharmaceutical composition according to the invention can additionally be one of one Active ingredient used according to the invention contain various active ingredients. Then there is a com- binati ^* onspräparat. The various active ingredients used can be prepared in a single dosage form, ie the active ingredients are mixed in the dosage form. However, it is also possible to prepare the different active substances in spatially separate dosage forms of the same or different types.

A combination preparation can be set up, for example, as part of insulin therapy for diabetes mellitus. The insulin is mixed with one or more compounds used according to the invention for i.m. Application prepared. It goes without saying that the connection used here at i.m. Application should be tissue compatible, especially should not cause tissue irritation.

In the indication for weight reduction according to the invention, the compound used can also be used as a food additive. Special dietary foods are created, to which the compound or compounds are added in defined concentrations. It is desirable to select compounds that are as tasteless as possible.

With regard to the active ingredient used according to the invention, it is possible that the substance is selected from the group consisting of "serine, cyberin, valine, leucine, isoleucine, proline, methionine, cysteine, aminoisobutyrate, aminooxyacetate, Chba, Fructose-1, 6-bisphosphate> glycerate-2, 3-bisphosphate, glycerate-3-phosphate, ribose-1/5-bisphosphate, ribulose-1, 5-bisphosphate and mixtures of such substances. Chba stands for 2-cyano-3-hydroxyl-but-2 ~ (4-trifluoromethyl-phenyl) -a id

The substance is preferably selected from the group consisting of compounds of the formula I and mixtures of such compounds,

Rl R3

Formula IC ¹ ^ —C ² H _b

R2 R4

where a and b may be the same or different and have values of 0 or 1, where Rl = -H, Cl-C18-alkyl, cycloalkyl or aryl, where R2 = -H, Cl-C18-alkyl, cycloalkyl or aryl, Cl-C8-hydroxyalkyl, Cl-C8-mercaptoalkyl, Cl-C8-ether, Cl-C8-thioether, Cl-C8-aminoalkyl, with Cl-C8-alkyl, -cycloalkyl or -phenyl, -CONHX2 or -CNHNHX2 N-substituted Cl-C8-aminoalkyl, aryl substituted with ^• -Hai and / or -0X1, -0X1, -SX1, -COO ^" , - (CH ₂ ) _n -C0OXl or -COOX1 with XI = -H , Cl-Clδ-alkyl, -cycloalkyl or -aryl, and with n = 1-8, where R3 = -CN, -C = N-X2, -COO ^" , -C00X2, -C0-X2, -CO-NHX2 with X2 = -H, Cl-C18-alkyl, -cycloalkyl or -aryl, where R4 = -H, -0-P, = 0, -aryl, -NHY or -CO-NHZ with Y = -H, -C0-R (R = Cl-C18-alkyl, -Cycloalkyl or -Aryl or -NHA, with A = H or Cl-C18-alkyl, -Cylcolalkyl or -Aryl) and Z = phenyl, naphthyl, with -Hai and / or -O-Hal and / or CA ₀ Hal _m and / or -N-C0-CA _o Hal _m and / or Cl-C8-alkyl, -cycloalkyl or -aryl substituted phenyl or with -Hai and / or -O-Hal and / or Cl-C8-alkyl, -cycloalkyl or -aryl-substituted naphthyl (Hai = -F, -Cl, or -Br), where m = 1 - 3 and o = 3 - m, where a and b correspond to the number of remaining carbon valences at C ¹ and C ² , a ring closure to C ¹ can be established via R3 with elimination of XI in R2 and X2 in R3.

Particularly preferred substances are characterized in that a = 1 and b = 0, Rl = -H

R2 = -H, Cl-C8-alkyl, -cycloalkyl or aryl, Cl-C8-hydroxyalkyl, Cl-C8-mercaptoalkyl, Cl-C8-aminoalkyl, N-substituted

Cl-C8 aminoalkyl, substituted aryl, -0X1, -SX1, R3 = -CN, R4 = = 0.

These particularly preferred substances are typically 2- or α-oxonitriles. These substances are highly effective amino acid analogs.

H _a can also be replaced by -SH or -SR2. The ring closure via R3 can also form a homo- or heteroatomic aromatic ring comprising Cl and C2, which further substituents from the above described groups, for example homo- or heteroaromatic aromatic rings (substituted or unsubstituted).

In connection with cycloalkyl and aryl groups, it should be noted that this means both homo- and heteroatomic aromatic groups. Examples of heterocyclic groups are: furanyl, thiophenyl, pyrrolyl, isopyrrolyl, 3-isopyrrolyl, pyrazolyl, 2-isoimidazolyl, triazolyl, oxazolyl, isoaxazolyl,

Thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperazinyl, triazinyl, oxazinyl, indenyl, benzofurnyl, benzothiofuranyl, indolyl, isoindazolyl, benzoxazolyl, it being possible for the groups mentioned to be partially hydrogenated. The groups mentioned can also be formed with the formation of a ring with the incorporation of Cl into the ring.

Specific connections 1 to 42 are given below by way of example.

0 ^l m '/ 9 X $ -7 HX ^f tιi-lO- / ^• ■ -1

Uli ir {■, r ⁽ • - \ 4 ~ l 'ζZ n? (VT

0 0 o ^~ ? -. V-5-U

/

H? S? -HP - /. 7 - sn fi? ^'02

V

ZV? "/? '^V7' ^ tO

V / P oτ

_/ ° 7 - ^r _. lP ^J i 't) C ^.? - ^Z i9-0

/

HP

^**

/ ^'

Λ / 9

01 u6θo / zo_ια / i3 «ι 8 / .0Z / .0 / Z0 OΛV

1/

/ -

^ J2

/ cu

Counterions for ionic compounds of the formula I are, for example Na ⁺ , K ⁺ , Li ⁺ or cyclohexylammonium.

The medicaments produced with the compounds used according to the invention can be administered orally, intramuscularly, peri-articularly, intra-articularly, intravenously, intraperitoneally, subcutaneously or rectally. However, intravenous is particularly preferred

Administration, especially in the case of Chba or aminooxyacetate (NH ₂ -CO-COOH) or oral administration.

The invention further teaches a process for the production of a medicament, which is characterized in that at least one compound used in accordance with the invention is mixed with a pharmaceutically suitable and physiologically tolerable carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries and is prepared to the desired dosage form.

Finally, the invention teaches a combination preparation for the treatment of diabetes mellitus containing insulin and one or more compounds used according to the invention and a dietetic food containing one or more compounds used according to the invention.

Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectables Solutions and preparations with a protracted release of active substances, in the production of which conventional auxiliaries such as carriers, explosives, binders, coatings, swelling agents, lubricants or lubricants, flavors, sweeteners and solubilizers are used.

Magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, milk protein, gelatin, starch, cellulose and their derivatives, animal and vegetable oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycols and solvents such as sterile water and a - or polyhydric alcohols, e.g. Called glycerin.

The medicaments are preferably produced and administered in dosage units, each unit containing as active ingredient a certain dose of the compound of the formula I according to the invention. In the case of solid dosage units such as tablets, capsules, coated tablets or suppositories, this dose can be 1 to 5000 mg, preferably 50 to 1000 mg, and in the case of injection solutions in ampoule form 0.3 to 300 mg, preferably 10 to 100 mg.

Daily doses of 20 to 5000 mg of active ingredient, preferably 100 to 500 mg, are indicated for the treatment of an adult patient weighing 50 to 100 kg, for example 70 kg. Under certain circumstances, however, higher or lower daily doses may also be appropriate. The daily dose can be administered either as a single dose in the form of a single dosage unit or else several smaller dosage units, or by Subsequent dispensing of divided doses takes place at certain intervals.

The invention is explained in more detail below on the basis of examples which merely illustrate embodiments.

Example 1: Weight Loss Products

A mixture of aminooxyacetate and conventional galenic auxiliaries is pressed into tablets, the proportions being chosen with the proviso that one tablet contains 750 mg of aminooxyacetate.

A person to be treated (70 kg) takes one of the above tablets with liquid immediately before each food intake (one tablet 3 times a day). Food is consumed according to the person's normal habits.

Within a treatment period of 4 weeks, a weight profile of people treated according to the invention is shown, which corresponds to the weight profile of a control group whose food intake is reduced by approximately 15 to 20% compared to the group of subjects.

Example 2: Dietary food.

A so-called half-fat margarine is made from vegetable fats, water and common emulsifiers and auxiliary substances as well as dyes. To 100 parts by weight Margarine, 2.5 parts by weight of aminooxyacetate are mixed in homogeneously and the mixture obtained is finally packaged.

Example 3: Combination preparation for the treatment of diabetes mellitus.

A customary insulin injection solution is prepared and 0.25 part by weight of aminooxyacetate is added to 10 parts by weight of this solution and packaged in ampoules in the usual insulin doses. The combination preparation obtained in this way is administered by a patient in accordance with the insulin treatment plan defined for this patient. injected.

Claims

Claims:

1. Use of a substance selected from the group consisting of "sugar phosphates, sugar phosphate analogs, amino acids, amino acid analogs, and mixtures of such substances" for producing a pharmaceutical composition for weight reduction and / or for preventing late damage in diabetes mellitus by modulating the association p36 / Malate dehydrogenase and / or transaminases.

2. Use according to claim 1, wherein the substance is selected from the group consisting of "serine, cycloserine, valine, leucine, isoleucine, proline, methionine, cysteine, aminoisobutyrate, aminooxyacetate, Chba, fructose-1, 6-bisphosphate, Glycerate-2, 3-bisphosphate, glycerate-3-phosphate,

Ribose-1,5-bisphosphate, ribulose-1,5-bisphosphate, analogues of such compounds and mixtures of such substances ".

3. Use according to claim 1, wherein the substance is selected from the group consisting of compounds of the formula I and mixtures of such compounds,

Rl _χ R3

Formula IC ^x H _a - C ² H _b

R2 R4 where a and b can be the same or different and have values of 0 or 1, where Rl = -H, Cl-C18-alkyl, cycloalkyl or aryl, where R2 = -H, Cl-C8-alkyl, -Cycloalkyl or aryl, Cl-C8-hydroxyalkyl, Cl-C8-mercaptoalkyl, Cl-C8-ether, Cl-Cδ-thioether, Cl-C8-aminoalkyl, with Cl-C8-alkyl, -cycloalkyl or -phenyl, - C0NHX2 or -CNHNHX2 N-substituted Cl-C8-aminoalkyl, with

-Hai and / or -0X1 substituted aryl, -0X1, -SX1, -COO ^" , - (CH ₂ ) _n -COOXl or -C00X1 with XI = -H, Cl-C18-alkyl, -cycloalkyl or -aryl, and with n = 1-8, where R3 = -CN, -C = N-X2, -COO ^" , -C00X2, -CO-X2, -CO-NHX2 with X2 = -H, Cl-C18-alkyl, - Is cycloalkyl or aryl, where R4 = -H, -0-P, = 0, -aryl, -NHY or -CO-NHZ with Y = -H, -CO-R (R - Cl-C18-alkyl, -Cycloal- kyl or -Aryl or -NHA, with A = H or

C1-C18-alkyl, -alkylcol-aryl) and Z = phenyl, naphthyl, with -Hai and / or -O-Hal and / or CA ₀ Hal _m and / or -N-CO-CA ₀ Hal _m and / or Cl-C8-alkyl, -cycloalkyl or -aryl substituted phenyl or naphthyl substituted with -Hai and / or -O-Hal and / or Cl-C8-alkyl, -cycloalkyl or -aryl (Hai = -F, -Cl, or -Br), where = 1 - 3 and o = 3 - m, where a and b correspond to the number of remaining carbon valences at C ¹ and C ² , with a ring closure to C ¹ below via R3

Elimination of XI in R2 and X2 in R3 can be set up

4. Use according to claim 3, wherein a = »=. 1 and b = 0, Rl = -H R2 = -H, Cl-C8-alkyl, cycloalkyl or aryl, Cl-C8-hydroxyalkyl, Cl-C8-mercaptoalkyl , Cl-C8-aminoalkyl, N-substituted Cl-C8-aminoalkyl, substituted aryl, -0X1, -SX1, R3 = CN, R4 = = 0.

5. Use according to one of claims 1 to 4, wherein the pharmaceutical composition for i.v. Application is prepared.

6. Use according to one of claims 1 to 5, wherein the pharmaceutical composition is prepared for administration in a daily dose of 0.1 to 20 mg per kg body weight.

7. Pharmaceutical composition containing insulin and one or more substances according to one of claims 1 to 6, wherein the ratio of the substances used to insulin (w / w) in the range 0.001: 100 to 10: 100, preferably 0.01: 100 to 3: 100, most preferably 0.1: 100 to 0.3: 100.

8. Dietary food containing one or more substances according to one of claims 1 to 6, wherein 0.01 to 10, preferably 0.1 to 10, most preferably 1 to 3, parts by weight of the substance are admixed to 100 parts by weight of food.