BACKGROUND OF THE INVENTION Metabolism is one of the basic principles of life and thus coordinated metabolism is essential for an effective function of any cell, organ and organism. It is known that changes in metabolism due to environmental influence or genetic alterations are major risk factors for many diseases, among them common diseases such as cardiovascular diseases, obesity or diabetes. The strong link between many of these diseases is reflected in the term metabolic syndrome.

Congestive Heart Failure (CHF) is a very complex disease, better described as a syndrome, in which the heart is not able to support the other organs adequately with blood. The body has many options to regulate the changing demand in oxy- gen and nutrients in the short term by increased heart rate and blood pressure or in the long term by increased contractility or metabolism.

However, upon an insult to the heart due to chronic pressure overload, ischemia, infection, toxic or genetic events, the body compensates for the loss of pumping power usually with mechanisms made for short term compensation. The chronic use of these compensatory mechanisms, however, leads to an overburdening of the heart muscle and finally into decompensation and heart failure. 15 Mio pa-

tients are afflicted worldwide by CHF. The current therapeutic regimen combines treatment of CHF symptoms by means of diuretics with reduction of stress for the diseased heart by lowering blood pressure and if heart failure is not too advanced by reducing adrenergic drive. Yet current therapy is still inadequate to stop pro- gression or induce reversion of the disease. Therefore, there was a need to dis- cover molecular differences, particularly differences in the metabolism, between failing and nonfailing human myocardium.

Surprisingly it has been found that novel tertiary amino acids are effective thera- peutic agents in the treatment and prevention of metabolic diseases such as car- diovascular diseases, obesity or diabetes.

SUMMARY OF THE INVENTION The present invention provides a tertiary amino acids represented by the formula (I) : wherein m is 0,1, 2, 3, 4 or 5 ; n is 0, 1, 2, 3, 49 p is 0,1, 2,3, 4 or 5 ; M is selected from the group consisting of

an alkali metal; an alkaline earth metal; hydrogen; ammonium, preferabyl NH4 ; a linear or branched optionally substituted alkyl with 1,2, 3,4, 5 or 6 C atoms, more preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobu- tyl, most preferably ethyl, n-propyl or isopropyl ; R1 is an optionally substituted aryl group; and R2 is an optionally substituted aryl group; or a compound according to formula (1) as a prodrug or salt, which can be used as a therapeutic agent; but not the compounds (II) to (XVI)

Additionally, the invention relates to a method of producing the compound of the invention comprising the steps of : a) coupling of a N-terminal protected amino acid in which the carboxylic acid functionality is protected as an ester by a protecting group b) removing the protective group from the N terminus of the amino acid, c) carrying out a reductive alkylation of the primary amino group of the amino acid, d) carrying out a reductive alkylation of the secondary amino group of the amino acid, and e) cleaving off the ester protecting group.

Furthermore, the invention relates to a pharmaceutical composition comprising the compound of the invention and auxiliary substances and/or additives.

Additionally, the invention relates to a method of preventing or treating a disease, said method comprising administering to a patient a pharmaceutically effective amount of a compound of the formula (1), but not the compounds (III), (VI), (VII) and (XIV).

Finally, the invention relates to a method of preventing or treating a metabolic disease such as cardiovascular diseases, obesity or diabetes, said method compris- ing administering to a patient a pharmaceutically effective amount of a compound of the formula (I), but not the compounds of the formula (VI) and (VII).

DETAILED DESCRIPTION OF THE INVENTION One subject of the present invention are tertiary amino acids represented by the above formula (I).

An amino acid in the context of the present invention is an amino acid of the gen- eral formula (XVII) HOOC- (CH2) p-CH2-NH2 (XVII) wherein p is defined as described above. The amino acid can be an a (p = 0), p (p = 1), y (p = 2), 8 (p = 3), s (p = 4) or amino acid (p = 5), preferably an a, ß, y or 8 amino acid, more preferably an a, ß or y amino acid, most preferably a ß- alanine.

In one embodiment of the invention M is selected from the group consisting of an alkali metal, preferably Li, Na, K, most preferably Na or K ; an alkaline earth metal, preferably Mg and Ca ; hydrogen; ammonium, preferably NH4; a linear or branched optionally substituted alkyl with 1, 2, 3, 4., 5 or 6 C atoms, more pref- erably methyl, ethyl, n-propyl, isopropyl9 n-butyl, isobutyl, most preferably ethyl, n-propyl or isopropyl. Examples of linear or branched alkyl groups with 1,2, 3,4, 5 or 6 C atoms include a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, n-pentyl group, n-hexyl group and the like.

The alkyl group can be substituted with e. g. a hydroxyl group or a halogen, pref- erably F, Cl, or Br, more preferably F or Cl. Examples of the halogen-substituted alkyl groups include a chloromethyl group, bromomethyl group, dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group, 4- chlorobutyl group, 5-chloropentyl group, 6-chlorohexyl group, difluoromethyl group, trifluoromethyl group and the like.

Examples of (CH2) m, wherein m is 0,1, 2,3, 4 or 5, include linear or branched alkylene groups with 0, 1, 2,3, 4 or 5 C atoms such as none, a methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, s- butylene group, isobutylene group, t-butylene group, n-pentylene group, isopenty- lene group, neopentylene group and the like.

Examples of (CH2) n, wherein n is 0,1, 2,3, 4 or 5, include linear or branched alkylene groups with 0, 1, 2,3, 4 or 5 C atoms such as none, a methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, s- butylene group, isobutylene group, t-butylene group, n-pentylene group, isopenty- lene group, neopentylene group and the like.

Examples of (CH2) p, wherein p is 0,1, 2, 3,4 or 5, include linear or branched alkylene groups with 0, 1, 2,3, 4 or 5 C atoms such as none, a methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, s- butylene group, isobutylene group, t-butylene group, n-pentylene group, isopellty- lene group, neopentylene group and the like.

Ri and R2 are an optionally substituted aryl group, wherein the substitution is in ortho, meta or para position or a combination thereof.

The Ri aryl group and/or the R2 aryl group can be an aryl group with 5,6, 7,8, 9 or 10 C atoms. Examples of the aryl groups with 5,6, 7, 8, 9 or 10 C atoms in- clude phenyl group, tolyl group, naphthyl group and the like. Preferably the Rl aryl group and/or the R2 aryl group are phenyl, respectively.

In a preferred embodiment of the invention the Ri phenyl group and/or the R2 phenyl group is substituted by one or more halogen atoms, preferably F, Cl, or Br, more preferably F or Cl, a linear or branched optionally substituted alkyl group with 1,2, 3, 4, 5 or 6 C atoms, preferably methyl, ethyl, n-propyl, isopropyl, n- butyl or isobutyl, even more preferably methyl, ethyl, n-propyl or isopropyl, most preferably methyl or ethyl, an optionally substituted 0-alkyl group with 1,2, 3,4, 5 or 6 C atoms, preferably 1, 2,3 or 4 C atoms, more preferably 0-methyl, 0- ethyl, 0-n-propyl, or 0-isopropyl, most preferably 0-methyl or O-ethyl, or a cyano group.

Examples of the alkyl-substituted aryl groups are benzyl, phenylethyl group, phenylpropyl group, phenylbutyl group, naphthylmethyl group and the like.

Examples of halogen-substituted aryl groups are o-fluorophenyl, m-fluorophenyl p-fluorophenyl, o-chlorophenyl, m-chlorophenyl p-chlorophenyl, o-bromophenyl, m-bromophenyl p-bromophenyl, difluorophenyl, dichlorophenyl, preferably 3,4- dichlorophenyl, dibromophenyl, fluorochlorophenyl, preferably o-fluoro-o- chlorophenyl.

Examples of 0-alkyl-substituted aryl groups are 0-methylphenyl, preferably o- methoxyphenyl, O-ethylphenyl, 0-propylphenyl.

Examples of cyano-substituted aryl groups are cyanophenyl, preferably o- cyanophenyl, m-cyanophenyl or p-cyanophenyl.

In a more preferred embodiment of the invention the Ri phenyl group and/or the R2 phenyl group is at least monosubstituted with a halogen, preferably with F, Cl or Br.

In another more preferred embodiment of the invention the Ri phenyl group and/or the R2 phenyl group is at least disubstituted with a halogen, preferably with F, Cl or Br.

In an even more preferred embodiment of the invention the Ri phenyl group or the R2 phenyl group is a 3,4-dichlorophenyl group or a 2-fluoro-6-chlorophenyl group.

In a preferred embodiment of the invention the substituent of the Ri aryl group and/or the R2 aryl group is small. A small substituent according to the present in- vention is a substituent which does not contain more than 10 C atoms, preferably not more than 6 C atoms, more preferably not more than 4 C atoms.

In another preferred embodiment of the invention the substituent of the Ri aryl group and/or the R2 aryl group is light. A light substituent according to the present invention is a substituent which has a molecular weight (relative molecular mass) of less than 100, preferably of less than 40.

In still another preferred embodiment the substituent is not N02.

In another preferred embodiment the substituent is not an 0-alkyl group, particu- larly not an 0-methyl group, provided there is only one substituent at the aryl groups.

In another preferred embodiment the substituent does not contain a heterocyclic group.

In a preferred embodiment the optionally substituted aryl group is an optionally substituted phenyl group. Examples of an optionally substituted phenyl groups are phenyl, o-fluorophenyl, m-fluorophenyl p-fluorophenyl, o-chlorophenyl, m- chlorophenyl p-chlorophenyl, o-bromophenyl, m-bromophenyl p-bromophenyl, difluorophenyl, dichlorophenyl, preferably 3,4-dichlorophenyl, dibromophenyl, fluorochlorophenyl, preferably 2-fluoro-6-chlorophenyl, benzyl group, phen- methyl group, phenylpropyl group, phenylbutyl group, 0-methylphenyl, preferably 3-0-methylphenyl or preferably 4-0-methylphenyl, 0-ethylphenyl and 0-propylphenyl.

In a more preferred embodiment the Ri aryl group as well as the R2 aryl group are substituted. In an even more preferred embodiment the R, aryl group as well as the R2 aryl group are a substituted phenyl groups. Most preferably the substituent is selected from the group consisting ofF, Cl, Br, 0-methyl and-CN.

In one embodiment of the present invention the compound can be in form of a prodrug. The prodrug is later transformed to the drug. This can be based e. g. on the enzymatic activation of a prodrug at the target site, in the blood or in a tissue of the patient.

In another embodiment of the present invention the compound can be in form of a salt. Examples for such salts are salts of alkali metals such as Li9 Na and K or al- kaline earth metals such as Mg and Ca or ammonium salts such as an NH4+ salto There are one or more potential chiral centers in the compounds according to the invention because of the presence of asymmetric carbon atoms in certain com- pounds of general formula 1. The presence of a single asymmetric carbon atom gives rise to two enantiomers and the presence of more than one asymmetric car-

bon atom gives rise to both diastereoisomers and the corresponding enantiomers.

The invention includes all such enantiomers, diastereoisomers and mixtures thereof.

In still another embodiment of the present invention the compound can be an es- sentially pure enantiomere or a mixture of enantiomers. An essentially pure enan- tiomer is at least 80 % pure, preferably at least 90 % pure, more preferably at least 95 % pure or most preferably at least 99 % pure.

In a preferred embodiment m, n and/or p are 1. Yet, in a more preferred embodi- ment of the invention m, n and/or p are 1 and M is hydrogen. In a most preferred embodiment m, n and/or p are 1 and M is hydrogen and Ri and 2 are optionally substituted phenyl groups.

In another preferred embodiment the compound comprises two cyclic compounds or rings. Preferably these rings are aryl groups.

Another subject of the invention is a method for producing a compound of the invention. The method comprises the following steps: a) coupling of a N-terminal protected amino acid in which the carboxylic acid functionality is protected as an ester by a protecting group b) removing the protective group from the N terminus of the amino acid, c) carrying out a reductive alkylation of the primary amino group of the amino acid, d) carrying out a reductive alkylation of the secondary amino group of the amino acid, and e) cleaving off the ester protecting group.

Step e) Compounds with which the invention is concerned may be prepared by the cleav- age of an ester of formula (XVIII):

in which Rl, R2, m, n and p are as defined in general formula (1) and R3 is a car- boxylic acid protecting group or a carrier removable to leave a hydroxy group by hydrogenolysis or hydrolysis. Benzyl is a preferred carboxylic acid protecting group for removal by hydrogenolysis and tert-butyl is a preferred carboxylic acid protecting group for removal by acid hydrolysis. Examples for carriers are resins, polymers such as polystyrene or polystyrene/polyethylene glycol, ArgoPore, a plate or a stationary phase that feature a linking group or bond that allows cleav- age by acid or base catalysed hydrolysis. The carrier is preferably a solid phase, more preferably a cross-linked polystyrene resin, most preferably Wang resin. In the case where the R3 group is a cross-linked polystyrene resin then the cleavage reaction is conducted in an appropriate solvent which swells the resin (e. g. DMF).

Step d) Compounds of general formula (XVIII) may be prepared by a reductive alkylation reaction of a secondary amine of formula (XIX):

in which RI, n and p are as defined in general formula (I) and R3 is as defined in relation to formula (XVIII). This reaction proceeds by condensation of the com- pound of general formula (XIX) with an aldehyde R2CHO to form an enamine which is then subsequently reduced. Reducing agents include certain metal hy- drides (e. g. sodium triacetoxy borohydride, triethylsilane or borane/pyridine) and hydrogen in the presence of a suitable catalyst.

Step c) Compounds of general formula (XIX) may be prepared by a reductive alkylation reaction of a primary amine of formula (XX): in which p is as defined in general formula (I) and R3 is as defined in relation to formula (XVIII). This reaction proceeds by condensation of the compound of general formula (XX) with an aldehyde RICHE to form an imine which is then

subsequently reduced. Reducing agents include certain metal hydrides (e. g. so- dium triacetoxy borohydride, triethylsilane or borane/pyridine) and hydrogen in the presence of a suitable catalyst.

Step b) Compounds of general formula (XX) may be prepared by the deprotection of an N-protected amino acid ester derivative of formula (XXI) : in which R3 is as defined in relation to formula (XVIII) and Z is a nitrogen pro- tecting group. In the widely used handbook by T. W. Greene and P. G. Wuts"Pro- tective Groups in Organic Synthesis"Second Edition, Wiley, New York, 1991, a number of nitrogen protecting groups are described together with procedures for deprotection. Suitable nitrogen protecting groups include carbamate derviatives such as Fmoc. Deprotection of Fmoc may be achieved by reaction with a suitable basic amine such as piperidine.

Step a) Compounds of general formula (XXI) may be prepared by the esterification of an N-protected amino acid derivative of formula (XXII) :

(XXII) in which Z is a nitrogen protecting group as defined for formula (XXI). Proce- dures for the esterification of the compound of formula (XXII) will be well known to those skilled in the art. The reaction is preferably conducted in the presence of an activating agent such as DIC in the presence of an organic base (e. g. DMAP).

Another object of the invention relates to a pharmaceutical composition compris- ing a compound of the invention and auxiliary substances and/or additives. Auxil- iary substances and/or additives are well-known to those skilled in the art and in- clude, but are not limited to, 0.01 to O. lmol/1 and preferably 0.05 mol/1 phosphate buffer or 0.8 % saline. Additionally, such auxiliary substances and/or additives may be aqueous or non-aqueous solvents. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and in- jectable organic esters such as ethyl oleate. Aqueous auxiliary substances and/or additives include water, alcoholic/aqueous solutions, emulsions or suspensions, saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.

Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenish- ers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, cheating agents, inert gases and the like.

The unit dose varies depending upon age, pathology, condition of diseases and the like. Especially preferred unit dose formulations contain 0.01 mg to 1000 mg, preferably 10 to 1000 mg of the compound of the invention. The pharmaceutical

composition of the present invention may be administered 1 to 3 times per day or administered intermittently with the above daily dose.

Still another object of the invention is a method of preventing or treating a dis- ease, wherein the method comprises administering to a patient a pharmaceutically effective amount of a compound of the formula (I), but not the compounds of the formula (III), (VI), (VII) and (XIV).

Still another object of the invention is a method of preventing or treating a meta- bolic disease such as cardiovascular diseases, obesity or diabetes, said method comprising administering to a patient a pharmaceutically effective amount of a compound of the formula (I), but not the compounds of the formula (VI) and (VII). Examples for such diseases are CHF hypertension, arrhythmia, coronary artery diseases, stable and unstable angina pectoris, arteriosclerosis, diabetes, hy- perglycemia, hyperinsulinemia, hyperlipidemia, obesity, and related diseases. As various conditions such as hypertension, arrhythmia, coronary artery diseases, stable and unstable angina pectoris, arteriosclerosis, diabetes, hyperglycemia, hy- perinsulinemia, hyperlipidemia, and obesity may lead to CHF and all these condi- tions are related to the metabolic syndrome mentioned above, said conditions are also examples for such diseases. Furthermore, psoriasis is supposed to be a dis- ease related to the metabolic syndrome. Thus psoriasis is also a condition to be treated by the method according to the present invention.

The compound may be orally administered in the dosage form such as granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions and the like, or intravenously, intramuscularly or subcuta- neously administered in the form of injections. Further, they may also be used in the form of suppositories. They may also be formed into powders which can be converted into solutions or the like for injection before use.

Abbreviations: CHF congestive heart failure DCM dichloromethane DIC diisopropylcarbodiimde DMAP 4-dimethylaminopyridine DMF dimethylformamide Fmoc 9-fluorenylmethoxycarbonyl TFA trifluoroacetic acid THF tetrahydrofuran TMOF trimethyl orthoformate While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention pro- vides many applicable inventive concepts that may be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illus- trative of specific ways to make and use the invention and do not delimit the scope of the invention.

EXAMPLES Synthesis of compounds Compounds represented by formula (I)

were synthesized (m, n and p = 1, M = H, Ri and R2 as shown in table 1). Compound No. Ri R2 I C/ CCH3 F Cl' N I .. Cl 1 \ 1 ber/ ..

CH,Table 1: Overview of the synthesized compounds 1-11 Ri and R2 represent the residue of the compounds used for the syn- thesis according to scheme 1 as well as the residue with respect to formula (I) ; The dotted lines in residues Ri and R2 denote the chemical bond link- ing the respective residue to the backbone of the compound shown in formula (I).

Synthesis was carried out according to scheme 1: c°" o step HO" NHFmoc HO 0 O-v-NHFmoc N^R step piperidine H sl step R2CHO/H+ 0 zu bzw HO N. i R2 60% TFAin

Scheme 1: Synthetic route for tertiary ß amino acids Step a Wang resin was swollen in 100 ml DMF (anhydrous) for 15 min. Then, the N Fmoc protected P alanine (11.4 g, 3 eq. ), DIC (5.7 ml, 3 eq. ) and a catalytic amount of DMAP were added and the mixture was shaken for 16 h at room tem- erature. The resin was then washed with several cycles of DCM/DMF and finally with DCM and MESH. Prior to the next synthetic step the resin was dried in vacuo.

Step b The resin from step a) was treated with an excess of 20 % (v/v) piperidine/DMF for 30 min at room temperature and subsequently washed according to the stan- dard wash and dry procedure as described for step a).

Step c The free amino functionalized resin was swollen in a minimal amount of 1: 1 THF: TMOF (100 ml) for 15 min after which the aldehyde RICHE (10 eq) and acetic acid (10 eq) were added and the mixture was for 16 h at room temperature. The resin was then washed thoroughly with 1: 9 TMOF: THF and suspended dried in a minimal amount of THF and NaBH (OAc) 3 (10 eq) added. The mixture was shaken for 16 h at room temperature prior to addition of methanol and shaking for 5 min. The resin was washed according to the standard wash and dry procedure as described for step a).

Step d) The secondary amine-functionalized resin from step c) was swollen in a minimal amount of DCM and 10 equivalents of acetic acid for 15 min, after which the al- dehyde (10 eq. ) and sodium triacetoxy borohydride (10 eq) were added and the reaction shaken for 16 h at room temperature. The resin was washed according to the standard wash and dry procedure as described for step a).

Step e) The resin was treated with 1: 1 (v/v) TFA: CH2Cl2 for 1 h at room temperature. After filtering the mixture, the resin was washed again with 1: 1 (v/v) TFA : CH CIy. The combined filtrate and washings are evaporated to dryness. The resulting products were purified by preparative reverse phase HPLC.