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 tetrazole-functionalized amino acids are effective therapeutic agents in the treatment and prevention of metabolic diseases such as cardiovascular diseases, obesity or diabetes.

SUMMARY OF THE INVENTION The present invention provides tetrazole-functionalized amino acids represented by the formula (I) : wherein n is 1, 2, 3, 4 or 5, preferably 1, 2 or 3, more preferably 1 or 2, most pre- ferably 1; M is selected from the group consisting of an alkali metal; an alkaline earth metal ;

hydrogen ; ammonium, preferably 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 ; Ri is selected from the group consisting of a linear or branched optionally substituted alkyl group, preferably an al- kyl group with 1, 2,3, 4,5, 6,7, 8, 9 or 10 C atoms, more preferably 4,5, 6,7, or 8 C atoms; - (CH2) m-X-R4, wherein m is 1,2, 3,4, 5 or 6, preferably 1,2, 3 or 4, more preferably 1,2, 3, most preferably 1 or 2 and wherein X is NH, CO, COO, SO2 or a chalcogen, preferably 0 or S and wherein R4 is a linear or branched optionally substituted alkyl group with 1,2, 3,4, 5, or 6 C at- oms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, more preferably methyl, ethyl, n-propyl or isopropyl, most preferably methyl or ethyl; an optionally substituted aryl group, wherein the aryl group is an aryl group with 5,6, 7,8, 9 or 10 C atoms, preferably 5 or 6 C atoms, most preferably 6 C atoms and wherein the one, two or more substituents are a hydroxyl group, a halogen, 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, more preferably methyl, ethyl, n-propyl or isopropyl, most pref- erably methyl or ethyl, a linear or branched optionally substituted 0-alkyl group with 1, 2,3, 4, 5 or 6 C atoms, preferably 0-methyl, 0-ethyl, 0- propyl, or 0-isobutyl, most preferably 0-methyl, 0-ethyl or 0-propyl ; an aralkyl group, wherein the alkyl group is a linear or branched option- ally substituted alkyl group with 1,2, 3,4, 5, or 6 C atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, most preferably

methyl, ethyl, n-propyl or isopropyl, and wherein the aryl group is an aryl group with 5,6, 7, 8, 9 or 10 C atoms, preferably 5 or 6 C atoms, most preferably 6 C atoms; and R2 is selected from the group consisting of 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, most preferably methyl, ethyl, n-propyl or isopropyl ; a linear or branched optionally substituted 0-alkyl group with 1,2, 3,4, 5 or 6 C atoms, preferably 0-methyl, 0-ethyl, 0-propyl, or 0-isobutyl, most preferably 0-methyl, 0-ethyl or 0-propyl ; - (CH2) p-Y-R5, wherein p is 0, 1, 2,3, 4, 5 or 6, preferably 0, 1, 2,3 or 4, more preferably 0,1, 2,3, most preferably 1 or 2, and wherein Y is NH, CO, COO, SO2 or a chalcogen, preferably 0 or S, and wherein Rs is 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 iso- butyl, even more preferably methyl, ethyl, n-propyl or isopropyl, most preferably methyl or ethyl ; and R3 is an optionally substituted phenyl ring, wherein the substitution is in or- tho, meta or para position or a combination thereof or a compound according to formula (I) as a prodrug or salt, which can be used as a therapeutic agent.

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) adding an aldehyde to form an imine with the primary amino group of the amino acid, d) forming a tetrazole ring by 1,3 dipolar reaction of the imine, an isoni- trile and an azide, 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.

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 invention.

DETAILED DESCRIPTION OF THE INVENTION One subject of the present invention are tetrazole-functionalized amino acids rep- resented by the above formula (I).

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; a linear or branched optionally substi- tuted alkyl with 1,2, 3,4, 5 or 6 C atoms, more preferably methyl, ethyl, n-propyl, isopropyl, 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 in- clude 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.

In one embodiment of the invention Ri is selected from the group consisting of a linear or branched optionally substituted alkyl group,- (CH2) m-X-R4, an optionally substituted aryl group and an optionally substituted aralkyl group.

In a preferred embodiment the Rl group is an alkyl group with 1,2, 3,4, 5,6, 7,8, 9 or 10 C atoms, more preferably 4,5, 6,7, or 8 C atoms. Examples of linear or branched alkyl groups with 1,2, 3,4, 5,6, 7,8, 9 or 10 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, isopentyl group, neopentyl group, n-hexyl group, isohexyl group, n-septyl, n-octyl, 1,2, 3,4-tetramethylbutyl group, n-nonyl, n-decyl group and the like. The alkyl group can be substituted with e. g. a hydroxyl group or a halogen, preferably 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.

In an embodiment the R, group is a- m-X-R4 group, wherein m is 1, 2,3, 4,5 or 6, preferably 1, 2,3 or 4, more preferably 1, 2,3, most preferably 1 or 2 and wherein X is NH, CO, COO, SO2 or a chalcogen, preferably O or S, and wherein R4 is 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, more preferably methyl, ethyl, n-propyl or isopropyl, most preferably methyl or ethyl.

Examples of the-(CH2) m-groups, wherein m is 1,2, 3,4, or 6, include linear or branched alkylene groups with 1, 2,3, 4,5 or 6 C atoms such as a methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, s-butylen group, isobutylene group, t-butylene group, n-pentylene group, isopen- tylene group, neopentylene group, n-hexylene group, isohexylene group and the like.

Examples for-X-R4 group include a-NH-R4 group such as a methylamino group, ethylamino group, n-propylamino group, n-butylamino group; a-CO-R4 group such as an acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaroyl group or hexanoyl group ; a-COO-R4 group such as a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butyloxycarbonyl group, t-butyloxycarbonyl group, n-pentyloxycarbonyl group, n-hexyloxycarbonyl group; a-SO2-R4 group such as a methylsulfonyl group, ethylsulfonyl group, n-propylsulfon group, isopropylsulfyi group, n-butylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group, n-hexylsulfonyl group ; an-0-R4 group such as a 0-methyl group, 0-ethyl group, 0-n-propyl group, 0-isopropyl group, 0-n-butyl group, 0-s-butyl group, 0-isobutyl group, 0-t-butyl group, 0-n-pentyl group, 0-n-hexyl group ; a-S-R4 group such as a S-methyl group, S-ethyl group, S-n-propyl group, S-isopropyl group, S-n-butyl group, S-s-butyl group, S-isobutyl group, S-t-butyl group, S-n-pentyl group, S-n-hexyl group.

In another embodiment of the invention the R, group is an optionally substituted aryl group, wherein the aryl group is an aryl group with 5,6, 7,8, 9 or 10 C at- oms, preferably 5 or 6 C atoms, most preferably 6 C atoms, and wherein the one, two, or more substituents are a hydroxyl group, a halogen, 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, more preferably methyl, ethyl, n-propyl or isopropyl, most pref- erably methyl or ethyl, a linear or branched optionally substituted 0-alkyl group with 1, 2,3, 4,5 or 6 C atoms, preferably 0-methyl, 0-ethyl, 0-propyl, or 0- isobutyl, most preferably 0-methyl, 0-ethyl or 0-propyl.

Examples of the aryl groups with 5,6, 7,8, 9 or 10 C atoms include phenyl group, tolyl group, naphthyl group and the like. In one embodiment the aryl group can be substituted, wherein the substituent is e. g. a hydroxyl group, a halogen, 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 or a linear or branched optionally sub- stituted 0-alkyl group with 1, 2,3, 4,5 or 6 C atoms.

Examples of the alkyl-substituted aryl groups are the 2,6-dimethylphenyl group, methylphenyl group such as 2-methylphenyl 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, 0-ethylphenyl, 0-propylphenyl.

In still another embodiment of the invention the Ri group is an optionally substi- tuted aralkyl group, wherein the alkyl group is 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, most preferably methyl, ethyl, n-propyl or isopropyl and wherein the aryl group is an aryl group with 5,6, 7,8, 9 or 10 C atoms, preferably 5 or 6 C atoms, most preferably 6 C atoms.

Examples of the aralkyl groups include a benzyl group, phenylethyl group, phenylpropyl group, phenylbutyl group, naphthylmethyl group and the like.

In a preferred embodiment Ri is selected from the group consisting of butyl, pref- erably isobutyl; octyl, preferably 1,1, 3, 3-tetramethylbutyl ; and a methyl- substituted phenyl ring, wherein the substituent is preferably in ortho position, such as 2-methylphenyl or 2,6-dimethylphenyl.

In one embodiment of the invention R2 is selected from the group consisting of a linear or branched optionally substituted alkyl group, a linear or branched option- ally substituted 0-alkyl group and a-(CH2) p-Y-Rs group.

The linear or branched optionally substituted alkyl group is 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, most preferably methyl, ethyl, n-propyl or isopropyl. Examples of such substituted and unsubstituted groups are mentioned above.

The linear or branched optionally 0-substituted alkyl group is a linear or branched optionally 0-substituted alkyl group with 1, 2, 3,4, 5, or 6 C atoms, preferably 0- -methyl,. O-ethyl, 0-propyl, or 0-isobutyl, most preferably 0-methyl, 0-ethyl or 0-propyl. The 0-alkyl group can be substituted with e. g. an hydroxyl group or a halogen, preferably F, Cl, or Br, more preferably F or Cl.

Examples of the- (CH2) p- groups, wherein m is 1,2, 3,4, or 6, include linear or branched alkylen groups with 1,2, 3,4, 5 or 6 C atoms such as a methylene group, ethylene group, n-propylene group, isopropylene group, n-butylene group, s-butylene group, isobutylene group, t-butylene group, n-pentylene group, isopen- tylene group, neopentylene group, n-hexylene group, isohexylene group and the like.

Examples for-Y-R5-group include a-NH-R5 group such as a methylamino group, ethylamin group, n-propylamino group, n-butylamino group, a-CO-Rs group such as an acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaroyl group or hexanoyl group; a-COO-Rs group such as a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butyloxycarbonyl group, t-butyloxycarbonyl group, n-pentyloxycarbonyl group, n-hexyloxycarbonyl group; a-S02-R5 group such as a methylsulfonyl group, ethylsulfonyl group, n-propylsulfon group, isopropylsulfyl group, n-butylsulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group, n-hexylsulfonyl group, an-O-Rs group such as a 0-methyl group, O-ethyl group, 0-n-propyl group, 0-isopropyl group, 0-n-butyl group, 0-s-butyl group, O-isobutyl group, 0-t-butyl group, 0-n-pentyl group, 0-n-hexyl group; a-S-Rs group such as a S-methyl group, S-ethyl group, S-n-propyl group, S-isopropyl group, S-n-butyl group, S-s-butyl group, S-isobutyl group, S-t-butyl group, S-n-pentyl group, S-n-hexyl group.

In another preferred embodiment is R selected from the group consisting of ethyl, isopropyl,- (CH2) 2-S-CH3.

In one embodiment of the invention R3 is an optionally substituted phenyl ring, wherein the substitution is in ortho, meta or para position or a combination thereof.

Examples of an optionally substituted phenyl ring 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, phenylethyl group, phenylpropyl group, phenylbutyl group, 0-methylphenyl, preferably o-methoxyphenyl, O-ethylphenyl, and 0-propylphenyl.

In a preferred embodiment of the invention the R3 phenyl ring is substituted with a halogen, 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 op- tionally 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, O-ethyl, 0-n-propyl, or 0-isopropyl, most preferably 0-methyl or 0-ethyl.

In a more preferred embodiment the R3 phenyl ring is substituted with Cl, pref- erably in para and in meta position, or with CH3, preferably in meta position, or unsubstituted.

In preferred embodiments n is 1. In an even more preferred embodiment n is 1 and M hydrogen.

In a even more preferred embodiment n is 19 ; M hydrogen, Ri a linear or branched alkyl group with 4,5, 6,7 or 8 C atoms or a phenyl group, R2 a linear or branched alkyl group with 1, 2,3 or 4 C atoms or a- (CH2) 2-S-CH3 group and R3 a phenyl group, preferably substituted with at least one halogen or at least one 0-methyl.

In another 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. an the enzymatic activation of a prodrug at a target site, in 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 Li, Na and K or al- kaline earth metals such as Mg and Ca or ammonium salts such as NH4+ salts.

There are one or more potential chiral centers in the compound 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 enantiomer or a mixture of enantiomers. An essentially pure enanti- omer is at least 80 % pure, preferably at least 90 % pure, more preferably at least 95 % pure or most preferably at least 99 % pure.

Another subject of the invention is a method for producing a compound of the invention. The method of producing a compound according to the invention com- prises the following steps: a) coupling of a N-terminal protected amino acid in which the carboxylic acid functionality is protected as an ester b) removing the protective group from the N terminus of the amino acid,

c) adding an aldehyde to form an imine with the primary amino group of the amino acid, d) forming a tetrazole ring by 1,3 dipolar reaction of the imine, an isoni- trile and an azide, and e) cleaving off the ester protecting group.

Step a Compounds of general formula (III) may be prepared by the esterification of a N- protected amino acid derivative of formula (II), in which R3 and n are defined in general formula (I) and in which Z is a nitrogen protective group. In the widely used handbook by T. W. Greene and P. G. Wuts"Protective Groups in Organic Synthesis"Second Edition, Wiley, New York, 1991, a number of nitrogen pro- tecting groups are described together with procedures for deprotection. Suitable nitrogen protecting groups include carbamate derivatives such as Fmoc. R° is a carboxylic 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 R° group is a cross-linked polystyrene resin then the cleavage reaction is conducted in an appropriate solvent which swells the resin (e. g. DMF).

Procedures for the esterification of the compound of formula (II) will be well

known to those skilled in the art. The reaction is preferably conducted in the pres- ence of an activating agent such as DIC in the presence of an organic base (e. g.

DMAP).

In one preferred embodiment of the invention a N terminal-protected, e. g. with Fmoc N terminal-protected, amino acid, preferably an a, P, y, 8, s or amino acid, more preferably an a, p, y or 8 amino acid, even more preferably an a, (3 or y amino acid and most preferably a P amino acid, is at the C terminus coupled to a carrier. The N terminal-protected amino acid is coupled by incubating the N ter- minal-protected amino acid with the carrier, preferably in the presence of DIC and/or a catalyst such as DMAP. The incubation time is for example between ap- proximately 1 h and 48 h, preferably 5 h to 24 h, more preferably 10 h and 20 h and most preferably 14 and 18 h. The incubation temperature is for example be- tween approximately 10 °C and 50 °C, preferably 15 °C to 30 °C, more preferably 20 °C and 25 °C and most preferably room temperature. Thereafter, the carrier- coupled amino acid is preferably washed and dried according to standard proce- dures known to a person skilled in the art. For instance it can be washed at least once, more preferably at least thrice, most preferably at least five times with e. g.

DCM, DMF, methanol or mixtures thereof and dried e. g. in vacuo.

Step b Compounds of general formula (IV) may be prepared by the deprotection of an N- protected amino acid ester derivative of formula (III). Deprotection of Fmoc may be achieved by reaction with a suitable basic amine such as piperidine.

In an preferred embodiment the carrier-coupled product of step a) is treated with piperidine, more preferably in the presence of DMF, most preferably 20 % v/v pideridine/DMF. The incubation time is for example between approximately 1 min and 5 h, preferably 5 min and 2 h, more preferably 15 min and 1 h and most preferably 30 min. The incubation temperature is for example between approxi- mately 10 °C and 50 °C, preferably 15 °C to 30 °C, more preferably 20 °C and 25 °C and most preferably room temperature. Thereafter, the carrier-coupled amino acid is preferably washed and dried according to standard procedures known to a person skilled in the art. It can be for instance washed at least once, more prefera- bly at least thrice, most preferably at least five times with e. g. DCM, DMF, methanol or mixtures thereof and dried e. g. in vacuo.

Step c Compounds of general formula (V) may be prepared by a reductive alkylation reaction of a primary amine of formula (IV). This reaction proceeds by condensa- tion of the compound of general formula (IV) with an aldehyde R2CHO in which R2 is as defined in general formula (I), to form an imine.

In a preferred embodiment the carrier-coupled product of step b) is swollen with a suitable solvent and then incubated with the appropriate aldehyde (R2CHO). Ex- amples for suitable solvents are TMOF, DCM, THF, preferably a mixture of TMOF, DCM, THF, most preferably a 1 : 1: 1 (v/v) solution of TMOF : DCM : THF.

The incubation time is for example between approximately 1 h and 48 h, refera- bly 5 h to 24 h, more preferably 10 h and 20 h and most preferably 14 and 18 h.

The incubation temperature is for example between approximately 10 °C and 50 °C, preferably 15 °C to 30 °C, more preferably 20 °C and 25 °C and most prefera-

bly room temperature. Thereafter, the product is preferably washed and dried ac- cording to standard procedures known to a person skilled in the art. It can be for instance washed at least once, more preferably at least thrice, most preferably at least five times with e. g. 1: 9 (v/v) TMOF: THF and dried e. g. in a stream of air.

Step d) Compounds of general formula (VI) may be prepared by 1,3 dipolar reaction of the imine of formula (V), an azide and an isonitrile, in which RI, is. as defined in general formula (I).

Preferably the carrier-coupled product of step c) is reacted with the appropriate isonitrile (C-N+-Ri) and an azide, preferably trimethylsilyl azide. If a resin is used as carrier, it can be swollen in advance, e. g. with DCM, preferably as de- scribed under step a). The reaction with the isonitrile and the azide can be carried out in the presence of a catalyst, e. g. dibutyltin oxide. The incubation time is for example between approximately 1 h and 48 h, preferably 2 h to 24 h, more pref- erably 5 h and 20 h and most preferably 6 and 10 h. The incubation temperature is for example between approximately 10 °C and 50 °C, preferably 15 °C to 30 °C, more preferably 20 °C and 25 °C and most preferably room temperature. In a pre- ferred embodiment, incubation can be carried out while shaking. Thereafter, the obtained tetrazole derivative is preferably washed and dried according to standard procedures known to a person skilled in the art. It can be for instance washed at least once, more preferably at least thrice, most preferably at least five times with e. g. DCM, DMF, methanol or mixtures thereof and dried e. g. in vacuo.

Step e)

Compounds of the invention (VII) may be prepared by the cleavage of an ester of formula (VI) and optionally modification of the carboxyl group. M is defined in the general formula (I).

Preferably the product of carrier-coupled step d) is treated with a cleaving reagent e. g. TFA, preferably a combination of TFA and CH2C12, most preferably 1 : 1 (v/v) TFA/CH2Cl2. Preferably the treatment is repeated 1 to 5 times, more pref- erably 3 times. The treatment lasts for example between approximately 1 min and 5 h, preferably 5 min and 3 h, more preferably 15 min and 2 h and most preferably 1 h. The incubation temperature is for example between approximately 10 °C and 50 °C, preferably 15 °C to 30 °C, more preferably 20 °C and 25 °C and most pref- erably room temperature. After the treatment the treated product is separated from the cleaving reagent, e. g. by filtration and evaporation of the solvent. Afterwards the product can be further purified e. g. by prep HPLC using the following condi- tions.

In one embodiment of the invention step e) can be followed by an esterfication of the carboxyl group, which was protected by the carrier.

In a preferred embodiment the method of producing a compound relates to a com- pound of the invention, wherein n is 1.

Another subject 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 0.1 mol/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, chelating agents, inert gases and the like.

The unit dose varies depending upon age, sex, 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 pharmaceu- tical composition of the present invention may be administered 1 to 3 times per day or administered intermittently with the above daily dose.

Still another subject 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 present invention. Examples for such diseases are CHF hyper- tension, arrhythmia, coronary artery diseases, stable and unstable angina pectoris, arteriosclerosis, diabetes, hyperglycemia, hyperinsulinemia, hyperlipidemia, obe- sity, and related diseases. As various conditions such as hypertension, arrhythmia, coronary artery diseases, stable and unstable angina pectoris, arteriosclerosis, dia- betes, hyperglycemia, hyperinsulinemia, hyperlipidemia, and obesity may lead to CHF and all these conditions are related to the metabolic syndrome mentioned above, said conditions are also examples for such diseases. Furthermore, psoriasis

is supposed to be a disease related to the metabolic syndrome. Thus psoriasis is also a condition to be treated by the method according to the present invention.

Yet another subject of the invention is the use of a composition for the manufac- ture of a medicament for the prevention or treatment a metabolic disease as de- fined and exemplified above.

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 (n = 1, M = H, Rl, R2 and R3 as shown in table 1).

Compound No. Rl R2 R3 Isomer

Table 1 : Overview of the synthesized compounds 1-10 RI, R2 and R3 represent the residues of the compounds used for the synthesis according to scheme 1 as well as the residues with respect to formula (I).

Compounds 4 and 9 show compounds which were not synthesized but which are accessible via the following scheme 1.

For compounds 1 and 6,2 and 5, and 7 and 8, it was possible to sepa- rate the respective diastereoisomers. The abbreviations DA and DB are used to distinguish between the purified diastereoisomers.

The dotted lines in residues Rl, R2, and R3 denote the chemical bond linking the respective residue to the backbone of the compound shown in formula (I).

Synthesis was carried out according to scheme 1: 0-OH 0 R3 stepa) U 1 HO NHFmoc W R3 R3 -v-NHFmoc (DI step b) piperidine step c) R2CHO C =-N step d) R Bu2SnO TMSiN3 SuzSn TMSiN3 Q R3 R R H 0-" I Jazz HON N o H N H II N N, ii i step e). N N 60% TFAinDCM Scheme 1: Synthetic route for tetrazole-functionalized (3-amino acids Step a) Wang resin was swollen in a minimal amount of DMF (anhydrous) for 15 min.

The N-Fmoc protected amino acid (2 eq). DIC (2 eq) and a catalytic amount of DMAP were added and the mixture was shaken for 16 h at room temperature. The resin was then washed with several cycles of DCM/DMF and finally with DCM and MeOH. 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 standard wash and dry procedure as described above.

Step c) A 1 : 1 : 1 solution of TMOF : DCM: THF (100 ml) was added to the resin, followed by 5 eq. of the appropriate aldehyde (R2CHO). The resultant slurries were shaken for 16 h at room temperature. The resins were then filtered and washed thoroughly with 1: 9 TMOF: THF and dried in a stream of air.

Step d) The resin from step c) was swollen in DCM and then a solution of the appropriate isonitrile (5 eq. ) in methanol was added followed by trimethylsilyl azide (5 eq.)<BR> and dibutyltin oxide (0.1 eq. ). The reactions were shaken overnight at room tem- perature. The resin was then washed with several cycles of DCM/DMF and finally with DCM. Prior to the next synthetic step the resin was dried in vacuo.

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: CH2Cl2. The combined filtrate and washings are evaporated to dryness. The resulting products were purified by reverse phase preparative HPLC.