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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06104—Dipeptides with the first amino acid being acidic
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/08—Tripeptides
  • C07K5/0802—Tripeptides with the first amino acid being neutral
  • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
  • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
• • C—CHEMISTRY; METALLURGY
  • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
  • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
  • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
  • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
  • C08G65/32—Polymers modified by chemical after-treatment
  • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the invention relates to new effectors of the dipeptidyl peptidase IN. These effectors can be used to specifically influence locally limited pathophysiological and physiological processes (inflammation, chemotaxis, autoimmune diseases, wound healing).
• the enzymatic activity and the binding activities of dipeptidyl peptidase IV and of enzymes with comparable or identical activity and of proteins with a related primary structure are determined by means of effectors (substrates, Pseudosubstrates, inhibitors, antibodies, binding proteins, binding antagonists, binding agonists, etc. influenced.
• proline-specific peptidases Due to the frequency of the occurrence of the amino acid proline in a large number of peptide hormones and the associated structural properties of these peptides, a function analogous to signal peptidases is discussed for proline-specific peptidases (Yaron and Naider, 1993); (Vanhoof et al., 1995). Due to its special structure, proline determines both conformation and stability of these peptides in its peptides by preventing them from breaking down
• DP IV or DP IV analog activity occurs in the bloodstream and in almost all organs, where it cleaves highly specific dipeptides from the N-terminus of biologically active peptides , when proline or alanine represent the adjacent residues of the N-terminal amino acid in their sequence. It is therefore assumed that this enzyme is involved in the regulation of the biological activity of polypeptides in vivo (Vanhoof et al., 1995).
• chemokines are substrates of DP IV and that their function is modulated by DP IV (Proost et al, 1998; Proost et al, 1998 ; Proost et al, 1999); (Shioda et al, 1998)). Due to their chemotactic effects, chemokines are significantly involved in the regulation of local immunological processes such as autoimmune processes, inflammation and wound healing (Nelson and
• a number of biologically active DP IV substrates (substance P, somatostatin, VIP, PACAP etc.) are involved in the regulation of neuronal, immunological and vasoactive processes in the skin (Scholzen et al, 1998); (Wallengren, 1997). Dipeptidyl peptidase IV thus represents an important switching point in regulating the activity of gastrointestinal, immunologically or neurologically active peptides and is therefore an interesting therapeutic target (Marchyns et al, 1999). However, the exact signal cascades have not yet been fully clarified.
• DP IV is an activation marker of T lymphocytes and a receptor for adenosine deaminase.
• the use of DP IV inhibitors has immunosuppressive effects in cell culture and in vivo (Ansorge et al, 1995; Reinhold et al, 1997; Kubota et ⁇ /., 1992).
• Lysyl-prolyl analogues derived from the N-terminal sequence of substance P showed a beneficial effect on wound healing, which is attributed to the structural similarity to substance P.
• systemically used irreversible DP IV inhibitors inhibited wound healing (Buntrock et al, 1988; Kohl et al, 1991; Kohl et al, 1989).
• DP IV inhibitors have so far been used systemically for the treatment of arthritis in animal models.
• DP IV inhibition was able to suppress the proliferation of 'mylin basic protein' -specific T cell clones (Reinhold et al, 1998).
• DP IV activity in various skin diseases (psoriasis, Liehen planus) and carcinogenic diseases of the skin, increased DP IV activity in keratinocytes and fibroblasts has been demonstrated (Novelli et al, 1996) (Raynaud et al, 1992).
• the fibroblast activation protein which is closely related to DP IV and has approximately 50% sequence homology to DP IV and is probably identical to the Seprase described by Pi ⁇ eiro-Sanchez et al., 1997, is also increasingly used by inactivated persons Fibroblasts expressed by epithelial carcinomas and healing wounds
• phosphorylated dipeptide (B) - /. -nitroanilides [KASPARI, A., et al., 1996] are substrates of the DP IV.
• DP IV inhibitors such as Glu (Gly) -Thia or Lys (Z-NO 2 ) -Thia [REINHOLD, D., et al., 1998] are completely transported.
• the task to be solved was to create connections that can be used to specifically influence locally limited pathophysiological and physiological processes.
• the object of the invention is to achieve a locally limited inhibition of DP IV or DP IV-analogous activity in order to be able to intervene in a targeted manner in the regulation of the activity of locally active peptide hormones.
• B A is an amino acid with at least one functional group in the side chain
• B is a chemical compound that is covalently bound to at least one functional group of the side chain of A, namely
• oligopeptides with a chain length of up to 20 amino acids, except homopolymers of glycine from up to 6 glycine monomers, or - polyethylene glycols with molar masses of up to 20,000 g / mol, and C is a thiazolidine, pyrrolidine, cyanopyrrolidine, hydroxyproline, dehydroproline or piperidine group which is in amide bond with A.
• At least one pharmaceutical composition is provided according to the invention.
• A is an amino acid, preferably an ⁇ -amino acid, particularly preferably a natural ⁇ -amino acid with at least one functional group in the side chain, preferably threonine, tyrosine, serine, arginine, lysine, aspartic acid, glutamic acid or cysteine,
• B is a chemical compound which is covalently bound to at least one functional group in the side chain of A, namely oligopeptides with a chain length of up to 20 amino acids, polyethylene glycols with molecular weights of up to 20,000 g / mol, optionally substituted organic amines, amides, Alcohols, acids or aromatics with 8 to 50 carbon atoms,
• C is a thiazolidine, pyrrolidine, cyanopyrrolidine, hydroxyproline, dehydroproline or piperidine group which is in the amide bond with A,
• alkyl may represent a Ci-50 alkyl group, preferably a C6-30 alkyl group, preferably a C ⁇ -12 alkyl group; for example an alkyl group can be a methyl, ethyl, propyl, isopropyl or butyl group;
• alk e.g. in the term “alkoxy” and the term “alkane” e.g. defined in the term “alkanoyl” as “alkyl”;
• aromatics are preferably substituted or unsubstituted phenyl, benzyl, naphthyl, biphenyl or anthracene groups, which preferably have at least 8 carbon atoms;
• alkenyl can represent a C2-10 alkenyl group, preferably a C2-6 alkenyl group, which has the double bond (s) at any position and can be unsubstituted or substituted;
• alkynyl can represent a C2-10 alkynyl group, preferably a C2-6 alkynyl group, which has the triple bond (s) at any position and can be unsubstituted or substituted;
• substituted or substituent may represent any substitution by one or more, preferably one or two alkyl, alkenyl, alkynyl, mono- or polyvalent acyl, alkanoyl, alkoxyalkanoyl or alkoxyalkyl groups; the above substituents can in turn have one or more, but preferably no, alkyl, alkenyl, alkynyl, mono- or polyvalent acyl, alkanoyl, alkoxyalkanoyl or alkoxyalkyl groups as side groups;
• organic amines, amides, alcohols or acids each having 8 to 50 carbon atoms, preferably having 10 to 20 carbon atoms can have the formulas (alkyl) 2 N or alkyl-NH-, -CO-N (alkyl): or -CO Have -NH (alkyl), -alkyl-OH or -alkyl-COOH.
• the compounds according to the invention can still bind to the active center of the enzyme dipeptidyl peptidase IV and analogous enzymes, but are no longer actively transported by the peptide transporter PepTl.
• the resulting one Reduced or severely restricted transportability of the compounds according to the invention ideally leads to local, topical inhibition of the DP IV and analogous enzymes.
• the compounds according to the invention or compounds used according to the invention can be present or used as racemates or as enantiomerically pure compounds, preferably in the L-threo or L-allo form, based on A. [Doesn't it have to be A here?)
• an effective effect of the inhibitors in the tissue to be treated can be achieved, and on the other hand systemic effects of the inhibitors can be largely avoided by locally limited, ie topical application of DP IV inhibitors.
• This achieves an effective and low-side effect on local physiological and pathophysiological processes (inflammation, psoriasis, arthritis, autoimmune diseases, allergies).
• the invention is based on the following facts:
• DP IV inhibitors are systemically distributed and inhibit DP IV and analogue activities throughout the organism. • A number of bioactive peptide substrates of DP IV are involved in the regulation of local signal cascades (chemotaxis, inflammation, neurotransmission).
• the side chain-modified DP IV inhibitors according to the invention have a high inhibitory potency, but are hardly or not absorbed and transported and therefore do not lead to demonstrable systemic effects.
• the invention thus provides new DP IV inhibitors and a novel approach for the use of the DP IV inhibitors in vivo.
• Corresponding inhibitors can be adapted to the type of application by chemical modifications or formulations. For example, Systemic distribution difficult or avoided due to voluminous hydrophilic substitutions on the side chain.
• the inhibitors can be administered in pharmaceutical and cosmetic preparations.
• the topical application comprises the local application of the inhibitors by direct application to the tissue to be treated (eg skin, wounds, tumors) by ointments, creams, cosmetics, or indirect application by plasters containing plasters, bandages or the like, by application to parts of the body (Mouth, nose, ears, eyes, lungs) in the form of drops, sprays, inhalants or the like, by direct injection into or around the tissue to be treated and by implanting materials containing effector.
• the topical application also includes oral or anal application of hard or non-absorbable effectors of dipeptidyl peptidase IV or DP IV-analogous sequences for the selective influencing of the gastrointestinal DP IV.
• the oligopeptides have chain lengths of 3 to 15, particularly preferably 4 to 10, amino acids and / or the polyethylene glycols with molecular weights of at least 250 g / mol, preferably of at least 1500 g / mol and up to 15000 g / mol, and / or the optionally substituted organic amines, amides, alcohols, acids or aromatics with at least 12 carbon atoms and preferably up to 30 carbon atoms.
• compositions containing at least one compound according to the invention, optionally in combination with conventional carriers or adjuvants.
• the compounds according to the invention or pharmaceutical or cosmetic compositions can be used for the topical influencing of the activity of dipeptidyl peptidase IV or analogous enzymes, in particular for the prophylaxis or therapy of skin or mucous membrane diseases, autoimmune diseases and inflammations such as e.g. Psoriasis, allergies, arthritis, tumors or autoimmune diseases can be used.
• the compounds and pharmaceutical or cosmetic compositions can be formulated and used as ointments, creams, cosmetics, plasters, bandages, drops, sprays, inhalants, implants or injection solutions.
• the adjuvants used according to the invention are known per se.
• the invention thus relates to the topical application of effectors of dipeptidyl peptidase IV and DP IV-analogous enzyme activities and DP IV-like proteins.
• the topical application allows a local modulation of the activities of the above-mentioned highly specific enzymes, which are crucially involved in the inactivation and activation of biologically active peptides (chemokines, substance P, VIP, PHM, PACAP, growth factors, etc.).
• the invention enables targeted intervention in local immunological processes (chemotaxis, inflammatory processes, autoimmune diseases) and an effective and targeted treatment of the associated pathophysiological and physiological processes (psoriasis, periodontitis, arthritis, allergies, inflammation).
• the invention enables the inhibitors to be readily used in high local concentrations.
• Example 1 Effect of side-chain modified glutamylthiazolidines as DP IV inhibitors which are difficult to transport
• Table 1 Transportability and inhibitor constants of selected DP IV inhibitors.
• the inhibitors have approximately the same Kj values compared to DP IV (Table 1), the plasma DP IV is inhibited significantly more slowly and altogether significantly less by the novel side chain-modified inhibitors. This means that these inhibitors are absorbed significantly less or not at all from the intestine. In the case of Glu (Gly) 5 -thia in particular, no systemic effect of the orally administered active ingredient is detectable.
• inhibitors can thus act as lead structures for the synthesis of novel topically applicable DP IV inhibitors without a systemic effect.
• Boc-Glu-Thia was modified on the ⁇ -carboxylic acid function by introducing residues of different sizes. These residues were coupled via their amino group to the ⁇ -carboxylic acid function by forming an amide bond. Depending on the rest, different coupling methods were used.
• the starting materials of the synthesis are dissolved in a 500-fold excess of DMF. After the end of the reaction, the DMF i.Vak. completely removed and the residue dissolved in plenty of methanol. After overlaying with ether, the product precipitates together with unreacted PEG. The fine cleaning was carried out by preparative HPLC separation on a gel filtration column (Pharmazia, Sephadex G-25, 90 ⁇ m, 260mm-100mm).
• Method A Peptide bond formation using a mixed anhydride method with CAIBE as an activating reagent 10 mmoles of N-terminally protected amino acid or peptide are dissolved in 20 ml of absolute THF. The solution is cooled to -15 ° C + 2 ° C. One after the other, 10 mmoles of N-MM and 10 mmoles of isobutyl chloroformate are added with stirring, strictly observing the specified temperature range. After about 6 minutes, 10 mmoles of the amino component are added. If the amino component is a salt, the reaction mixture is then mixed with further 10 mmol N-MM. The reaction mixture is then stirred in the cold for 2 h and at RT overnight.
• Method B Peptide bond formation using a mixed anhydride method with pivalic acid chloride as an activating reagent 10 mmoles of N-terminally protected amino acid or peptide are dissolved in 20 ml of absolute THF. The solution is cooled to 0 ° C. Ten millimoles of N-MM and ten millimoles of pivalic acid chloride are added in succession with stirring, strictly observing the specified temperature range.
• the mixture is cooled to -15 ° C. and 10 mmoles of the amino component are added after the lower temperature has been reached. If the amino component is a salt, the reaction mixture is then mixed with further 10 mmol N-MM. The reaction mixture is then stirred in the cold for 2 h and at RT overnight.
• Method C Peptide bond formation with TBTU as activating reagent 10 mmoles of the N-terminally protected amino acid or peptide and 10 mmoles of the C-terminally protected amino component are dissolved in 20 ml of absolute DMF. The solution is cooled to 0 ° C. 10 mmoles of DIPEA and 10 mmoles of TBTU are added in succession with stirring. The mixture is stirred at 0 ° C. for one hour and then at RT overnight. The DMF will be fully i. Vak. removed and the product worked up as described under Method A.
• Method D Preparation of an active ester (N-hydroxysuccinimide ester) 10 mmoles of N-terminally protected amino acid or peptide and 10 mmoles of N-hydroxysuccinimide are dissolved in 20 ml of absolute THF. The solution is cooled to 0 ° C. and 10 mmoles of diyclohexylcarbodiimide are added with stirring. The reaction mixture is stirred for a further 2 hours at 0 ° C. and then at RT overnight. The resulting N, N -dicyclohexylurea substance is filtered off, the LM i. Vak removed and the remaining product from EE / pentane recrystallized.
• active ester N-hydroxysuccinimide ester
• Method E Amide bond formation with N-hydroxysuccinimide esters 10 mmoles of the C-terminally unprotected amino component are placed in a NaHCO 3 solution (20 mmoles in 20 ml water). At RT, 10 mmoles of the N-terminally protected N-hydroxysuccinimide ester dissolved in 10 ml of dioxane are slowly added dropwise to this solution at RT. The reaction mixture is stirred further overnight and then the solvent i. Vak. away.
• Method F Cleavage of the Boc protective group lmmol Boc-protected amino acid pyrrolidide, thiazolidide or peptide is mixed with 3ml l, lN HCl / glacial acetic acid (method FI) or 3ml 1, ln HCl / dioxane (method F2) or 3ml 50% TFA in DCM (method F3) offset.
• the cleavage at RT is followed by means of DC.
• the compound is precipitated as hydrochloride with absolute diethyl ether, suction filtered and i. Vak. dried over P- t O ⁇ .
• the product is recrystallized from methanol / ether or reprecipitated.
• Method G Saponification 1 mmole of peptide methyl ester is dissolved in 10 ml of acetone and 11 ml of 0.1 M NaOH solution and stirred at RT. The course of saponification is followed by means of DC. After the reaction, the acetone i. Vak. away. The remaining aqueous solution is acidified with concentrated KH SO solution until a pH of 2-3 is reached. The product is then extracted several times with EA and the combined ethyl acetate fractions are washed with saturated NaCl solution, dried over NaSO 4 and removed i. Vak. the solvent. The crystallization takes place from EE / pentane.
• T cell triggering molecule Tpl03 is associated with dipeptidyl aminopeptidase IV activity. J.Immunol 144, 2908-2914. Hegen, M., Mittschreiber, H.-W., Hug, R., Demuth, H.U., Neubert, K., Barth, A., and Fleischer, B. (1993). Enzymatic activity of CD26 (dipeptidylpeptidase IV) is not required for its signaling function in T cells. Immunobiol. 189, 483-493.
• Putative N-terminal splitting enzyme of amyloid A4 peptides is the multicatalytic proteinase, ingensin, which is widely distributed in mammalian cells. FEBS Leu 257, 388-392.
• Proteinases 1 lysosomal cysteine proteinases. Protein Profile 2, 1581-1643. Kohl, A., Volk, HD, Diezel, W., Buntrock, P., and Diamantstein, T. (1989). The dipeptide Lys- Pro restores the diminished wound healing following treatment with anti-T-helper cell monoclonal antibody. IntJ ' . Immunopharmacol. 11, 237-240.

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