EP1644033A2

EP1644033A2 - Use of inhibitors of enzymes with aminopeptidase n and/or dipeptidylpeptidase iv activity and pharmaceutical preparations of said inhibitors for the treatment and prevention of dermatological diseases involving the hyperproliferation and modified differentiation conditions of fibroblasts

Info

Publication number: EP1644033A2
Application number: EP04740701A
Authority: EP
Inventors: Siegfried Ansorge; Harald Gollnick; Uwe Lendeckel; Klaus Martin-Luther-Univ. Biochemi/Tech. NEUBERT; Dirk Uni. Magdeburg Inst. Immunologie REINHOLD; Robert Uni. Magdeburg VETTER; B. Uni. Magdeburg Inst. Immunologie SCHRAVEN; Anja Uni. Magdeburg THIELITZ; Jürgen Martin-Luther-Universität FAUST
Original assignee: IMTM GmbH
Current assignee: IMTM GmbH
Priority date: 2003-07-08
Filing date: 2004-07-06
Publication date: 2006-04-12
Also published as: WO2005004906A2; CN100560129C; WO2005004906A3; JP2009513520A; US20070042938A1; DE10330842A1; CN1819840A

Abstract

The invention relates to a method for inhibiting the DNA synthesis of human fibroblasts that is necessary for proliferation, by the individual or combined action of inhibitors of alanyl-aminopeptidase (APN) and dipeptidylpeptidase IV (DP IV) that is expressed by said cells. The DNA synthesis (proliferation) of human fibroblasts is inhibited by a dosage-dependent administration of the APN and/or the DP IV. According to the invention, the application of inhibitors of the aforementioned enzyme or of preparations and administrable forms containing said inhibitors is eminently suitable for the treatment and prevention of dermatological diseases involving fibroblastic hyperproliferation and modified differentiation conditions of fibroblasts.

Description

Use of the inhibitors of enzymes with activities of the aminopeptidase N and / or the dipeptidyl peptidase IV and pharmaceutical preparations therefrom for the therapy and prevention of dermatological diseases with hyperproliferation and changed differentiation states of fibroblasts

description

The invention describes the inhibition of the DNA synthesis of fibroblasts necessary for the proliferation and differentiation by the action of inhibitors of aminopeptidase N (APN, EC 3.4.11.2, CD13) or / and dipeptidyl peptidase IV (DP IV, EC 3.4.14.5, CD26) as a result of the individual, simultaneous or immediately sequential application of respectively specific inhibitors of these enzymes or of inhibitors of enzymes of the same substrate specificity (APN- and / or DP IV-analogous enzyme activity) on the basis of amino acid derivatives, peptides or peptide derivatives, by which the proliferation (DNA synthesis) and differentiation of fibroblasts is suppressed and modulated.

A number of dermatological diseases are associated with hyperproliferation and changes in the differentiation states of fibroblasts. They include both benign fibroblastic hyperproliferative conditions (here in particular post-infectious, post-inflammatory and post-traumatic: hypertrophic scars, keloids, angiofibromas, dermatofibromas, fibrolipomas, ulcer scars), which also occur in the context of disseminated (myo-) fibromatoses (e.g. congenital fibromatosis) also malignant fibroblastic hyperproliferative states (e.g. fibrosarcomas, mixed tumors such as atypical fibroxanthoma, malignant fibrous histiocytoma, aggressive angiomyxoma, paraneoplasias). Form another group of diseases Fibrous autoimmune diseases such as localized and systemic scleroderma in its various forms (circumscript S., progressive-systemic S., CREST syndrome), dermatosclerosis in other collagenoses and the cutaneous variant of the graft-versus-host disease. Changes in the differentiation states of the fibroblasts are an expression of various fibrosing diseases with a currently largely unexplained atiology. These include the Liehen scierosus et atrophicus and the heterogeneous group of pseudoscleroderma (such as eosinophilic / proliferating fasciitis, exogenously caused pseudoscleroderma such as toxic oil syndrome, silicosis, porphyrias, eosinophilia-myalgia syndrome, Liehen associated myxoedema syndrome). There are also secondary sclerotherapy such as stasis fibrosis for chronic venous insufficiency and lipolymphedema, late fibrosis of alopecia androgenetica, and rare localized fibroblastic diseases (Dupuytren disease, Ledderhose disease, "knuckle pads", induration penis plastica).

Peptidases such as dipeptidyl petidase IV and aminopeptidase N or enzymes with a similar effect are particularly interesting for the regulation or modulation of interactions between cells, since they are partly located as ectoenzymes in the plasma membrane of the cells, interact with other extracellular structures, peptide messengers activate or inactivate by enzyme-catalyzed hydrolysis and are therefore important for cell-cell communication [Yaron A, et al .: Proline-dependent structural and biological properties of peptides and proteins. Grit Rev Biochem Mol Biol 1993; 28: 31-81; Vanhoof G, et al .: Proline motifs in peptides and their biological processing. FASEB J 1995; 9: 736-744].

It has been shown that membrane-active peptidases such as DP IV or APN play a key role in the process of activation and clonal expansion of immune cells, in particular T lymphocytes [Fleischer B: CD26 a surface protease involved in T-cell activation. Immunology Today 1994; 15: 180-184; Lendeckel U et al .: Role of alanyl aminopeptidase in growth and function of human T cells. International Journal of Molecular Medicine 1999; 4: 17-27; Riemann D et al .: CD13 - not just a marker in leukemia typing. Immunology Today 1999; 20: 83-88]. Various functions of mitogen-stimulated mononuclear cells (MNZ) or enriched T lymphocytes such as DNA synthesis, production and secretion of immunostimulatory cytokines (IL-2, IL-6, IL-12, IFN-γ) and helper functions for B cells ( IgG and IgM synthesis) can be inhibited in the presence of specific inhibitors of DP IV or APN [Schön E et al .: The dipeptidyl peptidase IV, a membrane enzyme involved in the proliferation of T lymphocytes. Biomed. Biochim. Acta 1985; 2: K9-K15; Schön E et al .: The role of dipeptidyl peptidase IV in human T lymphocyte activation. Inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro. Eur. J. Immunol. , 1987; 17: 1821-1826; Reinhold D et al .: Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor ß1 in PWM-stimulated PBMNC and T cells. Immunology 1997; 91: 354-360; Lendeckel U et al .: Induction of the membrane alanyl aminopeptidase gene and surface expression in human T-cells by mitogenic activation. Biochem. J. 1996; 319: 817-823; Kähne T et al .: Dipeptidyl peptidase IV: A cell surface peptidase involved in regulating T cell growth (review). Int. J. Mol. Med. 1999; 4: 3-15; Lendeckel U et al .: Role of alanyl aminopeptidase in growth and function of human T cells (review). Int. J. Mol. Med. 1999; 4: 17-27].

It is already known that the treatment of autoimmune diseases and graft rejection is possible by inhibiting the dipeptidyl petidase IV localized on immune cells with the aid of synthetic inhibitors (e.g. EP-A 0 764151, WO095 / 29691, EP-A 0 731 789, EP -A 0 528 858).

The invention is based on the surprising finding that the individual or simultaneous effect of inhibitors of on or in fibroblasts expressed dipeptidyl peptidase IV / DP IV or CD26 or of inhibitors of enzymes with the same substrate specificity (DP IV-analogous enzyme activity) and of inhibitors of aminopeptidase N / APN or CD13 or of inhibitors of enzymes with the same substrate specificity (APN-analogous enzyme activity), inhibits the proliferation (DNA synthesis) of fibroblasts.

Our invention shows that for the therapy and prevention of dermatological diseases with fibroblastic hyperproliferation and changed differentiation states, for their development the proliferation and the differentiated regulation of the DNA synthesis of fibroblasts is of central importance, the single or simultaneous application of inhibitors of DP IV and the APN or inhibitors of enzymes of the same substrate specificity (APN- and / or DP IV-analogous enzyme activity) or corresponding preparations and dosage forms thereof are suitable.

In particular, the invention is based on the findings that the DNA synthesis of fibroblasts is significantly inhibited by the administration of inhibitors of dipeptidyl peptidase IV or of inhibitors of enzymes with the same substrate specificity or / and of inhibitors of aminopeptidase N or of inhibitors of enzymes with the same substrate specificity becomes.

The above-mentioned diseases have hitherto been treated topically and / or systemically with immunosuppressants, glucocorticosteroids, non-specific anti-inflammatory agents and emollients, and symptomatically with physiotherapy. In systemic medications in particular, undesirable side effects often occur. These include Cushing's syndrome, osteoporosis, infections or diabetes mellitus. Local therapy focuses on local skin atrophy and increased skin vulnerability. Skin tumors can be propagated in both systemic and local immunosuppressive therapy. The use of DP IV or / and APN inhibitors would represent a completely new, probably very effective, possibly inexpensive form of therapy and a valuable alternative component of the existing therapy concepts, especially in the early stages.

The inhibitors of dipeptidyl peptidase IV applied according to the invention or inhibitors of enzymes with the same substrate specificity (DP IV-analogous enzyme activity) or / and inhibitors of aminopeptidase N or inhibitors of enzymes of the same substrate specificity (APN-analogous enzyme activity) can be used in pharmaceutically acceptable formulation complexes as inhibitors, substrates, Pseudo substrates, inhibitory peptides and peptide derivatives and as antibodies of these enzymes are used. The inhibitors according to the invention are used alone or in combination of several of them, preferably in combination of two of them.

Preferred effectors for the DP IV are Xaa-Pro dipeptides, corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters, dipeptide boronic acids (e.g. Pro-boro-Pro) and their salts, Xaa-Xaa- (Trp) -Pro- (Xaa) n-peptides (n = 0 to 10), corresponding derivatives and their salts or amino acid (Xaa) amides, corresponding derivatives and their salts, where Xaa is preferably an α-amino acid / amino acid or an -amino acid derivative / amino acid derivative N ^ε -4-nitrobenzyloxycarbonyl-L-lysine, L-proline, L-tryptophan, L-isoleucine, L-valine and cyclic amines, for example pyrrolidine, piperidine, thiazolidine and their derivatives, act as the amide structure. Such compounds and their preparation have been described in a previous patent (K. Neubert et al. DD296075A5). Tryptophan-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives (TSL) and (2S, 2S ', 2S ") - 2- [2' - [2" -amino-3 ^" - (indol-3 ^" '-yl) -1 ^" - oxoprolyl] -r, 2', 3 ^' , 4'-tetrahydro-6 ^' 8 ^' -dihydroxy-7-methoxyisoquinol-3-yl- carbonyl-amino] -4-hydromethyl-5-hydropentanoic acid (TMC-2A) used become. An exemplary, advantageously usable inhibitor of DP IV is Lys [Z (NO ₂ ] thiazolidide, in which Lys stands for an L-lysine residue and Z (NO ₂ ) stands for 4-nitrobenzyloxycarbonyl (cf. DD-A 296075) ,

According to the invention, inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) include, for example, actinonin, leuhistin, phebestin, amastatin, bestatin, probestin, ß-aminothiols, α-aminophosphinic acids, α-aminophosphinic acid derivatives, preferably D-Phe-ψ-PO ( OH) -CH ₂ ] -Phe-Phe and their salts. Preferred inhibitors for alanyl aminopeptidase are Bestatin (Ubenimex), Actinonin, Probestin, Phebestin, RB3014 or Leuhistin.

The inhibitors or pharmaceutical preparations containing them are administered simultaneously with known carriers. Included in the invention ^'are also pharmaceutical preparations containing two or more of the inhibitors of DP IV or of inhibitors of enzymes having DP IV-analogous enzyme activity and / or the APN or inhibitors of enzymes having APN-analogous enzyme activity in spaced formulation in Combination with known carrier, auxiliary and / or additives for simultaneous or immediately sequential administration with the aim of a common effect.

The administration takes place on the one hand as a topical application in the form of, for example, creams, ointments, pastes, gels, solutions, sprays, liposomes and nanosomes, shaking mixtures, "pegylated" formulations, degradable (ie degradable under physiological conditions) depot matrices, hydrocolloid dressings, Patches, micro swarms, prepolyomers and similar new carrier substrates, jet injection or other dermatological bases / vehicles including instillative application, and on the other hand as a systemic application for oral, transdermal, intravenous, subcutaneous, intracutaneous, intramuscular use in suitable formulations or in suitable galenics , The inhibitor (s) according to the invention and preparations which contain one or more of the inhibitors mentioned and, if appropriate, further components such as further inhibitors, as well as pharmaceutically acceptable additives, auxiliaries or carriers, come from a large number of dermatological diseases or conditions with hyperproliferation and changed differentiation states of fibroblasts as a preventive or therapeutic application. For example, prevention and therapy of both benign fibrosing and sclerosing diseases (here in particular post-infectious and post-traumatic: hypertrophic scars, keloids, dermatofibromas, fibrolipomas as well as disseminated (myo) fibromatoses) as well as malignant fibroblastic hyperproliferative conditions such as mixed fibrosis, such as mixed fibroids atypical fibroxanthoma, malignant fibrous histiocytoma, aggressive angiomyxoma, paraneoplasias), of fibrosing autoimmune diseases such as scleroderma (circumscribed scleroderma, progressive-systemic scleroderma, CREST syndrome), dermatosclerosis and host disease, other collagen desigenosis, lie-graft disease scierosus et atrophicus and the heterogeneous group of pseudoscleroderma (such as eosinophilic / proliferating fasciitis, exogenously caused pseudoscleroderma such as toxic oil syndrome, silicosis, porphyrias, eosinophilia-myalgia syndrome, bile myxoedematosus or borrelia -associated fibrosis), secondary sclerosis such as congestion fibrosis in chronic venous insufficiency and lipolymphedema, late fibrosis of alopecia androgenetica and rare localized fibroblastic diseases (M. Dupuytren, M. Ledderhose, "Knuckle pads", Induratio penis plastica).

The invention also relates to a method for the therapy and prevention of dermatological diseases with hyperproliferation and changed differentiation states of fibroblasts, which involves the administration of Inhibitors of dipeptidyl peptidase IV (DP IV) and of inhibitors of enzymes with the same substrate specificity (DP IV-analogous enzyme activity) or / and of inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) and of inhibitors of enzymes of the same substrate specificity (APN-analogous enzyme activity ) to a patient who needs treatment for the prevention and / or therapy of the abovementioned dermatological diseases.

In particularly preferred embodiments of the invention, an inhibitor or more inhibitors of the enzymes mentioned or one or more, these inhibitors, individually or preferably in combination, are administered to a patient suffering from one or more of the dermatological diseases mentioned in detail below or in need of prevention of the diseases mentioned below Containing pharmaceutical preparation (s) administered, which are selected from inhibitors of DP IV and particularly preferably from Xaa-Pro dipeptides (Xaa = α-amino acid or side chain-protected derivative), corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters, dipeptide boronic acids (eg Pro-boro- Pro) and their salts, Xaa-Xaa- (Trp) -Pro- (Xaa) n-peptides (Xaa = α-amino acid, n = 0 to 10), corresponding derivatives and their salts, amino acid (Xaa) -amides, corresponding Derivatives and their salts, where Xaa is an α-amino acid or a side chain-protected derivative t, preferably N ^ε -4-nitrobenzyloxycarbonyl-L-lysine, L-isoleucine, L-valine, L-tryptophan, L-proline, and cyclic amines, for example pyrrolidine, piperidine, thiazolidine and their derivatives, act as amide structure, and / or tryptophan-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives (TSL) and (2S, 2S ^' , 2S ^" ) - 2- [2' - [2 ^" -amino-3 "- (indole- 3 '"- yl) -1" -oxoprolyl] -r, 2', 3 ', 4 ^' -tetrahydro-6'8 ^' - dihydroxy-7-methoxyisoquinol-3-yl-carbonylamino] -4-hydromethyl- 5-hydropentanoic acid (TMC-2A), and APN inhibitors, particularly preferably actinonin, leuhistin, phebestin, amastatin, bestatin, probestin, β-aminothiols, α-aminophosphinic acids, -aminophosphinic acid derivatives, preferably D-ψ-Phe-PO (OH) -CH ₂ ] -Phe-Phe, and their salts.

In further preferred methods according to the invention, the inhibitors and, where appropriate, their combinations and pharmaceutical preparations containing them are used in the prevention and therapy of diseases and / or conditions with hyperproliferation and changed differentiation states of fibroblasts. For example, prevention and therapy of both benign fibrosing and sclerosing diseases (here in particular post-infectious and post-traumatic: hypertrophic scars, keloids, dermatofibromas, fibrolipomas as well as disseminated (myo) fibromatoses) as well as malignant fibroblastic hyperproliferative conditions such as mixed fibrosis, such as mixed fibroids atypical fibroxanthoma, malignant fibrous histiocytoma, aggressive angiomyxoma, paraneoplasias), of fibrosing autoimmune diseases such as scleroderma (circumscribed scleroderma, progressive-systemic scleroderma, CREST syndrome), dermatosclerosis and host disease, other collagen desigenosis, lie-graft disease scierosus et atrophicus and the heterogeneous group of pseudoscleroderma (such as eosinophilic / proliferating fasciitis, exogenously

Pseudoscleroderms such as toxic oil syndrome, silicosis, porphyria, eosinophilia-myalg e syndrome, lying myxoedematosus or borrelia-associated fibrosis), of secondary sclerotherapy such as e.g. in the context of stasis fibrosis in chronic venous insufficiency and lipolymphedema, in the fibrosing late stage of alopecia androgenetica and in rare localized fibroblastic diseases (M. Dupuytren, M. Ledderhose, "knuckle pads", induration penis plastica).

In prevention and / or therapy methods which are particularly preferred according to the invention, one or more of the DP IV and / or APN inhibitors mentioned are used in such a way that two or more the inhibitors of DP IV or inhibitors of enzymes with DP IV-analogous enzyme activity or / and inhibitors of APN or inhibitors of enzymes with APN-analogous enzyme activity in spatially separated formulations in combination with known carrier, auxiliary and / or Additives are administered simultaneously or immediately in succession with the aim of a common effect. The administration takes place as a systemic application for oral, transdermal, percutaneous, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, vaginal, sublingual application together with carrier, auxiliary and / or additives known per se and / or as a topical application in the form of Creams, ointments, pastes, gels, solutions, sprays, liposomes or nanosomes, "pegylated" formulations, degradable depot matrices, shaking mixtures, hydrocolloid dressings, plasters, microsponges, prepolyomers and similar new carrier substrates, jet injections and other dermatological bases for vehicles , including instillative application.

The invention is illustrated by the following examples. The examples show preferred embodiments of the invention. However, the invention is not limited to the preferred embodiments.

Examples

Example 1

Our investigations show that the DNA synthesis of human fibroblasts is inhibited in a dose-dependent manner by the administration of inhibitors of DP IV (Lys [Z (Nθ ₂ )] thiazolidide) and / or APN (actinonin).

Human fibroblasts strongly express DP IV and APN (Figure 1). The enzyme activity of the DP IV of vital cells is 57.3 + 12.4 pkat 10 ⁶ cells, that of the APN is 380.5 + 48.2 pkat / 10 ⁶ cells (n = 4). Accordingly, the mRNA of APN and DP IV can be detected on these cells (FIG. 2).

Fibroblasts from healthy donors were incubated for 48 h with the above-mentioned inhibitors and the DNA synthesis was then determined by measuring the ³ [H] thymidine incorporation, as described by Reinhold et al. (Reinhold D et al .: Inhibitors of dipeptidyl peptidase IV induce secretion of transforming growth factor β1 in PWM-stimulated PBMNC and T cells. Immunology 1997; 91: 354-360). Figure 3 shows the dose-dependent inhibition of DNA synthesis.

To measure the dose-dependent effect of DP IV (Lys [Z (N0 ₂ )] thiazolidide) and aminopeptidase N (actinonin) inhibitors on the DNA synthesis of human fibroblasts, the cells were incubated for 48 hours with the indicated concentrations of the inhibitors. Then ³ [H] -methyl-thymidine was added to the culture medium and after a further 6 hours the amount of ³ [H] -thymidine incorporated into the DNA was measured. The results are shown in FIG. 3.

Claims

claims

1. Use of inhibitors of dipeptidyl peptidase IV (DP IV) and of inhibitors of enzymes with the same substrate specificity (DP IV-analogous enzyme activity) or / and of inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) and of inhibitors of enzymes of the same substrate specificity ( APN-analogous enzyme activity) to inhibit the proliferation (DNA synthesis) of human fibroblasts.

2. Use according to claim 1, wherein the inhibitors of the DP IV Xaa-Pro dipeptides (Xaa = α-amino acid or side chain-protected derivative), corresponding derivatives, preferably dipeptide phosphonate diaryl esters, dipeptide boronic acids (eg Pro-boro-Pro) and their salts, Xaa -Xaa- (Trp) - Pro (Xaa) n peptides (Xaa = α-amino acid, n = 0 to 10), corresponding derivatives and their salts, amino acid (Xaa) amides, corresponding derivatives and their salts, where Xaa is an α-amino acid or a side-chain-protected derivative, preferably N ^ε -4-nitrobenzyloxycarbonyl-L-lysine, L-isoleucine, L-valine, L-tryptophan, L-proline, and the amide structure is cyclic amines, for example pyrrolidine, piperidine, Thiazolidine and its derivatives act, and / or tryptophan-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives (TSL) and (2S, 2S ^' , 2S ^" ) -2- [2 ^' - [2 ^" - amino-3 ^" - (indol-3 ^'" -yl) -1 ^" - oxoprolyl] -, 2 ^' , 3", 4'-tetrahydro-6'8'-dihydroxy-7-methoxyisoquinol-3-yl-carbonyl- amino] -4-methyl-5-hydro hydropent acid (TMC-2A).

3. Use according to claim 1, wherein amino acid amides, preferably N ^ε -4-nitrobenzyloxycarbonyl-L-lysine thiazolidide, pyrrolidide and piperidide, and the corresponding 2-cyanothiazolidide, 2-cyanopyrrolidide and 2-cyanopiperidide derivative, as DP IV- Inhibitors are used.

4. Use according to claim 1, wherein as inhibitors of APN actinonin, leuhistin, phebestin, amastatin, bestatin, probestin, ß-aminothiols, α-aminophosphinic acids, α-aminophosphinic acid derivatives, preferably D-ψ-Phe-PO (OH) -CH ₂ ] -Phe-Phe, and their salts act.

5. Use of inhibitor combinations according to one of claims 1 to 4 for the prevention and therapy of both benign fibrosing and sclerosing diseases (here in particular post-infectious and post-traumatic: hypertrophic scars, keloids, dermatofibromas, fibrolipomas as well as disseminated (myo) fibromatoses) as well as malignancies fibroblastic hyperproliferative states (e.g. fibrosarcomas, mixed tumors such as atypical fibroxanthoma, malignant fibrous histiocytoma, aggressive angiomyxoma, paraneoplasias), fibrosis autoimmune diseases such as scleroderma (circumscribed S., progressive-systemic S., dermatosis, dermatosis, CREST Graft-versus-host disease, the lying scierosus et atrophicus and the heterogeneous group of pseudoscleroderma (such as eosinophilic / proliferating fasciitis, exogenously caused pseudoscleroderma such as toxic oil syndrome, silicosis, porphyria, eosinophilia-myalgia syndrome, liehen ematosus or Borrelia-associated fibrosis), from secondary sclerotherapy such as in the context of stasis fibrosis in chronic venous insufficiency and lipolymphedema, in the fibrosing late stage of alopecia androgenetica and in rare localized fibroblastic diseases (M. Dupuytren, M. Ledderhose, "knuckle pads", induration penis plastica).

6. Pharmaceutical preparations comprising inhibitors of dipeptidyl peptidase IV (DP IV) or inhibitors of enzymes with DP IV-analogous enzyme activity and / or inhibitors of alanyl aminopeptidase (aminopeptidase N, APN) or inhibitors of enzymes with APN-analogous Enzyme activity in combination with carriers, additives and / or auxiliary substances known per se.

7. Pharmaceutical preparations according to claim 6, comprising as inhibitors of the DP IV Xaa-Pro dipeptides (Xaa = α-amino acid or side chain-protected derivatives), corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters, dipeptide boronic acids (e.g. Pro-boro-Pro ) and their salts, Xaa-Xaa- (Trp) -Pro- (Xaa) n-peptides (Xaa = α-amino acids, n = 0-10), corresponding derivatives and their salts or amino acids (Xaa) - amides, corresponding Derivatives and their salts, where Xaa is an α-amino acid or a side-chain protected derivative, preferably N ^ε -4-nitrobenzyloxycarbonyl-L-lysine, L-isoleucine, L-valine, L-tryptophan, L-proline, and cyclic amines as the amide structure, eg pyrrolidine, piperidine, thiazolidine and their derivatives act.

8. Pharmaceutical preparations according to claim 6, comprising as inhibitors of DP IV preferably amino acid amides, for example N ^ε -4-nitrobenzyloxycarbonyl-L-lysine-thiazole did, pyrrolidide and piperidide and the corresponding 2-cyanothiazolide d, 2-cyanopyrrolidide - and 2-cyano-piperidide derivative.

9. Pharmaceutical preparations according to claim 6, comprising as inhibitors of APN actinonin, leuhistine, phebestin, amastatin, bestatin, probestin, ß-aminothiols, oc-aminophosphinic acids, "x-aminophosphinic acid derivatives, preferably D-Phe-ψ [PO (OH ) -CH ₂ J-Phe-Phe and their salts.

10. Pharmaceutical preparations according to one of claims 6 to 9, comprising two or more of the inhibitors of DP IV or inhibitors of enzymes with DP IV-analogous enzyme activity and / or inhibitors of APN or inhibitors of enzymes with APN-analogous enzyme activity in space separate formulation in combination with known Carriers, auxiliaries and / or additives for simultaneous or immediately sequential administration with the aim of a common effect.

11. Pharmaceutical preparations according to claims 6 to 9 for systemic use for oral, transdermal, percutaneous, intravenous, subcutaneous, intracutaneous, intramuscular, rectal, vaginal, sublingual application together with known carrier, auxiliary and / or additives.

12. Pharmaceutical preparations according to claims 6 to 10 for topical use in the form of creams, ointments, pastes, gels, solutions, sprays, liposomes or nanosomes, "pegylated" formulations, degradable depot matrices, shake mixtures, hydrocolloid dressings, plasters, microsponges , Prepolyomers and similar new carrier substrates, jet injections or other dermatological basics, including instillative application.

13. A method for the therapy and prevention of dermatological diseases with hyperproliferation and changed differentiation states of fibroblasts, comprising the administration of inhibitors of dipeptidyl peptidase IV (DP IV) and of inhibitors of enzymes with the same substrate specificity (DP IV-analogous enzyme activity) and / or of inhibitors of Alanyl aminopeptidase (aminopeptidase N, APN) and inhibitors of enzymes of the same substrate specificity (APN-analogous enzyme activity).

14. The method according to claim 13, wherein one or more inhibitors of said enzymes or one or more pharmaceuticals containing these inhibitors individually or preferably in combination Preparation (s) are administered to a patient, which are selected from inhibitors of DP IV and particularly preferably from Xaa-pro dipeptides (Xaa = α-amino acid or side-chain-protected derivative), corresponding derivatives, preferably dipeptide phosphonic acid diaryl esters, dipeptide boronic acids (e.g. Pro-boro-Pro) and their salts, Xaa- Xaa- (Trp) -Pro- (Xaa) n-peptides (Xaa = α-amino acid, n = 0 to 10), corresponding derivatives and their salts, amino acid (Xaa) amides, corresponding derivatives and their salts, where Xaa is an α-amino acid or a side-chain-protected derivative, preferably N ^ε -4-nitrobenzyloxycarbonyl-L-lysine, L-isoleucine, L-valine, L-tryptophan, L-proline and cyclic amines, for example pyrrolidine, piperidine, thiazolidine and their derivatives, and / or tryptophan-1, 2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives (TSL) and (2S, 2S ', 2S ^" ) act as the amide structure -2- [2 ^' - [2 ^" -amino-3 ^" - (indole-3 ^' "-yl) -1" -oxoprolyl] -1 ^' , 2 ^' , 3 ^' , 4'-tetrahydro- 6 ^' 8'-dihydroxy-7-methoxyisoquinol-3-yl-carbonylamino] -4-hydromethyl-5-hydropentanoic acid (TMC-2A), and inhibitors of APN, particularly preferably actinonine, leuhistine, phebestin, amastatin, bestatin, Probestin, ß-aminothiols, α-aminophosphinic acids, α-aminophosphinic acid derivatives, preferably D-ψ-Phe-PO (OH) -CH ₂ ] -Phe-Phe, and their salts.