RU2156237C2 - Inhibitors of processes associated with dp-iv - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: invention describes inhibitors of process associated with DP-IV taken among compounds of the general formula: A-B (group I) where B means formula (I)

; n = 1 or 2; m = 0, 1 or 2; X means CH₂, S, SO, SO₂, O; Y means N; R means H, CN, CHO, B(OH)₂; A is bound to Y and a) when R means H, then A is alpha-aminoacyl group obtained from alpha-amino acid carrying cycloaliphatic side chain or beta-aminoacyl group of the general formula (II)

where p = 1-6 and in any case ring can contain unsaturated bonds and/or substitution with heteroatom; b) when R means CN then A corresponds to definition given in (a) and except for it can be obtained from any L-alpha-amino acid carrying lipophilic side chain and c) when R means CHO or B(OH)₂ then A means beta-aminoacyl group determined in (a); (group II): B, n, m, X as indicated above; R means H, CN; A is bound to Y and A means (i)

where a = 1-5; D means G-(CH₂)_b-(R₄)-R₃; G means NH or NMe; b = 1-12; g = 0 or 1; R₄ means Z-NH-(CH₂)_c or NH-Z-(CH₂)_c- where c = 1-12; Z means CO, CH₂; R₃ is CO₂H or its ester, CONH₂, CONR₅R₆, SO₂NH₂, SO₂NR₅R₆, OH, OR₅, substituted or unsubstituted aryl, NH₂, NR₅R₆, NHCOR₅, NHSO₂R₅, NH-CH(:NR₅)NR₅R₆; R₅ and R₆ are taken independently each of other among H, lower alkyl, fluoroalkyl groups or R₅ and R₆ in common with nitrogen atom to which they are bound form the chain C₃-C₈ or A means (ii)

where R¹ is H, Me; E is J-(CH₂)_b-(R₄)_q-R₃; J is CO; a, b, q, R₃ and R₄ correspond to definition given in (i); or it means (III)

where R² is H, Me; L means (CH₂)_d-(CO)_r-(CH₂)_b-(R₄)_q-R₃ where r = 1; d = 1-4; b, q, R₃ and R₄ correspond to definition given in (i). The above described inhibitors are highly active competitive inhibitors of DP-IV (values K are in the range from 10^-6 to 10^-10) and they exhibit chemical stability (t_1/2 > 24 h). EFFECT: inhibitors indicated above, valuable chemical properties. 4 cl, 8 tbl, 7 ex

Description

BACKGROUND OF THE INVENTION
DP-IV (EC 3.4.14.5), a membrane-bound serine protease, was first identified in rat kidneys by its ability to cleave dipeptides at the N-terminus of certain peptides (Hopsu-Havu VK and Glenner GG, Histochemie, 1966, 7, 197) . The dipeptides in this case must be of the type X-Pro or X-Ala, where X is any amino acid. X-Proline has been shown to cleave more efficiently than X-Ala.

 DP-IV is widespread in mammalian tissues, and large amounts of it are found in the kidneys, intestinal epithelium, and placenta (Yaron A. and Naider F., Critical Reviews in Biochem. Mol. Biol., 1993, 28 (1). 31). In the human immune system, an enzyme is expressed almost exclusively when CD4 type T lymphocytes are activated, in which case the enzyme is shown to be synonymous with the surface antigen of CD26 cells.

 The exact role of DP-IV in human physiology is not entirely clear, but recent studies have shown that the enzyme plays an important role in human physiology and pathophysiology, in particular in the processes below.

 (a) Immune response: DP-IV expression increases in T cells upon mitogenic or antigenic stimulation (Mattern, T. et al., Scand. J. Immunol., 1991, 33, 737). DP-IV inhibitors and antibodies to DP-IV have been shown to inhibit the proliferation of mitogen- and antigen-stimulated T cells in a dose-dependent manner (Schon E. et al. Biol. Chem. Hoppe-Seyler, 1991, 372, 305 and available links in the work).

It has been shown that various other functions of T-lymphocytes, such as cytokine production, IL-2 (IL-2) mediated cell proliferation and helper activity of B-cells, depend on the activity of DP-IV (Schon E. et al., Scand. J Immunol. 1989, 29, 127). Recently, DP-IV inhibitors derived from borproline have been reported (Flentke GR et al., Proc. Natl. Acad. Sci. USA, 1991, 88, 1556), which, despite their instability, have been shown to be effective in inhibiting antigen induced lymphocyte proliferation and IL-2 production in mouse CD4 ^* T helper cells. Such boric acid inhibitors have been shown to be effective in vivo in mice, causing antibody suppression, formation of an immune stimulant-induced formation (Kubota T. et al., Clin. Exp. Immunol., 1992, 89, 192). Also recently, in a number of other works, evidence was presented of the participation of DP-IV in the generation of the immune response (e.g., Tanaka T. et al., Proc. Natl. Acad. Sci. NY, 1993, 90, 4586; Hegen M. et al., Cell Immun., 1993, 146, 249, Subramanyan M. et at., J. Immunol., 1993, 150, 2544).

 A number of researchers explain the importance of DP-IV in that it binds to CD45 transmembrane phosphatase on the cell surface (Torimoto Y. et al., J. Immunol., 1991, 147, 2514). The CD45-DP-IV bond can be destroyed by DP-IV inhibitors or inactive site ligands. CD45 is known to be an integral component of the T-cell signaling system.

(b) A statement recently appeared in a press release from the Pasteur Institute in Paris (and subsequently at the presentation of the work of A.G. Govanesessian at the 8th St. Garda Conference in Paris, October 25-27, 1993 (Hovanessian AG, 8th Cent Gardes Meeting ) that DP-IV is necessary for the penetration of HIV-1 and HIV-2 viruses into CD4 ⁺ T cells, and researchers from the French group said that DP-IV interacts with them and can cleave the V3 loop of the glycoprotein viral envelope gp120 They also reported that inhibitors or antibodies to DP-IV successfully prevent entry of the virus into cell. It was previously known that the expression of CD26 in T cells was selectively reduced in HIV-1 infected patients (Valle-Blazquez M. et al., J. Immunol., 1992. 149, 3073), as well as the Tat protein HIV-1 binds to DP-IV (Subramanyam M. et al., J. Immunol., 1993, 150, 2544).

 (c) Recently, DP-IV in the pulmonary endothelium has been shown to be an adhesion molecule for lung metastases and rat prostate carcinoma cells (Johnson R.C. et al., J. Cell. Biol., 1993, 121. 1423). DP-IV is known to bind to fibronectin, with some tumor metastasizing cells carrying large amounts of fibronectin on their surface.

 (d) It has been shown that DP-IV binds to the enzyme adenosine deaminase [ADA] on the surface of T cells (Kameoka J. et al., Science, 1993. 261, 466). ADA deficiency causes severe combined immunodeficiency (SCID) in humans. The interaction of ADA-CD26 may shed light on the pathophysiology of TCID.

 (e) In fibroblasts of the skin of a person with psoriasis, rheumatoid arthritis (RA) and lichen planus, a high level of expression of DP-IV was detected (Raynaud F. et al., J. Cell Physiol., 1992, 151, 378).

 (e) In tissue homogenates taken from patients with benign prostatic hypertrophy and in prostatosomes, high DP-IV activity was detected. Prostatosomes are organelle-derived prostates that are important for imparting greater mobility to sperm (Vanhoof G et al., Eur J. Clin Chem. Clin. Biochem., 1992. 30. 333).

 (g) It has been shown that DP-IV is responsible for the degradation and inactivation of blood-circulating peptides having the penultimate amino acid at the N-terminus of proline or alanine, i.e. substance P, growth hormone releasing factor, and members of the glucagon / vasoactive intestinal peptide family (Mentheim R. et al., Eur. J. Biochem., 1993, 214.829).

 (h) Patients with periodontitis have an elevated level of DP-IV in the gums (Cox S.W. et al., Arch. Oral. Biol. 1992, 37, 167).

 (i) There are many other data indicating an increased (and sometimes even lower) level of DP-IV in various pathological conditions.

It follows from the above that potential DP-IV inhibitors can be used as drugs for the treatment of human diseases. Such inhibitors can be used as:
(a) Immunosuppressants, for example, in organ transplantation; suppressors of cytokine release, in particular, for various autoimmune diseases, such as intestinal inflammation, multiple sclerosis, rheumatoid arthritis.

 (b) Drugs that prevent the introduction of HIV into T cells, and therefore, can be used for the prevention and treatment of AIDS.

 (c) Drugs to prevent the development of metastases, especially with tumors of the breast and prostate, into the lungs.

 (d) Means for the treatment of skin diseases such as psoriasis, lichen planus.

 (e) Means for suppressing sperm motility and, therefore, as male contraceptives.

 (e) Means useful for use in benign prostatic hypertrophy.

DP-IV Inhibitors
Competitive inhibitors of DP-IV enzyme activity include only the above-mentioned unstable boric acids (t _1/2 30-90 min at pH 7) (Bachovchin et al., WO 91/16339, October 1991) having K values for DP-IV in the nanomolar range, and simple amino acid pyrrolidides or thiazolides (Neubert et al., DD 296075 A5, November 1991), which have very low strength (K _i > 0.1 μM). The proline aminoacyl aldehydes claimed in the same German patent cannot be synthesized due to easy intramolecular condensation of the N-terminal amino group with the aldehyde group.

The present invention discloses highly active competitive inhibitors of DP-IV (with K _i values ranging from 10 ^-6 to 10 ^-10 ), characterized by chemical stability (t _1/2 24 hours). They belong to three groups of compounds (Groups I, II and III).

Group I
These molecules have a structure that allows them to bind strongly to the active center of DP-IV and inhibit its proteolytic activity, without interfering with the attachment of any additional ligands capable of binding to the surface of DP-IV (i.e., not on its active center). Such Group I compounds can be used as immunosuppressants: anti-infection agents against HIV: agents that suppress the release of certain cytokines (e.g., IL-2, IL-6, γ-INF) from activated cells. Boric acids and pyrrolidides mentioned earlier also fall into this category.

Group II
These compounds originate from Group I compounds, however, unlike the latter, they contain long chain extensions to the side chains of the amino acid designated in the general structure as A. The compounds obtained are attached firmly to the active center of DP-IV, however long chain extensions emerge from the active the center of the enzyme and prevent the attachment of any other ligand capable of binding to the surface of DP-IV. Such compounds may have the same applications as Group I compounds, but in addition to them, they may also block the interaction of DP-IV with (i) CD45, (ii) V3 gp120 HIV-1 loop, (iii) tumor surface fibronectin cells and (iv) any other ligand important for activating T cells, introducing the virus into T cells, or adhering tumor cells.

Group III
This group includes new dimers in which two DP-IV inhibitors directed to the active site of the enzyme are linked by a long chain through the side chains of the amino acid residues designated in the general formula as A. Such dimers can competitively inhibit two DP-IV molecules and also inhibit binding additional ligands with a surface of DP-IV. The described dimers have the same applications as Group II compounds, but may be more effective.

где В представляет собой

n = 1 или 2; m = 0, 1 или 2; NH или NR, где R = низший алкил(C-C);
A прикрепляется к Y;
-Y = -N, -CH или C (когда -CO группа в A замещена группой CH= или CF=),
R=H, CN, CHO, B(ОН)₂, C≡C-R₇ или CH=N-R₈;
R₇=H, F, низший алкил(C₁-C₆), CN, NO₂, OR₉, CO₂R₉ или COR₉;
R₈=Ph, ОН, OR₉, OCOR₉ или OB_n;
R₉ = низший алкил (C₁-C₆); и либо один ω, либо оба ω могут отсутствовать.The invention relates to inhibitors of processes mediated by the action of DP-IV, which are characterized by the general formula:
AB (Groups I and II) or

where is

n is 1 or 2; m is 0, 1 or 2; NH or NR, where R = lower alkyl (CC);
A attaches to Y;
-Y = -N, -CH or C (when the -CO group in A is substituted with a group CH = or CF =),
R = H, CN, CHO, B (OH) ₂ , C≡CR ₇ or CH = NR ₈ ;
R ₇ = H, F, lower alkyl (C ₁ -C ₆ ), CN, NO ₂ , OR ₉ , CO ₂ R ₉ or COR ₉ ;
R ₈ = Ph, OH, OR ₉ , OCOR ₉ or OB _n ;
R ₉ = lower alkyl (C ₁ -C ₆ ); and either one ω or both ω may be absent.

 The structure of A depends on the nature of R in part B and on the nature of the group to which the obtained compound belongs.

где p= 1-6, а кольцо может содержать один или более гетероатомов, замещающих группу(ы) CH₂.Group I Compounds
(a) R = H
A denotes an aminoacyl group derived from an α-amino acid bearing a cycloaliphatic side chain (i.e., C ₄ to C ₁₀ , mono- or bicyclic), in which the ring may contain one or more heteroatoms, for example, L-cyclohexylglycine, L -cyclopentyl glycine, L-decahydronaphthylglycine, L-piperidyl glycine;
or
A represents a β-aminoacyl group of the general formula

where p = 1-6, and the ring may contain one or more heteroatoms replacing the group (s) CH ₂ .

 Both α and β-aminoacyl groups in (a) above can contain unsaturated bonds in their rings, i.e.

а также могут включать один или более гетероатомов.

and may also include one or more heteroatoms.

(b) R = CN; C = CR ₇ or CH = NR ₈
A corresponds to the definition given previously in (a) and can also be obtained from L-α-amino acids carrying a lipophilic side chain, for example, lle.

(c) R = CHO or B (OH) ₂
A represents a β-aminoacyl group corresponding to the definition given in (a). The obtained AB compounds are stable, unlike α-aminoacyl derivatives of the same type, which undergo small intramolecular cyclization. In compounds (B), B (OH ₂ ) may be present, for example, as a boronate ester.

приведенные соединения лабильны в воде, образуя свободные борные кислоты.

these compounds are labile in water, forming free boric acids.

или

где a = 1-5: D=G-(CH₂)_b-(R₄)_q-R₃; G=0, NH или NMe;
b = 0-12; q= 0-5;
D¹=D, где G ≠ 0;
R₄= Z-NH-(CH₂)_c- или NH-Z-(CH₂)_c-, где с = 1-12, a Z=CO, CH₂ или SO₂, и
R₃= CO₂H или его эфир [т.е. любой низший алкил, фторалкил или циклоалкил(C₁ - C₈), а также ароматический или гетероароматический (5- или 6-членные кольца, моно- или бициклические) эфир] , CONH₂; CONHNH₂; CONR₅R₆; CONHNR₅R₆, PO₃H (или его эфир, в соответствии с определением, данным для CO₂Н), SO₃H; SO₂NH₂, SO₂NR₅R₆, ОН, CR₅, арил или гетероарил (т.е. 5- или 6-членные кольца, моноциклические или бициклические) [включая замещенный арил или гетероарил с заместителями, выбранными из F, Cl, I, Br, ОН, OR₅, NO₂, SO₃H, SO₂NH₂, SO₂NR₅R₆, NH₂, NR₅R₆, CO₂R₅, CF₃, CN, CONH₂, CONR₅R₆,
NHCO₂R₅, CH(NR₅)NR₅R₆, NH-CH(: NR₅)NR₅R₆ и R₅] ; NH₂; NR₅R₆; NHCO₂R₅; NHSO₂NR₅R₆; NHCOR₅, NH-SO₂R₅; NH-CH(:NR₅)NR₅R₆; NHCONR₅R₆, сахар (который может присоединяться через эфирную или гликозидную связь); CO-аминосахар (присоединенный через -NH₂), например, глюкозамин или галактозамин; NHCO- аминосахар; или NHCS-аминосахар.Group II Compounds
When R = H, C≡CR ₇ or CH = NR ₈ , A is a derivative of an α-amino acid, the side chain of which carries a functional group, which is modified so that a long chain is formed that terminates in different groups of R ₃ . And it can have a structure related to the following three types:

or

where a = 1-5: D = G- (CH ₂ ) _b - (R ₄ ) _q -R ₃ ; G = 0, NH or NMe;
b is 0-12; q is 0-5;
D ¹ = D, where G ≠ 0;
R ₄ = Z-NH- (CH ₂ ) _c - or NH-Z- (CH ₂ ) _c -, where c = 1-12, a Z = CO, CH ₂ or SO ₂ , and
R ₃ = CO ₂ H or its ester [i.e. any lower alkyl, fluoroalkyl or cycloalkyl (C ₁ - C ₈ ), as well as aromatic or heteroaromatic (5- or 6-membered rings, mono- or bicyclic) ether], CONH ₂ ; CONHNH ₂ ; CONR ₅ R ₆ ; CONHNR ₅ R ₆ , PO ₃ H (or its ester, as defined for CO ₂ H), SO ₃ H; SO ₂ NH ₂ , SO ₂ NR ₅ R ₆ , OH, CR ₅ , aryl or heteroaryl (i.e., 5- or 6-membered rings, monocyclic or bicyclic) [including substituted aryl or heteroaryl with substituents selected from F, Cl, I, Br, OH, OR ₅ , NO ₂ , SO ₃ H, SO ₂ NH ₂ , SO ₂ NR ₅ R ₆ , NH ₂ , NR ₅ R ₆ , CO ₂ R ₅ , CF ₃ , CN, CONH ₂ , CONR ₅ R ₆ ,
NHCO ₂ R ₅ , CH (NR ₅ ) NR ₅ R ₆ , NH-CH (: NR ₅ ) NR ₅ R ₆ and R ₅ ]; NH ₂ ; NR ₅ R ₆ ; NHCO ₂ R ₅ ; NHSO ₂ NR ₅ R ₆ ; NHCOR ₅ , NH-SO ₂ R ₅ ; NH-CH (: NR ₅ ) NR ₅ R ₆ ; NHCONR ₅ R ₆ , sugar (which may be attached via an ether or glycosidic bond); CO-amino sugar (attached via -NH ₂ ), for example, glucosamine or galactosamine; NHCO-amino sugar; or NHCS amino sugar.

или

где R¹= H, Me; кольцо может также содержать большее число гетероатомов;
E= J-(CH₂)_b-(R₄)_q -R₃, J=CO, CH₂ или SO₂; при этом a, b, q, R₃, R₄ соответствуют определению, данному в п. (i)

где R² = H или Me; кольцо может также содержать один или более гетероатомов,
L = (CH₂)_d-[CO] _r- (CH₂)_b- (R₄)_q-R₃ или (CH₂)_e-NR¹- (CH₂)_b-(R₄)_q-R₃; r = 0 или 1; d = 0-4; e = 2-4; b, q, R₃ и R₄ соответствуют определению, данному в п. (i).In the above definition of R _{3, the} term “sugar” refers to any carbohydrate or oligosaccharide, and R ₅ and R ₆ are independently selected from H and alkyl, fluoroalkyl and cycloalkyl groups (up to 8 atoms), aryl, heteroaryl, and alkyl heteroaryl groups (up to 11 atoms) or R ₅ and R ₆ together form a chain (C ₃ to C ₈ )

or

where R ¹ = H, Me; the ring may also contain a larger number of heteroatoms;
E = J- (CH ₂ ) _b - (R ₄ ) _q -R ₃ , J = CO, CH ₂ or SO ₂ ; wherein a, b, q, R ₃ , R ₄ correspond to the definition given in paragraph (i)

where R ² = H or Me; the ring may also contain one or more heteroatoms,
L = (CH ₂ ) _d - [CO] _r - (CH ₂ ) _b - (R ₄ ) _q -R ₃ or (CH ₂ ) _e -NR ¹ - (CH ₂ ) _b - (R ₄ ) _q -R ₃ ; r is 0 or 1; d is 0-4; e is 2-4; b, q, R ₃ and R ₄ correspond to the definition given in paragraph (i).

где ω = CH₂, О, NH, CO, S, SO₂, Ph или NMe и независимо
ε = CH₂, О, NH, CO, S, SO₂, Ph или NMe.Group III
Compounds of group III are defined by the general formula:

where ω = CH ₂ , O, NH, CO, S, SO ₂ , Ph or NMe and independently
ε = CH ₂ , O, NH, CO, S, SO ₂ , Ph or NMe.

These compounds are symmetrical dimers. They can have any B structure, as defined above. A can be selected from any structure of group II [[(i), (ii) or (iii)], however, in this case, the terminal group R ₃ in each residue A is removed and replaced by a protected symmetric group [ε-ω-ε], which binds two halves of a dimer; ω may be absent, in which case both ε join together to form a chain connecting the two A - B parts; alternatively, both ε may be absent, and in this case only joins two A - B parts.

A structure of the type ε-ω-ε is chemically easily achievable, for example, in the form of NH-CO-NH, CO-NH-CO-, SO ₂ -NMe-SO ₂ ; for each specialist with an average level of knowledge in this field it is also obvious which structures are unattainable, for example, like -NH-NH-NH-. Specific examples of possible compounds are shown in Table 7.

Кроме того, в соединениях Групп I, II и III любая амидная связь, связывающая A и B или любой амид в боковых цепях A (в Группах II и III), может быть замещена с помощью известных методов соблюдения биоизостерии амидов, например:

замещают на

В Таблице 8 приведены примеры такого рода замещений.In all compounds described in Group II and Group III, certain —CH ₂ groups present in long chains can be substituted in accordance with a bioisostere, for example, using —O—, i.e. without affecting the inhibitory or binding activity against DP-IV. In the presence of groups such as, for example, —CONHCH ₂ CH ₂ NHCO, they may be substituted with the substituent below

In addition, in the compounds of Groups I, II, and III, any amide bond linking A and B or any amide in the side chains of A (in Groups II and III) can be substituted using known methods for maintaining the bioisostere of amides, for example:

replaced by

Table 8 provides examples of such substitutions.

Biochemistry
All compounds are tested in vitro against pure human DP-IV (obtained from M&E, Copenhagen, Denmark). Inhibition of DP-IV is determined using a Ala-Pro-AFC fluorescent substrate (K _m 0.8 μM) at three concentrations for each inhibitor. A typical test (total volume 0.4 ml) includes sodium-Gepes 83.3 mm, EDTA 1.67 mm. BSA 1.5 mg ml ^-1 , pH 7.8, DP-IV 25 μU / ml ^-1 inhibitor (in 10 mM acetate, pH 4.0). The beginning of the reaction is carried out by adding a substrate and excitation values at 395 nm and emission at 450 nm are noted every 30 seconds for 7.5 minutes. K _i values are determined using a Dickson graph.

Chemistry
In Tables 1 - 8, followed by schemes and a description of the experimental procedure for obtaining various structural types, 152 Examples of synthesized compounds are given. All final products were characterized by FAB mass spectrometry with an assessment of their purity by HPLC analysis with phase reversal; all intermediates were characterized by ¹ H NMR studies.

Table 9 shows the selected values of K _i in relation to DP-IV when determining them with inhibitors of various structural types.

 Schemes of the main methods for obtaining all classes of compounds are presented in table. 1a - 11a.

К раствору H-ProNH₂•HCI (225 мг, 1.50 ммоля) в сухом CH₂Cl₂ (15 см³) добавляют диизопропилэтиламин до тех пор, пока значение pH станет равным 9. Добавляют в виде одной порции BoclleONSu и перемешивают смесь в течение 16 часов в атмосфере азота. Затем выпаривают растворитель, а остаток обрабатывают стандартным способом, т.е. распределяют остаток между этилацетатом (60 см³) и 0,3 N раствором KHSO₄ (10 см³). Далее органический слой промывают насыщенным раствором NaHCO₃ (10 см³), водой (10 см³) и солевым раствором (5 см³). Раствор высушивают (Na₂SO₄) и выпаривают при пониженном давлении. Неочищенный продукт пропускают через короткую пробку силикагеля, элюируют с помощью смеси гексан : этилацетат (от 10:90 до 0:100) с получением 301 мг (92%) BoclleProNH₂, в виде бесцветной пены.Experimental Procedures for Case Studies
Example 1
2- (S) -cyano-1-isoleucylpyrrolidine (11)

To a solution of H-ProNH ₂ • HCI (225 mg, 1.50 mmol) in dry CH ₂ Cl ₂ (15 cm ³ ), diisopropylethylamine is added until the pH value is 9. Add BoclleONSu in one portion and mix the mixture for 16 hours in a nitrogen atmosphere. The solvent is then evaporated and the residue is treated in a standard manner, i.e. partition the residue between ethyl acetate (60 cm ³ ) and 0.3 N KHSO ₄ solution (10 cm ³ ). Next, the organic layer was washed with saturated NaHCO ₃ solution (10 cm ³ ), water (10 cm ³ ) and brine (5 cm ³ ). The solution was dried (Na ₂ SO ₄ ) and evaporated under reduced pressure. The crude product is passed through a short plug of silica gel, eluting with hexane: ethyl acetate (10:90 to 0: 100) to give 301 mg (92%) of BoclleProNH ₂ as a colorless foam.

¹ H NMR (CDCl ₃ ) δ (ppm); 6.90 (1H, brs); 5.51 (1H, brs); 5.18 (1H, d., J = 9.6 Hz): 4.62 (1H, dd., J = 2.6, 7.0 Hz); 4.29 (1H, dd., J = 8.4, 9.2 Hz); 3.79-3.58 (2H, m.); 2.36 (1H, m): 2.09-1.57 (5H, m); 1.43 (9H, s): 1.17 (1H, m); 0.95 (3H, doublet, J = 6.6 Hz); 0.90 (3H, t. J = 7.3 Hz)
Imidazole (84 mg, 1.24 mmol) is added to a solution of BoclleProNH ₂ in dry pyridine (10 cm ³ ) in a nitrogen atmosphere. The solution was cooled to a temperature of -35 ^° C, after which POCl ₃ (0.25 cm ³ , 2.48 mmol) was added dropwise. The reaction mixture is stirred at a temperature of from -30 to -20 ^o C for 60 minutes. The solution was then evaporated and the crude residue was subjected to silica gel column chromatography to obtain 180 mg (94%) of 2- (S) -cyano-1- [N- (t-butoxycarbonyl) isoleucyl] pyrrolidine as a colorless oil.

¹ H NMR (CDCl ₃ ) δ (ppm); 5.14 (1H, d. J = 9.2 Hz); 4.80 (1H, dd., J = 2.6, 7.1 Hz); 4.22 (1H, dd, J = 7.9, 9.1 Hz); 3.81 (1H, m); 3.71 (1H, m); 2.30-2.12 (4H, m); 1.75 (1H, m); 1.60 (1H, m); 1.42 (9H, s); 1.19 (1H, m); 0.97 (3H, d, J = 6.9 Hz); 0.91 (3H, t., J = 7.3 Hz).

¹³ C NMR (CDCl ₃ ) δ (ppm) 171.7; 155.6; 118.0; 79.6; 56.0; 46.5; 46.0; 37.8; 29.6; 28.1; 25.0; 24.2; 15.2; 10.9.

 Deprotection is carried out with stirring with trifluoroacetic acid for 60 minutes. Evaporation and lyophilization from water afforded 60 mg of 2- (S) -cyano-1-isoleucylpyrrolidine (11) as a white fluffy solid.

FAB Mass Spectrum: Calculation: 209.3, Found (M + H) ⁺ = 210.2.

¹ H NMR (D ₂ O) δ (ppm); 4.3 (1H, m); 3.64 (1H. D., J = 5.6 Hz); 3.16 (2H, m); 1.86-1.48 (5H, m); 0.98 (1H, m); 0.68 (1H, m); 0.51 (3H, d, J = 6.9 Hz); 0.38 (3H, t., J = 7.3 Hz).

¹³ NMR (D ₂ O) δ (ppm); 169.7: 119.7: 57.3; 48.6: 48.1; 36.9; 30.2; 25.8; 24.5; 15.4; 11.5.

К раствору BocGlu (OH) пирролидида (193 мг, 0,64 ммоля) и PyBop (500 мг, 0,96 ммоля) в CH₂Cl₂ (6 см³) добавляют диизопропилэтиламин для доведения значения pH раствора до 9. После перемешивания в течение 5 минут добавляют раствор бензил 8-амино-октаноата (200 мг, 0,77 ммоля) в CH₂Cl₂ (5 см³). Смесь перемешивают при комнатной температуре в течение 16 часов. Реакционную смесь обрабатывают согласно процедуре, описанной в Примере 1. Грубый остаток подвергают колоночной хроматографии (от 1% до 3% метанола в этилацетате) с получением 344 мг (99%) BocGlu [NH(CH₂)₇ CO₂Bn] пирролидида в виде бесцветного твердого вещества.Example 2
H-Glu (NH (CH ₂ ) ₇ CONH (CH ₂ ) ₃ NHZ] pyrrolidine (64)

To a solution of BocGlu (OH) pyrrolidide (193 mg, 0.64 mmol) and PyBop (500 mg, 0.96 mmol) in CH ₂ Cl ₂ (6 cm ³ ), diisopropylethylamine is added to adjust the pH of the solution to 9. After stirring in a solution of benzyl 8-amino-octanoate (200 mg, 0.77 mmol) in CH ₂ Cl ₂ (5 cm ³ ) is added over 5 minutes. The mixture was stirred at room temperature for 16 hours. The reaction mixture was processed according to the procedure described in Example 1. The crude residue was subjected to column chromatography (1% to 3% methanol in ethyl acetate) to obtain 344 mg (99%) of BocGlu [NH (CH ₂ ) ₇ CO ₂ Bn] pyrrolidide as colorless solid.

¹ H NMR (CDCl ₃ ) δ (ppm); 7.35 (5H, s), 6.63 (1H, pc, J = 6.7 Hz); 5.65 (1H, doublet, J = 8.3 Hz); 5.11 (2H, s); 4.36 (1H, dt., J = 2.6, 8.9 Hz); 3.55-3.20 (6H, m); 2.34 (2H, t. J = 7.3 Hz); 2.26 (2H, dd., J = 5.6. 7.3 Hz); 2.11-1.48 (10H, m): 1.43 (9H, s); 1.32-1.27 (6H, m).

A solution of BocGlu [NH (CH ₂ ) ₇ CO ₂ Bn] pyrrolidide (230 mg, 0.43 mmol) in ethyl acetate (10 cm ³ ) containing 10% palladium on carbon (50 mg) was bubbled with hydrogen. After 90 minutes, nitrogen was purged into the reaction vessel, the solution was filtered through celite, and the solvent was evaporated, to give 187 mg (98%) of BocGlu NH (CH ₂ ) ₇ CO ₂ H] pyrrolidide as a colorless oil.

To a solution of BocGlu [NH (CH ₂ ) ₇ CO ₂ H] pyrrolidide (125 mg, 0.28 mmol) and PyBop (221 mg, 0.43 mmol) in CH ₂ Cl ₂ (10 cm ³ ) diisopropylethylamine is added to pH 9 After stirring for 5 minutes, a solution of ZNH (CH ₂ ) ₃ NH ₂ • HCl (90 mg, 0.37 mmol) and diisopropylethylamine (38 mg, 0.37 mmol) is added in one portion. The solution was stirred for 18 hours and then treated in accordance with the standard procedure described in Example 1. The crude residue was subjected to column chromatography (2% to 15% methanol in ethyl acetate) to obtain 151 mg (85%) of BocGlu [NH (CH ₂ ) ₇ CONH (CH ₂ ) ₃ NHZ] pyrrolidide as a colorless oil.

¹ H NMR (CDCl ₃ ) δ (ppm); 7.35 (5H, s.); 6.60 (1H, unit., J = 7.2 Hz); 6.14 (1H, units., J = 7.2 Hz); 5.63 (1H, d, J = 8.3 Hz); 5.39 (1H, pc., J = 5.6 Hz); 5.10 (2H, s); 4.38 (1H, dt., J = 2.3, 9.2 Hz); 3.52-3.13 (10H. M); 2.26 (2H, t., J = 6.9 Hz); 2.17 (2H, t., J = 7.6 Hz): 1.98-1.48 (12H, m); 1.44 (9H, s); 1.38-1.23 (6H, m).

A solution of BocGlu [NH (CH ₂ ) ₇ CONH (CH ₂ ) ₃ NHZ] pyrrolidide (14 mg, 0.022 mmol) in 4N HCl / dioxane was stirred for 45 minutes. The solvent was evaporated and the residue was dissolved in water, filtered and lyophilized to give 13 mg of H-Glu [NH (CH ₂ ) ₇ CONH (CH ₂ ) ₃ NHZ] pyrrolidide (64) as a colorless oil.

ZNH(CH₂)₃CO₂NSu (570 мг, 1,7 ммоля) добавляют в виде одной порции к раствору 1-[N-(т-бутоксикарбонил) лизил] пирролидина (745 мг, 2.2 ммоля) в сухом CH₂Cl₂. Значение pH доводят до 9 с помощью диизопропилэтиламина, а смесь перемешивают в течение 60 минут. Растворитель выпаривают, а остаток обрабатывают по стандартной процедуре, описанной в примере 1. Колоночная хроматография (от 100% этилацетата до 15% метанола в этилацетате) дает 620 мг (68%) BocLys-[CO(CH₂)₃NHZ] пирролидида.FAB Mass Spectrum: Calculated: 531.3, Found (M + H) ⁺ = 532.3
Example 3
H-Lys [CO (CH ₂ ) ₃ NHSO ₂ Pfp) pyrrolidide (110)

ZNH (CH ₂ ) ₃ CO ₂ NSu (570 mg, 1.7 mmol) is added in one portion to a solution of 1- [N- (t-butoxycarbonyl) lysyl] pyrrolidine (745 mg, 2.2 mmol) in dry CH ₂ Cl ₂ . The pH was adjusted to 9 with diisopropylethylamine, and the mixture was stirred for 60 minutes. The solvent was evaporated and the residue was worked up according to the standard procedure described in Example 1. Column chromatography (100% ethyl acetate to 15% methanol in ethyl acetate) gave 620 mg (68%) of BocLys- [CO (CH ₂ ) ₃ NHZ] pyrrolidide.

¹ H NMR (CDCl ₃ ) δ (ppm); 7.42 (5H, s); 6.31 (1H, pc., J = 6.5 Hz); 5.58 (1H, d, J = 8.9 Hz); 5.39 (1H. Pcs., J = 6.9 Hz); 5.17 (2H, s); 4.44 (1H, m); 3.72-3.20 (8H, m); 2.29 (2H, t., J = 7.3 Hz); 2.14-1.83 (8H, m); 1.78-1.41 (4H, m); 1.43 (9H, s).

A mixture of BocLys [Co (CH ₂ ) ₃ NHZ] pyrrolidide (620 mg, 1.16 mmol) and 10% palladium-carbon in methanol (10 cm ³ ) containing one molecular equivalent of 2N HCl was bubbled with hydrogen. After 60 minutes, nitrogen is passed through the reaction mixture and filtered through celite. Evaporation of the solvent gave 282 mg (49%) of BocLys [Co (CH ₂ ) ₃ NH ₂ • HCl] pyrrolidide. The resulting product was dissolved in CH ₂ Cl ₂ (10 cm ³ ) and stirred in a nitrogen atmosphere. Before the addition of pentafluorobenzenesulfonyl chloride (45 mg, 0.17 mmol), diisopropylethylamine is added to pH 9. The mixture is stirred for 16 hours. The solvent is evaporated and the crude material is treated according to the standard procedure described in Example 1. Column chromatography (100% ethyl acetate to 10% methanol in ethyl acetate) gives 33 mg (31%) of BocLys [CO (CH ₂ ) ₃ NHSO ₂ Pfp] pyrrolidide in the form of a colorless oil.

¹ H NMR (CDCl ₃ ) δ (ppm); 7.19 (1H, pc., J = 6.3 Hz); 6.18 (1H, pc, J = 6.6 Hz), 5.50 (1H, d, J = 8.4 Hz), 4.38 (1H, m); 3.65-3.16 (8H, m); 2.36 (2H, t., J = 6.8 Hz); 2.01-1.82 (8H, m); 1.69-1.41 (4H, m); 1.43 (9H, s).

The described product is stirred in trifluoroacetic acid (10 cm ³ ) for 30 minutes. The solvent was evaporated and the residue was dissolved in water, filtered and lyophilized to give 30 mg of H-Lys [CO (CH ₂ ) ₃ -NHSO ₂ Pfp] Prl (110) as a colorless oil.

FAB mass spectrum: Calculated 514.2; Found (M + H) ⁺ = 515.2.

Пирролидин (0,88r, 12,4 ммоля) добавляют в раствор BocThrONSu (3,0 г, 9,5 ммоля) в сухом CH₂Cl₂ (30 см³) в атмосфере азота. Реакционную смесь перемешивают в течение 60 минут при комнатной температуре. Растворитель выпаривают, а остаток обрабатывают по стандартной методике, описанной в примере 1. Остаток подвергают колоночной хроматографии (гексан : этилацетат, 30:70) с получением 2,50 г (96%) 1-[N-(т-бутоксикарбонил)треонил]пирролидина в виде бесцветного масла.Example:
H-Thr [(CH ₂ ) ₅ CH ₃ ) pyrrolidide (143)

Pyrrolidine (0.88r, 12.4 mmol) is added to a solution of BocThrONSu (3.0 g, 9.5 mmol) in dry CH ₂ Cl ₂ (30 cm ³ ) under nitrogen. The reaction mixture was stirred for 60 minutes at room temperature. The solvent was evaporated and the residue was worked up according to the standard procedure described in Example 1. The residue was subjected to column chromatography (hexane: ethyl acetate, 30:70) to obtain 2.50 g (96%) of 1- [N- (t-butoxycarbonyl) threonyl] pyrrolidine as a colorless oil.

¹ H NMR (CDCl ₃ ) δ (ppm): 5.52 (1H, d, J = 6.5 Hz). 4.30 (1H, d, J = 7.4 Hz); 4.16 (2H, m); 3.72 (1H, m); 3.46 (3H, m); 1.98-1.82 (4H, m); 1.43 (9H, s), 1.19 (3H, d. J = 7.1 Hz).

To a solution of 1- [N- (t-butoxycarbonyl) threonyl] pyrrolidine in dry THF at 0 ^° C under nitrogen atmosphere was added sodium hydride (17 mg, 0.70 mmol). Before adding n-hexyl iodide (200 mg, 0.94 mmol), the mixture was stirred for 16 minutes. Then the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was treated according to the standard procedure described in Example 1. The crude product was subjected to column chromatography (hexane: ethyl acetate, 40:60) to obtain 25 mg (10%) of BocThr [(CH ₂ ) ₅ CH ₃ ] pyrrolidide (143 )

¹ H NMR (CDCl ₃₎ ) δ (ppm), 5.50 (1H, d, J = 6.9 Hz); 4.48 (1H, m); 3.70-3.32 (7H, m); 1.92-1.80 (6H, m); 1.52 (2H, m); 1.42 (9H, s); 1.30 (6H, m), 1.22 (8H, d, J = 6.9 Hz); 0.83 (3H, t., J = 7.9 Hz).

BocThr [(CH ₂ ) ₅ CH ₃ ] pyrrolidide (20 mg, 0.06 mmol) was stirred in 4N HCl / dioxane (5 cm ³ ) for 60 minutes. The solvent was evaporated and the residue was taken up in water, filtered and lyophilized to give H-Thr - [(CH ₂ ) ₅ CH ₃ ] pyrrolidide (20 mg) as an orange oil. The product was purified by phase reversal HPLC to obtain 15 mg (143) as a colorless oil.

FAB Mass Spectrum: Calculated: 256.2, Found (M + H) ⁺ = 257.3.

К раствору циклопентил трифенилфосфония бромида (287 мг, 0,69 ммоля) в сухом ТГФ (6 см³) в атмосфере азота при температуре -30^oC добавляют при перемешивании 1,6 N ⁿбутил лития (0,50 см³, 0,76 ммоля). Смесь перемешивают в течение 60 минут, после чего раствор охлаждают до температуры -50^oC с последующим добавлением по каплям раствора N-(т-бутоксикарбонил)-L-изолейцинала (125 мг, 0,58 ммоля, получен по методу Fehrentz and Castro, Synthesis, 1983, 676) в сухом ТГФ (4 см³). По окончании добавления температуру реакционной смеси медленно, в течение 3,5 часа доводят до комнатной.Example 5
H-lle-Ψ- [CH = CH) Pyrrolidide (149)

To a solution of cyclopentyl triphenylphosphonium bromide (287 mg, 0.69 mmol) in dry THF (6 cm ³ ) in a nitrogen atmosphere at a temperature of -30 ^° C, 1.6 N ⁿ butyl lithium (0.50 cm ³ , 0, 76 mmol). The mixture is stirred for 60 minutes, after which the solution is cooled to a temperature of -50 ^o C, followed by the dropwise addition of a solution of N- (t-butoxycarbonyl) -L-isoleucinal (125 mg, 0.58 mmol, obtained by the method of Fehrentz and Castro, Synthesis, 1983, 676) in dry THF (4 cm ³ ). Upon completion of the addition, the temperature of the reaction mixture was slowly brought to room temperature over 3.5 hours.

The reaction is stopped by the addition of a saturated solution of ammonium chloride (2 cm ³ ). The resulting mixture was diluted with water (10 cm ³ ) and extracted with diethyl ether ( ³ × 20 cm ³ ). The combined ether layers were washed with water (10 cm ³ ), dried (Na ₂ SO ₄ ) and evaporated to give 187 mg (> 100%) of the crude product. Column chromatography (90:10, hexane: Et ₂ O) gives 53 mg (34%) of Boc-lle- Ψ [CH = CH] pyrrolidide as a colorless oil
¹ H NMR (CDCl ₃ ) δ (ppm): 0.84 (3H, t, J = 6.9 Hz); 0.91 (3H, d, J = 7.3 Hz); 1.08 (1H, M); 1.44 (9H, s); 1.48 (1H, m): 1.64 (5H, m), 2.24-2.45 (4H, m): 4.08 (1H, br); 4.41 (1H, brs), 5.12 (1H, dt., J = 2.3, 8.9 Hz).

¹³ C NMR (CDCl ₃ ) σ (ppm) 155.8; 147.4: 119.1; 79.2; 54.8; 40.1; 34.2; 29.6; 28.9; 26.8; 26.6; 26.1; 15.0; 12.1.

 Processing this product with 4N HCl / dioxane for 35 minutes removes the Boc-protecting groups. The reaction mixture was evaporated, the residue was dissolved in water, filtered and lyophilized to give 24 mg (63%) of H-lle-Ψ [CH = CH] pyrrolidide (149) as a foamy solid.

FAB Mass Spectrum: Calculated 167.2, Found (M + H) ⁺ = 168.2.

N-(т-бутоксикарбонил)-L-изолейцинал (2,40 г, 11,2 ммоля) и 2- окси-1-трифенилфосфоранциклопентан (4,61 г, 13,4 ммоля, приготовлен по методу H.O. House и H.Babed, J. Org. Chem. 1963, 28, 90) нагревают при температуре кипячения с обратным холодильником в толуоле в атмосфере азота. Через 15 часов смесь охлаждают, а растворитель выпаривают. Колоночная хроматография (80:20, гексан : этилацетат) грубого остатка дает 2,33 г (74%) Boclle - Ψ [CH=CH] пирролидин-2-оне в виде бесцветного масла
¹H ЯМР (CDCl₃) δ (ppm); 6,29 (1H, дт., J=2,6, 9,2 Гц), 4,59 (1H, шд), 4,17 (1H, м); 2,82 (1H, м), 2,66-2,50 (2H, м); 2,34 (2H, т., J = 7,8 Гц), 1,96 (2H, к. , J = 7,6 Гц); 1,44 (1H, м); 1,43 (9H, с); 1,12 (1H, м); 0,89 (3H, д., J = 5,3 Гц); 0,88 (3H, т., J = 6,9 Гц).Examples 6 and 7
H-lle [(2R) -cyano-Ψ (CH = CH) pyrrolidide] (150)
H-lle [(2S) -cyano-Ψ (CH = CH) pyrrolidide] (151)

N- (t-butoxycarbonyl) -L-isoleucinal (2.40 g, 11.2 mmol) and 2-hydroxy-1-triphenylphosphorancyclopentane (4.61 g, 13.4 mmol, prepared by HO House and H.Babed , J. Org. Chem. 1963, 28, 90) are heated at reflux in toluene under nitrogen. After 15 hours, the mixture was cooled and the solvent was evaporated. Column chromatography (80:20, hexane: ethyl acetate) of the crude residue gives 2.33 g (74%) of Boclle - Ψ [CH = CH] pyrrolidin-2-one as a colorless oil
¹ H NMR (CDCl ₃ ) δ (ppm); 6.29 (1H, dt., J = 2.6, 9.2 Hz), 4.59 (1H, sd), 4.17 (1H, m); 2.82 (1H, m); 2.66-2.50 (2H, m); 2.34 (2H, t., J = 7.8 Hz); 1.96 (2H, q., J = 7.6 Hz); 1.44 (1H, m); 1.43 (9H, s); 1.12 (1H, m); 0.89 (3H, d, J = 5.3 Hz); 0.88 (3H, t., J = 6.9 Hz).

To a solution of Boclle-Ψ [CH = CH] pyrrolidin-2-one (180 mg, 0.64 mmol) and LiCN (0.5 M in DMF, 3.84 cm ³ , 1.92 mmol) in dry DMF (2 cm ³ ) diethyl cyanophosphonoacetate (0.30 cm ³ , 1.92 mmol) is added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 minutes. The mixture was diluted with water (20 cm ³ ) and then extracted with ethyl acetate (2 • 30 cm ³ ). The combined organic layers were washed with water (5 x 10 cm ³ ), dried (Na ₂ SO ₄ ) and evaporated to give 360 mg (> 100%) of the crude product. A portion of such a crude cyanophosphonate (284 mg, 0.64 mmol) was dissolved in dry THF and stirred under nitrogen. Tert-butanol (47 mg, 0.64 mmol) was added, then a solution of samarium (II) iodide (0.1 M in THF, 19.2 cm ³ , 1.92 mmol) was added dropwise. After complete addition, the reaction mixture was stirred for another 30 minutes and then 2N HCl (20 cm ³ ) was added. The mixture was extracted with diethyl ether (3 • 30 cm ³ ). The combined ether layers were washed with 10% Na ₂ S ₂ O ₃ solution (10 cm ³ ), water (2 • 10 cm ³ ) and brine (2 • 10 cm ³ ). The solution was dried (Na ₂ SO ₄ ), evaporated, and the obtained crude residue was subjected to column chromatography (90: 10, hexane: ethyl acetate) to obtain 122 mg (66%) of a mixture of Boclle diastereomers [2- (RS) - cyano-Ψ (CH = CH) pyrrolidine] as a colorless oil.

¹ H NMR (CDCl ₃ ) δ (ppm): 5.52 (1H, d, J = 9.6 Hz); 4.5 (1H, br), 4.12 (1H, m): 3.35 (1H, m): 2.57 (1H, m); 2.38 (1H, m); 2.17 (1H, m): 1.91 (2H, m); 1.69 (2H, m); 1.53 (1H, m); 1.43 (9H, s); 1.12 (1H, m); 0.92 (1.5H, d, J = 7.3 Hz); 0.91 (1.5H, d, J = 7.3 Hz); 0.89 (1.5H, d, J = 6.6 Hz); 0.86 (1.5 H, t., J = 6.9 Hz).

 Treatment of the resulting mixture of 4N HCl / dioxane diastereomers for 60 minutes removes the protecting groups. Evaporation of the solvent and subsequent HPLC with reversal of the phases of the obtained residue gives two pure diastereomers.

(150), (47 mg, 60%) FAB Mass spectrum: Calculated 192.2, Found (M + H) ⁺ = 193.2.

(151), (28 mg, 36%) FAB Mass spectrum: Calculated 192.2. Found (M + H) ⁺ = 193.2
The preparative methods described in relation to tables 1-8 and to examples from the first to the seventh, are part of the present invention.

Abbreviations
Boc tert-butyloxycarbonyl
Bn benzyl
BSA bovine serum albumin
ⁿ Bu n-butyl
Ch cyclohexyl
DMF, DMF dimethylformamide
DMP Dess Martin periodant
EDTA, EDTA Ethylenediaminetetraacetic Acid
FAB Fast Atom Bombing
Gua guanidil
HPLC, HPLC high performance liquid chromatography
ⁿ Hx n-hexyl
Mass spectrum. Mass spectrometry
mCPBA, mHPBA meta-chloroperbenzoic acid
Mol Wt, M.V. molecular weight
ONSu NO Succinimide
Pfp. pentafluorophenyl
Ph phenyl
Piperidil pip
Prl pyrrolidide
Py pyridine
PyBop benzotriazol-1-yl-hydroxy-tris-pyrrolidino-phosphonium hexafluorophosphate
WSCD, VRKD water-soluble carbodiimide
Z benzyloxycarbonyl
Analytical high performance liquid chromatography (HPLC) was performed on a Novapak C ₁₈ reverse phase column (particle size 4 microns, 8x100 mm) with linear gradients of increasing concentrations of acetonitrile in water, with a constant 0.1% concentration of trifluoroacetic acid; flow rate 1.5 ml / min.

 The individual gradients presented in the table were used. 9a and 10a.

 The study of toxicity in rats, see table. 11a.

Claims (4)

1. Inhibitors of processes associated with DP-IV, selected from compounds with the General formula AB (group I), where B means

n is 1 or 2;
m is 0, 1 or 2;
X is CH ₂ , S, SO, SO ₂ , O;
Y is N,
R is H, CN, CHO, B (OH) ₂ , A is attached to Y, and
a) when R is H, A is an alpha aminoacyl group derived from an alpha amino acid carrying a cycloaliphatic side chain, or is a beta aminoacyl group of the general formula

where p takes values from 1 to 6,
however, the ring in any case may contain unsaturated bonds and / or substitution with a heteroatom; b) when R is CN, A corresponds to the definition given in (a), and, in addition, can be obtained from any L-alpha amino acid carrying a lipophilic side chain, and c) when R is CHO or B (OH) ₂ , A means a beta-aminoacyl group as defined in (a);
(group II): B, n, m, X — as indicated above; R is H, CN; A attaches to Y, wherein A is

where a = 1 to 5;
D is G- (CH ₂ ) _b - (R ₄ ) _q -R ₃ ;
G is NH or NMe;
b = 1 to 12;
q is 0 or 1;
R ₄ means Z-NH- (CH ₂ ) _c or NH-Z- (CH ₂ ) _c -,
where c = 1 to 12;
Z is CO, CH ₂ ;
R ₃ = CO ₂ H or its ester, CONH ₂ , CONR ₅ R ₆ , SO ₂ NH ₂ , SO ₂ NR ₅ R ₆ , OH, OR ₅ , substituted or unsubstituted aryl, NH ₂ , NR ₅ R ₆ , NHCOR ₅ , NHSO ₂ R ₅ , NH-CH (: NR ₅ ) NR ₅ R ₆ ;
R ₅ and R ₆ are independently selected from H, lower alkyl, fluoroalkyl groups, or R ₅ and R ₆ , together with the nitrogen atom to which they are attached, form a C ₃ -C ₈ chain;
or A represents (ii)

where R ¹ = H, Me;
E = J- (CH ₂ ) _b - (R ₄ ) _q -R ₃ ; J = CO;
a, b, q, R ₃ and R ₄ correspond to the definition given in (i);
or represents (iii)

where R ² = H, Me;
L means (CH ₂ ) _d - (CO) _r - (CH ₂ ) _b - (R ₄ ) _q -R ₃ where
r = 1, d = 1 to 4;
b, q, R ₃ and R ₄ correspond to the definition given in (i). 2. Inhibitors of processes associated with DP-IV according to claim 1, which are compounds with the general formula: AB (group I), where B means

n is 1 or 2;
m is 0, 1 or 2;
X is CH ₂ , S, SO, SO ₂ ;
R is H, CN, CHO or B (OH) ₂ ;
a) when R is H, A is an alpha aminoacyl group derived from an alpha amino acid carrying a cycloaliphatic side chain,
or is a beta aminoacyl group of the general formula

where p takes values from 1 to 6,
however, the ring in any case may contain unsaturated bonds and / or substitution with a heteroatom;
b) when R is CN, A corresponds to the definition given in (a), and, in addition, can be obtained from any L-alpha amino acid carrying a lipophilic side chain, and c) when R is CHO or B (OH) ₂ , A means a beta-aminoacyl group as defined in (a). 3. The inhibitors according to claim 2, in which B is a 5-membered ring; n takes the value 1; X is CH ₂ or S; Y is N; R is CN. 4. The inhibitors according to claim 1, which is a compound with the General formula AB (group II), where B means

n is 1 or 2;
m is 0, 1 or 2;
X is CH ₂ , O, S, SO, SO ₂ ;
R is H or CN, A is attached to Y, wherein A is

where a is 1 to 5;
D is G- (CH ₂ ) _b - (R ₄ ) _q -R ₃ ;
G is NH or NMe;
b = 1 to 12;
q is 0 or 1;
R ₄ means Z-NH- (CH ₂ ) _c or NH-Z- (CH ₂ ) _c -, where c = 1 - 12, and Z means CO, CH ₂ ;
R ₃ means CO ₂ H or its ester, CONH ₂ , CONR ₅ R ₆ , SO ₂ NH ₂ , SO ₂ NR ₅ R ₆ , OH, OR ₅ , substituted or unsubstituted aryl, NH ₂ , NR ₅ R ₆ , NHCOR ₅ , NHSO ₂ R ₅ , NH-CH (: NR ₅ ) NR ₅ R ₆ ;
R ₅ and R ₆ are independently selected from H, lower alkyl, fluoroalkyl groups or R ₅ and R ₆ , together with the nitrogen atom to which they are attached, form a C ₃ -C ₈ chain;
or A represents (ii)

where R ¹ means H, Me;
E is J- (CH ₂ ) _b - (R ₄ ) _q -R ₃ ;
J is CO;
a, b, q, R ₃ and R ₄ correspond to the definition given in (i);
or A represents (iii)

where R ² means H or Me;
L means (CH ₂ ) _d - (CO) _r - (CH ₂ ) _b - (R ₄ ) _q -R ₃ where r = 1, d = 1 - 4;
b, q, R ₃ and R ₄ correspond to the definition given in (i).

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