RU2234496C2 - Derivatives of beta-alanine - Google Patents

Abstract

FIELD: organic chemistry, amino acids, pharmacy.

SUBSTANCE: invention relates to derivatives of β-alanine of the general formula (I):

wherein Q₁ or Q₃ mean CH or nitrogen atom (N) independently of one another but they can't mean simultaneously nitrogen atom (N); R¹ represents hydrogen atom (H), A, Ar or Hal; R² means hydrogen atom (H) or A; R³ means

,

or

;

each among R⁴ and R⁵ means independently hydrogen atom (H), A or Hal; R⁶ represents hydrogen atom (H) or A; A represents alkyl with 1-6 carbon atoms; Ar represents unsubstituted aryl; Hal means fluorine (F), chlorine (Cl), bromine (Br) or iodine (J) atom; n = 2, 3, 4, 5 or 6; m = 1, 2, 3 or 4, and to their physiologically acceptable salts or solvates also, and to methods for their preparing and to a pharmaceutical preparation eliciting property of inhibitor of integrins.

EFFECT: improved preparing method, valuable biological and medicinal properties of compounds.

7 cl, 27 ex

Description

The present invention relates to derivatives of β-alanine of the formula

wherein

each of Q ₁ , Q ₂ ,

Q ₃ or Q _4, independently of the others, is CH or N,

R ¹ represents H, A, Ar, Hal, OH, OA, CF ₃ or OCF ₃ ,

R ² is H or A,

each of R ⁴ and R ^5, independently of the other, is H, A, Hal, OH, OA, CF ₃ , OCF ₃ , CN, NH ₂ , NHA, NA ₂ or NH-C (O) A,

R ⁶ is H, A, - (CH ₂ ) _m —OH, - (CH ₂ ) _m —O — C (O) A, or - (CH ₂ ) _m —Ar,

A represents alkyl with 1-6 carbon atoms,

Ar is unsubstituted or one-, two- or trisubstituted aryl,

Hal represents F, Cl, Br or I.

n is 2, 3, 4, 5 or 6,

m is 1, 2, 3 or 4,

as well as from physiologically acceptable salts and solvates.

To some extent, such compounds are known from WO 97/26250 or WO 97/24124.

The aim of this invention was to obtain new compounds that would have valuable properties, in particular, those that could be used for the manufacture of drugs.

It was found that the compounds of formula I and their salts, along with good tolerance, possess very valuable pharmacological properties. First of all, they act as integrin inhibitors, in particular, interfering with the interaction of integrin receptors αvβ3 or αvβ5 with ligands, such as the binding of vitronectin to the integrin receptor αvβ3. Integrins are membrane-bound, heterodimeric glycoproteins consisting of the α subunit and the smaller β subunit. The relative affinity and specificity for ligand binding are determined by a combination of different α and β subunits. The compounds of this invention are most effective for integrins αvβ1, αvβ3, αvβ5, αllbβ3, as well as αvβ6 and αvβ8, preferably αvβ3 and αvβ5. In particular, strong selectively acting αvβ3 integrin inhibitors have been found. Integrin αvβ3 is expressed on a number of cells, for example, on endothelial cells, smooth muscle cells of vessels, for example, the aorta, cells involved in the destruction of bone matrix (osteoclasts) or tumor cells.

The effects of the compounds of this invention can, for example, be demonstrated by the method described by J.W. Smith et al. In J. Biol. Chem. 1990, 265, 12267-12271.

The dependence of the source of angiogenesis on the interaction between integrins in the walls of blood vessels and extracellular matrix proteins is described by R.S. Brooks, R.A. Clark and D.A. Cheresh in Science 1994, 264, 569-571.

The possibility of inhibiting this interaction and, thus, initiating apoptosis (programmed death) of angiogenic cells by means of a cyclic peptide was described by P.S. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T. Hu, G. Klier and D.A. Cheresh in Gell 1994, 79, 1157-1164. This work describes, for example, antagonists or antibodies to αvβ3, which, by initiating apoptosis, contribute to the shrinkage of tumors.

To experimentally prove the ability, including the compounds of the present invention, to prevent the attachment of living cells to the corresponding matrix proteins and, accordingly, the attachment of tumor cells to the latter, using an intercellular adhesion test, which is carried out similarly to the method described by F. Mitjans et al. , J. Gell Science 1995, 108, 2825-2838.

The compounds of formula I are able to inhibit the binding of metalloproteinases to integrins and thus inhibit the use of enzyme activity of proteinases by cells. An example of this is the inhibition of the binding of MMP-2- (matrix metalloproteinase-2-) to the vitronectin receptor αvβ3 via the cyclo-RGD peptide described in P. C. Brooks et al., Cell 1996, 85, 683-693.

Compounds of formula I blocking the interaction of integrin receptors with ligands, e.g., fibrinogen and fibrinogen receptor (glycoprotein IIb / IIIa), as antagonists inhibit the spread of tumor cells due to metastasis and, thus, can be used as antimetastatic substances during tumor removal operations Surgically or during surgery to treat a tumor. This corresponds to the following observations:

The spread of tumor cells of a local tumor in the vascular system occurs due to the formation of microaggregates (microthrombi), due to the interaction of tumor cells with platelets. In a microaggregate, tumor cells are screened and become unrecognizable to cells of the immune system. Microaggregates can be fixed on the walls of blood vessels, thereby facilitating the further penetration of tumor cells into the tissue. Since activated thrombocytes are involved in the formation of microthrombi resulting from the binding of ligands to the corresponding integrin receptors, e.g., αvβ3 or αllbβ3, the corresponding antagonists can be considered as inhibitors of metastasis.

The compounds of formula I can be used as active ingredients in drugs in human medicine and veterinary medicine, in particular for the prevention and / or treatment of diseases of the vascular system, thrombosis, myocardial infarction, arteriosclerosis, apoplexy, angina pectoris, tumor diseases, such as development or tumor metastasis, osteolytic diseases, such as osteoporosis, pathologically angiogenic diseases, such as inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, neovascular glaucoma, ulcerative colitis, regional ileitis, atherosclerosis, psoriasis, restenosis after angioplasty infection, multiple fungal infections, multiple fungal infections, multiple fungal infections, multiple fungal infections, multiple infections in acute renal failure and to accelerate the healing process of wounds.

The compounds of formula I can be used as antimicrobial agents during operations using biomaterials, implants, catheters or artificial heart pacemakers.

Moreover, they act as antiseptics. Antimicrobial activity can be demonstrated using the method described by P. Valentin-Weigund et al. In Infection and Immunity, 1988, 2851-2855.

Some compounds of formula I are, in particular, selectively acting integrin receptor inhibitors αvβ3 and αvβ6.

Some compounds of formula I are, in particular, selectively acting integrin receptor inhibitors αvβ5 and αvβ6.

Some compounds of formula I are, in particular, selectively active integrin receptor inhibitors αvβ3, αvβ5 and αvβ6.

The effect of such a compound on the integrin receptor αvβ5 and, thus, its activity as an inhibitor can be demonstrated, for example, by the method described by J.W. Smith et al. In J. Biol. Chem. 1990, 265, 12267-12271.

The effect of such a compound on the integrin receptor αvβ5 and, thus, its activity as an inhibitor can be demonstrated, for example, using the method described by J.W. Smith et al. In J. Biol. Chem. 1990, 265, 12267-12271.

These some compounds are particularly suitable for the treatment or elimination of pathological processes associated with the action of integrins αvβ3 and / or αvβ5 and αvβ6. Examples of angiogenic pathologies include skin diseases such as psoriasis, bullous pemphigus, dermatitis and erythema, as well as pulmonary fibrosis, cystic fibrosis, endometriosis, liver cirrhosis or periodontitis. These pathologies can be affected by inhibitors of αvβ3 and / or αvβ5. In particular, carcinoma, as well as the aforementioned skin diseases and pulmonary fibrosis and, in addition, epithelial cell pathologies are affected by αvβ6 inhibitors (References: Healy DL et al., Hum. Reprod. Update 1998, 4 (5), 736-40 ; Creamer D. et al., Br. J. Dermatol. 1997, 137, 851-5; Norrby K., APMIS. 1997, 105, 417-37; Creamer D. et al., Br. J. Dermatol. 1997 136, 859-65; Polverini PJ Crit. Rev. Oral. Biol. Med. 1995, 6, 230-47; Brown LF et al., J. Invest. Dermatol. 1995, 104, 744-9; Hoyt DG and al., Am. J. Physiol. 1997, 273, L612-7; Pilewski JM et al., ibid. 1997, 273, L256-63 or Goldman M. et al., Gene. Ther. 1996, 3, 811- 8).

A preferred field of application for these certain compounds is cancer therapy.

The methods used in cancer therapy, as a rule, are aimed at eliminating some area, segment in the zone of development of a solid tumor. Segments, among other things, represent the tumor development zone as such or the blood vessels that have grown into the tumor through which the tumor receives everything necessary for its growth. As soon as the tumor stops receiving nutrition, transcriptional activators, most often through hypoxic or hypoglycemic promoters, initiate the production and secretion of polypeptide growth stimulants. The latter activate the growth of blood vessels. To divide endothelial cells of blood vessels, anti-apoptotic signals are required, sent by receptors of the integrin family located on the cell surface. In particular, integrin receptors αvβ3 and αvβ5 are responsible for these signals (literature: P.C. Brooks, Eur. J. Cancer, 1996, 32A, 2423-2429; PC Brooks et al., Gell. 1994, 79, 1157-1164 )

Inhibition of these integrins receptors αvβ3 and / or αvβ5, in particular αvβ3, induces apoptosis of activated endothelial cells of a blood vessel that has grown into a tumor, while its normal bed, which is not used by the tumor, remains intact. The tumor loses its source of nutrition, as a result of which its development is suspended. The tumor itself, i.e. regenerated cancer cells, however, are not exposed to any effect, thus, after the cessation of therapy, tumor growth may again begin.

Integrin receptors on the surface of tumor cells are significantly different from those expressed on normal tissue. For example, in many carcinomas, a high expression of de-novo rare integrin αvβ6 was found, while αvβ3 is a characteristic sign of progressive malignant melanoma. It is further known that αvβ6 takes part in the mechanisms of tumor development itself and damage to healthy tissue by degenerate cells, i.e. metastasis.

Combination therapy, at the same time aimed at angiogenesis of tumor tissue and elimination of the latter as such, has so far been described exclusively as the use of integrin αvβ3 inhibitors in combination with cytotoxic substances (chemotherapy) or radiation (radiation therapy).

It was unexpectedly found that, using selectively acting integrin inhibitors αvβ3 and αvβ6, it is possible to manufacture a medicine for such a combination therapy. In this case, a synergistic effect is observed. Due to the high selectivity of inhibiting the integrin receptors αvβ3 and αvβ6, inhibition of other integrins, for example, α5β1 or αIIbβ3, which perform the most important functions, for example, in normal tissue, one should not be afraid.

Further, it was found that using selectively acting integrin inhibitors αvβ5 and αvβ6, similarly to using the combined use of selectively acting integrin inhibitors αvβ3, αvβ5 and αvβ6, it is also possible to manufacture a medicine for such a combination therapy. In this case, a synergistic effect may also be observed.

The compounds of formula I have at least one chiral center and, therefore, can take a number of stereoisomeric forms. All of these forms (e.g., D- and L-forms) and their mixtures (e.g. DL-forms) are included in this formula.

According to claim 1, the compounds of the present invention also include the so-called prodrug derivatives, i.e. compounds of the formula I modified with alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the body into the active compounds of this invention.

Further, free amino or hydroxyl groups as substituents of compounds of formula I may be provided with appropriate protecting groups.

Solvates of compounds of formula I are understood to mean adducts of inert solvent molecules to compounds of formula I resulting from their mutual attraction. Solvates are, for example, mono- or dihydrates or additive compounds with alcohols, such as with methanol or ethanol.

The objects of this invention are compounds of formula I and their salts and solvates according to claim 1, as well as a method for producing compounds of formula I, their salts and solvates, characterized in that

(a) a compound of formula II

in which Q ₁ , Q ₂ , Q ₃ , Q ₄ , R ¹ and n have the meanings given in

claim 1 of the claims,

react with a compound of formula III

in which R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings specified in claim 1

claims

and, if necessary, translate the radical R ⁶ ≠ H into the radical R ⁶ =

H, or

(b) a compound of formula IV

in which Q ₁ , Q ₂ , Q ₃ , Q ₄ , R ¹ , R ² and n have the meanings given

in claim 1 of the claims,

react with a compound of formula V

in which R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings indicated in claim 1

claims

and, if necessary, transfer the radical R ⁶ ≠ H to the radical R ⁶ = H,

or

(c) in the compound of formula I, one or more radicals R ¹ , R ² , R ³ , R ⁴ and / or R ^{5 are} converted to one or more radicals R ¹ , R ² , R ³ , R ⁴ and / or R ⁵ by , eg

i) alkylation of a hydroxyl group,

ii) hydrolysis of the ether group to a carboxyl group,

iii) esterification of a carboxyl group,

iv) alkylation of an amino group or

v) acylation of the amino group,

and / or

a basic or acidic compound of the formula I is converted by treatment with an acid or a base into one (one) of its salts or solvates.

In the above formulas, A is alkyl, is linear or branched and has 1-6, preferably 1, 2, 3, 4, 5, or 6 carbon atoms. In a preferred embodiment, A represents methyl, then ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, as well as pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl.

Particularly preferred A is methyl, ethyl, isopropyl, n-propyl, n-butyl or tert.-butyl.

Ar is unsubstituted or mono-, two- or trisubstituted A, CF ₃ , OH, OA, OCF ₃ , CN, NO ₂ or Hal aryl, which is phenyl, naphthyl, antryl or biphenylyl. In a preferred embodiment, Ar is unsubstituted or one-, two- or trisubstituted A, CF ₃ , OH, OA, OCF ₃ , CN, NO ₂ or Hal phenyl or naphthyl.

Thus, Ar is preferably phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o -, m- or p-tert.-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-, p- trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, further preferably 2,3-, 2,4-, 2,5-, 2 6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3- , 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4 - or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromph enyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl or 3-chloro-4-fluorophenyl, 4-fluoro-2-hydroxyphenyl, naphthalene -1-yl, naphthalen-2-yl or 2-, 3-, 4-, 5-, 6-, 7- or 8-methylnaphthalen-1-yl, 2-, 3-, 4-, 5-, 6 -, 7- or 8-ethylnaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-chloronaphthalen-1-yl, 2-, 3-, 4-, 5- 6-, 7- or 8-fluoronaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-bromonaphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-hydroxynaphthalen-1-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-methylnaphthalen-2-yl, 1-, 3-, 4 -, 5-, 6-, 7- or 8-ethylnaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-chloronaphthalen-2-yl, 1-, 3- , 4-, 5-, 6-, 7- or 8-fluoronaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-bromonaphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-hydro sinaftalin-2-yl.

Most preferably, Ar is phenyl, o-, m- or p-fluorophenyl, m- or p-chlorophenyl, p-methylphenyl, p-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 4-fluoro-2-hydroxyphenyl, naphthalene-1 -yl or naphthalene-2-yl.

B - (CH ₂ ) _m -Ar Ar has one of the preferred values given above, and the variable m may be 1 or 2. Particularly preferred value is (CH ₂ ) _m -Ar is benzyl.

B - (CH ₂ ) _m —OH m may be 1, 2, 3, or 4. In a preferred embodiment, (CH ₂ ) _{m —} OH is hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl, most preferably hydroxyethyl.

B - (CH ₂ ) _m —O — C (O) A A takes one of the above preferred meanings, m may be 1 or 2. In a particularly preferred embodiment, A is tert-butyl and m is 1.

Hal is preferably F, Cl or bromo.

n is 2, 3, 4, 5 or 6, particularly preferably 3, 4 or 5.

preferably 3- (trifluoromethoxy) - or 4- (trifluoromethoxy) phenyl.

preferably is biphenyl-4-yl, 4'-fluorobiphenyl-4-yl, 4'-fluorobiphenyl-3-yl, 3'-fluorobiphenyl-4-yl, 2'-fluorobiphenyl-4-yl, 4'-chlorobiphenyl- 4-yl, 3'-chlorobiphenyl-4-yl, 4'-methylbiphenyl-4-yl, 4 '- (trifluoromethyl) biphenyl-4-yl, 3'-chloro-4'-fluorobiphenyl-4-yl, 4' -fluoro-2-hydroxybiphenyl-4-yl, 4'-fluoro-2'-hydroxybiphenyl-4-yl, 4'-fluoro-2'-hydroxybiphenyl-3-yl, 4- (naphthalene-1-yl) phenyl, 4- (naphthalen-2-yl) phenyl or 4- (naphthalen-1-yl) -3-hydroxyphenyl.

in a preferred embodiment, is 2-, 3- or 4-nitrophenyl, 4-methyl-3-nitrophenyl, 4-chloro-3-nitrophenyl, 3-nitro-2-hydroxyphenyl or 3-bromo-6-hydroxy-5-nitrophenyl.

Each of Q ₁ , Q ₂ , Q ₃ or Q _4, independently of the others, is CH or N. Q _{1 is} preferably CH or N, Q ₂ is preferably CH, which is also the preferred value for Q ₃ and Q ₄ . Most preferably, Q ₁ , Q ₂ , Q ₃ and Q ₄ are CH.

R ¹ is H, A, Ar, Hal, OH, OA, CF ₃ or OCF ₃ , wherein A, Ar or Hal takes the above preferred or particularly preferred meanings. R ^{1 is} preferably H or A. Substituted R ¹ is preferably in the 4- or 6-position. Particularly preferred is the 4-position of the ring.

R ^{2 is} preferably H or A, in a particularly preferred embodiment N.

R ³ represents

where R ⁴ and R ⁵ independently from each other denote H, A, Hal, OH, OA, CF ₃ , OCF ₃ , CN, NH ₂ , NHA, NA ₂ or NH-C (O) A, and Ar takes one of the above values.

A particularly preferred value of R ⁴ is H, A, OH or Hal.

R ⁵ in a particularly preferred embodiment is H or OH.

A particularly preferred value of R ⁴ and R ⁵ in

is N.

In a particularly preferred embodiment, R ⁴ in

denotes H or OH, and Ar represents an unsubstituted or mono- or disubstituted Hal, A or CF ₃ phenyl or naphthyl.

A particularly preferred value of R ⁴ in

is H, A or Hal, and R ⁵ in a particularly preferred embodiment is H or OH.

R ^{3 is} preferably 2-, 3- or 4-trifluoromethoxyphenyl, 2-, 3- or 4-nitrophenyl, biphenyl-3-yl, biphenyl-4-yl, 3-methyl-, 4-methyl-, 5-methyl - or 6-methyl-2- (trifluoromethoxy) phenyl, 3-ethyl-, 4-ethyl-, 5-ethyl- or 6-ethyl-2- (trifluoromethoxy) phenyl, 2-methyl-, 4-methyl-, 5 -methyl- or 6-methyl-3- (trifluoromethoxy) phenyl, 2-ethyl-, 4-ethyl-, 5-ethyl- or 6-ethyl-3- (trifluoromethoxy) phenyl, 2-methyl-, 3-methyl- 5-methyl- or 6-methyl-4- (trifluoromethoxy) phenyl, 2-ethyl-, 3-ethyl-, 5-ethyl- or 6-ethyl-4- (trifluoromethoxy) phenyl, 3-methyl-, 4- methyl-, 5-methyl- or 6-methyl-2-nitrophenyl, 3-ethyl-, 4-ethyl-, 5-ethyl- or 6-ethyl-2-nitro phenyl, 2-methyl-, 4-methyl-, 5-methyl- or 6-methyl-3-nitrophenyl, 2-ethyl-, 4-ethyl-, 5-ethyl- or 6-ethyl-3-nitrophenyl, 2- methyl-, 3-methyl-, 5-methyl- or 6-methyl-4-nitrophenyl, 2-ethyl-, 3-ethyl-, 5-ethyl- or 6-ethyl-4-nitrophenyl, 3-chloro, 4 -chloro-, 5-chloro- or 6-chloro-2-nitrophenyl, 2-chloro, 4-chloro, 5-chloro or 6-chloro-3-nitrophenyl, 2-chloro, 3-chloro, 5-chloro- or 6-chloro-4-nitrophenyl, 3-nitro-2-hydroxyphenyl, 3-bromo-6-hydroxy-5-nitrophenyl, 4'-fluorobiphenyl-4-yl, 4'-fluorobiphenyl-3-yl , 3'-fluorobiphenyl-4-yl, 2'-fluorobiphenyl-4-yl, 4'-chlorobiphenyl-4-yl, 3'-chlorobiphenyl-4-yl, 4'-methylbiphenyl-4-yl, 4 '- ( trifluoromethyl) biphenyl-4-yl, 3'-chloro-4'- torbiphenyl-4-yl, 4'-fluoro-2-hydroxybiphenyl-4-yl, 4'-fluoro-2'-hydroxybiphenyl-4-yl, 4'-fluoro-2'-hydroxybiphenyl-3-yl, 4- ( naphthalen-1-yl) phenyl, 4- (naphthalen-2-yl) phenyl or 4- (naphthalen-1-yl) -3-hydroxyphenyl.

Particularly preferred values of R ³ are 4- (trifluoromethoxy) phenyl, 3- (trifluoromethoxy) phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, biphenyl-4-yl, 4-methyl-3-nitrophenyl, 4-fluoro- 2-hydroxyphenyl or 4-chloro-3-nitrophenyl, 4'-fluorobiphenyl-4-yl, 4'-fluorobiphenyl-3-yl, 3'-fluorobiphenyl-4-yl, 2'-fluorobiphenyl-4-yl, 4 ' -chlorobiphenyl-4-yl, 3'-chlorobiphenyl-4-yl, 4'-methylbiphenyl-4-yl, 4 '- (trifluoromethyl) biphenyl-4-yl, 3'-chloro-4'-fluorobiphenyl-4-yl 4'-fluoro-2-hydroxybiphenyl-4-yl, 4'-fluoro-2'-hydroxybiphenyl-4-yl, 4'-fluoro-2'-hydroxybiphenyl-3-yl, 4- (naphthalen-1-yl ) phenyl, 4- (naphthalen-2-yl) phenyl or 4- (naphthalen-1-yl) -3-hydroxyphenyl or 3-bromo-6-hydroxy-5-nitrophenyl.

R ⁶ is H, A, - (CH ₂ ) _m —OH, - (CH ₂ ) _m —O — C (O) A or - (CH ₂ ) _m —Ar, where A, - (CH ₂ ) _m - OH, - (CH ₂ ) _m —O — C (O) A and - (CH ₂ ) _m —Ar take one of the above preferred or particularly preferred values.

Compounds of formula I in which R ^{6 is} preferably A, - (CH ₂ ) _m —OH, - (CH ₂ ) _m —O — C (O) A or - (CH ₂ ) _m —Ar, as well as solvates thereof, are the so-called prodrugs, i.e. do not show activity during in vitro experiments, masking the biologically active carboxyl group. However, in the body in the process of metabolism, prodrugs take a biologically active form. The corresponding free acid, which corresponds to a compound of formula I with R ⁶ = H, including its salts and solvates, is in vitro active.

Accordingly, an object of the present invention are, in particular, compounds of formula I, in which at least one of the radicals mentioned has one of the above preferred meanings. Some preferred groups of compounds can be expressed by the following la-lk subformulas corresponding to formula I (radicals for which no detailed definition is given have the meanings indicated for formula I), where

In 1a

B lb

B lc

In Id, Q ₁ , Q ₂ , Q ₃ and Q _{4 of} formula I are CH.

In le, Q ₁ is N, and Q ₂ , Q ₃ and Q _{4 of} formula I are CH.

In 1f, R ¹ is H or A and

или

R ³ is

or

In 1g, R ¹ represents H or A,

или

R ³ is

or

and

Q ₁ represents N, and Q ₂ , Q ₃ and Q ₄ denote CH.

In 1h, R ¹ represents H or A,

Q ₁ , Q ₂ , Q ₃ and Q ₄ denote CH, and

или

R ³ is

or

In 4i, R ¹ represents H or A, and

или

R ³ is

or

In 1k, R ¹ represents H or A, and

или

R ³ is

or

Particularly preferred compounds of formula la are

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid or

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid,

as well as their physiologically acceptable salts and solvates.

Particularly preferred compounds of formula 1b are

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (2-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (2-nitrophenyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (2-nitrophenyl) propionic acid,

3- (2-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic methyl ester

acids

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (6-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} propionic acid or

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

as well as their physiologically acceptable salts and solvates.

Particularly preferred compounds of formula 1c are

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-biphenylyl) propionic acid or

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

as well as their physiologically acceptable salts and solvates.

Particularly preferred compounds of formula 1d are

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (2-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (2-nitrophenyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (2-nitrophenyl) propionic acid,

3- (2-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (6-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-biphenylyl) propionic acid or

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

as well as their physiologically acceptable salts and solvates.

Preferred compounds of formula 1e are

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} -3- (4-biphenylyl) propionic acid or

3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

as well as their physiologically acceptable salts and solvates.

Preferred compounds of formula 1f are

3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-biphenylyl) propionic acid or

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

as well as their physiologically acceptable salts and solvates.

The rest of the compounds of formula I according to claim 1, as well as starting materials, are obtained essentially by known methods described in the literature (e.g., in such standard works as Houben-Weyl, Methoden der organischen Chemie, publ. Georg- Thieme-Verlag, Stuttgart), namely, under known, suitable conditions for carrying out the aforementioned reactions. In this case, you can also use essentially known options, a detailed description of which is here, however, is not given.

If desired, the starting materials can be obtained in situ, without isolating them from the reaction mixture, but directly involving in further reactions to obtain compounds of formula I according to claim 1.

Several - identical or different from each other - protected amino and / or hydroxyl groups may also be present in the molecule of the starting material. If the protective groups present are different from each other, in many cases they can be cleaved selectively (cf .: TW Greene, PGM Wuts, Protective Groups in Organic Chemistry, 2nd edition, Wiley, New York 1991 or PJ Kocienski, Protecting Groups, 1st Edition, Georg Thieme Verlag, Stuttgart-New York, 1994, H, Kunz, N. Waldmann in Comprehensive Organic Synthesis, Volume 6 (publishers V.M. Trost, I. Fleming, E. Winterfeldt) Pergamon, Oxford, 1991, pp. 631-701).

The term "amino group protecting group" is well known and refers to groups that can be used to protect (block) the amino group from chemical reactions. Typical groups of this type are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the protective groups of the amino group are cleaved off at the end of the desired reaction (or reaction sequence), their nature and size are not of particular importance; however, preference is given to groups with 1-20, in particular 1-8, carbon atoms. The concept of "acyl group" in the context of this method is interpreted in the broadest sense. It relates to acyl groups which are derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, as well as, in particular, alkoxycarbonyl, alkenyloxycarbonyl, aryloxycarbonyl and, in particular, aralkoxycarbonyl groups. Examples of acyl groups of this type include alkanoyl, such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl, such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; alkenyloxycarbonyl, such as allyloxycarbonyl (Alok), aralkyloxycarbonyl, such as KB3 (synonym 3), 4-methoxybenzyloxycarbonyl (MO3), 4-nitrobenzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmok); 2- (phenylsulfonyl) ethoxycarbonyl; trimethylsilylethoxycarbonyl (Teoc) or arylsulfonyl, such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred amino protecting groups are BOC, Fmoc and Aloc, as well as CBZ, benzyl and acetyl.

The term “hydroxyl protecting group” is also well known and refers to groups that can be used to protect a hydroxyl group from chemical reactions. Typical groups of this type are the aforementioned unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups, as well as alkyl groups, alkyl, aryl or aralkylsilyl groups or O, O or O, S-acetals. The nature and size of the protective groups of the hydroxyl group do not play a special role, since it is again cleaved after the implementation of the desired chemical reaction or reaction sequence; preference is given to groups with 1-20, in particular 1-10 carbon atoms. Examples of protecting groups of a hydroxyl group include, but are not limited to, aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl or tert.-butyl, as well as allyl, alkylsilyl groups such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert.-bu tildifenilsilil (TBDFS), cyclic acetals, such as isopropylidene, tsiklopentiliden-, tsiklogeksiliden-, benzylidene, p-metoksibenziliden- or o, p-dimetoksibenzilidenatsetal, acyclic acetals, such as tetrahydropyranyl (THP), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) or methylthiomethyl (MTM). A particularly preferred hydroxyl protecting group is benzyl, acetyl, tert.-butyl or TBS.

The process of releasing compounds of formula 1 from their derivatives containing a functional group for a particular protective group used is known from the literature (e.g., TW Greene, PGM Wuts, Protective Groups in Organic Chemistry, 2nd edition, Wiley, New York 1991 or PJ Kocienski, Protecting Groups, 1st Edition, Georg Thieme Verlag, Stuttgart-New York, 1994). In this case, you can use essentially known, not described in detail here options.

The BOC and O-tert-butyl groups can, for example, be preferably cleaved using TFA in dichloromethane or 3-5 N HCl in dioxane at 15-30 ° C, and Fmoc group with a 5-50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 ° C. The alk group can be cleaved off under mild conditions with catalysis by a noble metal in chloroform at 20-30 ° C. A preferred catalyst is tetrakis (triphenylphosphine) palladium (0).

The starting compounds of formulas II-V are generally known. Even if they are new, they can be obtained by methods known per se.

Compounds of formula II, for example, are prepared in the presence of a base by connecting the corresponding 2-amino compound of a heterocycle, where Q ₁ , Q ₂ , Q ₃ or Q ₄ are as defined in claim 1 with the corresponding n-bromocarboxylic esters (Br- [CH ₂ ] _n -COOSG ¹ , where SG ¹ , as described above, is a hydroxyl protecting group), followed by cleavage of the protecting group under standard conditions.

Compounds of formula IV are prepared under standard conditions by combining (similarly to the peptide bond) compounds of formula II with a glycine derivative H ₂ N-CH ₂ -COOSG ² , where SG ² , as described above, is a hydroxyl protecting group.

Compounds of formula V (β-amino acids) can be prepared analogously to the method described by Skinner et al., J. Org. Chem. 1960, 25, 1756. As a result of the reaction of the corresponding R ³ -CHO aldehyde with malonic acid and ammonium acetate in an appropriate solvent (alcohols such as ethanol are particularly preferred), a β-amino acid of formula V is obtained, where R ⁶ is H. After esterification of this free acid of formula V under standard conditions, the compounds of formula V are obtained, wherein R ⁶ is A or - (CH ₂ ) _m —Ar.

In order to obtain compounds of formula III that are protected by the acid function of a β-amino acid of formula V (protection is carried out either by means of an appropriate protecting group or by R ⁶ representing A, - (CH ₂ ) _m —OH, - (CH ₂ ) _m - O — C (O) A or - (CH ₂ ) _m —Ar) is combined with the glycine derivative SG ³ —NH — CH ₂ —COOH. The substituent SG ³ of the glycine derivative SG ³ NH — CH ₂ —COOH, as described above, denotes a protecting group of the amino group, which is then cleaved. Conventional peptide synthesis methods are described, for example, in Houben-Weyl, 1.c., Volume 15 / II, 1974, pages 1-806.

Compounds of formula I can be prepared by reacting a compound of formula II with a compound of formula III, followed by cleavage of the protecting group and translation of the radical R ⁶ denoting A, - (CH ₂ ) _m —OH, - (CH ₂ ) _m —OC (O) A or - (CH ₂ ) _m -Ar, in the radical R ⁶ = N.

Compounds of formula I can also be prepared by reacting a compound of formula IV with a compound of formula V, followed by cleavage of the protecting group or radical R ⁶ denoting A, - (CH ₂ ) _m —OH, - (CH ₂ ) _m —OC (O ) A or - (CH ₂ ) _m -Ar, in the radical R ⁶ = H.

In a preferred embodiment, the addition reaction is carried out in the presence of a dehydrating agent, e.g. carbodiimide, such as dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (CED) or diisopropylcarbodiimide (DIC), hereinafter, nap. , propanphosphonic acid anhydride (cf. Angew. Chem. 1980, 92, 129), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, e.g. in a halogenated hydrocarbon such as dichloromethane, ether, such as tetrahydrofuran silt and dioxane, an amide such as DMF or dimethylacetamide, nitrile such as acetonitrile in dimethyl sulfoxide or in the presence of these solvents at temperatures in the range of about -10-40 ° C, preferably 0-30 ° C. Depending on the conditions, the reaction time can range from several minutes to several days.

The addition of a TBTU addition reagent (O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate) or O- (benzotriazol-1-yl) -N, N, N' hexafluorophosphate was extremely desirable. N'-tetramethyluronium, since in the presence of one of these compounds, racemization, although it takes place, is to a very small extent, and, in addition, the formation of cytotoxic by-products is not observed.

Instead of compounds of formula II and / or IV, derivatives of compounds of formula II and / or IV, preferably pre-activated carboxylic acid or carboxylic acid halide, symmetric or mixed anhydride or an activated ester can also be used. Similar radicals for activating the carboxyl group during typical acylation reactions are described in the literature (e.g., in standard works such as Houben-Weyl, Methoden der organischen Chemie, Georg-Thieme-Verlag, Stuttgart). To this end, activated esters are formed in situ, e.g. as a result of the addition of HOBT (1-hydroxybenzotriazole) or N-hydroxysuccinimide.

The reaction typically takes place in an inert solvent using a carboxylic acid halide in the presence of an acid acceptor, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.

It may also be appropriate to add an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or any other salt of a weak acid of an alkali or alkaline earth metal, preferably potassium, sodium, calcium or cesium.

The base of Formula I, using an acid, can be converted to the corresponding acid addition salt, for example, by reaction of equivalent amounts of a base and an acid in an inert solvent, such as ethanol, followed by evaporation. Acceptable for this reaction are, in particular, acids that form physiologically acceptable salts. Inorganic acids, for example, sulfuric acid, sulfuric acid, dithionic acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as for example phosphoric acid, sulfamic acid, as well as organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, stearic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid , gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylic acid, p-tolu lsulfokislota, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, parahlorfenoksiizomaslyanaya acid, cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalenemono- and disulfonic acids or laurylsulfuric acid. Salts of physiologically unacceptable acids, e.g. picrates, can be used to isolate and / or purify compounds of formula I.

On the other hand, using bases (e.g. sodium or potassium hydroxide or carbonate), the compounds of formula I can be converted to the corresponding metal salts, in particular those of alkali or alkaline earth metals, or to the corresponding ammonium salts.

The object of the present invention are also compounds of formula I according to claim 1 of the claims and their physiologically acceptable salts or solvates as active substances in the composition of drugs.

Further, an object of the present invention are compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates as integrin inhibitors.

The object of the present invention are also compounds of formula I according to claim 1 of the claims and their physiologically acceptable salts or solvates that can be used to eliminate diseases.

Further, an object of the present invention is the use of a combination of selectively acting integrin inhibitors, which is selected from the group of selectively acting integrin αvβ3 inhibitors, combined with selectively acting integrin αvβ6 inhibitors, selectively acting integrin αvβ5 inhibitors in combination with selectively acting integrin αvβ6 inhibitors or selectively acting integrin αvβ3 inhibitors combined with selectively acting integrin αvβ5 inhibitors and those int egrin αvβ6, in the manufacture of a medicament for eliminating pathological processes associated with the action of integrins αvβ3 and / or αvβ5 and αvβ6.

The object of the present invention is the use of a combination of selectively acting integrin inhibitors, which is selected from the group of selectively acting integrin αvβ3 inhibitors combined with selectively acting integrin αvβ6 inhibitors, selectively acting integrin αvβ5 inhibitors in combination with selectively acting integrin αvβ6 inhibitors or integrin αvβ3 inhibitors in combination with selectively active integrin αvβ5 inhibitors and integrin αvβ6 inhibitors in the manufacture of a medicament for I conduct cancer therapy, during which, on the one hand, the angiogenesis of the blood vessels that have grown in the tumor is blocked due to the inhibition of the integrin αvβ3 receptor and / or the integrin αvβ5 receptor, and, on the other hand, the development of the integrin αvβ6 receptor is inhibited, the tumor is stopped.

The object of the present invention is the use of a combination of selectively acting integrin αvβ3 inhibitors and / or integrin αvβ5 and αvβ6 integrins in the manufacture of a medicament for the elimination of diseases associated with cancer, such as solid tumor metastases, angiofibromatosis, retrolental fibroplasia, hemangioma or Kaposi hemangiosarcoma.

Listed below are some compounds of formula I, which are, in particular, selectively acting αvβ3 and αvβ6 integrin receptor inhibitors:

a) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid;

b) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

c) trifluoroacetate 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid;

g) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid or

e) 3- (biphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate.

Listed below are some compounds of formula I, which are, in particular, selectively active integrin receptor inhibitors αvβ5 and αvβ6:

a) 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid trifluoroacetate or

b) trifluoroacetate 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid.

Listed below are some compounds of formula I, which are, in particular, selectively acting integrin receptor inhibitors αvβ3, αvβ5 and αvβ6:

a) 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-methyl-3-nitrophenyl) propionic acid trifluoroacetate;

b) trifluoroacetate 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid;

c) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid;

d) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid or

e) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid hydrochloride.

The most suitable for use in the manufacture of drugs for the treatment or elimination of pathological processes associated with the action of integrins αvβ3 and / or αvβ5 and αvβ6, in particular for cancer therapy, as described above, are integrin inhibitors:

a) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid;

b) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

c) trifluoroacetate 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid;

g) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid;

e) 3- (biphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

e) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid;

g) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

h) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

methyl 3-nitrophenyl) propionic acid;

i) 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate;

j) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

trifluoromethoxyphenyl) propionic acid;

l) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-

trifluoromethoxyphenyl) propionic acid or

m) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid hydrochloride.

Further, an object of the present invention is the use of selectively acting integrin inhibitors, which are selected from the group including:

a) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid;

b) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

c) trifluoroacetate 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid;

g) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid;

e) 3- (biphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

e) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid;

g) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

h) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

methyl 3-nitrophenyl) propionic acid;

i) 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate;

j) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

trifluoromethoxyphenyl) propionic acid;

l) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-

trifluoromethoxyphenyl) propionic acid or

m) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid hydrochloride,

in the manufacture of a medicine for eliminating pathological processes associated with the action of integrins αvβ3 and / or αvβ5 and αvβ6.

The object of this invention is the use of selectively acting integrin inhibitors, which are selected from the group including:

a) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid;

b) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

c) trifluoroacetate 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid;

g) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid;

e) 3- (biphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

e) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid;

g) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

h) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

methyl 3-nitrophenyl) propionic acid;

i) 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate;

j) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

trifluoromethoxyphenyl) propionic acid;

l) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-

trifluoromethoxyphenyl) propionic acid or

m) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid hydrochloride,

in the manufacture of a medicine for the treatment of cancer, during which, on the one hand, the inhibition of the integrin receptor αvβ3 and / or the integrin receptor αvβ5 blocks the angiogenesis of the blood vessels that have grown in the tumor and, on the other hand, the development of the integrin receptor αvβ6 stops the tumor.

The object of this invention is the use of selectively acting integrin inhibitors αvβ3 and / or selectively acting integrin inhibitors αvβ5 and αvβ6, which are selected from the group including:

a) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid;

b) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

c) trifluoroacetate 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid;

g) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid;

e) 3- (biphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

e) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid;

g) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

h) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

methyl 3-nitrophenyl) propionic acid;

i) 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate;

j) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

trifluoromethoxyphenyl) propionic acid;

l) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-

trifluoromethoxyphenyl) propionic acid or

m) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid hydrochloride,

in the manufacture of a medicament for the elimination of diseases associated with cancer, such as solid tumor metastases, angiofibromatosis, retrolental fibroplasia, hemangioma or Kaposi’s hemangiosarcoma.

The most suitable for use in the manufacture of drugs for the treatment of cancer, in which, on the one hand, due to inhibition of the integrin receptor αvβ3, angiogenesis of ingrown blood vessels is blocked and, on the other hand, the development of the tumor is stopped as a result of inhibition of the integrin receptor αvβ6, β derivatives Alanine:

a) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid;

b) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate;

c) trifluoroacetate 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid;

g) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid or

e) 3- (biphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate.

The most suitable for use in the manufacture of drugs for cancer therapy, during which, on the one hand, due to inhibition of the integrin αvβ5 receptor, the angiogenesis of the blood vessels grown into the tumor is blocked and, on the other hand, the development of the tumor is stopped by inhibition of the integrin αvβ6 receptor, derivatives β-alanine:

a) 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid trifluoroacetate or

b) trifluoroacetate 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid.

The most suitable for use in the manufacture of drugs for cancer therapy, during which, on the one hand, due to inhibition of integrin receptors αvβ3 and αvβ5, angiogenesis of the blood vessels grown into the tumor is blocked and, on the other hand, tumor development is stopped as a result of inhibition of integrin receptor αvβ6, are derivatives of β-alanine:

a) 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-methyl-3-nitrophenyl) propionic acid trifluoroacetate;

b) trifluoroacetate 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid;

c) trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid;

d) trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid or

e) 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid hydrochloride.

In addition to using the selectively acting integrin receptor inhibitors of the present invention as an internal combination therapy using at least two integrin inhibitors, further combinations with conventional therapies such as radiation therapy, tumor vaccination, immunotherapy or chemotherapy are also possible. Such a combined therapeutic method (encompassing two approaches at once - internal and external) should further increase the effectiveness of treatment, first of all, make it possible to use small doses of toxic therapeutic agents and, thus, reduce dose-related side effects.

Further, an object of the present invention are pharmaceutical preparations containing at least one compound of formula I and / or one (one) of its physiologically acceptable salts or solvates, which are obtained, in particular, by non-chemical means. In this regard, the compounds of formula I can be suitably dosed in combination with at least one solid, liquid and / or semi-liquid carrier or excipient and, if appropriate, one or more other active substances.

These drugs can be used as drugs in human medicine and veterinary medicine. Acceptable carriers are organic or inorganic substances that can be administered enterally (e.g., orally), parenterally or topically and do not react with new compounds, for example, water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetate glycerin, gelatin, hydrocarbons, such like lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, liquids or drops are used, in particular, orally, suppositories are intended for rectal administration, solutions, preferably oily or aqueous, as well as suspensions, emulsions or implants are used parenterally, and ointments, creams or powders are intended for topical use. New compounds can also be lyophilized and the resulting lyophilisates used, for example, in the manufacture of injectable preparations. The aforementioned preparations can be sterilized and / or include auxiliary substances, such as lubricants, antioxidants, stabilizers and / or surfactants, emulsifiers, salts, with which you can change the osmotic pressure, buffers, dyes, flavorings and / or one or more additional active ingredients, e.g. one or more vitamins.

When using aerosols for inhalation, they must contain the active substance, either dissolved or suspended in the propellant or mixture of propellants (e.g., CO ₂ or polychlorofluorocarbons). The active substance in this case is used in finely divided form, and one or more additional physiologically tolerated solvents, for example, may be present. ethanol. Inhalation solutions can be used with conventional inhalers.

The compounds of formula I and their physiologically acceptable salts or solvates can be used as integrin inhibitors to eliminate diseases, in particular thrombosis, myocardial infarction, coronary diseases, arteriosclerosis, tumors, osteoporosis, inflammation and infections.

The compounds of formula I according to claim 1 and / or their physiologically acceptable salts also find use in the pathological processes that occur and develop as a result of angiogenesis, in particular in tumors or rheumatoid arthritis.

Some compounds of formula I and / or their solvates, as mentioned above, can be used to eliminate pathological processes associated with the action of integrins αvβ3 and / or αvβ5 and αvβ6, in particular for cancer therapy, during which, on the one hand, due to inhibition the integrin αvβ3 receptor and / or the integrin αvβ5 receptor blocks the angiogenesis of the blood vessels that have grown into the tumor and, on the other hand, the development of the integrin αvβ6 receptor is inhibited by the development of the tumor.

The substances of the present invention, as a rule, are administered similarly to the compounds described in the application WO 97/26250 or WO 97/24124, preferably in an amount of about 0.05-500 mg, in particular 0.5-100 mg per dose . The daily dose is preferably about 0.01-2 mg / kg body weight. However, the dosage for each patient depends on a number of factors, for example, on the effectiveness of a particular compound used, age, body weight, general health, gender, diet, time and method of administration, rate of elimination, combination of drugs and severity of the disease. Parenteral administration is preferred.

In addition, the compounds of formula I can be used as integrin ligands in the manufacture of affinity chromatography columns to obtain pure integrins.

In this case, the ligand, i.e. a compound of formula I, through a linking group, eg a carboxyl group, covalently binds to a polymer carrier.

Suitable polymer substrates are polymeric solid phases known in the chemistry of peptides, preferably having hydrophilic properties, for example, crosslinked polysaccharides such as cellulose, Sepharose or Sephadex ^® , acrylamide, polyethylene glycol-based polymers or Tentakelpolymere ^® polymers .

Materials for affinity chromatography performed to purify integrins are prepared under essentially known conditions typical of the condensation of amino acids.

The compounds of formula I contain one or more chiral centers and, thus, can be in racemic or optically active form. Present racemates by methods known per se, mechanically or chemically, can be resolved into enantiomers. In a preferred embodiment, diastereomers are formed from a racemic mixture which is reacted with an optically active resolving agent. Suitable resolving agents are, for example, optically active acids, such as the D- and L-forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids, such as β camphorsulfonic acid. It is also advisable to separate the enantiomers on a column filled with an optically active resolving agent (eg dinitrobenzoylphenylglycine); Suitable as eluent, for example, is a mixture of hexane / isopropanol / acetonitrile, e.g. in a volume ratio of 82: 15: 3.

Naturally, it is also possible to obtain optically active compounds of the formula I by the above methods using optically active starting materials.

All the above and below temperatures are given in ° C. In the following examples, the expression "conventional treatment" means: if necessary, water is added; if necessary, the pH of the mixture is stabilized in the range from 2 to 10, depending on the composition of the final product; the mixture is extracted with ethyl acetate or dichloromethane; the extract is separated, the organic phase is dried over sodium sulfate, evaporated and the precipitate is purified by silica gel chromatography, preparative HPLC and / or crystallization. The purified compounds, if necessary, freeze-dried.

WU = retention time (in minutes) during HPLC in the following systems:

Column: Lichrosorb RP-18 (5 μm) 250 × 4 mm;

Lichrosorb RP-18 (15 μm) 250 × 50 mm.

The gradients of acetonitrile (B) with 0.1% TFA (trifluoroacetic acid) and water (A) with 0.1% TFA are used as eluents. The gradient is expressed in volume percent acetonitrile.

Preferred gradient: 5 min at 20% B and 55 min at 90% B.

Detection at 225 nm.

The indicated retention time was obtained as a result of measurements using gradients of 5 min at 5% B and 40 min to 80% B.

Compounds purified by preparative HPLC were isolated as trifluoroacetate.

Mass spectrometry (MS) by means of BCA (accelerated atom bombardment): MS-BCA (M + H) ⁺ .

Example 1:

(1) 10.5 g of 4- (trifluoromethoxy) benzaldehyde, 5.72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol are refluxed for 8 hours and stirred overnight at room temperature. Then the cooled reaction mixture is suctioned off, washed with ethanol and ether, and dried in air. Get 3-amino-3- (4-trifluoromethoxyphenyl) propionic acid, so pl. 258-260 °.

7.5 g of 3-amino-3- (4-trifluoromethoxyphenyl) propionic acid is activated with thionyl chloride (1.2 equivalents) and esterified with methanol at boiling point under standard conditions. As a result of processing by the usual method, 3-amino-3- (4-trifluoromethoxyphenyl) propionic acid methyl ester, MS-ACC (M + H) ⁺ 263 are obtained.

(2) 0.364 g of [4- (pyridin-2-ylamino) butyrylamino] acetic acid [obtained as a result of a peptide bond of 4- (pyridin-2-ylamino) butyric acid with an aminoacetic acid methyl ester in the presence of HOBT / TBTU and subsequent saponification methyl ester, in each case, under standard conditions] is dissolved in 30 ml of DMF, after which 0.3 g of 3-amino-3- (4-trifluoromethoxyphenyl) propionic acid methyl ester is added and cooled to 30 ° C. By adding 0.321 g of TBTU and 0.045 g of HOBT, the mixture was neutralized with 0.22 ml of N-methylmorpholine (NMM). The reaction mixture was stirred for 2 days at room temperature. After distilling off the solvent, ethyl acetate is introduced, which absorbs the precipitate, after which it is washed with NaHCO ₃ and saturated NaCl and the treatment is carried out in the usual manner. 3- {2- [4- (4-methyl-pyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid methyl ester is obtained, MS-ACU (M + H) ⁺ 497.

(3) 280 mg of 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid methyl ester (feed) is dissolved in 30 ml of dioxane and 0 61 ml NaOH (2 mol / L). After stirring overnight at room temperature, the solvent is distilled off and treatment is carried out in the usual manner. 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid is obtained.

If you work with an excess of NaOH, get the sodium salt of 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid.

Using preparative HPLC, 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid trifluoroacetate is obtained, WU 24.93 min, MS-ACU (M + H) ⁺ 483.

Example 2:

(1) 0.06 mol of 2-nitrobenzaldehyde, 5.72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol are refluxed for 8 hours and stirred overnight at room temperature. Then the cooled reaction mixture is suctioned off, washed with ethanol and ether, and dried in air. Get 3-amino-3- (2-nitrophenyl) propionic acid, so pl. 222 ° C.

Subsequent esterification by activation with thionyl chloride and reaction with methanol under standard conditions give 3-amino-3- (2-nitrophenyl) propionic acid methyl ester.

(2) 3-Amino-3- (2-nitrophenyl) propionic acid methyl ester, similarly to Example 1 (2), is reacted with protected BOC glycine (BOC-Gly-OH). After cleavage of the protective group of the BOC of the amino group under standard conditions, methyl 3- (2-aminoacetylamino) -3- (2-nitrophenyl) propionic acid methyl ester hydrochloride, MS-BUA (M + H) ⁺ 317 are obtained.

(3) 360 mg of 3- (2-aminoacetylamino) -3- (2-nitrophenyl) propionic acid methyl ester hydrochloride was dissolved in 35 ml of DMF and 190 mg of 4- (4-methylpyridin-2-ylamino-butyric acid) was added. After cooling to 0 ° C., 450 mg of TBTU and 63 mg of HBOT are added to the reaction mixture. This is followed by neutralization of 0.15 ml of N-methylmorpholine and stirring overnight at room temperature. The solvent is distilled off, 30 ml of ethyl acetate are mixed into the precipitate, washed with 50% bicarbonate solution and saturated sodium chloride solution, and the treatment is carried out in the usual manner. 3- {2- [4- (4-methyl-pyridin-2-ylamino) butyrylamino] acetylamino} -3- (2-nitrophenyl) propionic acid methyl ester is obtained.

(4) 280 mg of 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (2-nitrophenyl) propionic acid methyl ester (feed) is dissolved in 30 ml of dioxane and 0 61 ml NaOH (2 mol / L).

After stirring overnight at room temperature, the solvent was distilled off and treatment was carried out in the usual manner. 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (2-nitrophenyl) propionic acid is obtained.

If excess NaOH is employed, the sodium salt of 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (2-nitrophenyl) propionic acid is obtained.

Using preparative HPLC, 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (2-nitrophenyl) propionic acid trifluoroacetate is obtained, WU 16.14 min, MS-ACU (M + H) ⁺ 444.

Example 3:

Similarly to Example 2, from 4- (4-methylpyridin-2-ylamino) butyric acid "AB" get

as a result of reaction with 3- (2-aminoacetylamino) -3- (3-trifluoromethoxyphenyl) propionic acid methyl ester hydrochloride

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid methyl ester;

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester, 3- (3-nitrophenyl methyl ester trifluoroacetate is obtained using preparative HPLC ) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid, WU * 19.09, MS-BUA (M + H) ⁺ 458 or

by reaction with 3- (2-aminoacetylamino) -3- (4-biphenylyl) propionic acid methyl ester hydrochloride

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid methyl ester.

Example 4:

After saponification of methyl esters of the compounds of Example 3, similarly to Example 2 (4) receive

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-

trifluoromethoxyphenyl) propionic acid;

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid sodium salt;

trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-

trifluoromethoxyphenyl) propionic acid; WU 24.40 min, MS-ACU (M + H) ⁺ 483;

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt;

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU 19.18 min, MS-ACU (M + H ) ⁺ 458;

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid;

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid sodium salt;

trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid, WU 17.68 min; MS-ACU (M + H) ⁺ 444 or

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

biphenylyl) propionic acid,

sodium salt of 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid,

trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-

biphenylyl) propionic acid, WU 25.65 min, MS-BUA (M + H) ⁺ 475.

Example 5:

Similarly to Example 2, from 5- (4-methylpyridin-2-ylamino) pentanoic acid "BC" get

as a result of reaction with 3- (2-aminoacetylamino) -3- (4-trifluoromethoxyphenyl) propionic acid methyl ester hydrochloride

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (3-trifluoromethoxyphenyl) propionic acid methyl ester hydrochloride

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid methyl ester;

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester; Using HPLC, methyl 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-) methyl ester

ilamino) pentanoylamino] acetylamino} propionic acid, WU 23.81 min, MS-ACU (M + H) ⁺ 486;

as a result of reaction with 3- (2-aminoacetylamino) -3- (2-nitrophenyl) propionic acid methyl ester hydrochloride

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (2-nitrophenyl) propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-amino-acetylamino) -3- (4-naphthalen-2-yl-phenyl) -propionic acid methyl ester hydrochloride

3- (4-naphthalen-2-yl-phenyl) -3- {2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-chloro-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester or

by reaction with 3- (2-aminoacetylamino) -3- (4-biphenylyl) propionic acid methyl ester hydrochloride

3-biphenyl-4-yl-3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester; Using preparative HPLC, 3-biphenyl-4-yl-3- {2- [5- (4-methylpyridin-2-) methyl ester trifluoroacetate is obtained

ilamino) pentanoylamino] acetylamino} propionic acid, WU 30.13 min, MS-BUA (M + H) ⁺ 503.

Example 6:

After saponification of methyl esters of the compounds of Example 5, similarly to Example 2 (4),

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid sodium salt,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid trifluoroacetate, WU 24.88 min, MS-ACU (M + H) ⁺ 497;

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid sodium salt,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid trifluoroacetate, WU 24.61 min, MS-ACU (M + H) ⁺ 497;

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

sodium salt of 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, WU 22.13 min, MS-ACU (M + H ) ⁺ 472;

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (2-nitrophenyl) propionic acid,

3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (2-nitrophenyl) propionic acid sodium salt,

trifluoroacetate 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (2-nitrophenyl) propionic acid, WU 16.98 min, MS-ACU (M + H) ⁺ 458;

3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, WU 17.29 min, MS-ACU (M + H) ⁺ 458;

3- (4-naphthalen-2-ylphenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-naphthalen-2-yl-phenyl) -3- {2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4-naphthalen-2-yl-phenyl) -3- {2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] acetylamino} propionic acid trifluoroacetate;

3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, WU 22.34 min, MS-ACU (M + H ) ⁺ 492 or

3-biphenyl-4-yl-3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3-biphenyl-4-yl-3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3-biphenyl-4-yl-3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, WU 27.09 min, MS-ACU (M + H) ⁺ 489.

Example 7:

Similarly to Example 2, from 4- (pyridin-2-ylamino) butyric acid "CD" get

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (2-nitrophenyl) propionic acid methyl ester hydrochloride

3- (2-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester or

by reaction with 3- (2-aminoacetylamino) -3- (4-biphenylyl) propionic acid methyl ester hydrochloride

3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid methyl ester.

Example 8:

After saponification of methyl esters from Example 7, similarly to Example 2 (4), get

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

trifluoroacetate 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid, WU 19.12 min, MS-ACU (M + H) ⁺ 444;

3- (2-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (2-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (2-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU 12.42 min, MS-ACU (M + H) ⁺ 430 or

3-biphenyl-4-yl-3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3-biphenyl-4-yl-3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3-biphenyl-4-yl-3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU 25.20 min, MS-ACU (M + H) ⁺ 461.

Example 9:

Similarly to Example 2, from 5- (pyridin-2-ylamino) pentanoic acid "DE" receive

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (2-nitrophenyl) propionic acid methyl ester hydrochloride

3- (2-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester or

by reaction with 3- (2-aminoacetylamino) -3- (4-biphenylyl) propionic acid methyl ester hydrochloride

3-biphenyl-4-yl-3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester, methyl ester trifluoroacetate is obtained using preparative HPLC

3-biphenyl-4-yl-3- {2- [5- (pyridin-2-

ilamino) pentanoylamino] acetylamino} propionic acid, WU 28.88 min, MS-BUA (M + H) ⁺ 489.

Example 10:

After saponification of methyl esters of the compounds of Example 9, similarly to Example 2 (4),

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, IU 19.78 min, MS-ACU (M + H) ⁺ 458;

3- (2-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (2-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (2-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, WU 12.80 min, MS-ACU (M + H) ⁺ 444 or

3-biphenyl-4-yl-3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3-biphenyl-4-yl-3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3-biphenyl-4-yl-3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, VU 25.84 min, MS-ACU (M + H) ⁺ 475.

Example 11:

Similarly to Example 2, from 4- (6-methylpyridin-2-ylamino) butyric acid "EF" receive

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester.

Similarly to Example 2, from 5- (6-methylpyridin-2-ylamino) pentanoic acid "FG" receive

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (6-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester.

Example 12:

After saponification of methyl esters of the compounds of Example 11, similarly to Example 2 (4),

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

sodium salt of 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate or

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (6-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (6-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (6-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate.

Example 13:

Similarly to Example 2, from 4- (pyrimidin-2-ylamino) butyric acid "GH" get

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester or

by reaction with 3- (2-aminoacetylamino) -3- (4-biphenylyl) propionic acid methyl ester hydrochloride

3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} -3- (4-biphenylyl) propionic acid methyl ester.

Similarly to Example 2, from 5- (pyrimidin-2-ylamino) pentanoic acid "NK" receive

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester or

by reaction with 3- (2-aminoacetylamino) -3- (4-biphenylyl) propionic acid methyl ester hydrochloride

3- {2- [5- (Pyrimidin-2-ylamino) pentanoylamino] acetylamino} -3- (4-biphenylyl) propionic acid methyl ester.

Example 14:

After saponification of methyl esters of the compounds of Example 13, similarly to Example 2 (4),

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} propionic acid,

sodium salt of 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} propionic acid,

trifluoroacetate 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} propionic acid, WU 16.33 min, MS-ACU (M + H) ⁺ 445;

3-biphenyl-4-yl-3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3-biphenyl-4-yl-3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3-biphenyl-4-yl-3- {2- [4- (pyrimidin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU 24.45 min, MS-ACU (M + H) ⁺ 462;

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate or

3-biphenyl-4-yl-3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3-biphenyl-4-yl-3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3-biphenyl-4-yl-3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate.

Example 15:

Similarly to Example 2, from 4- (6-methylpyridin-2-ylamino) butyric acid "EF" receive

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester.

After saponification of the methyl ester as in Example 2 (4),

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt;

3- (4-methyl-3-nitrophenyl) -3- {2- [4- (6-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU 20.10 min, MS-ACU (M + H ) ⁺ 458.

Example 16:

Similarly to Example 2, from 6- (4-methylpyridin-2-ylamino) hexanoic acid "KL" receive

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-methyl-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-methyl-3-nitrophenyl) -3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (3-nitrophenyl) propionic acid methyl ester hydrochloride

3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} -3- (3-nitrophenyl) propionic acid methyl ester or

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-chloro-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-chloro-3-nitrophenyl) -3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} propionic acid methyl ester.

After saponification of the above methyl esters, as in Example 2 (4),

3- (4-methyl-3-nitrophenyl) -3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} propionic acid,

3- (4-methyl-3-nitrophenyl) -3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} propionic acid sodium salt;

3- (4-methyl-3-nitrophenyl) -3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} propionic acid trifluoroacetate, WU 22.10 min, MC-WUA (M + H ) ⁺ 468;

3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} -3- (3-nitrophenyl) propionic acid,

sodium salt of 3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} -3- (3-nitrophenyl) propionic acid,

trifluoroacetate 3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} -3- (3-nitrophenyl) propionic acid, WU * 18.27 min, MS-BUA (M + H) ⁺ 472 or

3- (4-chloro-3-nitrophenyl) -3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} propionic acid,

3- (4-chloro-3-nitrophenyl) -3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} propionic acid sodium salt,

3- (4-chloro-3-nitrophenyl) -3- {2- [6- (4-methylpyridin-2-ylamino) hexanoylamino] acetylamino} propionic acid trifluoroacetate, VU 23.33 min, MS-ACU (M + H ) ⁺ 506.

Example 17:

Similarly to Example 2, from 7- (4-methylpyridin-2-ylamino) hexanoic acid "LM" receive

as a result of reaction with 3- (2-aminoacetylamino) -3- (3-nitrophenyl) propionic acid methyl ester hydrochloride

3- {2- [7- (4-methylpyridin-2-ylamino) heptanoylamino] acetylamino} -3- (3-nitrophenyl) propionic acid methyl ester.

After saponification of the methyl ester as in Example 2 (4),

3- {2- [7- (4-methylpyridin-2-ylamino) heptanoylamino] acetylamino} -3- (3-nitrophenyl) propionic acid,

sodium salt of 3- {2- [7- (4-methylpyridin-2-ylamino) heptanoylamino] acetylamino} -3- (3-nitrophenyl) propionic acid,

trifluoroacetate 3- {2- [7- (4-methylpyridin-2-ylamino) heptanoylamino] acetylamino} -3- (3-nitrophenyl) propionic acid, WU 20.98 min, MS-ACU (M + H) ⁺ 486.

Example 18:

Similarly to Example 2, from 5- (pyridin-2-ylamino) pentanoic acid "DE" receive

as a result of reaction with 3- (2-aminoacetylamino) -3- (3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (3-nitro-phenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-chloro-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-chloro-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (4’-fluorobiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (4’-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (4’-fluorobiphenyl-3-yl) propionic acid methyl ester hydrochloride

3- (4’-fluorobiphenyl-3-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (3’-fluorobiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (3’-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (2’-fluorobiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (2’-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (4’-chlorobiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (4’-chlorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (3’-chlorobiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (3’-chlorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (4’-methylbiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (4’-methylbiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- [4 ’- (trifluoromethyl) biphenyl-4-yl] propionic acid methyl ester hydrochloride

3- [4 ’- (trifluoromethyl) biphenyl-4-yl] -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (3'-chloro-4'-fluorobiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (3'-chloro-4'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-amino-acetylamino) -3- (4-naphthalen-1-yl-phenyl) -propionic acid methyl ester hydrochloride

3- (4-naphthalen-1-yl-phenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-amino-acetylamino) -3- (4-naphthalen-2-yl-phenyl) -propionic acid methyl ester hydrochloride

3- (4-naphthalen-2-yl-phenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester or

by reaction with 3- (2-amino-acetylamino) -3- (4'-fluoro-2-hydroxybiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (4'-fluoro-2-hydroxybiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methyl ester.

Example 19:

After saponification of methyl esters of the compounds of Example 18, similarly to Example 2 (4),

3- (3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

sodium salt of 3- (3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, WU * 16.07 min, MC-WUA (M + H) ⁺ 444;

3- (4-chloro-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

sodium salt of 3- (4-chloro-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

trifluoroacetate 3- (4-chloro-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid, WU * 18.67 min, MC-WUA (M + H) ⁺ 478;

3- (4'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino trifluoroacetate trifluoroacetate, VU 24.66 min, MS-ACU (M + H) ⁺ 493;

3- (4'-fluorobiphenyl-3-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4'-fluorobiphenyl-3-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4'-fluorobiphenyl-3-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, VU 25.36 min, MS-ACU (M + H) ⁺ 493;

3- (3'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (3'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (3'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, MS-BUA (M + H) ⁺ 493;

3- (2'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (2'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (2'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, MS-BUA (M + H) ⁺ 493;

3- (4'-chlorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4'-chlorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4'-chlorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, MS-BCA (M + H) ⁺ 510;

3- (3'-chlorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (3'-chlorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (3'-chlorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, MS-ACU (M + H) ⁺ 510;

3- (4'-methylbiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4'-methylbiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4'-methylbiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, MS-BUA (M + H) ⁺ 489;

3- [4 '- (trifluoromethyl) biphenyl-4-yl] -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- [4 '- (trifluoromethyl) biphenyl-4-yl] -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- [4 '- (trifluoromethyl) biphenyl-4-yl] -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, MS-BUA (M + H) ⁺ 543;

3- (3'-chloro-4'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (3'-chloro-4'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (3'-chloro-4'-fluorobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, MS-BUA (M + H) ⁺ 527;

3- (4-naphthalen-1-ylphenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-naphthalen-1-yl-phenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4-naphthalen-1-yl-phenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate, VU * 24.91 min, MS-ACU (M + H) ⁺ 525;

3- (4-naphthalen-2-yl-phenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4-naphthalen-2-yl-phenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4-naphthalen-2-yl-phenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate or

3- (4'-fluoro-2-hydroxybiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid,

3- (4'-fluoro-2-hydroxybiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid sodium salt,

3- (4'-fluoro-2-hydroxybiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid trifluoroacetate.

Example 20:

Similarly to Example 2, from 4- (pyridin-2-ylamino) butyric acid "CD" get

as a result of reaction with 3- (2-aminoacetylamino) -3- (3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-chloro-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- (4-chloro-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (4'-fluorobiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (4'-fluorobiphenyl-4-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (4'-fluorobiphenyl-3-yl) propionic acid methyl ester hydrochloride

3- (4'-fluorobiphenyl-3-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-amino-acetylamino) -3- (4-naphthalen-1-yl-phenyl) -propionic acid methyl ester hydrochloride

3- (4-naphthalen-1-yl-phenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (2-hydroxy-4-naphthalen-1-ylphenyl) propionic acid methyl ester hydrochloride

3- (4-naphthalen-1-yl-2-hydroxyphenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester or

as a result of reaction with 3- (2-amino-acetylamino) -3- (2-hydroxybiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (2-hydroxybiphenyl-4-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester.

Example 21:

After saponification of methyl esters of the compounds of Example 20, similarly to Example 2 (4),

3- (3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU * 15.50 min, MC-WUA (M + H) ⁺ 430;

3- (4-chloro-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

sodium salt of 3- (4-chloro-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

trifluoroacetate 3- (4-chloro-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid, WU * 18.31, MS-WUA (M + H) ⁺ 464;

3- (4'-fluorobiphenyl-4-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4'-fluorobiphenyl-4-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (4'-fluorobiphenyl-4-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU 24.53, MS-ACU (M + H) ⁺ 479;

3- (4'-fluorobiphenyl-3-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4'-fluorobiphenyl-3-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (4'-fluorobiphenyl-3-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU 25.06, MS-ACU (M + H) ⁺ 479;

3- (4-naphthalen-1-ylphenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-naphthalen-1-yl-phenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (4-naphthalen-1-yl-phenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU * 24.80, MS-WUA (M + H) ⁺ 511;

3- (4-naphthalen-1-yl-2-hydroxyphenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4-naphthalen-1-yl-2-hydroxyphenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (4-naphthalen-1-yl-2-hydroxyphenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate or

3- (2-hydroxybiphenyl-4-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (2-hydroxybiphenyl-4-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (2-hydroxybiphenyl-4-yl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate.

Example 22:

Similarly to Example 2, from 4- (4-methylpyridin-2-ylamino) butyric acid "AB" get

as a result of reaction with 3- (2-aminoacetylamino) -3- (4-nitrophenyl) propionic acid methyl ester hydrochloride

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-nitrophenyl) propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (3-nitro-2-hydroxyphenyl) propionic acid methyl ester hydrochloride

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitro-2-hydroxyphenyl) propionic acid methyl ester;

as a result of reaction with 3- (2-amino-acetylamino) -3- (4-chloro-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (4'-fluorobiphenyl-3-yl) propionic acid methyl ester hydrochloride

3- (4'-fluorobiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (4'-fluorobiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (4'-fluorobiphenyl-4-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-amino-acetylamino) -3- (4-naphthalen-1-yl-phenyl) -propionic acid methyl ester hydrochloride

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-1-ylphenyl) propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (4-naphthalen-1-yl-2-hydroxyphenyl) propionic acid methyl ester hydrochloride

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-1-yl-2-hydroxyphenyl) propionic acid methyl ester;

as a result of reaction with 3- (2-aminoacetylamino) -3- (5-bromo-2-hydroxy-3-nitrophenyl) propionic acid methyl ester hydrochloride

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (5-bromo-2-hydroxy-3-nitrophenyl) propionic acid methyl ester;

by reaction with 3- (2-amino-acetylamino) -3- (4-naphthalen-2-yl-phenyl) -propionic acid methyl ester hydrochloride

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-2-ylphenyl) propionic acid methyl ester;

as a result of reaction with 3- (2-amino-acetylamino) -3- (4'-fluoro-2'-hydroxybiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (4'-fluoro-2'-hydroxybiphenyl-4-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester;

by reaction with 3- (2-aminoacetylamino) -3- (4'-fluoro-2'-hydroxybiphenyl-3-yl) propionic acid methyl ester hydrochloride

3- (4'-fluoro-2'-hydroxybiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester or

as a result of reaction with 3- (2-amino-acetylamino) -3- (2-hydroxybiphenyl-4-yl) propionic acid methyl ester hydrochloride

3- (2-hydroxybiphenyl-4-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid methyl ester.

Example 23:

After saponification of methyl esters of the compounds of Example 22, similarly to Example 2 (4),

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-nitrophenyl) propionic acid,

sodium salt of 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-nitrophenyl) propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-nitrophenyl) propionic acid trifluoroacetate;

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitro-2-hydroxyphenyl) propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitro-2-hydroxyphenyl) propionic acid sodium salt,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitro-2-hydroxyphenyl) propionic acid trifluoroacetate;

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid,

sodium salt of 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid,

trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-chloro-3-nitrophenyl) propionic acid, WU 21.44 min, MS-ACU (M + H ) ⁺ 478;

3- (4'-fluorobiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4'-fluorobiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (4'-fluorobiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate, WU 26.32 min, MS-ACU (M + H) ⁺ 493;

3- (4'-fluorobiphenyl-4-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4'-fluorobiphenyl-4-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (4'-fluorobiphenyl-4-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate;

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalene-1-phenyl) propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-1-ylphenyl) propionic acid sodium salt,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-1-ylphenyl) propionic acid trifluoroacetate, VU * 25.44 min, MS-ACU (M + H) ⁺ 525;

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalene-1-yl-2-hydroxyphenyl) propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-1-yl-2-hydroxyphenyl) propionic acid sodium salt,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-1-yl-2-hydroxyphenyl) propionic acid trifluoroacetate;

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (5-bromo-2-hydroxy-3-nitrophenyl) propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (5-bromo-2-hydroxy-3-nitrophenyl) propionic acid sodium salt,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (5-bromo-2-hydroxy-3-nitrophenyl) propionic acid trifluoroacetate;

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-2-ylphenyl) propionic acid,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-2-ylphenyl) propionic acid sodium salt,

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-naphthalen-2-ylphenyl) propionic acid trifluoroacetate;

3- (4'-fluoro-2'-hydroxybiphenyl-4-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4'-fluoro-2'-hydroxybiphenyl-4-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (4'-fluoro-2'-hydroxybiphenyl-4-yl) -3- {2- {4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate;

3- (4'-fluoro-2'-hydroxybiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (4'-fluoro-2'-hydroxybiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (4'-fluoro-2'-hydroxybiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate or

3- (2-hydroxybiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid,

3- (2-hydroxybiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid sodium salt,

3- (2-hydroxybiphenyl-3-yl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid trifluoroacetate.

Example 24:

1. Hydrochlorides

1 mmol of trifluoroacetate 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid from Example 6 was dissolved in 10 ml of water and 0.1% was added dropwise. HCl solution. The solution is freeze dried. The operation is repeated several times.

Receive 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid hydrochloride, WU * 17.53 min, MS-ACU (M + H) ⁺ 458.

Similarly from

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid trifluoroacetate from Example 4 was prepared

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid hydrochloride, WU 15.13 min, MS-ACU (M + H) ⁺ 444.

2. Amphions

The corresponding addition of caustic soda solution similarly to Example 2 (4) contributes to the precipitation of amphion. The amphion corresponding to a compound such as 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid has the following analytical characteristics:

VU * 17.53 min, MS-ACU (M + H) ⁺ , mp 221-222 °.

The amphion corresponding to a compound such as 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid has the following analytical characteristics:

WU * 17.01 min, MS-BUA (M + H) ⁺ 444, mp 212-213 °.

3. Methanesulfonates

1 mmol of trifluoroacetate 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid from Example 6 was dissolved in 10 ml of water and methanesulfonic acid was added dropwise. The solution is freeze dried. 3- (3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid methanesulfonate is obtained.

Similarly from

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid trifluoroacetate from Example 4 was prepared

3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid methanesulfonate, WU * 17.07 min, MS-WUA (M + H) ⁺ 444 .

Example 25:

(1) 0.06 moles of 3-nitrobenzaldehyde, 5.72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol are refluxed for 8 hours and stirred overnight at room temperature. Then the cooled reaction mixture is suctioned off, washed with ethanol and ether, and dried in air. Get 3-amino-3- (3-nitrophenyl) propionic acid.

Subsequent N-acylation using phenylacetyl chloride under standard conditions produces 3- (3-nitrophenyl) -3-phenylacetylaminopropionic acid. This racemate is dissolved in 40 ml of water, after which the pH value of the solution with potassium hydroxide is stabilized at around 7.5. The enzyme penicillinamidase is added and shaken for 3 days. After separation of the enzyme by filtration and processing in the usual manner, (R) -3-amino-3- (3-nitrophenyl) propionic acid and (S) -3- (3-nitrophenyl) -3-phenylacetylaminopropionic acid are obtained.

(R) -3-amino-3- (3-nitrophenyl) propionic acid is similar to Example 2, activated with thionyl chloride and reacted with methanol under standard conditions, esterified to 3-amino-3- (3-nitrophenyl) propionic acid methyl ester and reacted with BOC-Gly-OH, 4- (4-methylpyridin-2-ylamino) butyric acid. As a result of ester cleavage, (R) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid is obtained.

If excess NaOH is used, the (R) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid sodium salt is obtained.

Using preparative HPLC, (R) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid trifluoroacetate is obtained, W * 16.89 min, MS -BUA (M + H) ⁺ 444.

(S) -3- (3-Nitrophenyl) -3-phenylacetylaminopropionic acid is treated with 10 ml of a solution of 6 N. HCl. Receive (S) -3-amino-3- (3-nitrophenyl) propionic acid, which, like the R-enantiomers, is subjected to further reactions. Receive

(S) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid,

the sodium salt of (S) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid,

trifluoroacetate (S) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid, WU * 16.89 min, MS-ACU (M + H) ⁺ 444.

Example 26: Prodrugs

1. As a result of the esterification of 3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid by activation with thionyl chloride and reaction with ethanol under standard conditions 3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid ethyl ester hydrochloride is formed, WU 27.95, MS-ACU ( M + H) ⁺ 520.

Similarly, as a result of esterification and subsequent preparative HPLC,

when processing 3- (4-chloro-3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid

3- (4-chloro-3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid ethyl ester trifluoroacetate, WU 27.57, MS-BUA (M + H) ⁺ 506;

when processing 3- (4-chloro-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid

3- (4-chloro-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid ethyl ester trifluoroacetate, WU * 15.29, MS-BUA (M + H) ⁺ 492;

in the treatment of (R) -3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid

(R) -3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid ethyl ester trifluoroacetate, WU * 20.61, MS-BUA ( M + H) ⁺ 472;

in the processing of (S) -3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid

(S) -3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid ethyl ester trifluoroacetate, VU * 20.61, MS-BUA ( M + H) ⁺ 472;

when processing 3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid

3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid ethyl ester hydrochloride, WU 27.95, MS-BUA (M + H) ⁺ 520 or

in the processing of 3- (4'-fluorobiphenyl-3-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid

3- (4'-fluorobiphenyl-3-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid ethyl ester trifluoroacetate, WU 30.26, MS-BUA (M + H) ⁺ 521.

2. As a result of the esterification of 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid by activation with thionyl chloride and reaction with tert.-butanol in standard Under conditions with subsequent preparative HPLC, 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid tert.-butyl ester trifluoroacetate forms, WU 27.20 , MS-BUA (M + H) ⁺ 500.

Similarly, through esterification receive

propanol

3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid propyl ester trifluoroacetate, WU * 22.24, MS-ACU (M + H) ⁺ 486;

isopropanol

3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid isopropyl ester trifluoroacetate, VU * 22.03, MS-ACU (M + H) ⁺ 486 or

butanol

3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid butyl ester trifluoroacetate, VU * 24.00, MS-ACU (M + H) ⁺ 500.

3. The introduction of 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid in the reaction with 2,2-dimethylpropionic acid chloromethyl ester in standard conditions with subsequent preparative HPLC, 3- {2- [4- (4-methyl-pyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionyloxymethyl ester of 2,2-dimethylpropionic acid trifluoroacetate is formed, WU 69, 68, MS-BUA (M + H) ⁺ 558.

4. The reaction of 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid with diethylene glycol under standard conditions followed by preparative HPLC results in the formation of complex glycol trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid ester.

5. The reaction of 3- (3-nitrophenyl) -3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} propionic acid with benzyl alcohol under standard conditions followed by preparative HPLC gives complex trifluoroacetate 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (3-nitrophenyl) propionic acid benzyl ester.

Example 27: Tests

In the tumor angiogenic blood vessels, the presence of integrin αvβ3 is clearly traced, which makes it possible to purposefully identify them using αvβ3-specific inhibitors.

It is possible, using the analysis method, to identify cell lines from human tumors in which, instead of integrin αvβ3, one can detect integrin αvβ6, for example, Detroit 562, HT-29 or UCLA-P3, or those including both integrins αvβ3 and αvβ6, for example, Ca1u- 3 and Saran-2. (Analysis method: immunoprecipitation and fluorescence-activated cell sorting analysis). These identified cell lines grow in rodent organisms with reduced immunity, e.g. nu / nu mice, like subcutaneous tumors.

As described above, the blocking of tumor growth integrin αvβ3 receptor inhibitors occurs by the fact that the blood vessels that have grown in the tumor begin to receive apoptotic signals leading to their programmed death (apoptosis). (Lit.: R.S. Brooks, Eur. J. Cancer 1996, 32A, 2423-2429, PC Brooks et al., Cell 1994, 79, 1157-1164 or S. Stomblad et al., J. Clin. Invest 1996, 98, 426-433.)

Integrin αvβ6 inhibitors act directly on tumor development. The synergistic effect of the combination therapy of the present invention is documented using the following series of tests, similar to the test systems developed by Mitjans et al., J. Cell. Sci. 1995, 108, 2825-2838: tumor cells expressing αvβ6 are implanted subcutaneously, e.g. in nu / nu mice. In the same way as in the case of the M21 Mitjans et al. Cell line, the dependence of the growth of these tumor cells in mice on the use of various integrin inhibitors is studied.

After implantation of tumor cells of mice thus prepared, they are isolated from the rest and divided into groups of 10 animals. The mice of this invention are treated daily by administering an intraperitoneal injection of an appropriate integrin inhibitor, observing tumor growth. The control group receives injections of sterile saline solution without pyrogen content. The size of the tumor is measured twice a week and its volume is calculated in accordance with the results.

The following examples relate to pharmaceuticals:

Example A: Injection Vials

Using 2 n. hydrochloric acid, a pH of a solution of 100 g of the active substance of formula I and 5 g of secondary acidic sodium phosphate in 3 l of double-distilled water is stabilized at around 6.5, sterilized by filtration, poured into injection bottles, lyophilized under sterile conditions and sterilely sealed. Each injection vial contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of the active substance of formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example B: Solution

A solution is prepared from 1 g of the active substance of the formula I, 9.38 g of NaH ₂ PO ₄ · 2H ₂ O, 28.48 g of Na ₂ HPO ₄ · 12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of twice distilled water. The pH of the solution is stabilized at around 6.8, supplemented to 1 liter and sterilized by radiation. This solution can be used in the form of eye drops.

Example D: Ointment

500 mg of the active ingredient of the formula I are mixed under aseptic conditions with 99.5 g of petroleum jelly.

Example D: Tablets

A mixture of 1 kg of the active substance of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate are pressed into tablets in the usual way, each of which contains 10 mg of the active substance.

Example E: Dragee

Similarly to Example D, tablets are pressed, after which they are coated in a conventional manner with a coating containing sucrose, potato starch, talc, tragacanth and dye.

Example G: Capsules

2 kg of the active substance of the formula I are filled in the usual manner on hard gelatin capsules, each of which contains 20 mg of the active substance.

Example 3: Ampoules

A solution of 1 kg of the active substance of formula I in 60 l of twice distilled water is sterilized by filtration, poured into ampoules, lyophilized under sterile conditions and sterilely sealed. Each ampoule contains 10 mg of active substance.

Example I: Inhalation aerosol

14 g of the active substance of formula I are dissolved in 10 l of isotonic NaCl solution, after which the resulting solution is poured into standard aerosol containers with a pump mechanism. The solution can be sprayed into the oral or nasal cavity. A single spray of aerosol (approximately 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims (7)

1. The compounds of formula I

in which Q ₁ or Q ₃ independently from each other denote CH or N, while they cannot simultaneously mean N; R ¹ represents H, A, Ar or Hal; R ² is H or A,

each of R ⁴ and R ^5, independently of the other, is H, A or Hal; R ⁶ represents H or A; A denotes alkyl with 1-6 carbon atoms; Ar is unsubstituted aryl; Hal is F, Cl, Br or 1; n is 2, 3, 4, 5 or 6; m is 1, 2, 3 or 4, as well as their physiologically acceptable salts and solvates. 2. The compounds according to claim 1 (a) 3- (4-methyl-3-nitrophenyl) -3- {2- [4- (pyridin-2-ylamino) butyrylamino] acetylamino} propionic acid, (b) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid, (c) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid, (d) 3- (2-nitrophenyl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid, (e) 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (2-nitrophenyl) propionic acid, (e) 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (2-nitrophenyl) propionic acid, (g) 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid, (h) 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (4-trifluoromethoxyphenyl) propionic acid, (i) 3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} -3- (3-trifluoromethoxyphenyl) propionic acid, (k) 3- {2- [4- (4-methylpyridin-2-ylamino) butyrylamino] acetylamino} -3- (biphenyl-4-yl) propionic acid, (l) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (6-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid, (m) 3- (4-chloro-3-nitrophenyl) -3- {2- [5- (4-methylpyridin-2-ylamino) pentanoylamino] acetylamino} propionic acid or (m) 3- (4-methyl-3-nitrophenyl) -3- {2- [5- (pyrimidin-2-ylamino) pentanoylamino] acetylamino} propionic acid. 3. The method of obtaining compounds of formula I according to claim 1, as well as their salts and solvates, by reacting a compound of formula II

in which Q ₁ , Q ₃ , and R ¹ and n have the meanings indicated in claim 1, with a compound of formula III

in which R ² , R ³ and R ⁶ have the meanings given in claim 1 and, if necessary, the radical R ⁶ ≠ H is converted to the radical R ⁶ = H, or in the compound of formula I one or more radicals R ¹ , R ² , R ³ , R ⁴ and / or R ^{5 are} converted to one or more radicals R ¹ , R ² , R ³ , R ⁴ and / or R ⁵ , for example, vi) alkylation of a hydroxyl group, vii) hydrolysis of an ether group to a carboxyl group, viii) esterification of a carboxyl group, ix) alkylation of an amino group or x) acylation of an amino group, and / or a basic or acidic compound of the formula I is converted by treatment with an acid or a base into one (one) of its salts or a salt cotton wool. 4. The method of obtaining compounds of formula I according to claim 1, as well as their salts and solvates by reacting a compound of formula IV

in which Q ₁ , Q ₃ , R ¹ , R ² and n have the meanings indicated in claim 1, with a compound of formula V

in which R ³ and R ⁶ have the meanings specified in claim 1 of the claims, and, if necessary, the radical R ⁶ ≠ H is converted to the radical R ⁶ = H, or in the compound of the formula I one or more radicals R ¹ , R ² , R ³ , R ⁴ and / or R ^{5 are} converted to one or more radicals R ¹ , R ² , R ³ , R ⁴ and / or R ⁵ by, for example, vi) alkylating a hydroxyl group, vii) hydrolyzing an ether group to a carboxyl group, viii) esterifying a carboxyl group, ix) alkylating an amino group or x) acylating an amino group, and / or a basic or acidic compound of the formula I is converted by treatment with an acid or a base into one (one) of its salts or a salt cotton wool. 5. The compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates as active substances in a pharmaceutical preparation having the properties of an integrin inhibitor. 6. The compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates as integrin inhibitors. 7. A pharmaceutical preparation having the properties of an integrin inhibitor, containing at least one compound of formula I according to claim 1 and / or one (one) of its physiologically acceptable salts or solvates.