Inhibitors of factor viia

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

 

The present invention relates to compounds of formula I,

in which R1, R2, R91, R92, R93, R94, R95, R96, R97, r, s and t have the values listed below. The compounds of formula I are useful pharmacologically active compounds. They have a potent antithrombotic effect and are suitable for the treatment and prevention of thromboembolic disease and restenosis. They are reversible inhibitors of the enzyme of the blood coagulation factor VIIa (F VIIa) and can basically be applied in cases where an undesired activity of factor VIIa, or States, for the treatment and prevention which may be useful in the inhibition of factor VIIa. In addition, this invention relates to methods of preparing compounds of the formula I, their use, in particular as active ingredients of drugs, and to include their medicines.

The ability to form blood clots is vital. The formation of a blood clot or thrombus is usually the result of tissue damage, which triggers the coagulation cascade, and has the effect of slowing or preventing bleeding in the cure of wounds. Other factors that directly is not directly associated with tissue damage, such as atherosclerosis and inflammation, can also initiate the coagulation cascade. Typically, there is a correlation between inflammation and coagulation cascade. The inflammatory mediators regulate the coagulation cascade, and the components of coagulation affect the production and activity of inflammatory mediators. However, under certain conditions the formation of blood clots in the circulatory system reaches an undesirable degree and is a source of painful conditions, potentially leading to pathological consequences. However, under such conditions it is undesirable to completely inhibit the blood clotting system, as this may cause bleeding, representing a threat to life. In the treatment of these conditions requires a well-balanced intervention in the blood clotting system, and there is still a need for substances exhibiting appropriate to achieve such a result pharmacological activity.

Coagulation of blood is a complex process involving gradually expanding series of reactions the activation of enzymes, in which Imogene plasma sequentially activated by limited proteolysis. Mechanical cascade of blood coagulation is divided into internal and external paths that converge in the activation of factor X. After the respective formation of thrombin flows through a single common path (see scheme 1). These facts suggest that the internal path plays an important role in maintaining and growing the formation of fibrin, whereas the inner path plays an important role in the initiation phase of coagulation of blood (.Cole, Aust. J.Med. Sci. 16 (1995) 87-93; G.J.Broze, Blood Coagulation and Fibrinolysis 6, Suppl. 1 (1995) S7-S13). Usually consider that the coagulation of blood physically initiated the formation of a complex of factor VIIa/tissue factor (TF). After the formation of this complex is rapidly initiates coagulation via activation of factors IX and X. the Newly-formed activated factor X, for example, factor XA, and then forms a one-to-one complex with factor Va and phospholipids with education prothrombinase complex, which is responsible for the conversion of soluble fibrinogen into insoluble fibrin by activated thrombin from its precursor prothrombin. Over time, the activity of a complex of factor VIIa/tissue factor (outer path) is suppressed under the action of the protein, protease inhibitor type Marten (Kunitz), TFPI, which in the formation of a complex with factor XA can directly inhibit the proteolytic activity of a complex of factor VIIa/tissue factor.

Figure 1: the Cascade of blood coagulation

To maintain the process of coagulation is inhibited when the external system is an additional factor Ha produceres is by thrombin-mediated activity in the inner path. Thus, thrombin plays a dual autocatalytic role Poreba its own products and the conversion of fibrinogen to fibrin. Autocatalytic nature of the formation of thrombin is an important protection against uncontrolled bleeding and ensures that if this threshold coagulation of blood will be completely. Thus, it is most desirable to develop agents that inhibit coagulation, not directly inhibiting thrombin, but inhibiting other stages of the coagulation cascade, such as the activity of factor VIIa.

In many clinical applications, there is an urgent need to prevent the formation of blood clots inside blood vessels, or in the treatment of certain anticoagulants. For example, approximately 50% of patients undergoing a complete replacement of hips, develops a thrombosis of deep veins (DVT). Currently available drugs, such as heparin and its derivatives do not satisfy the existing needs of many specific clinical applications. Approved at present therapies include the use of low molecular weight heparin (LMWH) in a xed-dose heparin in varying doses. Even when such modes drug in 10%-20% of patients developing DVT, and 5%-10% develop complications, is provided with internal bleeding.

Another clinical situation in which you require an improved anticoagulants, for subjects undergoing coronary intraluminal angioplasty and subjects with risk of myocardial infarction or who suffer from angina occurring with increasing frequency, intensity and duration. Now usually accepted therapy, which consists in the introduction of heparin and aspirin is associated with a 6-8% frequency of sudden blockage of blood vessels within 24 hours of the procedure. The frequency associated with bleeding complications after the use of heparin, require treatment with blood transfusion is approximately 7%. In addition, even though the number of detainees occlusions is significant, the introduction of heparin after the procedure is of no great value and may be harmful.

Widely used inhibitors of blood coagulation, such as heparin and related sulfated polysaccharides, such as LMWH and heparansulfate, exert their anticoagulant effects by stimulating the binding of the natural regulator of the coagulation process, anti-thrombin III, thrombin and factor XA. The inhibitory activity of heparin is mainly aimed at thrombin, which is inactivated in approximately 100 times faster than a factor of CA. Hir is Dean and hirulog are two additional thrombin-specific anticoagulant currently undergoing clinical trials. However, these anticoagulants that inhibit thrombin can also cause associated with bleeding complications. Preclinical studies in monkeys and dogs have shown that, if targets are enzymes that are included in the early stages of the coagulation cascade, such as factor XA or factor VIIa, preventing the formation of clots occurs without associated bleeding side effects that are observed when the effect of direct thrombin inhibitors (L.A.Marker et al., Thromb. Hemostas. 74 (1995) 464-472). Some peptides and peptide analogs that inhibit blood clotting by specific inhibition of factor XA are disclosed, for example, in WO-A-95/29189.

Specific inhibition of the catalytic complex of factor VIIa/tissue factor with monoclonal antibodies (WO-A-92/06711) or protein such as an inactivated by the action of chloromethylketone factor VIIa (WO-A-96/12800 and WO-A-97/47651) is extremely effective suppression of thrombus formation caused by severe damage to the arteries, or thrombotic complications associated with bacterial septicemia. There are also experimental evidence suggesting that the inhibition of the activity of factor VIIa/tissue factor inhibits restenosis occurring after angioplasty IP is by the use of the container (L.A.Marker et al., Haemostasis 26 (1996) S1:76-82). Of bleeding studies conducted on monkeys showed that inhibition of the complex of factor VIIa/tissue factor has the widest range of security regarding therapeutic efficacy and the risk of bleeding of any investigational approach using anticoagulant, including the inhibition of thrombin, the aggregation of platelets and factor XA (L.A.Harker et al., Thromb. Hemostas. 74 (1995) 464-472).

Specific inhibitor of factor VIIa, which has a favorable profile of properties can have great practical importance in medical practice. In particular, the inhibitor of factor VIIa can be effective when used at the present time medications such as heparin and related sulfated polysaccharides are inefficient or ineffective. Some inhibitors of factor VIIa have already been described, for example, in WO-A-89/09612. EP-A-987274 discloses compounds containing Tripeptide unit, which inhibits factor VIIa. However, the property profile of these compounds is not yet perfect, and there is a need for additional low molecular weight inhibitors of blood clotting specific to factor VIIa, which are effective and do not cause unwanted side effects. The present invention satisfies this need by before the provision of new compounds of the formula I, inhibiting the activity of factor VIIa.

Thus, the object of the present invention are the compounds of formula I,

where r denotes 0, 1, 2 or 3;

s denotes 0, 1, 2, 3 or 4;

t denotes 0, 1 or 2;

R1selected from the group comprising hydrogen, R11-CO - and R12-SO2-;

R11selected from the group comprising hydrogen, (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het-, Het-(C1-C4)-alkyl, (C1-C8)-alkyloxy-, (C6-C14)-aryloxy-, (C6-C14)-aryl-(C1-C4)-alkyloxy-, amino, (C1-C8)-alkylamino-, (C6-C14)-arylamino - and (C6-C14)-aryl-(C1-C4)-alkylamino-where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R12selected from the group comprising (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het-, Het-(C1-C4)-alkyl-, di((C1-C8)-alkyl)amino and di((C6-C14)aryl-(C1-C4)-alkyl)amino, where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R2putting the AET hydrogen, R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)nor R25(R26)N-CO-(CH2)p-D-(CH2)q-where D denotes the divalent residue-C(R31)(R32)-, bivalent (C6-C14)-Allenby residue or a divalent residue derived from an aromatic group Het, containing from 5 to 10 atoms in the cycle, of which 1, 2, 3 or 4 are the same or different heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, and the numbers k, m, n, p and q, which are independent from each other and can be identical or different, are 0, 1, 2, 3, 4, or 5, provided that if D denotes-C(R31) (R32- the sum of m+n cannot be equal to 0 and the sum of p+q cannot be equal to 0;

R21and R22that are independent of each other and can be identical or different, selected from the group comprising hydrogen, (C1-C12)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het and Het-(C1-C4)-alkyl-, where all these groups are unsubstituted or substituted by one or more identical or different substituents from the group comprising R40, (C1-C8)-alkylamino-, di-((C1-C8)-alkyl)-amino, (C6-C14)-aryl-(C1-C4 )-alkylamino-, (C6-C14)-arylamino, aminocarbonyl and aminocarbonyl-(C1-C8)-alkyl-, or R21and R22together with the carbon atom to which they are linked, form a saturated or unsaturated 3-8-membered carbocyclic structure, which may be condensed with one or two cyclic systems, which represents a heteroaromatic cycles containing from 5 to 10 atoms in the cycle, of which 1, 2 or 3 are identical or different heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, and/or (C6-C10) carbocyclic aromatic structure, where the resulting group R21(R22CR is unsubstituted or substituted by one or more identical or different substituents selected from the group comprising R40, (C1-C8)-alkylamino-, di-((C1-C8)-alkyl)-amino, (C6-C14)-aryl-(C1-C4)-alkylamino-, (C6-C14)-arylamino, aminocarbonyl and aminocarbonyl-(C1-C8)-alkyl-;

R23denotes hydrogen, R27-SO2or R28-CO-;

R24selected from the group comprising hydrogen, (C1-C8)-alkyl, (C6-C14)-aryl and (C6-C14)-aryl-(C1-C4)-alkyl-;

R25and R26who are independent from each other, and may be the same or different, selected from the group comprising hydrogen, (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het and Het-(C1-C4)-alkyl-, where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R27selected from the group comprising (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het-, Het-(C1-C4)-alkyl-, amino, (C1-C8)-alkylamino-, di-((C1-C8)-alkyl) amino-, (C6-C14)-arylamino and (C6-C14)-aryl-(C1-C4)-alkylamino-where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R28selected from the group comprising R27, (C1-C8)-alkyloxy-, (C6-C14)-aryloxy - and (C6-C14)-aryl-(C1-C4)-alkyloxy-where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R31and R32that are independent of each other and can be identical or different, are selected from the group comprising hydrogen, (C1-C12)-alkyl, (C6-C14)-aryl, (C6-C14 )-aryl-(C1-C4)-alkyl-, Het and Het-(C1-C4)-alkyl-, where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R40selected from the group comprising halogen, hydroxy, (C1-C8)-alkyloxy-, (C6-C14)-aryl-(C1-C8)-alkyloxy-, (C6-C14)-aryloxy-, (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C8)-alkyl, (C1-C8)-alkylsulfonyl, trifluoromethyl, acetylamino, amino, amidino, guanidino, oxo, nitro and cyano, where the group R40are independent from each other and can be identical or different;

R91, R92and R93that are independent of each other and can be identical or different, selected from the group comprising hydrogen, (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het and Het-(C1-C4)-alkyl-;

R94selected from the group comprising (C1-C4)-alkyl, (C6-C14)-aryl, amino, nitro, halogen, trifluoromethyl, hydroxy, (C1-C4)-alkyloxy-where groups R94are independent from each other and can be identical or different;

R95selected from the group comprising amidino, guanidino, ((C1-C4)-alkyl)oxycarbonate-, ((C1-C4)-alkyl)oxycarbonate and hydroxyamino-;

R96selected from the group comprising hydrogen, R98-(C1-C8)-alkyl-, R98-(C1-C8)-aryl-, R98-(C6-C14)aryl-(C1-C4)-alkyl-, R98-Het and R98-Het-(C1-C4)-alkyl-;

R97selected from the group comprising R99-(C1-C8)-alkyl-, R99-(C6-C14)aryl-, R99-(C6-C14)aryl-(C1-C4)-alkyl-, R99-Het and R99-Het-(C1-C4)-alkyl-;

R98and R99that are independent of each other and can be identical or different, selected from the group comprising hydroxycarbonyl-, (C1-C8-allyloxycarbonyl-, (C6-C14-aryloxyalkyl-, (C6-C14)-aryl-(C1-C4-allyloxycarbonyl, aminocarbonyl-, (C1-C8-alkylaminocarbonyl-, tetrazolyl, P(O)(OH)2, -S(O)2OH and-S(O)2NH2;

Het denotes a saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocyclic structure containing 3 to 10 atoms in the cycle, of which 1, 2, 3 or 4 are the same or different heteroatoms selected from the group comprising nitrogen, oxygen and sulfur;

in all their stereoisomeric forms and mixtures thereof in any ratio,and their physiologically acceptable salts.

All residues, which can occur more than once in the compounds of the formula I, for example residues of R40, R94or Het, can independently from each other to have the specified values, and in each case may be the same or different.

In this paper, the term alkyl, which should be understood in its broadest sense, denotes a hydrocarbon residue which may be linear, i.e. remotemachine, or branched, and which may be acyclic or cyclic residues of or include any combination of acyclic and cyclic subunits. In addition, the term alkyl in this document specifically includes saturated group and an unsaturated group, the latter group contain one or more, for example one, two or three double bonds and/or triple bond, provided that the double bond is not localized in cyclic alkyl group with formation of an aromatic system. All these statements are also applicable, if the alkyl group has substituents or occur as substituents on another residue, for example, on alkylarenes balance, allyloxycarbonyl residue or arylalkyl residue. Examples of alkyl residues containing from 1 to 20 carbon atoms, are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, Tetra is ecil, hexadecyl, octadecyl and eicosyl, n-isomers of all data residues, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 2,3,4-trimethylpentyl, Isodecyl, sec-butyl, tert-butyl or tert-pentyl.

Unsaturated alkyl residues are, for example, alkeline residues such as vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl, or alkyline residues, such as ethinyl, 1-PROPYNYL, 2-PROPYNYL (=propargyl) or 2-butynyl. Alkyl residues can also be unsaturated if they are replaced.

Examples of cyclic alkyl residues are cycloalkyl residues containing 3, 4, 5, 6, 7 or 8 carbon atoms in the cycle, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, which can also be substituted and/or unsaturated. Unsaturated cyclic alkyl groups and unsaturated cycloalkyl groups, such as, for example, cyclopentenyl or cyclohexenyl can be connected through any carbon atom. The term alkyl in this document also includes cycloalkyl-substituted alkyl groups, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl-, 1-cyclopropyl the Teal-, 1-cyclobutylmethyl-, 1-cyclopentylmethyl-, 1-cyclohexylethyl - 1-cycloheptylmethyl-, 1-cyclooctylmethyl-, 2-cyclopropylethyl-, 2-cyclobutylmethyl-, 2-cyclopentylmethyl-, 2-cyclohexylethyl-, 2-cycloheptylmethyl-, 2-cyclooctylmethyl-, 3-cyclopropylmethyl, 3-cyclobutylmethyl-, 3-cyclopentylpropionyl, 3-cyclohexylprop-, 3-cycloheptylmethyl-, 3-cyclooctylmethyl - etc. in these groups cycloalkyl subgroup, as well as acyclic subset can also be unsaturated and/or substituted.

Of course, a cyclic alkyl group should contain at least three carbon atoms and an unsaturated alkyl group should contain at least two carbon atoms. Thus, it should be understood that a group such as (C1-C8)-alkyl includes, among others, saturated acyclic (C1-C8)-alkyl, (C3-C8-cycloalkyl, cycloalkyl-alkyl groups, such as (C3-C7-cycloalkyl-(C1-C5)-alkyl-, where the total number of carbon atoms can vary from 4 to 8, and unsaturated (C2-C8)-alkyl such as (C2-C8)-alkenyl or (C2-C8)-quinil. Similarly, it should be understood that a group such as (C1-C4)-alkyl includes, among others, saturated acyclic (C1-C4)-alkyl, (C3-C4-cycloalkyl, cyclopropylmethyl-and nanosys the config, such as (C2-C4)-alkenyl or (C2-C4)-quinil.

If not defined otherwise, the term alkyl preferably includes acyclic saturated hydrocarbon residues containing from 1 to 6 carbon atoms which may be linear or branched, acyclic unsaturated hydrocarbon residues containing from 2 to 6 carbon atoms which may be linear or branched, such as (C2-C6)-alkenyl and (C2-C6)-quinil, and cyclic alkyl groups containing from 3 to 8 carbon atoms in the cycle, particularly, from 3 to 6 carbon atoms in the cycle. Of particular interest saturated acyclic alkyl residues formed such (C1-C4)-alkyl residues as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The above definitions relevant to the alkyl groups, are used not only to monovalent residues, and correspondingly to divalent residues, such as alkadiene group, alkylene group or polymethene group, examples of which include methylene, 1,2-ethylene (=ethane-1,2-diyl), 1,1-ethylene (=1-methyl-methylene), 1-isobutylamine, 1,3-propylene, 2,2-dimethyl-1,3-propylene, 1,4-butylene, but-2-EN-1,4-diyl, 1,2-cyclopropyl, 1,2-cyclohexyl, 1,3-cyclohexyl or 1,4-cyclohexene.

If not on the designated otherwise, and regardless of any specific substituent associated with alkyl groups specified in the definition of compounds of formula I, the alkyl groups generally can be unsubstituted or substituted by one or more, e.g. one, two, three or four identical or different substituents. The substituents of any type present in the substituted alkyl residues can be present in any desired position, provided that the substitution does not lead to the formation of unstable molecules. Examples of substituted alkyl residues are alkyl residues in which one or more, e.g. 1, 2, 3, 4 or 5 hydrogen atoms are replaced by halogen atoms, in particular fluorine atoms.

Examples of substituted cycloalkyl groups are cycloalkyl group, which bear as substituent one or more, e.g. one, two, three or four identical or different acyclic alkyl groups, for example, acyclic (C1-C4)-alkyl groups such as methyl groups. Examples of substituted cycloalkyl groups are 4-methylcyclohexyl, 4-tert-butylcyclohexyl or 2,3-dimethylcyclobutyl.

The term aryl refers to monocyclic or polycyclic hydrocarbon residue which contains at least one carbocyclic structures is, which has a conjugated PI-electron system. In (C6-C14)-aryl residue present from 6 to 14 carbon atoms in the cycle. Examples (C6-C14)-aryl residues are phenyl, naphthyl, biphenylyl, fluorenyl or anthracene. Examples (C6-C10)-aryl residues are phenyl or naphthyl. If not defined otherwise, and irrespective of any specific substituent linked to aryl groups specified in the definition of compounds of formula I, aryl residues, including, for example, phenyl, naphthyl and fluorenyl, as a rule, can be unsubstituted or substituted by one or more, for example one, two, three or four identical or different substituents. Aryl residues can be linked via any desired position, and substituted aryl residues, the substituents can be located in any desirable position.

In monosubstituted phenyl residues Deputy may be in position 2, 3 or 4, and terms 3 and 4 are preferred. If the phenyl group bears two Deputy, they may be in positions 2,3, 2,4, 2,5, 2,6, 3,4-or 3,5. In the phenyl residues, bearing three Deputy, deputies may be in positions 2,3,4, 2,3,5, 2,3,6, 2,4,5, 2,4,6-or 3,4,5. Raftiline residues may represent a 1-naphthyl and 2-naphthyl. In substituted nafti is lnyh residues, the substituents can be in any positions, for example, monosubstituted 1-naftalina residues in positions 2, 3, 4, 5, 6, 7 or 8 and monosubstituted 2-naftalina residues in positions 1, 3, 4, 5, 6, 7 or 8. Biphenylene residues may represent a 2-biphenylyl, 3-biphenylyl or 4-biphenylyl. Fluoroaniline residues may represent a 1-, 2-, 3-, 4 - or 9-fluorenyl. In monosubstituted fluorenyl residues linked through position 9, Deputy preferably present in positions 1, 2, 3, or 4.

Unless otherwise specified, the substituents that may be present in the substituted aryl groups are, for example, (C1-C8)-alkyl, especially (C1-C4)-alkyl, such as methyl, ethyl or tert-butyl, hydroxy, (C1-C8)-alkyloxy, especially, (C1-C4)-alkyloxy, such as methoxy, ethoxy or tert-butoxy, methylenedioxy, Ethylenedioxy, F, Cl, Br, I, cyano, nitro, trifluoromethyl, triptoreline, hydroxymethyl, formyl, acetyl, amino, mono - or di-(C1-C4)-alkylamino, ((C1-C4)-alkyl)carbylamine, such as acetylamino, hydroxycarbonyl, ((C1-C4)-alkyloxy)carbonyl, carbarnoyl, optionally substituted phenyl, benzyl optionally substituted on the phenyl group, optionally substituted, phenoxy, or benzyloxy, optionally substituted on the phenyl group. Substituted aryl group, which is may be in a specific position of the compounds of formula I, can independently from each other aryl group to be substituted by substituents selected from any desired subgroup of the substituents listed before and/or specified in the definition of this group. For example, a substituted aryl group may be substituted by one or more identical or different substituents selected from the group comprising (C1-C4)-alkyl, hydroxy, (C1-C4)-alkyloxy, F, Cl, Br, I, cyano, nitro, trifluoromethyl, amino, phenyl, benzyl, phenoxy and benzyloxy. Preferably, in the compounds of formula I is present not more than two nitro groups.

The above definitions related to aryl groups, respectively, applicable to the divalent residues derived from aryl groups, i.e. to Allenby groups such as phenylenebis, which can be unsubstituted or substituted 1,2-phenylene, 1,3-phenylene or 1,4-phenylene, or neftyanoye, which can be unsubstituted or substituted 1,2-naphthalenediol, 1,3-naphthalenediol, 1,4-naphthalenediol, 1,5-naphthalenediol, 1,6-naphthalenediol, 1,7-naphthalenediol, 1,8-naphthalenediol, 2,3-naphthalenediol, 2,6-naphthalenediol or 2.7-naphthalenediol. The above definition is applicable to aryl subgroup in the group arylalkyl-. Examples of groups arylalkyl-which can also be unsubstituted or substituted what about the aryl group, and alkyl group are benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 1-methyl-3-phenyl-propyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-(1-naphthyl)ethyl, 1-(2-naphthyl)ethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, or 9-fluorenylmethyl. All these formulations can also be applied to aromatic cycles, which can be condensed (or paired) with the loop formed by the groups R21and R22and the carbon atom that is attached to these groups.

The group Het includes groups containing 3, 4, 5, 6, 7, 8, 9 or 10 atoms in a loop in the source monocyclic or bicyclic heterocyclic system. In monocyclic group Het heterocyclic structure, preferably represents a 3-membered, 4-membered, 5-membered, 6-membered or 7-membered cycle, particularly preferably 5-membered or 6-membered cycle. In bicyclic group Het preferably there are two paired cycle, one of which is a 5-membered cycle or 6-membered heterocyclic structure, and the other represents a 5-membered or 6-membered heterocyclic or carbocyclic structure, i.e. bicyclic structure Het preferably contain 8, 9 or 10 atoms in the cycle, particularly preferably 9 or 10 atoms in the loop.

Het includes saturated heterocyclic structure, which is not Saderat cycles of double bonds, as well as monounsaturated and polyunsaturated heterocyclic systems, which contain one or more cycles, for example, one, two, three, four or five double bonds, provided that the resulting system is stable. Unsaturated cycles can be non-aromatic or aromatic, i.e. the double bond in the cyclic structures of the group Het may be located in such a way that the result is a conjugated system of PI electrons. Aromatic cycles in the group Het may represent a 5-membered or 6-membered cycles, i.e. aromatic group in the group Het contain from 5 to 10 atoms in the cycle. Thus, the aromatic cycles in the group Het include 5-membered and 6-membered monocyclic and bicyclic heterocycles heterocycles consisting of two 5-membered cycles, one 5-membered cycle and one 6-membered cycle, or two 6-membered cycles. In bicyclic aromatic groups in the group Het one or both of the loop may contain heteroatoms. Aromatic group Het may also be referred to traditional term heteroaryl, for which, respectively, can be used above and below to Het definitions and wording. All these formulations are also respectively applied to the heteroaromatic cycles, which can be condensed (or paired) with the cycle, educated the groups R 21and R22and the carbon atom that is attached to these groups.

Unless otherwise specified, the groups Het, or any other heterocyclic groups preferably contains 1, 2, 3 or 4 identical or different heteroatoms in the cycle selected from the group comprising atoms of nitrogen, oxygen and sulfur. Particularly preferably, if the data group contains 1 or 2 identical or different heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. Cyclic heteroatoms may be present in any desired number and in any position relative to each other, provided that the obtained heterocyclic system is known in this field and is stable and suitable as a subgroup in a drug substance. Examples of the original structures of heterocycles which can be derived group Het, are aziridine, oxirane, azetidine, pyrrole, furan, thiophene, dioxole, imidazole, pyrazole, oxazole, isoxazol, thiazole, isothiazol, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, Piran, thiopyran, pyridazine, pyrimidine, pyrazin, 1,2-oxazin, 1,3-oxazin, 1,4-oxazin, 1,2-thiazin, 1,3-thiazin, 1,4-thiazin, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine, indole, isoindole, benzofuran, benzothiophene, 1,3-benzodioxol, indazole, benzimidazole, benzoxazole, benzothiazole, quinoline, isoji the Olin, chroman, isochroman, cinnolin, hinzelin, cinoxacin, phthalazine, predominately, perioperative, pyridopyrimidines, purine, pteridine etc. and loop system, obtained from the above heterocycles by pairing (or condensation) with a carbocyclic structure, for example, benzo-conjugate, cyclopent-conjugate, cyclohexa-conjugate or cyclohepta-conjugate derivatives of these heterocycles.

The fact that many of the earlier names heterocycles are chemical names unsaturated or aromatic cyclic systems, does not mean that the group Het may be obtained only from the appropriate unsaturated cyclic system. In this case, the names are used only to describe the cyclic system in accordance with the size of the cycle and the number of heteroatoms, as well as their relative positions. As explained above, the group Het may be saturated or partly unsaturated, or aromatic, and, therefore, can be obtained not only from themselves listed above, heterocycles also from all their partially or completely hydrogenated analogs, as well as from their counterparts with a higher degree of unsaturation, if they are suitable. As examples of fully or partially hydrogenated analogues of the above heterocycles, and the which can be obtained of the group Het, can be mentioned the following groups: pyrrolin, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, dihydropyridines, tetrahydropyridine, piperidine, 1,3-dioxolane, 2-imidazolin, imidazolidin, 4,5-dihydro-1,3-oxazole, 1,3-oxazolidin, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazin (=morpholine), perhydro-1,4-thiazin (=thiomorpholine), peligrosa, indolin, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline and other

The remainder of the Het can be attached via any cyclic carbon atom, and, in the case of nitrogen-containing heterocycles, through any suitable cyclic nitrogen atom. For example, pyrrolidinyl residue may be a 1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, pyrrolidinyl residue may represent 1-pyrrolidinyl (=pyrrolidino), 2-pyrrolidinyl or 3-pyrrolidinyl, peredelnyj residue may be a 2-pyridyl, 3-pyridyl or 4-pyridyl, piperidinyl residue may be a 1-piperidinyl (=piperidino), 2-piperidinyl, 3-piperidinyl or 4-piperidinyl. Furyl can be a 2-furyl or 3-furyl, thienyl can be a 2-thienyl or 3-thienyl, imidazolyl can be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl or 5-imidazolyl, 1,3-oxazolyl can be a 1,3-oxazol-2-yl, 1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,thiazolyl can be a 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl, pyrimidinyl can be a 2-pyrimidinyl, 4-pyrimidinyl (=6-pyrimidinyl) or 5-pyrimidinyl, piperazinil can be a 1-piperazinil (=4-piperazinil=piperazine derivatives) or 2-piperazinil. Indolyl may be a 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl or 7-indolyl. Similarly, the remains of benzimidazolyl, benzoxazolyl and benzothiazolyl can join via position 2 and through any of the positions 4, 5, 6, and 7, benzimidazolyl through position 1. Chinolin can be a 2-chinolin, 3-chinolin, 4-chinolin, 5-chinolin, 6-chinolin, 7-chinolin or 8-chinolin, ethanolic can be a 1-ethanolic, 3-ethanolic, 4-ethanolic, 5-ethanolic, 6-ethanolic, 7-ethanolic or 8-ethanolic. In addition to attaching via any of the provisions specified for chinoline and izochinolina, 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline can also join via the nitrogen atom in position 1 and 2, respectively.

If not defined otherwise, and regardless of any substituents that are associated with groups Het, or any other heterocyclic groups which are indicated in the definition of compounds of formula I, the group Het may be unsubstituted or substituted on the carbon atoms in the cycle one or more, for example one, two, three, four sludge is five identical or different substituents, such as (C1-C8) -alkyl, especially (C1-C4)-alkyl, (C1-C8)-alkyloxy, especially (C1-C4)-alkyloxy, (C1-C4)-alkylthio, halogen, nitro, amino, ((C1-C4)-alkyl)carbylamine, such as acetylamino, trifluoromethyl, triptoreline, hydroxy, oxo, hydroxy-(C1-C4)-alkyl, such as hydroxymethyl or 1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, Ethylenedioxy, formyl, acetyl, cyano, methylsulphonyl, hydroxycarbonyl, aminocarbonyl, (C1-C4-allyloxycarbonyl, optionally substituted phenyl, optionally substituted, phenoxy, benzyl, optionally substituted on the phenyl group, benzyloxy, optionally substituted by phenyl group, and other Substituents may be present in any desired position, provided that the result is a stable molecule. Of course, oxoprop may not be present in the aromatic cycle. Each suitable cyclic nitrogen atom in the group Het independently may be unsubstituted, i.e. to bear a hydrogen atom or may be substituted, i.e. to carry Deputy, such as (C1-C8)-alkyl, for example, (C1-C4)-alkyl, such as methyl or ethyl, optionally substituted phenyl, phenyl-(C1-C4)-alkyl, for example benzyl, optionally substituted by f is Niley group, hydroxy-(C2-C4)-alkyl such as, for example, 2-hydroxyethyl, acetyl or another acyl group, methylsulphonyl or other sulfonyloxy group, aminocarbonyl, (C1-C4-allyloxycarbonyl, and other nitrogen-Containing heterocycles can also be present as N-oxides or as Quaternary salts. Cyclic sulfur atoms may be oxidized to a sulfoxide or to the sulfone. For example, tetrahydroquinoline residue may be present as S,S-dioxotetrahydrofuran residue, or thiomorpholine residue, such as 4-thiomorpholine, may be present as 1-oxo-4-thiomorpholine or 1,1-dioxo-4-thiomorpholine. Substituted group Het, which may be in a certain position of the compounds of formula I can independently of the other group Het can be substituted by substituents selected from any desired subgroup of the substituents listed above, and/or in the definition of this group.

Clarification regarding residue Het, respectively, can be applied to bivalent residues Het, including divalent heteroaromatic residues, which may be connected through any two cyclic carbon atom and in the case of nitrogen-containing heterocycles, through any carbon atom or any suitable nitrogen atom in the cycle, or through any two suitable nitrogen atom. For example, peridiniella about who's headed the remainder may represent a 2,3-pyridinyl, 2,4-pyridinyl, 2,5-pyridinyl, 2,6-pyridinyl, 3,4-pyridinyl or 3.5-pyridinyl and piperidinedione residue may represent, among others, 1,2-piperidinyl, 1,3-piperidinyl, 1,4-piperidinyl, 2,3-piperidinyl, 2,4-piperidinyl or 3.5-piperidinyl and piperazinyl residue may represent, among others, 1,3-piperazinyl, 1,4-piperazinyl, 2,3-piperazinyl, 2,5-piperazinyl, etc. the Above definitions are also respectively applied to the sub-group Het in the groups Het-alkyl-. Examples of such groups Het-alkyl which can be unsubstituted or substituted by subgroup Het, and the alkyl group is (2-pyridyl)methyl, (3-pyridyl)methyl, (4-pyridyl)methyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl or 2-(4-pyridyl)ethyl.

Halogen denotes fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, particularly preferably chlorine or bromine.

Optically active carbon atoms present in the compounds of formula I can independently of each other to have the configuration of R or S. Compounds of formula I may be present in the form of pure enantiomers or pure diastereomers or as mixtures of enantiomers and/or diastereomers, for example in the form of racemates. The present invention relates to the pure enantiomers and mixtures of enantiomers, as well as to pure diastereomers and mixtures dia is teleomeres. This invention includes a mixture of two or more stereoisomers of the formula I, and it includes all ratios of the stereoisomers in the mixtures. If the compounds of formula I can be present as E isomers or Z isomers (or CIS isomers or TRANS isomers), this invention relates both to the pure S-isomers and the pure Z-isomer, and mixtures of E/Z in any ratio. This invention also includes all tautomeric forms of compounds of formula I.

The diastereomers, E/Z isomers, can be separated into the individual isomers, for example, using chromatography. The racemates can be separated into two enantiomers by conventional methods, for example, by chromatography on chiral phases or by crystallization of the diastereomeric salts obtained with optically active acids or bases. Stereochemical homogeneous compounds of formula I can also be obtained by applying a uniform stereochemical initial substances, or by using stereoselective reactions.

The choice of introducing a compound of the formula I building-block configuration R or S, or, in the case of the presence in the compound of formula I amino acid units, the introduction of building-block representing a D-amino acid or L-amino acid, can vary, for example, on the desired characteristics of the connection forms of the crystals I. For example, the introduction of D-amino acid building block can provide increased stability in vitro or in vivo. The introduction of D-amino acid building block may also contribute to the achievement of the desired increase or decrease the pharmacological activity of this compound. In some cases it may be desirable that the connection remained active for only a short period of time. In such cases, the introduction of compound L-amino acid building-block creates the possibility for splitting compounds in vivo under the influence of endogenous peptidases of the subject, thereby limiting the effects of active compounds on the subject. A similar effect can also be observed in the compounds of the present invention as a result of changing the configuration of another building-block from S to R or Vice versa. Taking into account the medical needs, the person skilled in the art can determine the desired characteristics, for example, a suitable stereochemistry, the desired compounds of this invention.

Physiologically acceptable salts of the compounds of formula I are non-toxic salts which are physiologically acceptable, in particular salt used in the pharmaceutical industry. Such salts of compounds of formula I containing an acidic group such as carboxyl group COOH, are, for example, salts of alkaline what's metals or salts of alkaline earth metals, such as salts of sodium, potassium salts, magnesium salts and calcium salts, and salts formed with physiologically acceptable Quaternary ammonium ions, such as Tetramethylammonium or tetraethylammonium, and salts of acid added with ammonia and physiologically acceptable organic amines, such as methylamine, dimethylamine, trimethylamine, ethylamine, triethylamine, ethanolamine or Tris-(2-hydroxyethyl)amine. Basic groups contained in the compounds of the formula I, for example, an amino group, amidinopropane or guanidinium, agents, additive form of an acid salt, for example, such inorganic acids as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with organic carboxylic and sulfonic acids, such as formic acid, acetic acid, oxalic acid, citric acid, lactic acid, malic acid, succinic acid, malonic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonate acid or p-toluensulfonate acid. The compounds of formula I, which simultaneously contain a basic group and an acidic group, for example, amidinopropane and carboxyl groups can also be present in the form of zwitterions (betaines), which are also included within the scope of us who Otsego of the invention.

Salts of compounds of formula I can be obtained using conventional methods known to experts in this field, for example, by combining the compounds of formula I with an inorganic or organic acid or base in a solvent or dispersant, or from other salts by cation or anion exchange. The present invention also includes all salts of the compounds of the formula I which, owing to low physiological tolerability, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediate compounds for further chemical modifications of the compounds of formula I, or as the source of the substance to obtain physiologically acceptable salts.

In addition, the present invention includes all of the solvate of the compounds of the formula I, for example hydrates or adducts with alcohols. The invention also includes derivatives and modifications of the compounds of the formula I, for example, prodrugs, protected forms and other physiologically acceptable derivatives, including esters and amides, as well as active metabolites of compounds of formula I. These esters and amides are, for example, (C1-C4)-alkyl esters, unsubstituted amides or (C1-C4-alkylamide. The invention applies in particular to prolekarstvom and protected forms of the compounds of formula I, which can be converted into the compounds of formula I under physiological conditions. Suitable proletarienne forms of the compounds of formula I, i.e. chemically modified derivatives of the compounds of formula I, having improved the direction of the desired properties, for example with respect to solubility, bioavailability or duration of action, known to specialists in this field. More detailed information regarding proletarienne forms, can be found in the usual literature, such as, for example, Design of Prodrugs, H.Bundgaard (ed.), Eisevier, 1985, Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115-130; or H.Bundgaard, Drugs of the Future 16 (1991) 443, which are all incorporated herein by reference. Suitable proletarienne forms of the compounds of the formula I in particular are ester and amide proletarienne form carboxylic acid groups, acyl groups and urethane proletarienne form capable of acylation of nitrogen-containing groups such as amino groups, amidinopropane and guanidinium. In acyl and urethane proletarienne forms one or more, e.g. one or two hydrogen atoms on the nitrogen atoms of such groups substituted acyl group or a urethane group. Suitable acyl groups and urethane groups to acyl and urethane proletarienne forms are, for example, the group Rp1-CO - and p2O-CO-, in which Rp1denotes hydrogen, (C1-C18)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, (C6-C14)-aryl, Het - (C6-C14)-aryl-(C1-C4)-alkyl - or Het-(C1-C4)-alkyl-, in which Rp2has the meanings given for Rp1with the exception of hydrogen.

On the other hand, the concept of transformation of compounds of formula I in derived or Palekastro the form can also be considered from the point of view of protection or masking of such functional groups as amino, amidinopropane, guanidinium, carboxyl group, etc. that are present in the compound of formula I. As already indicated, the present invention also applies to all protected forms, for which some details below in the examples.

For example, the compounds of this invention may be chemically modified or protected by any of the amino group so that the amino group carries as substituent, for example, acetyl, cyclopentanecarbonyl, allyloxycarbonyl, propylenecarbonate, benzoyl or another such group, the same groups as described above may not necessarily be present for more substituents. The term amino group herein used in a broad sense to denote any ways the Noi to acetylation, amino groups, including primary or secondary amino group. Such amino groups can be, for example, at the N end of the compounds of formula I, or as substituents on the alkyl or aryl groups, or on the side chain of amino acid building blocks, i.e., R96, R97or R2. The term N-end refers to α-amino group of the first amino acid units present in the compound of formula I, written in the traditional manner of presentation of the peptide, i.e. to the group R1(R91)N. Specifically, the N-end compounds of this invention can be protected by associating it with aminosidine group.

The term protective group (or block group) is used herein in a broad sense to refer to traditional chemical group which may substitute the hydrogen atom is present in the amino group, and which is administered by reacting the amino group with aminosidine reagent, including, for example, α-amino group located at the N-end connection of the present invention. Aminosidine group protects other reactive with the amino group against undesirable reactions that can occur, for example, as a result of ectopeptidases on the target compound of formula I, and, for example, during the procedure of synthesis or storage connections. As already mentioned, modifikacia amino group can also provide additional benefits, including, for example, increasing the solubility or bioavailability of the compounds. Various aminosidine groups known in the field and include, for example, acyl groups such as formyl, acetyl, pillola, tert-butylacetyl, tert-butyloxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or benzoline group, and aminoaniline residues, which themselves can be modified using aminosidine group. Other aminosidine groups are described, for example, Gross and Meienhofer (eds.), The Peptides, vol. 3, Academic Press, 1981, or in Greene and Wuts, Protective Groups in Organic Synthesis, 2nd ed., pages 309-405, John Wiley&Sons, 1991, each of which is incorporated herein by reference. The product of any such modification, N-terminal amino group of the compounds of formula I is called the N-terminal derived.

The above statements concerning the protective groups of the amino groups of the compounds of formula I, respectively, are applied to the protective groups Aydinoglu and guanidinium. As the amino group, in these latter groups, which, for example, can represent the residue R95the hydrogen atom may be substituted acyl group, such as, for example, formyl, ((C1-C4)-alkyl)carbonyl, ((C1-C4)-alkyl)oxycarbonyl, (C6-C14-arylcarbamoyl, (C6-C14)-aryl-(C1-C4)-allyloxycarbonyl other, in order to improve the property profile of the compounds of formula I in the desired manner.

Similarly, the compounds of this invention can be chemically modified by any carboxyl group by introducing carboxyamide group. The term protective group (or block group) is also used herein in a broad sense to refer to traditional chemical group that may be substituted for a hydrogen atom, or hydroxyl group, or oxoprop carboxyl group (COOH) or all of carboxyl group. Carboxyl group, which mainly can be present in protected or modified form, may be, for example, as substituents on the alkyl or aryl groups or side chains of amino acid building blocks, i.e., R96, R97and R2. The carboxyl group may be protected or modified, for example, by conventional recovery carboxyl group or its derivative such as an ester, which leads to the formation of an alcohol group SN2HE or aldehyde group Cho, which are bonded to the COOH group. The carboxyl group can also be protected by transformation of the COOH group in the ester group, for example, through the formation of ester suitable for oral administration. When you esters, suitable for oral administration are well known in this field and include, for example, acyloxymethyl esters, such as (C1-C4)-acyloxymethyl esters, such as methoxymethyl, ethoxymethyl, isopropoxyethanol esters and the like; 1-(C1-C4)-alkyloxyaryl esters such as 1-methoxyethoxy, 1-ethoxyethyl, 1-propositional, 1-isopropoxyethanol esters and the like; 2-oxo-1,3-dioxolan-4-ylmethylene esters, such as 5-methyl-2-oxo-1,3-dioxolan-4-ymetray, 5-phenyl-2-oxo-1,3-dioxo-linen-4-ymetray esters and the like; (C1-C4)-alkylthiomethyl esters, such as methylthiomethyl, ethylthiomethyl, isopropylidenedioxy esters and the like; acyloxymethyl esters, such as pivaloyloxymethyl, acetoxymethyl esters and the like; 1-ethoxycarbonylmethyl ester; 1 acyloxy-1-substituted methyl esters, such as 1-ecotoxicology; 3-Caligraphy or 5,6-dimethyl-3-Caligraphy ester; 1-((C1-C4)-allyloxycarbonyl)ethyl esters, such as 1-(ethoxycarbonyl)ethyl ester; and 1-((C1-C4)-alkylaminocarbonyl)ethyl esters, such as 1-(methylaminorex)ethyl ester. The carboxyl group may be the also modified by replacing the entire carboxyl groups such Deputy, as a 2-thiazolyl, tetrazolyl, cyclohexyl or another group. Carboxyamide groups, such as those described above, are well known in the art (see, for example, Greene and Wuts, loc. cit, pages 224-276, which is incorporated herein by reference), and protect the carboxyl group against undesirable reactions, as discussed above with respect aminosidine group.

Structural unit-N(R92)-C(R96)(R97)-CO-present in the compounds of formula I, represents the balance α-amino acids, which is formally obtained from the corresponding α-amino acid by removing a hydrogen atom from the N-terminal amino group and hydroxyl group of the C-terminal carboxyl group, which is the usual procedure in peptide chemistry. Group R9and/or R97can thus be given to the respective groups associated with the Central carbon atom α-amino acids, i.e. if α-monosubstituted α-amino group, R96corresponds to the hydrogen atom attached to the Central carbon atom, and R97corresponds to the side chain of amino acids. As noted below, a structural unit-N(R92)-C(R96)(R97)-CO - may be included in the compounds of formula I using synthetic methods, by applying as a building-block of the corresponding amino acids Faure the uly HN(R 92)-C(R96)(R97)-COOH. Source of amino acids, which can be derived structural unit-N(R92)-C(R96)(R97)-CO-, can be natural or unnatural amino acids, examples of which are Aad, Asn, Asp, Gln, Glu, hGIn or hGlu. Functional group, such amino acids may be in protected form, or can be derivationally. Similarly, unit-N(R91)-CH(-(CH2)-(substituted phenyl))-CO-present in the compounds of formula I, represents the balance α-amino acids.

In addition to the compounds of formula I, the determination of which is described first, second object of the present invention are also the compounds of formula I, in which all residues, the group and the amount determined as described in the beginning, except that the residues R98and R99that in the second embodiment of the present invention are independent from each other and can be identical or different and are selected from the group comprising hydrogen, hydroxycarbonyl-, (C1-C8-allyloxycarbonyl-, (C6-C14-aryloxyalkyl-, (C6-C14)-aryl-(C1-C4-allyloxycarbonyl, aminocarbonyl-, (C1-C8-alkylaminocarbonyl-, tetrazolyl, -P(O)(OH)2, -S(O)2OH, and S(O)2NH2in all their stereoisomeric forms and mixtures in any who's ratios, and their physiologically acceptable salts, provided that, in this second embodiment of the present invention compounds acetyl-(4-amidinophenoxy)-cyclohexylglycine-(4-methylpyridinium)amide, acetyl-(4-amidinophenoxy)-cyclohexylglycine-(2-(3-methylpyridine)ethyl)amide, acetyl-(4-amidinophenoxy)-cyclohexylglycine-(2-(4-methylpyridine)ethyl)amide, acetyl-(4-amidinophenoxy)-cyclohexylglycine-(4-lidinopril)amide, acetyl-(4-amidinopropane)-cyclohexylglycine-(3-lidinopril)amide and acetyl-(4-amidinophenoxy)-cyclohexylglycine-(1-(4-methylpyridine)ethyl)amide are excluded. For this second embodiment of the present invention may be applied to the definition above and below, for example, related to alkyl groups, aryl groups or heterocyclic groups, or salts or stereoisomeric forms of the compounds, as well as related to the preferred values. In this second embodiment of the present invention the preferred value of R98and R99independently from each other, is hydrogen. As examples of the source of amino acids, of which in this second embodiment of the present invention can be obtained structural unit-N(R92)-C(R96)(R97)-CO-, can be mentioned Aad, Ala, Asn, Asp, Gln, Glu, hAla, hGln, hGlu, His, hIle, hLeu, hPhe, hTrp, hTyr, Ile, Leu, Nle, Na, Phe, Phg, Thi, Trp, Tyr, Val, tert-butylglycol (Tbg), neopentylglycol (Npg), cyclohexylglycine (Chg), cyclohexylamine (Cha), 2-titillans (Thia), 2,2-diphenylsiloxane acid or 2-(p-chlorophenyl)aminouksusnoy acid (cf. Houben-Weyl, Methods der organischen Chemie [Methods of Organic Chemistry], Volume 15/1 and 15/2, Georg Thieme Verlag, Stuttgart, 1974), where the functional groups of these amino acids may be in protected form, or may be derivatization.

Structural elements in the compounds of formula I have the following preferred values they can have, regardless of the values of other elements.

The number r, i.e. the number of groups of CH2in polymethene chain linking the phenyl group shown in the formula I and the carbon atom that carries the amino group, R1(R91)N preferably is 0, 1 or 2, more preferably 0 or 1, particularly preferably 1. Thus, preferably the group -(CH2)r- represents a direct bond, or one of the groups-CH2- or-CH2-CH2-, more preferably a direct bond or a group-CH2-, particularly preferably a group-CH2-.

The number of s, i.e. the number of the substituents R94present on the phenyl group shown in the formula I, preferably 0, 1 or 2, more preferably 0 or 1, particularly preferably 0. If all the substituents Rsup> 94present on the phenyl group are halogen atoms, especially fluorine atoms, more preferred value of s is 4. Position on the phenyl group, which is not linked to any substituent R94or R95-(CH2)t-bear hydrogen atoms. If, for example, s is 0, the phenyl group is the group of R95-(CH2)t-that is present in the compounds of formula I with any frequency, and four atoms of hydrogen. The group R95-(CH2)t- may be present in any desired position of the phenyl cycle, i.e. in position 2, 3 or 4. Preferably, the group R95-(CH2)t- is in position 3 or 4, more preferably, it is in position 4 (in relation to the group (CH2)r). The substituents R94can be in any desired position of the phenyl group, not occupied by the group R95-(CH2)t-. Thus, if R95-(CH2)t- is in position 4 and s is 1, only the substituent R94may be in position 2 or 3, where the position of 3 is preferred if R95-(CH2)t- is in position 3 (with respect to the group (CH2)rand s is 1, only the substituent R94can is in position 2, 4, 5 or 6, where the position 4 is the tsya preferred. If the group R95-(CH2)t- is in position 4 and s is 2, two Deputy R94can be in positions 2,3, 2,5, 2,6, or the provisions of 3.5, where the provisions of 3.5 are preferred.

The number of t, i.e. the number of groups CH2in polymethene chain linking the phenyl group shown in the formula I, and R95preferably 0 or 1, more preferably 0. Thus, preferably, the group -(CH2)t- represents a direct bond or a group-CH2-. More preferably, the group -(CH2)trepresents a direct link, i.e. R95directly linked to the phenyl group.

R1preferably represents R11-CO - or R12-SO2-, more preferably R11WITH-.

R11preferably means (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl, (C1-C8)-alkyloxy or (C6-C14)-aryl-(C1-C4)-alkyloxy-where all these groups may be unsubstituted or substituted by one or more identical or different substituents R40. More preferably, R11means (C1-C8)-alkyl, (C6-C14)-aryl or (C1-C8)-alkyloxy-, particularly preferably, (C6- 14)-aryl or (C1-C8)-alkyloxy-where all these groups may be unsubstituted or substituted by one or more identical or different substituents R40. (C1-C8)-alkyl group representing R11or present in the group representing R11preferably, a is a (C2-C8)-alkyl group, more preferably, (C2-C6)-alkyl group, for example, allyl group, or a group cyclopropylmethyl-. (C6-C14)-aryl group representing R11or present in the group representing R11preferably represents (C6-C10)-aryl group, more preferably phenyl group. Thus, among the particularly preferred groups R11present, for example, (C2-C6)-alkyloxy and phenyl, and these groups may be unsubstituted or substituted by one or more identical or different substituents R40.

As described above with respect to alkyl groups in General, an alkyl group representing R11or present in the group representing R11may be saturated or unsaturated and may be acyclic or cyclic. Preferably, the alkyl group representing R11or present in the group, representing R11that is an unsaturated acyclic alkyl group or a saturated alkyl group containing a cyclic group, such as cycloalkyl group, or a group cycloalkyl-alkyl-. More preferably, such alkyl group is an unsaturated acyclic alkyl group, for example, alkyl group containing one or two double bonds and/or triple bond, preferably one or two double bonds or one triple bond, particularly preferably one double bond, or a group cycloalkyl-alkyl-. Particularly preferably, such alkyl group is an unsaturated acyclic alkyl group. Examples of these preferred alkyl groups which R11or present, for example, in the group of alkyloxy-representing R11are ethynyl (=vinyl) CH2=CH-, 1-propenyl CH3-CH=CH-, 2-propenyl (=allyl) CH2=CH-CH2-, E - and Z-2-butenyl CH3-CH=CH-CH2-, 3-methyl-2-butenyl (CH3)2C=CH-CH2, 1,3-pentadienyl CH3-CH=CH-CH=CH-, cyclopropyl, cyclopropylmethyl-, 2-cyclopropylethyl, cyclopentyl, cyclopentylmethyl-, cyclohexyl or cyclohexylmethyl-. Thus, in the preferred embodiment of the present invention R11is an unsaturated (C2-C8/sub> )-alkyloxy-especially unsaturated (C2-C6)-alkoxy, especially unsaturated (C3-C6)-alkyloxy-containing one or two double bonds, especially one double bond, or represents a saturated (C3-C6-cycloalkyl-(C1-C2)-alkyloxy-especially saturated (C3-C6-cycloalkyl-metiloksi-especially cyclopropylmethoxy-, or represents phenyl, where alkyloxy, cycloalkylation - and phenyl groups can be unsubstituted or substituted by one or more identical or different substituents R40. In a more preferred embodiment of the present invention R11is an unsaturated (C2-C6)-alkyloxy-containing one double bond, especially unsaturated (C3-C6)-alkyloxy-especially allyloxy-, or cyclopropylmethoxy-where groups of alkyloxy, allyloxy and cyclopropylmethoxy - can be unsubstituted or substituted by one or more identical or different substituents R40. In a particularly preferred embodiment of the present invention R11is an unsaturated (C2-C6)-alkyloxy-containing one double bond, especially unsaturated (C3-C6)-alkyloxy-especially allyloxy-where groups of alkyloxy and aryloxy can be n is substituted or substituted by one or more identical or different substituents R 40.

If the group R11substituted by one or more substituents R40it is preferably substituted by one, two or three identical or different substituents R40especially preferably one or two substituents R40. The substituents R40present in the group R11preferably are the same or different groups selected from the group comprising halogen, (C1-C4)-alkyl and trifluoromethyl, where the halogen preferably represents fluorine, chlorine or bromine, especially bromine or chlorine. The substituents R40may be present in any desired position of the group R11.

R12preferably represents a (C1-C8)-alkyl, (C6-C14)-aryl, particularly preferably, (C1-C8) -alkyl or (C6-C10)-aryl, where all these groups may be unsubstituted or substituted by one or more identical or different substituents R40. If the group R12substituted by one or more substituents R40it is preferably substituted by one, two or three identical or different substituents R40especially preferably one or two substituents R40. The substituents R40present in the group R12preferably are the same or once the diversified groups, selected from the group comprising halogen, (C1-C4)-alkyl, acetylamino, nitro and trifluoromethyl, where the halogen preferably represents fluorine, chlorine or bromine, especially bromine or chlorine. The substituents R40may be present in any desired position of the group R12.

R2preferably represents R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)nor R25(R26)N-CO-(CH2)p-D-(CH2)q-, particularly preferably, R21(R22)CH-, R23-Het-(CH2)kor R23(R24)N-(CH2)m-D-(CH2)n-.

The group Het, which is present in the group R23-Het-(CH2)k-preferably represents a 5 - or 6-membered monocyclic or 9 - or 10-membered bicyclic saturated or aromatic heterocyclic group containing 1 or 2, especially 1, identical or different heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, and which preferably represent nitrogen atoms. More preferably, such a group Het represents a 5 - or 6-membered monocyclic saturated or aromatic heterocyclic group. The group Het in the group R23-Het-(CH2)k- may be associated with a group -(CH2)kthrough a carbon atom or a suitable nitrogen atom. Preferably, it is linked via a carbon atom. The group Het in the group R23-Het-(CH2)k- can be unsubstituted, i.e. to carry only the group R23and not have to bear additional substituents, or it can be substituted, i.e., to bear, in addition to R23additional substituents as described above for the heterocyclic groups in General. If the group Het carries, in addition to R23additional deputies, it preferably carries one, two or three identical or different substituent selected from the group comprising (C1-C4)-alkyl, (C1-C4)-alkyloxy, halogen, amino, (C1-C4)-alkylamino-, di-((C1-C4)-alkyl)-amino, trifluoromethyl, hydroxy and oxo.

The group R23present in the group R23-Het-(CH2)k-may be associated with any desired and suitable position in the group Het. If the group R23in the group R23-Het-(CH2)k- is an R27-SO2or R28-CO-, a group Het preferably represents a partially unsaturated or saturated group, especially a rich group, and contains the cyclic nitrogen atom that is not associated with the group (CH2)kwith the specified cyclic nitrogen atom linked to the group R23. If R23in the group R23-Het-(CH2)kis Soboh the R 27-SO2or R28-CO-, a group Het in the group R23-Het-(CH2)respecially preferably represents a saturated 5-membered or 6-membered cycle, which contains one nitrogen atom as a cyclic heteroatom, i.e. the group pyrrolidine or piperidine, and which is associated with the group (CH2)kthrough the position 3 in the case pyrrolidino group, or through position 3 or 4, especially from position 4, in the case piperidino group and the nitrogen atom which carries the group R23. If the group Het in the group R23-Het-(CH2)krepresents an aromatic heterocyclic group, the group R23in the group R23-Het-(CH2)k- preferably represents hydrogen.

D preferably represents a divalent residue-C(R31)(R32)-, bivalent (C6-C10)-Allenby residue or a divalent residue derived from an aromatic monocyclic or bicyclic group Het, containing from 5 to 10 cyclic atoms of which 1 or 2 are the same or different cyclic heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. D preferably represents a divalent residue-C(R31)(R32)-, divalent phenylenebis balance, especially 1,3-phenylene or 1,4-phenylene, or two is alenty residue, derived from a monocyclic aromatic group Het containing 5 or 6 cyclic atoms of which 1 or 2 are the same or different cyclic heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. D particularly preferably represents a divalent residue-C(R31)(R32) - or divalent phenylenebis balance. In the aromatic group Het representing D, preferably 1 or 2 nitrogen atom present in the form of cyclic heteroatoms. Allenbyi group Het representing D, can be substituted as described above for these groups in General.

Numbers k, m, n, p and q preferably equal independently of each other 0, 1, 2 or 3, more preferably 0, 1 or 2, particularly preferably 0 or 1, provided that when D represents-C(R31)(R32)-, the sum of m+n cannot be equal to 0, and the sum of p+q cannot be equal to 0. The number k is particularly preferably 0. In the compounds of formula I in which D represents-C(R31)(R32)and both R31and R32represent hydrogen, the sum of m+n is preferably equal to 2.

(C1-C12)-alkyl group representing the group R21or R22preferably represents an acyclic (C1-C8)-alkyl group, (C3-C8)-cycloalkyl group, or the group (C 3-C8-cycloalkyl-(C1-C4)-alkyl-, where (C1-C4)-alkyl group is acyclic. R21and R22preferably independently of one another represent hydrogen, an acyclic (C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl-, Het or Het-(C1-C4)-alkyl-, where all these groups are unsubstituted or substituted as defined above, and where (C1-C4)-alkyl group is acyclic, or R21and R22together with the carbon atom to which they are bound, form a loop, as described above. More preferably, one of the groups R21and R22represents hydrogen or (C1-C4)-alkyl, and the other of the groups R21and R22represents hydrogen, an acyclic (C1-C8)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cycloalkyl-(C1-C4)-alkyl, (C6-C10)-aryl, (C6-C10)-aryl-(C1-C4)-alkyl-, Het or Het-(C1-C4)-alkyl-, where all these groups are unsubstituted or substituted as indicated above, and where (C1-C4)-alkyl group is acyclic, or R21and R22together with the atom of carbon is a, with which they are linked, form a loop, as described above. Particularly preferably, one of the groups R21and R22represents hydrogen or acyclic (C1-C4)-alkyl, and the other of the groups R21and R22represents hydrogen, an acyclic (C1-C4)-alkyl, (C3-C7-cycloalkyl, (C6-C10)-aryl or Het-where all these groups are unsubstituted or substituted as defined above, or R21and R22together with the carbon atom to which they are bound, form a loop, as indicated above.

The group Het, present in R21or R22preferably represents a monocyclic or bicyclic saturated or aromatic heterocyclic group containing from 5 to 10 cyclic atoms, preferably monocyclic saturated or aromatic group containing 5 or 6 cyclic atoms of which 1 or 2, preferably 1, are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur, and preferably represents nitrogen. The group R21or R22which is substituted by one or more substituents, preferably is substituted by 1, 2 or 3 identical or different substituents. The substituents present in R21or R22preferably are selected from the group on the expectation by halogen, hydroxy, (C1-C4)-alkyloxy-, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, trifluoromethyl, acetylamino, amino, amidino, guanidino, oxo, nitro, cyano, (C1-C4)-alkylamino-, di-((C1-C4)-alkyl)-aminoiminomethyl and aminocarbonyl-(C1-C4)-alkyl-.

Saturated or unsaturated carbocyclic structure, which can be formed, R21and R22together with the carbon atom with which they are associated, may contain 3, 4, 5, 6, 7 or 8 cyclic atoms. Preferably, this cycle represents a saturated or unsaturated cyclopentane or cyclohexane structure. One or two relations of the loop formed by R21and R22together with the carbon atom to which they are bound, can be condensed (or paired) with the same or different aromatic cycles, which are preferably selected from the group comprising benzene, naphthalene, 5 - or 6-membered monocyclic heteroaromatic structure, and a 9 - or 10-membered bicyclic heteroaromatic structure, where the heteroaromatic structure preferably contain 1 or 2 identical or different heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. More preferably, the aromatic cycles, condensed on the carbon-carbon cycle formed by R21 and R22together with the carbon atom to which they relate is selected from the group comprising benzene and 5 - or 6-membered monocyclic heteroaromatic cycles containing 1 or 2 identical or different heteroatoms, especially 1 heteroatom selected from the group comprising nitrogen, oxygen and sulfur. Particularly preferred aromatic cycle, which may be condensed on communications, located in the loop formed by the R21and R22together with the carbon atom to which they relate, is benzene.

The resulting group, R21(R22)CH-, in which R21and R22together with the carbon atom to which they are bound, form a loop, and which optionally contains a condensed aromatic cycles, can be unsubstituted or substituted at any desired position of the loop formed by R21and R22together with the carbon atom to which they relate, and/or any desirable position optional condensed aromatic cycles. If the received cyclic group R21(R22)CH is substituted, it is preferably substituted by one or more, for example 1, 2 or 3 identical or different substituents, as defined above. Preferably, the substituents present in the received cyclic group, R21(R22)CH-, selected from the group on the expectation by halogen, hydroxy, (C1-C4)-alkyloxy-, (C1-C4)-alkyl, (C1-C4)-alkylsulfonyl, trifluoromethyl, acetylamino, amino, amidino, guanidino, oxo, nitro, cyano, (C1-C4)-alkylamino-, di-((C1-C4)-alkyl)-amino, aminocarbonyl and aminocarbonyl-(C1-C4) -alkyl-, especially from a group that includes acetylamino, amino, (C1-C4)-alkylamino - and di-((C1-C4)-alkyl)-amino.

R24preferably represents hydrogen, (C1-C8)-alkyl or (C6-C14)-aryl-(C1-C4)-alkyl, more preferably hydrogen, (C1-C4)-alkyl or phenyl-(C1-C4)-alkyl, especially hydrogen or (C1-C4)-alkyl, where the alkyl groups are preferably acyclic. Particularly preferably, R24represents hydrogen.

R25and R26preferably represent independently of one another hydrogen, (C1-C8)-alkyl or (C6-C14)-aryl-(C1-C4)-alkyl, more preferably hydrogen, (C1-C4)-alkyl or phenyl-(C1-C4)-alkyl, particularly preferably hydrogen or (C1-C4)-alkyl, where all these groups are unsubstituted or substituted by one or more, for example one, two or three identical or different substituents R 40and where the alkyl groups are preferably acyclic. Particularly preferably, one of the two groups R25and R26represents hydrogen and the other represents hydrogen or different from hydrogen. More preferably, both groups R25and R26represent hydrogen.

R27preferably represents a (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het - or di-((C1-C8)-alkyl)amino, more preferably, (C1-C4)-alkyl, (C6-C10)-aryl, Het - or di-((C1-C4)-alkyl)amino-, particularly preferably, (C1-C4)-alkyl or (C6-C10)-aryl, particularly preferably, (C6-C10)-aryl, where all these groups are unsubstituted or substituted by one or more identical or different substituents R40and where the alkyl groups are preferably acyclic. The group Het, representing R27preferably represents a monocyclic or bicyclic aromatic heterocyclic group containing from 5 to 10 atoms in the cycle, preferably monocyclic group containing 5 or 6 atoms in the cycle, of which 1 or 2 are heteroatoms selected from the group comprising nitrogen, oxygen, the sulfur, preferably, from the group including nitrogen and sulfur. The group R27which is substituted by substituents R40preferably substituted by 1, 2 or 3, especially 1 or 2, identical or different substituents R40. The substituents R40present in the group R27preferably selected from the group comprising halogen, especially bromine, chlorine and fluorine, (C1-C4)-alkyloxy-, (C1-C4)-alkyl, trifluoromethyl, acetylamino, nitro and cyano.

R28preferably represents a (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het - (C1-C8)-alkyloxy or (C6-C14)-aryl-(C1-C4)-alkyloxy-, more preferably, (C1-C4)-alkyl, (C6-C10)-aryl, Het - (C1-C4)-alkyloxy or (C6-C10)-aryl-(C1-C4)-alkyloxy-, particularly preferably, (C1-C4)-alkyl, (C6-C10)-aryl, (C1-C4)-alkyloxy or (C6-C10)-aryl-(C1-C4)-alkyloxy-, particularly preferably, (C1-C4)-alkyl, (C1-C4)-alkyloxy - or phenyl-(C1-C4)-alkyloxy-where all these groups are unsubstituted or substituted by one or more identical or different substituents R40and where alkyl groups are preferred is sustained fashion are acyclic. The group Het, representing R28preferably represents a monocyclic or bicyclic aromatic heterocyclic group containing from 5 to 10 cyclic atoms, preferably monocyclic group containing 5 or 6 cyclic atoms of which 1 or 2 are heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. The group R28which is substituted by substituents R40preferably substituted by 1, 2 or 3, especially 1 or 2, identical or different substituents R40. The substituents R40present in the group R28preferably are selected from the group comprising halogen, especially bromine, chlorine and fluorine, (C1-C4)-alkyloxy-, (C1-C4)-alkyl, trifluoromethyl, acetylamino, nitro and cyano.

(C1-C12)-alkyl group representing the group R31or R32preferably represents an acyclic (C1-C8)-alkyl group, (C3-C8)-cycloalkyl group, or the group (C3-C8-cycloalkyl-(C1-C4)-alkyl-, where (C1-C4)-alkyl group is acyclic. R31and R32preferably represent independently of each other hydrogen, an acyclic (C1-C8)-alkyl, (C6-C14)-aryl-(C1-C4)-alkyl, (C 3-C8-cycloalkyl-(C1-C4)-alkyl - and Het-(C1-C4)-alkyl-, where all these groups are unsubstituted or substituted by one or more, for example one, two or three identical or different substituents R40and where (C1-C4)-alkyl groups are acyclic. Preferably, one of the two groups R31and R32represents hydrogen and the other represents hydrogen, or different from hydrogen. Acyclic (C1-C8)-alkyl, present in the group R31or R32preferably represents an acyclic (C1-C4)-alkyl group, and (C6-C14)-aryl, present in the group R31or the group R32preferably represents a (C6-C10)-aryl group, more preferably phenyl group, where all these groups are unsubstituted or substituted by one or more identical or different substituents R40. The group Het is present in the group R31or R32preferably represents a monocyclic or bicyclic saturated or aromatic heterocyclic group that contains one or two identical or different cyclic heteroatom selected from the group comprising nitrogen, oxygen and sulfur, especially containing in is the quality of the cyclic heteroatoms of one or two nitrogen atom. The substituents R40present in the group R31or R32, preferably, are selected from the group comprising halogen, especially bromine, chlorine and fluorine, (C1-C4)-alkyloxy-, (C1-C4)-alkyl and trifluoromethyl.

R91, R92and R93preferably represent independently from each other hydrogen or (C1-C4)-alkyl, more preferably, independently of one another represent hydrogen or methyl, particularly preferably hydrogen.

R94preferably is selected from the group comprising (C1-C4)-alkyl and halogen, and the group R94are independent from each other and can be identical or different. More preferably, the substituents R94are the same or different halogen atoms. The atoms of halogen, representing groups of R34preferably represents chlorine and/or fluorine.

R95preferably represents amidinopropane, or its derivative, such as ((C1-C4)-alkyl)oxycarbonate, hydroxyamide, or other protected form or a derivative amidinopropane, as described above. More preferably, R95represents amidino, ((C1-C4)-alkyl)oxycarbonate or hydroxyamino-. Particularly preferably, R95represents the t amidinopropane, i.e. the group of H2N-C(=NH)-, also called the group aminoiminomethyl-or carbamimidoyl group.

R96preferably represents hydrogen, or R98-(C1-C8)-alkyl, more preferably hydrogen or R98-(C1-C4)-alkyl. Particularly preferably, R96represents hydrogen. R98preferably represents hydroxycarbonyl-, (C1-C8-allyloxycarbonyl or aminocarbonyl-, more preferably, hydroxycarbonyl-(C1-C4-allyloxycarbonyl or aminocarbonyl-.

R97preferably represents R99-(C1-C8)-alkyl -, or R99-(C6-C14)-aryl-(C1-C4)-alkyl-. More preferably, R97is an R99-(C1-C8)-alkyl-. As explained above for the alkyl group in General, (C1-C8)-alkyl, present in the group R97may be saturated or unsaturated and may be acyclic or cyclic. Preferably, such alkyl group is a saturated acyclic alkyl group, or a saturated cyclic alkyl group (=cycloalkyl group) or a rich group of type cycloalkenyl-, more preferably, a saturated acyclic alkyl group, or a rich cycloalkyl groups who, particularly preferably, a saturated acyclic alkyl group. If (C1-C8)-alkyl, present in the group R97represents a saturated acyclic alkyl group, R97preferably represents a group R99-(C1-C4)-alkyl-, where (C1-C4)-alkyl is a saturated acyclic alkyl, more preferably, one of the groups R99-CH2-, R99-CH2-CH2-, R99-CH2-CH2-CH2or R99-CH2-CH2-CH2-CH2-, particularly preferably the group R99-CH2-CH2-. If (C1-C8)-alkyl, present in the group R97represents a saturated cyclic alkyl group, R97preferably represents a group R99-(C3-C7-cycloalkyl-, more preferably, the group R99-(C3-C6-cycloalkyl-where cycloalkyl group is saturated, particularly preferably the group R99-cyclopropyl-, R99-cyclopentyl - or R99-cyclohexyl-. In this group, as R99-(C3-C7-cycloalkyl is, for example, R99-cyclopropyl-, R99-cyclopentyl - or R99-cyclohexyl-, R99may be present in any desired position cycloalkyl the Noah group, if cyclopropene group, for example, in position 2, in the case cyclopentyloxy group, for example, in position 2 or 3, in the case tsiklogeksilnogo group, for example, in position 2, 3 or 4, where the position of 4 is preferred. Especially preferred groups R97are groups of R99-CH2CH2and 2 - (R99-cyclopropyl, especially preferred is the group R99-CH2-CH2-.

R99preferably represents hydroxycarbonyl-, (C1-C8-allyloxycarbonyl-, (C6-C14)-aryl-(C1-C4-allyloxycarbonyl, aminocarbonyl-, (C1-C8-alkylaminocarbonyl or other derivative, or a protected form hydroxycarbonyl groups, such as ester or amide, as described above. More preferably, R99is hydroxycarbonyl-, (C1-C8-allyloxycarbonyl-, (C6-C14)-aryl-(C1-C4-allyloxycarbonyl, aminocarbonyl-, or (C1-C8-alkylaminocarbonyl-, particularly preferably hydroxycarbonyl-, (C1-C8-allyloxycarbonyl, aminocarbonyl or (C1-C8-alkylaminocarbonyl. Moreover, preferably, R99is hydroxycarbonyl or (C1-C8-allyloxycarbonyl-. Group (C1-C8)-alkyloxy-, present the existing group R 99preferably represents a group (C1-C4)-alkyloxy-. Dkilla group present in the group R99preferably represents a saturated acyclic group.

Preferred compounds of formula I are those compounds in which one or more of the residues, with preferred values, or with one or more specific values from the values listed in their respective definitions and General explanations for the corresponding residues, and all combinations of these preferred values and specific values are the subject of the present invention. And all preferred compounds of formula I are the subject of the present invention in all their stereoisomeric forms and mixtures in any ratio, and their physiologically acceptable salts. In addition, all preferred compounds of formula I are the subject of the present invention in the form of their proletarienne forms and other derivatives, as explained above, for example in the form of their esters, such as (C1-C4)-alkalemia and other esters, and amides, such as unsubstituted amides, (C1-C4-alkylamide and other amides.

For example, preferred compounds of formula I are compounds in which

R 1means R11-CO-;

R91denotes hydrogen;

r is 0 or 1;

s is 0, 1 or 2;

t is 0;

R94selected from the group comprising chlorine and fluorine;

R95means amidino or ((C1-C4)-alkyl)oxycarbonate-, and R95attached to position 4 of the phenyl cycle formula I; in all their stereoisomeric forms and mixtures in any ratio, and their physiologically acceptable salts. The compounds of this type contain a structural unit derived from 4-amidinopropane or 4-amidinopropane, which is optionally substituted by amidinopropane group ((C1-C4)-alkyl)oxycarbonyl-, and optionally substituted on the phenyl group by chlorine and/or fluorine, and replaced by N-terminal amino group, R11-CO-. In a particularly preferred group of these compounds s is 0 and amidinopropane is not substituted, i.e particularly preferred compounds of this type are compounds derived from 4-amidinopropane or 4-amidinopropane, particularly preferred are compounds derived from 4-amidinopropane, substituted by N-terminal amino group, R11-CO-.

Preferred compounds of formula I are compounds in which

R92and R96represent hydrogen;

R97means R99-CH2-CH2-;

R99, R97denote hydroxycarbonyl or ((C1-C8)-alkyl)oxycarbonyl-; in all their stereoisomeric forms and mixtures in any ratio, and their physiologically acceptable salts. The compounds of this type contain a structural unit, which represents the balance glutamic acid or its derivative, where the carboxylic acid group in the side chain into (C1-C8)-alkilany ester.

Especially preferred compounds of formula I are compounds in which

r is 1;

s is 0;a

t is 0;

R1denotes allyloxycarbonyl-;

R95denotes amidinopropane that is attached to position 4 of the phenyl cycle formula I;

R91, R92, R93and R96represent hydrogen;

R97means R99-CH2-CH2-;

R99denotes hydroxycarbonyl or ((C1-C4)-alkyl)oxycarbonyl-;

in all their stereoisomeric forms and mixtures in any ratio, and their physiologically acceptable salts.

In addition, preferred compounds of formula I are compounds in which the chiral centers are present essentially in the same configuration. Particularly preferably, if a chiral carbon atom, scotorum associated group, R 1(R91)N - and -(CH2)r-has the S-configuration, i.e. a structural unit R1(R91)N-CH(-(CH2)r(substituted phenyl))-CO - preferably is obtained from a derivative of L-amino acids. If R96denotes hydrogen, particularly preferably a chiral carbon atom, which is associated with the group R96and R97had the S-configuration, i.e. structural unit -(R92)N-CH(R97)-CO - preferably is obtained from a derivative of L-amino acids.

The present invention also relates to a method of reception, which can be obtained the compounds of formula I. the compounds of formula I mostly can be obtained by combining two or more elements (or building blocks)that can be obtained retrosynthetic of formula I. Upon receipt of the compounds of formula I can generally be useful or necessary in the course of the synthesis to introduce functional groups, the presence of which may lead to undesirable or adverse reactions synthesis step, in the form of precursors which are later converted into the target functional groups, or to temporarily block functional groups by using a protective group. Such protection methods well known to specialists in this field (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley and Son, 1991). As examples of groups of the precursor can be referred to the nitro group, which can then be converted by restoring, for example, by catalytic hydrogenation, amino, or can be mentioned ceanography, which subsequently can be converted into amidinopropane, or, in the recovery, aminomethyl group. The protective group or a blocking group), which may be present on functional groups include allyl, tert-butyl, benzyl, tert-butyloxycarbonyl (Vos), benzyloxycarbonyl (Z) and 9-fluorenylmethoxycarbonyl (Fmoc) as a protective group for hydroxyl, carboxyl, amino, guanidino and amidino groups.

In particular, when obtaining the compounds of formula I building blocks connected by one or more amide combinations (or condensations), i.e. through the formation of amide bonds between the carboxylic acid group (or similar group, such as sulfonic acid group) of one building block and the amino group (or similar group) of another building block. For example, the compounds of formula I can be obtained by combining the building blocks of the formulae II, III and IV through education essentially known manner amide group relations derived carboxylic acid CO-Y1depicted in formula II, and ATO is ω nitrogen compounds, depicted in formula III, and through the formation of additional amide bond between the carboxylic acid derivative CO-Y2depicted in formula III, and the nitrogen atom of the compounds depicted in formula IV.

In the compounds of formulas II, III and IV group, R1, R2, R91, R92, R93, R94, R95, R96, R97and r, s and t have the above definitions, but the functional groups in these compounds may also be present in the form of groups of precursors, which subsequently transform into groups present in the compounds of formula I, or a functional group can be present in protected form. Y1and Y2that may be the same or different, represent a hydroxyl or other, capable of nucleophilic substitution leaving group, i.e. the group COY1and COY2in the compounds of formulas II and III represent a carboxylic acid group COOH or an activated derivative of carboxylic acids, such as, for example, acid anhydrides, esters, such as (C1-C4)-alkalemia esters or activated esters or mixed anhydrides.

The initial compounds of formulas II, III and IV, as well as other compounds that use the camping in the synthesis of compounds of formula I for the introduction of some of the structural units, are commercially available or can be easily obtained from commercially available compounds using the following or similar methods, or techniques, which can be found in easily accessible for practical in the field of literature.

To obtain the compounds of formula I in the beginning of the compounds of formulas II and III can be subjected to condensation and then the intermediate product is subjected to condensation with the compound of the formula IV to obtain the compounds of formula I, or at the beginning of the compounds of formulas III and IV can be subjected to condensation and then the intermediate product is subjected to condensation with the compound of the formula II with obtaining the compounds of formula I. After any stage during the synthesis can be carried out under lock and unlock, as well as transformation groups predecessors in the target group, and can be made further modifications. For example, a group such as R1that is different from hydrogen, can already be present in the compound of formula II, which is used in the reaction combination with the compound of the formula III or with an intermediate compound obtained from compounds of formulas III and IV, but the group R1may also be entered after holding only one reaction combinations, or after both reactions combination. The synthetic strategy is to obtain the compounds of formula I, thus, it can widely vary, and it depends on the method of synthesis is preferred in this case.

Various General methods for the formation of amide linkages, which can be used in the synthesis of compounds of formula I, known to specialists in this field, for example from peptide chemistry. Stage combinations may be conducted through the use of free carboxylic acids, i.e. compounds of formula II or III, or an intermediate product of interaction, in which the group COY1or COY2interacting at this stage, is a group COOH, activated carboxylic acid group, preferably in situ, using a conventional condensing reagent such as carbodiimide, for example, dicyclohexylcarbodiimide (DCC) or diisopropylcarbodiimide (DIC), or carbanilate, for example, carbonyldiimidazole, or salt Urania, for example, O-((cyano-(etoxycarbonyl)-methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) or O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea hexaflurophosphate (HATU), or ether of Harborview acid, for example, ethylchloride or isobutylparaben, or tailhold, or anhydride propylphosphonic acid, or other, and then the interaction of the activated carboxylic acid derivative with aminoguanidinium. Amide bond can also the set formed by the interaction of the amino compounds with galogenangidridy carboxylic acid, especially with the acid chloride of the carboxylic acid, which can be obtained in a separate step or in situ from a carboxylic acid and, for example, thionyl chloride, or an ether or tiefer carboxylic acid, such as methyl ester, ethyl ester, phenyl ester, nitrophenylthio ester, pentafluorophenyl ester, methylthioribose ether, fortilog ether or 2-pyridylthio ether, i.e. the compounds of formula II or III, or with an intermediate product of the interaction in which Y1or Y2represents Cl, methoxy, ethoxy, optionally substituted, phenyloxy, methylthio, phenylthio or 2-pyridylthio.

The activation reaction and the reaction of the combination is usually carried out in the presence of an inert solvent (or diluent), for example, in the presence of an aprotic solvent, such as dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), hexamethylene phosphoric acid (NMRT), 1,2-dimethoxyethane (DME), dioxane, or other, or a mixture of such solvents. Depending on the specific method, the reaction temperature can vary within a wide range and may be, for example, from about -20°C to the boiling point of the solvent or diluent.

Also, depending on the specific method may be necessary or useful to add in the appropriate amount of one renesola auxiliary agents, for example, bases such as Quaternary amine, such as triethylamine or diisopropylethylamine, or alcoholate of an alkali metal, e.g. sodium methoxide or tert-butoxide potassium, to bring the pH, or to neutralize the generated acid or free base of the amino compounds used in the form of a salt of the acid is added, or N-hidroxizina, such as 1-hydroxybenzotriazole, or catalyst, such as 4-dimethylaminopyridine. Detailed descriptions of methods for obtaining activated derivatives of carboxylic acids and formation of amide bonds, and the sources of literature are given in various standard references, such as, for example, J.March, Advanced Organic Chemistry, 4th ed., John Wiley&Sons, 1992; or Houben-Weyl, Methods der organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag.

Then the protective group that can be present in the products obtained by reaction combinations are removed using standard methods. For example, tert-bucilina protective group, especially tert-bucilina ester group, which is a protective form of COOH group may be removed, i.e. converted into a carboxyl group, in the case of ester by treatment triperoxonane acid. Benzyl group can be removed by hydrogenation.

Fluorenylmethoxycarbonyl group mouthbut removed by secondary amines, such as piperidine. As already explained, after the reaction of a combination of functional groups can also be formed from suitable groups predecessors, or, if desired, using conventional methods can be additional reaction products of the combination, for example, the reaction of acylation or esterification reaction. In addition, then, using known methods may be turning into a physiologically acceptable salt or Palekastro form the compounds of formula I.

As examples of the introduction of specific functional groups can be given of the procedure of introducing Aydinoglu and guanidinium that represent, for example, the group R95. Amidine can be obtained from the cyano-containing compounds by the addition of alcohol in acid anhydrous conditions, for example, in methanol, or ethanol saturated with hydrogen chloride, and subsequent aminolysis. The following method of obtaining amidino is the addition of hydrogen sulfide to the cyano, with subsequent methylation received thioamide and then the interaction with ammonia. Another way is adding hydroxylamine to the cyano that leads to the formation of hydroxyamides. If desired, the connection of the N-O hydroxyamide can be split, for example, by catalytic hydrogenation, to obtain amidine.

is kinogruppa, which can be obtained from the nitro-precursor, can be turned into guanidino or nitroguanidine group, and the nitro-group is a protective group. For guanylurea or nitroguanidine amino group can be used the following reagents that are well known to specialists in this field, and which are all described in the literature: O-methylisoleucine, S-methylisothiazoline, nitro-3-methylisothiazoline, formamidinesulfinic acid, 3,5-dimethyl-1-personinformation nitrate, N,N'-di-tert-butyloxycarbonyl-S-methylisothiazoline, or N-allyloxycarbonyl - and N,N'-dialkylaminoalkyl-S-methylisothiazoline.

Basically, the reaction mixture containing the target compound of the formula I or an intermediate connection, process and, if necessary, the product is then purified by conventional methods known to experts in this field. For example, the synthesized compound can be purified by such well known methods, such as crystallization, chromatography or high performance liquid chromatography on reversed phase (RP-HPLC), or using other methods of separation based on, for example, differences in size, charge or hydrophobicity of the connection. In a similar way to characterize the compounds of this invention can be used well what about the known methods, such as the analysis of amino acid sequences, NMR, IR and mass spectrometry (MS).

The reactions described above and below, which is carried out in the framework of the synthesis of compounds of formula I, generally, can be carried out in accordance with conventional liquid-phase chemistry, as well as in accordance with the methods of solid-phase chemistry, both these areas are traditionally used in peptide synthesis. Among the various methods that can be applied, if the compounds of formula I get on a solid phase, may be mentioned the following method used to produce compounds in which hydroxycarbonyl group present in the group R96or the group R97. As a starting substance is used as a compound of the formula Fmoc-HN-C(R96)(R97)-CO-OPG, where Fmoc is a 9-fluorenylmethoxycarbonyl, PG represents a protective group of carboxylic acid, and R96and R97such as defined above, provided that one of the groups R96and R97there is free hydroxycarbonyl group COOH. These source connection attached to the Wang resin (S.S.Wang, J.Am. Chem. Soc. 95 (1973) 1328) by the interaction of the COOH group with resin. This is followed by removing the protective Fmoc group and the compound of formula II is subjected to interaction with the amino group. Followed by removing the protective g is uppy PG and the resulting carboxyl group is subjected to interaction with the compound of the formula IV. At the end of the connection is removed from the resin using triperoxonane acid. If you are using solid-phase synthesis methods, present functional groups can be modified or functional groups can be introduced into the formed connection while it is attached to the resin, or after removal of the compounds from the resin, to obtain, for example, N-terminal derivative, such as allyloxycarbonyl connection using the N-end, or the derivative of the carboxyl group, this group, for example, can be liderovna. The compound of this invention can also be synthesized by combining stages, carried out in accordance with the methods of liquid-phase organic chemistry, and use stages, carried out in accordance with the methods of solid-phase organic chemistry. The compound of this invention can also be synthesized using the automated synthesizer.

Compounds of the present invention inhibit the enzyme in the blood coagulation factor VIIa. In particular, they are specific inhibitors of factor VIIa. In this document the term specific, if used in respect of inhibiting the activity of factor VIIa, means that the compound of the formula I can inhibit the activity of factor VIIa, not inhibiting essentially the activity of the other specific proteases involved in the process to which gulali blood and/or fibrinolysis, including, for example, factor XA, plasmin, and thrombin (using the same concentration of the inhibitor). The activity of the compounds of formula I can be determined, for example, using the following analysis, or by other assays known to specialists in this field. Preferred compounds of the present invention are such compounds that have a Ki≤10 μm, particularly preferably ≤1 μm for the inhibition of factor VIIa, as determined in the analysis described below, and which preferably essentially does not inhibit the activity of other proteases that are included in the processes of coagulation and fibrinolysis compared to the inhibition of the factor VIIa (using the same concentration of the inhibitor). The compounds of this invention inhibit the catalytic activity of factor VIIa or directly in prothrombinase complex or in the form of a soluble subunit, or indirectly, by inhibiting the inclusion of factor VIIa in prothrombinase complex.

Due to the fact that the compounds of formula I possess inhibitory activity against factor VIIa, they are useful pharmacologically active compounds that can be used, for example, to influence the process of blood coagulation or clotting and fibrinolysis, as well as for treatment and prevention, for example, with techno-vascular diseases, thromboembolic diseases or re-stenosis. The compounds of formula I and their physiologically acceptable salts and proletarienne forms can be introduced to animals, preferably mammals, and especially humans, as pharmaceuticals for the treatment or prophylaxis. They can be entered individually, or in mixtures with one another or in the form of pharmaceutical preparations which allow enteral or parenteral administration and which contain as active ingredient an effective amount of at least one of the compounds of formula I and/or physiologically acceptable salts and/or its proletarienne forms, and pharmaceutically acceptable carrier.

Therefore, the present invention also relates to compounds of the formula I and/or their physiologically acceptable salts and/or their proletarienne forms intended for use as pharmaceuticals (or drugs), to the use of compounds of the formula I and/or their physiologically acceptable salts and/or their proletarienne forms, for obtaining pharmaceuticals for inhibition of factor VIIa or for influencing the process of coagulation of blood or fibrinoly, or for the treatment or prophylaxis of the diseases mentioned above or below, for example, to obtain the pharmaceutical the ski product for the treatment and prevention of cardiovascular diseases, thromboembolic diseases or re-stenosis. This invention also relates to the use of compounds of the formula I and/or their physiologically acceptable salts and/or their proletarienne forms, for the inhibition of factor VIIa or for influencing the process of blood coagulation or fibrinolysis or for therapy or prophylaxis of the diseases mentioned above or below, for example, for use in the treatment and prevention of cardiovascular disorders, thromboembolic diseases or re-stenosis, as well as to methods of treatment directed at these goals, including methods relating to the above treatment and prevention. In addition, the present invention relates to pharmaceutical preparations (or pharmaceutical compositions)which contain an effective amount of at least one of the compounds of formula I and/or physiologically acceptable salts and/or its proletarienne forms, and pharmaceutically acceptable carrier, i.e. one or more pharmaceutically acceptable carrier substances or environments for drugs) and/or incremental funds (or excipients).

The pharmaceutical preparations can be administered orally, for example in the form of Ellul, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatine capsules, solutions, syrups, emulsions, su is Pensi or aerosol mixtures. The introduction, however, can be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of solutions for injection or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example, aerosols or nasal sprays.

Pharmaceutical preparations in accordance with this invention get known for being the way that is familiar to specialists in this field, and pharmaceutically acceptable inert inorganic and/or organic media used in addition to the at least one compound of the formula I and/or its (their) physiologically acceptable salts and/or its (their) proletarienne forms. For more pills, tablets, coated tablets and hard gelatin capsules can be applied, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts and other

Carriers for soft gelatin capsules and suppositories can be, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils and other Appropriate media to obtain solutions, such as solutions for injection, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols,sucrose, invert sugar, glucose, vegetable oil and other Appropriate media for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5 to 90% by weight of compounds of the formula I and/or their physiologically acceptable salts and/or proletarienne forms. The amount of the active ingredient of the formula I and/or physiologically acceptable salts and/or proletarienne forms in the pharmaceutical preparations normally is from about 0.5 to 1000 mg, preferably, from about 1 to 500 mg

In addition to the active ingredients of the formula I and/or their physiologically acceptable salts and/or proletarienne forms and media, the pharmaceutical preparations can contain additives such as, for example, fillers, dezintegriruetsja means, connecting means, connecting means, moisturizing agents, stabilizers, emulsifiers, preservatives, sweeteners, coloring tools, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, soljubilizatory, agents that improve the ability to store, salts for modifying the osmotic pressure, covering agents or antioxidants. They can also contain two or more compounds of formula I and/or their physiological the automatic acceptable salts, and/or proletarienne forms. If the pharmaceutical preparation contains two or more compounds of formula I, the choice of individual compounds were carried out on the basis of the specific complete pharmacological profile of a pharmaceutical product. For example, high-performance connection with short duration of action may be combined with long-term connection having a lower efficiency. The flexibility allowed in the choice of substituents in the compounds of formula I, allows a high degree of control over biological and physico-chemical properties of compounds and thus creates the possibility of selecting the desired compounds. Furthermore, in addition to at least one compound of the formula I and/or physiologically acceptable salts and/or proletarienne forms, pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.

As inhibitors of factor VIIa the compounds of formula I and their physiologically acceptable salts and proletarienne forms are mainly suitable for the treatment and prevention of conditions in which the activity of factor VIIa has a value, or has an undesirable level, or which may have a beneficial effect Engibarov the e factor VIIa or decrease its activity, or to prevent, alleviate or cure of which, in the opinion of the physician, required the inhibition of factor VIIa or a decrease in its activity. Because the inhibition of factor VIIa affects blood coagulation and fibrinolysis, the compounds of formula I and their physiologically acceptable salts and proletarienne forms usually are suitable for reducing blood clotting, or for the treatment and prophylaxis of conditions in which the activity of factor VIIa is set or has an undesirable level, or which may have a beneficial effect of reducing blood clotting, or for the prevention, mitigation or cure of which, in the opinion of the physician, it is necessary to reduce the activity of the blood coagulation system. Thus, a separate subject matter of the present invention is the reduction or inhibition of unwanted blood clotting, especially for a subject, by introducing an effective amount of compound I or its physiologically acceptable salt or proletarienne form, and containing pharmaceuticals.

State, in which the use of compounds of formula I can be blagopriyatny effect include, for example, cardiovascular disorders, thromboembolic diseases or complications, such as those associated with infection or surgical intervention is m Compounds of the present invention can also be used to reduce the inflammatory response. Examples of specific diseases, for the treatment or prevention of which can be used the compounds of formula I are coronary heart disease, myocardial infarction, angina pectoris, restenosis of blood vessels, for example, restenosis after angioplasty, such as angioplasty PICA (posterior lower cerebellar artery), respiratory distress syndrome of adults, multiple failure, shock and disturbance associated with disseminated intravascular coagulation. Examples of related complications associated with surgery are thrombosis, such as thrombosis of deep and proximal veins, which can occur after surgery. From the point of view of pharmacological activity of the compounds of this invention can replace other anticoagulants, such as heparin. The use of the compounds of this invention can result in reduced cost compared with other anticoagulants.

When using compounds of formula I dose can vary within wide limits and is usually known to the physician, the dose is determined according to the individual conditions in each individual case. It depends on your specific applicable with the organisations, on the nature and severity of the disease to be treated, method and mode of administration, or whether the treatment of acute or chronic condition, or is prevention. The appropriate dosage can be established using clinical approaches, well known in this field. As a rule, the daily dose required to achieve the desired results in adult weighing about 75 kg is approximately from 0.01 to 100 mg/kg, preferably from about 0.1 to 50 mg/kg, particularly about 0.1 to 10 mg/kg (in each case in mg per kg of body weight). The daily dose may be divided, especially in the case of the introduction of relatively large quantities for several, for example 2, 3 or 4 separate introduction. Usually, depending on indidually reactions of the organism, may be necessary deviations greater or less than the prescribed daily dose.

The compound of the formula I can advantageously be used as anticoagulant outside of the subject. For example, the effective amount of the compounds of this invention can be brought into contact with their sample of blood to prevent its coagulation. In addition, the compound of the formula I and salts thereof can be used for diagnostic purposes, for example in in vitro diagnoses, and as auxiliary substances is involved in biochemical research. For example, the compound of the formula I can be used in the analysis to determine the presence of factor VIIa or for selection of factor VIIa in essentially pure form. The compound of this invention can be marked, for example, a radioactive isotope, and then the presence of the labeled compound associated with factor VIIa, can be determined by routine method used to determine the specific label. Thus, the compound of formula I or its salt can be successfully used as a probe to determine the location or quantity of the activity of factor VIIa in vivo, in vitro or ex vivo.

In addition, the compounds of formula I can be used as intermediate compounds for other compounds, in particular, other pharmaceutically active compounds, which can be obtained from compounds of the formula I, for example, by introduction of substituents or modification of functional groups.

It should be understood that modifications that do not materially affect various embodiments of the present invention, included in the invention disclosed in this specification. Accordingly, the following examples are intended to illustrate and not to limit the present invention.

Examples

Reduction

Allyloxycarbonyl Alloc

L-4-Amidinopropane pAph

L-Aspartyl Asp

tert-Butyl tBu

Dig orotan DCM

N,N'-Diisopropylcarbodiimide DIC

N,N-Aminobutiramida-N-ethylamine DIEA

N,N-Dimethylformamide DMF

Dimethyl sulfoxide DMSO

N-Ethylmorpholine NEM

9-Fluorenylmethoxycarbonyl Fmoc

L-Glutamyl Glu

N-Hydroxybenzotriazole HOBt

Pentafluorophenyl Pfp

Tetrahydrofuran THF

Triperoxonane acid TFA

O-((CYANOGEN(etoxycarbonyl)methylene)amino)-1,1,3,3-

tetramethylurea tetrafluoroborate TOTU

O-(7-Asobancaria-1-yl)-1,1,3,3-

tetramethylurea hexaphosphate HATU

The compounds of formula I called in accordance with the rules of peptide chemistry. Thus, for example, the name of Alloc-pAph-Glu-(4-aminobenzyl)amide means that in the corresponding connection unit L-4-amidinopropane linked through a peptide bond with unit L-glutamyl, and that α-amino group of L-4-amidinopropane bears allyloxycarbonyl group, and that in position 1 of glutamine instead of the free carboxyl groups present group of N-(4-aminobenzyl)carboxamide, i.e. that the compound has the following structural formula.

If at the final stage of synthesis of the compound using an acid, such as triperoxonane or acetic acid, for example, if removal of the tert-butilkoi groups use triperoxonane acid, or if the connection is purified by chromatography, ICP is lsua eluent, which contains an acid, but in some cases, depending on the processing procedure, for example, details of the process of freeze-drying, the connection get partially or completely in the form of salts of acid used, for example, in the form of a salt or acetic triperoxonane acid.

Example 1: Alloc-pAph-Glu-(4-aminobenzyl)amide

a) (S)-2-Allyloxycarbonyl-3-(4-cyanophenyl)propionic acid

A suspension of 50 g (0,221 mol) of (S)-2-amino-3-(4-cyanophenyl)propionic acid in 150 ml of water adjusted to pH 8 with 1 N NaOH. At a temperature of from 0 to 5°slowly add to 26.6 g (0,221 mol) of allylchloroformate in 225 ml of dioxane (pH value of 8 is supported by adding 1 N NaOH). After completion of the reaction (the control is carried out using thin-layer chromatography (TLC), the mixture is extracted with DCM and the aqueous layer was acidified to pH 2 with KHSO4. The residue is dissolved in DCM, dried (Na2SO4) and evaporated. The residue is recrystallized from a mixture of ether/petroleum gasoline, receiving 31 g (51%) specified in the connection header. MS 275,1 (M+1)+.

(b) Hydrochloride of the ethyl ester of (S)-2-allyloxycarbonyl-3-(4-carbamimidoyl)propionic acid (hydrochloride Alloc-pAph-OC2H5)

Dry gaseous hydrochloric acid is bubbled through a solution of 15 g (by 0.055 mol) of (S)-2-allyloxycarbonyl-3-(4-cyanophenyl)propionic key is lots in 200 ml of ethanol. After 5 h the mixture was kept overnight at 0°C. the Solvent is evaporated and the residue is treated with 250 ml of 3 M solution of ammonia in ethanol for 12 h at room temperature. The solvent is evaporated and the residue was washed with DCM and crystallized from ether, receiving of 17.5 g (90%) specified in the connection header. MS 320,3.

c) Hydrochloride (S)-2-allyloxycarbonyl-3-(4-carbamimidoyl)propionic acid (hydrochloride Alloc-pAph-OH)

17 g (0,048 mol) of the hydrochloride of the ethyl ester of (S)-2-allyloxycarbonyl-3-(4-carbamimidoyl)propionic acid is treated with 400 ml policecontributing hydrochloric acid for 3 h at room temperature. The solvent is evaporated (<30° (C) and the residue is stirred with ether. Yield 15 g (95%). MS 292,2 (M+1)+.

d) Hydrochloride Alloc-pAph-Glu(OtBu)-och3

To a solution of 1.3 g (of 3.97 mmol) of the hydrochloride Alloc-pAph-OH and 1.0 g (of 3.97 mmol) of the hydrochloride of H-Glu(OtBu)-och3in 15 ml of DMF is added 1.63 g (4,96 mmol) of TOTU and 1.14 g (9.9 mmol) of NEM. After 5 h at room temperature the solution is poured into 150 ml of brine and extracted with DCM. The organic layer is dried (NB2SO4) and evaporated, obtaining 1.7 g (81%) specified in the connection header. MS 491,2 (M+1)+.

e) Alloc-pAph-Glu(OtBu)-OH

1.7 g (3,17 mmol) of the hydrochloride Alloc-pAph-Glu(OtBu)-och3in 15 ml of THF and 50 ml of water is treated with 0.16 g (3.8 mmol) of the monohydrate of lithium hydroxide. H is RES 3 h the solvent is removed and the residue is dried from the frozen state, receiving 1,25 g (82%) specified in the connection header. MS 477,5 (M+1)+.

f) Alloc-pAph-Glu(OtBu-4-aminobenzyl)amide

To a solution of 56 mg (0.12 mmol) Alloc-pAph-Glu(OtBu)-HE and 13 μl (0.12 mmol) of p-aminobenzoylamino in 10 ml of DMF added 39 mg (0.12 mmol) of TOTU and 15 μl (0.12 mmol) of NEM at 3°C. After 12 h at room temperature the solvent is removed, receiving 0.15 g specified in the title compound, which was used in the next stage without additional purification. MS 581,4 (M+1)+.

g) Alloc-pAph-Glu-(4-aminobenzyl)amide

150 mg Alloc-pAph-Glu(OtBu)-4-aminobenzamide treated with 1 ml of 90% TFA. After 12 h add a mixture of ethyl acetate/D/methanol and the precipitate is filtered and dried, obtaining 55 mg specified in the connection header. MS 525,3 (M+1)+.

Example 2: Alloc-pAph-Glu-(3-aminobenzyl)amide

To a solution of 30 mg (0,064 mmol) Alloc-pAph-Glu(OtBu)-HE and 8 mg (0,064 mmol) 3-aminobenzoylamino in 5 ml of DMF added 21 mg (0,064 mmol) of TOTU and 8 μl (0,064 mmol) of NEM at 3°C. After 12 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature, add ethyl acetate and the precipitate is filtered and dried, obtaining 30 mg specified in the connection header. MS 525,4 (M+1)+.

Example 3: Alloc-pAph-Glu-(2-(4-AMINOPHENYL)ethyl)amide

To a solution of 30 mg (0,064 mmol) Alloc-pAph-Glu(OtBu)-HE and 8.5 µl (0,064 mmol) of 2-(4-AMINOPHENYL)ethylamine in 4 ml of DMF added 21 mg (0,064 mmol) of TOTU and 8 μl (0,064 mmol) of NEM at 3°C. Across the 12 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature, add ethyl acetate and the precipitate is filtered and dried, obtaining 30 mg specified in the connection header. MS 539,4 (M+1)+.

Example 4: Alloc-pAph-Glu-(2,4-dihydroxybenzyl)amide

To a solution of 30 mg (0,064 mmol) Alloc-pAph-Glu(OtBu)-HE and 14 mg (0,064 mmol) of 3,4-dihydroxybenzylamine in 5 ml of DMF added 21 mg (0,064 mmol) of TOTU and 16 μl (0,128 mmol) of NEM at 3°C. After 12 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature, add ethyl acetate and the precipitate is filtered and dried, receiving 45 mg specified in the connection header. MS 542,4 (M+1)+.

Example 5: Alloc-pAph-Glu-(2-aminobenzyl)amide

To a solution of 59 mg (0,124 mmol) Alloc-pAph-Glu(OtBu)-HE and 15 mg (0,124 mmol) of 2-aminobenzoylamino in 1.5 ml DMF added 41 mg (0,124 mmol) of TOTU and 28 mg (0,248 mmol) of NEM at 3°C. After 12 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature the solvent is evaporated and the residue purified by HPLC, receiving 1.5 mg specified in the connection header. MS 525,4 (M+1)+.

Example 6: Alloc-pAph-Glu-((RS)-2-amino-N-fluoren-9-yl) amide

To a solution of 60 mg (0,126 mmol) Alloc-pAph-Glu(OtBu)-HE and 34 mg (0,126 mmol) (RS)-2,9-diamino-N-Florina in 5 ml of DMF added 42 mg (0,126 mmol) of TOTU and 32 μl (0,252 mmol) of NEM at 3°C. After 12 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. the donkey 8 h at room temperature, add ethyl acetate and the precipitate is filtered and dried, receiving 50 mg specified in the connection header. MS 598,7 (M+1)+.

Example 7: Alloc-pAph-Glu-(3-ethoxycarbonylmethyl)amide

a) 3-Ethoxycarbonylmethylene

To a solution of 0.5 g (2.9 mmol) of 3-tert-butyloxycarbonyl in 8 ml DCM and 0.37 g (2.9 mmol) of NEM add a solution of 0.32 g (0.29 mmol) of ethylchloride in 2 ml of DCM. After 24 h at room temperature the mixture is washed with water and dried. The solvent is evaporated and the residue is stirred with 5 ml of TFA (90%). After 1 h the solvent is evaporated, receiving 0.6 g specified in the connection header. MS 147,0 (M+1)+.

b) Alloc-pAph-Glu-(3-ethoxycarbonylmethyl)amide

To a solution of 59 mg (0,124 mmol) Alloc-pAph-Glu(OtBu)-HE and 16 mg (0,124 mmol) 3-ethoxycarbonylmethylene in 1.5 ml DMF added 41 mg (0,124 mmol) of TOTU and 28 mg (0,248 mmol) DIEA in 3°C. After 12 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature the solvent is evaporated and the residue purified by HPLC, gaining 1.4 mg specified in the connection header. MS 549,2 (M+1)+.

Example 8: Alloc-pAph-Glu-((R)-1-(3-AMINOPHENYL)ethyl) - amide and Alloc-pAph-Glu-((S)-1-(3-AMINOPHENYL)ethyl)amide

a) (RS)-3-(1-amino-ethyl)phenylamine hydrochloride

The mixture 0,69 g (5,123 mmol) 1-(3-AMINOPHENYL)-ethanone, 0,43 g (x 6.15 mmol) of hydroxylamine, 0.50 g (x 6.15 mmol) of sodium acetate and 15 ml of ethanol is heated at 80°C for 8 hours the Solvent is removed and the OS is atok partitioned between water and ethyl acetate. The organic phase is dried, filtered and the solvent evaporated, receiving of 0.53 g of the oxime (MS 151,2 (M+1)+. of 0.53 g of the oxime is dissolved in 100 ml of methanol and hydronaut in a Parr apparatus (Parr apparatus) at room temperature. After 2 days the mixture was filtered through celite and the solvent evaporated. The residue is stirred with ether, saturated hydrogen chloride. The solvent is evaporated, getting 0,46 g specified in the connection header. MS 137,1 (M+1)+.

b) Alloc-pAph-Glu-((R)-1-(3-AMINOPHENYL)ethyl) - amide and Alloc-pAph-Glu-((S)-1-(3-AMINOPHENYL)ethylamide

To a solution of 59 mg (0,124 mmol) Alloc-pAph-Glu(OtBu)-HE and 18 mg (0.125 mmol) of (RS)-3-(1-amino-ethyl)phenylamine in 5 ml of DMF added 41 mg (0,124 mmol) of TOTU and 28 mg (0,248 mmol) DIEA in 3°C. After 12 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature the solvent is evaporated and the residue purified by HPLC, receiving 0.7 mg of diastereoisomer I (MS 539,2 (M+1)+) and 0.9 mg of diastereoisomer II (MS 539,2 (M+1)+.

Example 9: Alloc-pAph-Glu-((R)-1-(4-AMINOPHENYL)butyl)amide and Alloc-pAph-Glu-((S)-1-(4-AMINOPHENYL)butyl)amide

(RS)-4-(1-Aminobutyl)phenylamine synthesized according to the method described in example 8, starting from the corresponding ketone. To a solution of 60 mg (0,126 mmol) Alloc-pAph-Glu(OtBu)-HE and 24 mg (0,121 mmol) of (RS)-4-(1-aminobutyl)phenylamine in 5 ml of DMF added 42 mg (0,126 mmol) of TOTU and 32 μl (0,252 mmol) of NEM at 3°C. After 12 h at room temperature the PE the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature the solvent is evaporated and the residue purified by HPLC, receiving 3 mg of diastereoisomer I (MS 567,3 (M+l)+) and 3 mg of diastereoisomer II (MS 567,3 (M+1)+).

Example 10: Alloc-pAph-Glu(3-(3,5-dichlorobenzenesulfonyl)propyl)amide

a) N-(3-Aminopropyl)for 3,5-dichlorobenzenesulfonate

1,3-Diaminopropan (6 g, of 81.5 mmol) is dissolved in 45 ml of 1,4-dioxane and at 15-20°C for 3 hours while stirring, slowly add a solution of 3,5-dichlorobenzenesulfonate (2 g, 8,15 mmol) in 5 ml of 1,4-dioxane. Stirring is continued at room temperature. After 30 hours the precipitate is filtered off and the filtrate was concentrated in vacuo. The residue is distributed between ethyl acetate and water. The organic layer is separated, dried with magnesium sulfate, filtered and concentrated in vacuo, obtaining 2.0 g of the crude substance. 750 mg of the substance purified by HPLC, getting 675 mg specified in the title compounds as TFA salt (MS 283,0 (M+N)+). 200 mg of this product was dissolved in ethyl acetate and treated with 5 ml of dilute potassium carbonate solution. The organic layer is separated, dried, filtered and concentrated in vacuo, receiving not containing TFA specified in the header Amin.

b) Alloc-pAph-Glu-3-((3,5-dichlorobenzenesulfonyl)propyl) amide

N-(3-Aminopropyl)for 3,5-dichlorobenzenesulfonate (7 mg, and 23.4 mmol), Alloc-pAph-Glu(OtBu)HE (10 mg, a 19.5 mmol) and HOBt hydrate (9 mg, 58,5 µmol) dissolved in 2 ml of a mixture of DMF and DCM, 1:3. Then add DIC (6 μl, 39 mmol). After stirring for 3 h, the solution is left for a weekend at room temperature, then the solvent is removed and the residue purified by HPLC, receiving of 6.5 mg of the product of condensation. It is stirred in 4 ml of a mixture of TFA and DCM 1:1 within 2 hours After standing overnight, the solvent evaporated and the residue dissolved in DCM. After evaporation of the solvent the residue is purified by HPLC and lyophilizers, receiving 3.5 mg specified in the connection header. MS 685,4 (M+N)+.

Example 11: Alloc-pAph-Glu-(3-(naphthalene-2-sulfonylamino)methyl)benzyl)amide

a) (3-Aminomethylbenzoic)amide naphthalene-2-sulfonic acid

α,α'-Diamino-m-xylene (24 g, 176 mmol) was dissolved in 50 ml of 1,4-dioxane, and at 15-20°With added slowly over 3 hours with stirring naphthalene-2-sulphonylchloride (4 g, 17.6 mmol), dissolved in 50 ml of 1,4-dioxane. Stirring is continued at room temperature. After standing overnight the precipitate is filtered off and the filtrate was concentrated in vacuo. The residue is partitioned between DCM and water. The organic layer is separated and washed with water and 1 N Hcl. The oily layer formed between the organic and aqueous layer is separated. It hardens when standing. The obtained solid handle what dilatatum, sucked off and washed with ethyl acetate. The residue is dissolved in water and treated with potassium carbonate solution. The aqueous solution extracted three times with ethyl acetate and the combined organic phases are dried over magnesium sulfate, filtered and concentrated, obtaining 3.2 g specified in the connection header. MS 327,3 (M+H)+.

b) Alloc-pAph-Glu-(3-(naphthalene-2-sulfonylamino) methyl) benzyl)amide

(3-Aminomethylbenzoic)amide naphthalene-2-sulfonic acid (8 mg, and 23.4 mmol), Alloc-pAph-Glu (OtBu)-HE (10 mg, 19,5 microns) and HOBt hydrate (9 mg, 58,5 µmol) dissolved in 2 ml of a mixture of DMF and DCM, 1:3. Then add DIC (6 μl, 39 mmol). After 3 h the reaction mixture was concentrated and treated as described in example 10. After lyophilization get to 7.6 mg specified in the connection header. MS 729,4 (M+N)+.

Example 12: Alloc-pAph-Glu-(4-carbamoylmethyl-2-yl)amide

(a) Fmoc-Glu(OtBu)-(4-carbamoylmethyl-2-yl)amide

To a solution of 1.24 g (2.1 mmol) of Fmoc-Glu(OtBu)-OPfp in 10 ml of DMF is added a solution of 0.33 g (2.1 mmol) of 2-(2-aminothiazol-4-yl)-ndimethylacetamide in 10 ml of DMF for 15 minutes After 2 days at room temperature the solvent is evaporated and the residue is washed with ether, receiving 0,86 g specified in the connection header. MS 565,4 (M+H)+.

b) H-Glu(OtBu)-(4-carbamoylmethyl-2-yl)amide

The solution 0,86 g (of 1.52 mmol) Fmoc-Glu(OtBu)-(4-carbamoylmethyl-2-yl)amide in 5 ml of a mixture of DMF/piperidine (1:1) is stirred for 3 h at room the Oh temperature. The solvent is evaporated and the residue filtered through celite, getting 0,37 g specified in the connection header. MS 343,4 (M+N)+.

c) Alloc-pAph-Glu-(4-carbamoylmethyl-2-yl)amide

To a solution of 50 mg (0,17 mmol) Alloc-pAph-OH and 39,1 mg TOTU in 10 ml of DMF added to 58.8 mg (0,17 mmol) of H-Glu(OtBu)-(4-carbamoylmethyl-2-yl)amide and 21.8 μl of NEM. After 24 h at room temperature the solvent is removed and the residue partitioned between aqueous solution of NaHCO3and ethyl acetate. The organic phase is dried, filtered and evaporated. The residue is stirred for 16 h with 0.6 ml of TFA. Add 50 ml of ethyl acetate and 10 ml of ligroin and the precipitate is filtered off, receiving 59 mg specified in the connection header. MS 560,4 (M+1)+.

Example 13: Alloc-pAph-Glu-(4-amino-2-methylpyrimidin-5-ylmethyl)amide

To a solution of 53 mg (0.11 mmol) Alloc-pAph-Glu(OtBu)-HE and 15 mg (0.11 mmol) 4-amino-5-aminomethyl-2-methylpyrimidine in 5 ml of DMF added 37 mg (0,115 mmol) of TOTU and 14 μl of NEM at 3°C. After 12 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature, add ethyl acetate, isopropanol and methanol and the precipitate is filtered off, receiving 46 mg specified in the connection header. MS TO 541.3 (M+1)+.

Example 14: Alloc-pAph-Asp-(3-aminobenzyl)amide

To a solution of 50 mg (0,153 mmol) Alloc-pAph-OH and 50.3 mg (0,153 mmol) of the hydrochloride of H-Asp(OtBu)-3-aminobenzamide in 5 ml of DMF are added 50 mg (0,153 mmol) of TOTU and 60 μl of NEM during the ° C. After 12 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature, add ethyl acetate and the oily precipitate is separated and dried from the frozen state, receiving 82 mg specified in the connection header. MS 511,3 (M+1)+.

Example 15: Alloc-pAph-2-Aad-(3-aminobenzyl)amide

To a solution of 100 mg of the hydrochloride (0,305 mmol) Alloc-pAph-OH and 139 mg (0,305 mmol) of the hydrochloride H-2-Aad(OtBu)-(3-aminobenzyl)amide in 5 ml of DMF added 128 mg (0,389 mmol) of TOTU and 150 μl of NEM at 3°C. After 16 h at room temperature the solvent is removed and the residue is treated with 1 ml of 90% TFA. After 8 h at room temperature, add ethyl acetate and the precipitate is filtered, purified by HPLC and lyophilizers, receiving 43 mg specified in the connection header. MS 539,2 (M+1)+.

Example 16: ll-ph-Glu(och3)-(3-aminobenzyl)amide

50 mg (0,153 mmol) of the hydrochloride Alloc-pAph-OH and 75 mg (0,153 mmol) of the hydrochloride of N-Glu(och3)-(3-aminobenzyl) amide is subjected to interaction in accordance with the method described in example 15, receiving 22 mg specified in the connection header. MS TO 539.3 (M+1)+.

The following examples of compounds prepared as in methods similar to those described in the above examples.

Examples of compounds of formula Ia:

ExampleRandin the formula IaMS
173,5-dichlorophenyl685,4 (M+1)+
181-naphthyl729,4 (M+1)+

194-methoxyphenyl709,2 (M+1)+
20methyl617,1 (M+1)+
21dimethylamino644,1 (M+1)+
222-phenylethenyl705,2 (M+1)+
232-acetylamino-1,3-thiazol-5-yl685,4 (M+1)+
245-chlorothiophene-2-yl720,1 (M+1)+
254-forfinal697,2 (M+1)+

Examples of compounds of the formula Ib:

ExampleRbin the formula IbMS
263-bromophenyl697,1 (M+1)+
274-acetylaminophenol730,3 (M+1)+
284-methoxyphenyl647,2 (M+1)+
294-forfinal691,3 (M+1)+

Por the action of the compounds of formula IC:

ExampleRcin the formula IMS
303-bromophenyl723,3 (M+1)+
313-triptoreline711,1 (M+1)+
323-chlorophenyl677,1 (M+1)+
332,5-dichlorophenyl711,1 (M+1)+
345-chloro-3-methoxyphenyl682,2 (M+1)+

Example 35: ((S)-2-Allyloxycarbonyl-3-(4-carbamimidoyl)propionyl)-Glu-(3-(pyridine-3-ylsulphonyl)phenyl)amide (Alloc-pAph-Glu-(3-(pyridine-3-ylsulphonyl)phenyl)amide) MS 652,4 (M+1)+.

Example 36: ((R)-2-Allyloxycarbonyl-3-(4-carbamimidoyl)propionyl)-Glu-(3-(pyridine-3-ylsulphonyl)phenyl)amide (Alloc-D-pAph-Glu-(3-(pyridine-3-ylsulphonyl)phenyl)amide) MS 652,4 (M+1)+.

Examples of compounds of the formula Id:

ExampleRdin the formula IdMS
373-aminomethylbenzoic539,2 (M+1)+
383-aminopropyl477,4 (M+1)+
393,4-dichlorophenyl (a) 578,2 (M+1)+

403-carbamimidoyl (a)552,2 (M+1)+
411-(1-naphthyl)ethyl574,3 (M+1)+
421-(6-aminopyridine-3-yl)methyl526,3 (M+1)+
432,4-dihydroxypyrimidine-5-yl (a)us $ 530, 3 (M+1)+
441-phenyl-1-(4-pyridyl)methylfor 587.4 (M+1)+
451-(6-chloro-2-naphthyl)-1-(1-methylpiperidin-4-yl)-methyl (a)691,3 (M+1)+
461,1-diphenylmethyl586,2 (M+1)+
474-cyanobenzyl535,4 (M+1)+
484-dimethylaminobenzoyl553,1 (M+1)+
494-AMINOPHENYL511,4 (M+1)+
502-(2,5-dioxoimidazolidin-1-yl)ethyl546,4 (M+1)+
514-carbamoylmethyl553,4 (M+1)+
521-(piperidine-4-yl)methyl517,5 (M+1)+
531-(1-hydroxycyclohexyl)methyl532,2 (M+1)+
542-(pyridin-3-yl)ethyl/td> 525,4 (M+1)+
552-carbarnoyl-1-methylethyl505,5 (M+1)+
564-guanidines567,5 (M+1)+
572-carbarnoyl-1-(4-chlorophenyl)ethyl601,4 (M+1)+
581-(1-carbamimidoyl-4-yl)methyl ((a)459,6 (M+1)+
593-methylbenzyl524,5 (M+1)+
603-oregonensis568,5 (M+1)+
61(R)-1-(3-nitrophenyl)propyl583,2 (M+1)+
62(S)-1-(3-nitrophenyl)propyl583,2 (M+1)+
636-hydroxy-2,2-dimethylpropyl-4-yl596,3 (M+1)+
644-amino-N-fluoren-9-yl599,2 (M+1)+
653-acetaminophen519,2 (M+1)+
662-(4-AMINOPHENYL)-1-(4-methylsulfinylphenyl)ethylof 693, 3 (M+1)+

(a) was isolated as hydrochloride

Examples of compounds of formula I:

ExampleRein the formula SMS
3-bromophenyl745,1 (M+1)+
683-chlorophenyl699,3 (M+1)+
694-methoxyphenyl695,3 (M+1)+

Example 70: ((S)-2-(3-Bromobenzonitrile)-3-(4-carbamimidoyl)propionyl)-Glu-(3-aminobenzyl)amide. MS 659,1 (M+1)+.

Example 71: ((S)-2-(3-Chlorobenzylamino)-3-(4-carbamimidoyl)propionyl)-Glu-(3-aminobenzyl)amide. MS 579,2 (M+1)+.

Pharmacological testing

The ability of the compounds of formula I to inhibit factor VIIa or other enzymes such as factor XA, thrombin, plasmin, or trypsin, can be assessed by determining the concentration of the compounds of formula I, in which there is a 50% inhibition of enzyme activity, i.e. the values of the IC50that is associated with the inhibition constant Ki. In chromogenic assays using purified enzymes. The concentration of inhibitor that causes a 50% reduction in the rate of hydrolysis of the substrate, determined by the method of linear regression after plotting the relative velocity of hydrolysis (compared to eingeborenen control) versus log concentration of the compound of formula I. To calculate the inhibition constants Ki value IC50correct taking into account the competition of the substrate using the formula Ki=IC50/{1+(the substrate concentration/Km)}, the de miles is a constant Michaelis-Menten (Chen and Prusoff, Biochem. Pharmacol. 22 (1973), 3099-3108; I.H.Segal, Enzyme Kinetics, 1975, John Wiley&Sons, New York, 100-125 incorporated herein by reference).

a) Analysis by factor VIIa

Inhibitory activity (expressed as the inhibition constant Ki (FVIIa)) compounds of the formula I in relation to the activity of a complex of factor VIIa/tissue factor is determined using a chromogenic analysis essentially as described previously (J.A.Ostrem et al., Biochemistry 37 (1998) 1053-1059 incorporated herein by reference). Kinetic tests conducted at 25°With half microtitration plates (Costar Corp., Cambridge, Massachusetts), using the kinetic tablet reader (Molecular Devices Spectramax 250). For routine analysis requires 25 µl of a solution of human factor VIIa and TF (final concentration, respectively 5 nm and 10 nm), which combined with 40 μl of a solution of the inhibitor at different dilutions in a mixture of 10% DMSO/TBS-PEG buffer (50 mm Tris, 15 mm NaCl, 5 mM CaCl2, 0,05% PEG 8000, pH 8,15). After a 15-minute period inactivated analysis initiated by adding 35 ál of chromogenic substrate S-2288 (D-Ile-Pro-Arg-p-nitroanilide, Pharmacia Hepar Inc., the final concentration of 500 μm).

The following results were obtained analysis of the inhibition constants Ki (FVIIa)).

Example 1
Example of connectionsKi (FVIIa) (μm)Example of connectionsKi (FVIIa) (μm)
0,4Example 20,2
Example 30,8Example 40,7
Example 50,6Example 60,4
Example 70,8Example 100,68
Example 110,8Example 1244,1
Example 131,9Example 143,4
Example 1575,7Example 17of 6.49
Example 181,8Example 190,68
Example 202,03Example 210,62
Example 221,46Example 231,38
Example 240,89Example 251,88
Example 260,30Example 270,73
Example 280,28Example 290,59
Example 300,43Example 310,64
Example 320,56Example 330,67
Example 341,05Example 373,7
Example 383,82  

The following tests can be used to study the inhibition of other enzymes involved in the coagulation process, and other serine proteases under the action of the compounds of formula I and, consequently, to determine their specificity.

b) analysis of the factor Ha

For this analysis use the buffer TBS-PEG (50 mm Tris-CL, pH of 7.8, 200 mm NaCl, 0,05% (wt./about.) PEG-8000, 0,02% (wt./about.) NaN3). IC50determined by combining in appropriate wells half microtitration tablet Costar 25 μl of a solution of human factor XA (Enzyme Research Laboratories, Inc.; South Bend, Indiana) in TBS-PEG; 40 ál of 10% (vol./about.) DMSO in TBS-PEG (neighborly control) or rastvorov test compounds with different concentrations diluted with 10% (vol./about.) DMSO in TBS-PEG; and substrate S-2765 (N(a)-benzyloxycarbonyl-D-Arg-Gly-L-Arg-p-nitroanilide; Kabi Pharmacia, Inc.; Franklin, Ohio) in TBS-PEG.

The analysis is carried out by inactivated the compounds of formula I with the enzyme for 10 minutes Then the analysis initiated by adding substrate to obtain a final volume of 100 μl. The initial rate of hydrolysis of a chromogenic substrate is determined by measuring changes in absorbance at 405 nm using a kinetic tablet reader (Biotek Instruments (Ceres UV900HDi) at 25°on the linear portion of the curve time depending the (usually 1.5 min after substrate addition). The concentration of the enzyme is 0.5 nm, and the substrate concentration is 140 ám.

c) Thrombin analysis

For this analysis use the buffer TBS-PEG. The value of the IC50determine by the method described above for the analysis of factor XA, except that the substrate is S-2366 (L-PyroGlu-L-Pro-L-Arg-p-nitroanilide; Kabi), and the enzyme is human thrombin (Enzyme Research Laboratories, Inc.; South Bend, Indiana). The concentration of the enzyme is 175 μm.

d) Plastikowy analysis

For this analysis use the buffer TBS-PEG. The value of the IC50determine by the method described above for the analysis of factor XA, except that the substrate is S-2251 (D-Val-L-Leu-L-Lys-p-nitroanilide; Kabi), and the enzyme is human plasmin (Kabi). The concentration of the enzyme is 5 nm, and the concentration of the substrate is 300 μm.

e) Tripeny analysis

For this analysis use the buffer TBS-PEG containing 10 mm CaCl2. The value of the IC50determine by the method described above for the analysis of factor XA, except that the substrate is BAPNA (benzoyl-L-Arg-p-nitroanilide; Sigma Chemical Co.; St. Louis, Missouri), and the enzyme is bovine trypsin in the pancreas (Type XIII, processed TRNC; Sigma). The concentration of the enzyme is 50 nm, and the concentration of the substrate is 300 μm.

Rat arteriotony model bypass thrombosis

nitroboy activity of the compounds of this invention can be assessed using in vitro rat arteriovenous (AV) shunt. AV shunt circuit consists of a tube of length 20 cm of polyethylene (PE) 60 inserted in the right carotid artery, the tube length of 6 cm from RE 160 containing mercerized cotton thread with a length of 6.5 cm (5 cm immersed in the bloodstream), and the second tube of the RE 60 (20 cm), the final contour in the left jugular vein. Before inserting the entire path is filled normal saline.

The test compound is administered by continuous infusion into the tail vein using a syringe and catheter type butterfly. The compound is administered for 30 min, then the shunt open and blood leak within 15 min (total time 45 min infusion). At the end of the 15-minute period shunt clamp, thread carefully removed and weighed on an analytical balance. The percentage inhibition of clotting calculated using the mass of thrombus obtained from control rats, which were injected with saline.

1. The compound of the formula I

where r is 1, 2 or 3;

s is 0;a

t is 0;

R1selected from the group comprising hydrogen, R11-CO - and R12-SO2-;

R11selected from the group comprising (C6-C14)-aryl, (C1-C8)-alkyloxy-where all these groups are unsubstituted or substituted by one or more identical or different for what estately R 40;

R12selected from the group comprising (C6-C14)-aryl, where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R2means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)nor R25(R26)N-CO-(CH2)p-D-(CH2)q-where D denotes the divalent residue-C(R31) (R32)-, bivalent (C6-C14)-Allenby residue or a divalent residue derived from an aromatic group Het containing 5 or 6 atoms in the cycle, of which 1 or 2 are the same or different cyclic heteroatoms selected from the group comprising nitrogen, and sulfur, and the numbers k, m, n, p and q, which are independent from each other and can be identical or different, are 0, 1, 2, provided that when D represents-C(R31) (R32- the sum of m+n cannot be equal to 0 and the sum of p+q cannot be equal to 0;

R21and R22that are independent of each other and can be identical or different, selected from the group comprising hydrogen, (C1-C12)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het and Het-(C1-C4)-alkyl-, where all these gr is PPI are unsubstituted or substituted by one or more identical or different substituents from the group includes R40, di-((C1-C8)-alkyl)-amino, aminocarbonyl-,

or R21and R22together with the carbon atom to which they are linked, form a saturated or unsaturated 3-8-membered carbocyclic structure, which may be condensed with one or two cyclic systems, which represents a heteroaromatic cycles containing 5-10 atoms in the cycle, one of which represents oxygen, and/or (C6-C10) carbocyclic aromatic structure, where the resulting group R21(R22CH) - is unsubstituted or substituted by one or more identical or different substituents selected from the group comprising R40,

R23denotes hydrogen, R27-SO2or R28-CO-;

R24, R25and R26represent hydrogen;

R27selected from the group comprising (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, amino-, Het-a, di-((C1-C8)-alkyl) amino-,

where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R28selected from the group comprising R27, (C1-C8)-alkyloxy-;

R31and R32indicate in the location;

R40selected from the group comprising halogen, hydroxy, (C1-C8)-alkyloxy-, (C1-C8)-alkyl, (C6-C14)-aryl, (C1-C8)-alkylsulfonyl, trifluoromethyl, acetylamino, amino, amidino, guanidino, oxo, nitro and cyano, where the group R40are independent from each other and can be identical or different;

R91, R92and R93, R96represent hydrogen;

R95means amidino;

R97means R99-(C1-C8)-alkyl-;

R99selected from the group comprising hydroxycarbonyl-, (C1-C8-allyloxycarbonyl-;

Het denotes a saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocyclic structure containing 3 to 6 atoms in the cycle, of which 1 or 2 are the same or different heteroatoms selected from the group including nitrogen and sulfur; in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

2. The compound of formula I according to claim 1, in which R11means (C6-C10)-aryl or (C1-C8)-alkyloxy is, in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

3. The compound of formula I according to claim 1 and/or 2, to the torus g is 1, t is 0, s is 0 and R95means amidino, in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

4. The compound of formula I according to any one of claims 1 to 3, in which R96denotes hydrogen, R97means R99(C1-C8)-alkyl, and R99denotes hydroxycarbonyl-, (C1-C8-allyloxycarbonyl is, in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

5. The compound of formula I according to any one of claims 1 to 4, in which R2means R21(R22)CH-, R23-Het-(CH2)kor R23(R24)N-(CH2)m-D-(CH2)n-, and D denotes a divalent residue-C(R31) (R32)-, divalent phenylenebis residue or a divalent residue derived from an aromatic monocyclic group Het, in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

6. The compound of formula I according to any one of claims 1 to 5, in which

r is 1;

s is 0;a

t is 0;

R1denotes allyloxycarbonyl;

R2means R21(R22)CH-, R23-Het-(CH2)kor R23(R24)N-(CH2)m-D-(CH2)n;

D denotes a divalent shall STATCOM-C(R 31) (R32)-, divalent phenylenebis residue or a divalent residue derived from an aromatic monocyclic group Het;

R95means amidino;

R91, R92, R93and R96represent hydrogen;

R97means R99-CH2-CH2-;

R99denotes hydroxycarbonyl or ((C1-C4)-alkyl)oxycarbonyl-; in all its stereoisomeric forms and mixtures thereof in any ratio, and its physiologically acceptable salt.

7. The method of obtaining compounds of one or more of claims 1 to 6 of General formula I

where

r is 1, 2 or 3;

s is 0;a

t is 0;

R1selected from the group comprising hydrogen, R11-CO - and R12-SO2-;

R11selected from the group comprising (C6-C14)-aryl, (C1-C8)-alkyloxy-where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R12selected from the group comprising (C6-C14)-aryl, where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R2means R21(R22)CH-, R23 -Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)nor R25(R26)N-CO-(CH2)p-D-(CH2)q-where D denotes the divalent residue-C(R31) (R32)-, bivalent (C6-C14)-Allenby residue or a divalent residue derived from an aromatic group Het containing 5 or 6 atoms in the cycle, of which 1 or 2 are the same or different cyclic heteroatoms selected from the group comprising nitrogen, and sulfur, and the numbers k, m, n, p and q, which are independent from each other and can be identical or different, are 0, 1, 2, provided that when D represents-C(R31) (R32- the sum of m+n cannot be equal to 0 and the sum of p+q cannot be equal to 0;

R21and R22that are independent of each other and can be identical or different, selected from the group comprising hydrogen, (C1-C12)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het and Het-(C1-C4)-alkyl-, where all these groups are unsubstituted or substituted by one or more identical or different substituents from the group comprising R40, di-((C1-C8)-alkyl)-amino, aminocarbonyl-,

or R21and R22together with the carbon atom to which they relate, about atout saturated or unsaturated 3-8-membered carbocyclic structure, which may be condensed with one or two cyclic systems, which represents a heteroaromatic cycles containing from 5 to 10 atoms in the cycle, one of which represents oxygen, and/or (C6-C10) carbocyclic aromatic structure, where the resulting group R21(R22CH) - is unsubstituted or substituted by one or more identical or different substituents selected from the group comprising R40,

R23denotes hydrogen, R27-SO2or R28-CO-;

R24, R25and R26represent hydrogen;

R27selected from the group comprising (C1-C8)-alkyl, (C6-C14)-aryl, (C6-C14)-aryl-(C1-C4)-alkyl-, Het-a, di-((C1-C8)-alkyl)amino, where all these groups are unsubstituted or substituted by one or more identical or different substituents R40;

R28selected from the group comprising R27, (C1-C8)-alkyloxy-;

R31and R32represent hydrogen;

R40selected from the group comprising halogen, hydroxy, (C1-C8)alkyloxy-, (C1-C8)-alkyl, (C6-C14)-aryl, (C1-C8)-alkylsulfonyl, trifluoromethyl, acetylamino, amino, amidino, guanidino, the CSR nitro and cyano, where the group R40are independent from each other and can be identical or different;

R91, R92and R93, R96represent hydrogen;

R95means amidino;

R97means R99-(C1-C8)-alkyl-;

R99selected from the group comprising hydroxycarbonyl-, (C1-C8-allyloxycarbonyl-;

Het denotes a saturated, partially unsaturated or aromatic monocyclic or bicyclic heterocyclic structure containing 3 to 6 atoms in the cycle, of which 1 or 2 are the same or different heteroatoms selected from the group including nitrogen and sulfur, comprising the condensation of the compounds of formulas II

with compound III

and the subsequent condensation of the resulting intermediate product with a compound of formula IV

obtaining the compounds of formula I and group R1, R2, R91, R92, R93, R95, R96, R97and r, s and t have the meanings indicated above, or a functional group present in the form of groups predecessors, or in protected form, and Y' and Y2represent hydroxyl or able to nucleate gnome substitution leaving group.

8. Pharmaceutical drug that has inhibitory activity against factor VIIa, comprising at least one compound of formula I according to one or more of claims 1 to 6, and/or its physiologically acceptable salt and a pharmaceutically acceptable carrier.

9. The compound of formula I according to one or more of claims 1 to 6, and/or its physiologically acceptable salts, for use as an inhibitor of factor VIIa.

10. The compound of formula I according to one or more of claims 1 to 6, and/or its physiologically acceptable salts, are suitable in the treatment or prevention of thromboembolic diseases.



 

Same patents:

The invention relates to a simple, effective method of obtaining the N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2), which includes the first stage of implementation of the alkaline hydrolysis of N2-(1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-TRIFLUOROACETYL-L-lysyl-L-Proline (1) in a mixed solution consisting of water and a hydrophilic organic solvent using an inorganic base n number of molar equivalents (n3) per mole of the above compound (1), the second stage of neutralization of the hydrolysis product with the use of inorganic acid in an amount of (n-1) to n molar equivalents (n3) and remove inorganic salts, obtained at deposition from a solvent system suitable for reducing the solubility of the inorganic salt, and the third stage is crystallization of the compound (2) present in the mixture after removal of inorganic salts from the solvent at its isoelectric point and thereby removing the compound (2) in the form of crystals, salts containing salt of organic acid - derived triperoxonane acid remains dissolved in the mother

The invention relates to substituted derivatives of benzo (b) thiepin-1,1-dioxides and their additive salts with acids of the formula I, in which R1is methyl, ethyl, propyl, butyl; R2- H, HE; R3a balance of amino acids, the remainder of diaminoanisole, and the balance of amino acids, the remainder of diaminoanisole in case you need one - or multi-substituted aminoadenine group; R4is methyl, ethyl, propyl, butyl; R5is methyl, ethyl, propyl, butyl; Z is a covalent bond

The invention relates to nitrate ACE-inhibitor of formula I or II, where Y is phenyl, X is C(RIIIRIV, RIII, RIV, RVand RVI- hydrogen containing stoichiometric amount of nitric acid

The invention relates to biotechnology and can be used for Introduzione nucleic acids into cells

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

The invention relates to a new five-membered heterocyclic compounds of General formula I:

in which W denotes R1-A-C(R13); Y represents a carbonyl group; Z represents N(Rabout); And denotes phenylene; E denotes R10CO; means (C1-C6-alkylene, which may be unsubstituted or substituted (C1-C6)-alkyl; R0indicates if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C8)-alkyl; Rrepresents H or (C1-C6)-alkyl; R1denotes X-NH-C(=NH)-(CH2)p; p = 0; X denotes hydrogen, -HE, (C1-C6-alkoxycarbonyl or, if necessary, substituted in the aryl residue phenoxycarbonyl or benzyloxycarbonyl; R2, R2a, R2bdenote hydrogen; R3means R11NH - or-CO-R5-R6-R7; R4denotes a divalent(C1-C4)-alkalinity residue; R5denotes a bivalent residue of a natural or unnatural amino acid with a lipophilic side chain, selected from grupy residues, if necessary, replaced byin the aryl residue, and, if necessary, substituted (C6-C12)-aryl residues; R6represents a simple bond; R7denotes Het; R10denotes hydroxyl or (C1-C6)-alkoxygroup; R11means R12-NH-C(O) R12-NH-C(S) or R14a-O-C(O) R12means (C6-C14)-aryl-(C1-C6)-alkyl, if necessary substituted in the aryl residue; R13means (C1-C6)-alkyl; R14aindicates if necessary substituted heteroaryl, heteroaryl-(C1-C6)-alkyl, if necessary substituted in the heteroaryl residue, or R15; R15means R16or R16-(C1-C6)-alkyl; R16mean residue 3-12-membered monocyclic or 6 to 24-membered bicyclic, or 6-24-membered tricyclic ring; Het means a 5-7 membered monocyclic residue of a heterocycle bound over the nitrogen atom in the ring, containing, if necessary, another heteroatom from the group consisting of N, O or S; g and h denote 0 or 1, in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, the

The invention relates to substituted derivatives of imidazolidine formula 1

where W denotes the R1-A-C(R13or

where the ring system may be substituted by 1, 2 or 3 identical or different substituents R13and where L denotes C(R13and ml and m2 independently of one another denote 0, 1, 2, 3 or 4, and the sum of m l + m2 is 3 or 4; Y represents a carbonyl group; A represents a direct bond or a bivalent residue of a phenylene, A denotes a divalent (C1-C6)-alkalinity balance, and (C1-C6)-alkilinity the residue is unsubstituted or substituted by one or more identical or different residues from the series (WITH1-C8)-alkyl and (C3-C10-cycloalkyl-(C1-C6)-alkyl, F denotes R10CO., HCO, or R8O-CH2; R is H or (C1-C8)-alkyl, (C3-C12-cycloalkyl-(C1-C8)-alkyl or, if necessary, substituted (C6-C14)-aryl, and all residues R are independently from each other may be the continuously or repeatedly substituted by fluorine, or the rest of the X-NH-C(=NH) -R20, X - N, R2- N or (C1-C8) -alkyl; R3- N, (C1-C10) -alkyl, which optionally can be substituted one or more times by fluorine, optionally substituted (C6-C14)-aryl, optionally substituted heteroaryl, (C6-C12-bicycloalkyl, R11NH, COOR21, CONHR4or CONHR15; R4- (C1-C10)-alkyl, which is unsubstituted or substituted once or many times, equal or different residues from the series hydroxycarbonyl, aminocarbonyl, mono - or di-((C1-C10)-alkyl)-aminocarbonyl, (C1-C8-alkoxycarbonyl, R5, R6-CO, R5denotes optionally substituted (C6-C14)-aryl, R6denotes the residue of a natural or unnatural amino acid, R8- N or (C1-C10)-alkyl, and R8independently from each other may be the same or different, R10hydroxy, (C1-C10)-alkoxy, (C1-C8-alkylsulphonyl hydroxy-(C1-C6)-alkoxy, (C1-C8)-alkoxycarbonyl-(C1-C6)-alkoxy, amino, mono - or di-((C1-C10)-alkyl)-amino, or R8R8N-CO-(C1-C means R12a-O-CO-or R12a-S(OH)2, R12ameans (C1-C10)-alkyl, optionally substituted (C6-C14)-aryl, optionally substituted in the aryl residue (C6-C14)-aryl-(C1-C4)-alkyl, or R15, R13- N or (C1-C6)-alkyl, which may optionally be substituted one or more times by fluorine, R15means R16-(C1-C6)-alkyl, or R16; R16denotes a 6-membered to 24-membered bicyclic or tricyclic residue, R20denotes a direct bond or (C1-C6-alkylen; R21- N or (C1-C8)-alkyl, R30represents one of the residues R32(R)N-CO-N(R)-R31or R32(R)N-CS-N(R)-R31; R32-CO-N(R)-R31or R12AO-CO-N(R)-R31and R30cannot mean R32-CO-N(R)-R31,ifat the same time W denotes R1-A-C(R13), And denotes a direct bond and R1andR13- N, R31denotes the divalent residue of R33-R34-R35-R36and R36linked to the nitrogen atom in the ring of imidazolidine in formula 1, R32means (C1-C8)-alkyl, which, when neobloc substituted (C6-C14)-aryl, optionally substituted in the aryl (C6-C14)-aryl-(C1-C8)-alkyl or optionally substituted heteroaryl, R33denotes a direct bond, R34denotes a bivalent residue of a number (C1-C8-alkylene, optionally substituted (C6-C14)-Allen; R35denotes a direct bond or a bivalent residue (C1-C8)-alkylene; R36denotes a direct bond, e and h represent independently from each other 0 or 1; in all their stereoisomeric forms and their mixtures in all ratios, and their physiologically acceptable salts, process for the preparation of compounds I; pharmaceutical drug that has the ability to inhibit the adhesion and/or migration of leucocytes and/or VLA-4 receptor

The invention relates to substituted derivatives of propanolamine with bile acids of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives, where GS is a group of the bile acid of the formula II, R1connection with X, HE, R2connection with X, HE, -O-(C1-C6)alkyl, -NH-(C2-C6)-alkyl-SO3N, -NH-(C1-C6)-alkyl-COOH, R1and R2at the same time does not mean the relationship with X, X -

l,m, n- 0,1; L - (C1-C6)-alkyl, AA1, AA2independently amino acid residue, may be one - or multi-substituted amino group

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to the field of medicine and relates to new N-pinakamaraming tryptophanase of dipeptides of the formula

C6H5-(CH2)n-CO-NH-(CH2)m-CO-X-Trp-R,

where n=1-5;

m=1-3;

X=L or D-configuration;

R=OH, OCH3OC2H5, NH2, NHCH3,

as well as pharmaceutical compositions containing them

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts

The invention relates to a simple, effective method of obtaining the N2-(1(S)-carboxy-3-phenylpropyl)-L-lysyl-L-Proline (2), which includes the first stage of implementation of the alkaline hydrolysis of N2-(1(S)-alkoxycarbonyl-3-phenylpropyl)-N6-TRIFLUOROACETYL-L-lysyl-L-Proline (1) in a mixed solution consisting of water and a hydrophilic organic solvent using an inorganic base n number of molar equivalents (n3) per mole of the above compound (1), the second stage of neutralization of the hydrolysis product with the use of inorganic acid in an amount of (n-1) to n molar equivalents (n3) and remove inorganic salts, obtained at deposition from a solvent system suitable for reducing the solubility of the inorganic salt, and the third stage is crystallization of the compound (2) present in the mixture after removal of inorganic salts from the solvent at its isoelectric point and thereby removing the compound (2) in the form of crystals, salts containing salt of organic acid - derived triperoxonane acid remains dissolved in the mother

The invention relates to compounds of formula (1), where X and Y Is N or O; R1substituted alkyl, substituted arylalkyl or cycloalkyl; R2and R3Is h or alkyl; And a Is-C(O)-, -OC(O)-, -S(O)2-; R4- alkyl, cycloalkyl or (C5-C12)aryl; compounds of the formula (2), where X and Y are O, S or N; R1- alkyl, optionally substituted arylalkyl; R2and R3Is h or alkyl;- C(O)-; R6- Deputy, including the condensed heterocyclic rings; and compounds of the formula (3), where X and Y are O, S or N; R1- alkyl, alkylsilane, (C5-C12)arylalkyl, (C5-C12)aryl; R2and R3Is h or alkyl; R2' and R3' - N; R11, R12and E together form a mono - or bicyclic ring which may contain heteroatoms

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to (i) essentially crystalline melagatran in the form of hydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 21.1, 10.5, 7.6, 7,0, 6.7, 6.4, 6.2, 5.7, 5.4, 5.3, 5.22, 5,19, 5.07, 4.90, 4.75, 4,68, 4.35, 4.19, 4.00, 3.94, 3.85, 3.81, 3.73, 3.70, 3.63, 3.52, 3.39, 3.27, 3,23, 3.12, 3.09, 3.06, 2.75, 2.38, and 2.35 Å and/or water content 4.3%; and (ii) essentially crystalline melagatran in the form of anhydrate, which is characterized by x-ray diffraction pattern on powder having crystalline peaks with following d values: 17.8, 8.9, 8.1, 7.5, 6.9, 6.3, 5.9, 5.6, 5.5, 5.4, 5.3, 5.2, 5.0, 4.71, 4.43, 4.38, 4.33, 4.14, 4.12, 4.05, 3.91, 3.73, 3.61, 3.58, 3.56, 3.47, 3.40, 3.36, 3,28, 3.24, 3.17, 3.09, 3.01, 2.96, 2.83, 2.54, 2.49, 2.41, 2.38, and 2.35 Å. Invention also relates to a method for preparation of indicated form, a method for interconversion of anhydrite form, to use of indicated compounds as pharmaceutical agent, and to preparation of drugs. Pharmaceutical preparation is suitable for treatment of condition, in case of which inhibition of thrombin is needed or desirable. Invention provides a method for treatment of such condition.

EFFECT: increased chemical stability and solid state stability as compared to amorphous forms of melagatran.

14 cl, 4 dwg, 3 tbl, 9 ex

The invention relates to medicine and is a pharmaceutical combination containing antagonist of P2C-receptor and other antithrombotic agent, and their use for the treatment and prevention of thrombosis

The invention relates to medicine, specifically to pharmacology, and relates to means influencing the rheology of blood and platelet aggregation

The invention relates to medicine, therapy, and can be used for prevention of thrombosis and embolism

The invention relates to experimental medicine, cardiology
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