Derivatives amidinohydrolase, the method of production thereof and derivatives amidinohydrolase with antikoaguliruyuschey activity

 

(57) Abstract:

Use in medicine as an anticoagulant funds. The essence of the invention: derivatives of amidinopropane formula I

R-SO2NH-CHR1-CO-NH-CH(CH2C6H4CNHNH2) COHR2R3< / BR>
where

R - related in - or b - position of the naphthalene ring, which, if necessary, may be substituted one or two times alkoxy /C1- C3/ group, or tetraline ring associated b - position, or a phenyl ring, which, if necessary, may be substituted in the 2, 3, 6 - positions /C1- C4/ - alkilani, in the 4th position /C1- C4/ alkoxygroup R1= group A-B, where A = -/CH2/n-, n=1-4, B - group-COOH or SO3H, or R1- group A-B-C, where the values of A and B above, and group C is formed from N - linked beta - or gamma - amino acids or N-glucosinolates uranium acids or R1- tetrazol; R2and R3together with the nitrogen atom form piperidyl, 3 - hydroxy /C1- C4/ alkylpiperidines. The retrieval method, reagent I: derivative Dr - cyanovinylene: BOC H N CH2/C6H4CN/ COO NR2R3after removal of Wosu group, the residue is treated RSO2Cl, the resulting connection is a cyano transferred to amidinopropane, and, if necessary, otscheplaut protective group. 2 C. and 8 C.p. f-crystals, 2 tab.

The invention relates to the derivatives of midioverlan, to a method for producing these compounds, to their use and to pharmaceutical anticoagulation remedies that contain these compounds.

As is known, a number of pathophysiological conditions leads to the consumption of anti-thrombin III (at III), the major inhibitor of thrombin in plasma. The decrease in at III leads to an increased risk of thrombosis, as you know by the way, about the cases with congenital deficiency of at III. Decrease to values below 75% of normal entails thromboembolic complications. These complications often appear in the form of disseminated intravascular coagulation after surgery and in the state of shock. In many cases, there are life-threatening blood clots. For the treatment and prevention of thrombotic diseases in medicine apply still anticoagulants with different operating principle. For immediate combat the risk of thrombosis is used substances such as at III, heparin and lately also hirudin. Long put significant disadvantages.

Heparin, for example, on the basis of its polysaccharide structure, you can assign only parenteral and its action is based on functionally capable of the level of anti-thrombin III. Coumarins directly counteract the biosynthesis of protein, and are dependent on vitamin K coagulation factors II, VII, IX and X can no longer be available in sufficient quantity and thereby the potential of blood coagulation is reduced. Hence, the slowdown in activity over time. As known side effects appear hemorrhagic necrosis of the skin, nausea and hair loss.

Low molecular weight thrombin inhibitors, in contrast, have the advantage that they are regardless of cofactors act directly on thrombin, and communicate directly with the active site and thus would be close to the enzyme. On the basis of their chemical structures of these substances could potentially be administered orally.

Special prominence was derived amino acids on the basis of arginine-based and amidinothiourea. The first group is referred compounds such as D -, i.e. phenylalanyl-propyl-orgininally and monohydrate (2R,4R)-4-methyl-I-[N2-(3-methyl-1,2,3,4-tet is hydrated specific inhibitor of thrombin, which is also used in therapy. Other known derivatives of lidinopril-alanine is a beta naphthylmethyl-glycyl-R, S-4-amidinotransferase (NAPAP). In British patent N 0236 163 and 0236 164 described derivative of NAPAP. This glycine (NH2-CH2-COOH) has been replaced by another amino acid patterns (NH2-CHR1-COOH, where R1represents a lower alkyl group, a lower hydroxyalkyl group, phenyl group or 4-hydroxyphenylazo group. 4-amidinohydrolase (Aph) can be methylated to N-methyl-Aph.

In addition, for NAPAP were described various derivatives on education arylsulfonyl, "bridge" the glycine and piperidinium ring. Consistent with this are the most suitable alpha - or beta-naphthyl-sulfonylurea N aprivately chain, heteroaryl-sulfonyl group, as an 8-hendersonvil, in decimal degrees worse. Another disadvantage of these compounds, which applies especially to NAPAP-structures, is their limited portability, unfavorable pharmacokinetic behavior and partly in too small of specificity, with particular reference should be made too high antitrypsin activity. Oral application of substances to Rotel liver enzymes is not optimal, so substances in the intestine and in the liver too quickly undergo metabolism. Due to the substitution of the piperidine in the NAPAP Proline is possible to achieve better portability and more favorable pharmacokinetics. However, very decisive lack of connection Proline is undesirable loss of the inhibition of thrombin 100 times compared to NAPAP. In addition, until now there is no possibility to significantly improve the specificity of these compounds against thrombin and trypsin by the introduction of substituents.

Therefore, the task of the invention to provide new compounds on the basis of amidinothiourea, which on the basis of its antithrombotic activity superior to the known compounds have high enzymatic resistance, improved portability, specificity, and pharmacokinetics.

The subject of this invention are therefore compounds of the formula

(I)

where R' denotes the associated alpha - or beta-position of the naphthalene ring, which, if necessary, by means alkyl groups containing up to 3 C-atoms, and/or alkoxygroup respectively with 3 C-atoms to form derivatives, or associated in alpha - or beta-position C-atoms, and/or also alkoxygroup respectively with 3 C-atoms to form derivatives, phenyl ring, which, if necessary, by means alkyl groups containing up to 4 C atoms, and/or number of groups to 3 structure of O-X, where O is oxygen and X is hydrogen, methyl, ethyl, n-propyl, i-propyl or tert.-butyl, and/or group structure-COOY in which Y represents hydrogen, methyl, ethyl, n-propyl, i-propyl, tert. -butyl, i-butyl, i-pentyl or neo-pentyl, to form derivatives, or system chromane that with the number of alkyl groups of preferably up to 5, containing up to 3 C-atoms, to form derivatives;

R1represents a group of the structure A-B, A -(CH2)n- and n=1-4, and is acid function selected from the group of carboxyl functions, which if necessary can be etherification or exists as amide and esters contain alcohol with the number of C-atoms to 17, the function of sulfonic acids, acids of phosphorus, the function of boric acid and a group of tetrazole, or R1represents a group of the structure A-B-C, where A has the abovementioned meaning, represents a carbonyl or sulfonyl, the band is formed from N-linked alpha-, beta-, gamma - or Delta-amino and or different and represent alkyl groups with the number of C-atoms to 4, or together form a heterocyclic ring with the number of stages of the ring up to 8, which using the hydroxy-group or hydroxyalkyl with the number of C-atoms to 3 can form derivatives, and the hydroxy-group in case of need there is in esterified form, and the corresponding acids are carboxylic acids, which contain up to 17 C atoms, in which the indicated C-atom exists in the R - or S-structure, but is preferably in the R-structure.

These new compounds are distinguished by the fact that the amino acid R1in the formula (I) represents an acidic amino acid. Acidic amino acids are, for example, found in proteins amino acids glutamic acid and aspartic acid or cysteine acid, but also unnatural amino acids such as aminoarabinose acid or 3-phosphonoethyl or 2-amino-3-Voropayeva acid. Because these amino acids due to the asymmetrically substituted C-atom exist as chiral substances derived from these amino acids, the new compounds show different activity, predominantly the corresponding amino acids in L-form give the final compounds with higher efficiency.

Named in the structure of R1group a differs from enhan is acid, the mean mainly the alpha-, beta-, gamma - or Delta-amino acid. These amino acids are, for example, alpha-aminoadipyl acid, alpha-aminobutyric acid, gamma-aminobutyric acid, 4-aminobenzoic acid, 2-aminobenzoic acid, Epsilon-aminocaproic acid, 1-aminocyclohexanecarboxylic acid, 2-aminocyclohexanecarboxylic acid, 3-aminocyclohexanecarboxylic acid, 4-aminocyclohexanecarboxylic acid, 1-aminocyclopentane acid, 2-amino-4,5-dimethylisoxazol(3)-1,8-di-carboxylic acid, 2-amino - 3-hydroxy-4-methylbenzoic acid, alpha-amino - somalina acid, aminohydroxylation acid-aminoazo-butyric acid, alanine, b-alanine, dehydroalanine, s-allylglycine, alliin, 2-amino-3-methyl-butyl-1,3-thiazolin-5-carboxylic acid, 6-amino-penitsillanovaya acid, alpha-amino-Emelyanova acid, 1-amino-cyclopropanecarbonyl acid, asparagine, aspartic acid, alpha-amino-cork acid, azetidinone acid, aziridination acid, baiqian, s-benzylpenicillin, canavanine, citrulline, cysteine, cystathionine, jelloway acid, 3,4-dihydroxyphenylalanine, 4-sulfanilamilny, 2,2-dimethyl-1,3-thiazolidin-4-Cain, histidine, homoserine, Delta-hydroxy-lysine, gamma-hydroxy-Proline, b-hydroxyproline, isoleucine, Soeren, isovaline, kynurenine, lanthionine, lysenin, leucine, lysergic acid, methionine, mimosin, Minalin, norleucine, Norvaline, Antonin, pipecolinate acid, penicillamine, phenylalanine, P-phenyl-glycine, picolina acid, Proline, digitopolis, b-phenyl-serine, pyridyl-2-alanine, pyrrolidone-(5)-carboxylic acid-(2), (pyrazolyl-3)-alanine, cinoxacin-2-carboxylic acid, Roseann, sarcosin, selenocysteine, Selenomethionine, serine, statin, (1,3-thiazolyl-(2))-alanine, b-(1,3-thiazolyl-(2))-alanine, threonine, theronin, thyroxine, 1,3-thiazolin-2-carboxylic acid, tertiary leucine, tryptophan, tryptamine, tyrosine, valine. These amino acids for the case where they are optically active, can exist in the D - or L-form.

For the case where s is aminocarbonyl acid, to which is referred, for example, D - or L-glutamic acid or aspartic acid, one of these carboxyl groups can form derivatives, preferably to form derivatives of alpha-carboxyl group. Such derivatives are preferably amides, which are formed, for example, ammonia, methylamine the United uronic acid, such a connection can be represented the following General formula:

with X1-H, -OH, - CH3, O-acetyl

X2-H, -OH, - CH3, O-acetyl

X3-H, -OH, - CH3, O-acetyl.

Suddenly new connections are high in inhibitors of thrombin. Unexpected is that the resistance against homogenates of liver and intestines, as well as against trypsin and chymotrypsin significantly improved in comparison with known compounds.

Also unexpectedly found that the efficiency and specificity of the compounds according to the invention have a decisive influence group R'. Connection with R'= b-naphthyl-sulfonyl and R1ASp shows the relative inhibition of thrombin and trypsin are very similar activity, therefore, little specificity. The introduction of alkyl groups and/or hydroxyalkyl groups and/or hydroxyl groups and/or carboxyl groups on the residue of sulphonic acids R', which referred mainly to the group with the number of C-atoms to 3, especially predominantly methyl - and/or metoxygroup, you can achieve a significant increase in specificity against thrombin. This means that the substitution of one or more of these groups receive properties of substances, Katariina trypsin.

Thus, the properties of the substances of this interesting as thrombin inhibitors class of substances can have a decisive influence thanks described here samples derivatives, and leads to superior connections.

The particular efficiency, as seen in the Kivalues have structures according to the invention on the basis of R' is phenyl and R1-CH2-COOH (i.e., L-ASp), as well as formed from these compounds, and R' bears or alkyl groups containing up to 4 C-atoms, or groups of patterns O-X, in which O is oxygen, and X is hydrogen, methyl, ethyl, n-propyl, i-propyl or tert.-butyl-, or a group of the structure -- COOY in which Y is hydrogen, methyl, ethyl, n-propyl-, i-propyl, tert.-butyl, i-butyl, i-pentyl - or neo-pentyl-.

In a more narrow sense and without limitation, the following examples as R' suitable preferably the following groups:

6,7-dimethoxymethyl- (b-Dmn)

-5-methoxyethyl- (b-Mns)

2,2,5,7,8-pentamethylchroman- (Pmc)

5,6,7,8-tetrahydronaphthalen- (Thn)

5,6,7,8-TETRAMETHYLBUTYL- (Tmn)

phenyl- (Phl)

4-methoxy-2,3,6-trimetilfenil- (Mtr)

2,3,4,5,6-pentamethylbenzyl- (Pme)

4-methoxy-2,3,5,6-tetramethylene- (Mte)

4-hydroxy-2,3,6-trimetilfenil- (Htr)

4-carboxyphenyl- (Cph)

As a group C applied alpha-, beta-, gamma - or Delta-amino acids and their derivatives, and N-glycoside linked uronic acid, such as b-D-iminoglycinuria acid.

Unexpectedly, the compounds according to the invention are also improved tolerability and therefore superior to the compounds of the prior art. For example, the b-naphthyl-sulfonyl-L-ASp-D,L-Aph-Pip was defined LD50value (rat, IV) about 120 mg/kg, on the contrary, this value is the NAPAP is about 20 mg/kg Also found that the other carboxyl group on the group R' further improves the tolerability of the compounds according to the invention.

Better tolerance of the inhibitors according to the invention with acid groups manifests itself in a reduced release of histamine and reduced the fall in blood pressure.

The fact that these compounds along with strong antithrombine activity, specificity and a more favorable tolerability are characterized by improved resistance to enzymes, for example, against trypsin and chymotrypsin, and homogenates of liver and intestines, making these substances class interesting anticoagulants.

As another advantage of saadeddine particularly attractive.

Compounds according to the invention can be used as antithrombine money for therapy in order to prevent the formation of blood clots, or when the diagnosis.

The subject invention also includes obtaining derivatives of these compounds, especially compounds of ester. The latter are characterized by the fact that carboxypropyl etherification on the amino acid R1with the help of aliphatic alcohols with the number of C-atoms to 17. Thus, these esters are formed from alcohols as methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl, tert.-butyl, n-pentalogy, isopentylamine, neo-pentalogy, oktilovom, willowy, dodecyloxy, hexadecanoyl or heptadecanoyl alcohol. Due to the formation of derivatives with alcohols improves the solubility of the lipids according to the invention, which is a positive effect on the perception of the intestine.

If the residuals R2or R3there are a hydroxyl function, the latter can be, if necessary, tarifitsirovana carboxylic acids. Such carboxylic acids are, for example, acetic acid, succinic acid, trimethylhexane acid, hexacarbonyl acid, octacosanol the>As medinova function on the basis of the basic steps are usually as salts, inhibitors of thrombin according to the invention can also appear in various salt forms. The shape of the salt has a significant effect on the solubility of the compounds, as well as absorption in the case of therapeutic use. As salt forms here include formate, acetate, caproate, oleates or salts of carboxylic acids with the number of C-atoms to 16, chlorides, bromides, iodides, alkanesulfonyl with the number of C-atoms up to 10, salts of dicarboxylic acids and tricarboxylic acids like citrate or tartratami.

Especially preferred:

the compound of formula (I) in which R' denotes a b-naphthyl, R1denotes-CH2-COOX with X is hydrogen, R2and R3indicate together piperidine;

the compound of formula (I) in which R' denotes a b-6,7-dimethoxymethyl-, R1denotes-CH2-COOX with X is hydrogen, R2and R3indicate together piperidine;

the compound of formula (I) in which R' denotes a b-tetralin, R1denotes-H2-COOX with X is hydrogen, R2and R3indicate together piperidine;

the compound of formula (I) in which R' denotes 4-methoxy-2, is;

the compound of formula (I) in which R' denotes 4-carboxyphenyl-, R1denotes-CH2-COOX with X is hydrogen, R2and R3indicate together piperidine;

the compound of formula (I) in which R' denotes 4-hydroxy-2,3-6-trimetilfenil-, R1denotes-CH2-COOX with X is hydrogen, R2and R3indicate together piperidine;

the compound of formula (I) in which R' denotes 2,2,5,7,8-pentamethylchroman-, R1denotes-CH2-COOX with X is hydrogen, R2and R3indicate together piperidine;

the compound of formula (I), wherein X represents the residue of the alcohol, which has a number of C-atoms to 17;

the compound of formula (I), and R1has the structure -(CH2)n-SO3H n 1 4;

the compound of formula (I), and R1has the structure -(CH2)n-PO(OH)2n 1 4;

the compound of formula (I), wherein R2and R3indicate together 3-hydroxyethylpiperazine;

the compound of formula (I), characterized in that hydroxypoly etherification carboxylic acid, which contains a number of C-atoms to 17.

The subject of the invention is also a method for obtaining compounds of formula (I), characterized in that the protected cislo is notarialnaja, remove N-alpha-protective group, associate chloride sulfonyl with this group of nitrogen, transferred the cyano in amidinophenoxy and if necessary otscheplaut existing protective group on the third function of acidic amino acids.

To insert acidic amino acid, which is referred especially amino acids aspartic (ASp) or glutamic (GIu), you should return to the use of protected amino acids. With the blocking of N-alpha-function with a protective group. As protective groups are thus preferably groups such as urethane such as tert.-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z or Cbo), biphenyltetracarboxylic (Bpoc), dimethoxydimethylsilane (DdZ) or 9-fluorenylmethoxycarbonyl (Fmoc). Special attention should be paid to disguise carboxyl group in the side functions.

Here used are preferably esters, depending on the needs after synthesis can be split. If after synthesis intend to carry out the removal of masking the side groups are used preferably tertiary complex butyl ether. As N-alpha-protective groups are suitable, for example, usasem is uncle end connection must be esterified, then preferably the corresponding N-alpha-Z-protected amino acid alpha-tertiary complex butyl ether etherification with the desired alcohol, Z-group is removed by hydrogenolysis, the corresponding chloride sulfonyl turn derived from amino acids, tertiary complex butyl ether otscheplaut acidolysis and the isolated product is associated with aminopentyl derived cyanovinylene. So get a sulfa communication standard method, and the corresponding anhydrides of sulfonic acids bind with the amino group of an acidic amino acids. Obtaining compounds which contain R' group of the phenol, is protected through appropriate simple phenolic esters, particularly preferred tertiary butyl ethers, which after conversion into the chloride sulfonyl and get a sulfa communication hatshepsuts acidolysis and give, therefore, the final connection.

Free groups of the phenol can also be obtained by other known methods, for example, with the means demethylation, particularly preferably tribromide boron in an organic solvent, and should be mentioned dichloromethane.

The second possibility is that the first polufinalnoy. To obtain a tertiary complex butyl ether arylsulfonyl-amino acids or tertiary complex butyl ether heteroarylboronic-amino acids corresponding sulfonic acid chloride and tertiary butyl ester, alpha-methyl ester of the amino acids in turn dimethylformamide, with the addition of bases, for example, N-methylmorpholine or diisopropylethylamine. Methyl ester omelet using liquor and connecting with the derived Aph - or cianfanelli by carbodiimide reaction. Compounds according to the invention from the group of sulfonic acids (B SO3H), preferably cysteinsulfinic, can be obtained by using N-alpha-protected cysteinsulfinic. For this Boc-group is associated with the nitrogen of the amino acid and this compound is combined with cyanophenylacetic. After removal of the protective group reacts to the desired sulfonic acid chloride. You can also obtain the corresponding compound of cysteine with a free sulfoxidation function and then translate it with an oxidizer, for example, naturaline acid, in the acid. While I prefer to use Boc-Cys (SStBu) or Boc-Cys (Trt). Oxidation reactions OS is the group of alpha-, beta-, gamma-or Delta-amino acids get by known methods. Preferably introduced N-protected acidic amino acid, for example, aspartic, and as a protective group, preferably a final sulfonamidnuyu structure associated with carboxylterminal amino acid. While the alpha-carboxyl function is preferably protected as a methyl ester. Binding occurs mainly by means of the condensation type, carbodiimide, preferably using dicyclohexylcarbodiimide. The reaction can be added hydroxybenzotriazole. As a solvent used mainly dimethylformamide.

After the separation of the substances free alpha-carboxyl group as in the case of complex methyl ester saponification occurs.

These preliminary stage then bind using methods described here with aminopentyl of cyanovinylene and continue the reaction, i.e. get amidinophenoxy. To obtain the compounds according to the invention, and group C is N-glycoside linked uronic acid, first associate the N-alpha and C-alpha-protected acidic amino acid with a correspondingly protected carbohydrate Chemistry, 207, 71-79 (1990); Urge Z. and others Jetrahedron Letters 32 (9), 3445-3448 (1991); Walczyna R. and other Carbohydrate Research, 180, 147-151 (1988)). After removal of the nitrogen protective group of amino acids, the sulfonic acid chloride is associated, as described above, and otscheplaut C-alpha - carboxyl group. Then there is the connection to the amino group of the C-terminal portion, which is used preferably amidinohydrolase-amide, particularly preferably D-4-amidinopropane-piperidin. After the liberation from the protection of uronic acid substances purified by conventional means such as gel permeation chromatography or ion exchange chromatography.

For more amidinophenoxy connection of the p-cyanovinylene dissolved in pyridine and triethylamine and saturated with hydrogen sulfide. After 2-3 days the solution is put in hydrochloric acid water and produce sediment. After methylation by meteorologi means, preferably methyl iodide, and the transformation of ammonium salt such as ammonium acetate, in alcohol, preferably in methanol, get derived peptide with amidinothiourea. After processing acidolysis with triperoxonane acid or HCl in acetic acid to obtain the desired final product. Subsequent gel permeation chromatography for Rwith resonance and mass spectrometry on the identity, and by using liquid chromatography high pressure (HPLC) and thin layer chromatography for purity. For translation into the desired salt form is predominantly ion-exchange chromatography. When the corresponding connection is associated with carboxymethylamino ion exchange resins, for example CMRfractogel, and elute with the desired acid. The end product by lyophilization get in crystalline form. Other required salt forms can be obtained from the acetate salts.

The inhibitors according to the invention for activity measurement test according to different criteria, it is preferable that the determination of Ki-value IC50-values and partial-time education thromboplastin (PTT) in vivo and in vitro. To test the specificity determine the IC50-values against various semiprotect, especially thrombin and trypsin, and the test substance is incubated with pure enzyme, preferably trypsin, chymotrypsin or papain or homogenates of the liver or intestines, and from solutions at certain intervals of time selected sample, which is measured mainly using liquid chromatography high pressure. Thus, monetra split. The claimed compounds are talking about specific and highly active inhibitors of thrombin with a large antithrombin capability that exceeds the known still low molecular weight inhibitors, and which partially differ also by the possibility of intestinal applications, as it can be installed with the connection Mtr-L-Asp-D-Aph-Pip.

The subject of the invention is also a diagnostic or therapeutic agent containing the compound of formula (I).

In addition, the subject invention is the use of compounds of formula (I) in the method for obtaining diagnostic tools or treatments with antithrombotic action.

Abbreviations:

Aph amidinohydrolase

NAPAP b-naphthylmethyl-glycyl-D,L-p-amidinopropane-piperidin

ASp aspartic acid

Asr asparagine

GIu glutamic acid

CyS (SO3H) cysteine acid

b-Dmn 6,7-dimethoxymethyl

b-Mns 5-methoxymethyl

Pmc (2,2,5,7,8-pentamethylchroman

Thn 5,6,7,8-tetrahydronaphthalen

Tmn 5,6,7,8-TETRAMETHYLBUTYL

PhI phenyl-

Mtr 4-methoxy-2,3,6-trimetilfenil-

Tos 4-were

Pme 2,3,4,5,6-pentamethylbenzyl-

Mte 4-methoxy-2,3,5,6-tetramethylene-jocstarbunny

Bpoc biphenylenediisocyanate-

Ddz dimethoxydimethylsilane

The Fmoc fluorenylmethoxycarbonyl

Pip piperidine

OtBu tert.-butyl ester

OMe methyl ester

OEt ethyl ester

OiBu ISO-butyl ester (second-butyl ester)

OiPr ISO-propyl ester

OnPe neo-pentalogy ester

DC thin-layer chromatography

DCCI dicyclohexylcarbodiimide

DMF dimethylformamide

FAB-MS Fast atom bombardment mass spectrometry

DIPEA diisopropylethylamine

HOBt hydroxybenzotriazole

The following examples describe the invention more: D-R-lidinopril-alanyl-piperidin beta naphthylmethyl-L-aspartic acid

1. BOC-D-R-cyanovinylene-piperidin. 50 g (225 mmol) of p-cyanobenzaldehyde, 55 g (255 mmol) diethyl ether complex acetamidomalonate acid and 2 g of potassium iodide was heated to the boil in 250 ml of absolute dioxane. It was buried for 3 h with freshly prepared solution of 6 g (260 mmol) of sodium in ethanol. Even after 3 hours boiling under reflux was cooled to 80oand for 3 h was added 170 ml of sodium lye. The initial mixture was heated for 4 h to 95o. After cooling using the global liquor has established a pH value of 9 and two times were extracted with ethyl acetate. The aqueous phase with hydrochloric acid again brought to pH 1, and was crystallized N-acetyl-cyanovinylene. The crystals were collected, washed several times with water and dried in high vacuum.

Yield: 47 g (79,2% of theory).

Test for purity: thin layer chromatography Rf 0.5 (chloroform 50/methanol 10/glacial acetic acid 2,5/about. hours).

24 g of this product was dissolved by adding 4 N. sodium liquor in 3 l of water and set the pH to 6.0-6.5. Added 500 mg acylase and incubated original mix 4 days at 37o. After this, the solution by ultrafiltration was released from acylase and then agglomerated to a volume of 1 L. After establishing pH 1 was repeatedly extracted with ethyl acetate. The organic phase is washed with a little concentrated solution of sodium chloride, dried over sodium sulfate and the solvent evaporated. Got to 8.2 g of N-acetyl-D-cyanopyrrolidine (68% of theory). To 8 g of this compound was added 22 ml of glacial acetic acid and 4.3 ml of concentrated hydrochloric acid and 40 ml of water and heated for 24 h to a boil. After evaporation of the split-off solution and removal of adhering traces of acid with methanol was perioadele from methanol/diethyl simple Y with the addition of 7.5 ml of diisopropylethylamine. To this solution was added 6 g of tert.-Butylochka-carbonyl-oxyimino-2-phenyl-acetonitrile in 17 ml of dioxane and stirred overnight. Added 40 ml of water and 50 ml of ethyl acetate. The aqueous phase was separated and the organic phase was extracted again with 1-molar potassium bicarbonate. The combined aqueous phase was washed again with 10 ml simple diethyl ether and then with hydrochloric acid has established the value of pH 3. Was extracted 3 times with ethyl acetate, washed with sodium chloride solution and dried the organic phase over sodium sulfate. After evaporation of the solvent was obtained 5.6 g (78%) of Boc-D-cyanophenyl-alanine. 3,26 g (10 mmol) of Boc-D-cyanovinylene, 1,49 g (11 mmol) and Hobt 2,42 g (12 mmol) of DCCI, was dissolved in 50 ml DMF and stirred 1 h was Added 1 ml of piperidine and stirred over night. Besieged dicyclohexylphosphino was filtered, drove DMF and absorbed the residue in ethyl acetate. Washed 3 times with potassium bicarbonate, 3 times 1-molar potassium hydrosulfate and 3 times with a saturated solution of salt. After drying the organic phase with sodium sulfate and removal of the solvent gain of 3.16 g (80%) of Boc-D-cyanophenyl-alanyl-piperidine.

Purity: thin layer chromatography Rf of 0.27 (chloroform). in glacial acetic acid and stirred for 30 min at room temperature. Chip off the reagent drove in a vacuum, it was removed with toluene and the residue triturated with a small amount of simple diethyl ether. The crystals were collected and dried in vacuum.

Yield: 2.2 g (90% of theory).

3. Ddz-ASp (tBu)-D-cyanovinylene-piperidin. 2,88 g (7 mmol) of Ddz-ASp (tBu), 1.04 g HOBt, 1.73 g DCCl and of 2.06 g (7 mmol) cyano-i.e. phenylalanyl-piperidin-hydrochloride was dissolved in 50 ml of DMF. After the addition of 2.4 ml (14 mmol) of diisopropylethylamine was stirred 1 day in the dark at room temperature. The solvent is kept in vacuum, the residue was absorbed in ethyl acetate and washed 3 times with 1-molar solution of potassium hydrosulfate, 3 times with a solution of potassium bicarbonate and 2 times concentrated solution of common salt. The organic phase was dried over sodium sulfate and the solvent evaporated. The residue was stirred with simple diisopropyl ether, the crystals were collected and dried. Received 3,86 g (85% of theory) of Ddz-ASp (tBu)-D-cyano-phenyl-alanyl-piperidine.

4. b-naphthylmethyl-ASp (tBu)-D-cyanophenylacetic. 3.25 g (5 mmol) of Ddz-ASp (tBu)-D-cyanovinylene-piperidine was dissolved in 200 ml of 5-Noah triperoxonane acid in dichloromethane and stirred for 30 min at room temperature. The initial mixture was poured into 2-molarin times concentrated solution of common salt. After drying over sodium sulfate the solvent is evaporated and the oily precipitate was extracted three times simple diisopropyl ether. The oily residue was dissolved with the addition of 1,71 ml (10 mmol) DIPEA in dichloromethane, to which was added under stirring 1.13 g (5 mmol) of b-attilalongoria. The initial mixture was stirred over night at room temperature and then the organic phase is washed 3 times with a solution of NaHCO3, solution of potassium hydrosulfate and sodium chloride. After drying the organic phase over sodium sulfate drove the solvent and the resulting material was used without purification for further transformation.

5. b-naphthylmethyl-ASp(tBu)-D-amidino-fenilalanina-piperidin. Obtained in example 4, the compound was dissolved in 30 ml of dry pyridine, and after the addition of 1 ml of triethylamine for 3 hours was introduced gaseous hydrogen sulfide. After three days of aging at room temperature was poured into a mixture of 100 g of ice and 50 ml of concentrated hydrochloric acid. The precipitate was aspirated and washed with water. Tioned after drying was absorbed in 50 ml of acetone and mixed with 1.5 ml of methyl iodide. Boiled 30 min with phlegm. After cooling besieged simple diethyl ether. The precipitate solution is storytale the residue was absorbed in 30 ml of dry methanol was added 200 mg of ammonium acetate. Was heated for 3 hours to 60o. The solvent is evaporated in vacuum. The product was subjected to purification by chromatography on a Sephadex LH-20 in methanol.

Output: 630 mg.

Purity: DC:Rf of 0.55 (chloroform 50/methanol 10/glacial acetic acid 2,5/volume)

FAB-MS: M + H 636.

6. b-naphthylmethyl-ASp-D-amidino-phenylalaninamide. 500 mg selected in example 5, the substance was dissolved in 5 ml of 1,2 N. HCl in glacial acetic acid and was stirred 1 h at room temperature. After the solvent is evaporated, triturated the residue with a simple diethyl ether and collected on a porous glass filter. The product was dried over pjatiokisi phosphorus in deep vacuum. The crude substance was dissolved in water and was associated with the CM fractogel an ion exchanger. Elution was carried out with 5-Noah acetic acid. After lyophilization received 290 mg of the acetate salt. The correct structure was confirmed using 13C-nuclear magnetic resonance spectroscopy.

FAB MS: M + H 580.

6,7-dimethoxy-b-naphthalenesulfonyl-L-ASp-D-p-amidinopropane piperidin. Obtaining carried out by analogy with example 6. Instead of the acid chloride b-naphthalenesulfonate applied the acid chloride of 6,7-dimethoxy-b-naphthalenesulfonate.

FAB-MS: M + H RA-b-naphthalenesulfonyl-chloride and the above-mentioned method received 5,6,7,8-Tetra-b-naphthalenesulfonyl-L-ASp-D-p-amidinotransferase.

FAB-MS: M + H 584.

4-methoxy-2,3,6-trimethylphenylsulfonyl-L-ASp-D-p-amidinotransferase. When using 4-methoxy-2,3,6-trimethylphenylsulfonyl-chloride and the above-mentioned method was obtained 4-methoxy-2,3,6-trimethylphenylsulfonyl-L-ASp-D-p-amidinotransferase.

FAB-MS: M + H 602.

4-methoxy-2,3,6-trimethylphenylsulfonyl-L-CyS(SO3H)-D-p-amidinotransferase. When using 4-methoxy-2,3,6-trimethyl-phenyl-sulfonyl-chloride and the above-mentioned method was obtained 4-methoxy-2,3,6-trimethylphenylsulfonyl-L-CyS(SO3H)-D-p-amidinotransferase.

FAB-MS: M + H 638.

4-methoxy-2,3,6-trimethylphenylsulfonyl-L-asparaginyl-N-{ b-D-glyukopiranozil uronic acid]-D-p-lidinopril-alanyl-piperidin (Mtr-L-ASp(b-D-iminoglycinuria acid)-D-Asp-pip)

1. methyl-(2,3,4-tri-O-acetyl-b-D-glucopyranosyloxy)-uronate. 2 g of methyl-(2,3,4-tri-O-acetyl-b-D-glyukopiranozil-azide)-uronate was dissolved in 200 ml of ethyl acetate/methanol (2: 1; V:V), was added 2 g of palladium/charcoal, was established with the help of triethylamine value pH 7.5 and treated 1 h in a stream of hydrogen. The reaction mixture was filtered and the solvent evaporated.

Output: 1,9,

Purity: DC Rf of 0.35 (dichloromethane: acetone/ 2:1).

oC with 1.4 g of stage 1. Was stirred over night at room temperature and the solvent evaporated in vacuum. The residue was absorbed in chloroform, washed with water, dried with sodium sulfate and drove the solvent. The residue was purified on silica gel using chloroform/acetone (6:1 volume:volume).

Output: 1,7,

Control purity: DC Rf to 0.72 (chloroform:acetone/6:1).

3. 4-N-[methyl-(2,3,4-tri-O-acetyl-b-D-glyukopiranozil)uronate]-L-asparagine-complex tert.-butyl ether. 0.9 g stage II was dissolved in 20 ml of methanol, mixed with palladium/charcoal at the tip of the spatula and was first made 5 hours After filtering off the catalyst drove solvent and applied the residue (0.75 g) without further purification for subsequent reactions.

4. 2-N-(4-methoxy-2,3,6-trimethyl-benzazolyl)-4-N-[methyl-(2,3,4-tri-O-acetyl-b-D-glyukopiranozil)-uronate] -L-asparaginases tert.-butyl ether. 1.73 g of the preceding stage, 1.2 ml of diisopropylethylamine and 0.8 g Mtr-chloride was dissolved in 80 ml DMF and stirred overnight at room temperature. The solvent is evaporated in vacuo, the residue was absorbed in ethyl acetate and washed three times water is cromatografia on silica gel with dichloromethane/acetone (3:1 volume:volume).

Output: 1,57,

Purity: DC Rf 0,87 (dichloromethane:methanol/10:1).

5. 2-N-(4-methoxy-2,3,6-trimethyl-benzazolyl)-4-N-[methyl-(2,3,4-tri-O-acetyl-b-glyukopiranozil)-uronate] -L-asparagine. 2.2 g of stage IV was dissolved in 50 ml triperoxonane acid/dichloromethane (1:1 volume/volume) and stirred 1 h at room temperature. An acidic mixture is kept in vacuum and sticky traces of acid evaporated in vacuo with toluene. The product received without further purification was used for the next transformation.

Yield: 1.2 g

Purity: DC Rf of 0.7 (chloroform:methanol/3:1).

6. 2-N-(4-methoxy-2,3,6-trimethyl-benzazolyl)-4-N-[methyl-(2,3,4-tri-O-acetyl-b-D-glyukopiranozil)-uronate] -L-asparagine-Il-D-4-amidinopropane-piperidin. 1.0 g of the preceding stage, 0,23 g HOBt and 0.37 g of DCCI was dissolved in 50 ml of DMF and stirred at 4oC 30 minutes After this was added 0.4 g of D-4-amidino-phenylalanine-piperidine and 0.5 ml of N-methyl-research. The initial mixture was stirred over night at room temperature, was filtered and the solvent evaporated in vacuum. The crude product was chromatographically on silica gel with chloroform/methanol 5:1.

Output 1,2,

Purity: DC Rf of 0.7 (chloroform:methanol/3:1).


1.1 g of the previous step was dissolved in 50 ml of methanol and using 1 n sodium liquor has established a pH value of 9. After 2 hours at pH 8.5-9 was neutralized with aqueous methanol in HCL and the solvent evaporated in vacuum. The residue was chromatographically in methanol on a Sephadex R LH-20.

Yield: 0.9 g

Purity: DC Rf of 0.34 (chloroform:methanol:water/40:20:1).

8.2-N-(4-methoxy-2,3,6-trimethyl-benzazolyl)-4-N - b-D-glyukopiranozil)uronate-L-asparaginyl-D-4-amidinotransferase

0.9 g the last stage was absorbed in 100 ml of chloroform:methanol:water (40: 20:1 volume:volume) and mixed with 0.2 g of barium hydroxide. The mixture was stirred 3 hours at room temperature, using HCI in methanol has established a pH value of 3.5 and the solvent evaporated. The residue was chromatographically in methanol on a Sephadex RLH-20.

Output: 0,72 g

Purity: DC Rf of 0.32 (chloroform: methanol:water/8:6:1)

FAB-MS: 777,

4-metoki-2,3,6-trimethylbenzenesulfonyl-L-aspartic acid-(gamma-aminobutyric acid)-D-Aph-piperidin

1.4-methoxy-2,3,6-trimethylbenzenesulfonyl-L-aspartic acid-(gamma-aminobutyric acid-tertiary complex butyl ester)-D-cyanovinylene-piperidin

1 g Mtr-ASp-D-cyanovinylene-Piperi is a gamma-aminobutyric acid and 0.66 g of dicyclohexylcarbodiimide. First was stirred 1 h in an ice bath and then overnight at room temperature. Besieged dicyclohexylphosphino was filtered and the solvent evaporated in vacuum. The oily residue was swallowed up in ethyl acetate and 2 times washed with 1-molar solution of potassium bicarbonate, 1-molar solution of potassium hydrosulfate and a saturated solution of salt. After drying over sodium sulfate drove solvent.

Yield: 1.1 g

Purity: DC Rf 0,89 (chloroform:methanol/9:1).

2. 4-methoxy-2,3,6-trimethylbenzenesulfonyl-L-aspartic acid-(gamma-aminobutyric acid-tertiary complex butyl ester)-D-ApL-piperidin

Translation ceanography in amidinopropane carried out as the 1st example 5-1 stage.

Yield: 500 mg

Purity: DC Rf of 0.4 (chloroform:methanol:acetic acid/50:10: 2,5).

3. 3-methoxy-2,3,6-trimethylbenzenesulfonyl - L-aspartic acid-(gamma-aminobutyric acid)-D-ApL-piperidin

400 mg of the preceding stage is absorbed in 15 ml of 1.2 n HCL/acetic acid and stirred for 90 minutes at room temperature. An acidic mixture and drove twice stirred with toluene and evaporated toluene. The crude product was dissolved in 3 ml of methanol and Kristol: 320 mg

Purity: DC Rf of 0.25 (chloroform:methanol:acetic acid/50:10: 2,5).

FAB-MS: 686.

Lowering Matematicheskoe splitting using acylase in stage 1, the corresponding racemic D,L-cyanophenylacetic also transformed to compounds according to the invention, which are also highly effective thrombin inhibitors.

Determination of inhibition constants for thrombin

Constants of inhibition (Ki) for substances identified fermentations by known methods. Applied human thrombin was determined with a purity of 87% by active site titration". Test solution for Ki-definition consisted of a buffer solution (50 mmol, 75 mmol NaCI, pH 7.8. 37oC), 100 pM thrombin, 0.1 mmol substrate S2238 (CABI) and inhibitor, which ranged from 0 to 0.2 MM. Inhibitor and enzyme were incubated 10 minutes in advance, the reaction was started by addition of a chromogenic substrate S2238. To assess the kinetics applied mathematical algorithm for "tight connection", which was obtained using nonlinear regression Ki-values (table II) and was given the type of inhibition. The type of inhibition for all inhibitors was based on the comparison of more than 90%

Determination of the specificity of inhibi the Lena as the ratio of the Ki-values for trypsin and thrombin (table II). The concentration of inhibitor that causes a 50-percentage inhibition of enzyme activity, was identified as IC50(100 corresponds nestorienne enzymatic reaction). The value of the IC50for trypsin was determined as follows: trypsin from the pancreas of cattle was pre-incubated using increasing concentrations of inhibitor in 25 mmol Tris-HCL, 10 mmol CaCl2, pH 7.8 at 37oC for 10 minutes the Enzymatic reaction was initiated by addition of substrate chromosome TRV (7,110-5M). The release of pNA was measured after one hour at 405 nm. Likewise determined the IC50-values for thrombin, with the exception that applied the human thrombin, a buffer solution (50 mmol Tris-HCL, 50 mmol NaCI, pH 7.8) and 510-5M S2238. From the IC50-values for thrombin and trypsin were calculated K-value (Ki IC50IS + KM). The ratio of trypsin and thrombin were given specificity. The results are shown in table.2.

The scheme of synthesis 220

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DATA FOR COMPOUNDS CRC 220

Chemical name:

4-methoxy-2,3,6-trimethylphenylsulfonyl-asparagi-D-4-amidinopropane-piperidin hydroiodide

Structure:

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Molecular formula: C29deposits: 180-183oC

The value of speed [20D: -21.5o(c=1, methanol)

Nuclear resonance spectrum:

13C-NMR(CD3OD) 12.2(g), 18.4(g), 24.6(g), 25.3(t), 26.7(t), 27.2(t), 36.7(t), 39.3(t), 44.5(t), 47.5(t), 51.1(d), 54.1(d), 56.2(g), 113.4(d), 126.5(s), 128.0(s), 129.0(d), 130.9(s), 131.8(s), 140.3(s), 140.4(s), 145.0(s), 161.0(s), 168.2(s), 169.8(s), 171.8(s), 173.6(s)

1H-NMR(CD3OD) 1.34-1.70 (6H, pip-CH2), 2.14 (3H, s, mtr-CH3), 2.47 (2H, d, asp-CH2S 6.1 Hz), 2.56 (3H, s, mtr-CH3), 2.65 (3H, s, mtr-CH3), 2.88 (1H, dd, from a abx aph-CH2J113.4 HZ, J27.1 Hz), 3.11 (1H, dd, b from abx aphCH2J113.4 Hz, S26.4 Hz), 3.32-3.55 (4H, m, pip CH2), 3.86 (3H, s, OCH3), 4.02 (IH, t, asp-CH s 6.1 Hz), 5.08 (1H, dd, x from aph CH J17.1 Hz, J26.4 Hz), 6.75 (1H, s, arom.CH) to 7.4(2H,d,arom.CH J=8.4 Hz), 7.9 (2H, d, arom.CH J 8.4 Hz)

Mass spectrum m/z (FAB): 602 (M+H)+< / BR>
PHARMACOLOGICAL DATA: CRC 220

Ki (nM) thrombin: 2.5

Ki (nM) trypsin: 312

Specification trypsin/thrombin: 125

Acute toxicity LD5: 80 mg/kg

Half-time I/2 (nach IV - Bf1us Gabe): 205 mini

1. Derivatives amidinohydrolase General formula I

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where R is connected to or the position of the naphthalene ring, which if necessary can be substituted one or two times alkoxy-C1- C3group, or tetraline ring related for the position, or phenyl ring, which 1
- C4- alkoxygroup;

R1group A B, where A -(CH2)n-, n is 1 to 4, B is a group COOH or-SO3H, or R1group A B C, where A and B have the above meanings, and group C is formed from N-linked beta - or gamma-amino acids or N-glucosinolates uronic acids, or R1tetrazol;

R2and R3together with the nitrogen atom form piperidyl, 3-hydroxy-C1C4-alkylpiperidines.

2. Derivatives amidinohydrolase under item 1 of the formula I, where C is the atom exists in the R-configuration.

3. Derivatives amidinohydrolase on PP. 1 and 2 of the formula I, where R is naphthyl, R1CH2COOX with X is hydrogen, and R2and R3together piperidyl.

4. Derivatives amidinohydrolase on PP. 1 3 of the formula I, where R is-6,7-dimethoxymethyl, R1CH2COOX, X is hydrogen, and R2and R3together piperidyl.

5. Derivatives amidinohydrolase on PP. 1 4 of the formula I, where R is tetralin, R1CH2COOX, X is hydrogen, and R2and R3together piperidyl.

6. Derivatives amidinohydrolase on PP. 1 5 formula I, where R is 4-methoxy-2,3,6-trimetilfenil, R1CH2OOH, X is hydrogen, and R2and R3together piperidyl.

7. Derivatives amidinohydrolase p is isopenicillin on PP. 1 7 formula I, where R2and R3together represent 3-hydroxyethylpiperazine.

9. The method of obtaining derivatives of amidinothiourea General formula I

< / BR>
where R is connected to or the position of the naphthalene ring, which if necessary can be substituted one or two times alkoxy-C1- C3group, or tetraline ring related for the position, or phenyl ring, which if necessary can be substituted in the 2-, 3-, 6-positions of the C1C4-alkilani, 4-position C1- C4-alkoxygroup;

R1A B, where A -(CH2)n-, n 1 4, B group COOH or-SO3H, or R1group A B C, where A and B have the above meanings, and group C is formed from N-linked beta - or gamma-amino acids or N-glucosinolates uronic acids or R1-tetrazol, R2and R3together with the nitrogen atom form piperidyl, 3-hydroxy-C1C4-alkylpiperidines,

characterized in that the derived D-p-cyanoaniline formula II

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where R2and R3have the specified values,

after removal of BOC-group enter into interaction with the derived N-protected amino acids of formula III

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where R has the above C the crystals IV

RSO2Cl

in forming this connection the cyano transferred to amidinopropane and if necessary otscheplaut protective group.

10. Derivatives amidinohydrolase General formula I under item 1, with antikoaguliruyuschey activity.

 

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106 cl, 9 tbl, 61 ex

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