Bicyclic compounds, the method of suppressing the adhesion of platelets and composition for its implementation

 

(57) Abstract:

Describes new bicyclic compounds having a nucleus formed from two condensed six-membered rings, a and b, represented by formula I, or a pharmaceutically acceptable salt, MES or proletarienne derivative of this compound, in which the bicyclic nucleus of the rings a and b is selected from the group consisting of formulas (17)-(21), R3is an acidic group containing an acid radical selected from formula group (S), n = 0-6; R0is the same or different and are selected independently from hydrogen, alkyl linking group -(L)- is a bond or is selected from the formula-C(=O)-N(H)- and-C(H2)-O-, Q is the primary group and is selected from amidinopropane and piperidine. New bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIB/IIIA, to prevent thrombosis. Also describes a method of suppressing the adhesion of platelets and composition for its implementation. 13 C. and 12 C.p. f-crystals, 1 PL.

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>

The invention relates to bicyclic compounds useful as drugs, the neutralizing effect of glycoprotein IIb/IIIa, for pmmotion the narrowing of blood vessels, such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic persistent angina, unstable angina, ischemic attacks, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis or abrupt occlusion with subsequent angioplasty, carotid endarterectomy, anastomosis of vascular tissue, etc., These terms constitute the various violations, which are thought to be initiated by activation of platelets on the vessel walls.

Adhesion and aggregation of platelets presumably are an important part of the formation of a blood clot. This activity is mediated multiple bonding platelet glycoproteins. The active binding sites for fibrinogen, fibronectin and other clotting factors are placed on trombotsitnoy membrane glycoprotein complex IIb/IIIa. When the activated platelet agonist such as thrombin, the active center of glycoprotein IIb/IIIa to fibrinogen, which can lead to platelet aggregation and clot formation.

Still it was proposed to block the centers of formation of thrombus through the use of various marcheskie amino acid derivative N-amidinophenoxy.

U.S. patent15039805 offers various derivatives of benzoic acid and phenylacetic acid to inhibit the binding of fibrinogen with fibrinogen receptor, glycoprotein IIb/IIIa.

In international patent application PCT WO 93/00095 encouraged to use contains semicolonies ring bicyclic compounds.

Application EP1456835 describes bicyclic compounds having fused six-membered rings (derived hinzelin-3-alkanoyloxy acid), which reportedly have an overwhelming effect on platelet aggregation.

International patent application PCT WO 93/08174 describes repeptitive integranova suppressors, which are bicyclic systems with 6 - and 7-membered fused rings, which have therapeutic applications for diseases for which illustrates the blocking of platelet aggregation.

Patent application WO 94/12478 describes the preparation of 6,5-bicyclic compounds, for which it is established that they are effective in the inhibition of platelet aggregation.

Patent application WO 94/08962 describes the preparation of 6,5-bicyclic compounds, for which it is established that they are effective in suppressing Agroline, for which it is established that they have a neutralizing effect on fibrinogen receptor.

Article by Robert S. McDowell and others (Robert S. McDowell, et al.) "From Peptide to Non-Peptide. 1. The Elucidation of a Bioactive Conformation of the arginine-glycine-aspartic Acid Recognition Sequence", journal of the American chemical society (J. Am. Chem. Soc.), 1994, 116, S. 5069-5076, describes the structure of ones means of suppressing the binding of fibrinogen is a glycoprotein IIb/IIIa.

Publication of Brent K. Blackburn and Thomas R. of Hadaka (Brent K. Blackburn and Thomas R. Gadek) "Chapter 9. Glycoprotein IIb/IIIa Antagonists" in Annual reports in medicinal chemistry Annual Reports in Medical Chemistry) - 28, part II - "Cardiolvascular and Pulmonary Agents", S. 79-88 [in Russian], 1993, published by Academic Press, Inc., describes dipeptide as neutralizers interaction of glycoprotein IIb/IIIa and fibrinogen.

Article by Robert S. McDowell and others (Robert S. McDowell, et al.) "From Peptide to Non-Peptide. 2. The de Novo Design of Potent, Non-Peptidal Inhibitors of Platelet Aggregation Based on a Benzodiazepinedione Scaffold" in the journal of the American chemical society (J. Am. Chem. Soc.), 1994, 116, S. 5077-5083, describes benzodiazepinee, which is a tool that overwhelming platelet aggregation.

The quinoline compounds mentioned in the patent literature for a variety of applications in medicine. For example, European patent sisodiya quinoline, useful as suppressors of lipoxygenase and/or neutralizers leukotriene possessing anti-inflammatory and anti-allergic properties. These compounds must contain three aromatic rings, each terminated by oxygen or sulphur and possibly other groups.

In the field of cardiovascular and cerebral-vascular therapy there is a need for alternative tools that can be used in the prevention and treatment of blood clots.

In the present invention discovered that certain new bicyclic compounds block fibrinogen receptor glycoprotein IIb/IIIa, thereby inhibiting platelet aggregation and subsequent formation of a blood clot. Pharmaceutical compositions containing bicyclic compounds of the present invention, inhibit aggregation and are useful for the prevention and treatment of thrombogenic diseases, such as myocardial infarction, angina, strokes, peripheral arterial disease, spreading intravascular coagulation and venous thrombosis.

The present invention consists in a new bicyclic compound with a nucleus formed from two fused six-membered rings a and b represented by the formula is different

< / BR>
Another aspect of the present invention is a pharmaceutical composition containing the new bicyclic compound of the present invention.

Another aspect of the present invention is a method of suppressing platelet aggregation, suppression fibrinogenic binding or prevent thrombosis by introducing to a mammal bicyclic compounds of the present invention.

Another aspect of the present invention is a method of treating a human to alleviate the pathological effects of atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic ongoing angina, unstable angina, ischemic attacks, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and subsequent angioplasty, carotid endarterectomy and anastomosis of vascular tissue; the method comprises the introduction mentioned the new bicyclic compounds of the present invention.

Detailed description of the invention.

The term "alkyl" used herein refers to a monovalent straight or branched chain of the moiety of one to ten atoms angle is reicived them.

The term "halogenosilanes alkyl", as used here, means only that certain alkyl group, a substituted one, two or three halogen atoms selected from chlorine, fluorine, bromine and iodine. Examples of such groups include chloromethyl, bromacil, trifluoromethyl and the like.

The term "aryl", used alone, means homozygocity aromatic radical, linked or unlinked. Preferred aryl groups are phenyl, naphthyl, biphenyl, phenanthrene, naphthacene and the like.

The term "substituted aryl" denotes an aryl group, a substituted one, two or three substituents selected from halogen, hydroxyl, protected hydroxyl, cyanide groups, nitro groups, C1-C10-alkyl, C1-C10-ascocarp, trifloromethyl, amino, aminomethyl and the like. Examples of such groups are 4-chlorophenyl, 2-were, 3-methyl-4-hydroxyphenyl and 3-atocopherol.

The term "arylalkyl" means one, two or three aryl groups with multiple carbon atoms attached to the alkyl radical with several carbon atoms. Typical arylalkyl group is a benzyl group.

The term "anti carbon atoms, containing double carbon bond, including 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like, but not limited by them.

The term "alkylene", as used here, refers to divalent straight or branched chain group of one to ten carbon atoms, including but not limited to, -CH2-, -(CH2)2-, -(CH2)3, -CH(CH3)-, -CH(C2H5)-, -CH(CH3)CH2- and the like.

The term "albaniles", as used here, refers to divalent straight or branched chain group of from two to ten carbon atoms containing the double bond carbon-carbon bonds, including (but not limited to,- CH= CH-, -C(CH3)= CH-, -CH=CH-CH2-, -CH=C(CH3)-CH2-, -CH2CH(CH=CH2)CH2- and the like.

The term "akinyan", as used here, refers to divalent straight or branched chain group of from two to ten carbon atoms containing a triple bond of carbon-carbon, including (but not limited to)

< / BR>
and things like that.

The term "amidinopropane" refers to the radical having the structural formula

< / BR>
The term "primary radical" denotes organic and piperidine group.

The term "core group" means an organic group containing one or more basic radicals. The core group may consist of only one basic radical.

The term "nenterprise organic radical" refers to any organic Deputy, is present in the bicyclic compound with the formula (I), which is not harmful to the effectiveness of this compound as a neutralizer of glycoprotein IIb/IIIa.

The term "acid residue" refers to an organic radical, which is the proton donor. Examples of the acid radicals are

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
The term "acidic group" means an organic group containing one or more acid radical. The acid group may consist of only one acid radical.

Compounds according to the invention.

Compounds of the present invention have the General formula (I) below

< / BR>
and all pharmaceutically acceptable salt, solvate and proletarienne derivatives of this compound.

Bicyclic core of formula (I) is formed by the merger of two six-membered rings a and b, having carbon atoms, the United the ligature, that is, unsaturation, which will give the ring structure of the aromatic character. It should be understood that the United bridging bond carbon atoms either unsubstituted or substituted (hydrogen) depending on the degree of unsaturation in the bicyclic ring system. Atoms A1, A2AND3and a4rings a and B atoms1B2IN3IN4ring In formula (I) independently selected from carbon, oxygen, sulfur and nitrogen with the proviso that at least two atoms of B1IN2IN3IN4are carbon atoms. More precisely, A1AND3and a4are selected independently from carbon, oxygen, sulfur and nitrogen, and A2mode can be selected from carbon or nitrogen, provided that A2has an unsaturated bond, if a2- nitrogen, provided that at least two atoms of A1AND2AND3and a4are carbon atoms. Accordingly, B1IN2and IN4are selected independently from carbon, oxygen, sulfur and nitrogen, and B3mode can be selected from carbon or nitrogen, provided that IN3has an unsaturated bond, if IN3is nitrogen, provided that at least two atoms of B1B2
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Kernel, shown by formulas (1) to (16) above and from (17) to (30) below, have the numbering of the atoms in rings a and b and the relevant provisions of the deputies, as shown above in (1). For example, the kernel (Imm) and (Ipp)

< / BR>
< / BR>
would give different products within formula (I).

Compounds of the present invention corresponding to the formula (I) with nuclei from (1) to (19), the following formulas (Ia) to (Ie):

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Other bicyclic nuclei suitable for formation of compounds of formula (I) represented by the following formulas (17) to (21):

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Compounds of the present invention corresponding to the formula (I) with nuclei (17)-(21) below using the formulas from (If) to (Ii):

< / BR>
< / BR>
< / BR>
< / BR>
Bicyclic nuclear ring, substituted with =O, suitable for the formation of compounds according to formula (I) represented by the following formulas (22) to (27):

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Compounds of the present invention corresponding to the formula (I) with kisloroddonornymi whosoever eateth the ring, with substitution using =O, suitable for the formation of compounds according to formula (I) below using the formulas from (28) to (30):

< / BR>
< / BR>
< / BR>
Compounds of the present invention corresponding to the formula (I) with nuclei (28)-(30) below using the formulas from (In) to (Ip):

< / BR>
< / BR>
< / BR>
The most preferred engines for compounds of the present invention are isoquinoline, isohedron, naphthalene, tetrahydronaphthalene, tetralone, dihydronaphthalene and benzopyran.

Deputy R3is an acid group or its pharmaceutically acceptable salt or MES (or proletarienne derived mentioned oxide group and is preferably an acid group containing carboxyl functionality. The group R3may be the only Deputy of the atom IN3rings. Alternatively, when the atom3can take two links, these links can be engaged in a double bond with the group R3(at the double bond R3attached directly to the ring In formula (I) or the second R3group or the second group selected from hydrogen, C1-C10-alkyl, C1-C10-halogenosilanes of alkyl, C2-C10-alkenyl, Crappy, C1-C10-alkoxygroup, C1-C10-urlcategory, carboxyl group, acyl, cyano, halogen-, nitro - and sulfopropyl.

R3acid group, preferably selected from the groups that have members that are represented by the following formula:

< / BR>
< / BR>
< / BR>
< / BR>
The substituents R0are reiterferien organic radicals and are the same or different on each atom B1B2and B4and the same or different between atoms B1B2and B4and independently selected from hydrogen, C1-C10-alkyl, C1-C10-halogenosilanes of alkyl, C2-C10-alkenyl,2-C10-quinil,3-C10-cycloalkyl, aryl, C6-C12-arylalkyl, a hydroxyl group, a C1-C10-CNS group, C6-C12-arylalkenes group, amino group, substituted amino group, karamolegos group, carboxyl group, acyl, cyano, halogen-, nitro-, sulfo -, provided that only one atom of B1B2and IN4can also be substituted by =O or =s

The number n of the substituents R0the atoms of B1B2and IN4the ring is an integer h is
and IN4. Usually n is in the range from 2 to 6 for most compounds

according to the present invention. So, for example, when the ring is In a very, B2oxygen, a B1and IN4- carbon, the atom2there is no substituent R0as shown in structural formula (Iq) below:

< / BR>
For unsaturated rings In the number of available links available to the individual atoms of B1IN2and IN4decreases and the number of the substituents R0correspondingly less. So, for example, when the ring is unsaturated, B2is nitrogen, and B1and IN4- carbon, B2there is no substituent R0as shown in structural formula (Ir) below:

< / BR>
Atoms A1, A2AND3and a4ring And independently selected from carbon, hydrogen, sulfur and nitrogen, provided that at least two atoms of A1, A2AND3and a4are carbon atoms.

The substituents R10are the same or different on each of the atoms A1AND3and a4and the same or different between atoms A1AND3and a4and independently selected from hydrogen, C1-C10-alkyl, C1-C10-pcela, aryl, C6-C12-arylalkyl, hydroxyl group, CNS group6-C12-arylalkenes group, carboxyl group, acyl, cyano, halogen-, nitro and sulfo; provided that only one atom of A1AND3and a4may also be substituted by =O or =S, when on the same atom, the two available positions for substitution (i.e., when one or more of the dashed lines in the ring And the formula I is absent, and one of the atoms a is a carbon atom).

The number m of the substituents R10atoms A1AND3and a4ring a is an integer from 0 to 6 and depends on the amount of Unallocated amounts ties available in separate atoms A1AND3and a4similarly, substitution groups, R0on the ring, as described above. Usually n is in the range from 2 to 6 for most of the compounds of the present invention. Atom AND2rings And replaced only by a bridging group -(L) - when A2has only one Unallocated communication, however, when A2has two unoccupied communication, the second communication may be occupied by a group selected from hydrogen, alkyl, halogenosilanes1-C10-alkyl, C2-C10-alkenyl, C2-C10-Alki-CNS group, C7-C12-arylalkenes group, acyl, cyano, halogen-, nitro-, sulfo-and the main group.

The linking group -(L)- attached to the atom AND2ring a and is (i) a bond or (ii) divalent substituted or unsubstituted chain of 1-10 atoms (i.e., there are from 1 to 10 atoms in the chain between the binding of the divalent bonds if all the remaining atoms are located on the branches of these atoms in the chain). For example, when -(L)- is the communication connection according to the invention may have the structural formula (Is) that resembles the following:

< / BR>
Alternatively, when -(L)- is a linking group

< / BR>
The compound of the present invention may have a structural formula (It) resembles the following:

< / BR>
Alkylene, alkenylamine and alkenylamine groups are suitable for bonding groups. Preferred linking groups have from 1 to 4 chain atoms and correspond to the General formula:

< / BR>
< / BR>
< / BR>
< / BR>
where Z1, Z2, Z3and Z4are atoms selected from the group consisting of carbon, nitrogen, sulfur and oxygen. The connecting group containing three atoms in the chain, such as

< / BR>
< / BR>
< / BR>
< / BR>
where R is Vodonaeva, containing two atoms of the chain, such as:

< / BR>
< / BR>
Binder group

< / BR>
has CIS - and transforms, and both of these forms and their mixtures in all proportions are within the scope of this invention.

Asymmetric binders, for example, binders

< / BR>
< / BR>
can be flipped to its point of connection between the ring And the core and the core group Q, as shown by the formula (Iu) and (Iv) below:

< / BR>
< / BR>
Deputy Q in the formula (I) is the main group. The main group contains one or more basic radicals1. Suitable basic radicals contain one or more nitrogen atoms and contain amino-, imino-, amidinopropane, N-alkylamides, N,N'-dialkylamides, N-arylamidine, aminomethylenemalonate, aminoethylamino, guanidinium, aminoguanidinium, alkylamino, dialkylamino, trialkylamines, alkylidene, pyrrolidone, imidazolinone, pyrazolinone, meridiabuy, pyrazinium, pyrimidinium, indolizinyl, isoindolyl, 3H-indolinone, indolinone, 1H-indazolinone, urinology, 4H-hinolinovy, izohinolinove, hinolinovy, phthalazinium, naphthyridinone, hinoksalinovym, khinazolinov, indolinovoy, Amen entretenido, acridinium, pyrimidinium, phenantroline, phenazinium, phenarsazine, phenothiazinium, pyrrolidinone, imidazolidinyl, imidazolinium, pyrazolidinone, pyrazolinone, piperidino, piperazinyl, indolinyl, isoindolyl, hinkleyville, morpholinyl group, or any previous substituted amino-, imino-, amidino, aminoethylamino, aminoethylamino-, guanidino, alkylamino, dialkylamino, trialkylamine, tetrahydroisoquinoline, dihydroindole, alkylaminocarbonyl or a group represented by formula

< / BR>
Preferred basic radicals selected from amino, piperidino, guanidino-, and Aydinoglu. The most preferred basic radicals are radicals amidino and piperidino groups represented by formulas

< / BR>
The main group Q may take the form of a primary radical (such as Q1in the formula below 1w), branches off from the circular ring. Thus, the main group Q may contain two parts, namely (i) one or more basic radicals Q1and (ii) cyclic group, having from 5 to 8 ring atoms. The D ring is attached to the atom of A2rings And bicyclic nucleus through with the chosen from chlorine, fluorine or reintervenciisa organic radicals. The substituents R20can be in the amount of t, where t is an integer from zero to the number of unoccupied bonds in the ring D. the Primary radical Q1attached to the ring D, as shown by the formula (Iw) below

< / BR>
(attached to the atom A2through a bridging group).

Suitable ring D are formed from a nucleus selected from the group consisting of benzene, cycloheptadiene, cycloheptatriene, Cycloheptane, cyclohexane, cyclohexene, cyclohexadiene, cycloheptene, cyclooctadiene, cyclooctene, cyclooctatetraene, cyclooctene, cyclopentane, cyclopentene, imidazole, etoxazole, research, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydropyrimidine, 1H-tetrazole, thiazolidine, thiazole, thiopyran, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, dihydrofuran, dihydropyran, dioxane, doxepin, dioxolane, furan, oaxacana, tetrahydrofuran, tetrahydropyran, thiophene and tetrahydrothiophene.

General formula (Ix) are preferred for compounds of the present invention, having a basic moiety, attached to the circular is carbon, oxygen, sulfur and nitrogen;

AND2mode can be selected from carbon or nitrogen, provided that A2has Unallocated communication, if A2is nitrogen, provided that at least two atoms of A1, A2AND3and a4are carbon atoms;

B1B2IN4are selected independently from carbon, oxygen, sulfur and nitrogen;

B3mode can be selected from carbon or nitrogen, provided that B3has Unallocated communication, if B3is nitrogen, provided that at least two atoms of B1B2B3and B4are carbon atoms;

R3is an acidic group containing one or more acid radicals;

n is a number from 0 to 6;

R0are the same or different and are selected independently from hydrogen, alkyl, halogenosilanes of alkyl, alkenyl, quinil, cycloalkyl, aryl, arylalkyl, hydroxyl, CNS, arelaxing, amino, substituted amino, karamolegos, carboxyl, Alloway, cyano, halogen-, nitro-, sulfo -, = O or =S; provided that, if R0is =O or =S, then only one atom of B1IN2IN3and IN4may be a nitrogen atom;

m - Chechenenergo of alkyl, alkenyl, quinil, cycloalkyl, aryl, arylalkyl, hydroxyl, CNS, arelaxing, carboxyl, Alloway, cyano, halogen-, nitro-, sulfo -, =O and =S; provided that only one R10may be =O or =S;

t is a number from 0 to 3;

R20are the same or different and are selected independently from hydrogen, halogen, alkyl, halogenosilanes of alkyl, alkenyl, quinil, cycloalkyl, aryl, arylalkyl, hydroxyl, CNS, arelaxing, carboxyl, Alloway, cyano, halogen-, nitro-, sulfo;

the linking group -(L)- is a bond or a divalent substituted or unsubstituted chain of from 1 to 10 atoms selected from the group consisting of carbon, nitrogen, sulfur, and oxygen; and

D is a ring formed of 5 to 8 ring atoms, and said ring atoms independently selected from carbon, nitrogen, oxygen, or sulfur, provided that at least two atoms of ring D are carbon atoms;

w is a number from 1 to 3;

Q1- basic radical.

Compounds of the present invention, having the rings A, B and D, represented by the following formula (Iy)-(Iah) below

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Predpochtitelno a number from 0 to 8, as, for example, in specific groups Q:

< / BR>
< / BR>
The preferred embodiment of the compounds of the present invention represented by formula II below:

< / BR>
In the formula II the main group on the atom AND2the kernel has two parts, namely (i) six-membered ring D, which is attached to a linking group -(L)-, and (ii) the primary radical (basic radicals) Q1(where w is an integer from 1 to 3), attached to the ring D. the Basic radicals are as defined previously.

The atoms of D2D3D4D5and D6are selected independently from carbon, nitrogen, oxygen or sulfur, and the atom D1selected from carbon or nitrogen; provided that at least two of the atoms of D2D3D4D5and D6are carbon atoms. Q1is the main radical, as defined previously. Preferred ring structures with a branch Q1are those in which the atoms of D1D2D3D4D5and D6form a cyclic ring selected from the group consisting of benzene, pyridine, piperidine, 1,2-piperazine, 1,3-piperazine, 1,4-piperazine, Piran, thiopyran, tiebissou, cyclohexene and cyclohexane, the most preferred"ptx2">

The substituents R20are the same or different at each atom, D2D3D5and D6and the same or different between the atoms of D2D3D5and D6and are reiterferien organic radicals independently chosen from hydrogen, alkyl, halogenosilanes of alkyl, alkenyl, quinil, cycloalkyl, aryl, arylalkyl, hydroxyl, CNS, arelaxing, amino, substituted amino, karamolegos, carboxyl-, Alloway, cyano, halogen-, nitro and sulfo. The number p of the substituents R20is an integer from 0 to 8 depending on the total number of unemployed ties, available on a separate atoms of D2D3D5and D6.

Preferred compounds of the present invention are based on nuclei substituted by benzamidine of isoquinoline, isoquinoline, naphthalene, tetrahydronaphthalene, dihydronaphthalene, benzopyrene and tetralone, as partially shown by the formulas (III)-(IIIe) below:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where -(L)-, n, m, p, R0, R3, R10and R20are as previously defined. The most preferred compounds, in which R10and R20are hydrogen,D contains one or more (preferably 1 or 2) substituents, independently selected from chlorine or fluorine. Chloride and fluorine substituents can be added to any ring D, which, as described above, has from 5 to 8 members.

Illustrative compounds of the present invention with the replacement of six-membered rings D are shown by formulas (IV)-(IVb) below:

< / BR>
< / BR>
< / BR>
Without being bound to any theory of action it is believed that consuming the electron groups, such as fluorine, reduce the basicity of the main group and increase oral biopatent compounds of the present invention.

Specific compounds of the present invention isoquinoline type, which are highly preferred, represented by the following structural formulas (V)-(Vv) or pharmaceutically acceptable salts, solvate or proletarienne derivatives of these compounds are:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and mixtures of compounds (V)-(Vv).

Other specific compounds of the present invention naphthalene/tetraminnogo type, which are highly preferred, represented by the following structural formulas (VI)-(VIp) or Pharm

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and mixtures of compounds (VI)-(VIp).

Other preferred specific compounds of the present invention are represented by the following structural formulas (L)-(LXIII) and all pharmaceutically acceptable salts, solvate and proletarienne derivatives of these compounds are:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
and mixtures of any of the compounds (L)-(LXIII).

Other specific compounds of the present invention benzopyrano type, which are highly preferred, represented by the following structural formulas (VIII)-(IX) or pharmaceutically acceptable salts, solvate or proletarienne derivatives of these compounds are:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Other compounds of the present invention, having the bicyclic nucleus of the oxygen atom in the ring And represented by the following formulas (IX) to(IXl) below:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Compounds of the present invention have at least one acid functionally salts include, but are not limited to, salts of alkaline and alkaline earth metals, such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salt is traditionally prepared from the free acid by reacting the acid in solution with a base or by exposure of acid on anion-exchange resin in the salt loop.

Fall under the definition of pharmaceutically acceptable salts are relatively non-toxic inorganic and organic basic additional salts of the compounds of the present invention, for example, ammonium, Quaternary ammonium and amine reactions, derived from nitrogenous bases a significant basicity for the formation of salts of the compounds of the present invention (see , for example, S. M. Berge et. al., "Pharmaceutical Salts" J. Phar. Sci., 66: 1-19 (1977)).

The main part of the compounds of the present invention (group Q of formula I and the group Q1formula (II) can react with suitable organic or inorganic acids for forming the salts according to the invention. Examples of salts can be selected from the group consisting of acetate, bansilalpet, benzoate, bicarbonate, bisulfate, bitartrate, borate, camsylate, carbonate, chloride, clavulanate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, glycolate, lactobionate, laurate, malate, maliseet, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, oleate, oxalate, palmitate, Pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannat, tartrate, tosylate, triptorelin, triftorbyenzola and valerate.

Compounds according to formula (I) may also be in the form amphoteric ions, as they contain both acidic and basic functionality and is able to sameprocedure.

Certain compounds of the present invention possess one or more chiral centers and therefore may exist in optically active forms. Similarly, when the compounds contain alkenilovyh or alkenylamine group, there is the possibility of CIS - and transisomers forms of these compounds. R - and S - isomers and their mixtures, including racemic mixtures, as well as a mixture of CIS - and TRANS-isomers, are implied by the present invention. Additional asymmetric carbon atoms may be present in the replacement group, such as Akilova group. All such isomers and mixtures should be considered in the framework of the present invention. If desired an individual stereoisomer, it may be the th with the source material, containing asymmetric centers, and already dissolved or alternative using methods that give a mixture of stereoisomers, and the subsequent dissolution using known methods.

Proletarienne derivatives of the compounds of the present invention.

Prodrugs are derivatives of the compounds of the present invention, which are metabolically degradable group and become by solvolysis or under physiological conditions the compounds of the present invention which are pharmaceutically active in vivo. For example, ester derivatives of the compounds of the present invention are often active in vivo, but inactive in artificial. Other derivatives of the compounds of the present invention have activity as in the form of acid and acid derivative, but the form of the acid derivative often offers advantages of solubility, compatibility with tissues or delayed release in the body of a mammal (see, Bundgard, H. Design of Prodrugs, p. 7-9, 21-24, Elsevier, Amsterdam, 1985). Prodrugs include acid derivatives well known to practitioners, such as ester obtained by the reaction recognize the haunted aliphatic or aromatic esters, obtained from acid groups, branches off from the compounds of the present invention, are preferred prodrugs. In some cases it is desirable to obtain prodrugs of type double complex ester, such as (alkoxy)alkyl esters or ((alkoxycarbonyl)hydroxy)alkyl esters.

Preferred are C1-C8-alkalemia, C2-C8-alkenilovyh, arrouye, C7-C12-substituted arrowie and C7-C12-arylalkyl esters of the compounds of the present invention (formula I). In particular, the preferred C1-C4-alkalemia esters, for example, in which the acid group R3was converted into an ester forming group represented by one of the following formulas:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
Other specific proletarienne derivatives, which are compounds of the present invention, represented by formula (Xa) (Xb) shown below:

< / BR>
< / BR>
Acylated basic radical, which are part of the core group on the compounds of the present invention, has been found to significantly increase biopatent. Without being bound to any theory is meniu less prone to "food effect", they have good suitability for therapeutic feeding the animal without starvation.

Compounds of the present invention is advantageous manner can be a double proletarienne derivatives. For example, the acid group (R3can react, forming the ester, and the main group of Q (or basic radical Q1may, in addition to react, forming an acylated basic derivative. Moreover, proletarienne derivatives of the compounds of the present invention can be combined with other features described herein, to increase biopolyester, for example by substitution of fluorine atoms on the ring D compounds according to formula (II). These combined features result in this connection, as represented by formula (Xc):

< / BR>
Another highly preferred class of prodrugs of the present invention are those formed by the acylation of basic radicals (e.g., Q1), the compounds of the present invention. Allowa part acylated basic radical has the General formula:

< / BR>
where R is C1-C8-alkyl, C2-C8-alkenyl, aryl, C1-C4-alkyl, and X is oxygen. For example, the acylated prodrugs of the main radicals according to the invention are obtained, as shown by points a, b, C and D below:

A) acylation of amidine gives the group procarcinogen derived:

< / BR>
C) acylation of the cyclic amine, such as piperidine, gives the group procarcinogen derived:

< / BR>
(C) acylation of guanidine gives the group procarcinogen derived:

< / BR>
D) acylation of the primary amine gives the group procarcinogen derived:

< / BR>
where, for the above a, b, C and D, R is the same as defined above for acylated part of the main group.

Therapeutic compounds of the present invention include proletarienne derivatives of bicyclic compounds having a core formed of two fused six-membered rings, a and b, represented by the formula (Xd):

< / BR>
where A1AND3AND4are selected independently from carbon, oxygen, sulfur and nitrogen;

AND2mode can be selected from carbon or nitrogen, provided that A2has Unallocated communication, if a2is nitrogen, provided that at least two atoms of A1And
IN3mode can be selected from carbon or nitrogen, provided that IN3has Unallocated communication, if IN3is nitrogen, provided that at least two atoms of B1IN2IN3IN4are carbon atoms;

n is a number from 2 to 6;

R0are the same or different and are selected independently from hydrogen, alkyl, halogenosilanes of alkyl, alkenyl, quinil, cycloalkyl, aryl, arylalkyl, hydroxyl, CNS, arelaxing, amino, substituted amino, karamolegos, carboxyl, Alloway, cyano, halogen-, nitro-, sulfo -, =O or =S, provided that, if R0is =O or =S, then only one of the atoms of B1IN2IN3and IN4may be a nitrogen atom;

m is a number from 2 to 6;

R10are the same or different and are selected independently from hydrogen, alkyl, halogenosilanes of alkyl, alkenyl, quinil, cycloalkyl, aryl, arylalkyl, hydroxyl, CNS, arelaxing, carboxyl, Alloway, cyano, halogen-, nitro-, sulfo -, =O and =S; provided that only one R10may be =O or =S;

the linking group -(L)- is a bond or dvuhvalenten and oxygen; and

Q2is selected from (i) major groups, or (ii) major groups containing acylated basic radical;

R13is selected from (i) acid groups containing an acid radical, or (ii) an acid group-containing ester derivative of the acid radical;

provided that Q2is the primary group containing acylated basic radical, or R13is an acid group-containing ester derivative of the acid radical.

The preferred form proletarienne derivative is a compound with formula (Xd), with dual Palekastro functionality, i.e. where Q2is the primary group containing acylated basic radical, a R13is an acid group-containing ester derivative of the acid radical.

Another preferred form of the prodrug is a compound with formula (Xd), which is acylated part acylated basic radical has the General formula:

< / BR>
where R is C1-C8-alkyl, C2-C8-alkenyl, aryl, C7-C12-substituted aryl and C7-C12-arylalkyl, and X is a bond, C, O, S Il is erati two parts, namely, (i) one or more radicals selected from the main radicals or acylated basic radical, each of which is denoted by Q3and (ii) a cyclic group D (as previously defined by the formula Iw).

The General formula for proletarienne derivatives of the present invention describes a bicyclic compound having a nucleus formed from two fused six-membered rings, a and b, represented by the formula (Xe), or a pharmaceutically acceptable salt, solvate or proletarienne derivative of this connection:

< / BR>
where A1AND3AND4are selected independently from carbon, oxygen, sulfur and nitrogen;

AND2mode can be selected from carbon or nitrogen, provided that A2has Unallocated communication, if a2is nitrogen, provided that at least two atoms of A1AND2AND3and a4are carbon atoms;

B1B2IN4independently selected from carbon, oxygen, sulfur and nitrogen;

B3mode can be selected from carbon or nitrogen, provided that IN3has Unallocated communication, if B3is nitrogen, provided that at least two atoms of B1IN2IN3IN4is is selected from hydrogen, of alkyl, halogenosilanes of alkyl, alkenyl, quinil, cycloalkyl, aryl, arylalkyl, hydroxyl, CNS, arelaxing, amino, substituted amino, carboloy, carboxyl, Alloway, cyano, halogen-, nitro-, sulfo -, =O or =S, provided that, if R0is =O or =S, then only one atom of B1B2IN3and B4may be a nitrogen atom;

m is a number from 0 to 6;

R10are the same or different and independently selected from hydrogen, alkyl, halogenosilanes of alkyl, alkenyl, quinil, cycloalkyl, aryl, arylalkyl, hydroxyl, CNS, arelaxing, carboxyl, Alloway, cyano, halogen-, nitro-, sulfo -, =O and =S, provided that only one R10may be =O or =S;

t is a number from 0 to 3;

R20are the same or different and independently selected from hydrogen, halogen, alkyl, halogenosilanes of alkyl, alkenyl, quinil, cycloalkyl, aryl, arylalkyl, hydroxyl, CNS, arelaxing, carboxyl, Alloway, cyano, halogen-, nitro-, sulfo;

the linking group -(L)- is a bond or a divalent substituted or unsubstituted chain of 1-10 atoms, wybir mentioned ring atoms independently selected from carbon, nitrogen, oxygen or sulfur with the proviso that at least two atoms of ring D are carbon atoms;

w is an integer from 1 to 3;

Q3is selected from (i) basic radicals, or (ii) is acylated basic radical;

R13is selected from (i) an acid group-containing acid radical, or (ii) an acid group-containing ester derivative of the acid radical;

provided that Q3is acylated basic radical or R13is an acid group-containing ester derivative of the acid radical.

Integer w is preferably equal to 1.

In the formula (Xe) preferably, R20were chlorine and/or fluorine, a t equal to 1 or 2. Also preferred are compounds according to formula (Xe), where Q3is acylated basic radical, and R13is an acid group-containing ester derivative of the acid radical.

The most preferred acylated major groups are the basic radicals carbenoxolone esters ajdinovic, piperidinovyh or guanidino basic radicals. The most preferred radicals carbenoxolone C1

Preferred proletarienne derivatives of the compounds of the present invention, having different characteristics discussed in this section is represented by the formula (Xf)-(Xr) below:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R = -OMe, -OEt, -OPr, C1-C4alkyl; R15=Me, Et, Pr

< / BR>
< / BR>
< / BR>
where R = -H, -OMe, -OEt, -OPr,

X = -Cl, -F, -H,

R15= Me, Et, Pr.

The method of obtaining the compounds according to the invention

General scheme 1-33 synthesis given in the end of the description, are used to obtain the compounds of the present invention.

All of the schemes and the examples the following abbreviations are used:

TBAF is tetrabutylammonium fluoride

Tf (triplet)-sulfonate triptorelin

Boc - tertiary butoxycarbonyl

Bn - benzyl

But - tertiary butyl

DMF - formamid of dimetil

Cbz - benzyloxycarbonyl

EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide

DMAP - dimethylaminopyridine

LHMDS - hexamethyldisilazane lithium

THF - tetrahydrofuran

DIBAH - Diisobutylene aluminum

Boc 20th - di-tert-butylboronic

HMDS - hexamethyldisilazane

TsOH - p-toluensulfonate

MCPBA meta - chloroperoxybenzoic chlorid

TMEDA, N,N,N',N'-tetramethylethylenediamine

LDA - diisopropylamide lithium.

General comments.

Reaction schemes described reactions are performed using standard chemical methodologies described and specified in the standard literature. Starting materials are commercially available reagents and reactions are carried out in standard laboratory glassware at normal temperature and pressure, except in cases where specifically mentioned other conditions.

Circuit 1

< / BR>
Scheme 1 describes a method of obtaining a 2,6-disubstituted of athinodorou with ether-associated arginine isaster C6and the radical of acetic acid in position 2. In the first step of scheme 1 of isoquinoline (1) reacts with benzylbromide in the presence of potassium carbonate in irrigation acetone to obtain benzylating phenol (2). This compound reacts with sodium hydride and then alkiliruya nitrogen or by using alpha-bromo-tert-butyl acetate, or alpha-bromoethylamine to obtain 2-substituted isohedron (3A) (6-benzyloxy-3,4-dihydro-1-oxo-2(1H)isohedron acetic acid-1-dimethylethyl ester) or (3b). Benzyl group6then removed with the help of the 3 and allylbromide to obtain disubstituted isohedron (5). The compound (5) is then converted to Boc-protected amidin (6) with the help of several reactions, namely: (i) reaction of a nitrile with H2S, (ii) alkylation of intermediate thioamide methyliodide, (iii) reacting the intermediate of thioimidate with ammonium acetate, and (iv) then Boc-proektirovaniya formed of amidine to obtain compound (6). Connection (6) deprotection using neat TFA, giving (7) as a TFA salt.

Scheme 2

< / BR>
---- possible unsaturation

Scheme 2 describes the synthesis method suitable for the production of carbon substitution at position6bicyclic core. In this scheme, compound (4) (6-hydroxy-3,4-dihydro-1-oxo-2(1H)isoquinoline acetic acid 1,1-dimethyl ester) according to scheme 1 is converted into triflate (8) using triperoxonane anhydride and pyridine. Then this compound reacts with acetylene compound (9a) or (9b) in the presence of palladium to obtain acetylene-linked benzonitrile (10a) or (10b). The compound (10a) or (10b) is converted again using the same set of procedures, which is used for converting connection(5) (6-{(4-cyanophenyl)methoxy}-3,4-dihydro-1-oxo-2(1H)

Scheme 3

< / BR>
Scheme 3 describes the obtaining of athinodorou containing nitrogen substitution at position6. This scheme begins with triflate (8), the receipt of which is described previously in scheme 2. Triplet converted to complex arrowy ether (16) by using palladium, carbon monoxide and methanol. Ester (16) then muliverse lithium hydroxide in aqueous TFA solution. The free acid (7) is then subjected to Antonie Curtius rearrangement of (i.e., the formation of isocyanate by thermal decomposition of arylazides). Required acylase is formed using triphenylphosphorane, and then pyrolized on the place to obtain the isocyanate kotoroy Amin (19) using catalytic hydrogenation. Amin (19) then alleroed Parlamentului acid in the presence of EDCI and DMAP, giving aminosvyazannogo connection (20). The compound (20) is then converted to Boc-protected amidin (21) under the conditions of scheme 1, and this substance is then deprotected with TFA to obtain the compound (22).

Scheme 4

< / BR>
Amines (a)-(e):

(a) hexylamine

(b) benzylamine

(C) p-methoxyphenethylamine

(d) methylamine

(e) beta-amino-1-butylene

Scheme 4 describes obtaining 2,6-disubstituted of athinodorou, in which position 2 is substituted by share of aspartic acid. Figure 4 begins with the compound (3b), the receipt of which is described by scheme 1. Compound (3b) gives the proton LHMDS, and the resulting anion is then neutralized using alpha-bromo-t-butyl acetate to obtain compound (23). 6-benzyl group of compound (23) is removed using palladium and hydrogen to obtain the free phenol (24). The compound (24) then alkiliruya as described to obtain the compound (5) in scheme 1. Methyl ester (25) then spilivaya lithium hydroxide in THF to obtain the free carboxylate (26). Then the free carboxylate connected with various amines in the presence of EDCI and DMAP to obtain poliamidnykh closeme 1 of the Protocol (steps 5-6) to obtain Boc-protected amidino (28a)-(28e). Boc-protected amidin then deprotected with TFA to obtain the compounds (29a)-(29e).

Scheme 5

< / BR>
Types of acids:

(a) 4-etxebarria

(b) pentane

(C) hexane

(d) 2-(2-methoxyethoxy)acetic

(e) propionic

(f) butane

Scheme 5 describes obtaining 2,6-disubstituted of athinodorou, in which position 2 substituted by isosteres aspartic acid. Connection diagrams 5 differ from the compounds obtained according to scheme 4, in that the group R of the compound (36) according to scheme 5 does not contain amidnogo link as compounds (29a)-(29e) according to scheme 4. Connection (2), the source material, obtained by the method of scheme 1, then alleroed different activated acids (acid halides and anhydrides) to obtain the corresponding imides (30a)-(30e). Then imide selectively restored to its ekzoticheskogo carbonyl using DIBAH and then captured with acidic methanol to obtain alpha methoxyamino (31a) to(31e). Alternative alpha methoxyamine (31) can be obtained by reaction of the sodium salt of (2) with a suitable alpha chloroform (37). All alpha methoxyamine (31a)-(31g) react with the ester of boron TRIFLUORIDE in the presence of catenateall to obtain beta, beta-TLD the hydrogenation and phenols can be alkylated by the method shown in scheme 1 (steps 4-5) to obtain the ether-linked nitrile (34a)-(34g). This nitrile can then be converted to Boc-protected amidin (35a)-(35g), as shown in scheme 1 (steps 5-6). Then deprotection gives the final compound (36a)-(36g).

Scheme 6

< / BR>
Scheme 6 describes the formation of compounds of the present invention, having tetraline the core. 6-methoxy-2-tetralone (38) is reacted with tert-butyl diethylphosphonoacetate to get nenaydenko of ester (39). Subsequent hydrogenation removes unsaturation to obtain compounds (40). The compound (40) is processed by tribromide boron, and the crude product presterilized using HCl and ethanol to obtain (41). Phenol (41) then alkiliruya, as shown in scheme 1 (steps 4-5), giving (42). The nitrile can then be converted to Boc-protected amidin (43) as shown in scheme 1 (steps 5-6). Aydinbey ester (43) then muliverse using sodium hydroxide to obtain a compound (44), which is then deprotected with TFA and anisole to obtain the final product (45).

Scheme 7

< / BR>
Scheme 7 describes the formation of compounds according to the present sobremesa bromide (51) (obtained from dibromide and phthalimide potassium), giving adduct (46). This connection deprotected water hydrazino, giving Amin (47). The compound (47) is converted into the protected guanidine (49) using N,N'-bis(tert-butoxycarbonyl)-S-methyl-estimacion. Compound (49) deprotected using TFA, giving the product (50) in the form triptoreline salt.

Scheme 8

< / BR>
Scheme 8 describes the formation of compounds of the present invention, having an amine group as the main functionality.

The compound (33a), obtained according to scheme 5, is connected with alcohol (51) (obtained from 3-(4-pyridyl)-propanol using standard protocols) using triphenylphosphine and diethylazodicarboxylate, giving the compound (52). Compound (52) deprotected with pure TFA, giving the product (53) as a TFA salt.

Scheme 9

< / BR>
Scheme 9 describes obtaining 2-6 disubstituted of tetraline, in which position 2 is occupied by a radical-alkoxyalkane acid, and the position 6 contains either an ether-linked, benzamidine or component of the ether-linked 4-alkylpiperazine. The scheme starts with 6-methoxy-2-tetralone (60), which is sequentially processed by NaBH4and then DIBAH, giving dihydrexidine connection 62. Phenolic hydroxyl can be vibia 63 and 67, respectively. Both connections then alkiliruyutza using tert-butylbromide in conditions of phase transfer, giving connections 64 and 68. Nitrile 64 is converted to the Boc-protected amidin 65, and then the product 66 using the sequence of reactions described in scheme 1. The connection 68 is converted into a fully deprotection connection 69 by treatment with TFA.

Scheme 10

< / BR>
Scheme 10 describes how to obtain 2,6-disubstituted of tetraline, in which position 2 is a component of alpha-aminouksusnoy acid, and the position of the 6 - ether-linked 4-alkylpiperazine. Alcohol 67, obtained according to scheme 9, oxidized using DMSO and TFAA under conditions Swarna, giving the ketone (70), which mineralsa recovery using glycine tert-butyl ether complex, giving the connection 71. This material is then deprotected using TFA, giving connection 72.

Scheme 11

< / BR>
Scheme 11 outlines receiving 2,6-disubstituted of tetraline, in which position 2 contains the radical alpha aminouksusnoy acid, and the position 6 is occupied by ether-linked benzamidine. The synthesis begins with alcohol 63 (scheme 9), which oxidises with TFAA and DMSO (method Swarna), giving the ketone 73. This material is then mineralsa recovery using em Boc-derivative is converted to a protected amidin 77 using the sequence of reactions, bred in scheme 1. Then this material is completely deprotected using TFA, giving the connection 78. Similarly acutiloba derivative 75 is converted in connection 80.

Scheme 12

< / BR>
Scheme 12 outlines receiving tetraline with the radical of acetic acid at the C2and nedosvecheny benzamidine C6. In the first step, the tetralone 81 is restored by using NaBH4and the resulting unstable alcohol dehidrirana with TsOH in benzene, giving dihydronaphthalene 82. Assimilate connection 82 gives diol 83, which is then exposed TsOH in irrigating benzene. Thus formed is unstable 2-tetralone is not sealed, and allowed to react with the sodium salt of tert-butyldiethanolamine, giving unsaturated ester 84 in the form of a mixture of olefin isomers. This material is subjected to hydrogenation on palladium, which leads to the ultimacy of the olefin and the removal of the Cbz-group, providing aniline 85. The acylation of compounds 85 using 4-cyanobenzoic acid is performed using EDCI, and the resulting amide 86 is converted to the Boc-protected amidin 87 in the conditions previously described in scheme 1. Removing part of the Vos and the cleavage of tert-b is 3 describes the preparation of derivatives of tetralin, in which position 2 is substituted by a component-alkoxyalkane acid, and the position 6 is substituted by amylovesanime benzamidine. In this scheme, the connection 82 from the circuit 12 is introduced into the reaction with NaH and benzylbromide, giving tertiary carbamate 88. This material is then subjected to similariy and dehydration as described for compound 83 in scheme 12. Formed unstable 2-tetralone is immediately restored to alcohol 90 using NaBH4. This material alkiliruya using tert-butylbromide in conditions of phase transfer, resulting in the ether 91. Catalytic hydrogenation releases 6-amino component (92), which alleroed using 4-cyanobenzoic acid in the presence of EDCI, giving 93. Nitrile 93 is converted to the Boc-protected amidin 94 through several transformations described in scheme 1. Simultaneous deprotection this amidine and acid components is performed using TFA, giving the final product 95.

Scheme 14

< / BR>
Scheme 14 outlines the synthesis of tetralone with component acetic acid at position 2 and either nedosvecheny benzamidine or nedosvecheny 4-alkylpiperazine in position 6. The scheme begins with tetralone 96, which is introduced into the reaction with glio is by using Zn in HOAc, and the resulting compound is converted into aniline 98 first by removal of the acetate using 6N HCl, and then by conversion to an ester of the acid component with ethanol HCl. Then this material alleroed using 4-cyanobenzoic acid mediated EDCI, giving 99. Nitrile component connection 99 is converted to the Boc-protected amidin 100 using the sequence of reactions described in scheme 1. Emiliania ester component with NaOH, followed by TFA treatment, network connection 102.

Compounds containing nedosvecheny 4-alkylpiperazine, can be obtained by acylation of aniline 98 via connection 103, which gives similar 104. Emiliania of ester 104, followed by TFA-deprotecting of piperidine network connection 106.

Scheme 15

< / BR>
Scheme 15 describes a method of obtaining tetralone derivatives, in which position 2 is occupied by unsaturated acid, and position 6 is substituted or amylovesanime benzamidine or 4-alkylpiperidines. In the first step, compound 97 (scheme 14) can be converted to aniline 107 by removal of the acetate using 6N HCl and subsequent conversion into ester with ethanolic HCl. Then this Mat is erom case nitrile 111 can be transformed into amidin 112 using the sequence of reactions, described in scheme 1. Emiliania connection 112, followed by treatment with TFA, should give 114. Piperidinyl contact 108 may be subjected to emiliania and TFA-deprotection that this way gives compound 110.

Scheme 16

< / BR>
Scheme 16 describes the preparation of derivatives of dihydronaphthalene containing at position 2 component acetic acid, and at position 6 - nedosvecheny benzamidine. The tetralone 100 (scheme 14) is introduced into the reaction with NaBH4in ethanol, giving unstable alcohol 115. This material is treated with TsOH in THF, giving digidrirovanny product 116. Ester emiliania, followed by the release of amidine using TFA, to give the desired product 118.

Scheme 17

< / BR>
Scheme 17 outlines the total receipt of 2,6-disubstituted of tetralones, in which position 2 is substituted by a radical of acetic acid, and the position 6 contains nedosvecheny halogenosilanes benzamidine. Aniline 98 (obtained according to scheme 14) is introduced into the reaction with benzoic acid 119 (obtained by standard methods from 4-amino-2-Tortolla) in the presence of EDCI and DMAP. The resulting amide (120) is converted to the Boc-protected amidin 121 using procedures outlined in scheme 1. Then ester sothema 18

< / BR>
Scheme 18 describes a method of obtaining a 2,6-disubstituted naftalina with the radical of acetic acid at position 2 and broadcasting-associated arginine isaster in position 6. In the first step of scheme 18 bromonaphtalene 124 is subjected to Parametrierung with t-BuLi and the resulting anion is neutralized by atelocerata. The resulting adduct 125 is then reduced with NaBH4and the resulting alcohol alleroed using acetic anhydride. Catalytic hydrogenation removes the benzyl acetate and releases the 6-hydroxyl component, giving a connection 126. Then the free phenol alkiliruya using alpha-bromo-p-tolunitrile in the presence of K2CO3giving disubstituted naphthalene 127. Nitrile component is then converted to Boc-protected amidin 128 using the sequence of reactions previously described in scheme 1.

Emiliania of ester in connection 128, followed by removal of the Boc group with TFA gives the final connection 130.

Scheme 19

< / BR>
Scheme 19 describes how to obtain disubstituted derivatives of tetrahydroisoquinoline with component acetic acid at position 2, and either an ether-linked, benzamidine, or 4-alkyl piperidino what about isohedron 2 (scheme 1) using LiAlH4. This material is either Boc-protecting) that gives compound 131, or alkylation with tert-butylbromide, which gives rise to a connection 132. Boc-protected material is subjected to hydrogenation, which frees6-phenol, which is then alkiliruya using alpha bromatological, giving 137. Boc-group of this compound is cleaved using TFA, and then the resulting amine alkiliruya using tert-butylbromide, giving connection 138. This compound is converted to the Boc-protected amidin 139, and then in deprotection option 140 using procedures outlined in scheme 1. N-alkilirovanie connection 132 in this way is subjected to hydrogenation, and the resulting phenol alkiliruya using the appropriate 4-alkylpiperazine, giving the connection 134. This material deprotected using TFA, giving a connection 135.

Scheme 20

< / BR>
Scheme 20 describes obtaining 2,6-disubstituted derivatives of tetrahydroisoquinoline containing the radical of acetic acid at position 2 and nedosvecheny benzamidine in position 6. The synthesis starts from the acid hydrolysis of 6-acetaminop isohedron 141, giving aniline 142. Then the raw materials are subjected to the action of benzylbromide and who I restore using LiAlH4forming tetrahydroisoquinoline, which is immediately processed di-tert-butylborane. Formed Boc-protected material then hydrogenperoxide on palladium, giving aniline 143. This material alleroed using p-lambertini acid, giving a connection 144. Treatment of this material with TFA gives the secondary amine, which alkiliruya using tert-butylbromide, giving connection 145. The conversion of compound 145 in the Boc-protected amidin 146, and then in his deprotection homolog 147 is performed using the procedures described in scheme 1.

Scheme 21

< / BR>
Scheme 21 describes the synthesis method, suitable for the production of 2,6-disubstituted of tetralin containing propionate or propenoate component in position 2 and nedosvecheny benzamidine in position 6. In the first step, a complex nitroethyl 148 restored with the help of LiBH4and the resulting alcohol proektiruetsya as its TBS ether. Connection 149 is then subjected to hydrogenation, and the resulting aniline immediately treated with EDCI and p-lambertini acid amide giving 150. Celilova connection group 150 is removed, and the resulting alcohol is subjected to oxidation using DMSO and oxalicacid (method Swarna). That is Tata, which gives a partial mixture of olefin isomers 151 (CIS) and 152 (TRANS). The TRANS-isomer 152 is converted to the Boc-protected amidin, and then in deprotection connection 155 using the sequence described in scheme 1. CIS isomer is subjected to hydrogenation on palladium, gives the ultimate analogue 153. This material is also converted to the Boc-protected amidin, and then in his deprotection homolog 154, as described in scheme 1.

Scheme 22

< / BR>
Scheme 22 describes a method of synthesis of disubstituted of tetralin with radical alpha alkoxyalkyl acid2and carboxylating benzamidine C6. This scheme starts with 6-bromo-2-tetralone (156), which is restored by using NaBH4and the resulting alcohol proektiruetsya as its tert-butyldimethylsilyl (TBS) ether, giving connection 157. Processing

this connection with t-BuLi causes metal-halide exchange, and forming anion is neutralized with CO2. The resulting carboxylate immediately converted to the benzyl ester using benzyl alcohol and EDCI. TBS-group is removed during processing by using TBAF, resulting alcohol 158. Free secondary hydroxyl g the lat is released by catalytic hydrogenation, that gives compound 159. Amide 160 is the result of input connections 159 reaction with 4-cyanoimino in the presence of EDCI and DMAP. Nitrile 160 is converted to the Boc-protected amidin, and then fully deprotection connection 161 under the conditions described in scheme 1.

Scheme 23

< / BR>
Figure 23 outlines receiving tetraline with the radical of acetic acid WITH2and carboxylating benzamidine C6. In the first step brotherhood 156 is processed with ethylene glycol and TsOH in conditions of dehydration, which gives ketal 162. This material is treated with t-BuLi and the resulting anion is neutralized with CO2. Formed acid immediately turns into an ester with benzyl alcohol and EDCI that gives compound 163. Spirochetal contained in 163, cleaved with aqueous HCl in acetone, and the resulting ketone is introduced into the reaction with the sodium salt of tert-butyldiethanolamine, giving connection 164 in the form of a mixture of olefin isomers. Catalytic hydrogenation on palladium remove unsaturation and releases WITH6carboxylate, giving acid 165. Condensation of this compound with 4-aminobenzonitrile gives amide 166. The conversion of compound 166 in the Boc-protected vannoy in scheme 1.

Scheme 24

< / BR>
Scheme 24 describes the receipt of 3,7-disubstituted of benzopyrano, in which position 3 substituted component alpha alkoxyalkyl acid, and the position 7 substituted amylovesanime benzamidine. The synthesis begins with allelotyping aromatic hydrocarbon 169. Acetamide hydrolysis is performed using NaOH in EtOH (alkali Klasen), and the resulting aniline again proektiruetsya as its CBz-option. The free phenol is then alleroed acetic anhydride, giving connection 170. Olefin is reacted with MCPBA, giving the corresponding epoxy polymer, which programmirovaniya in the presence of NaI, giving a mixture of 3-hydroxy - 3-acetoxybenzoic. This mixture is treated with LiOH, which gives the alcohol 171. Alcohol component connection 171 is then converted into your TBS-ether, and the resulting connection alkiliruya nitrogen to obtain a fully secure connection 172. The release of hydroxyalkyl C3using TBAF, followed by alkylation using tert-butylbromide under conditions of phase transfer network connection 173. Catalytic hydrogenation provides aniline 174, which alleroed using 4-lambertini acid, yielding amide 175. This material spimosi sequence, described in scheme 1.

Scheme 25

< / BR>
Scheme 25 outlines receiving 2,6-disubstituted of tetralones, in which position 2 substituted explicilty component, and the position 6 is substituted or alkoxysilanes benzamidine or alkoxyphenyl 4-alkylpiperidines. In the first step, the tetralone 178 processed NaOH and Glyoxylic acid, giving adduct 179. This material is restored with Zn in acetic acid and the resulting acid (180) reacts with diphenyldiazomethane, giving benzhydryl ester 181. Then the free phenol can alkylaromatic using alpha-bromo-p-tolunitrile, giving 184 connection, or by using the appropriate 4-alkylpiperazine, giving connection 182. Nitrile 184 is then converted to the corresponding Boc-protected amidin 185 and then fully deprotection connection 186 using the sequence of reactions described in scheme 1. Connection 182 deprotected using TFA, giving connection 183.

Scheme 26

< / BR>
Scheme 26 describes a method of obtaining tetrahydroisoquinoline, in which position 2 is substituted by a radical examinados acid, and the position 6 contains essential-related benzamidine. In the first step isohedron 2 is processed LiAlH4and receive the correspondingly hydrogenation and the resulting phenol alkiliruya or using alpha bromatological, or by using the appropriate 4-alkylpiperazine, giving connections 191 and 189, respectively. Nitrile component connections 191 converted to Boc-protected amidin 192 using the procedures described in scheme 1. This material is then muliverse using NaOH, and the resulting acid is treated with TFA giving connection 193. Connection 190 is obtained using a similar sequence emiliania and deprotection.

Scheme 27

< / BR>
Scheme 27 describes the acylation amedieval component contained in the 2,6-disubstituted-tetralone 365 and 366, which are derived from compounds 102 and 123 circuits 14 and 17 (respectively) by conversion into ester with ethanol. The acylation is performed by reaction of compounds containing benzamidine, alkylchlorosilanes in the presence of aqueous base, thus obtained derivative 367 and 370. These materials can then be emiliania with ethanolic NaOH, which gives the free acid (see 371 in scheme 27).

Scheme 28

< / BR>
The procedure according to scheme 27 is General and has also been applied to compounds containing izohinolinove the core, as focustraversalpolicy or benzopyrene.

Scheme 29

< / BR>
Scheme 29 describes how to obtain 2,6-disubstituted of tetralones, in which position 2 is occupied by the radical of acetic acid, and the position 6 contains aminosvyazannogo 4-propenylbenzene component. In the first step, the alcohol 384 (obtained from 4-pyridylcarbinol through hydrogenation and proektirovaniya) oxidized using oxalicacid and DMSO, giving the corresponding aldehyde. This material is not separated, and reacts in crude form with the sodium salt triethylphosphate that will give the desired unsaturated ester 385. This material muliverse with

LiOH, and the resulting acid 386 is activated by oxalylamino, giving compound 387. Aniline 98 reacts with acid chloride 387, giving adduct 388. This compound is N-deprotected using TFA, giving ester 389 after salt exchange with HCl. Alternative emiliania using LiOH first gives the free acid 390, which can then N-depotentiate using TFA, giving compound 391.

Scheme 30

< / BR>
Scheme 30 describes obtaining 2,6-disubstituted of tetrahydroisoquinolines with the radical of acetic acid at position 2, and nedosvecheny 4-propanolamide in position 6. In the first step, 6-aminomaslanaya to caedwalla using TFA, connecting 393.

Scheme 31

< / BR>
Scheme 31 outlines receiving 2,6-disubstituted of tetralones, in which position 2 is occupied by acetic-acid component, and the position 6 supports nedosvecheny differentley. The first step to diftorbenzofenon 394 added lithium with n-utility, and the resulting anion is neutralized with CO2that gives acid 395. This compound is then treated with oxalylamino, and the resulting acid chloride 396 reacts with aniline 98, giving adduct 397. Nitrile component in connection 397 converted to Boc-protected amidin 398 using the sequence of reactions used to convert 5 6 as described in scheme 1. Connection 398 may depotentiate using TFA, giving compound 399. The alternate connection 398 can be completely deprotection first by splitting hard-essential component using NaOH, and then by deprotection of amidine using TFA, which gives the connection 400.

Scheme 32

< / BR>
Scheme 32 describes how to obtain 2,6-disubstituted of tetralones with acetic acid component in position 2 and nedosvecheny amidinopropane in position 6. In the first step pyridine 401 reagire the attachment 403 then reacts with the sodium salt of methanethiol, giving metaltometal. This intermediate compound is reacted with iodide of ammonium, giving amidin that Boc-proektiruetsya, giving connection 404. Connection 404 first reacts with ethanolic NaOH for cleavage of ester and then with TFA to deprotection of amidine, providing fully deprotection homolog 405.

Scheme 33

< / BR>
Scheme 33 describes how to obtain 2,6-disubstituted of tetralones in which nedosvecheny amidin contains a thiophene nucleus. In the first step thiophene 406 metallised using LDA, and the resulting anion is neutralized with CO2giving acid 407. This acid reacts with the compound 98 in the presence of EDCI, giving amide 408. Nitrile component in connection 408 is converted to the Boc-protected amidin 409 using the sequence of reactions used for the formation of compound 6 in scheme 1. The resulting connection first muliverse using ethanol NaOH, and then N-deprotected using TFA, giving connection 410 in the form of the TFA salt.

Scheme 34

< / BR>
Scheme 34 describes how to obtain 2,6-disubstituted of benzopyrano, in which position 2 contains explicilty component, and the position 6 contains nedosvecheny porozumienie benzamidine. The cooperation is essential-proektiruetsya. Then using Pd/C is removed unsaturated ring, which gives the lactone 202. This material is restored by using DIBAH, giving intermediate lactol, which reacts with ethoxycarbonylmethylene, giving benzopyran 204. This material is then N-deprotected using TFA, and the resulting aniline is reacted with the acid chloride derived from ferocity 119, giving adduct 307. This material is then subjected to the action of HCl in ethanol, giving the intermediate aminoether, which is not separated, but instead reacts with ammonia, which leads to the formation of compound 304. This material is then hydrolyzed with NaOH in ethanol, giving the desired free acid 308 after neutralization.

Examples

The following examples are given to allow the technician to use the present invention. These examples, however, should not be considered a limitation of the framework of the invention as defined in the claims.

Reference numbers used in the examples, refer to the respective compounds shown in the preceding diagrams 1-26 reactions.

Example 1

Obtain 6-{ { 4-(aminoiminomethyl)phenol}methoxy}-3,4 - dihydro-1-oxo-2(1H)-ethanolinduced sour trimerization) (1.0 g, 6,14 mmol), benzylbromide (1.0 g, 6,14 mmol), K2CO3(0,93 g, 6,74 mmol) and acetone (15 ml) was maintained under irrigation for 12 h, and then cooled to room temperature. Then the mixture was diluted EtOAc and filtered by H2O. the Organic material was dehydrated (MgSO4) and concentrated. The crude residue was precrystallization from EtOAc/hexane, giving 1,53 g (98%) of compound (2) (6-benzyloxy - 3,4-dihydro-1-oxo-2(1H)-isoquinoline) in the form of a dry white residue.

Part B:

In the solution of the lactam (2) (0.1 g, 0,39 mmol) in THF (4 ml) was added sodium hydride (0,017 g 60% dispersion in mineral oil, 0.43 mmol). The resulting mixture was maintained under irrigation within 1 h, and then cooled to room temperature. The mixture is then processed tert-butylbromide (0.07 g, 0.43 mmol). After 1 h the reaction was kind of balanced out by the addition of H2O (10 ml) and the resulting mixture was extracted with EtOAc. The combined extracts were dehydrated (using MgSO4) and concentrated. The crude material was purified by chromatography (silica gel, 2: 1 hexane:EtOAc) to give 0.14 g (99%) of compound (3a) as a white dry residue.

Part C:

A mixture of compound (3A) (0,13 g and 0.37 mmol), Pd/C (0.14 g, 10% on the yr is up. Then the filtrate was concentrated, giving of 0.13 g (100%) substance (4) in the form of mostly pure white dry residue.

Part D:

A mixture of compound (4) (1,00 g of 3.60 mmol), alpha-bromo-p-tolunitrile (0.71 g, of 3.60 mmol), K2CO3(0.50 g, of 3.60 mmol) and acetone (35 ml) was maintained under irrigation within 4 h, and then cooled to room temperature. The resulting mixture was concentrated, and the residue was chromatographically on silica (1:1 hexane/EtOAc), giving 1,38 g (98%) of compound (5) as a clear oil.

Part E:

A mixture of compound (5) (0,385 g, 0,982 mmol), pyridine (5.5 ml), and Et3N (0,55 ml) saturated with H2S and was left for 2 days. This solution was then diluted H2O, and the resulting mixture was extracted with EtOAc, and the extracts were concentrated. Untreated selected substance was introduced into a mixture of acetone (5 ml) and CH3I (2.5 ml), and maintained under irrigation within 1 h the mixture was cooled to room temperature and concentrated. Untreated selected substance was administered in MeOH (5 ml) and was treated with NH4The OAc. The resulting solution was maintained for 2 h at 60oC, and then concentrated. Untreated selected substance was administered in a solution of THF/H2

Part F:

A mixture of compound (6) (0,311 g, 0,612 mmol) and TFA (5 ml) was maintained at room temperature for 1 h, and then concentrated. The residue was added to H2O, and the mixture was filtered Et2O. the Remaining aqueous material was liofilizirovanny, giving 0.31 g of compound (7) in the form of a dry white residue.

1H NMR (300 MHz, CD3OD) 3,03 (t, J=6,5 Hz, 2H), 3,68 (t, J=6,5 Hz, 2H), 4,29 (s, 2H), and 5.30 (s, 2H), 6,94 (d, J=1,9 Hz, 1H), 7,0 (dd, J=1,9, 8,6 Hz, 2H), 7,69 (d, J=8,5 Hz, 2H), to 7.84 (d, J=8,5 Hz, 2H), 7,87 (d, J=8,6 Hz, 1H), IR (CHCl3) 2928, 1695, 1435, 1286 cm-1; MS (FAB) m/e 354,1451 (354,1454 calculated for C19H20N3O4).

Example 2

Obtain 6-{ { 4-(aminoiminomethyl) phenyl} ethyl}-3,4 - dihydro-1-oxo-2(1H)ethanolinduced acid triptoreline, the compound represented by formula (12a):

< / BR>
Part a:

To a solution of compound (4) (9.5 g, 34,2 mmol) and freshly distilled pyridine (250 ml) was added triftormetilfullerenov (5.8 ml, 34,2 mmol) at 0oC. the resulting solution was extracted with EtOAc, the extract was dehydrated (MgSO4) and concentrated. The crude material was purified by chromatography (silica gel, 4:1 hexane:ethyl acetate), giving 11,54 g (82,4%) of compound (8) (6-{{ (trifluoromethyl)-sulfonyl} oxy} -3,4 - dihydro-1-oxo-2(1H)ethanolicus acid-1,1-dimethylether complex) in the form of a dry white residue.

Part B:

A mixture of compound (8) (0,325 g of 0.79 mmol), the compound (9a) (0,141 g, 1.11 mmol), bis(triphenylphosphine)-palladium (II) chloride (of 0.014 g, 0.02 mmol), anhydrous DMF (2.5 ml) and freshly distilled Et3N (0.5 ml) was mixed with 90oC for 1 h was added H20 (25 ml) and the mixture was extracted using EtOAc (2 x 75 ml). The extracts were dehydrated on MgSO4and concentrated. The crude material was purified by column chromatography (silica gel, 5:2 hexane:EtOAc), giving 0,173 g (57%) of compound (10a) as an orange dry residue.

Part:

Following the General procedure used to obtain the compounds (6), (example 1, part E), the compound (11a) was obtained with a yield of 53% at the source of 0.13 g of compound (10a).

Part D:

Following the General procedure used to obtain the compounds (7), (example 1, part F), the compound (12a) (6-{{4-(aminoiminomethyl)phenyl}ethinyl} -3,4-is of (11a).

1H NMR (300 MHz, CD3OD) 3,11 (t, J=6,6 Hz, 2H), of 3.73 (t, J=7,8 Hz, 1H), 4,34 (s, 2H), 7,51 (s, 1H), 7,55 (d, J=7,8 Hz, 1H), 7,78 (d, J=8,7 Hz, 2H), 7,83 (d, J=7,4 Hz, 2H), of 7.97 (d, J=8,0 Hz, 1H); IR (KBr) 3355, 3085, 1709, 1610, 1183 cm-1; MS (FAB) m/e 348,1332 (348,1348 calculated for C20H18N3ABOUT3).

Example 3

Obtain 6-{ 2-{ 4-(aminoiminomethyl)phenyl} ethyl}-3,4 - dihydro-1-oxo-2(1H)-ethanolinduced acid triptoreline, the compound represented by the formula (15a):

< / BR>
Part a:

A mixture of compound (10a) (0.10 g, 0.26 mmol), Pd/C (0.10 g of 10% on carbon) and EtOAc (15 ml) was stirred in hydrogen atmosphere (glass bottle) for 1.5 h, then was filtered and concentrated, giving 0.10 g (100%) of compound (13a) in the form of impure dry white residue.

Part B:

Following the General procedure used in the preparation of compound (6) (example 1, part E), the compound (14a) is obtained with a yield of 78% when the original 0,095 g of compound (13a).

Part C:

Following the General procedure used to obtain compound (7) (example 1, part F), connection (15a) is obtained with a yield of 60% at the source of 0.09 g of compound (14a).

1H NMR (300 MHz, CD3OD), a 3.01 (m, 6H), to 3.64 (t, J=6,6 Hz, 2H), 4,28 (s, 2H), 7,10 (m, 3HO), 7,39 (d, J=8,2 Hz, 2H), to 7.67 (d, 8,2 Hz, 2H), to 7.77 (d, J= 8,4 Hz, 1H); IR (KBr) 3337, 3112, 1641, 1210, 1188 cm-1; MS (FAB) m/e 352,1655 (352,Il)benzoyl}amino}-3,4 - dihydro-1-oxo-2(1H)-ethanolinduced acid triptoreline, the compound represented by formula (22):

< / BR>
Part a:

A solution of compound (8) (example 2, part a) (5.0 g, 12.2 mmol), DMF (25 ml), palladium (II) acetate (0,082 g and 0.37 mmol), triphenylphosphine (0,19 g, 0.73 mmol), freshly distilled Et3N (3.4 ml, 24.4 mmol) and anhydrous MeOH (9,9 ml, 244 mmol) were mixed in the atmosphere WITH (glass tube) at a temperature of 65oC for 15 h and Then the reaction mixture was cooled and was diluted H2O. the resulting mixture was extracted with EtOAc (2 x 100 ml). The combined extracts were dehydrated (MgSO4) and concentrated. The crude material was purified by column chromatography (silica gel, 3: 1 hexane:EtOAc) to obtain 2,80 g (72%) of compound (16) (6-(methoxycarbonyl)-3,4-dihydro-1-oxo-2(1H)-izohinolinove acid-1,1-dimethylether complex) in the form of impure dry white residue.

Part B:

A solution of compound (16) (2.8 g, 8,7 mmol) and THF (87 ml) was treated aqueous LiOH (87 ml of 0.1 N solution of 8.7 mmol) and the resulting solution was aged at room temperature for 1 h Then the reaction mixture was concentrated to 1/2 volume and extracted with EtOAc. The aqueous material was then padillas (pH = 5) with 1N HCl, and the mixture is then extraverbal the means (17) in the form of a viscous oil. The remaining aqueous material was liofilizirovanny, giving of 2.06 g of compound (17) in the form of lithium salts.

Part C:

A solution of compound (17) (0,200 g, 0.66 mmol) and anhydrous toluene (50 ml) is treated with diphenylphosphorylacetate (of 282.3 ml of 1.31 mmol) and freshly distilled EtaN (of 0.18 ml of 1.31 mmol) and the resulting solution was maintained at a temperature of 85oC for 2 hours and Then reacting the compound was cooled to room temperature, and then processed benzyl alcohol (0,14 ml of 1.31 mmol) and stirred for another one hour. Then the reaction mixture was concentrated, and the crude dedicated substance was purified by column chromatography (silica gel, 1:1 hexane:EtOAc) gave 0.21 g (79%) of compound (18) (6-{(benzyloxycarbonyl)amino}-3,4-dihydro-1-oxo-2(1H)-izohinolinove acid-1,1-dimethylether complex) in the form of a dry white residue.

Part D:

A mixture of compound (18) (0.20 g, 0.49 mmol), EtOH (20 ml), EtOAc (20 ml) and Pd/C (0.2 g 10% C) were mixed in an atmosphere of hydrogen (glass tube) for 1 h, and then filtered and concentrated, giving was 0.138 g (100%) of compound (19) (6-amino-3,4-dihydro-1-oxo-2(1H)- ethanolicus acid-1,1-complex dimethylethylamine) in the form of a dry white residue.

Part F:

Following the General procedure used for the synthesis of compound (6) (example 1, part E), the compound (21) was obtained with a yield of 36% when the original 0.17 g of compound (20).

Part G:

Following the General procedure used for the synthesis of compound (7) (example 1, part F), the compound (22) was obtained with a yield of 76% at the source of 0.07 g of compound (21).

1H NMR (300 MHz, CD3OD) to 3.09 (t, J=6,6 Hz, 2H), and 3.72 (t, J=6,6 Hz, 2H), 4,32 (s, 2H), to 7.67 (d, 1H), 7,80 (br s, 1H), 7,94 (d, J=8,3 Hz, 3H), 8,16 (d, J=8,2 Hz, 2H); IR (CHCl3) 3354, 3007, 1634, 1538, 1196 cm-1; MS (FD) m/e 367.

Analytically calculated for C21H19F3N4O6: 52,50; H 3,99; N 11,66. Found: 52,62; H 4.2; N 11,41.

Example 5

Getting(+-)-6-{ {4-(aminoiminomethyl)phenyl}methoxy}-3,4-dihydro-1-oxo-beta{ mexiletineciclovir] -2(1H)-izohinolinove acid triptoreline, the compound represented by formula (2 is the group of (3b) was obtained with a yield of 60%, when the source lactam (2) and methylpropanoate.

Part B:

A solution of the compound (3b) (1,95 g, 6.0 mmol) and THF (10 ml) was added to a solution of LHMDS (obtained from n-BuLi and HMDS according to standard protocols, 6.6 mmol) and THF (10 ml) at -78oC. After 1 h, the solution was processed tert-butylbromide (1.1 ml, 6.6 mmol) and left to warm to room temperature. The mixture was diluted with EtOAc (100 ml) and was filtered by H2O. the Organic material was dehydrated (MgSO4) and concentrated. Chromatography (silica gel, 200-400 mesh, 2:1 hexane/EtOAc) gave 2.17 g (82%) of compound (23) in the form of a clear oil.

Part C:

Following the procedure used to obtain compound (4) (example 1, part C), the compound (24) was obtained with a yield of 94% when the original 2.17 g of compound (23).

Part D:

A mixture of compound (24) (1,79 g, 5,12 mmol), alpha-bromo-p-tolunitrile (1,11 g, 5,64 mmol), K2CO3(0,78 g, 5,64 mmol), Bu4NI (cat.) and DMF (10 ml) were mixed at 80oC for 3 h, and then cooled to room temperature. Then the mixture was diluted with EtOAc (100 ml) and was filtered by H2O. the Organic material was concentrated, and the crude dedicated substance was purified by chromatography (silica gel, 200-wedenoja (25) (0,46 g, 1.0 mmol), aqueous LiOH (11 ml, 0.1 mmol) and THF (11 ml) was stirred at room temperature for 3 h, and then concentrated to 1/2 volume. The remaining aqueous material was first rinsed Et2O, and then pagkilala to pH = 3 with 1N HCl. This mixture was extracted with EtOAc and the combined extracts were concentrated. The crude residue was introduced in CH2Cl2(5 ml) and was treated with hexylamine (0.15 ml, 1.1 mmol), EDCI (0,28, 1.5 mmol), and DMAP (cat.). The resulting mixture was aged at room temperature for 4 h and then was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude residue was purified by chromatography (silica gel 200-400 mesh, 1:1 hexane/EtOAc), giving 0.52 g (92%) of compound (27a) as a clear oil.

Part F:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (28a) was obtained with a yield of 75% with the original 0.52 g of compound (27a).

Part G:

Following the procedure to obtain compound (7) (example 1, part F), the compound (29a) was obtained with a yield of 82% at the source of 0.47 g of compound (28a).

1H NMR (300 MHz, CD3OD), or 0.83 (m, 3H), of 1.27 (m, 6H), of 1.45 (m, 2H), 2,71 (dd, J=8,0, or 15.9 Hz, 1H), 3,1 (m, 5H) and 3.59 (m, 2H), 5,28 (s, 2H), 5,48 (t ; MS (FAB) m/e 495,2612 (495,2607 calculated for C27H35N4O5).

Example 6

Getting(+-)-6-{ { 4-(aminoiminomethyl)phenyl}methoxy}-3,4-di-hydro-1-oxo-beta-{{(phenylmethyl)amino}carbonyl}-2(1H)-isohedron-propanoic acid triptoreline, the compound represented by formula (29b).

< / BR>
Part a:

Following the procedure used to obtain compound (27a) (example 5, part E) connection (27b) was obtained with a yield of 84% when the source and 0.46 g of compound (26) (example 5, part E) and 0.12 g of benzylamine.

Part B:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (28b) was obtained with a yield of 76% at the source of 0.45 g of compound (27b).

Part C:

Following the procedure used to obtain compound (7) (example 1, part F), the compound (29b) was obtained with a yield of 72% at the source of 0.41 g of compound (28b).

1H NMR (300 MHz, CO3OD), 2,70 (dd, J=7,2, only 16.1 Hz, 1H), 2,90 (br t, J=6,4 Hz, 2H), is 3.08 (dd, J=7,9, or 15.8 Hz, 1H), 3,60 (m, 2H), 4,3 (dd, J=5,7, and 14.9 Hz, 1H), 4,43 (dd, J=6.3, in the 14.8 Hz, 1H), 5,28 (s, 2H), 5,50 (t, J=7,5 Hz, 1H), 6,87 (m, 1H), 6,97 (dd, J=2.0 a, 8,6 Hz, 1H), 7,25 (m, 5H), 7,71 (d, J= 8,3 Hz, 2H), 7,87 (d, J=8,3 Hz, 2H), of 7.90 (d, J=8,5 Hz, 1H); IR (KBr) 3333,

3092, 1668, 1604, 1278, 1185 cm-1; MS (FAB) m/e 501,2151 (501,2138 calculated for C28H29N4O5).

the IMT}-2(1H)-isopinocampheol acid triptoreline, the compound represented by formula (29c).

< / BR>
Part a:

Following the General procedure used to obtain compound (27a) (example 5, part E) connection (27c) was obtained with a yield of 76% at the source and 0.46 g of compound (26) and 0.17 g of p-methoxyphenethylamine.

Part B:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (28c) was obtained with the yield of 85% at the source of 0.44 g of compound (27c).

Part C:

Following the procedure used to obtain compound (7) (example 1, part F), connection (29c) was obtained with the yield of 80% at the source of 0.45 g of compound (28c).

1H NMR (300 MHz, CD3OD), a 2.75 (m, 5H), was 3.05 (dd, J=7,4, to 15.8 Hz, 1H), 3,30 (m, 2H), 3,50 (m, 2H), 3,66 (s, 3H), and 5.30 (s, 2H), vs. 5.47 (t, J-7,7 Hz, 1H), 6,65 (d, J= 8,4 Hz, 2H), 6.90 to (m, 1H), 6,98 (dd, J=2,2, 8,5 Hz, 1H), 7,05 (d, J=8,4 Hz, 1H), 7,71 (d, J=8,4 Hz, 2H), 7,81 (d, J=8,4 Hz, 2H), of 7.90 (d, J=8,5 Hz, 1H).

Example 8

Getting(+-)-6-{{4-(aminoiminomethyl)phenyl}methoxy}-3,4-dihydro-beta- { (methylamino)carbonyl} -1-oxo-2(1H)-ethinlestradiol acid triptoreline, the compound represented by formula (29d).

< / BR>
Part a:

Following the General procedure used to obtain compound (27a), the connection (27d) was obtained with the yield of 80% at the source and 0.46 g of compound (26), 0.07 g of methyladenine (6) (example 1, part (E), the compound (28d) was obtained with a yield of 63% at the source of 0.37 g of compound (27d).

Part C:

Following the procedure used to obtain compound (7) (example 1, part F), connection (29d) was obtained with a yield of 76% at the source of 0.30 g of compound (28d).

1H NMR (300 MHz, CD3OD), a 2.75 (m, 4H), 3.0 a (m, 2H), 3,10 (dd, J=7,4, or 15.9 Hz, 1H), 3,60 (m, 2H), from 5.29 (s, 2H), 5,44 (t, J=7,6 Hz, 1H), make 6.90 (d, J= 2,2 Hz, 1H), 6,98 (dd, J=2,2, and 8.4 Hz, 1H), 7,69 (d, J=8,2 Hz, 2H), 7,82 (d, J=8,2 Hz, 2H), 7,89 (d, J=8,4 Hz, 1H); IR (KBr) 3335, 3105, 1668, 1605, 1480, 1278, 1185 cm-1; MS (FAB) m/e 425,1819 (425,1825 calculated for C22H25N4O5).

Example 9

Getting(+-)-6-{ { 4-(aminoiminomethyl)phenyl} methoxy}-beta-{{(2 - carboxyethyl)amino} carbonyl} -3,4-dihydro-1-oxo-2(1H)-ethinlestradiol acid triptoreline, the compound represented by formula (29e).

< / BR>
Part a:

Following the General procedure used to obtain compound (27a) (example 5, part E), the compound (27e) was obtained with a yield of 74% when the source and 0.46 g of compound (26), 0.2 g of beta-amino-1-butylamine hydrochloride and 0.15 ml Et3N

Part B:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (28e) was obtained with a yield of 65% at the source of 0.42 g of compound (27e).

Chastichno exit 89% at the source of 0.45 g of compound (28e).

1H NMR (300 MHz, CD3OD), a 2.75 (t, J=6,2 Hz, 2H), 2,65 (dd, J=8,2, 1589 Hz, 1H), 3,05 (m, 3H), at 3.35 (m, 2H), 3,50 (m, 2H), 5,28 (s, 2H), 5,49 (t, J= 7,7 Hz, 1H), 6.89 in (m, 1H), 6,95 (dd, J=2,2, and 8.4 Hz, 1H), 7,68 (d, J=8,5 Hz, 2H), to 7.84 (d, J=8,5 Hz, 2H), of 7.90 (d, J=8,4 Hz, 1H); IR (KBr) 3338, 3108, 1669, 1604, 1278, 1187 cm-1; MS (FAB) m/e 483.

Analytically calculated for C26H27N4O9F3: 52,35; H 4,56; N 9,39. Found: 52,43; H 4,82; N 9,13.

Example 10

Getting(+-)-6-{ { 4-(aminoiminomethyl)phenyl}methoxy}-b- (3-ethoxypropan)-3,4-dihydro-1-oxo-2(1H)-ethinlestradiol acid triptoreline, the compound represented by formula (36a):

< / BR>
Part a:

A solution of the compound (2) (example 1, part a) (6,53 g for 25.8 mmol) and THF (100 ml) was treated NaH (1.13 g of 60% dispersion in oil, 28.3 mmol) and the resulting mixture was maintained under irrigation within 1 h the Mixture was left to cool to room temperature, and then was treated with 4-ethoxy-butanolide (28.4 mmol, obtained from acid using standard protocols) and DMAP (cat.). The resulting mixture was stirred at room temperature for 16 h, then was diluted EtOAc. The organic mixture was filtered by H2Oh, and concentrated. The crude material was purified by chromatography (silica gel, 200-400 mesh, hexane/EtOAc, 4:1), which gave 6,12 g (65%) with the l) were processed DIBAH (3.9 ml, 21,68 mmol) at a temperature of -78oC. After 1 h the reaction was kind of balanced out by adding methanolic HCl (79 ml of a 1.1 M solution). The mixture then was diluted EtOAc and was washed with water and saturated aqueous NaHCO3. The organic material was concentrated and the crude residue was purified by chromatography (silica gel, 200-400 mesh, hexane/EtOAc/Et3N, 3:1:0.01), and giving 4.09 g (64%) of compound (31a) as a clear oil.

Part C:

A mixture of compound (31a) (3.25 g, 8,48 mmol), dimethyl-t-butylsilane-1-1-butoxide (9,24 g, 42,4 mmol) and CH2Cl2(30 ml) was treated with BF3Et2O (1.1 ml, 8,48 mmol) at -78oC. the resulting solution was left to warm to room temperature after 2 h, and then was kind of balanced out by the addition of saturated aqueous NaHCO3(20 ml). The resulting mixture was extracted with EtOAc, and the extracts were concentrated. The crude product was purified by chromatography (silica gel, 200-400 mesh, hexane/EtOAc 4:1), yielding 3.1 g (78%) of compound (32a) as a clear oil.

Part D:

Following the procedure used to obtain compound (4) (example 1, part C), the compound (33a) was obtained with a yield of 88% at the source of 3.1 g of compound (32a).

Part E:

Behind 95% at the source of 0.53 g of compound (33a).

Part F:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (35a) was obtained with a yield of 40%, with original 0.71 g of the compound (34a).

Part G:

Following the procedure used to obtain compound (7) (example 1, part F), the compound (36a) was obtained with the yield of 85% at the source of 0.32 g of compound (35a).

1H NMR (300 MHz, CD3OD) to 1.15 (t, J=6,9 Hz, 3H), of 1.40 and 1.80 (m, 4H), 2,60 (m, 2H), 2.95 and (m, 2H), 3,49 (m, 6H), 5,10 (m, 1H), from 5.29 (s, 2H), 6,94 (d, J= 2,3 Hz, 1H), 6,97 (dd, J=2,2, 8,7 Hz, 1H), of 7.70 (d, J=8,3 Hz, 2H), 7,82 (d, J= 8,5 Hz, 2H), a 7.85 (d, J=8,8 Hz); IR (KBr) 3334, 3105, 1668, 1604, 1134 cm-1; MS (FAB) m/e 454,2380 (454,2342 calculated for C25H32N3O5).

Example 11

Getting(+-)-6-{ { 4-(aminoiminomethyl)phenyl}methoxy}-6-butyl-3,4 - dihydro-1-oxo-2(1H)-ethinlestradiol acid triptoreline, the compound represented by formula (36b):

< / BR>
Part a:

Following the procedure used to obtain the connection (30a) (example 10, part a), the compound (30b) was obtained with a yield of 90% when the initial compound (2) (0.3 g) and pentane anhydride (0.24 g).

Part B:

Following the procedure used to obtain compound (31a) (example 10, part b), the compound (31b) was obtained with a yield of 83% when the original 0.39 g of the compound (30b).

H is obtained with a yield of 52% at the source of 0.33 g of compound (31a).

Part D:

Following the procedure used to obtain compound (4) (example 1, part C), the compound (33b) was obtained with a yield of 98% when the source is 0.22 g of compound (32b).

Part E:

Following the procedure used to obtain the compound (25) (example 5, part D), the compound (34b) was obtained with a yield of 95% at the source 0.17 g of compound (33b).

Part F:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (33b) was obtained with a yield of 56% at the baseline of 0.23 g of compound (34b).

Part G:

Following the procedure used to obtain compound (7) (example 1, part F), the compound (36b) was obtained with a yield of 89% at the source of 0.14 g of compound (33b).

1H NMR (300 MHz, CD3OD) to 0.89 (t, J=7,15 Hz, 3H), of 1.35 (m, 4H), of 1.65 (m, 2H), 2,60 (m, 2H), 2.95 and (m, 2H), 3,50 (m, 2H), of 5.05 (m, 1H), from 5.29 (s, 2H), 6,95 (m, 2H), of 7.70 (d, J=8,4 Hz, 2H), 7,84 (app t, J=8,2 Hz, 3H); IR (KBr) 3333, 3107, 1667, 1604, 1138 cm-1; MS (FAB) m/e 424.

Analytically calculated for C26H30N3O6: 58,10; H 5,12; N OF 7.82. Found: 57,85; H 5,56; N 7,56.

Example 12

Getting(+-)-6-{{4-(aminoiminomethyl)phenyl}methoxy}-3,4-dihydro-1 - oxo-b-pentyl-2(1H)-ethinlestradiol acid triptoreline, the compound represented by formula (36c):

< / BR>
The hours received with the release of 95% when the initial compound (2) (0.75 g) and hexasaccharide (0,43 g).

Part B:

Following the procedure used to obtain compound (31a) (example 10, part b), the compound (31c) was obtained with a yield of 64% at the baseline to 1.1 g of compound (30c).

Part C:

Following the procedure used to obtain compound (32a) (example 10, part C), the compound (32c) was obtained with the yield of 70% at the source of 0.80 g of compound (31c).

Part D:

Following the procedure used to obtain compound (4) (example 1, part C), the compound (33c) was obtained with a yield of 87% at the baseline to 0.69 g of compound (32c).

Part E:

Following the procedure used to obtain the compound (25) (example 5, part D), the compound (34c) was obtained with a yield of 88% at the source of 0.13 g of compound (33c).

Part F:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (35) was obtained with a yield of 65% at the source of 0.18 g of compound (34c).

Part G:

Following the procedure used to obtain compound (7) (example 1, part F), connection (36c) was obtained with the yield of 80% when the initial compound (35b).

1H NMR (300 MHz, CD3OD) of 0.90 (m, 3H), of 1.30 (m, 6H), to 1.60 (m, 2H), 1.26 in (m, 2H), 2,97 (m, 2H), of 3.45 (m, 2H), of 5.05 (m, 1H), and 5.30 (2, 2H), to 6.88 (m, 1H), 6,94 (m, 1H), of 7.70 (d, J=8,3 Hz, 2H), 7,83 (d, J=8,4 Hz, 2H), a 7.85 (d, J= 9 Hz, 1H">

Example 13

Getting(+-)-6-{ {4-(aminoiminomethyl)phenyl}methoxy}-3,4-dihydro-1-oxo-beta-(1,4-doxyhexal)-2(1H)-ethinlestradiol acid triptoreline, the compound represented by formula (36d):

< / BR>
Part a:

Following the procedure used to obtain the connection (30a) (example 10, part a), the compound (30d) was obtained with a yield of 81% during the initial compound (2) (2.0 g) and 2-methoxyacetanilide (2.35 g).

Part B:

Following the procedure used to obtain compound (31a) (example 10, part b), the compound (31d) was obtained with a yield of 52% at the source of 2.35 g of compound (30d).

Part C:

Following the procedure used to obtain compound (32a) (example 10, part C), the compound (32d) was obtained with a yield of 42% at the source of 0.57 g of compound (31d).

Part D:

Following the procedure used to obtain compound (4) (example 1, part C), the compound (33d) was obtained with a yield of 96% when the source of 0.30 g of compound (32d).

Part E:

Following the procedure used to obtain the compound (25) (example 5, part D), the compound (34d) was obtained with a yield of 91% at the baseline of 0.23 g of compound (33d).

Part F:

Following the procedure used to obtain the connection is Part of G:

Following the procedure used to obtain compound (7) (example 1, part F), connection (36d) was obtained with a yield of 98% at the baseline of 0.05 g of compound (35d).

1H NMR (300 MHz, CD3OD) 2,70 (t, J=6,2 Hz, 2H), 2,93 (t, J=6,2 Hz, 2H), 3,30 (s, 3H), 3,47-of 3.78 (m, 8H), 5,09 (br s, 1H), from 5.29 (s, 2H), to 6.88 (d, J= 2,2 Hz, 1H), 6,95 (dd, J=2,2, 8,7 Hz, 1H), 7,82 (d, J=8,0 Hz, 2H), 7,84-7,86 (m, 3H); IR (KBr) 3350, 3114, 1669, 1604, 1482, 1385, 1279, 1186, 1029, 842 cm-1; MS (FAB) m/e 456,3.

Analytically calculated for C26H30N3O8: 54,84; H 5,31; N, 7,38. Found: 54,61; H 5,26; N 7,37.

Example 14

Getting(+-)-6-{ {4-(aminoiminomethyl)phenyl}methoxy}-b-ethyl-3,4-dihydro-1-oxo-2(1H)-ethinlestradiol acid triptoreline, the compound represented by formula (36e):

< / BR>
Part a:

Following the procedure used to obtain the connection (30a) (example 10, part a), the compound (30e) was obtained with a yield of 69% when the initial compound (2) (1.5 g) and propanolamide (1.26 g).

Part B:

Following the procedure used to obtain compound (31a) (example 10, part B), the compound (31e) was obtained with a yield of 73% at the baseline of 1.2 g of compound (30e).

Part C:

Following the procedure used to obtain compound (32a) (example 10, part C), the compound (32e) was obtained with a yield of 49% at IP (4) (example 1, part (C), the compound (33e) was obtained with a yield of 89% at the source of 0.55 g of compound (32e).

Part E:

Following the procedure used to obtain the compound (25) (example 5, part D), the compound (34e) was obtained with a yield of 86% at the source of 0.36 g of compound (33e).

Part F:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (35e) was obtained with a yield of 36% at the source of 0.38 g of compound (34e).

Part G:

Following the procedure used to obtain compound (7) (example 1, part F), connection (36e) was obtained with a yield of 92% when the source is 0.22 g of compound (33e).

1H NMR (300 MHz, CD3OD) of 0.91 (t, J=7,3 Hz, 3H), 1,62 was 1.69 (m, 2H), 2,55-2,62 (m, 2H), 2,92-of 2.97 (m, 2H), 3,42-of 3.53 (m, 2H), 4,94 (m, 1H), from 5.29 (s, 2H), 6.89 in (d, J=2,5 Hz, 1H), 6,95 (dd, J=2,5, and 8.6 Hz, 1H), of 7.70 (d, J=8,4 Hz, 2H), 7,84-7,87 (m, 3H). IR (KBr) 3330, 3109, 2973 1670, 1604, 1481, 1344, 1256, 1041, 835 cm-1; MS (FAB) m/e 396,1923 (396,1923 calculated for C22H26N3O4).

Example 15

Getting(+-)-6-{ { 4-(aminoiminomethyl)phenyl} methoxy} -3,4-dihydro-1 - oxo-b-propyl-2(1H)-ethinlestradiol acid triptoreline, the compound represented by formula (36f):

< / BR>
Part a:

Following the procedure used to obtain the connection (30a) (example 10, part a), the compound (30f) is th B:

Following the procedure used to obtain compound (31a) (example 10, part B), the compound (31f) was obtained with a yield of 73% at the baseline of 0.6 g of compound (30f).

Part C:

Following the procedure used to obtain compound (32a) (example 10, part C), the compound (32f) was obtained with a yield of 46% at the source of 0.44 g of compound (31f).

Part D:

Following the procedure used to obtain compound (4) (example 1, part C), the compound (33f) was obtained with a yield of 90% at the source of 0.24 g of compound (32f).

Part E:

Following the procedure used to obtain the compound (25) (example 5, part D), the compound (34f) was obtained with a yield of 88% at the source of 0.16 g of compound (33f).

Part F:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (35f) was obtained with a yield of 44% at the baseline to 0.19 g of compound (34f).

Part G:

Following the procedure used to obtain compound (7) (example 1, part F), connection (36f) was obtained with a yield of 66% at the source of 0.085 g of compound (35f).

1H NMR (300 MHz, CD3OD) of 0.95 (t, J=7,3 Hz, 3H), 1,29-of 1.36 (m, 2H), 1,54-1,71 (m, 2H), 2,56-2,62 (m, 2H), 2.91 in-2,96 (m, 2H), 3.43 points-of 3.53 (m, 2H), 5,09 (br s, 1H), from 5.29 (s, 2H), to 6.88 (d, J=2,1 Hz, 1H), of 6.96 (dd, J=2,1, 8,5 Hz, 1H), of 7.70 (d, J=8,2 Hz, 2 C23H28N3O4).

Example 16

Getting(+-)-6-({ 4-(aminoiminomethyl)phenyl} methoxy} -3,4-dihydro-1 - oxo-b-phenyl-(1H)-ethinlestradiol acid triptoreline, the compound represented by formula (36g):

< / BR>
Part a:

Isohedron (2) (1.0 g, 3.95 mmol) and 60 wt.% NaH, suspended in mineral oil (0,174 g, 4.35 mmol), was watered in THF (40 ml) for 1 h the Mixture was cooled to room temperature, and was added to one portion of the alpha methoxyethylamine (0,683 g, 4.35 mmol) (see Leibigs, Ann. Chem., 191, 1932). The reaction mixture is stirred over night at room temperature. The mixture was diluted with water (100 ml) and was extracted with EtOAc (2 x 50 ml). The combined extracts were dehydrated on anhydrous sodium sulfate and concentrated. The residue was chromatographically on silica gel, buyowner hexane/EtOAc to 2:1 aspect ratio. Received of 1.02 g of compound (31g) as a clear oil (68% of theoretical).

Part B:

Following the procedure used to obtain compound (32a) (example 10, part C), the compound (32g) was obtained with a yield of 36% at the baseline to 2.29 g of compound (31g).

Part C:

Following the procedure used to obtain compound (4) (example 1, part C), the connection (lsemaj to obtain the compound (25) (example 5, part D), the compound (34g) was obtained with a yield of 91% with the original 0,675 g of compound (33g).

Part E:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (35g) was obtained with the yield of 50% at the source of 0.80 g of compound (34g).

Part F:

Following the procedure used to obtain compound (7) (example 1, part F), connection (36g) was obtained with a yield of 79% at the source of 0.43 g of compound (35g).

1H NMR (300 MHz, CO3OD) was 2.76-3,30 (m, 5H), 3,47-of 3.54 (m, 1H), 5,27 (s, 2H), 6,38 (t, J=7,4 Hz, 1H), at 6.84 (d, J=2,3 Hz, 1H), of 6.96 (dd, J=2,3, and 8.7 Hz, 1H), 7,28-7,40 (m, 5H), to 7.68 (d, J=8,2 Hz, 2H), 7,81 (d, J=8,2 Hz, 2H), to $ 7.91 (d, J=8,7 Hz, 1H); IR (KBr) 3328, 3107, 1671, 1604, 1421, 1278, 1189, 1134, 1020 cm-1; MS (FAB) m/e 444,1931 (444,1923 calculated for C26H26N3O4).

Example 17

Obtain 6-{ { 3-(aminoiminomethyl)phenyl} ethinyl} -3,4-dihydro-1-oxo - 2(1H)-ethanolinduced acid triptoreline, the compound represented by formula (12b):

< / BR>
Part a:

Following the procedure used to obtain the compound (10a) (example 2, part B), the compound (10b) was obtained with a yield of 54% when the initial compound (8) (example 2, part a) and 0.9 g of compound (9b).

Part B:

Following the procedure used to obtain compound (6) (example 1, part E), with the ur, used to obtain compound (7) (example 1, part F), the compound (12b) was obtained with a yield of 87% at the baseline 0.01 g of the compound (11b).

1H NMR (300 MHz, CO3OD) of 3.07 (t, J=6,5 Hz, 2H), 3,70 (t, J=6,6 Hz, 2H), or 4.31 (s, 2H), 7,46 (s, 1H), 7,50 (d, J=8,2 Hz, 1H), 7,63 (t, J=7,8 Hz, 1H), 7,78 (d, J=7,6 Hz, 1H), 7,88 (d, J=7,7 Hz, 1H), 7,92 (s, 1H), of 7.96 (d, J=4,8 Hz, 1H); IR (CHCl3) 3010, 1647, 1607, 1277, 1156 cm-1; MS (FAB) m/e 348,1338 (348,1348 calculated for C20H18N3O3).

Example 18

Obtain 6-{ 2-{ 3-(aminoiminomethyl)phenyl} ethinyl}-3,4-dihydro-1-oxo - 2(1H)-ethanolinduced acid triptoreline, the compound represented by the formula (15b):

< / BR>
Part a:

Following the procedure used to obtain the compounds (13a) (example 2, part a), the compound (13b) was obtained with a yield of 98% at the source of 0.13 g of compound (10b).

Part B:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (14b) was obtained with a yield of 64% at the source 0.09 g of the compound (13b).

Part C:

Following the procedure used to obtain compound (7) (example 1, part F), the compound (15b) was obtained with a yield of 86% when the original 0.09 g of the compound (14b).

1H NMR (300 MHz, CO3OD) of 3.00 (m, 6H), of 3.65 (t, J=6,6 Hz, 2H), 4,28 (s, 2H), to 7.09 (s, 1H), 7,13 (d, J=8,2 Hz, 1H), 7,49 (m, 2H), /SUB>H22F3N3O5: 56,77; H AMOUNTS TO 4.76; N 9,03. Found: 56,65; H 4,71; N 8,73.

Example 19

Obtain 6-{ {4-(aminoiminomethyl)phenyl}methylaminomethyl}-3,4 - dihydro-1-oxo-2(1H)-ethanolinduced acid triptoreline, the compound represented by formula 50:

< / BR>
Part a:

A solution of compound (17) (6-carboxy-3,4-dihydro-1-oxo-2(1H)- ethanolicus acid-1,1-complex dimethylethylamine) (0.20 g, 0.66 mmol), p-cyanobenzylidene (0.10 g, 0.66 mmol), EDCI (0.15 g, 0.8 mmol), and DMAP (0.18 g, 1.4 mmol) in CH2Cl2(7.0 ml) was maintained at room temperature for 18 h and then concentrated. The residue was purified by chromatography (silica gel 200-400 mesh, 25:1 CHCl3/MeOH), giving 0,98 g(37%) 6-{{ (4-cyanophenyl)methylamino} carbonyl} -3,4-dihydro-1-oxo-2(1H)-isoquinoline acetic acid-1,1-complex dimethylethylamine in the form of a dry white residue.

Part B:

Following the procedure used to obtain compound (6) (example 1, part E), [[4-(1,1-dimethylethoxysilane aminoiminomethyl)-phenyl]methylaminomethyl]-3,4-dihydro-1-oxo - 2(1H)isoquinoline acetic acid-1,1-complex dimethylethylamine was obtained with a yield of 38% during the initial 6-{{(4-cyanophenyl)methylamino} carbonyl}-3,4-dihydro-1-oxo-2(1H)-isoquinoline acetic acid-1,1-slo the example 1, part (F), 6-{{4-(aminoiminomethyl)phenyl}methylaminomethyl}-3,4 - dihydro-1-oxo-2(1H)-ethanolinduced acid trifenatate was obtained with a yield of 83%, with original 0.05 g [[4-(1,1 - dimethylaminocarbonylmethyl)phenyl]methylaminomethyl]-3,4-dihydro - 1-oxo-2(1H)-ethanolicus acid-1,1-complex dimethylethylamine.

1H NMR (300 MHz, CD3OD) of 3.14 (t, J=6,4 Hz, 2H), of 3.73 (t, J=6,7 Hz, 2H), 4,34 (br s, 2H), and 4.68 (d, J=5,9 Hz, 2H), 7,6 (d, J=8,4 Hz, 2H), 7,79 (m, 4H), 8,03 (d, J=8,0 Hz, 1H); IR (KBr) 3327, 3109, 1670, 1639, 1190 cm-1; MS (FD) m/e 381.

Example 20

Getting 40 (+-)-6-[[4-(aminoiminomethyl)phenyl]methoxy]-1,2,3,4 - tetrahydronaphthalen-2-acetic acid triptoreline, the compound represented by formula (45):

< / BR>
Part a:

Having a temperature of 0oC suspension of 650 mg (16.3 mmol, 60% dispersion in mineral oil) of NaOH in THF were processed 2,70 ml (3.0 g, to 13.6 mmol) triethylphosphate. After stirring at 0oC for 0.25 h, the solution of 2.0 (11.3 mmol) of 6-methoxy-2-tetralone (38) (see scheme 6) in 10 ml THF was added dropwise. The cooling bath was removed, and the reaction proceeded with stirring at room temperature for 16 hours the Reaction was kind of balanced out by adding 50 ml of brine. Were separated by two layers, and the organic phase was dehydrated in Na2

Part B:

To a solution of 1.00 g (4,06 mmol) of the compound (39) in 20 ml EtOH was added a suspension of 0.2 g of 10% Pd/C in 10 ml EtOH. The mixture was hydrogencarbonate at a pressure of 50 pounds/inch2for 3 h at room temperature. The catalyst was filtered off, and the reaction is evaporated in vacuo, giving 1.10 g of oil. Purification by radial chromatography (SiO2with 5% EtOAc in hexane) gave 910 mg (3,66 mmol, 90%) of compound (40) as a clear oil.

Part C:

Having a temperature of -78oC a solution of 100 mg (0.40 mmol) of the compound (40) in 4 ml of CH2Cl2processed BBr3(1.0 ml 1M solution in CH2Cl2). After 4 h the reaction reached room temperature, and stirred at room temperature for 18 hours the Reaction was cooled to -78oC and was treated with 5 ml EtOH. The mixture was heated and stirred at room temperature for 3 hours the Volatiles were evaporated in vacuo, and the residue was dissolved in 5 ml of EtOH, and the mixture is stirred for 2 hours Evaporation of EtOH gave a brown oil, which was again dissolved in 20 ml of EtOH, and the solution was treated with a stream of HCl (g) for 10 minutes the Reaction was completed and stirred at room the was were 41 mg (0.30 mmol) of K2CO3, 8 mg (0.05 mmol) of NaI and 57 mg (0.29 mmol) of alpha-bromo-p-tolunitrile. The reaction stirred at room temperature for 16 h, the DMF was removed in vacuum. The residue was divided between 10 ml of H2O and 10 ml of EtOAc. The organic layer was separated, washed with 10 ml of H2O and dehydrated in Na2SO4. Evaporation in vacuum gave 91 mg of dry residue. Purification of dry residue by radial chromatography (SiO2, 25% EtOAc in hexane) gave 82 mg (0.24 mmol, 60% of the compound (40)) of the compound (42) in the form of a dry white residue.

Part D:

Following the procedure used to obtain compound (6) (example 1, part E), the compound (43) was obtained with the yield of 50% at the source 0,429 g of compound (42).

Part E:

A solution of 250 mg (0.54 mmol) of the compound (43) in 5 ml EtOH was treated with 0.5 ml of 5N aqueous NaOH (2.5 mmol). The reaction stirred at room temperature for 6 h, was added 3.0 ml of 1N aqueous citric acid (3.0 mmol). EtOH was evaporated in vacuum. White dry residue was filtered, rinsed H2O and dried in vacuum to obtain 130 mg of the acid (44) in the form of a white powder. The residue was suspenderbelt in 1 ml of anisole, and the mixture was treated with 10 ml triperoxonane acid. The reaction lane2O, and the solution was extracted with hexane (5 x 5 ml). The aqueous layer was liofilizirovanny to obtain 96 mg (0.26 mmol, 48% of the compound (43)) triptoreline salt of compound (45) in the form of a dry white residue.

MS (FD) m/e 339 (M+1, 100). IR (KBr) 3301, 3145, 2915, 1711, 1664, 1503, 1437, 1196, 1143, 1057 cm-1.

Analytically calculated for C27H34N2O51,5 H2O: 55,11; H VS. 5.47; N OF 5.84. Found 55,46; H 5,15; N The 5.45.

Example 21

Obtain 6-[[4-(guanidinate)phenyl] methoxy] -3,4-dihydro-1-oxo - 2(1H)-ethanolinduced acid triptoreline, the compound represented by the formula:

< / BR>
Part a:

The mixture of compounds (4) and (51) (obtained from dibromide and phthalimide potassium using standard protocols), K2CO3and DMF was maintained at 80oC for 4 h, and then was left to cool to room temperature. The reaction mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated, and the crude dedicated substance was purified on silica, giving the compound (46) as a clear oil.

Part B:

A mixture of hydrazine hydrate (0,079 ml of a 85% aqueous solution of H2O, 1.4 mmol), compound (46) (0.075 g, 0.14 mmol) and EtOH (3 ml) was maintained at 60oC t is alas aqueous NaHCO3. The organic material was concentrated, giving to 0.055 g (100%) of the compound (47) as a clear oil.

Part C:

A mixture of compound (47) (0,049 g, 0.12 mmol) N,N'-bis(tert-butoxycarbonyl)-S-methylisothiazoline (0,043 g, 0.15 mmol) and THF (1 ml) was maintained at room temperature for 60 h, and then concentrated. Chromatography (2: 1 hexane/EtOAc) gave 0,073 g (90%) of the compound (49) as a clear oil.

Part D:

Following the procedure used to obtain compound (7) (example 1, part F), compound (50) was obtained with a yield of 78% at the source of 0.07 g of compound (49).

1H NMR (300 MHz, CD3OD) 3,05 (bt, 2H), 3,65 (bt, 2H), 4,28 (s, 2H), 5,20 (s, 2H), 6.90 to (m, 2H), 7,35 (d, 2H), 7,50 (d, 2H), a 7.85 (d, 2H); IR (KBr) 3364, 3199, 1736, 1687, 1633, 1609, 1179 cm-1; MS (FAB) m/e 383,1732 (383,1717 calculated for C20H23N4O2).

Example 22

Getting 6[4-(piperidine-4-yl)propyloxy]-3,4-dihydro-1-oxo-(3-ethoxypropan)-1-oxo-2(1H)-ethinlestradiol acid triptoreline, the compound represented by the formula:

< / BR>
Part a:

A solution of the compound (33a) (0,053 g, 0.14 mmol) and alcohol (51) (obtained from 3-(4-pyridyl)-propanol using standard protocols), triphenylphosphine (0,046 g, 0,17 mmol), diethylazodicarboxylate (0,028 ml, 0,17 mmol is OK purified by chromatography (1:1 hexane/EtOAc), giving 0,047 g (61%) of compound 52 in the form of a clear oil.

Part B:

Following the procedure used to obtain compound (7) (example 1, part F), compound (53) was obtained with a yield of 95% at the source 0,042 g of compound (52).

1H NMR (300 MHz, CD3OD) of 1.13 (t, J=7,0 Hz, 3H), 1,27-to 1.98 (m, 15H), 2,58 (m, 2H), 2,96 (m, 4H), 3,28-3,51 (m, 6H), was 4.02 (t, J=6,1 Hz, 2H), of 5.05 (m, 1H), 6.75 in (br s, 1H), 6,83 (d, J=8,7 Hz, 1H), 7,82 (d, J=8,6 Hz, 1H); MS (FAB) m/e 447.

Analytically calculated for C27H39N2O7: 57,85; H 7,01; N 5,00. Found: 58,13; H 7,18; N 5,28.

Example 23

Obtaining the compounds represented by formula 66:

< / BR>
Part a:

A solution of DIBAH in toluene (100 ml of a 1.5 M solution, 150 mmol) and 6-methoxy-2-tetralone (60) (5,19 g, 28 mmol) was aged under irrigation for 17 h, then was cooled to 0oC. This solution was kind of balanced out by slow addition of saturated aqueous NH4Cl (25 ml) and then 1N HCl (25 ml) and slowly heated to room temperature with stirring. The obtained gelatinous mixture was filtered through Selita and colorless aqueous filtrate was extracted with EtOAc. The combined extracts were washed 1N HCl, H2O and brine, dehydrated (MgSO4) and concentrated in vacuo. The crude material very reddish-brown dry residue.

Part B:

To a solution of compound 62 (1.64 g, 10 mmol) in DMF (40 ml) at -5oC was slowly added hydroxide designed (Triton, 4,5 ml, 10 mmol). After 0,75 h stirring was added alpha-bromo-p-tolunitrile (1.98 g, 10 mmol) in dry form, and the solution is gradually during the night was warmed to room temperature. The mixture was diluted EtOAc, washed H2O, 1N HCl, saturated NaHCO3and brine, dehydrated (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography (silica gel 230-400 mesh mesh, toluene: EtOAc gradient) to obtain 2,05 g (73%) of compound 63 in the form of a dry white residue.

Part C:

To a vigorously stirred mixture of compound 63 (2.0 g, 7,16 mmol), KOH (50% w/v aqueous, 20 ml) and acid tetrabutylammonium sulfate (1.25 g, 3.58 mmol) in benzene (30 ml) was added dropwise pure tert-butylbromide (3,51 ml, 21,72 mmol). The mixture is stirred at room temperature for 3 h, then was diluted EtOAc and was washed 1N HCl, saturated NaHCO3H2O and brine, dehydrated (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography (silica gel 230-400 mesh mesh, toluene:EtOAc gradient) to obtain 2.38 g (85%) of compound 64 as a bexample 1, part E), compound 65 was obtained with a yield of 63% at the source of 2.33 g of compound 64.

Part E:

Following the General procedure described to obtain compound 7 (example 1, part F), compound 66 was obtained with a yield of 98% in the original 1.78 g of compound 65. MS (FD) m/e 355.

Example 24

Obtaining the compounds represented by formula 69:

< / BR>
Part a:

To a solution of compound 62 (0.64 g, 3.9 mmol) in DMF (25 ml) at -5oC was slowly added hydroxide designed (Triton, 1.77 ml, 3.9 mmol). After stirring for 0.5 h was added to a clean 1-tBOC-4-(3-bromopropyl)piperidine (1.19 g, 3.9 mmol) and the solution was left to warm to room temperature gradually overnight. The mixture was diluted EtOAc, washed H2O, 1N HCl, saturated NaHCO3and brine, dehydrated (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography (silica gel 230-400 mesh mesh, toluene:EtOAc gradient) to obtain 1,37 g (90%) of compound 67 as a colorless resin.

Part B:

To a vigorously stirred mixture of compound 67 (1,32 g, 3.4 mmol), KOH (50% w/v aqueous, 10 ml) and acid tetrabutylammonium sulfate (0.6 g, 1.7 mmol) in benzene (15 ml) was added dropwise pure tert-bouti who EtOAc and was washed 1N HCl, H2O and brine, dehydrated (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography (silica gel 230-400 mesh mesh, toluene:EtOAc gradient) to obtain 1.56 g (91%) of compound 68 in the form of a pale yellow oil.

Part C:

A mixture of compound 68 (1.51 g, 3 mmol) and TFA (15 ml) stirred at room temperature for 2 h, and then concentrated in vacuum. To the obtained oil was added Et2O/hexane, and after the destruction of the ultrasound was obtained dry residue. The material was filtered, rinsed Et2O and dehydrated to obtain 1 g (77%) of compound 69 in the form of reddish-brown dry residue. MS (FD) m/e 348.

Example 25

Obtaining the compounds represented by the formula 72:

< / BR>
Part a:

To a solution of DMSO (of 0.26 ml, 3.6 mmol) in CH2Cl2(13 ml), cooled to -78oC, was added dropwise net anhydride trifenatate (0.51 ml, 3.6 mmol). The colorless solution was stirred for 0.25 h at -78oC, then the connection 67 (0.7 g, 1.8 mol) in CH2Cl2(12 ml) was added dropwise within 5 minutes the Solution is stirred 1 h at -78oC, then was left to warm to room temperature and again stirred for 1.5 hours At Chi who ALOS for 1.5 hours The solution was diluted CH2Cl2(50 ml) and was washed 1N HCl, saturated NaHCO3H2O and brine, dehydrated (MgSO4) and concentrated to obtain 0.7 g (> 99%) of compound 70 as a colorless oil which was immediately used in the next step without further purification.

Part B:

A mixture of compound 70 (0,70 g, 1.8 mmol), NaBH3CN (0.12 g, 1.8 mmol), glycine-t-butyl ether complex (of 0.47 g, 3.6 mmol), glacial HOAc (0.1 ml, 1.8 mmol) and powdered molecular filters 3A (0.4 g) in absolute EtOH (20 ml) stirred at room temperature for 17 hours the Mixture was filtered, the filtrate was concentrated and the resulting oil is re-dissolved in EtOAc/H2O and using 1N NaOH pH was brought to 7.4. The layers were separated, and the aqueous layer was extracted with EtOAc. The EtOAc extracts were combined and were washed with saturated NaHCO3H2O and brine, dehydrated (Na2SO4) and concentrated. Untreated selected substance was purified by chromatography (silica gel 230-400 mesh mesh, toluene:EtOAc gradient) to obtain 0.17 g (19%) of compound 71 in the form of a colourless resin.

Part C:

A mixture of compound 71 (0.2 g, 0.4 mmol) and TFA (10 ml) stirred at room temperature for 3 h, and trasloco was obtained dry residue. The material was filtered, rinsed Et2O and dehydrated to obtain 0.2 g (87%) of compound 72 in the form of reddish-brown dry residue. MS (FD) m/e 347.

Example 26

Obtaining the compounds represented by formula 78:

< / BR>
Part a:

To a solution of DMSO (of 0.28 ml, 4 mmol) in CH2Cl2(13 ml), cooled to -78oC, was added dropwise clean triftoratsetata anhydride high (0.56 ml, 4 mmol). Cloudy white solution was stirred for 0.25 h at -78oC and then for 5 min was added dropwise compound 63 (0,558 g, 2 mmol) in CH2Cl2(12 ml). The solution was mixed for 1 h at -78oC, then was left to warm to room temperature and again stirred for 1.5 hours were Added net diisopropylethylamine (0.8 ml, 4.6 mmol), and stirring at room temperature continued for 1 h the Solution was diluted CH2Cl2(50 ml) were washed 1N HCl, saturated NaHCO3H2O and brine, dehydrated (MgSO4) and concentrated to obtain 0.55 g (> 99%) of compound 73 as a pale yellow dry residue, which was immediately used in the next step without further purification.

Part B:

A mixture of compound 73 (0.55 g, 2 mmol), NaBHregular filters 3A (0.4 g) in absolute EtOH (25 ml) stirred at room temperature for 17 hours The mixture was filtered, the filtrate was concentrated, and the obtained resin were re-dissolved in EtOAc/H2O and using 1N NaOH pH was brought to 7.5. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with saturated NaHCO3H2O and brine, dehydrated (Na2SO4) and concentrated, yielding 0.8 g (99%) of compound 74 in the form of a colourless resin, without additional purification.

Part C:

A mixture of compound 74 (0,784 g, 2 mmol), K2CO3(0,829 g, 6 mmol) and BOC2O (0,873 g, 4 mmol) in THF/H2O (1:1, 20 ml) stirred at room temperature for 5 hours THF was evaporated in vacuo and the aqueous residue was diluted with brine (50 ml) and was extracted with EtOAc. The combined extracts were washed with brine, dehydrated (MgSO4) and concentrated. The crude material was purified by chromatography (silica gel 230-400 mesh mesh, toluene: EtOAc gradient) to obtain 0.74 g (75%) of compound 76 in the form of a pale yellow dry residue.

Part D:

Following the General procedure used to obtain compound 6 (example 1, part E), compound 77 was obtained with a yield of 31% at the source of 0.66 g of compound 76.

Part E:

Following the General procedure, the x 0,22 g of compound 77. MS (FD) m/e 354.

Example 27

Obtaining the compounds represented by the formula 80:

< / BR>
Part a:

Compound 74 was dissolved (1,96 g, 5 mmol) in CH2Cl2(20 ml) was added pyridine (2 ml, 26 mmol) then dropwise was added pure acetic anhydride (to 0.47 ml, 5 mmol). Golden solution was stirred at room temperature for 6 h, then was washed 1N HCl, H2O and brine, dehydrated (MgSO4) and concentrated. The crude material was purified by chromatography (silica gel 230-400 mesh mesh, toluene:EtOAc gradient), giving 0,86 g (39%) of compound 75 as a white dry residue.

Part B:

Following the General procedure used to obtain compound 6 (example 1, part E), compound 79 was obtained with a yield of 81% during the initial 1.19 g of compound 75.

Part C:

Following the General procedure used to obtain compound 7 (example 1, part F), compound 80 was obtained with a yield of 92% at the source of 0.96 g of compound 79. MS (FD) m/e 396.

Example 28

Obtaining the compounds represented by formula 88:

< / BR>
Part a:

A mixture of compound 81 (3,9 g, 13.3 mmol) and EtOH (20 ml) was treated NaBH4(1.0 g, to 26.6 mmol). The mixture was maintained under irrigation within 1 concentrically, and the residue, thus obtained, was subjected to dehydration using TsOH (cat.) in irrigating benzene. Untreated sulemaniyah the mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude residue was purified by chromatography (5:1 hexane/EtOAc), giving 2.6 g of compound 82.

Part B:

A mixture of compound 82 (2.6 g, 9.5 mmol), NMO (1,53 g, 11.3 mmol), tBuOH (8 ml), H2O (8 ml) and acetone (8 ml) was treated with OsO4(0.1 ml of 1 mg/ml solution in CCl4), and the mixture was stirred at room temperature overnight. Then the mixture was diluted EtOAc and filtered by H2O and saturated aqueous NaHCO3. The organic material was then concentrated. The crude residue was precrystallization from EtOAc/hexane, giving 2.8 g of compound 83 as a white dry residue.

Part C:

Diol 83 (2.8 g) was suspenderbelt in benzene was added (0.1 g) TsOH. Then the mixture was maintained under irrigation for 15 minutes Then the solution was diluted EtOAc and washed with 0.1 N aqueous NaOH. The organic material was then concentrated. The crude residue was introduced in THF (25 ml) and the resulting solution was added to a mixture of NaH (0.5 g 60% dispersion in oil, 14.7 mmol), triethylphosphate EtOAc and filtered by H2O. the Organic material was concentrated and the crude dedicated substance was purified on silica (3: 1 hexane/EtOAc), giving 2,52 g of compound 84 in the form of a clear oil.

Part D:

A mixture of compound 84 (of 2.51 g, 6,87 mmol), Pd/C (10% on carbon, 2.5 g) and EtOH (20 ml) was maintained in an atmosphere of H2(glass bottle) for 2 h, and then filtered and concentrated. The residue was dissolved in CH2Cl2(5 ml) and was treated p-cyanobenzoic acid (1,21 g, 8.3 mmol), EDCI (1.6 g, 8.3 mmol) and DMAP (cat.). The resulting solution was stirred for 4 h and then was diluted EtOAc and filtered by H2O. the Organic material was concentrated, and the obtained dry material was kristalizovyvatsja from (EtOAc/hexane) to give 1.35 g (54%) of compound 86 as a white dry residue.

Part E:

Following the General procedure described for obtaining the compound (6) (example 1, part E), compound 87 was obtained with the yield of 80% at the source of 1.35 g of compound 86.

Part F:

Following the General procedure described to obtain compound 7 (example 1, part F), compound 88 was obtained with a yield of 70% at the baseline of 0.2 g of compound 87.

1H NMR (300 MHz, CD3OD) of 1.5 (m, 1H), 2,0 (m, 1H), 2,2 (m, 1H), 2,4 (m, 2H), 2,45 (dd, J=10,2, an increase of 16.2 Hz, 1H), 2.91 in (which but for C20H22N3O3).

Example 29

Obtaining the compounds represented by the formula 95:

< / BR>
Part a:

The mixture of compounds 82 and NaH in THF was treated with benzylbromide and Bu4NI (cat. ), and the resulting solution was left at room temperature for 2 hours Then the solution was diluted EtOAc and filtered by H2O. the Organic material was concentrated, giving almost pure compound 88 as a yellow oil.

Part B:

A mixture of compound 88 (1.0 g, 2,71 mmol), NMO (0.40 g, 3.0 mmol), t-BuOH (2.0 ml), acetone (2.0 ml) and H2O (2 ml) was treated with OsO4(0.1 ml of 1 mg/ml solution CCl4), and the compound obtained was left for the night. The mixture then was diluted EtOAc and washed with saturated aqueous NaHCO3and H2O. the Organic material was concentrated and the crude residue was introduced in benzene (25 ml) and was treated TsOH (cat.). The resulting mixture was maintained under irrigation for 15 min, and then concentrated. Untreated selected substance was administered in EtOH and processed NaBH4(0.25 g) and were left for 1 h the mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude dedicated substance was purified by chromatog the Oia 90 (0.18 g, 0.64 mmol) and t-butylbromide (0.18 g, 0.95 mmol), benzene (5 ml), 50% NaOH (5 ml) and Bu4NHSO4(cat.) vigorously stirred at room temperature for 12 hours the mixture then was diluted EtOAc and filtered by H2O. the Organic material was concentrated, and the crude dedicated substance was purified by chromatography (5:1 hexane/EtOAc) gave 0.09 g (35%) of compound 91 in the form of a clear oil.

Part D:

A mixture of compound 91 (0.31 g) and 10% Pd/C (0.3 g) in EtOAc was maintained in an atmosphere of H2(glass tube) for 4 h, and then filtered and the filtrate was concentrated. The crude residue was introduced in CH2Cl2(5 ml) and was treated p-cyanobenzoic acid (0.12 g, 0.70 mmol), EDCI (0,23 g of 0.79 mmol) and DMAP (cat.). The resulting solution was aged at room temperature for 2 h, then was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude residue was purified on silica (3: 1 hexane/EtOAc) gave 0.24 g of compound 93 in the form of a clear oil.

Part E:

Following the General procedure used to obtain compound 6 (example 1, part E), compound 94 was obtained with a yield of 56% at the baseline of 0.23 g of compound 93.

Cha is obtained with a yield of 63% at the source of 0.16 g of compound 94.

1H NMR (300 MHz, CD3OD) 1,90 (m, 1H), 2.05 is (m, 1H), 2,7-3,3 (m, 4H), 3,90 (m, 1H), 4,20 (s, 2H), 7,10 (d, J=8,0 Hz, 1H), 7,40 (m, 2H), of 7.90 (d, J=8,3 Hz, 2H), 8,15 (d, J=8,3 Hz, 2H); IR (KBr) 3326, 2936, 1664, 1598 cm-1; MS (FAB) m/e 368.

Analytically calculated for C22H22N3O6F3: 54,89; H BR4.61; N, 8,73. Found: 54,90; H Of 4.67; N 8,50.

Example 30

Obtaining the compounds represented by formula 102:

< / BR>
Part a:

The mixture tetralone 96 (5.0 g, 24.6 mmol), monohydrate glucosinolate (8,4 g, 93,6 mmol), NaOH (4.35 g, 168,9 mmol), methanol (50 ml) and H2O (50 ml) was maintained under irrigation for 1.25 h, then was cooled to 0oC. Then the reaction was padillas (under stirring) of concentrated HCl. The precipitate (97) (5.8 g) was collected by filtration.

Part B:

A mixture of compound 97 (20,0 g, 77.2 mmol) and Zn (14.1 g, 216 mmol) in HOAc (160 ml) and H2O (60 ml) was maintained under irrigation for 1.25 h and then filtered. The filtrate was diluted H2O, and the resulting mixture was extracted with EtOAc. The combined extracts were concentrated. Untreated selected substance was injected in concentrated HCl (100 ml) and was maintained under irrigation for 0.5 hours. Then the mixture was diluted H2O (300 ml) and was cooled to 5oC. the Mixture OSTO is done by filtering and was dehydrated in a vacuum. Then this material was suspenderbelt in EtOH, and the resulting solution was saturated with HCl (g). Then the mixture was concentrated. Thus formed material was suspenderbelt in H2O, and the pH of the resulting solution was brought to 10 by using crystalline NaOH. This material was extracted with EtOAc, and the extracts were concentrated. The crude product was precrystallization from EtOAc/hexanol, giving of 12.1 g of pure compound 98 in the form of reddish-brown dry residue.

Part C:

A mixture of compound 98 (6.8 g, 27.5 mmol), p-lambertini acid (4.4 g, 30.2 mmol), EDCI (7,86 g, 41.2 mmol), DMAP (0.1 g) and CH2Cl2(10 ml) stirred at room temperature for 4 h the mixture then was diluted EtOAc and filtered by H2O. Then the organic material was concentrated, yielding the crude compound 99 in the form of reddish-brown dry residue. Recrystallization from EtOAc/hexanol gives 7,86 g of pure compound 99.

Part D:

Following the General procedure described to obtain compound 6 (example 1, part E), compound 100 was obtained with a yield of 74% at the source of 7.85 g of compound 99.

Part E:

Following the General procedure described to obtain compound 7 (example 1, part F), connect the(2.0 g, 4.1 mmol) and EtOAc (5 ml) was treated with NaOH (0,49 g, 12.1 mmol) and the resulting solution was aged at room temperature for 2 hours Then the solution was concentrated and the resulting residue was introduced in H2O. the Aqueous material was first washed EtOAc, and then carefully pagkilala (pH = 4) with KHSO4. The formed precipitate was collected by filtration and was dehydrated in a vacuum. This material is then processed TFA (10 ml) for 1 h, and then concentrated. The crude material was introduced into a hot H2O, filtered, and then liofilizirovanny, giving a net connection 102 in the form of a white powder.

1H NMR (300 MHz, CD3OD) of 2.0 (m, 1H, in), 2.25 (m, 1H), 2,50 (dd, J=6,4, and 16.4 Hz, 1H), 2,90 (dd, J=4.2, and of 16.5 Hz, 1H), 2,90-3,2 (m, 3H), 7,6 (dd, J=1,9, 8,6 Hz, 1H), 7,80 (s, 1H), 7,95 (m, 3H), 8,14 (d, J=8,3 Hz, 2H); IR (KBr) 3330, 3108, 1712, 1669, 1538 cm-1; MS (FAB) 366.

Analytically calculated for C22H20N3O6AF3: 55,12; H 4,20; N 8,76. Found: 54,88; H Or 4.31; N 8,46.

Example 31

Obtaining the compounds represented by the formula 118:

< / BR>
Part a:

A mixture of compound 100 (0.2 g, 0.4 mmol) and EtOH (10 ml) was treated NaBH4(0.025 g, 0.4 mmol) and left at room temperature for 1 h the mixture was then concentrated, and the residue was dissolved in EtOAc. E is (cat.). The resulting solution was maintained under irrigation for 1.5 hours the mixture was concentrated, and the residue was introduced into EtOAc, the resulting solution was washed with 0.1 N NaOH, and then concentrated. Chromatography (1:1 hexane/EtOAc) to give 0.08 g of pure compound 116 in the form of a dry white residue.

Part B:

Following the General procedure described for connection 102 (example 30, part F), compound 118 was obtained with the yield of 80% at the source of 0.08 g of compound 116.

1H NMR (300 MHz, CD3OD) of 2.34 (br t, J=8,0 Hz, 2H), and 2.83 (br t, J=8,0 Hz, 2H), or 3.28 (s, 2H), 6,40 (s, 1H), 7,0 (d, J=8,7 Hz, 1H), 7,5 (m, 2H), 7,92 (d, J= 8,3 Hz, 2H), 8,10 (d, J= 2H); IR (KBr) 3385, 3089, 1716, 1672, 1194 cm-1; MS (FAB) m/e 350,1505 (350,1505 calculated for C20H20N3O3).

Example 32

Obtaining the compounds represented by the formula 123:

< / BR>
Part a:

A mixture of compound 98 (0.14 g, of 0.58 mmol), acid 119 (0,095 g of 0.58 mmol), EDCI (0.16 g, 0.86 mmol), DMAP (cat.) and CH2Cl2(3 ml) was maintained at room temperature during the night. Then the mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude residue was purified on silica (hexane/EtOAc 2:1), giving 0,095 g (40%) of compound 120.

Part B:

Following the General procedure described for the gender CLASS="ptx2">

Part C:

A mixture of compound 121 (0.04 g, 0.08 mmol), NaOH (0.003 g, 0.08 mmol) and EtOH (5 ml) was maintained at room temperature for 6 h, and then concentrated. The residue was dissolved in H2O and pagkilala to pH = 4 with KHSO4. The resulting mixture was extracted with EtOAc, and the extracts were concentrated. Chromatography (EtOAc) gave of 0.014 g of compound 122. Processing of this material TFA (5 ml) for 1 h followed by concentration gave of 0.014 g of compound 123.

1H NMR (300 MHz, CD3OD) of 2.0 (ddd, J=4,5, 13,0, 25,8 Hz, 1H), 2,30 (m, 1H), 2,45 (dd, J=6,4, and 16.5 Hz, 1H), 2,90 (dd, J=5,7, and 16.5 Hz, 1H), 2,9-3,2 (m, 3H), 7,6 (m, 1H), to 7.75 (m, 3H), 7,95 (m, 2H); IR (KBr) 3341, 3118, 1664, 1205 cm-1; MS (FAB) m/e 384.

Example 33

Obtaining the compounds represented by the formula 130:

< / BR>
Part a:

A mixture of 2-bromo-6-benzyloxyaniline (124) (1.0 g, 3.2 mmol) and THF (25 ml) was treated with t-BuLi (4,2 ml, 1.7 M solution in pentane, 7.0 mmol) at -78oC. After 1 h was added diethyloxalate (0.5 ml, 3.5 mmol) and the resulting mixture was left to warm to room temperature. The reaction mixture then was diluted EtOAc and filtered by H2O. the Organic layer was concentrated. The crude material was purified by chromatography (3:1 hexane/EtOAc) gave 0.52 g of pure compound 125.

2O (10 ml). After 1 h, the solution was concentrated to an anhydrous condition, and the residue was passed through a plug of silica (4:1 hexane/EtOAc). The material thus obtained was subjected to catalytic hydrogenation using 10% Pd/C (glass tube). After removal of catalyst by filtration and concentration turns out to 0.48 g (35%) of the desired compound 126.

Part C:

A mixture of compound 126 (of 0.48 g, 2.1 mmol), alpha-bromo-p-tolunitrile (0.45 g, 2.3 mmol), K2CO3(0.32 g, 2.3 mmol), Bu4NI (cat.) and DMF (5 ml) was maintained at 80oC for 4 h, and then was left to cool to room temperature. This solution was diluted EtOAc, and the resulting solution was filtered by H2O. the Organic material was then concentrated. The crude residue was precrystallization from EtOAc/hexane, yielding 0.33 g (45%) of compound 127 in the form of a reddish-brown residue.

Part D:

Following the General procedure described to obtain compound 6 (example 1, part E), compound 128 was obtained with the yield of 50% at the source of 0.33 g soedirman) were mixed at room temperature for 5 h, and then was concentrated. The residue was introduced into the H2Oh, and the resulting solution was extracted with EtOAc. Then the pH of the aqueous material was brought to 4 with HCl (1N), and the resulting mixture was extracted with EtOAc. The extracts were concentrated, and the crude material was processed TFA (10 ml) for 1 h at room temperature. The reaction mixture was then concentrated to an anhydrous state, yielding 0.07 g of compound 130 in the form of a dry white residue.

1H NMR (300 MHz, CD3OD) of 3.85 (s, 2H), and 5.2 (s, 2H), 7,2-7,4 (m, 3H), of 7.6 to 7.9 (m, 7H); IR (KBr) 3334, 3106, 1695, 1669, 1130 cm-1; MS (FAB) m/e 335.

Analytically calculated for C22H19N2O5F3: 58,93; H 4,27; N 6,25. Found: 58,70; H 4,46; N 5,97.

Example 34

Obtaining the compounds represented by the formula:

< / BR>
Part a:

A mixture of compound 2 (0.5 g, 2.0 mmol) and THF (10 ml) was treated LiAlH4(0.15 g, 4.0 mmol), and then was maintained under irrigation within 2 hours the Mixture was cooled to room temperature, and then was extinguished H2O and 15% NaOH. The resulting mixture was filtered and concentrated. This procedure allowed the allocation of 0.45 g of material, the purity of which was essential for the next transformation. Part of this material (0.2 Ivalice at room temperature for 15 hours The mixture then was diluted EtOAc and was washed2O. the Organic material was concentrated and the crude residue was purified on silica (2,5:1 hexane/EtOAc) to give 0.34 g (90%) of compound 132.

Part C:

A mixture of compound 132 (0.1 g, 0.28 mmol) and Pd/C (10% on carbon, 0.1 g), and EtOAc was maintained in an atmosphere of H2within 12 h, and then filtered and concentrated. Chromatography (1,5:1 hexane/EtOAc) gave 0,039 g (52%) of compound 133.

Part D:

A mixture of compound 133 (0,073 g, 0.28 mmol), NaH (0,012 g 60% dispersion in oil, 0.31 mmol) in THF (10 ml) stirred at room temperature for 1/2 h and then treated with a solution of 1-t-4-(3-bromopropyl)piperidine (0,093 g, 0.31 mmol) in THF (1 ml). The resulting solution was maintained under irrigation within 2 h, and then cooled to room temperature. The reaction mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the resulting material was chromatographically on silica (3:1 hexane/EtOAc), giving 0,086 g of alkylated product. This material (0,076 g) was dissolved in TFA (5 ml) and was maintained at room temperature for 1 h This material was then concentrated. The crude residue was introduced into a 10% HCl (5 ml) and liofilizirovanny, d is 2H), of 1.95 (m, 2H), 3.0 a (m, 2H), 3,2 (m, 2H), 3,4 (m, 2H), 3,65 (br s, 2H), 4,0 (t, J=6,2 Hz, 2H), 4,18 (s, 2H), of 4.45 (s, 2H), PC 6.82 (m, 2H), 7,15 (d, J= 8,4 Hz, 1H); IR (KBr) 3406, 2946, 1741, 1614 cm-1; MS (FAB) m/e 333,2182 (333,2178 calculated for C19H29N2O3).

Example 35

Obtaining the compounds represented by the formula 140:

< / BR>
Part a:

A mixture of compound 2 (0.5 g, 2.0 mmol) and THF (10 ml) was treated LiAlH4(0.15 g, 4.0 mmol) and the resulting mixture was maintained under irrigation for 16 hours the Mixture was cooled to room temperature, and then was extinguished using H2O and 15% NaOH. The resulting mixture was filtered and concentrated. The crude reduction product was introduced in THF/H2O (1:1, 10 ml) and was treated Boc2O (0.64 g, 2.9 mmol) and K2CO3(0,41 g, 2.9 mmol). The resulting mixture was stirred at room temperature for 2 h, then was diluted EtOAc. Organic material was filtered by H2O and concentrated. Untreated selected substance was chromatographically on silica (1: 1 hexane/EtOAc), giving of 0.58 g of pure compound 131.

Part B:

A mixture of compound 131 (0,58 g), Pd/C (10% on carbon, of 0.58 g) and EtOAc (30 ml) was maintained in an atmosphere of H2(glass tube) for 1 h, and then filtered and concentrated. Floor2CO3(0.3 g, 2.1 mmol), alpha-bromo-p-tolunitrile (0,42 g, 2.1 mmol), Bu4NI (cat.) and acetone was maintained under irrigation within 6 hours the Reaction mixture then was diluted EtOAc and was washed2O. the Organic material was concentrated and the crude residue was purified by chromatography (1:1 hexane/EtOAc) to give 0.34 g of compound 137.

Part D:

A mixture of compound 137 (0.34 g, were 0.94 mmol) and TFA (10 ml) was maintained at room temperature for 1 h, and then concentrated. The residue was introduced into a saturated aqueous NaHCO3and the resulting mixture was extracted with EtOAc. The extracts were combined and concentrated. The crude residue was introduced in CH3CN (10 ml) and the resulting solution was processed TO a2CO3(0.14 g, 1.0 mmol) and tert-butylbromide (0.20 g, 1.0 mmol). The resulting mixture was stirred at 60oC for 2.5 h, then was diluted EtOAc. Organic material was filtered by H2O and concentrated. The crude residue was purified on silica (2,5:1 hexane/EtOAc) to give 0.18 g of compound 138.

Part E:

Following the procedure described to obtain compound 6 (example 1, part E), compound 139 was obtained with a yield of 33% at the source of 0.18 g of compound 138.

1H NMR (300 MHz, CD3OD) 3,19 (m, 2H), 3,62 (m, 2H), of 4.05 (s, 2H), 4,21 (s, 6H), 6,92 (m, 2H), 7,11 (d, J=8,3 Hz, 1H), 7,65 (d, J=8,4 Hz, 2H), 7,82 (d, J=8,4 Hz, 2H); IR (KBr) 3333, 3104, 1668, 1617, 1191 cm-1; MS (FAB) m/e 340,1.

Example 36

Obtaining the compounds represented by the formula 146:

< / BR>
Part a:

A mixture of compound 141 (12.3 g, a 60.2 mmol) and 5N HCL (75 ml) was maintained under irrigation for 12 h, and then concentrated to an anhydrous state. The residue was introduced into a saturated aqueous NaHCO3and this mixture was extracted with EtOAc. Then the extracts were dehydrated in Na2SO4and concentrated. The crude product was purified on silica (15:85 MeOH/CH2Cl2), giving 5.0 g of compound 142 in the form of reddish-brown dry residue.

Part B:

A mixture of compound 142 (2.6 g, 16.0 mmol), benzyl bromide (5.5 g, 32,0 mmol), K2CO3(4,43 g of 32.0 mmol), CH3CN (30 ml) and Bu4NI (cat.) was aged under irrigation for 3.5 h, then was diluted EtOAc and filtered by H2O. the Organic material was dehydrated and concentrated. Chromatography (15:85 MeOH/CH2Cl2) has allowed to identify the fraction containing both mono-and dibenzylamine material. This compound was dissolved in THF, and the resulting solution was treated LiAlHtribals. The crude product is allocated thus, immediately introduced in THF/H2O and processed Boc2O (3,84 g, 17.6 mmol) and K2CO3(6.6 g, 48,0 mmol). After 1 h the mixture was diluted EtOAc and filtered by H2O and brine. The organic material was concentrated, and the crude dedicated substance was purified on silica, yielding 6.25 g of a mixture of monobenzyl and dibenzylamine of tetrahydroisoquinolines. This mixture was subjected to catalytic hydrogenation (Pd/C) in EtOH, giving 1.92 g of pure compound 143 after chromatography (1:3 MeOH/CH2Cl2on the silicon dioxide.

Part C:

A mixture of compound 143 (1.92 g, 8.2 mmol) p-lambertini acid (1.2 g, 8.2 mmol), EDCI (1.7 g, 9.0 mmol) and DMAP (cat.) in CH2Cl2(20 ml) was maintained at room temperature for 2 hours the Mixture then was diluted EtOAc and washed with water. The organic material was then concentrated, yielding the crude compound 144, the purity of which was significant for the following reaction. The crude substance 144 was dissolved in TFA and was left at room temperature for 1 h, and then concentrated. The residue was introduced into a saturated aqueous NaHCO3and the resulting mixture was exchangerubles with EtOAc. The organic extracts conciatori was important in the next step. A mixture of this material (1.2 g, 4.7 mmol), t-butylbromide (0,99 g, 5.1 mmol), K2CO3(0,70 g, 5.1 mmol), Bu4NI (cat.) and CH3CN stirred at room temperature for 3 hours the Mixture then was diluted EtOAc and washed with water. Organic material was dehydrated using Na2SO4and concentrated. Chromatography (1:9 MeOH/CHCl3) gave of 0.62 g of compound 145 as a yellow oil.

Part E:

Following the General procedure used to obtain compound 6 (example 1, part E), the compound 146 was obtained with a yield of 26% at the baseline of 0.1 g of compound 145.

Part F:

Following the General procedure used to obtain compound 7 (example 1, part F), compound 147 was obtained with the yield of 80% with the original 0,034 g of compound 146.

1H NMR (300 MHz, CD3OD) of 3.23 (m, 2H), 3,62 (m, 2H), 4,10 (s, 2H), 4,51 (m, 2H), 7,2 (d, J=8,2 Hz, 1H), 7,6 (m, 1H), of 7.75 (s, 1H), 7,92 (d, J=8,4 Hz, 2H), 8,16 (d, J=8,4 Hz, 2H).

Example 37

Obtaining the compounds represented by the formula 155:

< / BR>
Part a:

A solution of ester 148 (0,81 g of 3.23 mmol) and THF (7 ml) was treated LiBH4(0.14 g, 6.5 mmol) and left at room temperature for 6 hours the Mixture then was diluted EtOAc and filtered by H2O. the Organic material concentration is a (0.65 g, 3.1 mmol), TBSCl (0.51 g, 3.5 mmol), imidazole (0.24 g, 3,47 mmol) and DMF (5 ml) was maintained at room temperature for 1 h Then the mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude residue was purified on silica (5:1 hexane/EtOAc) to give 0.96 g of pure compound 149.

Part B:

A mixture of compound 149 (0.96 g) and Pd/C (10% on carbon, 0.96 g) in EtOAc was maintained in an atmosphere of H2(glass tube) for 1 h, and then filtered and concentrated. Untreated selected substance was administered in CH2Cl2(5 ml) and was treated p-lambertini acid (0.45 g, 3.1 mmol), EDCI (0.64 g, to 3.34 mmol) and DMAP (cat.). The resulting solution was aged at room temperature for 2 h, then was diluted EtOAc. Organic material was filtered by H2O, and then concentrated. Chromatography (1:1 hexane/EtOAc) gave 1,09 g of pure compound 150.

Part C:

A mixture of compound 150 (1,09 g at 2.59 mmol) and TBAF (5,2 ml of 1M solution in THF, 5.2 mmol) was maintained at room temperature for 1 h the mixture was diluted EtOAc, washed H2O, and then concentrated, yielding 0.71 g of practically pure primary alcohol. This material (0.65 g, 2,11 mmol) oxadiazon, introduced in THF (5 ml) and added to a mixture of t-butyldiethanolamine (0.71 g, 3.2 mmol), NaH (0,13 g 60% dispersion in oil, 3.2 mmol) and THF (10 ml). After 1 h the mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude residue was fraktsionirovanija on silica (5: 1 hexane/EtOAc) to give 0.27 g of compound 151, 0,197 g of compound 152 and 0.47 g again received the original alcohol.

Part D:

Following the procedure described to obtain compound 7 (example 1, parts E and F), the compound 155 was obtained with a yield of 54% at the source of 0.27 g of compound 152.

1H NMR (300 MHz, CD3OD) of 1.65 (m, 1H), 2.05 is (m, 1H), 2,60-2,95 (m, 5H), to 5.85 (d, J=15,5 Hz, 1H), 7,05 (dd, J=9,6, to 15.8 Hz, 1H), 7,10 (d, J=8,3 Hz, 1H), and 7.4 (m, 2H), to $ 7.91 (d, J=8,4 Hz, 2H), 8,17 (d, J=8,4 Hz, 2H); IR (KBr) 3313, 3102, 1670, 1203 cm-1; MS (FAB) m/e 364.

Analytically calculated for C23H22N3O5F3: C 57,86; H 4,65; N 8,80. Found: C 57,59; H 4,84; N 8,78.

Example 38

Obtaining the compounds represented by the formula 154:

< / BR>
Part a:

A mixture of compound 151 (0.18 g, 0.43 mmol) and Pd/C (10% on carbon, 0.18 g) in EtOH was maintained in an atmosphere of H2(glass tube) for 30 min, and then filtered and concentrated. Chromatography (3:1 hexane/EtOAc) to give 0.09 g of soedineniya 7 (example 1, parts E and F), compound 154 was obtained in 51% yield when the source of 0.09 g of compound 153.

1H NMR (300 MHz, CD3OD) of 1.4 (m, 1H), 1,7 (m, 3H), of 1.97 (m, 1H), 2,4 (m, 3H), 2,85 (m, 3H), was 7.08 (d, J=8,3 Hz, 1H), 7,40 (m, 2H), of 7.90 (d, J=8,4 Hz, 2H), 8,17 (d, J= 8,4 Hz, 2H); IR (KBr) 3317, 3102, 2926, 1708, 1666, 1142 cm-1; MS (FRB) m/e 366,1815 (366,1818 calculated for C21H24N3O3).

Example 39

Obtaining the compounds represented by the formula 161:

< / BR>
Part a:

A mixture of 6-brometalia 156 (1.0 g, 4.4 mmol) and EtOH (10 ml) was treated NaBH4(1 g) at room temperature. After 1 h the mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated to an anhydrous state and the untreated selected substance was dissolved in anhydrous DMF (10 ml) and was treated TBSCl (1.0 g, 6.6 mmol) and imidazole (0.45 g, 6.6 mmol). The resulting solution was left overnight at room temperature. This mixture then was diluted EtOAc and filtered by H2O and concentrated. Untreated selected substance was purified on silica (hexane), yielding 0.8 g of compound 157 (52%) as a clear oil.

Part B:

A mixture of compound 157 (1,93 g, 5.7 mmol) and THF (25 ml) was treated with t-BuLi (8,4 ml of 1.7 M solution in pentane) at -78oC. After 30 min spray dry CO22O, padillas 1N HCl and was extracted with EtOAc. The extracts were concentrated, giving of 1.59 g of the crude acid. A portion (0.5 g, and 1.63 mmol) of this material was dissolved in CH2Cl2(2.0 ml) and the resulting solution was treated benzyl alcohol (0,19 g, 1.8 mmol), EDCI (0.34 g, 1.8 mmol) and DMAP (cat.). This mixture was left for 2 h and then was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude residue was treated TBAF (1.8 ml 1M solution in THF, 1.8 mmol). After 25 min the mixture was diluted EtOAc and was washed2O. the Organic material was concentrated, yielding 0.45 g of compound 158 in the form of almost pure oil.

Part C:

A mixture of compound 158 (0.45 g, to 1.59 mmol), t-butylbromide (0.96 g, 4.9 mmol), benzene (5 ml), 50% aqueous NaOH (5 ml) and Bu4NHSO4(cat.) vigorously stirred at room temperature for 5 hours the Mixture then was diluted EtOAc and was washed2O. the Organic material was concentrated and the crude residue was purified on silica (5:1 hexane/EtOAc), giving of 0.44 g (69%) of the desired alkylated product as a clear oil. A mixture of this material (of 0.44 g, 1.1 mmol), Pd/C (10% on carbon, of 0.44 g) and EtOAc (10 ml) were mixed in an atmosphere of H2(article is the first connection 159.

Part D:

A mixture of compound 159 (0.29 grams, of 0.94 mmol) and EDCI (0.2 g, 1.0 mmol), 4-aminobenzonitrile (0.12 g, 1.0 mmol), DMAP (cat.) and CH2Cl2(5 ml) was maintained at room temperature for 4 h the mixture then was diluted EtOAc and filtered by H2O. the Organic material was then concentrated. Chromatography (2,5: 1 hexane/EtOAc) gave a fraction (0.28 g) containing the desired amide 160 and the fact that by assumption is a symmetric anhydride 159. This material was fed to the next step.

Part E:

The material obtained in the previous step (0.28 g), was introduced in pyridine (20 ml) and TEA (2 ml) and the resulting solution saturated with H2S. This mixture was left at room temperature for 12 h and then was diluted EtOAc and filtered by H2O. the Organic material was concentrated, and the crude mixture was chromatographically on silica (EtOAc), giving of 0.13 g of pure intermediate thioamide. This material is then processed as described in example 1, part E, yielding 0.07 g of pure Boc-protected material. This material was introduced in TFA and stirred at room temperature for 1 h, and then concentrated, which gave 0,056 g of compound 161.

1H NMR (300 MHz, CD3OD) 1,92-2,17 (m, 2H), 2,80-up 3.22 (m, 4H), 4tx2">

Example 40

Obtaining the compounds represented by the formula 168:

< / BR>
Part a:

A mixture of compound 156 (1.25 g, 5.5 mmol), ethylene glycol (3.4 g, 55 mmol), TsOH (cat) and benzene (25 ml) was maintained under irrigation with removal of H2O for 3 hours Then the mixture was diluted EtOAc, and the resulting solution was filtered by 1N NaOH. The organic material was then concentrated, and the crude residue was purified by chromatography (5:1 hexane/EtOAc) gave to 1.15 g (77%) of compound 162 in the form of a clear oil.

Part B:

A solution of compound 162 (1,15 g, 4.3 mmol) and THF (15 ml) is treated with t-BuLi (6.3 ml 1M solution in pentane, to 10.7 mmol) at -78oC for 30 min, and then was extinguished by the addition of CO2(g). The reaction mixture was left to warm to room temperature and then was diluted H2O. the resulting mixture was padillas concentrated HCl and was extracted with EtOAc. The organic extracts were concentrated, and the crude highlighted the substance was injected in CH2Cl2(10 ml) and was treated benzyl alcohol (0,58 g, 5.4 mmol), EDCI (1,02 g, 5.4 mmol) and DMAP (cat.). The resulting solution was aged overnight at room temperature and then was diluted EtOAc and filtered by H2O. the Organic mater), containing the desired product 163 and benzyl alcohol in a ratio of 1:1. This material is suitable for use in the next reaction.

Part C:

The above mixture was dissolved in acetone (20 ml) and was treated 1N HCl (2 ml) and was maintained under irrigation for 1 h Then the mixture was diluted EtOAc and washed with saturated aqueous NaHCO3. The organic material was then concentrated. Untreated selected substance was administered in THF and added to a mixture of t-butyldiethanolamine (1.1 g, is 4.93 mmol), NaH (0.1 g, 60% dispersion in oil, is 4.93 mmol) and THF (25 ml) at -78oC. the resulting solution was left to warm to room temperature and then was aged under irrigation for 1 h Then the mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated, and the crude dedicated substance was purified on silica (2,5:1 hexane/EtOAc), giving of 0.47 g of compound 164 in the form of a mixture of olefin isomers.

Part D:

A mixture of compound 164 (0,47 g) and Pd/C (10% on carbon, to 0.47 g) in EtOH was maintained in an atmosphere of H2(glass tube) for 2 h, then was filtered and concentrated, yielding 0.29 grams of practically pure connection 165.

Part E:

A mixture of compound 165 who was rivals under 100oC in a sealed tube for 2 h and then was diluted EtOAc and filtered by H2O. the Organic material was concentrated, and the residue was chromatographically on silica (80:1 CHCl3/THF) to give 0.28 g (69%) of compound 166.

Part F:

Following the procedure described to obtain compound 6 (example 1, part E), compound 67 was obtained with a yield of 56% at the source of 0.28 g of compound 166.

Part G:

Following the procedure described to obtain compound 7 (example 1, part F), compound 168 was obtained with a yield of 91% when the source is 0.22 g of compound 167.

1H NMR (300 MHz, CD3OD) of 1.5 (m, 1H), 2,0 (m, 1H), 2,2 (m, 1H), 2,35 is 2.55 (m, 3H), 2.95 and (m, 3H), 7,05 (d, J=of 8.25 Hz, 1H), and 7.4 (m, 2H), to 7.93 (d, J=8,4 Hz, 2H), 8,15 (d, J=8,4 Hz, 2H); IR (KBr) 3322, 3104, 1712, 1667 cm-1; MS (FAB) m/e 352,1654 (352,1661 calculated for C20H22N3O3).

Example 41

Obtaining the compounds represented by formula (177):

< / BR>
Part a:

A mixture of compound 169 (3.5 g) and the alkali Klasen (NaOH in EtOH) (75 ml) was maintained under irrigation within 6 h, and then cooled. The mixture was concentrated to 1/2 volume, and the remaining aqueous material was prevented to pH=7 with concentrated HCl. The mixture then was extracted with EtOAc and the combined extracts conzoom (to 3.92 g, 23 mmol). The mixture is vigorously stirred for 1 h and then was diluted EtOAc and washed with water. The organic material was concentrated and the crude residue was subjected to acylation using Ac2O (5 ml) in pyridine (10 ml). After 2 h the mixture was concentrated to an anhydrous condition, and the residue was chromatographically (3: 1 hexane/EtOAc), giving 6.42 per g of pure compound 170.

Part B:

A mixture of compound 170 (6.42 per g, 19,75 mmol), MCPBA (4,27 g, 24,69 mmol) and CH2Cl2(40 ml) was maintained at room temperature for 15 hours At this time, the mixture was diluted EtOAc and washed with saturated aqueous NaHCO3and H2O. Then the organic material was concentrated. The crude material was introduced in acetone (450 ml) and was treated NaI (4 g). The resulting solution was maintained under irrigation within 4 h, and then cooled. The mixture was concentrated, dissolved in EtOAc, was washed H2O and concentrated again. This material was then treated with 0.1 N LiOH (290 ml) in THF (290 ml) for 12 h the Mixture was diluted EtOAc and was washed with water, and the remaining organic material was concentrated. Chromatography (2:1 hexane/EtOAc) gave 3.58 g of compound 171.

Part C:

A mixture of compound 171 (6.8 g, 2.6 mmol), TBSCl (0,43 g 2,9 IMO the fact was diluted EtOAc and filtered by H2O. the Organic material was concentrated, giving almost pure TBS-ether. A mixture of this material (0,98 g, 2.4 mmol) and THF (10 ml) was treated NaH (0.07 g 60% dispersion in oil, 2.6 mmol) and left for 1 h the Mixture was then treated with benzylbromide (0.45 g, 2.6 mmol) and Bu4NI (cat.) and was left for 5 hours Then the mixture was diluted EtOAc and filtered by H2O. the Organic material was then concentrated. The crude residue was introduced in THF and was treated TBAF (2,9 ml of 1M solution in THF, 2.9 mmol). After 1 hours at room temperature the mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude material was chromatographically on silica (hexane/EtOAc 1:1), giving 0,94 g (95%) of compound 172.

Part D:

Following the procedure used to obtain compound 68 (example 24, part B), the compound 173 was obtained with a yield of 80% at the source of 0.43 g of compound 172.

Part E:

A mixture of compound 173 (0.65 g, of 1.16 mmol) and Pd/C (10% on carbon, 0.65 g) in EtOH (10 ml) was maintained in the atmosphere2(glass tube) for 2.5 h and then filtered, and the filtrate was concentrated. The crude material was then introduced in CH2Cl2(5 ml) and was treated EDCI (0,23 g, 1, is the temperature value within 1 h, and then it was diluted EtOAc. The resulting mixture was filtered by H2O and then concentrated. The crude residue was chromatographically on silica (1:2 hexane/EtOAc) to give 0.32 g (71%) of compound 175.

Part F:

Following the procedure used to obtain compound 6 (example 1, part E), the compound 176 was obtained with the yield of 59% when the original 0.31 g of compound 175.

Part G:

Following the procedure used to obtain compound 7 (example 1, part F), compound 177 was obtained with the yield of 70% at the baseline of 0.23 g of compound 176.

1H NMR (300 MHz, CD3OD) to 2.85 (dd, J=5,4, and 16.4 Hz, 1H), 3,06 (dd, J=4,4, of 16.5 Hz, 1H), 4,0-4,2 (m, 5H), 7,05 (d, J=of 8.25 Hz, 1H), 7,18 (m, 1H), 7,22 (s, 1H), 7,92 (d, J= 8,4 Hz, 2H), 8,10 (d, J=8,4 Hz, 2H); IR (KBr) 3340, 1667, 1603, 1201 cm-1; MS (FAB) m/e 370.

Analytically calculated for C21H20N3O7F3: C 52,18; H 4,17; N 8,69. Found: C 52,15; H Was 4.02; N 8,54.

Example 42

Obtaining the compounds represented by the formula 186:

< / BR>
Part a:

To a mixture of compound 178 (2.17 g, a 13.4 mmol) and glyoxylate sodium (4,25 g, or 37.4 mmol) was added 1N NaOH (50 ml, 50 mmol). The solution was mixed for 4 h at room temperature, brought to pH=1 with concentrated HCl was added 5N HCl (200 ml), and within 24 h podderzhivanie extracts were washed with brine, was dehydrated (MgSO4) and was concentrated in vacuo, giving a solid residue, which was combined with the above precipitate, which was given to 3.02 g (99%) of compound 179 as a brown dry residue without further purification.

Part B:

To a stirred solution of compound 179 (0.95 g, 4,36 mmol) in glacial HOAc/H2O (2: 1, 15 ml) was added zinc dust (1.0 g, of 15.3 mmol). The mixture was watered for 2 h, cooled to room temperature, it was diluted EtOAc and was washed 1N HCl, H2O and brine. Organic material was dehydrated (MgSO4) and concentrated which gave 0,89 g (93%) of compound 180 in the form of a brown dry residue without further purification.

Part C:

Connection 180 (0.88 g, 4.0 mmol) was dissolved in THF/EtOAc (1:4, 25 ml), was added diphenyldiazomethane (0.97 g, 5.0 mmol) in dry form, and the red solution stirred 5 days at room temperature, then was watered for 4 hours the Mixture was diluted EtOAc, was washed 1N HCl, saturated NaHCO3H2O and brine, dehydrated (MgSO4) and concentrated in vacuo. Untreated selected substance was purified by chromatography (silica gel 230-400 mesh mesh, toluene:EtOAc gradient) to obtain 0,77 g (50%) of compound 181 in the form of reddish-max 2
CO3(0,276 g, 2 mmol) in dry form. After 0.5 h stirring at room temperature was added alpha-bromo-p-tolunitrile (0.40 g, 2.0 mmol) in dry form, and the solution stirred at room temperature for 4 h the Mixture was diluted EtOAc, washed H2O, 1N HCl, saturated NaHCO3and brine, dehydrated (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography (silikagelevye preparation plate 8: 2 toluene:EtOAc), giving 0,83 g (83%) of compound 184 in the form of light yellow dry residue.

Part E:

Following the General procedure described to obtain compound 6 (example 1, part E), the compound 185 was obtained with a yield of 41% at the baseline to 0.8 g of compound 184.

Part F:

Following the General procedure described to obtain compound 6 (example 1, part F), the compound 186 was obtained with the yield 41%) at the baseline of 0.8 g of compound 185; MS (FD) m/e 355.

Example 43

Obtaining the compounds represented by the formula 190:

< / BR>
Part a:

A mixture of compound 2 (1.0 g, 3.95 mmol) and THF (20 ml) was treated LiAlH4(0,30 g, 7.9 mmol) and was maintained under irrigation within 2 hours the Mixture was cooled to room temperature, and then was extinguished with water and 15% NaOH. Receiving the pyridine (10 ml) and was treated with methylacetylene (0,38 ml, 4.3 mmol). The resulting mixture was aged at room temperature for 1 h and then was diluted EtOAc and washed with water. The organic material was concentrated and the crude residue was purified on silica (3:1 hexane/EtOAc), giving 0.65 g of compound 187.

Part B:

A mixture of compound 187 (0.65 g) and Pd/C (10% on carbon, 0.65 g) and EtOH (10 ml) was maintained in an atmosphere of H2(glass tube) for 2 h, and then filtered, and the filtrate was concentrated. This process gave 0.45 g of practically pure connection 188.

Part C:

A mixture of compound 188 (0,098 g, 0.42 mmol), NaH (0,018 g 60% dispersion in oil, 0.46 mmol) and THF (2 ml) were mixed under irrigation for 0.5 h, and then processed 1-tBOC-4-(3-bromopropyl) piperidine (0,141 g, 0.42 mmol). The resulting mixture was maintained under irrigation for 8 h and then was diluted EtOAc, washed H2O and brine. The organic material was concentrated, and the crude dedicated substance was purified on silica (1,5:1 hexane/EtOAc) to give 0.11 g of compound 189.

Part D:

A mixture of compound 189 (0.11 g, 0.25 mmol), NaOH (0.02 g, 0.5 mmol) and EtOH (5 ml) was maintained at room temperature for 1 h, and then concentrated. The residue was administered which you have focused. The crude residue was treated TFA (5 ml) for 1 h, and then concentrated. The residue was administered in 0.1 N HCl and liofilizirovanny, giving 0,051 g of compound 190.

1H NMR (300 MHz, CD3OD) of 1.2 to 1.7 (m, 6H), 1.8 m (m, 2H), 1,95 (m, 2H), 2,9 (m, 4H), to 3.35 (m, 2H, in), 3.75 (m, 2H), 3,95 (m, 2H), 4,6 (m, 2H), and 6.25 (m, 2H), and 7.1 (m, 1H); IR (KBr) 2940, 1735, 1653, 1187 cm-1; MS (FAB) m/e 347.

Example 44

Obtaining the compounds represented by the formula 193:

< / BR>
Part a:

A mixture of compound 188 (0,19 g, 0.81 mmol), NaH (0,021 g, 60% dispersion in oil, 0.89 mmol) and THF (5 ml) stirred at room temperature for 0.5 h, and then processed alpha-bromo-p-tolunitrile (0.17 g, 0.89 mmol). The resulting mixture was maintained under irrigation for 8 h and then was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude residue was purified on silica (1:1 hexane/EtOAc), giving 0,22 g of compound 191.

Part B:

Following the procedure described to obtain compound 6 (example 1, part E), the compound 192 was obtained with a yield of 44% when the source is 0.22 g of compound 191.

Part C:

A mixture of compound 192 (0.12 g, 0.27 mmol), NaOH (0,22 g, 0.55 mmol), EtOH (5 ml) was maintained at room temperature for 1 h, and then concentrated. Was osteolineage. The crude residue thus obtained was extracted with MeOH, and the combined extracts were filtered and concentrated. The selected material was processed TFA (5 ml) for 1 h, and then concentrated. Thus, the allocated 0.05 g compound 193.

1H NMR (300 MHz, CD3OD) only 2.91 (m, 2H), and 3.72 (m, 2H), 4,6 (m, 2H, in), 5.25 (s, 2H), 6,8 (m, 2H), 7,0 (m, 1H), 7,6 (d, J=8,3 Hz, 2H), 7,8 (d, J=8,3 Hz, 2H); IR (KBr) 3336, 3114, 1668, 1506 cm-1; MS (FAB) m/e 354.

Example 45

Getting ethyl-rat-(6-(4-(aminoiminomethyl)phenylmethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by the formula 194:

< / BR>
Step A: Obtaining ethyl-rat-(6-(4-(tianfei)methoxy)-3,4-dihydro-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (195)

< / BR>
6.0 g (25,4 mmol) ethyl-rat-(3,4-dihydro-6-hydroxy-2H-1 - benzopyran-2-yl)acetate (obtained according to European patent application EP 129906, which is incorporated here by reference) and 4.9 g (25,0 mmol) of 4-labelsalready was dissolved in 36 ml of dehydrated acetone, was added 3.5 g (to 25.3 mmol) of potassium carbonate. After stirring overnight at 50oC was added 0.3 g (1.3 mmol) of benzopyrene and the reaction continued for the same amount of time. Inorganic dry OST the e with hexane/acetone (40:5 was obtained pure nitrile. Yield: 6.7 g (76%) of pale yellow solids tPL75-76oC.

Step B: Obtaining ethyl-rat-(3,4-dihydro-6-(4-ethoxycarbonylmethyl) phenylmethoxy)-2H-1-benzopyran-2-yl)acetate hydrochloride, an intermediate represented by the formula (196):

< / BR>
rate of 7.54 g (of 21.2 mmol) of the nitrile from step (A) was suspendibility in 340 ml of anhydrous ethanol. The suspension was cooled in an ice bath and saturated with gaseous hydrogen chloride (about 5 hrs). Per night sedimentation was formed a clear solution. The solution was evaporated to the dry state in a vacuum, and the compound (196) was mixed with hexane, filtered by suction and was dehydrated in a vacuum. Output: to 6.43 g (70%) of pale yellow powder, tPL118-119oC.

Step C: the connection (194), ethyl-rat-(6-(4-(aminoiminomethyl)phenylmethoxy)-3,4-dihydro-2H-1 - benzopyran-2-yl)acetate hydrochloride.

385 ml of a saturated solution of ammonia in ethanol was cooled with ice and added to 6.43 g (of 14.8 mmol) of the intermediate from step b of Intermediate compound from step B was mixed overnight at room temperature, and the solvent was removed in vacuum. The remaining dry announced compound was mixed with hexane, filtrov-125oC.

Example 46

Getting rat-(6-(4-(aminoiminomethyl)phenylmethoxy)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetic acid triptoreline, the compound represented by formula (197)

< / BR>
Step A: Obtaining ethyl-rat-(6-(4-(N-tert-butoxycarbonyl (aminoiminomethyl))phenylmethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (198):

< / BR>
3.7 g (9.1 mmol) of amidine of example 45 was dissolved in 55 ml of a mixture of THF/H2O 1: 1. After addition of 1.65 g (11.9 mmol) of potassium carbonate, 1,99 g (9.1 mmol) of Boc2O was added dropwise, and the mixture is stirred over night at room temperature. Then the mixture was diluted with 100 ml of ethyl acetate. The organic layer was separated, washed with water, dehydrated on sodium sulfate and concentrated in vacuo, giving a clean protected amidin. Output: 4,3 (100%) oil.

Step B: Getting rat-(6-(4-(N-tert-butoxycarbonyl(aminoiminomethyl) phenylmethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl)acetic acid, an intermediate compound represented by formula (199):

< / BR>
to 5.2 g (11.1 mmol) of ester from step A was dissolved in 75 ml of ethanol. After adding 36 ml of 2N aqueous sodium hydroxide and the mixture was heated to 60oC on resetreset. The organic layer was separated, dehydrated on sodium sulfate, concentrated in vacuo, and the residue by chromatography on silica gel with dichloromethane/ethanol 40: 5 was announced carboxylic acid. Yield: 2.0 g (41%) of white powder, tPL220-222oC (dec).

Step C: Getting rat-(6-(4-(aminoiminomethyl)phenylmethoxy)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetic acid trifenatate.

0.15 g (0.34 mmol) of protected amidine from step B and 2.8 ml triperoxonane acid were mixed and stirred at room temperature for 1.5 hours the Solvent was removed in vacuo, and the announced amidon was obtained after addition of 10 ml of water. The product was filtered with suction, stirred again with 10 ml of water, filtered and dehydrated in a vacuum. Yield: 0.09 g (58%) of white powder, tPL210-212oC.

Example 47

Getting ethyl-rat-(6-(N-(4-(aminoiminomethyl)benzoyl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (200):

< / BR>
Step A: Obtaining tert-butyl(2-oxo-2H-1-benzopyran-6-yl)carbamate, intermediate compounds represented by the formula (201):

< / BR>
100 g (523 mmol) of 6-nitrocoumarin was dissolved in 600 ml of anhydrous ethane is NII, while the temperature rose to 45oC, was observed gas evolution. The reaction mixture was watered for 3 h and was diluted 200 ml of ethanol. The hot mixture was filtered through Selita was filtered and 200 ml of hot ethanol. Unprotected amine was obtained after cooling, filtering with suction, washing with hexane and drying in vacuum. Another portion of amine was obtained by concentration of the filtrate. The total output of the intermediate amine was 74,

The crude amine was dissolved in 300 ml of a mixture of THF/H2O 1:1 and was maintained in an argon atmosphere. Was added 110 g (504 mmol) Boc2O and 95 g (687 mmol) of anhydrous potassium carbonate. The reaction mixture is stirred over night at room temperature, it was diluted with 750 ml of water and was extracted with ethyl acetate (3 x 1 l). The combined organic layers were dehydrated on sodium sulfate and concentrated in vacuum. The residue was dissolved in 2 l of dichloromethane and stirred in the presence of 1 kg of silica gel, which was filtered by suction and rinsed with dichloromethane. The filtrate was concentrated in vacuo, giving the declared connection. An analytical sample was purified by chromatography on silica gel with dichloromethane-2-oxo-2H-1-benzopyran-6-yl)carbamate, intermediate compounds represented by the formula (202):

< / BR>
85 g (325 mmol) of coumarin from step A was dissolved in a mixture of 1150 ml of ethanol and 115 ml of acetic acid, and the solution was poured in a hydrogenation autoclave. 6 g 10% Pd/C was added, and it was all hydrogenerators at room temperature and a hydrogen pressure of 20 ATM. Two days were added 3 g of Pd/C and the reaction continued for another two days. The catalyst was removed by filtration, and the filtrate was concentrated in vacuum. The residue was dissolved in 1 l of ethyl acetate, was washed with 500 ml saturated aqueous sodium bicarbonate, dehydrated on sodium sulfate, and the solvent was removed in vacuum. Announced the lactone is purified by chromatography on silica gel with dichloromethane containing 1% ethanol. Yield: 21 g (25%) of colorless crystals, tPL158-159oC.

Step C: Obtain tert-butyl-rat-(3,4-dihydro-2-hydroxy-2H-1-benzopyran-6-yl)carbamate, intermediate compounds represented by the formula (203):

< / BR>
21 g (79,8 mmol) of the lactone from the previous step was dissolved in 340 ml of anhydrous dichloromethane and was maintained in an argon atmosphere. The solution was cooled to -70oC and was maintained at this temperature, while for 45 min on drops gobblestone was slowly added 20 ml of methanol, and the mixture was poured into 1 l of saturated aqueous solution of ammonium chloride. Solid components were removed by filtering through Selita and rinsed with dichloromethane. The filtrate was dehydrated on sodium sulfate, concentrated in vacuo, giving a net declared connection, as recorded its1H-NMR. Yield: 16.5 g (78%) of yellow oil.

Step D: Getting ethyl-rat-(6-(N-tert-butoxycarbonylamino)-3,4-dihydro-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (204):

< / BR>
11.2 g (42,2 mmol) of the compound from step C and 14.7 g (42,2 mmol) of ethoxycarbonylmethylene was dissolved in 130 ml of anhydrous toluene and irrigated for 22 hours, the Reaction mixture was cooled to room temperature, and was added 300 mg of sodium hydride. Even after 5 h of heating, the mixture was poured into 1 l of ice water. The mixture was extracted three times using ethyl acetate, and the combined organic layers were washed with 300 ml of water, was dehydrated on sodium sulfate and concentrated in vacuum. Benzopyran (204) was obtained from the residue by chromatography on silica gel with dichloromethane. Yield: 5.5 g (39%) of colorless amorphous solids tPL67-69oC.

Step E: Getting ethyl-rat-(6-(-(4-( (205):

< / BR>
2.0 g (6.0 mmol) of the protected amine from the previous step was treated 6 ml triperoxonane acid and stirred for 2 h at room temperature. The mixture was scavenged by saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. The organic layer was dehydrated on sodium sulfate and concentrated under reduced pressure, remained dark oil from unprotected ethyl-rat-(6-amino-3,4-dihydro-2H-1-benzopyran-2-yl)acetate. It was dissolved in 40 ml of anhydrous THF, was treated with 4 ml of anhydrous pyridine and 1.0 g (6.0 mmol) of 4-canbesold, and stirred overnight at room temperature. The mixture was poured into ice-cold aqueous solution of bicarbonate and was extracted with ethyl acetate. The organic layer was sequentially washed with an aqueous solution of copper sulfate (II) and brine, dehydrated on sodium sulfate and concentrated in vacuum. Nitrile (205) was obtained from the residue by chromatography on silica gel with dichloromethane/ethanol 96:4. Yield: 1.4 g (64%) of pale yellow crystals, tPL146-148oC.

Step F: Obtaining ethyl-rat-(6-(N-(4-aminoiminomethyl)benzoyl)amino)- 3,4-dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride. 1.4 g (3,8 moltobene carried out. After stirring over night at room temperature the solvent was removed under reduced pressure and the residue was treated with saturated solution of ammonia in ethanol. The reaction mixture is stirred for three days, was evaporated in vacuum, and the compound was obtained as a yellow oil by chromatography on silica gel with dichloromethane/ethanol 65:35 with 5% ammonia in ethanol. Crystalline sample for analytical and biological tests was obtained by stirring with a mixture of ethanol/ether-hydrogen chloride/ether. Yield: 0.9 g (56%) of yellow crystals, tPL253oC (dec).

Example 48

Getting rat-(6-(N-(4-aminoiminomethyl)benzoyl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetic acid, a compound represented by the formula (206):

< / BR>
0.2 g (0.48 mmol) of ester from example 47 was added to a mixture of 4 ml of ethanol and 0.5 ml of 2N aqueous sodium hydroxide. The mixture was diluted with water until, until it turned into a clear solution. After a light heat he stirred at room temperature for 3 h and was pagkilala with 2N acetic acid, was formed precipitate, which was filtered, rinsed with water and dehydrated in in the philosophy. Yield: 0.16 g (95%) of colorless amorphous dry residue tPL290-291oC (dec).

Example 49

Getting rat-(6-(N-(4-carbamoylmethyl)amino)-3,4-dihydro-2H-1 - benzopyran-2-yl)acetic acid, a compound represented by the formula (207):

< / BR>
Method A:

of 0.47 g (1.12 mmol) of ester from example 47 was added to a mixture of 5 ml ethanol and 5 ml of 2N aqueous sodium hydroxide. The mixture was heated in a steam bath for 15 min, cooled to room temperature and brought to pH= 4 with 2N aqueous hydrochloric acid, a precipitate was formed. The precipitate was filtered by suction, and amide (207) were purified by suspension in a small amount of hot ethanol. Yield: 60 mg (15%) of a beige amorphous solids tPL273-274oC.

Method B:

0,7 (1.92 mmol) of the nitrile from example 47, step E was dissolved in 15 ml of 98% formic acid, and for 4 h after the mixture was passed a stream of gaseous hydrogen chloride. The reaction mixture is stirred over night at room temperature, and the solvent was removed in vacuum. The remaining dry solids were mixed with water, filtered by suction, and successively washed with ethanol and ether. Amide was suspendable hot the ptx2">

Example 50

Getting ethyl-rat-(6-(N-(4-aminoiminomethyl)benzoyl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)propanoate hydrochloride, a compound represented by formula (208):

< / BR>
Step A: Obtaining ethyl-rat-3-(3,4-dihydro-2-methyl-6-nitro-4 - oxo-2H-1-benzopyran-2-yl)propanoate, intermediate compounds represented by the formula (209):

< / BR>
to 5.4 g (29,8 mmol) 2-hydroxy-5-nitroacetophenone (received by way of the Journal of the American Chemical Society, 1954, 76, 4993, the consideration of which is included here by reference), 5.8 g (40,2 mmol) ethyl-4-oxopentanoate, and 1.7 ml of pyrrolidine was dissolved in 50 ml of toluene, and the mixture was heated for 6 h with azeotropic removal of water. The mixture was concentrated in ethyl acetate. The solution was sequentially washed 1N aqueous hydrochloric acid and brine, dehydrated on sodium sulfate, and the solvent was removed under reduced pressure. Chromanone (209) crystallized from the resulting residue. Output: 5.3v g (58%) of a pale-yellow amorphous solidsPL88-90oC.

Step B: Obtaining ethyl-3-(3,4-dihydro-4-hydroxy-2-methyl-6-nitro - 2H-1-benzopyran-2-yl)propanoate, intermediate compounds represented by the formula (210):

< / BR>
3.2 g (10.4 mmol) of chromanone from step A was dissolved in 100 ml of ethanol. Mature for 5 hours The reaction mixture was concentrated in vacuum, popcicles with 1N aqueous hydrochloric acid and was extracted with ethyl acetate. The organic layer was dehydrated on sodium sulfate, and the solvent was removed under reduced pressure. Benzopyran (210) was obtained by chromatography on silica gel with dichloromethane containing 41% ethanol. Yield: 2.0 g (62%) of oil.

Step C: Getting ethyl-rat-3-(2-methyl-6-nitro-2H-1-benzopyran-2-yl)propanoate, intermediate compounds represented by the formula (211):

< / BR>
2.0 g (6.5 mmol) of the alcohol from the previous step was dissolved in 75 ml of toluene, was added a catalytic amount of 4-toluenesulfonic acid. The mixture was watered for 7 h, while water azeotrope was removed. The reaction mixture was washed with an aqueous solution of sodium bicarbonate, the organic layer was dehydrated on sodium sulfate, and concentrated in vacuum. Declared chromen was obtained from the residue by chromatography on silica gel with ethyl acetate/hexane 1:3. Output: 0,85 g (45%) of oil.

Step D: Getting ethyl-rat-3-(6-amino-3,4-dihydro-2-methyl-2H-1 - benzopyran-2-yl)propanoate, intermediate compounds represented by the formula (212):

< / BR>
1.6 g (5.5 mmol) of 6-nitropropene from the previous Sha the century She stirred overnight at room temperature in an atmosphere of 20 bar hydrogen until recovery is complete. The catalyst was removed by filtration, and ethanol was distilleries in vacuum. The reaction mixture was diluted with ethyl acetate, was washed with a concentrated aqueous solution of sodium bicarbonate, dehydrated on sodium sulfate and concentrated at low pressure, giving crude announced amine, which was clean, as was observed1H-NMR. Yield: 1.6 g oil, darkening with time.

Step E: Getting ethyl-rat-(6-(N-(4-lebensohl)amino)-3,4 - dihydro-2-methyl-2H-1-benzopyran-2-yl) propanoate, the compound represented by formula (213):

< / BR>
1.6 g (6.1 mmol) of the crude amine from step D was dissolved in 40 ml of anhydrous THF. Consistently was added anhydrous pyridine and 1.0 g (6.0 mmol) of 4-lebensohl chloride. The mixture is stirred over night at room temperature and was poured into ice-cold aqueous solution of sodium bicarbonate. It was extracted with ethyl acetate, and the organic layer was filtered aqueous copper sulfate (II) and brine, dehydrated on sodium sulfate and concentrated in vacuum. Pure nitrile was obtained by chromatography on silica gel with dihl nametil)benzoyl)amino)- 3,4-dihydro-2-methyl-2H-1-benzopyran-2-yl)propanoate hydrochloride.

1.5 g (3.8 mmol) of the nitrile from step E was dissolved in 50 ml of anhydrous ethanol. The solution was cooled in an ice bath, saturated with gaseous hydrogen chloride and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was treated with saturated solution of ammonia in ethanol. He stirred a further 24 h at room temperature, concentrated in vacuum and chromatographically on silica gel with dichloromethane/ethanol 65:35 with 5% ammonia in ethanol, giving the advertised amicin in the form of oil. Crystalline sample for analytical and biological tests were obtained by stirring in a mixture of ethanol/ether-hydrogen chloride/ether. Output: 0,94 g (55%) of yellow crystals, tPL118-120oC.

Example 51

Getting rat-(6-(N-(4-carbamoylmethyl)amino)-3,4-dihydro-2 - methyl-2H-1-benzopyran-2-yl)propanoic acid, a compound represented by formula (214):

< / BR>
0.5 g (1.12 mmol) of ester from example 50 was added to a mixture of 5 ml of 2N aqueous sodium hydroxide and 5 ml of ethanol. The reaction mixture was stirred under heating in a steam bath for 20 min, at this time the mixture turned into a clear solution, and then brought to pH=4 by which hate sodium and concentrated in vacuum. The reaction mixture was purified by chromatography on silica gel with chloroform/ethanol 1: 1. The remaining oil obtained from the pure fractions were treated with 2 ml triperoxonane acid and stirred for 2 h at room temperature. The solvent was removed under reduced pressure, and declared amide was kristalizovyvatsja of the residue by treatment with ethanol. Yield: 70 mg (16%) of a beige amorphous solids tPL237-238oC.

Example 52

Getting ethyl-rat-3-(6-(4-aminoiminomethyl)phenylmethoxy)-2 - methyl-2H-1-benzopyran-2-yl)propanoate hydrochloride, a compound represented by formula (215):

< / BR>
Step A: Obtaining 4-((3-acetyl-4-hydroxyphenoxy)methyl)benzonitrile, intermediate compounds represented by the formula (216):

< / BR>
45 g (296 mmol) of 2,5 dihydroxyacetophenone and 58,4 g (298 mmol) of 4-labelsalready was dissolved in 650 ml of anhydrous acetone was added 45 g (326 mmol) of potassium carbonate and 4.5 g of potassium iodide. After irrigation for 6.5 h inorganic solids were removed by filtration and were washed with acetone. The combined filtrates were concentrated in vacuo, and the residue was mixed with 600 ml of hot methanol. The methanol solution was cooled to room temperature and was dehydrated in vacuum at 40oC. Output: 69,5 g (88%) of beige crystals, tPL123-127oC.

Step B: Obtaining ethyl-rat-3-(6-(4-cianfanelli-3,4-dihydro-2 - methyl-4-oxo-2H-1-benzopyran-2-yl)propanoate, intermediate compounds represented by the formula (217):

< / BR>
30 g (to 112.2 mmol) acetophenone from the previous step, with 20.4 g (141,5 mmol) ethyl-4-oxopentanoate and 9.6 ml of pyrrolidine was dissolved in 500 ml of anhydrous toluene. The mixture is stirred 20 h at room temperature, then was watered 5.5 hours with azeotropic removal of water. The mixture was concentrated under reduced pressure and the remaining oil was mixed for 30 min in 200 ml of aqueous 2N hydrochloric acid. It was extracted with dichloromethane, and the organic layer was sequentially washed 2N hydrochloric acid, water and brine. Then it was dehydrated on the grid with cells of 0.4 nm and concentrated in vacuo, leaving a brown oil, which was chromatographically on silica gel with dichloromethane. Hardening oily benzopyran (217) took place by mixing with aqueous 2N hydrochloric acid. The compound was filtered by suction, was sequentially washed with water and hexane, and was dehydrated in a vacuum. Output: 12,27 g (28%) of yellow crystals, tPL
< / BR>
0.18 g (2.0 mmol) of chromanone from step B was dissolved in 10 ml of anhydrous ethanol was added 40 mg (1.06 mmol) of sodium borohydride. After stirring over night at room temperature was added 40 mg hydride and stirring continued for 4 h until, until the end of the reconstruction. The solvent was removed in vacuo, and the residue was treated with a mixture of water and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dehydrated on the grid with cells of 0.4 nm. After concentration under reduced pressure benzopyran was obtained by chromatography on silica gel with dichloromethane containing 2% ethanol. Output: 0,46 g (57%) of oil.

Step D: Getting ethyl-rat-3-(6-(4-cianfanelli)-2-methyl-2H-1 - benzopyran-2-yl)propanoate, intermediate compounds represented by the formula (219):

< / BR>
380 mg (0.96 mmol) of the compound from the previous step was dissolved in 25 ml of toluene. After adding a catalytic amount of 4-toluenesulfonic acid and the mixture was heated for 1 h with azeotropic removal of water until the completion of the reaction. The mixture was twice washed with a saturated water bicarbonate by chromatography on silica gel with dichloromethane. Yield: 230 mg (63%) of oil.

Step E: Getting ethyl-rat-3-(6-(4-aminoiminomethyl)phenylmethoxy)-2 - methyl-2H-1-benzopyran-2-yl)propanoate hydrochloride.

1.5 g (4.0 mmol) of the nitrile from the previous step was dissolved in 100 ml of anhydrous ethanol. The solution was cooled to 5-10oC was saturated with hydrogen chloride, stirred at room temperature overnight and concentrated in vacuum. The remaining brown oil was treated with 100 ml of saturated solution of ammonia in ethanol and stirred for 2 days. The solvent was removed in vacuo, and the announced amidon was obtained from the residue by chromatography on silica gel with dichloromethane/ethanol 95:5, and the reduction ratio up to 80: 20. Yield: 1.19 g (69%) of yellow amorphous solids tPL<50C.

Example 53

Getting rat-3-(6-(4-(aminoiminomethyl) phenylmethoxy)-2-methyl - 2H-1-benzopyran-2-yl)propanoic acid hydrochloride, compounds represented by the formula (220):

< / BR>
200 mg (0,464 mmol) of ester from example 52 was dissolved in 5 ml of ethanol. Added two drops of water and 0.64 ml of 0.9 ethanol solution ethylate sodium, and the mixture is stirred for 3 h at 50oC. After adding more of the same number of ethylate on what was trowels by suction, repeatedly rinsed with ethanol and hexane. Untreated dry residue was heated in a mixture of 4 ml of water and 1 ml of aqueous 2N hydrochloric acid for several minutes and stirred 2 h at room temperature. The mixture was evaporated to the dry state, and declared hydrochloride was suspenderbelt three times in 3 ml of hot isopropanol. The hot solutions were scivales, were combined and concentrated to an anhydrous state. The residue was washed twice with ether, and dehydrated in a vacuum. Yield: 68 mg (36%) of a beige amorphous solids tPL56oC.

Example 54

Getting rat-(3,4-dihydro-6-(4-(piperidine-4-yl)butoxy)-2H-1 - benzopyran-2-yl)acetic acid triptoreline, compounds represented by formula (225):

< / BR>
Step A: Obtaining ethyl-rat-(6-(4-(1-(tert-butoxycarbonyl)piperidine - 4-yl)butoxy)-3,4-dihydro-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (226):

< / BR>
0,92 g (3.9 mmol) of ethyl-rat-(3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-yl)acetate (obtained in European patent application EP 129906, which is incorporated here by reference) was dissolved in 25 ml of anhydrous DMF. The solution was cooled to -5oC, and dropwise added to 1.8 ml of 40% aqueous hydroxide benzyl-1-(tert-butoxycarbonyl)piperidine (obtained according to European patent application EP 478328, which is incorporated here by reference). The mixture is stirred at -5oWith another 3 h, warmed to room temperature, stirred overnight and poured into 150 ml of ethyl acetate. Then she was sequentially washed with water, 1N aqueous-hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dehydrated on sodium sulfate and concentrated in vacuum. Announced compound was obtained by chromatography on silica gel with hexane/ethyl acetate 4:1. Yield: 0.64 g (35%) of colorless oil.

Step B: Obtaining rat-(6-(4-(1-(tert-butoxycarbonyl)piperidine-4 - yl)butoxy)-3,4-dihydro-2H-1-benzopyran-2-yl)acetic kilty, intermediate compounds represented by the formula (227):

< / BR>
0.64 g (1.35 mmol) of ester from step A was dissolved in 10 ml of ethanol and was added 5.6 ml of 1N ethanol solution ethylate sodium. The reaction mixture was stirred at room temperature for seven days and was concentrated to an anhydrous state at reduced pressure. The residue was treated with water and were prevented 10% aqueous solution of KHSO4. It was extracted with ethyl acetate. The organic layer was dehydrated on sodium sulfate, and restoratlon solidify with time.

Step C: Getting rat-(3,4-dihydro-6-(4-(piperidine-4-yl)butoxy)- 2H-1-benzopyran-2-yl)acetic acid trifenatate.

0.4 g (0.9 mmol) of the protected piperidine from the previous step was treated 6 ml triperoxonane acid. The mixture was mixed for 2 h at room temperature and was evaporated in vacuum. After addition of water the mixture was extracted with ether, and the organic layer was dehydrated on sodium sulfate and concentrated under reduced pressure. Announced the compound was purified by chromatography on silica gel with dichloromethane/ethanol 96: 4. Yield: 120 mg (29%) of a beige oil which was partially harden.

Example 55

Getting rat-(6-(5-(aminoiminomethyl)intoxi)-3,4-dihydro-2H-1 - benzopyran-2-yl)acetic acid triptoreline, intermediate compounds represented by the formula (253):

< / BR>
Step A: Obtaining ethyl-rat-(6-(5-Canpotex)-3,4-dihydro-2H-1 - benzopyran-2-yl)acetate, an intermediate represented by the formula (254):

< / BR>
2,109 g (9,27 mmol) ethyl-rat-(3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-yl)acetate (obtained according to European patent application EP 129906, which is incorporated here by reference) and 2.0 g (11,4 mmol) 6-bromopentanoate of triethylenediamine, and the mixture was watered for 10 h, and then stirred at room temperature for 2 days. Inorganic solid residue was removed by filtration and was rinsed with acetone and the combined filtrates were concentrated in vacuo. Nitrile (254) was obtained from the residue by chromatography on silica gel with dichloromethane containing 4% ethanol. Output: 1,32 g (43%) oil.

Step B: Obtaining ethyl-rat-(6-(5-(aminoiminomethyl)intoxi)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride, an intermediate represented by the formula (255):

< / BR>
1,25 g (of 3.77 mmol) of the nitrile from step A was dissolved in 50 ml of anhydrous ethanol. The solution was cooled to 0oC and saturated with hydrogen chloride. After stirring overnight, he became concentrated in vacuum. The residue was treated with a mixture of 10 ml of liquid ammonia and 50 ml of anhydrous ethanol, and stirred overnight at room temperature. The solvent was removed under reduced pressure and the remaining material was sequentially mixed with ethanol and dichloromethane. The solids were removed by filtration after each procedure, and the filtrate was concentrated under reduced pressure. Untreated declared the connection obtained from poslednego%) of white powder, tPL82-84oC.

Step C: Getting ethyl-rat-(6-(5-(N-tert - butoxycarbonyloxyimino)intoxi)-3,4-dihydro-2H-1-benzopyran - 2-yl)acetate, an intermediate represented by the formula (256):

< / BR>
0.7 g (1.82 mmol) of amidine from step B was dissolved in 11 ml of THF/H2O 1:1. After adding 335 g (2,42 mmol) of potassium carbonate and 0.4 g (1,83 mmol) Boc2O and the mixture was mixed overnight at room temperature. She was diluted to 25 ml of ethyl acetate. The aqueous layer was separated and was extracted with ethyl acetate. The combined organic layers were washed with water, dehydrated on sodium sulfate and concentrated in vacuo to an anhydrous state, giving the crude protected amidin used in the next step. Yield: 0.87 g of a yellow oil.

Step D: Getting rat-(6-(5-(N-tert-butoxycarbonyloxyimino) intoxi)-3,4-dihydro-2H-1-benzopyran-2-yl)acetic acid, an intermediate compound represented by the formula (257):

< / BR>
A mixture of 13 ml of ethanol and 6 ml of 2N aqueous sodium hydroxide was added to 0,81 g (is 1.81 mmol) of ester from the previous step. The mixture is stirred at room temperature for 4 h and was kind of balanced out with diluted acetic acid. On the ü by filtration and were washed, and the combined filtrates were concentrated under reduced pressure. Carboxylic acid (257) was obtained by chromatography on silica gel with dichloromethane and increasing the polarity by the addition of 3% ethanol. Yield: 215 mg (28%) oil.

Step E: Getting rat-(6-(5-(aminoiminomethyl)intoxi)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetic acid trifenatate. 112 mg (0,266 mmol) of protected amidine from Step D was treated at room temperature for 1 h the Solvent was removed in vacuo, and the residue was mixed with 10 ml of water, at this time declared the compound precipitated. The product was filtered by suction, washed successively with water and ether, and dehydrated in a vacuum. Another portion was obtained from the combined filtrates, which were washed twice with ether, and concentrated under reduced pressure. Total yield: 91 mg (79%) of a beige powder, tPL132-134oC.

Example 56

Getting rat-3-(6-(N-(4-(aminoiminomethyl)benzoyl)amino)-3,4 - dihydro-2-methyl-2H-1-benzopyran-2-yl)propanoic acid, a compound represented by formula (258):

< / BR>
0.4 g (0.9 mmol) of ester from example 50 was added to a mixture of 8 ml of ethanol and 0.5 ml of 2N aqueous sodium hydroxide. All this peremeshivaete. Announced compound precipitated from the solution. It was filtered, rinsed with water and dehydrated in a vacuum. Yield: 280 mg (82%) of colorless amorphous powder tPL278-280oC (dec).

Example 57

Getting ethyl-rat-(3,4-dihydro-6-(N-(4-((methylamino)iminomethyl) benzoyl)amino)-2H-1-benzopyran-2-yl)acetate hydrochloride, a substance represented by formula (260):

< / BR>
Step A: Obtaining ethyl-rat-(3,4-dihydro-6-(N-(4-((methylamino) iminomethyl)benzoyl)amino)-2H-1-benzopyran-2-yl)acetate hydrochloride, an intermediate represented by the formula (261):

< / BR>
2.0 g (5.5 mmol) of the nitrile from example 47, step E was dissolved in 65 ml of anhydrous ethanol. The solution was cooled with ice and saturated with gaseous hydrogen chloride. He stirred over night at room temperature and was concentrated under reduced pressure, giving an intermediate compound in the form of crystalline solids which was used in the next step. Yield: 2.4 g (98%).

Step B: Obtaining ethyl-rat-(3,4-dihydro-6-(N-(4-((methylamino) iminomethyl)benzoyl)amino)-2H-1-benzopyran-2-yl)acetate hydrochloride.

1.35 g (3.0 mmol) of the crude intermediate from the previous step in 50 ml of anhydrous ethanol keerulisemani. Was added 5 ml of a solution of methylamine, and the stirring was continued for another 6 h, while the temperature was maintained below 5oC. was Obtained a clear solution which was concentrated under reduced pressure. The declared connection crystallizability after treatment of the residue with ethanol and purified by heating the suspension in ethanol. Yield: 0.9 g (69%) of yellow amorphous solids tPL278-279oC.

Example 58

Getting rat-(3,4-dihydro-6-(N-(4-((methylamino)iminomethyl) benzoyl)amino)-2H-1-benzopyran-2-yl)acetic acid, a compound represented by formula (262):

< / BR>
To 207 mg (0.48 mmol) of ester from example 57 was added 4 ml of ethanol, 0.5 ml of 2N aqueous sodium hydroxide solution and three drops of water, and the mixture is stirred over night at room temperature. Formed precipitate. He was brought to pH=5 with 2N acetic acid, and the compound was filtered by suction, washed successively with water and ethanol, and dehydrated in a vacuum. Yield: 0.12 g (68%) of pale yellow powder, tPL275-276oC (dec).

Example 59

Getting ethyl-rat-(6-(N-(4-((benzoyl)amino)iminomethyl)benzoyl)amino)- 3,4-dihydro-2H-1-benzopyran-2-yl)acetate, the connection performance is metiletilpiridin in 20 ml of anhydrous dichloromethane was cooled to -20oC and added dropwise at this temperature was added a solution of 0.15 g (1.1 mmol) of benzoylchloride in 2 ml of dichloromethane. The mixture became transparent when slowly heated to room temperature and stirred for 3 hours After addition of water the mixture was extracted with ethyl acetate. The organic layer was dehydrated on sodium sulfate and concentrated under reduced pressure. Declared benzoate was obtained by chromatography on silica gel with dichloromethane/ethanol 96:4 in the form of oil. Crystalline sample for analytical and biological tests was obtained by stirring with ether. Yield: 0.21 g (43%) of a beige powder, tPL149-150oC (dec).

Example 60

Getting rat-9-(6-aminoiminomethyl-2-methyl-2H-1-benzopyran-2 - yl)nonanalog acid, a compound represented by formula (264)

< / BR>
Step A: Obtaining ethyl-rat-9-(6-cyano-3,4-dihydro-2-methyl-4 - oxo-2H-1-benzopyran-2-yl)nonanoate, intermediate compounds represented by the formula (265):

< / BR>
5-cyano-2-hydroxyacetophenone was obtained by processing 4-acetoxybenzoic (Arch. Pharm. 1977, 310, 119, consideration of which is included here by reference), and ethyl-10-oxohexanoate by PdCl2catalyst oxidation ) of acetophenone, 35,0 g (153,3 mmol) of ester and 7 ml of pyrrolidine was dissolved in 160 ml of toluene. After exposure for 1 h at room temperature the solution was heated with azeotropic removal of water for 8 hours, the Solvent was removed in vacuo, and the residue was dissolved in dichloromethane. It was rinsed with water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were dehydrated on sodium sulfate and concentrated under reduced pressure. Announced chromanone was obtained by chromatography on silica gel with dichloromethane. Output: 12,6 g (22%) oil.

Step B: Obtaining ethyl-9-(6-cyano-3,4-dihydro-4-hydroxy-2-methyl - 2H-1-benzopyran-2-yl)nonanoate, intermediate compounds represented by the formula (266):

< / BR>
of 12.6 g (to 33.9 mmol) of chromanone from step A was dissolved in 300 ml of anhydrous ethanol. 2.6 g (of 68.7 mmol) of boron hydrate of sodium was added in small portions while the temperature was maintained below 25oC. the Solution is stirred overnight, concentrated in vacuo, hydrolizable with ice and aqueous hydrogen chloride, and was extracted three times with dichloromethane. The combined organic layers were dehydrated on sodium sulfate and concentrated under reduced daala.

Step C: Getting ethyl-rat-9-(6-cyano-2-methyl-2H-1-benzopyran-2-yl)nonanoate, intermediate compounds represented by the formula (267):

< / BR>
11.2 g (30.0 mmol) of the compound from step B was dissolved in 200 ml of toluene. Was added a catalytic amount of p-toluenesulfonic acid, and the solution was heated with azeotropic removal of water for 7 hours the Mixture was washed with saturated aqueous sodium bicarbonate solution was dehydrated on sodium sulfate and concentrated under reduced pressure. Declared benzopyran was purified by chromatography on silica gel with dichloromethane. Yield: 3.0 g (28%) oil.

Step D: Getting ethyl-rat-9-(6-aminoiminomethyl-2-methyl-2H-1 - benzopyran-2-yl)nonanoate hydrochloride, an intermediate represented by the formula (268):

< / BR>
1.5 g (4.2 mmol) Hramina from the previous step was dissolved in 50 ml of anhydrous ethanol. The solution was saturated with hydrogen chloride and stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was treated with saturated solution of ammonia in ethanol. He stirred overnight and concentrated to an anhydrous state under reduced pressure, giving a net declared amidin. Yield: 1.4 g (81%) of oil.

of sodium hydroxide and 5 ml of acetonitrile were added to 0.6 g (1,47 mmol) of ester from the previous step, and the mixture was heated for 30 min in the steam room. The mixture was brought to pH=7 with 2N acetic acid, the formed precipitate. It was filtered by suction, was sequentially washed with ice water and acetone and dehydrated in a vacuum. Yield: 0.4 g (79%) of white powder, tPL223-225oC (dec).

Example 61

Getting rat-(3,4-dihydro-6-(2-(piperidine-4-yl)ethoxy)-2H-1 - benzopyran-2-yl)acetic acid triptoreline, the compound represented by formula (269):

< / BR>
Step A: Obtaining ethyl-rat-(6-(2-(1-(tert-butoxycarbonyl)piperidine-4 - yl)ethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (270):

< / BR>
To a solution of 2.2 g (7.5 mmol) of 4-(2-bromacil)-1-(tert-butoxycarbonyl)piperidine (obtained by bromirovanii 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)ethanol in European patent application EP 478328) in 50 ml of anhydrous acetonitrile was added 2,84 g (8,72 mmol) of anhydrous cesium carbonate. After adding dropwise the solution of 3.05 g (12.9 mmol) of ethyl-rat-(3,4-dihydro-6-hydroxy-2H-1-benzopyran-2-yl) acetate (obtained according to European patent application EP 129906) in 20 ml of anhydrous acetonitrile, the solution was mixed overnight at room temperature. Added ur. The mixture was filtered through Selita, which was rinsed with acetonitrile and acetone. The filtrate was concentrated under reduced pressure, and the residue was sequentially mixed with hexane/ethyl acetate 4:1 and twice with ethyl acetate. The combined solution, separated from the insoluble material was concentrated in vacuo, and the compound (270) was obtained by chromatography on silica gel with hexane, then hexane/ethylcatechol 4: 1. Yield: 1.9 g (86%) of yellow oil, which eventually solidify.

Step B: Obtaining rat-(6-(2-(1-(tert-butoxycarbonyl)piperidine-4 - yl)ethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl)acetic acid, an intermediate compound represented by formula (271):

< / BR>
To a solution of 1.5 g (3.35 mmol) of ester from the previous step in 100 ml of ethanol was added 6.8 ml of 2N aqueous sodium hydroxide, and the mixture is stirred over night at room temperature. The mixture was brought to pH= 5 using dilute acetic acid, and concentrated under reduced pressure. Announced the acid was obtained by chromatography on silica gel with dichloromethane followed by addition of up to 3% ethanol. Yield: 0.54 g (38%) of a beige oil.

Step C: Getting rat-(3,4-dihydro-6-(2-(piperidine-4-yl)ethoxy)- 2 who was peremeshivaesh 2.3 ml triperoxonane acid at room temperature for 30 min, and the mixture was concentrated to the dry state in a vacuum, leaving a clean declared connection. Yield: 115 mg (95%) of a brown resin.

Example 62

Getting ethyl-rat-(6-(N-(4-aminoiminomethyl-2-chlorobenzoyl)amino)- 1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetate hydrochloride, a compound represented by formula (278):

< / BR>
Step A: Obtaining ethyl-rat-(6-(N-(2-chloro-4-lebensohl)-1 - oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetate hydrochloride, a compound represented by formula (280):

< / BR>
5.7 g (of 31.4 mmol) of 2-chloro-4-lambertini acid, which was obtained by oxidation of 3-chloro-4-methyl-benzonitrile (Chem. Ber. 1936, 69, 537, consideration of which is included here by reference) was dissolved in 300 ml of toluene, and added of 10.25 g (86,2 mmol) chloride tiomila. After 4 h of irrigation was added the same amount of chloride tonila, and heating was continued overnight. The solvent was removed under reduced pressure, the residue was dissolved in 100 ml of toluene and again concentrated in vacuo, leaving the crude acid chloride as a yellow oil. Yield: 4.1 g (65%). A solution of 0.98 g (of 3.96 mmol) of tetralone 98 and 3.3 ml of anhydrous pyridine in 33 ml of anhydrous THF was cooled with ice, was added dropwise a solution of 1.0 g (5.0 mmol) of Nera, stirred overnight, and poured into ice water. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate, and then brine, and was dehydrated on sodium sulfate. The product was concentrated under reduced pressure, and the residue was mixed with hexane, giving crystalline nitrile (280), which was filtered and dehydrated in vacuum at 50oC. Yield: 1.5 g (92%) of a beige crystalline solids tPL173-175oC.

Step B: Obtaining ethyl-rat-(6-(N-(2-chloro-4-(ethoxycarbonylmethyl) benzoyl)amino)-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetate hydrochloride, an intermediate represented by the formula (281):

< / BR>
1,35 (3.3 mmol) of the nitrile from step A was suspendibility in 50 ml of anhydrous ethanol, and the temperature of the mixture was maintained below 5oC, while the mixture is stirred and saturated with hcl (approximately 6 hours). After a night of settling for another 3 h was passed a stream under reduced pressure, and the residue was mixed with hexane, giving crystalline announced compound, which was filtered and dehydrated in a vacuum. Yield: 1.3 g (80%) of a beige crystalline solids tPL234-235Talin-2-yl)acetate hydrochloride.

1.2 g (2,43 mmol) of the compound from the previous step was introduced into 50 ml of a cooled saturated solution of ammonia in ethanol. After stirring over night at room temperature was added 20 ml of an ethanol solution, and stirring is continued for the same amount of time. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was mixed with hexane, giving the crude crystalline announced compound, which was purified by chromatography on silica gel with chloroform/methanol 8:1. Yield: 0.2 g (18%) of beige crystalline powder, tPL225-226oC.

Example 63

Getting rat-(6-(N-(4-aminoiminomethyl-2-chlorobenzoyl)amino)-1 - oxo-1,2,3,4-tetrahydronaphthalen-2-yl)acetic acid, a compound represented by formula (282):

< / BR>
0.2 g (0.43 mmol) of ester from example 62 mixed with 5 ml of ethanol and 0.7 ml of 2N aqueous sodium hydroxide were mixed at room temperature over night. The reaction mixture was brought to pH=4 with 2N acetic acid, the precipitate was filtered by suction, washed successively with water and acetone and dehydrated in a vacuum. Output: 0,13 g (75%) of white powder, tPL240-242oC.


< / BR>
Hydrochloride 4-guanidinopentanoic acid was obtained from 4-aminobenzoic acid by the procedure described in the literature (Recl. Trav. Chim. Pays-Bas, 1953, 72, 643, consideration of which is included here by reference). It was heated in the chloride tionale for 1 h, and then concentrated to an anhydrous state, giving the crude hydrochloride benzoylchloride. of 0.62 g (of 1.85 mmol) of the compound from example 47, step D, stirred for 1 h at room temperature in 2 ml of triperoxonane acid, and the mixture was concentrated in vacuo to an anhydrous state. The mixture was treated with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was dehydrated on sodium sulfate and concentrated at low temperature, and the oily residue was dissolved in 20 ml of anhydrous pyridine, followed by addition of 0.44 g (1.88 mmol) of the crude hydrochloride of 4-guanidinopentanoic. After stirring over night at room temperature the mixture was poured into 100 ml of water, the formed precipitate, which was collected by filtration, rinsed with water and dehydrated in a vacuum. Announced the compound was purified by chromo dry residue.

Example 65

Getting rat-(6-(N-(4-aminoiminomethyl)amino)benzoyl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetic acid, a compound represented by formula (284):

< / BR>
0.08 g (0.2 mmol) of ester from example 64 was dissolved in 30 ml of ethanol, after which was added 0.4 ml of 2N aqueous sodium hydroxide solution. The mixture is stirred at room temperature for two days, and concentrated to an anhydrous state at reduced pressure. The residue was dissolved in water and the solution was kind of balanced out with acetic acid, at this time declared the acid formed as a precipitate. It was filtered with suction, rinsed with water and dehydrated in a vacuum. Output: 0,045 g (61%) of a beige crystalline solids tPL258-260oC.

Example 66

{BL-43}

Ethyl-rat-3-(6-(4-aminoiminomethyl)phenylmethoxy)-3,4-dihydro-2 - methyl-4-oxo-2H-1-benzopyran-2-yl)propanoate hydrochloride, a compound represented by formula (299):

< / BR>
Example 67

Rat-3-(6-(4-aminoiminomethyl)phenylmethoxy)-3,4-dihydro-2-methyl-4 - oxo-2H-1-benzopyran-2-yl)propanoic acid hydrochloride, a compound represented by formula (300):

< / BR>
Example 68

Getting ethyl-rat-(3,4-dihydro-6-(N-(4-((ethoxycarbonyl) Imin the ü) benzopyrano from example 47, 0.3 ml of triethylamine and 20 mg of 4-dimethylaminopyridine was dissolved in 20 ml of anhydrous dichloromethane, and the solution was cooled to -20oC. At this temperature, was added dropwise 119 mg (1.1 mmol) of ethylchloride in 2 ml of anhydrous dichloromethane, and after 30 min the solution was warmed to room temperature and stirred for another 2 hours the Mixture was poured into cold water, and the organic layer was dehydrated on sodium sulfate and concentrated under reduced pressure. The remaining crystalline announced compound was mixed with ether, filtered and dehydrated in a vacuum. Yield: 360 mg (79%) of pale yellow solids tPL163-165oC.

Example 69

Getting ethyl-rat-(6-(N-(4-aminoiminomethyl)-2-perbenzoic)amino)- 3,4-dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (304):

< / BR>
Step A: Obtaining ethyl-rat-(6-(N-(4-cyano-2-perbenzoic)amino-3,4 - dihydro-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (307):

< / BR>
5.0 g (30.3 mmol) of the acid 119 was heated for 1 h under irrigation in 50 ml of chloride tiomila containing one drop of DMF. The reaction mixture was concentrated under reduced pressure, and the crude ethyl(6-amino-3,4-dihydro-2H-1-benzopyran-2-yl)acetate in 200 ml of anhydrous THF and 20 ml of anhydrous pyridine, which was obtained in accordance with example 47, step E, from 10.0 g (29,8 mmol) protected derivative using 20 ml triperoxonane acid. After stirring over night at room temperature the mixture was poured into ice water containing sodium bicarbonate. Sediment announced nitrile was filtered by suction, was heated for a few minutes in ethanol and again filtered after cooling, and the crystals were washed with hexane and was dehydrated in a vacuum. Yield: 8.6 g (75%) of a beige amorphous solids tPL154-155oC.

Step B: Obtaining ethyl-rat-(6-(N-(4-aminoiminomethyl)-2 - perbenzoic)amino)-3,4-dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride.

4.5 g (to 11.8 mmol) of the nitrile from the previous step in 150 ml of anhydrous ethanol was cooled to 0oC and saturated with gaseous hydrogen chloride. After stirring over night at room temperature the mixture was concentrated under reduced pressure. The crystalline residue was treated with 150 ml of a saturated ethanol solution of ammonia and again stirred overnight. Untreated declared substance was obtained after concentration in vacuum, recrystallization from ethanol, followed by crystallization of specialitie rat-(6-(N-(4-aminoiminomethyl)-2-perbenzoic)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetic acid, the compound represented by formula (308):

< / BR>
1.2 g (a 2.75 mmol) of ester from example 69 stirred overnight at room temperature in a mixture of 20 ml ethanol and 5 ml of 2N aqueous sodium hydroxide solution. The mixture was brought to pH=4 with 2N acetic acid, and the precipitate announced compounds were filtered by suction, was sequentially rinsed with water and acetone, and was dehydrated in vacuum at 50oC. Yield: 0.84 g (82%) of pale yellow powder, tPL250oC.

Example 71

Getting ethyl-rat-(3,4-dihydro-6-(N-(4-ethylamino)iminomethyl) benzoyl)amino)-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (309):

< / BR>
1.8 g (4.0 mmol) of the crude intermediate from example 57, step A, was dissolved in 50 ml of ethanol. The solution was cooled with ice, and added 2 ml of 50% ethanol solution of ethylamine. The solution was mixed overnight at room temperature and the solvent was removed under reduced pressure. The residue was mixed with a small amount of ethanol, giving pure crystalline announced compound, which was filtered and dehydrated in a vacuum. Yield: 1.6 g (89%) of a pale yellow powder, tPL290-291oC.

the second acid, the compound represented by formula (310):

< / BR>
1.8 g (4.0 mmol) of the crude compound from example 57, step A, was dissolved in 50 ml of ethanol. The solution was cooled with ice, was added 2 ml of 50% ethanol solution of dimethylamine. The solution was mixed overnight at room temperature, the solvent was removed under reduced pressure. The residue was mixed with a small amount of ethanol, giving pure crystalline announced compound, which was filtered and dehydrated in a vacuum. Yield: 1.35 g (75%) of white powder, tPL248oC.

Example 73

Getting ethyl-rat-(3,4-dihydro-6-(N-(4-((dimethylamino)iminomethyl) benzoyl)amino)-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (311):

< / BR>
1.8 g (4.0 mmol) of the crude compound from example 57, step A, was dissolved in 50 ml of ethanol. The solution was cooled with ice, was added 2 ml of 50% ethanol solution of dimethylamine. The solution was mixed overnight at room temperature, the solvent was removed under reduced pressure. The residue was mixed with a small amount of ethanol, giving pure crystalline announced compound, which was filtered and dehydrated in a vacuum. Yield: 1.35 g (75%) of benjamina) iminomethyl)benzoyl)amino)-2H-1-benzopyran-2-yl)acetate, the compound represented by formula (312):

< / BR>
To 417 mg (1.0 mmol) of amidine from example 47, 0.3 ml of triethylamine and 20 mg of 4-dimethylaminopyridine in 40 ml of dichloromethane was added at 0oC 104 mg (1.1 mmol) of methylchloroform, and the mixture is stirred over night at room temperature. Formed white precipitate, which was collected by filtration and was chromatographically on silica gel with dichloromethane/ethanol 9:1, giving a net declared carbamate. Yield: 0.21 g (48%) of white powder, tPL204-206oC.

Example 75

Getting ethyl-rat-(6-(N-(4-(aminoiminomethyl)-2-chlorobenzoyl)amino)- 3,4-dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (313):

< / BR>
Step A: Obtaining ethyl-rat-(6-(N-(2-chloro-4-lebensohl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (314):

< / BR>
3.0 g (to 8.94 mmol) benzopyrano from example 47, step D, was mixed with 6 ml triperoxonane acid for 2 h at room temperature. The mixture was treated with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was dehydrated on sodium sulfate, and the solvent was removed in vacuo, giving crude illegal the RA crude 2-chloro-4-canbesold in anhydrous THF, which was obtained from 1.1 g (6.1 mmol) of 2-chloro-4-lambertini acid (Chem. Ber. 1936, 69, 537, consideration of which is included here by reference) according to example 62, step A, was added dropwise at 0oC. After stirring overnight at room temperature the mixture was poured into ice water containing sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic layer was sequentially washed with an aqueous solution of copper sulfate (II) and brine, dehydrated on sodium sulfate and concentrated under reduced pressure. Nitrile (314) was obtained from the residue by chromatography on silica gel with chloroform/methanol 96:4. He was crystallized from pure fractions after mixing with a small amount of ethanol. Yield: 1.1 g (46%) of beige crystals, tPL152-154oC.

Step B: Obtaining ethyl-rat-(6-(N-(4-(aminoiminomethyl)-2 - chlorobenzoyl)amino)-3,4-dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride.

1.1 g (was 2.76 mmol) of the nitrile from the previous step was dissolved in 25 ml of ethanol, and the solution was cooled to 0oC and saturated with gaseous hydrogen chloride. He stirred over night at room temperature, followed by concentration under reduced pressure. OS is the pressure of the solvent in vacuo the remaining is declared the connection precrystallization from ethanol/water/ether. Yield: 0.9 g (72%) of pale yellow powder, tPL225-226oC.

Example 76

Getting rat-(6-(N-(4-(aminoiminomethyl)-2-chlorobenzoyl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetic acid, a compound represented by formula (314):

< / BR>
0.3 g (0.66 mmol) of ester from example 75 was mixed overnight at room temperature with a mixture of 5 ml ethanol and 0.5 ml of 2N aqueous sodium hydroxide solution. The mixture was brought to pH=5 with 2N acetic acid. The precipitate of the claimed compounds were filtered by suction, was sequentially rinsed with water and acetone and dehydrated in a vacuum. Output: 0,19 g (74%) of white powder, tPL269-270oC (dec).

Example 77

Getting ethyl-rat-(3,4-dihydro-6-(N-(3-piperidine-4 - yl)propenyl)amino)-2H-1-benzopyran-2-yl)acetate triptoreline, the compound represented by formula (327):

< / BR>
Step A: Obtaining ethyl-rat-(6-(N-(3-(1-(tert-butoxycarbonyl)piperidine - 4-yl)propenyl)amino)-3,4-dihydro-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (329):

< / BR>
0.85 grams of 3.33 mmol) of the acid 386 was dissolved in a mixture of 23 ml of anhydrous dichloromethane and 0.26 ml of anhydrous DMF. The solution was maintained at a temperature between -10oC and 0oC, in this atur mixture was added dropwise to a solution of 0.5 ml of triethylamine and the crude ethyl(6-amino-3,4-dihydro-2H-1-benzopyran-2-yl)acetate (obtained using triperoxonane acid of 1.5 g (4.5 mmol) of Boc-protected amidine, as described in example 47) in 35 ml of anhydrous dichloromethane. After stirring for 90 min at this temperature, the mixture was poured into ice water, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water, dehydrated on sodium sulfate and concentrated under reduced pressure. Announced the compound was purified by chromatography on silica gel with dichloromethane/ethanol 80:1. Output: 0,81 g (51%) of oil.

Step B: Obtaining ethyl-rat-(3,4-dihydro-6-(N-(3-(piperidine-4 - yl)propenyl)amino)-2H-1-benzopyran-2-yl)acetate trifenatate. 0,81 g (1,71 mmol) of the protected piperidine from the previous step was mixed for 2 h at room temperature in 6 ml triperoxonane acid. The mixture was poured into ice-cold water, brought to pH=7 with sodium bicarbonate and was extracted with dichloromethane. The organic layer was dehydrated on sodium sulfate and concentrated under reduced pressure, and the residue was mixed with a mixture of hexane and ether gave crystalline declared substance was collected by filtration and was dehydrated at 50oC in vacuum. Yield: 0.18 g (22%) of reddish crystals, tPL72-73oC.

Prisoedinenie represented by formula (330):

< / BR>
0.1 g (0.2 mmol) of ester from example 77 stirred overnight at room temperature in a mixture of 2.5 ml of ethanol and 0.35 ml of 2N aqueous sodium hydroxide solution. The reaction mixture was cooled with ice and brought to pH= 5,5 with 2N acetic acid. The residue of the stated acid was filtered by suction, washed with a small amount of cold water and was dehydrated at 50oC in vacuum. Yield: 42 mg (59%) of beige crystals, tPL175-178oC.

Example 79

Getting ethyl-rat-(6-(N-(4-(aminoiminomethyl)benzoyl)amino)-3,4 - dihydro-4, -dimethyl-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (331):

< / BR>
Step A: Obtaining tert-butyl(3,4-dihydro-4,4-dimethyl-2-oxo-2H-1 - benzopyran-6-yl)carbamate, intermediate substance represented by the formula (332):

< / BR>
To a suspension of 1.5 g of 10% Pd/C in 300 ml of ethanol was added in an argon atmosphere 29,2 g (132,0 mmol) of 3,4-dihydro-4,4-dimethyl-6-nitro-2-oxo-2H-1-benzopyran (obtained by nitration of 3,4-dihydro-4,4-dimethyl-2-oxo-2H-1-benzopyran in accordance with J. Am. Chem. Soc., 1970, 92, 4377, consideration of which is included here by reference) and 21.4 g (339,4 mmol) of ammonium formate. For about 1 h the temperature was polychaetous through Selita, which were washed with 500 ml of hot ethanol. The combined filtrates were concentrated under reduced pressure to a volume of 100 ml, and the formed precipitate was filtered by suction. The second portion of the crude 6-amino-3,4-dihydro-4,4-dimethyl-2-oxo-2H-1-benzopyran was obtained after further concentration. The two portions were combined and dissolved in 80 ml of THF, and then added 80 ml of water, to 25.3 g (183 mmol) of potassium carbonate and 29.9 g (133,8 mmol) Boc2O and 2.5 g of potassium carbonate and stirring continued over night. The mixture was poured into 300 ml of water and was extracted with ethyl acetate, and the organic layer was dehydrated on sodium sulfate and concentrated under reduced pressure. The first portion of the advertised connection crystallizability of the oily residue with diisopropyl ether. The additional amount was obtained from the concentrated source of fluid by chromatography on silica gel with toluene and crystallization of the oily pure fractions using diisopropyl ether. Total yield: 31.6 (82%) of colorless crystals, tPL106-108oC.

Step B: Obtaining tert-butyl rat-(3,4-dihydro-4,4-dimethyl-2 - hydroxy-2H-1-benzopyran-6-yl)carbamate, intermediate SLOs in 450 ml of anhydrous THF and cooled to -70oC in argon atmosphere. At this temperature for 1 h was added dropwise 133 ml of 25% aqueous solution of DIBAH in toluene, and the mixture is stirred for another 2 h, the Mixture was carefully extinguished 35 ml of methanol and warmed to room temperature, then poured into 1000 ml of a saturated aqueous solution of ammonium chloride. After vigorous mixing of the upper organic layer to solidify the jelly-like state, jelly was separated and mixed with 1000 ml of ethyl acetate. Then the mixture was filtered through Selita and were washed with 500 ml of ethyl acetate. The combined filtrates were dehydrated on sodium sulfate and concentrated in vacuo giving a brown resin, which was obtained pure declared acetal by chromatography on silica gel with toluene/acetone 95:5. Output: 25,9 g (81%) of a yellow resin.

Step C: Getting ethyl-rat-(6-(N-tert-butoxycarbonylamino)-3,4 - dihydro-4,4-dimethyl-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (334):

< / BR>
To a solution of 25.9 g (88,3 mmol) of the compound from step B in 150 ml of toluene was added to 32.4 g (93,0 mmol) of ethoxycarbonylmethylene, and then 0.6 g (15 mmol) of 60% sodium hydride in small portions. The mixture was heated to 120oC for 3 h, cooled igenom pressure, the compound (334) was obtained by chromatography on silica gel with hexane/ethyl acetate 4:1 to 1:1. Yield: 6.9 g (22%) of colorless crystals, tPL116-119oC.

Step D: Getting ethyl-rat-(6-(N-(4-lebensohl)amino)-3,4 - dihydro-4,4-dimethyl-2H-1-benzopyran-2-yl)acetate, an intermediate represented by the formula (335):

< / BR>
2,18 g (6.0 mmol) of the compound from the previous step was deprecatively by mixing 10 ml triperoxonane acid as described in example 47, step E, and a brown oil from the crude 6-aminobenzophenone was dissolved in 40 ml of anhydrous pyridine. After adding 0,99 g (6.0 mmol) of 4-canbesold the mixture stirred at room temperature overnight. It was concentrated in vacuo to an anhydrous state and three times was dissolved in toluene followed by concentration under reduced pressure to remove the remaining pyridine. Declared nitrile was kristalizovyvatsja brown residue after mixing with a small amount of ethanol. It was filtered by suction, washed with cold ethanol and dehydrated in a vacuum. Yield: 1.7 g (72%) of white powder, tPL163-165oC.

Step E: Getting ethyl-rat-(6-(N-(4-aminoiminomethyl)bentolila from step D in 100 ml of anhydrous ethanol was cooled with ice and saturated with gaseous hydrogen chloride. After settling overnight at room temperature, it was concentrated to anhydrous state under reduced pressure, and the residue was dissolved in 50 ml of 10% ethanol solution of ammonia. The mixture is stirred at room temperature for 3 days to complete the reaction. The solvent was removed in vacuo and the gummy residue was dissolved in toluene/acetone 7:3. The first portion of the declared amidine was crystallizability from the solution, and the other portion was obtained by chromatography on silica gel using the same solvent mixture. Total yield: 1.6 g (83%) of yellow crystalline solids tPL122-124oC.

Example 80

Getting rat-(6-(N-(4-aminoiminomethyl)benzoyl)amino)-3,4 - dihydro-4,4-dimethyl-2H-1-benzopyran-2-yl)acetic acid, a compound represented by formula (336):

< / BR>
0.3 g (0.67 mmol) of ester from example 79 was suspendibility in 100 ml of ethanol, followed by adding 1 ml of aqueous 2N sodium hydroxide. The mixture is stirred at room temperature for 4 h the Mixture was filtered, the filtrate was concentrated to an anhydrous state under reduced pressure, and the residue was dissolved in water. The solution was then scavenged by diluted acetic cue in vacuum at 50oC. Yield: 0.2 g (78%) of yellow crystalline solids tPL248-250oC.

Example 81

Getting ethyl-rat-(3,4-dihydro-6-(N-(4-((propylamino)iminomethyl) benzoyl)amino)-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (337):

< / BR>
To a solution of 0.8 g (1.8 mmol) of the crude intermediate from example 57, step a in 20 ml of ethanol was added at 0oC 0.3 ml of n-Propylamine. The mixture is stirred over night at room temperature and was concentrated under reduced pressure. The residue was treated with ethanol and ether, giving pure crystalline announced compound, which was collected by filtration and was dehydrated in a vacuum. Output: 0,63 g (76%) of white powder, tPL271-273oC.

Example 82

Getting rat-(3,4-dihydro-6-(N-(4-((propylamino)iminomethyl) benzoyl)amino)-2H-1-benzopyran-2-yl)acetic acid, a compound represented by formula (338):

< / BR>
0.25 g (0.54 mmol) of ester from example 81 stirred at room temperature overnight with 5 ml of ethanol and 0.7 ml of 2N aqueous sodium hydroxide. The mixture was brought to pH=4 with 2N acetic acid, the precipitated acid (338) was filtered by suction, consistently is UP>C (dec).

Example 83

Getting rat-(6-(N-(4-(butylamino)iminomethyl)benzoyl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (339):

< / BR>
The connection was obtained from 0.8 g (1.8 mmol) of the crude intermediate from example 57, step A, and 0.3 ml of n-butylamine as described in example 81. Yield: 0.6 g (71%) of pale yellow powder, tPL265-267oC.

Example 84

Getting rat-(6-(N-(4-(butylamino)iminomethyl)benzoyl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetic acid, a compound represented by formula (340):

< / BR>
0.25 g (of 0.53 mmol) of ester from example 83 hydrolethalus declared in acid as described in example 82. The yield of 0.13 g (60%) of white powder, tPL240-241oC (dec).

Example 85

Getting ethyl-rat-(3,4-dihydro-6-(N-(4-(propoxycarbonyl) iminomethyl)benzoyl)amino)-2H-1-benzopyran-2-yl)acetate, a compound represented by formula (341):

< / BR>
417 mg (1.0 mmol) of the compound from example 47, 0.3 ml of triethylamine, 20 mg of 4-diethylaminopentane and 135 mg (1.1 mmol) of propylchloride was dissolved in 20 ml of dichloromethane at 0oC, followed by stirring overnight at room temperature. After adding the same volume centered at reduced pressure, giving the crude announced compound, which was recrystallization from dichloromethane/hexane. Yield: 0.27 g (58%) of a pale-yellow amorphous solids tPL183-184oC.

Example 86

Getting propyl-rat-(6-(N-(4-(aminoiminomethyl)benzoyl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (342):

< / BR>
A solution of 0.5 g (1.37 mmol) of the nitrile from example 47, step E, in 50 ml of n-propanol was cooled with ice and saturated with gaseous hydrogen chloride. After stirring over night at room temperature the mixture was concentrated under reduced pressure, and the residue was treated with 50 ml of saturated ammonia solution in n-propanol. The mixture is again stirred overnight at room temperature, the solvent was removed in vacuo, and the remaining advertised amidon was precrystallization of n-propanol. Yield: 0.36 g (61%) of yellow powder, tPL238-240oC (dec).

Example 87

Obtaining methyl-rat-(6-(N-(4-(aminoiminomethyl)benzoyl)amino)-3,4 - dihydro-2H-1-benzopyran-2-yl) acetate hydrochloride, a compound represented by formula (343):

< / BR>
Suspension of 0.35 g (1.0 mmol) of the acid from example 48 in 20 ml of methanol was cooled to 0oC and saturated with gazoobrazovania (343) precrystallization from methanol/ether. Output: 0.29 grams (72%) of yellow crystals, tPL235-237oC.

Example 88

Getting ethyl-rat-(3,4-dihydro-6-(N-(2-fluoro-4-((methoxycarbonylamino)iminomethyl)benzoyl)amino)-2H-1-benzopyran-2-yl)acetate, a compound represented by formula (349):

< / BR>
436 mg (1.0 mmol) of amidine from example 69, 0.3 ml of triethylamine and 20 mg of 4-dimethylaminopyridine was dissolved in 29 ml of dichloromethane followed by the addition of 104 mg (1.1 mmol) of methylchloroform at 0oC. After stirring overnight at room temperature formed a white precipitate of the stated substances. It was filtered by suction and was sequentially washed with water and ether. Yield: 0.35 g (77%) of pale yellow powder, tPL202-204oC.

Example 89

Getting ethyl-rat-(3,4-dihydro-6-(N-(4-(ethoxycarbonyl) iminomethyl)-2-perbenzoic)amino)-2H-1-benzopyran-2-yl)acetate, a compound represented by formula (350):

< / BR>
Declared carbamate was obtained as described in example 88, 435 mg (1.0 mmol) of amidine of example 69 and 119 mg (1.1 mmol) of ethylchloride. The connection was precrystallization from dichloromethane/hexane. Yield: 0.35 g (74%) of white powder, tPL168-169oC.

Example 90

Getting ethyl-rat-(3,4-dihydro-6-(N-(2-f is armoloy (351):

< / BR>
Announced compound was obtained as described in example 85, of 436 mg (1.0 mmol) of amidine of example 69 and 135 mg (1.1 mmol) of propylphosphonate. Output: 0.29 grams (60%) of white crystalline solids tPL157-159oC.

Example 91

The proposed method for obtaining the rat-4-aminoiminomethyl-N-(3,4 - dihydro-2-(1H-tetrazol-5-yl)methyl-2H-1-benzopyran-6-yl)benzamide, compound represented by formula (352):

< / BR>
Step A: Obtaining tert-butyl-rat-(2-lanmeter-3,4-dihydro-2H-1 - benzopyran-6-yl)carbamate, intermediate compounds represented by the formula (353):

< / BR>
Step B: Obtaining tert-butyl-rat-(3,4-dihydro-2-(1H-tetrazol-5 - yl)methyl-2H-1-benzopyran-6-yl)carbamate, intermediate compounds represented by the formula (354):

< / BR>
Step C: Getting rat-4-cyano-N-(3,4-dihydro-2-(1H-tetrazol-5 - yl)methyl-2H-1-benzopyran-6-yl)benzamide, compound represented by the formula (355):

< / BR>
Example 92

Getting ethyl-rat-(3,4-dihydro-6-(N-(4-(N-phenylethylamine) iminomethyl)benzoyl)amino)-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (356):

< / BR>
The mixture of 0.49 g (1.1 mmol) of the intermediate from example 57, step A, and 0.5 ml benzoylamino in 15 ml of anhydrous ethanol were mixed for Obedinenie was crystallizability from ethanol/ether. The crystals were collected by filtration, washed with ether, and dehydrated in a vacuum. Output: 0,49 g (88%) of pale yellow crystals, tPL254-256oC.

Example 93

Getting rat-(3,4-dihydro-6-(N-(4-(N'-phenylethylamine) iminomethyl)benzoyl)amino)-2H-1-benzopyran-2-yl)acetic acid, a compound represented by formula (357):

< / BR>
0.2 g (0,39 mmol) of ester from example 92 was added to a mixture of 10 ml ethanol and 0.5 ml of 2N aqueous sodium hydroxide solution. After a light heating the mixture stirred over night at room temperature. The mixture was brought to pH=4 with 2N acetic acid, and the precipitate declared acid was filtered by suction, was sequentially rinsed with water and acetone and dehydrated in a vacuum. Yield: 0.12 g (69%) of pale yellow powder, tPL220oC (dec).

Example 94

Getting ethyl-rat-(3,4-dihydro-6-(N-(4-(pentylamine)iminomethyl) benzoyl)amino)-2H-1-benzopyran-2-yl)acetate hydrochloride, a compound represented by formula (363):

< / BR>
To a suspension of 447 mg (1.0 mmol) of the intermediate from example 57, step a in 15 ml of anhydrous ethanol at 0oC was added 0.5 ml of n-pentylamine. The mixture turned into a clear solution after stirring in the rest of the announced connection precrystallization from ethanol/ether. Yield: 0.33 g (68%) of pale yellow crystals, tPL267-269oC.

Example 95

Getting rat-(3,4-dihydro-6-(N-(4-((pentylamine)iminomethyl) benzoyl)amino)-2H-1-benzopyran-2-yl)acetic acid, a compound represented by formula (364):

< / BR>
0.15 g (0.31 mmol) of ester from example 94 was mixed overnight at room temperature in a mixture of 10 ml ethanol and 0.7 ml of 2N aqueous sodium hydroxide solution. The mixture was brought to pH=4 with 2N acetic acid, the residue of the stated acid was filtered, successively washed with water and acetone and dehydrated in a vacuum. Yield: 98 mg (75%) of colorless crystals, tPL223-225oC.

Reference numbers in the following examples are reaction schemes 27-33 above.

Example 96

Getting connection 368

< / BR>
A mixture of compound 365 (1,25 g, 2.0 mmol), H2O (5 ml) and THF (5 ml) was treated with propylphosphonate (0.34 g, 2.7 mmol) and K2CO3(0,19 g, 13.5 mmol) at room temperature. After 1 h the mixture was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude residue was precrystallization from EtOAc/hexane, yielding 0.8 g of the compound 368 in the form of a dry white residue.

1H NMR (30=6,2, of 16.3 Hz, 1H), 2,42 (m, 1H), 2,11 (m, 1H), up to 1.98 (m, 1H), 1,60 (m, 2H), 1,16 (t, J=7,0 Hz, 3H), of 0.91 (t, J=7,3 Hz, 3H); IR (KBr) 1737, 1661, 1603, 1525, 1256 cm-1; MS (FAB) m/e 480.

Example 97

Getting connection 367

< / BR>
Following the procedure used to obtain the connection 368, compound 267 was obtained with a yield of 91% at the source of 0.50 g of compound 365 and 0.10 g of ethylchloride.

1H NMR (300 MHz, CDCl3) 8,55 (s, 1H), 7,80 (m, 5H), of 7.48 (d, J=8,8 Hz, 1H), 4.26 deaths (m, 4H), 3,05 (m,4H), 2,52 (m, 1H), 2,28 (m, 1H), 2.0 (m, 1H), 1,39 (t, J=7,1 Hz, 3H), 1,32 (t, J=7,2 Hz, 3H); IR (KBr) 1727, 1686, 1661, 1602, 1256 cm-1; MS (FAB) m/e 466.

Analysis for C22H27N3O6. Calculation: C 64,51; H Of 5.85; N 9,03. Found: C 64,77; H By 5.87; N 8,82.

Example 98

Getting 369 connection:

< / BR>
Following the procedure used to obtain the connection 368, 369 connection was obtained with a yield of 87% at the source of 0.26 g of compound 366 and 0.07 g of ethylchloride.

1H NMR (300 MHz, CDCl3) 8,64 (app d, J=to 15.0 Hz, 1H), 8,20 (t, J=7,9 Hz, 1H), 8,01 (d, J=8,5 Hz, 1H), to 7.84 (d, J=a 12.7 Hz, 1H), 7,79 (s, 1H), 7,72 (s, J= 8,3 Hz, 1H), 7,42 (d, J=8,7 Hz, 1H), 4,24 (m, 4H), of 3.13 (m, 4H), 2,44 (m, 1H), and 2.26 (m, 1H), 1,99 (m, 1H), 1,37 (t, J=7,0 Hz, 3H), of 1.28 (t, J=7,3 Hz, 3H); IR (KBr) 1731, 1673, 1520, 1256 cm-1.

Example 99

Getting connection 370:

< / BR>
Following the procedure used to obtain the connection 368, connection 370 was obtained with a yield of 86% , H) to 8.20 (t, J=8,1 Hz, 1H), and 8.0 (d, J=8,5 Hz, 1H), to 7.84 (d, J=12,8 Hz, 1H), 7,78 (s, 1H), 7,72 (d, J= 8,2 Hz, 1H), 7,41 (d, J=8,4 Hz, 1H), 4,17 (m, 4H), 3.0 a (m, 4H), 2,42 (m, 1H, in), 2.25 (m, 1H), 2,0 (m, 1H), 1,78 (m, 2H), 1,28 (t, J=7,3 Hz, 3H), and 1.00 (t, J=7,5 Hz, 3H); IR (KBr) 1733, 1662, 1520, 1251 cm-1; MS (FAB) m/e 498.

Example 100

Getting 371 connection:

< / BR>
The mixture of compounds 368 (0.11 g, 0.23 mmol) and EtOH (5 ml) was treated with NaOH (1.1 ml of 2N solution, 2.3 mmol) and the resulting solution was stirred for 5 h at room temperature. The reaction mixture was then concentrated, and the residue was introduced into the H2O. This material was extracted with EtOAc, and the extracts were removed. The remaining aqueous material was pagkilala to pH=5 with 1N HCl, and the resulting material was extracted with EtOAc. The extracts were dehydrated (MgSO4) and concentrated, yielding 0.06 g (57%) of the desired acid 371 in the form of a dry white residue.

1H NMR (300 MHz, CD3OD) of 8.0 to 7.9 (m, 5H), 7,79 (br s, 1H), to 7.64 (dd, J= 2,1, 8,6 Hz, 1H), 4,11 (t, J=6,7 Hz, 2H), 3,15-2,95 (m, 3H), 2,89 (dd, J= 5,6, and 16.4 Hz, 1H), 2,48 (dd, J=6,6, and 16.5 Hz, 1H), and 2.27 (m, 1H), 2.06 to (m, 1H), 1,71 (m, 2H), and 1.00 (t, J=7,4 Hz, 3H); MS (FD) m/e 452.

Example 101

Getting 381 connection:

< / BR>
Following the procedure used to obtain the connection 368, 381 connection was obtained with a yield of 47% source 0,082 g of compound 374 and 0.13 g of propylphosphonate.

-1
; MS (FAB) m/e 481.

Analysis for C25H28N4O6. Calculation: C 62,49; H Of 5.82; N 11,66. Found: C 62,65; H By 5.87; N 11,43.

Example 102

Getting 391 connection:

< / BR>
Step A:

The mixture of alcohol 334 (5.0 g, 23.5 mmol, obtained from 4-pyridylcarbinol through hydrogenation and proektirovaniya) and CH2Cl2(25 ml) was added to a solution of oxalicacid (2.8 ml, 32.5 mmol), DMSO (2.5 ml, is 34.9 mmol) and CH2Cl2(25 ml) at -78oC. After 1 h the reaction was treated Et3N (6.5 ml, 46.5 mmol) and left to warm to room temperature. This mixture was diluted EtOAc and filtered by H2O. the Organic material was dehydrated (MgSO4) and concentrated. The crude residue was introduced in THF (25 ml) and added to a mixture of triethylphosphate (6,23 g of 28.2 mmol), NaH (1.12 g of 60% dispersion in oil, of 28.2 mmol) and THF (25 ml) with a temperature of -78oC. This mixture was left to warm to room temperature. After 1 h the mixture was diluted EtOAc and filtered by H2O. the Organic phase was concentrated, and the crude material was purified by chromatography (3:1 hexane/EtOAc), giving 4.7 g (71%) of compound 1016 in the form of a clear oil.

Step C:

Oxalicacid (of 0.08 ml, 1.0 mmol) was added to a mixture of compound 386 and benzene (5 ml). Was added one drop of DMF, and the mixture is stirred at room temperature for 1 h the resulting solution was concentrated, yielding the crude acid chloride 387 in the form of oil. This material was dissolved in CH2Cl2(5 ml) and was added to a solution of aniline 98 (0.17 g, 0.69 mmol), pyridine (5 ml) and CH2Cl2(5 ml). The resulting mixture was stirred at room temperature for 1 h and then was diluted EtOAc and filtered by H2O. the Organic material was concentrated and the crude material was purified by chromatography on silica (1,5:1 hexane/EtOAc) to give 0.25 g (90%) of compound 388 in the form of a dry white residue.

Step D:

A solution of compound 388 (0.24 g, 0.49 mmol) and THF (10 ml) was treated LiOH (10 ml of 0.1 N solution in H2O, 1.0 mmol) and stirred at room temperature overnight. This mixture is then concentrated to polarstate concentrated. The crude acid 390 was dissolved in TFA (10 ml), was defended for 1 h at room temperature, and then concentrated. Thus formed material was dissolved in 1N HCl, and the resulting solution was liofilizirovanny, yielding 0.15 g (80%) of compound 391 in the form of a white powder.

1H NMR (300 MHz, CDCl3) 7,89 (d, J=8,5 Hz, 1H), 7,68 (s, 1H), 7,51 (d, J= 8,5 Hz, 1H), 6.87 in (dd, J=6,5, to 15.4 Hz, 1H), 6,20 (d, J=to 15.4 Hz, 1H), 3,44 (br d, J=12,8 Hz, 2H), 3.0 a (m, 6H), and 2.6 (m, 1H), 2,4 (m, 1H, in), 2.25 (m, 1H), is 2.05 (m, 3H), of 1.70 (m, 2H); IR (KBr) 3384, 2953, 1726, 1672, 1533 cm-1; MS (FAB) m/e 357.

Analysis for C20H25N2O4Cl. Calculation: C 61,14; H 6,41; N 7,13. Found: C 61,40; H 6,60; N 7,18.

Example 103

Getting 389 connection:

< / BR>
A solution of compound 388 (0,60 g, 1.2 mmol) and TFA (10 ml) was maintained at room temperature for 1 h, and then concentrated. The residue was dissolved in H2O (10 ml) was treated with HCl (2.5 ml of 1N solution, 2.5 mmol) and the resulting solution was liofilizirovanny, giving 0,49 g (95%) of compound 389 in the form of a white powder.

1H NMR (300 MHz, CDCl3) 7,92 (d, J=8,6 Hz, 1H), 7,72 (s, 1H), 7,54 (d, J= 8,7 Hz, 1H), 6,93 (dd, J=6,5 and 15.6 Hz, 1H), 6,24 (d, J=15,5 Hz, 1H), 4,18 (q, J= 7,1 Hz, 2H), 3,49 (m, 2H), 3,10 (m, 5H), 2,82 (dd, J=6,3, and 16.4 Hz, 1H), to 2.65 (m, 1H), of 2.51 (dd, J=6,2, and 16.4 Hz, 1H), 2,3 (m, 1H), 2,1 (m, 3H), by 1.68 (m, 2H), 1,22 (t, J=7,0 Hz, 3H); IR (KBr) 3346, 3286, 2935, 1734, 1676, 1584 cm-1; MS (FAB) m/e 385.

Step B:

A mixture of compound 395 (0.28 g and 1.51 mmol), DMF (1 drop) and benzene (10 ml) was treated with oxalylamino at room temperature. This mixture was mixed for 30 min and then concentrated. The crude residue was introduced in CH2Cl2(5 ml) and added to a solution of compound 98 (0,38 g and 1.51 mmol), pyridine (3 ml) and CH2Cl2(3 ml). This mixture is stirred at room temperature for 0.5 h, then was diluted EtOAc and washed with water. The organic material was concentrated, and the residue was chromatographically on silica (1:1 hexane/EtOAc) to give 0.56 g connect the saw to obtain compound 6 (example 1, part E).

Step D:

Amidin 398 converted into a fully deprotection connection 400 using the General procedure described for connection 130 (example 33, part E).

1H NMR (300 MHz, CD3OD) 7,98 (d, J=8,6 Hz, 1H), 7,74 (s, 1H), 7,68 (m, 2H), to 7.64 (d, J= 8,6 Hz, 1H), 3.0 a (m, 3H), 2,88 (dd, J=6,4, 16,6 Hz, 1H), 2,46 (dd, J= 6, 4, and 16.6 Hz, 1H, in), 2.25 (m, 1H), 2,0 (m, 1H); IR (KBr) 3306, 1660, 1603, 1426, 1039 cm-1; MS (FAB) m/e 402.

Example 105

Getting connection 405:

< / BR>
Step A:

The intermediate compounds (402):

< / BR>
To a mixture of N-oxide of nicotinic acid (8.8 g, 63 mmol) in 100 ml anhydrous DMF was added Et3N (32 g, 316 mmol), which gave a homogeneous solution. The mixture was processed TMSCl (34 g, 316 mmol) and stirred for 30 min at room temperature before adding NaCN (12.4 g, 253 mmol). The reaction was heated to 100oC for 16 h, then was cooled to room temperature and filtered. The filtrate was concentrated to the dry state in a vacuum, was treated 2N aqueous HCl (150 ml) and was extracted several times with CH2Cl2. The extracts were dehydrated on MgSO4was concentrated to an anhydrous condition and was purified by chromatography (SiO2, 1% v/v MeOH-CHCl3), giving to 4.01 g of dry residue.

2Cl2processed 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.4 g, 12.2 mmol). The reaction stirred at room temperature for 60 h the Mixture was applied on a substrate made of silica gel and washed with 0.5% v/v MeOH-CHCl3giving 2.76 g (90%) of compound 408 in the form of a dry white residue.

Step C:

The intermediate compounds (409):

< / BR>
A solution of nitrile 403 (0,214 g, or 0.57 mmol) in 50 ml of 1M solution of CH3SH in EtOH was treated with 75 g (1.1 mmol) CH3SNa, and the mixture is stirred at room temperature for 2 hours was Added dry NH4I (0.7 g) and the mixture was heated under irrigation until the reaction was over, that showed thin layer chromatography. The solution was concentrated to an anhydrous condition, and the residue was introduced into a 5 ml THF. The solution was processed in K2CO3(0.75 g, 5.4 mmol), Boc2O (1.2 g, 5.4 mmol), THF (5 ml) and H2O (5 ml) and the mixture stirred over night. The reaction mixture was diluted EtOAc and filtered by H2O. the Organic layer was dehydrated on MgSO4was concentrated to an anhydrous condition and was purified by chromatogr the natural amidin (70 mg, 0.14 mmol) 404 was mixed with EtOH (2 mg) and 1N aqueous NaOH (0,57 ml). The reaction stirred at room temperature overnight (16 h) and padillas HOAc (1 ml). This product is concentrated to the anhydrous state, then was purified by chromatography (SiO2a 5: 1: 94 v/v MeOH/HOAc/CHCl3). The resulting foam was processed triperoxonane acid (5 ml) and anisole (5 ml) for 60 hours and Then the reaction was concentrated to an anhydrous state, giving 25 mg of compound 405 in the form of dry residue.

Example 106

Getting connection 410:

< / BR>
Step A:

In dried over a flame flask was added Diisopropylamine (of 3.85 ml, 27,45 mmol) and anhydrous THF (20 ml, distilled from CaH). The mixture was mixed under nitrogen atmosphere and cooled to -78oC. To this solution was added n-BuLi so that the solution temperature did not rise above -70oC. In a separate dried over a flame flask was added 2-thiophenecarbonitrile (2.0 g, and 18.3 mmol) and anhydrous THF (20 ml). The solution was cooled to -78oC and stirred under nitrogen atmosphere for 15 minutes a Solution of 2-thiophenecarbonitrile then transferred using a hollow needle into a solution of LDA, and the reaction mixture stirred for another 1 h at -78oC. When the solution had reached room temp is in KOH (100 ml, 0.01 M) and were washed EtOAC (2 x 75 ml). The aqueous layer was then pagkilala to pH=2 with concentrated HCl and saturated NaCl. The product was extracted with EtOAc (4x100 ml) and the combined organic extracts were concentrated in vacuum. The precipitate was purified by column chromatography on silica gel 60 (230-400 mesh mesh) with leaching the product with 20% MeOH in CHCl3(2% v/v acetic acid). Appropriate fractions were combined and concentrated in vacuo, giving 760 mg (27%) of compound 407 in the form of reddish-brown dry residue.

Step B:

To connect 407 (260 mg, 1.7 mmol) was added to compound 98 (420 mg, 1.7 mmol), EDCI (520 mg, of 2.72 mmol), 4-DMAP (catalytic amount) and CH2Cl2(6 ml). The mixture is stirred at room temperature for 12 h and then was diluted EtOAc (40 ml) and the organic portion was washed with HCl (40 ml, 0.1 M), NaOH (40 ml, 0.1 M) and H2O (40 ml). Then the organic layer was concentrated in vacuo and the resulting residue was purified by column chromatography on silica gel 60 (230-400 mesh mesh) with leaching the product with 10% THF in CHCl3. Appropriate fractions were combined and concentrated in vacuo, yielding 200 mg (31%) of compound 408 in the form of reddish-brown dry residue.

The step is of 6 (example 1, part E).

Step D:

Amidin 409 was transformed into a fully deprotection connection 410 using the General procedure described for connection 130 (example 33, part E).

1H NMR (300 MHz, CD3OD) 2,02 (m, 1H), and 2.26 (m, 1H), 2,48 (dd, J=6,4, a 10.1 Hz, 1H), 2,86 (dd, J=5,7 and 10.7 Hz, 1H), 3,11 (m, 3H), 7,63 (dd, J=2, and 6.6 Hz, 1H), 7,76 (bs, 1H), 7,95 (m, 2H), 8,03 (d, J=4,1 Hz, 1H, 2H); IR (KBr) 3322, 3096, 1667, 1585, 1537, 1502, 1425, 1384, 1342, 1284, 1267 cm-1; MS (FAB) m/e 372,2; tPL205-208 (dec).

Analysis for C20H18N3O6F3S. Calculation: C 49,48; H 3,74; N 8,66. Found: C 49,45; H 3,76; N 8,44.

Testing methods.

Identification of compounds which are active inhibitors trombotsitnoy adhesion (ETS), is possible by using the observation that compounds that block the binding of fibrinogen to glycoprotein complex IIb-IIIa in the laboratory, is also able to inhibit initiated by thrombin or ADP adhesion of human platelets and thrombus formation in vivo. This observation provides the basis for efficient ETS by assessing the ability of the test materials to disrupt the interaction of fibrinogen-glycoprotein IIb-IIIa.

The following testing methods were used to evaluate compounds for this image is S="ptx2">

11 - Test ELISA IIb-IIIa:

In the following test glycoprotein IIb-IIIa is prepared in purified form by using a method such as, for example, described in Fitzgerald L. A. et al. Anal. Biochem. (1985) 151:169-177 (consideration of which is included here by reference). Glycoprotein IIb-IIIa is applied to microtitre plate. Coated carrier is then in contact with the fibrinogen and the test material (e.g., compounds according to formula (I) and held for sufficient time to place the maximum binding of fibrinogen to the immobilized glycoprotein IIb-IIIa. Fibrinogen is usually provided with a concentration of approximately 5-50 nm, and the test material may optionally be added to the dilution. Normal aging time ranges from 2 to 4 h at 25oC, time and temperature are interdependent.

After keeping the solution containing fibrinogen and the test material is removed, and the level of binding of fibrinogen is measured by counting associated with the glycoprotein IIb-IIIa fibrinogen. Can be any suitable means of fixation, however, is traditionally used labeled fibrinogen, for example, using biotinylated labels. Such ways is shelled receptor trombotsitnoy glycoprotein IIb-IIIa were prepared so that as described in Fitzgerald L. A. et al., Anal. Biochem. (1985) 151:169-177 (1985). Vitronektinove receptor was prepared as described in Smith, J. W. J. Biol. Chem (1988) 263:18726-18731. After cleaning, the receptors were placed in 0.1% Triton X-100 at a concentration of 0.1-1.0 mg/ml

Receptors were applied to the cells in 96-cell ELISA plates with flat bottom (microcarpa Linbro plate EIA-Plus, Flow Laboratories) after dilution 1: 2000 solution of 20 mm Tris-HCl, 150 mm NaCl, 1 mm CaCl2, pH=7,4 to reduce the concentration of Triton X-100 to below its critical micellar concentration and add 100 ul to each cell. Then cells were stored overnight at 4oC, and then wisesales until dry. Additional active sites were blocked by adding bovine serum albumin (ABS) at a concentration of 35 mg/ml in buffer for 2 h at 30oC to prevent nonspecific binding. Then cells were washed with binding buffer (50 nm Tris-HCl, 100 mm NaCl, 2 mm CaCl21 mg/ml anti-lock brakes).

The corresponding ligands (fibrinogen, factor von Willebrand's disease, or vitronectin) were combined with Biotin using commercially available reagents and standard protocols. Labeled ligands were added in covered receptors in the absence of the test samples. After incubation, cells were wisesales until dry, and bound ligand was calculated.

Bound protein was fixed by adding antibiotin antibodies coupled to alkaline phosphatase, followed by the addition of substrate (p-nitrophenyl-phosphate) and determining the optical density of each cell at 405 nm. Reduced color was observed in the cells of the aged with the test samples, which inhibit the binding of ligand to the receptor.

12 - study of the adhesion of platelets.

In addition to the previously described study ELISA IIb-IIIa, a study of the adhesion of human PRP/ADP useful in assessing therapeutic compounds.

Platelet-rich plasma was prepared from blood of healthy donors-people for use in determining the suppression of the compounds clumping of platelets. Blood was collected through a 21-dimensional overlapping hollow needle using the double injection into 1/10 volume of 3.8% tinatawag citrate.

Platelet-rich plasma was prepared at room temperature by centrifugation tarirovannoj whole blood at 100 x g for 12 minutes platelet-Rich plasmas is the centrifugation tarirovannoj whole blood at 12000 x g for 2 minutes

Adhesion of platelets was investigated in a 4-channel device clumping of platelets (PAP-and, Biodata, Hatboro, PA) according to the manufacturer's instructions. Inhibition of adhesion of platelets was studied by adding various amounts of adenosine diphosphate (ADP) to stir the human platelet-rich plasma. Human platelet-rich plasma was stored with the test compound for 1 min at 37oC before the addition of various aggregating agents, often ADP 5 μm, but also and 1 μg/ml collagen, 1 μm U46619 and 0.3 μm activating factor platelet.

Table of survey results

Example1ELISA IIb-IIIa

Adhesion: the human PRP/ADP

[see table at the end of the description]

Note: NT = not tested.

Pharmaceutical compositions

Pharmaceutical compositions containing compounds of the present invention can be applied orally in the form of tablets, capsules, solutions, emulsions or suspensions, inhalation of liquid or solid particles, in the form of a spray, through the skin by means of such devices as percutaneous patch (as, for example, described in U.S. patents15296222 and 5271940, the consideration of which is included here by reference) illmer, formula Xd, Xe) is partially well-suited for use by skin absorption and delivery systems. The reception can also be parenterally, for example, in the form of injection solutions.

Tablets are prepared by mixing the active ingredient (active ingredient is one or more compounds of the present invention from those which correspond to formula I, II, Xd or Xe) with pharmaceutically inert, inorganic or organic carriers, diluents and/or excipients. Examples of fillers that can be used for tablets are lactose, corn starch or its derivatives, talc, stearic acid or its salts. Examples of suitable excipients for soft gelatin capsules are vegetable oils, waxes, fats, semi-solid or liquid polyols.

Suitable fillers for the preparation of solutions and syrups are water, polyols, saccharose, invert sugar and glucose.

Suitable excipients for injection solutions are water, alcohols, polyols, glycerol and vegetable oils.

These pharmaceutical products may additionally contain preservatives, solvents, Ryuusei agents and antioxidants.

The pharmaceutical compositions according to this invention for parenteral injection contain pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for obtaining sterile injectable solutions or dispersions prior to use.

The active ingredient can also be in the form of microcapsules.

Examples of formulations with the active ingredient are described below:

Part 1

Hard gelatin capsules are prepared using the following ingredients: - (mg/capsule)

Active ingredient - 250,0

Starch - 305,0

Magnesium stearate - 5,0

The above ingredients are mixed and filled in hard gelatin capsules of 560 mg.

Part 2

Tablets are prepared using the following ingredients: - (mg/tablet)

Active ingredient - 250,0

Microcrystalline cellulose - 400,0

Colloidal silicon dioxide - 10,0

Stearic acid - 5,0

The components are mixed and compressed into tablets each weighing 665 mg

Part 3

Dry inhalation powder is prepared from the following components: - wt.%

Active inhalation device.

Part 4

Tablets, each containing 60 mg of active ingredient, are prepared as follows: - (mg)

Active ingredient - 60,0

Starch - 45,0

Microcrystalline cellulose - 35,0

Polyvinylpyrrolidone (as 10% solution in water) - 4,0

Sodium carboximetilkrahmal - 4,5

Magnesium stearate and 0.5

Talc - 1,0

Total - 150,0

The active ingredient, starch and cellulose were passed through a mesh filter120 mesh U.S. and thoroughly mixed. The solution of polyvinylpyrrolidone is mixed with the obtained powders which are then passed through a filter mesh 16 mesh US. Formed pellets were dehydrated at 50-60oC and passed through a filter mesh 16 mesh US. Sodium carboximetilkrahmal, magnesium stearate and talc, previously passed through the strainer 30 mesh U.S., then added to the granules which, after mixing were compacted in teletrauma machine into tablets each weighing 150 mg

Part 5

Capsules, each containing 80 mg of the drug, were prepared as follows: - (mg)

Active ingredient - 80,0

Starch - 109,0

Magnesium stearate - 1,0

Total - 190,0

The active ingredient, cellsa hard gelatin capsules of 190 mg.

Part 6

Candles, each containing 225 mg of active ingredient, are prepared as follows:

Active ingredient - 225 mg

Saturated glycerides of fatty acids - Up to 2000 mg

The active ingredient is passed through the filter mesh 60 mesh U.S. and suspendered in saturated glycerides of fatty acids, pre-melted minimum required amount of heat. The mixture is then poured into candle form nominal amount of 2.0 g and cooled.

Part 7

Suspensions, each containing 50 mg of drug per dose of 5.0 ml, prepared as follows:

Active ingredient - 50,0

Xanthan gum - 4,0

Sodium-carboxymethylcellulose - (11%)

Microcrystalline cellulose (89%) - 50.0 mg

Sucrose is 1.75 grams

Sodium benzoate 10.0 mg

Flavor - q.v.

Dye - q.v.

Purified water To 5.0 ml

Medication, sucrose and xanthan gum are blended, are passed through the strainer 10 mesh U.S., and then mixed with the previously prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose in water. Sodium benzoate, flavoring and dye diluted small kolicevo volume.

Part 8

Capsules, each containing 150 mg of the drug, are prepared as follows: - (mg)

Active ingredient - 150,0

Starch - 407,0

Magnesium stearate - 3,0

Total - 560, 0m

The active ingredient, cellulose, starch and magnesium stearate are blended, are passed through the strainer 20 mesh U.S., and the mixture was filled in hard gelatin capsules with a volume of 560 mg.

Method of application

The present invention provides a method for prevention or treatment of thrombosis in mammals, particularly in humans. The method comprises the administration to a human or mammal a therapeutically effective amount of the compounds of the present invention. Inhibitors of adhesion of platelets according to the invention is therapeutically useful to prevent the formation of thrombus. Such treatment is indicated, in particular (but is not limited to this list), atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic unstable angina, transient ischemic attacks, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and/or thrombosis with subsequent angioplasty, carotid endarterectomy, anastomosis of vascular tissues Gstrict circulation"). These syndromes are various associated with narrowing and blockage of vascular disorders, which presumably triggered by the activation of platelets on the vessel walls.

ETS can be used to prevent or stop the formation of blood clot in unstable angina and arterial embolization or thrombosis, as well as in the treatment or prevention of myocardial infarction (mi) and education parietal thrombus after THEM. Disorders associated with the brain, perhaps the treatment or prevention of transient ischemic attacks and treatment trombulak attacks or developing seizures.

ETS can also be used to prevent clumping of platelets, embolization or fading when unorganized circulation patterns, including improvement of renal dialysis, cardiopulmonary contours, hemoperfusion and plazmofereza.

TIS prevents the adhesion of platelets, embolization or losses associated with intravascular devices, and taking them results in a better use intraaortic balloon pumps, ventricular assistive devices and arterial catheters.

ETS will also be floor is sung Vena cava, thrombosis of the renal vein or the portal vein and thrombosis pulmonary veins.

Also amenable to the treatment of various disorders caused by fading of platelets, such as thrombotic thrombocytopenic purpura.

In addition, the ETS according to the present invention can be used in numerous non-therapeutic applications where it is desirable to suppress adhesion of platelets. For example, can be achieved by improved storage of platelets and whole blood by adding significant amounts of connections, the number of which will vary depending on the intended storage time, storage conditions, end-use of the stored material, etc.

Preferred compounds according to the present invention in the form of pharmaceutical compositions. Thus, the compounds of the present invention can be administered orally, parenterally, topicaine, rectal, and so on, in the desired unit dosage.

Used here, the term "parenteral" refers without limitation, subcutaneous, intravenous, intra-arterial input by injection or infusion. The term "topicaine" refers to input and rectal, by inhalation spray, as well as more General ways of entering through efticiency the compositions of the present invention may be varied so to enter such a number of active compounds (compounds), which is effective to achieve the desired therapeutic response in the individual patient.

The selected dosage level will depend on the activity of specific compounds of path I, the severity of treatable diseases, as well as the status and history of the disease treated patient. However, the prior art it is known that the initial dose of the connection must be less than that required to achieve the desired therapeutic effect, and then the dose is gradually increased until, until the desired effect is not achieved. Optionally, the effective daily dose may be divided into multiple doses for purposes of simplicity of the technique, for example, from two to four separate doses per day. It is clear, however, that the specific dose level for any particular patient will depend on many factors, including body weight, General health, diet, time and input method, combinations with other drugs and the severity treatable disease.

The range of therapeutic dosages of from about 0.01 to about 10,000 mg/day, preferably from 1 to 300 mg/day.

Many modifications and changes to this izobilnyi execution options offered only as examples, and the invention is limited only by the terms of the attached claims.

1. Bicyclic compound having a nucleus formed from two condensed six-membered rings, a and b, represented by formula I, or a pharmaceutically acceptable salt, MES or proletarienne derivative of this connection:

< / BR>
where the bicyclic nucleus of the rings a and b is selected from the group consisting of formulas (17) - (21)

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
R3is an acidic group containing an acid radical selected from the formulas

< / BR>
< / BR>
< / BR>
< / BR>
n = 0 - 6;

R0is the same or different and are selected independently from hydrogen, alkyl,

the linking group -(L)- is a bond or is selected from formulas

< / BR>
Q is the primary group and is selected from amidinopropane and piperidine.

2. Connection on p. 1, represented by formula I (f

< / BR>
3. Connection on p. 1, represented by formula Ig

< / BR>
4. Connection on p. 1, represented by formula Ih

< / BR>
5. Connection on p. 1, represented by formula Ii:

< / BR>
6. Connection on p. 1, in which the acid radical of the acid group, R3that represents a group

< / BR>
7. Connection p. the torus Q contains a basic moiety, choose from amidinopropane and piperidyl.

9. Connection on p. 1, in which the linking group - (L)- is selected from the groups represented by formulas

< / BR>
< / BR>
10. Bicyclic compound or its pharmaceutically acceptable salt, MES or proletarienne derivative, having a core formed of two condensed six-membered rings selected from formula Iaf, Iag and Iah

< / BR>
< / BR>
< / BR>
where R3is an acidic group containing an acid radical selected from the formulas

< / BR>
< / BR>
< / BR>
< / BR>
n = 0 - 6;

R0is the same or different and are selected independently from hydrogen, alkyl,

t = 0 - 3;

R20is the same or different and independently selected from hydrogen, halogen free;

the linking group -(L) - is a bond or is selected from formulas

< / BR>
< / BR>
D is phenyl or thiophene;

Q1- basic moiety and is selected from amidino and guanidino.

11. Connection on p. 10, in which ring D is selected from phenyl and thiophene.

12. Connection on p. 10, in which Q1is selected from amidino and guanidino.

13. Connection on p. 10, in which R20is chlorine or fluorine, and t = 1 or 2.

14. Co20, R0, R3, p, n and L as defined in paragraph 10.

15. Compound selected from the group consisting of compounds represented by the following formulae VIII - IX or a pharmaceutically acceptable salt, MES or proletarienne derivative of this connection:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or any mixture of the compounds (VIII - IX).

16. The pharmaceutical composition of suppressing adhesion of platelets containing bicyclic compounds on PP.1 - 15 effective amount, carrier or diluent.

17. Bicyclic compound on PP.1 - 15 or its pharmaceutically acceptable salt that is used to atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and subsequent angioplasty, carotid endarterectomy and anastomosis of vascular tissues.

18. A method of inhibiting the binding of fibrinogen on the active centers of glycoprotein IIb-IIIa in a mammal including man, by introducing at least one connection on p. 1 effective is consistent of the two condensed six-membered rings, A and b represented by the formula Xd

< / BR>
where a1AND2AND3AND4are carbon atoms;

B1B2B4are selected independently from carbon atoms, oxygen;

IN3independently selected from carbon atoms or nitrogen, provided that IN3unfilled communication, if IN3is nitrogen, provided that at least two of the atoms IN1IN2IN3IN4are carbon atoms;

n = 0 - 6;

R0is the same or different and are selected independently from hydrogen, alkyl,

the linking group -(L)-is a bond or is selected from formulas

< / BR>
< / BR>
Q2the main group and is selected from amidinopropane and piperidyl,

R13acid group-containing acid or a radical selected from the formulas

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
or1-C4ester acid radical.

20. Proletarienne derived bicyclic compounds selected from the group consisting of compounds represented by formulas Xg, Xh, Xi, Xk, Xl

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R = -OMe, -OEt, -OPr;

R15= Me, Et, Pr.

21. Proletarienne derived bicyclic Conn>where R = -OMe, -OEt, -OPr;

R15= -Me, Et, Pr.

22. The pharmaceutical composition of suppressing adhesion of platelets containing bicyclic connection on p. 19 in an effective amount, carrier or diluent.

23. The method of suppressing the adhesion of platelets in a mammal by introducing a bicyclic compounds on p. 1 or 19 in an effective amount.

24. A method of inhibiting the binding of fibrinogen by probing the active sites of the glycoprotein IIb-IIIa with a compound under item 1 or 19.

25. A method of inhibiting the binding of fibrinogen on the active centers of glycoprotein IIb-IIIa in a mammal, including man, by introducing at least one connection on p. 19 in an effective amount for atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, transient ischemic attacks, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis and subsequent angioplasty, carotid endarterectomy and anastomosis of vascular tissues.

 

Same patents:

-alaninemia and their derivatives, method for the treatment glycolipoprotein diseases, the prevention of ischemic myocardial damage, the pharmaceutical composition" target="_blank">

The invention relates to derivatives of indole-2-carboxamide that can be used as inhibitors of glycogen phosphorylase, and to methods of treatment of glycogenolysis-dependent diseases or conditions using these compounds and pharmaceutical compositions containing these compounds

The invention relates to new derivatives of chromone General formula 1, in which ring a is unsubstituted or one-deputizing halogen, and where the ring is unsubstituted or substituted by one to four substituents selected from the group consisting of lower alkyl, hydroxyl, lower alkoxyl, lower alkylthio or halogen, and their salts, also describes a method of production thereof and pharmaceutical composition based on compounds of the formula I, which has antagonistic activity against neirokinina 1

The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives

Herbicide // 2070798
The invention relates to chemical herbicides used in agriculture, in particular the use of 6-amino-benzodioxan-1,4 as a herbicide

The invention relates to a new derivative of hydrazine, which can be used as a pesticide on rice field, upland field, fruit garden in the woods or where hygiene environment

The invention relates to non-steroidal anti-inflammatory drugs, particularly to substituted dihydrobenzofuran and related compounds

The invention relates to new derivatives of amino(thio)ethers of the formula I

< / BR>
where X represents oxygen, sulfur, sulfinil, sulfonyl or, if R0and R1together are not alkalinous chain with 1 to 3 atoms, CH2:

Z represents -(CH2)n1-(CHA)n2-(CH2)n3and

n1 = 0, 1, 2 or 3,

n2 = 0 or 1,

n3 = 0, 1, 3 or 3, provided that

n1 + n2 + n3 < 4;

R0represents hydrogen or A;

R1represents hydrogen, A, OA, phenoxy, Ph, OH, F, Cl, Br, CN, CF3, COOH, COOA, acyloxy with 1-4 carbon atoms, carboxamido, -CHNH2, -CH2NHA, -CH2NA2,

-CH2NHAc, -CH2NHSO2CH3,

or

R0and R1together represent alkylenes chain with 1 to 3 carbon atoms or alkenylamine chain with 2 to 3 carbon atoms;

R2represents hydrogen, A, Ac, or-CH2-R4;

R3represents-CH2-R4or-CHA-R4;

R4is a Ph, 2-, 3 - or 4-pyridyl (unsubstituted or monosubstituted R5) or thiophene (unsubstituted, mono - or disubstituted by A, OA, OH, F, Cl, Br, CN and/or CF3or the other what it is, di-, tri-, Tetra-, or pentamidine F, CF3partially or fully fluorinated A, A and/or OA;

R6, R7, R8and R9each independently represents H, A, OA, phenoxy, OH, F, Cl, Br, I, CN, CF3, NO2, NH2, NHA, NA2, Ac, Ph, cycloalkyl c 3-7 carbon atoms, -CH2NH2, -CH2NHA, -CH2NA2, -CH2N HAC or-CH2NHSO2CH3or two coming together constitute the remainder alkylenes chain with 3-4 carbon atoms, and/or R1and R6together predstavljaet a chain with 3 or 4 carbon atoms;

A represents alkyl with 1-6 carbon atoms;

Ac is alkanoyl with 1-10 carbon atoms or aroyl with 7 to 11 carbon atoms;

Ph represents phenyl (unsubstituted or substituted R5, 2-, 3 - or 4-pyridium or phenoxyl group);

and physiologically acceptable salts, their derivatives
Up!