Amides, pharmaceutical composition, methods of reducing the secretion of apolipoprotein b, the connection

 

(57) Abstract:

Describes amides of the formula I

< / BR>
where X represents CH2, CO, CS or SO2Y is selected from: a direct link, aliphatic hydrocarbonrich radicals containing up to 20 carbon atoms, which may be monogamist hydroxy; and (C1-C10)alkoxy, (C1-C10)acyl, (C1-C10)acyloxy or (C6-C10)aryl, NH and O, provided that when X represents CH2Y denotes a direct bond, Z is selected from the following groups: (1) H, halogen, cyano, (2) hydroxy, (C1-C10)alkoxy, (C1-C10)alkylthio, (C1-C10)acyl, thiophenecarbonitrile, (C1-C10)alkoxycarbonyl, (3) di(C1-C10)alkylamino, (C6-C10)aryl(C1-C10)alkylamino, provided that Y cannot be O or NH, (4) unsubstituted vinyl, (C6-C10)aryl, (C3-C8)cycloalkyl and their condensed mesoprosopic, (C7-C10)politically, (C4-C8)cycloalkenyl, (C7-C10)politicologie, (5) (C6-C10)aaltio, (C6-C10)aryl(C1-C10)alkoxy,

(C6-C10)aryl(C1-C10)and from the group containing monocyclic radicals and condensed polycyclic radicals, where these radicals contain from 5 to 10 ring atoms, where these radicals contain from 1 to 4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and where the individual rings of the mentioned radicals may be independently saturated, partially saturated or aromatic, provided that, if X denotes CH2Z represents H or is selected from groups (4) and (6), where, when Z contains one or more rings, these rings may each independently have from 0 to 4 substituents independently chosen from halogen, hydroxy, cyano, nitro, oxo, thioxo, aminosulfonyl, phenyl, phenoxy, phenylthio, halogenfrei, benzyl, benzyloxy, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino, di(C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino(C1-C10)alkoxy, (C1-C3)perfluoroalkyl, (C1-C10)acyl, (C1-C10)acyloxy, (C1-C10)acyloxy(C1-C10)alkyl and pyrrolidinyl, and its pharmaceutically debate of such conditions, as atherosclerosis. 5 C. and 32 C.p. f-crystals, 1 table.

The technical field to which the invention relates

The present invention relates to compounds that are inhibitors of microsomal protein transport triglycerides and/or secretion of apolipoprotein b (APO b) and which accordingly can be used for the prevention and treatment of atherosclerosis and its clinical consequences, to reduce the level of lipids in blood serum, as well as for prevention and treatment of related diseases. In addition, the present invention relates to compositions containing compounds used for the treatment of atherosclerosis, obesity and related diseases and/or conditions, as well as to methods of their use.

Background of the invention

Microsomal protein transport triglycerides (MTB) catalyzes the transfer of triglyceride, cholesterol ester and phospholipids. It is considered as a possible agent involved in the process of unification of APO B-containing lipoproteins - biomolecules responsible for the formation of atherosclerotic plaques. Cm. the publication of the application for the European Patent N 0643057 A1, publication on the application for a European Patent N 0584446 A2 and Wetterau with the use in the treatment of atherosclerosis, Such compounds are also applicable in the treatment of other diseases and conditions in which through inhibition of MTB and/or secretion of APO b In the serum can be lowered cholesterol and triglycerides. Such conditions include hypercholesterolemia, hypertriglyceridemia, pancreatitis and obesity, and hypercholesterolemia, hypertriglyceridemia and hyperlipidemia associated with pancreatitis, obesity and diabetes.

Summary of the invention

The invention relates to compounds of formula I:

< / BR>
where X represents CH2, CO, CS or SO2,

Y is selected from:

direct connection (i.e., covalent bonds),

aliphatic hydrocarbonrich radicals containing up to 20 carbon atoms, this radical may be mono-substituted by hydroxy, (C1-C10)alkoxy, (C1-C10)acyl, (C1-C10)acyloxy or (C6-C10)aryl,

NH and O,

provided that when X represents CH2then Y represents a direct link,

Z is selected from the following groups:

(1) H, halogen, cyano,

(2) hydroxy, (C1-C10)alkoxy, (C1-C10)alkylthio, (C1-C10)acyl, thiophenecarbonitrile, (C1-C10)alkoxy is 1-C10)alkylamino, provided that Y cannot be O or NH,

(4) unsubstituted vinyl, (C6-C10)aryl, (C3-C8) cycloalkyl and condensed besprovodnyh, (C7-C10)politically, (C4-C8)cycloalkenyl, (C7-C10)politicologie,

(5) (C6-C10)aryloxy, (C6-C10) aaltio, (C6-C10)aryl (C1-C10)alkoxy, (C6-C10)aryl (C1-C10)alkylthio, (C3-C8)cycloalkane, (C4-C8)cycloalkenyl,

(6) heterocyclyl selected from the group consisting of monocyclic radicals and condensed polycyclic radicals, where these radicals contain from 5 to 14 ring atoms, where these radicals contain from 1 to 4 heteroatoms selected independently from oxygen, nitrogen and sulfur, and where the individual rings of the mentioned radicals may be independently saturated, partially saturated or aromatic,

provided that if X is CH2Z represents H or is selected from groups (4) and (6),

where, when Z contains one or more rings, these rings may each independently contain from 0 to 4 substituents independently selected from Halensee, benzyloxy, (C1-C10)alkyl, (C1-C10)alkoxy, (C1-C10)alkoxycarbonyl, (C1-C10)alkylthio, (C1-C10)alkylamino, (C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino, di(C1-C10)alkylaminocarbonyl, di(C1-C10)alkylamino (C1-C10)alkoxy, (C1-C3)perfluoroalkyl, (C1-C3)perforamce, (C1-C10)acyl, (C1-C10)acyloxy, (C1-C10)acyloxy (C1-C10)alkyl and pyrrolidinyl,

and its pharmaceutically acceptable salts.

Link to Z as "heterocyclyl" means any single ring or condensed ring system containing at least one heteroatom in the ring, independently selected from O, N, and S. Thus, a polycyclic condensed ring system containing one or more carbocyclic condensed saturated, partially unsaturated or aromatic rings (usually benzene rings) is included in the definition heterocyclyl, because the system also includes at least one condensed ring which contains at least one of the foregoing heteroatoms. As the EP, benzene) rings or heterocyclic rings.

Link to Z, which contains one or more of the rings" means any (single or condensed) cyclic radical or radicals contained in Z. Ring may be carbocyclic or heterocyclic, saturated or partially saturated and aromatic or not aromatic.

A link to a condensed polycyclic ring system, or a radical implies that all rings in the condensed system.

The reference to "halogen" in the description refers to fluorine, chlorine, bromine and iodine, unless otherwise indicated.

The reference to the Deputy "aryl" (for example, (C6-C10)aryl) implies that the ring or Deputy is carbocyclic. Aromatic radicals which contain 1 or more heteroatoms, included as a subgroup of the term "heterocyclyl" as listed above.

The reference to the Deputy "acyl" refers to an aliphatic or cyclic hydrocarbon radical attached to the carbonyl group through which attached the Deputy.

The reference to "alkyl" and "alkoxy" includes both linear and branched radicals, it should be borne in viduy ("normal") radical, whereas the isomers of branched-chain, such as "isopropyl" or "isopropoxy" are listed separately.

Central benzo-heterocyclic system of the formula I, i.e. a condensed bicyclic ring system, attached via a nitrogen ring-to-XYZ, for convenience, denoted here as 1,2,3,4-tetrahydroisoquinoline while this definition will be used particularly frequently in the case of designations of the compounds of the present invention as a 2-substituted amides 1,2,3,4-tetrahydroisoquinoline-6-yl. It should be noted that somewhat less, in the case of designation of a Deputy in connection specified Central ring system can be called as 6-substituted part of the 3,4-dihydro-1H-isoquinoline-2-yl.

Defined above subgroup of compounds of formula I include those in which:

X denotes CH2, CO or SO2,

Y is selected from:

direct communications, NH,

(C1-C10)alkylene and (C2-C10)Alcanena, each of which may be substituted by phenyl,

provided that if X is CH2Y represents a direct link,

Z is selected from the following groups:

(1) H,

(2) (C1-C10)alkoxy, (C1-C10)alkylthio,

(3) (C1-Cis slowiy, that Y is not NH,

(4) unsubstituted vinyl, (C6-C10)aryl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl,

(5) (C6-C10)aryloxy,

(6) heterocyclyl selected from the group containing five - and six-membered heterocyclic radicals, which may be saturated, partially unsaturated or aromatic, and their condensed besprovodnye, where these radicals may contain from 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulfur,

provided that if X is CH2Z is selected from groups (4) and (6),

where, when Z contains one or more rings, these rings may each independently have from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, di(C1-C6)alkylaminocarbonyl, (C1-C3)perforamce, (C1-C10)acyl and (C1-C10)acyloxy,

and their pharmaceutically acceptable salts.

A more specific subgroup includes those compounds of the above subgroups, where X denotes methylene, Y is a direct bond and Z is selected from (C6-C10)aryl, (C3-C8)cycloalkyl and (C4-Casanoi subgroup, unsubstituted vinyl, and their pharmaceutically acceptable salts. Specific values for each illustrative values are given next.

Another more specific subgroup includes those compounds of the above subgroups, where X denotes methylene or CO, Y is a direct bond, and Z is heterocyclyl selected from thiophenyl, pyrrolidinyl, pyrrolyl, furanyl, thiazolyl, isoxazolyl, imidazolyl, 1,2,4-triazolyl, pyridyl, pyrimidinyl and their condensed bicyclic (ortho) besprovodnyh, including benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophene, benzothiazole, chinoline, ethenolysis and hintline, each of which can have from 0 to 3 independent substituents listed for Z in the above subgroup, and their pharmaceutically acceptable salts.

Particular values of Z as heterocyclyl, which can carry 0-3 independent substituents specified for Z in the above sub-group include 2 - and 3-thiophenyl, 2 - and 3-benzo[b]thiophenyl, 1-, 2 - and 4-imidazolyl, 2-benzimidazolyl, 2-, 4 - and 5-thiazolyl, 2-benzothiazolyl, 3-, 4 - and 5-isoxazolyl, 2-honokalani, 1-, 2 - and 3-pyrrolidinyl, 2-, 3 - and 4-pyridyl, 2 - and 4-pyrimidinyl, 2-, 3 - and 4-chinoline, 1-, 3 - and 4-isoquinoline, 1-, 2 - and 3-indolyl, 1-, 2 - and 3-isoindolyl, 2 - and 3-tx2">

A preferred group of compounds includes compounds where:

X denotes CH2or CO

Y represents a direct link,

Z denotes

H, unsubstituted vinyl, phenyl, imidazolyl, thiazolyl, thiophenyl, 1,2,4-triazolyl, pyridinyl and pyrimidinyl, each of which can have from 0 to 3 independent substituents described above for the above subgroups,

and their pharmaceutically acceptable salts. Specific values of Z (as heterocyclyl) for this preferred groups include specific values stated above.

Within the above preferred group, subgroup includes those compounds where X denotes CO.

The second sub-group within the above preferred group includes the compounds where X is CH2.

In addition, the invention relates to pharmaceutical compositions suitable for treating conditions including atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, and diabetes, containing the compound of formula I, as defined above, and pharmaceutically acceptable carrier.

Compounds of the present invention inhibit or reduce the secretion And the mechanisms. The compounds are useful in all diseases or conditions in which increased levels of APO B, serum cholesterol and/or triglycerides. In accordance with this invention also relates to a method of treatment of a condition, such as atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, and diabetes, which is the introduction to a mammal, especially a human, in need of such treatment, the compounds of the above formula I in a quantity sufficient to reduce the secretion of apolipoprotein Century Subgroup of the above-mentioned conditions include atherosclerosis, obesity, pancreatitis, and diabetes. A more specific subgroup includes atherosclerosis.

The term "treatment" in the context of the present description applies to preventive treatment and treatment aimed at the weakening of pre-existing conditions.

Further, the present invention relates to a method of reducing the secretion of APO In mammals, especially in humans, which includes the introduction of the specified mammal reduce APO B (secretion) of the amount of the compounds of formula I, above.

Some of the intermediate compounds are also proposed as characteristic isotoxin-ethyl)-4-hydroxymethylene] - amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

2-(2-hydroxymethyl-5-nitro-phenyl) -ethanol,

tert-butyl ester 6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 6-amino-3,4-dihydro-1H-isoquinoline-2 - carboxylic acid and

2-(5-amino-2-hydroxymethyl-phenyl)-ethanol.

The average person skilled in the art it is clear that some of the compounds of formula I are asymmetrically substituted carbon atom, and accordingly may exist and be isolated in optically active and racemic forms. Some compounds can have polymorphism. It must be considered that the present invention encompasses any racemic, optically active, polymorphic or stereoisomeric form, or mixtures thereof, which possess the properties used in the treatment of atherosclerosis, obesity and other mentioned in the present description States, with well-known methods for producing optically active forms (for example, by separation of the racemic form by recrystallization, by synthesis from optically active source product, chiral synthesis, or by chromatographic separation using a chiral stationary phase) and how to determine effective Any chemist understands some combinations of substituents or radicals listed in the invention are compounds that are less stable under physiological conditions (for example, compounds containing analnye or acetaline communication). Accordingly, such compounds are less preferred.

"Aliphatic hydrocarbononly radical" in the context of the present description means a divalent organic radical with an open circuit that contains only carbon and hydrogen. The specified radical is a linking group, designated as Y. the Radical may be linear or branched and/or saturated or unsaturated, containing up to three unsaturated bonds, double, or triple, or a mixture of double and triple bonds. Both valencies can be on different carbon atoms or on the same carbon atom, and therefore the term "alkylidene" refers to this definition. Typically, the radical is classified as a (C1-C20) alkalinity radical, (C2-C20)alkenylamine radical or (C2-C20)alkynylaryl radical. Typically, the radical will contain 1-10 carbon atoms, although it is possible more long chains, which are also included in the scope of the present isobela 1-20, preferably 1-10, carbon atoms obtained by removing two hydrogen atoms from the corresponding saturated acyclic hydrocarbon. Examples of compounds containing 1-10 carbon atoms include linear-chain radicals of the formula (CH2)nwhere n takes values from 1 to 10, such as methylene dimetilan, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptameron, octamethylene, nonmotile, etc. are also Included alkylidene radicals, such as ethylidene, propylidene, butylidene and second-butylidene. Also includes isomers of branched-chain, such as 1,1-dimethyltrimethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene and 3.3-dimethylpentylamine.

Alkenylamine radicals include straight or branched radicals having 2 to 20 carbon atoms, preferably 2-10 carbon atoms, which is obtained by removing two hydrogen atoms from the corresponding acyclic hydrocarbon group containing at least one double bond. Examples alkenylamine radicals having one double bond include ethenylene (vinile), propylen, 1-butylen, 2-butylen and isobutylene. Alkenylamine radicals containing two double bonds (sometimes referred to as alkadiene and 2,6-decadiene. Example alkalinous radical containing three double bonds (alkalinity radical) is 9,11,13-heptadecadiene.

Akinleye radicals include straight or branched radicals having 2 to 20 carbon atoms, preferably 2-10 carbon atoms, which is obtained by removing two hydrogen atoms from the corresponding acyclic hydrocarbon group containing at least one triple bond. Examples of such compounds include ethynylene, propylen, 1-Butylin, 1-pentikinen, 1-geksanalem, 2-Butylin, 2-pentikinen, 3,3-dimethyl-1-Butylin etc.

The following are examples of other radicals and substituents listed above, which are not restrictive. It should be borne in mind that, if mentioned cyclic or polycyclic radical, which may be associated with different atoms of the ring, and when it is not specified what that means refers to all possible attachment points regardless of what the atom is carbon or trivalent nitrogen. For example, the reference (unsubstituted) "naphthyl" means the naphthas-1-yl and naphthas-2-yl, the reference to "pyridyl" means 2-, 3 - or 4-pyridyl, the reference to "indolyl means attaching or linking to any of the put and, propoxy, isopropoxy, butoxy, isobutoxy, pentox, hexose, heptose etc.

Examples (C1-C10)alkylthio groups include the corresponding sulfur-containing compounds listed above (C1-C10)alkoxy, which include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, pentylthio, hexylthio, Reptilia group, etc.

Examples (C1-C10)acyl include such values (C1-C10)alkanoyl as formyl, acetyl, propionyl, butyryl and isobutyryl. Also include other conventional cycle-containing radicals, such as benzoyl.

Examples (C1-C10)acyloxy include such values (C1-C10)alkanoyloxy as formyloxy, atomic charges, propionyloxy, butyryloxy, isobutyryloxy. Also includes other conventional cycle-containing radicals, such as benzoyloxy.

Examples (C1-C10) alkoxycarbonyl include methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and isobutoxide.

Examples (C1-C10)alkylamino include methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino.

Examples of di(C1-Oh groups.

Examples (C6-C10)aryl (C1-C10)alkylamino are benzylamino, (1-phenylethyl)amino and (2-phenylethyl)amino.

Examples (C6-C10)aryl include phenyl and naphthyl.

Examples (C3-C8)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Examples fused with benzene derivatives (C3-C8)cycloalkyl include 1,2,3,4-tetrahydronaphthalene, indanyl and fluorenyl.

Examples of politically include substituted and 2-bicyclo [2.2.1]heptyl.

Examples (C4-C8)cycloalkenyl include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.

Examples politicologie include bicyclo [3.1.1]hept-2-enyl.

Examples (C6-C10)aryloxy groups include phenoxy, naphthyloxy group.

Examples (C6-C10)aristeo groups include phenylthio, naphthylthio group.

Examples (C6-C10)aryl (C1-C10)alkoxy groups include benzyloxy, venlafaxi group.

Examples (C6-C10)aryl (C1-C10)alkylthio groups include benzylthio, feniletilic group.

Examples (C3-C8)CEC the si group.

Examples (C4-C8)cycloalkenyl groups include cyclobutenyl, cyclopentyloxy, cyclohexyloxy, cycloheptenyl group.

Examples of heterocyclic substituents, which represents a five-membered monocyclic radicals include furanyl, thiophenyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazole, 1,2,3-triazolyl, 1,3,4-thiadiazoles and 1,2,4-triazol etc.

Examples of heterocyclic substituents, which represents a six-membered monocyclic radicals include 2H - and 4H-pyranyl, pyridyl, piperidinyl, piperazinil, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, thiomorpholine, 1,3,5-triazinyl etc.

Examples of heterocyclic substituents, which represents a condensed besprovodnye membered heterocyclic radicals include indolyl, isoindolyl, indolinyl, benzofuranyl, benzothiophene, benzimidazole, benzthiazole and carbazolyl.

Examples of heterocyclic substituents, which represents a condensed besprovodnye six-membered heterocyclic radicals include chinoline, ethenolysis, hintline, phthalazine, phenothiazinyl, acridines and f is a mini-radicals, different from the above condensed benzene ring systems include purines and pteridines.

Examples (C1-C10)alkyl include methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, pentyl, hexyl, etc.

Examples (C1-C3)perfluoroalkyl include trifluoromethyl, pentafluoroethyl and heptafluoropropyl.

Examples (C1-C3)perforamce groups include triptoreline, pentaborate group.

Compounds of the present invention can be easily subdivided into groups based on a linking group formed by nitrogen 1,2,3,4-tetrahydroisoquinoline ring shown in formula (I), together with the group-XYZ, which connects XYZ radical with the specified nitrogen rings. Such categories include the

< / BR>
< / BR>
As can be seen from the examples of linking groups, in the case of amides and thioamides (X=CO or CS, respectively) Y is preferably a direct link or hydrocarbide. In these compounds, where Y represents a direct bond, connection takes place preferably via a carbonyl or thiocarbonyl group to the aliphatic (i.e., open circuit) the carbon atom in z Specified aliphatic Connection may also preferably be carried out via a carbonyl or thiocarbonyl group, a cyclic carbon atom. Under cyclic nitrogen atom" is understood saturated or unsaturated carbon atom contained in (saturated, partially unsaturated or aromatic) carbocyclic or heterocyclic ring. For compounds where Y is hydrocarbide, the binding is carried out via a carbonyl or thiocarbonyl group to an aliphatic carbon atom in y

For ureas and thioureas, where X=CO or CS, respectively, a Y=NH, linking preferably carried out via the amino group to a cyclic carbon atom in z For some ureas and thioureas (X=CO, Y = direct link) amine nitrogen is part of Z. In this case, the binding is carried out preferably through the remote amino group to an aliphatic carbon atom in the remainder of Z.

For sulfonamides according to the invention X= SO2and Y preferably denotes hydrocarbide or direct connection. For sulfonamides, where Y denotes hydrocarbide, linking through sulfonyloxy group to the aliphatic carbon atom in y For sulfonamides, where Y denotes a direct connection, connection through sulfonyloxy group to the cyclic carbon atom in z For sulforidazine through X directly to the amine nitrogen in Z.

N-alkyla (X=CH2Y = direct link) preferably form a connection through a methylene group to the cyclic carbon atom at z

For carbamates, where X=CO, Y=O, the binding is carried out preferably through oxy (O) part due to the cyclic carbon atom in the remaining part of the z carbamates, where X=CO, Y = direct link, axisbase is part of Z, and in this case, the connection is preferably a cyclic or aliphatic carbon atom in the remaining part of Z, and most preferably to an aliphatic carbon atom in the remainder of Z.

In those compounds of formula I, where Y denotes hydrocarbide, joining Z through an aliphatic carbon atom in Y, preferably for H or a cyclic carbon atom or heteroatom in Z.

The group of compounds listed below and in the Examples section taken on the basis of the above-described structural categories.

Preferred compounds include the following, which, where possible, divided into categories in accordance with the type of binder groups shown above in the diagram partially illustrating its structure.

AMIDES

(2-Pentanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-Cyclobutanecarbonyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(Thiophene-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2 Butyryl-1,2,3,4 - tetrahydroisoquinoline-6-yl)- amide 4'-trifluoromethyl-biphenyl-2 - carboxylic acid,

(2-Ethoxyacetic-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-[(4-Fluoro-phenyl)-acetyl] -1,2,3,4-tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(3-Methyl-butyryl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-but-3-enoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-Methoxyacetyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-Ethylthioethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(6-Diethylcarbamoyl-cyclohex-3-enacarbil) -1,2,3,4-tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(Cyclopent-1-enyl-acetyl)-1,2,3,4-is Koskinen-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(Tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(Thiophene-3-yl-acetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(Pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid.

UREA

Phenylamide 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4 - dihydro-1H-isoquinoline-2-carboxylic acid,

Exiled 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino] -3,4 - dihydro-1H-isoquinoline-2-carboxylic acid,

Benzylated 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H - isoquinoline-2-carboxylic acid,

6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino] -3,4 - dihydro-1H-isoquinoline-2-carboxylic acid [(R)-1-phenyl-ethyl]-amide,

Pyridine-2-alamid 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino] -3,4-dihydro-1H-isoquinoline - 2-carboxylic acid,

SULFONAMIDES

[2-(Propane-2-sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-Dimethylsulphamoyl-1,2,3,4-tetrahydroisoquinoline-6-yl)- amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(2-Triptoreline-benzazolyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-the 3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid

N-ALKYLA

[2-(2,6,6-Trimethyl-cyclohex-2-animetal)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(2,4-Dichlorobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] - amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(1,5 a,6,9,9 a,9b-Hexahydro-4H-dibenzofuran-4A-ylmethyl)- 1,2,3,4-tetrahydroisoquinoline-6-yl]amide 4'-trifluoromethyl-biphenyl-2 - carboxylic acid,

(2-Thiophene-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(1H-Pyrrol-2-ylmethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-furan-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

5-[6-[(4'-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4 - dihydro-1H-isoquinoline-2-ylmethyl]-furan-2-ymetray ether acetic acid,

(2-Thiophene-3-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(2,5-Dimethoxy-tetrahydrofuran-3-ylmethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-Benzyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-Pyridine-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-imide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(3-Chloro-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-Pyrimidine-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)- amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(3-Nitro-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(1H-Imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(1-Methyl-pyrrole-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(1H-Benzimidazole-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-Thiazol-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(1-Methyl-imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[2-(1H-[1,2,4] Triazole-3-ylmethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl] - amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

[(2-Allyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid.

CARBAMATES

Tert-butyl ester 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino] -3,4-dihydro-1H-isoquinoline-2 - carboxylic what-tetrahydroisoquinoline-6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(1-Phenylethyl)-amide 6-[(4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-3,4-dihydro-1H - isoquinoline-2-carboxylic acid,

(2-Pyridine-2-ylmethyl-1,2,3,4 - tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl - biphenyl-2-carboxylic acid,

[2-(1H-Imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline- -6-yl] -amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid,

(2-Thiazol-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl-biphenyl-2-carboxylic acid and

[2-(1H-[1,2,4] Triazole-3-ylmethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl] - amide 4'-trifluoromethyl-biphenyl-2 - carboxylic acid.

Detailed description of the invention

In the description below uses the conventional chemical abbreviations and acronyms; Me (methyl), Et (ethyl), THF (tetrahydrofuran), SIDE (tert-butyloxycarbonyl, a protective group), Ms (methanesulfonyl, mesyl), TFU (triperoxonane acid), Ac (acetyl), RP (treatment phase), GHWR (liquid chromatography high resolution).

The compounds of formula I can be obtained by methods which include well-known in chemistry methods produce similar compounds. Such methods for obtaining the compounds of formula I, above, include the following objects of the invention and illustrated in the following descriptions is correspondingly different. The methods include processing the compounds of formula II

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which gives the left part of the molecule (i.e., radical contained in the formula II with hydrogen removed from tetrahydroisoquinoline ring) reagent, which adds the right (XYZ) part. Reagents capable of supplying the right part, are generally commercially available or are well described in the scientific literature. Compound of formula II is 4'-triptorelin-2-carboxylic acid (1,2,3,4-tetrahydroisoquinoline-6-yl)amide, which for convenience is called in the present description to simply as "compound II". The left part of the molecule, which is included in the compounds of the present invention, represents the radical 6-[(4'-trifluoromethyl)Biden-2 - ylcarbonyl]-3,4-dihydro-1H-isoquinoline-2-yl.

The methods can usually be done:

(a) for compounds of formula I, where X denotes a carbonyl by treatment of compound (II) carboxylic acid of the formula: Z-Y-COOH in the presence of the binding reagent. In a typical case, the binding reagent is carbodiimide, preferably 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, which is known as the EDC (EDC) and may be available commercially. As described in U.S. patent 5416193, the EDC can be easily polymer to be applied heating. The normal duration of the reaction varies from several minutes to 48 hours, usually during the night;

(b) for compounds of formula I, where X denotes a carbonyl or thiocarbonyl, by treating the compound (II) an activated form of the corresponding carboxylic acid or thiocarbonic acid, in the presence of a base. Usually activated form is an acid chloride of the appropriate acid of the formula: Z-Y-COCl or Z-Y-CSCl, respectively. The reason is, for example, amine, which can be easily associated with the polymer to reduce the cleanup procedure, the typical associated base polymer-bound, is morpholinomethyl-polystyrene. The reaction is usually carried out at room temperature under stirring, shaking or using any other form of agitation during the period of time required for the reaction, if not ended, at least was good enough, usually within 2-48 hours, usually during the night.

The compounds obtained as described above in (a) and (b) form a structural types, as indicated earlier, amides and thioamides;

(C) for compounds of formula I, where X denotes a carbonyl or thiocarbonyl, and Y represents NH, by about the Z-N=C=S. The resulting products are compounds of the present invention, which is referred here to the structural type of ureas and thioureas, respectively. The reaction mainly takes place in an inert solvent, usually in a halogenated hydrocarbon such as 1,2-dichloroethane, usually within 2-48 hours, usually during the night;

(g) for compounds of formula I, where X denotes sulfonyl, by treating the compound (II) appropriate sulphonylchloride formula Z-Y-SO2Cl. The product refers to the structural type of sulfonamides. The reaction is usually conducted in an inert solvent such as a halogenated hydrocarbon (for example, 1,2-dichloroethane), at room temperature for several hours or more, usually during the night;

(d) for compounds of formula I where X is CH2and Y is a direct link, by treatment of compound II with an aldehyde of the formula Z-CHO in the presence of triacetoxyborohydride sodium. It is necessary rehabilitation amination, as described Abdel-Magid et al., Tetrahedron Lett., 31 (39), 5595-5598 (1990). The product refers to the structural type N-Akilov. The reaction is carried out in an appropriate solvent such as a halogenated hydrocarbon, n is at room temperature, although if you want to speed up the reaction rate can be applied heating;

(e) for compounds of formula I where X is CH2and Y is a direct link, by treating the compounds of formula III

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the corresponding compound of the formula Z-CH2-NH2in the presence of methylchloride, usually in the amount of two equivalents;

(g) for compounds of formula I, where X denotes thiocarbonyl, by treating the corresponding compounds of formula I, where X denotes CO, pentasulfide P4S10. The reaction can be carried out in a known manner with the use of stoichiometric quantities of P4S10(or excess of it if you want) and heated together with the corresponding amidon in an inert solvent, such as pyridine, xylene, benzene, chlorobenzene or toluene. The reaction is usually carried out at the boiling temperature under reflux over a period of time from several minutes to several hours.

The compound of formula II can be obtained by the method shown in scheme 1, and specifically confirmed in example 1. In accordance with scheme 1, the hydrobromide of 2-(4-bromophenyl)ethylamine interacts with ethyl formate in the presence of a base with poluchenierazreshenija cyclization, then treated with gaseous hydrohalogenation (e.g., HCl) to form hydrohalogenation salt, hydrogenogenic 7-bromo-3,4-dihydroisoquinoline. Hydrohalogenation salt then restore with getting 7-bromo-1,2,3,4-tetrahydroisoquinoline. The recovered product nitrous by treatment with potassium nitrate in concentrated sulfuric acid and produce the appropriate fraction to obtain 7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline. Bronirovannyi product is then subjected to interaction with di-tert-butyl dicarbonate in the presence of a base to protect the nitrogen tetrahydroisoquinoline ring, getting in the tert-butyl ester of 7-bromo-6-nitro-3,4-dihydro-1H - isoquinoline-2-carboxylic acid. Then the ether hydronaut in the presence of palladium-on-calcium carbonate with the formation of the corresponding ester of 6-amino-3,4-dihydro-1H-isoquinoline-2 - carboxylic acid. Then Amin is subjected to the interaction of 4'-trifluoromethyl-biphenyl-2-carboxylic acid with the formation of the tert-butyl ester 6-[(4'-triptorelin-2-carbonyl)amino] - 3,4-dihydro-1H-isoquinoline-2-carboxylic acid. This product may be further subjected to unprotect a known manner to obtain the compound (II), 4'-triptorelin-the et can be obtained with the second method, shown in scheme 2. In accordance with scheme 2 nitrobenzoic acid (1) is treated with diethylmalonate in the presence of a base to form compound (2). Further, the compound (2) can be treated with a water-alcohol base for the implementation of the hydrolysis and decarboxylation to produce in the resulting compound (3). The compound (3) can optionally be treated with acetic anhydride in toluene or other hydrocarbon solvent with getting anhydride (3a). The reduction of compound (3) or (3a) gives the corresponding diol (4), which can be further processed by methylchloride with the formation of dimesylate, who later cyclist using ammonia, obtaining the compound (5). Thereafter, the compound (5) is usually subjected to N-protection with obtaining the compound (6), which, in turn, restore with the formation of the corresponding amine (7). Amin (7) can then be treated with acid chloride 4'-triptorelin-2-carboxylic acid (obtained by treating the corresponding free acid with thionyl chloride) with formation of the corresponding amide analogue (8) of compound II. Compound (8) can be subjected to unprotect the usual way, as shown and discussed in figure 1, in Reema 3, based on the diol (4), first shown in scheme 2. In accordance with the scheme (3) diol (4) recover hydrogen in the presence of a catalyst of platinum-on-coal to obtain the corresponding aminodiol (9). Then aminodiol (9) may be subjected to interaction with the acid chloride of 4'-triptorelin-2 - carboxylic acid to obtain compound III. Compound III may, as shown, then be cyklinowanie ammonia in the presence of a catalyst to obtain compound (II).

As also shown in scheme 3, compound III can also directly interact with the corresponding amine of formula Z-CH2-NH2in the presence of base and catalyst with the formation of the compounds of formula I indicated in scheme 3, where X denotes CH2and Y is a direct link.

For the selection of compounds according to the invention can be used conventional methods and/or methods of purification and separation, known to every person skilled in the art. Such methods include all types of chromatography (IHVR, column chromatography with the use of such widely used adsorbents like silica gel, and thin-layer chromatography, recrystallization and methods differentiated (i.e., liquid-liquid is irginia "pharmaceutically acceptable salt" is intended to define, but not limited to such salts as the hydrochloride, hydrobromide, sulfate, hydrosulfate, phosphate, hydrogen phosphate, dihydrophosphate, acetate, succinate, citrate, methanesulfonate (mesilate) and p-toluensulfonate (toilet). In the case of many compounds can be easily obtained also salt polyaddition.

Salt add acid compounds of the present invention is easily produced by the interaction of the basic forms with the appropriate acid. When salt is a salt monoosnoc acid (e.g. hydrochloride, hydrobromide, p-toluensulfonate, acetate), HYDROFORM dibasic acid (i.e., a hydrosulfate, succinate) or digitiform trehosnovnoy acid (for example, dihydrophosphate, citrate), using at least one molar equivalent, and usually a molar excess acid. However, when you need to get a salt such as sulfate, hemisuccinate, phosphate or phosphate, typically use a precise chemical equivalents of acid. Free base and the acid is usually combined in a co-solvent from which the desired salt precipitates, or alternatively, may be isolated by concentration and/or addition of herstories.

Compounds of the present invention are introduced orally and with whom the service dosed oral forms. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The active compound will be presented in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described below. So for the purposes of oral administration, the compounds can be combined with a suitable solid or liquid carrier or diluent to obtain capsules, tablets, powders, syrups, solutions, suspensions, etc., the Pharmaceutical compositions can, if necessary, contain additional components such as flavors, sweeteners, fillers, etc.

Tablets, pills, capsules, etc. can also include a binder, such as resin tragakant, Arabian gum, corn starch or gelatin; excipients such as dicalcium phosphate, loosening agent, such as corn starch, potato starch, alginic acid, lubricating substance, such as magnesium stearate, sweetening agents such as sucrose, lactose or saccharin. When the dosage unit form is a capsule, it may contain, in addition to the specified visualize as cover, or to physical modification of dosage units. For example, tablets may be coated with dellcom, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetener, as well as methyl - or propylparaben as preservatives, a dye and flavoring such as cherry or orange flavors.

These active compounds may also be introduced parenterally. For the purposes parenterale introduction connections can be combined with sterile aqueous or organic medium to obtain injectable solutions or suspensions. Solutions or suspensions of these active compounds can be obtained in water, mixed appropriately with surface-active substance, such as hydroxypropylcellulose. Can also be obtained dispersion in sesame or peanut oil, ethanol, water, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures, vegetable oils, n-methyl-glucamine, polyvinylpyrrolidone and oil mixtures, as well as in aqueous solutions of water-soluble pharmaceutically acceptable salts of the compounds. For the purposes of normal conditions hraneniya in this way, injectable solutions can then be administered intravenously, intraperitoneally, subcutaneously or intramuscularly.

The pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions or sterile powders for the preparation of the place of sterile injectable solutions or dispersions. In all cases the form must be sterile and have fluidity in such an extent to ensure the ease of its injection. It must be stable under conditions of manufacture and storage and must be protected from contamination by microorganisms, such as bacteria and fungi.

The dose of injected compounds of formula I will typically vary according to factors well known in this field, taking into account the severity of the patient's condition to be treated and the route of administration of the drug. Typically, the compound of formula I will be administered warm-blooded animal (such as man) so that the effective dose, the daily dose, administered in a single dose or divided into parts, ranged from about 0.1 to about 15 mg/kg body weight, preferably from about 1 to about 5 mg/kg of body weight. The total daily dose at the same time, will usually be from 1 to 1000 mg, preferably from 5 to 350 mg. of their agents, including Other means of reducing lipids. These tools include inhibitors of the biosynthesis of cholesterol, in particular inhibitors HM COA reductase and inhibitors of squalene synthetase; substances that increase the secretion of bile acids, fibrates, inhibitors of cholesterol intake, and Niacin.

The analyzed compound is considered active if it is active in any of the following test experiments.

The active compounds according to the invention can be assessed by determining the inhibition of the secretion of APO In Hep2 cells.

Hep2 cells grown in the medium of Dulbecco in the modification of the Needle with the addition of 10% amniotic cow serum /growth environment, Flexible (Gibco)/ 96-alopecia plateau for cultivation in a humidified atmosphere containing 5% carbon dioxide until the merge cells by about 70%. Test compounds are dissolved to a concentration of 10-20 mm in dimethyl sulfoxide and then this mixture was diluted to a concentration of 1 μm in the growth environment. In the growth environment prepare serial dilutions (1:1) of the basic solution and add 100 ál of each of them to separate sockets on 96-alopecia cultural plateau containing Hep2 cells. After 24 hours, take the train, using this indicator as a control, the concentration of APO A1. Inhibitors are defined as compounds that are able to reduce the secretion of APO b Into the environment without affecting the secretion of APO A1. Research method IFTTA (ELISA) for determination of APO takes place as follows. Dilute to a concentration of 5 μg/ml in phosphate-buffered solution/azide (FBI + 0,02% sodium azide) monoclonal antibody against human APO /Chemicon (Chemicon)/ and add 100 ál of the mixture to each slot 96-alopecia plateau /Nunc Maxisorb (NUNC Maxisorb)/. After incubation over night at room temperature a solution of antibodies are selected and nests washed three times with a mixture of FBI/azide. Nonspecific sites on the plateau were blocked by incubating nests within 1-3 hours in a solution of 1% (weight-volume) bovine serum albumin (BSA) prepared from a mixture of FBI/azide. 100 μl of the growth medium at different dilutions from Hep2 cells or APO In controls (prepared in 0,004% Tween 20/1% BSA in FBI/azide) is added to each nest and incubated for 18 hours. The contents of the nests is sucked off, washed three times with 0.1% tween-20 FBI) before adding 100 ál of secondary antibody in a dilution of 1/1000 goat APO In to the man /Chemicon (Chemicon)/. the ri times, as outlined above. After that, for each nest add 100 ál of dilution 1:1600 (FBI/1% BSA/2 mm MgCl2) antimony rabbit IgG linked to alkaline phosphatase (Sigma) and incubated for one hour at room temperature. After the extraction of the contents of the nest it washed four times specified above and add to each socket 100 ál of 1 mg/ml p-nitrophenylphosphate /PNF (pNPP, Sigma) in 25 mm Na (bi)carbonate/2 mm MgCl2pH of 9.5, and spend incubation for 20-30 minutes, then the reaction is stopped by adding 50 μl of 0.3 N NaOH. Proberaum absorption of the contents of each nest at 405 nm and subtract the background absorption at the wavelength of 650 nm. The concentration of APO In calculated using a standard curve constructed on the basis of a standard curve for purified low-density lipoproteins, which are explored in parallel in the same test. APO A1 is measured similarly, except that instead of the antibodies used for APO In use antibodies to APO A1 /Chemicon/ (Chemicon), and the incubation of the antigen is not carried out at room temperature and at 37o.

The activity can also be demonstrated if the analyzed connection directly inhibiton the inhibition of the transfer of radioactively labeled triglyceride from donor vesicles to acceptor vesicles in the presence of soluble MTB person. The procedure for preparation of MTB based on the method described in the literature (Wetterau and Zilvezsmit, Biochem. Biophys. Acta. 1986, 875, 610).

At the same time large pieces of human liver, frozen at a temperature of -80oC, thawed on ice, cut and washed several times in ice-cold 0.25 M sucrose. All subsequent phases carried out on ice. 50% homogenate in 0.25 M sucrose prepared using a Teflon pestle Potter Elvehjem (Polter - Elvehjem). The homogenate was diluted (1:1) 0.25 M sucrose and centrifuged at 10,000 x g for 20 minutes at a temperature of 4oC. the Precipitate resuspended in the sucrose and re-centrifuged at 10,000 x g for 20 minutes. Supernatant combine and further microsome assay precipitated by centrifugation speed 105000 x g for 75 minutes. Supernatant discarded, and containing microsome assay precipitate is suspended in a minimum volume of 0.25 M sucrose, diluted to 3 ml per gram of the original weight of the liver with 0.15 M Tris HCl, pH 8.0. This suspension is separated into 12 fractions and centrifuged speed 105000 x g for 75 minutes. Supernatant drop, and sediments containing microsome assay, stored at freezing temperatures of -80oC until needed. For the preparation of MTB before Issledovanie with stirring, add 1.2 ml of 0.54% solution desoxycholate (pH 7,4) for the destruction of the membrane microsomes. After 30-minute incubation on ice with weak stirring, the suspension is centrifuged with the speed 105000 x g for 75 minutes. The supernatant, containing soluble MTB, dialist in 2-3 days with 4 changes of buffer for the study (150 mm Tris-HCl, 40 mm NaCl, 1 mm EDTA, 0.02% of NaN3, pH 7,4). MTB from human liver is stored at a temperature of 4oC and immediately before the definition is diluted in the ratio 1:5 with buffer for the study mentioned above. Drugs MTB did not demonstrate a significant loss transfer activity when stored over 30 days.

Liposomes get in a nitrogen atmosphere at room temperature when scoring in the bath dispersion containing 400 μm of egg phosphatidylcholine (PC), 75 µm of cardiolipin from bovine heart and 0.82 μm /14C/-triolein (110 Ci/mol) in the buffer for the study. Add the appropriate amount of lipids in chloroform and carry out the drying in a stream of nitrogen before hydrating using buffer for the study. Acceptor liposomes prepared in nitrogen atmosphere at room temperature sounding in the bath dispersion containing 1.2 mm PF, 2,3 µm triolein and 30 gr /3H/-PF (50 Ci/mol) in the buffer for the study. Donor and acceptor liposomes centrifuged with the single-layer liposomes carefully select and store them at a temperature of 4oC to use in research activity on transfer.

Activity MTB measured using a test migration, which initiate the mixing of donor and acceptor vesicles with the addition of soluble MTB and tested compound. To 100 μl of either 5% BSA (control) or 5% BSA containing the analyzed connection, add 500 ál buffer for the study, 100 µl of the donor liposomes, 200 ál of acceptor liposomes and 100 µl of the diluted protein of MTB. After incubation at a temperature of 37oC for 45 minutes transfer triglyceride stopped by the addition of 500 μl of 50% (weight/volume) suspension of DEAE cellulose in the buffer for the study. After 4 minutes of mixing the donor liposomes, who contacted with DEAE cellulose, selectively precipitated at low-speed centrifugation. An aliquot of the supernatant containing acceptor liposomes, count on the counter for the determination of 3H and 14C to determine the percentage recovery of acceptor liposomes and the percentage of migrated triglycerides occurring on the kinetics of the first order. Inhibition of the transport of triglyceride is defined as the decrease in the radioactivity of 14C in comparison with kontrolerov MTB can also be measured in vivo in accordance with the following test.

Male mice (20-30 g, different strains) were obtained using a probe (0.25 ml/25 g body weight) dose of test compound, suspended in an aqueous solution of 0.5% methylcellulose. Dose solutions of the compounds were given or many times within a few days, or alternatively in one dose 90 minutes before killing mice whose blood was collected to obtain serum. Serum was studied on the content of triglycerides using commercially available enzymatic test /Triglyceride G: WAKO fine chemicals (Triglyceride G: Wako Fine Chemicals)/. Inhibitors of MTB was determined by their ability to reduce the amount of triglyceride in the serum compared with control mice that received only the filler.

The present invention is illustrated below by examples, but the examples in no way should be construed as limiting the present invention to specific details of these examples.

Example 1

This example illustrates how to obtain the intermediate compound of formula II, N-[2-(4-bromophenyl)ethyl]formamide.

500 g (1.78 mol) of the hydrobromide of 2-(4-bromophenyl) ethylamine, 1 l (12.4 mol) ethylformate and 248 ml (1.78 mol) of triethylamine are mixed and heated at a temperature of the Anna water and ethyl acetate. The organic layer is separated and washed with 1 l of water and salt solution. The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 378 g of solid substance.

MS (Cl): 245 (M + MO4+)

The hydrochloride of 7-bromo-3,4-dihydroisoquinoline

A 12-liter three-neck round bottom flask is heated to 150oC 4 kg of polyphosphoric acid and mix. To stir the polyphosphoric acid is added 530 g (3.75 mol) of phosphorus pentoxide with three portions of about 176,7 g each. After dissolving phosphorus pentoxide add 378 g (of 1.66 mol) of N-[2-(4-bromophenyl)ethyl]formamide. The reaction temperature then raise to 200oC and incubated for 2 hours. After this time the temperature is allowed to drop to 160oC and pour the mixture into 16 l of ice. The mixture is stirred for 0.5 hour, alkalinized to pH 12 10 N. the sodium hydroxide solution and extracted three times with 3 l of dichloromethane. The combined organic layers are washed with 1 l of saturated solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated to oil. The oil is dissolved in 2.5 l of methanol and saturated with anhydrous gaseous HCl. The resulting solution was concentrated to a volume of 1 l and add the doctrine 219 g of solid substance.

MS (Cl): (M + H+) 210

7-bromo-1,2,3,4-tetrahydroisoquinoline

219 g (0.89 mol) of the hydrochloride of 7-bromo-3,4-dihydroisoquinoline mixed with 1.5 liters of water and heated to 50oC. 33,7 g (0.89 mol) of sodium borohydride added in portions over 0.5 hours and up to this time the temperature to 62oC. Then the reaction mixture was cooled to ambient temperature and extracted three times 1 l of dichloromethane. The combined organic layers are washed with 1 l of saturated solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated to obtain 173 g of oil.

MS (C1): (M + H+) 212

7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline

In a five-liter three-neck round bottom flask gently dissolved in 950 ml of concentrated sulfuric acid 173 g (0,813 mol) of 7-bromo-1,2,3,4-tetrahydroisoquinoline. The resulting solution was cooled to a temperature of -5oC and added dropwise a solution of 82.7 g (0,816 mol) of potassium nitrate in 1 liter of concentrated sulfuric acid. After the addition the reaction mixture was kept at -5oC for 15 minutes and poured into 3 l of ice. The mixture is alkalinized to pH 14 with 50% sodium hydroxide solution. The basic solution is extracted with three times 1 l of dichloromethane. Objednavacim sodium sulfate, filter and concentrate to obtain 201 g of oil. Oil, pre-adsorbed on silica gel, to be applied on the column with 4 kg of silica gel and elute with a gradient of 1-5% methanol/dichloromethane. The fractions containing the product are combined and concentrated to obtain 115 g of a solid substance.

1H NMR (300 MHz, CDCl3) to 7.61 (s, 1H), 7,38 (c, 1H), 4,10 (s, 2H), 3,20 (t, 2H), 2,90 (t, 2H).

Tert-butyl ester of 7-bromo-6-nitro-3,4-dihydro-1H-isoquinoline - 2-carboxylic acid

115 g (0,447 mol) of 7-bromo-6-nitro-1,2,3,4 - tetrahydroisoquinoline unite from 45.2 g (0,447 mol) of tea, 97.5 g (0,447 mol) di-tert-butyl dicarbonate, 3.2 liters of dioxane and 0.5 l of water and stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated to remove dioxane, was added 1 l of saturated sodium bicarbonate and extracted twice 1 l of dichloromethane. The organic layer is extracted with brine, dried over magnesium sulfate and concentrated. The obtained solid is recrystallized from isopropanol to obtain 118 g of solid substance.

1H NMR (250 MHz, DMSO) 7,89 (s, 1H), 7,81 (s, 1H), 4,58 (s, 2H), of 3.56 (t, 2H), of 2.81 (t, 2H), of 1.42 (s, 9H).

Tert-butyl ester 6-amino-3,4-dihydro-1H-isoquinoline-2 - carboxylic acid

59 carbonate calcium and 49 g of ammonium acetate in 1 l of acetic acid hydronaut in a Parr apparatus for 5 hours. The reaction mixture was filtered through celite, concentrated, alkalinized to pH 12 using 4 n sodium hydroxide and extracted with methylene chloride.

The organic layer is washed with water, brine, dried over magnesium sulfate and concentrated to obtain 40 g of butter.

1H NMR (300 MHz, DMSO) to 4.87 (s, 2H), 4,27 (s, 2H), 3,44 (t, 2H), 2.57 m (t, 2H), 1.39 in (s, 9H).

Tert-butyl ester 6-[(4'-triptorelin-2 - carbonyl)amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid

7.6 g (29 mmol) of 4'-triptorelin-2-carboxylic acid and 7.1 g (29 mmol) of tert-butyl methyl ether 6-amino-3,4 - dihydro-1H-isoquinoline-2-carboxylic acid, 100 mg DMAP and 6.1 g (32 mmol) EDC mixed with 130 ml of methylene chloride for 12 hours. The reaction mixture is extracted with twice 150 ml of 1 N. HCl, twice with 150 ml of 1 N. NaOH, 150 ml of water, brine and concentrate to obtain 14 g of a beige foam.

MS (C1): 519 (M + Na+)

1H NMR (250 MHz, CDCl3) of 4.49 (s, 2H), 3,60 (t, 2H), 2,77 (t, 2H).

(1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-trifluoromethyl - biphenyl-2-carboxylic acid

4 g (8 mmol) of tert-butyl ester 6-[(4'-trifluoromethyl - biphenyl-2-carbonyl)-amino] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid and 6 ml (78 mmol) TFU (trifa and the organic layer extracted with 3 x 50 ml of saturated sodium bicarbonate and saline. The organic layer is dried over sodium sulfate and concentrated to obtain 3.1 g of a solid substance.

MS (C1): 397 (M + N+)

The following compounds classified as amides according to the above criteria, are synthesized using the procedure described in method A.

Method A

In a glass vial with a screw-stopper put 150 ál at 0.020 M solution of carboxylic acid in 1,2-dichloroethane (3.0 mmol), then 83 μl 0,030 M (1,2,3,4-tetrahydroisoquinoline-6-yl)amide 4'-triptorelin-2-carboxylic acid in 1,2-dichloroethane (2.5 µmol), then 25 mg associated with polymer morpholinobutyrophenone (2.5 µmol/g = 62 µmol). After shaking at 20oC for 16 hours taken and diluted with 10 µl to 100 µl of methanol for subsequent GHUR treatment phases and mass spectrometric (MS) analysis. The polymer is removed by filtration and the filtrate concentrated to dryness in vacuo.

Example 2

The above described method A to obtain [2-(3-cyclopentylpropionyl)- 1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid by reacting the compound (II) with 3-cyclopentylpropionate in the presence of polymer linked research.

(2-Phenylacetyl-1,2,3,4-tetrahydroisoquinoline-6-yl)amide 4'-triptorelin-2-carboxylic acid

MS (C1): 515 (M + H+)

1H NMR (250 MHz, CDCl3) 4,68 and a 4.53 (s, 2H), 3,80 (s, 2H), 3,80, and 3,61 (t, 2H), was 2.76 and at 2.59 (t, 2H).

(2-Benzoyl-1,2,3,4 - tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 501 (M + H+)

[2-(Furan-2-carbonyl) -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 491 (M + H+)

[2-(4-Chlorobutyryl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 501 (M + H+)

(2-Benzyloxyethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 545 (M + H+)

[2-(4-Heptylbenzoic)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 599 (M + H+)

[2-Bicyclo[2.2.1] hept-5-ene-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6 - yl]-amide 4'-triptorelin-2-carboxylic acid

MS (C1): 517 (M + H+)

(2-(5-Methyl-3-phenylisoxazol-4-carbonyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl]-amide 4'-trifluoromethyl-biphenyl-2 - carboxylic kinil-2-carboxylic acid

MS (C1): 607 (M + H+)

[2-(3,3-Dimethylbutyryl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 495 (M + H+)

(2-Phenoxyacetyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 531 (M + H+)

2-Oxo-1-phenyl-2-[6-[(4'-triptorelin-2-carbonyl) amino]-3,4-dihydro-1H-isoquinoline-2-yl] ethyl ester acetic acid

MS (C1): 573 (M + H+)

[2-(Thiophene-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 507 (M + H+)

[2-(2,2,5,7-Tetramethyl-1-oxonian - 4-carbonyl) -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 611 (M + H+)

(2-Octanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 523 (M + H+)

(2-Octadec-9-enoyl-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 661 (M + H+)

[2-(Cinoxacin-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 553 (M + H+)

Methyl ester of 4-oxo-4-[6-[(4'-triptorelin-2 - carbonyl) amino] -3,4-dihydro-1H-isoquinoline-2-yl] melanotropin-2-carboxylic acid

MS (C1): 577 (M + H+)

(2-Pentanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 481 (M + H+)

(2-Isobutyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 467 (M + H+)

(2-Decanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 551 (M + H+)

(2-Octadecanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 663 (M + H+)

(2-Hexanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 495 (M + H+)

[2-(3-Phenylpropionyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 529 (M + H+)

(2-Cyclohexanecarbonyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 507 (M + H+)

(2-Cyclobutanecarbonyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 479 (M + H+)

[2-(2-Ethyl-hexanoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 523 (M + H+)

Methyl ester of 3-oxo-3-[6[(4'-pR> Methyl ester 5-oxo-5-[6-[(4'-trifluoromethyl-biphenyl-2-carbonyl) amino] -3,4-dihydro-1H-isoquinoline-2-yl] pentanoic acid

MS (C1): 525 (M + H+)

[2-(2-Chloro-propionyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 487 (M + H+)

Ethyl ester of 5-oxo-5-[6-[(4'-trifluoromethyl-biphenyl-2 - carbonyl) amino] -3,4-dihydro-1H-isoquinoline-2-yl] pentanoic acid

MS (C1: 539 (M + H+)

[2-(3-Methoxyphenyl) acetyl] -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 545 (M + H+)

[2-(Thiophene-2-ylacetic)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 521 (M + H+)

1H NMR (250 MHz, CDCl3) 4,68 and 4,60 (s, 2H), of 3.97 (s, 2H), 3,80, and of 3.69 (t, 2H), 2,71 (m, 2H).

(2 Butyryl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 467 (M + H+)

Methyl ester of 4-oxo-4-[6-[(4'-triptorelin-2 - carbonyl) amino] -3,4-dihydro-1H-isoquinoline-2-yl] butyric acid

MS (C1): 511 (M + H+)

(2-Octadec-11-enoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 661 (M + H+)

METHOD B

EDC (EDC) associated with the polymer
oC for 16 hours. After cooling, the resin is filtered off, washed with 2 x 200 ml DMF, 2 times in 300 ml THF and dried at 50oC in a vacuum Cabinet for 20 hours. IR 2131 cm-1.

Interaction

In a glass vial with a screw tube was placed 50 μl 0,050 M acid solution in 1,2-dichloroethane (2.5 µmol), then 50 μl 0,050 M of compound (II) in 1,2-dichloroethane (2.5 µmol), and then 30 μl of 0.017 M DMAP in 1,2-dichloroethane (0.5 Microm), then 25 mg associated with polymer 1-(3-dimethylaminopropyl)-3-ethyl - carbodiimide (1.0 µmol/g = 25 Microm). After shaking for 16 hours at 20oC select the 10 ml and diluted to 100 μl with methanol for GHUR treatment phases and MS analysis. The polymer is removed by filtration and the filtrate concentrated to dryness in vacuo.

Example 40

[2-(Naphthalene-2-ylacetic)-1,2,3,4-tetrahydroit the Talin-2-luxusni acid in the presence associated with polymer EDC, as described above in Method B.

MS (C1): 565 (M + H+)

Examples 41-97

The following compounds are obtained by interaction of the compound (II) with a suitable corresponding carboxylic acid in the presence associated with polymer EDC ways, similar to that described in Example 40.

[2-(2,2-Dimethylpropionic)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 481 (M + H+)

[2-(2,2-Dimethylpentyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 509 (M + H+)

[2-(3-Hydroxy-2-phenylpropionyl)- 1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 545 (M + H+)

[2-(2-Phenylbutyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 543 (M + H+)

[2-(3-Methyl-4-oxopentanoic)-1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2 - carboxylic acid

MS (C1): 509 (M + H+)

[2-(2-Ethylbutyryl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 495 (M + H+)

(2-Ethoxyacetic-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic Ki is biphenyl-2-carboxylic acid

MS (C1): 533 (M + H+)

(2-Phenylthiazol-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 547 (M + H+)

(2-Benzyldimethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 561 (M + H+)

[2-(3-Methylbutyryl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 481 (M + H+)

[2-(3-Chlorobutyryl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 501 (M + H+)

(2-but-3-enoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 465 (M + H+)

[2-(1-Acetylpyrrolidine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 536 (M + H+)

[2-[4-Oxo-2-thioxothiazolidin-3-yl)-acetyl] -1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 570 (M + H+)

[2-(Pyridine-4-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 502 (M + H+)

[2-(Quinoline-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (Snil-2-carboxylic acid

MS (C1): 569 (M + H+)

[2-(-Methoxyphenylacetyl)-1,2,3,4-tetrahydroisoquinoline - 6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 545 (M + H+)

[2-(3-Chloro-2,2-dimethylpropionic)- 1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 515 (M + H+)

(2-Cyanoacetyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 464 (M + H+)

(2-Methoxyacetyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 469 (M + H+)

[2-[(4-Chlorophenyl)-acetyl] -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 549 (M + H+)

(2-Ethylthioethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 499 (M + H+)

[2-(3-Phenylprop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 525 (M + H+)

[2-(3-Hydroxybutyryl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 483 (M + H+)

[2-[(1H-Indol-3-yl)-acetyl] -1,2,3,4-tetrahydroisoquinoline - 6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 554 (M is about acid

MS (C1): 516 (M + H+)

[2-(Pyridine-2-ylacetic)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 516 (M + H+)

1H NMR (300 MHz, CDCl3) of 4.67 (s, 2H), 3,99 (s, 2H), of 3.77 (m, 2H), was 2.76 and to 2.65 (t, 2H).

[2-[(4-Nitrophenyl)-acetyl-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 560 (M + H+)

[2-(6-Diethylcarbamoyl-3-enacarbil) -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2 - carboxylic acid

MS (C1): 604 (M + H+)

[2-(Adamantane-1-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 559 (M + H+)

[2-[(3-Chlorophenyl) acetyl] -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 549 (M + H+)

(2-Diphenylacetyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 591 (M + H+)

[2-[(2,4-Dichlorophenyl) acetyl] -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 583 (M + H+)

[2-(2-Phthalimidobutyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 584 (M + H+)

[2-(Bi (M + H+)

(2-o-Tolylacetic-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 529 (M + H+)

(2-m-Tolylacetic-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 529 (M + H+)

[2-(4-Phenyl-but-3-enoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 541 (M + H+)

[2-(Cyclopent-1-unilateral)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 505 (M + H+)

[2-[(3,4,5-Trimethoxyphenyl) acetyl]-1,2,3,4-tetrahydroisoquinoline-6 - yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 605 (M + H+)

[2-(Adamantane-1-ylacetic)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 573 (M + H+)

[2-(9H-Fluoren-9-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 589 (M + H+)

[2-[(3-Triptoreline) acetyl] -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 583 (M + H+)

[2-(1-Methylcyclohexanecarboxylic)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, a
MS (C1): 598 (M + H+)

[2-(4-Methyl-2-oxopentanoic)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 509 (M + H+)

[2-(3-Methoxycyclohexanone)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 537 (M + H+)

(2-Gex-3-enoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 493 (M + H+)

Tert-butyl ether 2-[6-[(4'-triptorelin-2 - carbonyl) amino]-3,4-dihydro-1H-isoquinoline-2 - carbonyl]pyrrolidine-1-carboxylic acid

MS (C1): 594 (M + H+)

[2-(Tetrahydrofuran-3-carbonyl)- 1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 495 (M + H+)

[2-(-Oxo-thiophene-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 552 (M + NH+)

[2-(Thiophene-3-yl-acetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 521 (M + H+)

[2-[(6-Methoxy-3-oxonian-1-yl) acetyl] -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 600 (M + 2)

[2-(1-Acetyl-pyrrolidin-2-carbonyl)- 1,2,3,4-tetrahydroisoquinoline)- 1,2,3,4-tetrahydroisoquinoline

-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 533 (M + H+)

Example 98

Compound II (200 mg, 0.50 mmol), Pikalyovo acid (62 mg, of 0.60 mmol) and EDC (116 mg, of 0.60 mmol) are mixed in 10 ml of methylene chloride 14 hours. The reaction mixture is concentrated and cleaned using flash chromatography on silica gel (eluent: 70-100% E SLA/hexane). The product is a [2-(pyridine-2-carbonyl) -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, 98% yield.

MS (C1): 502 (M + H+)

1H NMR (250 MHz, CDCl3) 4,81 and 4,69 (s, 2H), 3,92 and to 3.73 (t, 2H), and 2.83 (m, 2H).

Method IN

In a glass vial with a screw-stopper put 150 ál at 0.020 M solution of isocyanate in 1,2-dichloroethane (3.0 mmol), then 83 μl 0,030 M (1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid (compound II) in 1,2-dichloroethane (2.5 Microm). After shaking for 16 hours at 20oC select the 10 ml and diluted to a volume of 100 μl methanol for GHUR treatment phases and MS analysis. The reaction mixture is concentrated to dryness in vacuo.

Example 99

Phenylamide 6-[(4'-triptorelin-2-carbonyl)-amino] - 3,4-dihydro-1H-isoquinoline-2-carboxylic acid get as SUP>H NMR (250 MHz, DMSO) 4,56 (s, 2H), 3,66 (t, 2H), 2,77 (t, 2H).

Examples 100-103

The following compounds obtained by the reaction of compound II with a suitable corresponding isocyanate by methods similar to that described in Example 99.

Exiled 6-[(4'-triptorelin-2-carbonyl) amino]-3,4 - dihydro-1H-isoquinoline-2-carboxylic acid

MS (C1): 524 (M + H+)

Ethyl ether ({6-[(4'-triptorelin-2-carbonyl) amino]-3,4-dihydro-1H-isoquinoline-2-carbonyl} amino) acetic acid

MS (C1): 526 (M + H+)

Benzylated 6-[(4'-triptorelin-2-carbonyl) -amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid

MS (C1): 530 (M + H+)

[(R)-1-Phenylethyl] amide 6-[(4'-triptorelin-2-carbonyl) -amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid

Note: the Product is obtained according to the Method of using the compound (II) and (R)-(+)--methylbenzenesulfonate

MS (C1): 544 (M + H+)

1H NMR (250 MHz, CDCl3) of 5.06 (m, 1H): 4,66 (D. 1H), 4,46 (s, 2H): of 3.56 (t, 2H); 2,78 (t, 2H): of 1.52 (d, 3H).

Example 104

Pyridine-2-alamid 6-[(4'-triptorelin-2-carbonyl) amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid get method similar to that described Ohsawa. A; Arai, H; Igeta. H; Chem. Pharm. Bull. 1980, 28, 3570.

Yield 23%.


In a glass vial with a screw-stopper put 150 ál at 0.020 M solution of sulphonylchloride in 1,2-dichloroethane (3.0 mmol), then 83 μl 0,030 M of compound (II) in 1,2-dichloroethane (2.5 mmol), then 25 mg associated with polymer-morpholinomethyl-polystyrene (2.5 mmol/g = 62 µmol). After shaking for 16 hours at 20oC select the 10 ml and dilute it to 100 μl of methanol for GHUR treatment phases and MS analysis. The polymer is removed by filtration, and the filtrate concentrated to dryness in vacuo.

Example 105

[2-(Naphthalene-1-sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid get Method G by reacting the compound (II) with naphthalene-1-sulphonylchloride.

MS (C1): 604 (M + H+)

Examples 106-111

The following connections get Method D as described in Example 105, by reacting the compound (II) with the corresponding sulphonylchloride.

Methyl ester 2-[6-[(4'-triptorelin-2-carbonyl) amino]-3,4-dihydro-1H-isoquinoline-2-sulfonyl] benzoic acid

MS (C1): 595 (M + H+)

[2-(Propane-2-sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 520 (M + NH4+)

[2-(3-MS (C1): 555 (M + NH4+)

[2-(butane-1-sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 534 (M + NH4+)

(2-Dimethylsulphamoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 521 (M + NH4+)

[2-(2-Trifloromethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 638 (M + NH4+)

Example 112

This example illustrates the method of obtaining the compound where the group in XYZ connecting with XYZ tetrahydroisoquinolinium ring is thiocarbamoyl.

In a glass vial with a screw-stopper put 150 ál at 0.020 M solution thioisocyanate (cyclopropylidene) in 1,2-dichloroethane (3.0 mmol), then 83 μl 0,030 M 4'-triptorelin-2-carboxylic acid (1,2,3,4-tetrahydroisoquinoline-6-yl) amide in 1,2-dichloroethane (2.5 mkcol). After shaking for 16 hours at a temperature of 20oC select the 10 ml and diluted to a volume of 100 μl methanol for GHUR treatment phases and MS analysis. The reaction mixture is concentrated to dryness under vacuum, thus obtaining (2-cyclopropanecarbonyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-Tr is ol), connection II (5 mmol), acetic acid (7.5 mmol) and triacetoxyborohydride sodium (10 μmol) in 300 μl of 1,2-dichloroethane shaken for 60 hours at room temperature. Select a sample volume of 7.5 μl and diluted with 93 μl of methanol for TLC and MS analysis. The remaining sample is evaporated to dryness in a vacuum. The crude solid is dissolved in 500 μl of ethyl acetate and washed with 300 μl of 5% sodium bicarbonate. The organic layer is concentrated to dryness in vacuo.

Example 113

[2-(2,6,6-Trimethylcyclohex-2-animetal)-1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid get METHOD E by reacting the compound (II) with 2,6,6-trimethylcyclohex-2-anisaldehyde.

MS (C1): 533 (M + H+)

Examples 114-162

The following compounds are given as in Example 113, METHOD E by reacting the compound (II) with a suitable corresponding aldehyde.

(2-Cyclohex-3-animetal-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 491 (M + H+)

[2-(3-Methylbenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 501 (M + H+)

[2-(4-Dimethylaminobenzoyl)-1,2,3,4 - tetrahed the ZIL)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 517 (M + H+)

[2-(2-Terbisil)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 505 (M + H+)

[2-(3,4-Dichlorobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 555 (M + H+)

[2-(4-Isopropylbenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 529 (M + H+)

(2-Biphenyl-4-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 564 (M + 2)

[2-(3-Phenoxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 580 (M + 2)

[2-(4-Methoxynaphthalene-1-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6 - yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 568 (M + 2)

(2-Naphthalene-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 538 (M + 2)

[2-(4-Methylthiophenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 533 (M + H+)

[(9-Ethyl-9H-carbazole-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'- triptorelin-2-carboxylic acid

MS (C1): 605 (M + 2)

[2-(4-tert-ether Butylbenzylamine 3-[6-[(4'-triptorelin-2-carbonyl) amino]-3,4-dihydro-1H-isoquinoline-2-ylmethyl]-cyclohexanecarboxylic acid

MS (C1): 566 (M + 2)

[2-(2-tert-Butylthioethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 576 (M + 2)

(2-Cyclohexylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 494 (M + 2)

[2-(3-Terbisil)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 505 (M + H+)

(2-Benzo[1,3] dioxo-5-ylmethyl-1,2,3,4 - tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 531 (M + H+)

(2-Naphthalene-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 538 (M + 2)

[2-(2-Methoxy-naphthalene-1-ylmethyl)- 1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 568 (M + 2)

[2-(4-Benzyloxy-3-methoxybenzyl)- 1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 624 (M + 2)

[2-(1,3,4-Trimethylcyclohex-3-animetal)-1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 533 (M + H+)

[2-[2-(4-Chlorophenylthio) benzyl] -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 629 (M + H+ MS (C1): 555 (M + H+)

[2-(1,5 a,6,9,9 a,9b-Hexahydro-4H-dibenzofuran-4a-ylmethyl) - 1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2 - carboxylic acid

MS (C1): 585 (M + H+)

{ 2-[4-(2-Diethylaminoethoxy) benzyl]-1,2,3,4 - tetrahydroisoquinoline-6-yl} amide 4'-triptorelin-2-carboxylic acid

MS (C1): 603 (M + 2)

[2-(2-Trifloromethyl)-1,2,3,4-tetrahydroisoquinoline-6 - yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 555 (M + H+)

[2-(6,6-Dimethylbicyclo[3.1.1] hept-2-ene-2-ylmethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2 - carboxylic acid

MS (C1): 531 (M + H+)

[2-(2-Benzyloxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 594 (M + 2)

[2-(4-Phenoxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] -amide 4'-triptorelin-2-carboxylic acid

MS (C1): 579 (M + H+)

[2-(4-Dimethylaminonaphthalene-1 - ylmethyl)- 1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 580 (M + H+)

[2-(4-Pyrrolidin-1-ylbenzyl)- 1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 557 (M + 2)

(2-Thiophene-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-trif 2,69 (m, 4H).

[2-(1H-Indol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 526 (M + H+)

[2-(1H-Pyrrol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6 - yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 476 (M + H+)

1H NMR (300 MHz, DMSO) of 3.54 (s, 2H), 3.43 points (s, 2H), 2,72 (m, 2H), 2,60 (m, 2H).

(2-Furan-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 477 (M + H+)

1H NMR (250 MHz, DMSO) of 3.65 (s, 2H), 3,47 (s, 2H), 2,71 (m, 2H), 2,65 (m, 2H).

[2-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-yl - ethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 598 (M + 2)

[2-(2,5-Dimethyl-1-phenyl-1H-pyrrol-3-ylmethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 581 (M + 2)

[2-(3,5-Dimethyl-1-phenyl-1H-pyrazole-4-ylmethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2 - carboxylic acid

MS (C1): 582 (M + 2)

(2-Benzofuran-2-ylmethyl-1,2,3,4 - tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2 - carboxylic acid

MS (C1): 527 (M + H+)

[2-(2-methyl-1H-indol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-trifloromethyl the Idro-1H-isoquinoline-2-ylmethyl}-furan-2-ymetray ether acetic acid

MS (C1): 549 (M + H+)

1H NMR (300 MHz, CDCl3) 5,02 (s, 2H), 3,70 (s, 2H), 3,60 (s, 2H), and 2.83 (t, 2H), 2,75 (t, 2H), 2,07 (s, 3H).

[2-(3-Methylthiophene-2-ylmethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 507 (M + H+)

(2-Thiophene-3-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

MS (C1): 493 (M + H+)

[2-(2-Methyl-1H-indol-3-ylmethyl) -1,2,3,4-tetrahydroisoquinoline-6 - yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 540 (M + H+)

Ethyl ester of 2-methyl-5-[6-[(4'-triptorelin-2-carbonyl)-amino - 3,4-dihydro-1H - isoquinoline-2-ylmethyl] furan-3-carboxylic acid

MS (C1): 563 (M + H+)

[2-(2,5-dimethoxytetrahydrofuran-3-ylmethyl)-1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2 - carboxylic acid

MS (C1): 541 (M + H+)

[2-(1-methyl-1H-indol-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

MS (C1): 557 (M + NH+)

Ethyl ester 2-[6-[(4'-triptorelin-2-carbonyl) amino]-3,4-dihydro-1H-isoquinoline-2-ylmethyl] cyclopropanecarbonyl acid

MS (C1): 523 (M + H+)

METHOD W

The following compounds are obtained by the restoration amstwo this method is the same as a Method of E and also includes the use of triacetoxyborohydride sodium except for some changes, usually in the choice of solvent and reaction temperature used for each connection is specified, all modifications. In addition, unless specifically agreed otherwise, use 1.5-2 equivalents of carbonyl compounds. For the compounds obtained by this procedure, States that allocate basis. For use in biological screening free base in most cases turn into salt - monohydrochloride conventional methods.

Example 163

(2-Benzyl-1,2,3,4-tetrahydroisoquinoline-6-yl)-amide 4'-triptorelin-2-carboxylic acid is produced by the interaction of the compound (II) with benzaldehyde using a method similar to what was described Abdel. Magid et al., with the following modifications:

Solvent: DSE

Yield 56%.

MS (C1): 487 (M + H+)

1H NMR (250 MHz, DMSO) 3,62 (s, 2H), 3.46 in (s, 2H), 2,74 (m, 2H), 2.63 in (m, 2H).

Examples 164-193

The following compounds are obtained by interaction of the compound (II) with a suitable corresponding aldehyde according to the method similar to that described Abdel. Magid et al., with appropriate modifications.

(2-Feast of the fir: THF

The output 62%

MS (C1): 488 (M + H+)

1H NMR (300 MHz, CDCl3) is 3.82 (s, 2H), 3,63 (s, 2H), 2, (m, 2H), 2,77 (m, 2H).

(2-Pyridin-3-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

Solvent: THF

MS (C1): 488 (M + H+)

(2-Pyridine-4-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

Solvent: THF

MS (C1): 488 (M + H+)

(2-Quinoline-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

Solvent: DCA

Exit 66%

MS (C1): 538 (M + H+)

1H NMR (250 MHz, CDCl3) to 3.99 (s, 2H), to 3.67 (s, 2H), 2,82 (s, 4H).

[2-(6-Methylpyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline - 6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

Exit 63%

MS (C1): 502 (M + H+)

1H NMR (250 MHz, CDCl3) 3,79 (s, 2H), 3,63 (s, 2H), 2,81 (s, 2H), was 2.76 (s, 2H), by 2.55 (s, 3H).

[2-(6-Bromopyridin-2-ylmethyl)- 1,2,3,4 - tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 568 (M + H+)

[2-(6-Formylpyridine-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

The solution is inolin-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 521 (M + H+)

[2-(3-Chlorobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

Exit 69%

MS (C1): 521 (M + H+)

1H NMR (300 MHz, DMSO) to 3.64 (s, 2H), 3,47 (s, 2H), 2,74 (t, 2H), 2,64 (t, 2H).

[2-(4-Chlorbenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 521 (M + H+)

(2-Pyrimidine-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

Solvent: methylene chloride; used 6 equiv. aldehyde

Exit 61%

MS (C1): 489 (M + H+)

1H NMR (250 MHz, DMSO) a 3.87 (s, 2H), 3,60 (s, 2H), 2,77 (m, 4H).

[2-(3-Nitrobenzyl) -1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

The output 76%

MS (C1): 532 (M + H+)

1H NMR (300 MHz, CDCl3) a 3.75 (s, 2H), to 3.58 (s, 2H), 2,84 (t, 2H), by 2.73 (t, 2H).

[2-(3-Methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 517 (M + H+)

[2-(3-Trifluoromethyl-benzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic who] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 512 (M + H+)

[2-(3-Hydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 503 (M + H+)

[2-(3,5-Dichlorobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 556 (M + H+)

[2-(3,5-Bis-trifloromethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 622 (M + H+)

3-{ 6-[(4'-Triptorelin-2-carbonyl)-amino] -3,4-dihydro-1H - isoquinoline-2-ylmethyl}phenyl ether acetic acid

Solvent: DSE

MS (C1): 545 (M + H+)

[2-(3-Sulfamoylbenzoyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 566 (M + H+)

[2-(1H-Imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: 7:3 THF: DSE

Exit 59%

MS (C1): 477 (M + H+)

1H NMR (300 MHz, CDCl3) 3,79 (s, 2H), to 3.58 (s, 2H), 2,82 (m, 2H), 2,74 (m, 2H),

[2-(1-Methyl-1H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic Kikot (s, 3H), of 3.57 (s, 2H), 3,51 (s, 2H), 2,77 (t, 2H), 2,65 (t, 2H).

[2-(1H-Benzimidazole-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

Yield 83%.

MS (C1): 527 (M + H+)

1H NMR (250 MHz, DMSO) to 3.89 (s, 2H), to 3.58 (s, 2H), was 2.76 (m, 4H).

[2-(1H-Imidazol-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

Yield 66%.

MS (C1): 477 (M + H+)

1H NMR (250 MHz, DMSO) to 3.56 (s, 2H), 3.46 in (s, 2H), 2,72 (m, 2H), 3,63 (m, 2H).

(2-Thiazol-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

Yield 38%.

MS (C1): 494 (M + H+)

1H NMR (250 MHz, DMSO) to 3.99 (s, 2H), to 3.64 (s, 2H), was 2.76 (s, 4H).

[2-(3-Methylbenzo[b] thiophene-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: DSE

MS (C1): 557 (M + H+)

[2-(1-Methyl-1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid

Solvent: 7:3 THF; DSE

Yield 72%

MS (C1): 491 (M + H+)

1H NMR (300 MHz, DMSO) 3,66 (s, 2H), 3,63 (s, 3H), 3,47 (s, 2H), 2,70 (m, 2H), 2,62 (m, 2H).

MS (C1): 478 (M + H+)

1H NMR (250 MHz, CDCl3) a 3.87 (s, 2H), 3,63 (s, 2H), and 2.79 (s, 4H)

(2-Methyl-1,2,3,4-tetrahydroisoquinoline-6-yl) - amide 4'-triptorelin-2-carboxylic acid

Solvent: THF: used 3 equivalent of aldehyde

MS (C1): 411 (M + H+)

Example 194

This example shows how to obtain the compound of formula II as an illustration of scheme 2. Numbers in parentheses next to each of the target compounds correspond to the numbers shown in scheme 2.

A. Dimethyl 2-(carboxy-5-nitrophenyl)malonic acid (2)

Through a solution of 2-chloro-4-nitrobenzoic acid (75 g, 372 mmol) in diethylmalonate (900 ml) miss nitrogen for 15 minutes. Add sodium methoxide (48,3 g, 894 mmol) in one portion and the temperature spontaneously as the result of an exothermic reaction rises to 48oC. Fifteen minutes later add the copper bromide (1) (5,4 g, 37 mmol) in one portion and the reaction mixture is heated to a temperature of 70oC for 24 casw for complete consumption of 2-chloro-4-nitrobenzoic acid. To the cooled reaction mixture is added water (900 ml) and then hexane (900 ml). The aqueous layer was separated, add toluene (900 ml), filtered through celite and the aqueous layer was separated. To the aqueous layer add fresh toluene (1800 ml) and the biphasic mixture was acidified with 6 N. aqueous HCl (90 ml). The resulting white precipitate and the contents stirred for 18 hours. The product is filtered and dried to obtain a white solid product (78,1 g, 70%). So pl. = 153oC.

1H NMR (CD3)2SO of 8.37 (d, J = 1 Hz,1H), 8,30 (d, J = 1 Hz, 2H), of 5.82 (s, 1H) a 3.83 (s, 6H).

13C NMR (CD3)2SO 168,0, 167,3, 149,4, 137,1, 135,8, 132,5, 125,4, 54,5, 53,4, 123,7. Analysis. Calculated for C11H10NO8: 48,49, OF 3.73 H, H 4,71. Found: 48,27, H and 3.72, H 4.76,

B. 2-Carboxymethyl-4-nitrobenzoic acid (3)

To a solution of dimethyl 2-(carboxy-5-nitrophenyl) malonic acid (25,0 g, 84 mmol) in methanol (200 ml) is added sodium hydroxide (5 g, 125 mmol) in water (200 ml). After 3 hours the reaction is completed, the methanol is removed in vacuo, and the contents cooled to 0oC and acidified with concentrated HCl (37 ml). The aqueous layer was extracted twice with ethyl acetate (200 ml, then 100 ml), the combined organic layers dried over magnesium sulfate, most of the solvent mustache obtain 19.3 g of product as a white solid. So pl. = 180-82oC.

IR (KBr) 3080, 3055, 2983, 1707, 1611, 1585, 1516, 1491, 1424, 1358, 1298, 1237 cm-1.

13C NMR (CD3)2)SO 172,3, 167,5, 149,2, 138,8, 137,3, 132,1, 127,2, 122,4, 39,8. Analysis calculated for C9H17NO6. WITH 48,01, H 3,13, N 6,22. Found: 47,67, H 3,19, N Of 6.31.

century 2- (2-Hydroxymethyl-5-nitrophenyl) ethanol (4)

A solution of 2-carboxy-4-nitrobenzoic acid (3.0 g, 13.3 mmol) in THF (60 ml) is treated with a complex of borane-THF (53.3 per ml, 53.3 per mmol) for 15 minutes at 0oC. the Reaction mixture was stirred for 18.5 hours, quenched by addition of THF/water (1: 1, 30 ml), water (20 ml) and the layers separated. The aqueous layer was re-extracted with THF (30 ml), the combined organic phase was washed with brine, dried over magnesium sulfate and the solvent is removed in vacuum to obtain the product as a white solid product (2,05 g, 78%), So pl. = 79-81oC.

IR (KBr) 3277, 3192, 2964, 2932, 1614, 1525, 1507, 1170, 1134, 1089, 1067 cm-1.

13C NMR (CD3)2)SO 149,1, 146,6, 139,2, 127,8, 124,3, 121,3, 61,2, 60,6, 34,9. Analysis calculated for C9H11NO4: 54,82, H 5,62, N 7,10. Found: 54,54, H 5,49, N 7,07.

in'. 2-(2-Hydroxymethyl-5-nitrophenyl)ethanol (4), an alternative way

A mixture of 2-carboxymethyl-4-nitrobenzoic acid (13 g, 57,7 mmol what IR for 5 hours. The solvent is removed in vacuo to obtain 6-nitrosopropane-1,3-dione (compound (3a) in scheme 2) in the form of a yellow solid product (10,51 g, 88%). To a solution of 6-nitrosopropane-1,3-dione (2 g, to 9.66 mmol) in THF (40 ml) at 0oC is added dropwise within 40 minutes balancerationality complex (35,6 ml, 1M in THF). The contents stirred for 18 hours at a temperature of 25oC, cooled to a temperature of 0oC, stop the reaction by adding methanol (30 ml) and stirred the mixture for 1 hour. The solvent is removed in vacuo, add ethyl acetate (30 ml) and the organic phase is washed with 10% aqueous hydrochloric acid. The aqueous acidic layer is subjected to re-extraction with ethyl acetate (30 ml), the combined organic layers dried with magnesium sulfate and evaporated under vacuum to the content of ethyl acetate in 2 ml. of This solution is filtered through silica gel and washed with methylene chloride (30 ml) to remove impurities. Then through silica gel miss ethyl acetate, remove the solvent in vacuo and get a solid substance, which is stirred in methylene chloride and filtered to yield diol as a white solid, 1,38 g, 73%.

year 6-Nitro-1,2,3,4-tetrahydroisoquinoline (5)

To a solution of 2-(2-HYDR what about the drops for more than 10 minutes methanesulfonanilide (0.9 ml, 11,63 mmol). TLC shows completion of the reaction after 30 minutes.

1H NMR (CDCl3) 8,17-11 (m, 2H), 7,65 (d, J = 9 Hz, 1H), are 5.36 (s, 2H), 4,49 (t, J = 6 Hz, 2H), 3,25 (t, J = 6 Hz, 2H), is 3.08 (s, 3H), 2,98 (s, 3H).

The reaction mixture was washed with 10% aqueous HCl, saturated aqueous sodium bicarbonate and saline. The organic layer is dried with magnesium sulfate, the methylene chloride is removed in vacuo and treated the rest THF (3 x 100 ml). The product (1.9 g) was used directly in the next stage without additional purification. Ammonia (50 ml) is added to dimesylate (1.9 g) in THF (30 ml) at a temperature of -78oC. the Contents are heated to a temperature of 24oC for 60 hours, the ammonia is distilled off, and the solvent is removed in vacuum to obtain crude product (786 mg, 82%). Add toluene and the solution is filtered through magnesium sulfate, the solvent is removed in vacuum, obtaining 721 mg (75%) of oil of amber.

1H NMR (CDCl3) of 7.97 (s, 1H), 7,95 (d, J = 9 Hz, 1H), 7,15 (d, J = 9 Hz, 1H), 4,07 (s, 2H), 3.15 in (t, J = 6 Hz, 2H), 2,89 (t, J = 6 Hz, 2H), 1,98 (user.s, 1H).

D. Tert-butyl ester 6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (6)

To a solution of 6-nitro-1,2,3,4-tetrahydroisoquinoline (840 mg, 4,71 mmol) in methylene chloride (17 ml) containing triethylamine (0,rbonate sodium, separate the phases, the organic layer dried over magnesium sulfate and the solvent is removed in vacuum to obtain the product as a pale white solid (1.2 g, 92%). So pl. = 138-41oC.

IR (KBr) 3056, 3018, 2982, 2935, 1734, 1684, 1612, 1522, 1399, 1236 cm-1.

1H NMR (CDCl3) of 8.04 (t, J = 5 Hz, 1H), 8,01 (s, 1H), 7,26 (t, J = 5 Hz, 1H) and 4.65 (s, 2H), 3,68 (t, J = 6 Hz, 2H), 2,93 (t, J = 6 Hz, 2H), 1,49 (s, 9H).

that is, Tert-butyl ester 6-amino-3,4-dihydro-1H-isoquinoline-2 - carboxylic acid (7)

Tert-butyl ester 6-nitro-3,4-dihydro-1H-isoquinoline-2 - carboxylic acid (82 mg, 0.29 mmol) in THF (2 ml) hydronaut 5% Pt-C (50% relative humidity, 10 mg) at a pressure of 50 pounds per square inch (283446 PA) for 5 hours. The catalyst is filtered off, the solvent is removed in vacuum and chromatographic on silica gel with ethyl acetate/hexane to obtain 42 mg (57%) of product.

IR (KBr) 3005, 2975, 2928, 1685, 1627, 1509, 1423, 1365, 1166 cm-1.

1H NMR (CDCl3) of 6.90 (d, J = 6 Hz, 1H), 6,56 (d, J = 6 Hz, 1H), 6.48 in (c, 1H), 4,47 (s, 2H), 3,60 (m, J = 6 Hz, 4H), by 2.73 (t, J = 6 Hz, 2H), 1,49 (s, 9H).

The product obtained by the method described in example 194 above may interact with 4'-triptorelin-2-carboxylic acid as described in Example 1, to obtain the N-protected compound (II), which then is a way to obtain the compound (II) in accordance with scheme 3. The numbers in brackets correspond to the numbers shown in figure 3.

A. 4'-Triptorelin-2-carbonylchloride

A solution of 4'-(trifluoromethyl)-2-biphenylcarbonic acid (remaining 9.08 g, 34 mmol), thionyl chloride (12 ml) and dimethylformamide (0.05 ml) is heated at boiling temperature under reflux for 2 hours. NMR shows completion of the reaction. Thionyl chloride is distilled off, replacing it with toluene (56 ml). The solvent is removed in vacuum to obtain the carboxylic acid as a white solid (9,46 g, 97%).

1H NMR (CDCl3) to 8.12 (DD, J = 1 Hz, 8 Hz, 1H), 7,70-7,37 (m, 7H).

13C NMR CDCl3(CO) 168.

B. [3-(2-Hydroxy-ethyl)-4-hydroxymethylene] amide 4'-triptorelin-2-carboxylic acid (10)

Pt-C (50% wet, 200 mg) are added to a solution of 2-(2-hydroxymethyl-5-nitrophenyl)ethanol (1.0 g, 5 mmol) in THF (40 ml) and the reaction mixture hydronaut for two hours at a pressure of 50 pounds per square inch (283446 PA). NMR shows the complete reaction with the formation of 2-(5-amino-2-hydroxymethylene)ethanol (compound (9) according to scheme 3).

1H NMR (CDCl3) was 7.08 (d, J = 2 Hz), 1H), 6,54-6,50 (m, 2H), 4,51 (s, 2H), 3,82 (t, J = 6 Hz, 2H), 3,80-2,95 (user.S., 4H), 2,84 (t, J = 6 Hz, 2H).

The catalyst is filtered off, l-2-carbonylchloride (1.44 g, 5 mmol) in THF (10 ml). The contents stirred for 24 hours, the solvent is removed in vacuum and add ethyl acetate (40 ml). The organic phase is washed with water (2 x 40 ml), dried with magnesium sulfate, removed of the solvent in vacuum and treat the residue with toluene (3 x 40 ml). Upon removal of solvent receive 2,11 g of white solid product, which is left in methylene chloride (21 ml) for 18 hours, then the product is filtered and dried to obtain specified in the header of the product in the form of a white solid product, 1,71 g (81%).

1H NMR (CD3)2SO 10,22 (s, 1H), 7,73 (d, J = 8 Hz, 2H), 7,62-28 (m, 8H), 7,20 (d, J = 8 Hz, 1H), 4,96 (user.S., 1H), 4,69 (user.S., 1H), 4,43 (s, 2H), 3,51 (t, J = 7 Hz, 2H), to 2.67 (t, J = 7 Hz, 2H).

IR (KBr) 3264, 3232, 3127, 3124, 3106, 2956, 2928, 1649, 1613, 1533, 1328, 1129 cm-1.

13C NMR (CD3)2SO (CO amide) 167,7, aliphatic hydrocarbons 62,3, 61,1; 36,0. Analytical data for C23F3H20NO3(calculated %): 66,50, H is 4.85, N 3,37. Found: 66,29, H 4,79, N 3,27.

century (1,2,3,4-Tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid (compound II)

To a solution of [3-(2-hydroxyethyl)-4-hydroxymethylene]- amide 4'-triptorelin-2-carboxylic acid (214 mg, 0.51 mmol) and triethylamine (of 0.18 ml) in THF (8.5 ml) is added p is. Contents are then cooled to -78oC and add the ammonia, after which the reaction mixture is stirred for 18 hours at 25oC. Solvents are removed in vacuo, add methylene chloride (10 ml) and aqueous 1 n HCl solution and the contents stirred for 1 hour. The phases are separated and the aqueous phase is alkalinized with an aqueous solution of sodium hydroxide to pH 12. The organic phase is extracted with methylene chloride (4 x 10 ml), the solvent is removed in vacuum to obtain 108 mg of a white solid product, which chromatographic on silica gel, elwira 5% methanol/methylene chloride with 0.5% ammonium hydroxide. The product is obtained in the form of a white solid product (40 mg, 20%).

1H NMR (CDCl3) 7,76-6,83 (m, 11H), with 3.89 (s, 2H), 3,52 (d, J = 7 Hz, 0.5 H), 3.04 from (t, J = 6 Hz, 2H), 2,74 (m, 0.5 H) to 2.66 (t, J = 7 Hz, 2H), and 2.27 (s, 1H).

13C NMR (CD3Cl) (aliphatic hydrocarbons) 47,8, 43,6, 29,1.

Examples 196-197 demonstrate the method of preparing compounds according to the invention, which is illustrated in figure 3.

Example 196

(2-benzyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

To a solution of [3-(2-hydroxyethyl)-4-hydroxymethylene] amide 4'-triptorelin-2-carboxylic acid (100 mg, 0.24 moazam completion of the reaction after 30 minutes. Add benzylamine (0,132 ml) and the contents stirred for 18 hours at 25oC and 60 hours at 50oC. the Solvent is removed in vacuum, the residue is dissolved in methylene chloride (15 ml), washed with a buffer with a pH of 9, the phases are separated and the organic phase is dried with magnesium sulfate. Removal of solvent in vacuo gives the crude product as a white solid (204 mg), which contribute in CDCl3, filtered and dried to obtain the product as a white solid (46 mg, 39%). So pl. = 230-32oC.

1H NMR (CD3)2SO 7,73 (d, J = 8 Hz, 2H), 7,60-23 (m, 12H), 7,17 (d, J = 8 Hz, 1H), 6.87 in (d, J = 8 Hz, 1H), 3,60 (s, 2H), 3.43 points (s, 2H), 2,71 (m, 2H), 2,62 (m, 2H).

Analytical data for C30F3H25N2O (calculated %): 74,06, H 5,18, N 5,76. Found: 74,08, H 5,38, N 5,76.

Example 197

(2-allyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid

Methanesulfonanilide (0,41 ml of 0.53 mmol) is added dropwise to a solution of triethylamine (0,084 ml of 0.60 mmol) and [3-(2-hydroxyethyl)-4-hydroxymethylene] amide 4'-triptorelin-2-carboxylic acid (0.1 g, 0.24 mmol) in THF (2 ml) at -20oC. 15 minutes after you have finished adding contribute allylamine (and 0.09 ml, 1.2 mmol), soderman removed in vacuum, add methylene chloride (10 ml) and the organic phase is washed with water to pH 12 (10 ml). The organic solvent is removed in vacuum to obtain 281 mg of crude product. This material chromatographic on silica gel, carrying out elution with 10% methanol/methylene chloride to obtain the product as a white solid (91 ml, 87%)

1H NMR (CDCl3) 7,80 (d, J = 8 Hz, 1H), 7,68 (l, J = 8 Hz, 2H), 7,60-7,42 (m, 5H), 6,93-6,83 (m, 3H), 6,00 and 5.86 (m, 1H), 5,27-5,17 (m, 2H), 3,55 (s, 2H) and 3.15 (d, J = 7 Hz, 2H), and 2.83 (t, J = 6 Hz, 2H), 2,69 (t, J = 6 Hz, 2H), 1,66 (user.S., 1H).

13C NMR (CD3Cl) (only aliphatic carbon) 61,4, 55,6, 50,3, 29,1.

Reduction of triglycerides (30%) in mice are presented in table 1.

1. Amides of the formula I

< / BR>
where X represents CH2, CO, CS or SO2,

Y is selected from a direct link, aliphatic hydrocarbonrich radicals containing up to 20 carbon atoms, which may be monogamist hydroxy; (C1- C10)alkoxy, (C1- C10)acyl, (C1- C10)acyloxy or (C6- C10)aryl, NH and O,

provided that when X represents CH2Y represents a direct link,

Z is selected from the following groups: (1) H, halogen, cyano; (2) hydroxy, (C1- C10)alkoxy, (C1
- C10)alkylamino, (C6- C10)aryl(C1- C10)alkylamino, provided that Y cannot be O or NH, (4) unsubstituted vinyl, (C6- C10)aryl, (C3- C8)cycloalkyl and their condensed besprovodnyh, (C7- C10)politically, (C4- C8)cycloalkenyl, (C7- C10)politicologie, (5) (C6- C10)aryloxy, (C6- C10)aaltio, (C6- C10)aryl(C1- C10)alkoxy, (C6- C10)aryl(C1- C10)alkylthio, (C3- C8)cycloalkane, (C4- C8)cycloalkenyl, (6) heterocyclyl selected from the group consisting of monocyclic radicals and condensed polycyclic radicals, where these radicals contain from 5 to 10 ring atoms, where these radicals contain from 1 to 4 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, and where the individual rings of the mentioned radicals may be independently saturated, partially saturated or aromatic, provided that if X is CH2Z represents H or is selected from groups (4) and (6), where, when Z contains one or more rings, these rings may each, independently, onila, phenyl, phenoxy, phenylthio, halogenfrei, benzyl, benzyloxy, (C1- C10)alkyl, (C1- C10)alkoxy, (C1- C10)alkoxycarbonyl, (C1- C10)alkylaminocarbonyl, di(C1- C10)alkylamino, di(C1- C10)-alkylaminocarbonyl, di(C1- C10)alkylamino(C1- C10)alkoxy, (C1- C3)perfluoroalkyl, (C1- C10)acyl, (C1- C10)acyloxy, (C1- C10)acyloxy (C1- C10)alkyl and pyrrolidinyl,

and its pharmaceutically acceptable salts.

2. Connection on p. 1 and its pharmaceutically acceptable salts, where X denotes CH2, CO or SO2Y is selected from: a direct link, NH, (C1- C10)alkylene and (C2- C10)Alcanena, each of which may be substituted by phenyl, provided that when X is CH2Y denotes a direct bond, Z is selected from the following groups: (1) H, (2) (C1- C10)alkoxy, (C1- C10)alkylthio, (3) di(C1- C10)alkylamino, (C6- C10)aryl (C1- C10)alkylamino, provided that Y represents NH, (4) unsubstituted vinyl, (C6- C10)aryl, (C3- C8)cycloalkyl, (C4- C8)cycloalkenyl, (5) (Cthe Kie radicals, which may be saturated, partially unsaturated or aromatic, and their condensed besprovodnyh, where these radicals may contain from 1 to 3 ring heteroatoms independently selected from oxygen, nitrogen and sulfur, provided that when X is CH2Z is selected from groups (4) and (6), where, when Z contains one or more rings, these rings may each independently have from 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, (C1- C6)alkyl, (C1- C6)alkoxy, di(C1- C6)alkylaminocarbonyl, (C1- C10)acyl and (C1- C10)acyloxy.

3. Connection on p. 2 and its pharmaceutically acceptable salts, where X denotes methylene, Y denotes a direct bond, Z is selected from (C6- C10)aryl, (C3- C8)cycloalkyl and (C4- C8)cycloalkenyl, each of which can have from 0 to 3 of these independent deputies.

4. Connection on p. 2 and its pharmaceutically acceptable salts, where X denotes methylene or CO, Y represents a direct bond and Z represents heterocyclyl selected from thiophenyl, pyrrolidinyl, pyrrolyl, furanyl, thiazolyl, isoxazolyl, imidazolyl, 1,2,4-triazolyl, sing from 0 to 3 of these independent deputies.

5. Connection on p. 2 and its pharmaceutically acceptable salts, where X denotes CH2or CO, Y represents a direct bond, Z represents H, unsubstituted vinyl, phenyl, imidazolyl, thiazolyl, thiophenyl, 1,2,4-triazolyl, pyridinyl and pyrimidinyl.

6. Connection on p. 5, where X denotes CO.

7. Connection on p. 5, where X denotes CH2.

8. Connection on p. 1, where the connecting group formed by a ring nitrogen 1,2,3,4-tetrahydroisoquinoline ring shown in the formula I, together with the group - XYZ, which concatenates the specified XYZ part with the specified ring nitrogen, selected from

< / BR>
9. Connection on p. 8 where the specified bridge group is Amida.

10. Connection on p. 9, selected from the group consisting of: (2-phenylacetyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid (2-phenoxyacetyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid (2-pentanoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid (2-cyclobutanecarbonyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, [2-(thiophene-2-yl-acetyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-(2-ethoxyacetic-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, {2-[(4-forfinal)acetyl] -1,2,3,4-tetrahydroisoquinoline-6-yl} amide 4'-triptorelin-2-carboxylic acid, [2-(3-methylbutyryl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid (2-but-3-enoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid (2-methoxyacetyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid (2-ethylthioethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, [2-(6-diethylcarbamoyl-3-incarbone)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, [2-(cyclopent-1-unilateral)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, (2-Gex-3-enoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, [2-(tetrahydrofuran-3-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, [2-(thiophene-3-ylacetic)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid [2-(pyridine-2-carbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid.

11. Connection on p. 8 where the specified bridge group is ostenil-2-carbonyl)amino] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid, exiled 6-[(4'-triptorelin-2-carbonyl)amino] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid, benzylamine 6-[(4'-triptorelin-2-carbonyl)amino] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid [(R)-1-phenylethyl] amide 6-[(4'-triptorelin-2-carbonyl)amino] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid and pyridine-2-alamid 6-[(4'-triptorelin-2-carbonyl)amino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid.

13. Connection on p. 8 where the specified bridge group is a sulfonamide.

14. Connection on p. 13, selected from the group consisting of: [2-(propane-2-sulfonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid (2-dimethylsulphamoyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid [2-(2-trifloromethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid.

15. Connection on p. 8 where the specified bridge group is a remnant of thiourea.

16. Connection on p. 15, which is a (2-cyclopropanecarbonyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid.

17. Connection on p. 8 where the specified binder logex-2-animetal)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, [2-(2,4-dichlorobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, [2-(1,5 a, 6,9,9 a, 9b-hexahydro-4H-dibenzofuran-4a-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid (2-thiophene-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, [2-(1H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid (2-furan-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, 5-{ 6-[(4'-triptorelin-2-carbonyl)amino] -3,4-dihydro-1H-isoquinoline-2-ylmethyl} furan-2-ymetray ether acetic acid, (2-thiophene-3-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, [2-(2,5-dimethoxytetrahydrofuran-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid (2-benzyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, (2-pyridine-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid (2-quinoline-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, [2-(3-Chlorobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] laiformaadiline-2-carboxylic acid, [2-(3-nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, [2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, [2-(1-methylpyrrole-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, [2-(1H-benzimidazole-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid (2-thiazol-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, [2-(1-Mei-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, [2-(1H-/1,2,4/triazole-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid and [(2-allyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid.

19. Connection on p. 8, where the specified binding group is a carbamate.

20. Connection on p. 19, which represents a tert-butyl ester 6-[(4'-triptorelin-2-carbonyl)amino] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid.

21. Connection on p. 8, where the specified binder group is timid.

22. Connection on p. 8, selected from the group Y, ([R]-1-phenylethyl) amide 6-[(4'-triptorelin-2-carbonyl)amino] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid (2-pyridin-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, [2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid, (2-thiazol-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid [2-(1H-[1,2,4]triazole-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid.

23. Connection on p. 22, which is [2-(thiophene-2-ylacetic)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid.

24. Connection on p. 22, which represents a (1-phenylethyl) amide 6 -[(4'-triptorelin-2-carbonyl)amino] -3,4-dihydro-1H-isoquinoline-2-carboxylic acid.

25. Connection on p. 22, which represents a (2-pyridin-2-ylmethyl-1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid.

26. Connection on p. 22, which is [2-(1H-imidazol-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid.

27. Connection on p. 22, Coteau acid.

28. Connection on p. 22, which is [2-(1H-[1,2,4]triazole-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-6-yl] amide 4'-triptorelin-2-carboxylic acid.

29. Pharmaceutical composition for reducing the secretion of apolipoprotein B in mammals containing the compound of formula I under item 1 in an effective amount and a pharmaceutically acceptable carrier.

30. The composition according to p. 29, optionally containing an agent that reduces the content of lipids.

31. The way to reduce the secretion of apolipoprotein B in mammals for the treatment of a condition selected from the group including atherosclerosis, pancreatitis, obesity, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, and diabetes, which consists in the introduction of a mammal in need of such treatment, the compounds of formula I on p. 1 in a quantity sufficient to reduce the secretion of apolipoprotein B.

32. The method according to p. 31, where the specified condition selected from the group including atherosclerosis, pancreatitis, obesity, and diabetes.

33. The method according to p. 32, where the specified condition is a atherosclerosis.

34. The way to reduce the secretion of apolipoprotein B in mammals, which consists in the introduction of the specified mlekopitayushchie from: (1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid, [3-(2-hydroxyethyl)-4-hydroxymethylene] amide 4'-triptorelin-2-carboxylic acid, 2-(2-hydroxymethyl-5-nitrophenyl)ethanol, tert-butyl ester 6-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid and 2-(5-amino-2-hydroxymethylene)ethanol.

36. Connection on p. 35, selected from: (1,2,3,4-tetrahydroisoquinoline-6-yl) amide 4'-triptorelin-2-carboxylic acid [3-(2-hydroxyethyl)-4-hydroxymethylene] amide 4'-triptorelin-2-carboxylic acid.

37. Connection on p. 35, which represents a tert-butyl ester 6-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid.

 

Same patents:

The invention relates to bicyclic compounds having a core formed of two condensed six-membered cycles, such as isoquinoline, izoliranim, tetrahydronaphthalene, dihydronaphthalene or tetralone, replaced both acidic and basic functional groups, which are useful in the inhibition of aggregation of erythrocytes

The invention relates to new compounds of formula I, where b and E are independently selected from CH or N; R4is hydrogen, halogen, hydroxy; G represents the compounds of formula II (a, b, c) and their optical and geometric isomers; and nontoxic pharmaceutically acceptable acid salt additive

The invention relates to tetraethylammonium compounds of the formula I

< / BR>
and their pharmaceutically acceptable salts,

where R1represents one or more substituents selected from H, halogen, hydroxy, alkyl with 1 to 3 carbon atoms (optionally substituted by hydroxyl), alkoxyl with 1 to 3 carbon atoms, alkylthio with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, nitro, cyano, Polygalaceae with 1 to 3 carbon atoms, polyalkyloxy with 1 to 3 carbon atoms, phenyl (optionally substituted by one or more substituents selected from halogen, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon atoms), or R1is carbamoyl, optional alkilirovanny one or two alkyl groups, each independently from 1 to 3 carbon atoms;

R2represents an aliphatic group containing 1 to 3 carbon atoms, optionally substituted by hydroxy or alkoxy containing 1 to 3 carbon atoms;

E represents alkylenes chain containing 2 to 5 carbon atoms, optionally substituted by one or more alkyl groups containing 1 to 3 atom is dinasovymi or different and are independently an alkyl of 1 3 carbon atoms, alkoxy with 1 to 3 carbon atoms, halogen, hydroxy, polyaluminum with 1 to 3 carbon atoms, polyalkyloxy with 1 to 3 carbon atoms, cyano, alkylthio with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, alkylsulfonyl with 1 to 3 carbon atoms, phenyl (optionally substituted by one or more substituents selected from halogen, alkyl with 1 to 3 carbon atoms or alkoxy with 1 to 3 carbon atoms), carbamoyl, optional alkilirovanny one or two alkyl groups, each of which is independently from 1 to 3 carbon atoms, or G represents a phenyl ring having condensed with him heterocyclic or aromatic carbocyclic ring,

and O-acylated derivatives

The invention relates to the chemical and petrochemical industry, more precisely, to receive dialkylamino aromatic acids, in particular N,N-diethyltoluamide-m-Truelove acid

The invention relates to a derived benzazepine with condensed nitrogen-containing aromatic 5-membered cycle, represented by formula I

The invention relates to bicyclic compounds having a core formed of two condensed six-membered cycles, such as isoquinoline, izoliranim, tetrahydronaphthalene, dihydronaphthalene or tetralone, replaced both acidic and basic functional groups, which are useful in the inhibition of aggregation of erythrocytes

The invention relates to medicine, namely, pulmonology, and is used to correct psevdoallergicakie reactions in patients with chronic obstructive lung disease

The invention relates to medicine, namely, neurology

The invention relates to the technology of known derivatives hinolincarbonova acid, in particular to a method for producing derivatives of 3-hinolincarbonova acid

The invention relates to medicine, namely to the chemical-pharmaceutical industry and relates to aqueous concentrated solution of argatroban

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

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

13 cl, 3 tbl, 35 ex

FIELD: medicine, oncohematology.

SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

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