C-glycoside derivatives and their salts

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

 

The technical field

This invention relates to a C-glycoside derivatives and their salts. More specifically this invention relates to a C-glycoside derivatives and their salts, useful as inhibitors of cotransporter Na+-glucose. Derivatives of C-glycosides and their salts of this invention are applicable for the treatment of various diseases associated with diabetes, including insulin-dependent diabetes (type 1 diabetes), non-insulin-dependent diabetes (type 2 diabetes), insulinorezistentne disease and obesity, as well as to prevent these diseases.

The level of technology

In recent years there has been a need in medicine for inhibiting the reabsorption of glucose by cotransporter Na+-glucose (SGLT) in the gastrointestinal tract and kidneys (the inhibitor of cotransporter Na+-glucose) as an antidiabetic agent for rapid normalization of hyperglycemia and improving the energy balance in the body. It is believed that this inhibitor cotransporter Na+-glucose is an excellent agent for the treatment or prevention of various diseases associated with diabetes, such as insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes), as well as insulinorezistentne diseases and obesity.

As compounds used as inhibitors of cotransporter Na +-glucose is known, for example, phloridzin (phloridzin), described in the publication Welch, C.A. et al., J. Natt., 1989, 119 (11), 1698, and synthetic O-glycoside derivatives described in publications Hongu, M. et al., Chem. Pharm. Bull., 1998, 46 (1), 22; JP-A-11-21243. These compounds, as reported, eliminate excess glucose from the blood into the urine and reduce the level of glucose in the blood by inhibiting the reabsorption of glucose by cotransporter Na+-glucose in the gastrointestinal tract or kidneys.

However, since any of these compounds is a derivative of O-glycoside, including On-glucosido connection formed between glucose and aglionby fragment, there is a problem associated with a reduction inhibitory effect due to hydrolysis of the O-glycosides due under the action of glucosidase or similar compounds in the small intestine after oral absorption.

In addition, in the case floridana (phloridin) phloretin, which is aglionby fragment floridana known as a strong inhibitor of the Transporter glucose facilitated diffusion type. For example, it was reported that cerebral glucose concentration decreases with the introduction of phloretin in a vein of rats (e.g., Stroke, 1983, 14, 388). The phloretin also known as inhibitor of the Transporter of vitamin C (Wang, Y. et al., Biochem. Biophys. Res. Commun., 2000, 267, 488-494).

Therefore, an attempt was made to use the with C-glycoside, obtained by the conversion of oxygen glucosides connection O-glycoside in carbon, as an inhibitor of cotransporter Na+-glucose.

For example, in the publication of JP-A-2001-288178 (Patent document 1), compounds represented by following formula effective in the inhibition of cotransporter Na+-glucose and applicable as a drug or a preventive agent for diabetes and as a hypoglycemic agent.

Chemical formula

where R1represents H, HE, a lower alkyl group, -O-lower alkyl group and the like; R2represents H, -COO-lower alkyl group and the like; R5represents-CH2HE, -CH2LLC-lower alkyl group and the like; And1represents a pyridine, furan, thiophene, quinoline, indole and the like; n is 0, 1, 2 or 3, and m is 0 or 1 (for a more detailed description of the characters above formulas, see Patent document 1).

In addition, in the description of WO 01/27128 (Patent document 2) States that the compound represented by the below formula can be used as an inhibitor of cotransporter Na+-glucose for the treatment of obesity or type 2 diabetes.

Chemical formula

where R1, R2and R2aindependently represent an atom bodoro is a, HE, OR5, alkyl, CF3, OCHF2, OCF3and the like; R3and R4independently represent a hydrogen atom, HE, OR5A, -O-aryl, -O-CH2aryl, alkyl, cycloalkyl, CF3and the like; And a represents O, S, NH or (CH2)nand n is 0, 1, 2 or 3 (for a more detailed description of the characters above formulas, see Patent document 2).

As explained above, the derivatives of C-glycosides to a certain extent applicable to the treatment of diabetes due to the inhibitory action against cotransporter Na+-glucose. However, due to the increase lately in the number of cases of diabetes, which is a disease related to lifestyle, and which could even be called one of the most common diseases in Japan, in clinical practice diabetes increases the need for compounds with a chemical structure different from the structures of known compounds, and showing a more rapid and effective inhibitory activity against cotransporter Na+-glucose.

Description of the invention

The authors of this invention, it was found that the C-glycoside derivatives, which contain a ring In ((1) a saturated or unsaturated eight-deletechannel the bicyclic heterocycle containing 1 to 4 heteroatoms, selected the C N, S and O, (2) a saturated or unsaturated five - or six-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O, (3) saturated or unsaturated eight-deletechannel bicyclic carbocycle or (4) a benzene ring)associated with the ring A ((1) a benzene ring, (2) five - or six-membered monocyclic heteroaryl ring containing 1 to 4 heteroatoms selected from N, S and O, or (3) a saturated or unsaturated eight-deletechannel the bicyclic heterocycle containing from 1 to 4 heteroatoms selected from N, S and O)by-X- (communication or lower alkylene), and the ring And is directly related to the glucose residue (where values of ring A, ring b and X are correlated in such a way that (1) when ring a is a benzene ring, the ring is a benzene ring or (2) when ring a is a benzene ring, the ring represents a saturated or unsaturated eight-deletechannel the bicyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O, including a benzene ring, or a saturated or unsaturated eight-deletechannel bicyclic carbocycle, including a benzene ring, and X is attached to the ring in a part other than the benzene ring included in the ring), and correspond to the following formula (I), the region which indicate significant inhibitory activity against cotransporter Na +-glucose, the result of which was successfully implemented by the invention. That is, this invention relates to compounds represented by formula (I)or their salts (hereinafter in the description of the compounds of this invention and their salts are sometimes called by the General term "compound of the present invention"). The compound of the present invention can suitably be used as an inhibitor of cotransporter Na+-glucose when using compounds as the active ingredient, particularly as a therapeutic agent or preventive agent for diabetes.

The chemical structure of the compounds of this invention differs from the structure of the compounds of Patent documents 1 and 2 so that the ring a and ring In the compounds of this invention at the same time may not represent a benzene ring. That is, this invention provides an inhibitor of cotransporter Na+-glucose having a new structure.

In particular, the invention provides derivatives of C-glycoside, described below, and their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, the use of these compounds for obtaining inhibitor cotransporter Na+-glucose or antidiabetic agent, and methods of treatment of diabetes.

[1] Derived C-glycoside is ormula (I) and their salts:

Chemical formula

where ring a is a (1) a benzene ring, (2) five - or six-membered monocyclic heteroaryl ring containing 1 to 4 heteroatoms selected from N, S and O, or (3) a saturated or unsaturated eight-deletechannel the bicyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O;

the ring represents (1) a saturated or unsaturated eight-deletechannel the bicyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O, (2) a saturated or unsaturated five - or six-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O, (3) saturated or unsaturated eight-deletechannel bicyclic carbocycle, or (4) a benzene ring;

X represents a bond or a lower alkylene;

(where values of ring A, ring b and X are correlated in such a way that (1) when ring a is a benzene ring, the ring is a benzene ring or (2) when ring a is a benzene ring, the ring represents a saturated or unsaturated eight-deletechannel the bicyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O, including a benzene ring, or a saturated or unsaturated eight-deletechannel bellicheck the th carbocycle, includes a benzene ring, X is attached to the ring in a part other than the benzene ring included in the ring; in particular, this correlation is specifically means that the ring a and the ring may not simultaneously be benzene rings and which, when the ring a is a benzene ring and the ring is benzofuran or indan, X not attached to the benzene ring, forming part of a ring, and to a furan ring or a cyclopentane ring).

R1-R4each individually represents a hydrogen atom, a lower alkyl, -C(=O)-lower alkyl or-lower alkylene-aryl; and

R5-R11each individually represents a hydrogen atom, lower alkyl, cycloalkyl, halogen, halogen-substituted lower alkyl, -HE, =O, -NH2, lower alkyl-sulfonyl-, halogen-substituted lower alkyl-sulfonyl-, arylsulfonyl-, aryl, saturated or unsaturated five - or six-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O, lowest alkylene-OH, -lower alkylene-O-lower alkyl, -lower alkylene-O-C(=O)-lower alkyl, -lower alkylene-O-lower alkylene-COOH, -lower alkylene-O-lower alkylene-C(=O)-O-lower alkyl, -lower alkylene-NH2-the inferior alkylene-NH-lower alkyl, -lower alkylene-N(lower alkyl)2-the inferior alkylene-NH-C(=O)-lower alkyl, -COOH, -CN, -C(=O)-O-nishiuchi, -C(=O)-NH2, -C(=O)-NH-lower alkyl, -C(=O)-N(lower alkyl)2, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-NH-lower alkyl, -O-lower alkylene-C(=O)-N(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(HE), -O-lower alkylene-NH2, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N(lower alkyl)2, -NH-SO2-lower alkyl, -NH-SO2-halogen-substituted lower alkyl, -NH-lower alkylene-OH, -NH-C(=O)-lower alkyl, -NH-C(=O)-NH2, -NH-C(=O)-NH-lower alkyl, -NH-C(=O)-N(lower alkyl)2or-NH-C(=O)-O-lower alkyl;

where-N(lower alkyl)2in R5-R11apart from the case when it is formed of the same low alkilani, includes the case where it is formed of different lower alkilani. -N(lower alkyl)2includes, for example, methylaminopropyl.

[2] Derived C-glycoside and their salts according to the above item [1], where the ring a in the formula (I) represents (1) a benzene ring or (2) five - or six-membered monocyclic heteroaryl ring containing 1 to 4 heteroatoms selected from N, S and O.

[3] Derived C-glycoside and their salts according presents you the e item [2], where the ring in the formula (I) represents (1) a saturated or unsaturated eight-deletechannel the bicyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O, or (2) a saturated or unsaturated five - or six-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O.

[4] Derived C-glycoside and their salts according to the above item [3], where the ring a in the formula (I) is a benzene ring, and the ring is a saturated or unsaturated eight-deletechannel the bicyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O.

[5] Derived C-glycoside and their salts according to the above item [4], where X in the formula (I) represents methylene.

[6] Derived C-glycoside and their salts according to the above item [5], where R1-R4in the formula (I) are hydrogen atoms.

[7] Derived C-glycoside and their salts according to the above item [1], where the derived C-glycoside of the formula (I) represents at least one compound selected from the group comprising (1S)-1,5-anhydrous-1-[3-(1-benzothieno-2-ylmethyl)phenyl]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-hydroxyphenyl]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-methoxyphenyl]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-ylmethyl)-2-(2-hydroxyethoxy)phenyl]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(methylamino)phenyl]-D-glucit, (1S)-1,5-anhydrous-1-{[5-(1-benzothieno-2-ylmethyl)-2-[(2-hydroxyethoxy)amino]phenyl}-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-methoxyphenyl]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-chlorophenyl]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-forfinal]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2,4-acid]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-chloro-2-methoxyphenyl]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-chloro-2-hydroxyphenyl]-D-glucit, (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-fluoro-2-hydroxyphenyl]-D-glucit and (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-fluoro-2-methoxyphenyl]-D-glucit.

[8] the Pharmaceutical composition containing the derivative C-glycoside or its salt according to any of the above items[1]-[7].

[9]The pharmaceutical composition according to above item [8], where the composition is an inhibitor of cotransporter Na+-glucose.

[10] the Pharmaceutical composition according to above item [8], where the composition is an antidiabetic agent.

[11] the Application of the derived C-glycoside and their salts according to any one of above items [1]to[7] for inhibitor cotransporter Na+-glucose or antidiabetic agent.

[12 method for the treatment of diabetes, includes introduction to the patient an effective amount derived C-glycoside and their salts according to any of the above items[1]-[7].

The best option is the implementation of the present invention

The best option is the implementation of the present invention will be described in detail below.

Examples of "five - or six-membered monocyclic heteroaryl ring containing 1 to 4 heteroatoms selected from N, S and O include pyridine, pyrimidine, pyrazin, thiophene, pyrrole, furan, thiazole, oxazole, imidazole, triazole and tetrazole. Preferred among them are pyridine, thiophene, furan and tetrazole.

Examples of a saturated or unsaturated eight-decatizing bicyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O"s, include benzofuran, benzothiophene, indole, benzoxazole, benzothiazole, benzimidazole, quinoline, isoquinoline, hinzelin, cinoxacin and tetrahydroisoquinoline. Preferred among them are benzofuran, benzothiophene, benzoxazole and benzothiazole.

Examples of the "saturated or unsaturated five - or six-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from N, S and O"s, include pyridine, pyrimidine, pyrazin, thiophene, pyrrole, furan, thiazole, oxazole, imidazole, triazole, tetrazole, morpholine, piperidine, pyrrolidine and piperazine. Preferred is considerable among them are pyridine, thiophene, furan, tetrazole, morpholine, piperidine and pyrrolidine.

Examples of a saturated or unsaturated eight-decatizing bicyclic carbocycle include indan, inden, tetrahydronaphthalen. Preferred among them is inden.

In defining formulas in this specification, the term "lower(Aya)" applies, except in special cases, a linear or branched carbon chain containing 1-6 carbon atoms. Accordingly, the examples of "lower alkyl" include linear or branched alkali containing 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl. Preferred among them are alkali containing 1-3 carbon atoms, especially preferred methyl and ethyl.

As "lower alkylene" in addition to methylene, ethylene, propylene and butylene, can be used branched lower alkylene. Preferred among them are methylene and ethylene.

Examples of "cycloalkyl include three to eight-membered cycloalkyl. Preferred among them are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Examples of the "halogen atom" include fluorine atom, chlorine atom, bromine atom and iodine atom. Preferred among them are fluorine atom, chlorine atom and bromine atom.

Examples of "g the lågen-substituted lower alkyl and halogen-substituted lower alkylene" include lower alkyl, substituted as defined above by a halogen atom, and a lower alkylen, defined above substituted by a halogen atom, respectively. Especially preferred among these are the lower alkyl and lower alkylene substituted by one or more fluorine atoms.

The term "aryl" refers to a mono-to tricyclic aromatic hydrocarbon group containing 6-14 carbon atoms. Examples of aryl include phenyl, naphthyl, anthranol and tenantry. Preferred among them are phenyl and naphthyl.

Examples of "lower alkylaryl" include benzyl and phenethyl.

Examples of acyl include formyl, acetyl, propionyl, butyryl, valeryl and pivaloyl. Preferred among them is acetyl.

In R5-R11group "=O" represents oxoprop. However, when the ring a or the ring is a pyridine ring, "=O" sometimes means N-oxide pyridine ring, and in this case, the ring is exoperidium.

In addition, the compounds of this invention include a mixture or a product of different stereoisomeric forms, such as tautomers, or optical isomers.

The compounds of this invention can form acid-salt or additive, depending on the type of Deputy salts with bases. Specific examples of such salts include acid additive salts with a mineral is diversified acid, such as hydrochloric acid, Hydrobromic acid, itestosterone acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate acid and econsultancy acid, or acidic amino acids such as aspartic acid and glutamic acid; salts with inorganic bases, e.g. sodium, potassium, magnesium, calcium and aluminium salts; organic bases such as methylamine, ethylamine, and ethanolamine; or with basic amino acids such as lysine and ornithine; and ammonium salt.

The compounds of this invention include hydrates and various pharmaceutically acceptable solvate and polymorph.

Of course, the compounds of the present invention should not be limited to the compounds described in the following examples, but include all compounds of the above formula (I) (derived C-glycoside) and their pharmaceutically acceptable salts.

In addition, the compounds of this invention include the so-called prodrugs, which are compounds, the method is passed in the body during metabolism can be transformed into compounds of the above formula (I) or their salts. As a group, to obtain prodrugs of the compounds of this invention may be taken by the group, described in the publication Prog. Med. 5: 2157-2161 (1985), or group described in the publication "Development of Pharmaceuticals", vol. 7, Molecular Design, 163-198 (Hirokawa Shoten, 1990).

The compounds of this invention (compounds of the above formula (I) or their pharmaceutically acceptable salts can be obtained by various methods of synthesis using the characteristics based on their basic structure or structures of the Deputy. In this case, it may be efficient from the point of view of the method of obtaining substitute functional groups suitable protecting group, i.e. a group which can easily turn into a functional group, in the initial compound or intermediate product depending on the type of functional group. Then optional protective group is removed to obtain the target compound. Examples of such functional groups include hydroxyl group and carboxyl group, examples of the protective group for such functional groups include protective groups described in the publication Greene and Wuts, "Protectove Groups in Organic Synthesis", Thrird Edition. These groups may suitably be used in accordance with the conditions of the reactions.

Examples of receipt

Examples of typical methods for obtaining the compounds of this image is etenia will be described below:

The method of obtaining 1

In the method of obtaining 1 is the reaction of the accession of the halide (1) to the derived aldehyde (2) with subsequent restoration, the reaction accession derived lactone (4), followed by reduction to obtain a compound of formula (I) and removing the protective groups from the compound (I) to obtain the compound (I'), as shown in the following synthesis scheme.

The scheme of synthesis

where ring A, ring B, X and R1-R11in formulas take the values defined above.

The reaction joining halide (1) to the derived aldehyde (2) is carried out in the presence of alkyllithium reagent, such as n-utility, second-utility or tert-utility, in a suitable solvent. Specific examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and diglyme, and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from about -100°With up to approximately 180°C, preferably in the range of from about -80°With up to about 30°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

Subsequent reaction of the recovery is carried out in the presence of a suitable reset is novices and acid catalyst in a suitable solvent. Specific examples of reducing agents include triethylsilane, triisopropylsilane and tert-butyldimethylsilyl. Specific examples of the acid catalyst include a complex of boron TRIFLUORIDE-diethyl ether, triperoxonane acid and trimethylsilyltrifluoromethane. Specific examples of the solvent include halogenated, such as chloroform, dichloromethane and 1,2-dichloroethane; ethers, such as diethyl ether, tetrahydrofuran and diglyme; acetonitrile; and mixtures of these solvents; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from about -100°With up to approximately 180°C, preferably in the range of from about -40°With up to about 20°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

Subsequent reaction of the accession derived lactone (4) is carried out in the presence of alkyllithium reagent, such as n-utility, second-utility or tert-utility, in a suitable solvent. Specific examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and diglyme, and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature usually find the camping in the range of from about -100° With up to approximately 180°C, preferably from approximately -80°With up to about 30°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

Subsequent reaction of the recovery is the same as described above for the reaction of recovery.

Removing the protection is carried out in the presence of a metal catalyst such as palladium/carbon, palladium hydroxide, or platinum/carbon, in a suitable solvent in the atmosphere of hydrogen or in the presence of a Lewis acid in a suitable solvent. Specific examples of the Lewis acid include trichloride boron, tribromide boron and trichloride aluminum. Specific examples of the solvent include ethers such as tetrahydrofuran and dioxane; esters such as ethyl acetate; alcohols such as methanol and ethanol; acetonitrile; and mixtures of these solvents, and the solvent is appropriately selected in accordance with types of the reaction substrate or the reaction conditions. The reaction temperature is in the range from about -100°With up to approximately 180°C, preferably from about -40°With up to about 20°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

The method of obtaining 2

In the method of obtaining 2 are reaction accession derived aldehyde (5) to the halide (6) after the existing recovery the reaction accession derived lactone (4) with subsequent restoration of obtaining the compound (I) and removing the protecting compound (I) to obtain the compound (I'), as shown in the following synthesis scheme.

The scheme of synthesis

where ring A, ring B, X and R1-R11in formulas take the values defined above.

The reaction accession derived aldehyde (5) to the halide (6) is similar to the reactions of addition of the halide (1) to the derived aldehyde (2).

Alternative reaction joining can be carried out by the interaction of the compound (6) with compound (5) in a suitable solvent using a Grignard reagent obtained using as reagent metal, such as magnesium. Specific examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and diglyme; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from approximately 0°With up to approximately 180°C, preferably from about 20°C to about 80°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

Subsequent reaction of the recovery is similar reactions vos is Stanovlenie, described in the method of obtaining 1.

Subsequent reaction of the accession derived lactone (4) is similar to the reactions of addition of the derived lactone (4) in the method of obtaining 1.

Subsequent reaction of the recovery is carried out similarly to the reaction of the recovery method of obtaining 1.

The removal of the protection is the same as removing the protection described in the method of obtaining 1.

The method of obtaining 3

In the method of obtaining 3 is the substitution reaction of compound (8) with compound (9) in a suitable solvent, followed by alkylation of the halide (11) to obtain the compound (I) and removing the protecting compound (I) to obtain the compound (I').

The scheme of reactions

where ring A, ring B, X and R1-R11in formulas take the values defined above, and Y represents a group which is subject to removal. Examples of the group which is subject to elimination, are halide, acetoxy, triptoreline, tripterocalyx.

The substitution reaction is carried out in a suitable solvent in the presence of a suitable Grignard reagent. Specific examples of the Grignard reagent include methylmagnesium, ethylmagnesium and isopropylaniline. Specific examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and diglyme; benzene; and mixtures of these solvents; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from approximately 0°With up to approximately 180°C, preferably from about 20°C to about 80°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

The alkylation is conducted in the presence of a suitable base. Specific examples of the base include potassium hydroxide; sodium hydroxide; and Grignard reagents include methylmagnesium, ethylmagnesium and isopropylaniline. Specific examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and diglyme; benzene; and mixture of these solvents; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from approximately 0°With up to approximately 180°C, preferably from about 20°C to about 80°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

The removal of the protection is the same as removing the protection described in the Method of obtaining 1.

The method of obtaining 4

In the Method of obtaining a 4 in alcohol (12) security is introduced, followed what eakley accession derived lactone (4), then restore with the subsequent removal of the protection to obtain compound (13), which undergoes oxidation and reaction of the joining connection (15), followed by reduction to obtain compound (I) and removing the protecting compound (I) to obtain the compound (I').

The scheme of synthesis

where ring A, ring B, X and R1-R11in formulas take the values defined above, and Y and Z are halogen or hydrogen.

The alcohol (12) security is introduced in accordance with the General method, for example, enter an appropriate protective group such as tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and tetrahydropyranyl group. Then, a reaction accession derived lactone (4) in a suitable solvent in the presence of alkyllithium reagent, such as n-utility, second-utility and tert-utility. Specific examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and diglyme; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from about -100°With up to approximately 180°C, preferably from approximately -80°With up to about 30°With, although it varies depending on the type and the output connections, the reaction conditions, etc.

Subsequent reaction of the recovery is carried out similarly to the reaction of recovery described in the method of obtaining 1.

Subsequent removal of the protection is carried out in a suitable solvent in the presence of a suitable catalyst. Examples of catalysts include tetrabutylammonium fluoride, a complex of boron TRIFLUORIDE and ethyl ether, hydrogen fluoride, acetic acid and p-toluensulfonate acid. Examples of the solvent include ethers such as tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; water and a mixture of these solvents; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from about -100°With up to approximately 180°C, preferably from about 20°C to about 80°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

The subsequent oxidation is carried out in a solvent in the presence of a suitable oxidant. Specific examples of the oxidant include manganese dioxide, hydrogen peroxide and chlorproma pyridinium. Specific examples of the solvent include ethers such as tetrahydrofuran and dioxane; halogenated, such as chloroform, dichloromethane and 1,2-dichloroethane; and mixtures of these solvents is; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from about -100°With up to approximately 180°C, preferably from about 20°C to about 80°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

Subsequent reaction of the joining is carried out similarly to the reactions of addition of the halide (1) to the derived aldehyde (2)described in the production method of (1).

Subsequent reaction of the recovery is carried out similarly to the reaction of recovery described in the method of obtaining 1.

The removal of the protection is the same as removing the protection described in the method of obtaining 1.

The method of obtaining 5

In the method of obtaining 5 connection (16) alone or the compound (16) with the metal is exposed(are) interaction to obtain a metal-containing reagent that undergoes interaction with compound (17) in the presence of a palladium catalyst and optionally a suitable phosphine to obtain the compound (I)and compound (I) is removed protection to obtain the compound (I').

The scheme of reactions

where ring A, ring B, X and R1-R11in formulas take the values defined above, Y represents the Oh group, which is subject to removal. Examples of the group which is subject to elimination, are halogen, acetoxy, triptoreline, cryptometrics. Z represents a hydrogen atom, MeS-, Ra3Sn - (RaO)2B-. Rarepresents lower alkyl.

Specific examples of the metal used in the reaction with compound (16) with compound (17), including copper, zinc, iron and magnesium. Specific examples of the palladium catalyst include tetranitropentaerithrite (0), palladium acetate (II)dichloride bestlifeinsurance (II) and tridimensionality (0). Specific examples of the phosphine include triphenylphosphine, triphenylphosphine, diphenylphosphinite, diphenylphosphinoethyl, dicyclohexylphosphino and titrat-butylphosphine. Specific examples of the solvent include ethers such as diethyl ether, tetrahydrofuran and diglyme; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature usually ranges from about 20°With up to approximately 180°C, preferably from about 40°C to about 100°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

The removal of the protection is the same as removing the protection described in the method of obtaining 1.

The method of obtaining 6

In the method of obtaining 6 nitrile compound is subjected to a cyclization reaction to obtain the alkylated compound (I) with subsequent removal of the protection to obtain the compound (I)'.

The scheme of synthesis

where ring A, ring B, X and R1-R11in formulas take the values defined above, Y represents a group which is subject to removal. Examples of the group which is subject to elimination, are halogen, acetoxy, triptoreline, tripterocalyx.

The cyclization reaction is carried out in a suitable solvent in the presence of the appropriate azido-derivative and amine hydrochloride. Specific examples of azido-derivative include sodium azide and trimethylsilyl. Specific examples of the amine include triethylamine, triisopropanolamine and diisopropylethylamine. Specific examples of the solvent include dimethylformamide; dimethylsulfoxide; N-organic; 1,3-dimethyl-2-imidazolidinone; and mixtures of these solvents; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from about -100°With up to approximately 180°C, preferably from about 20°C to about 80°With, although it varies depending on the type of source connect the developments the reaction conditions, etc.

The alkylation is carried out in a suitable solvent in the presence of halide (13) and the appropriate amine. Specific examples of the amine include triethylamine, diisopropylethylamine and pyridine. Examples of the solvent include ethers such as tetrahydrofuran and dioxane; dimethylformamide; acetonitrile; and a mixture of these solvents; and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from about -100°With up to approximately 180°C, preferably from about 20°C to about 80°With, although it varies depending on the type of starting compounds, reaction conditions, etc.

Removing the protection is carried out in the presence of a suitable base. Specific examples of the base include sodium hydroxide; potassium hydroxide; sodium carbonate; potassium carbonate; sodium methoxide and ethoxide sodium. Specific examples of the solvent include alcohols such as methanol and ethanol; water and mixtures of these solvents, and the solvent is appropriately selected in accordance with the type of the reaction substrate or the reaction conditions. The reaction temperature is usually in the range from about -100°With up to approximately 180°C, preferably from about 20°C to about 80°although it is varies depending on the type of the original compounds, the reaction conditions, etc.

EXAMPLES

Further, the compounds of this invention will be described in more detail using examples. Because the source of the substance to obtain the compounds of this invention include the new compounds, methods of obtaining these compounds are also described in the reference examples.

Reference example 1

Potassium carbonate (2,08 g) is added to a solution of 5-bromo-2,4-dihydroxybenzaldehyde (1,09 g) in acetone (20 ml) and the mixture is stirred for 30 minutes at room temperature. Then to the reaction mixture add chloromethylation ester (1.01 g) and the mixture is stirred over night at room temperature. To the reaction mixture are added water and toluene, the toluene layer is separated and then washed with saturated sodium hydrogen carbonate solution and saturated salt solution, then dried and filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain a solid residue. The solid residue was washed with diisopropyl ether and dried, obtaining 5-bromo-2,4-bis(methoxyethoxy)benzaldehyde (0,91 g).

Reference example 2

N-Bromosuccinimide (7,35 g) and benzoyl peroxide (196 mg) are added to a solution of 4-bromo-2-methylbiphenyl (5.0 g) in carbon tetrachloride (150 ml) and the mixture is refluxed under stirring overnight. After cooling to room temperature the s, the reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solution is filtered and the solvent is evaporated under reduced pressure to a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 4-bromo-2-(dibromomethyl)biphenyl (7.9 g). To a solution of 4-bromo-2-(dibromomethyl)biphenyl acetic acid (240 ml) is added sodium acetate (9.6 g) and the resulting mixture is refluxed with stirring for two days. The mixture is cooled to room temperature, added 4M hydrochloric acid (50 ml) and the resulting mixture is refluxed with stirring for two hours. The reaction mixture is cooled to room temperature, the solvent is evaporated under reduced pressure to obtain a residue, the residue is added ethyl acetate and the resulting mixture was sequentially washed with 1M hydrochloric acid and saturated salt solution and dried over anhydrous magnesium sulfate. After filtration the solvent is evaporated from the filtrate under reduced pressure to obtain a residue, the residue is dried, receiving 4-bromobiphenyl-3-carbaldehyde (of 5.05 g).

Reference example 3

The imidazole (3.3 grams) and tert-butyldiphenylchlorosilane (10.0 g) is added to a solution of (3-bromo-5-forfinal)methanol (5.0 g) in dimethylformamide (50 ml) and the mixture is stirred over night pikantnoi temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give [(3-bromo-5-terbisil)oxy](tert-butyl)diphenylsilane (9.5 g).

Compounds of reference examples 4, 5 and 6 received in accordance with the method described in reference example 3.

Reference example 7

To a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-(3-([[tert-butyl(diphenyl)silyl]oxy]methyl)phenyl)-D-glucit (5,93 g) in tetrahydrofuran (45 ml) is added palladium on carbon (10%, 500 mg) and the mixture is stirred for 20 hours at room temperature in a hydrogen atmosphere. The reaction mixture was filtered through celite, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue, the residue (3,47 g) dissolved in pyridine (40 ml). In the resulting solution was added acetic anhydride (2,68 ml) and 4-dimethylaminopyridine (catalytic amount) and the resulting mixture is stirred for 16 hours at room temperature. Then to the reaction mixture was added dropwise methanol (50 ml), the solvent is evaporated under reduced pressure and the resulting residue is subjected compatible with the private evaporation with toluene. The resulting residue is dissolved in a mixture of ethyl acetate-toluene (3:2), washed, and dried over magnesium sulfate. The solvent from the mixture obtained is evaporated under reduced pressure to obtain a residue, the residue (4,48 g) dissolved in tetrahydrofuran (100 ml), added dropwise 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (8,12 ml) and the resulting solution was stirred for two hours at room temperature. The reaction mixture is evaporated and purified column chromatography on silica gel, receiving (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[3-(hydroxymethyl)phenyl]-D-glucit (1.30 grams).

Reference example 8

Triphenylphosphine (926 mg) and tetrabromophenol (1,17 g) are added to a solution of (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[3-(hydroxymethyl)phenyl]-D-glucit (1.29 g) in dichloromethane (40 ml) under cooling in an ice bath and the mixture was stirred for 20 minutes at room temperature. To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution (60 ml) and the organic layer separated. The mixture is then dried over magnesium sulfate and the solvent is evaporated under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel, receiving (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[3-(methyl bromide)phenyl]-D-glucit (1.04 g).

Reference example 9

A solution of n-utility (1.56 mol) in n-hexane is (50 ml) was added dropwise to a solution of 1-(benzyloxy)-2-bromo-4-methylbenzene (20 g) in tetrahydrofuran (250 ml) at -78° In an argon atmosphere and the resulting mixture is stirred for one hour at the same temperature. To the reaction mixture is added dropwise a solution of 2,3,4,6-Tetra-O-benzyl-D-(+)-glucan-1,5-lactone (35,0 g) in tetrahydrofuran (200 ml) at -78°and the resulting mixture is stirred for one hour at the same temperature. To the mixture is added 1M aqueous solution of hydrochloric acid (10 ml) and the temperature of the mixture was raised to room temperature. Then to the mixture is added anhydrous magnesium sulfate (50 g) and the mixture is stirred for one hour at room temperature. The mixture is filtered, filtet evaporated and the resulting residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-were]-D-glucopyranose (37 g). Triisopropylsilane (31 ml) and a complex of boron TRIFLUORIDE and diethyl ether (12,6 ml) was added to a solution of 2,3,4,6-Tetra-O-benzyl-1-C-[2-(benzyloxy)-5-were]-D-glucopyranose in a mixture of dichloromethane-acetonitrile (1:3) (400 ml) under cooling in an ice bath in an argon atmosphere and the mixture is stirred for one hour at the same temperature. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, filtered and then the solvent is evaporated from the filtrate under reduced pressure to receive the drug residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-were]-D-glucit (16,9 g).

Reference example 10

of 1.56 M Solution of n-utility in n-hexane (14,5 ml) was added dropwise to a solution of [(3-bromo-5-terbisil)oxy](tert-butyl)diphenylsilane (10 g) in tetrahydrofuran (100 ml) at -78°in argon atmosphere and the resulting mixture is stirred for half an hour at the same temperature. To the reaction mixture is added dropwise a solution of 2,3,4,6-Tetra-O-benzyl-D-(+)-glucono-1,5-lactone (12.2 g) in tetrahydrofuran (100 ml) at -78°and the resulting mixture is stirred for two hours at the same temperature. To the mixture is added 1M aqueous solution of hydrochloric acid (10 ml) and the temperature of the mixture was raised to room temperature. Then to the mixture is added anhydrous magnesium sulfate (50 mg) and the mixture is stirred for one hour at room temperature. The mixture is filtered, the filtrate evaporated and the residue purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 2,3,4,6-Tetra-O-benzyl-1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-forfinal]-D-glucopyranose (6 g). Triethylsilane (1.3 ml) and a complex of boron TRIFLUORIDE and diethyl ether (0.9 ml) is added to a solution of 2,3,4,6-Tetra-O-benzyl-1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-forfinal]-D-glucopyranose what s in a mixture of dichloromethane-acetonitrile (1:1) (120 ml) under cooling in an ice bath in an argon atmosphere and the mixture is stirred for one hour at the same temperature. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and filtered, then the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-forfinal]-D-glucit (4,2 g). 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (9.5 ml) is added dropwise to a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)-5-forfinal]-D-glucit in tetrahydrofuran (90 ml) and the mixture is stirred for one hour at room temperature. The reaction mixture is evaporated and the resulting residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-fluoro-5-(hydroxymethyl)phenyl]-D-glucit (0.5 g).

Compounds of reference examples 11, 12 and 13 receive in accordance with the method described in reference example 10.

Reference example 14

Methanol (75 ml) and Pd(OH)2(168 mg) are added to a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[2-(benzyloxy)-5-were]-D-glucit (16,8 g) in ethyl acetate (150 ml) and the resulting mixture is stirred overnight in a hydrogen atmosphere. Specificeret through celite and the filtrate evaporated. The obtained solid residue is recrystallized from ethyl acetate. To a solution of the obtained white crystals (6.6 g) in pyridine (30 ml) is added acetic anhydride (15 ml) and the mixture is stirred over night at room temperature. To the reaction mixture is added methanol, the solvent is evaporated under reduced pressure and the resulting residue is subjected to co-evaporation with toluene. The obtained solid residue is recrystallized from ethanol, receiving (1S)-1-[2-(acetoxy)-5-were]-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-D-glucit (9,1 g).

Reference example 15

N-bromosuccinimide and (α,α'-Azotobacter)nitrile is added to (1S)-1-[2-(acetoxy)-5-were]-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-D-glucit (9,1 g) in carbon tetrachloride (180 ml) and the mixture refluxed with stirring for two hours. The mixture is cooled to room temperature, poured into water and extracted with chloroform. The organic layer is washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent is evaporated under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1-[2-(acetoxy)-5-(methyl bromide)phenyl]-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-D-glucit (7,8 g).

The compound of reference example 16 get in soo is required by the method, described in reference example 9.

Reference example 17

3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)-4-perbenzoate (1.20 g) was dissolved in morpholine (10 ml) and the mixture is stirred for 24 hours at 110°C. the Mixture is cooled to room temperature and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography (n-hexane-ethyl acetate)to give 3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)-4-morpholinomethyl (0,93 g).

Reference example 18

1.01 M solution of hydride diisobutylaluminium in toluene (2.1 ml) is added dropwise to a solution of 3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)-4-morpholinosydnonimine (700 mg) in toluene (10 ml), cooled to -78°C. in the argon atmosphere and the mixture is stirred for 1.5 hours. To the mixture is added aqueous saturated solution of ammonium chloride and the resulting mixture extragere chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)-4-martinbaselierit (517 g).

Reference example 19

Manganese dioxide (740 mg added to a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-fluoro-5-(hydroxymethyl)phenyl]-D-glucit (0.5 g) in chloroform (10 ml) and the mixture is stirred for 24 hours. The mixture is filtered through celite, washed with chloroform and the filtrate evaporated. The resulting residue is dried, obtaining 3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)-5-forbindelse (0.4 g).

Compounds of reference examples 20-22 receive in accordance with the method of reference example 19.

Reference example 23

1.6 M solution of n-utility in n-hexane (4.6 ml) is added dropwise to a solution of 1-bromo-3-(dimethoxymethyl)benzene (1.7 g) in tetrahydrofuran (20 ml) at -78°and the mixture is stirred for half an hour. To the reaction mixture is added dropwise a solution of 2,3,4,6-Tetra-O-benzyl-D-(+)-glucan-1,5-lactone (4.0 g) in tetrahydrofuran (20 ml) and the mixture is stirred for one hour. To the mixture is added saturated aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The organic layer was washed with saturated aqueous salt solution and dried over anhydrous sodium sulfate. The solution is filtered and the solvent is evaporated from the filtrate under reduced pressure. The resulting residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 2,3,4,6-Tetra-O-benzyl-1-[3-dimethoxymethyl]phenyl]-D-glucopyranose (1,83 g). To a solution of 2,3,4,6-Tetra-O-benzyl-1-C-3-dimethoxymethyl]phenyl]-D-glucopyranose in a mixture of acetone-water (2:1) (30 ml) was added sulfamic acid (0.51 g) and sodium chlorite (0.6 g) and the mixture is stirred for eight hours PR is room temperature. To the mixture of ten percent hydrochloric acid to bring the pH to 2 and the mixture extracted with chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 3-(2,3,4,6-Tetra-O-benzyl-D-glucopyranose-1)eventing acid (1.3 g). Triethylsilane (0.63 ml) and triperoxonane acid (0.15 ml) are added to a solution of 3-(2,3,4,6-Tetra-O-benzyl-D-glucopyranose-1)eventing acid in dichloromethane (15 ml) and the mixture is stirred for 15 hours at room temperature. To the reaction mixture is added 10% aqueous sodium hydroxide solution and the mixture extracted with dichloromethane. The organic layer was washed with saturated aqueous salt solution and dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)benzoic acid (0.85 grams). the hydrochloride of N,O-dimethylhydroxylamine (0.14 g), triethylamine (0.2 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.28 g) are added to a solution of 3-(2,3,4,6-Tetra-O-benzyl-βD-glyukopiranozil)benzoic acid in dichloromethane (10 ml) and the mixture is stirred for four hours at room temperature. Then the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration the solvent is evaporated from the filtrate under reduced pressure to obtain a residue, the residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)-N-methyl-N-methoxybenzamide (0,42 g).

The compound of reference example 24 receive in accordance with the procedure described in example 47.

Reference example 25

Diisopropylamine (2,34 g) dissolved in tetrahydrofuran (60 ml). 1,58 M solution of n-utility in n-hexane (13.3 ml) added dropwise to the mixture at -78°and the mixture is stirred for half an hour at 0°C. Then the reaction mixture is added 2,6-dichloropyrazine (2,98 g) at -78°and the mixture is stirred for ten minutes. Then to the mixture is added a solution of 2,3,4,6-Tetra-O-benzyl-D-(+)-glucono-1,5-lactone (10.8 g) in tetrahydrofuran (100 ml) and the mixture is stirred for three hours at -78°C. the Reaction mixture was washed with a saturated solution of ammonium chloride and the aqueous layer was extragere diethyl ether. The organic layer is dried over sodium sulfate, the solvent of the solution is evaporated under reduced pressure to obtain a residue and the residue is purified to Nochnoi chromatography on silica gel (n-hexane-ethyl acetate), getting 2,3,4,6-Tetra-O-benzyl-1-(3,5-dichloropyrazine-2-yl)-D-glucopyranose (9,07 g). Received 2,3,4,6-Tetra-O-benzyl-1-(3,5-dichloropyrazine-2-yl)-D-glucopyranose (of 7.93 g) dissolved in dichloromethane (90 ml)to the mixture add triethylsilane cases (36.8 ml) and triperoxonane acid (17,7 ml) and the mixture is stirred for 19 days at room temperature. The reaction mixture was washed with a saturated solution of sodium bicarbonate and the aqueous layer was extracted with chloroform. The organic layer is dried over sodium sulfate, the solvent is evaporated under reduced pressure to obtain a residue and the residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-(3,5-dichloropyrazine-2-yl)-D-glucit (2.15 g).

Reference example 26

1,3-Dibromobenzyl (25 g) and a solution of the Grignard reagent obtained with the use of magnesium metal in ether (50 ml), added to a solution of 5-ethylthiophen-2-carboxaldehyde (5.0 g) in tetrahydrofuran (50 ml) at 0°and the resulting mixture is stirred for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure, the obtained residue is purified column chromatography on forces is the Kagel (n-hexane-ethyl acetate), receiving (3-bromophenyl)-(5-ethyl-2-thienyl)methanol (5,57 g). The complex of boron TRIFLUORIDE and diethyl ether (1,57 ml) and triethylsilane (3,83 ml) was added to a solution of (3-bromophenyl)(5-ethyl-2-thienyl)methanol in acetonitrile (20 ml) at -40°and the resulting mixture is stirred for two hours. To the reaction mixture is added saturated aqueous potassium carbonate solution and the resulting mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. After filtration the solvent is evaporated from the filtrate under reduced pressure to obtain a residue, the residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 2-(3-bromobenzyl)-5-methylthiophene (3.77 g).

Compounds of reference examples 27 and 28 receive in accordance with the method of reference example 26.

Reference example 29

of 1.56 M Solution of n-utility in hexane (23,7 ml) was added dropwise to a solution of 3-methyl-1-benzothiophene (5.0 g) in tetrahydrofuran (50 ml) at -78°in argon atmosphere and the mixture is stirred for half an hour at the same temperature. Then to the mixture is added dropwise a solution of 3-bromobenzaldehyde (6,05 g) in tetrahydrofuran (6 ml) and the mixture is stirred for half an hour. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated the aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue, the residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (3-bromophenyl)-(3-methyl-1-benzothieno-2-yl)methanol (10.0 g) as a colorless oily substance. To a solution of (3-bromophenyl)-(3-methyl-1-benzothieno-2-yl)methanol in dichloromethane (100 ml) at -30°add complex of boron TRIFLUORIDE and diethyl ether (4,42 ml) and triethylsilane (9,58 ml) and the resulting mixture is stirred for half an hour. After that, the reaction mixture is heated to -10°C, stirred at this temperature for 10 minutes, add saturated aqueous solution of sodium carbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue, the residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 2-(3-bromobenzyl)-3-methyl-1-benzothiophen (of 6.68 g).

Compounds of reference examples 30-36 receive in accordance with the method of reference example 29.

Reference example 37

Benzo[b]thiophene (1.12 g) was dissolved in tetrahydrofuran (50 ml). The resulting solution was cooled to -78°to the resulting solution was added dropwise 1,58 M p is the target n-utility in hexane (10.5 ml) and the resulting mixture is stirred for 15 minutes at -78° C. Then, to the mixture is added dropwise a solution of 5-chloro-2-bromobenzaldehyde (3.15 g) in tetrahydrofuran (50 ml) and the resulting mixture is stirred for two hours at room temperature. To the reaction mixture is added saturated aqueous solution of ammonium chloride and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. To the residue is added ethyl acetate and water and the mixture extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue, the residue is purified column chromatography on silica gel (n-hexane-ethyl acetate), obtaining (1-benzothieno-2-yl)-(5-bromo-2-chlorophenyl)methanol and 4.75 g). The imidazole (1.08 g) and tert-butyldimethylchlorosilane (2,99 g) are added to a solution of (1-benzothieno-2-yl)-(5-bromo-2-chlorophenyl)methanol in dimethylformamide (100 ml) and the mixture is stirred for three hours at 70°C. To the reaction mixture, water is added and the mixture extracted with diethyl ether. The organic layer is dried over magnesium sulfate, the solvent is evaporated under reduced pressure to obtain a residue, the residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give [1-benzothieno-2-yl-(5-bromo-2-chlorophenyl)methoxy]-(tert-butyl)dimethylsilane (3,34 g).

Compounds of reference examples 38, 39 and 40 receive in accordance with the methods of the Oh reference example 37.

Reference example 41

Aluminium chloride (8,9 g) and 4-ethylbenzylamine (5,96 g) are added to a solution of 2-bromothiophene (3.2 ml) in dichloromethane (50 ml) at 0°and the resulting mixture is stirred for four hours at room temperature. To the reaction mixture is added 10% hydrochloric acid and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (5-bromo-2-thienyl)(4-ethylphenyl)methanon (8,97 g). The complex of boron TRIFLUORIDE and diethyl ether (1,57 ml) and triethylsilane (3,83 ml) was added to a solution of (5-bromo-2-thienyl)(4-ethylphenyl)methanone in acetonitrile (20 ml) at -40°and the mixture is stirred for two hours. To the reaction mixture is added saturated aqueous solution of potassium carbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue, the residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 2-bromo-(4-active compounds)thiophene (of 6.78 g).

Reference when the EP 42

1 M Solution of ethylmagnesium in tetrahydrofuran (2,98 ml) was added dropwise to the pyrrole (0.2 g) and the resulting mixture is stirred for half an hour. The solvent is evaporated from the filtrate under reduced pressure to obtain a residue, the residue is dissolved in benzene (5.0 ml)solution was added 4-ethylbenzylamine (663 mg) and the resulting mixture is stirred for five hours at 60°C. To the reaction mixture is added saturated aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain residue, which is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 2-(4-active compounds)-1H-pyrrole (0.12 g).

Reference example 43

1.5 M Solution of n-utility in hexane (21 ml) was added dropwise to a solution of 6,7-dimethylbenzofuran (4.1 g) in tetrahydrofuran (100 ml) at -78°in argon atmosphere and the resulting mixture is stirred for half an hour. Then to the mixture is added tri-n-butylalcohol (8,4 ml) and the mixture is stirred for one hour. To the reaction mixture is added saturated aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution is dried over anhydrous sodium sulfate. The mixture is filtered, the filtrate evaporated and the resulting residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give tri-n-butyl-(6,7-dimethylbenzofuran-2-yl)tin (10.8 g).

Compounds of reference examples 44-49 receive in accordance with the method of reference example 43.

Reference example 50

Sodium borohydride (1.3 g) are added to a solution of 6-methylinden-1-she (5.0 g) in methanol (50 ml) at 0°and the resulting mixture is stirred for one hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate evaporated to obtain 6-methylinden-1-ol (5.5 g). To a solution of 6-methylinden-1-ol in toluene (50 ml) is added monohydrate p-toluensulfonate acid (0.2 g) and the mixture is stirred for 20 minutes. The temperature of the reaction mixture is again brought to room temperature, the reaction mixture is washed successively with water, 5% aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered and the filtrate is concentrated and receiving 5-methyl-1H-inden (5.5 g).

The compound of reference example 51 receive in accordance with the method of reference example 50.

Reference example 52

Water (0.6 ml) and N-bromosuccinimide (6,1 g) are added to a solution of 5-methyl-1H-indene (4.4 g) in dimethyl sulfoxide (50 ml) and the resulting mixture was stirred at room temperature for 40 minutes. The reaction mixture was poured into ice water and the resulting mixture extracted with ether. The organic layer is washed successively with water, 5% aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered, the filtrate evaporated and the obtained crystals are washed with hexane to obtain after filtration of 2-bromo-6-methylinden-1-ol (4.4 g). To a solution of 2-bromo-6-methylinden-1-ol in toluene (50 ml) is added monohydrate p-toluensulfonate acid (0.1 g) and the resulting mixture is stirred for 20 minutes. The temperature of the reaction mixture is again brought to room temperature and the reaction mixture is washed successively with water, 5% aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain residue, which was purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 2-bromo-5-methyl-1H-inden (1.7 g).

The compound of reference example 53 receive in accordance with the method of reference example 52.

Reference example 54

2-Bromo-1H-inden (3.0 g) and a solution of the Grignard reagent obtained with the use of metallic magnesium in tetrahydrofuran (20 ml), added to a solution of 3-(2,3,4,6-Tetra-O-benzyl-β-D-glucopon nosil)-N-methyl-N-methoxybenzamide (6,99 g) in tetrahydrofuran (20 ml) at 0° C and the resulting mixture is stirred for two hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain residue, which was purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1H-inden-2-yl)-[3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenyl]metano (0.84 g).

Reference example 55

Pentamethylbenzyl (3,62 g) is dissolved in a solution of methyl-4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)benzoate (1.31 g) in dichloromethane (150 ml)to the resulting mixture at -78°With added dropwise 1M solution of trichloride boron in n-heptane (6,83 ml) and the resulting mixture is stirred for two hours at the same temperature. Then to the reaction mixture at -78°With added dropwise methanol (40 ml). After this mixture is allowed to warm to room temperature and the solvent is evaporated under reduced pressure to obtain residue, which was purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (2R,3S,4S,4aR,10bS)-7-(1-benzothieno-2-ylmethyl)-3,4-dihydroxy-2-(hydroxymethyl)-3,4,4A,10b-tetrahydropyrido[3,2-c]sokumen-6(2H)-he (420 mg).

Example 1

1,58 M solution of n-utillity the n-hexane (2.4 ml) is added dropwise to a solution of benzo[b]thiophene (504 mg) in tetrahydrofuran (10 ml) at -78° In an argon atmosphere and the resulting mixture is stirred for two hours at the same temperature. To the reaction mixture is added dropwise a solution of 3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)benzaldehyde (of 1.57 g) in tetrahydrofuran (45 ml) and the resulting mixture was stirred at the same temperature for five hours. To the reaction mixture are added water (60 ml) and the mixture extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate). To a solution of the residue (1.6 g) in dichloromethane (25 ml) under cooling in an ice bath is added dropwise triethylsilane (of 0.67 ml) and the solution of a complex of boron TRIFLUORIDE and diethyl ether (447 ml) in dichloromethane (15 ml) and the resulting mixture is stirred for two hours at the same temperature. To the reaction mixture is added a saturated solution of sodium bicarbonate, the organic layer separated and dried over anhydrous magnesium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[(1-benzothieno-2-yl)methyl]phenyl]-D-gluco the (1.56 g).

Compounds of examples 2-16 receive in accordance with the method of example 1.

Example 17

1,58 M solution of n-utility in n-hexane (1,18 ml) was added dropwise to a solution of 3-(4-methoxybenzyl)thiophene (0,38 g) in tetrahydrofuran (10 ml) at -78°and the resulting mixture is stirred for one hour. To the reaction mixture is added dropwise a solution of 2,3,4,6-Tetra-O-benzyl-D-(+)-glucono-1,5-lactone (1.0 g) in tetrahydrofuran (10 ml) and the mixture is stirred for one hour. To the reaction mixture is added 1.0 M hydrochloric acid and the mixture extracted with ethyl acetate. The mixture was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-chloroform-acetone). To a solution of the obtained residue (0,94 g) in chloroform (1.0 ml) and acetonitrile (5.0 ml) under cooling in an ice bath, add triisopropylsilane (0,78 ml) and a complex of boron TRIFLUORIDE and diethyl ether (0,32 ml) and the resulting mixture is stirred for half an hour. To the reaction mixture is added triethylamine (1.0 ml) and the solvent is evaporated under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 1,4:5,9-dianhydro-6,7,8,10-Tetra-O-benzyl-2,dideoxy-2-(4-methoxybenzyl)-1-thio-D-glycero-D-Glo-DECA-1,3-d-genital (0,72 g).

Compounds of examples 18-24 receive in accordance with the method of example 17.

Example 25

2-[3-Bromo-4-(methoxyethoxy)benzyl]-1-benzothiophen (17,4 g) dissolved in tetrahydrofuran (200 ml). 1,58 M solution of n-utility in n-hexane (30,4 ml) was added dropwise to the mixture at -78°and the resulting mixture is stirred for one hour at -78°C. thereafter, to the reaction mixture add a solution of 2,3,4,6-Tetra-O-benzyl-D-(+)-glucono-1,5-lactone (21,6 g) in tetrahydrofuran (150 ml) and the resulting mixture is stirred for three hours at -78°C. the Reaction mixture was washed with a saturated solution of ammonium chloride and water layer is extracted with ethyl acetate. The combined organic layer is dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure to obtain a residue. The obtained solid product is recrystallized (hexane-ethyl acetate)to give 1-[5-(1-benzothieno-2-ylmethyl)-2-(methoxyethoxy)phenyl]-2,3,4,6-Tetra-O-benzyl-D-glucopyranose (25,3 g). This product is dissolved in dichloromethane (500 ml). To the resulting solution at -40°With add triethylsilane (14.7 ml) and a complex of boron TRIFLUORIDE and diethyl ether (4,1 ml) and the mixture is stirred for four hours at -20°C. the Reaction mixture was washed with a saturated solution of sodium bicarbonate and the aqueous layer was extracted with chloroform. The combined organic closeout over sodium sulfate, then the solvent is removed from the mixture under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(methoxyethoxy)phenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (21.8 g).

Compounds of examples 26-29 receive in accordance with the procedure described in example 25.

Example 30

(1S)-1,5-Anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(methoxyethoxy)phenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (21,7 g) dissolved in ethyl acetate (135 ml). To the mixture is added a 4M solution of hydrochloric acid in ethyl acetate (135 ml) and the resulting mixture is stirred for 14 hours at room temperature. The reaction mixture is evaporated, the obtained residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-hydroxyphenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (18.6 g).

The compounds of examples 31 and 32 receive in accordance with the method of example 30.

Example 33

(1S)-1,5-Anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-hydroxyphenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (763 mg) dissolved in dimethylformamide (10 ml). To the mixture is added potassium carbonate (207 mg) and methyliodide (0,095 ml) and the resulting mixture is stirred for 16 hours at room temperature. The reaction mixture was diluted with sodium sulfate, washed with water and saturated of rest the rum salt. The organic layer is dried with sodium sulfate and the solvent is evaporated under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-methoxyphenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (736 mg).

Connection examples 34-40 receive in accordance with the method of example 33.

Example 41

Tert-butyl[2-(4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenoxy)ethyl]carbamate (910 mg) was dissolved in tetrahydrofuran (20 ml), the resulting solution was added alumoweld lithium (76 mg) and the mixture refluxed with stirring for seven hours. To the reaction mixture an aqueous solution of sodium hydroxide and the precipitate removed by filtration through celite. The filtrate is evaporated, the resulting residue was diluted with chloroform and dried over sodium sulfate. The solvent is evaporated under reduced pressure to obtain residue, which was purified column chromatography on silica gel (chloroform-methanol)to give (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-[2-methylamino]ethoxy]phenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (612 mg).

Example 42

Tert-butyl[2-(4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenoxy)ethyl]carbamate (906 mg) dissolved in acetonitrile (10 ml), add auth methanol (0,08 ml), the sodium iodide (300 mg) and acetylchloride (0.28 mg) and the resulting mixture is stirred for one hour at room temperature. To the mixture add diisopropylethylamine (0,70 ml) and the mixture is stirred for 1.5 hours at room temperature. To the mixture add acetylchloride (0,14 ml) and diisopropylethylamine (0.35 ml) and the resulting mixture is stirred for 14 hours at room temperature. The reaction mixture was diluted with 1M hydrochloric acid and extracted with diethyl ether. The organic layer is dried over sodium sulfate and the solvent is evaporated from him under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give N-[2-(4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenoxy)ethyl]ndimethylacetamide (387 mg).

Example 43

(1S)-1,5-Anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-hydroxyphenyl]-D-glucit (1,33 g) dissolved in a mixture of acetic anhydride-pyridine (1:2) (30 ml) and the mixture is stirred for 25 hours at room temperature. The reaction mixture is evaporated and the resulting solid residue is washed with ethanol, receiving (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[2-acetoxyphenyl-5-(1-benzothieno-2-ylmethyl)-D-glucit (1,93 g).

The compound of example 44 receive in accordance with the method of example 43.

Example 45

(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[2-acetoxyphenyl-5-(1-benzothia the-2-ylmethyl)-D-glucit (1,93 g) dissolved in acetonitrile (30 ml). To the resulting solution was added 1,1,3,3-tetramethylguanidine (1.6 ml) and the mixture is stirred for 2.5 hours at 50°C. the Reaction mixture is evaporated, the resulting residue was diluted with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layer is dried over sodium sulfate. The solvent is evaporated under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-hydroxyphenyl]-D-glucit (1.85 g).

The compound of example 46 receive in accordance with the method of example 45.

Example 47

(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-hydroxyphenyl]-D-glucit (570 mg) was dissolved in dimethylformamide (10 mg), the resulting solution was added potassium carbonate (0,69 g), cyclopentylamine (0.54 ml) and potassium iodide (83 mg) and the mixture was stirred for two days at 50°C. the Reaction mixture was diluted with ethyl acetate and washed with water. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(cyclopentyloxy)phenyl]-D-glucit (393 mg).

The compound of example 4 receive in accordance with the method of example 47.

Example 49

(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-hydroxyphenyl]-D-glucit (570 mg) was dissolved in tetrahydrofuran (10 ml). To the resulting solution was added 2-propanol (0,38 ml), diethylazodicarboxylate (0.63 ml) and triphenylphosphine (1,05 g) and the mixture is stirred for two days at room temperature. To the mixture is added 2-propanol (0,23 ml), diethylazodicarboxylate (0,31 ml) and triphenylphosphine (0.52 g) and the resulting mixture is stirred for four hours at room temperature. The reaction mixture is evaporated and the resulting residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(isopropoxy)phenyl]-D-glucit (544 mg).

Example 50

Sodium hydride (60%) was suspended in dimethyl sulfoxide (3 ml) and the mixture is stirred for half an hour at 60°C. To this mixture a solution of (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-hydroxyphenyl]-D-glucit (571 mg) in dimethyl sulfoxide (2 ml) and the mixture is stirred for one hour at room temperature. Then add (S)-(-)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (of 0.21 ml) and the resulting mixture was stirred for seven hours at 80°C. the Reaction mixture was diluted with water and extracted with dichloromethane. The organic layer is dried over sodium sulfate and the solvent in Privat under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-{[(4R)-2,2-dimethyl-1,3-dioxolane-4-yl]methoxy}phenyl)-D-glucit (77 mg).

Example 51

2,6-Lutidine (3.98 ml) and the anhydride triftormetilfullerenov acid (3,45 ml) was added to a solution of (1S)-1,5-anhydrous-1-[5-(bestien-2-ylmethyl)-2-hydroxyphenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (13.1 g) in dichloromethane (150 ml), cooled to -20°C. in the argon atmosphere and the mixture is stirred for three hours. To the mixture is added 2,6-lutidine (2.00 ml) and the anhydride triftormetilfullerenov acid (1.73 ml) and the resulting mixture is stirred for one hour. To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted three times with chloroform. The organic layer is washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solid is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-1-[5-(bestien-2-ylmethyl)-2-triftormetilfullerenov]-2,3,4,6-Tetra-O-benzyl-D-glucit (13,9 g).

Example 52

(1S)-1,5-Anhydrous-1-[5-(bestien-2-ylmethyl)-2-triftormetilfullerenov]-2,3,4,6-Tetra-O-benzyl-D-glucit (5,67 g) is astonaut in the mixed solvent, consisting of dimethyl sulfoxide (30 ml) and methanol (25 ml). To the resulting mixture add palladium (II) acetate (285 mg), 1,3-bis(diphenylphosphino)propane (524 mg) and triethylamine (1,94 ml) and the mixture is stirred for two days at 55°C in an atmosphere of carbon monoxide. The mixture is cooled to room temperature and then extracted three times with ethyl acetate. The organic layer was washed with water twice and saturated salt solution and dried over anhydrous magnesium sulfate. The solid is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give methyl-4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)benzoate (2,74 g).

Example 53

Methyl-4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)benzoate (5,26 g) dissolved in tetrahydrofuran (5 ml). To the resulting solution was added methanol (10 ml) and water 10 M sodium hydroxide solution (10 ml) and the mixture is stirred for 21 hours at 60°C. the Reaction mixture is cooled to room temperature, acidified by adding 6 M hydrochloric acid, then extracted three times with chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solid substance removing filter the cation and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is dried in vacuum, obtaining 4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)benzoic acid (5,13 g).

The compound of example 54 receive in accordance with the method of example 53.

Example 55

Oxalicacid (0.16 ml) and a drop of dimethylformamide are added to a solution of [4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenoxy]acetic acid (770 mg) in dichloromethane (10 ml) under ice cooling and the mixture is stirred for two hours at room temperature. The reaction mixture is evaporated under reduced pressure and the resulting residue is dissolved in dichloromethane (15 ml). To the solution was added aqueous ammonia (28%, 10 ml) and the mixture is stirred for one hour at room temperature. The organic layer is separated and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, resulting in a residue [4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenoxy]ndimethylacetamide (740 mg).

The compound of example 56 receive in accordance with the procedure described in example 55.

Example 57

4-(1-Benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)benzoic acid (2,23 g) dissolved in toluene (20 ml), the resulting solution was added triethylamine (0,590 ml) and the mixture cooled to 0°C. To the obtained mixture is carefully added dropwise diphenylprop related (of 0.67 ml) and the mixture is stirred for 2.5 hours at room temperature. The reaction mixture is diluted with toluene and then washed with aqueous 1% sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous magnesium sulfate. Solids are removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is dissolved in toluene (20 ml) and the mixture is stirred for three hours at 130°C. To the mixture is added 2-propanol (30 ml) and the mixture is stirred for 16 hours at 110°C. the Mixture is cooled to room temperature, add water to the mixture and the mixture is extracted three times with chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solid is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give tert-butyl 4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenylcarbamate (1.50 g).

Example 58

tert-Butyl 4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenylcarbamate (1,11 g) dissolved in ethyl acetate (3 ml). To the mixture while cooling in an ice bath, add 4 M solution of hydrochloric acid in ethyl acetate (3 ml) and the temperature of the mixture is brought to room temperature. After that, the mixture of AC who're asked for three hours. To the mixture is added aqueous 1M sodium hydroxide solution and the mixture is extracted three times with chloroform. The organic layer was washed with aqueous 1 M sodium hydroxide solution and saturated salt solution and dried over anhydrous magnesium sulfate. The solid is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (chloroform-methanol-aqueous ammonia)to give (1S)-1,5-anhydrous-1-[2-amino-5-(1-benzothieno-2-ylmethyl)phenyl]-2-(2,3,4,6-Tetra-O-benzyl-D-glucit (576 mg).

Example 59

Alumoweld lithium (68 mg) are added to dry tetrahydrofuran (15 ml) in an argon atmosphere and the resulting solution was slowly added dropwise a solution of tert-butyl 4-(1-benzothieno-2-ylmethyl)-2-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenylcarbamate (1.27 g) in anhydrous tetrahydrofuran (15 ml). The reaction mixture is stirred for two hours at 75°C. After completion of the reaction the mixture is cooled to room temperature. To the mixture successively added water (1.0 ml), aqueous 15% sodium hydroxide solution (10 ml) and again water (3.0 ml) and the mixture is stirred at room temperature. The solid precipitate is removed by filtration through celite and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. To the residue add hloroform, the mixture was washed with saturated salt solution and dried over anhydrous sodium sulfate. The solid precipitate is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(methylamino)phenyl]-2-(2,3,4,6-Tetra-O-benzyl-D-glucit (737 mg) as a colorless viscous substance.

Connection examples 60-62 receive in accordance with the method of example 59.

Example 63

To a solution of (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(hydroxyethoxy)phenyl]-2-(2,3,4,6-Tetra-O-benzyl)-D-glucit (1.35 g) in tetrahydrofuran (20 ml) add phthalimide (294 mg), triphenylphosphine (525 mg) and diethylazodicarboxylate (0,32 ml) and the resulting mixture is stirred for six hours at room temperature. To the reaction mixture add silica gel (3 g) and the mixture is dried by drying under reduced pressure and purified column chromatography. The residue is dissolved in tetrahydrofuran (15 ml) and ethanol (15 ml). To the mixture is added dropwise hydrazinehydrate (0.54 ml) and the mixture is stirred for 24 hours at room temperature. Insoluble substances are removed by filtration and the filtrate evaporated to a residue. To the residue is added chloroform and insoluble substances are again removed by filtration. iltram washed with water, dried over magnesium sulfate and evaporated. The resulting residue is purified column chromatography, obtaining the (1S)-1,5-anhydrous-1-[2-(aminoethoxy)-5-(1-benzothieno-2-ylmethyl)phenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (960 mg).

Example 64

(1S)-1,5-Anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(methylamino)phenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (179 mg) was dissolved in dichloromethane (3 ml). To the resulting solution was added 35% formalin (0,008 ml) and acetic acid (0,02 ml) and the mixture is stirred at room temperature. To the mixture add triacetoxyborohydride sodium (74 mg) and the mixture is stirred for 11 hours. To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution and after decomposition of the excess reagent, the mixture is extracted three times with chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solid precipitate is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(dimethylamino)phenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (124 mg).

Example 65

1,58 M Solution of n-utility in n-hexane (2.2 ml) is added dropwise to a solution of [1-benzothieno-2-yl-(5-bromo-2-forfinal)methoxy](tert-butyl)dimethylsilane (1.50 g) in anhydrous tet is hydrofuran (15 ml), cooled to -78°C. in the argon atmosphere and the resulting mixture is stirred for half an hour. Then to the reaction mixture add a solution of 2,3,4,6-Tetra-O-benzylguanine (1.90 g) in anhydrous tetrahydrofurane (20 ml) and the resulting mixture is stirred for 1.5 hours with a gradual increase of temperature from -78°0°C. To the mixture is added saturated aqueous solution of ammonium chloride and the mixture is extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated salt solution and dried over anhydrous magnesium sulfate. Solids are removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (chloroform-n-hexane-acetone). The obtained residue (1.52 g) was dissolved in digidratirovannogo tetrahydrofuran (15 ml). To the mixture is added 1.0 M solution of Tetra-n-butylammonium in tetrahydrofuran (2.0 ml) and the resulting mixture is stirred for 65 minutes at room temperature. The solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate). To a solution of the obtained residue (500 mg) in acetonitrile (5 ml) add triethylsilane (0,239 ml) and a complex of boron TRIFLUORIDE dietrologia ether (0,175 ml) and the resulting mixture is stirred for five hours. To the mixture is added saturated aqueous sodium hydrogen carbonate solution and after decomposition of the excess reagent, the mixture is extracted three times with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over anhydrous sodium sulfate. The solid is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give 1,5-anhydrous-1-[3-(1-benzothieno-2-ylmethyl)-4-forfinal-2,3,4,6-Tetra-O-benzyl-D-glucit (150 mg) in the form of a viscous substance light yellow color.

Connection examples 66-68 receive in accordance with the procedure of example 65.

Example 69

Magnesium (granules; 131 mg) and 1,2-dibromethane (drop) is added to tetrahydrofuran (10 ml) in an argon atmosphere. To the obtained mixture is carefully added dropwise a solution of 2-(1-benzothieno-2-ylmethyl)-4-bromophenylacetate (1.5 g) in tetrahydrofuran (15 ml) and the temperature of the mixture raised from room temperature to 60°to obtain a Grignard reagent. After cooling the mixture to room temperature, to the resulting reagent add a solution of 2,3,4,6-Tetra-O-benzyl-D-(+)-glucono-1,5-lactone (only 2.91 g) in tetrahydrofuran (20 ml) and the mixture is stirred for three hours. To the reaction mixture add the feast upon the config aqueous solution of ammonium chloride and the mixture is extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride and saturated salt solution and dried over anhydrous magnesium sulfate. Solids are removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate). To a solution of the obtained residue (600 mg) in acetonitrile (6 ml) at -20°With add triethylsilane (0,146 ml) and a complex of boron TRIFLUORIDE and diethyl ether (0,105 ml) and the resulting mixture is stirred for three hours. Triethylsilane (0,073 ml) and a complex of boron TRIFLUORIDE and diethyl ether (0,048 ml) was again added to the mixture. The temperature of the mixture was raised to -10°and the mixture is stirred for two hours. To the reaction mixture is added saturated aqueous solution of sodium bicarbonate to decompose the excess reagent and the mixture is extracted three times with chloroform. The organic layer was washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solid is removed by filtration and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-1-[3-(1-benzothieno-2-ylmethyl)-4-methoxyphenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (394 mg).

Connected to the e of example 70 receive in accordance with the method of example 69.

Example 71

A solution of 2-bromopyridine (342 mg) in tetrahydrofuran (13 ml) was added dropwise to to 1.59 M solution of n-utility in hexane (1,36 ml) at -78°in argon atmosphere and the mixture was stirred at the same temperature for one hour. Then to the mixture is added dropwise a solution of 3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)benzaldehyde (1.13 g) in tetrahydrofuran (35 ml) and the mixture is stirred for 2.5 hours. To the reaction mixture are added water (40 ml), the mixture is extracted with ethyl acetate and the organic layer is dried over anhydrous magnesium sulfate. The mixture is filtered, the solvent is evaporated from the filtrate under reduced pressure to obtain residue, which was purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[hydroxy(pyridin-2-yl)methyl]phenyl]-D-glucit (0,99 g). To a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[hydroxy(pyridin-2-yl)methyl]phenyl]-D-glucit (1.78 g) in tetrahydrofuran (12 ml) at room temperature is added sodium hydride (60%, 202 mg) and the resulting mixture is stirred for half an hour. To the mixture under ice cooling are added dropwise carbon disulfide (1,15 ml), the mixture was stirred at the same temperature for two hours and another two hours at room temperature. To the reaction mixture under cooling in an ice bath is added dropwise metriod the d (of 0.28 ml) and the resulting mixture is stirred for 2.5 hours at the same temperature. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure to obtain residue, which was dissolved in toluene (20 ml). To the resulting solution add anti-hydride (3.28 ml) and a a'-azodiisobutyronitrile (82 mg) and the mixture refluxed with stirring for 64 hours. The solvent is evaporated from the filtrate under reduced pressure to obtain residue, which was purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[(pyridine-2-yl)methyl]phenyl]-D-glucit (1.51 g).

The compound of example 72 receive in accordance with the method of example 71.

Example 73

(1S)-1,5-Anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[(hydroxymethyl)phenyl]-D-glucit (631 mg) and phthalimide (154 mg) was dissolved in tetrahydrofuran (10 ml). To the resulting mixture while cooling with ice add diethylazodicarboxylate (of 0.18 ml) and triphenylphosphine (303 mg) and the mixture is stirred for 20 hours at room temperature. The reaction mixture is evaporated to obtain a residue, which was purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-C-{3-[(1,3-dioxo-1,3-dihydro-2H-isoindole-2-yl)methyl]phenyl}-D-glucit 784 mg).

Example 74

To a solution of zinc powder (86 mg) in tetrahydrofuran (2.0 ml) in an argon atmosphere add 1,2-dibromethane (one drop) and the resulting mixture is refluxed for five minutes. To the mixture at room temperature add trimethylchlorosilane (drop) and the mixture is stirred for 15 minutes. Then to the resulting mixture of (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-(3-methyl bromide-6-methoxy)phenyl-D-glucit (700 mg) and the mixture refluxed for one hour. To the mixture is added 2-bromo-1H-inden (128 mg) and tetrakis(triphenylphosphine)palladium(0) (76 mg) and the resulting mixture is refluxed for five hours. The temperature of the mixture was lowered to room temperature and add saturated aqueous solution of ammonium chloride. Insoluble substances are removed by filtration and the filtrate is extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure to obtain residue, which was purified column chromatography on silica gel (chloroform-utilized), receiving (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[3-[(1H-inden-2-yl)methyl-6-methoxy]phenyl]-D-glucit (190 mg).

Connection examples 75-79 receive in accordance with the method of example 74.

Example 80

p> Active zinc (131 mg) is suspended in tetrahydrofuran (2 ml). To the suspension is added 1,2-dibromoethane (0,07 ml) and the suspension is stirred for five minutes at 60°C. Then added to the mixture of trimethylchlorosilane (0.10 ml) and the mixture is stirred for 10 minutes at room temperature. Then to the mixture add a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-[3-(methyl bromide)phenyl]-D-glucit (694 mg) in tetrahydrofuran (3 ml) and the mixture is stirred for one hour at 60°C. Then added to the mixture of 2-(methylthio)benzothiazole (181 mg) and tetrakis(triphenylphosphine)palladium(0) (231 mg) and the mixture is stirred for 15 hours at 60°C. the Precipitate is removed by filtration and the filtrate evaporated. The obtained residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and a saturated solution of salt. The organic layer is dried over sodium sulfate and the solvent is evaporated under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-(1,3-benzothiazol-2-ylmethyl)phenyl]-D-glucit (355 mg).

Example 81

A suspension of (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[3-(methyl bromide)phenyl]-D-glucit (501 mg) in 1,4-dioxane (10 ml), 1-methyl-2-(tributylstannyl)-1H-indole (546 mg), Tris(dibenzylideneacetone)diplegia (92 mg), 2-(dicyclohexylphosphino)beef the Nile (88 mg), of potassium fluoride (174 mg) and cesium carbonate (652 mg) is stirred for 18 hours at 60°C. the Insoluble matter is removed by filtration and the solvent is evaporated from the filtrate to obtain a residue. The residue is purified column chromatography on silica gel, receiving (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-{3-[(1-methyl-1H-indol-2-yl)methyl]phenyl}-D-glucit (280 mg).

Connection examples 82-91 receive in accordance with the method of example 81.

Example 92

Tetranitropentaerithrite(0) (43 mg) and dimethyl-1-benzothieno-3-ylboronic (132 mg) are added to a solution of 1-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)-3-(trifloromethyl)benzene (280 mg) in toluene (10 ml) at room temperature. To the obtained mixture is added saturated aqueous sodium hydrogen carbonate solution (4 ml) and the mixture is stirred for four hours at 90°C. To the reaction mixture are added ethyl acetate and a saturated salt solution, insoluble materials are removed by filtration through celite and the organic layer is extracted. The organic layer is washed with water and saturated salt solution, dried over anhydrous magnesium sulfate and evaporated to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-1-[3-(1-benzothieno-3-yl)phenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (170 mg).

Example 93

The palladium hydroxide/lead (20%, 800 mg) are added to a suspension of 1.4:5,9-dianhydro-6,7,8,10-Tetra-O-benzyl-2,3-dideoxy-2-(4-methoxybenzyl)-1-thio-D-glycero-D-DECA-1,3-danitol (0,72 g) in tetrahydrofuran (5.0 ml) and 2% methanol solution of hydrochloric acid (10 ml) and the resulting mixture stirred for 18 hours in an atmosphere of hydrogen (1 ATM). The reaction mixture was filtered through celite and the filtrate evaporated. Then to the residue add pyridine (3.0 ml)and acetic anhydride (1.5 ml) and the mixture is stirred over night at room temperature. The solvent is evaporated under reduced pressure and the resulting residue is subjected to co-evaporation with toluene. The resulting residue is purified column chromatography on silica gel (n-hexane-ethyl acetate), obtaining 6,7,8,10-Tetra-O-acetyl-1,4:5,9-dianhydro-2,3-dideoxy-2-(4-methoxybenzyl)-1-thio-D-glycero-D-DECA-1,3-danitol (0,13 g).

Example 94

0.76 M Solution isopropylacrylamide in tetrahydrofuran (27,6 ml) was added dropwise to a solution of 2-(4-active compounds)-1H-pyrrole (4,14 g) in tetrahydrofuran (10 ml) and the resulting mixture is stirred for two hours. To the reaction mixture are added dropwise 2,3,4,6-Tetra-O-benzyl-D-glucopyranoside (3.80 g) and the resulting mixture is stirred for five hours. To the reaction mixture is added saturated aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The organic layer is washed us is on a salt solution and dried over anhydrous sodium sulfate. After filtration the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-(4-active compounds)-1H-pyrrol-2-yl]-D-glucit (1.89 g).

Example 95

Sodium hydride (60%, 15 mg) are added to a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-(4-active compounds)-1H-pyrrol-2-yl]-D-glucit (210 mg) in dimethylformamide (3.0 ml) and the resulting mixture is stirred for 15 minutes at room temperature. Then to the mixture add methyliodide (0,185 ml) and the mixture is stirred for half an hour. To the reaction mixture, water is added and the mixture extracted with diethyl ether. The organic layer is washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-(4-active compounds)-1-methyl-1H-pyrrol-2-yl]-D-glucit (143 g).

Example 96

(1S)-1,5-Anhydrous-2,3,4,6-Tetra-O-benzyl-1-(1H-pyrrol-2-yl)-D-glucit (773 mg) are added to a suspension of tetrabutylammonium (42.2 mg) and potassium hydroxide (150 mg) in benzene (5.0 ml) and to this mixture 4-ethylbenzylamine (331 mg). The resulting mixture is stirred in ECENA two hours at room temperature. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over anhydrous sodium sulfate. The mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[1-(4-active compounds)-1H-pyrrol-2-yl]-D-glucit (695 mg).

Example 97

To a solution of (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-(1H-tetrazol-5-yl]-D-glucit of 0.85 g) in tetrahydrofuran (10.0 ml) is added triethylamine (0.6 ml) and to the resulting mixture is added 4-ethylbenzylamine (0.50 g). The mixture is stirred for 17 hours at room temperature. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The mixture is filtered and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[2-(4-active compounds)-1H-tetrazol-5-yl]-D-glucit (0,22 g).

Example 98

2,3,4,6-Tetra-O-benzyl-1-(3,5-dichloropyrazine-2-yl)-D-glucopyranose (of 7.93 g) dissolved in dichloromethane (90 ml), the resulting solution was added treat Lilan cases (36.8 ml) and triperoxonane acid (17,7 ml) and the resulting mixture is stirred for 19 days at room temperature. The reaction mixture was washed with a saturated solution of sodium bicarbonate and the aqueous layer was extracted with chloroform. The combined organic layer is dried over sodium sulfate and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl acetate)to give (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-(3,5-dichloropyrazine-2-yl)-D-glucit (2.15 g).

Example 99

1,58 M Solution of n-utility in n-hexane (2,15 ml), diluted with tetrahydrofuran (20 ml)to the resulting solution at -78°With added dropwise 2,2,6,6-tetramethylpiperidine (0,64 ml) and the mixture is stirred for one hour at 0°C. thereafter, to the mixture at -78°add a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-(3,5-dichloropyrazine-2-yl)-D-glucit (2,09 g) in tetrahydrofuran (20 ml) and the mixture is stirred for one hour at -78°C. Then added to the mixture of 4-ethylbenzaldehyde (1,28 ml) and the resulting mixture is stirred for 1.5 hours at -78°C. the Reaction mixture was washed with saturated aqueous ammonium chloride and the aqueous layer was extracted with diethyl ether. The combined organic layer is dried over sodium sulfate, filtered and the solvent is evaporated from the filtrate under reduced pressure to obtain a residue. The residue is purified column chromatography on silica gel (n-hexane-ethyl shall citat), receiving (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-(3,5-dichloro-6-[(4-ethylphenyl)(hydroxy)methyl]pyrazin-2-yl)-D-glucit (842 mg).

Example 100

Pentamethylbenzyl (1,57 g) and 1.0 M solution of trichloride boron in n-heptane (2,97 ml) was added to a solution of (1S)-1,5-anhydrous-1-[3-[(5-methyl-1-benzothieno-2-yl)methyl]phenyl]-2,3,4,6-Tetra-O-benzyl-D-glucit (538 mg) in dichloromethane (25 ml) and the resulting mixture is stirred for one hour. After completion of the reaction to decompose the excess reagent add methanol (5 ml) and the resulting mixture was evaporated under reduced pressure to remove solvent to obtain a residue. The residue is purified column chromatography on silica gel (chloroform-methanol)to give (1S)-1,5-anhydrous-1-[3-[(5-methyl-1-benzothieno-2-yl)methyl]phenyl]-D-glucit (274 mg).

Connection examples 101-153 receive in accordance with the method of example 100.

Example 154

1 M Solution of tribromide boron in n-heptane (4,54 ml) was added dropwise to a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[3-[(benzothiophen-2-yl)methyl]phenyl]-D-glucit (0,77 g) and pentamethylbenzene (2.3 g) in dichloromethane (20 ml) at -78°in argon atmosphere and the resulting mixture is stirred for 90 minutes. To the reaction mixture at -78°With added dropwise methanol and the mixture is allowed to warm to room temperature with stirring. After that, the solvent is evaporated under reduced pressure to receive the receiving residue, to the residue again add methanol (20 ml) and the mixture evaporated to a residue. Then to the residue add toluene and the resulting mixture was evaporated to a residue. The resulting residue is purified column chromatography on silica gel (chloroform-methanol) to obtain an amorphous yellow substance (390 mg). The product is subjected to additional purification column chromatography with reversed phase, receiving (1S)-1,5-anhydrous-1-[3-(1-benzothiophen-2-yl)methyl]phenyl]-D-glucit (270 mg).

The compound of example 155 receive in accordance with the procedure of example 154.

Example 156

(1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[5-(1-benzothiophen-2-ylmethyl)-2-(cyclopentyloxy)phenyl]-D-glucit (381 mg) was dissolved in methanol (10 ml). To the solution add sodium methoxide (32 mg) and the resulting mixture is stirred for three hours at room temperature. The reaction mixture was neutralized with acidic ion exchange resin and the resin removed by filtration. The filtrate is evaporated and the resulting residue is purified column chromatography on silica gel (chloroform-methanol)to give (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-yl)methyl]-2-(cyclopentyloxy)phenyl]-D-glucit (215 mg).

Connection examples 157-178 receive in accordance with the procedure of example 156.

Example 179

(1S)-1,5-anhydrous-1-{5-[1-benzothieno-2-ylmethyl]-2-[(2-dimethylamino)ethoxy]phenyl}-2,3,4,6-Tetra-O-benzyl-D-glucit (520 mg) is dissolved in dihormati is e (25 ml). To the solution add pentamethylbenzyl (1.39 g) and the resulting mixture is cooled to -78°C. To the mixture is added 1.0 M solution of trichloride boron in n-heptane (3.4 ml) and the resulting mixture is stirred for four hours at -78°C. To the reaction mixture is added methanol and the solvent is evaporated under reduced pressure to obtain a residue. To the residue is added a mixture of toluene : diethyl ether (1:1) and the resulting mixture was extracted with saturated aqueous sodium bicarbonate. The water is evaporated under reduced pressure and the resulting residue is purified column chromatography with reversed phase (methanol-water). Finally, the obtained solid product was washed with diethyl ether, obtaining the (1S)-1,5-anhydrous-1-{5-[1-benzothieno-2-ylmethyl]-2-[(2-dimethylamino)ethoxy]phenyl}-D-glucit (104 mg).

Example 180

Aqueous 1M sodium hydroxide solution (1.5 ml) are added to (2R,3S,4S,4aR,10bS)-7-(1-benzothieno-2-ylmethyl)-3,4-dihydroxyindoline)-3,4,4A,10b-tetrahydropyrido[3,2-c]sokumen-6-(2H)-ONU (80 mg) and the resulting mixture is stirred for two hours. After that the reaction mixture is neutralized by adding 1M aqueous hydrochloric acid (1.5 ml). The reaction mixture is evaporated and the resulting residue is purified column chromatography with reversed phase (water-methanol)to give 4-(1-benzothieno-2-ylmethyl)-2-(β-D-glyukopiranozil)benzoic acid (67 mg).

P the emer 181

N-Methylmorpholin (412 mg) and trimethylchlorosilane (295 mg) are added to a solution of (2R,3S,4S,4aR,10bS)-7-(1-benzothieno-2-ylmethyl)-3,4-dihydroxy-2-hydroxymethyl)-3,4,4A,10b-tetrahydropyrido[3,2-c]sokumen-6(2H)-ONU (280 mg) in tetrahydrofuran (14 ml) at -5°and the resulting mixture is stirred for 12 hours at 40°C. To the reaction mixture is added toluene and water and the organic layer is extracted. The organic layer is washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The obtained residue (384 mg) was dissolved in tetrahydrofuran (15 ml) and to the solution at -10°add alumoweld lithium (56 mg). The mixture is stirred for three hours while cooling with ice, then add decahydrate sodium sulfate. The resulting mixture was filtered through celite and the filtrate evaporated to obtain a residue. The residue is purified column chromatography with reversed phase (water-methanol)to give (1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(hydroxymethyl)phenyl]-D-glucit (90 mg).

Example 182

a 20% Solution of hydrochloric acid in methanol (three drops) and 5% palladium-carbon (0.1 g) are added to a solution of (1H-inden-2-yl)[3-(2,3,4,6-Tetra-O-benzyl-β-D-glyukopiranozil)phenyl]methanone (0.84 g) in methanol (10 ml) and the resulting mixture stirred for 18 hours in a hydrogen atmosphere. The reaction mixture is filtered, the solvent is evaporated from the filtrate under reduced d is the pressure to obtain residue, which is purified column chromatography on silica gel (chloroform-methanol)to give (1S)-1,5-anhydrous-1-[3-[(2,3-dihydro-1H-inden-2-yl)methyl]phenyl]-D-glucit (16 mg).

Connection examples 183 and 184 receive in accordance with the method of example 182.

Example 185

To a solution of pyrrole (64 mg) in dimethylformamide (10 ml) under cooling in an ice bath, add sodium hydride (42 mg) and the resulting mixture is stirred for half an hour at room temperature. The mixture is then cooled to -30°With, to the mixture are added dropwise a solution of (1S)-2,3,4,6-Tetra-O-acetyl-1,5-anhydrous-1-[3-(methyl bromide)phenyl]-D-glucit (80 mg) in tetrahydrofuran (2 ml) and the resulting mixture is stirred for one hour at room temperature. To the mixture is added methanol (10 ml) and sodium methoxide (44 mg) and the resulting mixture is stirred for one hour at the same temperature. After completion of the reaction, the reaction mixture is evaporated to obtain a residue. The residue is purified column chromatography with reversed phase (water-methanol)to give (1S)-1,5-anhydrous-1-[3-(1H-pyrrol-1-ylmethyl)phenyl]-D-glucit (18 mg).

Example 186

The palladium hydroxide on carbon (20%, 130 mg) are added to a suspension of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[5-(4-active compounds)-1H-pyrrol-2-yl]-D-glucit (400 mg) in a mixture of ethyl acetate-acetic acid (10:1) (11 ml) and the resulting mixture is stirred for one hour in an atmosphere of bodoro is a (1 ATM). The reaction mixture was filtered through celite and the filtrate evaporated to obtain a residue. The residue is purified column chromatography on silica gel (chloroform-methanol)to give (1S)-1,5-anhydrous-1-[5-(4-active compounds)-1H-pyrrol-2-yl]-D-glucit (25 mg).

The compound of formula 187 receive in accordance with the procedure of example 186.

Example 188

Palladium/carbon (10%, 450 mg) are added to a solution of (1S)-1,5-anhydrous-2,3,4,6-Tetra-O-benzyl-1-[1-(4-active compounds)-1H-pyrrol-2-yl]-D-glucit (587 mg) in a mixture of ethyl acetate-methanol-acetic acid (10:2:1) (39 ml) and the resulting mixture is stirred for 22 hours in an atmosphere of hydrogen. The reaction mixture was filtered through celite and the filtrate evaporated to obtain a residue. The residue is purified column chromatography on silica gel (chloroform-methanol)to give (1S)-1,5-anhydrous-1-[1-(4-active compounds)-1H-pyrrol-2-yl]-D-glucit (59 mg).

Structural formulas and physical-chemical properties of the compounds of reference examples presented in the following tables 1-6. Structural formulas and physical-chemical properties of the compounds of the examples presented in the following tables 7-36.

Symbols in the tables have the following meanings:

S. p.: the number of the reference example; Approx.: the number of the example; Structure: structural formula; Me: methyl group; Et: ethyl group; Bn: benzyl group; Bu: bucilina group; TBDMS: tert-butyldimethylsilyl the TBDPS group: tert-butyldiphenylsilyl group; AC: acetyl group; Tf: trifloromethyl group; Data: characteristic data; NMR spectrum, nuclear magnetic resonance (as internal standard TMS is used); MS: the value obtained by the method of mass spectroscopy).

The compounds presented in tables 37-39, can be easily obtained by methods similar to those described in the examples and examples, or with slight modifications of these methods are obvious to the skilled in this field. Tables 37-39 following tables 1-36.

Industrial applicability

Because the C-glycoside derivatives and their salts (compounds of the present invention) have the ability to have an inhibitory effect on cotransporter Na+-glucose and reduce the level of blood glucose data connection applicable for the treatment or prevention of diabetes, such as insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes), insulinorezistentne diseases, and obesity, for example, as a medicine, particularly as an inhibitor of cotransporter Na+-glucose.

Significant effects of inhibition of cotransporter Na+-glucose and reducing the amount of glucose in the blood the compounds of this invention were confirmed represented on the more pharmacological tests (examples of biological tests 1 and 2).

An example of biological test 1

The inhibition activity of cotransporter Na+the sugar man (human SGLT2)

(1) preparation of expression vector of human SGLT2

First, from the total RNA of the human kidney (BD Biosciences Clontech) with the participation of the reverse transcriptase synthesize single-stranded cDNA using Superscript II (manufactured by Invitrogen Corporation) and degenerate hexamer. Then, using cDNA as template, a DNA fragment encoding human SGLT2 (Wells, R.G. et al., Am. J. Physiol., 1992, 263(3) F459), amplified by PCR reaction using Pyrobest DNA polymerase (manufactured by Takara Bio Inc.). That is, Hind III site and the EcoRI site is inserted at the 5'-end and 3'end of the DNA, respectively, using primers.

Amplificatory fragment of clone into pCR2.1-Topo vector using a set of Topo TA Cloning Kit (manufactured by Invitrogen Corporation) and cloned vector transferout into competent cell of Escherichia coli JM109. Ampicillin-resistant clones were cultured in LB medium containing ampicillin (100 mg/l). Plasmid purified from cultivated Escherichia coli using the method of Hanahan (Hanahan) (see Maniatis et al., "Molecular Cloning"). A DNA fragment encoding SGLT2 person get splitting plasmids by Hind III/EcoRI and are ligated and clone on the same site expression vector cloned cDNA 3.1 (produced by Invitrogen Corporation) with ispolzovaniem ligase (manufactured by Roche Diagnostics). Legirovannye clone transferout into competent cell of Escherichia coli JM109 as described above and cultured in LB medium containing ampicillin, and the expression vector of human SGLT2 is obtained using the method of Hanahan.

(2) Obtaining expressed in human cells SGLT2

The expression vector of human SGLT2 transferout in Cho-K1 cell, using Lipofectamine2000 (produced by Invitrogen Corporation). Cells cultivated in Ham''s F12 medium (produced by Nissui Pharmaceutical Co., Ltd.), containing penicillin (50 IU/ml, the production of Dainippon Pharmaceutical Co., Ltd.), streptomycin (50 μg/ml, the production of Dainippon Pharmaceutical Co., Ltd.), Geneticin (40 μg/ml, the production of Invitrogen Corporation) and 10% fetal calf serum in the presence of 5% CO2at 37°within two weeks and get Geneticin-resistant clones. Get the cell that stably expresses human SGLT2, showing the sodium-dependent uptake of methyl-α-D-glucopyranoside (method of quantitative determination of the absorption of methyl-α-D-glucopyranoside described in the next paragraphs).

(3) Inhibition of the uptake of methyl-α-D-glucopyranoside

After removal of the medium Cho cells that stably expressive SGLT2 person in each well add buffer solution pre-treatment (buffer solution with pH 7.4, containing choline chloride (140 mm), KCl (2 mm), chlorine is the ID of calcium (1 mm), magnesium chloride (1 mm), 2-[4-(2-hydroxyethyl)-1-piperazinil]econsultancy acid (10 mm) and Tris(hydroxymethyl)aminomethan (5 mm)) in an amount of 100 μl per well and incubated at 37°C for 20 minutes.

11 μl of methyl-α-D-(U-14C)glucopyranoside (manufactured by Amersham Pharmacia Biotech) is mixed with 1000 μl of buffer solution for absorbing, containing the test compound (buffer solution with pH 7.4, containing NaCl (140 mm), KCl (2 mm), calcium chloride (1 mm), magnesium chloride (1 mm), methyl-α-D-glucopyranoside (50 μm), 2-[4-(2-hydroxyethyl)-1-piperazinil]econsultancy acid (10 mm) and Tris(hydroxymethyl)aminomethan (5 mm)to prepare a buffer solution for absorption. For the control group are prepared in buffer solution for absorption without test compounds. In addition, to determine the background absorption of the prepared buffer solution to absorb without test compounds, including choline chloride (140 mm) instead of sodium chloride.

After removal of the buffer solution pre-treatment, add buffer solution to absorb (25 μl per well) and incubated at 37°C for two hours. After removal of the buffer solution for absorption type buffer rinse solution (buffer solution with pH 7.4, containing choline chloride (140 mm), KCl (2 mm), calcium chloride (1 mm), gloriamarie (1 mm), methyl-α-D-glucopyranoside (10 mm), 2-[4-(2-hydroxyethyl)-1-piperazinil]econsultancy acid (10 mm) and Tris(hydroxymethyl)aminomethan (5 mm)) in an amount of 200 μl per well. The mixture is immediately removed. This washing operation is conducted again. 0.5% Solution of lauryl sodium (25 μl per well) is added to solubilize the cells. 75 μl of Microscint 40 (manufactured by PerkinElmer, Inc.) add to solubilizing cells and using microcirculation counter TopCount (produced by Perkin Elmer, Inc.), determine the radiation activity. The value obtained by subtracting the values of the background absorption from the absorption values of the control group is taken as 100%. The concentration at which 50% inhibition above the absorption values (the value of the IC50) calculate from the graph the concentration-inhibition using the method of least squares. As a result of this test shows that the compounds of this invention exhibit significant inhibition activity cotransporter Na+-glucose. The values of the IC50typical compounds of this invention are presented in table 40.

Table 40
ConnectionIC50(nm)ConnectionIC50(nm)
Example 11713Example 14221
Example 13414Example 1506,5
Example 141the 3.8Example 1746,6

An example of biological tests 2

Experience confirm the hypoglycemic activity

This experience is used fattened mice KK-Ay(CLEA Japan, Inc., the male). The test compound suspended in 0.5% solution of methylcellulose c concentration of 1 mg/10 ml Determine the mass of each mouse. Suspension of the test compound administered orally at a dose of 10 ml/kg Control group of mice injected only 0.5% solution of methylcellulose. Each group consists of six mice. Blood taken from the tail vein immediately before introducing the compound and through one, two, four and eight hours after administration of the compound. The glucose content in the blood was determined using the analyzer glucose CII Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.). Effect hypoglycemic activity is determined by calculating the area under the curve (area under curve - AUC) of the glucose content in the blood - the time using the trapezoidal method from values of glucose through 0-8 hours after administration of the compounds and calculation speed (%) reduction in AUC in the group taking drugs is, compared with the control group.

In the compounds of this invention exhibit significant hypoglycemic activity. The hypoglycemic activity of typical compounds of this invention are shown in table 41.

Table 41
ConnectionHypoglycemic activity (%)
Example 13439
Example 14134

As can be seen from the results of examples 1 and 2 biological tests, the compounds of this invention exhibit significant inhibition activity cotransporter Na+-glucose and a significant hypoglycemic activity. Therefore, it is expected that the compounds of this invention can serve as an antidiabetic agent, which has the same or more potent effect in comparison with traditional antidiabetic agents.

Pharmaceutical composition containing one or more compounds of this invention and their pharmaceutically acceptable salts, are prepared in the form of tablets, powder, granules, fine grinding, granules, capsules, pills, liquids, drugs for injection, suppositories, ointments, Velcro, etc. using a carrier, filler or other additives, traditionally ispolzuemykh to obtain the drug, and is administered orally or parenterally.

The amount of the compounds of this invention, designed for clinical introduction in the human body, is determined appropriately taking into account symptoms, weight, age, sex, etc. of the patient, which introduces a connection, and is in the range from 0.1 to 500 mg per day for oral administration or in the range from 0.01 to 100 mg per day for parenteral administration one or more times a day. Since the amount intended for the introduction, changes depending on various conditions, it may be sufficient to enter the connection in a smaller amount than the above number.

As solid compositions for oral administration the compounds of this invention are tablets, powders, granules, etc. In such solid compositions one or more active compounds are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or alumosilicate magnesium. The composition may contain additives other than the inert diluent, such as a lubricating substance, such as magnesium stearate additive for distribution, such as calcixerollic, stabilizer, for example sucrose, solubilizer, for example the EP glutamic acid and aspartic acid, adjuvant to solubilize etc. introduced in the traditional way. Tablet or pill may optionally be covered with a film of glucose or soluble in the stomach or intestines of a substance, such as sucrose, gelatin, hydroxypropylcellulose or phthalate of hydroxypropylmethylcellulose.

Liquid composition for oral administration includes pharmaceutically acceptable preparations, such as emulsion drug, the drug solution, suspension preparation the preparation of the syrup, the preparation of the elixir and the like, and contains a generally used inert diluent such as purified water and ethanol. In addition to the diluent composition may contain adjuvants, such as a solubilizer, wetting agent, suspendida additive, sweetener, flavoring, fragrance and preservative.

Injectable drug for parenteral administration include sterilized aqueous or nonaqueous solution, suspension and emulsion. Examples of the solvent for the aqueous solution or suspension include distilled water and saline solution for injection. Examples of the solvent for non-aqueous solutions or suspensions include propylene glycol, polyethylene glycol, vegetable oil such as olive oil; alcohols such as ethanol; and Polysolvate 80 (trade name).

This composition could critique the sustained fashion to contain additives, such as an additive to give isotonicity of the solution, preservative, wetting agent, emulsifier, dispersing agent, a stabilizer (e.g., lactose), a solubilizer and adjuvant to solubilize. These compounds are sterilized by filtration through a bacterial filter and adding disinfectant substances or, for example, by irradiation. These compounds can be used for preparing sterilized solid compositions and dissolving the composition in sterilized water or a solution for injection before use.

Table 1
S. p.STRUCTUREDATA
1FAB-MS (m/z); 307 [M+H]+
2EI-MS (m/z); 261 [M]+
3FAB-MS (m/z); 443 [M]+
4FAB-MS (m/z); 459 [M]+
5EI-MS (m/z); 518 [M-H]-
61H-NMR (CDCl3); of 1.09 (9H, s), 4,70 (2H, s), 5,1 (2H, C)of 6.61 (1H, d), 7,32-of 7.48 (11H, m), 7,63-of 7.70 (5H, m)
7FAB-MS (m/z); 439 [M+H]+
8FAB-MS (m/z); 502 [M+H]+
91H-NMR (CDCl3); to 2.29 (3H, s), 3,54-are 3.90 (6H, m), 3,98 (1H, d), 4,40-and 4.68 (4H, m), 4.75 V-of 5.05 (6H, m), 6.75 in-7,43 (28H, m)

Table 2
S. p.STRUCTUREDATA
10FAB-MS (m/z); 648 [M+H]+
11FAB-MS (m/z); 665 [M+H]+
12EI-MS (m/z); 748 [M+Na]+
13EI-MS (m/z); 777 [M+Na]+
14FAB-MS (m/z)481 [M+H]+
15FAB-MS (m/z); 559 [M+H]+
16ES-MS (m/z); 666 [M+Na]+
17 FAB-MS (m/z); 711 [M+H]+

Table 3
S. p.STRUCTUREDATA
18ES-MS (m/z); 714 [M+H]+
19ES-MS (m/z); 669 [M+Na]+
20ES-MS (m/z); 685 [M+Na]+
21ES-MS (m/z); 746 [M+Na]+
22FAB-MS (m/z); 753 [M+H]+
231H-NMR (CDCl3); to 3.33 (3H, s), 3,47 (3H, s), 3,61-3,84 (7H, m), 4,28-4,96 (8H, m), 6.89 in-7,39 (20H, m), 7,42 (1H, t), of 7.55 (1H, d), 7,66 (1H, d), 7,81 (1H, s)
24ES-MS (m/z); 749 [M+H]+
25FAB-MS (m/z); 671 [M+H]+

Table 4
S. p.STRUCTUREDATA
26 1H-NMR (CDCl3); of 1.27 (3H, t), was 2.76 (2H, DD), Android 4.04 (2H, s), 6,60 (2H, d), 7,16-7,39 (4H, m)
271H-NMR (CDCl3); of 2.16 (3H, s), Android 4.04 (2H, s), PC 6.82 (1H, d), 7,07 (1H, d), 7,12-7,34 (4H, s)
28FAB-MS (m/z); 203 [M-H]-
291H-NMR (CDCl3); a 2.36 (3H, s), 4,18 (2H, s), 7,14-to 7.18 (2H, m), 7,25-7,40 (4H, m), the 7.65 (1H, d), 7,74 (1H, d)
301H-NMR (CDCl3); to 4.16 (2H, s), 7,13 (1H, d), 7,15-7,19 (2H, m), 7,33-7,38 (3H, m), 7,42 (1H, s), to 7.67 (1H, m), 7,87 (1H, m)
31EI-MS (m/z); 364 [M+H]+
32EI-MS (m/z)334 [M+H]+
33FAB-MS (m/z)423 [M+H]+
34EI-MS (m/z); 364 [M+H]+
35EI-MS (m/z)380 [M+H]+

Table 5
S. p.STRUCTURE DATA
36EI-MS; 230 [M]+
37FAB-MS (m/z)467 [M]+
38FAB-MS (m/z); 451 [M]+
39FAB-MS (m/z); 451 [M]+
40FAB-MS (m/z); 493 [M]+
411H-NMR (CDCl3); to 1.22 (3H, t), 2,63 (2H, HF), a 4.03 (2H, s), 6,55 (1H, d), 6,85 (1H, d), 7,14 (4H, s)
421H-NMR (CDCl3); to 1.22 (3H, t), 2,62 (2H, HF), 3,44 (2H, s), 5,96-6,01 (1H, m), 6,14 (1H, DD), of 6.65 (1H, DD), 7,00-7,28 (4H, m)
431H-NMR (CDCl3); of 0.90 (9H, m), 1,12-of 1.39 (12H, m)to 1.60 (6H, m), is 2.37 (3H, s), is 2.44 (3H, s), 6,83 (1H, s), 6,98 (1H, d), 7,26 (1H, m)
441H-NMR (CDCl3); to 0.88 (9H, m), 1,12-1,38 (14H, m), 1,58 (4H, m), 2,42 (3H, s), 2,47 (3H, s), for 6.81 (1H, s), at 6.84 (1H, s), 7,14 (1H, s)
451H-NMR (CDCl3); of 0.91 (9H, m), 1,08-1,62 (18H, m), 2,43 (3H, s), for 6.81 (1H, s), 7,02 (1H, is), to 7.32 (1H, s), of 7.36 (1H, d)

Table 6
S. p.STRUCTUREDATA
461H-NMR (CDCl3); of 0.90 (9H, m)to 1.14 (6H, m)of 1.36 (6H, m)to 1.61 (6H, m), of 2.34 (3H, s), is 2.40 (3H, s), is 2.44 (3H, s), to 6.80 (1H, s), 6,83 (1H, s)
471H-NMR (CDCl3); of 0.90 (9H, m)to 1.14 (6H, m)of 1.35 (6H, m)to 1.60 (6H, m), of 2.34 (3H, s), 2,42 (3H, s), 6.87 in (1H, s), 7,00 (1H, d), of 7.23 (1H, d)
481H-NMR (CDCl3); to 0.89 (9H, m)of 1.12 (6H, m)of 1.33 (6H, m)of 1.57 (6H, m), 2,32 (3H, s)to 2.35 (3H, s), is 6.78 (1H, d), 7,28 (2H, s)
49ES-MS (m/z); 431 [M+H]+
501H-NMR (CDCl3); 2,39 (3H, s)to 3.35 (2H, s), 6,52-is 6.54 (1H, m), 6,82-6,84 (1H, m), 6,99-to 7.35 (2H, AB kV), 7,22 (1H, s)
511H-NMR (CDCl3); is 2.37 (3H, s), 3,55 (2H, s), 6.87 in (1H, s), of 6.96-of 7.25 (2H, AB kV), 7,11 (1H, s)
521H-NMR (CDCl3); to 2.29 (6H, s)to 3.33 (2H, s), of 6.45 (1H, d), to 6.80 (1H, d), 7,18 (1H, s), 7,24 (1H, s)
53 1H-NMR (CDCl3); and 2.26 (3H, s), and 2.27 (3H, s), 3,53 (2H, s), 6,85 (1H, s), was 7.08 (1H, s), 7,14 (1H, s)
541H-NMR (CDCl3); 3,52-4,06 (6H, m)to 4.33 (1H, d), 4,45-4,95 (10H, m), of 6.75 (1H, d), to 7.67-7,86 (4H, m), 6.90 to-7,98 (27H, m), 8,23 (1H, s)
55FAB-MS (m/z); 413 [M+H]+

Table 7
Approx.STRUCTUREDATA
11H-NMR (CDCl3); 3,51 (1H, m)and 3.59 (1H, m), of 3.73-3,81 (5H, m), 4,21-4,24 (3H, m), 4,35 (1H, d), 4,50 with 4.65 (3H, m), 4,82-4,94 (3H, m), 6.87 in-6,89 (2H, m), 6,97 (1H, s), 7,13-7,40 (24H, m), 7,66 (1H, d), to 7.68 (1H, d)

FAB-MS (m/z); 746 [M-H]-
21H-NMR (CDCl3); to 2.41 (3H, s), 3,48-3,59 (2H, m), 3,76-3,82 (5H, m), 4,20 (2H, s), 4,22 (1H, d), 4,34 (1H, d), of 4.54 (1H, d), 4,62-of 4.66 (2H, m), a 4.86 (1H, d), to 4.87 (1H, d), 4,94 (1H, d), 6.87 in-6,89 (3H, m),? 7.04 baby mortality-7,40 (24H, m)of 7.55 (1H, d)

FAB-MS (m/z); 759 [M-H]-
31H-NMR (CDCl3); 7,52-7,58 (2H, m), 7,11-7,40 (23H, m), 6,85-of 6.90 (3H, m), 4,84-4,94 (3H, m), 4,51-of 4.67 (3H, m), 4,36 (1H, d), 4,24 (1H, d), 4,19 (2H, s), 3.72 points-is 3.82 (5H, m), 3,48-3,62 (2H, m)

FAB-MS (m/z); 781 [M]+
4 1H-NMR (CDCl3); 3,48-of 3.60 (2H, m), 3,76-3,82 (5H, m), 4,20 (2H, s), 4,24 (1H, d), 4,36 (1H, d), of 4.54 (1H, d), br4.61-4,85 (2H, m), a 4.86 (1H, d), 4,88 (1H, d), is 4.93 (1H, d), 6.87 in-6,91 (3H, m), 6,94-7,01 (1H, m), 7,13-7,39 (23H, m), 7,56 (1H, DD)

FAB-MS (m/z); 763 [M-H]-
51H-NMR (CDCl3); to 2.29 (3H, s), 3,47-3,59 (2H, m), of 3.73-3,82 (5H, m), 4,17 (2H, s), 4,22 (1H, d), 4,34 (1H, d), a 4.53 (1H, d), 4,63 (2H, d), a 4.86 (1H, d), to 4.87 (1H, d), to 4.92 (1H, d), 6.87 in-6,89 (2H, m), 6,97-7,03 (1H, m), 7,11 and 7.36 (23H, m), 7,55 (1H, DD)

ES-MS (m/z); 801 [M+Na]+

Table 8
Approx.STRUCTUREDATA
61H-NMR (CDCl3); of 2.28 (3H, s), 3,47-to 3.58 (2H, m), of 3.73-3,82 (5H, m), 4,18 (2H, s), 4,22 (1H, d), 4,34 (1H, d), a 4.53 (1H, d), 4,63 (2H, d), a 4.86 (1H, d), to 4.87 (1H, d), to 4.92 (1H, d), 6,86-6,89 (2H, m), 7,11 and 7.36 (23H, m), 7,53-7,56 (2H, m)

ES-MS (m/z); 817 [M+Na]+
71H-NMR (CDCl3); to 1.35 (9H, s), 3,49-3,59 (2H, m), 3,76-3,82 (5H, m), 4,20 (2H, s)to 4.23 (1H, d), 4,34 (1H, d), 4,56 (1H, d), 4,63 (1H, d), with 4.64 (1H, d), a 4.86 (1H, d), to 4.87 (1H, d), 4,94 (1H, d),

6,86-to 6.88 (2H, m)6,94 (1H, USS), 7,08 and 7.36 (22H, m), 7,40 (1H, USS), 7,60 to 7.62 (2H, m)

ES-MS (m/z); 825 [M+Na]+
81H-NMR (CDCl3); 3,49-3,59 (2H, m), of 3.77-of 3.80 (5H, m), 3,81 (3H, s), 4,20 (2H, s)to 4.23 (1H, d), 4,35 (1H, d), of 4.54 (1H, d), 4,62-of 4.66 (2H, m), a 4.86 (1H, d), 4,88 (1H, d), is 4.93 (1H, d), 6,86-of 6.90 (3H, m), 7,05 (1H, d), 7,10 and 7.36 (22H, m), 7,40 (1H, USS), 7,53 (1H, d)

FAB-MS (m/z); 777 [M+H]+
91H-NMR (CDCl3); at 2.93 (6H, s), 3,49-3,59 (2H, m), of 3.73-3,82 (5H, m), 4,18 (2H, s)to 4.23 (1H, d), 4,34 (1H, d), 4,55 (1H, d), 4,63 (1H, d), with 4.64 (1H, d), a 4.86 (1H, d), to 4.87 (1H, d), is 4.93 (1H, d), for 6.81-6,91 (5H, m), 7,11-7,35 (21H, m), 7,40 (1H, USS), 7,49 (1H, d)

ES-MS (m/z); 790 [M+H]+
101H-NMR (CDCl3); to 1.14 (6H, t)to 3.34 (4H, HF), 3,49-3,59 (2H, m), of 3.73-3,82 (5H, m), 4,17 (2H, s), 4,22 (1H, d), 4,33 (1H, d), a 4.53 (1H, d), 4,63 (1H, d), with 4.64 (1H, d), a 4.86 (1H, d), to 4.87 (1H, d), 4,94 (1H, d), 6,76 (1H, DD), PC 6.82 (3H, m), 7,10-7,35 (21H, m), 7,40 (1H, USS), 7,47 (1H, d)

FAB-MS (m/z); 818 [M+H]+
111H-NMR (CDCl3); 2,92 (4H, USS), of 3.60 (1H, m), 3,71 is 3.76 (8H, m), 3,98 (1H, m), 4,17-4,24 (2H, m), 4,39-4,59 (5H, m), 4,86-4,94 (4H, m), 6,70-6,72 (2H, m)6,94 (1H, s), 7,08-7,30 (23H, m), 7,46 (2H, m), 7,56-to 7.59 (1H, m)

ES-MS (m/z); 832 [M+H]+

Table 9
Approx.STRUCTUREDATA
121H-NMR (CDCl3); 3,40-3,63 (2H, m)

3,70-3,90 (5H, m), 4,15-of 4.25 (3H, m), 4,42 (1H, d), 4,50-of 4.66 (3H, m), 4,82-4,96 (3H, m), 6,88-,35 (26H, m), to 7.59-the 7.65 (1H, m), to 7.67-7,72 (1H, m)

ES-MS (m/z); 787 [M+Na]+
131H-NMR (CDCl3); 3,61-3,66 (2H, m)

3,71-3,88 (4H, m), 3,95 (1H, d), 4,18 (2H, s), 4,37 (1H, d), 4,51 (1H, d), br4.61 (1H, d), 4,63 (1H, d), a 4.83-4,94 (4H, m), 6,93-of 6.96 (3H, m), 7,13-7,31 (21H, m), 7,35 (1H, d), of 7.48 (1H, d), 7,58 (1H, d), to 7.67 (1H, d)

ES-MS (m/z); 803 [M+Na]+
141H-NMR (CDCl3); to 3.33 (3H, d), 3,54-a 3.87 (6H, m), 3,98-of 4.05 (1H, m), 4,16-4,34 (2H, m), of 4.44-4,78 (5H, m), 4,82-5,07 (5H, m), 6,91-6,98 (3H, m), 7,05-7,35 (21H, m), 7,41 (1H, d), 7,52 (1H, d), a 7.62 (1H)

ES-MS (m/z); 841 [M]+
151H-NMR (CDCl3); 3,56-of 3.60 (1H, m)

3,66-a 3.83 (5H, m)to 4.01 (1H, d), 4.09 to-4,24 (2H, m), 4,43 with 4.65 (4H, m), and 4.75 (1H, USS), 4,82-4,99 (5H, m), 6,63 (1H, d), to 6.88 (2H, d), 6,93 (1H, s), 7,06-7,40 (26H, m), 7,56 (1H, d), the 7.65 (1H, d)

EI-MS (m/z); 894 [M+Na]+
161H-NMR (CDCl3); 3,48-of 3.60 (2H, m)

to 3.73-3,81 (5H, m), 4,10 (2H, s), 4,24 (1H, d), 4,37 (1H, d), of 4.54 (1H, d), 4,62-of 4.66 (2H, m), a 4.86 (1H, d), 4,88 (1H, d), 4,94 (1H, d), 6,32 (1H, d), 6.87 in-6,90 (2H, m), 7,11-7,43 (26H, m)

ES-MS (m/z); 753 [M+Na]+
171H-NMR (CDCl3); 3,47-4,07 (12H, m), 4,42-4,70 (5H, m), 4.80 to of 4.95 (3H, m), 7,75-7,38 (26H, m)

EI-MS (m/z); 726 [M]+

td align="right" namest="c0" nameend="c2"> Table 10
Approx.STRUCTUREDATA
181H-NMR (CDCl3); to 1.21 (3H, t), 2,62 (5H, kV), 3,49-4,13 (7H, m), 4,10 (2H, s), 4,43-4,95 (8H, m), 6,69-7,34 (26H, m)

ES-MS (m/z); 747 [M+Na]+
191H-NMR (CDCl3); a 2.36 (3H, s), 3,51-3,82 (7H, m)4,06 (2H, s)to 4.23 (1H, d), 4,35 (1H, d), 4,54-4,96 (6H, m), 6,51-7,33 (26H, m)

ES-MS (m/z); 728 [M+NH4]+
20IH-NMR (CDCl3); to 1.21 (3H, t), 2,70 (2H, DD), 3,49-3,82 (7H, m), 4,07 (2H, s)to 4.23 (1H, d), 4,35-4,95 (7H, m), 6,53 (2H, DD), 6.89 in and 7.36 (24H, m)

ES-MS (m/z); 742 [M+NH4]+
211H-NMR (CDCl3); and 2.14 (3H, s), 3,48-3,81 (7H, m)4,06 (2H, s), 4,20-4,96 (8H, m), 6,77 and 7.36 (26H, m)

ES-MS (m/z); 728 [M+NH4]+
221H-NMR (CDCl3); to 7.67 (1H, d), to 7.61 (1H, d), 7,11-7,38 (24H, m), 6.89 in (2H, d), 4,84-4,94 (3H, m), 4,63 (2H, d), of 4.54 (1H, d), 4,33 (1H, d), 4,22 (1H, d), 4,19 (2H, s), 3.72 points-is 3.82 (5H, m), 3,48-3,62 (2H, m), of 2.34 (3H, s)< / br>
FAB-MS (m/z); 760 [M]+
231H-NMR (CDCl3); 3,49-of 3.77 (6H, m)

4,05-4,22 (3H, m), 4,40-5,00 (8H, m), 6,85-7,74 (27H, m)

FAB-MS (m/z); 751 [M+H]-
241H-NMR (CDCl3); 7,83 (1H, USD), the 7.65 (1H, DD), 7,15-7,40 (24H, m), 6,93 (1H, s), 6.89 in (2H, DD), 4,84-4,94 (3H, m), 4,63 (2H, d), a 4.53 (1H, d), 4,34 (1H, d), 4,22 (1H, d), 4,19 (2H, s), 3.72 points-is 3.82 (5H, m), 3,48-3,62 (2H, m)

Table 11
Approx.STRUCTUREDATA
251H-NMR (CDCl3); the 3.35 (3H, s), 3,59-3,61 (1H, m), 3.72 points-is 3.82 (5H, m), 3,93 (1H, d), 4,12-4,22 (2H, m), 4,43 (1H, d), 4,51 (1H, d), 4,60 (1H, d), with 4.64 (1H, d), 4,73-rate 4.79 (1H, ush.), to 4.87 (1H, d), 4,88 (1H, d), of 4.95 (1H, d), 5,03 is 5.07 (2H, m), 6,85-to 6.88 (2H, m), of 6.96 (1H, s), 7,09-7,31 (22H, m), 7,42 (1H, d), 7,56 (1H, d), 7,66 (1H, d)

EI-MS (m/z); 829 [M+Na]+
261H-NMR (CDCl3); 3,37 (3H, s)to 3.41 (3H, s), 3,50-of 3.80 (4H, s)4,00 (1H, d), 4,10-4,72 (8H, m), 4,84-5,23 (8H, m), 6.73 x-7,02 (4H, m), 7,07-7,39 (21H, m), 7,51 (1H, d), 7,63 (1H, d)

ES-MS (m/z); 889 [M+Na]+
271H-NMR (CDCl3); 3,17-4,01 (13H, m), 4,10 (1H, d), 4,19 (1H, d), 4,36-5,00 (8H, m), 6,46 (1H, s), 6,85-7,40 (24H, m), 7,52 (1H, d), 7,63 (1H, m)

FAB-MS (m/z); 808 [M+H]+
281H-NMR (CDCl3); 3.45 points to 5.35 (17H, m), 6,70-a 7.85 (33H, m)

ES-MS (m/z); 845 [M+Na]+
29 1H-NMR (CDCl3); 3,50 of 3.56 (1H, m), 3,60-of 3.64 (1H, m), 3,71 (1H, d), 3,75-a-3.84 (4H, m), of 4.12 (2H, s), or 4.31 (1H, d), 4,32 (1H, d), 4,56 (1H, d), with 4.64 (1H, d)and 4.65 (1H, d), 4,88 (1H, d), 4,89 (1H, d), 4,96 (1H, d), 6,36 (1H, s), at 6.84-6.87 in (2H, m), 7,10-7,40 (25H, m), 7,55 (1H, d)

FAB-MS (m/z); 731 [M+H]+
301H-NMR (CDCl3); 3,54-to 3.58 (1H, m), 3,67-of 3.77 (4H, m), 3,83-of 3.97 (2H, m), 4,05-4,17 (2H, m), 4,37-4,48 (3H, m), to 4.52-to 4.62 (2H, m), a 4.83-of 4.95 (3H, m), 6.90 to-of 6.96 (3H, m), 7,08-7,34 (22H), 7,60 (1H, d), to 7.67-of 7.69 (2H, m)

EI-MS (m/z); 785 [M+Na]+

Table 12
Approx.STRUCTUREDATA
311H-NMR (CDCl3); 3,44-the 3.65 (2H, m)

3,70-to 3.92 (4H, m), 4,13-4,27 (3H, m), 4,37 (1H, d), 4,50-of 4.67 (3H, m), 4.80 to 4,96 (3H, m), 6.75 in-7,05 (3H, m), 7,08-7,35 (22H), 7,56 (1H, d), to 7.67 (1H, d)

FAB-MS (m/z); 761 [M-H]-
321H-NMR (CDCl3); 3,51-3,59 (1H, m)

3,63-of 3.78 (4H, m), 3,84-4,00 (2H, m), 4.04 the-4,16 (1H, m), 4.26 deaths-and 4.40 (2H, m), 4,43-br4.61 (4H, m), 4,82-of 4.95 (3H, m), 6.90 to-6,98 (2H, m), 6,99-7,03 (1H, m), 7,05-to 7.09 (1H, m), 7,12-7,37 (20H, m), 7,56-7,63 (1H, m), 7,66-7,72 (1H, m), 7,80-7,88 (1H, m)

FAB-MS (m/z); 795 [M-H]-
331H-NMR (CDCl3); to 3.58-3,62 (1H, m)

3,71-3,82 9H, m)to 3.92 (1H, d), 4,15-4,19 (2H, m), and 4.40 (1H, d), to 4.52 (1H, d), br4.61 with 4.65 (2H, m), 4,84-4,88 (2H, m), 4,94 (1H, d), at 6.84-6.89 in (3H, m), to 6.95 (1H, s), 7,11-7,31 (21H, m), 7,42 (1H, d), 7,56 (1H, d), the 7.65 (1H, d)

EI-MS (m/z); 799 [M+Na]+
341H-NMR (CDCl3); 3,53-3,82 (9H, m)

3,97-4,20 (1H, m), 4,17-4,32 (2H, m), to 4.41-of 4.66 (4H, m), to 4.73 (1H, USS), 4,81-of 4.95 (3H, m), 6,83-6,94 (4H, m), 7,09-7,32 (20H, m), 7,38-the 7.43 (1H, m), of 7.48-of 7.55 (1H, m), 7,58-to 7.64 (1H, m)

ES-MS (m/z); 811 [M]+
351H-NMR (CDCl3); to 3.38 (3H, s), 3,56-3,62 (2H, m), 3,64-3,81 (7H, m), 3,92 (1H, d), 3.95 to 4,08 (2H, m), 4,14 (1H, d), 4,19 (1H, d), and 4.40 (1H, d), 4,51 (1H, d), to 4.62 (1H, d), 4,63 (1H, d), 4,84-4,88 (2H, m), is 4.93 (1H, d), 6,84-to 6.88 (3H, m), of 6.96 (1H, s), 7,09-7,31 (21H, m), 7,39 (1H, s), EUR 7.57 (1H, d), 7,66 (1H, d)

EI-MS (m/z); 843 [M+Na]+
361H-NMR (CDCl3); 3,40-the 3.65 (3H, m)

3,70-3,98 (7H, m), 4,05-4,47 (6H, m), 4,50-4,70 (3H, m), 4.80 to of 4.95 (3H, m), 6,80-of 6.96 (3H, m), 7,06-7,40 (21H, m), 7,55 (1H, d), 7,66 (1H, d)

FAB-MS (m/z); 806 [M-H]-

Table 13
Approx.STRUCTUREDATA
371H-NMR (CDCl3); of 1.40 (9H, s), 3,32-to 3.38 (2H, m), to 3.58-3,61 (1H, m), 3,71-a 3.83 (6H, m), 3.95 to a 4.03 (2H, m), 4,13 (1H, d), 4,18 (1H, d), 4,45-to 4.52 (2H, m), 4,56-4,63 (2H, m), 4,84-4,89 (2H, m), 4,7 (1H, d), are 5.36-5,44 (1H, d), 6,77 (1H, d), PC 6.82 (2H, d), 6,98 (1H, s), 7,06-7,32 (21H, m), 7,35 (1H, s), to 7.59 (1H, d), to 7.67 (1H, d)

EI-MS (m/z); 928 [M+Na]+
381H-NMR (CDCl3); 3,61 (1H, m), and 3.72 (3H, s), of 3.73-a-3.84 (5H, m)4,00 (1H, d), 4,15-4,19 (2H, m)to 4.41 (1H, d), 4,48-4,55 (3H, m), 4,59-of 4.66 (2H, m), 4,84-4,96 (4H, m), 6,74 (1H, d), 6,86-of 6.90 (2H, m), of 6.96 (1H, s), 7,08-7,32 (21H, m), 7,41 (1H, s), EUR 7.57 (1H, d), 7,66 (1H, d)

FAB-MS (m/z); 836 [M+H]+
391H-NMR (CDCl3); of 1.28 (3H, t), 3,56-3,62 (1H, m), 3,67-a-3.84 (5H, m), 4,08 (1H, d), 4,19-4,27 (4H, m), 4,45-to 4.52 (4H, m), 4,56 with 4.65 (2H, m), 4,74 (1H, USS), a 4.83-is 4.93 (3H, m), to 6.80 (1H, s), 6,88-to 6.95 (3H, m), 7,08-7,32 (20H, m), 7,40 (1H, s), 7,53-to 7.67 (1H, m), 7,63-to 7.67 (1H, m)

ES-MS (m/z); 905 [M+Na]+
401H-NMR (CDCl3); 1,25 (3H, t), to 3.58-a 3.87 (8H, m), 4,10 (2H, s), 4,12-4,19 (3H, m), 4,34-4,37 (2H, m), 4,49 (1H, d), 4,55 (1H, d), to 4.62 (1H, d), 4,84-4,96 (3H, m), of 6.45 (1H, d), 6.90 to-of 6.96 (3H, m), 7,08-7,31 (22H, m), 7,60 (1H, d), to 7.68 (1H, d)

ES-MS (m/z); 848 [M+H]+
411H-NMR (CDCl3); is 2.40 (3H, s), 2,90 (2H, t), 3,57-3,61 (1H, m), 3,71-with 3.79 (6H, m), 3,94-Android 4.04 (3H, m), 4,14 (1H, d), 4,19 (1H, d), to 4.38 (1H, d), 4,51 (1H, d), 4,58-4,63 (2H, m), a 4.86 (1H, d), to 4.87 (1H, d), is 4.93 (1H, d), 6,83-6,87 (3H, m), of 6.96 (1H, s), 7,08-7,31 (21H, m), 7,37 (1H, s), EUR 7.57 (1H, d), 7,66 (1H, d)

FAB-MS (m/z); 820 [M+H]+
421 H-NMR (CDCl3); to 1.70 (3H, s), 3,37-3,50 (2H, m), 3,59-3,63 (1H, m), 3,68-3,83 (7H, m), 3,92 (1H, d), 4,08-of 4.12 (1H, m), 4,17 (1H, d), 4,22 (1H, d), of 4.44 (1H, d), to 4.52 (1H, d), 4,59 (1H, d), 4,63 (1H, d), is 4.85 (1H, d), 4,91 (2H, s), 6,76-6,83 (3H, m), of 6.99 (1H, s), 7,08-7,33 (N, m), 7,42 (1H, s), to 7.59 (1H, d), to 7.67 (1H, d)

EI-MS (m/z); 848 [M+H]+

Table 14
Approx.STRUCTUREDATA
431H-NMR (CDCl3); at 1.73 (3H, s), from 2.00 (3H, s)2,04 (6H, s), a 2.36 (3H, s), 3,80 (1H, DDD), 4.09 to (1H, DD), is 4.21 (2H, s), 4,30 (1H, DD), 4,57-4,63 (1H, m), 5,17-5,22 (1H, m), 5,28-5,32 (2H, m), 6,98 (1H, s),? 7.04 baby mortality (1H, d), 7.24 to-to 7.32 (3H, m), of 7.36 (1H, d), to 7.67 (1H, d), 7,73 (1H, d)

FAB-MS (m/z); 612 [M+H]+
441H-NMR (CDCl3); of 1.74 (3H, s)to 1.99 (3H, s)2,02 (3H, s)2,04 (3H, s), a 2.36 (3H, s), 3.75 to 3,82 (1H, m), 4,07 (1H, DD), 4,22 (2H, USS), 4,28 (1H, DD), 4,55 (1H, d), 5,13-5,33 (3H, m), to 6.88 (1H, d), of 7.00 (1H, s), 7,22-7,37 (3H, m), of 7.64 for 7.78 (2H, m)

EI-MS (m/z); 653 [M+Na]+
451H-NMR (CDCl3)and 1.60 (3H, s)to 1.98 (3H, s), is 2.05 (3H, s)a 2.12 (3H, s), 3,83-3,88 (1H, m), 4,10 (2H, s), 4,17 (1H, DD), to 4.33 (1H, DD), to 4.52-4,56 (1H, m), 5,27-5,31 (3H, m), 6.87 in-6,89 (2H, m)6,94 (1H, d), 6,97 (1H, s), 7,16-7,31 (2H, m), of 7.64 (1H, d), 7,71 (1H, DD)

FAB-MS (m/z); 570 [M+H]+
46sup> 1H-NMR (CDCl3); to 1.59 (3H, s)to 1.98 (3H, s), is 2.05 (3H, s)a 2.12 (3H, s), 3,80-a 3.87 (1H, m), 4,07 (1H, t), or 4.31 (1H, DD), 4,47-a 4.53 (1H, m), to 5.21-and 5.30 (3H, m), of 6.66 (1H, d), 6,83 (1H, d), of 6.96 (1H, s), 7,22-to 7.32 (2H, m), to 7.64 (1H, d), 7,71 (1H, d)

EI-MS (m/z); 611 [M+Na]+
471H-NMR (CDCl3); 1,60 was 1.69 (2H, m), 1,71 (3H, s), 1,78-of 1.92 (6H, m), from 2.00 (3H, s)2,036 (3H, s)2,040 (3H, s), 3,78-a 3.83 (1H, m), 4,10-4,18 (3H, m), 4.26 deaths (1H, DD), 4.75 V-4,85 (2H, m), 5,20 (1H, t), and 5.30-of 5.40 (2H, m), 6,80 (1H, d), to 6.95 (1H, s), to 7.15 (1H, DD), 7,20-7,30 (3H, m), the 7.65 (1H, d), 7,71 (1H, d)

FAB-MS (m/z); 638 [M+H]+
481H-NMR (CDCl3); at 1.73 (3H, s)to 1.99 (3H, s)2,02 (3H, s)2,04 (3H, s), of 3.77-of 3.85 (4H, m), 4.09 to 4,19 (3H, m), 4,24 (1H, DD), 4,77-a 4.86 (1H, m), 5,16-5,24 (1H, m), 5,28 is 5.38 (2H, m), is 6.61 (1H, d), of 6.96 (1H, s), 7,20-7,32 (3H, m), the 7.65 (1H, d), 7,72 (1H, d)

EI-MS (m/z); 625 [M+Na]+

Table 15
Approx.STRUCTUREDATA
491H-NMR (CDCl3); to 1.35 (3H, d), of 1.36 (3H, d), 1,72 (3H, s), from 2.00 (3H, s)2,03 (3H, s)2,04 (3H, s), 3,81-of 3.85 (1H, m), 4,11-to 4.14 (3H, m), 4,24 (1H, DD), 4,50-4,56 (1H, m)to 4.92 (1H, OSS), to 5.21 (1H, t), 5,32 is 5.38 (2H, m), for 6.81 (1H, d), of 6.96 (1H, s), to 7.15 (1H, DD), 7,21-7,30 (3H, m), 7,66 (1H, d), 7,72 (1H, DD)

EI-MS (m/z); 613 [M+H]+
501 H-NMR (CDCl3); to 1.42 (3H, s)of 1.50 (3H, s), 1,71 (3H, s)to 1.99 (3H, s)2,04 (6H, s), 3,81-3,86 (1H, m), 3,97-4,06 (3H, m), 4,10-4,22 (4H, m), 4,27 (1H, DD), 4,48-of 4.54 (1H, m), 4.80 to the 4.90 (1H, ush.), to 5.21 (1H, t), 5,31 (1H, t), 5,35-of 5.45 (1H, ush.), PC 6.82 (1H, d), to 6.95 (1H, d), 7,17-7,31 (4H, m), 7,66 (1H, d), 7,72 (1H, DD)

FAB-MS (m/z); 685 [M+H]+
511H-NMR (DMSO-d6), 3,62-a-3.84 (6H, m), was 4.02 (1H, d), 4,19 (2H, s), of 4.44-4,62 (5H, m), a 4.83-4,88 (3H, m), 6,83 (2H, m), of 6.99 (1H, s), 7,06-7,33 (22H, m), 7,44 (1H, d), 7,60 (1H, m), 7,68 (1H, m)

ES-MS (m/z); 917 [M+Na]+
521H-NMR (DMSO-d6); 3,55 (1H, m), 3,71 (3H, s), 3,76-3,86 (6H, m), 4,22 (2H, s), to 4.38 (1H, d), to 4.52 (1H, d), br4.61 (1H, d), 4,63 (1H, d), 4,84-is 4.93 (3H, m), lower than the 5.37 (1H, d), 6.90 to-6,93 (2H, m), of 6.96 (1H, s), 7,12-7,30 (21H, m), to 7.59 (2H, m), 7,68 (1H, d), 7,74 (1H, d)

ES-MS (m/z); 827 [M+Na]+
531H-NMR (DMSO-d6); 3,56-3,81 (7H, m), 4,24 (1H, d), 4,32 (2H, s), 4,45-4,59 (3H, m), 4,73-4,78 (3H, m), lower than the 5.37 (1H, d), at 6.84 (2H, d), 7,01-7,40 (22H, m), 7,66 (2H, m), to 7.77 (2H, d), and 12.9 (1H, s)

FAB-MS (m/z); 791 [M+H]+
541H-NMR (CDCl3); 3,62 (1H, m), 3,69-a 3.83 (5H, m)to 3.99 (1H, d), 4,18 (2H, s), 4,25-4,68 (7H, m), is 4.85 (1H, d), is 4.93 (2H, s), 6,72-of 6.78 (3H, m), 7,00 (1H, m), 7.03 is-to 7.09 (2H, m), 7,13-7,19 (3H, m), 7.23 percent and 7.36 (17H, m), 7,63 (1H, d), of 7.70 (1H, d)

FAB-MS (m/z); 819 [M-H]-

Table 16
Approx.STRUCTUREDATA
551H-NMR (CDCl3); of 3.54 (1H, m), 3.72 points-a 3.87 (5H, m), 3,91 (1H, d), 4,18 (2H, s), the 4.29 (1H, m), 4,40-4,55 (6H, m), 4.63 to-4,70 (2H, m), 4,88-4,96 (3H, m), 6,72-to 6.80 (3H, m), 7,00 (1H, s),? 7.04 baby mortality-7,10 (2H, m), 7,14 (1H, d), 7,21-of 7.36 (19H, m), a 7.62 (1H, d), of 7.70 (1H, d) FAB-MS (m/z); 819 [M-H]-
561H-NMR (CDCl3); of 2.81 (3H, s), 2,85 (3H, s), 3,54-a 3.83 (6H, m), 3,91 (1H, d), 4,12-to 4.23 (2H, m), to 4.41-4,66 (7H, m), 4,84 is equal to 4.97 (3H, m), 6,80-6,85 (2H, m)6,91 (1H, d), of 6.96 (1H, d), 7,08-7,33 (21H, m), 7,42 (1H, USS), 7,56 (1H, d), to 7.64 (1H, d)

FAB-MS (m/z); 849 [M+H]+
571H-NMR (CDCl3); to 1.48 (9H, s), 3,53 (1H, m), 3,70-of 3.85 (5H, m), is 4.15 (2H, s), 4,35 (2H, t), 4,55-4,63 (4H, m), 4,85-of 4.95 (3H, m), 6.90 to-6,95 (3H, m), 7,10-7,31 (23H, m), 7,60 (1H, d), of 7.69 (1H, d), with 8.05 (1H, m)

ES-MS (m/z); 884 [M+Na]+
581H-NMR (CDCl3); to 3.52 (1H, d), 3,71-3,90 (5H, m)4,06 (1H, m), 4,10 (2H, s), 4,32-br4.61 (5H, m), 4,85 is equal to 4.97 (3H, m), 6,92-of 6.96 (3H, m), 7,07-7,32 (23H, m), 7,60 (1H, d), to 7.68 (1H, d)

ES-MS (m/z); 762 [M+H]+
591H-NMR (CDCl3); 2,62 (3H, s), 3,52 (1H, d), 3,74-3,93 (5H, m), 4,11 (2H, s)to 4.33 (2H, m), 4,45 with 4.64 (4H, m), 4,85-4,96 (4H, m), 6.90 to (2H, m), of 6.96 (1H, s), 7,09-7,33 (23H, m), to 7.59 (1H, d), to 7.68 (1H, d)

FAB-MS (m/z); 76 [M+H] +
601H-NMR (CDCl3); is 3.08-3,14 (2H, m), 3,51-3,66 (3H, m), 3,70-3,88 (5H, m), 3,98-4,07 (1H, m), 4,10 (2H, s), 4,32 (1H, d), 4,34 (1H, d), 4,45-4,60 (4H, m), 4,84-5,01 (4H, m), of 6.65 (1H, d), 6.89 in-6,91 (2H, m), 6,97 (2H, m), 7,06-7,33 (21H, m), to 7.59 (1H, d), to 7.68 (1H, d) ES-MS (m/z); 806 [M+H]+

Table 17
Approx.STRUCTUREDATA
611H-NMR (CDCl3); to 3.56 (1H, m), 3,67-of 3.80 (6H, m), 3,83-to 3.92 (2H, m), 3,98 (1H, m), a 4.03 (1H, d), 4,11 (1H, m)to 4.16 (2H, s), 4,39-4,53 (5H, m), 4,81-of 4.95 (3H, m), 6,79-6,85 (3H, m), of 6.99 (1H, s),? 7.04 baby mortality-to 7.09 (2H, m), 7,11-7,17 (3H, m), 7,19-7,33 (17H, m), 7,60 (1H, d), of 7.69 (1H, d)

FAB-MS (m/z); 808 [M+H]+
621H-NMR (CDCl3); 3,38-4,15 (12H, m), 4,19-or 4.31 (2H, m), 4,36-of 4.66 (4H, m), 4.80 to 4,94 (3H, m), 6,80-6,98 (3H, m), 7.03 is-7,10 (1H, m), 7,12-7,35 (21H, m), 7,52-of 7.60 (1H, m), to 7.61-of 7.69 (1H, m)

EI-MS (m/z); 863 [M+Na]+
631H-NMR (CDCl3); of 2.97 (1H, m), 2,95 (1H, m)and 3.59 (1H, USS), 3,71-3,82 (6H, m), 3,89-of 3.97 (1H, m), 4,18 (2H, d), 4,43 (1H, d), 4,47 with 4.65 (3H, m), 4,84 is equal to 4.97 (3H, m), 6,79-6,87 (2H, m), 6,98 (1H, s), 7,08-7,17 (2H, m), 7.18 in-7,34 (20H, m), 7,39 (1H, s), 7,58 (1H, d), to 7.67 (1H, d)

FAB-MS (m/z); 807 [M+H]+
64 1H-NMR (CDCl3); 2,69 (6H, s), 3,64-3,82 (5H, m), 3,93 (1H, d), of 4.16 (2H, d), 4,37 (1H, d), 4,48 (1H, d), 4,58 with 4.64 (2H, m), 4,85-4,94 (4H, m), 6,76 (2H, m)6,94 (1H, s), 7,10-7,28 (22H, m), the 7.43 (1H, m), 7,49 (1H, d), 7,60 (1H, d)

ES-MS (m/z); 790 [M+H]+
651H-NMR (CDCl3); 3,42-of 3.48 (1H, m), 3,55-to 3.58 (1H,m), 3.72 points-of 3.78 (4H, m), 3,83 (1H, d), 4,14-4,30 (3H, m), 4,39 (1H, d), 4,51-of 4.67 (4H, m), a 4.83-4,94 (2H, m), 6,86-of 6.90 (1H, m), 6,98 (1H, USS), 7,06-7,37 (24H, m), EUR 7.57-of 7.60 (1H, m), 7,66-of 7.69 (1H, m)

EI-MS (m/z); 787 [M+Na]+
661H-NMR (CDCl3); 3,42-of 3.48 (1H, m), 3,50-of 3.64 (1H, m), 3.72 points-of 3.78 (4H, m), 3,88 (1H, d), 4,19 (1H, d), 4,22-4,34 (2H, m), 4,35 is 4.45 (1H, m), 4,50 with 4.65 (4H, m), is 4.85 (1H, d), 4,89 (1H, d), of 6.90 (2H, d), 6,94 (1H, s), 7,10-7,42 (23H, m), 7,56 (1H, d), the 7.65 (1H, d)

Table 18
Approx.STRUCTUREDATA
671H-NMR (CDCl3); 3,60-3,68 (1H, m), of 3.73-of 3.85 (3H, m), 3,92-to 4.23 (3H, m), 4,42-4,78 (8H, m), a 4.83-of 4.95 (2H, m), 6,85-6,98 (3H, m), 7,05-7,39 (23H, m), 7,54-to 7.61 (1H, m), 7,62-of 7.69 (1H, m)
681H-NMR (CDCl3); 3,40-3,63 (4H, m), 3,68-are 3.90 (4H, m), 4,10-and 4.40 (4H, m), 4,45-4,75 (5H, m), 4.80 to of 4.95 (3H, m), with 5.22 (2H, s), 6,84-to 6.95 (3H, m), 7,05-7,40 (23H, m), 7,54 (1H, d), the 7.65 (1H, d)
69 1H-NMR (CDCl3); 3,47-of 3.78 (1H, m), a 3.87 (3H, s), 4,13-the 4.29 (4H, m)to 4.33 (1H, d), 4,49-of 4.75 (4H, m), 4,84-4,94 (3H, m), 6,86-to 6.95 (3H, m), 7,06-7,37 (23H, m), 7,58 (1H, d), 7,66 (1H, d)

FAB-MS (m/z); 775 [M-H]-
701H-NMR (CDCl3); 3,48-3,62 (2H, d), and 3.72-3,82 (5H, m), 4,19 (2H, s), 4,22 (1H, d), 4,34 (1H, d), a 4.53 (1H, d), 4,63 (2H, d), 4,84-4,94 (3H, m), 6.89 in (2H, DD), 6,93 (1H, s), 7,15-7,40 (24H, m), the 7.65 (1H, DD), 7,83 (1H, USD)
711H-NMR (CDCl3); 3,50 (1H, m)to 3.58 (1H, m), 3,74-3,81 (5H, m)to 4.16 (2H, s), 4,22 (1H, d), 4,34 (1H, d), to 4.52 with 4.65 (3H, m), 4,85-4,94 (3H, m), 6.87 in-6,89 (2H, m), 7,00-7,06 (2H, m), 7,15 and 7.36 (22H, m), 7,45 (1H, dt), and 8.50 (1H, m)

FAB-MS (m/z); 692 [M+H]+
721H-NMR (CDCl3); 3,36-3,62 (5H, m), is 4.21 (1H, d), 4,30 (2H, s)to 4.52 (1H, d), 4,60 (1H, d), to 4.62 (1H, d), a 4.83-equal to 4.97 (3H, m), 6,84-of 6.90 (2H, m), 7,12-7,78 (26H, m)

FAB-MS (m/z); 765 [M+H]+
731H-NMR (CDCl3); 3,50-3,60 (2H, m), 3.72 points-3,81 (5H, m), 4,22 (1H, d), 4,36 (1H, d), of 4.54 (1H, d), 4,62-of 4.66 (2H, m), 4.72 in-4,94 (5H, m), PC 6.82-6.87 in (2H, m), 7,11-7,13 (3H, m), 7,19-7,40 (18H, m), 7,53 (1H, s), 7,65-to 7.68 (2H, m,), to 7.77-7,80 (2H, m)

EI-MS (m/z); 782 [M+Na]+

Table 19
Approx.STRUCTUREDATA
1H-NMR (CDCl3); at 1.73 (3H, s), from 2.00 (3H, s)2,04 (3H, s), is 2.05 (3H, s)of 3.25 (2H, s), 3,74 (2H, s), 3,82 (3H, s), a-3.84 (1H, m), 4,14 (1H, DD), 4.26 deaths (1H, DD), to 4.92 (1H, m), 5,23 (1H, m), 5,33 (2H, m), 6,46 (1H, s), 6,79 (1H, d), 7,08-to 7.35 (6H, m)

ES-MS (m/z); 567 [M+H]+
751H-NMR (CDCl3); to 2.29 (3H, s), 2,32 (3H, s), of 3.43 (2H, m)to 3.58 (2H, m), 3,83 (1H, m), 3,88 (1H, m)to 3.99 (2H, s), 4,48 (1H, d), and 6.25 (1H, s), 6,83 (1H, d), 7,10 (1H, d), to 7.15 (1H, s), 7,20 (2H, s)

ES-MS (m/z); 608 [M]+
761H-NMR (CDCl3); 3,26 (2H, s), 3,40 (2H, m), 3,53 (2H, m)to 3.67 (1H, DD), 3,76 (2H, s), 3,82 (3H, s), 3,86 (1H, m), 4,70 (1H, d), 6.48 in (1H, s)6,91 (1H, d), 7,01 (1H, m), 7.03 is-7,22 (3H, m), 7,29 (1H, d), 7,32 (1H, d)

ES-MS (m/z); 622 [M]+
771H-NMR (CDCl3); 1,71 (3H, s)to 1.99 (3H, s)to 2.06 (3H, s), 2,11 (3H, s), 3,82 (1H, m), 4,14 (1H, m), 4,25 (2H, s), 4,27 (1H, DD), 4,39 (1H, d), 5,10 (1H, t), with 5.22 (1H, t), 5,31 (1H, t), 7,28-7,38 (6H, m), 7,45 (1H, m,), to 7.67 (1H, m)

ES-MS (m/z); 540 [M+H]+
781H-NMR (CDCl3); to 1.76 (3H, s), a 2.01 (3H, s), is 2.05 (3H, s), is 2.09 (3H, s)to 2.35 (3H, s), 3,81 (1H, m), 4,30 (1H, DD), 4,60 (1H, d), 4,80 (2H, s), 5,16-of 5.34 (4H, m), 7,03 (1H, d), 7,40-to 7.59 (4H, m), of 7.70 (1H, DD), 8,32 (1H, d)

ES-MS (m/z); 598 [M+H]+
79 1H-NMR (CDCl3); to 1.75 (3H, s)to 1.99 (3H, s)to 2.06 (3H, s), of 2.08 (3H, s), 3,82 (1H, m), 4,13 (1H, m), 4,17 (2H, s), 4,27 (1H, DD), 4,37 (1H, d), 5,11 (1H, t), with 5.22 (1H, t), 5,31 (1H, t), 7,21-to 7.32 (4H, m), 8,43 (2H, m,), 8,53 (1H, s)

ES-MS (m/z); 501 [M+H]+

Table 20
Approx.STRUCTUREDATA
801H-NMR (CDCl3); 3,49-of 3.54 (1H, m)

to 3.58-3,62 (1H, m), 3,74-3,82 (5H, m), 4,25 (1H, d), 4,37 (1H, d), of 4.44 (2H, s)4,55 (1H, d), 4,63 (2H, d), a 4.86 (1H, d), 4,88 (1H, d), is 4.93 (1H, d), 6,88-of 6.90 (2H, m), 7,10-of 7.48 (24H, m), 7,71 (1H, d), 7,97 (1H, d)

FAB-MS (m/z); 748 [M+H]+
811H-NMR (CDCl3); by 1.68 (3H, s)to 1.98 (3H, s), is 2.05 (3H, s)to 2.06 (3H, s), of 3.54 (3H, s), 3,82 (1H, m), 4,11-4,16 (2H, m), 4,17 (1H, d), 4,28 (1H, DD), 4,35 (1H, d), 5,10 (1H, t), 5,18-5,33 (2H, m), 6,24 (1H, s), 7,07 (1H, m), 7,13-7,20 (3H, m), 7,21-7,31 (3H, m), 7,54 (1H, d)

FAB-MS (m/z); 552 [M+H]+
821H-NMR (CDCl3); of 1.74 (3H, s), from 2.00 (3H, s)2,04 (6H, s)to 2.35 (3H, s), 3,55 (3H, s), 3,81 (1H, m), 4,10 (1H, DD), of 4.13 (2H, s), 4,30 (1H, DD), 4,59 (1H, d), a total of 5.21 (1H, m), 5,23-of 5.34 (2H, m), of 6.26 (1H, USS), of 6.99 (1H, d), 7,05-7,20 (3H, m), 7,26 (1H, m), 7,33 (1H, d), 7,55 (1H, m)

FAB-MS (m/z); 610 [M+H]+
831H-NMR (CDCl3); of 1.64 (3H, s), 1,90 (3H, s), 2,12(3H, C)2,60 (3H, s), of 3.96 (1H, m), 3,98 (2H, s), 4,17 (1H, m), 4,32 (1H, DD), 4,56 (1H, m), 5,24-of 5.34 (3H, m), of 6.31 (1H, s), to 6.88 (1H, m), 7,00-of 7.48 (7H, m)

FAB-MS (m/z); 553 [M-H]-
841H-NMR (CDCl3); of 1.74 (3H, s), from 2.00 (3H, s)2,04 (3H, s), is 2.05 (3H, s)to 2.35 (3H, s), 3,82 (1H, m), 4.09 to (3H, m), 4,30 (1H, DD), 4,60 (1H, m), 5,20-5,32 (3H, m), of 6.29 (1H, s), of 6.96-7.03 is (3H, m), 7,18 (1H, d), 7,37 (1H with)

ES-MS (m/z); 642 [M+NH4]+
851H-NMR (CDCl3); at 1.73 (3H, s), a 2.01 (3H, s)2,04 (3H, s)2,07 (3H, s), a 2.36 (3H, s), 2,39 (3H, s)to 2.41 (3H, s), 3,80 (1H, m), 4,07 (1H, m), 4,30 (1H, DD), 4,59 (1H, d), 5,19 (1H, m), and 5.30 (2H, m), 6,32 (1H, s), for 6.81 (1H, S), 7,01 (1H, S), 7,03 (1H, S), 7,25 (1H, S), 7,35 (1H, s)

ES-MS (m/z); 642 [M+NH4]+

Table 21
Approx.STRUCTUREDATA
861H-NMR (CDCl3); to 1.79 (3H, s)to 1.99 (3H, s), is 2.05 (3H, s), is 2.09 (3H, s), of 2.34 (3H, s)to 2.35 (3H, s), 3,80 (1H, m), 4,07 (2H, s), 4,11 (1H, m), 4,28 (1H, m), 4,60 (1H, m), 5,28 (1H, m), 6,30 (1H, s), 6,93 (1H, d), 7,02 (3H, m), 7,26 (1H, m), 7,35 (1H, s)

ES-MS (m/z); 628 [M+NH4]+
871H-NMR (CDCl3); of 1.74 (3H, s), from 2.00 (3H, s)2,04 (3H, s), is 2.05 (3H, s), 2,32 (3H, s)to 2.35 (3H, s), a 2.36 (3H, s), of 2.38 (3H, s), 3,81 (1H, m), 4,08 (2H, s), 4.09 to (1H, m), 430 (1H, DD), 4,59 (1H, d), 5,20 (1H, m), and 5.30 (2H, m), of 6.29 (1H, s), 6,79 (1H, s), 7,02 (1H, d), 7,26 (1H, m), 7,37 (1H, d)

ES-MS (m/z); 656 [M+NH4]+
881H-NMR (CDCl3); of 1.74 (3H, s), from 2.00 (3H, s)2,04 (6H, s), 2,32 (3H, s), of 2.34 (3H, s)to 2.35 (3H, s), 3,80 (1H, m), of 4.12 (3H, m), 4,30 (1H, DD), 4,59 (1H, m)to 4.92 (1H, m), a total of 5.21 (1H, m) and 5.30 (2H, m), 6,36 (1H, s), 7,00 (1H, d), 7,02 (1H, d), 7,12 (1H, d), 7,26 (1H, m), of 7.36 (1H, s)

ES-MS (m/z); 642 [M+NH4]+
891H-NMR (CDCl3); of 1.65 (3H, s)to 1.99 (3H, s), is 2.05 (3H, s), of 2.08 (3H, s)a 2.12 (3H, s), 2,31 (3H, s), of 2.33 (3H, s), 3,86 (1H, m), of 3.94 (2H, s)to 4.16 (1H, m), or 4.31 (1H, DD), to 4.52 (1H, m), 5,28 (3H, m), of 6.20 (1H, s), 6,85 (2H, m), 6,98 (1H, s), 7,13 (1H, s), 7,19 (1H, s)

ES-MS (m/z); 642 [M+NH4]+
901H-NMR (CDCl3); 1,12 (1H, d), is 1.73 (2H, s), 1,98-2,12 (10H, m), of 2.33 to 2.35 (3H, DD), 3,79-3,81 (1H, m), 4,06-4.09 to (1H, d), 4,18 (2H, s), 4,28-to 4.33 (1H, DD), 4,58-4,60 (1H, m), 5,28-and 5.30 (2H, m), 6,92 (1H, s), 7,00-7,02 (1H, d), 7,12-7,13 (1H, d), 7.23 percent-7,31 (3H, m)

ES-MS (m/z); 636 [M+NH4]+
911H-NMR (CDCl3); to 1.67 (3H, s), from 2.00 (3H, s)to 2.06 (3H, s)a 2.12 (3H, s), 3,83-to 3.89 (1H, m), a 4.03 (2H, s), 4,17 (1H, DD), 4,32 (1H, DD),

4,50-4,59 (1H, m), 5.25 to 5.35 (3H, m), 6,70-7,03 (4H, m), 7,10-of 7.25 (2H, m)

FAB-MS (m/z); 521 [M+H]+

Table 2
Approx.STRUCTUREDATA
921H-NMR (CDCl3); 3,50-3,92 (7H, m)to 4.33 (1H, DD), 4,49 (1H, d), 4.53-in-4,70 (3H, m), 4,85-5,00 (3H, m), 6,92 (2H, d), 7,06-7,93 (27H, m)

EI-MS (ES):756 [M+Na]+
931H-NMR (CDCl3); to 1.79 (3H, s), from 2.00 (3H, s)2,04 (3H, s), of 2.08 (3H, s), 3,76-of 3.85 (6H, m)to 4.16 (1H, DD), 4.26 deaths (1H, DD), br4.61 (1H, d), 5,07-5,31 (3H, m), 6,77-of 6.90 (4H, m), 7,07 (2H, d)

EI-MS; 534
941H-NMR (CDCl3); to 1.19 (3H, t), at 2.59 (2H, HF), 3,40-3,98 (9H, m), 4,22 (1H, d), 4,33 (1H, d), 4,45-to 4.62 (4H, m), 4.80 to 4,96 (3H, m), 5,95 (1H, DD), 6,18 (1H, DD), 6,85-7,33 (26H, m), 8,17 (1H, s)

FAB-MS (m/z); 708 [M+H]+
951H-NMR (CDCl3); of 1.20 (3H, t), at 2.59 (2H, HF), 3,40 (3H, s), 3,49 of 3.56 (1H, m), 3,65-of 3.78 (5H, m), 3,91 (2H, s), a 4.03 (1H, d), or 4.31 (1H, d), 4,39 (1H, d), 4,47 with 4.64 (3H, m), 4,82-equal to 4.97 (3H, m) 5,94 (1H, d), of 6.20 (1H, d), 6,98-7,34 (26H, m)

FAB-MS (m/z); 722 [M+H]+
961H-NMR (CDCl3); of 1.18 (3H, t), 2,58 (2H, HF), 3,38 is-3.45 (1H, m), 3,60-of 3.78 (5H, m), 4,11 (1H, d), or 4.31 (1H, d), 4,40-4,63 (4H, m), 4.80 to of 4.95 (3H, m), to 5.08 (1H, d), of 5.15 (1H, d), 6,17 (1H, DD), of 6.31 (1H, DD), only 6.64 (1H, DD), 6,97-7,33 (24H, m)

FAB-MS (m/z); 708 [M+H]+
97 1H-NMR (CDCl3); to 1.21 (3H, t), 1,71 (3H, s), a 2.01 (3H, s), is 2.05 (3H, s)2,07 (3H, s), 2.63 in (2H, DD), 3,88 (1H, dddd), is 4.15 (1H, DD), 4,28 (1H, DD), to 4.87 (1H, d), 5,23 (1H, t), 5,33 (1H, t), of 5.55 (1H, DD), 5,71 (2H, s), 7,18-7,29 (4H, m) FAB-MS (m/z); 519 [M+H]+
981H-NMR (CDCl3); of 1.10 (3H, t), of 2.50 (2H, HF), 3,63-3,68 (1H, m), 3.72 points-is 3.82 (3H, m), 3,90 (1H, t), 4,10-to 4.23 (4H, m), 4,49 (1H, d), 4,59-of 4.66 (3H, m), 4,78 (1H, d), a 4.86-equal to 4.97 (3H, m), is 6.78 (2H, d), 6,97 (2H, d), 7,09-7,33 (20H, m)

EI-MS (m/z); 789 [M+H]+

Table 23
Approx.STRUCTUREDATA
991H-NMR (CDCl3); to 1.15 (3H, t), of 2.54 (2H, HF), 3,63-3,68 (1H, m), 3,74-3,81 (3H, m), a 3.87 (1H, t), 3,93-4,00 (2H, m), 4,11 (2H, s), 4,43 (1H, d), 4,48 (1H, d), a 4.53 (1H, d), 4,59 (1H, d), to 4.62 (1H, d), to 4.87 (1H, d), 4.92 in (2H, s), of 6.75 (2H, d),? 7.04 baby mortality (2H, d), 7,08-7,34 (20H, m), at 8.36 (1H, s), 8,48 (1H, s)
1001H-NMR (CD3OD); of 2.44 (3H, s), 3,35-to 3.49 (4H, m), 3,59-3,71 (1H, m), 3,86-to 3.89 (1H, m), 4,18 (1H, d), is 4.21 (2H, s), 6,97 (1H, s), 7,05-was 7.08 (1H, m), 7,22-to 7.32 (3H, m), 7,39 (1H, USS), 7,46 (1H, USS), 7,58 (1H, d)

FAB-MS (m/z); 399 [M-H]-
1011H-NMR (CD3OD); 3,34-to 3.49 (4H, m)

3,59-3,71 (1H, m), 3,86-to 3.89 (1H, m), of 4.12 (1H, d), to 4.23 (2H, s), 6,99-7,05 (2H, m), 7.23 percent-yield of 7.40 (5H, m), of 7.70 (1H, m)

FAB-MS (m/z)403 [M-H]-
1021H-NMR (CD3OD); of 7.69 (1H, d), 7,66 (1H, d), 7,40 (1H, s), 7,20 was 7.36 (4H, m), 7,05 (1H, s), 4,24 (2H, s), 4,13 (1H, d); 3,86 (1H, DD), 3,70 (1H, DD), 3,33-to 3.50 (4H, m)

FAB-MS (m/z)420 [M]+
1031H-NMR (CD3OD); 7,71 (1H, d), the 7.65 (1H, d), 7,15-to 7.35 (6H, m), 4,22 (2H, s), 4,10 (1H, d), 3,88 (1H, DD), 3,68 (1H, m), 3,32-to 3.49 (4H, m), is 2.37 (3H, s)

FAB-MS (m/z)400 [M]+
1041H-NMR (CD3OD); of 2.34 (3H, s), 3,32-of 3.46 (4H, m), 3,66-3,70 (1H, m), a 3.87 (1H, DD), 4,10 (1H, d), 4,22 (2H, s), 7,01-7,06 (1H, m), 7,16-7,19 (1H, m), 7,27-7,37 (4H, m), of 7.70 (1H, DD)

FAB-MS (m/z); 417 [M-H]-
1051H-NMR (CD3OD); a 2.36 (3H, s), 3.33 and-to 3.49 (4H, m), 3,66-3,70 (1H, m), 3,86-to 3.89 (1H, m), 4,10 (1H, d), 4,22 (2H, s), 7,17-7,19 (1H, m), 7,24 (1H, DD), 7,27-7,31 (2H, m), 7,34 (1H, USS), the 7.65 (1H, d), of 7.69 (1H, d)

FAB-MS (m/z)433 [M-H]-

Table 24
Approx.STRUCTUREDATA
1061H-NMR (CD3OD); of 1.36 (9H, s), 3,35-to 3.49 (4H, m), 3,67-3,71 (1H, m), 3,86-3,71 (1H, s), of 4.12 (1H, d), is 4.21 (2H, s), 7,02 (1H, m), 7,15-7,31 (3H, m), 7,33 (1H, DD), 7,39 (1H, USS), a 7.62 (1H, d), to 7.67 (1H, d)
FAB-MS (m/z)442 [M]+
1071H-NMR (CD3OD); 3,35-3,47 (4H, m), 3,67-3,71 (1H, m), 3,81 (3H, s), 3,86-to 3.89 (1H, m), of 4.12 (1H, d), is 4.21 (2H, s)6,86 (1H, d), of 6.99 (1H, s), 7,18 (1H, d), 7.23 percent-7,31 (3H, m), 7,39 (1H, s), 7,56 (1H, d)

FAB-MS (m/z)415 [M-H]-
1081H-NMR (CD3OD); to 2.94 (6H, s), 3,35-to 3.49 (4H, m), 3,67-3,71 (1H, m), 3,86-to 3.89 (1H, m), of 4.12 (1H, d), 4,19 (2H, s), 6,92 (1H, DD), to 6.95 (1H, s), 7,10 (1H, d), 7,17-7,31 (3H, m), 7,39 (1H, USS), 7,54 (1H, d)

FAB-MS (m/z)430 [M+H]+
1091H-NMR (CD3OD); of 1.13 (6H, t)to 3.36 (4H, HF), 3,39-to 3.41 (4H, m), 3,67-3,71 (1H, m), 3,86-to 3.89 (1H, m), of 4.12 (1H, d), 4,18 (2H, s), at 6.84 (1H, m)6,91 (1H, s), 7,02 (1H, s), 7,22-7,30 (3H, m), 7,39 (1H, s), 7,51 (1H, d)

FAB-MS (m/z); 458 [M+H]+
1101H-NMR (CD3OD); to 7.84 (1H, m), 7,74 (1H, m), 7,39 (1H, s), 7,14-7,34 (6H, m), 4,24 (2H, s), 4,10 (1H, d); a 3.87 (1H, DD), of 3.69 (1H, DD), 3,30-to 3.50 (4H, m)

FAB-MS (m/z)386 [M]+
1111H-NMR (CD3OD); 3,35-to 3.50 (4H, m), 3,67-3,71 (1H, m), 3,86-to 3.89 (1H, m), 4,10 (2H, s), 4,13 (1H, d), 6,44 (1H, s), 7,13-to 7.18 (2H, m), 7,26 and 7.36 (4H, m), 7,41 (1H, USS), 7-45-7,47 (1H, m)

FAB-MS (m/z)369 [M-H]-
1121H-NMR (CD3OD); 3,35-3,50 (4H, IS), 3,67-and 3.72 (1H, m), 3,88 (1H, DD), 4,14 (1H, d), of 4.49 (2H, s), 7,32-the 7.43 (4H, m), of 7.48-7,53 (2H, m), to $ 7.91-to 7.93 (2H, m)

FAB-MS (m/z)388 [M+H]+

Table 25
Approx.STRUCTUREDATA
1131H-NMR (CD3OD); to 2.42 (3H, s), 3,34-of 3.94 (6H, m), 4.09 to (2H, s)to 4.16 (1H, d), 6,57-6,62 (2H, m), 7,20 was 7.36 (4H, m)

ES-MS (m/z)373 [M+Na]+
1141H-NMR (CD3OD); of 1.27 (3H, t), and 2.79 (2H, DD), 3,39-to 3.52 (4H, m), 3,74-of 3.94 (2H, m), 4,10 (2H, s), 4,17 (1H, d), 6,62 (2H, DD), 7,20-7,37 (4H, m)

ES-MS (m/z)382 [M+NH4]+
1151H-NMR (CD3OD); of 2.21 (3H, s), 3,35-to 3.52 (4H, m), of 3.73-of 3.94 (2H, m), 4,11 (2H, s), is 4.15 (1H, d), at 6.84 (1H, d), 7,10 (1H, d), 7,14-7,33 (4H, m)

ES-MS (m/z)368 [M+NH4]+
1161H-NMR (CD3OD); 3,39-of 3.43 (2H, m), 3,44-to 3.58 (2H, m), 3,67-to 3.73 (2H, m), 3,86 (1H, m), 4,14 (2H, s), of 4.57 (1H, d), is 6.78 (1H, d), 7,02 (1H, s), was 7.08 (1H, DD), 7,24 (1H, m), 7,31 (1H, d), to 7.64 (1H, d), 7,71 (1H, d)

EI-MS (m/z)402 [M]+
1171H-NMR (CD3OD); 3,36-3,39 (2H, m), 3.46 in-3,54 (2H, m), 3,63-3,68 (1H, m), 3,81-3,86 (4H, m), of 4.12 (2H, s), 4,69 (1H, d), 6,94 (1H, d),? 7.04 baby mortality (1H, s), 7,20-7,28 (3, m), 7,39 (1H, d), to 7.64 (1H, d), 7,71 (1H, d)

FAB-MS (m/z)416(M+H)+]
1181H-NMR (CD3OD); 3,38-3,56 (7H, m), 3,64-3,68 (1H, m), 3,74 is 3.76 (2H, m), 3,82 (1H, d), 4,17 (2H, t), 4,19 (2H, s), 4,70 (1H, d), 6,94 (1H, d),? 7.04 baby mortality (1H, s), 7,19-7,28 (3H, m), 7,40 (1H, d), the 7.65 (1H, d), 7,71 (1H, d)

FAB-MS (m/z); 483 [M+Na]+
1191H-NMR (CD3OD); a 1.96 (3H, s), 3,39-to 3.41 (2H, m), 3.46 in-to 3.52 (3H, m), 3,59-3,70 (2H, m), 3,86 (1H, d), 4,01-to 4.14 (2H, m), 4,17 (2H, s), 4.72 in (1H, d), 6,92 (1H, d),? 7.04 baby mortality (1H, d), 7.18 in-7,29 (3H, m), 7,42 (1H, d), to 7.64 (1H d), 7,71 (1H, DD)

FAB-MS (m/z)488 [M+H]+

Table 26
Approx.STRUCTUREDATA
1201H-NMR (CD3OD); 2,43 (3H, s), 2,88-to 2.99 (2H, m), 3,37-3,39 (2H, m), 3,45-3,55 (2H, m), 3,64-3,68 (1H, m), 3,85 (1H, DD), 4.09 to to 4.15 (2H, m), 4,18 (2H, s), of 4.67 (1H, d), 6,94 (1H, d),? 7.04 baby mortality (1H, s), 7,19-7,29 (3H, m), 7,40 (1H, d), the 7.65 (1H, d), 7,71 (1H, d)

EI-MS (m/z)460 [M+H]+
1211H-NMR (CD3OD); 3,59-of 3.42 (2H, m)

3,47 is 3.57 (2H, m), 3,66 (1H, m), of 3.78 (3H, s), 3,85 (1H, d), 4,18 (2H, s), 4.72 in-4,74 (3H, m), 6.87 in (1H, d),? 7.04 baby mortality (1H, s), 7.18 in-7,30 (3H, m), 7,44 (1H, d), the 7.65 (1H, d), 7,72 (1H, m)

FAB-MS (m/z)475 [M+H]+
122 1H-NMR (CD3OD); 3,39-of 3.43 (2H, m)

3,50-of 3.54 (2H, m)to 3.67 (1H, m), 3,86 (1H, d), 4,18 (2H, s), 4,56-4,70 (2H, m), 4,78 (1H, m), 6.87 in (1H, d), 7,03 (1H, s), 7,17-7,30 (3H, m), 7,44 (1H, d), to 7.64 (1H, d), 7,72 (1H, d)

FAB-MS (m/z); 459 [M-H]-
1231H-NMR (CD3OD); 3,39-of 3.43 (2H, m)

3,48-of 3.53 (2H, m), 3,68 (1H, m), 3,86 (1H, d), 4,19 (2H, s), 4,48-4,63 (2H, m), 4,69 (1H, d, J=9.3 Hz), 6.89 in (1H, d),? 7.04 baby mortality (1H, s), 7,13-7,30 (3H, m), 7,45 (1H, d), the 7.65 (1H, d), 7,71 (1H, d)

FAB-MS (m/z); 458 [M-H]-
1241H-NMR (CD3OD); of 2.97 (3H, s), of 3.07 (3H, s), 3,36-of 3.43 (2H, m), 3.46 in-3,54 (2H, m), 3,62-3,68 (1H, m), a-3.84 (1H, d), 4,18 (2H, s), 4,73-4,87 (3H, m)6,91 (1H, d),? 7.04 baby mortality (1H, s), 7,15-7,29 (3H, m), 7,44 (1H, d), to 7.64 (1H d), 7,71 (1H, DD)

FAB-MS (m/z)488 [M+H]+
1251H-NMR (CD3OD); 3,38-of 3.42 (2H, m)

3,47-to 3.52 (2H, m)to 3.67 (1H, m), 3,82-of 3.94 (3H, m), a 4.03-4,12 (2H, m), 4,17 (2H, s), was 4.76 (1H, m)6,94 (1H, d),? 7.04 baby mortality (1H, s), 7,17-7,28 (3H, m), 7,42 (1H, d), the 7.65 (1H, d), 7,71 (1H, d)

FAB-MS (m/z)447 [M+H]+
1261H-NMR (CD3OD); 3,38-3,50 (3H, m)

3,62-3,74 (2H, m), a 3.87-are 3.90 (1H, m), of 4.13 (2H, s)to 4.33 (1H, d), PC 6.82 (1H, d), 7,02 (1H, s), 7,05-was 7.08 (1H, m), 7,19-7,28 (3H, m), 2,78 (3H, s), to 7.64 (1H, d), of 7.70 (1H, d)

FAB-MS (m/z)402 [M+H]+

Table 27/u>
Approx.STRUCTUREDATA
1271H-NMR (CD3OD); 2,78 (3H, s), 3,36-3,51 (3H, m), 3,68 is 3.76 (2H, m), 3,85-3,88 (1H, m), 4,11 (2H, s), 4.26 deaths (1H, d), of 6.65 (1H, d), of 7.00 (1H, s), 7,12 (1H, DD), 7,17-7,27 (3H, m), a 7.62 (1H, d), of 7.69 (1H, d)

FAB-MS (m/z)416 [M+H]+
1281H-NMR (CD3OD); 3,15-3,20 (2H, m), 3,36 is 3.40 (1H, m), 3,45-3,47 (2H, m), 3,69-a 3.83 (6H, m), a 3.87 (1H, DD), 4,10 (2H, s), 4.26 deaths (1H, d), to 6.67 (1H, d), of 7.00 (1H, s), 7,10 (1H, DD), 7,13 (1H, d), 7,19-of 7.25 (2H, m), 7,63 (1H d), of 7.70 (1H, d)

FAB-MS (m/z); 446 [M+H]+
1291H-NMR (CD3OD); was 2.76 (6H, s), to 3.58 is 3.40 (4H, m), 3,66 (1H, DD), 3,85 (1H, m), is 4.21 (2H, s), 7,06 (1H, s), 7,20-7,29 (4H, m), 7,47 (1H, s), the 7.65 (1H, d), 7,71 (1H, d)

FAB-MS (m/z)430 [M+H]+
1301H-NMR (CD3OD); 2,89-to 2.94 (2H, m), 3,02-of 3.07 (2H, m), 3,36-3,37 (1H, m), 3,56-3,61 (1H, m), 3,70 of 3.75 (1H, m), 3,78-a 3.87 (5H, m), is 4.21 (2H, s), is 4.85 (1H, d), 7,05 (1H, s), 7,17 (1H, d), 7,20-7,29 (3H, m), 7,44 (1H, d), the 7.65 (1H, d), 7,72 (1H, d)

FAB-MS (m/z); 472 [M+H]+
1311H-NMR (CD3OD); 3,34-to 3.52 (4H, m), 3,66-and 3.72 (1H, m), a 3.87 (1H, d), 4,22 (2H, s), 4,46-4,56 (1H, m), 6,98-was 7.08 (2H, m), 7.18 in-to 7.32 (3H, m), 7,49 (1H, DD), 7,66 (1H, d), 7,72 (1H, d)

EI-MS (m/z); 405 [M+H]+
132 1H-NMR (CD3OD); 3,41-3,44 (2H, m)

3,49-3,55 (2H, m), 3,66-3,70 (1H, m), 3,86 (1H, d), 4,24 (2H, s), 4,71-4,74 (1H, m), 7,07 (1H, s), 7,21-7,29 (3H, m), 7,34 (1H, d), 7,55 (1H, s), 7,66 (1H, d), 7,73 (1H, d)

FAB-MS (m/z); 419 [M-H]-
1331H-NMR (CD3OD); 3,33-of 3.46 (4H, m), 3,62-3,68 (1H, m), a-3.84 (1H, DD), was 4.02 (1H, d), 4,18 (2H, DD), to 6.80 (1H, d), 7,03 (1H, d), 7,11-7,27 (4H, m), a 7.62 (1H, m), 7,69 (1H, m)

FAB-MS (m/z)401 [M-H]-
1341H-NMR (CD3OD); 3,34 is-3.45 (4H, m), 3,65 at 3.69 (1H, m), 3,85 (3H, s)4,06 (1H, d), 4,20 (2H, d), of 6.96 (1H, d), of 7.00 (1H, d), 7.18 in-7,31 (4H, m), to 7.61 (1H, d), of 7.69 (1H, d)

FAB-MS (m/z)415 [M-H]-

Table 28
Approx.STRUCTUREDATA
1351H-NMR (CD3OD); 3,33-of 3.53 (4H, m), 3,60-and 3.72 (1H, m), 3,80-of 3.94 (3H, m), as 4.02 is 4.13 (3H, m), 4,27 (2H, DD), of 6.96 (1H, d), 7,06 (1H, s), 7.18 in-7,38 (4H, m), 7,63 (1H, d), of 7.70 (1H, d)

FAB-MS (m/z); 446[M+H]+
1361H-NMR (CD3OD); of 2.21 (6H, s), 2,70 (2H, t), 3,23 is 3.40 (4H, m), 3,52-3,63 (1H, m), 3,76 (1H, d), 3,94-4,22 (5H, m), 6.87 in (2H, d), 7,05-7,27 (4H, m), 7,47-7,53 (1H, m), 7,56-7,63 (1H, m)

FAB-MS (m/z); 474[M+H]+
1371H-NMR (CD3OD); 3,26-to 3.52 (4H, m), of 3.69 (1H, DD), a 3.87 (1H, d), of 4.12 (1H, d), 4,36 (2H, DD), 7,20-7,29 (m, 2H), 7,34 (1H, DD), 7,40 (1H, d), of 7.48 (1H, d), to 7.64 (1H, d), 7,73 (1H, d)

FAB-MS (m/z)420[M+H]+
1381H-NMR (CD3OD); 3,38-to 3.49 (3H, m), 3,68 (1H, DD), a 3.87 (1H, m), 4,11 (1H, d); to 4.23 (2H, d), 7,05-was 7.08 (2H, m), 7,21-7,30 (1H, m), 7,33-7,38 (1H, m), the 7.43 (1H, d); 7,66 (1H, d); 7,72 (1H, d)

FAB-MS (m/z); 404[M+]
1391H-NMR (CD3OD); 3,33-of 3.53 (3H, m), 3,70 (1H, DD), 3,88 (1H, DD), 4,13 (1H, d), 4,25 (2H, s), 6,94-6,99 (1H, m), 7,05-7,11 (2H, m), 7,20-to 7.32 (3H, m), to 7.67 (1H, d), 7,73 (1H, d)

ES-MS (m/z); 427[M+Na]+
1401H-NMR (CD3OD); 3,36-of 3.54 (4H, m), 3,64 is 3.76 (1H, m)to 3.89 (1H, d), 4,12-4,22 (3H, m), 6,78 (1H, s), 7,16-7,52 (10H, m), 7,58 (1H, d), 7,78 (1H, d)

FAB-MS (m/z)461[M-H]-

Table 29
Approx.STRUCTUREDATA
1411H-NMR (CD3OD); 3,24-3,30 (2H, m)to 3.36 (1H, t), of 3.43 (1H, t), 3,51 is 3.57 (1H, m), of 3.73 (1H, DD), of 3.75 (3H, s), of 3.78 (3H, s), 4,00 (1H, d), of 4.05 (1H, d), 4,51 (1H, d), 6,53 (1H, s), 6.87 in (1H, d), was 7.08 (1H, DDD), 7,14 (1H, DDD), 7,19 (1H, s),7,51 (1H, d), 7,58 (1H, DD)

ES-MS (m/z); 469 [M+Na]+
1421H-NMR (CD3OD); 3,24-3,39 (3H, m), of 3.45 (1H, t)to 3.58 (1H, DD), 3,74 (1H, DD), of 3.97 (1H, d), a 4.03 (1H, d), 4,35 (1H, d), 6,28 (1H, s), 6.89 in (1H, s), 7,02 (1H, s), 7,06-7,17 (2H, m), 7,51 (1H, d), to 7.59 (1H, DD)

FAB-MS (m/z); 419 [M+H]+
1431H-NMR (CD3OD); 3,35 of 3.56 (4H, m), of 3.69 (1H, DD), 3,85 (1H, d), 4.09 to is 4.21 (2H, m), 4,55 (1H, d), to 6.57 (1H, d), 7,01 (1H, s), 7.18 in-7,30 (2H, m), 7,33 (1H, d), to 7.64 (1H, d), 7,71 (1H, d, J=7,8 Hz)

EI-MS (m/z)420 [M]+
1441H-NMR (CD3OD); 3,37-of 3.53 (4H, m), 3,66-to 3.73 (1H, m), 3,82-to 3.89 (1H, m), 4.26 deaths (2H, DD), 4,56 (1H, d), to 6.88 (1H, s), 6,98 (1H, s), 7.18 in-7,29 (2H, m), 7,40 (1H, s), 7,63 (1H, d), 7,72 (1H, d)

EI-MS (m/z); 458 [M+Na]+
1451H-NMR (CD3OD); 3,35-3,39 (2H, m), 3,44-of 3.48 (2H, m), 3,62 at 3.69 (1H, m), 3,83 (3H, s), 3,84-3,86 (1H, m), the 4.29 (2H, DD), br4.61-and 4.68 (1H, m), of 6.99 (1H, s),? 7.04 baby mortality (1H, s), 7.18 in-7,29 (2H, m), of 7.48 (1H, s), 7,63 (1H, d), 7,72 (1H, d)

FAB-MS (m/z)449 [M-H]-
1461H-NMR (CD3OD); 3,37-3,51 (4H, m), 3,62 at 3.69 (1H, m), 3,81-are 3.90 (3H, m, 4,10 (2H, DD), 4,30 (2H, DD), 4.72 in (1H, d), of 7.00 (1H, s), 7,07 (1H, s), 7,19-7,29 (2H, m), and 7.5 (1H, s), to 7.64 (1H, d), 7,72 (1H, is)

EI-MS (m/z); 503 [M+Na]+
1471H-NMR (CD3OD); 3,30-to 3.50 (4H, m), of 3.69 (1H, DD), a 3.87 (1H, DD), 4,10 (1H, d), 4,24 (2H, s), 7,14-7,34 (6H, m), 7,39 (1H, s), 7,74 (1H, m), to 7.84 (1H, m)

FAB-MS (m/z)386 [M]+
1481H-NMR (CD3OD); 2,61-of 2.97 (5H, m), 3,54-with 3.79 (6H, m), 4,07 (1H, d), 4,17-of 4.95 (4H, m), 7.03 is-7,24 (7H, m), 7,51 (1H, s)

EI-MS (m/z)370 [M]+

Table 30
Approx.STRUCTUREDATA
1491H-NMR (CD3OD); 2,61-of 2.97 (5H, m)

3,54-with 3.79 (6H, m), 4,07 (1H, d), 3,33-to 3.52 (4H, m), the 3.65 (1H, DD), a 3.87 (1H, DD), 4,16-4,22 (2H, m), 4,37 (1H, d), 7,00-7,33 (5H, m), 7,60-7,76 (2H, m)

FAB-MS (m/z); 392 [M]+
1501H-NMR (CD3OD); to 1.19 (3H, t), at 2.59 (2H, HF), 3,39-3,50 (2H, m), of 3.56 (1H, t), 3,66 (1H, DD), 3,88 (1H, DD), to 4.01 (1H, t), 4,28 (2H, s), and 4.75 (1H, d), 7,12 (2H, d), 7,18 (2H, d)

FAB-MS (m/z)429 [M+H]+
1511H-NMR (CD3OD); of 1.20 (3H, t), 2,60 (2H, HF), 3,45 of 3.56 (3H, m)to 3.64 (1H, t), 3,70 of 3.75 (1H, m)to 3.89 (1H, DD), 4,17 (2H, s), 4,37 (1H, d), 7,13 (2H, d), 7,19 (2H, d), 8,40 (1H, s), 8,56 (1H, s)

I-MS (m/z); 361 [M+H]+
1521H-NMR (CD3OD); 3,39-3,51 (4H, m), 3,70 (1H, DD), 3,88 (1H, DD), 4.09 to (2H, s), 4,19 (1H, d), to 6.43 (1H, s), 7,20-to 7.35 (7H, m), 7,54 (1H, d)

EI-MS (m/z)393 [M+Na]+
1531H-NMR (CD3OD); 3,40-3,59 (4H, m), 3,66 is 3.76 (1H, m), 3,90 (1H, DD), 4,24 (1H, d), of 7.36-7,42 (2H, m), 7,44-EUR 7.57 (4H, m), to 7.67 (1H, USS), 7,89-of 7.96 (2H, m)

FAB-MS (m/z)372 [M+H]+
1541H-NMR (CD3OD); 3,34-to 3.49 (4H, m)

to 3.67 (1H, m), a 3.87 (1H, d), of 4.12 (1H, d), 4,24 (2H, s), 7,06 (1H, s), 7,06-7,33 (5H, m), 7,40 (1H, s), the 7.65 (1H, d), 7,72 (1H, d)

FAB-MS (m/z); 385 [M-H]-
1551H-NMR (CD3OD); 3,23-to 3.49 (4H, m), of 3.69 (1H, DD), a 3.87 (1H, m), 4,10 (1H, d), 4,14 (2H, s), to 7.15 (1H, m), 7.18 in-7,31 (4H, m), of 7.36 (1H, s), 7,73 (1H, dt), 8,42 (1H, m)

FAB-MS (m/z); 332 [M+H]+

Table 31
Approx.STRUCTUREDATA
1561H-NMR (CD3OD); 1,61-of 1.65 (2H, m), 1,79-1,90 (6H, m), 3,34 is 3.40 (2H, m), 3,44-of 3.48 (1H, m), 3,61-3,66 (2H, m), 3,83 (1H, DD), 4,17 (2H, s), 4,60 (1H, d), 4.80 to around 4.85 (1H, m), 6,93 (1H, d),? 7.04 baby mortality (1H, d), 7,17-7,29 (3H, m)that was 7.36 (1H, d), the 7.65 (1H, d), 7,70-7,72 (1H, m)
EI-MS (m/z); 471 [M+H]+
1571H-NMR (CD3OD); of 1.33 (6H, t), 3,36-3,39 (2H, m), 3.46 in-3,50 (1H, m), 3,57-to 3.67 (2H, m), a-3.84 (1H, DD), 4,17 (2H, s), 4,54-br4.61 (1H, m), of 4.67 (1H, d), 6,94 (1H, d), 7,05 (1H, d), 7,17-7,29 (3H, m), 7,38 (1H, d), the 7.65 (1H d), 7,71 (1H, DD)

EI-MS (m/z)445 [M+H]+
1581H-NMR (CD3OD); 3,38-of 3.42 (2H, m), 3.45 points-of 3.54 (2H, m), 3,64-3,74 (3H, m), a 3.87 (1H, DD), 3,93-3,98 (1H, m), a 4.03-4,12 (2H, m), 4,18 (2H, s), 4.72 in (1H, d), of 6.96 (1H, d),? 7.04 baby mortality (1H, s), 7,19-7,22 (1H, m), 7,24 (1H, DD), 7,28 (1H, DD), 7,40 (1H, d), the 7.65 (1H, d), 7,71 (1H, d)

EI-MS (m/z); 477 [M+H]+
1591H-NMR (CD3OD); 3,33-of 3.42 (2H, m), 3.43 points-to 3.52 (2H, m), 3,61-3,68 (1H, m), 3,80-3,86 (4H, m), 4,12-4,24 (2H, m), 4,63 (1H, d), 6,79 (1H, d), 7,02 (1H, s), 7.18 in-7,30 (2H, m), 7,41 (1H, d), to 7.64 (1H, d), 7,72 (1H, DD)

EI-MS (m/z)457 [M+Na]+
1601H-NMR (CD3OD); 3,32-of 3.48 (4H, m), of 3.57 (3H, s)to 3.67 (1H, m), 3,86 (1H, m), 4.09 to (1H, d, J=9.3 Hz), 4,17 (2H, s), from 6.22 (1H, s), 6,97 (1H, m), was 7.08 (1H, m), 7,14 (1H, m), 7.24 to to 7.32 (4H, m), the 7.43 (1H, d)

EI-MS (m/z)382 [M-H]-
1611H-NMR (CD3OD); 3,38-3,55 (4H, m), of 3.56 (3H, s), of 3.69 (1H, m), 3,86 (1H, m)4,06 (2H, s), of 4.54 (1H, d, J=9,2 Hz), 6,17 (1H, s), of 6.75 (1H, d), 6,92-7,00 (2H, m), 7,06 (1H, m), 7,20-7,27 (2H, m), 7,42 (1H, d)

EI-MS (m/z)400 [M+H] +

Table 32
Approx.STRUCTUREDATA
1621H-NMR (CD3OD); 3,44 (2H, m), of 3.56 (2H, m), of 3.77 (1H, DD), 3,88 (1H, m), 4,17 (1H, d), 4,28 (2H, s), 7,31-7,38 (5H, m), 7,44 (1H, s)to 7.50 (1H, m), to 7.61 (1H, m)

ES-MS (m/z)372 [M+H]+
1631H-NMR (CD3OD); of 3.46 (1H, m), of 3.56 (1H, m), with 3.79 (1H, DD), to 3.89 (1H, d), 4,20 (2H, s), a 4.53 (1H, d), 6,85 (1H, d), 7,17 (1H, d),

7,33 (3H, m), 7,49 (1H, m), to 7.61 (1H, m)

ES-MS (m/z)388 [M+H]+
1641H-NMR (CD3OD); 3,38-3,44 (2H, m)

3,45-to 3.58 (2H, m), 3,70 (1H, m), a 3.87 (1H, m)to 4.01 (2H, s), 4,58 (1H, d), to 6.39 (1H, s), is 6.78 (1H, d), 7,06-to 7.18 (3H, m), 7,30 and 7.36 (2H, m), 7,44 (1H, m)

FAB-MS (m/z); 385 [M-H]-
1651H-NMR (CD3OD); to 2.35 (3H, s), of 2.38 (3H, s), of 3.46 (1H, m), of 3.56 (3H, m), 3,81 (1H, m), 3,88 (1H, DD), to 4.01 (2H, s), 4,51 (1H, d), of 6.26 (1H, d), 6,83 (1H, d), of 6.96 (1H, d), 7,11 (1H, d), to 7.15 (1H, d), 7,25 (1H, s)< / br>
ES-MS (m/z); 413 [M-H]-
1661H-NMR (CD3OD); 2,39 (3H, s), is 2.40 (3H, s), of 3.60 (4H, m), 3,82 (1H, m)to 3.89 (1H, m)4,00 (1H, s), 4,51 (1H, d), of 6.31 (1H, d), to 6.80 (1H, s), 6,83 (1H, DD), 7,01 (1 is, C), 7,11 (1H, d), from 7.24 (1H, s)

ES-MS (m/z); 414 [M]+
1671H-NMR (CD3OD); is 2.40 (3H, s), 3,37-to 3.58 (4H, m), 3,82 (1H, m), 3,88 (1H, m)4,00 (2H, s), 4,50 (1H, d), of 6.29 (1H, s), 6,83 (1H, d), of 6.99 (1H, d), 7,10 (1H, d), 7.23 percent (1H, m), 7,32 (2H, m)

ES-MS (m/z); 399 [M-H]-

Table 33
Approx.STRUCTUREDATA
1681H-NMR (CD3OD); 2,31 (3H, s), of 2.34 (3H, s), a 2.36 (3H, s), of 3.45 (1H, m), 3,57 (3H, m), 3,81 (2H, m)to 4.01 (2H, s), 4,51 (1H, d), 6,28 (1H, s), is 6.78 (1H, s), 6,83 (1H, d), 7,12 (1H, d), 7,26 (1H, s)

ES-MS (m/z); 427 [M-H]-
1691H-NMR (CD3OD); 2,31 (3H, s), of 2.34 (3H, s), of 3.45 (1H, m)to 3.58 (3H, m), 3,83 (1H, m), a 3.87 (1H, m)to 4.01 (2H, s), 4,49 (1H, d), 6.35mm (1H, s), at 6.84 (1H, d), 6,98 (1H, d), 7,11 (2H, m), 7,21 (1H, s) ES-MS (m/z); 413 [M-H]-
1701H-NMR (CD3OD); to 2.29 (3H, s), 2,32 (3H, s), of 3.43 (2H, m)to 3.58 (2H, m), 3,83 (1H, m), 3,88 (1H, m)to 3.99 (2H, s), 4,48 (1H, d), and 6.25 (1H, s), 6,83 (1H, d), 7,10 (1H, d), to 7.15 (1H, s), 7,20 (2H, s)

ES-MS (m/z); 413 [M-H]-
1711H-NMR (CD3OD); 3,26 (2H, s), 3,40 (2H, m), 3,53 (2H, m)to 3.67 (1H, DD), 3,76 (2H, s) is 3.82 (3H, C), 3,86 (1H, m), 4,70 (1H, d), 6.48 in (1H, s)6,91 (1H, d), 7,01 (1H, m), 7.03 is-7,22 (3H, m), 7,29 (1H, d), 7,32 (1H, d)

ES-MS (m/z); 421 [M+Na]+
1721H-NMR (CD3OD); 2,31 (3H, s), 3,20 (2H, s), 3,23-of 3.43 (4H, m), 3,60 (1H, d), 3,68 (2H, s), 3,76 (1H, d), 4,36 (1H, t), 4,47 (1H, d), is 4.85 (2H, OSS), to 4.92 (1H, USS), 6.42 per (1H, s), of 6.73 (1H, d), 6,84-of 6.96 (2H, m), 7,03 (1H, s), 7,16 (1H, s), 7,19 (1H, d), a total of 8.74 (1H, USS)

ES-MS (m/z); 398 [M]+
1731H-NMR (CD3OD); of 2.23 (6H, s)3,18 (2H, s), 3,40-3,51 (4H, m), 3,68 (2H, s), 3,70 (1H, d), 3,86 (1H, d), 4,07 (1H, t), 4,50 (1H, d), of 4.57 (2H, s), and 4.68 (1H, d), 4,91 (1H, d), to 6.39 (1H, s), 6.75 in-6,98 (2H, m), 6,99 (1H, s), was 7.08 (1H, s), 7,19 (1H, d), 8,42 (1H, s)

ES-MS (m/z)412 [M]+

Table 34
Approx.STRUCTUREDATA
1741H-NMR (CD3OD); 3.25 to a 3.87 (3H, m)

3,67-and 3.72 (1H, DD), 3,84-a 3.87 (1H, DD), 4,11 (2H, s), 4,55-of 4.57 (1H, d), 6,74-6,77 (1H, d), of 6.96 (1H, s),? 7.04 baby mortality-7,06 (1H, DD), 7,11-for 7.12 (1H, d), 7,28-7,29 (1H, d), 7,34-to 7.35 (1H, d)

ES-MS (m/z); 431 [M+Na]+
1751H-NMR (CD3OD); 3.27 to of 3.48 (4H, m), 3,61 (1H, DD), of 3.77 (1H, DD), of 3.96 (2H, s), 4,46 (1H, d), of 6.65 (1H, d), 6,68-of 6.71 (1H, m), is 6.78 (1H, DD), 6,91 (1H, DD), 7,06 (1H, DD), 7,16 (1H, d)

-
1761H-NMR (CD3OD); 3,36 of 3.56 (5H, m), of 3.77 (1H, DD), 4,16 (1H, d), 4,20 (2H, s), 7,19-7,37 (4H, m), 8,42 (1H, d), 8,49 (2H, d)

EI-MS (m/z); 332 [M]+
1771H-NMR (CD3OD); 3,29-3,44 (4H, m)

of 3.64 (1H, DD), of 3.75 (3H, s), 3,82-are 3.90 (3H, m)to 4.33 (1H, d), for 6.81 (2H, d), 6,92 (2H, s), 7,11 (2H, d)

FAB-MS (m/z)365 [M-H]-
1781H-NMR (CD3OD); of 1.20 (3H, t), 2,63 (2H, DD), 3,34-3,86 (6H, m), 4,56 (1H, d), 4,84 (2H, s), 7,21 (2H, d), 7,32 (2H, d)

FAB-MS (m/z)351 [M+H]+
1791H-NMR (CD3OD); and 2.27 (6H, s), 2,61 is 2.75 (2H, m), or 3.28 (1H, t), 3,36-3,47 (2H, m), 3,68 (1H, d), 4,01-4,10 (4H, m), 4,18 (2H, s)to 4.52 (1H, d), to 6.95 (1H, d), 7,15-7,21 (2H, m), 7.23 percent-7,34 (3H, m), 7,73 (1H, d), 7,83 (1H, d)

FAB-MS (m/z); 474 [M+H]+
1801H-NMR (CD3OD); 3,31-of 3.54 (4H, m), and 3.72 (1H, DD), 3,88 (1H, DD), 4,30 (2H, s), 5,19 (1H, d), was 7.08 (1H, s), 7,20-to 7.35 (3H, m), 7,68 (1H, d), 7,71-7,80 (3H, m)

FAB-MS (m/z)429 [M-H]-

Table 35
Approx.STRUCTUREDATA
181 1H-NMR (CD3OD); 3,38-of 3.53 (4H, m)3,68 (1H, DD), 3,88 (1H, DD), 4,24 (2H, s)4,55 (1H, d), of 4.66 (1H, d), to 4.73 (1H, d), 7,06 (1H, d), 7,19-7,30 (3H, m), 7,34 (1H, d), 7,54 (1H, d), 7,63-7,74 (2H, m)

FAB-MS (m/z)415 [M-H]-
1821H-NMR (CD3OD); 2,61-of 2.97 (5H, m), 3,54-with 3.79 (6H, m), 4,07 (1H, d), 4,17-of 4.95 (4H, m), 7.03 is-7,24 (7H, m), 7,51 (1H, s)

EI-MS (m/z)370 [M]+
1831H-NMR (CD3OD); 3,34-3,51 (4H, m), 3,66-3,70 (1H, m), a 3.87 (1H, DD), 4,13 (1H, d), and 4.40 (2H, s), 7,26 (1H, d), 7,31-7,40 (3H, m), of 7.48-7,52 (2H, m), EUR 7.57-to 7.61 (1H, m), 7,81 (1H, d)
1841H-NMR (CD3OD); 3,29-to 3.50 (4H, m), 3,64-3,70 (1H, m), 3,70 (3H, s), 3,86 (1H, DD), 4.09 to (1H, d), 4,35 (2H, s), 7,18 (1H, d), 7,21-7,37 (5H, m), the 7.43 (1H, DD), 7,60 (1H, DD)

FAB-MS (m/z); 385 [M+H]+
1851H-NMR (CD3OD);1H-NMR (CD3OD); 3,32-to 3.50 (4H, m), of 3.69 (1H, DD), a-3.84 (1H, DD), 4,10 (1H, d), 5,07 (1H, d), equal to 6.05 (2H, t)6,70 (2H, t), 7,05 (1H, d), 7,25-to 7.35 (3H, m)

FAB-MS (m/z); 320 [M+H]+
1861H-NMR (CD3OD); to 1.19 (3H, t), 2,58 (2H, HF), 3,24-of 3.46 (4H, m), the 3.65 (1H, DD), 3,80-3,86 (3H, m), 4,15 (1H, d), 5,73 (1H, d), of 6.02 (1H, d), 7,07 (1H, d), 7,12 (1H, d)

FAB-MS (m/z)348 [M+H]+

Table 36
Approx.STRUCTUREDATA
1871H-NMR (CD3OD); of 1.10 (3H, t), 2.49 USD (2H, HF), 3,19-3,63 (7H, m), 3,70-a 3.83 (4H, m), 4,16 (1H, d), 5,71 (1H, d), 6,01 (1H, d), to 6.95 (1H, d), 6,98 (1H, d)

FAB-MS (m/z); 360 [M-H]-
1881H-NMR (CD3OD); of 1.20 (3H, t), 2,60 (2H, HF), 3,20-3,39 (3H, m), of 3.56 (1H, DD), 3,66 (1H, DD), to 3.73 (1H, DD), 4,17 (1H, d), 5,13 (1H, d), with 5.22 (1H, d), the 6.06 (1H, DD), 6,23 (1H, DD), 6,70 (1H, DD), 7,06 (2H, d), 7,13 (2H, e)

FAB-MS (m/z)348 [M+H]+

Table 37

Table 38

Table 39

1. The derived C-glycoside of the formula (I) or its pharmaceutically acceptable salt

where ring a is a (1) a benzene ring, (2) five - or six-membered monocyclic heteroaryl ring containing 1, 2 or 4 heteroatoms, selected from N and S, except tetrazolo, or (3) unsaturated deletechannel the bicyclic heterocycle containing 1 heteroatom, representing About;

the ring represents (1) an unsaturated eight-deletechannel the bicyclic heterocycle, sod is Rashi 1 or 2 heteroatoms, selected from N, S and O, (2) a saturated or unsaturated five - or six-membered monocyclic heterocycle containing 1 or 2 heteroatoms selected from N, S and O, (3) unsaturated deletechannel bicyclic carbocycle or (4) a benzene ring;

X represents a bond or a lower alkylene;

where values of ring A, ring b and X are correlated so that, (1) when ring a is a benzene ring, the ring is a benzene ring or (2) when ring a is a benzene ring, and ring b is an unsaturated eight-deletechannel the bicyclic heterocycle containing 1 or 2 heteroatoms selected from N, S and O, including a benzene ring, or an unsaturated deletechannel bicyclic carbocycle, including a benzene ring, X is attached to the ring in a part other than the benzene ring included in the ring In;

R1-R4each individually represents a hydrogen atom, -C(=O)-lower alkyl or-lower alkylene-aryl; and

R5-R11each individually represents a hydrogen atom, lower alkyl, halogen, -HE, =O, -NH2, halogen-substituted lower alkyl-sulfonyl-, phenyl, a saturated six-membered monocyclic heterocycle containing 1 or 2 heteroatoms selected from N and O, lowest alkylene-OH, -lower alkyl, -COOH, -CN, -C(=O)O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(HE), -O-lower alkylene-NH2, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N(lower alkyl)2, -NH-lower alkylene-IT or-NH-C(=O)-lower alkyl.

2. The derived C-glycoside or its pharmaceutically acceptable salt according to claim 1 in which the ring a in the formula (I) represents (1) a benzene ring or (2) five - or six-membered monocyclic heteroaryl ring containing 1, 2 or 4 heteroatoms, selected from N and S, except tetrazolo.

3. The derived C-glycoside or its pharmaceutically acceptable salt according to claim 2, where the ring in the formula (I) represents (1) an unsaturated eight-deletechannel the bicyclic heterocycle containing 1 or 2 heteroatoms selected from N, S and O, or (2) a saturated or unsaturated five - or six-membered monocyclic heterocycle containing 1 or 2 heteroatoms selected from N, S and O.

4. The derived C-glycoside or its pharmaceutically acceptable salt according to claim 3 in which the ring a in the formula (I) is a benzene ring, and ring b is an unsaturated the first eight-deletechannel the bicyclic heterocycle, containing 1 or 2 heteroatoms selected from N, S and O.

5. The derived C-glycoside or its pharmaceutically acceptable salt according to claim 4, where X in the formula (I) represents methylene.

6. The derived C-glycoside or its pharmaceutically acceptable salt according to claim 5, where R1-R4in the formula (I) are hydrogen atoms.

7. The derived C-glycoside or its pharmaceutically acceptable salt according to claim 1, where the derived C-glycoside of the formula (I) represents at least one compound selected from the group including

(1S)-1,5-anhydrous-1-[3-(1-benzothieno-2-ylmethyl)phenyl]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-hydroxyphenyl]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-methoxyphenyl]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(2-hydroxyethoxy)phenyl]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2-(methylamino)phenyl]-D-glucit,

(1S)-1,5-anhydrous-1-{5-(1-benzothieno-2-ylmethyl)-2-[(2-hydroxyethoxy)amino]phenyl}-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-methoxyphenyl]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-chlorophenyl]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-forfinal]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-2,4-acid]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-chloro-methoxyphenyl]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-chloro-2-hydroxyphenyl]-D-glucit,

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-fluoro-2-hydroxyphenyl]-D-glucit and

(1S)-1,5-anhydrous-1-[5-(1-benzothieno-2-ylmethyl)-4-fluoro-2-methoxyphenyl]-D-glucit.

8. The pharmaceutical composition inhibiting activity of cotransporter Na+-glucose rights containing an effective amount derived C-glycoside or its pharmaceutically acceptable salt according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, where the composition has antidiabetic activity.

10. The application of the derived C-glycoside or its pharmaceutically acceptable salt according to any one of claims 1 to 7 to obtain inhibitor cotransporter Na+-glucose as an antidiabetic agent.

11. A method of treating diabetes comprising the administration to a patient an effective amount derived C-glycoside and its pharmaceutically acceptable salt according to any one of claims 1 to 7.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to diazacycloalkanes of the general formula (I): wherein G1 represents condensed polycyclic group. Compounds are selective and strong acting agonists of oxytocin and can useful in treatment of erectile dysfunction. Also, invention describes a pharmaceutical composition based on compounds of the formula (I) and their using in manufacturing the pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

31 cl, 136 ex

FIELD: organic chemistry, pharmaceuticals.

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EFFECT: new oxytocin antagonists.

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

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36 cl, 1 dwg, 16 tbl, 131 ex

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EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical composition.

6 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (1): wherein each R1 and R2 represents independently (C1-C6)-alkyl, (C3-C6)-alkenyl, (C3-C6)-cycloalkyl-(C1-C3)-alkyl or (C3-C6)-cycloalkyl wherein each of them can be substituted possibly with halogen atom in the amount from 1 to 3; R3 represents isoxyzolydine-2-ylcarbonyl or tetrahydroisoxazine-2-ylcarbonyl wherein each ring is substituted possibly with one hydroxy-group; Q represents -CO- or -C(R4)(R5)- (wherein R4 represents hydrogen atom or (C1-C4)-alkyl, and R5 represents hydrogen atom or hydroxy-group); Ar represents 5-10-membered aromatic ring system wherein up to 4 ring atoms can be represented by heteroatoms chosen independently from nitrogen, oxygen and sulfur atoms and wherein this ring system is substituted possibly with one or more substitute. Proposed compounds can be used for modulation of autoimmune disease. Also, invention describes methods for synthesis of compounds of the formula (1) and pharmaceutical composition based on compounds of the formula (1).

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

14 cl, 44 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes glycine-substituted thieno[2,3-D]-pyrimidines of the formula (I): wherein X represents oxygen atom (O) or H,H; A represents sulfur atom (S), -NH, -N(R6), O or a bond; R1 represents (C1-C4)-alkyl, (C2-C4)-alkenyl, unsubstituted or substituted phenyl, thienyl, pyridyl; R2 represents hydrogen atom (H), (C1-C4)-alkyl, (C1-C4)-alkoxy-(C2-C4)-alkyl or hydroxy-(C2-C4)-alkyl; R3 and R4 are chosen independently from H, (C1-C4)-alkyl and hydroxy-(C1-C4)-alkyl; R5 represents H or (C1-C4)-alkyl, and R6 represents (C1-C4)-alkyl. Compound possess agonistic activity with respect to glycoprotein hormone, in particular, to compounds possessing agonist activity with respect to luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Also, invention describes pharmaceutical compositions containing such compounds and using these compounds in medicinal therapy, in particular, for fertilization control.

EFFECT: valuable biological and medicinal properties of compounds.

11 cl, 1 tbl, 27 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

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

wherein R1 means hydrogen atom; R2 means phenyl or phenyl mono- or di-substituted substituted with the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, perfluoro-(lower)-alkyl; R3 and R4 in common with carbon atoms to which they are bound form phenyl optionally and independently mono-, di- or tri-substituted with halogen atom or perfluoro-(lower)-alkyl, or form 5-, 6- or 7-membered saturated cycle optionally comprising heteroatom chosen from oxygen (O) and sulfur (S) atom and optionally and independently mono-substituted with (lower)-alkyl wherein indicated saturated cycle is condensed in ortho-position with 5-membered aromatic cycle optionally comprising S atom as a heteroatom, or with phenyl optionally and independently mono- di-substituted with the group: halogen atom, (lower)-alkyl, perfluoro-(lower)-alkyl or (lower)-alkoxy-group, and their pharmaceutically acceptable salts. Also, invention describes a method for synthesis of compounds, a pharmaceutical composition and using compounds for treatment and/or prophylaxis of DPP-IV-associated diseases. Compounds are used in treatment of such diseases as diabetes mellitus being first of all non-insulin dependent diabetes mellitus and damaged tolerance to glucose.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

16 cl, 1 tbl, 39 ex

FIELD: organic chemistry, medicine, gynecology.

SUBSTANCE: invention relates to novel tetracyclic heterocompounds of the formula (I): wherein X, Y, Z, R1 - R4, n and m has values given in the invention description and used as selective modulating agents for estrogen receptors. Also, invention relates to a method for synthesis of these compounds and pharmaceutical compositions comprising thereof, and their using in treatment and/or prophylaxis of disorders mediated by one or more estrogen receptors. Proposed compounds are useful in treatment and/or prophylaxis of disorders associated with depleting estrogen and comprising such disorders as rush of blood, vaginal dryness, osteopenia and osteoporosis, hormone-dependent cancer and hyperplasia of breast, endometrium, uterus cervix and prostate, endometriosis, uterus fibroma, osteoarthritis that can be used as contraceptive agents both separately and in combination with progestogen or progestogenous antagonist.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

25 cl, 7 tbl, 171 ex

FIELD: organic chemistry, chemical technology, medicine, oncology.

SUBSTANCE: invention relates to a method for isolation of epotilons used in medicine in treatment of cancer diseases. Method for desorption of epotilons A, B, D and/or E from synthetic resin is based on using low-polar or nonpolar solvent chosen from the group comprising (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Used aromatic solvent is chosen from the group including naphthalene, benzene or naphthalene and benzene substituted with one or some substitutes chosen from the following group: (lower)-alkyl, (lower)-alkoxy-group, halogen atom, nitro-group and (lower)-alkoxy-(lower)-alkyl wherein prefix "(lower)" means that radical comprises up to 7 carbon atoms. Solvent is removed to the required level but up to preparing a dry residue preferably. If necessary, residue is dissolved in mixture alcohol/hydrocarbon in the corresponding volume ratio. Alcoholic phase is evaporated until dry and then alcoholic extract is crystallized from mixture alcohol and hydrocarbon. Then formed crystallized product is dissolved in mixture nitrile/water but preferably in mixture acetonitrile/water taken in the ratio = 2:3 (vol./vol.). Formed solution is applied on column (if necessary, after separation for some distillates) for preparative chromatography in reversed phase followed by elution with mixture nitrile/water, removing nitrile and extraction of an aqueous phase with ester. Ester extract is evaporated and formed product is subjected for crystallization. Method for preparing epotilons A, B, D and/or E from resin or reaction mixture involves the following steps: (a) desorption of epotilons with low-polar or nonpolar solvent chosen from the group including (lower)-alkyl halides and aromatic solvents, or mixture of two or more amount of such solvents being the desorption step can be repeated up to achievement of the more complete desorption; (b) removal of solvent used in desorption from formed solutions by evaporation; (c) optional crystallization of epotilon(s) after desorption and first of all for crystallization of epotilon B by addition of mixture of alcohol with hydrocarbon and the following evaporation of alcoholic phase until dry and crystallization of epotilon B from the corresponding mixture of solvents; (d) (obligatory step) separation of epotilons by method of chromatography in reversed phase and the following dissolving a residue obtained in previous step in suitable solvent, elution with mixture nitrile/water and removing nitrile from epotilon-containing fractions by evaporation. If necessary, water remained with epotilon is extracted with ester followed by evaporation of epotilon-containing ester phase until dry; (e) optional purification by adsorption chromatography method, and final recrystallization of purified epotilon from corresponding solvents or mixture of solvents. If necessary, in this process between each step formed solutions or suspensions are concentrated, and/or liquid or solid components are separated of one another. Separation of epotilons A and B is carried out by chromatography method based on a mobile layer modeling. Invention provides simplifying methods for preparing large amounts of epotilons for satisfying requirement in these agents.

EFFECT: improved isolating method.

12 cl, 2 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to a novel crystalline form of (1S,2S,3R,4S,5R,8R,9S,10R,13S)-4-acetoxy-2-benzoyloxy-9,10-[(1S)-2-(dimethylamino)ethylideneoxy]-5,20-epoxy-1-hydroxytax-11-ene-13-yl-(2R,3S)-3-(tert.-butoxycarbonylamino)-3-(3-fluoro-2-pyridyl)-2-hydroxypropionate that shows the diffraction picture of roentgen rays in powder with characteristic peaks at diffraction angles (θ)= 6.2o, 10.3o, 10.7, 11.4o and 12.0, and a method for its preparing. Method involves carrying out the crystallization step by using organic solvent chosen from group consisting of ketone type solvent, nitrile solvent type and their mixture, or mixture of said solvent and water. Also, invention relates to an antitumor agent based on the prepared crystalline form. Invention provides the stable quality of a medicinal agent based on its lower hygroscopicity.

EFFECT: improved and valuable properties of compounds.

8 cl, 5 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for synthesis of new compounds, namely, 1,11-dialkyl-3,5-dihydrofuro-[2',3':3,4]-cyclohepta[c]isochromens of the formula: (Ia-f): wherein (Ia): R means hydrogen atom (H); R1 means hydrogen atom (H); (Ib): R means bromine atom (Br); R1 means hydrogen atom (H); (Ic): R means chlorine atom (Cl); R1 means hydrogen atom (H); (Id): R means hydrogen atom (H); R1 means bromine atom (Br): (Ie): R means hydrogen atom (H); R1 means chlorine atom (Cl); (If): R means methoxy-group (-OCH3); R1 means hydrogen atom. Method involves formation of condensed tetracyclic system as result of the successive recyclization reactions of furan ring of derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol and the secondary cyclization of formed isochromen ketone in boiling of solution containing derivatives of 2-bis-(5-methyl-2-furylmethyl)phenylmethanol of the formula: in ethanol medium in the presence of hydrogen chloride alcoholic solution for 15-40 min. Invention provides synthesis of new derivatives of isochromens possessing the potential anti-inflammatory activity.

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

1 cl, 2 tbl, 5 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a novel method for preparing 14β-hydroxy-1,4-carbonate-desacetylbaccatin III and intermediate substances used in preparing new derivatives of taxane and possessing an antitumor activity. Method involves the following stages: a) protection of hydroxyls at positions 7 and 10 in 10-desacetylbaccatin III wherein R and R1 are taken among hydrogen atom, (C1-C10)-alkyl or aryl, (C1-C10)-alkyl- or aryl-carbonyl, trichloroacetyl, (C1-C4)-trialkylsilyl; preferably, when R and R1 are similar then they represent trichloroacetyl; when they are different then, preferably, R represents trichloroacetyl and R1 represents acetyl; or R represents triethyl or trimethylsilyl and R1 represents acetyl; b) two-stage oxidation to yield a derivative oxidized to carbonyl at position 13 and hydroxylated at position 14; c) carboxylation of vicinal hydroxyls at positions 1 and 14 to yield 1,14-carbonate derivative; d) reduction of carbonyl at position 13; e) removal of protective groups at positions 7 and 10. Also, invention relates to intermediate substances. Invention provides preparing intermediate substances used in synthesis of taxane.

EFFECT: improved preparing method.

8 cl, 8 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new bis-tetrahydrofuranbenzodioxolyl sulfonamide compounds of the formula (I): , its salts, stereoisomers and racemates that are effective inhibitors of protease activity. Also, invention relates to pharmaceutical preparations, methods for inhibition of retrovirus proteases, in particular, to resistant retrovirus proteases, to many drugs, methods for treatment and prophylaxis of infection or disease associated with retrovirus infection in mammals and to methods for inhibition of retrovirus replication. Invention provides preparing new derivatives of bis-tetrahydrofuranbenzodioxalyl sulfonamides eliciting the valuable pharmaceutical properties.

EFFECT: valuable medicinal properties of compound and composition, improved treatment method.

16 cl, 2 dwg, 3 tbl

The invention relates to new derivatives epothilone formula I, where the bond indicated by a wavy line indicates that the bond “a” is either CIS-or TRANS-form; (I) R2absent or represents oxygen; “a” denotes a single or double bond; “b” is absent or represents a simple bond; and “C” is absent or represents a simple bond, provided that when R2denotes oxygen, then “b” and “C” both represent a simple bond and a represents a simple bond; if R2no, the “b” and “C” both are absent and “a” represents a double bond; and if “a” represents a double bond, R2“b” and “C” are absent; R3denotes a radical selected from the group comprising hydrogen; (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; -CH2-OH; R4and R5independently of one another denote hydrogen; R1denotes a radical of the structure (a-d); (II) if R3means (ness.)alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl; -CH2F; CH2-HE; and other symbols except for the R1have the values listed above in their characters except for the R1have the above values, R1can also represent a fragment of formula (j); or a salt of the compounds of formula I, if there is a salt-forming group

The invention relates to a method for producing 1,4:3,6-dianhydro-D-sorbitol, which is an intermediate in the production of lekarstvennyh drugs on the basis of its mono - or dinitropropane

The invention relates to a method for epoxidation prehiring of olefin, which includes the interaction prehiring of the olefin with oxygen source in the presence of salt catalyst

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

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