Ester derivatives and their medical application

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 ex

 

The present invention relates to a new ester derivative, as well as to pharmaceutical compositions containing the new ester derivative, which selectively inhibits microsomal triglyceriderich protein (hereinafter also presented in abbreviated form as MTP in the small intestine, or its salt. In addition, the present invention relates to a tool for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension, containing the new ester or its pharmaceutically acceptable salt as an active ingredient, which selectively inhibits MTP in the small intestine. The present invention also relates to means for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension, with a new action that has not been known before.

It is known that hyperlipidemia, diabetes, hypertension or the like is one of the risk factors for arteriosclerosis. Hyperlipidemia is a condition that occurs when the concentration of lipid, such as cholesterol, in the blood are abnormally high. Types of hyperlipidemia include, depending on the reasons, the primary hyperlipidemia caused by genetic abnormalities in the enzyme, protein, lipoprotein, and the like, which take the Uch shall participate in the metabolism of low density lipoprotein (LDL; LDL), secondary hyperlipidemia caused by various diseases or introduction of drugs, and acquired hyperlipidemia, mostly arising from overeating.

Lipid, taken from the food is absorbed in the small intestine under the action of bile acids and secreted through the lymphatic vessels in the form of chylomicrons in the blood. Triglyceride (TG; TG) part of chylomicrons secreted hydrolyzed to free fatty acids under the action of lipoprotein lipase (LPL; LPL)located in the capillary vessels, turning into remnant of chylomicrons with a high content of cholesterol ester (EH; CE), which can then be absorbed into the liver through receptor remnants of chylomicrons by the liver. Further, in the liver absorbed remnant of chylomicrons and free fatty acids are converted into OH and TG, respectively, which then, together with apolipoprotein B, synthesized on the rough endoplasmic reticulum, form a lipoprotein very low density lipoproteins (VLDL; VLDL). Lamp is transferred to the Golgi apparatus, modified and secreted outside the cells, becoming under the action of LPL-lipoprotein, intermediate density (BOB; IDL). BOB under the action of hepatic trigliceridos (PTP; HTGL) is converted to LDL and the resulting lipids are distributed in peripheral tissues.

It has long been known that in EMA described above education chylomicrons in the small intestine or lonp in liver microsomal fractions of the small intestine or liver, there is protein, with TG - or OH-portable activity. This protein, namely MTP (microsomal triglyceriderich protein: below is also abbreviated as MTP), was purified and isolated from microsomal fractions of bovine liver Wetterau et al. in 1985 (J. R. Wetterau et al. Chem. Phys. Lipids 38, 205-222(1985)). However, MTP attracted great attention in the field of clinical medicine only once in 1993, it became known that the reason the beta lipoproteinemia is the lack of MTP. In other words, the disease is characterized by the fact that although genes associated with apolipoprotein B, normal, apolipoprotein found In serum with difficulty, the level of serum cholesterol 50 mg/DL or below, the level of triglyceride in serum is very low. This information showed that MTP is an essential protein involved in the interaction between apolipoprotein b and triglycerides or EH, i.e. education lonp or chylomicron, and plays an important role in their secretion. Therefore, the idea arose that the MTP inhibitors can be an excellent antihyperlipidemic agent which can inhibit the production of lipoproteins, such as chylomicrons, lamp and the like. In addition, the inhibition of MTP in the small intestine and thereby inhibiting the production of chylomicron, you can expect to be suppressed excessive absorption of triglycerides responsible for hyperlipidemia,which will lead to the creation of a new type antihyperlipidemic funds.

Because the lipid nature insoluble in water, the lipid in the blood combined with the hydrophilic protein known as apolipoprotein, and exists in the form of so-called lipoprotein. All lonp, BOB, LDL or chylomicrons, etc. associated with hyperlipidemia, represent lipoprotein.

MTP exists in microsome fractions of hepatocytes and intestinal epithelial cells and catalyzes the transfer of TG or OH in the cells. In the liver and the small intestine, together with the synthesis of apolipoprotein b (apolipoprotein B100 in the liver and apolipoprotein B in the small intestine), TG and EH are combined with the corresponding apolipoprotein In due portable MTP activity with the formation of lonp or chylomicron. The result of these lipoproteins are secreted outside the cells in the form of lamp in the liver or chylomicrons in the small intestine. It should be said that MTP required to construct these lipoproteins. That is, if you block the activity of MTP, it will be Engibarov transfer of lipid, such as TG and OH, etc. so it may be ingibirovalo education lipoprotein.

On the other hand, it is known that, mainly LDL closely associated with the development of arteriosclerosis. That is, penetrating through the endothelium of the blood vessels LDL is deposited in the extracellular matrix of the vessel wall, where oxidative denaturation and lipid peroxides is or denatured proteins induce a series of inflammatory reactions. The result is the emigration of macrophages in the blood vessels leading to the deposition of lipid or the formation of layers of foam cells, migration or proliferation of smooth muscle cells and enlargement of the intercellular matrix, etc. that leads to the growth of atherosclerotic plaques. Based on the above, it is possible to assume that it is possible to prevent or to treat arteriosclerosis, coronary artery disease or hypertension, lowering LDL.

As already mentioned, it is possible to inhibit the formation of lipoproteins, such as chylomicrons, lonp, LDL, etc. by inhibiting the action of MTP. Therefore, it was expected that it will be possible regulation of triglycerides, cholesterol and lipoproteins, such as LDL, etc. in the blood and the regulation of lipid in cells by regulating the activity of MTP, and therefore expected the creation of new tools for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, diabetes, obesity or hypertension, as well as funds for the treatment or prevention of pancreatitis, hypercholesterolemia, hyperglyceridemia etc.

However, the increase in the number and use of MTP inhibitors have been reported some cases of fatty liver and increased concerns about hepatotoxicity (M. Shiomi and T. Ito, European Journal of Pharmacology, 431, p. 127-131 (2001)). Perhaps because even in case of rendering inhibit the subsequent steps on MTP in the small intestine compound absorbed from the intestine and the like, and remains in the blood or liver, which leads to inhibition of MTP in the liver.

As usual, we checked the possibility of applying the methods of combination therapy using different combinations antihyperlipidemic drugs. However, co-administration, e.g., drugs of the type of statin and drug type resin, there are undesirable side effects, such as elevated GOT (AST) GPT (Alt), constipation, blocking the absorption of vitamins A, D, E and K, and the like. On the other hand, with co-administration of drugs of the type of statin and drug type fibrate experience side effects, such as rhabdomyolysis or increased CPK (CPK). Thus, with regard to combination therapy for hyperlipidemia, it is desirable drug for combined introduction that can be entered in combination with traditional antihyperlipidemic drug, without causing any of the above side effect.

Here are examples of known compounds with MTP inhibitory activity.

The following compound disclosed in WO 97/26240.

The following compound disclosed in WO 97/43257.

The following compound disclosed in WO 98/23593.

(In this formula, G represents a phenyl, heterocyclyl, -CH2CN, diphenylmethyl, C2-C12alkyl, C2-C12perfluoroalkyl, C3-C8cycloalkyl, C3-C8cycloalkenyl, -(CH2)n-COOH, -(CH2)n-COO-alkyl, etc.)

The following compound disclosed in WO 99/63929.

The following compound disclosed in WO 2000/5201.

The following compound disclosed in J. Med. Chem. (2001), 44(6) p. 851-856.

The following compound disclosed in EP 1099701.

The following compound disclosed in WO 2001/77077.

The following compound disclosed in J. Med. Chem. (2001), 44(6) p. 4677-4687.

The following compound disclosed in WO 2002/4403.

In these publications, however, not disclosed compound containing ester as an integral part of the structure, and there is no disclosure or assumptions data, which indicate that the open compound selectively inhibits MTP in the small intestine, rarely affecting the MTP in the liver.

Further, in WO 2002/28835 revealed the following compound represented by the formula:

where L is an unsaturated 3-10-membered heterocycle, which can is t to be replaced by a suitable substitute,

Y is -(A1)m(A2)n(A4)k-[in the formula A1represents the lowest alkylene or lower albaniles, moreover, these two groups can be substituted by the appropriate Deputy; A2represents-N(R3)-, -CO-N(R3)-, -NH-CO-NH-, -CO-O-, -O-, -O-(CH2)2-N(R3)-, -S-, -SO - or-SO2- (in this formula, R3represents hydrogen or a suitable proxy); A4represents the lowest alkylene, lower albaniles or lower akinyan and k, m and n are each 0 or 1].

However, the compound disclosed in this patent differs from the compounds of the present invention according to the structure in relation to the fragment-Y-L-. In addition, in this patent there is no disclosure or assumptions of data showing that the open compound selectively inhibits MTP in the small intestine, rarely affecting the MTP in the liver.

In addition, in WO 2003/72532 revealed the following connection, selectively inhibiting MTP in the small intestine, which is represented by the formula:

where Alk2represents alcander or alkerdeel;

m represents 0 or an integer from 1 to 3;

D represents C1-C6alkyl, C2-C6alkenyl, C2-C7alkoxycarbonyl, -N(R42)-CO(R43) (where R42depict is to place a hydrogen or C 1-C6alkyl, and R43represents a C6-C14aryl or C7-C16aralkyl) or

where R5, R6and R7independently represent, each, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, carboxyl, halogen, cyano, nitro, halogen, C1-C6alkyl, C1-C6acyl, hydroxy, amino, optionally substituted C6-C14aryl or -(CH2)r-CON(R16)(R17) (where R16and R17independently are each hydrogen, C1-C6alkyl or halogen-C1-C6alkyl and r represents 0 or an integer from 1 to 3); a ring represents a C6-C14aryl, C7-C15arylcarboxamide, C8-C17aralkylamines, heterocyclic residue, C3-C7cycloalkyl or C7-C16aralkyl or ring C, taken together with R7and R8may form a group of the formula:

R8and R9independently are each hydrogen, C1-C6alkyl, optionally substituted C6-C14aryl, hydroxy-C1-C6alkyl, -CON(R18)(R19) (where R18and R19are the same or different and are each hydrogen, C1/sub> -C6alkyl, C3-C7cycloalkyl, halogen-C1-C6alkyl, C2-C12alkoxyalkyl or optionally substituted C6-C14aryl), -COO(R20) or (CH2)s-OCOR(R20) (where R20represents hydrogen, C1-C6alkyl or C3-C7cycloalkyl and s represents 0 or an integer from 1 to 3), -N(R21)(R22) (where R21and R22are the same or different and are each hydrogen, C1-C6alkyl, C1-C6acyl or C1-C6alkylsulfonyl or R21and R22together with the nitrogen atom to which they are attached, can form a group of the formula:

or R8and R9taken together, may form a C3-C7cycloalkyl.

However, the compound disclosed in this patent publication is different from the compounds of the present invention according to the chemical structure in relation to the fragment -(Alk2)m-CR8R9-.

In addition, in WO2005/21486 revealed the following connection formula:

where R1and R2are the same or different and are each hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C1-C6alkoxy, halogen-(C1-C6alkyl, halogen- 1-C6alkyloxy, optionally substituted C6-C14aryl, optionally substituted C7-C16aralkyl, optionally substituted C6-C14aryloxy, optionally substituted C7-C16aralkylated, optionally substituted C7-C15arylcarbamoyl, optionally substituted heterocyclic ring, C2-C7alkoxycarbonyl, halogen, C2-C6alkenyl, C1-C6acyl, cyano, -N(R40)(R41) (where R40and R41are the same or different and are each hydrogen, C1-C6alkyl or optionally substituted C6-C14aryl) or -(CH2)r-O-CO-R100(where R100represents a C1-C6alkyl, C1-C6alkoxy or C2-C12alkoxyalkyl and r represents 0 or an integer from 1 to 3);

ring a represents a C6-C14aryl, heterocyclic ring,

X represents-COO-(CH2)n-, -CON(R10)-(CH2)n- or-N(R10)-CO-(CH2)n- (where R10represents hydrogen, C1-C6alkyl or C3-C8cycloalkyl and n represents 0 or an integer from 1 to 3);

R3, R4and R200are the same or different and represent the Wallpaper, each hydrogen, hydroxy, halogen, optionally substituted C1-C6alkyl, C1-C6alkoxy, halogen-(C1-C6alkyl, C7-C16aralkylated, C1-C6acyl, C3-C10alkoxycarbonyl, optionally substituted heterocyclic ring, -CON(R11)(R12)[where R11and R12are the same or different and are each hydrogen, optionally substituted C1-C6alkyl, optionally substituted C6-C14aryl, optionally substituted C7-C16aralkyl or C1-C6alkoxy, or R11and R12together with the nitrogen atom to which they are attached, can form a group of the formula:

(where R0represents hydrogen, hydroxy, C1-C6alkyl or C1-C6acyl and p represents 0 or an integer of 1 or 2)], -(CH2)q'-N(R13)(R14)[where R13and R14are the same or different and are each hydrogen, C1-C6alkyl, C2-C7alkoxycarbonyl or C1-C6acyl or R13and R14together with the nitrogen atom to which they are attached, can form a group of the formula:

(where p has the same meaning as defined above) very lovely and q' represents 0 or an integer from 1 to 3], -CO(R15) [where R15represents hydroxy, C1-C6alkyl, C1-C6alkoxy, optionally substituted C6-C14aryloxy or C7-C16aralkylated] or -(CH2)r'-O-CO-R100'[where R100'represents a C1-C6alkyl, C1-C6alkoxy, C2-C12alkoxyalkyl or-N(R40)(R41) (R40and R41have the same meanings as defined above and r' represents 0 or an integer from 1 to 3];

ring B represents a

(where k represents 0 or an integer of 1 or 2) or a nitrogen atom that is attached to R10together with R3, R10and ring B may form a group of the formula:

(where R300represents an optionally substituted C1-C6alkyl);

Alk1represents alcander or alkerdeel;

Alk2represents alcander or alkerdeel;

l represents 0 or an integer from 1 to 3;

m represents 0 or an integer from 1 to 3;

ring C is a

(q represents 0 or an integer from 1 to 4);

R5, R6and R7are the same or different and are each hydrogen, C1-C6and the keel, C1-C6alkoxy, C2-C7alkoxycarbonyl, carboxyl, halogen, cyano, nitro, halogen, C1-C6alkyl, C1-C6acyl, hydroxy, amino, optionally substituted C6-C14aryl, -(CH2)r-CON(R16)(R17) (where R16and R17are the same or different and are each hydrogen, C1-C6alkyl or halogen-C1-C6alkyl and r represents 0 or an integer from 1 to 3) or -(CH2)r-O-CO-R100”(where R100”represents a C1-C6alkyl, C1-C6alkoxy or C2-C12alkoxyalkyl and r represents 0 or an integer from 1 to 3);

R8and R9are the same or different and are each hydrogen, optionally substituted C1-C6alkyl or optionally substituted C6-C14aryl;

E represents-O - or-N(R90)- (where R90represents hydrogen or C1-C6alkyl);

Y represents-O-CO-O-, -O-CO-, -CO-O-, -CO-O-C(R110)(R111)-O-CO-, -CO-O-C(R110)(R111)-O-CO-O-, -O-CO-O-C(R110)(R111)-O-CO-, -O-CO-C(R110)(R111)-O-, -O-CO-C(R110)(R111)-C(R110)(R111)-O - or-O-C(R110)(R111)-CO-O- (where R110and R111are the same or different and represent, each, ogorodili C 1-C6alkyl; provided that when Y represents

-CO-O-, R3represents -(CH2)r'-O-CO-R100'(R100'and r' have meanings as defined above).

However, the compound disclosed in this patent publication is different from the compounds of the present invention according to the chemical structure:

Disclosure of the invention

Although the development of new antihyperlipidemic drugs used due to their MTP inhibitory activity continued up to the present time, these medicines are not satisfactory from the point of view of the rate of their disappearance in the blood or liver, causing side effects such as fatty liver, etc. Therefore, the development of antihyperlipidemic drugs, which may disappear in the blood or liver very quickly, is highly desirable. The technical problem to be solved by using the present invention is to create excellent antihyperlipidemic drugs having high inhibitory activity, which is observed in traditional MTP inhibitors, and very quickly metabolisable in the blood or liver.

The authors of the present invention and those who were involved in its creation, p is ovely intensive research, to create a new MTP inhibitor, which does not cause the above side effect, such as fatty liver. As a result they had found the MTP inhibitor that selectively inhibits MTP in the small intestine, but essentially did not inhibit MTP in the liver, significantly reduces unnecessary TG or cholesterol without causing a side effect, such as fatty liver, etc. it Was also unexpectedly found that the compound having the structure of ester represented by the following formula [1], very quickly loses MTP inhibitory activity in plasma or liver S9. So the ester compound according to the present invention has been found very useful as antihyperlipidemic drugs that are subjected to very rapid metabolism in the blood or liver.

Thus, in accordance with the present invention include:

<1> ester compound of the formula [1]:

where

R1represents 1) halogen, 2) C1-C6alkyl, 3) C1-C6alkoxy or (4) -CO-C1-C6alkoxy (where C1-C6alkyl or C1-C6alkoxy in paragraphs 2), 3) and 4) is optionally substituted by the same or different one or more substituents selected from the group As defined below,

[group A]:

1) halogen,

2) hydroxy,

3) C1-C6alkoxy,

4) -NR8R9where R8and R9are the same or different and represent, each, (a) hydrogen, (b) C1-C6alkyl, or (c) nitrogen-containing saturated a heterocycle containing a monocycle formed when R8, R9and the adjacent nitrogen atom are taken together

5) -CONR8R9where R8and R9are the same or different and are each hydrogen or C1-C6alkyl, or a nitrogen-containing saturated a heterocycle containing a monocycle formed when R8, R9and the adjacent nitrogen atom are taken together

6) -COR10where R10represents (a) hydrogen, (b) hydroxy, (c) C1-C6alkyl, or (d) C1-C6alkoxy,

7) -NR11COR10where R10represents hydrogen, hydroxy, C1-C6alkyl or C1-C6alkoxy and R11represents (a) hydrogen or (b) C1-C6alkyl,

8) -NR11CONR8R9where R8and R9are the same or different and represent hydrogen, C1-C6alkyl or a nitrogen-containing saturated a heterocycle containing a monocycle formed when R8, R9and the adjacent nitrogen atom are taken together and R11represents adored or C 1-C6alkyl,

9) -NR11SO2R12where R11represents hydrogen or C1-C6alkyl, and R12represents a C1-C6alkyl, and

10) -SO2R12where R12represents a C1-C6alkyl

(where C1-C6alkyl or C1-C6alkoxy in paragraphs (1)to (10) can be optionally substituted by the same or different one or more substituents selected from group A, as defined above, and nitrogen rich heterocycle containing monocycle, in paragraphs 4)and 5), or 8) may be optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6of alkyl, provided that when the substituted alkyl, alkoxy or nitrogen rich heterocycle containing monocycle selected as a substituent, these groups may be substituted as stated above, but you can choose alkyl, alkoxy or nitrogen-containing heterocycle containing monocycle, as a delegate of the Deputy and the Deputy may be, in turn, optionally substituted, and while this multiple substitution is not particularly limited, it is preferably carried out five times, more preferably two times, and particularly preferably once);

R2represents 1) hydrogen or (2) C1-C6alkyl (where C1-C6alkyl in paragraph (2) is optionally substituted by the same or different one or more substituents selected from group A defined above);

R3, R4and R5are the same or different and represent, each, 1) hydrogen or (2) the Deputy selected from the group B defined below:

[group B]:

1) halogen,

2) hydroxyl,

3) C1-C6alkyl, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above,

4) C1-C6alkoxy, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above,

5) cycloalkylcarbonyl, which is optionally substituted by one or more substituents selected from group A, as defined above, and C1-C6of alkyl, substituted the same or different one or more substituents selected from group A, as defined above,

6) aralkyl, which is optionally substituted by one or more substituents selected from group A, as defined above, and C1-C6of alkyl, substituted the same or different one or more substituents, wybran the mi from group A, defined above,

7) aralkylated, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above,

8) -COR13where R13represents a

(a) hydroxy,

(b) C1-C6alkyl, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above,

(c) C1-C6alkoxy, which is optionally substituted by the same or different one or more substituents selected from group A defined above; C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A defined above; aralkylated, optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A defined above; -CO-aralkylated, optionally substituted by the same or different one or more substituents selected from group A, determine elenai above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A defined above; and saturated or unsaturated heterocycle, containing at least one heteroatom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above,

(d) cycloalkyl, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above,

(e) cycloalkylcarbonyl, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above,

(f) aralkyl, which is optionally substituted by the same or different od is them or more substituents, selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above,

(g) aralkylated, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above,

(h) C3-C14carbocycle, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above, or

(i) -OR19where R19represents a C3-C14saturated or unsaturated carbocycle, optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above, or a saturated or unsaturated heterocycle, containing at least one gateroad is m, selected from nitrogen atom, oxygen atom and sulfur atom, optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above,

9) -NR14R15where R14and R15are the same or different and represent, each,

(a) hydrogen,

(b) C1-C6alkyl, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, or

(c) nitrogen-containing saturated a heterocycle containing a monocycle formed when R14, R15and the adjacent nitrogen atom are taken together

10) -CONR14R15where R14and R15have the same meanings as defined above,

11) -NR16COR13where R13has the same meaning as defined above, and R16represents a

(a) hydrogen or

(b) C1-C6alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above,

12) -NR16CONR14R15where R14, R15and R16have the same meanings as defined above,

13) -SR17, where the R 17represents a

(a) C1-C6alkyl, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, or

(b) cycloalkyl, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above,

14) -SOR17where R17has the same meaning as defined above,

15) -SO2R17where R17has the same meaning as defined above,

16) -SO2NR14R15where R14and R15have the same meanings as defined above,

17) C3-C14saturated or unsaturated carbocycle, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above,

18) a saturated or unsaturated heterocycle, containing at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6of alkyl, it is certainly substituted by the same or different one or more substituents, selected from group A and-CO-aralkylated (specified-CO-aralkylated is optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A),

19) aryloxy, which is optionally substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from group A, as defined above, and

20) nitrile;

R6and R7are the same or different and represent, each, 1) hydrogen, 2) C1-C6alkyl or (3) nitrogen-containing saturated a heterocycle containing a monocycle formed when R6, R7and the adjacent nitrogen atom are taken together (where C1-C6alkyl in paragraph (2) is optionally substituted by the same or different one or more substituents selected from group A; and nitrogen-containing saturated the heterocycle in paragraph (3), containing the monocycle can be substituted by the same or different one or more substituents selected from group A, as defined above, and C1-C6the alkyl);

the ring And to Liza B and ring C are the same or different and are each 1) C 3-C14saturated or unsaturated carbocycle or 2) a saturated or unsaturated heterocycle, containing at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom;

-X - represents 1) -(CH2)l- (where l is an integer from 1 to 4), 2) -(CH2)m-NR18-(CH2)n-where R18represents a C1-C6alkyl and m and n are the same or different and are each an integer from 0 to 2 or 3)

where m and n have the same meanings as defined above, and the specified C1-C6an alkyl group in paragraph (2) is optionally substituted by the same or different one or more substituents selected from group A, as defined above,

or its pharmaceutically acceptable salt,

<2> ester compound according to the item <1>, where the position of substitution for-X - in the benzene ring of the formula [1] is h-position, or pharmaceutically acceptable salt,

<3> ester compound according to the item <1>, which is represented by the formula [2]:

where

R1'represents a

1) C1-C6alkyl, which is optionally substituted by the same or different one or more Halogens, or

2) -CO-C1-C 6alkoxy;

R2'represents a

1) hydrogen or

2) C1-C6alkyl,

R3', R4'and R5'are the same or different and represent, each,

1) hydrogen,

2) halogen,

3) C1-C6alkyl, which is optionally substituted by the same or different one or more Halogens,

4) C1-C6alkoxy,

5) -COR13'where R13'represents a

(a) hydroxy,

(b) C1-C6alkyl,

(c) C1-C6alkoxy, which is optionally substituted by the same or different one or more substituents selected from (1) hydroxy, (2) C1-C6alkoxy, which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6of alkyl, where R11'represents hydrogen or C1-C6alkyl, (4) -CONR8'R9'where R8'and R9'are the same or different and are each hydrogen or C1-C6alkyl, or a nitrogen-containing saturated a heterocycle containing a monocycle formed when R8', R9'and the adjacent nitrogen atom taken together, (5) -CO-C1-C6alkoxy, optionally substituted phenyl, (6) phenyl, optionally substituted by the same or different one or more substituents selected from halogen, C1-Csub> 6alkoxy and-CO-C1-C6alkoxy, and (7) heterocycle selected from pyridyl, tetrazolyl and tanila, all of which can be substituted by the same or different one or more C1-C6alkyl groups, or

(d) -OR19'where R19'represents a C3-C14saturated or unsaturated carbocycle or piperidyl, which is optionally substituted-CO-C1-C6the alkyl,

6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from-CONR8'R9'(R8'and R9'have the same meanings as defined above) and -- CO-aralkylated, or

7) nitrile;

R6'and R7'are the same or different and represent, each,

1) hydrogen,

2) C1-C6alkyl or

3) nitrogen-containing saturated a heterocycle containing a monocycle formed when R6', R7'and the adjacent nitrogen atom are taken together;

Y1, Y2and Y3are the same or different and represent, each,

1) carbon atom, or

2) a nitrogen atom;

-X'- is a

1) -(CH2)l-where l is an integer from 1 to 3,

p> 2) -CH2-NR18'-CH2-where R18'represents a C1-C6alkyl, or

3)

or its pharmaceutically acceptable salt,

<4> ester compound according to the item <1>, which is represented by the formula:

where R1”represents a

1) C1-C6alkyl, which is optionally substituted by the same or different one or more Halogens, or

2) -CO-C1-C6alkoxy;

R2”represents a

1) hydrogen or

2) C1-C6alkyl;

R3”, R4”and R5”are the same or different and represent, each,

1) hydrogen,

2) halogen,

3) C1-C6alkyl, which is optionally substituted by the same or different one or more Halogens,

4) C1-C6alkoxy or

5) -COR13”where R13”represents a C1-C6alkoxy, optionally substituted by the same or different one or more substituents selected from (1) phenyl, (2) -CO-NR8”R9”where R8”and R9”are the same or different and are each hydrogen or C1-C6alkyl, or (3) a heterocycle selected from pyridyl, tetrazolyl and tanila, and the heterocycle is a Ki is optionally substituted by the same or different one or more C 1-C6alkyl groups;

R6”and R7”are the same or different and represent, each,

1) hydrogen,

2) C1-C6alkyl or

3) nitrogen-containing saturated a heterocycle containing a monocycle formed when R6”, R7”and the adjacent nitrogen atom are taken together; and

Y2and Y3are the same or different and represent, each,

1) carbon atom, or

2) a nitrogen atom,

or its pharmaceutically acceptable salt,

<5> ester compound according to the item <1>, which is selected from the group consisting of

(1) phenyl ether {3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}acetic acid (hereinafter referred to as compound 1-3),

(2) 4-fortunelounge ether {3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}acetic acid (hereinafter referred to as compound 1-4),

(3) phenyl ester of 3-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionic acid (hereinafter referred to as compound 1-1),

(4) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-5),

(5) ethyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl) - Amin is]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-6),

(6) isopropyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-7),

(7) propyl ether of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-8),

(8) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(5-methyl-4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-9),

(9) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-3-fermenting acid (hereinafter referred to as compound 1-10),

(10) methyl ether 3-chloro-4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-11),

(11) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-3-methoxybenzoic acid (hereinafter referred to as compound 1-12),

(12) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy)benzoic acid (hereinafter referred to as compound 1-13),

(13) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-Carbo who yl)amino]phenyl}butyryloxy)-2-methylbenzoic acid (hereinafter referred to as compound 1-14),

(14) methyl ester of 4-(4-{3-(pyrrolidin-1-carbonyl)-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-15),

(15) ethyl ester of 3-fluoro-4-(4-{3-(pyrrolidin-1-carbonyl)-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-16),

(16) 4-ethoxycarbonylphenyl ester 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid (hereinafter referred to as compound 3-1),

(17) 2-fluoro-4-ethoxycarbonylphenyl ester 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid (hereinafter referred to as compound 3-2),

(18) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-2-methoxybenzoic acid (hereinafter referred to as compound 1-17),

(19) methyl ester 4-[2-({3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]benzyl}methylamino)acetoxy]benzoic acid (hereinafter referred to as compound 2-1),

(20) methyl ester 2-chloro-4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-18),

(21) methyl ester of 4-(4-{3-dimethylcarbamoyl-4[2-(5-triptorelin-2-yl)benzoylamine]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-19),

(22) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-3-triftorperasin acid (hereinafter referred to as compound 1-20),

(23) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-2-triftorperasin acid (hereinafter referred to as compound 1-21),

(24) 4-(3-methyl-[1,2,4]oxadiazol-5-yl)phenyl ether 4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyric acid (hereinafter referred to as compound 1-2),

(25) 4-acetylphenyl ether 4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyric acid (hereinafter referred to as compound 1-22),

(26) 4-cyanovinylene ether 4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyric acid (hereinafter referred to as compound 1-23),

(27) benzyl ester 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-24),

(28) 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid (hereinafter referred to as compound 1-25),

(29) methyl ester of 4-(4-{3-(morpholine-4-carbonyl)-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzo is Noah acid (hereinafter referred to as compound 1-26),

(30) methyl ester of 4-(3-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionyloxy)benzoic acid (hereinafter referred to as compound 1-27),

(31) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[3-(4-triptoreline)pyridine-4-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-30),

(32) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[3-(4-triptoreline)pyridine-4-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-29),

(33) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-28),

(34) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-31),

(35) methyl ester 5-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]pyridine-2-carboxylic acid (hereinafter referred to as compound 1-32),

(36) dimethyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)isophthalic acid (hereinafter referred to as compound 1-33),

(37) methyl ether 3-chloro-4-(4-{3-dimethylcarbamoyl-4-[('-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-5-methylbenzoic acid (hereinafter referred to as compound 1-34),

(38) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid (hereinafter referred to as compound 1-35),

(39) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid (hereinafter referred to as compound 1-36),

(40) isopropyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid (hereinafter referred to as compound 1-37),

(41) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-fluoro-5-methoxybenzoic acid (hereinafter referred to as compound 1-38),

(42) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]for 3,5-dimethoxybenzoic acid (hereinafter referred to as compound 1-39),

(43) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-ethoxybenzoyl acid (hereinafter referred to as compound 1-40),

(44) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)Buti is yloxy]-3-fluoro-5-methylbenzoic acid (hereinafter referred to as compound 1-41),

(45) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-ethyl-5-fermenting acid (hereinafter referred to as compound 1-42),

(46) ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]for 3,5-dimethoxybenzoic acid (hereinafter referred to as compound 1-43),

(47) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl) butyryloxy]for 3,5-dimethoxybenzoic acid (hereinafter referred to as compound 1-44),

(48) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methyl-5-triftorperasin acid (hereinafter referred to as compound 1-45),

(49) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[2-(4-ethoxycarbonylphenyl)-6-methylpyridin-3-carbonyl]amino}phenyl)butyryloxy]-5-methylisophthalic acid (hereinafter referred to as compound 4-2),

(50) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methoxy-5-methylbenzoic acid (hereinafter referred to as compound 1-46),

(51) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butir is Loxy]-3-methoxy-5-triftorperasin acid (hereinafter referred to as compound 1-47),

(52) ethyl ester of 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid (hereinafter referred to as compound 1-48),

(53) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-ethoxy-5-methoxybenzoic acid (hereinafter referred to as compound 1-49),

(54) methyl ester 3-bromo-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid (hereinafter referred to as compound 1-50),

(55) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-utilizatorului acid (hereinafter referred to as compound 1-51),

(56) 1-ethyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylisophthalic acid (hereinafter referred to as compound 1-52),

(57) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxyisoflavone acid (hereinafter referred to as compound 1-53),

(58) 1-ethyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-CT is of IMT]amino}phenyl)butyryloxy]-5-methoxyisoflavone acid (hereinafter referred to as compound 1-54),

(59) methyl ester of 2'-{2-dimethylcarbamoyl-4-[3-(4-methoxycarbonylpropionyl)propyl]phenyl-carbarnoyl}biphenyl-4-carboxylic acid (hereinafter referred to as compound 4-3),

(60) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[2-(4-ethoxycarbonylphenyl)-6-methylpyridin-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid (hereinafter referred to as compound 4-1),

(61) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[2-(4-ethoxycarbonylphenyl)-6-methylpyridin-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid (hereinafter referred to as compound 4-4),

(62) methyl ester sulfonate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid (hereinafter referred to as compound 1-55),

(63) methyl ester sulfonate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid (hereinafter referred to as compound 1-56),

(64) methyl ester sulfonate 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]for 3,5-dimethoxybenzoic acid (hereinafter referred to as compound 1-57),

(65) methyl ester benzosulfimide 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)p is ridin-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid (hereinafter referred to as compound 1-58),

(66) methyl ester of methansulfonate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid (hereinafter referred to as compound 1-59),

(67) methyl ester toluene-4-sulfonate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid (hereinafter referred to as compound 1-60),

(68) methyl ester naphthalene-1,5-disulfonate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid (hereinafter referred to as compound 1-61),

(69) methyl ester hydrochloride and 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid (hereinafter referred to as compound 1-62),

(70) isopropyl ether sulfate 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-63),

(71) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]for 3,5-dimethylbenzoic acid (hereinafter referred to as compound 1-64),

(72) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptime fenil)pyridine-3-carbonyl]amino}phenyl)butyryloxy]for 3,5-dimethylbenzoic acid (hereinafter referred to as compound 1-65),

(73) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]-3-methylbenzoic acid (hereinafter referred to as compound 1-66),

(74) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]-3-ethylbenzoyl acid (hereinafter referred to as compound 1-67),

(75) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]-3-isopropylbenzoic acid (hereinafter referred to as compound 1-68),

(76) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methylbenzoic acid (hereinafter referred to as compound 1-69),

(77) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]isophthalic acid (hereinafter referred to as compound 1-70),

(78) ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-71),

(79) 1-isopropyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]isophthalic acid (hereinafter referred to as compound 1-72),

(8) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-ethylbenzene acid (hereinafter referred to as compound 1-73),

(81) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-isopropylbenzoic acid (hereinafter referred to as compound 1-74),

(82) propyl ester 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid (hereinafter referred to as compound 1-75),

(83) 2-isopropoxyethanol ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-76),

(84) 2-acetylaminofluorene ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-77),

(85) benzyloxycarbonylamino ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-78),

(86) 4-chlorobenzylamino ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-79),

(87) benzyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to also as soedinenie-80),

(88) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-81),

(89) pyridine-2-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-82),

(90) pyridine-3-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-83),

(91) pyridine-4-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-84),

(92) dimethylcarbamodithioato ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-85),

(93) methoxycarbonylmethyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-86),

(94) 3-chlorobenzylamino ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-87),

(95) 4-propionitriles the Fira 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid (hereinafter referred to as compound 1-88),

(96) 2-benzyloxyethanol ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-89),

(97) 3-benzyloxypropionic ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-90),

(98) 2-(2-oxopyrrolidin-1-yl)ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-91),

(99) 3-hydroxypropionic ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-92),

(100) 4-bucharestilfov ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid (hereinafter referred to as compound 1-93),

(101) pyridine-3-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-94),

(102) 4-(2-methyl-2H-tetrazol-5-yl)phenyl ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid (hereinafter referred to as compound 1-95),

(103) 4-methoxybenzylthio ester 4-[4-(-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-96),

(104) 3-methoxybenzamido ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-97),

(105) thiophene-2-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-98),

(106) thiophene-3-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-99),

(107) 6-methylpyridin-2-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-100),

(108) 6-methylpyridin-2-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-101),

(109) isopropoxycarbonyloxymethyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-102),

(110) 4-(tert-butoxycarbonyl)benzyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to also as the connection is of 1-103),

(111) 4-(2-benzyloxycarbonylamino-2H-tetrazol-5-yl)phenyl ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid (hereinafter referred to as compound 1-104),

(112) 4-(2-dimethylcarbamoyl-2H-tetrazol-5-yl)phenyl ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid (hereinafter referred to as compound 1-105),

(113) 1-phenethyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-106),

(114) indan-1-silt ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-107),

(115) 1,2,3,4-tetrahydronaphthalen-1 silt ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-108),

(116) 1-acetylpiperidine-4-silt ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid (hereinafter referred to as compound 1-109),

(117) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylisophthalic acid (hereinafter referred to as Conn is out 1-110),

(118) 1-isopropyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylisophthalic acid (hereinafter referred to as compound 1-111),

(119) ethyl ester of 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid (hereinafter referred to as compound 1-112),

(120) dimethylcarbamodithioato ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid (hereinafter referred to as compound 1-113),

(121) 2-acetylaminofluorene ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid (hereinafter referred to as compound 1-114),

(122) 4-(2-isopropyl-2H-tetrazol-5-yl)phenyl ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid (hereinafter referred to as compound 1-115),

(123) 1-ethyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-utilizatorului acid (hereinafter referred to as compound 1-116),

(124) 3-methyl ester 1-propyl ester 4-[4-(3-dimethylcarbamoyl-4-{[methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxyisoflavone acid (hereinafter referred to as compound 1-117),

(125) ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methoxy-5-(1-methoxyphenyl)benzoic acid (hereinafter referred to as compound 1-118),

(126) ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methoxy-5-methylbenzoic acid (hereinafter referred to as compound 1-119),

(127) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-ethyl-5-methoxybenzoic acid (hereinafter referred to as compound 1-120),

(128) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methoxy-5-methylbenzoic acid (hereinafter referred to as compound 1-121),

(129) ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-ethyl-5-methoxybenzoic acid (hereinafter referred to as compound 1-122) and

(130) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-isopropylnaphthalene acid (hereinafter referred to as compound 1-123),

or its pharmaceutically acceptable salt,

<6> a pharmaceutical composition containing the traveler ester compound according to any one of paragraphs < 1>-<5> or its pharmaceutically acceptable salt,

<7> pharmaceutical composition which is effective for treatment or prevention of a disease selected from hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension, containing the ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt,

<8> inhibitor of microsomal triglyceriderich protein containing ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt,

<9> a means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b-containing ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt,

<10> method for the treatment or prevention of a disease selected from hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension, which provides an introduction to the mammal pharmaceutically effective amount of the ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt,

<11> method of inhibiting microsomal triglyceriderich protein, which contains an introduction Miu is apicauda pharmaceutically effective amount of the ester compound according to any one of paragraphs < 1>-<5> or its pharmaceutically acceptable salt,

<12> the way to reduce the level of at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b, which contains an introduction to the mammal pharmaceutically effective amount of the ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt,

<13> a commercial package containing a pharmaceutical composition according to paragraph <6> or <7> and related written material indicating that the pharmaceutical composition can or should be used for the treatment or prevention of a disease selected from hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension,

<14> the use of the ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension,

<15> the use of the ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt for the manufacture of a medicinal product which inhibits microsomal triglyceriderich protein,

<16>the use of the ester compound according to any one of paragraphs < 1>-<5> or its pharmaceutically acceptable salt for the manufacture of a medicinal product which reduces the level of at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b,

<17> pharmaceutical composition according to paragraph <6> or <7> for combined use with a drug selected from the group consisting of (1) the means for the treatment and/or prophylaxis of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of diabetes and (4) the means for the treatment and/or prevention of hypertension,

<18> inhibitor of microsomal triglyceriderich protein paragraph <8> for combined use with a drug selected from the group consisting of (1) the means for the treatment and/or prophylaxis of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of diabetes and (4) the means for the treatment and/or prevention of hypertension,

<19> a means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b, paragraph <9> for combined use with a drug selected from the group consisting of the C (1) funds for the treatment and/or prevention of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of diabetes and (4) the means for the treatment and/or prevention of hypertension,

<20> method for the treatment or prevention of a disease selected from hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension on the item <10>, which further comprises a combined use with a drug selected from the group consisting of (1) the means for the treatment and/or prophylaxis of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of diabetes and (4) the means for the treatment and/or prevention of hypertension,

<21> method of inhibiting microsomal triglyceriderich protein paragraph <11>, which further comprises a combined use with a drug selected from the group consisting of (1) the means for the treatment and/or prophylaxis of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of diabetes and (4) the means for the treatment and/or prevention of hypertension,

<22> the way to reduce the level of at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b, paragraph <12>, the cat is which further comprises the combined use of the medicinal product, selected from the group consisting of (1) the means for the treatment and/or prophylaxis of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of diabetes and (4) the means for the treatment and/or prevention of hypertension,

<23> a commercial package containing a pharmaceutical composition according to paragraph <6> or <7> for combined use with a drug selected from the group consisting of (1) the means for the treatment and/or prophylaxis of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of diabetes and (4) the means for the treatment and/or prevention of hypertension, and the related statement indicating that the pharmaceutical composition can or should be used for the treatment or prevention of a disease selected from hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension,

<24> the use of the ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt for the manufacture of a medicine for treatment or prevention of a disease selected from the group consisting of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension, in combination with a drug selected from the group consisting of (1) the means for the treatment and/or prophylaxis of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of diabetes and (4) the means for the treatment and/or prevention of hypertension,

<25> the use of the ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt for the manufacture of a medicine for inhibiting microsomal triglyceriderich protein in combination with a drug selected from the group consisting of (1) the means for the treatment and/or prophylaxis of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of diabetes and (4) the means for the treatment and/or prevention of hypertension, and

<26> the use of the ester compound according to any one of paragraphs <1>-<5> or its pharmaceutically acceptable salt for the manufacture of medicines to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b, in combination with a drug selected from the group consisting of (1) the means for the treatment and/or prophylaxis of hyperlipidemia, (2) means for the treatment and/or prophylaxis of obesity, (3) the means for the treatment and/or prevention of dia the ETA and (4) the means for the treatment and/or prophylaxis of hypertension.

The present invention relates to a medicinal product with excellent MTP inhibitory activity is effective against hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension. In addition, because the drug has excellent MTP inhibitory activity, which quickly lost in the plasma or liver function, in accordance with the present invention may be offered a drug selectively inhibiting MTP in the small intestine, i.e. offered useful MTP inhibitor, which does not cause side effect on the liver.

The best way of carrying out the invention

The definition of each substituent used in the description of the present invention.

“C1-C6alkyl” refers to an unbranched or branched alkyl with 1-6 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl and 2-ethylbutyl and the like, among which C1-C4alkyl is preferred. Special is on the preferred as 1-C6the alkyl is methyl, ethyl or isopropyl.

“C1-C4alkyl” refers to an unbranched or branched alkyl with 1-4 carbon atoms, including, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, among which methyl, ethyl or isopropyl is preferred.

A preferred example, C1-C6the alkyl for R1and R2is methyl, the preferred example, C1-C6the alkyl for R3, R4and R5is methyl, ethyl or isopropyl and the preferred example, C1-C6the alkyl for R6and R7is methyl.

“Halogen” means fluorine, chlorine, bromine or iodine, and preferred is fluorine, chlorine or bromine.

Preferred examples of the halogen for R3, R4and R5is fluorine, chlorine or bromine.

“C1-C6alkoxy” refers to alkoxygroup, where the alkyl part is C1-C6alkyl”defined above, and includes, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka, pentyloxy, 2-methylbutoxy, 1 ethylpropoxy, hexyloxy, isohexyl, 4-methylpentylamino, 3 methylpentane, 2-methylpentane, 1 methylpentylamine, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1-dimethylbutyl and, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino, 1 ethylbutyrate, 2-ethylbutyrate and the like. A preferred example, C1-C6alkoxy is C1-C4alkoxy.

“C1-C4alkoxy” refers to alkoxygroup, where the alkyl part is C1-C4alkyl”defined above, and includes, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka and the like. Preferably C1-C4alkoxy represents methoxy, ethoxy, propoxy or isopropoxy.

A preferred example, C1-C6alkoxy for R3, R4and R5is C1-C4alkoxy and particularly preferred is methoxy or ethoxy.

A preferred example, C1-C6alkoxy for R13is C1-C4alkoxy and particularly preferred is methoxy, ethoxy, propoxy or isopropoxy.

“Carbocycle” or “C3-C14saturated or unsaturated carbocycle” refers to saturated or unsaturated cyclic hydrocarbon group with 3 to 14 carbon atoms and includes, in particular, aryl, cycloalkyl, cycloalkenyl and their condensed carbocycle.

In this case, the “aryl” refers to aromatic hydrocarbon group with 6 to 14 carbon the atoms and specifically includes a phenyl, naphthyl, biphenyl, antonil, asurini, financial, indenyl, pentalene and the like. A preferred example of the aryl is an aromatic hydrocarbon group with 6-10 carbon atoms, and particularly preferred is phenyl.

In this case, “cycloalkyl” refers to saturated cycloalkyl group with 3-8 carbon atoms and specifically includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. A preferred example of cycloalkyl is cycloalkyl with 3-6 carbon atoms, which specifically includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Especially preferred is cyclopropyl or cyclohexyl.

In addition, “cycloalkenyl” refers to cycloalkenyl group with 3-8 carbon atoms and contains at least one double bond, preferably 1 or 2 double bonds. A concrete example is cyclopropyl, cyclobutyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl (2,4-cyclohexadiene-1-yl, 2,5-cyclohexadiene-1-yl and so on), cycloheptenyl, cyclooctyl or the like.

An example of condensed carbocycle formed by condensation of these groups “aryl”, “cycloalkyl” or “cycloalkenyl” is indanyl, fluorenyl, 1,4-dihydronaphtho, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,-tetrahydro-2-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, peritonitis or the like.

Preferable example of “carbocycle” or “C3-C14saturated or unsaturated carbocycle” for ring A, ring B and ring C includes aryl, more preferably phenyl.

“Aralkyl is arylalkyl group, where the aryl portion represents an aryl, as defined above, and the alkyl part is C1-C6alkyl”defined above. Specific examples of such aralkyl include benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 6-phenylhexa and the like. A preferred example of aralkyl is arylalkyl group, where the alkyl part is C1-C4alkyl”defined above.

“Aralkylated” refers to arielalexisxrp, where the aryl portion represents an aryl, as defined above, and CNS part represents a C1-C6alkoxy as defined above. Specific examples of such aralkylated include benzyloxy, penetrate, 1 venlafaxi, 3 phenylpropoxy, 4-phenylbutyrate, 6-phenylhexanoic and the like. A preferred example of aralkylated is arielalexisxrp, where CNS part represents a C1-C4alkoxy as defined above, and particularly preferred is benzyloxy.

“Cycloalkyl the hydroxy” refers to cycloalkylation, where cycloalkyl part is a “cycloalkyl”defined above, and CNS part represents a C1-C6alkoxy as defined above, and specifically includes cyclopropylmethoxy, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethoxy and the like. A preferred example of cycloalkenes is cycloalkylcarbonyl, where CNS part represents a C1-C4” alkoxy, as defined above.

“Aryloxy” refers to alloctype, where the aryl portion represents “aryl”as defined above, and specifically includes phenoxy, naphthyloxy, biphenyloxy and the like.

“Heterocycle” or “saturated or unsaturated heterocycle, containing at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom” refers to 5 - or 6-membered saturated or unsaturated (including partially saturated and fully saturated) monocyclic the heterocycle containing, besides carbon atom, at least one heteroatom, preferably 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, the condensed heterocycle of several compounds, and condensed ring between the said heterocycles and carbocycles selected from benzene, and cyclopentane cyclohexane.

“Saturated 5 or 6-membered monocyclic heterocycle” includes pyrrolidinyl, 2-oxopyrrolidin, tetrahydrofuryl, tetrahydrothieno, imidazolidinyl, pyrazolidine, 1,3-DIOXOLANYL, 1,3-oxathiolane, oxazolidine, thiazolidine, isothiazolinones, piperidyl (for example, 2-piperidyl, 4-piperidyl etc), piperidino, piperazinil, tetrahydropyranyl, tetrahydropyranyl, dioxane (for example, 1,4-dioxane), morpholinyl, morpholino, thiomorpholine, thiomorpholine, 2-oxopyrrolidin, 2-oxopiperidine, 4-oxopiperidine, 2,6-dioxopiperidin and the like.

“Unsaturated 5 - or 6-membered monocyclic heterocycle” includes pyrrolyl, furyl, thienyl, imidazolyl, 1,2-dihydro-2-Oxymetazoline, pyrazolyl, thiazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazole, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, oxadiazolyl (e.g., 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, furutani etc), pyridyl, pyrimidinyl, 3,4-dihydro-4-oxopyrimidine, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, triazinyl, oxadiazolyl, imidazolyl (for example, 2-imidazoline, 3-imidazoline etc), pyrazolyl (for example, 1-pyrazolyl, 2-pyrazoline, 3-pyrazoline etc), oxazolyl (for example, 2-oxazolyl, 3-oxazolyl, 4-oxazolyl etc), isoxazolyl (for example, 2-isoxazoline, 3-isoxazolyl, 4-isoxazolyl etc), thiazolyl (for example, 2-thiazolyl, 3-thiazolyl, 4-thiazolyl etc), isothiazoline (for example, -isothiazoline, 3-isothiazolone, 4-isothiazoline etc), pyranyl, (for example, 2H-pyranyl, 4H-pyranyl etc.), 2-oxopropyl, 2-oxo-2,5-dihydrofuran, 1,1-dioxo-1H - isothiazolin and the like.

“Condensed heterocycle” includes indolyl (for example, 4-indolyl, 7-indolyl), isoindolyl, 1,3-dihydro-1,3-dikshithar, benzofuranyl (for example, 4-benzofuranyl, 7-benzofuranyl etc), indazole, isobenzofuranyl, benzothiophenes (for example, 4-benzothiophenes, 7-benzothiophene etc), benzoxazolyl (for example, 4-benzoxazolyl, 7-benzoxazolyl etc), benzimidazolyl (for example, 4-benzimidazolyl, 7-benzimidazolyl etc), benzothiazolyl (for example, 4-benzothiazolyl, 7-benzothiazolyl etc), indolizinyl, hinely, dihydroxyaryl, ethanolic, 1,2-dihydro-2-oxoindole, hintline, honokalani, cinnoline, phthalazine, hinolinol, peril, pteridinyl, indolinyl, isoindolyl, 5,6,7,8-tetrahydroquinoline, 1,2,3,4-tetrahydroquinoline, 2-oxo-1,2,3,4-tetrahydroquinolin, benzo[1,3]dioxole, 3,4-methylenedioxyphenyl, 4,5-ethylenedioxythiophene, 2H-chromenes, bromanil, isopropanol, benzofurazanyl and the like.

“Heterocycle” or “saturated or unsaturated heterocycle, containing at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom” means preferably a 5 - or 6-membered saturated or unsaturated (including partial saturation of the full saturation) monocyclic heterocycle, containing, besides carbon atom, at least one heteroatom, preferably 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, and includes particularly preferably pyridyl, tetrazolyl, oxadiazolyl (e.g., 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, furutani etc), thienyl, piperidyl (for example, 2-piperidyl, 4-piperidyl etc), piperidino, 2-oxopyrrolidin and the like.

Preferred examples of the “heterocycle” or “saturated or unsaturated heterocycle, containing at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom”for ring A, ring B and ring C is an unsaturated 5 - or 6-membered monocyclic heterocycle, and more preferred is pyridyl.

“Nitrogen-containing saturated a heterocycle containing a monocycle formed when R6, R7and the adjacent nitrogen atom are taken together”, “nitrogen-containing saturated a heterocycle containing a monocycle formed when R8, R9and the adjacent nitrogen atom are taken together” or “nitrogen-containing saturated a heterocycle containing a monocycle formed when R14, R15and the adjacent nitrogen atom are taken together” means a heterocycle containing 5 - or 6-membered monocycle containing at least one nitrogen atom. Con the specific examples of the above heterocycles are pyrrolidine, piperidyl (for example, 2-piperidyl, 4-piperidyl etc), piperidino, morpholinyl, morpholino, thiomorpholine, piperadine, piperazine derivatives, pyrrolidine or the like.

“Optionally substituted by the same or different one or more substituents” refers to the case where the substitution is performed in the interval from a minimum number of one Deputy to the maximum possible number of substituents. For example, methyl may be substituted by 1-3 substituents, and ethyl may be substituted by 1-5 substituents. When the substitution is performed by two or more substituents, they are the same or different from each other, and there are no particular restrictions on the position of substitution, and therefore it is arbitrary.

The term "optionally substituted by the same or different one or more substituents" means preferred optionally substituted by same or different 1 to 5 substituents, and particularly preferably an "optionally substituted by same or different 1 to 3 substituents".

The following is a detailed description of each Deputy.

R1preferably represents

1) C1-C6alkyl, optionally substituted by the same or different one or more halogen (specified optionally substituted C1-C6alkyl preferably represents C1-C4Alki is, optionally substituted by the same or different one or more halogen, and more preferably C1-C4alkyl, optionally substituted by same or different 1 to 3 halogen, and more preferably methyl, optionally substituted by same or different 1 to 3 halogen, and most preferably methyl, optionally substituted by three halogen atoms. In particular, examples of such alkyl is trifluoromethyl, trichloromethyl, tribromoethyl or the like, and more preferably trifluoromethyl), or

2) -CO-C1-C6alkoxy (more preferred example of the specified-CO-C1-C6alkoxy is-CO-C1-C4alkyl. Specific examples include-CO-methoxy, -CO-amoxi, -CO-propoxy, -CO-isopropylate, -CO-butoxy, -CO-isobutylene, -CO-tert-Butylochka or the like, and more preferred is-CO-methoxy).

R2preferably represents

1) hydrogen or

2) C1-C6alkyl (preferable example of the specified C1-C6the alkyl is C1-C4alkyl, volumouse methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferred is methyl)

R3, R4and R5are the same or different and represent, each, preferred is compulsory:

1) hydrogen,

2) halogen (preferably includes fluorine, chlorine and bromine),

3) C1-C6alkyl, optionally substituted by the same or different one or more halogen (specified optionally substituted C1-C6the alkyl is more preferably C1-C4alkyl, optionally substituted by the same or different one or more halogen, more preferably C1-C4alkyl, optionally substituted by same or different 1 to 3 halogen, most preferably methyl, optionally substituted by same or different 1 to 3 Halogens, and particularly preferably methyl, optionally substituted by the same or different 3 Halogens. Specific examples include trifluoromethyl, trichloromethyl, tribromoethyl or the like, and more preferably trifluoromethyl),

4) C1-C6alkoxy (more preferred examples of the specified C1-C6alkoxy are C1-C4alkoxy. Preferred examples of alkoxy are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka or the like, and more preferred examples are methoxy or ethoxy),

5) -COR13where R13represents a

(a) hydroxy,

(b) C1-C6alkyl (specified C1-C6alkyl which m is more preferably C 1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and still more preferably methyl, ethyl and propyl),

(c) C1-C6alkoxy, which is optionally substituted by the same or different one or more substituents selected from the

(1) hydroxy,

(2) C1-C6alkoxy, which is optionally substituted aryl (specified optionally substituted C1-C6alkoxy represents more preferably C1-C4alkoxy, optionally substituted aryl, and includes, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka and the like, all of which are optionally substituted by phenyl, and more preferably benzyloxy, penetrate and 1 phenylethane),

(3) -NR11CO-C1-C6of alkyl, where R11represents hydrogen or C1-C6alkyl (specified C1-C6alkyl preferably represents C1-C4alkyl, and includes, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl),

(4) -CONR8R9where R8and R9are the same or different and are each hydrogen, C1-C6 alkyl (specified C1-C6alkyl is more preferably C1-C4alkyl includes, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl), or nitrogen-containing saturated a heterocycle containing a monocycle formed when R8, R9and the adjacent nitrogen atom are taken together (specified nitrogen-containing heterocycle includes, in particular, pyrrolidinyl, piperidyl (for example, 2-piperidyl, 4-piperidyl etc), piperidino, morpholinyl, morpholino, thiomorpholine, piperazinil, piperazine derivatives, pyrrolidine and the like),

(5) -CO-C1-C6alkoxy, where the specified C1-C6alkoxy optionally substituted by phenyl, and examples specified-CO-C1-C6alkoxy is preferably-CO-C1-C4alkoxy, including, in particular, -CO-methoxy, -CO-amoxi, -CO-propoxy, -CO-isopropylate, -CO-butoxy, -CO-isobutylene, -CO-tert-Butylochka and the like, and more preferably-CO-methoxy and-CO-isopropylate,

(6) aryl, optionally substituted by the same or different one or more substituents selected from halogen (specified by the halogen is preferably fluorine, chlorine or bromine and preferably chlorine), C1-C6alkoxy (specified C1-C6alkoxy is is conducted preferably C 1-C4alkoxy, including, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka and the like, and more preferably methoxy) and-CO-C1-C6alkoxy (specified-CO-C1-C6alkoxy is preferably-CO-C1-C4alkoxy, including, in particular, -CO-methoxy, -CO-amoxi, -CO-propoxy, -CO-isopropylate, -CO-butoxy, -CO-isobutylene, -CO-tert-Butylochka and the like, and more preferably-CO-isopropoxy), and optionally substituted aryl is preferably a phenyl, optionally substituted by the same or different one or more substituents selected from chlorine, methoxy and-CO-isopropylate, and more preferably a phenyl, optionally substituted by same or different 1 to 3 substituents selected from chlorine, methoxy and-CO-isopropylate, and

(7) heterocycle selected from pyridyl, tetrazolyl and tanila [said heterocycle is optionally substituted by the same or different one or more C1-C6alkyl groups (the specified C1-C6alkyl preferably represents C1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl)],

and not necessarily replaced by the 1-C6alkoxy is preferably C1-C4alkoxy, optionally substituted by the same or different one or more substituents selected from the above items (1)to(7), and includes, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka and the like, and more preferably methoxy, ethoxy, propoxy, isopropoxy, which are all optionally substituted by the same or different one or more substituents selected from paragraphs (1)to(7), or

(d) -OR19where R19represents a saturated or unsaturated carbocycle with 3-14 carbon atoms (indicated carbocycle includes, in particular, aryl, cycloalkyl, cycloalkenyl, condensed carbocycle formed when these rings are condensed, or the like, and more preferably condensed carbocycle formed when the aryl and cycloalkyl condensed, and examples of such carbocycles are indenyl, indanyl, pentalene, fluorenyl, 1,4-dihydronaphtho, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl or the like, more preferably condensed carbocycle formed when the aryl and cycloalkyl condensed, and even more preferably of indanyl, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro the-2-naphthyl) or piperidyl, optionally substituted-CO-C1-C6the alkyl (specified-CO-C1-C6alkyl represents preferably-CO-C1-C4alkyl, including, in particular, -CO-methyl, -CO-ethyl, -CO-propyl, -CO,-isopropyl, -CO-butyl, -CO-isobutyl, -CO-sec-butyl, -CO-tert-butyl and the like, and more preferably-CO-methyl),

6) a heterocycle selected from oxadiazolyl and tetrazolyl {the heterocycle is optionally substituted C1-C6the alkyl [the specified C1-C6alkyl preferably represents C1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl and isopropyl], optionally substituted by the same or different one or more substituents selected from-CONR8R9where R8and R9are the same or different and represent, each,

(a) hydrogen,

(b) C1-C6alkyl (specified C1-C6alkyl preferably represents C1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl), or

(c) nitrogen-containing saturated a heterocycle containing a monocycle formed when R8, R9and see iny the nitrogen atom are taken together (specified nitrogen-containing saturated the heterocycle includes, in particular, pyrrolidinyl, piperidyl (for example, 2-piperidyl, 4-piperidyl and the like), piperidino, morpholinyl, morpholino, thiomorpholine, piperazinil, piperazine derivatives, pyrrolidine and the like), and-CO-aralkylated (specified-CO-aralkylated includes, in particular, -CO-benzyloxy, -CO-penetrate, -CO-1-phenylethane, -CO-3-phenylpropoxy, -CO-4-phenylbutyrate, -CO-6-phenylhexanoic and the like, and more preferably-CO-penetrox)}, or

7) nitrile;

R6and R7are the same or different and represent, each,

1) hydrogen,

2) C1-C6alkyl (specified C1-C6alkyl preferably represents C1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl), or

3) nitrogen-containing saturated a heterocycle containing a monocycle formed when R6, R7and the adjacent nitrogen atom are taken together (specified nitrogen-containing saturated the heterocycle includes, in particular, pyrrolidinyl, piperidyl (for example, 2-piperidyl, 4-piperidyl etc), piperidino, morpholinyl, morpholino, thiomorpholine, piperazinil, piperazine derivatives, pyrrolidine and the like and preferably pyrrolidinyl, morpholino);

Y1, Y2and Y3are the same or different, and before whom represent, each,

1) carbon atom, or

2) a nitrogen atom;

-X - preferably represents:

1) -(CH2)l-where l represents preferably an integer from 1 to 3,

2) -CH2-NR18-CH2-where R18represents a C1-C6alkyl (specified C1-C6the alkyl is preferably C1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl), or

3)

Examples of the substituent represented by the formula

(where R1, R2ring a and ring B have the same meanings as defined above for the formula [1]), in the formula [1]are

(where R1and R2have the same meanings as defined above for the formula [1]), preferably the following Deputy represented by the formula:

(where R1', R2', Y1, Y2and Y3have the same meanings as defined above for formula [2]), in the formula [2].

Specific examples of the following substituent represented by the formula

(where R1', R2', Y1, Y2and Y3have the same meanings as op is edelenyi above formula [2]), in the formula [2]are

(where R1'and R2'have the same meanings as defined above for formula [2]). In particular, as examples

where R1'and R2'have the same meanings as defined above for formula [2], or

where R1'and R2'have the same meanings as defined above for formula [2]. Particularly preferred examples are the substituents represented by the formula

where R1'and R2'have the same meanings as defined above.

The most preferred example is the following Deputy represented by the formula

(where R1”, R2”, Y2and Y3have the same meanings as defined above for formula [3]), in the formula [3]. Specific examples of the following substituent represented by the formula

(where R1”, R2”, Y2and Y3have the same meanings as defined above for formula [3]), in the formula [3] are

where R1”and R2”have the same meanings as defined above for formula [3].

The ring C in the formula [1] represents Soboh is preferably the following Deputy, represented by the formula

where R3', R4'and R5'have the same meanings as defined above for formula [2], and, in particular

where R3', R4'and R5'have the same meanings as defined above for formula [3], and more preferably the following Deputy represented by the formula

where R3”, R4”and R5”have the same meanings as defined above for formula [3], in particular

where R3”, R4”and R5”have the same meanings as defined above for formula [3].

R3and R4are the same or different and are each, preferably

1) hydrogen,

2) halogen (the halogen preferably represents fluorine, chlorine or bromine),

3) C1-C6alkyl, optionally substituted by the same or different one or more halogen (specified optionally substituted C1-C6the alkyl is more preferably C1-C4alkyl, optionally substituted by the same or different one or more halogen, more preferably C1-C4alkyl, optionally substituted by same or different 1 to 3 halogen, most preferred is methyl nutrient, optionally substituted by the same or different 1 to 3 Halogens, and particularly preferably methyl, optionally substituted by the same or different 3 Halogens. Specific examples are trifluoromethyl, trichloromethyl, tribromoethyl or the like, and more preferably trifluoromethyl),

4) C1-C6alkoxy (specified C1-C6alkoxy preferably represents C1-C4alkoxy, including, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka and the like, and more preferably methoxy, ethoxy), or

5) -COR13where R13represents a C1-C6alkoxy (preferably C1-C4alkoxy) and specifically includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka and the like, and more preferably methoxy;

R5represents preferably

1) hydrogen,

2) halogen (the halogen preferably includes fluorine, chlorine and bromine),

3) -COR13where R13represents a

(a) hydroxy,

(b) C1-C6alkyl (specified C1-C6alkyl is more preferably C1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like is, and even more preferably methyl, ethyl and propyl),

(c) C1-C6alkoxy, where the specified C1-C6alkoxy is optionally substituted by the same or different one or more substituents selected from the

(1) hydroxy,

(2) C1-C6alkoxy, optionally substituted aryl (specified optionally substituted C1-C6alkoxy represents more preferably C1-C4alkoxy, optionally substituted aryl, and includes, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka and the like, optionally substituted all-phenyl, and more preferably benzyloxy, penetrate and 1 phenylethane),

(3) -NR11CO-C1-C6of alkyl, where R11represents hydrogen or C1-C6alkyl (specified C1-C6alkyl preferably represents C1-C4alkyl and includes, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl),

(4) -CONR8R9where R8and R9are the same or different and are each hydrogen, C1-C6alkyl (specified C1-C6alkyl is more preferably C1-C4alkyl, which includes, the particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl), or nitrogen-containing saturated a heterocycle containing a monocycle formed when R8, R9and the adjacent nitrogen atom are taken together (specified nitrogen-containing saturated the heterocycle includes, in particular, pyrrolidinyl, piperidyl (for example, 2-piperidyl, 4-piperidyl etc), piperidino, morpholinyl, morpholino, thiomorpholine, piperazinil, piperazine derivatives, pyrrolidine and the like),

(5) -CO-C1-C6alkoxy (specified C1-C6alkoxy is optionally substituted by phenyl, and examples specified-CO-C1-C6alkoxy is preferably-CO-C1-C4alkoxy, including, in particular, -CO-methoxy, -CO-amoxi, -CO-propoxy, -CO-isopropylate, -CO-butoxy, -CO-isobutylene, -CO-tert-Butylochka and the like, and more preferably-CO-methoxy and-CO-isopropoxy),

(6) phenyl, optionally substituted by the same or different one or more substituents selected from halogen (the halogen preferably represents fluorine, chlorine or bromine and preferably chlorine), C1-C6alkoxy (specified C1-C6alkoxy preferably represents C1-C4alkoxy, including, in particular, methoxy, ethoxy, PR is poxi, isopropylate, butoxy, isobutoxy, tert-Butylochka and the like, and more preferably methoxy) and-CO-C1-C6alkoxy (specified-CO-C1-C6alkoxy represents preferably-CO-C1-C4alkoxy, including, in particular, -CO-methoxy, -CO-amoxi, -CO-propoxy, -CO-isopropylate, -CO-butoxy, -CO-isobutylene, -CO-tert-Butylochka and the like, and more preferably-CO-isopropoxy), and optionally substituted phenyl is preferably phenyl, optionally substituted by the same or different one or more substituents selected from chlorine, methoxy and-CO-isopropylate, and more preferably a phenyl, optionally substituted by same or different 1 to 3 substituents selected from chlorine, methoxy and-CO-isopropylate, and

(7) heterocycle selected from pyridyl, tetrazolyl and tanila [said heterocycle is optionally substituted by the same or different one or more C1-C6alkyl groups (the specified C1-C6alkyl preferably represents C1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl)],

and optionally substituted C1-C6alkoxy is preferably C1-C 4alkoxy, optionally substituted by the same or different one or more substituents selected from the above-described items (1)to(7), and includes, in particular, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-Butylochka and the like, optionally substituted by the same or different one or more substituents selected from paragraphs (1)to(7), and more preferably methoxy, ethoxy, propoxy, isopropoxy, optionally substituted by the same or different one or more substituents selected from paragraphs (1)-(7), or

(d) -OR19where R19represents a saturated or unsaturated carbocycle with 3-14 carbon atoms (indicated carbocycle includes, in particular, aryl, cycloalkyl, cycloalkenyl and condensed carbocycle formed when these rings are condensed, and the like, and more preferably condensed carbocycle formed when the aryl and cycloalkyl condensed, and examples of such carbocycles are indenyl, indanyl, pentalene, fluorenyl, 1,4-dihydronaphtho, 1,2,3,4-tetrahydro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl, 5,6,7,8-tetrahydro-2 - naphthyl or the like, more preferably condensed carbocycle formed when phenyl and cycloalkyl condensed, comprising indanyl, 1,2,3,4-then it is carbonated the ro-1-naphthyl, 1,2,3,4-tetrahydro-2-naphthyl) or piperidyl, optionally substituted-CO-C1-C6the alkyl (specified-CO-C1-C6alkyl represents preferably-CO-C1-C4alkyl, including, in particular, -CO-methyl, -CO-ethyl, -CO-propyl, -CO,-isopropyl, -CO-butyl, -CO-isobutyl, -CO-sec-butyl, -CO-tert-butyl and the like, and more preferably-CO-methyl),

4) a heterocycle selected from oxadiazolyl and tetrazolyl {the heterocycle is optionally substituted C1-C6the alkyl [the specified C1-C6alkyl preferably represents C1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl and isopropyl], optionally substituted by the same or different one or more substituents selected from-CONR8R9where R8and R9are the same or different and represent, each,

(a) hydrogen,

(b) C1-C6alkyl (specified C1-C6alkyl preferably represents C1-C4alkyl, including, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, and more preferably methyl), or

(c) nitrogen-containing saturated a heterocycle containing monocycle, education is hydrated then when R8, R9and the adjacent nitrogen atom are taken together (specified nitrogen-containing saturated the heterocycle includes, in particular, pyrrolidinyl, piperidyl (for example, 2-piperidyl, 4-piperidyl and the like), piperidino, morpholinyl, morpholino, thiomorpholine, piperazinil, piperazine derivatives, pyrrolidine and the like), and-CO-aralkylated (specified-CO-aralkylated includes, in particular, -CO-benzyloxy, -CO-penetrate, -CO-1-phenylethane, -CO-3-phenylpropoxy, -CO-4-phenylbutyrate, -CO-6-phenylhexanoic and the like, and more preferably-CO-penetrate)}, or

5) nitrile.

The preferred position of substitution-X - in the benzene ring of the formula [1] is the h-position.

Preferred ester compound represented by the formula [1], is a compound of the formula [2], and more preferred is a compound fomula [3]. The alkyl group represented by R1', R2', R3', R4', R5', R13'and R18'in the formula [2], and the alkyl group represented by R1”, R2”, R3”, R4”and R5in the formula [3], have the same meanings as defined for the alkyl group represented by R1, R2, R3, R4, R5, R13and R18; alkoxygroup represented by R3', R4', R5'and R13'in the formula [2], and alkoxygroup represented by R 3”, R4”, R5”and R13”in the formula [3], have the same meanings as previously defined for alkoxygroup represented by R3, R4, R5and R13; halogen represented by R3', R4' and R5'in the formula [2], and the halogen represented by R3”, R4”and R5in the formula [3], have the same meanings as previously defined for halogen represented by R3, R4, R5and R13; R6'and R7'in the formula [2] and R6”and R7”in the formula [3], have the same meanings as previously defined for R6and R7; -CO-C1-C6alkoxygroup represented by R1'as the substituent in the formula [2], and-CO-C1-C6alkoxygroup represented by R1”as the substituent in the formula [3], have the same meanings as previously defined for a-CO-C1-C6alkoxygroup represented by R1; R8'and R9'in the formula [2] have the same meanings as previously defined for R8and R9; the alkyl group represented by R8”and R9”in the formula [3], has the same meaning as previously defined for the alkyl group represented by R8and R9; the alkyl group represented by R11'as Deputy to alkoxygroup represented by R13'in the formula [2], has the same meaning as the earlier for certain alkyl groups, presents R11as Deputy to alkoxygroup represented by R13; and carbonyl represented by R19'group-OR19'presented R13'in the formula [2], has the same meaning as defined previously for carbocycle represented by R19.

“Pharmaceutically acceptable salt” may include any salt, just could be formed of a non-toxic salt of the compound represented by the formula [1]. Pharmaceutically acceptable salt of the compound represented by the formula [1]can be obtained by adding the desired acid or base to the compound represented by the formula [1], dissolved in a solvent, and collecting the precipitated precipitated solids by filtration or concentration under reduced pressure. Examples of solvents used in this reaction are ethers (e.g. diethyl ether, tetrahydrofuran, diisopropyl ether, 1,4-dioxane (hereinafter commonly referred to as dioxane), 1,2-dimethoxyethane, dimethyl ether of diethylene glycol (also called as diglyme), etc.); alcohols (e.g. methanol, ethanol, isopropanol, n-propanol, tert-butanol, etc.); hydrocarbons (e.g. benzene, toluene, hexane, xylene, etc.); halogenated hydrocarbons (e.g. methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.); polar dissolve Italy (for example, acetone, methyl ethyl ketone, N,N-dimethylformamide, dimethyl sulfoxide and so on); or water, and they can be used individually or in combination of two or more of these solvents. Examples of acids used are inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, Hydrobromic acid, etc. or organic acids (e.g. oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, triperoxonane acid, gluconic acid, ascorbic acid, methanesulfonate acid, benzolsulfonat acid, paratoluenesulfonyl acid, naphthalene-1,5-disulfonate acid and so on). Examples used bases are inorganic bases (e.g. sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide, etc.), organic bases (for example, methylamine, diethylamine, triethylamine, triethanolamine, Ethylenediamine, Tris(hydroxymethyl)methylamine, guanidine, Collin, cinchonine etc) or amino acids (e.g. lysine, arginine, alanine and so on).

The present invention encompasses a hydrated compound, a hydrate and a solvate of each compound or its pharmaceutically acceptable salt.

In addition, the uschestvuyut various isomers of the compounds, represented by the formula [1]. For example, there may be E - and Z-geometric isomers. In addition, when there is asymmetric carbon atom, there can exist enantiomers and diastereoisomers as a stereoisomer, due to the presence of asymmetric carbon atoms and can exist in tautomeric isomers. Accordingly, all of these isomers and their mixtures are included in the scope of the present invention. In addition to the compounds represented by formula [1], the present invention may include as an equi-join their prodrugs and metabolites.

In this case, the term “prodrug” refers to a derivative of the compound of the present invention, which has a group capable of chemical or metabolic transformation, and manifests pharmaceutical activity after hydrolysis or solvolysis or conversion under physiological conditions. The prodrug can be used to improve oral absorption or for delivery to the destination. As in medicine are well established, what should be degradable group and how that group is introduced into the connection, in the present invention can be used known technology itself, such specified. Place modification for education specified prodrugs, for example,is the location of highly reactive functional groups, such as hydroxy, carboxyl, amino, thiol and the like.

For example, you can specify a derived, in which the Deputy, such as-CO-C1-C6alkyl, -CO2-C1-C6alkyl, -CONH-C1-C6alkyl, -CO-C2-C6alkenyl, -CO2-C2-C6alkenyl, -CONH-C2-C6alkenyl, -CO-aryl, -CO2-aryl, -CONH-aryl, -CO-heterocycle, -CO2-heterocycle, -CONH-heterocycle, etc. where any of the specified C1-C6of alkyl, C2-C6alkenyl, aryl and heterocycle may be substituted with halogen, C1-C6by alkyl, hydroxy, C1-C6alkoxy, carboxyla, amino, amino acid residue, -PO3H2, -SO3H, residue-CO-poly (ethylene glycol), residue-CO2-glycol, the remainder is simple monoalkyl ether-CO-poly (ethylene glycol) or a simple balance monoalkyl ether-CO2-poly (ethylene glycol)attached to the hydroxy-group connections.

You can also specify as an example, a derivative in which the Deputy, such as-CO-C1-C6alkyl, -CO2-C1-C6alkyl, -CO-C2-C6alkenyl, -CO2-C2-C6alkenyl, -CO2-aryl, -CO-aryl, -CO-heterocycle, -CO2-heterocycle, etc. where any of the specified C1-C6of alkyl, C2-C6alkenyl, aryl and heterocycle may be someseni is halogen, C1-C6by alkyl, hydroxy, C1-C6alkoxy, carboxyla, amino, amino acid residue, -PO3H2, -SO3H, residue-CO-poly (ethylene glycol), residue-CO2-glycol, the remainder is simple monoalkyl ether-CO-polyethylene glycol, the remainder is simple monoalkyl ether-CO2-poly (ethylene glycol) or-PO3H2etc)attached to the amino group of the connection.

In addition, you can specify as an example, a derivative in which the Deputy, such as C1-C6alkoxy, aryloxy etc. (where specified C1-C6alkoxy or aryloxy may be substituted with halogen, C1-C6by alkyl, hydroxy, C1-C6alkoxy, carboxyla, amino, amino acid residue, -PO3H2, -SO3H, a residue of polyethylene glycol or remnant simple monoalkyl ether of polyethylene glycol and so on)attached to the carboxyl group.

“C2-C6alkenyl” refers to an unbranched or branched alkenylphenol group with 2-6 carbon atoms, and its examples include vinyl, n-propenyl, Isopropenyl, n-butenyl, Isobutanol, second-butenyl, tert-butenyl, n-pentenyl, isopentenyl, neopentyl, 1-methylpropenyl, n-hexenyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl etc.

The connection is possible under the present invention may in some cases include water substances a hydrate or solvate, and may also include their metabolites. In addition, the compounds of the present invention include the racemates and optically active compounds. Optically active compounds are preferably those compounds in which one enantiomer predominates with an excess of about 90% or higher, more preferably with an excess of about 99% or above.

“Pharmaceutical composition” includes so-called “composition”containing a pharmaceutically active ingredient and a pharmaceutically acceptable carrier, and includes a combination of one drug with other drugs. Needless to say that the pharmaceutical composition of the present invention may be combined with any other drugs in a clinically acceptable limits. So you can say that the pharmaceutical composition of the present invention is a pharmaceutical composition for combined use with other drugs.

In addition, the compounds of the present invention can be administered to the people, but also animals such as mouse, rat, hamster, rabbit, cat, dog, cow, horse, sheep, monkey and the like. Thus, the pharmaceutical composition of the present invention is useful as a medicinal cf is DSTV not only for people, but for animals.

“MTP in the small intestine” means microsomal triglyceriderich protein (MTP), existing in the intestinal epithelial cells.

“MTP in the liver” means MTP, existing in hepatocytes.

The expression “selectively inhibits MTP in the small intestine” means that the level of inhibition of at least about 5 times higher, preferably about 10 times higher than the inhibition of MTP in other parts of the body such as the liver and heart, especially the liver. For example, this means that when introduced into a living organism compound that inhibits MTP in the small intestine, the compound is metabolized to a number at which it essentially does not inhibit MTP in the liver. More specifically, on the basis of tests on metabolic stability in liver S9 or tests for metabolic stability in plasma, this means that when tested using liver S9 or plasma of a human or mammal (e.g., hamster, etc.) residual ratio unchanged form after 10 or 60 minutes after incubation is, for example, less than about 50%, preferably less than about 30%, more preferably less than about 10% and even more preferably less than about 5%. In addition, on the basis of tests on metabolic stability using S9 in the small intestine of a human or mammal (the example hamster etc), this means that the residual ratio of the unmodified form about 5 times or more, preferably 10 times or more higher than in the case of treatment of liver S9. Unmodified form means a compound that does not undergo metabolism in a living organism and a chemical structure in which a living organism is not changed. The compound of the present invention has a characteristic property of inhibition, selective with respect to MTP in the small intestine.

The expression is metabolized to a number, in which the residual inhibitor of MTP in the liver essentially did not inhibit MTP in the liver means that almost all oral introduced MTP inhibitors are metabolized to the inactive metabolite before they reach the liver, or the liver and essentially do not show MTP inhibitory activity in the liver, i.e. inhibitors of MTP turn into such MTP inhibitors, which essentially does not inhibit the release of triglycerides from the liver. In particular, this means the state when the TG-releasing activity of the liver remains at the level of about 80% or more, preferably about 90% or more, more preferably 100% of the normal level. From the point of view of metabolism this means that the ratio of the inactive metabolite to an unmodified form in the blood of the portal vein is closer the LNO 8 or more to 1 within one hour after the introduction of hamsters, i.e. about 80% or more funds (connection) is metabolized before reaching the liver, or, on the basis of tests on metabolic stability in liver S9, this means that 10 minutes after I tested with S9 human or mammalian animal (e.g., hamster, etc.) residual factor unmodified form is about 20% or less, preferably about 10% or less, more preferably about 8% or less. The compound of the present invention has a distinctive property to be metabolised to a number at which it essentially does not inhibit MTP in the liver.

The expression “the MTP inhibitor is not essentially inhibits MTP in the liver” has essentially the same meaning with the above expression is metabolized to a number, in which the residual inhibitor of MTP in the liver essentially did not inhibit MTP in the liver” refers to the state when the TG-releasing activity of the liver remains at the level of about 80% or more, preferably about 90% or more, more preferably 100% of the normal level. The compound of the present invention has the distinguishing property that essentially does not inhibit MTP in the liver.

The compound of the present invention or its pharmaceutically acceptable salt may include as an active ingredient in the composition of the headlights is aseptically compositions (preferably, pharmaceutical compositions for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension), inhibitors of microsomal triglyceriderich protein or means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b, together with a pharmaceutically acceptable carrier.

As a “pharmaceutically acceptable carrier” is used by various organic or inorganic substances-carriers, which are traditionally used as materials for the manufacture of dosage forms in the form of fillers, lubricants, binders, loosening substance, a solvent, a solubilizer, a suspending substances, isotonic agents, buffers, soothing agents and so on, If necessary, can be used as pharmaceutical additives such as preservative, antioxidant, colorant, sweetener, etc. Preferred examples of the specified filler include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, etc. Preferred examples of the specified lubricants include magnesium stearate, calcium stearate, talc, colloidal silicon dioxide, etc. Preferred examples of the specified binding is th substances include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, etc. Preferred examples of the specified loosening substances include starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, sodium carboximetilkrahmal etc. Preferred examples of the specified solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, propylene glycol ester of fatty acid, etc. are Preferable examples of the specified solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. Preferred examples of the specified suspending substances include surfactants (e.g., steartrimonium, sodium lauryl sulfate, lauramidopropyl acid, lecithin, benzylaniline, benzathine, glycerol monostearate, etc.), polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose etc. Preferred examples of the specified isotonic substances include sodium chloride, glycerin, D-mannitol, etc. Preferred examples of the specified buffer include phosphate, acetate, carbonate, citrate, etc. Preferred examples of the specified soothing substances include benzyl alcohol, etc. Preferred examples of the specified preservative include esters of peroxybenzoyl acid, chlorbutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid, sorbic acid, etc. are Preferable examples of the specified antioxidant include sulfites, ascorbic acid, etc. are Preferable examples of the specified sweeteners include aspartame, saccharin sodium, stevia, etc. Preferred examples of the mentioned dyes include food dyes such as food yellow No. 5, food red No. 2 and food blue No. 2, lacquer dyes for food, iron oxide, etc.

When the compound of the present invention or its pharmaceutically acceptable salt is used as an active ingredient for pharmaceutical compositions (preferably, pharmaceutical compositions for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension), inhibitors of microsomal triglyceriderich protein or means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b, they can be whodini systematically and topically and orally or parenterally. Although the dose depends on age, body weight, symptom, therapeutic efficacy, or the like, the daily dose for an adult is typically in the range of from 0.1 mg to 1 g per dose and can be entered on one or several times per day. In addition, the compound of the present invention can be introduced to people and animals, other than humans, in particular mammal for the treatment or prophylaxis of these diseases.

In the manufacture of the compounds of the present invention or their pharmaceutically acceptable salts in the form of solid and liquid compositions for oral administration or injection dosage forms and so on for parenteral administration can be used suitable additives, such as diluents, dispersancy, adsorbents, soljubilizatory etc. in Addition, the composition according to the present invention can be manufactured in the form of known forms, such as tablets, pills, powders, granules, suppositories, injectable form, eye drops, solutions, capsules, lozenges, aerosols, elixirs, suspensions, emulsions, syrups, etc.

When the pharmaceutical composition of the present invention (preferably a pharmaceutical composition for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hipertensi is), inhibitors of microsomal triglyceriderich protein or as a means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b, made in the form of solid preparations such as tablets, pills, powders, granules, etc. are examples of these additives include lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, alumosilicate magnesium or powdered silicon dioxide. When the compounds of the present invention is made in the form of tablets or pills, the medicine can be supplied with gastrointestinal or enteric film coating containing substance, such as white sugar, gelatin, hydroxypropylcellulose or phthalate of hydroxymethylcellulose. In addition, tablets or pills may be multi-layered, containing two or more layers.

As an example, the pharmaceutical compositions of the present invention (preferably pharmaceutical compositions for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension), inhibitors of microsomal triglyceriderich protein or means to reduce, at least the, one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL, BOB and apolipoprotein b, are also capsules filled with liquid, semi-solid or solid content, obtained by dissolving the compounds of the present invention or their pharmaceutically acceptable salts in the solvent and additive. Examples of these solvents are purified water, ethanol, vegetable oil, etc. from which it is preferable to use ethanol or a mixture of purified water and ethanol. Any additive usually used in the manufacture of capsules, can be used without any particular limitations. Such additives include, for example, propylene glycol esters of fatty acids; polyethylene glycols with low molecular weight such as polyethylene glycol 200-600, etc., their esters with glycerol and fatty acids and medium chain triglycerides and fatty acids; alcohols/polyols, such as stearyl alcohol, cetanol, polyethylene glycol, etc. or their esters; lipids, such as sesame oil, soybean oil, peanut oil, corn oil, hydrogenated oil, paraffin oil, bleached wax; fatty acids, such as triethylcitrate, triacetin, stearic acid, palmitic acid, myristic acid, etc. and their derivatives. Decree the basic supplements are suitable for preparation of liquid or semi-solid contents. Capsules of the present invention as such additives are preferred propylene glycol esters of fatty acids. Examples of propylene glycol esters of fatty acids are propilenglikolmonostearata (Capmul PG-8 (trade name), Sefol 218 (trade name), Capryo 190 (trade name)), propilenglikolmonostearata (Lauroglycol FCC (trade name)), propilenglikolmonostearata (Myverol P-O6 (trade name)), propilenglikolstearat, propilenglikolmonostearata, propilenglikolstearat (Propymuls (trade name)), propilenglikolstearat/dicaprate (Captex (trademark) 200 (trade name)), propilenglikolstearat, propilenglikolstearat and propilenglikolmonostearata (Captex (trademark) 800 (trade name)). Although there are no particular limitations on the materials that make up the capsule of the present invention, but they include, for example, polysaccharides derived from natural products such as agar, salt of alginic acid, starch, xanthan gum, dextran etc.; proteins such as gelatin, casein, etc.; chemically processed foods, such as hydroxyacyl, pullulan, hydroxypropylcellulose, hypromellose, polyvinyl alcohol or its derivatives, derivatives of acrylic polymer, polyvinylpyrrolidone or its derivatives, polyethylene glycol, etc.

When pharmac ticheskie compositions of the present invention (preferably a pharmaceutical composition for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension), inhibitors of microsomal triglyceriderich protein or as a means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b are liquid dosage forms for oral administration, such as pharmaceutically acceptable emulsions, soljubilizatory, suspensions, syrups or elixirs, etc. used diluents include, for example, purified water, ethanol, vegetable oils, emulsifiers, etc. In addition to these solvents in these liquid dosage forms can be entered auxiliary substances such as wetting agents, suspendresume substances, sweeteners, seasonings, flavorings or preservatives.

When the pharmaceutical compositions of the present invention (preferably a pharmaceutical composition for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension), inhibitors of microsomal triglyceriderich protein or as a means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b, t is Auda dosage forms for parenteral administration, such as injecting drugs, use of sterilized aqueous or nonaqueous solutions, solubilization, suspendresume substances, emulsifiers, etc. are Examples of the aqueous solutions of solubilization and suspendida substances include distilled water for injection, saline solution, cyclodextrin and derivatives thereof; organic amines such as triethanolamine, diethanolamine, monoethanolamine, triethylamine, etc.; and inorganic alkaline solutions. When using aqueous solutions can also be added, for example, propylene glycol, polyethylene glycol or vegetable oils, such as olive oil, or alcohols, such as ethanol. In addition, can be used as a solubilizer surfactant (for mixed micelle formation), such as polyoxyethylene hydrogenated castor oil, esters of fatty acids and sucrose or lecithin or hydrogenated lecithin (for liposomeencapsulated). Further, as for the parenteral dosage forms of the present invention, they can be made in the form of emulsions containing non-aqueous soljubilizatory, such as vegetable oil with lecithin, polyoxyethylene hydrogenated castor oil or polyoxyethylene-polyoxypropyleneglycol etc.

In addition, ACC is accordance with the present invention offers a pharmaceutical composition for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension, inhibitors of microsomal triglyceriderich protein or as a means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL, BOB and apolipoprotein Century, That is, the present invention differs selective inhibition of MTP (microsomal triglyceriderich protein) in the small intestine. Moreover, the pharmaceutical composition or an agent which essentially did not inhibit MTP in the liver, and only inhibits MTP in the small intestine, is desirable. In particular, it is preferable that the inhibition of the specified tool MTP in the liver was approximately 1/3 or less, preferably 1/100 or less compared with inhibition in the small intestine when the evaluation value ED50or ED20.

In a preferred embodiment, therapeutic or prophylactic agent of the present invention for these diseases inhibit MTP in the small intestine and then metabolized in the small intestine, liver and blood to the amount by which the residual means that reach the liver, is not essentially inhibits MTP in the liver. Especially preferred is that by oral administration of 300 mg/kg of the compounds of the present invention CoE the rate of inhibition of the release of triglycerides in the liver, provide a residual connection, under the liver, is about 20% or less, preferably less than about 10%, more preferably about 0%. In particular, it is desirable that when the analysis method described below in the examples, tests, factor inhibiting specified by means of the release of triglycerides in the liver is about 40% or less, preferably about 20% or less.

“Combined use” means the use of multiple active ingredients as drugs, including, in particular, the combined use of medicines, the use of sets and separate introduction of the same or different by way of introduction.

The pharmaceutical compositions of the present invention (preferably a pharmaceutical composition for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension), inhibitors of microsomal triglyceriderich protein or as a means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL, BOB and apolipoprotein b, can be used in combination with other pharmaceutical compositions or agents. As other means may, for example, to serve drug the remedies for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension, and they can be used separately or in combination with two or more types of these medicines. For example, in combination can be used from one to three other medicines.

Examples of “means for the treatment and/or prevention of hyperlipidemia include drug type of statin, more specifically, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or tseriwastatina.

Examples of “means for the treatment and/or prevention of obesity include mazindol or orlistat.

Examples of “means for the treatment and/or prevention of diabetes include insulin preparations, medicines on the basis of sulfonylureas, the promoters of insulin secretion sulfonamidnuyu medicines medicines on the basis of biguanide, inhibitors of α-glucosidase, drugs that improve insulin resistance and so on, in particular insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, Metformin hydrochloride, the hydrochloride of buformin, voglibose, acarbose, pioglitazone hydrochloride, etc.

Examples of “means for the treatment and/or prevention of hypertension include loop diuretics, inhibitors and hotelsintriago enzyme, antagonists of angiotensin II receptor, calcium antagonists, β-blockers, α,β-blockers and α-blockers, and more specifically furosemide extended actions, captopril, captopril extended actions, enalapril maleate, alacepril, hydrochloride of delapril, cilazapril, lisinopril, hydrochloride benazepril, hydrochloride of imidapril, hydrochloride of temocapril, hydrochloride inapril, trandolapril, perindopril of erbumine, losartan potassium, candesartan of cilexetil, hydrochloride of nicardipine, hydrochloride of nicardipine extended actions, nilvadipine, nifedipine, nifedipine extended actions hydrochloride benidipine, diltiazem hydrochloride, diltiazem hydrochloride extended actions, nisoldipine, nitrendipin, hydrochloride, manidipine, hydrochloride barnidipine, hydrochloride efonidipine, mesilat of amlodipine, felodipine, cilnidipine, aranidipine, hydrochloride propranolol, propranolol hydrochloride extended actions, pindolol, pindolol extended actions hydrochloride indenolol, hydrochloride carteolol, hydrochloride carteolol extended actions hydrochloride bunitrolol, hydrochloride bunitrolol extended actions, atenolol, hydrochloride acebutolol, metoprolol tartrate, metoprolol tartrate extended actions, nipradilol sulphate penbutolol, hydrochloride tilisolol, carvedilol, bisoprolol fumarate, GI is rochloride of betaxolol, hydrochloride celiprolol, malonate of bopindolol, hydrochloride bevantolol, hydrochloride labetalola, hydrochloride arotinolol, hydrochloride of amosulalol, prazosin hydrochloride, terazosin hydrochloride, mesilate of doxazosin, hydrochloride bunazosin, hydrochloride bunazosin extended actions, urapidil and mesilate fentolamina, etc.

There are no particular restrictions on the coordination in time of administration of the pharmaceutical compositions of the present invention (preferably pharmaceutical compositions for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes or hypertension), inhibitors of microsomal triglyceriderich protein or means to reduce at least one of blood lipid selected from triglyceride, total cholesterol, chylomicron, lonp, LDL and apolipoprotein b, or combined drug of the present invention, and they can be introduced simultaneously or with some time.

The number of such drugs for the combined application can be determined on the basis of their clinical doses and can be selected properly depending on the subjects, age, body weight, symptom, treatment time, dosage form, route of administration, combination, etc. there are No special restrictions to the new form of the medicinal product for the combined application and may be sufficient, to these pharmaceutical compositions or agents and other drugs for the combined application teamed up during the introduction.

General provisions receive

Next will be illustrated as an example of the process of obtaining the compound represented by the formula [1], but needless to say that this invention is not limited to this process. When the connection of the present invention, the reaction order can be changed accordingly. First, the reaction can be initiated with acceptable stugiii or acceptable designated replacement. For example, the compound represented by formula (C)can be introduced before the introduction of the compounds represented by formula (V), and Vice versa.

In addition, can be made arbitrary replacement of substituents (conversion or additional modification of substituents) at each stage. In the presence of functional groups, it can be protected or exempt from protection. Further, in order to accelerate the reaction, can be used in an appropriate manner any other reagents than those provided previously. The source material, the receipt of which is not described, is a commercially available product or compound that can be easily obtained by a combination of known methods of synthesis.

Next, the reaction at each stage can be the ü carried out in the usual way and the separation and purification can be conducted by the appropriate selection or combination of traditional methods, such as crystallization, recrystallization, column chromatography, preparative HPLC, etc. In some cases, the separation and purification of don't and can carry out the next stage.

Pharmaceutically acceptable salt of the compound represented by the formula [1]can be obtained by adding the desired acid or base to a solution of compound represented by formula [1], which is dissolved in the solvent, and collecting the obtained solid substance, or by concentrating it under reduced pressure. Examples of the solvent used in the reaction are ethers such as diethyl ether, tetrahydrofuran, diisopropyl ether, dioxane, 1,2-dimethoxyethane, diglyme and so on; alcohols such as methanol, ethanol, isopropanol, n-propanol, tert-butanol, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.; polar solvents such as acetone, methyl ethyl ketone, N,N-dimethylformamide, dimethyl sulfoxide and etc; esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; or water, and they can be used individually or in combination of two or more of these solvents. Examples of acids are used inorganically acid, such as aristolochiaceae acid, sulfuric acid, phosphoric acid, Hydrobromic acid, etc. or organic acids such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, triperoxonane acid, gluconic acid, ascorbic acid, methanesulfonate acid, benzolsulfonat acid, paratoluenesulfonyl acid, naphthalene-1,5-disulfonate acid, etc. Examples used bases are inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide and so on; organic bases, such as methylamine, ethylamine, triethylamine, triethanolamine, Ethylenediamine, Tris(hydroxymethyl)methylamine, guanidine, Collin, cinchonine etc.; or amino acids such as lysine, arginine, alanine, etc.

The method of obtaining 1

where R1-R7and X are each the same meanings as defined for the formula [1], Y represents a halogen, such as chlorine, iodine and bromine, and Alk represents a C1-C6alkyl.

Stage 1: Reaction of Sandmeyer

The compound represented by formula (2)may be obtained by treating aniline derivative represented by the formula (1), with sodium nitrite in an aqueous acidic solution of the acid or water suspensions with conversion to the diazonium salt and the engagement of diazonium salt with potassium halide or a halide of sodium, preferably the potassium iodide or sodium iodide (reaction Sandmeyer).

The aqueous acidic solution used in the reaction includes, for example, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid and the like, which can be used individually or in combination of two or more of these solvents. Preferred aqueous acidic solution is a mixed aqueous solution of sulfuric and phosphoric acids.

The reaction temperature is from about -20 ºC to 120 ºC, preferably from about 0 ° C to room temperature.

The reaction time is from about 10 minutes to 8 hours, preferably from about 30 minutes to 4 hours.

Stage 2: Reaction amidation

The compound represented by formula (3)can be obtained by the interaction of carboxylic acid represented by the formula (2), with oxalylamino or thionyl chloride in a solvent to obtain the carboxylic acid or the carboxylic acid with the amine represented by the formula (D), in a solvent in the presence of a base. This reaction is a conventional amidation reaction carried out using a carboxylic acid and an amine.

Examples of the solvent used for obtaining carboxylic acids are ethers, such as diethyl e is Il, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.; or esters such as ethyl acetate, methyl acetate, butyl acetate, etc. that can be used individually or in combination of two or more of these solvents. The preferred solvent used in this reaction include methylene chloride, chloroform and toluene containing catalytic amount of N,N-dimethylformamide.

The reaction temperature is about -20 ° C to 120 ºC, preferably from about 0 ° C to room temperature.

The reaction time is from about 10 minutes to 8 hours, preferably from about 30 minutes to 4 hours.

Examples of the solvent used in the amidation reaction between the acid chloride of the acid and amine are ethers, such as diethyl ether, tetrahydrofuran, diisopropyl ether, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.; or esters such as ethyl acetate, methyl acetate, butyl acetate, etc. that can be used in owani individually or in combination of two or more of these solvents. The preferred solvent used in this reaction include methylene chloride, chloroform, toluene, ethyl acetate and tetrahydrofuran.

Examples of the base used in the reaction are organic bases such as triethylamine, pyridine, dimethylaminopyridine and N-methylmorpholine; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; carbonates of alkali metals such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, among which triethylamine, sodium hydroxide or sodium bicarbonate is preferred.

The reaction temperature is about 0 ° C to 80 ° C, preferably from about 0 ° C to room temperature.

The reaction time is from about 10 minutes to 48 hours, preferably from about 30 minutes to 24 hours.

Alternatively, the compound represented by formula (3)can be obtained by condensation of compounds represented by formula (2), with the compound represented by formula (D), in the presence of, for example, water-soluble carbodiimide, such as hydrochloride, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (hereinafter referred to as WSC), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl (DPPA), carbonyldiimidazole (CDI) and hexaphosphate bromo-Tris-pyrrolidinone (Pybrop), or the if necessary, condensation using a combination of acid additives (for example, 1-hydroxy-1H-benzotriazole (HOBT), etc. and the base. In addition, the compound represented by formula (3)can also be obtained by converting the compound represented by formula (2), a mixed anhydride with the subsequent implementation of the interaction with the compound represented by formula (D), in the presence of a base.

Stage 3: the Negishi Reaction (Negishi)

The compound represented by formula (4)can be obtained by the reaction of cross-linking between the compound represented by formula (3), and the compound represented by formula (A) (reagent reformed (Reformatsky)), in a solvent in the presence of a catalyst containing palladium and phosphorus ligand.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and so on; esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; or polar solvents, such as acetone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, etc. that can to be used individually or in combination the two or more of these solvents. The preferred solvent used in this reaction includes ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and diglyme; and polar solvents such as N,N-dimethylformamide and N,N-dimethylacetamide.

Examples of the catalyst used in this reaction are dichloride bis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0) and the like, and dichloride bis(triphenylphosphine)palladium(II) is preferred.

The reaction temperature is about -20 ° C to 120 ºC, preferably from about 0 ° C to room temperature.

The reaction time is from about 10 minutes to 8 hours, preferably from about 30 minutes to 4 hours.

Stage 4: Recovery nitro

This reaction is a normal reaction for reduction of the nitro group attached directly to aromatic ring. The compound represented by formula (5)can be obtained by hydrogenation of nitro compounds represented by formula (4), in a solvent in the presence of a catalyst.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and so on; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol, etc.; or esters such as the acetate, methyl acetate, butyl acetate etc; which can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is an alcohol solvent such as methanol, ethanol, isopropyl alcohol and tert-butanol, or a mixed solvent of specified alcoholic solvent and tetrahydrofuran and/or water.

The catalyst used in this reaction include palladium-on-carbon, palladium hydroxide, Raney Nickel and platinum oxide, among which palladium-on-carbon is preferred.

The reaction temperature is about 0 ° C to 120 ºC, preferably from about room temperature up to 50ºC.

The reaction time is from about 30 minutes to 8 hours, preferably from about 1 hour to 96 hours.

Alternatively, the compound represented by formula (5)can also be obtained by the interaction of the nitro compounds represented by formula (4)with metal reagent, such as iron, zinc, tin, and tin chloride, in the presence or in the absence of acid at room temperature or when heated.

Stage 5: implementation of the interaction of carboxylic acids with amine

This stage is the normal reaction between the acid chloride of the acid and am the nome and connection represented by formula (6)can be obtained by condensation of the carboxylic acid represented by the formula (B)with an amine represented by the formula (5), in a solvent in the presence of a base.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.; or esters such as ethyl acetate, methyl acetate, butyl acetate, etc. that can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is methylene chloride, chloroform, toluene, ethyl acetate or tetrahydrofuran.

Examples of the base used in the reaction are organic bases such as triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine etc.; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; carbonates of alkali metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. among which triethylamine, sodium hydroxide or sodium bicarbonate is I who is preferred.

The reaction temperature is about 0 ° C to 80 ° C, preferably from about 0 ° C to room temperature.

The reaction time is from about 10 minutes to 48 hours, preferably from about 30 minutes to 24 hours.

Stage 6: hydrolysis Reaction

The compound represented by the formula (7)can be obtained by hydrolysis of the ester compounds represented by the formula (6), in a solvent in the presence of a base.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and so on; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol, etc.; or water, which can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is a mixed solvent of tetrahydrofuran and ethanol or methanol.

Examples of the base used in the reaction include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; or carbonates of alkali metals such as sodium carbonate, potassium carbonate and so on, among which sodium hydroxide is preferred.

The reaction temperature is about 0 ° C to 120 ºC, predpochtitel is but from about room temperature to 80ºC.

The reaction time is from about 1 hour to 24 hours, preferably from about 2.5 hours to 12 hours.

Stage 7: the Condensation of carboxylic acids with phenol

This stage is a normal reaction of condensation between the carboxylic acid and phenol. One of the target compounds represented by formula (8), i.e. the compound of the present invention represented by formula [1]can be obtained by condensation of the carboxylic acid represented by the formula (7), with a phenol represented by the formula (C), in a solvent in the presence of a base and a condensing agent.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and so on; esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; or polar solvents, such as acetone, N,N-dimethylformamide, dimethylsulfoxide, etc. that can be used separately or in a combination of two or more of these solvents. A preferred example of the solvent used in this reaction is tetrahydrofuran, acetone, methylene chloride or N,N-dimetil is mamid.

Examples of the base used in the reaction are organic bases such as triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine and so on, among which dimethylaminopyridine is preferred.

Examples of the condensing agent used in this reaction are of WSC hydrochloride, dicyclohexylcarbodiimide (DCC), diphenylphosphoryl (DPPA), carbonyldiimidazole (CDI) or hexaphosphate bromo-Tris-pyrrolidinone (Pybrop) or, if necessary, a combination of acid additives (for example, 1-hydroxy-1H-benzotriazole (HOBT), and so on) and the condensing agent, among which the hydrochloride of 1-ethyl-3-(3'- dimethylaminopropyl)carbodiimide is preferred.

The reaction temperature is about 0 ° C to 80 ° C, preferably from about 0 ° C to room temperature.

The reaction time is from about 1 hour to 48 hours, preferably from about 3 hours to 24 hours.

As an alternative way carboxylic acid represented by the formula (7)can be converted into a mixed anhydride, which can then be subjected to interaction with phenol represented by the formula (C), in the presence of a base.

In addition, other compounds represented by formula (8)can be obtained by transformation or modification of the substituent connected and, represented by the formula (8). For example, carboxylic acid represented by the formula (8)can be obtained by hydrogenation of compounds represented by formula (8)where any of the substituents R3-R5has a benzyl ester linkage, in a solvent in the presence of a catalyst.

The solvent and the base used in this reaction are the same as described above for stage 4.

Examples of compounds obtained by the method of obtaining 1, include connections from 1-1 to 1-123.

The method of obtaining 2

Below is illustrated the connection is represented by the formula [1], where X represents -(CH2)m-NR18-(CH2)n(m, R18and n have each the same meanings as defined for the formula [1]):

where R1-R7, R18ring A, ring B, ring C, m, and n have each the same meanings as defined for the formula [1], Z-represents a halogen ion such as chlorine ion, iodine ion and bromine ion, and Alk represents a C1-C6alkyl.

Stage 21: Reaction linking

The compound represented by formula (22)can be obtained by exposure to compounds represented by formula (21), the reaction of cross-linking by Steele (Stille) trialkyl-1-albanialove (for example, tributylammonium etc) or reaction winelog the binding Suzuki (Suzuki) 1-alkenylboronic acid (for example, complex pinacolone ether vinylboronic acid complex debutalbum ether vinylboronic acid and so on) in a solvent in the presence of a palladium complex and in the presence or in the absence of bases and additives.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; esters such as ethyl acetate, methyl acetate, butyl acetate and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and so on; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol, etc.; polar solvents such as acetone, N,N-dimethylformamide, dimethylsulfoxide, etc.; or water, which can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is a hydrocarbon solvent, such as benzene, toluene, hexane, xylene, etc.

Examples of the palladium complex used in this reaction are dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II), etc. among which tetrakis(triphenylphosphine)alladi(0) is preferred. In the case of palladium-on-carbon, palladium (II)acetate, Tris(dibenzylideneacetone)diplegia (0) or bis(dibenzylideneacetone)palladium(0) used additive such as triphenylphosphine, tri-o-tolylphosphino, tri-n-butylphosphine, three(2-furyl)phosphine, diphenylphosphinite etc.

Examples of the base used in the reaction are sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, triethylamine or the like. The reaction of the vinyl binding Suzuki 1-alkenylboronic acids carried out using any of the specified grounds.

The reaction temperature is from approximately-20ºC to 200ºC, preferably from about 0 ° C to 150 º C.

The reaction time is from about 10 minutes to 24 hours, preferably from about 1 hour to 12 hours.

Stage 22: Reaction of formation of carbonyl

The compound represented by the formula (23)can be obtained by turning directly to the connection represented by the formula (22), the aldehyde or ketone of olefins in a solvent through a 1,2-diol without highlighting.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; polar solvents such as acetone, etc.; or water that may be used in alone or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is a mixed solvent of acetone and water.

Examples of the reagent for the direct conversion of olefin to aldehyde or ketone via 1,2-diol are ozone-dimethyl sulfide, metaperiodate sodium-osmium tetroxide and so on, among which metaperiodate sodium-osmium tetroxide is preferred. The above reaction can be multi-stage or two-stage reaction.

The reaction temperature is about -20 ° C to 80 ° C, preferably from about 0 ° C to room temperature.

The reaction time is from about 10 minutes to 24 hours, preferably from about 1 hour to 6 hours.

Stage 23: the Reaction of reductive amination

The compound represented by the formula (24)can be obtained by reductive amination of compounds represented by formula (23), and compounds represented by the formula (E), in a solvent in the presence or in the absence of acid.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloro is an etc; or esters, such as ethyl acetate, methyl acetate, butyl acetate etc; which can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is a halogenated hydrocarbon solvent such as methylene chloride, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.

Examples of the reducing agent used in this reaction are sodium borohydride, cyanoborohydride sodium, triacetoxyborohydride sodium hydrogen/palladium-on-carbon and so on, among which triacetoxyborohydride sodium is preferred.

Examples of the acid used in this reaction are acetic acid, hydrochloric acid, p-toluensulfonate acid, methanesulfonate acid, etc. among which hydrochloric acid or acetic acid is preferred.

The reaction temperature is about -20 ° C to 80 ° C, preferably from about 0 ° C to room temperature.

The reaction time is from about 10 minutes to 24 hours, preferably from about 30 minutes to 6 hours.

Stage 24: hydrolysis Reaction

The compound represented by the formula (25)can be obtained by hydrolysis of the ester compounds represented by the formula (24), in which rastvoritele in the presence of a base. When a complex ester (24) is a benzyl ether, benzyl group can be removed by hydrogenolysis.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and so on; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol, etc.; or water; which can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is a mixed solvent of tetrahydrofuran and ethanol or methanol.

Examples of the base used in the reaction include alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide and so on, among which sodium hydroxide is preferred.

The reaction temperature is about 0 ° C to 120 ºC, preferably from about room temperature to 80ºC.

The reaction time is from about 1 hour to 24 hours, preferably from about 2 hours to 12 hours.

Stage 25: condensation Reaction between the carboxylic acid and phenol

This stage is a normal reaction of condensation. One of the target compounds represented by formula (26)can be obtained by condensation of carboxylic acid, is expressed by the formula (25), with a phenol represented by the formula (C), in a solvent in the presence of a base and a condensing agent.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and so on; esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; polar solvents such as acetone, N,N-dimethylformamide, dimethyl sulfoxide and so on; which can be used separately or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is tetrahydrofuran, acetone, methylene chloride or N,N-dimethylformamide.

Examples of the base used in the reaction are organic amines such as triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine and so on, among which dimethylaminopyridine is preferred.

Examples of the condensing agent used in this reaction are of WSC hydrochloride, dicyclohexylcarbodiimide (DCC), diphenylphosphoryl (DPPA), carbonyldiimidazole (CDI) or hexaphosphate bromo-Tris-pyrrolidinone (Pybrop) or, if the necessary the combination of acid additives (for example, 1-hydroxy-1H-benzotriazole (HOBT), and so on) and the condensing agent, among which the hydrochloride of 1-ethyl-3-(3'- dimethylaminopropyl)carbodiimide is preferred.

The reaction temperature is about 0 ° C to 80 ° C, preferably from about 0 ° C to room temperature.

The reaction time is from about 1 hour to 48 hours, preferably from about 3 hours to 24 hours.

As an alternative way carboxylic acid derivative represented by the formula (25)can be converted into a mixed anhydride with the subsequent implementation of the interaction with phenol represented by the formula (C), in the presence of a base.

In addition, other compounds represented by formula (26)can be obtained by transformation or modification of the substituent in the compound represented by the formula (26). For example, the compound represented by the formula (26)can be obtained by hydrogenation of compounds represented by formula (26)where any of the substituents R3-R5has a benzyl ester linkage, in a solvent in the presence of a catalyst. The solvent and the base used in this reaction are the same as described above for stage 4 of the method of obtaining 1.

The compound obtained by the method of obtaining 2, includes connection 21.

The method of obtaining 3

Below is illustrated the connection is represented by the formula [1], where X is a

(where m is 0 and n has the same meaning as defined above for the compounds of formula [1]):

where R6, R7and n have each the same meanings as defined for the formula

[1], Y represents a halogen, such as fluorine, chlorine, iodine and bromine, and Alk represents a C1-C6alkyl.

Stage 31: Aromatic nucleophilic substitution

The compound represented by the formula (32)can be obtained by the interaction of the compounds represented by formula (3)obtained in stage 2 of the method of obtaining 1, with the compound represented by the formula (31), in a solvent in the presence of a base.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and so on; esters such as ethyl acetate, methyl acetate, butyl acetate and so on; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol, etc.; polar will dissolve the Lee, such as acetone, N,N-dimethylformamide, dimethylsulfoxide, etc.; or water, which can be used individually or in combination of two or more of these solvents.

A preferred example of the solvent used in this reaction is acetone, N,N-dimethylformamide, dimethylsulfoxide or the like.

Examples of the base used in the reaction are potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydride, triethylamine, pyridine, tert-piperonyl potassium, sodium acetate, potassium fluoride, utility, finality or the like, among which potassium carbonate is preferred.

If necessary, may be a combination of a copper catalyst (e.g. copper iodide, etc.) or palladium catalyst (e.g. palladium acetate, etc.) with a phosphorus ligand (for example, 2,2-bis(diphenylphosphino)-1,1-bination etc).

The reaction temperature is from about -40 ° C up to 200ºC, preferably from about 80 ° C to 150 º C.

The reaction time is from about 60 minutes to 24 hours, preferably from about 4 hours to 8 hours.

Following a methodology similar to that described in connection with the stages 4-7 way to obtain 1, it is possible to obtain the compound represented by the formula (8), i.e. the compound represented by the formula [1] according to the present invention.

Primarykeyname, obtained by the method of obtaining 3 include compounds 3-1 and 3-2.

The method of obtaining 4

Below is illustrated the connection is represented by the formula [1], where R1represents a-CO-C1-C6alkoxy:

where R2-R7and X are each the same meanings as defined for the formula [1], and Alk represents a C1-C6alkyl group.

Stage 41: hydrolysis Reaction

The compound represented by the formula (42)can be obtained by hydrolysis of the ester compounds represented by the formula (41), similar to receipt by the techniques described in connection with stages 1-3 of the method of obtaining 1, in a solvent in the presence of a base.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and so on; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol, etc.; or water, which can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is a mixed solvent of tetrahydrofuran and ethanol or methanol.

Examples of the base used in the reaction include hydroxides of alkali metals, the same is as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; or carbonates of alkali metals such as sodium carbonate, potassium carbonate and so on, among which sodium hydroxide is preferred.

The reaction temperature is about 0 ° C to 120 ºC, preferably from about room temperature to 80ºC.

The reaction time is from about 1 hour to 24 hours, preferably from about 1 hour to 6 hours.

Stage 42: Reaction of esterification

The compound represented by the formula (43)can be obtained by treating the carboxylic acid represented by the formula (42), alkylhalogenide (for example, benzylbromide etc) in accordance with the usual esterification reaction, in a solvent in the presence of a base. At this stage, choose the protective group is removed under conditions other than alkaline conditions, such as complex benzyl ether complex p-methoxybenzyloxy ether, etc.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme etc; or polar solvents, such as acetone, N,N-dimethylformamide, dimethylsulfoxide, etc. that can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in these reactions is, is N,N-dimethylformamide.

Examples of the base used in the reaction are organic bases such as triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine etc; alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; or a carbonate of an alkali metal such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. among which potassium carbonate or sodium bicarbonate is preferred.

The reaction temperature is about 0 ° C to 120 ºC, preferably from about room temperature to 80ºC.

The reaction time is from about 1 hour to 24 hours, preferably from about 1 hour to 6 hours.

At this stage you can choose complex tert-butyl ether removed by the acid, and complex allyl ether removed by hydrogenation using a palladium catalyst.

Stage 43: Reaction nitrogroup reduction

This reaction is a normal reaction for reduction of the nitro group attached directly to aromatic ring. Derived amine represented by the formula (44)can be obtained by treating the nitro compounds represented by the formula (43), metal reagent in a solvent in the presence or in the absence of acid at room temperature is or when heated.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and so on; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol and so on; esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; or water, which can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is a mixed solvent of ethanol, tetrahydrofuran and water.

An example of a metal reagent used in this reaction is iron, zinc, tin or tin chloride, among which iron is preferred.

The reaction temperature is about 0 ° C to 120 ºC, preferably from about room temperature to 100ºC.

The reaction time is from about 30 minutes to 8 hours, preferably from about 1 hour to 5 hours.

When the ester group in nitrosoaniline ester group is not removed by hydrogenation, such as complex tert-butyl ether and complex allyl ether, specified ester compound is subjected to hydrogenation with palladium-on-carbon, palladium hydroxide, Raney Nickel or platinum oxide obtaining from the relevant connection represented by the formula (44).

Stage 44: amidation Reaction of a carboxylic acid with the amine

This stage is a normal reaction of condensation between the acid chloride of the acid and the amine. The compound represented by the formula (45)can be obtained by condensation of the carboxylic acid represented by the formula (F) with an amine represented by the formula (44), in a solvent in the presence of a base.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and so on; esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; or water, which can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is chloroform, toluene, ethyl acetate or tetrahydrofuran.

Examples of the base used in the reaction are organic bases such as triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine etc; alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.;or a carbonate of an alkali metal, such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. among which triethylamine or sodium bicarbonate is preferred.

The reaction temperature is about 0 ° C to 80 ° C, preferably from about 0 ° C to room temperature.

The reaction time is from about 10 minutes to 48 hours, preferably from about 30 minutes to 24 hours.

Stage 45: removing the protective ester group

This stage is the removal of the protective ester group. When using benzyl ether, etc. removed by the hydrogenation of the carboxylic acid represented by the formula (46)can be obtained by hydrogenation of ester represented by the formula (45), in a solvent in the presence of a catalyst.

Examples of the solvent used in this reaction are ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme and so on; alcohols such as methanol, ethanol, isopropyl alcohol, tert-butanol, etc.; or esters such as ethyl acetate, methyl acetate, butyl acetate, etc. that can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is an alcohol solvent, such as methane is, ethanol, isopropyl alcohol, tert-butanol or a mixed solvent of specified alcohol and tetrahydrofuran.

Examples of the catalyst used in this reaction are palladium-on-carbon, palladium hydroxide, Raney Nickel, platinum oxide, etc. among which palladium-on-carbon is preferred.

The reaction temperature is about 0 ° C to 120 ºC, preferably from about room temperature up to 50ºC.

The reaction time is from about 30 minutes to 8 hours, preferably from about 1 hour to 4 hours.

In addition, tert-butyl ester can be removed by acid, and allyl ester can be removed by using a catalyst, such as dichlorobis(triphenylphosphine)palladium(II) or tetrakis(triphenylphosphine)palladium(0).

Stage 46: the condensation of the carboxylic acid and phenol

This stage is a normal reaction of condensation between the carboxylic acid and phenol. One of the target compounds represented by formula (47), i.e. the compound represented by the formula [1] according to the present invention can be obtained by condensation of the carboxylic acid represented by the formula (46), with a phenol represented by the formula (C), in a solvent in the presence of a base and a condensing agent.

Examples of the solvent used in this reaction are about the tide esters, such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diglyme, etc.; hydrocarbons, such as benzene, toluene, hexane, xylene and so on; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and so on; esters such as ethyl acetate, methyl acetate, butyl acetate, etc.; or polar solvents, such as acetone, N,N-dimethylformamide, dimethylsulfoxide, etc. that can be used individually or in combination of two or more of these solvents. A preferred example of the solvent used in this reaction is tetrahydrofuran, acetone, chloroform or N,N-dimethylformamide.

Examples of the base used in the reaction are organic amines such as triethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine and so on, among which dimethylaminopyridine is preferred.

Examples of the condensing agent used in this reaction are the hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (WSC.HCl), dicyclohexylcarbodiimide (DCC), diphenylphosphoryl (DPPA), carbonyldiimidazole (CDI) or hexaphosphate bromo-Tris-pyrrolidinone (Pybrop) or, if necessary, a combination of acid additives (for example, 1-hydroxy-1H-benzotriazole (HOBT), and so on) and the condensing agent, among which the hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (WSC.HCl) is preferred.

The reaction temperature is about 0 ° C to 80 ° C, preferably from about 0 ° C to room temperature.

The reaction time is from about 1 hour to 48 hours, preferably from about 3 hours to 24 hours.

As an alternative way carboxylic acid derivative represented by the formula (7)can be converted into a mixed anhydride with the subsequent implementation of the interaction with phenol represented by the formula (C), in the presence of a base.

Examples of compounds obtained by the method of obtaining 4 include connections from 4-1 to 4-4.

The raw materials used in the present invention, for example, the compound represented by formula (B), the compound represented by formula (C), and the connection 21 ways to get 1-4 can be easily obtained by known methods or in the following ways described below.

EXAMPLES

The present invention is shown in detail in the following working examples, reference examples, examples, test examples and manufacture of dosage forms, but it should be understood that the present invention is not limited to these examples.

Reference example 1

Getting 6-methyl-2-(4-triptoreline)nicotinic acid

On the diagram above reactions, Me means methyl, WSC mean 1-ethyl-3(3'-dimethylaminopropyl)carbodiimide, DMAP means dimethylaminopyridine and DMF (DMF means dimethylformamide. Hereinafter in this description, each symbol has the same meaning as defined above.

a) Methyl ester of 2-chloro-6-methylnicotinic acid

2-Chloro-6-methylnicotinic acid (25,0 g) suspended in a mixture of solvents, including dimethylformamide (100 ml) and chloroform (100 ml)and the resulting suspension was added dimethylaminopyridine (21,3 g) and methanol (4,67 g). Finally hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (WSC) (33,5 g) was added to the mixture, followed by stirring at room temperature for 6 hours. After the reaction mixture was concentrated, added to it in ethyl acetate (300 ml). The mixture was washed successively with water, 10% ammonium chloride, water and a saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 1:4, vol/about.) obtaining specified in the title compound (24.6 g) as a colourless oil.

b) Methyl ester of 6-methyl-2-(4-triptoreline)nicotinic acid

Methyl ester 2-chloro-6-methylnicotinic acid (18.6 g) and 4-triftormetilfullerenov acid (22,0 g) was dissolved in a mixture solvent of ethanol (100 ml) and toluene (100 ml) and the resulting solution was added 2 M sodium carbonate (100 ml) and tetrakis(triphenylphosphine)p is lady(0) (2,90 g). The mixture was stirred at 120ºC for 3 hours under heating. Was added to the reaction solution, ethyl acetate (200 ml). The aqueous layer was separated. The organic layer was washed sequentially with 0.1 N. sodium hydroxide, water and saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 1:4, vol/about.) obtaining specified in the connection header (25,8 g) as a colourless oil.

c) 6-Methyl-2-(4-triptoreline)nicotinic acid

Methyl ester of 6-methyl-2-(4-triptoreline)nicotinic acid (7,26 g) was dissolved in methanol (30 ml). To the solution was added 4 M sodium hydroxide (7.2 ml) at 0ºC under refrigeration. The mixture was stirred at 45°C for 3 hours. Water (30 ml) was added to the mixture at 0°C by cooling with subsequent acidification (pH 3) 1 M hydrochloric acid (30 ml) to obtain the precipitate. The precipitate was filtered and dried to obtain specified in the title compound as a colourless solid (6.5 g).

1H-NMR (δ, 300 MHz, CDCl3): of 2.66 (3H, s), to 7.61 (2H, d, J=8,3 Hz), to 7.67 (2H, d, J=8,3 Hz), 7,27 (1H, d, J=7.9 Hz), 8,18 (1H, d, J=7.9 Hz).

Reference example 2

Obtaining methyl ester 3-ethyl-5-fluoro-4-hydroxybenzoic acid

On the diagram above reactions, Me means methyl; conc. H2SO4 means concentrated sulfuric acid; NBS means of N-bromosuccinimide; THF (THF means tetrahydrofuran; MOMCl means simple chloromethylation ether; nBu is n-butyl; PdCl2(PPh3)2means dichlorobis(triphenylphosphine)palladium(II); Pd/C is palladium-on-carbon and Et means ethyl. Hereinafter in this description, each symbol has the same meaning as defined above.

a) Methyl ester of 3-fluoro-4-hydroxybenzoic acid

To a solution of 3-fluoro-4-hydroxybenzoic acid (3.0 g) in methanol (30 ml) was added concentrated sulfuric acid (3 ml) and the mixture is boiled under reflux for 5 hours. The reaction solution was allowed to stand for cooling to room temperature and then concentrated in vacuum. The residue was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated to obtain specified in the connection header (2,99 g).

b) Methyl ester of 3-bromo-5-fluoro-4-hydroxybenzoic acid

To a solution of methyl ester of 3-fluoro-4-hydroxybenzoic acid (1.0 g) in THF (10 ml) was added N-bromosuccinimide (1.26 g) under ice cooling and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed sequentially with saturated water is the first sodium bicarbonate solution and saturated salt solution, was dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 3:1, vol/about.) obtaining specified in the connection header (1,16 g). (The above THF means tetrahydrofuran).

c) Methyl ester of 3-bromo-5-fluoro-4-methoxyethoxymethyl acid

To a solution of methyl ester 3-bromo-5-fluoro-4-hydroxybenzoic acid (637 mg) in acetone (7 ml) was added potassium carbonate (708 mg) and simple chloromethylation ester (412 mg) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 9:1, vol/about.) obtaining specified in the title compound (608 mg).

d) Methyl ester of 3-fluoro-4-methoxyethoxy-5-vinylbenzoic acid

To a solution of methyl ester 3-bromo-5-fluoro-4-methoxyethoxymethyl acid (300 mg) and vinylboronic acid dibutylamino ester (226 mg) in a mixture of toluene (4 ml) - ethanol (2 ml) was added dichlorobis(triphenylphosphine)palladium(II) (36 mg) and aqueous solution (1 ml), sodium carbonate (217 mg). The mixture was stirred at 100ºC for 8 hours and then gave it to stand for cooling to room temperature. Received ner is stormie material was filtered through a layer of celite and the filtrate was concentrated in vacuum. The residue was diluted with ethyl acetate, washed with water and saturated salt solution and dried over anhydrous sodium sulfate. After concentration in vacuo the residue was purified column chromatography on silica gel (hexane:ethyl acetate = 30:1, about./about.) obtaining specified in the title compound (190 mg).

e) Methyl ester of 3-fluoro-4-hydroxy-5-vinylbenzoic acid

A solution of methyl ester of 3-fluoro-4-methoxyethoxy-5-vinylbenzoic acid (185 mg) in a mixture of THF (2 ml) of 3 N. hydrochloric acid (1 ml) was stirred at 60ºC for 3 hours under heating. The mixture was allowed to stand for cooling to room temperature, diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate and saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 9:1, vol/about.) obtaining specified in the title compound (121 mg). (The above THF means tetrahydrofuran).

f) Methyl ester 3-ethyl-5-fluoro-4-hydroxybenzoic acid

A suspension of methyl ester of 3-fluoro-4-hydroxy-5-vinylbenzoic acid (121 mg) and 10% palladium-on-carbon (20 mg) in a mixture of THF (1 ml) - methanol (1 ml) was first made at room temperature over night under moderate pressure (3 kg/cm2). Kata is isator was filtered through a layer of celite and the filtrate was concentrated to obtain specified in the title compound (121 mg).

1H-NMR (δ, 300 MHz, DMSO-D6): to 1.14 (3H, t, J=7.5 Hz), 2.63 in (2H, square, J=7.5 Hz), 3,80 (3H, s), 7,52 (1H, DD, J=1,9, up 10.9 Hz), 7,56 (1H, s).

Reference example 3

Obtaining methyl ester 3-fluoro-4-hydroxy-5-methylbenzoic acid

On the diagram above reactions THF means tetrahydrofuran and PdCl2(dppf) mean (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II). Further, in this specification, each symbol has the same meaning as defined above.

a) Methyl ester of 3-fluoro-4-methoxyethoxy-5-methylbenzoic acid

To a solution of methyl ester 3-bromo-5-fluoro-4-methoxyethoxymethyl acid (301 mg) and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (42 mg) in dioxane (5 ml) was added dimethylzinc (2 M toluene solution) (2,1 ml). The mixture was stirred at 120ºC for 3 hours under heating and then cooled to 0ºC was added thereto, methanol (0.3 ml). The mixture was diluted with ether, washed with 1 M hydrochloric acid and saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 50:1, about./about.) obtaining specified in the title compound (197 mg).

b) Methyl ester of 3-fluoro-4-hydroxy-5-methylbenzoic acid

Methyl ester of 3-fluoro-4-methoxyethoxy-5-methylbenzoic acid (194 mg) processing ivali way similar to that described in reference example 2e), with specified title compound (140 mg).

1H-NMR (δ, 300 MHz, CDCl3): 2,30 (3H, s), 3,88 (3H, s), of 5.55 (1H, d, J=4.9 Hz), a 7.62 (1H, DD, J=1,9, 12,5 Hz), 7,66 (1H, s).

Reference example 4

Obtain 1-ethyl ester 3-methyl ester 4-hydroxy-5-methylisophthalic acid

On the diagram above reactions Et means ethyl; conc. H2SO4means concentrated sulfuric acid; DMF means dimethylformamide; MOMCl means simple chloromethylation ether; Me denotes methyl and PdCl2(dppf) mean (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II). Hereinafter in this description, each symbol has the same meaning as defined above.

a) 1-Ethyl ester 4-hydroxyisophthalic acid

To a solution of 4-hydroxyisophthalic acid (10.0 g) in ethanol (100 ml) was added concentrated sulfuric acid (3.0 ml) and the mixture is boiled under reflux for 4 hours. The reaction solution was allowed to stand for cooling to room temperature and poured it into ice water. Was added sodium bicarbonate with stirring to achieve a pH of 10-11. Obtained in the precipitate solid was filtered. To the filtrate was added concentrated hydrochloric acid to achieve a pH of 2-3 and precipitated in the sediment solid-Hotfile revival. The filtered solid was recrystallized from a mixture of methanol and water (2:1, vol/about.) obtaining specified in the connection header (4.53 in).

b) 1-Ethyl ester 3-methyl ester 4-hydroxyisophthalic acid

To a solution of 1-ethyl ester 4-hydroxyisophthalic acid (4,51 g) in DMF (36 ml) was added methyliodide (3,66 g) and sodium hydrogen carbonate (2.16 g). The mixture was stirred at 60ºC for 2 hours and then gave it to stand for cooling to room temperature. Solid matter deposited in the sediment after adding water, was filtered to obtain specified in the connection header (4,20 g).

c) 1-Ethyl ester 3-methyl ester 5-bromo-4-hydroxyisophthalic acid

1-Ethyl ester 3-methyl ester 4-hydroxyisophthalic acid (4,51 g) was treated in a manner similar to stage b) of reference example 2, to obtain specified in the connection header (4,21 g).

d) 1-Ethyl ester 3-methyl ester 5-bromo-4-methoxyethoxymethyl acid

1-Ethyl ester 3-methyl ester 5-bromo-4-hydroxyisophthalic acid (4,20 g) was treated in a manner similar to stage c) of reference example 2, to obtain specified in the connection header (4,36 g).

e) 1-Ethyl ester 3-methyl ester 4-hydroxy-5-methylisophthalic acid

1-Ethyl ester 3-methyl ester 5-bromo-4-methoxyethoxymethyl acid (3.0 g) about amityvale way a similar stage a) of reference example 3, to obtain specified in the connection header (1,69 g).

1H-NMR (δ, 300 MHz, CDCl3): of 1.39 (3H, t, J=7.2 Hz), is 2.30 (3H, s), 3,98 (3H, s), 4,36 (2H, square, J=7,2 Hz), 8,00 (1H, s), 8,42 (1H, d, J=2.2 Hz), of 11.45 (1H, s).

Reference example 5

Obtain methyl ester of 4-hydroxy-3-methyl-5-triftorperasin acid

On the diagram above reactions, Me means methyl; conc. H2SO4means concentrated sulfuric acid; NBS means of N-bromosuccinimide; THF means tetrahydrofuran; MOMCl means simple chloromethylation ether and PdCl2(dppf) mean (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II). Hereinafter in this description, each symbol has the same meaning as defined above.

a) Methyl ester of 4-hydroxy-3-triftorperasin acid

To a solution of 4-hydroxy-3-triftorperasin acid (395 mg) in methanol (5 ml) was added concentrated sulfuric acid (0.4 ml) and the mixture is boiled under reflux for 6 hours. The reaction mixture was allowed to stand for cooling to room temperature and concentrated it in a vacuum. The residue was diluted with ethyl acetate, washed with water and saturated salt solution and concentrated to obtain specified in the title compound (403 mg).

b) Methyl ester of 3-bromo-4-hydroxy-5-cryptomelane the second acid

Methyl ester of 4-hydroxy-3-triftorperasin acid (394 mg) was treated in a manner similar to stage b) of reference example 2, to obtain the specified title compound (412 mg).

c) Methyl ester of 3-bromo-4-methoxyethoxy-5-triftorperasin acid

Methyl ester of 3-bromo-4-hydroxy-5-triftorperasin acid (831 mg) was treated in a manner similar to stage c) of reference example 2, to obtain the specified title compound (905 mg).

d) Methyl ester of 4-hydroxy-3-methyl-5-triftorperasin acid

Methyl ester of 3-bromo-4-methoxyethoxy-5-triftorperasin acid (500 mg) was treated in a manner similar to stage a) and stage (b) of reference example 3, to obtain the specified title compound (157 mg).

1H-NMR (δ, 300 MHz, CDCl3): of 2.33 (3H, s), 3,91 (3H, s), by 5.87-of 5.89 (1H, m), 8,02 (1H, s), 8,08 (1H, s).

Reference example 6

Obtaining methyl ester 3-ethoxy-4-hydroxy-5-methoxybenzoic acid

On the diagram above reactions NBS means of N-bromosuccinimide; THF means tetrahydrofuran; Me means methyl; DMF means dimethylformamide and conc. H2SO4means concentrated sulfuric acid. Hereinafter in this description, each symbol has the same meaning as defined above.

a) 3-Bromo-5-ethoxy-4-hydroxybenzaldehyde

3 Ethoxy-4-guide is oxybenzaldehyde (5.0 g) was treated in a way similar to stage b) of reference example 2, to obtain specified in the connection header (4,85 g).

b) 3-Ethoxy-4-hydroxy-5-methoxybenzaldehyde

To a suspension of sodium hydride (843 mg) in THF (5 ml) was added methanol (675 mg) under ice cooling and the mixture was stirred at room temperature for 0.5 hours. Was added to a mixture of 3-bromo-5-ethoxy-4-hydroxybenzaldehyde (1.29 g) in dimethylformamide (10 ml) and copper chloride(I) (31 mg) and the mixture was stirred at 120ºC for 4 hours under heating. The mixture was allowed to stand for cooling to room temperature, diluted with ethyl acetate, washed with 1 N. hydrochloric acid, dried over anhydrous sodium sulfate and then concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 2:1, vol/about.) obtaining specified in the title compound (630 mg).

c) 3-Ethoxy-4-hydroxy-5-methoxybenzoic acid

To a solution of 3-ethoxy-4-hydroxy-5-methoxybenzaldehyde (578 mg), sodium dihydrophosphate (1,41 g) and amigorena acid (429 mg) in a mixture of dioxane (6 ml) - water (10 ml) was added an aqueous solution (3 ml) of sodium chlorite (400 mg) under ice cooling. The mixture was stirred for 2 hours under ice cooling. Was added to a mixture of hydrochloric acid and the reaction mixture was extracted with ethyl acetate. The extract was washed with 10% aqueous sodium thiosulfate and saturated of rest the rum salt, was dried over anhydrous sodium sulfate and concentrated to obtain specified in the title compound (586 mg).

d) Methyl ester of 3-ethoxy-4-hydroxy-5-methoxybenzoic acid

3 Ethoxy-4-hydroxy-5-methoxybenzoic acid (586 mg) was treated in a manner similar to stage a) of reference example 5, to obtain the specified title compound (558 mg).

Reference example 7

Getting 4-(2-isopropyl-2H-tetrazol-5-yl)phenol

On the diagram above reactions DMF means dimethylformamide; iPrI means isopropylated; Pd/C is palladium-on-carbon; THF means tetrahydrofuran and Me means methyl. Hereinafter in this description, each symbol has the same meaning as defined above.

a) 5-(4-Benzyloxyphenyl)-2H-tetrazol

To a solution of 4-benzyloxybenzoate (2.0 g) in dimethylformamide (15 ml) was added sodium azide (932 mg) and ammonium chloride (767 mg). The mixture was stirred at 110ºC overnight when heated and then allowed it to stand for cooling to room temperature. Was added to a mixture of 1 N. aqueous sodium hydroxide to bring the pH to about 10, after which the mixture was washed with diethyl ether. To the aqueous layer was added 1 N. hydrochloric acid and the resulting suspended solid was filtered to obtain specified in the connection header (to 2.29 g).

b) 5-(4-Be selectively)-2-isopropyl-2H-tetrazol

5-(4-Benzyloxyphenyl)-2H-tetrazole (500 mg) was added to a suspension of sodium hydride (96 mg) in dimethylformamide (5 ml) under cooling with ice. The mixture was stirred at room temperature for 0.5 hours. After adding to the mixture of isopropylidene (405 mg) and the mixture was stirred at 60ºC for 2 hours under heating. The reaction mixture was allowed to stand for cooling to room temperature, diluted with ethyl acetate, washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 4:1, vol/about.) obtaining specified in the title compound (571 mg).

c) 4-(2-Isopropyl-2H-tetrazol-5-yl)phenol

To a solution of 5-(4-benzyloxyphenyl)-2-isopropyl-2H-tetrazole (521 mg) in a mixture of THF (5 ml) - methanol (5 ml) was added to 7.5% palladium-on-carbon (60 mg). The mixture was stirred at room temperature for 3.5 hours in an atmosphere of hydrogen. The catalyst was filtered through a layer of celite. The filtrate was concentrated to obtain specified in the title compound (352 mg).

1H-NMR (δ, 300 MHz, CDCl3): to 1.70 (6H, d, J=6.4 Hz), 5,09 (1H, Sept., J=6.4 Hz), 5,59 (1H, s), to 6.95 (2H, d, J=8.7 Hz), of 8.04 (2H, d, J=8.7 Hz).

Reference example 8

Obtaining 2-(4-ethoxycarbonylphenyl)-6-methylnicotinic acid

On the diagram above reactions BnH means benzyl alcohol; DMAP means 4-dimethylaminopyridine; WSC mean 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide; DMF means dimethylformamide; Pd(PPh3)4means tetrakis(triphenylphosphine)palladium(0); Pd/C is palladium-on-carbon; THF means tetrahydrofuran; Me means methyl, Et means ethyl. Hereinafter in this description, each symbol has the same meaning as defined above.

a) Benzyl ether of 2-chloro-6-methylnicotinic acid

To a solution of 2-chloro-6-methylnicotinic acid (3.0 g), benzyl alcohol (2,27 g), 4-dimethylaminopyridine (2,56 g) in DMF (10 ml) was added the hydrochloride of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (WSC) (as 4.02 g). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed successively with water, saturated aqueous sodium bicarbonate, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 4:1, vol/about.) obtaining specified in the title compound (3.6 g).

b) Benzyl ether of 2-(4-ethoxycarbonylphenyl)-6-methylnicotinic acid

Benzyl ether of 2-chloro-6-methylnicotinic acid (1.0 g) and 4-methoxycarbonylpropionyl acid (722 mg) was treated in a manner similar to stage b) of reference example 1, to obtain the decree of the tion in the title compound (1.13 g).

c) 2-(4-Ethoxycarbonylphenyl)-6-methylnicotinic acid

Benzyl ether of 2-(4-ethoxycarbonylphenyl)-6-methylnicotinic acid (1.12 g) was treated in a manner similar to stage c) of reference example 7, to obtain specified in the header of the compound (821 mg).

1H-NMR (δ, 300 MHz, CDCl3): of 2.66 (3H, s), 3,93 (3H, s), 7,25 (1H, d, J=8,3 Hz), EUR 7.57 (2H, d, J=8,3 Hz), 8,07 (2H, d, J=8,3 Hz)to 8.14 (1H, d, J=8,3 Hz).

Reference example 9

Obtain methyl ester of 4-hydroxy-3-methoxy-5-methylbenzoic acid

On the diagram above NIS means N-iodosuccinimide; conc. H2SO4means concentrated sulfuric acid; MOMCl means simple chloromethylation ether; iPr2NET means diisopropylethylamine; Me means methyl; THF means tetrahydrofuran (THF) and Pd(PPh3)4means tetrakis(triphenylphosphine)palladium(0). Hereinafter in this description, each symbol has the same meaning as defined above.

a) Methyl ester of 4-hydroxy-3-iodine-5-methoxybenzoic acid

To a solution of 4-hydroxy-3-methoxybenzoic acid methyl ester (5.0 g) in tetrahydrofuran (20 ml) was added N-iodosuccinimide (6,17 g) at 0°C and the mixture was stirred for 1 hour. Precipitated precipitated solid was filtered, washed with water and dried to obtain specified in the connection header (9.60 g).

b) Methyl ester of 3-IO the-5-methoxy-4-methoxyethoxymethyl acid

To a solution of methyl ester 4-hydroxy-3-iodine-5-methoxybenzoic acid (4.6 g) in chloroform (30 ml) was sequentially added diisopropylethylamine (3.88 g) and simple chloromethylation ester (1.88 g) under ice cooling and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed sequentially with ethyl acetate, 1 N. hydrochloric acid, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 3:1, vol/about.) obtaining specified in the title compound (2.70 g).

c) Methyl ester of 3-methoxy-4-methoxyethoxy-5-methylbenzoic acid

To a solution of methyl ester of 3-iodine-5-methoxy-4-methoxyethoxymethyl acid (700 mg) in THF (7 ml) was added tetrakis(triphenylphosphine)palladium(0) (115 mg) and 2 M solution (1.20 ml) dimethylzinc in THF and the mixture was stirred at 80ºC for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with 1 N. hydrochloric acid, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuum to obtain specified in the header of the compound (767 mg) as a crude pale yellow oil.

d) Methyl ester of 4-hydroxy-3-methoxy-5-methylbenzoic acid

To a solution of methyl ester 3-methox the-4-methoxyethoxy-5-methylbenzoic acid (650 mg) in THF (5 ml) was added 6 N. hydrochloric acid (5 ml) and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 4:1, vol/about.) obtaining specified in the title compound (365 mg).

1H-NMR (δ, 300 MHz, CDCl3): of 2.27 (3H, s), 3,88 (3H, s), 3,93 (3H, s), equal to 6.05 (1H, s), 7,41 (1H, d, J=1,8 Hz), 7,52 (1H, d, J=1,8 Hz).

Reference example 10

Obtain methyl ester of 4-hydroxy-3-methoxy-5-triftorperasin acid

On the diagram above reactions DMF means dimethylformamide and THF means tetrahydrofuran. Hereinafter in this description, each symbol has the same meaning as defined above.

a) Methyl ester of 3-methoxy-4-methoxyethoxy-5-triftorperasin acid

To a solution of methyl ester of 3-iodine-5-methoxy-4-methoxyethoxymethyl acid (500 mg) in DMF (5 ml) was added copper iodide(I) (135 mg) and persulfonic(debtor)acetic acid methyl ester (409 mg). The mixture was stirred at 120ºC for 2 hours. The reaction temperature was then raised up to 140ºC, followed by stirring for 15 minutes. The reaction solution was diluted with ethyl acetate, washed with saturated solution of thiosul the ATA sodium, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuum to obtain specified in the title compound (453 mg) of the crude brown oil.

b) Methyl ester of 4-hydroxy-3-methoxy-5-triftorperasin acid

To a solution of methyl ester of 3-methoxy-4-methoxyethoxy-5-triftorperasin acid (453 mg) in THF (4 ml) was added 6 N. hydrochloric acid (4 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with ethyl acetate, washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 4:1-3:1, vol/about.) obtaining specified in the title compound (186 mg).

1H-NMR (δ, 300 MHz, CDCl3): to 3.92 (3H, s)to 4.01 (3H, s), 6,50 (1H, s), of 7.69 (1H, d, J=1.7 Hz), to $ 7.91 (1H, d, J=1.7 Hz).

Reference example 11

Getting the dimethyl ester of 4-hydroxy-5-methylisophthalic acid

On the diagram above reactions conc. H2SO4means concentrated sulfuric acid; Me means methyl; NBS means of N-bromosuccinimide; THF means tetrahydrofuran (THF) and Pd(dppf)Cl2means (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II). Hereinafter in this description, each character has a t is some set to the same value as specified above.

a) Dimethyl ether 4-hydroxyisophthalic acid

To a solution of 4-hydroxyisophthalic acid (16.0 g) in methanol (150 ml) was added concentrated sulfuric acid (5 ml) and the mixture is boiled under reflux for 22 hours. Then the reaction solution was allowed to stand for cooling to room temperature, diluted with water (150 ml) was added sodium bicarbonate (15 g). The precipitate was filtered off, washed successively with a mixture of water - methanol (1:1, vol/about.) (150 ml) and with water and dried to obtain specified in the connection header (17,45 g).

b) Dimethyl ether of 5-bromo-4-hydroxyisophthalic acid

To a solution of dimethyl 4-hydroxyisophthalic acid (10,51 g) in THF (100 ml) was added N-bromosuccinimide (9,34 g) under ice cooling and the mixture was stirred at room temperature for 2 hours. To the reaction solution were added successively water (200 ml) and saturated aqueous sodium bicarbonate solution (100 ml). The precipitate was filtered off, washed successively with saturated aqueous sodium bicarbonate solution and water and dried to obtain specified in the title compound (12.5 g).

c) Dimethyl ether of 5-bromo-4-methoxyethoxymethyl acid

To a solution of dimethyl 5-bromo-4-hydroxyisophthalic acid (12.3 g) in chloroform (130 ml) is therefore added diisopropylethylamine (8,24 g) and methoxymethane (4.11 g) under ice cooling and the mixture was stirred at room temperature overnight. The reaction solution was washed sequentially 1 N. hydrochloric acid, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 5:1, vol/about.) obtaining specified in the connection header (charged 8.52 g).

d) Dimethyl 4-hydroxy-5-methylisophthalic acid

To a solution of dimethyl 5-bromo-4-methoxyethoxymethyl acid (6,00 g) in dioxane (60 ml) was added to the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (600 mg) and 1 M solution (20 ml) diethylzinc in hexane and the mixture was stirred at 120ºC for 5.5 hours under heating. The reaction solution was allowed to stand for cooling to room temperature and was added dropwise 1 M hydrochloric acid (40 ml). After diluting the reaction solution with ethyl acetate (100 ml), the insoluble material was filtered through a layer of celite. The organic layer was separated, washed successively with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 9:1, vol/about.) obtaining specified in the connection header (2,97 g).

1H-NMR (δ, 300 MHz, CDCl3): 2,30 (3H, s), 3,90 (3H, s), 3,98 (3H, s), 8,00 (1H, is, J=2.3 Hz), 8,42 (1H, d, J=2.3 Hz), 11,46 (1H, s).

Working example 1-1

Phenyl ester of 3-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionic acid (compound 1-1)

a) 5-Iodine-2-nitrobenzoic acid

Sulfuric acid (40 ml) was poured in water (240 ml). After cooling the solution to 0ºC was added 5-amino-2-nitrobenzoic acid (23,6 g) and then was added phosphoric acid (200 ml). After cooling down to 10ºC to the mixture was added dropwise within 15 minutes with an aqueous solution (20 ml) of sodium nitrite (9.2 grams). The mixture was stirred at room temperature for 1 hour and filtered through a layer of celite. The filtrate was added dropwise to aqueous solution (400 ml) of potassium iodide (30 g). After the mixture was stirred at room temperature overnight, obtained in the precipitate solid was filtered to obtain specified in the title compound (30.0 g).

b) 5-Iodine-N,N-dimethyl-2-nitrobenzamide

5-Iodine-2-nitrobenzoic acid (15.5 g) was dissolved in chloroform (30 ml). To the solution was added at 0°C oxalicacid (13,4 g) and then added DMF (dimethylformamide) (0.1 ml). The mixture was stirred at room temperature for 2 hours and then concentrated. After adding to the residue of toluene, the mixture was again concentrated. The concentrated solution of the residue in ethyl acetate (60 ml) was added dropwise to the mixed is Astaro 50% (wt./mass.) aqueous dimethylamine (7.5 ml), saturated aqueous sodium bicarbonate solution (60 ml) and toluene (60 ml) under stirring and ice cooling. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated salt solution and concentrated to obtain specified in the title compound (15.3 g).

c) Ethyl ester of 3-(3-dimethylcarbamoyl-4-nitrophenyl)propionic acid

5-Iodine-N,N-dimethyl-2-nitrobenzamide (2.00 g) was dissolved in tetrahydrofuran (20 ml) and to the solution was added dichloride bis(triphenylphosphine)palladium(II) (0,128 g). After cooling to 0ºC to the mixture was added dropwise a 0.5 M brainy a solution of 3-ethoxy-3-oxopropyl (22.5 ml), the mixture was stirred at room temperature overnight. The reaction solution was concentrated, dissolved in ethyl acetate (100 ml), washed sequentially 1 N. hydrochloric acid (30 ml) and saturated salt solution (30 ml) and dried over sodium sulfate. Then the mixture was purified column chromatography on silica gel (ethyl acetate:hexane = 3:2, vol/about.) obtaining specified in the title compound (1.52 g) as a brown oil.

d) Ethyl ester of 3-(4-amino-3-dimethylcarbamoyl)propionic acid

Ethyl ester of 3-(3-dimethylcarbamoyl-4-nitrophenyl)propionic acid (1.52 g) was dissolved in the mixture solvent is THF (tetrahydrofuran) (15 ml) and ethanol (15 ml). RA is Toru was added to 7.5% (wt./mass.) palladium-on-carbon (300 mg), followed by stirring overnight at normal pressure in a hydrogen atmosphere. The reaction solution was filtered through a layer of celite and concentrated to obtain specified in the connection header (0,950 g) as a pale yellow oil.

e) Ethyl ester of 3-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionic acid

Ethyl ester of 3-(4-amino-3-dimethylcarbamoyl)propionic acid (1.52 g) was dissolved in ethyl acetate (10 ml) and to the solution was added trimethylamine (533 mg). After cooling to 0°C. to the mixture was added 4'-triptorelin-2-carbonylchloride (synthesized from the corresponding carboxylic acid 0,529 g) and the mixture was stirred at room temperature overnight. After filtering off the insoluble material, the filtrate was concentrated and was purified column chromatography on silica gel (ethyl acetate:hexane = 3:2, vol/about.) obtaining specified in the connection header (0,843 g).

f) 3-{3-Dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionic acid

Ethyl ester of 3-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionic acid (0,843 g) was dissolved in ethanol (4 ml) and to the solution was added 4 N. aqueous sodium hydroxide (1 ml). The mixture was stirred at room temperature for 2 hours, concentrated, acidified 1 N. hydrochloric acid and was extracted with ethyl acetate. The extract was washed with water and co is centered with obtaining specified in the connection header (0,740 g) as a colourless solid.

g) Phenyl ester of 3-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionic acid

4-Dimethylaminopyridine (30 mg), phenol (23 mg) and 3-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionic acid (100 mg) was dissolved in acetone (1 ml). After addition of WSC hydrochloride (50 mg) and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated and was purified column chromatography on silica gel (ethyl acetate:hexane = 1:1, vol/about.) obtaining specified in the title compound (compound 1-1) (0,088 g) as a colourless solid.

Working example 1-2

4-(3-Methyl-[1,2,4]oxadiazol-5-yl)phenyl ether 4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butane acid (compound 1-2)

a) 4-(3-Methyl-[1,2,4]oxadiazol-5-yl)phenol

To a mixed solution of 4-hydroxybenzoic acid (1.0 g) in a mixed solution (15 ml) of toluene and THF (toluene:THF = 2:1, vol/about.) added carbonyldiimidazole (1.29 g) and the mixture was stirred at room temperature for 1 hour. Then to the mixture was added N-hydroxyacetamido (644 mg), after which the mixture was boiled under reflux at about 150ºc for 2 hours. The reaction solution was allowed to stand for cooling to room temperature, diluted with ethyl acetate, washed successively with water and saturated the second salt solution, was dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (ethyl acetate:hexane = 1:1, vol/about.) obtaining specified in the title compound (132 mg).

b) 4-(3-Methyl-[1,2,4]oxadiazol-5-yl)phenyl ether 4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butane acid

4-(3-Methyl-[1,2,4]oxadiazol-5-yl)phenol (64 mg) and 4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butane acid (200 mg) (synthesized separately by a method similar to that described in working example 1-1) was treated with (WSC condensation) in a manner similar to stage g) of the working example 1-1, to obtain specified in the title compound (compound 1-2) (112 mg).

Working examples from 1-3 to 1-116

Compounds of working examples from 1-3 to 1-116 shown in tables 1-24, received a manner similar to the method for producing a 1 or a working example 1-1. Structure and NMR data of these compounds and compounds of working examples 1-1 to 1-2 are shown in tables 1-24. In the following tables connection working examples from 1-3 to 1-116 correspond to connections from 1-3 to 1-116, respectively.

Table 1
ExampleStructureYAM is (δ, 300 or 400 MHz, CDCl3)
1-12,73-3,07 (10H, m), 6,69-7,01 (2H, m), 7,07 (1H, d, J=1.9 Hz), 7.18 in-7,34 (5H, m), 7,44-7,58 (2H, m), a 7.62 (4H, users), of 7.69 (1H, DD, J=1.5 Hz, 7.2 Hz), with 8.33 (1H, J=8.7 Hz), 9,05 (1H, users).

1-22,04 (2H, Quint., J=7.5 Hz), 2,47 (3H, s), to 2.57 (2H, t, J=7.5 Hz), 2,70 (2H, t, J=7.5 Hz), 2,87 (3H, users), to 2.94 (3H, users), 7,00 (1H, d, J=1.5 Hz), 7,22-7,26 (3H, m), 7,38 to 7.62 (7H, m), of 7.69 (1H, DD, J=7,5, 1.5 Hz), 8,12-8,15 (2N, m), 8,30 (1H, d, J=8,3 Hz), 8,97 (1H, s).
1-3is 2.88 (3H, users), to 2.94 (3H, users), of 3.80 (2H, s), 7,02 (2H, d, J=7.5 Hz), 7,19-7,27 (2H, m), 7,31-the 7.43 (4H, m), 7,45-7,58 (2H, m), a 7.62 (4H, users), of 7.70 (1H, DD, J=1.5 Hz, 7.5 Hz), 8,42 (1H, d, J=8.7 Hz), 9,16 (1H, users).
1-42,87 (3H, users), to 2.94 (3H, users), with 3.79 (2H, s), 6,95-to 7.09 (4H, m), 7,20 (1H, d, J=1.9 Hz), 7,34-7,44 (2H, m), 7,45-7,58 (2H, m), a 7.62 (4H, users), of 7.70 (1H, DD, J=1.5 Hz, 7.5 Hz), 8,42 (1H, d, J=8.7 Hz), 9,14 (1H, users).

1-5 2,03 (2H, Quint., J=7.4 Hz), of 2.56 (2H, t, J=7.4 Hz), 2,69 (2H, t, J=7.4 Hz), 2,85 (3H, users), 2,95 (3H, user. C)3,91 (3H, s), 7,00 (1H, d, J=1.9 Hz), 7,14 (2H, d, J=8,8 Hz), 7,22-7,28 (1H, m), 7,40 (1H, DD, J=1,4, 7.5 Hz), 7,46-7,56 (2H, m), of 7.64 (4H, s), of 7.69 (1H, DD, J=1,4, 7.5 Hz), 8,07 (2H, d, J=8,8 Hz), 8.30 to (1H, d, J=8,4 Hz), 8,99 (1H, s)
1-61.39 (3H, t, J=7.2 Hz), 1,95 is 2.10 (2H, m), of 2.56 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7.5 Hz), 2,86 (MN, users), to 2.94 (3H, users), 4,37 (4H, square, J=7,2 Hz), 7,00 (1H, 1.9 Hz), 7,13 (2H, d, J=8.7 Hz) 7,22-7,28 (1H, m),7.40 (1H, DD, J=1.5 Hz, 7.2 Hz), 7,44-EUR 7.57 (2H, m), a 7.62 (4H, users), of 7.69 (1H, DD, J=1.9 Hz, 7.5 Hz), 8,07 (2H, d, J=8.7 Hz), 8,29 (1H, d, J=8.7 Hz), 8,98 (1H, users).

Table 2
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-71,34 (6N, d, J=6.3 Hz), a 2.01 (2H, Quint., J=7,4 Hz)to 2.54 (2H, t, J=7.4 Hz), to 2.67 (2H, t, J=7.4 Hz), and 2.83 (3H, users), 2, 93 (3H, users), with 5.22 (1H, Sept., J=6.3 Hz), 6,98 (1H, d, J=1,8 Hz), 7,10 (2H, d, J=8.6 Hz), 7,20-7,26 (1H, m), 7,38 (1H, d, J=7,4 Hz), 7,43-7,56 (2H, m), 7,60 (4H, s), to 7.67 (1H, d, J=7,4 Hz), of 8.04 (2H, d, J=8,8 Hz), of 8.27 (1H, d, J=8.4 and Hz), 8,97 (1H, s).

1-8 to 1.00 (3H, t, J=7.4 Hz), 1,71-to 1.82 (2H, m), a 2.01 (2H, Quint., J=7,4 Hz)to 2.54 (2H, t, J=7.4 Hz), to 2.67 (2H, t, J=7.4 Hz), and 2.83 (3H, users), with 2.93 (3H, users), 4.26 deaths (2H, t, J=6.8 Hz), 6,98 (1H, d, J=l,8 Hz), 7,11 (2H, d, J=8,8 Hz), 7,20-7,26 (1H, m), 7,38 (1H, d, J=7,6 Hz), 7,43-7,56 (2H, m), 7,60 (4H, s), to 7.67 (1H, d, J=7,4 Hz), with 8.05 (2H, d, J=8,8 Hz), of 8.28 (1H, d, J=8,4 Hz), 8,97 (1H, s).
1-91,96 is 2.10 (2H, m), is 2.44 (3H, s)to 2.55 (2H, t, J=7.2 Hz), 2,61 (2H, t, J=7.4 Hz), 2,86 (3H, users), 2.94 (3H, users), 3,91 (3H, s), of 6.99 (1H, d, J=1.9 Hz), 7,14 (2H, J=8.7 Hz), 7.18 in-7,31 (3H, m), 7,55-to 7.64 (5H, m), of 8.06 (2H, d, J=8.7 Hz), 8,29 (1H, d, J=8.7 Hz), 8.95 (1H, users).

1-101,96-2,07 (2H, m), 2.57 m (2H, dt, J=2,1, 7,2 Hz), 2,68 (2H, dt, J=2,1, 7.5 Hz), and 2.83 (3H, users), with 2.93(3H, users), 3,90 (3H, d, J=2.3 Hz), 6, 98 (1H, s), 7,13-7,19 (1H, m), 7,20-7,26 (1H, m), 7,35-7,40(1H, m), 7,43-rate of 7.54 (2H, m), to 7.59 (4H, d, J=2.1 Hz), 7, 67(1H, d, J=7,7 Hz), 7,78-7,86 (2H, m), of 8.28 (1H, DD, J=2,1, 8.5 Hz), 8,98 (1H, s).
1-111,99-of 2.09 (2H, m)2,60 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7.4 Hz), 2,84 (3H, users),2.93 (MN, users), 3,90 (3H, s), 6,98 (1H, d, J=1.6 Hz), 7,17 (1H, d, J=8,4 Hz), 7,21-7,26 (1H, m), 7,37 (1H, d, J=7,6 Hz), 7,44-rate of 7.54 (2H, m), 7,60 (4H, s), 7,66 (1H, d, J=7,2 Hz),7.94 (1H, DD, J=2.0 a, and 8.4 Hz), 8,11 (1H, d,J=2.0 Hz), of 8.28 (1H, d, J=8.5 Hz), 8,98 (1H, s).

Table 3
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-12a 2.01 (2H, Quint., J=7,4 Hz)to 2.55 (2H, t, J=7.4 Hz), 2,69 (2H, t, J=7.4 Hz), and 2.83 (3H, users), 2, 92 (3H, users), 3,85 (3H, s), 3,90 (3H, s), of 6.99 (1H, d, J=l,8 Hz), 7,05 (1H, d, J=8.1 Hz), 7,21-7,28 (1H, m), 7,37 (1H, DD, J=1,1, 7,7 Hz), 7,43-of 7.55 (2H, m), 7,60 (4H, s), 7,63-of 7.69 (3H, m), of 8.27 (1H, d, J=8,3 Hz), 8, 98 (1H, s).
1-132,03 (2H, Quint., J=7.5 Hz), of 2.56 (2H, t, J=7.5 Hz), to 2.66 (3H, s), 2,70 (2H, t, J=7.5 Hz), 2,86 (6N, users), 3, 91 (3H, s), 7,00 (1H, d, J=1,8 Hz), 7,11-7,16 (2H, m), 7,25-7,29 (2H, m), 7,63-the 7.65 (2H, m), 7,86-a 7.92 (3H, m), 8,04-of 8.09 (2H, m), of 8.37 (1H, d, J=8,3 Hz), 9,12 (1H, s).

1-141,95-of 2.08 (2H, m), of 2.54 (2H, t, J=7.2 Hz), 2,60 (3H, s), 2,69 (2H, t, J=7.5 Hz), 2,86 (3H, users), to 2.94 (3H, users), 3,88 (3H, s), 6,92-7,02 (3H, m), 7,22-7,28 (1H, m), 7,40 (1H, DD, J=1.5 Hz, 7.2 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, users), 7, 69 (1H, DD, J=1.5 Hz and 7.6 Hz), of 7.96 (1H, d, J=9.4 Hz), 8,29 (1H, J=8.7 Hz), 8,99 (1H, users).
1-151,77-to 1.87 (2H, m), 1,88-to 1.98 (2H, m), 1,98-of 2.09 (2H, m), of 2.56 (2H, dt, J=2.1 a, 7,4 Hz), 2,70 (2H, t, J=7.4 Hz), 3,35-of 3.42 (2H, m), 3,47-3,55 (2H, m)to 3.92 (3H, d, J=2.1 Hz), 7,11-to 7.18 (3H, m), 7,21-7,27 (1H, m), 7,38 (1H, dt, J=l,6, and 7.4 Hz), 7,44-of 7.55 (2H, m), 7,60 (4H, d, J=2.1 Hz), to 7.68 (1H, DD, J=1,6, 7,2 Hz), 8,04-of 8.09 (2H, m), of 8.27 (1H, DD, J=2,1, 8.6 Hz), to 9.66 (1H, s).

1-161.39 (3H, t, 7.2 Hz), 1,78 of 1.99 (4H, m), 2,04 (2H, Quint., J=7,2 Hz), 2,60 (2H, t, J=7.2 Hz), a 2.71 (2H, t, J=7.2 Hz),3.40 (2H, t, J=6.4 Hz), 3,52 (2H, t, J=7.0 Hz), to 4.38 (2H, square, J=7,2 Hz), 7,16-7,20 (2H, m), 7,22-7,27 (1H, m), 7,39 (1H, DD, J=1,4, 7,4 Hz), 7,44-7,56 (2H, m), 7,60 (4H, s), to 7.68 (1H, DD, J=1,6, 7,4 Hz), 7,82-a 7.85 (2H, m), of 8.28 (1H, d, J=8,4 Hz)9,68 (1H, s).

Table 4
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-172,02 (2H, Quint., J=7,4 Hz)to 2.55 (2H, t, J=7.4 Hz), 2,69 (2H, t, J=7.4 Hz), 2,85 (3H, users), 2,95 (3H, user. C), 3,88 (3H, s)to 3.89 (3H, s)6,70-6,72 (2H, m), 7,00 (1H, d, J=2.1 Hz), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=7,5, and 1.4 Hz), 7,46-7,62 (6N, m)of 7.69 (1H, DD, J=7,5, and 1.4 Hz), the 7.85 (1H, d, J=9,l Hz), 8,30 (1H, d, J=8.6 Hz), 8,98 (1 is, C).
1-182,02 (2H, Quint., J=7,4 Hz)to 2.55 (2H, t, J=7.4 Hz), 2,68 (2H, t, J=7.4 Hz), 2,86 (3H, users), 2,95 (3H, users), to 3.92 (3H, d, 0.7 Hz), of 6.99 (1H, d, J=l,8 Hz), 7.03 is-was 7.08 (1H, m), 7,21-7,27 (2H, m), 7,40 (1H, DD, J=0.7 and 7.4 Hz), 7,46-7,56 (2H, m), of 7.64 (4H, s), of 7.69 (1H, DD, J=l,4, 7,7 Hz), 7,89 (1H, DD, J=0.7 and 8.6 Hz), 8,29 (1H, d, J=8,4 Hz), 8,98 (1H, s).

1-19is 2.05 (2H, Quint., J=7,6 Hz), 2,58 (2H, t, J=7,6 Hz), of 2.72 (2H, t, J=7,6 Hz), 3,01 (6N, (C), 3,91 (3H, s), 7,08-7,28 (4H, m), 7,52-7,73 (5H, m), of 7.96 (1H, DD, J=8,3, 1.5 Hz), 8,05-8,08 (2H, m), of 8.25 (1H, d, J=8,3 Hz), 8,86 (1H, s), 9.28 are (1H, s).
1-202.04 (2H, Quint., J=7.4 Hz), 2,61 (2H, t, J=7.4 Hz), 2,69 (2H, t, J=7.4 Hz), 2,87 (3H, users), to 2.94 (3H, users), of 3.95 (3H, s), 7,00 (1H, d, J=1.9 Hz), 7.23 percent-7,62 (N, m)of 7.69 (1H, DD, J=7,2, 1.5 Hz), 8,23-at 8.36 (3H, m), of 9.00 (1H, ).
1-212,03 (2H, Quint., J=7.5 Hz), to 2.57 (2H, t, J=7.5 Hz), 2,69 (2H, t, J=7.5 Hz), 2,87 (3H, users), to 2.94 (3H, users), 3,93 (3H, s), 7,00 (1H, d, J=2.3 Hz), 7,19-of 7.70 (10H, m), of 7.69 (1H, d, J=7,6 Hz), 7,86 (1H, d, J=8.7 Hz), 8,30 (1H, d, J=8,3 Hz), 8,97 (1H, s).

1-222,03 (2H, Quint., J=7,6 Hz), of 2.56 (2H, t, J=7,6 Hz)at 2.59 (3H, s), 2,69 (2H, t, J=7,6 Hz), 2,87 (3H, users), to 2.94 (3H, users), 7,00 (1H, d, J=1.9 Hz), 7,15-7,26 (3H, m), 7,38 to 7.62 (7H, m), of 7.69 (1H, DD, J=7,5, 1.5 Hz), 7,98-8,00 (2N, m), 8,30 (1H, d, J=8,3 Hz), 8,98 (1H, s).
Table 5
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-232,02 (2H, Quint., J=7, 4 Hz), of 2.56 (2H, t, J=7.4 Hz), 2,69 (2H, t, J=7.4 Hz), 2,86 (3H, users), to 2.94 (3H, users), of 6.99 (1H, d, J=1.9 Hz), 7.18 in-7,26 (3H, m), 7,38-7,69 (10H, m), 8,29 (1H, d, J=8.6 Hz), of 8.95 (1H, s).

1-242,02 (2H, Quint., J=7.5 Hz), to 2.55 (2H, t, J=7.5 Hz), 2,69 (2H, t, J=7.5 Hz), 2,86 (3H, users), with 2.93 (3H, users), are 5.36 (2H, s), of 6.99 (1H, d, J=1.1 Hz), 7,12-7,26 (3H, m), 7,34-to 7.61 (N, m)of 7.69 (1H, DD, J=7,2, 1.1 Hz), 8,09-8,11 (2N, m), 8,29 (1H, d, J=8,3 Hz), 8,98 (1H, s).
1-252,03 (2H, Quint., J=7,2 Hz), of 2.56 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7.2 Hz), 2,86 (3H, users), to 2.94 (3H, user. C)to 7.00 (1H, d, J=1.5 Hz), 7,14-7,26 (3H, m), 7,38 to 7.62 (7H, m), of 7.69 (1H, DD,J=7,2, 1.5 Hz), 8,09-to 8.12 (2H, m), compared to 8.26 (1H, d, J=8,3 Hz), 8,98 (1H, s).

1-262,04 (2H, Quint., J=7.4 Hz), to 2.57 (2H, t, J=7.4 Hz), a 2.71 (2H, t, J=7.4 Hz), 3,41-3,71 (8H, m)to 3.92 (3H, s), of 6.99 (1H, d, J=1,8 Hz), 7,10-7,16 (2H, m), 7.23 percent-7,29 (1H, m), 7,41 (1H, DD, J=0,9, 7,4 Hz), 7,46-7,69 (7H, m), 8,05-8,13 (3H, m), 8,79 (1H, s).
1-27was 2.76-is 3.08 (1H, m), 3,91 (3H, 2), 6,99-7,06 (1H, m), was 7.08 (2H, d, J=9.0 Hz), 7,19-7,58 (4H, m), a 7.62 (4H, s), 7,66-7,72 (1H, m), with 8.05 (2H, d, J=9.0 Hz), with 8.33 (1H, d, J=8.7 Hz), 9,03 (1H, users).

1-282,04 (2H, Quint., J=7.5 Hz), to 2.57 (2H, t, J=7.5 Hz), a 2.71 (2H, t, J=7.5 Hz), 2,86 (6N, users), 7,01 (1H, d, J=l,9 Hz), 7,14 (2H, d, J=8.7 Hz), 7.24 to to 7.32 (1H, m), 7,42 (1H, DD, J=4,9 Hz, 7.9 Hz), 7,66 (2H,d, J=8,3 Hz), 7,89 (2H, d, J=8,3 Hz), 8,03 (1H, DD, J=7.9 Hz, 1.9 Hz), 8,07 (2H, d, J=8.7 Hz), at 8.36 (1H, d, J=8.7 Hz), 8,79 (1H, DD, J=1.9 Hz, 4.9 Hz), of 9.21 (1H, users).

Table 6
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-291,36 (6N, d, J=6.4 Hz), 2,04(2H, Quint., J=7.5 Hz), to 2.57 (2H, t, J=7.5 Hz), a 2.71 (2H, t, J=7.5 Hz), 2,86 (6N, user. C)of 5.24(1H, Sept., J=6.4 Hz), 7,01 (1H, d, J=1,8 Hz), 7,12 (1H, d, J=8.7 Hz), 7.24 to to 7.32 (1H, m), 7,41 (1H, DD, J=4,8 Hz, 7.9 Hz), 7,66 (2H, d, J=7.9 Hz), 7,89 (2H, d, J=7.9 Hz), 7,99-of 8.04 (1H, m), of 8.06 (2H, d, J=8.7 Hz), at 8.36 (1H, d, J=8.7 Hz), 8,80 (1H, DD, J=1.9 Hz, 4.8 Hz), 9,12 (1H, users).

1-302,00-2,09 (2H, m), to 2.57 (2H, t, J=7.4 Hz), a 2.71 (2H, t, 7.7 Hz), 2,84-2,98 (6N, m) , 3,91 (3H, s), 7,03 (1H, d, J=2.2 Hz), 7,13 (2H, d, J=8.6 Hz), 7,21-7,31 (1H, m), EUR 7.57 (1H, d, J=4.6 Hz), 7,63 (2H, d, J=8.5 Hz), to 7.68 (2H, d, J=8.5 Hz), 8,07 (2H, d, J=8.6 Hz), of 8.28 (1H, d, J=8,3 Hz), 8,63-8,76 (2H, m), 9,29 (1H, m)
1-311,36 (6N, d, J=6.3 Hz), 2,03 (2H, Quint., J=7.4 Hz), of 2.56 (2H, t, J=7.4 Hz), 2,70 (2H, t, 7.7 Hz), 2,84-2,99 (6N, m), 5,24 (1H, Sept., J=6.3 Hz), 7,03 (1H, d, J=2.2 Hz), 7,12 (2H, d, J=8,2 Hz), 7.23 percent-7,29 (1H, m), EUR 7.57 (1H, d, J=4.9 Hz), to 7.64 (2H, d, 8,3 Hz), to 7.68 (2H, d, 8,3 Hz), of 8.06 (2H, d, J=8,2 Hz), of 8.28 (1H, d, J=8.6 Hz), 8,67-8,81 (2N, m), of 9.30 (1H, m).

1-322,04 (2H, Quint., J=7.5 Hz), 2,61 (2H, t, J=7.5 Hz), to 2.67 (3H, s), 2,70 (2H, t, J=7.5 Hz), 2,87 (6N, users), to 4.01 (3H, s), 7,00 (1H, d, J=2.2 G is), 7,25-7,28 (2H, m), 7,60-7,66 (3H, m), 7,86-a 7.92 (3H, m), 8,19 (1H, d, J=9.0 Hz), at 8.36(1H, d, J=8.7 Hz), charged 8.52 (1H, d, J=2.7 Hz), 9,10 (1H, s).
1-332.04 (2H, Quint., J=7,2 Hz), of 2.64 (2H, t, J=7.2 Hz), a 2.71 (2H, t, J=7.2 Hz), 2,87 (3H, users), to 2.94 (3H, users), a 3.87 (3H, s), of 3.94 (3H, s),? 7.04 baby mortality (1H, d, J=1.9 Hz), to 7.15 (1H, d, J=8.7 Hz), 7,25-7,30 (1H, m), 7,39 (1H, DD, J=1,1 Hz, 7.5 Hz), 7,44-EUR 7.57 (2H, m), of 7.69 (1H, DD, J=1.9 Hz, 7.2 Hz), by 8.22 (1H, DD, J=2.3 Hz, 8.7 Hz), 8,30 (1H, d, J=8.7 Hz), 8,68 (1H, d, J=2.3 Hz), of 9.00 (1H, users).

Table 7
ExampleStructureNMR (δ, 300 or 400 MHz, CDC13)
1-342,07 (2H, Quint., J=7,2 Hz), 2,22 (3H, s)of 2.64 (2H, t, J=7.2 Hz), 2,73 (2H, t, J=7.2 Hz), 2,86 (3H, users), to 2.94 (3H, users), 3,91 (3H, s), 7,01 (1H, d, J=1.9 Hz), 7,25 (1H, DD, J=1.9 Hz, 8.7 Hz), 7,40 (1H, DD, J=l l Hz, 7.2 Hz), 7,44-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=l,9 Hz, 7.2 Hz), 7,83 (1H, d, J=1.9 Hz), of 7.96 (1H, d, J=1.9 Hz), 8,30 (1H, d, J=8.7 Hz), of 9.00 (1H, users).
1-352,07 (2H, Quint., J=7,1 Hz), 2,22 (3H, s)of 2.64 (2H, t, J=7,1 Hz)to 2.67 (3H, s), by 2.73 (2H, t, J=7,1 Hz), 2,87 (6N, users), 3,91 (3H, s), 7,02 (1H, d, J=1.9 Hz), 7,25-7,0 (2H, m), 7, 63-7, 66 (2H, m), 7,83-of 7.96 (5H, m), of 8.37 (1H, d, J=8.7 Hz), to 9.15 (1H, s).

1-36to 2.06 (2H, Quint., J=7.2 Hz), 2.63 in(2H, t, J=7.2 Hz), to 2.66 (3H, s), by 2.73 (2H, t, J=7.2 Hz), 2,86 (6N, users), 3,88 (3H, s), 3,93 (3H, s), 7,02 (1H, d, J=2.3 Hz), 7,26 (1H, d, J=7.9 Hz), 7,27-to 7.32 (1H, m), 7,55 (1H, d, J=1,9 Hz), the 7.65 (2H, d, J=8,3 Hz), of 7.75 (1H, d, J=1.9 Hz), 7,87 (2H, d, J=8,3 Hz), to $ 7.91 (1H, d, J=7.9 Hz), at 8.36 (1H, d, J=8.7 Hz), to 9.15 (1H, users).
1-371,37 (6N, d, J=6.0 Hz), to 2.06 (2H, Quint., J=7.2 Hz), 2.63 in (2H, t, J=7.2 Hz), to 2.67 (3H, s), by 2.73 (2H, t, J=7.2 Hz), 2,86 (6N, users), 3,88 (3H, in), 5.25 (1H, Sept., J=6.0 Hz), 7,02 (1H, d, J=2.3 Hz), 7,26 (1H, d, J=7.9 Hz), 7,27-7,31 (1H, m), 7,54 (1H, d, J=1.9 Hz), the 7.65 (2H, d, J=8,3 Hz), 7,73 (1H, d, J=1.9 Hz), 7,87 (2H, d, J=8,3 Hz), to $ 7.91 (1H, d, J=7.9 Hz), 8,87 (1H, d, J=8.7 Hz), 9,16 (1H, users).

1-381,37 (6N, t, J=6.0 Hz), was 2.05 (2H, Quint., J=7,2 Hz), 2,62 (2H, t, J=7.2 Hz), to 2.66 (3H, s), of 2.72 (2H, t, J=7.2 Hz), 2,87 (6N, users), the 3.89 (3H, s), of 5.24 (1H, Sept., J=6.0 Hz), 7,02 (1H, d, J=1.9 Hz), 7,25-7,30 (2H, m), 7,46-7,49 (2H, m), 7,63-7,66 (2H, m), 7,86-to 7.93 (3H, m), of 8.37 (1H, d, J=8,3 Hz), 9,16 (1H, s).
Table 8
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-39is 2.05 (2H, Quint., J=7,2 Hz), 2,61 (2H, t, J=7.2 Hz), to 2.66 (3H, s), by 2.73 (2H, t, J=7.2 Hz), 2,86 (6N, users), 3,86 (6N, C)to 3.92 (3H, s), 7,03 (1H, d, J=1.9 Hz), 7,25-7,33 (4H, m), 7,63-7,66 (2H, m), 7,86-to 7.93 (3H, m), at 8.36 (1H, d, J=8.7 Hz), to 9.15 (1H, s).

1-40of 1.37 (3H, t, J=6.8 Hz), to 2.06 (2H, Quint., J=7.2 Hz), 2.63 in (2H, t, J=7.2 Hz), to 2.67 (3H, s), is 2.74 (2H, t, J=7.2 Hz), 2,86 (6N, user. s), 3.92 (3H, s), of 4.12 (2H, square, J=6,8 Hz), 7,03 (1H, d, J=1.9 Hz), 7,25-7,31 (2H, m), 7,53 (1H, d, J=1.9 Hz), 7,63-7,66 (2H, m), 7,73 (1H, d, J=1.9 Hz), 7,86-7.93 (3H, m), of 8.37 (1H, d, J=8,3 Hz), 9,16 (1H with).
1-41to 2.06 (2H, Quint., J=7,2 Hz), of 2.23 (3H, s), 2.63 in (2H, t, J=7.2 Hz), to 2.67 (3H, s), of 2.72 (2H, t, J=7.2 Hz), 2,87 (6N, users), 3,91 (3H, s), 7,01 (1H, d, J=1.9 Hz), 7,25-7,29 (2H, m), 7,63-to 7.68 (3H, m), 7,74 (1H, s), 7,86-to 7.93 (3H, m)of 8.37 (1H, d, J=8.6 Hz), 9,16 (1H, s).

1-42of 1.20 (3H, t, J=7,7 Hz)to 2.06 (2H, Quint., J=7.5 Hz), 2,55-to 2.65 (4H, m), 267 (3H, C)of 2.72 (2H, t, J=7.5 Hz), 2,87 (6N, user. C), 3, 92 (3H, s), 7,01 (1H, d, J=2.3 Hz), 7,25-7,29 (2H, m), 7,63-of 7.69 (3H, m), 7,76 (1H, s), 7, 86-7,93 (3H, m), of 8.37 (1H, d, J=8,3 Hz), 9,16 (1H, s).
1-43of 1.33 (3H, t, J=6.9 Hz), of 1.93 (2H, Quint., J=7,1 Hz), to 2.57 (2H, t, J=7,l Hz), 2,60 (3H, s), 2,70 (2H, t, J=7,1 Hz), 2,78 (3H, s), 2,87 (3H, s), 3,82 (6N, (C), 4,34 (2H, square, J=6.9 Hz), to 7.15 (1H, d, J=1.5 Hz), 7,27-7,30 (2H, m), 7,44 (2H, DD, J=2,2, 7.9 Hz), 7,80-to $ 7.91 (6N, m), 10,13 (1H, s),

1-441,38 (6N, d, J=6.4 Hz), was 2.05 (2H, Quint., J=7,1 Hz), 2,60 (2H, t, J=7,l Hz)to 2.67 (3H, s), by 2.73 (2H, t, J=7,1 Hz), 2,86 (6N, users), 3,86 (6N, in), 5.25 (1H, Sept., J=6.4 Hz),? 7.04 baby mortality (1H, d, J=2.3 Hz), 7,25-to 7.32 (4H, m), the 7.65 (2H, d, J=8.7 Hz), 7,86-to 7.93 (3H, m), at 8.36 (1H, d, J=8,2 Hz), 9,16 (1H, s).

Table 9
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-45is 2.05 (2H, Quint., J=7,2 Hz), of 2.23 (3H, s), 2,62 (2H, t, J=7.2 Hz), to 2.67 (3H, s), 2,70 (2H, t, J=7.2 Hz), 2,87 (6N, user. C)of 3.94 (3H, s), 7,01 (1H, d, J=l,8 Hz), 7,25-7,29 (2H, m), the 7.65 (2H, d, J=8,l Hz), 7,88 (2H, d, J=8.1 HZ), TO $ 7.91 (1H, d, J=,1 Hz), 8,14-8,19 (2H, m), scored 8.38 (1H, d, J=8.1 Hz), 9,16 (1H, s).

1-46is 2.05 (2H, Quint., J=7,2 Hz), 2,19 (3H, s), 2,60 (2H, t, J=7.2 Hz), to 2.67 (3H, s), by 2.73 (2H, t, J=7.2 Hz), 2,8 6 (3H, users), of 3.84 (3H, s), 3,91 (3H, s), 7,02 (1H, d, J=1.9 Hz), 7.24 to 7,31 (2H, m), of 7.48 (1H, d, J=1.9 Hz), 7,56 (1H, d, J=1.9 Hz), to 7.64 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=8,3 Hz), 7,92 (1H, d, J=7.9 Hz), at 8.36 (1H, d, J=8,3 Hz)to 9.15 (1H, users).
1-472,04 (2H, Quint., J=7, 2 Hz), 2,61 (2H, t, J=7.2 Hz), to 2.66 (3H, s), a 2.71 (2H, t, J=7.2 Hz), 2,86 (6N, users), 3,91 (3H, s), of 3.96 (3H, s), 7,02 (1H, d, J=1.9 Hz), 7.23 percent-7,31 (2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,83 (1H, d, J=1.5 Hz), 7,88 (2H, d, J=8,3 Hz), 7,92 (1H, d, J=7.9 Hz), 7,94 (1H, d, J=1.5 Hz), of 8.37 (1H, d, J=8,3 Hz), 9,16 (1H, users).

1-48of 1.40 (3H, t, J=7.2 Hz), to 2.06 (2H, Quint., J=7.2 Hz), 2.63 in (2H, t, J=7.2 Hz), to 2.67 (3H, s), by 2.73 (2H, t, J=7.2 Hz), 2,86 (6N, users), 3,88 (3H, s), 4,39 (2H, square, J=7,2 Hz), 7,03 (1H, d, J=l,9 Hz), 7.24 to 7,31 (2H, m), 7,55 (1H, d, J=1.9 Hz), 7,65 (2H, d, J=8,3 Hz), of 7.75 (1H, d, J=l,9 Hz), 7,88 (2H, d, J=8,3 Hz), 7,92 (1H, d, J=7.9 Hz), of 8.37 (1H, d, J=8,3 Hz), 9,16 (1H, users).

1-49 of 1.36 (3H, t, J=7,1 Hz), was 2.05 (2H, Quint., J=7,2 Hz), 2,60 (2H, t, J=7.2 Hz), to 2.67 (3H, s), is 2.74 (2H, t, J=7.2 Hz), 2,86 (6N, users), 3,86 (3H, s)to 3.92 (3H, s), 4,10 (2H, square, J=7,1 Hz),? 7.04 baby mortality (1H, d, J=1.9 Hz), 7,25-7,31 (4H, m), the 7.65 (2H, d, J=7,9 Hz), 7,88 (2H, d, J=7.9 Hz), 7,92 (1H, d, J=7.9 Hz), at 8.36 (1H, d, J=8,3 Hz), 9,16 (1H, s).
Table 10
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-502,07 (2H, Quint., J=7.2 Hz), 2.63 in (2H, t, J=7.2 Hz), to 2.67 (3H, s), is 2.74 (2H, t, J=7.2 Hz), 2,86 (6N, users), a 3.87 (3H, s), 3,93 (3H, s), 7,03 (1H, d, J=1.9 Hz), 7,25-7,31 (2H, m), to 7.59 (1H, d, J=1.9 Hz), the 7.65 (2H, d, J=8,3 Hz), 7,86-to 7.93 (4H, m), of 8.37 (1H, d, J=8,3 Hz)to 9.15 (1H, s).

1-51to 1.21 (3H, t, J=7.5 Hz), to 2.06 (2H, Quint., J=7.5 Hz), 2,60 (2H, square, J=7.5 Hz), to 2.66 (3H, s), 2,67-2,78 (4H, m), 2,86 (6N, users), 3,86 (3H, s), of 3.94 (3H, s), 7,05 (1H, d, J=1.9 Hz), 7.23 percent-7,33 (2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=8,3 Hz), a 7.92 (1H, d, J=7.9 Hz), 8,13 (1H, d, J=1.9 Hz), of 8.37 (1H, d, J=8,3 Hz), charged 8.52 (1H, d, J=1.9 Hz), to 9.15 (1H, users).

1-52 of 1.40 (3H, t, J=7.2 Hz), to 2.06 (2H, Quint., J=7,1 Hz in), 2.25 (3H, s)to 2.67 (2H, t, J=7,1 Hz)to 2.67 (3H, s), by 2.73 (2H, t, J=7,1 Hz),2.87 (6N, user. C), 3,86 (3H, s), and 4.40 (2H, square, J=7,2 Hz), 7,05 (1H, d, J=1.9 Hz), 7,25-to 7.32 (2H, m), the 7.65 (2H, d, J=8,3 Hz),7.88 (2H, d, J=8,3 Hz), 7,92 (1H, d, J=7.9 Hz), 8,11 (1H, d, J=2.3 Hz), at 8.36 (1H, d, J=8,3 Hz)and 8.50 (1H, d, J=2.3 Hz), to 9.15 (1H, c).
1-53to 2.06 (2H, Quint., J=7,2 Hz), to 2.65 (2H, t, J=7.2 Hz), to 2.67 (3H, s), is 2.74 (2H, t, J=7.2 Hz),2.87 (6N, users), a 3.87 (3H, s), 3,90 (3H, s), 3,95 (ZN, C), 7,05 (1H, d, J=1.9 Hz), 7,25-to 7.32 (2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,80 (1H, d, J=1.9 Hz),7.88 (2H, d, J=8,3 Hz), 7,92 (1H, d, J=7.9 Hz), of 8.25 (1H, d, J=2.2 Hz), at 8.36 (1H, d, J=8,3 Hz)to 9.15 (1H, s).

1-54of 1.41 (3H, t, J=7.2 Hz), to 2.06 (2H, Quint., J=7,2 Hz), to 2.65 (2H, t, J=7.2 Hz), to 2.67 (3H, s), is 2.74 (2H, t, J=7.2 Hz),2.87 (6N, user. C)a 3.87 (3H, s), 3,90 (3H, s)to 4.41 (2H, square, J=7,2 Hz),:7,05 (1H, d, J=2.2 Hz), 7,25-to 7.32 (2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,80 (1H, d, J=1.9 Hz),7.88 (2H, d, J=7.9 Hz), 7,92 (1H, d, J=7.9 Hz), 8,24 (1H, d, J=1.9 Hz), at 8.36 (1H, d, J=8,3 Hz)to 9.15 (1H, s).
Table 11
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-55 a 2.00 (2H, Quint., J=7,1 Hz), 2,22 (3H, s), 2,61 (3H, s), of 2.72 (4H, t, J=7,1 Hz), 2,78 (3H, s), is 2.88 (3H, s), a 3.87 (3H, s), 7,16 (1H, d, J=1.9 Hz), 7,30 (1H, DD, J=1,5, 8,3 Hz), 7,82 (2H, d, J=8,3 Hz), 7,88-to $ 7.91 (5H, m), 10,14 (1H, s).

1-562,04 (2H, Quint., J=7.2 Hz), 2.63 in (2H, t, J=7.2 Hz), 2,73 (2H, t, J=7.2 Hz), 2,79-2,99 (N, m), 3,86 (3H, s)to 3.92 (3H, s), 5,09 (2H, users), 7,01 (1H, d, J=1.5 Hz), 7.23 percent-7,30 (1H, MC), 7,54 (1H, d, J=1.5 Hz), to 7.61 (1H, d, J=2.3 Hz), 7,66 (2H, d, J=8,3 Hz), 7,73 (1H, d, J=1.5 Hz), 7,81 (1H, d, J=8,3 Hz), 7,92 (2H, d, J=8,3 Hz), 8,44 (1H, d, J=8,3 Hz), for 9.90 (1H, users).
1-57of 1.93 (2H, Quint., J=7,2 Hz), to 2.57 (2H, t, J=7.2 Hz), 2,61 (3H, s), 2,70 (2H, t, J=7.2 Hz), 2,78 (3H, s), 2,87 (3H, s), 3,82 (3H, s), 3,88 (3H, s), 7,14 (1H, s), 7,28-7,30 (3H, m), 7,45 (1H, d, J=8,3 Hz), 7,49 (1H, d, J=8,3 Hz), 7,81-a 7.92 (5H, m), 10,15 (1H, s).

1-58a 2.00 (2H, Quint., J=7,1 Hz), 2,22 (3H, s), 2,61 (3H, s), of 2.72 (4H, t, J=7,1 Hz), 2,78 (3H, s), is 2.88 (3H, s), a 3.87 (3H, s), 7,16 (1H, d, J=1.9 Hz), 7,27-to 7.35 (4H, m), 7,43-7,49 (2H, m), 7,58-to 7.61 (2H, m), 7,83 (2H, d, J=8,3 Hz), 7,89-a 7.92 (5H, m), 10,14 (1H, s).
1-59a 2.00 (2H, Quint, J=7,1 Hz), 2,22 (3H, s), of 2.34 (3H, s), 2,61 (3H, s), of 2.72 (4H, t, J=7,1 Hz), 2,78 (3H, s), is 2.88 (3H, s), a 3.87 (3H, s), 7,16 (1H, d, J=1.9 Hz), 7,30 (1H, DD, J=1,9, 8,3 Hz), 7,43-7,49 (2H, m), 7,83 (2H, d, J=8,3 Hz), 7,8 9-7,92 (5H, m), 10,14 (1H, s).
1-60a 2.00 (2H, Quint., J=7,1 Hz), 2,22 (3H, s)to 2.29 (3H, s), 2,61 (3H, s), of 2.72 (4H, t, J=7,1 Hz), 2,78 (3H, s), is 2.88 (3H, s), a 3.87 (3H, s), 7,10-7,16 (3H, m), 7,30 (1H, DD, J=1,9, 8,3 Hz), 7,43-7,49 (4H, m), 7,83 (2H, d, J=8,3 Hz), 7,89-to $ 7.91 (5H, m), 10,14 (1H, s).

Table 12
ExampleStructureNMR (δ, 300 or 400 MHz, CDC13)
1-61a 2.00 (2H, Quint., J=7,1 Hz), 2,22 (3H, s), 2,61 (3H, s), of 2.72 (4H, t, J=7,1 Hz), 2,78 (3H, s), is 2.88 (3H, s), a 3.87 (3H, s), 7,16 (1H, d, J=1.5 Hz), 7,30 (1H, DD, J=1,5, 8,3 Hz), 7,38-7,49 (3H, m), 7,83 (2H, d, J=8,3 Hz), 7,89-7,93 (6N, m), 8,86 (1H, d, J=8.7 Hz), 10,14 (1H, s).
1-62a 2.00 (2H, Quint., J=7,1 Hz), 2,22 (3H, s), 2,61 (3H, s), of 2.72 (4H, t, J=7,1 Hz), 2,78 (3H, s), is 2.88 (3H, s), a 3.87 (3H, s), 7,16 (1H, d, J=1.5 Hz), 7,30 (1H, DD, J=1,5, 8,3 Hz), 7,43-7,49 (2H, m), 7,83 (2H, d, J=8,3 Hz), 7,89-a 7.92 (5H, m), 10,15 (1H, s).
1-63 1,31 (6N, d, J=6.0 Hz), a 1.96 (2H, Quint., J=7.5 Hz), 2,59-of 2.64 (5H, m), 2,69 (2H, t, J=7.5 Hz), 2,77 (3H, s), 2,87 (3H, s)to 5.13 (1H, Sept., J=6.0 Hz), 7,16 (1H, d, J=l,9 Hz), 7,26 (2H, d, J=8.7 Hz), 7,28-7,31 (1H, m), 7,43-7,49 (2H, m), 7,81 (2H, d, J=8,3 Hz), of 7.90 (3H, d, J=7.9 Hz), 7,98 (2H, d, J=8.7 Hz), 10,13 (1H, s).

1-64is 2.05 (2H, Quint., J=7.5 Hz), 2,17 (6N, (C), 2,61 (2H, t, J=7.5 Hz), a 2.71 (2H, t, J=7.5 Hz), 2,87 (3H, users), 2,95 (3H, users), the 3.89 (3H, s), 7,01 (1H, d, J=1.9 Hz), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=1.5 and 7.5 Hz), 7,46-EUR 7.57 (2H, m,), a 7.62 (4H, s), of 7.69 (1H, DD, J=l,5, 7.5 Hz), 7,76 (2H, s), 8,31 (1H, d, J=8,3 Hz), 8,99 (1H, s).
1-65to 2.06 (2H, Quint., J=7.5 Hz), 2,17 (6N, (C), 2,61 (2H, t, J=7, 5 Hz), 2, 67 (3H, s), of 2.72 (2H, t, J=7.5 Hz), 2,87 (6N, users), the 3.89 (3H, s), 7,01 (1H, d, J=1,8 Hz), 7,25-7,29 (2H, m), the 7.65 (1H, d, J=8,3 Hz), 7,76 (2H, ), 7,88 (2H, d, J=8,3 Hz), to $ 7.91 (1H, d, J=7.9 Hz), of 8.37 (1H, d, J=8.7 Hz), 9,14 (1H, s).

Table 13
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-66 2,04 (2H, Quint., J=7.5 Hz), measuring 2.20 (3H, s), 2,58 (2H, t, J=7.5 Hz), 2,70 (2H, t, J=7.5 Hz), 2,86 (3H, users), to 2.94 (3H, users), 3,90 (3H, s), 7,00 (1H, d, J=2.3 Hz), 7,06 (1H, d, J=8,3 Hz), 7,21-7,28 (1H, m), 7,40 (1H, DD, J=1,5 Hz, J=7.5 Hz), 7,44-EUR 7.57 (2H, m), a 7.62 (4H, users), of 7.69 (1H, DD, J=1.5 Hz, J=7.5 Hz), 7,89 (1H, DD, J=1.9 Hz, J=8,3 Hz), to 7.93 (1H, users), 8,30 (1H, d, J=8,3 Hz), 8,99 (1H, users).

1-67of 1.20 (2H, t, J=7,6 Hz), 2,04 (2H, Quint., J=7,2 Hz), 2,52-2,61 (4H, m), 2,70 (2H, t, J=7.2 Hz), 2,86 (3H, users), to 2.94 (3H, users), 3,91 (3H, s), 7,01 (1H, d, J=1.9 Hz), 7,06 (1H, d, J=8.6 Hz), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=1.5 and 7.5 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,9, 7,1 Hz), of 7.90 (1H, DD, J=1,9, to 8.7 Hz), of 7.97 (1H, d, J=2.3 Hz), 8,31 (1H, d, J=8,3 Hz), 8,99 (1H, s).
1-681,23 (6N, d, J=6.8 Hz), was 2.05 (2H, Quint., J=7,1 Hz)at 2.59 (2H, t, J=7,1 Hz), 2,70 (2H, t, J=7,1 Hz), 2,86 (3H, users), 2,95 (3H, users), to 3.02 (1H, Sept., J=6.8 Hz), 3,91 (3H, s), 7,00-was 7.08 (2H, m), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=1,1, 7.5 Hz), 7,46-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,9, 7,1 Hz), 7,89 (1H, DD, J=1,9, 8,3 Hz), 8,02 (1H, d, J=2.2 Hz), 8,31 (1H, d, J=8,3 Hz), 8,99 (1H, c).

1-69is 2.05 (2H, Quint., J=7,2 Hz), measuring 2.20 (3H, s)at 2.59 (2H, t, J=7.2 Hz), to 2.67 (3H, s), a 2.71 (2H, t,J=7.2 Hz), 2,87 (6N, users), 3,90 (3H, s), 7,01 (1H, d, J=l,9 Hz), 7,06 (1H, d, J=8,3 Hz), 7,25-7,29 (2H, m), the 7.65 (2H, d, J=7.9 Hz), 7,86-7,94 (5H, m), of 8.37 (1H, d, J=8,3 Hz), 9,14 (1H, s),
1-70is 2.05 (2H, Quint., J=7,2 Hz), to 2.65 (2H, t, J=7.2 Hz), to 2.67 (3H, s), of 2.72 (2H, t, J=7.2 Hz), 2,86 (6N, users), a 3.87 (3H, s), of 3.95 (3H, s),? 7.04 baby mortality (1H, d, J=2.3 Hz), 7,16 (1H, d, J=8,3 Hz), 7,25-to 7.32 (2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=8.1 Hz), 7,92 (1H, d, J=7.9 Hz), by 8.22 (1H, DD, J=2,3, 8,3 Hz), of 8.37 (1H, d, J=8.7 Hz), 8,68 (1H, d, J=2.3 Hz), to 9.15 (1H, s).

Table 14
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-71of 1.39 (3H, t, J=7.2 Hz), 2,03 (2H, Quint., J=7.5 Hz), of 2.56 (2H, t, J=7.5 Hz), to 2.67 (3H, s), 2,70 (2H, t, J=7.5 Hz), to 4.38 (2H, square, J=7,2 Hz), 7,01 (1H, d, J=2.3 Hz), 7,14 (2H, d, J=8.6 Hz), 7,25-7,29 (2H, m), the 7.65 (2H, d, J=7.9 Hz), 7,88 (2H, d, J=7, 9 Hz), 7, 92 (1H, d, J=7.9 Hz), 8,08 (2H, d, J=8.6 Hz), of 8.37 (1H, d, J=8.6 Hz), 9,13 (1H, s).
1-721,38 (6N, d, J=6.0 Hz), was 2.05 (2H, Quint., J=7,1 Hz),2.64 (2H, t, J=7,1 Hz)to 2.67 (3H, s), of 2.72 (2H, t, J=7,1 Hz), 2,86 (6N, users), a 3.87 (3H, s), 5,27 (1H, Sept., J=6.0 Hz),? 7.04 baby mortality (1H, d, J=1.9 Hz), 7,14 (1H, q, j =8,3 Hz), 7,25-7,31 (2H, m),7.65 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=7.9 Hz), 7,92 (1H, d, J=7.9 Hz), by 8.22 (1H, DD, J=1,9, 8.6 Hz), of 8.37 (1H, d, J=8.6 Hz), 8, 65 (1H, d, J=2.2 Hz), to 9.15(1H, s).

1-73to 1.21 (3H, t, J=7.5 Hz), 2,07 (2H, Quint., J=7,1 Hz), to 2.57 (2H, square, J=7.5 Hz), to 2.65 (2H, t, J=7,1 Hz)to 2.67 (3H, s), is 2.74 (2H, t, J=7,1 Hz), 2,87 (6N, user. C)to 3.92 (3H, s), 7,02 (1H, d, J=1.9 Hz), 7,25-7,30(2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,8 6-7,93 (4H, m), 7,98 (1H, d, J=1.9 Hz), of 8.37 (1H, d, J=8,3 Hz)to 9.15 (1H, s),
1-741,22 (6N, d, J=7,2 Hz), 2,07 (2H, Quint., J=7,2 Hz), to 2.65 (2H, t, J=7.2 Hz), to 2.67 (3H, s), is 2.74 (2H, t, J=7.2 Hz), 2,87 (6N, users), 2,99 (1H, Sept., J=7,2 Hz), to 3.92 (3H, s), 7,02 (1H, d, J=2.2 Hz), 7,25-7,30 (2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,86-to 7.93 (4H, m), of 7.97 (1H, d, J=l,8 Hz), of 8.37 (1H, d, J=8.6 Hz), to 9.15 (1H, s).
1-75of 1.03 (3H, t, J=7.5 Hz), of 1.80 (2H, Sextus., J=7.5 Hz), to 2.06 (2H, Quint., J=7.5 Hz), 2.63 in (2H, t, J=7.5 Hz), to 2.67 (3H, s), by 2.73 (2H, t, J=7.5 Hz), 2,87 (6N, user. C), 3,88 (3H, s), the 4.29 (2H, t, J=7.5 Hz), 7,03 (1H, d, J=1.9 Hz), 7.23 percent-to 7.32 (2H, m), 7,56 (1H, d, J=1,8 Hz), the 7.65 (2H, d, J=7.9 Hz), 7,74 (1H, d, J=1,8 Hz), 7,88 (2H, d, J=7.9 Hz), 7,92 (1H, d, J=7,9 Hz), of 8.37 (1H, d, J=8,3 Hz), 9,16 (1H, users).

Table 5
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-761,19 (6N, d, J=6.3 Hz), 2,03 (2H, Quint., J=7.4 Hz), of 2.56 (2H, t, J=7.4 Hz), 2,69 (2H, t, J=7.4 Hz), 2,85 (3H, users), to 2.94 (3H, users), 3,62-3.68 (1H, m), 3,74 (2H, t, J=5.0 Hz), of 4.44 (2H, t, J=5.0 Hz), of 6.99 (1H, d, J=2.1 Hz), 7,14 (2H, d, J=8,5 Hz), of 7.23-7,27 (1H, m), 7,40 (1H, DD, J=1.4 Hz, 7.4 Hz), 7,46-7,56 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1.7 Hz, 7.4 Hz), of 8.09 (2H, d, J=8.5 Hz), 8,30 (1H, d, J=8,4 Hz), 8,98 (1H, s).

1-772,00-2,05 (5H, m), of 2.56 (2H, t, J=7.5 Hz), 2,70 (2H, t, J=7.5 Hz), 2,86 (3H, users), 2,95 (3H, users), the 3.65 (2H, dt, J=5.6 Hz, 10.5 Hz), 4,42 (2H, t, J=5.6 Hz), 5,77-of 5.89 (1H, m), 7,00 (1H, d, J=0.9 Hz), to 7.50 (2H, d, J=8.6 Hz), 7.24 to 7,26 (1H, m), 7,40 (1H, DD, J=1.4 Hz, 7.4 Hz), 7,46-7,56 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1.4 Hz, 7.4 Hz), 8,07 (2H, d, J=8.6 Hz), 8,29 (1H, d, J=8,4 Hz), 8,98 (1H, s).
1-782,03 (2H, Quint., J=7.5 Hz), of 2.56 (2H, t, J=7.5 Hz), 2,69 (2H, t, J=7.5 Hz), 2,86 (3H, users), to 2.94 (3H, users), 4,89 (2H, s), 5,23 (2H, s), 7,00 (1H, d, J=1.9 Hz), 7,16 (2H, d, J=8.7 Hz), 7,22-7,27 (1H, m), of 7.36 (5H, users), 7,40 (1H, DD, J=1.5 Hz, J=7,2 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, users), 7, 69 (1H, DD, J=1.5 Hz, J=7.5 Hz), 8,12 (N, d, J=8.7 Hz), 8,29 (1H, d, J=8,3 Hz), 8,98 (1H, users).

1-792,02 (2H, Quint., J=7,2 Hz), of 2.56 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7,1 Hz), 2,86 (3H, users), with 2.93 (3H, users), 5,32 (2H, s), of 6.99 (1H, d, J=1.9 Hz), 7,14 (2H, d, J=8.7 Hz), 7,21-7,27 (1H, m), 7,32-7,37 (5H, m), 7,44-EUR 7.57 (2H, m,), to 7.61 (4H, users), to 7.68 (1H, DD, J=1.9 Hz, J=7,2 Hz), 8,08 (2H, d, J=8.7 Hz), 8,29 (1H, d, J=8.7 Hz), 8,97 (1H, s).
1-802,03 (2H, Quint., J=7,1 Hz), of 2.56 (2H, t, J=7,1 Hz)to 2.66 (3H, s), 2,69 (2H, t, J=7,1 Hz), 2,86 (6N, users), are 5.36 (2H, s), 7,00 (1H, d, J=1.9 Hz), 7,14 (2H, d, J=8.7 Hz), 7.24 to 7,27 (2H, m), 7,34-7,44 (5H, m), of 7.64 (2H, d, J=8,3 Hz), 7,87 (2H, d, J=8,3 Hz), to $ 7.91 (1H, d, J=7.9 Hz), 8,11 (2H, d, J=8.7 Hz), at 8.36 (1H, d, J=8,3 Hz), 9,12 (1H, s).

Table 16
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-811,36 (6N, d, J=6,1 Hz), 2,03(2H, Quint., J=7,1 Hz), of 2.56 (2H, t, J=7,1 Hz)to 2.67 (3H, s), 2,70 (2H, t, J=7,1 Hz), 2,86 (6N, users), of 5.24 (1H, Sept., J=6,1 Hz), 7,00 (1H, d, J=1.9 Hz), 7,13 (2H, d, J=8.7 Hz), 7,25-7,27 (2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=,3 Hz), to $ 7.91 (1H, d, J=8.0 Hz), 8,07 (2H, d, J=8.7 Hz), of 8.37 (1H, d, J=8.7 Hz), 9,13 (1H, s).
1-822,03 (2H, Quint., J=7,1 Hz), of 2.56 (2H, t, J=7,1 Hz), 2,69 (2H, t, J=7,1 Hz), 2,87 (3H, users), to 2.94 (3H, users), of 5.48 (2H, s), 7,00 (1H, d, J=1,8 Hz), 7,16 (2H, d, J=8.7 Hz), 7.23 percent-7,26 (2H, m), 7,38-7,56 (4H, m), a 7.62 (4H, s), to 7.67-7,74 (2H, m), 8,15 (2H, d, J=8,3 Hz), 8,30 (1H, d, J=8.7 Hz), 8,61-to 8.62 (1H, m), 8,98 (1H, s).

1-832,02 (2H, Quint., J=7,2 Hz), of 2.56 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7.2 Hz), 2,86 (3H, users), to 2.94 (3H, users), 5,38 (2H, s), 7,00 (1H, d, J=1.9 Hz), to 7.15 (2H, d, J=9.0 Hz), 7.23 percent-7,26 (1H, m), 7,38-EUR 7.57 (4H, m), to 7.61 (4H, s), to 7.67-7,79 (2H, m), of 8.09 (2H, d, J=8.7 Hz), 8,30 (1H, d, J=8.7 Hz), 8,30 (1H, d, J=8.7 Hz), 8,61 (1H, DD, J=1,9, a 4.9 Hz), 8,72 (1H, d, J=1.9 Hz), 8,97 (1H, s).
1-842,03 (2H, Quint., J=7,2 Hz), to 2.57 (2H, t, J=7.2 Hz), 2,70 (2H, t, J=7.2 Hz), 2,86 (3H, users), to 2.94 (3H, users), 5,38 (2H, s), 7,00 (1H, d, J=1.9 Hz), 7,18 (2H, d, J=9.0 Hz), 7.23 percent-7,26 (1H, m), 7,32 (2H, d, J=6,1 Hz), 7,40 (1H, DD, J=1,1, 7.9 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,5, with 7.6 Hz), 8,13 (2H, d, J=9.0 Hz), 8,30 (1H, d, J=8.6 Hz), 8,63 (2H, d, J=6.0 Hz), 8,97 (1H, s).

1-85 2,03 (2H, Quint., J=7.5 Hz), of 2.56 (2H, t, J=7.5 Hz), 2,69 (2H, t, J=7.5 Hz), 2,86 (3H, users), to 2.94 (3H, users), of 3.00 (3H, s), 3.04 from (3H, s), of 4.95 (2H, s), 7,00 (1H, d, J=1.5 Hz), to 7.15 (2H, d, J=8.7 Hz), 7,22-7,27 (1H, m), 7,37-7,42 (1H, m), 7,44-EUR 7.57 (2H, m), a 7.62 (4H, s), 7,66-7,71 (1H, m)to 8.14 (2H, d, J=8.7 Hz), 8,29 (1H, d, J=8,3 Hz), 8,99 (1H, users).

Table 17
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-862,03 (2H, Quint., J=7,2 Hz), of 2.56 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7.2 Hz), 2,86 (3H, users), to 2.94 (3H, users), with 3.79 (3H, s), a 4.86 (2H, s), 7,00 (1H, d, J=1.9 Hz), 7,16 (2H, d, J=9.0 Hz), 7,22-7.28 (1H, m), 7,40 (1H, DD, J=1,5 Hz, J=7.5 Hz), 7,45-7,58 (2H, m), a 7.62 (4H, users), of 7.69 (1H, DD, J=1.5 Hz, J=7,2 Hz), to 8.12 (2H, d, J=9.0 Hz),8.29 (1H, d, J=8,3 Hz), 8,98 (1H, users).

1-872,03 (2H, Quint., J=7,2 Hz), of 2.56 (2H, t, J=7.2 Hz), 2,60 (2H, t, J=7.2 Hz), 2,86 (3H, users), with 2.93 (3H, users), 5,32 (2H, s), of 6.99 (1H, d, J=1.5 Hz), to 7.15 (2H, d, J=8.7 Hz), 7,21-7,34 (4H, m), of 7.36-EUR 7.57 (4H, m), to 7.61 (4H, users), 7,68-of 7.69 (1H, m), 8,10 (2H, d, J=8.7 Hz), 8,29 (1H, d, J=8,3 Hz), of 8.90 (1H, users).

1-88to 1.22 (3H, t, J=7.2 Hz), 2,03 (2H, Quint., J=7.5 Hz), of 2.56 (2H, t, J=7.5 Hz), 2,69 (2H, t, J=7.5 Hz), 2,87 (3H, users), with 2.93 (3H, users), 2,99 (2H, square, J=7,2 Hz), 7,00 (1H, d, J=l,9 Hz), 7,16 (2H, d, J=8.7 Hz), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=1,5, 7.5 Hz), 7,45-7,56 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,9, 7,2 Hz), 8,00 (2H, d, J=8.7 Hz), 8,30 (1H, d, J=8,3 Hz), 8,98 (1H, s).

1-892,03 (2H, Quint., J=7.5 Hz), of 2.56 (2H, t, J=7.5 Hz), 2,70 (2H, t, J=7.5 Hz), 2,86 (3H, user. C)to 2.94 (3H, users), of 3.80 (2H, t, J=4.9 Hz), 4,50 (2H, t, J=4.9 Hz), 4,60 (2H, s), 7,00 (1H, d, J=1.9 Hz), to 7.15 (2H, d, J=8.7 Hz), 7.23 percent-7,41 (7H, m), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,9, 7.5 Hz), of 8.09 (2H, d, J=9.0 Hz), 8,30 (1H, d, J=8.7 Hz), 8,98 (1H, s).

1-901,98-2,11 (4H, m), of 2.56 (2H, t, J=7.5 Hz), 2,70 (2H, t, J=7.5 Hz), 2,87 (3H, users), to 2.94 (3H, users), 3,62 (2H, t, J=6.0 Hz), of 4.44 (2H, t, J=6.4 Hz), to 4.52 (2H, s), 7,00 (1H, d, J=1.9 Hz), 7,12 (2H, d, J=8.7 Hz), 7.23 percent-7,33 (6N, m), 7,40 (1H, DD, J=1.5 and 7.5 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,5, 7,2 Hz), 8,03(2H, d, J=9.0 Hz), 8,30 (1H, d, J=8.7 Hz), 8,98(1H, s).

Table 18
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-911,98-of 2.08 (4H, m), of 2.38 (2H, t, J=7.5 Hz), of 2.56 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7.2 Hz), 2,87 (3H, users), to 2.94 (3H, users), a 3.50 (2H, t, J=7.2 Hz), 3,68 (2H, t, J=5,2 Hz), of 4.45 (2H, t, J=5,2 Hz), of 4.45 (2H, t, J=5,2 Hz), 7,00 (1H, d, J=1,8 Hz), to 7.15 (2H, d, J=8.7 Hz), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=1.5 and 7.5 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,5, 7,2 Hz), of 8.06 (2H, d, J=8.7 Hz), 8,30 (1H, d, J=8,3 Hz), 8,98 (1H, s).

1-92to 1.83 (1H, users), 1,96-of 2.08 (4H, m), of 2.56 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7.2 Hz), 2,86 (3H, users), to 2.94 (3H, users), and 3.72-of 3.80 (2H, m), of 4.49 (2H, t, J=6.0 Hz), 7,00 (1H, d, J=1,8 Hz), to 7.15 (2H, d, J=8.7 Hz), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=1.5 and 7.5 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,9, 7,2 Hz), 8,07 (2H, d, J=8.7 Hz), 8,30 (1H, d, J=8,3 Hz), 8,98 (1H, s).
1-93to 1.00 (3H, t, J=7.5 Hz), 1.77 in (2N, Sextus., J=7,6 Hz), 2,03 (2H, Quint., J=7,1 Hz), of 2.56 (2H, t, J=7,1 Hz), 2,69 (2H, t, J=7,1 Hz), 2,87-2,95 (8H, m), 7,00 (1H, d, J=2.2 Hz), 7,16 (2H, d, J=8.7 Hz), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=1.5 and 7.5 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, ), of 7.69 (1H, DD, J=l,5, 7.2 Hz), 8,00 (2H, d, J=8.7 Hz), 8,30 (1H, d, J=8,3 Hz), 8,98 (1H, s).

1-942,03 (2H, Quint., J=7,2 Hz), of 2.56(2H, t, J=7.2 Hz), to 2.66 (3H, s), 2,70 (2H, t, J=7.2 Hz), 2,86 (6N, users), 5,38 (2H, s), 7,00 (1H, d, J=1.9 Hz), to 7.15 (2H, d, J=8.7 Hz), 7,25-to 7.35 (3H, m), of 7.64 (2H, d, J=7.9 Hz), 7,75-7,79 (1H, m), 7,87 (2H, d, J=8,3 Hz), to $ 7.91 (1H, d, J=7.9 Hz), of 8.09 (2H, d, J=8.7 Hz), of 8.37 (1H, d, J=8.7 Hz), 8,61 (1H, DD, J=1.5 and 4.6 Hz), 8,72 (1H, d, J=1.9 Hz), 9,12 (1H, s).
Table 19
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-952.05 (2H, Quint., J=7.5 Hz), to 2.57 (2H, t, J=7.5 Hz), a 2.71 (2H, t, J=7.5 Hz), 2,87 (3H, users), 2,95 (3H, users), and 4.40 (3H, s), 7,01 (1H, d, J=1.9 Hz), 7,20 (2H, d, J=8, 6 Hz), 7.24 to 7,28 (1H, m), 7,40 (1H, DD, J=1,9, 7.9 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,5, with 7.6 Hz), 8,16 (2H, d, J=8.6 Hz), 8,31 (1H, d, J=8, 6 Hz), of 9.00 (1H, s).

1-962,02 (2H, Quint., J=7.5 Hz), to 2.55 (2H, t, J=7.5 Hz), 2,69 (2H, t, J=7.5 Hz), 2,86 (3H, users), to 2.94 (3H, users), 3,82 (3H, s), from 5.29 (2H, s)6,91 (2H, d, J=8.7 Hz), of 6.99 (1H, d, J=1.9 Hz), 7,12(2H, d, J=8.7 Hz), 7,21-7,27 (1H, m), 7, 34-7, 42 (3H, m), 7, 44-7,57 (2H, m), to 7.61 (4H, users), to 7.68 (1H, DD, J=1.9 Hz, J=7.5 Hz), 8,08 (2H, d, J=8.7 Hz), 8,29(1H, d J=8.7 Hz), 8,98 (1H, users).
1-972,02 (2H, Quint., J=7,2 Hz), of 2.56 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7.2 Hz), 2,85 (3H, users), to 2.94 (3H, users), 3,82 (3H, s)5,33 (2H, s), to 6.88 (2H, DD, J=2.3 Hz, J=7.9 Hz), 6,95-7,05 (3H, m), 7,14 (2H, d, J=8.7 Hz), 7,21-7,27 (1H, m), 7,30 (1H, t, J=7.9 Hz), 7,39 (1H, DD, J=1.5 Hz, J=7.5 Hz), 7,44-7,58 (2H, m), to 7.61 (4H, users), of 7.69 (1H, DD, J=1.5 Hz, J=7.5 Hz), 8,10 (1H, d, J=8.7 Hz), 8,29 (1H, d, J=8,3 Hz), 8,98 (1H, users).

1-982,02 (2H, Quint., J=7,2 Hz), to 2.55 (2H, t, J=7.2 Hz), 2,69 (2H, t, J=7.2 Hz), 2,85 (3H, users), to 2.94 (3H, users), of 5.50 (2H, s), 6,99-7,02 (2H, m), 7,13 (2H, d, J=9.1 Hz), 7,16-7,17 (1H, m), 7,22-7,26 (1H, m), 7,34 (1H, DD, J=1,9, at 5.3 Hz), 7,40 (1H, DD, J=1,9, a 7.6 Hz), 7,47-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,9, 7,2 Hz), of 8.09 (2H, d, J=9.0 Hz), 8,30 (1H, d, J=8.7 Hz), 8,99 (1H, s).
1-992,02 (2H, Quint., J=7.5 Hz), to 2.55 (2H, t, J=7.5 Hz), 2,69 (2H, t, J=7.5 Hz), 2,85 (3H, users), to 2.94 (3H, users), are 5.36 (2H, s), 7,00 (1H, d, J=1.9 Hz), 7,14 (2H, d, J=8.6 Hz), 7,16-to 7.18 (1H, m), 7.23 percent-7,26 (1H, m), 7,33-rate of 7.54 (5H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,9, 7,2 Hz), of 8.09 (2H, d, J=8.7 Hz), 8,30 (1H, d, J=8.7 Hz), 8,99 (1H, s).

Table 20
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-1002,03 (2H, Quint., J=7.5 Hz), 2,54 at 2.59 (5H, m)to 2.67 (3H, s), 2,70 (2H, t, J=7.5 Hz), 2,86 (6N, user. C)5,44 (2H, s), 7,00 (1H, d, J=1.9 Hz), 7,11 (1H, d, J=8.0 Hz), 7,16 (2H, d, J=8.6 Hz), 7.23 percent-7,29 (3H, m), to 7.59 (1H, d, J=7.9 Hz), the 7.65 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=8,3 Hz), to $ 7.91 (1H, d, J=8,0 Hz), 8,15(2H, d, J=8.6 Hz), of 8.37 (1H, d, J=8.6 Hz), 9,13 (1H, s).
1-1012,03 (2H, Quint., J=7,1 Hz), of 2.56 (2H, t, J=7,1 Hz), to 2.57 (3H, s), 2,69 (2H, t, J=7,1 Hz), 2,8 6 (3H, users), to 2.94 (3H, users), 5,44 (2H, s), 7,00 (1H, d, J=1.9 Hz), 7,11 (1H, d, J=7.9 Hz), 7,16 (2H, d, J=9.0 Hz), 7,22 (2H, d, J=7.9 Hz), 7,40 (1H, DD, J=l,9 and 7.6 Hz), 7, 43-7, 62 (7H, m), of 7.69 (1H, DD, J=1,9, a 7.6 Hz), 8,15 (2H, d, J=8.6 Hz), 8,30 (1H, d, J=8,3 Hz), 8,99 (1H, s).

1-1021,28 (6N, d, J=6.4 Hz), 2,03 (2H, Quint., J=7.2 Hz),2.56 (2H, t, J=7.2 Hz), 2,70 (2H, t, J=7.2 Hz), 2,87 (3H, users), to 2.94 (3H, users), 4,80 (2H, s), 5,12 (1H, Sept., J=6.4 Hz), 7,00 (1H, d, J=1.9 Hz), 7,17 (2H, d, J=8.7 Hz), 7,22-7,26 (1H, m), 7,40 (1H, DD, J=1.5 Hz, J=7.5 Hz), 7,44-7.57 (2H, m), a 7.62 (4H, users), of 7.69 (1H, DD, J=1.9 Hz,J=7.5 Hz), 8,13 (2H, d, J=8.7 Hz),8,30 (1H, d, J=8,3 Hz), 8,99 (1H, users).
1-1031,59 (N, C)2,02(2H, Quint., J=7.5 Hz), of 2.56 (2H, t, J=7.5 Hz), 2,69 (2H, t, J=7.5 Hz), 2,86 (3H, users), to 2.94 (3H, user. C)of 5.40 (2H, s), 7,00 (1H, d, J=1.9 Hz), to 7.15 (2H, d, J=8.7 Hz), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=1,6 and 7.6 Hz), 7,47 (2H, d, J=8,3 Hz), 7,51-rate of 7.54 (2H, m), to 7.61 (4H, s), of 7.69 (1H, DD, J=1,6 and 7.6 Hz), 8,01 (2H, d, J=8,3 Hz), 8,11 (2H, d, J=9.0 Hz), 8,30 (1H, d, J=8.7 Hz), 8,98 (1H, s).

1-1042,04 (2H, Quint., J=7,2 Hz), to 2.57 (2H, t, J=7.2 Hz), a 2.71 (2H, t, J=7.2 Hz), 2,87 (3H, users), to 2.94 (3H, users), of 5.26 (2H, s)5,49 (2H, s), 7,02 (1H, d, J=1.9 Hz), 7,21 (2H, d, J=8.7 Hz), 7,25-7,28 (1H, m), 7,33-EUR 7.57 (8H, m), a 7.62(4H, s), of 7.69 (1H, DD, J=1,5, with 7.6 Hz), 8,18 (2H, d, J=8.7 Hz), 8,31 (1H, d, J=8,2 Hz), of 9.00 (1H, s).
Table 21
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-1052,04 (2H, Quint., J=7.5 Hz), to 2.57 (2H, t, J=7.5 Hz), 2,70 (2H, t, J=7.5 Hz), 2,87 (3H, users), to 2.94 (3H, users), totaling 3.04 (3H, s), 3,14 (3H, s)5,54 (2H, s), 7,02 (1H, d, J=1.9 Hz), 7,20 (2H, d, J=8.6 Hz), 7.24 to 7,28 (1H, m), 7,40 (1H, DD, J=1.5 and 7.5 Hz), 7,45-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,9, 7,2 Hz), 8,19 (2H, d, J=8.7 Hz), 8,31 (1H, d, J=8,3 Hz), 9,01 (1H, s).

1-106to 1.67 (3H, d, J=6.4 Hz), represented 2.02 (2H, Quint., J=7.5 Hz), of 2.56 (2H, t, J=7.5 Hz), 2,69 (2H, t, J=7.5 Hz), 2,8 6 (3H, user. C)to 2.94 (3H, users), 6,12 (1H, square, J=6.4 Hz), 7,00 (1H, d, J=2.3 Hz), 7,14 (2H, d, J=8.7 Hz), 7.23 percent-EUR 7.57 (N, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,5, 7,2 Hz), 8,10 (2H, d, J=8.7 Hz), 8,30 (1H, d, J=8,3 Hz), 8,99 (1H, s).

1-1072,02 (2H, Quint., J=7.5 Hz), 2,17-of 2.28 (1H, m), 2.55 (2H, t, J=7.5 Hz), 2,59-a 2.71 (3H, m), 2,80-2,99 (7H, m), 3,13 is 3.23 (1H, m), of 6.45 (1H, DD, J=4.2, and a 7.2 Hz), of 6.99 (1H, d, J=1.9 Hz), 7,11 (2H, d, J=8.7 Hz), 7,22-to 7.32 (4H, m), 7,39 (1H, DD, J=1,5, with 7.6 Hz), 7,46-7,56 (3H, m), to 7.61 (4H, s), to 7.68 (1H, DD, J=1.5 and 7.5 Hz), 8,07 (2H, d, J=8.7 Hz), 8,30 (1H, d, J=8,3 Hz), 8,99 (1H, s).

1-1081,84-of 1.92 (1H, m), 1,97 with 2.14 (5H, m)to 2.55 (2H, t, J=7.2 Hz), 2,68 (2H, t, J=7.2 Hz), 2,80-2,95 (8H, m), 6,24 (1H, t, J=4.6 Hz), of 6.99 (1H, d, J=1.9 Hz), 7,11 (2H, d, J=8.7 Hz), 7,17-to 7.35 (5H, m), 7,39 (1H, DD, J=l,5, 7,9 Hz), 7,45-7,56 (2H, m), to 7.61 (4H, s), to 7.68 (1H, DD, J=1.5 and 7.5 Hz), 8,08 (2H, d, J=9.0 Hz), 8,30 (1H, d, J=8,3 Hz), 8,99 (1H, s).

1-1091,76-to 1.87 (M, m), 1.93 and-of 2.08 (4H, m)to 2.13 (3H, s), of 2.56 (2H, t, J=7.2 Hz), 2,70 (2H, t, J=7.2 Hz), 2,86 (3H, users), 2,95 (3H, users), 3,37-of 3.60 (2H, m), 3,65-of 3.78 (1H, m), 3,88-3,98 (1H, m), to 5.21 is 5.28 (1H, m), 7,00 (1H, d, J=2.2 Hz), to 7.15 (2H, d, J=8.6 Hz), 7.23 percent-7,26 (1H, m), 7,40 (1H, DD, J=1,5, with 7.6 Hz), 7,46-EUR 7.57 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1.5 and 7.5 Hz), 8,07 (2H, d, J=8.6 Hz), 8,30 (1H, d, J=8,3 Hz), 8,98 (1H, s).

Table 22
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-110to 2.06 (2H, Quint., J=7.5 Hz), of 2.25 (3H, s), 2,65-2,70 (5H, m), by 2.73 (2H, t, J=7.5 Hz), 2,87 (6N, users), 3,86 (3H, s), 3,93 (3H, s), 7,05 (1H, d, J=1.9 Hz), 7,25-to 7.32 (2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=8,3 Hz), a 7.92 (1H, d, J=7.9 Hz), 8,11 (1H, d, J=1.5 Hz), of 8.37 (1H, d, J=8.7 Hz), 8,51 (1H, d, J=1.9 Hz), 9,16 (1H, s).
1-1111,38 (6N, d, J=6.0 Hz), to 2.06 (2H, Quint., J=7,2 Hz), of 2.25 (3H, s), 2,65-2,69 (5H, m), by 2.73 (2H, t, J=7.2 Hz), 2,87 (6N, users), 3,86 (3H, s), of 5.26 (1H, Sept., J=6.0 Hz), 7,05 (1H, d, J=1.9 Hz), 7,25-to 7.32 (2H, m), the 7.65 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=7.9 Hz), 7,92 (1H, d, J=7.9 Hz), of 8.09 (1H, d, J=1.9 Hz), of 8.37 (1H, d, J=8.7 Hz), 8,48 (1H, d, J=1.9 Hz), 9,16 (1H, s).

1-112 of 1.39 (3H, t, J=7.2 Hz), of 2.08 (2H, Quint., J=7,2 Hz), of 2.23 (3H, s)of 2.64 (2H, t, J=7.2 Hz), to 2.67 (3H, s), by 2.73 (2H, t, J=7.2 Hz), 2,87 (6N, users), 4,37 (2H, square, J=7,2 Hz), 7,02 (1H, d, J=1.9 Hz), 7,25-7,30 (2H, m), the 7.65 (2H, d, J=7.9 Hz), 7,83-7,89 (3H, m), 7,92 (1H, d, J=7.9 Hz), of 7.97 (1H, d, J=1.9 Hz), scored 8.38 (1H, d, J=8,3 Hz), 9,16 (1H, s).
1-113to 2.06 (2H, Quint., J=7,1 Hz), 2,63 (2H, t, J=7,1 Hz)to 2.67 (3H, s), by 2.73 (2H, t, J=7,1 Hz), 2,87 (6N, users), a 3.01 (3H, s), 3.04 from (3H, s), a 3.87 (3H, s), equal to 4.97 (2H, s), 7,03 (1H, d, J=1.9 Hz), 7,25-7,30 (2H, m), a 7.62 (1H, d, J=1.9 Hz), the 7.65 (2H, d, J=8,3 Hz), to 7.84 (1H, d, J=1.9 Hz), 7,88 (2H, d, J=8,3 Hz), 7,92 (1H, d, J=7.9 Hz), of 8.37(1H, d, J=8.7 Hz), 9,17 (1H, s).

1-114a 2.01 (3H, s)to 2.06 (2H, Quint., J=7,1 Hz)of 2.64 (2H, t, J=7,1 Hz)to 2.67 (3H, s), by 2.73 (2H, t, J=7,1 Hz), 2,87 (6N, users), 3,66 (2H, DD, J=5,3 and 11.1 Hz), with 3.89 (3H, s), 4,42 (2H, t, J=5.3 Hz), 5,80 (1H, users), 7,02 (1H, d, J=1.9 Hz), 7,25-7,31 (2H, m), 7,56 (1H, d, J=l,9 Hz), the 7.65 (2H, d, J=8,3 Hz), 7,73 (1H, d, J=1.9 Hz), 7,88 (2H, d, J=8,3 Hz), 7,92 (1H, d, J=7.9 Hz), of 8.37 (1H, d, J=8,3 Hz)to 9.15 (1H, s).

Table 23
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3
1-1151,70 (6N, d, J=6.8 Hz), 2,04 (2H, Quint., J=7,2 Hz), to 2.57 (2H, t, J=7.2 Hz), a 2.71 (2H, t, J=7.2 Hz), 2,87 (3H, users), 2,95 (3H, users), 5,10 (1H, Sept., J=6.8 Hz), 7,01 (1H, d, J=2.3 Hz), 7,19 (2H, d, J=8.7 Hz), 7,25-7,28 (1H, m), 7,40 (1H, DD, J=1.5 and 7.5 Hz), 7,45-rate of 7.54 (2H, m), a 7.62 (4H, s), of 7.69 (1H, DD, J=1,9, 7,2 Hz), 8,18 (2H, d, J=8.7 Hz), 8,31 (1H, d, J=8,2 Hz), of 9.00 (1H, s).

1-116to 1.22 (3H, t, J=7.5 Hz), of 1.41 (3H, t, J=7.2 Hz), to 2.06 (2H, Quint., J=7.5 Hz), 2,61 (2H, square, J=7.5 Hz), 2,65-2,70 (5H, m), by 2.73 (2H, t, J=7.5 Hz), 2,87 (6N, users), 3,86 (3H, s), and 4.40 (2H, square, J=7,2 Hz), 7,05 (1H, d, J=1.9 Hz), 7,26 (1H, d, J=7.9 Hz), 7,30 (1H, DD, J=1,9, 8,3 Hz), the 7.65 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=7.9 Hz), to $ 7.91 (1H, d, J=7.9 Hz), 8,13 (1H, d, J=1.9 Hz), of 8.37 (1H, d, J=8.6 Hz), 8,51 (1H, d, J=1.9 Hz), to 9.15 (1H, s).

1-117of 1.03 (3H, t, J=7.2 Hz), a 1.75-to 1.87 (2H, m)to 2.06 (2H, Quint., J=7,1 Hz)to 2.65 (2H, t, J=7,l Hz)to 2.66 (3H, s), is 2.74 (2H, t, J=7,1 Hz), 2,86 (6N, users), a 3.87 (3H, s)to 3.89 (3H, s), or 4.31 (2H, square, J=6,8 Hz), 7,05 (1H, d, J=2.3 Hz), 7,26 (1H, d, J=7.9 Hz), 7,30 (1H, DD, J=2,3, and 8.7 Hz), the 7.65 (2H, d, J=8,3 Hz), 7,80 (1H, d, J=1.9 Hz), 7,88 (2H, d, J=7.9 Hz), to $ 7.91 (1H, d, J=7.9 Hz), 8,23 (1H, d, J=1.9 Hz), at 8.36 (1H, d, J=8,3 Hz)to 9.15 (1H, s).

1-1181,39 (6N, d, J=6.0 Hz), to 2.06 (2H, Quint., J=7.5 Hz), of 2.64 (2H, t, J=7.5 Hz), to 2.66 (3H, s), is 2.74 (2H, t, J=7.5 Hz), 2,8 6 (6N, users), a 3.87 (3H, s),3.90 (3H, s), 5,27 (1H, Sept., J=6.0 Hz), 7,05 (1H, d, J=1.9 Hz), 7,26 (1H, d, J=7.9 Hz), 7,30 (1H, DD, J=1,9, 8,3 Hz), the 7.65 (2H, d, J=8,3 Hz), 7,79 (1H, d, J=1.9 Hz), 7,88 (2H, d, J=8,3 Hz), 7.91 (1H, d, J=7.9 Hz), 8,21 (1H, d, J=1.9 Hz), at 8.36 (1H, d, J=8.6 Hz), to 9.15 (1H, s).
Table 24
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
1-119of 1.39 (3H, t, J=7.2 Hz), was 2.05 (2H, Quint., J=7.5 Hz), 2,19 (3H, s), 2,60 (2H, t, J=7.5 Hz), to 2.66 (3H, s), by 2.73 (2H, t, J=7.5 Hz), 2,8 6 (6N, user. C)of 3.84 (3H, s), 4,37 (2H, d, J=7,2 Hz), 7,02 (1H, d, J=1.9 Hz), 7.23 percent-to 7.32 (2H, m), of 7.48 (1H, d, J=1.9 Hz), 7,56 (1H, d, J=1.9 Hz), to 7.64 (2H, d, J=8,3 Hz), 7,87 (2H, d, J=8,3 Hz), to $ 7.91 (1H, d, J=7,9 Hz), at 8.36 (1H, d, J=8.7 Hz), 9,14 (1H, users).

1-120to 1.19 (3H, t, J=7.5 Hz), was 2.05 (2H, Quint., J=7.5 Hz), 2,49-of 2.64 (4H, m)to 2.66 (3H, s), by 2.73 (2H, t, J=7.5 Hz), 2.86 (6N, user. C)of 3.84 (3H, s), 3,91 (3H, s), 7,02 (1H, d, 1=1,9 Hz), 7.23 percent-7,31 (2H, m), 7,49 (1H, d, J=1.9 Hz), to 7.59 (1H, d, J=1.9 Hz), to 7.64 (2H, d, J=8,3 Hz),7,87 (2H, d, J=8.3 and the C), to $ 7.91 (1H, d, J=7.9 Hz), at 8.36 (1H, d, J=8,3 Hz), 9,14 (1H, users).
1-1211,36 (6N, d, J=6.2 Hz), was 2.05 (2H, Quint., J=7.5 Hz), 2,19 (3H, s), 2,60 (2H, t, J=7.5 Hz), to 2.66 (3H, s), by 2.73 (2H, t, J=7.5 Hz), 2,86 (6N, users), of 3.84 (3H, s), of 5.24 (1H, Sept., J=6.2 Hz), 7,02 (1H, d, J=1.9 Hz), 7.23 percent-to 7.32 (2H, m), 7,47 (1H, d, J=1.9 Hz), 7,54 (1H, d, J=1.9 Hz), to 7.64 (2H, d, J=8,3 Hz), 7,88 (2H, d, J=8,3 Hz), to $ 7.91 (1H, d, J=7.9 Hz), at 8.36 (1H, d, J=8,4 Hz), 9,14 (1H, users).

1-122to 1.19 (3H, t, J=7,6 Hz)of 1.40 (3H, t, J=7,1 Hz), was 2.05 (2H, Quint., J=7.5 Hz), 2,49-of 2.64 (4H, m)to 2.67 (3H, s), by 2.73 (2H, t, J=7.5 Hz), 2.86 (6N, user. C)of 3.84 (3H, s), to 4.38 (2H, square, J=7,1 Hz), 7,02 (1H, d, J=2.3 Hz), 7.23 percent-7,31 (2H, m), 7,49 (1H, d, J=1.9 Hz), 7,58 (1H, d, J=1.9 Hz), the 7.65 (2H, d, J=8,3 Hz), 7,87 (2H, d, J=8,3 Hz), to $ 7.91 (1H, d, J=7,9 Hz), at 8.36 (1H, d, J=8.5 Hz), 9,14 (1H, users).
1-1231,23 (6N, d, J=6,8 Hz)to 2.06 (2H, Quint., J=7.5 Hz), 2,65 was 2.76 (7H, m), 2,87 (6N, user. C)3,10 (1H, Sept., J=6.8 Hz), 3,85 (MN, C)3,94 (ZN, C), 7,05 (1H, d, J=1.9 Hz), 7,26 (1H, d, J=7.9 Hz), 7,30 (1H, DD, J=1,9, to 8.7 Hz), the 7.65 (2H, d, J=7.9 Hz), 7,88 (2H, d, J=7.9 Hz), to $ 7.91 (1H, d, J=7.9 Hz), 8,19 (1H, d, J=2.2 Hz), of 8.37 (1H, d, J=8,3 Hz), 8,51 (1H, d, J=2.2 Hz), to 9.15 (1H, s),

Working example 2-1

Methyl ester 4-[2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethyl shall iphenyl-2-carbonyl)amino]benzyl}methylamino)acetoxy]benzoic acid (Compound 2-1)

a) 4'-Triptorelin-2-carboxylic acid (2-dimethylcarbamoyl-4-vinylphenol)amide

To a solution of 4'-triptorelin-2-carboxylic acid (2-dimethylcarbamoyl-4-itfeel)amide (1,32 g) in toluene (15 ml) was added tributyltinhydride (935 mg) and tetranitropentaerithrite (0) (142 mg) and the mixture was stirred at 140°C for 1.5 hours under heating. The reaction solution was allowed to stand for cooling to room temperature and concentrated it in a vacuum. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=2:1, vol/about.) obtaining specified in the connection header (783 mg).

b) 4'-Triptorelin-2-carboxylic acid (2-dimethylcarbamoyl-4-formylphenyl)amide

To a mixed solution of 4'-triptorelin-2-carboxylic acid (2-dimethylcarbamoyl-4-vinylphenol)amide (774 mg) in a mixture of acetone (10 ml) - water (10 ml) was added osmium tetroxide (10% (wt./mass.) the microcapsule; 449 mg) and metaperiodate sodium (944 mg). The mixture was stirred at room temperature for 4 hours and filtered through a layer of celite. The filtrate was concentrated in vacuum. The residue was diluted with ethyl acetate, washed successively with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate=3:2, vol/about.) with the receipt of which is shown in the title compound (570 mg).

c) Methyl ether ({3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]benzyl}methylamino)acetic acid

To a solution of 4'-triptorelin-2-carboxylic acid (2-dimethylcarbamoyl-4-formylphenyl)amide (137 mg) and methyl ester hydrochloride N-methylglycine (45 mg) in dichloromethane (2 ml) was added triacetoxyborohydride sodium (97 mg). The mixture was stirred at room temperature for 4 hours, diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate solution and saturated salt solution, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel (chloroform:methanol=100:1, vol/about.) obtaining specified in the title compound (120 mg).

d) ({3-Dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]benzyl}methylamino)acetic acid

To a mixed solution of methyl ester ({3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]benzyl}methylamino)acetic acid (120 mg) in a mixture of THF (1 ml) - methanol (3 ml) was added 4 N. aqueous sodium hydroxide (0.2 ml). The mixture was stirred at 50°C for 2 hours under heating, dawali her to stand for cooling to room temperature and concentrated in vacuum. After adding water to the residue to the water solution was added in portions of 1 N. chloritoid is one acid under ice cooling, to bring the pH to 6-7, followed by its extraction with ethyl acetate four times. The extract was dried over anhydrous sodium sulfate and concentrated to obtain specified in the title compound (110 mg).

e) Methyl ester 4-[2-({3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]benzyl}methylamino)acetoxy]benzoic acid

{3-Dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]benzyl}methylamino)acetic acid (107 mg) was treated in a manner similar to stage d) of the working example 1-1, to obtain specified in the title compound (Compound 2-1)(62 mg).

Structure and NMR data of the obtained compound are shown in table 25.

Table 25
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
2-1the 2.46 (3H, s), 2,85 (3H, users), to 2.94 (3H, users), a 3.50 (2H, s), 3,71 (2H, s)to 3.92 (3H, s), 7,14-7,26 (3H, m), 7,35-7, 62 (8H, m), of 7.70 (1H, DD, J=7,1, 1.2 Hz), 8,06-of 8.09 (2H, m), 8,35 (1H, d, J=8,3 Hz), 9,12 (1H with).

Working example 3-1

4-Ethoxycarbonylphenyl ester 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid (With the Association 3-1)

a) 5-Chloro-N,N-dimethyl-2-nitrobenzamide

To a solution of 5-nitro-2-chlorbenzoyl acid (1 g), 1-hydroxybenzotriazole (1,14 g), and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.42 g) in N,N'-dimethylformamide (10 ml) was added dimethylaminohydrolase (0,61 g) and triethylamine (1 ml). The mixture was stirred all day and all night, and then added water. The reaction solution was extracted with ethyl acetate and the extract was washed with saturated aqueous sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and concentrated to obtain specified in the title compound (1.13 g).

b) Ethyl ester of 1-(3-dimethylcarbamoyl-4-nitrophenyl)piperidine-4-carboxylic acid

Ethyl ester of 5-chloro-N,N-dimethyl-2-nitrobenzamide (1,131 g), 4-piperidinecarboxylic acid (0,77 ml) and potassium carbonate (1.4 g) was subjected to the interaction of N,N'-dimethylformamide (20 ml) at 100°C for 2 hours. Was added to the reaction solution, water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate solution and saturated salt solution, dried over magnesium sulfate and concentrated to obtain specified in the connection header (1,578 g).

c) Ethyl ester 1-(4-amino-3-dimethylcarbamoyl)piperidine-4-carboxylic acid

Ethyl ester of 1-(3-dimethylcarbamoyl-4-nitrophenyl)Piperi the Jn-4-carboxylic acid (1,578 g) was dissolved in tetrahydrofuran (5 ml) and ethanol (5 ml). After adding a solution of 7.5% (wt./mass.) palladium on carbon (0,316 g) and the mixture was stirred for 5 hours at normal pressure in a hydrogen atmosphere. The reaction solution was filtered through a layer of celite and concentrated to obtain specified in the title compound, which was used in subsequent reactions without highlighting.

d) Ethyl ester 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid

Ethyl ester of 1-(4-amino-3-dimethylcarbamoyl)piperidine-4-carboxylic acid was dissolved in toluene (5 ml) and to the solution was added triethylamine (1,87 ml). The solution was cooled to 0ºC and add to it 4'-triptorelin-2-carbonylchloride (synthesized from the corresponding carboxylic acid; 1.44 g). The mixture was stirred at room temperature overnight. Insoluble material was filtered. After removal of insoluble material by filtration, the filtrate was concentrated and was purified column chromatography on silica gel (acetone:hexane = 5:1, vol/about.) obtaining specified in the connection header (1,287 g).

e) 1-{3-Dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid

Ethyl ester of 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid was dissolved in methanol 5 ml) and to the solution was added 4 N. aqueous sodium hydroxide (1.5 ml). The solution was stirred at room temperature for 2 hours, concentrated and acidified 1 N. hydrochloric acid. Obtained in the precipitate solid was filtered and washed with water to obtain specified in the connection header (1,064 g).

f) 4-Ethoxycarbonylphenyl ester 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid

4-Dimethylaminopyridine (59 mg), 4-methoxycarbonylpropionyl ester (56 mg) and 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid (200 mg) was dissolved in acetone (3 ml). After addition of WSC hydrochloride (85 mg) and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated and was purified column chromatography on silica gel (acetone:hexane = 5:1-3:1, vol/about.) obtaining specified in the title compound (Compound 3-1) (0.124 g).

Working example 3-2

2-Fluoro-4-ethoxycarbonylphenyl ester 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid (Compound 3-2)

Instead of 4-ethoxycarbonylphenyl of ester 3-fluoro-4-methoxycarbonylpropionyl ester was subjected to reactions similar to those described in the working example 3-1, to obtain 2-fluoro-4-ethoxycarbonylphenyl the th ester 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid (Compound 3-2).

Structure and NMR data of the compounds obtained in the working examples 3-1 and 3-2 shown in table 26.

Table 26
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
3-11,97 e 2.06 (2H, m), 2,12-of 2.21 (2H, m), 2,66-2,77 (1H, m), 2,78-3,01 (8H, m), 3,60 (2H, d, J=12.3 Hz), to 3.92 (3H, s)6,70 (1H, d, J=2.5 Hz), 6,98 (1H, DD, J=2,5, and 9.3 Hz), 7,14-7,19 (2H, m), 7,39 (1H, DD, J=1,4, the 7.4 Hz), 7,45-of 7.55 (2H, m), a 7.62 (4H, q, j 2.1 Hz), to 7.67 (1H, DD, J=1,6 and 7.6 Hz), 8,05-8,10 (2H, m), 8,13 (1H, DD, 2,1, to 9.3 Hz), 8,59 (1H, s).
3-22,00-2,09 (2H, m), 2,14-2,22 (2H, m), 2,72-3,02 (9H, m), 3,53-3,63 (2H, m), 3,93 (3H, s)6,70 (1H, d, J=3.0 Hz), 6,98 (1H, DD, J=3.0 a, and 9.3 Hz), 7,21 (1H, DD, J=7,5, 8,5 Hz), 7,39 (1H, DD, J=1,2, 7.5 Hz), 7,45-7,55 (2H, m), a 7.62 (4H, s), to 7.67 (1H, DD, J=1,2, 7,4 Hz), 7,82-7,89 (2H, m)to 8.14 (1H, d, J=8,8 Hz), at 8.60 (1H, s).

Working example 4-1

Methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[2-(4-ethoxycarbonylphenyl)-6-methylpyridin-3-carbonyl]amino}phenyl)butylochki]-5-methylbenzoic acid (Compound 4-1)

a) 4-(3-Dimethylcarbamoyl-4-nitrophenyl)butane acid

Ethyl ester of 4-(3-dimethylcarbamoyl-4-nitrophenyl)butane acid (1.5 g) was treated with the method (hydrolysis), a similar stage f) of the working example 1-1, to obtain specified in the connection header (1,37 g).

b) Benzyl ester 4-(3-dimethylcarbamoyl-4-nitrophenyl)butane acid

To a solution of 4-(3-dimethylcarbamoyl-4-nitrophenyl)butane acid (1,37 g) in DMF (10 ml) was added potassium carbonate (880 mg) and benzylbromide (922 mg). The mixture was stirred at 60ºC for 3.5 hours under heating and then gave it to stand for cooling to room temperature. After adding thereto water the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:ethyl acetate = 1:1, vol/about.) obtaining specified in the title compound (1.39 g).

c) Benzyl ether of 4-(4-amino-3-dimethylcarbamoyl)butane acid

To a mixed solution of benzyl ester 4-(3-dimethylcarbamoyl-4-nitrophenyl)butane acid (1.39 g) in THF (5 ml), ethanol (15 ml) and water (5 ml) was added ammonium chloride (1.0 g). After heating to 100ºC to the mixture was added iron (838 mg) for two times. The mixture is then boiled under reflux for 1.5 hours, allowed to stand for cooling to room temperature and filtered through a layer of celite. The filtrate was concentrated in vacuum. The residue was diluted with ethyl acetate, washed PEFC is therefore a saturated solution of sodium bicarbonate, water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated to obtain specified in the connection header (1,14 g).

d) Methyl ester of 4-{3-[4-(3-benzyloxycarbonylamino)-2-dimethylcarbamodithioato]-6-methylpyridin-2-yl}benzoic acid

To a solution of 2-(4-ethoxycarbonylphenyl)-6-methylnicotinic acid (322 mg) and DMF (one drop) in chloroform (3 ml) was added oxalicacid (0,21 ml) under cooling with ice. The mixture continued to stir for one hour and then concentrated. The residue was diluted with chloroform and slowly added dropwise to a solution of benzyl ester of 4-(4-amino-3-dimethylcarbamoyl)butane acid (400 mg) and triethylamine (273 mg) in ethyl acetate (5 ml) under cooling with ice. The mixture was stirred at room temperature overnight, diluted with ethyl acetate, washed with water and saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified column chromatography on silica gel (hexane:acetone = 2:1, vol/about.) obtaining specified in the title compound (582 mg).

e) Methyl ester of 4-{3-[4-(3-carboxypropyl)-2-dimethylcarbamodithioato]-6-methylpyridin-2-yl}benzoic acid

Methyl ester of 4-{3-[4-(3-benzyloxycarbonylamino)-2-dimethylcarbamodithioato]-6-methylpyridin-2-yl]benzoic acid (579 mg) processing ivali way similar to stage c) of reference example 7, to obtain the specified title compound (507 mg).

f) Methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[2-(4-ethoxycarbonylphenyl)-6-methylpyridin-3-carbonyl]amino}phenyl)butylochki]-5-methylbenzoic acid

Methyl ester of 4-{3-[4-(3-carboxypropyl)-2-dimethylcarbamodithioato]-6-methylpyridin-2-yl}benzoic acid (1.0 g) and methyl ether 3-chloro-4-hydroxy-5-methylbenzoic acid (390 mg) was treated in a manner similar to stage d) of the working example 1-1, to obtain specified in the title compound (Compound 4-1) (1.24 g).

Working examples 4-2 to 4-4

Connection working examples 4-2 to 4-4, shown in table 27, received a manner similar to the method for producing a 4 or a working example 4-1. Structure and NMR data of the compounds of working examples 4-1 to 4-4 are shown in table 27. In the following table, the compounds of working examples 4-2 to 4-4 correspond to connections from 4-2 to 4-4, respectively.

Table 27
ExampleStructureNMR (δ, 300 or 400 MHz, CDCl3)
4-12,07 (2H, Quint., J=7,1 Hz), of 2.23 (3H, s)of 2.64 (2H, t, J7,1 Hz), to 2.67 (3H, s), of 2.72 (2H, t, J=7,1 Hz), of 2.81 (3H, users), 2,87 (3H, users), 3,91 (6H, s), of 6.99 (1H, d, J=1.9 Hz), 7.24 to 7,29 (2H, m), 7,80-to 7.84 (3H, m), 7,92 (1H, d, J=7.9 Hz), of 7.97 (1H, d, J=2.3 Hz), with 8.05 (2H, d, J=8.7 Hz), of 8.37 (1H, d, J=8,3 Hz), 9,04 (1H, s).
4-2is 2.05 (2H, Quint., J=7,2 Hz), of 2.25 (3H, s)to 2.67 (2H, t, J=7.2 Hz), to 2.67 (3H, s), of 2.72 (2H, t, J=7.2 Hz), 2,82 (3H, users), of 2.86 (3H, users), 3,86 (3H, s), 3,91 (3H, s), 3,93 (3H, s), 7,02 (1H, d, J=1.9 Hz), 7.24 to 7,31 (2H, m), of 7.82 (2H, d, J=8,3 Hz), 7,92 (1H, d, J=7,6 Hz), with 8.05 (2H, d, J=8,3 Hz), 8,11 (1H, d, J=1.9 Hz), at 8.36 (1H, d, J=8,3 Hz), 8,51 (1H, d, J=2.2 Hz), 9,04 (1H, s).
4-32,02 (2H, Quint., J=7,2 Hz), of 2.56 (2H, t, J=7.2 Hz), 2,68 (2H, t, J=7.2 Hz), of 2.81 (3H, users), to 2.94 (3H, users), 3,91 (6H, s), 6,97 (1H, d, J=2.2 Hz), to 7.15 (2H, d, J=8.7 Hz), 7,22-7,29 (1H, m), 7,41-7,58 (5H, m), of 7.70 (1H, DD, J=1,9, 7.5 Hz), 8,03 (2H, d, J=8,3 Hz), 8,07 (2H, d, J=8.7 Hz), 8,32 (1H, d, J=8.7 Hz), 8,89 (1H, s).
4-4to 2.06 (2H, Quint., J=7.2 Hz), 2.63 in (2H, t, J=7.2 Hz), to 2.67 (3H, s), of 2.72 (2H, t, J=7.2 Hz), of 2.81 (3H, users), of 2.86 (3H, users), 3,88 (3H, s), 3,91 (3H, s), 3,93 (3H, s), of 6.99 (1H, d, J=1.9 Hz), 7,26-7,29 (2H, m), 7,55 (1H, d, J=1,6 Hz), of 7.75 (1H, d, J=1.9 Hz), 7,82 (2H, d, J=8,3 Hz), to 7.93 (1H, d, J=7.9 Hz), of 8.06 (2H, d, J=8,3 Hz), of 8.37 (1H, d, J=8.7 Hz), 9,04 (1H, s).

Example 1 test

Test for inhibition of milliosmoles triglyceride (TG)-carrying active the STI, show inventory

Microsomal triglyceriderich protein (MTP) of the intestinal microsome assay person (produced by Tissue Transforming Technologies, Inc.) was purified as described below. Human small bowel microsome were dialyzed in 10 mm phosphate buffer (300 ml, pH 6.8) twice for about 2 hours and once for at least another 12 hours at about 4ºC. After dialysis, the mixture was centrifuged at 4ºC and 15,000×g for 5 minutes and then extracted supernatant. Pre-extracted supernatant was purified column chromatography on diethylaminoethyl (DEAE) Sepharose using FPLC (Fast Performance Liquid Chromatography) for liquid Express chromatography and purified materials used for the tests described below.

Small single-vesicle (SUV) liposome (hereinafter described as a donor, containing 0.25% (mol/mol)triolein and 5% (mol/mol) cardiolipin), consisting of triolein, labeled14With, and not labeled the SUV liposome (hereinafter described as acceptor containing 0.25% (mol/mol)triolein) were prepared as described below.

First, to prepare the donor, evaporated under a stream of nitrogen gas phosphatidylcholine solution containing phosphatidylcholine labeled3N, cardiolipin solution and trolleinaya solution containing triolein labeled14(Each solution was dissolved in a suitable the content of inorganic fillers solvent) or, to prepare the acceptor, evaporated under a stream of nitrogen gas phosphatidylcholine solution containing phosphatidylcholine labeled3N, and cardiolipin solution (each solution was dissolved in a suitable organic solvent). To obtain emulsion was added an appropriate amount of buffer for the reaction (15 mm Tris-HCl buffer containing 1 mm EDTA.Na2, 40 mm NaCl and 0.5% (wt./about.) bullish sivertone albumin, pH 7.4). The emulsion was treated with ultrasound while cooling with ice and centrifuged at 4ºC and 159000×g for 2 hours. Each of the obtained supernatant was used as donor or acceptor.

Every radioactivity in the acceptor and the donor was measured by liquid scintillation counter and prepared mixed solution of acceptor and donor with reaction buffer so that the radioactivity created by the donor, was 16000 disintegrations per minute/400 µl, and the radioactivity created by the acceptor, was 4000 disintegrations per minute/400 µl. Was mixed with 400 μl of a mixed solution of donor and acceptor, 45 μl of the reaction buffer, 50 μl of RTMS (20 μg/ml) and 5 μl of sample dissolved in DMSO (dimethyl sulfoxide), or 5 μl of DMSO (total volume: 500 ál). The mixture is incubated at 37°C for 1.5 hours. At the end of incubation to the above solution was added 1.25 ml of a suspension of DEAE-cellulose (66,7% (vol./about.)) in 15 mm Tris-HCl buffer (pH 7,), containing 1 mm EDTA.Na2. The mixture was centrifuged to separate the donor (adsorbiroval on DEAE-cellulose in the form of sediment) and acceptor (supernatant). Liquid scintillation counter measured the radioactivity in the acceptor. The value obtained by subtracting the radioactivity in the empty group of radioactivity in the acceptor DMSO group was defined as MTP-mediated TG-transferring activity and compared with the value obtained by subtracting the radioactivity in the clean group of radioactivity in the group with the sample. In this case, an empty group was obtained by adding 10 mm phosphate buffer (pH 6.8), containing 250 mm NaCl, instead of MTP. The ratio of inhibition (%) was calculated from the values obtained at the following uravneniy.

The ratio of inhibition (%) = (1 minus ((radioactivity group in the sample minus the radioactivity empty groups)/(radioactivity DMSO group minus the radioactivity empty groups))) × 100.

Based on the above-mentioned equation was determined by a 50% ratio of inhibition (IC50).

The results are shown in tables 28-32. In tables 28-32 “+++” indicates the value of the IC50less than 10 nm, “++” indicates the value of the IC50in the range from 10 nm to less than 100 nm and “+” shows the value of the IC50in the range from 100 nm to 1000 nm.

Example 2 test

Test for metabolic stability in which Iceni S9

Human liver S9 (final concentration: 2 mg protein/ml) suspended in 100 mm califorina buffer (pH 7.4, containing β-nikotinamidadenindinukleotida: 1.3 mm, D-glucose-6-phosphate: 3.3 mm magnesium chloride: 3.3 mm glucose-6-phosphatedehydrogenase: 0,4 U/ml). The suspension was mixed with sample solution dissolved in DMSO. The solution was incubated at 37º for 0, 10 and 60 minutes and was added acetonitrile containing formic acid (final concentration: 0.1 per cent). The solutions were centrifuged and determined the concentration of the sample (unmodified form) in the supernatant by high-performance liquid chromatography with mass spectrometry (LC/MS; LC/MS). On the basis of the obtained data to calculate the residual ratio (%) according to the following equation.

Residual ratio (%) = number of sample through 0, 10 or 60 minutes after incubation/number of sample in zero time after incubation × 100.

Example 3 testing

Test for metabolic stability in plasma

The sample, dissolved in DMSO, was added to plasma or different animals (mouse and hamster). The solutions were incubated at 37°C for 0, 10 and 60 minutes and was added acetonitrile containing formic acid (final concentration: 0.1 per cent). The solutions were centrifuged and determined the concentration of the sample (unmodified form) in the supernatant method the m high-performance liquid chromatography with mass spectrometry (LC/MS; LC/MS). On the basis of the obtained data to calculate the residual ratio (%) according to the following equation.

Residual ratio (%) = number of sample through 0, 10 or 60 minutes after incubation/number of sample in zero time after incubation × 100.

In relation to the compounds obtained in the working examples of the present invention (compounds from 1-1 to 1-115, 2-1, 3-1, 3-2 and 4-1 to 4-4), results in a residual factor in human liver S9 and plasma are shown in tables 28-32.

In these tables, the residual ratio in the buffer was determined by stability in buffer (pH 7.4), as described below.

The test on the stability in buffer (pH 7.4)

The sample, dissolved in DMSO, mixed with a mixed solution of 100 mm califofnia buffer and acetonitrile in the ratio of 7:3 (vol/vol.). The mixture is incubated at 37º for 0, 10 and 60 minutes and added to it acetonitrile containing formic acid (final concentration: 0.1 per cent). The solution was centrifuged and determined the concentration of the sample (unmodified form) in the supernatant by high-performance liquid chromatography with mass spectrometry (LC/MS; LC/MS). On the basis of the obtained data to calculate the residual ratio (%) in the buffer by the following equation.

The residual ratio in the buffer (%) = number of sample through 0, 10 or 60 minutes after incubation/if estvo sample at zero time after incubation × 100.

Table 28
Connection # Human intestinal MTP
(IC50(nm))
The residual factor in human liver S9
(%/10 min)
The residual factor in human liver S9
(%/60 min)
The residual ratio in human plasma
(%/10 min)
The residual ratio in human plasma
(%/60 min)
The residual ratio in the buffer
(%/10 min)
The residual ratio in the buffer
(%/60 min)
1-1++008040101104
1-2+++002009897
1-300 58510198
1-4005759995
1-5+++00110100101
1-6+++00530102102
1-7+++006009898
1-8+++0071129998
1-9+++003409497
1-10+++000010198
1-11+++00009999
1-12+++00100100103
1-13+++002409597
1-14+++20 430101104
1-15+++4042098100
1-16+++203098103
1-17++0000100105
1-18+++000010198
1-19++0000107100
1-20++000010299
1-21++0000104103
1-22++00809698
1-23++002109999
1-24+++106949595
1-2540 895999101

+++
Table 29
Connection # Human intestinal MTP
(IC50(nm))
The residual factor in human liver S9
(%/10 min)
The residual factor in human liver S9
(%/60 min)
The residual ratio in human plasma
(%/10 min)
The residual ratio in human plasma
(%/60 min)
The residual ratio in the buffer
(%/10 min)
The residual ratio in the buffer
(%/60 min)
1-26++0023099102
1-27++0010097102
1-280000101102
1-29+++104109898
1-30++00009999
1-31++00260101102
1-32000010097
1-33+++000 098102
1-34+++16452098103
1-35+++50430100105
1-36+++3000100103
1-37+++3711009999
1-38++11200101102
1-39 +++520098104
1-40+++5000100102
1-41+++40370103106
1-42+++50520103103
1-43+++42130101103
1-44+++12413 099100
1-45+++1228948101102
1-46+++5239099102
1-47+++140009697
1-48+++166009997
1-49+++6100100100
1-50 +++720097103

Table 30
Connection # Human intestinal MTP
(IC50(nm))
The residual factor in human liver S9
(%/10 min)
The residual factor in human liver S9
(%/60 min)
The residual ratio in human plasma
(%/10 min)
The residual ratio in human plasma
(%/60 min)
The residual ratio in the buffer
(%/10 min)
The residual ratio in the buffer
(%/60 min)
1-51+++8323098101
1-52+++134120 100101
1-53+++5233100106
1-54+++1020097105
1-55+++
1-56+++
1-57+++
1-58what++
1-59+++
1-60+++
1-61+++
1-62+++
1-63+++
1-64+++2149893100101
1-65+++809894104104
1-66+++30678101103
1-67+++307717103105
1-68+++1137718101103
1-69++ 007011101106
1-70+++0000101104
1-71+++00530102105
1-72+++4000113112
1-73+++1007819101101
1-74+++24977 19102101
1-75+++23300113124

Table 31
Connection # Human intestinal MTP
(IC50(nm))
The residual factor in human liver S9
(%/10 min)
The residual factor in human liver S9
(%/60 min)
The residual ratio in human plasma
(%/10 min)
The residual ratio in human plasma
(%/60 min)
The residual ratio in the buffer
(%/10 min)
The residual ratio in the buffer
(%/60 min)
1-76+++5250199100
1-77 +++0059299100
1-78+++1025129797
1-79+++204009695
1-80+++5040100101
1-81+++415129997
1-82+++0017 0100103
1-83+++003909999
1-84+++1021099101
1-85+++00614103102
1-86+++0040099103
1-87+++112602100104
1-88 +++00390102101
1-89+++63490102104
1-90+++70500102103
1-91+++00310100105
1-92+++00716102107
1-93+++4052 0107109
1-94+++0041999102
1-95+++008229103102
1-96+++15700100109
1-97+++137490100104
1-98+++605010199
1-99 +++60509899
1-100+++00120102102

+++
Table 32
Connection # Human intestinal MTP
(IC50(nm))
The residual factor in human liver S9
(%/10 min)
The residual factor in human liver S9
(%/60 min)
The residual ratio in human plasma
(%/10 min)
The residual ratio in human plasma
(%/60 min)
The residual ratio in the buffer
(%/10 min)
The residual ratio in the buffer
(%/60 min)
1-101+++30420 100103
1-102+++0046098101
1-103+++48129955105111
1-104+++145781710196
1-105+++308443101101
1-106+++1304909899
1-1071136329899
1-108+++25589179898
1-109+++005039999
1-110+++5026099102
1-111+++4133009999
1-112+++27848 099100
1-113+++8210103104
1-114+++14320104108
1-115+++0085409898
2-1++004709595
3-1++2063698102
3-2 ++202409497
4-1+++0025099101
4-2+++203409897
4-3+++1000101102
4-4+++40009997

Example 1 test (test for inhibition of milliosmoles triglyceride (TG)-transferring activity shown ICTR) it is clear that new soedineniya the present invention and their pharmaceutically acceptable salts possess excellent MTP-inhibiting activity. In addition, example 2 test (test for metabolic stability in liver S9), it is clear that the new compounds of the present invention and their pharmaceutically acceptable salts are metabolized quickly, even if a small amount of the active compound reaches the liver. And yet, from example 3 test (test for metabolic stability in plasma) it is obvious that the new compounds of the present invention and their pharmaceutically acceptable salts are rapidly metabolized in plasma.

From the results, as indicated above, it is clear that the new compounds of the present invention and their pharmaceutically acceptable salts can inhibit the absorption of lipids in the small intestine. In addition, the presented results show that the compound is rapidly metabolized in plasma or liver and therefore compounds of the present invention does not inhibit MTP in the liver, and selectively inhibit MTP in the small intestine.

Thus, selective inhibition of MTP activity in the small intestine of the new compounds of the present invention and their pharmaceutically acceptable salts may decrease the absorption of lipids, allowing the regulation of triglyceride, cholesterol and lipoproteins, such as LDL, etc. in the blood or regulation of lipids in the cells. In addition, as new compounds according to the present image is the shadow and their pharmaceutically acceptable salts have no effect on hepatic MTP, in the liver does not accumulate triglyceride. Therefore, you can expect inhibiting the occurrence of fatty liver as a harmful side effect. Thus, we can say that the new compounds of the present invention and their pharmaceutically acceptable salts can become the new MTP inhibitors, do not have harmful effects, i.e. new tools for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension, as well as for the treatment or prevention of pancreatitis, hypercholesterolemia, hypertriglyceridemia, etc. that essentially only inhibit MTP in the small intestine, because disappear faster than traditional MTP inhibitors.

Making 1 (manufacture of capsules)
1)Connection 1-130 mg
2)Finely ground cellulose10 mg
3)Lactose19 mg
4)Magnesium stearate1 mg

1), 2), 3) and 4) with eshivot and fill with a mixture of a gelatin capsule.

Manufacturer 2 (manufacture of capsules)

Capsules are made in a manner similar to the production of 1, using the compound from 1-2 to 1-123, compound 2-1, connections from 3-1 to 3-2 or connections from 4-1 to 4-4 instead of compound 1-1.

3 manufacturer (manufacture of tablets)
1)Connection 1-130 g
2)Lactose50 g
3)Corn starch15 g
4)Calcium carboxymethylcellulose44 g
5)Magnesium stearate1 g

All the number 1), 2) and 3) and 30 g of 4) are mixed with water, dried under vacuum and passed through a sieve to obtain a granular powder. With granular powder mix 14 g of 4) and 1 g of 5) and the mixture is compressed on a tablet machine. In this way receive 1000 tablets containing 30 mg of the compound of working example 1 on one tablet.

Making 4 (production of tablets)

Tablets are made of STRs is obom, similar to the production of 1, using the compound from 1-2 to 1-123, compound 2-1, connections from 3-1 to 3-2 or connections from 4-1 to 4-4 instead of compound 1-1.

Industrial applicability

The present invention is useful for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes or hypertension, as well as for the treatment or prevention of pancreatitis, hypercholesterolemia, hypertriglyceridemia, and the like.

1. Ester compound, which is represented by the formula [2]:

where R1'represents a
1) C1-C6alkyl, which is optionally substituted by the same or different one or more Halogens, or
2) -CO-C1-C6alkoxy;
R2'represents a
1) hydrogen or
2) C1-C6alkyl,
R3', R4'and R5'are the same or different and represent, each,
1) hydrogen,
2) halogen,
3) C1-C6alkyl, which is optionally substituted by the same or different one or more halogen,
4) C1-C6alkoxy,
5) -COR13'where R13'represents a
(a) hydroxy,
(b) C1-C6alkyl,
(c) C1-C6alkoxy, which is optionally substituted by the same or different one or more the substituents, selected from (1) hydroxy, (2) C1-C6alkoxy, which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6of alkyl, where R11'represents hydrogen, (4) -CONR8'R9'where R8'and R9'are the same or different and represent, each, C1-C6alkyl, (5) -CO-C1-C6alkoxy, optionally substituted phenyl, (6) phenyl, optionally substituted by the same or different one or more substituents selected from halogen, C1-C6alkoxy and-CO-C1-C6alkoxy, and (7) heterocycle selected from pyridyl, tanila and

which all may be substituted by the same or different one or more C1-C6alkyl groups, or
(d) -OR19'where R19'represents a group
or group
or piperidyl, which is optionally substituted-CO-C1-C6the alkyl,
6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted C1-C6the alkyl, optionally substituted by the same or different one or more substituents selected from-CONR8'R9'(R8'and R9'have the same meanings as particularly the e above) and WITH aralkylated, or
7) nitrile;
R6'and R7'are the same or different and represent, each,
1) C1-C6alkyl or
2) nitrogen-containing 5 - or 6-membered saturated, the heterocycle containing a monocycle formed when R6', R7'and the adjacent nitrogen atom are taken together, and optionally including oxygen as a heteroatom;
Y1, Y2, Y3are the same or different and represent
1) all carbon atoms or
2) one of the Y1, Y2, Y3represent the nitrogen atom and the others are carbon atoms;
Y4represent a carbon atom or nitrogen;
-X'represents a
1) -(CH2)1where l is an integer from 1 to 3,
2) -CH2-NR18'-CH2-where R18'represents a C1-C6alkyl, or
3);
or its pharmaceutically acceptable salt.

2. Ester compound according to claim 1, where Y1represents a carbon atom, and one of the Y2and Y3represents a nitrogen atom and the other is a carbon atom.

3. Ester compound according to claim 2, where Y2represents a nitrogen atom, a Y1and
Y3represent a carbon atom.

4. Ester compound according to claim 1, which is represented by the formula

or its pharmaceutically acceptable salt.

5. Ester compound according to claim 1, which is represented by the formula

or its pharmaceutically acceptable salt.

6. Ester compound according to claim 1, which is represented by the formula

or its pharmaceutically acceptable salt.

7. Ester compound according to claim 1, which is represented by the formula

or its pharmaceutically acceptable salt.

8. Ester compound according to claim 1, which is represented by the formula

or its pharmaceutically acceptable salt.

9. Ester compound according to claim 1, which is represented by the formula:

where R1"represents a
1) C1-C6alkyl, which is optionally substituted by the same or different one or more Halogens, or
2) -CO-C1-C6alkoxy;
R2"represents a
1) hydrogen or
2) C1-C6alkyl;
R3", R4"and R5"are the same or different and represent, each,
1) hydrogen,
2) halogen,
3) C1-C6alkyl, which is optionally substituted by the same or different one or more halogen,
4) C1-C6alkoxy or
5) -COR13"where R13"/sup> represents a C1-C6alkoxy, which is optionally substituted by the same or different one or more substituents selected from
(1) phenyl,
(2) -CO-NR8"R9"where R8"and R9"are the same or different and represent, each, With1-C6alkyl, and
(3) a heterocycle selected from pyridyl and tanila, and said heterocycle is optionally substituted by the same or different one or more C1-C6alkyl groups;
R6"and R7"are the same or different and represent, each,
1) C1-C6alkyl or
3) nitrogen-containing 5 - or 6-membered saturated, the heterocycle containing a monocycle formed when R6", R7"and the adjacent nitrogen atom are taken together; and
Y2and Y3are the same or different and represent, each,
1) all carbon atoms or
2) one of the Y2and Y3represents a nitrogen atom and the other is a carbon atom;
or its pharmaceutically acceptable salt.

10. Ester compound according to claim 1, which is selected from the group
consisting of:
(1) phenyl ether {3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}acetic acid,
(2) 4-fortunelounge ether {3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)am is but]phenyl}acetic acid,
(3) phenyl ester of 3-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionic acid,
(4) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(5) ethyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(6) isopropyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(7) propyl ether of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(8) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(5-methyl-4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(9) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-3-fermenting acid,
(10) methyl ether 3-chloro-4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(11) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-3-methoxybenzoic acid,
(12) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy)benzoic acid
(13) methyl ester of 4-(4-{3-dimetil rebamol-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-2-methylbenzoic acid,
(14) methyl ester of 4-(4-{3-(pyrrolidin-1-carbonyl)-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(15) ethyl ester of 3-fluoro-4-(4-{3-(pyrrolidin-1-carbonyl)-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(16) 4-ethoxycarbonylphenyl ester 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid,
(17) 2-fluoro-4-ethoxycarbonylphenyl ester 1-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}piperidine-4-carboxylic acid,
(18) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-2-methoxybenzoic acid,
(19) methyl ester 4-[2-({3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]benzyl}methylamino)acetoxy]benzoic acid
(20) methyl ester 2-chloro-4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(21) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[2-(5-triptorelin-2-yl)benzoylamine]phenyl}butyryloxy)benzoic acid
(22) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-3-triftorperasin acid,
(23) methyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butir is Loxy)-2-triftorperasin acid,
(24) 4-(3-methyl[1,2,4]oxadiazol-5-yl)phenyl ether 4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyric acid,
(25) 4-acetylphenyl ether 4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyric acid,
(26) 4-cyanovinylene ether 4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyric acid,
(27) benzyl ester 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(28) 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(29) methyl ester of 4-(4-{3-(morpholine-4-carbonyl)-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)benzoic acid
(30) methyl ester of 4-(3-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}propionyloxy)benzoic acid
(31) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[3-(4-triptoreline)pyridine-4-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(32) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[3-(4-triptoreline)pyridine-4-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(33) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(34) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[2-(4-three is timeteller)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(35) methyl ester 5-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]pyridine-2-carboxylic acid,
(36) dimethyl ester of 4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)isophthalic acid,
(37) methyl ether 3-chloro-4-(4-{3-dimethylcarbamoyl-4-[(4'-triptorelin-2-carbonyl)amino]phenyl}butyryloxy)-5-methylbenzoic acid,
(38) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid,
(39) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid,
(40) isopropyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid,
(41) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-fluoro-5-methoxybenzoic acid,
(42) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]for 3,5-dimethoxybenzoic acid,
(43) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)Boutillon and]-5-ethoxybenzoyl acid,
(44) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-fluoro-5-methylbenzoic acid,
(45) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-ethyl-5-fermenting acid,
(46) ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]for 3,5-dimethoxybenzoic acid,
(47) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]for 3,5-dimethoxybenzoic acid,
(48) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methyl-5-triftorperasin acid,
(49) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[2-(4-ethoxycarbonylphenyl)-6-methylpyridin-3-carbonyl]amino}phenyl)butyryloxy]-5-methylisophthalic acid,
(50) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methoxy-5-methylbenzoic acid,
(51) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methoxy-5-triftorperasin acid,
(52) ethyl ester of 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptime ylphenyl)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid,
(53) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-ethoxy-5-methoxybenzoic acid,
(54) methyl ester 3-bromo-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid,
(55) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-utilizatorului acid,
(56) 1-ethyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylisophthalic acid,
(57) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxyisoflavone acid,
(58) 1-ethyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxyisoflavone acid,
(59) methyl ester of 2'-{2-dimethylcarbamoyl-4-[3-(4-methoxycarbonylpropionyl)propyl]phenylcarbamoyl}biphenyl-4-carboxylic acid,
(60) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[2-(4-ethoxycarbonylphenyl)-6-methylpyridin-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid,
(61) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[2-(4-methoxycarbonyl the l)-6-methylpyridin-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid,
(62) methyl ether sulfate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid,
(63) methyl ether sulfate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid,
(64) methyl ether sulfate 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]for 3,5-dimethoxybenzoic acid,
(65) methyl ester benzosulfimide 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid,
(66) methyl ester of methansulfonate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid,
(67) methyl ester toluene-4-sulfonate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid,
(68) methyl ester naphthalene-1,5-disulfonate 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid,
(69) methyl ester hydrochloride and 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-what ethylbenzoic acid,
(70) isopropyl ether sulfate 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(71) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]for 3,5-dimethylbenzoic acid,
(72) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]for 3,5-dimethylbenzoic acid,
(73) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]-3-methylbenzoic acid,
(74) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]-3-ethylbenzoyl acid,
(75) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]-3-isopropylbenzoic acid,
(76) methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methylbenzoic acid,
(77) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]isophthalic acid,
(78) ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(79) 1-isopropyl ester 3-methyl ester 4-[4-(3-who metilcarbamat-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]isophthalic acid,
(80) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-ethylbenzene acid,
(81) methyl ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-isopropylbenzoic acid,
(82) propyl ester 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid,
(83) 2-isopropoxyethanol ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(84) 2-acetylaminofluorene ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(85) benzyloxycarbonylamino ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(86) 4-chlorobenzylamino ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(87) benzyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(88) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(89) pyridine-2-ilma is silt ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(90) pyridine-3-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(91) pyridine-4-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(92) dimethylcarbamodithioato ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(93) methoxycarbonylmethyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(94) 3-chlorobenzylamino ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(95) 4-propionitrile ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid,
(96) 2-benzyloxyethanol ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(97) 3-benzyloxypropionic ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(98) 2-(2-oxopyrrolidin-1-yl)ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(99) 3-hydroxypropionic ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-Carbo who yl)amino}phenyl)butyryloxy]benzoic acid
(100) 4-bucharestilfov ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid,
(101) pyridine-3-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(102) 4-(2-methyl-2H-tetrazol-5-yl)phenyl ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid,
(103) 4-methoxybenzylthio ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(104) 3-methoxybenzamido ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(105) thiophene-2-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(106) thiophene-3-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(107) 6-methylpyridin-2-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]benzoic acid
(108) 6-methylpyridin-2-Eletropaulo ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(109) isopropoxycarbonyloxymethyl ester 4-[4-(3-dimethylcarbamoyl-4-{('-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(110) 4-(tert-butoxycarbonyl)benzyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(111) 4-(2-benzyloxycarbonylamino-2H-tetrazol-5-yl)phenyl ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid,
(112) 4-(2-dimethylcarbamoyl-2H-tetrazol-5-yl)phenyl ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid,
(113) 1-phenethyl ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(114) indan-1-silt ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(115) 1,2,3,4-tetrahydronaphthalen-1 silt ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy]benzoic acid
(116) 1-acetylpiperidine-4-silt ester 4-[4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyryloxy] benzoic acid
(117) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylisophthalic acid,
(118) 1-isopropyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylisobutyl the howling acid,
(119) ethyl ester of 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methylbenzoic acid,
(120) dimethylcarbamodithioato ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid,
(121) 2-acetylaminofluorene ether 3-chloro-4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxybenzoic acid,
(122) 4-(2-isopropyl-2H-tetrazol-5-yl)phenyl ester 4-(3-dimethylcarbamoyl-4-{(4'-triptorelin-2-carbonyl)amino}phenyl)butyric acid,
(123) 1-ethyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-utilizatorului acid,
(124) 3-methyl ester 1-propyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-methoxyisoflavone acid,
(125) 1-isopropyl ester 3-methyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)-butyryloxy]-5-methoxyisoflavone acid,
(126) ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methoxy-5-methylbenzoic acid,
(127) methyl who Fira 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-ethyl-5-methoxybenzoic acid,
(128) isopropyl ester of 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-methoxy-5-methylbenzoic acid,
(129) ethyl ester 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-3-ethyl-5-methoxybenzoic acid and
(130) dimethyl 4-[4-(3-dimethylcarbamoyl-4-{[6-methyl-2-(4-triptoreline)pyridine-3-carbonyl]amino}phenyl)butyryloxy]-5-isopropylnaphthalene acid,
or its pharmaceutically acceptable salt.

11. Pharmaceutical composition having MTP inhibitory activity containing a pharmaceutically effective amount of the ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

12. Pharmaceutical composition having selective MTP inhibitory activity in the small intestine containing a pharmaceutically effective amount of the ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

13. Inhibitor of microsomal triglyceriderich protein, which is an ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt.

14. Inhibitor of microsomal triglyceriderich protein content is a first pharmaceutically effective amount of the ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

15. Means for inhibiting the absorption of lipids in the small intestine, which represents an ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt.

16. Means for inhibiting the absorption of lipids in the small intestine containing a pharmaceutically effective amount of the ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

17. The method of treatment or prophylaxis of a disease selected from hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension comprising administration to a mammal pharmaceutically effective amount of the ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt.

18. The method of inhibition of microsomal triglyceriderich protein, comprising the administration to a mammal pharmaceutically effective amount of the ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt.

19. Method of inhibiting the absorption of lipids in the small intestine, comprising the administration to a mammal pharmaceutically effective amount of the ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt.

20. The use of the ester compound according to any one of claims 1 to 10 or headlamp is asepticheski acceptable salts for the manufacture of a medicinal product for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension.

21. The use of the ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt for the manufacture of a medicinal product which inhibits the absorption of lipids in the small intestine.

22. Use item 21, where the drug is used for treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes and hypertension.

23. The use of the ester compound according to any one of claims 1 to 10 or its pharmaceutically acceptable salt for the manufacture of a medicinal product which inhibits microsomal triglyceriderich protein.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

,

where R1 is selected from formulae

, and ,

n equals 0; R6 and R7 are independently selected from hydrogen, C1-C6alkyl, cyanoC1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; or R6 and R7 together with a carbon atom to which they are bonded form a 6-member heterocycloalkyl with one nitrogen atom; wherein any alkyl in R6 and R7 can optionally contain a methylene group substituted with an O atom; wherein any aryl in R6 and R7 or formed by a combination of R6 and R7 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, -XC(O)OR10; where X denotes a bond; R10 is independently selected from C1-C6alkyl; R8 is selected from C5-C9heteroarylC0-C4alkyl containing 2-3 heteroatoms independently selected from N, O and S; wherein any heteroaryl in R8 can be optionally substituted with one radical independently selected from: halide, C1-C6alkyl, C3-C6cycloalkyl; R2 denotes hydrogen; R3 and R4 are independently selected from hydrogen, C1-C6alkyl, C3-C6cycloalkylC0-C4alkyl and C6arylC0-C4alkyl; wherein any alkyl in R3 and R4 can optionally contain a methylene group substituted with a S(O)2 group; R5 is selected from C5-C6heterocycloalkyl with 1-2 heteroatoms selected from N and O, and NR12R13; where R12 and R13 are independently selected from C1-C6alkyl; as well as pharmaceutically acceptable salts and isomers thereof. The invention also relates to use of compounds of formula (I) in preparing a medicinal agent, and to a pharmaceutical composition having cathepsin S inhibiting properties, which contains a therapeutically effective amount of the compound of formula (I) in combination with a pharmaceutically acceptable filler.

EFFECT: obtaining compounds which can be used as cathepsin S inhibitors.

10 cl, 12 dwg, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - arylamidrazone derivatives of formula ,

where R1 is a C2-C8 alkyl group or a C2-C8 alkoxy group, which can be substituted with a halogen or a C1-C8 alkoxy group; a 5-7-member aromatic heterocycle containing 1 or 2 oxygen, nitrogen or sulphur atoms, or phenyl, which can be substituted with a halogen, a C1-C8 alkyl group, a haloC1-C8alkyl group or a C1-C8alkoxy group; or NR4R5; R2 and R3 are identical or different, and each is a hydrogen atom, a halogen atom, a halogenC1-C8alkyl group, a C1-C8alkyl group, a C2-C6alkynyl group, a C1-C8alkoxy group, a cyano group, a C2-C6alkanoyl group or a C1-C8alkylsulphonyl group; A is a benzene, pyridine, quinoline or isoquinoline ring; D is a single bond or methylene; m assumes values from 1 to 3 and n assumes values from 1 to 5, having antagonistic effect on S1P3 receptors, as well as to medicinal agents and pharmaceutical compositions containing such compounds as an active ingredient.

EFFECT: improved properties.

13 cl, 161 ex, 19 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds selected from a group comprising piperazine compounds of formula I: , where X is -CH2- or a bond; n equals 1; R1 is alkyl; cycloakyl; hydroxyethyl; benzo[1,3]dioxolyl; phenyl, which can be mono-substituted with a halide, alkyl, alkoxy, -CF3 or alkylcarbonyl; or phenyl which is di- or tri-substituted with substitutes independently selected from alkyl and halide; pyridyl which can be mono-substituted with a halide, alkyl or -CF3; furanyl which can be mono-substituted with methyl, hydroxymethyl or bromine, or furanyl which is disubstituted with an alkyl; thienyl which can be mono-substituted with methyl or chromium; pyrimidinyl; isoquinolinyl; benzhydryl; imidazolyl optionally mono-substituted with an alkyl; or thiazolyl; or X is -C(=O)- and R1 is hydrogen; R2 is indolyl, imidazolyl optionally mono-substituted with alkyl; phenyl which can be mono-substituted with a halide, alkyl, hydroxy or cyano, or phenyl which is disubstituted with a halide; pyridyl; benzothienyl; thiazolyl or thienyl; R3 is indolyl, pyridyl which can be mono-substituted with alkoxy, alkoxyalkoxy, NR31R32, morpholine, piperadine, oxopiperidinyl, oxopyrrolidinyl, pyridyl or phenyl; or phenyl which is mono-substituted with phenyl, pyridyl, alkyl, alkoxy, dialkylamino, morpholine, N-benzyl-N-alkylamino, (dialkylamino)alkoxy, phenylalkoxy or tetrahydroisoquinolinyl; or R3 denotes the group: , where Z is phenyl or pyridyl; R31 is 2-C1-C5alkoxyethyl, phenyl, pyridyl, phenylalkyl, hydroxyalkylcarbonyl, alkylcarbonyl, cycloalkylcarbonyl or phenylcarbonyl; R32 is hydrogen or methyl; R35 is alkyl, alkylcarbonyl, phenyl, pyridyl or pyrimidinyl; and R4 is phenyl-CH=CH-, where the phenyl can be mono-, di- or tri-substituted with substitutes independently selected from halide, alkyl, alkoxy and -CF3; or phenyl-CH2-CH2, where the phenyl is disubstituted with -CF3; and to optically pure enantiomers thereof, mixtures of enantiomers, such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, mixtures of diastereomeric racemates and mesoforms, such as salts of such compounds. The invention also relates to a pharmaceutical composition, as well as to use of compounds in any of claims 1-4.

EFFECT: obtaining novel biologically active compounds with antimalarial activity.

8 cl, 138 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to a compound of formula (I) where Q represents a bond, CH-NR3 R4, NR5 or oxygen atom; X represents CH or nitrogen atom; Y represents a bond, CH2, oxygen atom or NR6; Z represents CH or nitrogen atom; R1, R2 represent, independently, hydrogen, halogen; R3, R4 represent, independently, hydrogen, (C1-C6)-alkyl; R5 represents hydrogen, (C1-C6)-alkyl, (CO)R7, SO2- (C1-C6)-alkyl or benzyl; R6 represents hydrogen, (C1-C6)-alkyl; R7 represents (C1-C6)-alkyl, phenyl, benzyl, OR8 or NR9R10; R8 represents (C1-C6)-alkyl; R9 represents hydrogen, (C1-C6)-alkyl; R9 represents hydrogen, (C1-C6)-alkyl; R11, R12 represent, independently, hydrogen or (C1-C6)-alkyl; and to their pharmaceutically acceptable salts; provided when X represents nitrogen atom, Y cannot represent oxygen atom or NR6; and except for the compounds (E)-N-hydroxy-3-(4-{(E)-3-[4-(4-methylpiperazine-1-yl)phenyl]-3-oxopropenyl}phenyl) acrylamide; (E)-N-hydroxy-3-{4-[(E)-3-(4-moropholine-4-ylphenyl)-3-oxopropenyl] phenyl}acrylamide; (E)-3-(3-flour-4-[(E)-3-(4-morpholine-4-ylphenyl)-3-oxopropenyl]phenyl}-N-hydroxyacrylamide. Also, the invention refers to a method for producing the compounds of formula (I), to a pharmaceutical composition, as well as to application of one or more compounds of formula (I), (la), (lb), (Ic).

EFFECT: producing new biologically active compounds which exhibit histone deacetylase inhibitor activity.

21 cl, 53 ex, 10 tbl

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to new crystalline modifications of N-α-(2,4,6-triisopropylphenylsulphonyl)-3-hydroxyamidino-(L)-phenylalanine-4-ethoxycarbonyl piperazide and/or its salts. Such crystalline modifications have high stability particularly at low hygroscopicity compared to known amorphous forms of the compound.

EFFECT: invention relates to a method of obtaining such new crystalline modifications, to pharmaceutical compositions containing these new crystalline modifications and their use as an anti-tumour agent.

26 cl, 7 tbl, 13 ex, 20 dwg

FIELD: chemistry.

SUBSTANCE: present invention pertains to derivatives of 1-(4-benzylpiperazin-1-yl)-3-phenylpropenone, which are antagonists of the chemokine (CCR-1) receptor, with general formula I or its pharmaceutical salts or ester, where substitutes are defined in the description text. The invented compounds can be used for making pharmaceutical compositions, as well as in pharmaceutics for making medicinal agents, with inhibiting effect on chemokine (CCR-1) receptors.

EFFECT: obtaining compounds, used as medicinal agents, with inhibiting effect on chemokine receptors.

10 cl, 113 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1 and their pharmaceutically acceptable salts as inhibitors of post-proline aminopepdidases, as well as to pharmaceutical composition based on them and application for manufacturing such composition, and to method of inhibition with their application. Compounds can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose. In general formula 1 ,

either G1 represents -CH2-X2-(CH2)a-G3, and G2 represents H, or G2 represents -CH2-(CH2)a-G3, and G1 represents H; G3 is selected from group according to general formula 2 ,

group according to general formula 3

and group according to general formula 4 ;

a is 0, 1 or 2; b is 1 or 2; X1 is selected from CH2, S, CF2, CHF and O; X2 is selected from CH2; X3, X4 and X5 are selected from N; X6 is selected from NH; X7 is selected from NH; R1 is selected from H and CN; R2 represents H; R3 is selected from H, Cl, OH, NH2, NH-C1-C10alkyl and N(C1-C10alkyl)2; R4, R5, R6, R7 and R8 are independently selected from H, Br, Cl, F, OH, NO2; R9 represents H; R10, R11, R12, R13 and R14 are independently selected from H, Cl and CF3; R15 and R16 are independently selected from H, C1-C10alkyl, C1-C10alkenyl, C3-C10cycloalkyl, C3-C10cycloalkenyl, quinoline, naphtyl and -CH2-L-R17; R17 is selected from C1-C10alkyl, phenyl, naphtyl, quinolinyl and indolyl; L is selected from covalent bond, CH=CH and -C6H4-; on condition that when R15 and R16 both represent H, and b is 1, then X1 does not represent S or CH2.

EFFECT: obtaining compounds that can be applied for treatment of diseases mediated by activity of post-proline aminopeptidases, such as type II diabetes and disturbed tolerance to glucose.

58 cl, 10 tbl, 1705 ex

FIELD: chemistry, pharmaceutical.

SUBSTANCE: invention pertains to compounds with formula I , where: n is an integer equal 1 or 2; p is an integer from 1 to 7; A is chosen from one or more radicals X and/or Y; X represents methylene group, substituted when necessary by one or two C1-6-alkyl groups; Y represents C2-alkenyl, C2-alkenyl; G represents a single bonds, oxygen or C=O. The compound can be used as ferment FAAH inhibitor for pain killing, inflammation or nerve-degenerative diseases. Description is given of the method of obtaining compounds, pharmaceutical compositions based on them and their use.

EFFECT: design of a method of obtaining alkylhomopiperazinecarboxylates and their use for pain killing, treating inflammation or nervous degenerative diseases.

11 cl, 2 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carboxylic acid represented by the general formula (I): , their pharmaceutically acceptable salts or esters wherein values Y, L, X, T, Z, M, R1, W and are given in the invention claim. Proposed compounds possess insulin-sensitizing effect and they are double agonists with respect to PPARα and γ, and triple agonists with respect to PPARα, β(δ) and γ. Except for, the invention relates to a medicinal agent and pharmaceutical compositions based on the claimed derivatives of carboxylic acid, to methods for prophylaxis or treatment of diseases, and to using derivatives carboxylic acid for preparing a medicinal agent.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

56 cl, 2 tbl, 609 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: medicine.

SUBSTANCE: there is described application of 1-hetaryl-2-nitro-2-(3-phenyl-1,2,4-oxadiazole-5-yl)ethanes of general formula I a-m 1a, e, and R1=NO2, R2=H; 1b, f, to R1=NO2, R2=Me; 1c, g, l R1=CO2Et, R2=H; 1d, h, m R1 =CO2Et, R2 =Me; 1a-d R2 =piperidino; 1e-h R3 =1-pyrrolidinyl, 1j-m R3=morpholino as psychotropic substances.

EFFECT: substances are low-toxic and have an evident psychotropic effect on rats.

4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to sulphonic 2-nitro-2-(3-aryl-1,2,4-oxadiazole-5-yl)ethane derivatives of formula I a-g la R=3-NO2C6H4, R1=NO2, R2=H; b R=3-NO2C6H4, R1=NO2, R2=CH3; c R=4-CH3OC6H4, R1=NO2, R2=H; d R=4-CH3OC6H4, R1=NO2, R2=CH3; e R=4-CH3OC6H4, R1=CO2Et, R2=H; f R=4-CH3OC6H4, R1=CO2Et, R2=CH3; g R=4-CH3C6H4, R1=CO2Et, R2=H.

EFFECT: preparation of the compound exhibiting antileprous and antituberculous activity.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the following compounds: N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trofluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl-1H-imidazole-4-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4-(,2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazole-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trifluoro-1-methyl-ethoxy)-benzamide, 3-chloro-N-[2-[(N,N-dimethylglicyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide, 3-chloro-N-(2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-[(3-hydroxy)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide, as well as to their pharmaceutically acceptable salts.

EFFECT: obtained compounds and salts can be used for treatment cell proliferative diseases and disorders by modulating activity of mitotic kinesin CENP-E.

26 cl, 102 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of novel sulphone derivatives of 2-nitro-2-(3-aryl-1,2,4-oxadiazol-5-yl)ethane of general formula I, which can be used as potential antimicobacterial preparations Ia-g, where la R-3-NO2C6H4, R1=NO2, R2=H; b R=3-NO2C6H4 R1=NO2, R2=CH3; c R=4-CH3OC6H4, R1=NO2, R2=H; d R=4-CH3OC6H4, R1=NO2, R1=CH3; e R=4-CH3OC6H4 R1=CO2Et, R2=H; f R=4-CH3OC6H4, R1=CO2Et, R2=CH3; g R=4-CH3C6H4, R1=CO2Et, R2=H. The method involves heating and mixing substituted 2-nitro1-chloro-2-(3-aryl-1,2,4-oxadiazol-5-yl)ethane with an equimolar amount of sodium 4-tolysulphinate in a solvent and then holding the reaction mixture at room temperature.

EFFECT: method avoids solvent preparation and increases output of the desired product.

1 cl, 2 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel 5-6-member nitrogen-containing heterocyclic compounds, selected form derivatives of pyridine, pyrimidine, imidasoline, oxadiasoline, such as, for instance , which possess inhibiting activity with respect to aspartylprotease, such as "ВАСЕ-1".

EFFECT: obtaining pharmaceutical composition, method of aspartylprotease inhibition aimed at application of compounds for preparation of medication intended for treatment of state, mediated by aspartylprotease, such as "ВАСЕ-1".

4 cl, 1 tbl, 1832 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to tritium-labelled 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid of formula I .

EFFECT: obtaining a tritium-labelled analogue of a physiologically active compound which is used to correct a range of genetic disorders.

1 cl, 2 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a malononitrile compound with formula (I): where one of X1, X2, X3 and X4 stands for CR100, where R100 is a group with formula (II) each three of the other X1, X2, X3 and X4 is nitrogen or CR5, under the condition that, from one to three of X1, X2, X3 and X4 stands for nitrogen, Z is oxygen, sulphur or NR6. The malononitrile compound can be used a pesticide in agriculture.

EFFECT: obtaining a new pest control compound and its use as an active ingredient of a pesticide composition.

18 cl, 180 ex

FIELD: chemistry.

SUBSTANCE: compound of formula I , its diastereomers or salts, where dot line represents optional double bond, m and p independently stand for 0, 1, 2 or 3; R1 stands for H, -N(R8)-C(O)-NR6R7, -N(R8)-S(O)2-NR6R7, -N(R8)-C(O)-N(R8a)-S(O)2-NR6R7, etc.; R1a stands for H or group OH; or R1 or R1a together form oxo; or R1 and R1a together with carbon atom, to which they are bound, form optionally substituted oxo spiro-condensed heterocyclic group, representing fully saturated 5-member monocyclic group, containing 2 nitrogen atoms; R2 stands for heteroaryl, (heteroary)alkyl, representing 5-6-member aromatic ring, contaning 1 nitrogen atom and/or 1 atom of oxygen and/or sulphur, and optionally condensed with aryl ring; aryl, (aryl)alkyl, alkyl, alkenyl or cycloalkyl, representing partly or fully saturated C3-C6 monocyclic structure, any of which can be optionally, independently, substituted with one or more groups T1, T2 or T3; J stands for bond, C1-4 alkylene, R3 stands for -R5, -C(Z1)-R5, -N(R8a1)-C(Z1)-R5, -N(R8a1)-C(Z1)-O-R5, -N(R8a1)-S(O)2-R5; R4 stands for alkyl, halogenalkyl, cycloalkyl, aryl, which can be optionally condensed with heteroaryl 6-member ring, containing 1-2 heteroatoms, selected from group SO2, N, etc.; R5 stands for -NR6aR7a or heteroaryl, (heteroaryl)alkyl, representing 5-6-member aromatic ring, which contains 1-3 nitrogen atoms and/or 1 or 2 atoms of oxygen or sulphur, optionally condensed with heteroaryl ring, representing 6-member aromatic ring, containing 1 nitrogen atom, etc.; R6a, R7a independently represent H, alkyl, aryl, (aryl)alkyl, heteroaryl, representing 5-6-member aromatic ring, which contains 1-2 nitrogen atoms, optionally condensed with aryl or heteroaryl ring, representing 6-member aromatic ring with 1 nitrogen atom; any of which can be optionally, independently, substituted with one or more groups T1c, T2c or T3c; R6, R7, R8, R8a, R8a1 R8a2, and R9, independently, represent H, alkyl, hydroxy, alkoxy, (hydroxy)alkyl, (alkoxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, -NR12R13, cycloalkyl, (cycloalkyl)alkyl, optionally condensed with aryl; aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl, etc.; R10, R10a, R11 and R11a, independently, represent H, alkyl, aryl, (aryl)alkyl, , hydroxy, (hydroxy)alkyl; heteroaryl, (heteroaryl)alkyl, representing 5-member aromatic ring, which contains 2 nitrogen atoms, or R11 and R11a can together form oxogroup, or R10a can together with R11a form bond, or R10 can together with R9 form saturated 3-4-member cycle; R12 and R13, independently, represent H, alkyl; W represents =NR8a2, =N- CO2R8a2, =N- CN; X represents C(=O), C=N-CN; Z1represents =O, or =N-CN; RX represents one optional substituent, bound with any suitable carbon atom in cycle, independently selected from T1g, T2g or T3g. Compounds of formula I are applied for manufacturing medication for treatment of IKur-mediated disorders.

EFFECT: cycloalkyl compounds, useful as inhibitors of potassium channels function.

13 cl, 694 ex, 1 tbl

Amid derivative // 2336273

FIELD: chemistry.

SUBSTANCE: invention relates to amid derivatives of formula (I), method of disease treatment and pharmaceutical composition based on them. Compounds can be applied in treatment of different herpes virus infections. In general formula (I) , Z: 1,2,4-oxydiazol-3-yl, 4-oxazolyl, 1,2,3-triazol-2-yl or 2-pyridyl, A: phenyl, which can have a substitute (substitutes) selected from group, including lower alkyl, halogen, halogen-substituted lower alkyl, O-lower alkyl, O-lower alkylene -OH, CN, OH, O-lower alkylene-phenyl, O-lower alkylene-O-lower alkyl, NH2, NH-lower alkyl, N-(lower alkyl)2 ,NH-lower alkylene-OH, NH-lower alkylene-O-lower alkyl, O-lower alkylene- NH2, O-lower alkylene-NH-lower alkyl and O-lower alkylene-N(lower alkyl)2; heteroaryl, representing monocyclic 6-member ring, which contains nitrogen atom as heteroatom or bicyclic 9-member ring, containing 1-2 heteroatoms selected from nitrogen and/or sulfur, which can have a substitute (substitutes), selected from lower alkyl; or phenyl group, condensed with saturated 5-member hydrocarbon cycle; or phenyl group, condensed with saturated 5-member heterocyclic cycle, which contains 1-2 heteroatoms, selected from nitrogen and/or oxygen, which can have a substitute (substitutes), selected from group, including lower alkyl, halogen, -C(O)-lower alkyl, lower alkylene-O-lower alkyl, on condition, that aryl group, condensed with saturated hydrocarbon cycle or aryl group, condensed with saturated heterocyclic cycle is bound with nitrogen atom through carbon atom in aromatic cycle, X: CO, R3: C3-C6cycloalkyl, which can have a substitute (substitutes), selected from group, which includes oxo, OH, halogen, CN, O-lower alkyl, -C(O)-NH2, -C(O)-NH-lower alkyl, -C(O)-N(lower alkyl)2, lower alkylene-OH, lower alkylene-O-lower alkyl; aryl, selected from phenyl, naphtyl, which can have a substitute (substitutes), selected from halogen; pyridyl; 9-member bicyclic heteroaryl, containing 1-3 heteroatoms, selected from S, N, O; or saturated heterocyclic group, representing monocyclic 6-member group, which contains 1-2 heteroatoms selected from S, SO, SO2, N, O, which can have a substitute (substitutes), selected from halogen.

EFFECT: obtaining amid derivatives that can be applied for treating various herpes virus infections.

17 cl, 26 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: described is 2-alkyl-cycloalk(en)yl-carboxamides of formula

, in which X, s, R1 , L, R2 and A assume values given in the formula of invention, a method of producing said compounds, an agent and use of said compounds against unwanted microorganisms.

EFFECT: higher activity compared to existing compounds, low toxicity and high toleration by plants.

6 cl, 8 tbl, 6 ex

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