Compositions for activation of lipoprotein lipase containing benzene derivatives

FIELD: medicine.

SUBSTANCE: invention refers to an agent for activation of lipoprotein lipase containing a benzene derivative of general formula (1) which is used for preventing and treating hyperlipidemia and obesity. The invention also refers to the benzene derivatives of general formula (1a).

EFFECT: composition improvement.

8 cl, 6 tbl, 9 ex

 

The technical FIELD TO WHICH the INVENTION RELATES

The present invention relates to compositions intended for the activation of lipoprotein lipase activity (hereinafter referred to as “LPL”), as well as to the derivatives of benzene. In addition, the invention is directed to the use of compounds activating LPL, to obtain LPL-activating compositions, and method of activation of LPL by the use of such compounds.

BACKGROUND of the INVENTION

Modern society called the society of gluttony, and dramatically increased the number of people diagnosed with hyperlipidemia, obesity, etc. Serious risk of hyperlipidemia, obesity and these diseases is that they cause diabetes, and arteriosclerosis, which can lead to myocardial infarction, ischemic stroke, etc.

Accordingly, for the prevention or treatment of hyperlipidemia, obesity and related diseases, was conducted a number of studies in the field of pharmaceuticals and chemotherapy to alleviate pathological conditions associated with these diseases, such as chemotherapy for activation of LPL (lipoprotein lipase) and chemotherapeutic agents designed for this purpose. It is believed that activation of LPL effective for prophylaxis or treatment of hyperlipidemia, obesity, arteriosclerosis, cataracts, it is hexie, nephrosis, etc. In various publications described the relationship between the activation of LPL and these diseases. For example, the relationship between activation of LPL and arteriosclerosis described in J. Clin. Invest., 92, 411 (1993). The relationship between activation of LPL and cataracts described in Biol. Phar. Bull., 19, 1570 (1996). The relationship between activation of LPL and cachexia described in Anticancer Research, 19, 4099 (1999). The relationship between activation of LPL and nephrosis described in Metabolism, 49, 588 (2000). The relationship between activation of LPL and hyperlipidemia described in Diabetes, 44, 414 (1995). The relationship between activation of LPL and obesity described in Diabetologia, 43, 875 (2000).

DISCLOSURE of INVENTION

The authors of the present invention investigated compounds having LPL-activating effect, with the aim of obtaining pharmaceutical drugs (chemotherapeutic agents), showing efficacy in the prevention and treatment of hyperlipidemia, obesity and related disorders, and as a result of these studies found that specific compounds represented by following General formula (1), significantly activate LPL. Although these compounds can include some known connections, up to the present time it was not known that they activate LPL. Work on this invention was completed as a result of further studies based on the above data.

The content of this izaberete the Oia disclosed in the following claims 1 to 42:

1. Method of activation of LPL in the body of a patient in need of treatment aimed at such activation comprising the administration to a patient an effective amount of a derivative of benzene, where the derivative of benzene represented by the General formula (1):

where R1represents hydrogen, hydroxy, lower alkyl, lower alkoxygroup, lower alkoxycarbonyl, carboxy or substituted phenyl lower alkyl; and

R2represents hydrogen; lower alkyl; 1,2,3,4-tetrahydronaphthyl; replaced by cycloalkyl lower alkyl; phenyl; phenyl having one or two substituent selected from the group consisting of halogen, lower alkoxygroup, cyano, halogen-substituted lower alkyl, and halogen-substituted lower alkoxygroup; substituted phenyl lower alkyl; substituted phenyl lower alkyl, a benzene ring which has one or two substituent selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cyano, nitro, lower alkoxycarbonyl, carboxy, lower alkoxygroup and halogen-substituted lower alkoxygroup; or lower alkyl, substituted by one cycloalkyl and one phenyl or halogen-substituted by phenyl; or

R1and R2combined with each other with the formation of fragment-CH=C(Ph)-, where Ph means phenyl;

R3performance is possessing a hydrogen or a lower alkoxygroup; and

Z represents a group selected from the groups listed below in paras.(a)to(h):

(a) imidazo[2,1-b]thiazol-6-yl or imidazo[2,1-b]thiazol-6-yl having one lower alkyl substituent;

(b) benzimidazole-2-yl;

(c) benzothiazol-2-yl;

(d) imidazo[1,2-a]pyrimidine-2-yl;

(e) imidazol-4-yl, having as a substituent one phenyl or phenyl substituted halogen-substituted lower alkyl;

(f) imidazo[1,2-a]pyridine-3-yl;

(g) imidazo[1,2-a]pyridine-5-yl; and

(h) a group represented by the following formula:

where R4represents hydrogen, lower alkyl or halogen;

R5means hydrogen, lower alkyl, halogen, hydroxy, lower alkoxygroup, substituted phenyl lower alkoxygroup;

R6means hydrogen, lower alkyl, carboxy or halogen-substituted lower alkyl;

R7represents hydrogen, lower alkyl, halogen, halogen-substituted lower alkyl, lower alkoxycarbonyl, carboxy, cyano, carbarnoyl, or phenyl; and

R8is hydrogen or lower alkyl,

however, provided that when Z is a group (e), R1means lower alkoxygroup, R2is substituted by a phenyl lower alkyl, and R3means hydrogen.

2. The method according to claim 1, where the derivative of benzene is a compound of the General formula (1), where Z group (a).

3. The method according to claim 1, where the derivative of benzene is a compound of the General formula (1), where Z is a group (b).

4. The method according to claim 1, where the derivative of benzene is a compound of the General formula (1), where Z is a group (d).

5. The method according to claim 1, where the derivative of benzene is a compound of the General formula (1), where Z is a group (e).

6. The method according to claim 1, where the derivative of benzene is a compound of the General formula (1), where Z is a group (f),(g) or (h).

7. The method according to claim 1, where the derivative of benzene is a compound described in any of items (1-1)to(1-4):

(1-1), the compound of formula (1), where R1means lower alkoxygroup, and R2represents phenyl, phenyl, benzene ring which as substituents are one or two halogen atom, substituted phenyl lower alkyl group, a lower alkyl group, substituted phenyl, benzene Colisee which there are one or two substituent selected from the group consisting of halogen and cyano, or R1and R2combined with the formation of fragment-CH=C(Ph)- (where Ph means phenyl, and Z is a group (h);

(1-2), the compound of formula (1), where R1is the lowest alkoxygroup, R2is lower alkyl substituted by phenyl, which in the benzene ring as substituents have the tsya one or two halogen atom, and Z is a group (a);

(1-3) the compound of formula (1), where R1is the lowest alkoxygroup, R2means lower alkyl, substituted phenyl, or lower alkyl, substituted phenyl, a benzene ring which as substituents are one or two halogen atom, and Z is a group (f); and

(1-4) the compound of formula (1), where R1is the lowest alkoxygroup, R2represents lower alkyl, substituted phenyl, and Z stands for a group (e).

8. The method according to claim 1, where the patient who needs treatment, aimed at the activation of LPL, is patient with hyperlipidemia.

9. The method according to claim 1, where the patient who needs treatment, aimed at the activation of LPL, is patient with obesity.

10. The method according to claim 1, where the derivative of benzene is a compound selected from the group consisting of 2-(4-benzyloxy-3-methoxyphenyl)imidazo[1,2-a]pyridine, 2-[4-(4-cyanobenzyl)-3-methoxyphenyl]imidazo[1,2-a]pyridine, 2-[4-(4-bromo-2-forbindelse)-3-methoxyphenyl]imidazo[1,2-a]pyridine and 2-[4-(4-chlorobenzoyloxy)-3-methoxyphenyl]imidazo[1,2-a]pyridine.

11. The method according to claim 1, where the derivative of benzene is a 6-[4-(4-chlorobenzoyloxy)-3-methoxyphenyl]imidazo[2,1-b]thiazole.

12. The method according to claim 1, where the derivative of benzene is a 4-(4-benzyloxy-3-methoxyphenyl)-2-(4-triptoreline)imidazole.

13 Composition, activating LPL, which includes pharmaceutically acceptable carrier and a derivative of benzene represented by the General formula (1):

where R1represents hydrogen, hydroxy, lower alkyl, lower alkoxygroup, lower alkoxycarbonyl, carboxy or substituted phenyl lower alkyl; and

R2represents hydrogen; lower alkyl; 1,2,3,4-tetrahydronaphthyl; replaced by cycloalkyl lower alkyl; phenyl; phenyl having one or two substituent selected from the group consisting of halogen, lower alkoxygroup, cyano, halogen-substituted lower alkyl, and halogen-substituted lower alkoxygroup; substituted phenyl lower alkyl; substituted phenyl lower alkyl, a benzene ring which has one or two substituent selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cyano, nitro, lower alkoxycarbonyl, carboxy, lower alkoxygroup and halogen-substituted lower alkoxygroup; or lower alkyl, substituted by one cycloalkyl and one phenyl or halogen-substituted by phenyl; or

R1and R2combined with each other with the formation of fragment-CH=C(Ph)-, where Ph means phenyl;

R3represents hydrogen or lower alkoxygroup; and

Z represents a group selected from the groups read the Lenna below in paras.(a)to(h):

(a) imidazo[2,1-b]thiazol-6-yl or imidazo[2,1-b]thiazol-6-yl having one lower alkyl substituent;

(b) benzimidazole-2-yl;

(c) benzothiazol-2-yl;

(d) imidazo[1,2-a]pyrimidine-2-yl;

(e) imidazol-4-yl, having as a substituent one phenyl or phenyl substituted halogen-substituted lower alkyl;

(f) imidazo[1,2-a]pyridine-3-yl;

(g) imidazo[1,2-a]pyridine-5-yl; and

(h) a group represented by the following formula:

where R4represents hydrogen, lower alkyl or halogen;

R5means hydrogen, lower alkyl, halogen, hydroxy, lower alkoxygroup, substituted phenyl lower alkoxygroup;

R6means hydrogen, lower alkyl, carboxy or halogen-substituted lower alkyl;

R7represents hydrogen, lower alkyl, halogen, halogen-substituted lower alkyl, lower alkoxycarbonyl, carboxy, cyano, carbarnoyl, or phenyl; and

R8is hydrogen or lower alkyl,

however, provided that when Z is a group (e), R1means lower alkoxygroup, R2is substituted by a phenyl lower alkyl, and R3means hydrogen.

14. LPL-activating the composition according to item 13, where the derivative of benzene is a compound of General formula (1), where Z is a group (a).

15. LPL-activating the composition according to item 13, where the derivative of benzene is a compound of General formula (1), where Z is a group (b).

16. LPL-activating the composition according to item 13, where the derivative of benzene is a compound of General formula (1), where Z is a group (d).

17. LPL-activating the composition according to item 13, where the derivative of benzene is a compound of General formula (1), where Z is a group (e).

18. LPL-activating the composition according to item 13, where the derivative of benzene is a compound of General formula (1), where Z is a group (f), (g) or (h).

19. LPL-activating the composition according to item 13, where the derivative of benzene is a compound described in any of items (1-1)to(1-4):

(1-1), the compound of formula (1), where R1means lower alkoxygroup, R2represents phenyl, phenyl, benzene ring which as substituents are one or two halogen atom, substituted phenyl lower alkyl group, a lower alkyl group, a substituted phenyl, a benzene ring which has one or two substituent selected from the group consisting of halogen and cyano, or the substituents R1and R2combined with the formation of fragment-CH=C(Ph)- (where Ph means phenyl, and Z is a group (h);

(1-2), the compound of formula (1), where R1is the lowest alkoxygroup, R2is lower alkyl, substituted phenyl, benzene ring, whose deputies have is by one or two halogen atom, and Z is a group (a);

(1-3) the compound of formula (1), where R1is the lowest alkoxygroup, R2means lower alkyl, substituted phenyl, or lower alkyl, substituted phenyl, a benzene ring which as substituents are one or two halogen atom, and Z is a group (f); and

(1-4) the compound of formula (1), where R1is the lowest alkoxygroup, R2represents lower alkyl, substituted phenyl, and Z stands for a group (e).

20. The pharmaceutical composition according to item 13, where the derivative of benzene is a compound selected from the group consisting of 2-(4-benzyloxy-3-methoxyphenyl)imidazo[1,2-a]pyridine, 2-[4-(4-cyanobenzyl)-3-methoxyphenyl]imidazo[1,2-a]pyridine, 2-[4-(4-bromo-2-forbindelse)-3-methoxyphenyl]imidazo[1,2-a]pyridine and 2-[4-(4-chlorobenzoyloxy)-3-methoxyphenyl]imidazo[1,2-a]pyridine.

21. The pharmaceutical composition according to item 13, where the derivative of benzene is a 6-[4-(4-chlorobenzoyloxy)-3-methoxyphenyl]imidazo[2,1-b]thiazole.

22. The pharmaceutical composition according to item 13, where the derivative of benzene is a 4-(4-benzyloxy-3-methoxyphenyl)-2-(4-triptoreline)imidazole.

23. The pharmaceutical composition according to item 13, used for the treatment or prophylaxis of hyperlipidemia.

24. The pharmaceutical composition according to item 13 used against obesity.

25. The product is Noah benzene, represented by the General formula (1a)

where

(2-1) R1arepresents a lower alkoxygroup; R2ais lower alkyl, substituted phenyl, a benzene ring which has one or two substituent selected from the group consisting of halogen, cyano, nitro; and Zarepresents a group (a);

(2-2) R1arepresents a lower alkoxygroup; R2ais hydrogen, phenyl; phenyl substituted by one or two lower alkoxycarbonyl; lower alkyl substituted by phenyl; or lower alkyl substituted by phenyl, the benzene ring has one or two substituent selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cyano, nitro, lower alkoxygroup and halogen-substituted lower alkoxygroup; and Zais a group (d),(f) or (g);

(2-3) R1ais the lowest alkoxygroup, R2ais lower alkyl, substituted phenyl, and Zarepresents a group (e); or

(2-4) R1ais hydroxy or lower alkoxygroup, and R2arepresents a 1,2,3,4-tetrahydronaphthyl, lower alkyl, substituted cycloalkyl, phenyl; phenyl having one or two substituent selected from the group consisting of halogen, lower alkoxygroup, cyano, halogenase the CSOs lower alkyl and halogen-substituted lower alkoxygroup; lower alkyl, substituted phenyl, a benzene ring which has one or two substituent selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cyano, nitro, lower alkoxycarbonyl, carboxy, lower alkoxygroup and halogen-substituted lower alkoxygroup; or lower alkyl substituted by one cycloalkyl and one phenyl or halogen-substituted by phenyl; or R1aand R2acombined with each other with the formation of fragment-CH=C(Ph)- (where Ph denotes phenyl, and Zais a group (h).

26. A derivative of benzene A.25 described in any of items (3-1)to(3-4):

(3-1), the compound wherein R1arepresents a lower alkoxygroup, and R2ais phenyl, phenyl substituted by one or two halogen atoms, or lower alkyl, substituted phenyl, a benzene ring which has one or two substituent selected from the group consisting of halogen and cyano, or R1and R2combined with the formation of fragment-CH=C(Ph)- (where Ph means phenyl), and Zais a group (h).

(3-2) connection, where R1arepresents a lower alkoxygroup, R2ais lower alkyl, substituted phenyl, a benzene ring which as substituents have one or two halogen atom, and Zais own the th imidazo[2,1-b]thiazol-6-yl,

(3-3) connection, where R1ais the lowest alkoxygroup, R2arepresents lower alkyl, substituted phenyl, or lower alkyl, substituted phenyl, a benzene ring which as substituents are one or two halogen atom, and Zais a group (f).

(3-4) connection, where R1ais the lowest alkoxygroup, R2ais lower alkyl, substituted phenyl, and Zarepresents a group (e).

27. A derivative of benzene A.25, where Zain the General formula (1a) is a group (d),(f) or (g).

28. A derivative of benzene A.25, where R2ain the General formula (1a) is lower alkyl, substituted phenyl, a benzene ring which has one or two substituent selected from the group consisting of halogen, cyano and nitro; and Zais a group (a).

29. A derivative of benzene A.25, where Zain the General formula (1a) represents a group (e).

30. A derivative of benzene A.25, where Zain the General formula (1a) is a group (h).

31. A derivative of benzene A.25 selected from the group consisting of 2-[4-(4-cyanobenzyl)-3-methoxyphenyl]imidazo[1,2-a]pyridine, 2-[4-(4-bromo-2-forbindelse)-3-methoxyphenyl]imidazo[1,2-a]pyridine, 2-[4-(4-chlorobenzoyloxy)-3-methoxyphenyl]imidazo[1,2-a]pyridine, 6-[4-(4-chlorobenzoyloxy)-3-methoxyphenyl]imidazo[2,1-b]thiazole and 4-(4-gasoline is hydroxy-3-methoxyphenyl)-2-(4-triptoreline)imidazole.

32. The use of a derivative of benzene 13 for receiving LPL-activating composition.

33. The use of a derivative of benzene 13 for obtaining a composition for prophylaxis or treatment of hyperlipidemia.

34. The use of a derivative of benzene 13 for receiving the composition against obesity.

35. Pharmaceutical composition comprising a derivative of benzene A.25, as well as pharmaceutically acceptable carrier.

36. The pharmaceutical composition according A.25 used as LPL-activating composition.

37. The pharmaceutical composition according A.25 used as a composition for prophylaxis or treatment of hyperlipidemia.

38. The pharmaceutical composition according A.25 used as compositions against obesity.

39. A method of preventing hyperlipidemia in a patient in need of such prevention, including introducing into the patient an effective amount of at least one derivative of benzene A.25.

40. A method of treating obesity in a patient in need of such treatment, comprising introducing into the patient an effective amount of at least one derivative of benzene A.25.

41. The use of a derivative of benzene indicated in paragraph 13, for the prevention or treatment of hyperlipidemia.

42. The use of a derivative of benzene 13 for the prevention or treatment of obesity.

About spodnie benzene according to the present invention

Below are described more fully derivatives of benzene represented by the General formula (1) (hereinafter simply referred to as "connections 1" of the present invention)used in LPL-activating compositions of the present invention.

The deputies, included in the General formula (1)representing the connection 1 and used throughout the text of the application correspond to the following description. The term "lower"used to radicals containing carbon atoms, in the present application refers to radicals containing 1-6 carbon atoms.

Examples of lower alkyl groups include C1-6linear or branched alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.

Examples of the lower alkoxygroup include C1-6linear or branched alkoxygroup, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy etc.

Examples of the lower alkoxycarbonyl groups include C1-6linear or branched alkoxycarbonyl groups, such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, 1-methylethanolamine, butoxycarbonyl, 2-methylpropanesulphonic, 1,1-dimethylethoxysilane, pentyloxybenzoyl, hexyloxybenzoyl etc.

Examples of substituted phenyl lower alkoxygroup vkluchaut 1-6linear or branched alkoxygroup having one phenyl substituent, such as 1-phenylethane, 2-phenylethane, 3 phenylpropoxy, 2-phenylpropoxy, 4-phenylbutyrate, 5-phenylpentane, 6-phenylhexanoic etc.

Examples of the 1,2,3,4-tetrahydronaphthalene groups include 1,2,3,4-tetrahydronaphthalen-1-yl and 1,2,3,4-tetrahydronaphthalen-2-yl.

Examples of substituted cycloalkyl lower alkyl groups include C1-6alkyl groups having one C3-8cycloalkenyl Deputy, such as cyclopropylmethyl, 2-cyclopropylethyl, 3-cyclopropylmethyl, 4-cyclopropylmethyl, 5-cyclopropylmethyl, 6-cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl etc.

Examples cycloalkyl groups include C3-8cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.

Examples of phenyl groups having one or two substituent selected from the group consisting of halogen, lower alkoxygroup, cyano, halogen-substituted lower alkyl and halogen-substituted lower alkoxygroup include 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-forfinal, 4-bromophenyl, 4-iopener, 3,4-dichlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-trifloromethyl, 3-trifloromethyl, 4-triptime Setenil, 4-tetrabromodiphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,4-acid, 3,4-acid, 3,5-acid, 4-ethoxyphenyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-(1,1-dimethylmethoxy)phenyl, 4-pentyloxide, 4-hexyloxyphenyl, 2-triptoreline, 3-triptoreline, 4-triptoreline, 2,4-bis(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl, 3,5-bis(trifluoromethyl)phenyl, 4-tetrafluorethylene, 4-heptachlorobiphenyl, 4-nonoperatively, 4-undecafluoropentyl, 4-tridecafluorohexyl etc.

Examples of halogen atoms include fluorine, chlorine, bromine, iodine, etc

Examples of the lower alkoxygroup include1-6linear or branched alkoxygroup, such as methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylpropoxy, pentyloxy, hexyloxy etc.

Examples of halogen-substituted lower alkyl groups include C1-6perhalogenated group, in particular C1-6performanceline group. Replacement halogen atoms meet the requirements listed above, i.e. selected from the group consisting of fluorine, chlorine, bromine and iodine. Specific examples are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, nonattributed, undecafluoropentyl, tridecafluorohexyl etc.

Examples of halogen-substituted lower alkoxygroup include C1-6perhalogenated, in particular, C1-6performax the group. Replacement halogen atoms meet the requirements listed above, i.e. selected from the group consisting of fluorine, chlorine, bromine and iodine. Specific examples are triptoreline, pentaborate, heptafluoropropoxy, nonattributable, undecafluoropentyl, tridecafluorohexyl etc.

Examples of substituted phenyl lower alkyl groups include C1-6alkyl group, who as Deputy has one phenyl group, for example benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 4-phenylbutyl, 5-fenilpentil, 6-phenylhexa etc.

Examples of lower alkyl groups, substituted phenyl, a benzene ring which has one or two substituent selected from the group consisting of halogen, lower alkyl, halogen-substituted of alkyl, cyano, nitro, lower alkoxycarbonyl, carboxy, lower alkoxygroup and halogen-substituted lower alkoxygroup include:

(1) lower alkyl groups, substituted phenyl, a benzene ring as a substituent has only halogen atoms:

2-tormentil, 3-tormentil, 4-tormentil, 2,4-diferensial, 2.5-diferensial, 2,6-diferensial, 3,5-diferensial, 2-Chlorobenzyl, 3-Chlorobenzyl, 4-Chlorobenzyl, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 4-bromobenzyl, 4-jogbani, 4-bromo-2-tormentil, 4-chloro-2-tormentil, 1-(4-chlorophenyl)ethyl, 2-(4-chlorophenyl)ethyl, 3-(4-chloro who enyl)propyl, 2-(4-chlorophenyl)propyl, 4-(4-chlorophenyl)butyl, 5-(4-chlorophenyl)pentyl, 6-(4-chlorophenyl)hexyl, etc.

(2) a lower alkyl group substituted by a phenyl lower alkyl Deputy: 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-active compounds, 4-(1,1-dimethylethyl)benzyl, 4-propylbenzyl, 4-butylbenzyl, 4-pentylbenzoyl, 4-hexylbenzoyl, 1-(4-were)ethyl, 2-(4-were)ethyl, 3-(4-were)propyl, 4-(4-were)butyl, 5-(4-were)pentyl, 6-(4-were)hexyl, etc.

(3) a lower alkyl group substituted with phenyl halogen-substituted lower alkyl group (in particular, C1-6perhalogenated group) as a substituent in a benzene ring:

2-trifloromethyl, 3-trifloromethyl, 4-trifloromethyl, 4-pentafluorobenzyl, 4-(2,2,2-triptorelin)benzyl, 4-heptafluoropropyl, 4-nonoperatively, 4-undecafluoropentyl, 4-tridecafluorohexyl, 1-(4-trifloromethyl)ethyl, 2-(4-triptoreline)ethyl, 3-(4-triptoreline)propyl, 4-(4-triptoreline)butyl, 5-(4-triptoreline)pentyl, 6-(4-triptoreline)hexyl and the like;

(4) a lower alkyl group substituted with phenyl, which is substituted by cyano: cyanophenyl-C1-6alkyl groups such as 2-cyanobenzyl, 3-cyanobenzyl, 4-cyanobenzyl, 1-(4-cyanophenyl)ethyl, 2-(4-cyanophenyl)ethyl, 3-(4-cyanophenyl)propyl, 4-(4-cyanophenyl)butyl, 5-(4-cyanophenyl)PE is Teal, 6-(4-cyanophenyl)hexyl and the like;

(5) a lower alkyl group substituted with phenyl, which is substituted by a nitro-group: nitrophenyl-C1-6alkyl groups such as 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 1-(4-nitrophenyl)ethyl, 2-(4-nitrophenyl)ethyl, 3-(4-nitrophenyl)propyl, 4-(4-nitrophenyl)butyl, 5-(4-nitrophenyl)pentyl, 6-(4-nitrophenyl)hexyl and the like;

(6) a lower alkyl group substituted by phenyl, which substituted lower alkoxycarbonyl:

C1-6alkoxycarbonylmethyl-C1-6alkyl groups such as 2-methoxycarbonylbenzyl, 3-methoxycarbonylbenzyl, 4-methoxycarbonylbenzyl, 4-ethoxycarbonylbutyl, 4-propoxycarbonyl, 4-butoxycarbonylmethyl, 4-pentyloxybiphenyl, 4-hexyloxyphenyl, 1-(4-ethoxycarbonylphenyl)ethyl, 2-(4-ethoxycarbonylphenyl)ethyl, 3-(4-ethoxycarbonylphenyl)propyl, 4-(4-ethoxycarbonylphenyl)butyl, 5-(4-ethoxycarbonylphenyl)pentyl, 6-(4-ethoxycarbonylphenyl)hexyl and the like;

(7) a lower alkyl group substituted with phenyl, which is substituted by carboxyla: carboxyphenyl-C1-6alkyl groups such as 2-carboxybenzoyl, 3-carboxybenzoyl, 4-carboxybutyl, 1-(4-carboxyphenyl)ethyl, 2-(4-carboxyphenyl)ethyl, 3-(4-carboxyphenyl)propyl, 4-(4-carboxyphenyl)butyl, 5-(4-carboxyphenyl)pentyl, 6-(4-carboxyphenyl)hexyl and the like;

(8) a lower alkyl group substituted by phenyl, which zamienniki alkoxygroup: 2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, 4-ethoxybenzyl, 4-propoxyphenyl, 4-butoxyphenyl, 4-interoceanic, 4-hexyloxybenzoyl, 1-(4-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 3-(4-methoxyphenyl)propyl, 4-(4-methoxyphenyl)butyl, 5-(4-methoxyphenyl)pentyl, 6-(4-methoxyphenyl)hexyl, 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl etc.;

(9) low alkoxygroup, substituted phenyl, which is substituted by halogen-substituted lower alkoxygroup:

2-cryptomaterial, 3-cryptomaterial, 4-cryptomaterial, 4-pentafluorobenzyl, 4-(2,2,2-triptoreline)benzyl, 4-heptafluoropropoxy, 4-nanoformulations, 4-undecafluoropentyl, 4-tridecafluorohexyl, 1-(4-trifloromethyl)ethyl, 2-(4-trifloromethyl)ethyl, 3-(4-trifloromethyl)propyl, 4-(4-trifloromethyl)butyl, 5-(4-trifloromethyl)pentyl, 6-(4-trifloromethyl)hexyl and the like; and

(10) such other lower alkyl groups substituted with phenyl Deputy: 5-fluoro-2-trifloromethyl, 2-fluoro-5-trifloromethyl, 5-fluoro-2-methylbenzyl, 5-fluoro-2-methoxybenzyl, 4-methoxy-3-methoxycarbonylbenzyl, 3-methoxy-4-methoxycarbonylbenzyl etc.

Examples of halogen-substituted lower phenyl groups include 4-forfinal, 4-chlorophenyl, 4-bromophenyl, 4-iopener, 3-chlorophenyl, 2-chlorophenyl, etc.

Examples of lower alkyl groups having one cycloalkenyl for estatel and one phenyl or halogenhydrines Deputy, include α-cyclopropylmethyl, α-cyclopropyl-4-Chlorobenzyl, α-cyclopropyl-4-tormentil, α-cyclopropyl-4-bromobenzyl, α-cyclopropyl-4-jogbani, α-cyclopropyl-3-Chlorobenzyl, α-cyclopropyl-2-Chlorobenzyl, α-cyclobutylmethyl, α-cyclopentylmethyl, α-cyclohexylethyl, α-cycloheptylmethyl, α-cyclooctylmethyl etc.

Examples (a), i.e. imidazo[2,1-b]thiazol-6-yl or imidazo[2,1-b]thiazole-6-Il, with one lower alkyl Deputy, include imidazo[2,1-b]thiazol-6-yl, 2-methylimidazo[2,1-b]thiazol-6-yl, 3-methylimidazo[2,1-b]thiazol-6-yl, 5-methylimidazo[2,1-b]thiazol-6-yl, 2-ethylimidazole[2,1-b]thiazole-6-yl, 2-propylimidazol[2,1-b]thiazol-6-yl, 2-butylimidazole[2,1-b]thiazol-6-yl, 2-intimidate[2,1-b]thiazol-6-yl, 2-hexyl[2,1-b]thiazol-6-yl, etc.

Examples (e), i.e., imidazol-4-yl having one phenyl substituent or one phenyl substituent, a substituted halogen-substituted lower alkyl include 2-phenylimidazol-4-yl, 5-phenylimidazol-4-yl, 2-(4-triptoreline)imidazol-4-yl, 5-(4-triptoreline)imidazol-4-yl, 2-(3-tryptophanyl)imidazol-4-yl, 2-(2-triptoreline)imidazol-4-yl, 2-(4-pentabromodiphenyl)imidazol-4-yl, 2-(4-heptachlorobiphenyl)imidazol-4-yl, 2-(4-nonoperatively)imidazol-4-yl, 2-(4-undecafluoropentyl)imidazol-4-yl, etc.

Among the compounds of the present invention, preferable from the point of view of pharmacological activity are the compounds described the data in PP. (I)to(V) below:

(I) compounds represented by the General formula (1), where Z represents (a);

(II) compounds represented by the General formula (1), where Z is a (b) or (c);

(III) compounds represented by the General formula (1), where Z is a (d);

(IV) compounds represented by the General formula (1), where Z is a (e); and

(V) compounds represented by the General formula (1), where Z is a (f),(g) or (h).

Among the above compounds, preferred are compounds related to PP. (I), (IV) and (V). Especially preferred are those compounds where Z represents (a), (e) or (h).

Connection (1) (active connection LPL-activating compositions of the present invention) and new derivatives of benzene (hereinafter referred to as "compounds (1a)" of the present invention, which will be described later in this description include sodium salts, potassium salts, and also salts similar to the alkali metals; calcium salts, magnesium salts and salts of such alkaline earth metals; as well as salts of copper and other salts. These salts can be obtained by known methods. Mentioned salts obtained in this way have pharmacological activity, identical compounds in free form and also used in LPL-activating compositions and such compositions.

In addition, compounds (1) and compound (1a) include their pharmaceutically acceptable acid additive salts, such as hydrochloride, nitrates, sulphates, hydrobromide, phosphates, carbonates, acetates, lactates, citrates, etc. Such acid additive salts can be obtained by known methods. These acid additive salts have pharmacological activity, which is identical to the pharmacological activity of the compounds in free form. Therefore, the present invention relates, furthermore, to acid additive salts and pharmaceutical compositions, such as LPL-activating compositions and the like containing such an acid additive salt as active ingredients.

In addition, compounds (1) and compound (1a) can include optical isomers, including as asymmetric center of one of the carbon atoms. The present invention also relates to racemates, which are mixtures of the aforementioned optical isomers, optically active forms mentioned optical isomers and LPL-activating compositions containing as active ingredients or referred to the racemates, or optical isomers. These optical isomers can be divided according to known methods of separation.

Methods for obtaining compounds (1)

Compounds (1) according to the present invention, hung the basis of the type of substituent Z, specifically, depending on which of the groups described above in paras. (a)to(h), included in their structure, may be known compounds or can be obtained by known methods.

For example, compounds where Z represents imidazo[2,1-b]thiazol-6-yl or imidazo[2,1-b]thiazol-6-yl, containing one lower alkyl substituent, and denoted by the symbol (a)may be any compounds described in published examined patent application of Japan No. 291976/1995, or have the structure of the carbon skeleton, similar to the compounds described in this publication. These compounds can be obtained according to method 1 or method 3 described in the above publications, or can be obtained by analogy with these methods. More specifically, these compounds can be obtained by introducing into the reaction of cyclization as starting compounds (2), described in method 1 above publications or corresponding compounds having suitable Deputy, and compounds (3) or corresponding compounds having suitable Deputy. Alternatively, they can be obtained by hydrolysis of compounds (1c), described in method 3 above mentioned publication, or corresponding compounds having suitable Deputy, and attach to the obtained compounds corresponding halides. Conn is the link for these reactions can be selected in accordance with the above-mentioned publication.

Compounds where Z represents a benzimidazole-2-yl, and which are indicated by symbol (b)can be obtained according to the method described in published European patent application No. 694535, or they can be obtained by analogy with this method. More specifically, these compounds can be obtained according to the method described in the lines 24-58 page 6 mentioned publication, by introducing into the reaction of cyclization as starting compounds o-phenylenediamines having a suitable Deputy.

Compounds where Z represents benzothiazol-2-yl, and which are indicated by the symbol (c), can be obtained according to the methods described in USP 3876791, or by analogy with these methods. More specifically, these compounds can be obtained in accordance with methods described in lines 40-56 2nd columns and rows 39-50 3rd column descriptions for the specified patent. The details of these methods are described in USP 3669979; 3647812; 3095422; and in J. Medicinal Chem. 14 (1971): 248. More specifically, the desired compounds where Z represents benzothiazol-2-yl, and which are indicated by the symbol (c), can be obtained, for example, the interaction of suitable o-aminothiophenol and aromatic acids in the presence of trichloride phosphorus, when conducting the reaction in the presence of boric acid as a catalyst, or by condensation of suitable o-aminophenols and aromatic aldehydes.

p> Compounds where Z represents imidazo[1,2-a]pyrimidine-2-yl, and which are indicated by the symbol (d)may be compounds represented by the General formula Ia in published European patent application No. 113236 or similar compounds. These compounds can be obtained according to the method described in the above publication, or by analogy with this method. More specifically, these compounds can be obtained according to the method described in said publication with line 15 page 7 to line 28 to page 8, or in example 1, using appropriate starting compounds, similar amines of General formula II and α-halogenation General formula III of this publication.

Compounds in which Z represents an imidazol-4-yl or imidazol-4-yl having a phenyl substituent and which are indicated by the symbol (e), can be obtained according to the methods described in published unverified application for Japan patent No. 163861/2001, or by analogy with these methods. More specifically, these compounds can be obtained according to the methods of obtaining 1 and 2 of example 8, and so on, by reacting compounds of α-diketones of General formula (II), and compounds corresponding to benzaldehyde General formula (III). Alternatively, compounds in which Z is denoted by (e), can be obtained by the interaction of suitable compounds corresponding 2-acetophenone, which is substituted by halogen atom in the 2-position of General formula (IV)and compounds of benzamidenafil compounds represented by the General formula (V) given publication.

α-Diketones of General formula (II) can be obtained by known methods. Examples of such methods are, for example, (1) the interaction of the appropriate amino acid with the appropriate alkyl, aryl or allylamine derivatives of metals (see Tetrahedron.Lett.24(23) (1983):2375); (2) the interaction of suitable halogenation with arylacetylenes (see Tetrahedron Lett. (1971): 2941); (3) introduction the reaction of suitable α-arylketones (J. Org. Chem.53 (1988): 129;J. Org. Chem.24 (1995): 516;Tetrahedron Lett.(1972): 1175;Org. Syn.32 (1952): 35;J. Org. Chem.14(1949): 836;Am. Chem. Soc.71 (1949): 3760;J. Am. Chem. Soc.71 (1949): 1585; etc.), and similar methods.

Compounds where Z is a specific heterocyclic group denoted by the symbol (h)may be a compound described, for example, in published unverified application for Japan patent No. 291972/1995. These compounds can be obtained in accordance with the methods described in this manual or by analogy with these methods. More specifically, these compounds can be obtained according to methods 1-3, examples 1-20, etc. In particular, compounds in which Z represents a specific heterocyclic group denoted by the symbol (h) can be obtained by: (method 1) introduction to the cyclization reaction of suitable compounds, similar compounds (2), and compounds similar to the compounds (3) this publication; (method 2) hydrolysis of compounds similar to the compounds (1b); or (method 3) interaction of cycloalkylation (4) with compounds similar to the compounds (1c).

The above-mentioned literature sources included in the present application by reference.

Compounds where Z represents imidazo[1,2-a]pyridine-3-yl, indicated by the symbol (f), and compounds where Z represents imidazo[1,2-a]pyridine-5-yl, indicated by the symbol (g) (compound represented by the General formula (4)) can be obtained, for example, by the method shown in the reaction scheme 1:

(Reaction scheme 1)

where R1, R2and R3correspond to the above definitions; X is halogen; B refers to boron; the substituents R and Rbmay be the same or different and independently represent hydrogen or lower alkyl, or R and Rbcombined with each other with the formation of the lower alkylene, which may have a lower alkyl substituent; and Zbis a group (f) or (g).

The compound (4)shown in the reaction scheme 1, is produced by interaction of the compound (2) with a slight excess of compound (3). This reaction can be carried out in a suitable inert solvent such as N,N-dime informed (DMF), N,N-dimethylacetamide (DMA), or equivalent, in the presence of an aqueous solution containing excess relative to the compound (2) quantity of potassium phosphate, and in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium. The temperature of the reaction is chosen in the range from 50°C to the boiling point of the solvent. The reaction is completed in about 5-50 hours.

The compound (2) can be obtained according to the method described in J. Org. Chem., 60, 7508 (1995). The compound (3) can be obtained according to the method described in J. Org. Chem., 30(12), 4085 (1965) and published unverified application for Japan patent No. 324688/1998.

Compounds of the present invention, where Z is the Zb(i.e. compounds of the present invention, other than the compound (4) in reaction scheme 1), can be obtained by methods similar to the above-mentioned methods of producing compounds where Z is a group, designated one of the symbols (a)-(e) and (h).

The connection 1 of the present invention, where R2is hydrogen (for example, compounds represented by the General formula (4) in reaction scheme 1, where R is hydrogen)can be converted into compounds having the desired R2according to the following reaction scheme 2:

where R1Arepresents hydrogen, hydroxy, lower alkyl, lower alkoxy is the SCP, lowest alkoxycarbonyl, carboxyl or lower alkoxygroup substituted by phenyl. R2Arepresents lower alkyl; 1,2,3,4-tetrahydronaphthyl; lower alkyl substituted by cycloalkyl; phenyl; phenyl having 1 or 2 substituent selected from the group consisting of halogen, lower alkoxygroup, cyano, halogen-substituted lower alkyl and halogen-substituted lower alkoxygroup; lower alkyl substituted by phenyl; lower alkyl, substituted phenyl, a benzene ring which has one or two substituent selected from the group consisting of halogen, lower alkyl, halogen-substituted lower alkyl, cyano, nitro, lower alkoxycarbonyl, carboxyl, lower alkyl, substituted phenyl, substituted one or two substituents selected from the group consisting of lower alkoxygroup and halogen-substituted lower alkoxygroup, or lower alkyl substituted by one cycloalkyl and one phenyl or halogen-substituted by phenyl. Y represents halogen, or-B(OH)2. R3and Z correspond to the above definitions.

The transformation shown in the reaction scheme 2 can be carried out, as described below in accordance with the type of the substituent Y in the compound (5).

In particular, if Y is a halogen, the compounds (1a) and (5) is injected into the reaction in a suitable inert solvent, such as DMF, DMA is there a similar, in the presence of potassium carbonate, cesium carbonate or a similar alkali. As the compound (5), and the alkali is usually used in a quantity equimolar to or greater than equimolar relative to the compound (1a). The reaction is usually carried out at temperatures from 0°C to room temperature for from about 5 to about 100 hours.

If Y is-B(OH)2the compounds (1a) and (5) is injected into the reaction in a suitable inert solvent, such as DMF, DMA, dichloromethane or similar solvent, in the presence of triethylamine, N,N-dimethylaniline, or a similar reason, if necessary, further adding acetate of copper (II). Such reagents as the compound (5), the base and the copper acetate (II) can be used in the reaction in a quantity equimolar to or greater than equimolar relative to the compound (1a). The reaction is usually carried out at temperatures from 0°C to room temperature for from about 5 to about 100 hours.

As indicated above, the derivatives of benzene represented by the General formula (1a)are new compounds.

Compounds of General formula (1a), where Z is a group (f) or (g)may be obtained by the method shown in the above reaction scheme 1.

Compounds of General formula (1a), where Z is a group (a)can be obtained by the method described in example 23, or an equivalent method.

Compounds of General formula (1a), where Z is a group (e), can be obtained by the method described in example 95, or an equivalent method.

Compounds of General formula (1a), where Z is a group (h), can be obtained by the method described in example 1, or an equivalent method.

The desired compound (compound 1), as shown in the above schemes reactions, as well as their salts, can be easily isolated and cleaned in accordance with conventional methods for the extraction. Examples of such techniques include adsorption chromatography, preparative thin-layer chromatography, recrystallization, solvent extraction, etc.

The pharmaceutical compositions according to the present invention

Connection 1 (including their salts, which applies to all below) activate lipoprotein lipase (LPL) and applicable for the prophylaxis or treatment of hyperlipidemia, arteriosclerosis, obesity, etc. Therefore, the present invention additionally relates to a means for prevention and treatment of hyperlipidemia, compositions for the prevention and treatment of hyperlipidemia, means against obesity and compositions against obesity.

LPL-activating compositions (including products for the prevention and treatment of Hyper is epidemie, anti-obesity and so on) of the present invention is manufactured in the form of pharmaceutical compositions (in the form of pharmaceutical preparations)containing compound 1 and pharmaceutically acceptable carriers. Examples of pharmaceutically acceptable carriers that are suitable for use in the pharmaceutical compositions of the present invention include fillers, means for increasing the volume, binding agents, agents for improving wetting, dezintegriruetsja tools, surfactants, lubricants and the like diluents and excipients that are commonly used depending on the way of using of pharmaceutical drugs. Select the appropriate media in accordance with standrtnoe dosage form of a pharmaceutical preparation, which is expected to receive.

For the pharmaceutical compositions can be selected a number of standard dosage forms according to their therapeutic purpose. Typical examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections (solutions, suspensions, etc.), ointments, etc.

In the manufacture of tablets, pharmaceutically acceptable carriers include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, Kremnev the Yu acid, potassium phosphate and like excipients; water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone and similar binders; sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose with a low degree of substitution, dried starch, sodium alginate, powdered agar, powdered kelp, sodium bicarbonate, calcium carbonate and similar dezintegriruetsja means; esters of polyoxyethylenesorbitan and fatty acids, sodium lauryl sulfate, monoglyceride of stearic acid and similar surfactants, sucrose, stearin, cacao butter, hydrogenated fats and similar disintegration inhibitors; Quaternary ammonium bases, sodium lauryl sulfate, and similar tools to improve absorption; glycerin, starch and similar tools to improve wetting; starch, lactose, kaolin, bentonite, colloidal silica and similar absorbents; purified talc, stearate, boric acid powder, polyethylene glycol and similar lubricants; etc. in Addition, tablets may optionally be provided with conventional coatings, such as coatings sugar-based coatings on the basis of gelatin, the enteric coating and the film and coatings, to constitute a two-layer or multi-layer tablets, etc.

In the manufacture of pills, pharmaceutically acceptable carriers include, for example, glucose, lactose, starch, cacao butter, gidrirovannoe vegetable oil, kaolin, talc and the like excipients; powdered gum Arabic, powdered tragakant, gelatin, ethanol and the like binders; kelp, agar and the like dezintegriruetsja substances; etc

In the manufacture of suppositories, pharmaceutically acceptable carriers include, for example, polyethylene glycol, cacao butter, higher alcohols and their esters, gelatin, semisynthetic glycerides, etc.

Capsules can be produced in the usual way, as a rule, by the conclusion of compound 1 in combination with the above-mentioned pharmaceutically acceptable carriers in hard gelatin capsules, soft gelatin capsules, etc.

If the pharmaceutical compositions of the present invention are dosage forms that are intended for injection, such as solutions, emulsions, suspensions and the like, they are preferably sterilized and isotonic with blood. In the case of obtaining compositions for injection, examples of applicable solvents are water, ethanol, macrogol, propylene glycol, ethoxycarbonyl isostearoyl alcohol, polioksidony izote relevy alcohol, esters of polyoxyethylenesorbitan and fatty acids, etc. In this case, common salt, glucose or glycerin may be used in pharmaceutical preparations in a quantity sufficient for isotonic solutions. In addition, you can add the usual additional co-solvents, buffers, soothing tools.

If the pharmaceutical compositions of the present invention are ointments, such as paste, cream, gel and the like, examples of applicable solvents are white petrolatum, paraffin, glycerin, cellulose compounds, polyethylene glycol, silicone, bentonite, etc.

In addition, the pharmaceutical compositions of the present invention optionally may be used dyes, preservatives, flavorings, flavor additives, sweeteners and the like, as well as other pharmaceuticals.

The amount of active compound contained in the pharmaceutical compositions of the present invention, is not limited and can be selected in accordance with necessity from a wide range of values. Generally, it is preferable that the active compound is present in an amount of from about 0.5 to about 90 wt.%, preferably from about 1 to about 85 wt.% by weight of the pharmaceutical composition.

Route of administration pharmaceutical drugs the the ATA according to the present invention is not limited to, and you can select them in accordance with the specific form of the drug, the patient's age, his gender, severity of disease and other conditions. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally. Injections are administered intravenously, intramuscularly, intracutaneously, subcutaneously or administered intraperitoneally, individually or in combination with glucose, amino acids or similar conventional liquid fillers. Suppositories administered intrarectally.

The dosage of the pharmaceutical preparation of the present invention can be selected appropriately in accordance with the way of administration, patient age, his gender, severity of disease and other conditions. Typically, the pharmaceutical preparation is administered in an amount such that the active ingredient, i.e. the compound (1)was enrolled in the adult human body at a dosage from about 0.5 to about 20 mg, and preferably from about 1 to about 10 mg per kilogram of body weight. Pharmaceutical drugs can be given in a single dose or divide the required daily amount to several doses (2 to 4) during the day.

Methods of treatment and prevention according to the present invention

In the present invention, a method of activation of LPL in the body of a patient in need of such activation,including placing the patient at least one compound 1 in number effective to activate LPL.

In addition, the invention is directed to a method of preventing hyperlipidemia in a patient who is in need of such prevention, including placing the patient at least one compound 1 in the amount effective for the prophylaxis of hyperlipidemia.

The invention additionally relates to a method of treating hyperlipidemia in a patient in need of such treatment, comprising administration to the patient at least one compound 1 in a quantity effective for the treatment of hyperlipidemia.

In addition, the invention relates to a method of preventing obesity in a patient who is in need of such prevention, including placing the patient at least one compound 1 in a quantity effective for the prevention of obesity.

The present invention also relates to a method of treating obesity in a patient in need of such treatment, comprising administration to the patient at least one compound 1 in a quantity effective for the treatment of obesity.

In addition, the present invention relates to the use of compounds 1 to obtain LPL-activating compositions, to the use of compounds 1 to obtain preventive compositions against hyperlipidemia, use of the compounds 1 to obtain therapeutic compositions against hyperlipidemia, and so is the use of compounds 1 to obtain compositions against obesity.

The BEST OPTION of carrying out the INVENTION

The following examples are intended to further illustrate the present invention, but the scope of the invention is not limited to these examples.

In these examples, unless otherwise specified,the1H-NMR spectroscopy was carried out using dimethyl sulfoxide-D6(DMSO-d6) as solvent and tetramethylsilane was used (TMS) as internal standard.

Example 1

Obtaining 2-(4-benzyloxy-3-methoxyphenyl)imidazo[1,2-a]pyridine

Stage 1

At 0°C for 75 minutes was added 28.5 g (to 75.8 mmol) tribromide of phenyltrimethylammonium to 120 ml of a solution of 12.0 g (72.2 mmol) of 4'-hydroxy-3'-methoxyacetophenone in anhydrous tetrahydrofuran. The resulting mixture was stirred for 2 hours at 0°C and 30 minutes at room temperature. Thus obtained suspension was concentrated under reduced pressure, mixed with 100 ml of a mixture of ethyl acetate/hexane (1:1 vol/vol) and was stirred for 30 minutes at 0°C. the Crystalline tribromide of phenyltrimethylammonium present in the suspension were removed by vacuum filtration and washed with 50 ml of a mixture of ethyl acetate/hexane (1:1 volume/volume). The filtered solution was concentrated under reduced pressure, obtaining 30 g of the crude product.

At room temperature, 14,g (158,9 mmol) of 2-aminopyridine was added to 150 ml of the solution obtained above crude product (30 g) in acetonitrile. The mixture was stirred for 45 minutes at 50°C and 30 minutes at 80°C. the Reaction mixture was left to stand at room temperature overnight, was collected in the precipitate crystals by vacuum filtration and washed with about 50 ml of acetonitrile. Thus obtained crystals were dried at 80°C under reduced pressure, getting 19,0 g of the hydrobromide of 2-(4-hydroxy-3-methoxyphenyl)imidazo[1,2-a]pyridine. This compound is hereinafter referred to as "the compound of example 145".

Stage 2

At 0°C was added to 15.4 g (byr111.4 mmol) of potassium carbonate to 106 ml suspension of 17.0 g (52,9 mmol) of the compound obtained in stage 1 (the compound of example 145), in anhydrous DMF. The mixture was stirred for 60 minutes, adding dropwise 10.4 g (of 60.8 mmol) benzylbromide, and additionally stirred for another 60 minutes at 0°C and 24 hours at room temperature. The reaction mixture was cooled to 0°C was added 30 ml of water. After stirring for 10 minutes, was added 300 ml of water and then the mixture was stirred for another 1 hour. Precipitated precipitated crystals were separated by vacuum filtration, washed with 100 ml of water and dried at 60°C under reduced pressure, obtaining of 18.2 g of crude crystals.

Thus obtained crude crystals (18.2 g) was recrystallized from methanol-water, getting crystals (15,18 g) of the desired connection is possible (compound of example 1).

Obtaining the compounds of examples 2-11, 13-22, 26, 27, 30-41, 44-47, 50 to 75, 80-83, 85-94, 96-104, 114, 115, 119, 121, 123, 125-130, 134, 136 and 138-149.

Compounds of examples 2-11, 13-22, 26, 27, 30-41, 44-47, 50 to 75, 80-83, 85-94, 96-104, 114, 115, 119, 121, 123, 125-130, 134, 136 and 138-149 received, repeating the techniques described for stage 1 and stages 1 and 2 of example 1 and using the appropriate starting compound.

Example 12

Obtaining 3-(4-benzyloxy-3-methoxyphenyl)imidazo[1,2-a]pyridine

Stage 1

The solution to 4.23 g (to 16.9 mmol) 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-kilfenora in 200 ml of dry DMF was added 5.0 g (25,4 mmol) 3-bromoimidazo[1,2-a]pyridine, 0.39 g (0.34 mmol) of tetrakis(triphenylphosphine)palladium [0] (Pd(PPh3)4where Ph means phenyl) and 42,25 ml of 2M aqueous solution of potassium phosphate. The resulting mixture was stirred for 20 hours at 80°C. After completion of the reaction drove DMF under reduced pressure and the residue was purified on a column of silica gel (eluent: methanol/methylene chloride = 2/98-4/96).

The crystals obtained in the described manner, and recrystallized from methanol-hexane, obtaining 2,82 g 3-(4-hydroxy-3-methoxyphenyl)imidazo[1,2-a]pyridine (yield: 70%). This connection will be referred to as "the compound of example 131".

Stage 2

To 1 ml of DMF was added 24 mg (0.1 mmol) of the compound obtained in stage 1 (the compound of example 131), 65 mg (0.2 mmol) of cesium carbonate and 17 mg (0 mmol) of benzylbromide. This mixture was stirred over night at room temperature. Drove DMF under reduced pressure and the residue was purified using preparative plate TLC (eluent: methanol/methylene chloride = 1/98)to give 28 mg of the desired compound with a yield of 83% (compound of example 12").

Obtaining the compounds of examples 105-113, 116-118, 120, 122, 124, 132, 133, 135 and 137

Connection examples 105-113, 116-118, 120, 122, 124, 132, 133, 135 and 137 received, repeating the techniques described for stage 1 and stages 1 and 2 of example 12 using the appropriate starting compounds.

Example 23

Obtain 6-[4-(4-chlorobenzoyloxy)-3-methoxyphenyl]imidazo[1,2-b]thiazol

Stage 1

To 600 ml of a solution of 100 g of 4'-hydroxy-3'-methoxyacetophenone in anhydrous THF for 3 hours at 0°C was added 237,5 g tribromide of phenyltrimethylammonium, then was stirred at 0°C for 6 hours and for 13 hours at room temperature. Thus obtained reaction mixture was concentrated under reduced pressure, mixed with 500 ml of ethyl acetate and stirred at 0°C for 1 hour. Precipitated precipitated crystals were removed by vacuum filtration and the filtered solution was concentrated under reduced pressure, getting 265 g of oily substance.

This oily substance was dissolved in 400 ml of anhydrous DMF and the resulting solution was added to 60 g of 2-aminate the ash, followed by stirring at room temperature for 30 minutes and at 40°C for 3.5 hours. Thus obtained reaction mixture was diluted with 400 ml of ethyl acetate and left for 15 hours at room temperature. Precipitated precipitated crystals were collected via vacuum filtration. These crystals were washed with ethyl acetate and dried under reduced pressure, getting 153 g of a transparent crystalline salt thiazole, i.e. bromide 2-amino-3-[2-(4-hydroxy-3-methoxyphenyl)-2-oxoethyl]thiazole-3-FL.

To 590 ml of n-butanol was added 152,6 g obtained above salt thiazole and stirred at 100°C for 45 hours and 120°C for 1 hour. After cooling, the reaction solution was diluted with 600 ml ethyl acetate and left to stand for 3 hours at room temperature. Precipitated precipitated crystals were separated by vacuum filtration, washed with ethyl acetate and dried under reduced pressure, getting 140,8 g transparent crystalline hydrobromide 6-(4-hydroxy-3-methoxyphenyl)imidazo[2,1-b]thiazole.

Melting point: 253-254°C.

1H-NMR (DMSO-d6, δ): 8,43 (1H, s)8,23 (1H, d,J=4.6 Hz), to 7.64 (1H, d,J=4.6 Hz), 7,40 (1H, d,J=and 2.1 Hz), 7,25 (1H, DD,J=2,1, 8,3 Hz)6,91 (1H, d,J=8,3 Hz), 3,86 (3H, s).

Stage 2

Potassium carbonate (106 g) was added to 490 ml of a suspension of 120 g of compound obtained in stage 1, in anhydrous DMF. After paramasivan is within 2 h, to this mixture at 0°C was added to 82.9 g of p-chlorobenzylamino and was stirred for 3 hours at 0°C for 42 hours at room temperature. The reaction mixture was mixed with 500 ml of methanol and 450 ml of water and stirred at 70°C for 30 minutes After cooling the mixture to room temperature, precipitated precipitated crystals were collected by vacuum filtration, washed with 50% methanol and water and dried under reduced pressure receiving 102 g of the desired compound in the form of transparent crystals (compound of example 23").

Obtaining the compounds of examples 24, 25, 42, 43, 48, 49 and 84

Connection examples 24, 25, 42, 43, 48, 49 and 84 received, reproducing method described in example 23, using appropriate starting compounds.

Example 28

Obtaining 2-(4-benzyloxy-3-methoxyphenyl)imidazo[1,2-a]pyrimidine

To 30 ml of a solution of 3.9 g (16 mmol) of 4'-hydroxy-3'-methoxy-2-bromoacetophenone in acetonitrile was added 3.2 g (34 mmol) of 2-aminopyrimidine and stirred the mixture at 65°C for 2 hours. Precipitated precipitated crystals were separated by vacuum filtration and was dissolved in 100 ml of 50% methanol. This solution was mixed with 1.3 g of sodium bicarbonate and stirred at room temperature for 10 minutes. Precipitated precipitated crystals were separated by vacuum filtration and recrystallized from 50 ml of 50% methanol, obtaining 2.4 g of 2-(4-hydroc and-3-methoxyphenyl)imidazo[1,2-a]pyrimidine, which corresponds to a yield of 62%. Melting point: 230-233°C.

1H-NMR (DMSO-d6, δ): of 9.21 (1H, s)of 8.92 (1H, DD,J=2,1, 6,7 Hz), 8,48 (1H, DD,J=2,1, 4,1 Hz), of 8.25 (1H, s), EUR 7.57 (1H, d,J=1.5 Hz), 7,54 (1H, DD,J=of 1.5, 7.9 Hz), 7,02 (1H, DD,J=4,1, 6,7 Hz)6,86 (1H, d,J=7.9 Hz), a 3.87 (3H, s).

To 4.2 ml of a suspension of 0.50 g (2.1 mmol) obtained above in connection anhydrous DMF at 0°C was added 0.34 g (2.5 mmol) of potassium carbonate. The mixture was stirred for 30 min, was added dropwise 0,41 g (2.4 mmol) of benzylbromide and then was stirred for 15 min at 0°C, for 20 min at room temperature and for 16 hours at 40°C. the resulting reaction mixture at room temperature was added to 20 ml of water and was stirred for 1 hour. Then was collected in the precipitate crystals by vacuum filtration, getting to 0.72 g of the crude crystals of the desired compound.

These crude crystals were purified on a column of silica gel (10 g silica gel, eluent: methylene chloride/methanol=50/1). The desired compound was recrystallized from a mixture of methylene chloride/diethyl ether and was obtained 0.55 g of product (yield: 79%).

Obtaining compounds of example 29

The compound of example 29 was received, reproducing method described in example 28, using appropriate starting compounds.

Example 76

Obtaining 2-(4-benzyloxy-3-methoxyphenyl)be the of imidazole

Stage 1

In 20 ml of methylene chloride suspended 2.0 g (7.7 mmol) of 4-benzyloxy-3-methoxybenzoic acid. To this suspension was added DMF (0.05 g) and thionyl chloride (0.68 ml). The mixture was stirred at 50°C for 2 hours. To this mixture at 0°C was added dropwise 20 ml of pyridine, which at room temperature was dissolved 2-nitroaniline in the amount of 1.1 g (8.0 ml). The resulting mixture was stirred for 2 hours at room temperature and to the mixture was added water for the extraction phase of methylene chloride. The extract was dried over anhydrous magnesium sulfate and drove the solvent. Thus obtained crystals are recrystallized from a mixture of methylene chloride-hexane, obtaining 1.5 g of crystals of N-(2-nitrophenyl)-4-benzyloxy-3-methoxybenzamide.

1H-NMR (DMSO-d6, δ): 11,32 (1H, users), 8,99 (1H, d,J=8.0 Hz), of 8.27 (1H, d,J=a 7.6 Hz), of 7.70 (1H, DD,J=to 7.6 and 7.6 Hz), to 7.59 (1H, d,J=2.0 Hz), 7,51 (1H, DD,J=2,0, a 8.4 Hz), 7,30-7,47 (5H, m), 7,20 (1H, DD,J=of 7.6, 8.0 Hz), of 6.99 (1H, d,J=8,4 Hz).

Stage 2

Crystals (1.5 g)obtained in the previous phase, suspended in 100 ml of ethanol. The resulting suspension was mixed with 4.5 g of dihydrate of tin chloride and stirred at 80°C for 2 hours. The reaction mixture was added to ice-cold saturated solution of sodium bicarbonate (50 ml) and filtered through celite to remove the insoluble washes the century The filtered solution was diluted with 200 ml of ethyl acetate. The mixture of an ethyl acetate phase was sequentially washed with water and saturated salt solution. The organic phase (an ethyl acetate phase), thus obtained, was dried over anhydrous magnesium sulfate. The solvent is kept off and the residue was recrystallized from diethyl ether, obtaining the desired compound in the amount of 1.2 g

Obtaining compounds of example 77

The compound of example 77 was obtained by playback of the techniques described in example 76, using the appropriate starting compound.

Example 78

Obtaining 2-(4-benzyloxy-3-methoxyphenyl)benzothiazole

2.0 g (7.7 mmol) of 4-benzyloxy-3-methoxybenzoic acid suspended in methylene chloride (10 ml). To this suspension was added 0.05 g of DMF and 0.68 ml of thionyl chloride and then stirred at 50°C for 2 hours the resulting solution is added dropwise at 0°C was added to the solution, which was obtained by dissolving 1.2 g (9.3 mmol) of 2-aminothiophenol in 10 ml of pyridine at room temperature. Then the mixture was stirred over night at room temperature, was diluted with water and extracted with ethyl acetate (2 times × 50 ml). The extracts were dried over anhydrous magnesium sulfate and drove the solvent. The obtained residue was dissolved in 30 ml of toluene. Toluene solution was boiled under reflux the night, driving away in this water. The toluene was removed from the solution by distillation under reduced pressure and the residue was purified on a column of silica gel (eluent: ethyl acetate/hexane=1/5). The solvent is kept at reduced pressure. Thus obtained crystals were subjected to recrystallization from a mixture of methylene chloride-hexane, and obtained the desired compound in the amount of 0.18 g

Example 95

Getting 4-(4-benzyloxy-3-methoxyphenyl)-2-(4-triptoreline)imidazole

The potassium bicarbonate (2.9 g, 29,0 mmol) and α-bromo-4-benzyloxy-3-methoxyacetophenone (1.9 grams, 7,3 mmol) suspended in a mixture of water (2.5 ml) and THF (10 ml). To this suspension at a temperature of 70°C was added to 2.4 g (7.3 mmol) of 4-triftorperasin and then was stirred for 1 hour. This mixture was cooled to room temperature, was mixed with 70 ml of ethyl acetate and stirred for 30 minutes. Thus obtained solution is then washed with water and saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is kept at reduced pressure. The residue was purified on a column of silica gel (eluent: ethyl acetate/hexane=1/1) and the remaining substance was dissolved in a mixture of 20 ml of ethyl acetate and 5 ml of ethanol. At room temperature to this solution was added dropwise to 1.9 ml of 4 n hydrochloric acid in 1,4-dioxane. The resulting guide is chlorid was collected by filtration and dried overnight at 60°C and reduced pressure, getting the desired compound in the amount of 2.0 g (yield: 59%).

Obtaining compounds of example 79

The compound of example 79 was received, reproducing method described in example 95, by using appropriate starting compounds.

In the below table 1 shows the structure and properties (melting point, the data spectroscopy1H-NMR data and mass spectroscopy) of compounds obtained in the above examples. Abbreviations in the tables mean:

Me: methyl

MeO: methoxy

Et: ethyl

EtO (OEt): amoxi

n-Pr: n-propyl

n-PrO O-n-Pr: n-propoxy

t-Bu: tert-butyl

Table 1
Example No.StructureThe pace. plvl. (°C)1H-NMR (CDCl3) δ ppmMass spectrum (EI)
1128-129,58,07 (1H, d, J=6.8 Hz), 7,76 (1H, s), to 7.59 to 7.62 (2H, m), 7,46 (2H, d, J=7,6 Hz), 7,27-7,39 (4H, m), to 7.15 (1H, DD, J=6,8 and 7.6 Hz), 6,93 (1H, d, J=8,4 Hz), 6,74 (1H, DD, of 6.8 and 7.6 Hz), 5,19 (2H, s), of 4.00 (3H, s)-
2 103-1048,11 (1H, d, J=6.4 Hz), 7,74 (1H, d, J=2.0 Hz), to 7.67 (1H, DD, J=2.0 a, and 8.4 Hz), 7,63 (1H, d, J=9,2 Hz), 7,47 (2H, d, J=7,6 Hz), 7,38 (2H, DD, J=7,2, 7,6 Hz), 7,31-7,33 (1H, m), 7.23 percent-7,26 (1H, m), of 6.99 (1H, d, J=8,4 Hz)6,94 (1H, DD, 6,4, 8.0 Hz), with 5.22 (2H, s)to 4.01 (3H, s)-

m/z 349,1 (MH+)
3115-1178,17 (1H, d, J=6.8 Hz), 7,73 (1H, d, J=2.0 Hz), 7,66 (1H, DD, J=2.0 a, and 8.4 Hz), a 7.62 (1H, d, J=9,2 Hz), 7,47 (2H, d, J=7,6 Hz), 7,38 (2H, DD, of 7.6, 8.0 Hz), 7,27-7,37 (1H, m), 7,25 (1H, DD, J=6,8, and 9.2 Hz), 6,99 (1H, d, J=8,4 Hz), 6,93 (1H, DD, J=6,4, 6,8 Hz), with 5.22 (2H, s)to 4.01 (3H, s)-
4115-1178,08 (dt, J=7,9, 1.1 Hz, 1H), 7,78 (d, J=0.5 Hz, 1H), 7,63-to 7.61 (overlapping signals, 2H), 7,60-7,53 (m, 1H), 7,38 (DD, J=8,2, 2.2 Hz, 1H), 7,30-7,25 (m, 1H), 7.18 in? 7.04 baby mortality (overlapping signals, 3H), 6,97 (d, J=8,2 Hz, 1H), 6.75 in (DDD, J=6,7, and 6.6, 1.1 Hz, 1H), 5,26 (s, 2H), 4,01 (s, 3H)m/z 349,2 (MH+)
5117-1188,08 (dt, J= 7,9, 1.1 Hz, 1H), to 7.77 (d, J=0.6 Hz, 1H), 7,63-7,58 (overlapping signals, 2H), 7,39-7,12 (overlapping signals, 5H), 7,02-of 6.96 (m, 1H), 6,91 (d, J=8,2 Hz, 1H), 6.75 in (DDD, J=6,7, and 6.6, 1.1 Hz, 1H), 5,17 (s, 2H), 4,01 (s, 3H)

6144-146of 8.09 (1H, userd, J=6.6 Hz), 7,78 (1H, s), to 7.61 (1H, userd, J=9.1 Hz), 7,60 (1H, d, J=2.1 Hz), 7,40 was 7.45 (2H, m), 7,38 (1H, DD, J=2,1, 8,3 Hz), 7,13-7,17 (1H, m), 7,02-was 7.08 (2H, m), 6,92 (1H, d, J=8,3 Hz), 6,76 (1H, ushort, J=6.6 Hz), 5,14 (2H, s), of 4.00 (3H, s)-
7172-173of 8.09 (1H, userd, J=6.6 Hz), 7,78 (1H, s), 7,56-to 7.64 (6H, m), 7,37 (1H, DD, J=2,1, 8,3 Hz), 7,13-7,17 (1H, m), 6.90 to (1H, d, J=8,3 Hz), 7,76 (1H, ushort, J=6.6 Hz), of 5.24 (2H, s)to 4.01 (3H, s)-
8125-1268,10 (1H, userd, J=6.6 Hz), 7,80 (1H, s), 759-7,69 (4H, m), 7,38 (1H, DD, J=2,1, 8,3 Hz), 7,13-to 7.18 (1H, m),? 7.04 baby mortality-to 7.09 (1H, m), 6.89 in (1H, d, J=8,3 Hz), 6,77 (1H, ushort, J=6.6 Hz), lower than the 5.37 (2H, s), Android 4.04 (3H, s)-
9155-1578,08 (1H, d, J=7,2 Hz), 7,76 (1H, s), 7,58 to 7.62 (2H, m), 7,35 (1H, d, J=8.0 Hz), 7,34 (2H, d, J=8.0 Hz), 7,17 (2H, d, J=8.0 Hz), 7,12-to 7.15 (1H, m), 6,93 (1H, d, J=8.0 Hz), 6,74 (1H, DD, J=6,8, 7,2 Hz), 5,16 (2H, s), of 4.00 (3H, s), of 2.34 (3H, s) -

10141-1438,07 (userid, J=6,9, 0.8 Hz, 1H), to 7.77 (s, 1H), 7,62-to 7.59 (m, 2H), 7,41-7,32 (overlapping signals, 5H), 7,17-7,11 (m, 1H), 6.90 to (DD, J=8,4, 0.7 Hz, 1H), 6,77-6,72 (m, 1H), 5,14 (s, 2H), 4.00 points (s, 3H)m/z 365,2 (MH+)
1188-89of 8.09 (1H, userd, J=6.6 Hz), 7,79 (1H, s), to 7.61 (1H, d, J=9.1 Hz), EUR 7.57 (1H, d, J=2.1 Hz), was 7.45 (1H, DD, J=2,1, 8,3 Hz), 7,12-7,17 (1H, m), 6,93 (1H, d, J=8,3 Hz), 6,76 (1H, ushort, J=6.6 Hz), of 4.00 (3H, s)to 3.92 (3H with)-
12129-131(CD3OD) 8,29 (d, 1H), 7,65 (m, 2H), 7,50-7,28 (m, 5H), 7,20 (m, 1H), 7,01 (m, 3H), to 6.80 (m, 1H), total of 5.21 (s, 2H), 3,92 (s, 3H)m/z 331 (MH+)
13171-1738,10 (userd, 1H, J=6,7 Hz), 7,8-7,9 (2H, m), 7,78 (1H, s), to 7.61 (1H, userd, J=9.1 Hz), 7,3-7,5 (5H, m), 7,1-7,2 (1H,m), of 7.0, and 7.1 (2H,m), 6,76 (1H, ushort, J=6,7 Hz), 5,11 (2H, s)-
14 241 to 2438,39 (1H, userd, J=8.5 Hz), 8,15 (1H, userd, J=6,7 Hz), and 7.6 to 7.7 (2H,m), 7,3-7,5 (6H, m), 7,20 (1H, userd, J=7.9 Hz), 6,98 (1H, d, J=8.5 Hz), 5,23 (2H, s), 4,11 (3H, s), 2,73 (3H, s)-

15135-1367,86 (1H, users), to 7.68 (1H, s), to 7.59 (1H, d, J=2.0 Hz), 7,52 (1H, d, J=9,2 Hz), 7,49 (2H, d, a 7.6 Hz), 7,27-7,38 (4H, m), 7,00 (1H, DD, J=2.0 a, 9,2 Hz), 6,92 (1H, d, J=8,4 Hz), 5,19 (2H, s), of 4.00 (3H, s), is 2.30 (3H with)-
16171-173of 7.96 (1H, userd, J=7,0 Hz), 7,69 (1H, s), 7,58 (1H, d, J=2.0 Hz), 7,45-7,47 (2H, m), 7,27-7,39 (5H, m), 6,93 (1H, d, J=8.5 Hz), 6,59 (1H, DD, J=1,8, 7,0 Hz), 5,19 (2H, s), of 4.00 (3H, s), 2,39 (3H, s)-
17172-1738,45-of 8.47 (1H, m), a 7.85 (1H, users), of 7.69 (1H, userd, J=9.4 Hz), to 7.59 (1H, d, J=2.1 Hz), 7,45-7,47 (2H, m), 7,35-7,39 (3H, m), 7,28-to 7.32 (2H, m), to 6.95 (1H, d, J=8.5 Hz), 5,20 (2H, s)to 4.01 (3H, s)-
18177-179to 8.12 (1H, m), 7,74 (1H, is), 7,54-EUR 7.57 (2H, m), 7,44-7,47 (2H, m), 7,28-7,39 (4H, m), 7,12 (1H, DD, J=2,1, 9.7 Hz), 6,93 (1H, d, J=8,2 Hz), 5,20 (2H, s), of 4.00 (3H, s)-

19139-1408,10 (1H, userd, J=6,7 Hz), 7,74 (1H, d, J=2.1 Hz), the 7.65 (1H, DD, J=2,1, 8.5 Hz), a 7.62 (1H, userd, J=9.1 Hz), 7,39-7,42 (2H, m), 7,33 and 7.36 (2H, m), 7,22-7,26 (1H, m), to 6.95 (1H, d, J=8.5 Hz), 6,93 (1H, ushort, J=6,7 Hz), to 5.17 (2H, s)to 4.01 (3H, s)-
20104-1058,11 (1H, userd, J=6,7 Hz), 7,74 (1H, d, J=2.1 Hz), 7,66 (1H, DD, J=2,1, 8.5 Hz), 7,63 (1H, userd, J=9.1 Hz), 7,31-7,37 (1H, m), 7,19-7,27 (3H, m), 6,97-7,02 (1H, m), of 6.96 (1H, d, J=8.5 Hz), 6,93 (1H, ushort, J=6,7 Hz), to 5.21 (2H, s), was 4.02 (3H, s)-
21114-1158,10 (1H, userd, J=6,7 Hz), 7,79 (1H, s), 7,60-7,63 (2H, m), of 7.48 (1H, users), 7,38 (1H, DD, J=2,1, 8.5 Hz), 7,27-to 7.35 (3H, m), 7,13-to 7.18 (1H, m)6,91 (1H, d, J=8.5 Hz), 6,76 (1H, ushort, J=6,7 Hz), 5,16 (2H, s), was 4.02 (3H, s)-

8,10 (userd, J=6,6 Hz, 1H), 7,79 (s, 1H), of 7.64-EUR 7.57 (overlapping signals, 3H), 7,45 (d, J=8.5 Hz, 1H), 7,40 and 7.36 (m, 1H), 7,31-7,26 (m, 1H), 7,19-7,13 (m, 1H), 6.89 in (d, J=8.6 Hz, 1H), 6,77 (DDD, J=6,8, of 6.7, 1.1 Hz, 1H), 5,12 (s, 2H,), to 4.01 (s, 3H)
22138-139m/z 399,1 (M+)
23126-1287,66 (1H, s), 7,47 (1H, d, J=2.1 Hz), 7,42 (1H, d, J=4.4 Hz), 7,38-7,40 (2H, m), 7,32-to 7.35 (2H, m), 7.23 percent (1H, DD, J=2,1, 8,2 Hz), 6.87 in (1H, d, J=8,2 Hz), PC 6.82 (1H, d, J=4.4 Hz), 5,14 (2H, s), 3,98 (3H, s)-
24130-1327,66 (1H, s), 7,47 (1H, d, J=2.1 Hz), 7,43-7,46 (2H, m), 7,42 (1H, userd, J=4.4 Hz), 7,35-7,39 (2H, m), 7,28-to 7.32 (1H, m), 7.23 percent (1H, DD, J=2,1, 8,2 Hz), make 6.90 (1H, d, J=8,2 Hz), 6,83 (1H, userd, J=4.4 Hz), 5,19 (2H, C)to 3.99 (3H, s)-
25228-230(DMSO-d6) 8,29 (1H, d, J=4.6 Hz), 7,66 (1H, d, J=4.6 Hz), 7,32-of 7.48 (6H, m), 7,19 (2H, m), 5,16 (2H, s), 3,86 (3H, s), 2.63 in (3H, s)-

26114-1157,89 (1H, userd, J=6,7 Hz), 7,63 (1H, userd, J=9,1 Hz), 7,46 (1H, d, J=2.1 Hz), 7,40-7,42 (1H, m), 7,33 and 7.36 (1H, m), 7,20 (1H, DD, J=2,1, 8.5 Hz), 7,15-7,19 (1H, m)6,94 (1H, d, J=8.5 Hz), 6,85 (1H, dt, J=0,9, 6,7 Hz)to 5.17 (2H, s)to 3.99 (1H, s), 2.63 in (3H, s)-
27118-1207,88 (1H, userd, J=6,7 Hz), 7,63 (1H, userd, J=9.1 Hz), 7,44 (1H, d, J=2.1 Hz), 7,35 (2H, d, J=7.9 Hz), 7,14-7,20 (4H, m), of 6.96 (1H, d, J=8,2 Hz), at 6.84 (1H, dt, J=1,2, 6,7 Hz), is 5.18 (2H, s), 3,98 (3H, s), 2,62 (3H with), to 2.35 (3H, s)-
28168-169and 8.50 (1H, DD, J=1,8, 4,1 Hz), 8,39 (1H, DD, J=1,8, 6,7 Hz), of 7.75 (1H, d, J=2.1 Hz), 7,73 (1H, s), 7,29-7,47 (6H, m), 6,93 (1H, d, J=8,2 Hz), 6,83 (1H, DD, J=4,1, 6,7 Hz), to 5.21 (2H, s)to 4.01 (3H, s)-
29216-2188,51 (1H, DD, J=2,1, 4,1 Hz), 8,40 (1H, DD, J=2,1, 6,7 Hz), 7,76 (1H, d, J=1,8 Hz), of 7.75 (1H, s), 7,39-7,42 (3H, m), 7,33-7,39 (2H, m), 6.90 to (1H, d, J=8.5 Hz), 6,85 (1H, DD, J=4,1, 6,7 Hz)to 5.17 (2H, s)4,01 (3H, s)-

30175-1778,11 (userd, J=6,6 Hz, 1H), 7,80 (s, 1H), 7,69-EUR 7.57 (prekriven the signals 6H), 7,38 (userid, J=8,4, 1.8 Hz, 1H), 7,20-to 7.15 (m, 1H), 6,88 (userd, J=8.5 Hz, 1H), 6,78 (ushort, J=6,7 Hz, 1H), 5,24 (s, 2H), was 4.02 (s, 3H)m/z 356,2 (MH+)
31136-137of 8.09 (1H, userd, J=6,7 Hz), 7,78 (1H, s), 7,60-7,63 (2H, m), 7,49 (2H, d, J=8,2 Hz), 7,37 (1H, DD, J=2,1, 8,2 Hz), 7,33 (2H, d, J=8,2 Hz), 7,13-7,17 (1H, m), 6.89 in (1H, d, J=8,2 Hz), 6,76 (1H, ushort, J=6,7 Hz), 5,13 (2H, s), of 4.00 (3H, s)-
32140-1427,88 (1H, users), of 7.70 (1H, s), to 7.59 (1H, d, J=1,8 Hz), 7,51 (1H, d, J=9.1 Hz), 7,38-7,40 (2H, m), to 7.32 and 7.36 (3H, m), 7,00 (1H, DD, J=1,5, and 9.1 Hz), 6.89 in (1H, d, J=8.5 Hz), further 5.15 (2H, s), of 4.00 (3H, s), 2,31 (3H, C)-
33130-132to 7.67 (s, 1H), 7,63 (d, J=1.9 Hz, 1H), 7,55 (d, J=9.1 Hz, 1H), 7,49-7,26 (overlapping signals, 6H), to 7.15 (DD, J=9,0, 6,9 Hz, 1H), 6,95 (d, J=8,3 Hz, 1H), 6,61 (userd, J=6,8 Hz, 1H), total of 5.21 (s, 2H), was 4.02 (s, 3H), 2,62 (s, 3H)m/z 345,1 (MH+)

3499-1007,98 (d, 1H), to 7.77 (s, 1H), 7,60 (s, H), 7,25 is 7.50 (m, 6H), 6,94 (d, 2H), 6,65 (t, 1H), 5,20 (s, 2H), 4.00 points (s, 3H), 2,65 (s, 3H)m/z 345 (MH+)
35165-167of 8.09 (1H, userd, J=7,0 Hz), 7,78 (1H, s), to 7.61 (1H, userd, J=9.1 Hz), to 7.59 (1H, d, J=2.1 Hz), of 7.36-7,40 (3H, m), 7,12-7,17 (1H, m), to 6.95 (1H, d, J=8,2 Hz), 6,88-6,92 (2H, m), 6,76 (1H, ushort, J=7,0 Hz), 5,12 (2H, s), to 3.99 (3H, s), of 3.80 (3H, s)-
36215-218(DMSO-d6) 8,49 (1H, d, J=6,7 Hz), of 8.28 (1H, s), 7,88 (2H, d, J=8,8 Hz), 7,54 (1H, d, J=9.1 Hz), 7,40 (2H, d, J=8,8 Hz), 7,20-of 7.23 (1H, m), 7,06 (2H, d, J=8.5 Hz), to 6.95 (2H, d, J=8.5 Hz), 6.87 in (1H, dt, J=0,9, 6,7 Hz), is 5.06 (2H, s), 3,76 (3H, s)-
37229-231(DMSO-d6) 8,49 (1H, d, J=6,7 Hz), 8,29 (1H, s), 7,89 (2H, d, J=8,8 Hz), 7,46-7,56 (5H, m), 7,20-of 7.23 (1H, m), was 7.08 (2H, d, J=8,8 Hz), 6.87 in (1H, ushort, J=6,7 Hz), 5,16 (2H, s)-
38197-2008,21-of 8.25 (2H, m), 8,10 (1H, userd, J=6,7 Hz), 7,80 (1H, s), 7,60-the 7.65 (4H, m), 7,38 (1H, DD, J=2,1, 8,2 Hz), 7,14-7,19 (1H, m), 6.89 in (1H, d, J=8,2 Hz), 6,77 (1H, ushort, J=6,7 Hz), 5,28 (2H, s), a 4.03 (3H) -

td align="center"> 43
39123-1248,09-8,11 (1H, m), 7,80 (1H, d, J=2.3 Hz), 7,78 (1H, s), 7,72 (1H, DD, J=2,3, 8.5 Hz), to 7.61 (1H, userd, J=9.1 Hz), 7,31-of 7.48 (5H, m), 7,12-7,16 (1H, m), to 6.95 (1H, d, J=8.5 Hz), 6.75 in (1H, dt, J=1,2, 6,7 Hz), 5,13 (2H, s), a 2.36 (3H, s)-
40239-240(DMSO-d6) 8,49 (1H, userd, J=6.6 Hz), of 8.37 (1H, s), compared to 8.26 (1H, d, J=2.5 Hz), of 8.04 (1H, DD, J=2.5 and 8.7 Hz), 7,51-EUR 7.57 (3H, m), 7,21-7,42 (5H, m), to 6.88 (1H, ushort, J=6,6 Hz in), 5.25 (2H, s)-
41154-155(CD3OD) 8,42 (userd, 1H), 8,21 (s, 1H), 7,60-7,47 (overlapping signals, 3H), 7,19-7,12 (overlapping signals, 6H), 6,94 (ushort, 1H), free 5.01 (s, 2H), 3,93 (s, 6H)m/z 361,2 (MH+)
42134-1367,66 (1H, s)of 7.48-to 7.50 (2H, m), 7,47 (1H, d, J=2.1 Hz), 7,41 (1H, d, J=4,7 Hz), 7,32-7,34 (2H, m), 7.23 percent (1H, DD, J=2,1, 8,2 Hz), 6,86 (1H, d, J=8,2 Hz), for 6.81 (1H, d, J=4,7 Hz), 5,12 (2H, s), 3,98 (3H, s)-
156-1587,53 (1H, s), 7,44 (1H, d, J=2.1 Hz), 7,37-7,39 (2H, m), 7,31-7,34 (2H, m), 7,20 (1H, DD, J=2,1, 8,3 Hz), 7,10-7,11 (1H, m), 6,85 (1H, d, J=8,3 Hz)to 5.13 (2H, s), of 3.97 (3H, s), 2,42 (3H, d, J=1.7 Hz)-

44242-243(DMSO-d6) 9,17 (1H, s), 8,46 (1H, s), 7,88 (2H, d, J=8,3 Hz), to 7.59-to 7.67 (5H, m), 7,47 (1H, DD, J=2,1, 8,3 Hz), 7,10 (1H, d, J=8,3 Hz), of 5.26 (2H, s)to 3.89 (3H, s)-
45251-253(DMSO-d6) 9,17 (1H, s), to 8.45 (1H, s), 7,58-to 7.64 (3H, m), 7,45-7,51 (5H, m), 7,11 (1H, d, J=8,3 Hz), 5,14 (2H, s), a 3.87 (3H, s)-
46182-1838,88 (1H, s), to 7.84 (1H, s), 7,71 (1H, DD, J=1,7, 9.6 Hz), to 7.59-to 7.61 (2H, m), 7,32-7,40 (5H, m)6,91 (1H, d, J=8,3 Hz), 5,16 (2H, s), of 4.00 (3H, s), of 3.95 (3H, s)-
47179-181of 8.37 (1H, d, J=2.1 Hz), 8,10 (1H, userd, J=6.6 Hz), 8,07 (1H, DD, J=2,1, ,7 Hz), 7,83 (1H, s), to 7.61 (1H, userd, J=9.1 Hz), 7,50-7,51 (2H, m), 7,37-7,41 (2H, m), 7,29-7,33 (1H, m), 7,14-7,19 (1H, m), to 7.09 (1H, d, J=8.7 Hz), 6,77 (1H, dt, J=0,8, and 6.6 Hz), of 5.24 (2H, s), 3,93 (3H, s)-
48179-181to 7.68 (1H, s), to 7.67 (2H, userd, J=8,2 Hz), EUR 7.57 (2H, userd, J=8,2 Hz), 7,49 (1H, d, J=2.1 Hz), 7,42 (1H, d, J=4.4 Hz), 7,24 (1H, DD, J=2,1, 8,2 Hz), 6,85 (1H, d, J=8,2 Hz), PC 6.82 (1H, d, J=4.4 Hz), with 5.22 (2H, s), to 3.99 (3H, s)-

49189-1918,23 is 8.25 (2H, m), to 7.67 (1H, s), 7,62-the 7.65 (2H, m), 7,49 (1H, d, J=2.1 Hz), 7,42 (1H, d, J=4,7 Hz), 7,24 (1H, DD, J=2,1, 8,2 Hz), 6,86 (1H, d, J=8,2 Hz), PC 6.82 (1H, d, J=4,7 Hz), at 5.27 (2H, s), of 4.00 (3H, s)-
50125-1268,10 (1H, userd, J=6.6 Hz), of 8.04 (2H, d, J=8,3 Hz), 7,78 (1H, s), a 7.62 (1H, userd, J=9.1 Hz), to 7.61 (1H, d, J=1.7 Hz), 7,53 (2H, d, J=8,3 Hz), was 7.36 (1H, DD, J=1,7, 8,3 Hz), 7,13-to 7.18 (1H, m), 6.89 in (1H, d, J=8,3 Hz), 6,76 (1H, DD, J=6,6, 7,1 Hz), a 5.25 (2H, s), was 4.02 (3H, s), 3,91 (3H, s)-
51245-247(The IVS-d 6) 8,84 (1H, userd, J=6.6 Hz), 8,76 (1H, s), 7,87-to 7.99 (4H, m), 7,74 (1H, d, J=2.1 Hz), EUR 7.57-to 7.59 (3H, m), 7,46 (1H, ushort, J=6.6 Hz), 7.23 percent (1H, d, J=8.7 Hz), 5,28 (2H, s), 3,93 (3H, s)-
52163-1658,82 (s, 1H), 8,45 (s, 1H), 7,30-the 7.65 (m, 8H), 7,13 (d, 1H), 5,14 (s, 2H), a 3.87 (s, 3H)m/z 399, 401 (MH+)
53155-1568,40-at 8.36 (m, 1H), 7,88 (s, 1H), 7,60 (d, J=1.9 Hz, 1H), 7,46-7,29 (overlapping signals, 7H), 6,93 (d, J=8,2 Hz, 1H), 5,19 (s, 2H), 4.00 points (s, 3H)m/z 433,1 (MH+)

54187-1897,72 (1H, users), 7,71 (1H, userd, J=6.4 Hz), 7,47 (1H, d, J=2.1 Hz), 7,42-7,44 (2H, m), 7,34-7,38 (2H, m), 7,27-7,31 (1H, m), 7,25 (1H, DD, J=2,1, 8.5 Hz), 6,86 (1H, d, J=8.5 Hz), of 6.71 (1H, DD, J=6,4 and 7.6 Hz), 6,64 (1H, userd, J=7,6 Hz)to 5.17 (2H, in), 3.75 (3H, s)-
55140-141for 7.78 (s, 1H), of 7.75 (d, 1H), of 7.70 (d, 1H), 7,25-of 7.55 (m, 11H), to 6.95 (d, 1H), 6,60 (t, 1H), of 5.40 (s, 2H), 5,20 (s, 2H), 4.00 points (s, 3H) m/z 437 (MH+)
56155-157of 7.96 (1H, users), 7,73-7,76 (2H, m), 7,68 (1H, userd, J=1,8 Hz), of 7.48-7,51 (2H, m), 7,31 and 7.36 (3H, m), 7,17 (1H, userd, J=9.1 Hz), to 6.88 (1H, d, J=8,2 Hz)to 5.13 (2H, s), a 4.03 (3H, s)to 2.35 (3H, s)-
57168-169of 7.97 (1H, users), 7,78 (1H, userd, J=9.4 Hz), 7,73 (1H, s), 7,72 (1H, d, J=2.1 Hz), to 7.67 (2H, d, J=8.5 Hz), EUR 7.57 (2H, d, J=8.5 Hz), 7,37 (1H, DD, J=2,1, 8,2 Hz), 7,20 (1H, userd, J=9.4 Hz), 6.87 in (1H, d, J=8,2 Hz), of 5.24 (2H, s), of 4.05 (3H, s), is 2.37 (3H, s)-

58111-1138,10 (1H, userd, J=6.6 Hz), 7,80 (1H, s), to 7.61-7,63 (2H, m), 7,44 (1H, t, J=7.9 Hz), 7,39 (1H, DD, J=2,1, 8,3 Hz), 7,25-7,31 (2H, m), 7,14-to 7.18 (1H, m), 6,93 (1H, d, J=8,3 Hz), 6,77 (1H, dt, J=0,8, and 6.6 Hz), 5,20 (2H, s), of 4.00 (3H, s)-
59169-1718,10 (1H, d, J=6.6 Hz), 7,76 (1H, s), 7,60 (1H, d, J=8,3 Hz), 7,49-7,53 (2H, m), of 7.36 was 7.45 (5H, m), 7,12-7,17 (1H, m), 7,00 (1H, d, J=8,3 Hz), 6,76 (1H, dt, J=0,8, and 6.6 Hz), 5,70 (1H, s), 5,16 (2H, s)-
60157-158of 8.09 (1H, userd, J=6.6 Hz), to 7.77 (1H, s), to 7.59 to 7.62 (2H, m), 7,45-of 7.48 (2H, m), 7,28-739 (4H, m), 7,12-7,17 (1H, m), to 6.95 (1H, d, J=8,3 Hz), 6,76 (1H, ushort, J=6.6 Hz), 5,19 (2H, s), 4,27 (2H, q, J=7,1 Hz), 1,50 (3H, t, J=7,1 Hz)-
61126-1278,08-8,10 (1H, m), 7,78 (1H, s), to 7.59-7,63 (2H, m), 7,46-of 7.48 (2H, m), 7,28-7,40 (4H, m), 7,12-7,17 (1H, m), of 6.96 (1H, d, J=8.5 Hz), 6,76 (1H, dt, J=1,2, 6,7 Hz), is 5.18 (2H, s), of 4.13 (2H, t, J=6.8 Hz), 1,86-1,95 (2H, m)a 1.08 (3H, t, J=7,6 Hz)-

62122-124of 8.09 (1H, userd, J=6.6 Hz), 7,74 (1H, s), 7,66 (1H, d, J=2.1 Hz), to 7.61 (1H, d, J=8.7 Hz), 7,28-7,51 (11H, m), 7,12-7,17 (1H, m), 7,00 (1H, d, J=8,3 Hz), 6,76 (1H, ushort, J=6.6 Hz), of 5.26 (2H, s), 5,19 (2H, s)-
63136-137to 7.84 (1H, users), 7,74 (1H, s), to 7.59 (1H, d, J=2.1 Hz), 7,43-7,46 (2H, m), 7,27-7,38 (5H, m)6,91 (1H, d, J=8,3 Hz), 5,19 (2H, s), of 4.00 (3H, s), is 2.30 (3H, s)-
64 136-1387,86 (1H, users), 7,76 (1H, s), 7,60 (1H, d, J=2.1 Hz), 7,29-7,40 (6H, m), to 6.88 (1H, d, J=8,3 Hz), 5,14 (2H, s), of 4.00 (3H, s), 2,31 (3H, s)-
65175-1767,86 (1H, users), to 7.77 (1H, s), 7,66 (2H, d, J=7.9 Hz), a 7.62 (1H, d, J=2.1 Hz), 7,56 (2H, d, J=7.9 Hz), 7,38 (1H, DD, J=2,1, 8,3 Hz), 7,30 (1H, d, J=1.2 Hz), 6,86 (1H, d, J=8,3 Hz), 5,23 (2H, s), was 4.02 (3H, ), 2,31 (3H, s)-
66175-1768,25-8,23 (m, 1H), 7,74 (s, 1H), EUR 7.57 (d, J=1.8 Hz, 1H), 7,52-7,19 (overlapping signals, 8H), 6,93 (d, J=8,3 Hz, 1H), 5,20 (s, 2H), 4.00 points (s, 3H)m/z 409,1 (M+)

67206-208(DMSO-d6) 9,17 (1H, s), 8,48 (1H, d, J=7,1 Hz), 8,21 (1H, s), 7,44-7,53 (6H, m), 7,31 (1H, DD, J=1,7, 8,3 Hz), 7.18 in-7,22 (1H, m), 7,01 (1H, d, J=8,3 Hz), 6,85 (1H, ushort, J=6.6 Hz), 5,14 (2H, s)-
68136-137of 8.09 (1H, userd, J=6.6 G is), for 7.78 (1H, s), to 7.59 to 7.62 (2H, m), 7,32-7,41 (5H, m), 7,13-7,17 (1H, m), 6,92 (1H, d, J=8,3 Hz), 6,76 (1H, dt, J=0,8, and 6.6 Hz), 5,14 (2H, s)to 4.23 (2H, q, J=7,1 Hz), for 1.49 (3H, t, J=7,1 Hz)-
69155-1568,10 (1H, users), of 7.70 (1H, s), EUR 7.57 (1H, d, J=2.1 Hz), 7,32-7,39 (5H, m), 7,03 (1H, users), 6,89 (1H, d, J=8,3 Hz), further 5.15 (2H, s), of 4.00 (3H, s)of 2.64 (3H, s)-
70166-1678,19 (1H, s), 7,66 (1H, s), to 7.59 (1H, d, J=1,8 Hz), 7,32-7,40 (5H, m), 6.89 in (1H, d, J=8.5 Hz), further 5.15 (2H, s), of 4.00 (3H, s), 2,68 (3H, s), 2,42 (3H, s)-

71121-1238,10 (1H, userd, J=6.6 Hz), 7,79 (1H, s), a 7.62 (1H, userd, J=9.1 Hz), EUR 7.57 (1H, d, J=2.1 Hz), 7,42 (1H, DD, J=2,1, 8,3 Hz), 7,13-to 7.18 (1H, m), 6,92 (1H, d, J=8,3 Hz), 6,77 (1H, ushort, J=6.6 Hz), of 4.00 (3H, s), 3,90 (2H,, d, J=7,1 Hz), of 1.31-1.42 (1H, m), to 0.63 and 0.68 (2H, m), of 0.35-0.40 (2H, m)-
72164-1658,11 (1H, userd, J=7,1 Hz), of 7.90-7,94 (2H, m), 7,81 (1H, s), a 7.62 (1H, d, J=9.1 Hz), 7,32-7,38 (2H, m),? 7.04 baby mortality-7,19 (6H, m), 6,77 (1H, ush RT, J=7,1 Hz)-
73132-133of 7.96 (1H, userd, J=6.6 Hz), of 7.75 (1H, s), 7,60 (1H, d, J=1.7 Hz), 7,37-7,40 (3H, m), 7,31-to 7.35 (2H, m), 6,93 (1H, userd, J=6.6 Hz), make 6.90 (1H, d, J=8,3 Hz), 6,66 (1H, t, J=6.6 Hz), further 5.15 (2H, s)to 4.01 (3H, s), 2,66 (3H, s)-
74144-146of 7.97 (1H, userd, J=6.6 Hz), 7,76 (1H, s), 7,66 (2H, d, J=8.7 Hz), to 7.61 (1H, d, J=2.1 Hz), EUR 7.57 (2H, d, J=8.7 Hz), 7,39 (1H, DD, 2,1, 8,3 Hz)6,94 (1H, userd, J=7,1 Hz), 6.87 in (1H, d, J=8,3 Hz), to 6.67 (1H, DD, J=6,6 and 7.1 Hz), 5,23 (2H, s), was 4.02 (3H, s)to 2.66 (3H, s)-

75164-1667,76 (1H, s), 7,73 (1H, userd, J=6.6 Hz), to 7.64 (1H, users), 7,50-7,52 (2H, m), 7,29-7,40 (8H, m), to 6.88 (1H, d, J=8,3 Hz), 6,59 (1H, DD, J=6,6, 7,1 Hz), 6,44 (1H, userd, J=7,1 Hz), of 5.39 (2H, s), 5,14 (2H, s)to 3.99 (3H, C)-
76219-221(DMSO-d6) 12,74 (1H, s), 7,80 (1H, d, J=2.1 Hz), 7,72 (1H, DD, J=2,1, 8,3 Hz), to 7.61-to 7.64 (1H, m), 7,47-7,52 (3H, m), 7,40-7,44 (2H, m), 7,33-7,37 (1H, m), 7,22 (1H, d, J=8,3 Hz) 7,14-7,19 (2H, m), by 5.18 (2H, s), 3,90 (3H, s)-
77204-206(DMSO-d6) 11,96 (1H, users), 7,83 (1H, d, J=2.0 Hz), of 7.75 (1H, usher.), the 7.65 (1H, DD, J=2.0 a, and 8.4 Hz), 7,46 (1H, usher.), 7,35-7,44 (4H, m), 7.18 in-7,24 (2H, m), to 6.95 (1H, d, J=8,4 Hz)to 5.17 (2H, s), 3,98 (3H, s)-
78108-1098,03 (1H, d, J=8,4 Hz), 7,87 (1H, d, J=7,6 Hz), 7,73 (1H, d, J=2.0 Hz), 7,52 (1H, DD, J=2.0 a, 8,8 Hz), 7,45-of 7.48 (3H, m), 7,28-7,39 (4H, m), to 6.95 (1H, d, J=8,8 Hz), of 5.24 (2H, s), a 4.03 (3H, s)m/z 348,0 (MH+)

79190-192(DMSO-d6) 8,30-8,32 (2H, m), by 8.22 (1H, s), 7,73 (1H, userd, J=1.7 Hz), of 7.64-7,66 (3H, m), EUR 7.57 (1H, DD, J=1,7, 8,3 Hz), 7,34-of 7.48 (5H, m), 7,19 (1H, d, J=8,3 Hz), 5,16 (2H, s), 3,91 (3H, s)-
80162-163of 8.09 (1H, d, J=1,8 Hz), 7,80 (1H, s), to 7.59 (1H, d, J=2.1 Hz), 7,32-7,40 (5H, m), 7,25 (1H, d, J=1,8 Hz), make 6.90 (1H, d, J=8,2 Hz), further 5.15 (2H, s), of 4.00 (3H, s)-
187-189of 8.09 (1H, d, J=1.5 Hz), 7,81 (1H, s), to 7.67 (2H, d, J=7.9 Hz), to 7.61 (1H, d, J=2.1 Hz), EUR 7.57 (2H, d, J=7.9 Hz), 7,39 (1H, DD, J=2,1, 8,2 Hz), 7,25 (1H, d, J=1.5 Hz), to 6.88 (1H, d, J=8,2 Hz), 5,23 (2H, s), as 4.02 (3H, s)-
82122-124of 7.97 (1H, d, J=6,7 Hz), 7,76 (1H, s), to 7.61 (1H, d, J=2.5 Hz), the 7.43 (1H, ushort, J=7,6 Hz), 7,40 (1H, DD, J=2.5 and 8.5 Hz), 7.24 to 7,30 (2H, m), 6,92-to 6.95 (1H, m), 6,93 (1H, d, J=8.5 Hz), to 6.67 (1H, t, J=6,7 Hz), 5,19 (2H, s)to 4.01 (3H, s)to 2.66 (3H, s)-

83147-1487,87-7,88 (1H, m), of 7.70 (1H, s), to 7.59 (1H, d, J=2.1 Hz), 7,51 (1H, d, J=9.1 Hz), 7,44 (1H, t, J=7.9 Hz), was 7.36 (1H, DD, J=2,1, 8,3 Hz), 7.24 to 7,30 (2H, m), 7,00 (1H, DD, J=1,7, and 9.1 Hz), 6,92 (1H, d, J=8,3 Hz), 5,19 (2H, s)to 3.99 (3H, s), 2,31 (3H, s)-
84109-111to 7.67 (1H, s)of 7.48 (1H, d, J=1,8 Hz), the 7.43 (1H, d, J=7.9 Hz), 7,42 (1H, d, J=4,7 Hz), 7.23 percent-7,31 (3H, m), 6.90 to (1H, d, J=8.5 Hz), for 6.81 (1H, d, J=4,7 Hz), is 5.18 (2H, s), of 3.97 (3H, s)-
85 168-169of 7.75 (1H, s), 7,72 (1H, userd, J=7,1 Hz), 7,47-7,52 (4H, m), 7,29-7,40 (6H, m), to 6.88 (1H, d, J=8,3 Hz), to 6.58 (1H, ushort, J=7,1 Hz), 6,44 (1H, userd, J=7,1 Hz), of 5.39 (2H, s), 5,12 (2H, s)to 3.99 (3H, s)-
86169-1707,76 (1H, s), 7,73 (1H, userd, J=6.6 Hz), 7,65-to 7.67 (3H, m), 7,50-7,58 (4H, m), 7,30-7,41 (4H, m)6,86 (1H, d, J=8,3 Hz), 6,59 (1H, ushort, J=6.6 Hz), 6,44 (1H, userd, J=6.6 Hz), of 5.39 (2H, s), with 5.22 (2H, s)to 4.01 (3H, C)-

87108-109to 7.77 (1H, s), 7,74 (1H, userd, J=6.6 Hz), 7,51-7,53 (2H, m), 7,25-7,46 (7H, m), 6,92 (1H, d, J=8,3 Hz), 6,59 (1H, ushort, J=6.6 Hz), 6,45 (1H, userd, J=6.6 Hz), of 5.40 (2H, s), 5,19 (2H, s), of 4.00 (3H, s)-
88189-191(DMSO-d6) is 8.75 (1H, users), 8,42 (1H, DD, J=2.1 a, 5,4 Hz), to 7.68 (1H, d, J=2.1 Hz), 7,56 (1H, DD, J=2,1, 8,3 Hz), 7,35-7,49 (7H, m), 7,22 (1H, d, J=8,3 Hz), is 5.18 (2H, s), of 4.12 (3H, s), 3,90 (3H, s)-
89132-134 7,76 (1H, s), 7,74 (1H, d, J=6,7 Hz), to 7.67 (1H, d, J=2.0 Hz), 7,37-7,40 (3H, m), 7,32-to 7.35 (2H, m), to 6.88 (1H, d, J=8,2 Hz), to 6.67 (1H, DD, J=6,7, and 7.6 Hz), 6,44 (1H, d, J=7,6 Hz), 5,14 (2H, s), Android 4.04 (3H, s)that is 4.00 (3H, s)-
90220-222(DMSO-d6) 8,28 (1H, s), to 7.99 (1H, DD, J=0,8, and 6.6 Hz), to 7.59 (1H, d, J=1.7 Hz), 7,44-7,51 (5H, m), was 7.08 (1H, d, J=8,3 Hz), to 6.67 (1H, ushort, J=6.6 Hz), 6.48 in (1H, DD, J=0,8, and 6.6 Hz), 5,12 (2H, s), a 3.87 (3H, s)-

91119-1208,10 (1H, userd, J=6,7 Hz), 7,79 (1H, s), 7,60-7,63 (2H, m)to 7.50 (1H, ushort, J=7.9 Hz), 7,39 (1H, DD, J=2,1, 8,2 Hz), 7,09-to 7.18 (3H, m)6,94 (1H, d, J=8,2 Hz), 6,74-of 6.78 (1H, m), a total of 5.21 (2H, s), of 4.00 (3H, s)-
92138-139of 8.09 (1H, userd, J=6,7 Hz), 7,78 (1H, s), 7,60-7,63 (2H, m), 7,55 (1H, d, J=8,2 Hz), 7,40 (1H, d, J=2.1 Hz), 7,37 (1H, DD, J=2,1, 8,2 Hz), 7,26 (1H, DD, J=2,1, 8,2 Hz), 7,13-7,17 (1H, m), 6.89 in (1H, d, J=8,2 Hz), 6,76 (1H, ushort, J=6,7 Hz), 5,23 (2H, s), was 4.02 (3H, s)-
93137-1388,0 (1H, d, J=6,7 Hz), 7,80 (1H, s), 7,60-7,63 (2H, m), 7,49-7,56 (1H, m), 7,40 (1H, DD, J=2,1, 8.5 Hz), 7,13-to 7.18 (1H, m), of 6.96 (1H, d, J=8.5 Hz), 6,80-of 6.90 (2H, m), 6,77 (1H, ushort, J=6,7 Hz), 5,19 (2H, s), of 4.00 (3H, C)-
94115-1178,10 (1H, userd, J=6,7 Hz), 7,80 (1H, s), a 7.62 (1H, userd, J=9.1 Hz), to 7.61 (1H, d, J=2.1 Hz), 7,40 (1H, DD, J=2,1, 8,2 Hz), 7,28-7,33 (1H, m), 7,13-to 7.18 (1H, m), 6,93-7,06 (3H, m), 6,77 (1H, ushort, J=6,7 Hz), 5,23 (2H, C)was 4.02 (3H, s)-

95247-249(DMSO-d6) 8,51 (2H, d, J=8,3 Hz), compared to 8.26 (1H, s), of 8.04 (2H, d, J=8,3 Hz), 7,73 (1H, d, J=2.1 Hz), 7,56 (1H, DD, J=2,1, 8,3 Hz), 7,33-7,49 (5H, m), 7,19 (1H, d, J=8,3 Hz)to 5.17 (2H, s), 3,91 (3H, s)-
96178-1808,24-of 8.25 (1H, m), of 7.75 (1H, s), EUR 7.57 (1H, d, J=2.1 Hz), to 7.50 (1H, d, J=9.5 Hz), 7,32-7,40 (5H, m), 7,21 (1H, DD, J=2,1, 9.5 Hz), make 6.90 (1H, d, J=8,3 Hz), further 5.15 (2H, s), of 4.00 (3H, s)-
97165-1668,24-of 8.25 (1H, m), of 7.75 (1H, s), to 7.67 (2H, d, J=8,3 Hz), to 7.59 (1H, d, J=2.1 Hz), and 7.7 (2H, d, J=8,3 Hz), 7,51 (1H, d, J=9.6 Hz), 7,35 (1H, DD, J=2,1, 8,3 Hz), 7,22 (1H, DD, J=2,1, 9.6 Hz), to 6.88 (1H, d, J=8,3 Hz), 5,23 (2H, s)to 4.01 (3H, s)-
98164-1658,10 (1H, users), of 7.70 (1H, s), EUR 7.57 (1H, d, J=2.1 Hz), 7,27-7,46 (6H, m), 7,03 (1H, users), 6,92 (1H, d, J=8,3 Hz), 5,20 (2H, s)to 4.01 (3H, s)of 2.64 (3H, s)-

99177-1788,11 (1H, users), 7,71 (1H, s), 7,66 (2H, d, J=8,3 Hz), to 7.59 (1H, d, J=1.7 Hz), 7,56 (2H, d, J=8,3 Hz), was 7.36 (1H, DD, J=1,7, and 8.7 Hz),? 7.04 baby mortality (1H, users), 6,87 (1H, d, J=8.7 Hz), 5,23 (2H, s)to 4.01 (3H, s)of 2.64 (3H with)-
100158-1608,19 (1H, s), the 7.65 (1H, s), 7,58 (1H, d, J=1,8 Hz), 7,44-7,46 (2H, m), 7,27-7,38 (4H, m), 6,92 (1H, d, J=8,2 Hz), 5,20 (2H, s)to 4.01 (3H, s), 2,68 (3H, s), 2,42 (3H, s)-
101180-1818,19 (1H, s), 7,66 (1H, s), the 7.65 (2H, d, J=8,3 Hz), 7,60 (1H, d, J=2.1 Hz), 7,56 (2H, d, J=8,3 Hz), was 7.36 (1H, DD, J=2,1, 8,3 Hz)6,86 (1H, d, J=8,3 Hz), 5,23 (2H, s)to 4.01 (3H, s), 2,68 (3H, s), 2,42 (3H with) -
102-8,08 (userd, J=6,6 Hz, 1H), to 7.77 (users, 1H), 7,63-to 7.59 (overlapping signals, 2H), 7,40 and 7.36 (overlapping signals, 5H), 7,17 for 7.12 (m, 1H), of 6.96 (d, J=8,2 Hz, 1H), 6.75 in (ushort, J=6,7 Hz, 1H), 5,16 (s, 2H), 4.00 points (s, 3H), of 1.31 (s, 9H)m/z 387,3 (MH+)

m/z 345,2 (MH+)
103239,5-2416,79 (DDD, 1H, J=1,1, 6,7, 6,7 Hz), and 7.1 (d, 1H, 0.5 Hz,), 7,15-7,21 (m, 1H), 7,34-7,39 (m, 1H), 7,44-7,49 (overlapping signals, 2H), EUR 7.57 (d, 1H, J=8.5 Hz), the 7.65 (d, 1H, J=8.5 Hz), 7,87-to $ 7.91 (overlapping signals, 4H), to 8.14 (d, 1H, J=6.9 Hz), by 8.22 (d, 1H, J=1.4 Hz)m/z 311,3 (MH)+
104136-137of 8.25 (s, 1H), 7,79 (s, 1H), 7,60 (s, 1H), 7,55 (d, 1H), 7,40 (d, 1H), 7,25 (d, 1H), 7,19 (d, 1H), 7,15 (d, 2H), PC 6.82 (d, 2H), 6,5 (s, 1H), 5,20 (s, 2H), 3,92 (s, 3H)m/z 367 (MH+)
105-(CD3OD) scored 8.38 (d, 1H), 7,62-rate of 7.54 (m, 2H), 7,47-7,22 (overlapping signals, 6H), 7,14 (s, 1H), 6,98-6,89 (m, 3H), 5,50 (kV, 1H), 3.96 points (s, 3H), of 1.70 (d, 3H)
106-8,55 (d, J=7,1 Hz, 1H), 7,72 (users, 1H), 7.62mm (d, J=9.1 Hz, 1H), 7,40-7,29 (overlapping signals, 4H), 7.23 percent-7,20 (DD, J=8,2, 1.9 Hz, 1H), 7,16-7,13 (d, J=8,2 Hz, 1H), 7,08-6,92 (overlapping signals, 4H), 3,86 (s, 3H)m/z 317,3 (MH+)

107-(CD3OD) 8,48 (userd, 1H), 7,70-7,55 (overlapping signals, 4H), 7,40-7,28 (overlapping signals, 3H), 7.24 to 7,08 (overlapping signals, 3H), 6,98 (ushort, 1H), total of 5.21 (s, 2H), 3,92 (s, 3H)m/z 415,2 (MH+)
108148-149of 8.28 (1H, d, J=6.8 Hz), of 7.70 (2H, d, J=7,6 Hz), to 7.67 (1H, d, J=8.0 Hz), the 7.65 (1H, s), 7,60 (2H, d, J=7,6 Hz), 7,19 (1H, DD, J=7,6, 8.0 Hz), 7,07 (1H, s), 7,06 (1H, d, J=8.0 Hz), 6,97 (1H, d, J=8.0 Hz), to 6.80 (1H, DD, J=6,8, 7,6 Hz)-
109-8,30 (d, 1H), 7,70 to 7.62 (m, 1H), 7,50-7,32 (overlapping signals, 4H), 7,25-to 7.15 (m, 1H), 7,12-of 6.96 (overlapping signals, 4H), 6,80 (ushort, 1H), 5,20 (s, 2H, 3,98 (s, 3H)m/z 365,2 (MH+)
110-(CD3OD) 8,48 (userd, 1H), to 7.67-7,56 (overlapping signals, 2H), 7,40-7,32 (m, 1H), 7.23 percent-7,10 (overlapping signals, 3H), 6,98 (ushort, 1H), of 6.68 (d, 2H), 6,45 (t, 1H), 5,17 (s, 2H), 3,95 (s, 3H), of 3.80 (s, 6H)m/z 391,3 (MH+)

111-8,32 (userd, J=6,9 Hz, 1H), 7,70-to 7.67 (overlapping signals, 2H), 7,26-7,21 (m, 1H), 7,13 (d, J=1.9 Hz, 1H), 7,08-7,01 (overlapping signals, 3H), of 6.96-6.89 in (overlapping signals, 3H), 6,83 (ushort, J=6,9 Hz, 1H), 3,94 (s, 3H), 3,82 (s, 3H)m/z 347,3 (MH+)
112-(CD3OD) and 8.50 (d, 1H), 7,70-7,55 (overlapping signals, 3H), 7,44-7,30 (overlapping signals, 2H), 7,27-7,08 (overlapping signals, 5H), 6,97 (t, 1H), 5,22 (s, 2H), 3,92 (s, 3H)m/z 349,2 (MH+)
113-(CD3OD) 8,48 (userd, 1H), 7,70-7,55 (perekryvanie the signals, 2H), 7,50-7,32 (overlapping signals, 5H), 7,22-7,08 (overlapping signals, 3H), 6,99 (ushort, 1H), 5,19 (s, 2H), 3,92 (s, 3H), of 1.37 (s, 9H)m/z 387,3 (MH+)
114148-1493,88 (s, 3H), 6,83-6,91 (m, 1H), 6.90 to (d, 1H, J=9.0 Hz), 6,99 (d, 1 H, J=8,3 Hz), 7,21-7,32 (overlapping signals, 4h), 7,38 (DD, 1 H, J=1,2, 8,2 Hz), to 7.64 (d, 1 H, J=1.9 Hz), 7,69 (d, 1 H, J=9,3 Hz), 7,82 (d, 1 H, J=0.5 Hz), 8,13 (DDD, 1H, J=1,1, 1,2, 6,8 Hz)m/z to 351.3 (MH+)

115108-109of 8.09 (d, 1H), 7,89 (d, 1H), of 7.70 (d, 1H), EUR 7.57 (d, 1H), 7,35 (d, 1H), 7,29 (d, 1H), 715-6,82 (m, 5H), to 3.92 (s, 3H)m/z 351 (MH+)
116164-1667,70-to 7.59 (m, 3H), 7,50 (d, 2H), 7,45-7,34 (m, 3H), 7,26 (DD, 1H), 7,15 (m, 2H),? 7.04 baby mortality (d, 1H), 6.73 x (d, 1H, in), 5.25 (s, 2H), 3,98 (s, 3H)m/z 331 (MH+)
117-of 8.28 (dt, 1H), 7,71-7,63 (m, 2H), to 7.61-rate of 7.54 (m, 1H), 7,50-7,42 (d, 1H), 7,34-7,27 (m, 1H), 7,22-7,14 (m, 1H), 7,10-7,00 (overlapping signals, 2H), 6,99-6,92 (who, 1H), 6,84 to 6.75 (ushort, 1H), 5,20 (s, 2H), 3,98 (s, 3H)m/z 399,1 (MH+)
118-(CD3OD) 8,29 (d, 1H), 7,65 (m, 2H), 7,50-7,28 (m, 5H), 7,20 (m, 1H), 7,01 (m, 3H), to 6.80 (m, 1H), total of 5.21 (s, 2H), 3,92 (s, 3H)m/z 331 (MH+)
119-(DMSO-d6) 13,40 (user., 1H), which 9.22 (s, 1H), and 8.50 (s, 1H), 7,DD, 2H), 7,60 (d, 1H), 7,30-of 7.55 (m, 6H), 7,16 (d, 1H), 5,15 (s, 1H), 3,88 (s, 3H)m/z 375 (MH+)
120155-1577,72-to 7.59 (overlapping signals, 7 H), 7,27-7,12 (overlapping signals, 3H), 6,98 (d, J=8,1 Hz, 1H), 6,72 (DD, J=6,9, 1.0 Hz, 1H), 5,28 (s, 2H), of 3.94 (s, 3H)m/z 356,1 (MH+)

tr>
121-by 8.22 (DD, J=6,9, 1.1 Hz, 1H), 7,86-7,81 (overlapping signals, 3H), to 7.61-7,53 (overlapping signals, 4H), 7,39-7,33 (m, 1H), was 7.08 (d, J=8,2 Hz, 1H), 6,99-6,95 (overlapping signals, 2H), of 3.77 (s, 3H)m/z 342,4 (MH+)
122133-1358,30 (d, 1H), 7,80-7,60 (overlapping signals, 6H), 7,20 (m, 1H), 7,15-6,90 (overlapping signals, 3H), 6,80 (t, 1H), and 5.30 (s, 2H), 3,95 (s, 3H)m/z 399 (MH+)
123-8,08 (dt, J=7,7, 1.1 Hz, 1H), 7,74 (users, 1H), 7,62-7,56 (overlapping signals, 2H), 7,39-7,26 (overlapping signals, 4H), 7,22 (DD, J=8,4, 1.8 Hz, 1H), 7.18 in for 7.12 (m, 1H), 6,78-6,70 (overlapping signals, 2H), 4,55 (d, J=8.0 Hz, 1H), 4.00 points (s, 3H), 1,46-to 1.38 (m, 1H), 0,74 is 0.67 (m, 1H), 0,62-0,51 (overlapping signals, 2H), 0,44-0,38 (m, 1H)m/z 405,2 (MH+)
124-7,74-of 7.60 (m, 7H), 7,26 (m, 1H), 7,16 (m, 2H), 7,00 (d, 1H), 6,74 (d, 1H), 5,31 (s, 2H), 3,98 (s, 3H)m/z 399 (MH+)
125-to 7.64 (d, 2H), 7,25-of 7.55 (m, 7H), to 6.95 (d, 1H), 6,47 (s, 1H), 5,20 (s, 2H), 4.00 points (s, 3H), 2,58 (s, 3H), 2,48 (s, 3H)m/z 359 (MH+)

126 -8,04-8,03 (m, 1H), 7,78 (s, 1H), to 7.61-7,52 (overlapping signals, 2H), of 7.48-7,42 (overlapping signals, 2H), 7,41-7,26 (overlapping signals, 4H), 7,11? 7.04 baby mortality (m, 1H), 6,93 (d, J=8.5 Hz, 1H), 5,20 (s, 2H), 4.00 points (s, 3H)m/z 349,1 (MH+)
127-8,14 (userd, J=6,9 Hz, 1H), 7,83 (users, 1H), 7,72-7,65 (overlapping signals, 2H), 7,39 (DD, J=8,3, 1.9 Hz, 1H), 7,27-7,21 (m, 1H), 7,17-7,14 (overlapping signals, 2H), 7,02 (d, J=8,2 Hz, 1H), 6,99-6,95 (overlapping signals, 2H), 6,86 (DDD, J=6,8, of 6.7, 1.1 Hz, 1H), 3,88 (, 3H)m/z 401,3 (MH+)
128-8,55 (s, 1H), 7,86 (s, 1H), of 7.70 (d, 1H), 7,60 (d, 1H), 7,7,25-of 7.55 (m, 7H), of 6.96 (d, 2H), 5,20 (s, 2H), 4.00 points (s, 3H)m/z 356 (MH+)
129-8,03 (userd, J=6,9 Hz, 1H), to 7.61-EUR 7.57 (overlapping signals, 2H), 7,50 (d, J=1.9 Hz, 1H), 7,16-7,00 (overlapping signals, 5H), 6,95-6,92 (overlapping signals, 2H), 6,72 (DDD, J=6,8, of 6.7, 1.1 Hz, 1H), 4,57 (t, J=7,0 Hz, 1H), a 4.03 (s, 3H), 2,96-2,87 (m, 2H), 2,15-2,05 (m, 1H), 2,02-of 1.92 (m, 2H), of 1.85 and 1.80 (m, 1H)m/z 3713 (MH +)

130-of 8.09 (dt, J=8.0 a, 1,1 Hz, 1H), 7,79 (d, J=0.6 Hz, 1H), of 7.64-to 7.61 (overlapping signals, 2H), 7,50 (userd, J=8,8 Hz, 2H), 7,39 (DD, J=8,4, 1.9 Hz, 1H), 7,26-7,13 (overlapping signals, 3H), 6,92 (d, J=8,3 Hz, 1H), 6,76 (DDD, J=6,8, of 6.7, 1.1 Hz, 1H), 5,17 (s, 2H), 4.00 points (s, 3H)m/z 415,1 (MH+)
131-(CD3OD) 8,42 (d, 1H), 7,60 (m, 2H), 7,35 (m, 1H) 7,17-of 6.90 (m, 4H), to 3.92 (s, 3H)m/z 241 (M+1)
132-(CD3OD) 8,55 (apparent d, 1H), 7,78-of 7.70 (m, 2H), of 7.64-7,35 (overlapping signals, 6H), 7,31 (s, 1H), 7,19-7,13 (m, 3H), 5,62 (kV, 1H), of 4.05 (s, 3H), of 1.81 (d, 3H)m/z 345,3 (MH+)
133118-119of 8.25 (s, 1H), of 7.70 (d, 1H), 7,55 (d, 1H), EUR 7.57 (d, 1H), 7,35 (d, 1H), 7,29 (d, 1H), 7,15 (d, 2H),PC 6.82 (d, 2H), 5,20 (s, 2H), 3,92 (s, 3H)m/z 349 (MH+)
134 149-1508,07 (apparent d, J=7.7 Hz, 1H), 7,73 (s, 1H), 7,62-EUR 7.57 (m, 2H), 7,41 (apparent d, J=7.7 Hz, 2H), 7,33 (ushort, J=7,4 Hz, 2H), 7,27-7,22 (m, 2H), 7,17 for 7.12 (m, 1H), 6,77-of 6.73 (m, 2H), are 5.36 (q, J=6,4 Hz, 1H), 4,01 (s, 3H), 1,71 (d, J=6.3 Hz, 3H)m/z 345,2 (MH+)

135113-113,58,24 (dt, J=8,9, 1.1 Hz, 1H), to 7.64 (dt, J=9,0, 1.1 Hz, 1H), 7,60 (s, 1H), 7,45-7,26 (overlapping signals, 5H), 7,19-7,13 (m, 1H), 7,02 (d, J=1.9 Hz, 1H), 6,93 (DD, J=8,2, 1.9 Hz, 1H), at 6.84 (d, J=8.5 Hz, 1H), 6,77 (DDD, J=6,9, 6,8, 1.1 Hz, 1H), 5,38 (kV, J=6,6 Hz, 1H), 3,94 (s, 3H), 1,74 (d, J=6.4 Hz, 3H)m/z 345,1 (MH+)
136-of 8.90 (d, 1H), 8,73 (s, 1H), 8,15 (s, 1H), 7,63 (s, 1H), 7,30-of 7.60 (m, 7H), 7,20 (m, 1H), 5,18 (s, 2H), 3,88 (s, 3H)m/z 399 (MH+)
137177-178(CD3OD) of 7.82 (s, 1H), to 7.59-7,51 (m, 2H), 7,41 (m,1H), 7,22 (d, 1H), 7,14 (DD, 1H), 6,95 (d, 1H), to 6.88 (DD, 1H), 3,98 (s, 3H)m/z 241 (M+1)
138 95-97to 8.12 (dt, J=7,9, 1.1 Hz, 1H), 7,84 (users, 1H), 7,72 (d, J=1.9 Hz, 1H), 7,66-7,63 (m, 1H), 7,44-7,42 (m, 1H), 7,34-7,26 (overlapping signals, 2H), 7,21-18 (m, 1H), 7,16-6,98 (overlapping signals, 3H), 6,78 (DDD, J=6,7, and 6.6, 1.1 Hz, 1H), 3.96 points (s, 3H)m/z 317,3 (MH+)

139-8,13 (dt, J=8.0 a, 1,1 Hz, 1H), 7,84 (users, 1H), 7,66 (d, J=1.9 Hz, 1H), 7,56-of 7.48 (overlapping signals, 3H), 7,42 (DD, J=8,3, 1.9 Hz, 1H), 7,27-7,20 (m, 1H), 7,07 (d, J=8,3 Hz, 1H), 7,01-6,95 (overlapping signals, 2H), 6,85 (DDD, J=6,8, of 6.7, 1.1 Hz, 1H), 3,85 (s, 3H)m/z 385,3 (MH+)
140-8,07 (DD, J=6,7, 1.1 Hz, 1H), 7,73 (users, 1H), to 7.61-7,56 (overlapping signals, 2H), 7,45-7,42 (overlapping signals, 2H), was 7.36-7,11 (overlapping signals, 5H), 6,77-6,72 (overlapping signals, 2H), 4,57 (d, J=8.0 Hz, 1H), 4.00 points (s, 3H), 1,51 was 1.43 (m, 1H), 0.74 and is 0.67 (m, 1H), 0,62-0,52 (overlapping signals 2H), 0,47-0,40 (m, 1H)m/z 371,2 (MH+)
141-of 8.25 (d, 1H), 7,95 (s, 1H), of 7.90-of 7.70 (m, 6H), at 7.55 (d, 1H), 7,35 (DD, 1H), 7,10 (d, 1H), 6.90 to (t, 1H), of 5.40 (s, 2H), 4,20 (3H) m/z 399 (MH+)
142-to 9.20 (s, 1H), 8,66 (s, 1H), 8,25 (DD, 1H), with 8.05 (d, 1H), 7,81 (d, 2H), 7,32-to 7.64 (m, 10H), 7,28 (d, 1H), 5,20 (s, 2H), of 3.94 (s, 3H)m/z 407 (MH+)

143-8,10 (dt, J=8.0 a, 1,1 Hz, 1H), to 7.77 (users, 1H), 7,63-7,60 (overlapping signals, 2H), 7,35 (DD, J=8,4, and 2.1 Hz, 1H), 7.18 in for 7.12 (m, 1H), 6,93 (d, J=8.5 Hz, 1H), 6,76 (DDD, J=6,8, of 6.7, 1.1 Hz, 1H), 6,62 (d, J=2.2 Hz, 2H), 6,39 (t, J=2,2 Hz, 1H), further 5.15 (s, 2H), 4,01 (s, 3H), 3,79 (s, 6H)m/z 391,2 (MH+)
144-to 9.20 (s, 1H), 8,66 (s, 1H), 8,25 (DD, 1H), with 8.05 (d, 1H), 7,81 (d, 2H), 7,32-to 7.64 (m, 10H), 7,28 (d, 1H), 5,20 (s, 2H), of 3.94 (s, 3H)m/z 407 (MH+)
145-8,30 (d, 1H), 7,95 (s, 1H), 7,80-of 7.70 (m, 2H), 7,50-7,30 (m, 3H), 7,10 (d, 1H), 6,95 (t, 1H), 4,15 (s, 3H)m/z 241 (MH+)
146 -8,14 (userd, J=6,9 Hz, 1H), 7,87 (users, 1H), 7,73 (d, J=1.9 Hz, 1H), 7,65 (userd, J=9,3 Hz, 1H), 7,45 (DD, J=8,2, 1.9 Hz, 1H), 7,34 (d, J=9.1 Hz, 1H), 7.23 percent-7,17 (m, 1H), 7,08-7,03 (overlapping signals, 2H), 6,85-6,79 (overlapping signals, 2H), 3,94 (s, 3H)m/z 385,2 (M+)

147-8,16 (userd, J=6,6 Hz, 1H), of 7.90 (users, 1H), to 7.77 (d, J=1.9 Hz, 1H), 7,65 (DD, J=8,5, 0.6 Hz, 1H), 7,53-7,49 (overlapping signals, 2H), 7,33 (users, 2H), 7,25-7,19 (m, 1H), 7,14 (d, J=8,2 Hz, 1H), 6,83 (DDD, J=6,8, of 6.7, 1.1 Hz, 1H), 3,91 (s, 3H)m/z 453,2 (MH+)
148-8,07 (d, J=6,9 Hz, 1H), 7,74 (s, 1H), to 7.61-EUR 7.57 (m, 2H), 7,37-7.23 percent (overlapping signals, 5H), 7,14 (DDD, J=8.0 a, and 6.6, 1.4 Hz, 1H), 6,77-of 6.73 (m, 2H), 5,33 (kV, J=6,6 Hz, 1H), 4.00 points (s, 3H), 1,68 (d, J=6.6 Hz, 3H)m/z 379,1 (MH+)
149276-278--

Pharmacological test 1

Test the increased expression of LPL mRNA

For easy and quick detection the Oia increase the mRNA expression of the human LPL used the test with luciferase. The main idea of this analysis is as follows: luciferase emits light when interacting with luciferine (substrate). The expression of LPL mRNA was controlled by 5'-UTR and 3'-UTR (promoter regions) LPL gene. With the introduction of these promoter regions of the gene LPL in commercially available plasmid (e.g., plasmid, produced Clonetics Corp.) to obtain plasmid (reporter plasmid), which stably expresses the luciferase in human cells, this plasmid expresses the luciferase only under conditions which may increase the expression of LPL mRNA. Therefore, if the substrate is introduced into an expression system and the amount of expression of luciferase (luciferase activity) is quantified by the largest chemoluminescence, can be quantified expression of LPL mRNA.

In the present example, this test was carried out as follows: using the plasmids for analysis of luciferase produced Cloneth, which included the human LPL gene 5'-UTR (Enerback, S., et al., Mol.Cell.Biol. 12 (10) (1992): 4622-4633) and 3'-UTR (Wion, K.L., et al., Science 235 (1987): 4796, 1638-1641), transformed isolated from the human body cell line SW872 liposarcoma (access number ATCC No. HTB-92) to obtain the cell line HTB-92/p387/p383, which stably expresses the luciferase.

Cell line HTB-92/p387/p383 was introduced in 225 cm2the culture flask with ku is turalei medium and cultivated at 37°C in the absence of CO 2to achieve confluently. As the culture medium used environment Leibowitz L-15 containing 10% FBS, 1% GlutaMaxII, 10 μg/ml of streptomycin, 1 μg/ml of puromycin, 250 μg/ml of hygromycin B). After reaching confluently cells were collected, placed in a 384-well plate in the amount of 20,000 cells/well and cultured in culture medium in a quantity of 50 μl/well in the same conditions that were described above (37°C, the absence of CO2). After 3 days of culturing, the culture medium was replaced with DMEM containing no phenol red, 50 µl per well (containing 10% FBS, 1% GlutaMax, 10 U/ml penicillin, 10 μg/ml of streptomycin, 1 μg/ml puromycin, 250 μg/ml of hygromycin, 1 μm dexamethasone, 0.5 µm IBMX; differentiating the environment), and cells were cultured for another 5 days at 37°C in the presence of CO2for differentiation.

Then the culture medium was replaced with 50 μl/well of medium containing the compound of the present invention (the compound obtained in one of examples) as the test substance, where the compound was diluted in DMSO to the desired concentration in the range of 10-4M to 3×10-10M Cells were cultured for 5 days at 37°C in the presence of CO2.

After 5 days of cultivation in each well is injected with a solution of luciferase substrate (manufactured by Promega Corporation) in an amount of 30 μl/moons is near. The cells were left to stand for 10 minutes at room temperature and measured the luciferase activity using a luminometer (device for determining scintillation microplate; The Wallac MicroBeta Trilux, production Perkin Elmer, Inc.).

As control was used cells that were cultured and differentiated in a differentiating medium obtained by the addition of 0.1% DMSO to the above-mentioned DMEM (differentiating environment), not containing phenol red (i.e. cultured and differentiated for 5 days and then stimulated for 5 days). The luciferase activity in these control cells was measured as described above. The value of EC50(the concentration of the test compound, which is able to increase the amount of LPL mRNA expression compared to control at 50%, units: M) was calculated on the basis of a straight line obtained by drawing the graph of the results of tests carried out for different concentrations of the tested compounds. Maximum induction (values Max. ind) was calculated in accordance with the following equation:

The Value Of Max. ind = Lt/Lc

where Lt represents the maximum luciferase activity in response to stimulation of the test substance; Lc is the value of luciferase activity in the control sample.

The following table 2 shows the results from the ATA (value EC 50and Max. ind) test compounds of the present invention with examples, which show, by the method of any of the example was obtained corresponding connection.

Table 2
ExampleThe increase in LPL
(max ind)
The increase in LPL
(values EC50)
13,06,3
41,72,0
51,63,6
301,96,7
1031,97,4
1091,53,0
1141,57,2
1172,23,3
1321,76,2
1,76,4
1351,85,2
1382,02,0

As can be seen from the presented data, the compounds of the present invention significantly increase the expression of LPL mRNA. The results obtained show that the compounds of the present invention have excellent LPL-reinforcing effect, even compared to ethyl 4-[(4-bromo-2-cyanophenyl)carbarnoyl]benzyl-phosphonate, which, as you know, also has the ability to activate LPL, with the value Max. ind. for him is about 1.2.

Pharmacological test 2

The study of therapeutic effects on the model triglyceride hyperlipidemia caused by the intake of olive oil

To conduct this test used the SD rats aged 6 weeks (purchased from Charles River Japan).

At 5 weeks of age rats were divided according to body weight in the test group and the control group (6 animals per group.

They measured a certain number of compounds obtained in the examples and put them in a mortar of agate. Compounds were subjected to uniform grinding and suspended, gradually adding in a mortar with 5% aqueous solution of the se is malabika. Samples for testing were prepared by gradual addition of 5% aqueous solution of gum Arabic. Then these test samples were subjected to the action of ultrasound for 10 minutes to homogenize. Test samples were prepared as needed.

The rats of test groups orally was administered compounds of the present invention, so that the rats received compound in the amount of 10, 30 or 100 mg/kg of the Compounds of the present invention was administered in the form of a 5% suspension in gum Arabic, as described above.

Rats from the control group orally introduced a 5% aqueous solution of gum Arabic (not containing the compounds of the present invention) in an amount of 5 ml/kg of body weight. The introduction was performed once a day continuously for one week at a specific time of the day, after the rats had reached the age of 6 weeks. The test was performed in the absence of dietary restrictions (rats had free access to water and food), but the rats were not given food after the last injection of the compounds, or a 5% aqueous solution of gum Arabic.

Two hours after the final injection, rats from both groups orally was administered olive oil 3 ml/kg of body weight.

Two hours after administration of olive oil the blood was collected from the abdominal aorta of rats respective groups using heparinisation the second syringe. At 4°C was separated plasma by centrifugation and measured the level of triglycerides in the plasma. As the measuring instrument used automatic analyzer Hitachi 7170. Using the values measured for the animals of the test and control groups, the expected reduction in the level of triglycerides in plasma (%), according to the following equation:

The decrease in the concentration of triglycerides in plasma (%)=(1-E/C)×100,

where E represents the average level of triglycerides in the plasma in each of the test groups; and C denotes the average level of triglycerides in the plasma in the control group.

The following table 3 shows the results of administration of compounds of the present invention, obtained in the various examples in the above amounts.

Table 3
Compounds of the present inventionDosage (mg/kg)Reduction of triglycerides in plasma (%)
Connection example 11026
3050
10076
The compound of example 101048
3067
10074
The compound of example 231066
3078
10077
The compound of example 581031
3066
10079
The compound of example 951028
3065
10081

As is evident from the results table, the compounds of the present invention significantly reduce the levels of triglycerides in the plasma.

Pharmacological test 3

Test for combating obesity in fatty Zucker rats

Fatty Zucker rats are obese rats found Zucker et al. in 1961, as mutants among rats 13 M, which are the two who are a hybrid rats 13C and M. Unlike normal offspring, these rats (fa/fa) is clearly distinguishable obesity begins to appear at the age of about 3 weeks. As they grow, the difference in mass between fatty rats and normal rats increases. Line fatty Zucker rats currently stored in a number of organizations as a simple model of obesity and is easily accessible.

This test was performed using this rat model to evaluate the anti-obesity compounds of the present invention. The method of obtaining test specimens and methods of testing are described below:

(1) a Method of obtaining test samples

Test samples were obtained by the same procedure as in test example 2;

(2) testing Methodology

Fatty rats and lean Zucker rats (both species of rats were purchased from Charles River Japan) were purchased at 5 weeks of age. Animals were divided in groups (10 rats per group) according to body weight, which they reached to 6 weeks. After acclimatization, the animals began to implement the introduction of test samples upon reaching the age of 8 weeks. The test samples were administered orally using coercive power over the probe, so that the compounds of the present invention, contained in a test sample, fell in the body of the animal in the 100 mg/kg of body weight (dozer the wka test specimen: 5 ml/kg body weight). The test samples were injected once a day for 4 weeks at a certain time of day.

As a control group rats instead of the test samples were administered the same amount of 5% aqueous solution of gum Arabic (5 ml/kg body weight).

Rats from all groups were weighed on the last day of introduction. The average body weight of rats from all test groups compared with the average body weight (standard weight) rats of the control group, to determine the mass change (difference of mass). The difference of weights expressed relative to the standard weight. The calculated values thus acquired the name "the change in mass percentage. If the difference with the standard weight was negative, it was marked by the symbol “-” (minus).

During the test period, the rats of the respective groups had free access to feed for rats (“CRF-1”manufactured by Oriental Yeast, Co., Ltd.) and water (tap water).

(3) the Results

The following table 4 shows the results from the above tests that were used as test samples of the compounds of the present invention obtained in the above examples.

Table 4
The test sampleFrom the change of the mass (%)
None (control)0
The compound obtained in example 1-8
The compound obtained in example 10-15
The compound obtained in example 58-19
The compound obtained in example 95-15

(4) Analysis of results

The results given in the table above show that the tested compounds of the present invention showed an excellent ability to counteract obesity.

Pharmacological test 4

Test for anti-obesity using mice AKR

The purpose of this test was to study whether the compounds of the present invention to suppress the increase of mass in a model of obesity induced by diet, mice AKR/J, which is considered closer to the people. The mouse model used in this test demonstrates the correlation between increased body weight and increased levels of leptin in the blood, and, therefore, the anti-obesity can be defined as from the point of view of reduction of body weight and reduction of leptin levels (see J. Clin. Ivest. 99(3), 1 Feb, 1997: 385-90).

In addition, this test allows to evaluate therapeutic effect on diabetes. I.e. it was reported that in mice AKR/J feeding a food with a high fat content may be insulinemia (see Am. J. Physiol. 266 (5 Pt 1), May 1994: R1423-8). Accordingly, it is known that insulinemia strongly associated with diabetes (see, e.g., J. Cardiovasc. Nurs. 16(2), Jan. 2002: 17-23). Therefore, this test can confirm therapeutic effect of the compounds of the present invention, used as test compounds for diabetes.

The test was performed, as described below:

As normal food for rats used powdered CRF-1 (Charles River Formula 1 production Oriental Yeast, Co., Ltd.). As a food with a high content of fat used food, which was obtained by mixing CRF-1 with 18% safflower oil (Oriental Yeast, Co., Ltd.).

Test compounds were mixed with food with a high fat content in the amount of 1 mg to 1 g CRF-1.

Mice AKR/J (CLEA Japan, Inc.) acquired at the age of 4 weeks. Their roughly divided into two groups according to body weight, when the mouse has reached the age of 5 weeks. At this time, all mice were given normal write.

Then mice from the same group (8 mice) continued to be fed a normal diet (normal diet). The mice of the other groups (8 × (the number of tested compounds + 1) the mouse is) gave food with a high fat content (group with high fat diet).

Daily measured the body weight of mice in each group. When comparing the body weight of mice in the group with high fat diet on body weight of mice in the group with normal diet, there was a noticeable increase in body weight of mice in the group with high fat diet was further divided into groups (8 mice per group) and food (food with a high fat content), which gave these mice was replaced by a mixture of food with a high fat content with the tested compounds. These mice continued to grow in the same way for 7 weeks (group "test connection + high fat diet" (n=8 per group for one of the tested compound). Specifically, the introduction of the test compounds was continued for 7 weeks. As control was used a group of mice that continued to give food with a high fat content without test compounds (control group with high fat diet; n=8).

4 hours after feeding on the last day of a 7-week test (the last day of the test), measured the body weight of mice in the group "test connection + high fat diet". The blood was collected from the abdominal aorta of mice, using a heparinized syringe, and determined the levels of leptin and insulin in plasma using an ELISA kit (manufactured by Morinaga). Mice of the other groups (group with normal diet and the control group with high power is Oh fat) continued to hold until the last day of the test, as described above, and 4 hours after the last feeding on the last day of the test, carried out measurements according to the method similar to that described above.

Comparing the mean values of test results (body weight, leptin levels and insulin levels) group "test connection + high fat diet", where as the test compounds used compounds obtained in the above examples (examples 10 and 58) (hereinafter referred to as group "connection example 10, mixed with food with a high fat content and the compound of example 58, mixed with food with a high fat content) with the corresponding mean values (standard values) the results obtained for the control group mice with high fat diet, with the aim of setting changes (differences) parameters. The difference expressed in percentage values relative to the standard values. The calculated value was received the name of "change of body weight (%)", "the change in the level of leptin (%)" and "changing insulin levels (%)". In the table below, the symbol “-” (minus) indicates a negative difference with the standard values.

Table 5 shows the changes in body weight (%), changes in the level of leptin (%) and changes in insulin levels (%) for mice of group "connection example 10, mixed with food is high fat content", group "connection example 58, mixed with food of high fat", the group with normal diet and the control group with high fat diet.

Table 5
Test groupChange in body mass (%)Changes in the level of leptin (%)Changing insulin levels (%)
the control group with high fat diet000
group "connection example 10, mixed with food of high fat"-15-68-54
group "connection example 58, mixed with food of high fat"-10-55-12
the group with normal diet-15-70-41

As can be seen from the results are placed in table 36, both compounds of the present invention obtained in examples 10 and 58, perfectly counteract expect the structure and has an excellent therapeutic effect on diabetes.

It is believed that all other compounds obtained in the examples and included in the scope of the present invention, capable of displaying in pharmacological tests 1-4 these results, which are almost identical to the results given in tables 33-36.

Pharmacological test 5

Study of the effect of the increase in LPL activity in normal rats

As the test objects used SD rats aged 6 weeks (purchased from Charles River Japan). Rats were divided into groups according to body weight at 5 weeks of age. Rats from each test group oral introduced a 5% suspension of gum Arabic in an amount of 5 ml/kg of body weight, and suspension contain the test compound of the present invention in an amount such that the dosage of the compounds of the present invention was 30 mg/kg of body weight in one group and 100 mg/kg of body weight in the other group. Rats from the control group orally introduced a 5% suspension of gum Arabic (not containing the test compounds of the present invention) in an amount of 5 ml/kg of body weight. Each of the samples of the oral suspension was administered every day at a certain time of day for one week, starting from the moment when the rats reached the age of 6 weeks.

4 hours after administration of the last sample of the suspension was sampled skeletal tissues is ysz rats fixed them by freezing and stored in liquid nitrogen. The activity of LPL in tissues of skeletal muscles was measured by the following method.

The method of measuring the activity of LPL in skeletal muscle

1) Preparation of the extract of tissues of skeletal muscles

Soleus muscle homogenized in a chilled solution of 0.05 mol/l buffer NH4OH-NH4Cl (pH 8.5)containing 0.5 U/ml heparin wet weight tissue 100 mg. After standing on ice for 60 min with vigorous stirring at intervals of 15 min, the homogenate was centrifuged at 3000 rpm and 4°C for 10 minutes and separated supernatant.

2) Determination of the activity of LPL in skeletal muscle

The substrate solution was prepared by mixing 2 µci glycerin three[1-14C]oleate, of 0.133 g unlabeled triolein, 0.9 ml of 1% Triton X-100 and 0.9 ml of 4% bovine serum albumin in 0.2 mol/l buffer Tris-HCl (pH 8,6) and 10.2 ml of 0.2 mol/l buffer Tris-HCl (pH 8,6). This mixture was emulsiable the action of ultrasound on ice for 3 minutes

In a glass test tube was mixed with 0.1 ml of tissue extract, 0.05 ml V / V heat inactivated rat serum and 0.15 ml of 4% bovine serum albumin in 0.2 mol/l buffer Tris-HCl (pH 7,4). The enzymatic reaction was started by adding 0.2 ml of substrate solution and held for 30 min at 37°C.

The reaction was stopped by adding 2 ml of a mixture of 1.5 mol/l of H2SO4/2-propanol (1:40, volume/volume is m) and in a test tube was added 1 ml of distilled water and 3 ml of hexane. After vigorous shaking for 10 min at room temperature, the tube was centrifuged for 10 min at 3000 rpm/min

The top layer (3.5 ml) was collected into a new tube and mixed with 1 ml of 0.1 mol/l KOH.

The tube was vigorously shaken for 10 min at room temperature and then centrifuged for 10 min at 300 rpm

After removal of the upper layer, 1 ml of the lower layer (aqueous phase) was transferred into a vial for counting, neutralize 50 μl of 1.3 mol/l HCl and mixed with 4 ml of the scintillator. Measured radioactivity using a counter for counting scintillation liquids.

The increase in LPL activity (%) was calculated on the basis of measured values of LPL activity in the control group and test groups according to the following formula:

The increase in LPL activity (%) = (average value for the test group)/(average value for the control group)×100-100

The results are shown in the following table 6.

Table 6
The results of measuring the activity of LPL in tissues
ExampleDosageThe increased activity of LPL in skeletal muscle relative to control (%)
30 mg/kg56
100 mg/kg75
1030 mg/kg22
100 mg/kg55
2330 mg/kg18
100 mg/kg15
3030 mg/kg22
100 mg/kg31
8530 mg/kg9
100 mg/kg36
9530 mg/kg13
100 mg/kg25

Below are examples of pharmaceutical compositions according to the present invention.

Example composition 1

Getting pills

Using the compound of example 1 as an active ingredient, obtained tablets (10,000 pieces), each of which contained 300 mg AK the active ingredient, in accordance with the following formula:

Connection example 13000 g
Lactose (the Pharmacopoeia of Japan)335 g
Corn starch (Pharmacopoeia of Japan)165 g
Carboxymethylcellulose calcium (Pharmacopoeia of Japan)125 g
Methyl cellulose (Pharmacopoeia of Japan)60 g
Magnesium stearate (Pharmacopoeia of Japan)15 g

The compound of example 1, lactose, corn starch, carboxymethylcellulose calcium, taken in the quantities listed in the above formulation was mixed sufficiently, the mixture was granulated using an aqueous solution of methyl cellulose granules were sifted through a sieve of 24 mesh, mixed with magnesium stearate and pressed the mixture, receiving tablets.

Example composition 2

Getting capsules

Using the compound of example 95 as the active ingredient, received gelatin capsules (10000 capsules), each of which contained 200 mg of the active ingredient, in accordance with the following re what aptoroy.

The compound of example 952000
Crystalline cellulose (Pharmacopoeia of Japan)300 g
Corn starch (Pharmacopoeia of Japan)170 g
Talc (Pharmacopoeia of Japan)20 g
Magnesium stearate (Pharmacopoeia of Japan)10 g

Each of the ingredients in the above recipe, finely crushed and then thoroughly mixed the ingredients with each other to obtain a homogeneous mixture. Then got the desired capsule, placing the mixture in gelatin capsules having a size suitable for oral administration.

1. Means for activating LPL, including derivative of benzene represented by the General formula (I):

where R1represents a lower alkoxygroup; R2, R3and Z are such as defined in any of items (1-1)to(1-4):
(1-1) R2represents phenyl, phenyl, benzene ring which as substituents are one or two halogen atom, a lower alkyl group, substituted phenyl, lower alkyl group, semese the s-phenyl, in a benzene ring which has one or two substituent selected from the group consisting of halogen and cyano, or R1and R2combined with the formation of fragment-CH=C(Ph)- (where Ph means phenyl);
R3represents hydrogen or lower alkoxygroup; and Z is a group represented by the below formula:

where R4represents hydrogen, lower alkyl or halogen;
R5means hydrogen, lower alkyl, halogen, hydroxy, lower alkoxygroup, substituted phenyl lower alkoxygroup;
R6means hydrogen, lower alkyl, carboxy or halogen-substituted lower alkyl;
R7represents hydrogen, lower alkyl, halogen, halogen-substituted lower alkyl, lower alkoxycarbonyl, carboxy, cyano, carbarnoyl, or phenyl; and
R8is hydrogen or lower alkyl;
(1-2) R2is lower alkyl substituted by phenyl, which in the benzene ring as substituents are one or two halogen atom; R3represents hydrogen or lower alkoxygroup; and Z represents imidazo[2,1-b]thiazol-6-yl or imidazo[2,1-b]thiazol-6-yl having one lower alkyl substituent;
(1-3) R2means lower alkyl, substituted phenyl, or lower alkyl, substituted phenyl, in the benzene ring to which the CSOs as substituents are one or two halogen atom; R3represents hydrogen or lower alkoxygroup; and Z represents imidazo[1,2-a]pyridine-3-yl; and
(1-4) R2represents lower alkyl substituted by phenyl; R3represents hydrogen; and Z represents an imidazol-4-yl, having as a substituent one phenyl or phenyl substituted halogen-substituted lower alkyl.

2. Means for activating LPL according to claim 1, where R2, R3and Z such as defined in item (1-1).

3. Means for activating LPL according to claim 1, where R2, R3and Z are such as defined in subparagraph (1-2).

4. Means for activating LPL according to claim 1, where R2, R3and Z are such as defined in subparagraph (1-3).

5. Means for activating LPL according to claim 1, where R2, R3and Z are such as defined in subparagraph (1-4).

6. Means for activating LPL according to any one of claims 1 to 5, which are used for the prevention or treatment of hyperlipidemia.

7. Means for activating LPL according to any one of claims 1 to 5, which are used for the prevention or treatment of obesity.

8. A derivative of benzene represented by the General formula (1A)

where R1arepresents a lower alkoxygroup; R2aand Z are such as defined in any of items (2-1)to(2-4):
(2-1) R2ais lower alkyl substituted by phenyl, which in the benzene ring as substituents have I one or two halogen atom, and Z represents imidazo[2,1-b]thiazol-6-yl or imidazo[2,1-b]thiazol-6-yl having one lower alkyl substituent;
(2-2) R2ameans lower alkyl, substituted phenyl, or lower alkyl, substituted phenyl, a benzene ring which as substituents are one or two halogen atom; and Z represents imidazo[1,2-a]pyridine-3-yl;
(2-3) R2arepresents lower alkyl, substituted phenyl, and Z represents an imidazol-4-yl, having as a substituent one phenyl or phenyl substituted halogen-substituted lower alkyl;
(2-4) R2arepresents phenyl, phenyl, benzene ring which as substituents are one or two halogen atom, a lower alkyl group, a substituted phenyl, a benzene ring which has one or two substituent selected from the group consisting of halogen and cyano, or R1aand R2acombined with the formation of fragment-CH=C(Ph)- (where Ph means phenyl; and Z is a group represented by the below formula:

where R4represents hydrogen, lower alkyl or halogen;
R5means hydrogen, lower alkyl, halogen, hydroxy, lower alkoxygroup, substituted phenyl lower alkoxygroup;
R6means hydrogen, lower alkyl, carboxy or halogen-substituted n is SSI alkyl;
R7represents hydrogen, lower alkyl, halogen, halogen-substituted lower alkyl, lower alkoxycarbonyl, carboxy, cyano, carbarnoyl, or phenyl; and
R8is hydrogen or lower alkyl.



 

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12 cl, 1 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

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29 cl, 178 ex

FIELD: chemistry.

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16 cl, 479 ex

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13 cl, 23 ex, 2 tbl

FIELD: chemistry.

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23 cl, 3 tbl, 25 ex

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19 cl, 3 tbl, 192 ex

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15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: medicine, pharmaceutics.

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4 cl, 27 ex

FIELD: medicine, pharmaceutics.

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22 cl, 16 tbl, 422 ex

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22 cl, 43 ex

FIELD: chemistry.

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2 cl, 2 tbl, 10 ex

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FIELD: medicine, pharmaceutics.

SUBSTANCE: there are produced new diazepane substituted compounds representing various heterocyclic systems, including condensed, pharmaceutical compositions containing said compounds.

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13 cl, 1 tbl

New compounds // 2458920

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula or to its pharmaceutically acceptable salts wherein -A-(R1)a means a group; -B-(R2)b means a group specified in the patent claim 1, R3 means hydrogen; X means CH2 or O; and Y means CH2. Also, the invention refers to a pharmaceutical composition exhibiting FGFR inhibitor activity on the basis of the declared compound.

EFFECT: there are produced new compounds and based pharmaceutical composition which can find application in medicine for preparing a cancer drug.

8 cl, 1 tbl, 180 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: pyrazolo[1,5-a]-pyrimidine compounds according to the invention are specified in a group consisting of: N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-ethylmethanesulphonamide; {2-fluor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-nitro-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-chlor-5-[3-cyano-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylmethanesulphonamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-fluor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-chlor-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-methanesulphonamide, N-{2-methyl-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2-methoxy-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide, N-{2,4-difluor-5-[3-(thiophene_2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide and N-{5-fluor-2-methoxy-3-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methylacetamide.

EFFECT: preparing pyrazolo[1,5-a]pyrimidine compounds, their pharmaceutically acceptable salts and hydrates showing an ability to inhibit GABAA receptors, and applicable for treating and preventing anxiety, epilepsy and sleeping disorders, including insomnia, as well as for inducing a sedative-hypnotic, analgesic and sleeping effects and myorelaxation.

14 cl, 6 tbl, 4 dwg, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of general formula (I):

in the form of a separate stereoisomer or mixed stereoisomers or in the form of its pharmaceutically acceptable salt wherein R1 is indazolyl or substituted indazolyl; R6 is C6aryl or C6-12aryl substituted by halogen, hydroxy, cyano and C1-6alkoxy; or C6heterocyclyl containing 1-2 heteroatoms specified in nitrogen or oxygen; each X2 and X3 independently mean hydrogen, hydroxy or phosphate.

EFFECT: prepared compounds may be used for preparing a drug preparation for treating or preventing cancer, particularly acute myeloid leukemia.

6 cl, 6 tbl, 8 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I , and pharmaceutically acceptable salts thereof, where L denotes O, S, or CH2; Y denotes N or CH; Z denotes CR3; G denotes CH; R1 denotes a heteroaryl ring of formula , where D1 denotes S, O; D2 denotes N or CR12; D3 denotes CR12; R2 denotes (C6-C10)-aryl; 5-9-member mono- or bicyclic heteroaryl with 1 or 2 heteroatoms independently selected from N or S; a saturated or partially saturated (C3-C7)-cycloalkyl; or a saturated 5-6-member heteocyclyl with 1 heteroatom selected from N, where said aryl, heteroaryl, cycloalkyl and heterocyclyl are optionally substituted with one or two groups independently selected from (C1-C6)-alkyl, F, Cl, Br, CF3, CN, NO2, OR6, C(-O)R6, C(=O)OR6, C(=O)NR6R7, saturated 6-member heterocyclyl with 2 heteroatoms independently selected from N or O, and S(O)2R6, and where said alkyl is optionally substituted with one -OR8 group; R3 denotes H; (C1-C6)-alkyl; (C2-C6)-alkenyl; Cl; Br; OR6; SR6; phenyl; or a 6-member heteroaryl with 1 heteroatom selected from N, where said alkyl and alkenyl are optionally substituted with one group selected from C(=O)OR8, -OR8, -NR8R9; or a saturated 6-member heterocyclyl with 1 heteroatom selected from N or O.

EFFECT: disclosed compounds are used in treating and preventing diseases mediated by insufficient level of glucokinase activity, such as sugar diabetes.

16 cl, 479 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present patent claim discloses sulphonyl-substituted compounds of formula QUIN which are used for the purpose of a method for producing a macrocyclic compound of formula (I)

EFFECT: compounds of formula (I) are effective active agents for treating Hepatitis C viral (HCV) infection.

8 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of general formula 1:

wherein Q, X1, X2, Y, Z, R1, R2, R3, R3', R4, R4', R5, R6, R6' have the values specified in the description.

EFFECT: compounds are the IAP inhibitors which can be used as therapeutic agents for malignant diseases.

13 cl, 20 ex

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